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PubmedSumm118200 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: chronic kidney disease ( ckd ) patients experience a high mortality rate from cardiovascular ( cv ) diseases [ 1 , 2 ] . endothelial dysfunction characterized by a disruption in the delicate balance among vasodilation ,
oxidative stress , inflammation , thrombosis , and fibrinolysis maintained by the endothelium has been linked to increased cardiovascular disease ( cvd ) risk [ 36 ] .
not only do changes in renal endothelial function affect the progression of renal disease , but also systemic endothelial dysfunction significantly contributes to the severity of cardiovascular complications in ckd .
ckd patients usually have hypertension and/or diabetes , two of the conventional cardiovascular risk factors that are associated with endothelial dysfunction .
in addition , likely other renal specific mechanisms may contribute to endothelial dysfunction in ckd .
in early ckd one of the first serum parameters to be altered is a decrease in the serum 1,25-dihydroxyvitamin d3 levels , which raises the question of whether deficient vdr activation may be one of the renal specific risk factors for endothelial dysfunction in ckd .
in addition , preclinical studies show that vdr may be involved in modulating smooth muscle cell proliferation / differentiation , the renin - angiotensin system , inflammation , thrombosis , and fibrinolysis ; many of these factors are involved in endothelial function [ 11 , 12 ] .
vitamin d3 is made in the skin , but requires activation into the active hormone , 1,25-dihydroxyvitamin d3 ( 1,25(oh)2d3 , calcitriol ) , for its proper functions .
calcitriol exerts its functions via binding to a nuclear receptor , the vitamin d receptor ( vdr ) .
calcitriol and its analogs such as paricalcitol ( 19-nor-1,25(oh)2d2 ) that activate vitamin d receptor ( vdr ) are commonly used to manage hyperparathyroidism secondary to ckd .
numerous clinical observations show that vdr activation therapy was associated with a survival benefit in ckd patients with an effectiveness order of : paricalcitol > calcitriol > no vdr activation therapy , independent of the parathyroid hormone ( pth ) and calcium levels ; the survival benefit of vdr activation agents is likely associated with a decrease in cardiovascular - related mortality [ 1418 ] .
the mechanism(s ) of action for the cardiovascular and survival benefit of vdr activation agents in ckd is still not well understood .
vdr has been identified in more than 30 different tissues in the human body including the vasculature , and emerging evidence suggests that vdr may play a role in modulating cardiovascular functions .
vitamin d and vitamin d analogs that activate vdr ( vdr agonists or activators , vdras ) have been shown to modulate inflammation , thrombosis , and vasolidation , which are some of the important risk factors associated with endothelial dysfunction .
however , it is not well studied how vdras affect endothelial function in ckd .
the 5/6 nephrectomized ( nx ) uremic rat model is a useful model for studying renal insufficiency and has been used extensively for the evaluation of vdras on modulating serum calcium and pth . besides having elevated pth
, the 5/6 uremic rats develop endothelial dysfunction , left ventricular hypertrophy , and proteinuria . in this study
, we employed paricalcitol to investigate whether vdr activation mitigates the detrimental effect of uremia on endothelial function in the 5/6 nx rats .
our results demonstrate that uremia significantly compromises endothelial function while paricalcitol improves endothelial function in uremic rats in a dose - dependent manner independent of serum pth levels or blood pressure .
paricalcitol ( 19-nor-1 , 25-dihydroxyvitamin d2 , 19-nor-1 , 25(oh)2d2 ) , and cinacalcet ( n-[1-(r)-()-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-aminopropane hydrochloride ) were provided by abbott laboratories .
the investigation conforms with the guide for the care and use of laboratory animals published by the us national institutes of health ( nih publication no . 85 - 23 , revised 1996 ) , and all experiments were approved by the abbott laboratories internal animal care and use committee .
the nephrectomy was performed on rats weighing ~200 g with a standard two - step surgical ablation procedure .
rats of established uremia were studied at week 6 after surgery . in the paricalcitol studies ,
5/6 nephrectomized rats received vehicle ( 5% etoh/95% propylene glycol ; 0.4 ml / kg ; i.p . ) or paricalcitol ( doses as indicated ) 3x / wk over a period of 12 days ( 6 doses total ) , and blood was drawn on days 0 ( 24 hours before the first dose of treatment ) and 13 ( 24 hours after the last dose of treatment ) , and assayed for creatinine , bun , pth , total calcium ( ca ) and/or ionized ca ( ica ) , and phosphorus ( pi ) .
in the cinacalcet studies , uremic rats were treated with vehicle ( cavitron , 1.65 ml / kg ; p.o ) or cinacalcet ( 30 mg / kg ; p.o . )
daily for 13 days , and blood was drawn on days 0 and 13 ( 2 hours postdose ) for testing .
untreated uremic rats were compared with vehicle - treated uremic rats to investigate the effect of vehicle .
thoracic aortas were excised , cut into sections and an aortic ring suspended in 10 ml tissue baths under 0.5 grams of resting tension in a modified krebs solution containing ( in mmol / l ) 120 nacl , 20 nahco3 , 11 dextrose , 4.7 kcl , 2.5 cacl2 , 1.5 mgso4 , and 1.2 kh2po4 equilibrated with 5% co295% o2 ( ph 7.4 at 37c ) .
tension was recorded with grass ft03 isometric transducers ( astro - med , west warwich , ri ) connected to a grass 7d polygraph and a ponemah data acquisition system ( data - sciences intl , st .
aortas were sensitized by addition of phenylephrine ( pe , 3 m ) with 10-minute washouts between intervals .
aortas were precontracted with pe ( 3 m ) , and the endothelium - dependent vasodilator acetylcholine ( ach ) was added in half - log increments ( 1 nm30 m ) at 35 minute intervals , allowing time for the effect of ach to plateau .
after a 60-minute washout , aortas were precontracted with pe ( 3 m ) and subsequently treated with endothelial - independent vasodilator sodium nitroprusside ( snp ; 1 nm1 m ) at 35 minute intervals , allowing time for the effect to plateau . in a separate study ,
sham and 5/6 nx rats were treated with vehicle or paricalcitol at 0.16 g / kg and aortic rings were preincubated with 100 m l - name ( n - omega - nitro - l - arginine methyl ester ) for 1 hour prior to the addition of pe to induce contraction . due to the limited availability of the tissue bath chambers ,
different treatments were independently given to different groups of uremic rats in order to properly prepare the aortic rings for relaxation studies .
serum pth was measured using a rat intact pth elisa kit obtained from alpco / immutopics , inc .
serum ca , pi , creatinine , and bun concentrations were measured using an abbott aeroset .
blood ica was determined using an i - stat portable clinical analyzer with an 7 + cartridge . in a separate study , male sprague - dawley
briefly , animals were anesthetized with 3% isoflurane , and a flexible catheter attached to a ta11pa - c40 radio transmitter ( data sciences , st .
paul , mn ) was inserted in the abdominal aorta just below the renal arteries , the procedure as recommended by data sciences international .
the transmitter was secured to the abdominal muscle and remained in the abdominal cavity for the duration of the experiment .
after surgery , rats were housed in individual cages positioned over an rpc-1 radiotelemetry receiver ( data sciences , st .
rats at 6 weeks after nephrectomy were treated with vehicle ( 5% etoh/95% propylene glycol ; 0.4 ml / kg ; i.p . ) or paricalcitol at 0.042 g / kg , 3x / week for 14 days .
, 3x / week ) plus enalapril ( 10 mg / kg , p.o .
, via drinking water , daily for 8 days , then switched to 30 mg / kg for another 6 days .
the 30 mg / kg enalapril treatment did not further reduce blood pressure ) . for serum chemistry data ,
differences between sham and uremic rats with different treatments were assessed using a one - way anova followed by a dunnett 's post - hoc test .
a paired t - test was used to assess differences between baseline day 0 ( before treatment ) and day 13 ( after treatment ) or as indicated . for vascular function , ach and snp - induced relaxations
differences in vascular function were determined using a two - way anova , followed by a bonferonni post - hoc test .
we examined the effect of uremia and paricalcitol treatment on acetylcholine - induced endothelial - dependent relaxation of aortic rings from sham and 5/6 nx rats .
as shown in figure 1(a ) , the maximal aorta relaxation response to acetylcholine in sham rats was 96.2 5.3% with an ec50 of 137 nm .
relaxation was significantly reduced in uremic 5/6 nx vehicle - treated rats ( 50.3 7.0% , p < .01 , with an ec50 of 211 nm ) .
there was no difference in the relaxation response between vehicle - treated and untreated uremic rats ( data not shown ) .
the altered response to acetylcholine in the 5/6 nx rat indicates compromised endothelial function . as shown in figure 1(b ) , the vascular relaxation produced by snp ( endothelial - independent vasodilator ) was not significantly different between the sham and 5/6 nx rats , indicating that the aorta vascular smooth muscle relaxant response is intact and functional .
figure 1(a ) also shows that 2-week treatment with paricalcitol produced dose - dependent improvement in acetylcholine - induced endothelial - dependent relaxation .
treatment with 0.083 g / kg of paricalcitol increased the maximal relaxation response to acetylcholine to 90.5 3.8% ( p
treatment with 0.042 g / kg of paricalcitol shifted the ec50 to 121 nm , and increased the maximal relaxation response to acetylcholine to 77.5 6.9% ( p < .05 ) . to a lesser degree , treatment with 0.021 g / kg of paricalcitol increased the maximal relaxation response to acetylcholine to 58.2 6.0% with an ec50 at 105 nm .
figure 1(b ) shows that paricalcitol had no significant effect on snp - induced endothelial - independent relaxation . as shown in figures 2(a ) and 2(b ) , the serum creatinine and bun levels were significantly elevated in the 5/6 nephrectomized ( nx ) rats compared to sham rats , indicating a uniform disease state .
paricalcitol at the three tested doses had no significant effect on either creatinine or bun ( versus day 0 ) .
figure 2(c ) shows that , as expected , paricalcitol effectively suppressed serum pth in a dose - dependent manner ( a reduction of 41.6 7.2% , 41.6 7.4% and 48.2 8.3% at 0.021 , 0.042 and 0.083
total serum calcium ( ca ) , phosphorus ( pi ) , and ionized ca ( ica ) levels were not significantly different in the 5/6 nx rats versus sham .
paricalcitol significantly increased serum ca and ica at 0.042 and 0.083 g / kg ( figures 2(d ) and 2(e ) ) .
paricalcitol at the three doses had no effect on the pi levels ( figure 2(f ) ) . to investigate whether paricalcitol improves endothelial function via lowering blood pressure
, we examined blood pressure and heart rate in these animals . the angiotensin - converting enzyme ( ace ) inhibitor enalapril was used as a control .
mean arterial pressure ( map ) , systolic pressure ( sp ) , and diastolic pressure ( dp ) were elevated in 5/6 nx rats ( figures 3(a)3(c ) ) .
enalapril exhibited a modest and stable effect on reducing mean arterial pressure , systolic pressure , and diastolic pressure , but had no effect on heart rate .
as a comparison , paricalcitol at 0.042 g / kg had no significant effects on blood pressure or heart rate ( figure 3 ) .
consistent with the study in figure 2 , paricalcitol had no significant effect on the creatinine , bun , and serum pi levels , while it effectively suppressed pth and also significantly increased total serum ca ( data not shown ) .
enalapril did not show a significant effect on the creatinine , bun , pth , serum ca , or pi levels ( data not shown ) .
these results demonstrate that paricalcitol at 0.042 g / kg did not affect blood pressure , suggesting that the effect of paricalcitol at 0.042 g / kg on improving endothelial function is independent of blood pressure control .
to investigate whether serum pth suppression mediated by paricalcitol may have resulted in improved endothelial function in the uremic rats , we took an indirect approach and tested cinacalcet , a calcimimetic known to suppress pth via interacting with the calcium sensing receptor independent of vdr . consistent with the other two studies
( figures 2 and 3 ) , the serum creatinine and bun levels were elevated in the 5/6 nx rats compared to sham rats , which were not significantly affected by cinacalcet treatment at 30 mg / kg for 13 days ( data not shown ) .
cinacalcet at 30 mg / kg after 13 days of treatment resulted in a decrease in serum pth ( a 66.8% reduction versus before treatment , figure 4(a ) ) and total serum ca ( a 23% reduction , figure 4(b ) ) .
cinacalcet significantly elevated serum phosphorus by 18% ( versus before treatment ; data not shown ) .
figure 4(c ) shows that the maximal aorta relaxation response to acetylcholine for the cinacalcet - treated group was 41.8 4.2% with an ec50 of 202 nm , which was not significantly different from the uremic 5/6 nx vehicle - treated group . as shown in figure 4(d ) , while there was no significant difference in snp - induced endothelial - independent relaxation between sham and uremic rats , cinacalcet exhibited a modest effect on reducing the vascular relaxation produced by snp .
these results suggest that pth suppression is not linked to endothelial function improvement in the uremic rats and the effect of paricalcitol on improving endothelial function may be independent of pth suppression . to further investigate how vdr activation improves endothelial function , we tested the effect of l - name . in this particular study ,
the maximal aorta relaxation response to acetylcholine in sham rats was 74.5 3.6% with an ec50 of 157 nm .
relaxation was significantly reduced in uremic 5/6 nx vehicle - treated rats ( 31.4 4.7% with an ec50 of 358 nm ) . as shown in figure 5(a ) , paricalcitol ( 0.16 g / kg , i.p . , 3x / weeks for two weeks ) increased the maximal relaxation response to acetylcholine to 52.3 9.6%
addition of l - name at 100 m during the aorta ring assay completely abolished the effect of paricalcitol on improving endothelial function . in this study ,
the serum pth level was significantly reduced while the serum calcium level was not altered by paricalcitol ( figures 5(b ) and 5(c ) ) .
previously it has been shown that , in spontaneously hypertensive rats ( shr ) with impaired endothelial function , oral cholecalciferol ( vitamin d3 ) treatment significantly improved the endothelium - dependent vascular relaxation and hyperpolarization induced by acetylcholine .
wong et al . have also shown that calcitriol acutely reduced endothelium - dependent contractions in the aorta of the spontaneously hypertensive rat .
reported that , in the 5/6 nephrectomized rats fed a special diet that induced severe hyperphosphatemia , paricalcitol at 0.2 g / kg reduced vasoconstriction but increased calcification in the large artery .
as a comparison , our results show that paricalcitol improves endothelial function in the 5/6 nx rats with normal serum phosphate levels .
more importantly , our data demonstrate that paricalcitol does not affect blood pressure in the uremic rats during the treatment period , suggesting that the effect of paricalcitol on improving endothelial function is independent of blood pressure control .
our observation is consistent with the finding made by bodyak et al . that paricalcitol attenuated the development of left ventricular abnormalities in the dahl salt - sensitive rat ( a different experimental model from the 5/6 nephrectomized uremic rats ) without a significant effect on blood pressure .
have also reported that , in the 5/6 nephrectomized rats fed a special diet that induced severe hyperphosphatemia , paricalcitol at 0.2 g / kg did not affect blood pressure . in a study reported by mizobuchi et al . , 5/6 nephrectomized uremic rats developed significant hypertension , which was not affected by paricalcitol ( 0.8 g / kg ) during a 4-month treatment period , while enalapril effectively lowered blood pressure .
however , it is worth mentioning that , in the study by freundlich et al . , the systemic blood pressure , which increased in all groups with renal ablation ( versus sham rats ) , was significantly lower in rats treated with paricalcitol at either 0.1 or 0.3 g / kg .
at this point it is not known why the results were different from different laboratories on a seemly similar uremic rat model .
many drugs that improve endothelial function also control hypertension , making it difficult to delineate the effects of these drugs on these two parameters . like ckd patients , the 5/6 nx rats have severe hypertension and endothelial dysfunction .
the observation from this study implies that it is possible to improve endothelial function in ckd independent of blood pressure control . in this study , due to the short duration of the treatment ( 2 weeks ) ,
a study by freundlich et al . reported that the plasma creatinine level , elevated in all groups with renal ablation , started to decline after two weeks of paricalcitol ( 0.1 and 0.3 g / kg ) treatment in the 5/6 nephrectomized uremic rats , eventually reaching levels comparable to sham rats and significantly lower than in nontreated 5/6 nx rats .
previously it has been shown that , during a 4-month treatment period following nephrectomy , the increase in serum creatinine was less in the paricalcitol ( 0.8 g / kg ) group than in the untreated group , although the difference failed to reach a statistical significance .
elevated pth has been shown to play a role in various cardiovascular disorders including abnormal vasodilation .
previously it has also been demonstrated that , in patients with primary hyperparathyroidism , parathyroidectomy significantly improved endothelial vasodilatory function .
the current study shows that pth suppression is not linked to endothelial function improvement in the uremia rat since cinacalcet , a calcimimetic , does not show a significant effect on improving endothelial function although it suppresses pth effectively .
these data are of interest as they are consistent with the clinical observations that the survival benefit of vdr activation therapy in hemodialysis patients is observed across different serum pth levels [ 14 , 15 ] .
we noticed the inconsistent effects of paricalcitol on aortic relaxation from study to study as evident in figures 1 and 5 .
paricalcitol at 0.083 g / kg in figure 1 study almost normalized endothelial function to the sham level , while paricalcitol at 0.16 g / kg in figure 5 study only partially improved endothelial function .
paricalcitol at a higher dose may decrease local activity of calcitriol or paricalcitol via cyp24 induction .
paricalcitol at the higher dose can also increase vascular calcification , which leads to reduced aortic relaxation .
alternatively , it may be the result of the inconsistent effects of paricalcitol on serum calcium in different batches of 5/6 nephrectomized uremic rats .
it is of interest to note that changes in the serum calcium levels may affect endothelial function .
calcium is required for the activity of nitric oxide synthase , and thus , increasing extracellular or intracellular calcium concentrations may stimulate nitric oxide ( no ) production . an increase in serum calcium
may also alter the intracellular calcium level , leading to opening of endothelial calcium - sensitive potassium channels ( k(+ ) channels ) and vessel relaxation .
reported that high - calcium diet enhanced resistance artery relaxation in the 5/6 nx rats likely mediated by k(+ ) channels .
this effect was independent of the degree of renal impairment and blood pressure , but was associated with improved calcium metabolism because plasma levels of pth and phosphate were decreased and serum calcium was increased . at the dose range of 0.0210.16 g / kg that was used in this study ,
paricalcitol sometimes raises serum calcium ; the effects vary from studies to studies and the causes for this variation is not well understood .
for example , noonan et al . have shown that paricalcitol at 0.083 and 0.167 g /
kg raised serum calcium levels while wu - wong et al . reported that paricalcitol at 0.17 g / kg did not affect serum calcium levels .
as shown in figures 1 and 2 , paricalcitol at 0.083 g / kg raised serum calcium and completely normalized endothelial function to the sham level .
as a comparison , paricalcitol at 0.167 g / kg ( figure 5 ) did not raise serum calcium and only partially normalized endothelial function .
consistent with this notion , since serum calcium was significantly lower in the cinacalcet study ( figure 4 ) , we can not rule out the possibility that the lack of effect of cinacalcet on endothelial function may be due to the decrease in serum calcium levels after cinacalcet treatment .
have shown that , in the shr rat model , cholecalciferol improved endothelial function likely mediated by endothelium - derived hyperpolarizing factor , but not nitric oxide .
however , mounting evidence has shown that the systemic no deficiency is the principal cause for endothelial dysfunction in ckd . in a clinical study on hemodialysis patients , passauer et al .
reported that endothelial dysfunction in uremic patients as determined by endothelium - dependent vasodilation in response to increased doses of acetylcholine is mainly attributed to reduced no activity .
have also reported that the decrease of no production was the key factor linked to endothelial dysfunction in the 5/6 nx rats .
our data support the role of no in ckd that l - name completely abolished the effect of paricalcitol on improving endothelial function in the uremic rats .
the results suggest that paricalcitol treatment restores the systemic no activity in the 5/6 uremic rats . beside
decreased nitric oxide generation , the accumulation of asymmetric dimethylarginine ( adma , an endogenous nitric oxide inhibitor ) is also known to contribute to endothelial dysfunction .
we did a search but did not find any published work on vdr activation and adma .
although it is beyond the scope of this study , preliminary data from employing dna microarray technology to analyze the aortic gene expression profiling in the 5/6 nx rats show that uremia is associated with abnormal expression of genes involved in increasing oxidative stress and paricalcitol treatment normalizes many of these genes .
we hope the observations made in this study will stimulate others to investigate further about the role of vdr in regulating nos , adma , and other factors involved in oxidative stress
. in summary , vdr activation by paricalcitol significantly improves endothelial function in the 5/6 nx uremic rats .
more importantly , the effect of paricalcitol is independent of blood pressure control and the serum pth levels . although randomized clinical studies are needed to confirm the cardiovascular and survival benefit of vdr activation therapy in ckd patients , data from the current study provide an important new insight that vdr activation improves endothelial function in uremia , which may be one of the mechanisms responsible for the cardiovascular benefit associated with these drugs in ckd .
Output:
| endothelial
dysfunction increases cardiovascular disease
risk in chronic kidney disease ( ckd ) .
this study
investigates whether vdr activation affects
endothelial function in ckd .
the 5/6
nephrectomized ( nx ) rats with experimental
chronic renal insufficiency were treated with or
without paricalcitol , a vdr activator .
thoracic
aortic rings were precontracted with
phenylephrine and then treated with
acetylcholine or sodium nitroprusside .
uremia
significantly affected aortic relaxation
( 50.0 7.4% in nx rats versus 96.2
5.3% in sham at 30 m acetylcholine ) .
the endothelial - dependent relaxation was improved to 58.2 6.0% , 77.5 7.3% , and 90.5 4.0% in nx rats treated with paricalcitol at 0.021 , 0.042 , and 0.083 g / kg for two weeks , respectively , while paricalcitol at 0.042 g / kg did not affect blood pressure and heart rate .
parathyroid hormone ( pth ) suppression alone did not improve endothelial function since cinacalcet suppressed pth without affecting endothelial - dependent vasorelaxation .
n - omega - nitro - l - arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function .
these results demonstrate that vdr activation improves endothelial function in ckd . |
PubmedSumm118201 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: eosinophilic granulomatosis with polyangitis ( egpa ) is one of the rarest but still potentially life threatening systemic necrotizing vasculitis predominantly affecting small vessels . named css for many years
, this eponym has now been recognized as egpa by the 2012 revised international chapel hill consensus conference nomenclature of vasculitides . here
we describe a patient who presented with an inability to walk and asymptomatic skin rash . he had been treated for encephalopathy and bronchial asthma in the past .
laboratory investigations helped to reach the final diagnosis of css with mononeuritis multiplex , skin , and pulmonary involvement .
a 45-year - old male presented with two weeks history of multiple asymptomatic red lesions on his hands and lower limbs , difficulty in breathing , fever , and weakness of both legs with difficulty in walking .
the physical examination revealed multiple palpable purpuric papules and plaques distributed over the dorsum of hands and posterior aspect of the legs [ figure 1 ] with left foot drop .
palpable purpura on the leg routine investigations revealed a prominent eosinophilia of 29% and erythrocyte sedimentation rate ( esr ) of 28 mm / h .
immunofluorescence assay for antinuclear antibodies was negative and perinuclear antineutrophil cytoplasmic antibodies ( p anca ) or cytoplasmic anca were not detected in his serum .
rheumatoid factor was positive at 233.4 iu / ml . a chest radiograph showed emphysematous lung fields with prominent bronchovascular markings consistent with bronchial asthma but no prominent infiltrates were noted .
motor and sensory nerve conduction studies showed reduced compound muscle action potential amplitudes from both posttibial and left common peroneal nerves indicative of sensory motor peripheral neuropathy . a skin biopsy of the purpuric lesion revealed leucocytoclastic small vessel vasculitis comprising of inflammatory infiltrate of neutrophils and eosinophils [ figure 2 ] .
there was extravasation of red blood cells and occasional granulomas comprising of palisading histiocytes , eosinophils and lymphocytes in the deep dermis [ figure 3 ] .
direct immunofluorescence showed blood vessel wall staining with igm , c3 and fibrinogen [ figure 4 ] .
leucocytoclastic vasculitis in superficial dermis ( h and e 40 ) red granuloma in the deep dermis comprising palisading histiocytes , eosinophils and lymphocytes ( h and e 40 ) direct immunofluorescence : blood vessel wall staining with igm , c3 and fibrinogen the patient received oral corticosteroids ( prednisolone ) at a dose of 1 mg / kg / day , and the dose was tapered after one month .
skin lesions and his general condition showed improvement following treatment and he is on regular follow - up .
it was in 1951 that jacob churg and lotte strauss first described a syndrome characterized by asthma and a strikingly uniform clinical picture with fever and eosinophilia , and symptoms of cardiac failure , renal damage and peripheral neuropathy resulting from vascular embarrassment in various systems of organs .
they considered the observed tissue alteration to be a distinct histopathologic entity , which they termed allergic granuloma .
the presence of any four or more of the six classification criteria developed by the american college of rheumatology ( acr ) [ table 1 ] yielded a sensitivity of 85% and a specificity of 99.7% .
strauss syndrome eosinophilic granulomatosis with polyangitis is a rare disease , with an annual incidence of 0.54.2 cases/10 .
it usually occurs between 14 and 79 years of age , with a mean age of 48 years ; pediatric cases have also been reported .
immunogenetic factors may confer susceptibility to egpa . the human leukocyte antigen ( hla)-drb1 * 04 and * 07 alleles and the related hla - drb4 gene
are associated with an increased risk of developing egpa . like most forms of vasculitides ,
the occurrence of egpa is likely to require a combination of inherited risk determinants and environmental triggering factors , including antigens and/or infections , which by themselves are insufficient to cause complications .
the formation of antineutrophil cytoplasmic autoantibody ( anca ) may be favored by a genetic predisposition , such as a genetically determined , severe 1-antitrypsin deficiency ( which also inhibits proteinase 3 ) , or genetic heterogeneity of the anca antigen itself .
anca mediates the activation and adherence of neutrophil and eosinophil polymorphonuclear cells to the endothelium , and the release of toxic components , thus damaging the endothelium and initiating the vasculitic process .
anca positivity is seen only in ~38% of egpa and compared to anca - negative patients , they more frequently suffer from peripheral neuropathy , renal involvement , and purpura , whereas , endomyocardial involvement and lung infiltrates prevailed in the anca - negative subsets .
other biologic abnormalities such as positive rheumatoid factor , increased esr and immune complexes are considered to be nonspecific .
three phases have been described in the natural history of the disease although they do not always occur successively .
it is traditionally described to evolve through a prodromic , allergic phase characterized by asthma and rhinosinusitis , followed by a second phase with the onset of blood and tissue eosinophilia .
spontaneous or treatment - induced remission of the disease can occur at this stage , but recurrence is frequent .
asthma is found in 95100% of patients and may precede the systemic disease manifestations by many years .
it generally arises in adulthood , and its severity varies ; unlike in classical bronchial asthma , in egpa , it does not show the typical seasonal exacerbations .
the vasculitic phase is heralded by constitutional symptoms and often by an apparently paradoxical improvement of asthma .
peripheral neuropathy is characterized by axonal damage on electrophysiological studies and frequently affects the peroneal , tibial , ulnar , and median nerves ; the most common pattern is mononeuritis multiplex , often complicated by asymmetric foot or wrist drop , but it may also evolve as a symmetric or asymmetric polyneuropathy ; sensory deficits and neuropathic pain are also frequent . skin involvement is seen in 81.3% of patients , palpable purpura of the lower extremities as seen in our patient is the most frequent manifestation .
subcutaneous nodules of the limbs and scalp are seen in about 30% of the patients .
skin infarction , livedo reticularis , erythematous and bullous lesions , macular erythema , and urticaria may also be seen .
the objective is to induce clinical remission as quickly as possible , and then to sustain it as long as possible . in cases that fail to respond to steroids , or those with life threatening complications , immunosuppressants like cyclophosphamide
biologic agents such as the anti - interleukin-5 mepolizumab and possibly rituximab are promising treatment options . our patient
he was initially labelled as bronchial asthma and treated with oral steroids for prolonged duration , following which he developed sepsis and encephalopathy .
accurately recognising egpa is thus imperative as there is significant treatment related morbidity . though he responded to high dose corticosteroids ,
a significant fraction of patients in the vasculitic phase remain unresponsive , underlining the importance of early diagnosis in managenent .
Output:
| churg strauss syndrome is a rare disease manifested by hypereosinophilia , vasculitis and tissue infiltration .
this report describes the case of a 45-year - old man who presented with a history of fever , difficulty in breathing , reddish lesions over the extremities and inability to walk since two weeks .
the cutaneous features prompted us to conduct serial lab investigations which led to an early , potentially life saving diagnosis . |
PubmedSumm118202 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the epidermal growth factor receptor ( egfr ) is a transmembrane glycoprotein that constitutes one of the four members of the erbb family of tyrosine kinase receptors .
the small - molecule tyrosine kinase receptor inhibitors ( tkis ) are in clinical use to treat non - small cell lung cancer ( nsclc ) .
the two tkis used at present are erlotinib and gefitinib , usually employed in selected patients with nsclc and showing variable responses . .
the response to these tkis varies by the type of egfr mutations found in the tumor .
the deletion on exon 19 and the l858r substitution on exon 21 constitute the most frequent mutations .
the other , less common mutations include insertions or in - frame duplications on exon 20 .
the significance of this resistance conferred by different insertion mutations on exon 20 is not well established .
we herein present a case of disease progression despite the use of erlotinib in a patient who expressed a novel insertion mutation on exon 20 .
written informed consent was obtained from the patient for the publication of this case report and any accompanying images .
a copy of the written consent is available for review from the editor in chief of this journal .
she was diagnosed with stage iib nsclc ( adenocarcinoma ) and underwent lobectomy in 2009 .
the ct - guided biopsy of the spinal mass confirmed metastatic disease consistent with adenocarcinoma of the lung .
biopsy material from the bone lesion was sent to genzyme genetics laboratories to test the egfr mutation and anaplastic lymphoma kinase ( alk ) translocation .
in addition , she was started on carboplatin and pemetrexed , and she received proton radiation therapy of the mediastinum .
chemotherapy was discontinued after five cycles ( september 26 , 2011december 12 , 2011 ) due to thrombocytopenia .
since the laboratory was unable to process for egfr mutations on the metastatic bone lesion , the sample from the earlier lobectomy was sent for testing for egfr mutation and alk translocation status .
the laboratory results showed that the rearrangement involving the alk gene was negative , and the patient had a pro772_his773insglncyspro mutation on exon 20 .
since there is no confirmatory data on the tki response of this unique type of egfr mutation , we decided to use erlotinib .
the patient 's eastern cooperative oncology group ( ecog ) performance status was 1 at the beginning of the treatment .
she was started on 150 mg of oral erlotinib ( tarceva ) daily and tolerated it well .
the biomarkers and repeat imaging revealed disease progression after 6 weeks of treatment with erlotinib .
her ecog performance status declined to 2 , most likely due to disease progression , as evident on the posttreatment pet scan ( fig .
the c - helix facilitates the correct orientation of amino acids and ends at met766 .
the preferential location of the majority of the insertion mutations is following the c - helix .
the insertion mutations on exon 20 were found to be mutually exclusive with other genetic alterations in nsclc except pik3ca .
these insertions vary from three to twelve base pairs and account for 11% of all egfr mutations .
patients who never smoked were found to have the highest incidence ; sex , ethnicity and stage at diagnosis have not shown any correlations .
the insertion mutations on exon 20 seem to have poor response to tkis . the variable response to tkis
preclinical data suggest less favorable responses to reversible tkis ( gefitinib and erlotinib ) . these exon 20 insertions were also found to be far less sensitive to irreversible tkis ( neratinib and afatinib ) when compared to l858r and exon 19 mutations . in clinical settings , the reported response to reversible tkis ( both gefitinib and erlotinib ) remains inconstant . in the taiwanese population , the treatment response to gefitinib
was found to be 25% , which was much lower when compared to exon 19 and l858r mutations .
the coexisting point mutations on exon 20 that rendered the patients resistant to gefitinib were g719a , v769l , w731 stop , l858r , l 861q and dele749_t751insva .
the type of coexisting mutation seems to affect the response of these insertions to tkis .
the exon 20 mutation ( s768i+g719x ) seemed to show some response to gefitinib while it coexisted with a mutation on exon 18 rather than as a single mutation .
the response of malignant pleural effusions to gefitinib has also been reported in nsclc patients with egfr mutations .
the patients carrying mutations , including those with a deletion on exon 19 , missense on exon 21 and a mutation on exon 18 , responded to gefitinib . however , a patient carrying an in - frame insertion mutation on exon 20 ( p772_h773instyrasnpro+h773y ) was found to have progression of pleural effusion while on gefitinib .
in contrast , another patient carrying an in - frame insertion ( s768 ) on exon 20 of his tumor was reported to show response to gefitinib and was found to have stable disease so that gefitinib was used as a second - line therapy .
our patient was a never - smoker and was identified to have a pro772_his773insglncyspro mutation on exon 20 .
this mutation at amino acid 772 has not been reported in the literature [ 5 , 7 , 9 , 11 , 12 ] ( table 1 ) .
these insertion mutations on this amino acid account for 17% of all insertion mutations on exon 20 .
another , recently reported insertion mutation , p772_h773insval , is characterized by an insertion of a nucleotide triplet gtt .
this patient was not offered a tki and was treated with six courses of cisplatin / pemetrexed chemotherapy and had disease progression .
the patient was reported to have disease stabilization on second - line chemotherapy with docetaxel .
the response to tkis on exon 20 insertion - mutated nsclcs was studied in eight different representative mutations of exon 20 in vitro .
the insertion mutations located in the c - helix showed response to tki when compared to the ones located in the loop following the c - helix . the a763_y764inspheglngluala mutation located in the c - helix showed response to erlotinib or other tkis .
the novel insertion mutation pro772_his773insglncyspro , which was identified in our patient , is most likely located in the loop following the c - helix .
this lack of response confirms the resistance of this particular mutation to tkis . as reported earlier
, these insertion mutations seem to confer resistance to tkis even when they coexist with other mutations .
reaffirm the poor response to tkis for the mutations that exist on this particular loop of exon 20 .
Output:
| the epidermal growth factor receptor ( egfr ) is a transmembrane glycoprotein tyrosine kinase receptor .
the small - molecule tyrosine kinase receptor inhibitors ( tkis ) are in clinical use to treat non - small cell lung cancer with egfr mutations .
variable tumor responses to erlotinib and gefitinib have been observed .
the response to these tkis varies by the type of egfr mutations found in the tumor .
the deletion on exon 19 and the l858r substitution on exon 21 constitute the most frequent mutations and are known to show good response to tkis
. however , mutations on exon 20 are less common and seem to respond poorly to tkis . in clinical settings , the reported response of exon 20 mutations to reversible tkis ( both gefitinib and erlotinib ) remains inconstant .
the type of coexisting mutation seems to affect the response of these insertions to tkis .
we herein present a case of disease progression despite the use of erlotinib in a female patient who had a novel insertion mutation on exon 20 .
our patient was a never - smoker and was identified to have a pro772_his773insglncyspro mutation on exon 20 .
she had previously been treated with cisplatin and gemcitabine and then with carboplatin and pemetrexed .
she was treated with erlotinib upon intolerance to second - line chemotherapy and did not respond .
our patient had a novel insertion mutation on exon 20 , which was found to be resistant to erlotinib . |
PubmedSumm118203 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: periodontitis is a chronic multifactorial inflammatory disease that is characterized by the progressive destruction of the tooth - supporting tissues , such as the periodontal ligament ( pdl ) .
pathogenic microorganisms embedded in a biofilm on the tooth surface can trigger local synthesis of proinflammatory mediators and matrix - degrading proteases by infiltrating and resident cells of the periodontium . as a consequence of the exaggerated immunoinflammatory and proteolytic processes ,
the periodontal tissues are subjected to degradation and resorption , which can result in periodontal pocket formation and even tooth loss [ 14 ] .
the national health and nutrition examination survey iii that analyzed the health and nutritional status in the united states revealed that approximately half of the us population aged 30 years suffers from periodontitis .
it is widely accepted that periodontitis has a significant negative impact on physical , psychological , and social aspects of life and also affects systemic health in affected individuals [ 68 ] .
the main goal of periodontal therapy is to arrest the inflammatory and tissue - destructive processes by reducing or eliminating the pathogenic microorganisms in the periodontal pockets .
conventional periodontal treatment comprises nonsurgical or surgical debridement , sometimes applied in combination with antibiotics , and achieves periodontal healing mainly by repair .
regenerative healing can be stimulated by the application of bioactive molecules , such as enamel matrix derivative ( emd ) , during periodontal surgery [ 1113 ] .
a great number of in vitro studies have demonstrated that emd stimulates the synthesis of growth factors , such as vascular endothelial growth factor ( vegf ) and transforming growth factor ( tgf ) 1 , matrix molecules , such as collagen type i ( col1 ) and periostin ( postn ) , osteogenesis - related factors , such as runt - related transcription factor ( runx ) 2 , calcium deposition , and in vitro wound healing [ 14 , 15 ] .
it is widely accepted that the regeneration - promoting activities of emd are induced at least in part by these mechanisms .
moreover , it has been shown that the beneficial effects of emd on periodontal regeneration are mediated , at least partially , by bone morphogenetic protein ( bmp ) and tgf , because fractions of emd contain bmp- and tgf-like activity and emd stimulates bmp and tgf synthesis in periodontal cells [ 1619 ] .
binding of tgf and bmp to their receptor complexes triggers smad ( sma- and mad - related protein ) and non - smad signaling cascades [ 20 , 21 ] .
regeneration of periodontal tissues is often an unpredictable challenge due to a number of as yet unidentified local and systemic factors that can modulate healing processes .
previous studies suggest that microbial , inflammatory , and biomechanical signals can interfere with the beneficial effects of emd on periodontal cells , emphasizing the critical role of the cell environment for optimal periodontal regeneration [ 2227 ] .
in addition , recent meta - analyses have revealed that obesity , metabolic syndrome , and diabetes mellitus are significantly associated with periodontitis , and it has been suggested that adipokines might be a critical pathomechanistic link in these associations [ 2831 ] .
adipokines are cytokines released from the adipose tissue and regulate food intake and energy expenditure but also immunoinflammatory processes [ 32 , 33 ] . since the serum levels of a number of proinflammatory adipokines , such as nicotinamide phosphoribosyltransferase ( nampt ) , are increased in obesity and some obesity - related diseases , it has been speculated that such adipokines could enhance periodontal inflammation and , thereby , increase the risk of periodontitis or compromise periodontal healing in obese individuals [ 3438 ] .
nampt is mainly produced by macrophages and adipocytes in the adipose tissue , triggers nfb activation , and elicits synthesis of inflammatory mediators . increased serum levels of nampt have been found in obesity , metabolic syndrome , type 2 diabetes , atherosclerosis , and other diseases [ 3436 ] .
therefore , elevated nampt levels could be one mechanism , whereby these diseases contribute to the initiation and progression of periodontitis .
interestingly , nampt is also present at high levels in gingival crevicular fluid ( gcf ) , gingival tissues , and serum from patients afflicted with periodontitis , irrespective of the presence of obesity [ 4042 ] .
these observations indicate that nampt is also produced locally in the periodontium and may play a role in the etiopathogenesis of periodontitis .
our previous experiments have demonstrated that periodontal pathogens upregulate nampt in periodontal cells and , additionally , that nampt could contribute to periodontal inflammation and destruction by stimulating periodontal cells to produce proinflammatory and proteolytic molecules [ 43 , 44 ] .
therefore , this in vitro study sought to examine whether the regenerative capacity of periodontal cells in the presence of emd is modulated by nampt .
a better understanding of the interactions between regenerative molecules and local as well as systemic factors may help better predict and even improve the outcome of currently applied periodontal treatment approaches .
pdl cells from 18 periodontally healthy donors , who underwent tooth extraction for orthodontic reasons , were used for the experiments .
informed consent and approval of the ethics committee of the university of bonn were obtained .
the cells were grown in dulbecco 's minimal essential medium ( dmem , invitrogen , karlsruhe , germany ) supplemented with 10% fetal bovine serum ( fbs , invitrogen ) , 100 units penicillin , and 100 g / ml streptomycin ( invitrogen ) at 37c in a humidified atmosphere of 5% co2 .
cells between 3rd and 5th passage were seeded ( 50,000 cells / well ) on culture plates and grown to 80% confluence . one day prior to the experiments , the fbs concentration was reduced to 1% .
medium was changed every second day . in order to simulate regenerative conditions in vitro ,
pdl cells were treated with emd ( emdogain , straumann , freiburg , germany ) in the presence and absence of nampt . as in our previous studies ,
emd was applied at a concentration of 100 g / ml because this concentration had been used by several investigators before and ensured that our data were comparable with those of other studies [ 2427 ] . in order to investigate the effects of nampt , various concentrations of this adipokine ( 30 , 100 , and 300 ng / ml ; biomol , hamburg , germany )
the standard concentration of nampt was 100 ng / ml . this concentration correlates well with the studies by pradeep and coworkers , who have reported a nampt concentration of 98.32 ng / ml in gingival crevicular fluid [ 4042 ] .
however , these studies only included a small number of patients , so that even higher concentrations can be expected in some individuals and were therefore also studied in a subset of our experiments . in the present study , cells were exposed to emd and/or nampt for up to 14 d ( figure 1 ) . in order to analyze the intracellular mechanisms used by nampt to modulate the actions of emd , cells were preincubated with specific inhibitors against nfb ( pyrrolidine dithiocarbamate , pdtc ; 10 m ; calbiochem , san diego , ca , usa ) , mek1/2 ( u0126 ; 10 m ; calbiochem ) , jnk ( sp600125 ; 10 m ; calbiochem ) , and p38 ( sb203580 ; 10 m ; calbiochem ) signaling pathways 1 h before experiments .
rna was extracted by using an rna extraction kit ( qiagen , hilden , germany ) , and a total of 1 g of rna was reverse transcribed using iscripttm select cdna synthesis kit ( bio - rad laboratories , munich , germany ) at 42c for 90 min followed by 85c for 5 min .
expression of vegf , tgf1 , and its receptor tgfr2 , bmp receptors ( bmpr1a , bmpr1b , and bmpr2 ) , col1 , postn , and runx2 was detected by real - time pcr using the icycler iq detection system ( bio - rad laboratories ) , sybr green ( bio - rad laboratories ) , and specific primers ( quantitect primer assay , qiagen ) ( figure 1 ) .
one l of cdna was amplified as a template in a 25 l reaction mixture containing 12.5 l 2x quantifast sybr green pcr master mix ( qiagen ) , 2.5 l of primers , and 9 l deionized water .
the mixture was heated initially at 95c for 5 min and then followed by 40 cycles with denaturation at 95c for 10 s and combined annealing / extension at 60c for 30 s. glyceraldehyde-3-phosphate dehydrogenase was used as an endogenous control .
the protein levels of vegf and tgf1 in the supernatants of pdl cells were analysed by commercially available enzyme - linked immunosorbent assay ( elisa ) kits ( r&d systems , minneapolis , mn , usa ) according to the manufacturer 's instructions ( figure 1 ) .
the absorbance was measured by using a microplate reader ( powerwave x , biotek instruments , winooski , vt , usa ) at 450 nm .
the data were normalized by cell number that was determined with an automatic cell counter ( moelab , hilden , germany ) . the calcium accumulation in pdl cell cultures following 14 d of treatment with emd and/or nampt
was analyzed by using alizarin red s staining ( merck kgaa , darmstadt , germany ) and cetylpyridinium chloride ( sigma - aldrich chemie , munich , germany ) , as described in our previous studies ( figure 1 ) [ 24 , 25 ] .
briefly , cell monolayers were washed with pbs , fixed in 4% paraformaldehyde ( merck kgaa ) for 10 min , and washed again with deionized water .
afterwards , cells were incubated with 40 mm alizarin red s ( ph 4.2 ) for 15 min , rinsed with deionized water , and subsequently incubated with 10% ( w / v ) cetylpyridinium chloride in 10 mm sodium phosphate ( ph 7.0 ) in order to extract the alizarin red s that was retained in the cell cultures .
the detached cells and cetylpyridinium chloride were collected and centrifuged at 20,000 g for 10 min .
afterwards , the pellets were discarded and the supernatants that contained the extracted stain were transferred into a 96-well plate to analyze the absorbance at 562 nm using a microplate reader . in order to examine the effect of nampt on wound fill , an in vitro wound healing model was used , as in our previous experiments [ 24 , 25 ] .
briefly , cells were grown until confluence and 3 mm wide wounds were created in a standardized manner in the cell monolayers . the wounded cell monolayers were treated with emd and , simultaneously , with various concentrations of nampt ( 0 , 30 , 100 , and 300 ng / ml ) for 5 d. at every day , the wounds were documented by inverse microscopy ( axiovert 25 c , 5x objective , carl zeiss , oberkochen , germany ) and digital photography ( kodak dc 290 , kodak , stuttgart , germany ) ( figure 1 ) .
measurement and analysis of the wound widths were performed with special software ( alpha digidoc 1000 , alpha innotech , san leandro , ca ) .
pdl cells were fixed with 4% paraformaldehyde in pbs ph 7.4 for 10 min , washed with pbs , and treated with 0.1% triton x-100 ( sigma - aldrich , munich , germany ) for 5 min .
then , cells were washed again and blocked with nonfat dry milk ( bio - rad laboratories ) for 1 h. after washing , cells were incubated with a rabbit anti - smad1/5/8 antibody ( santa cruz biotechnology , santa cruz , ca , germany ) for 90 min and with cy3-conjugated goat anti - rabbit igg ( abcam , cambridge , ma , usa ) for 45 min .
cells were observed under a 20x objective using an axioplan 2 imaging microscope ( carl zeiss ) .
the images were captured with a pvcam camera and the visiview capturing software ( visitron systems , puchheim , germany ) ( figure 1 ) .
phosphorylation of smad1/5/8 was analyzed from whole lysate ( 20 to 40 g protein ) of cells treated with emd in the presence or absence of nampt ( figure 1 ) .
cells were washed twice with ice cold pbs and collected in ripa buffer ( sigma - aldrich ) supplemented with protease inhibitors ( sigma - aldrich ) .
equal amounts of protein were resolved through sds - polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes ( bio - rad laboratories ) .
the membranes blocked with 5% nonfat milk were probed with a specific rabbit anti - psmad1/5/8 antibody ( cell signalling technology , danvers , ma , usa ) .
the binding of the primary antibody was revealed with horseradish peroxidase- ( hrp- ) labeled goat anti - rabbit igg ( jackson immunoresearch , suffolk , uk ) .
lightning chemiluminescence reagent ( thermo fisher scientific , rockford , il , usa ) was used as an hrp substrate .
all blots were reprobed with rabbit anti - smad1/5/8 ( santa cruz biotechnology ) and mouse anti--actin antibodies ( abcam , cambridge , uk ) to assure equal input of proteins .
parametric ( t test and anova followed by the post hoc tukey 's test ) and nonparametric tests ( wilcoxon and mann - whitney u - tests ) were applied for statistical analysis by using the ibm spss statistics 20 software .
since the regeneration - promotive effects of emd are at least partly mediated by upregulation of growth factors , we first sought to determine whether these emd actions on pdl cells are modulated by nampt .
as expected from previous studies , emd caused a significant upregulation of vegf and tgf1 in pdl cells at 1 d and 3 d. however , the emd - stimulated vegf und tgf1 expressions were significantly reduced in the presence of nampt at both time points , as shown in figures 2(a ) and 2(b ) .
interestingly , nampt did not induce a significant downregulation of the constitutive vegf and tgf1 expressions ( figures 2(a ) and 2(b ) ) .
dose response experiments revealed that the inhibitory effects of nampt on the emd - stimulated vegf and tgf1 upregulation were similar over a wide range of concentrations ( figures 2(c ) and 2(d ) ) . by preincubation of cells with a specific inhibitor against the jnk signaling pathway
, the inhibitory effects of nampt on the emd - induced vegf and tgf1 expressions were completely blocked at 1 d. however , inhibition of nfb , mek1/2 , or p38 signaling did not interfere with the actions of nampt at this time point ( data not shown ) .
the inhibitory effects of nampt on the emd - stimulated vegf and tgf1 expressions were also found at protein level , as analyzed by elisa after 3 d ( table 1 ) .
therefore , we next studied whether actions of emd on matrix molecules are modulated by nampt .
emd increased significantly the expression of col1 and postn at 1 d and 3 d , but these stimulatory effects were significantly inhibited by nampt for col1 at 1 d and for postn at 1 d and 3 d ( figures 2(e ) and 2(f ) ) .
nampt had no regulatory effects on the spontaneous expression of col1 and postn ( figures 2(e ) and 2(f ) ) .
next , we wondered whether nampt would also interfere with the stimulatory effects of emd on osteogenesis .
as expected , emd stimulated significantly the expression of runx2 , an osteogenesis - associated transcription factor , at 1 d and 3 d ( figure 3(a ) ) .
interestingly , the emd - induced runx2 expression was also significantly downregulated by nampt , which reached significance at 1 d ( figure 3(a ) ) . furthermore ,
treatment of cells with emd for 14 d caused a pronounced calcium accumulation in cell cultures , as determined by alizarin red s staining ( figures 3(b ) and 3(c ) ) . when cells were simultaneously treated with emd and nampt , the calcium accumulation was significantly reduced as compared to emd - stimulated cultures in the absence of nampt ( figures 3(b ) and 3(c ) ) .
nampt also caused a dose - dependent inhibition of the emd - stimulated wound healing ( figure 4(a ) ) .
the emd - induced wound closure was significantly reduced by 100 ng / ml of nampt and even more pronounced by 300 ng / ml of nampt at 3 , 4 , and 5 d , whereas 30 ng / ml of nampt had only a significantly inhibitory effect at 5 d ( figure 4(a ) ) .
at least some actions of emd seem to be mediated by bmp or tgf because emd has been shown to possess bmp- and tgf-like activity and , additionally , to upregulate these molecules in periodontal cells .
as shown in figure 4(b ) , emd increased significantly the constitutive expression of bmpr1a , bmpr1b , bmpr2 , and tgfr2 at 1 d. however , nampt caused a significant downregulation of the emd - stimulated expression of these receptors at this time point ( figure 4(b ) ) .
similar results were found for 3 d ( data not shown ) . in the absence of emd , a significant inhibition by nampt
next , we sought to unravel intracellular mechanisms , whereby nampt abrogates regeneration - promotive actions of emd . as shown in figure 5(a ) , emd caused a pronounced accumulation of smad1/5/8 in the nucleus of emd - treated cells at 60 min . however , in the presence of nampt , this emd - stimulated nuclear translocation of smad1/5/8 was reduced . in the absence of emd , no obvious effect of nampt on the smad1/5/8 nuclear translocation was observed ( figure 5(a ) ) .
further experiments revealed that emd stimulated the phosphorylation of smad1/5/8 in a time - dependent manner , as evidenced by immunoblotting ( figure 5(b ) ) .
as shown in figure 5(c ) , the emd - stimulated smad1/5/8 phosphorylation was inhibited in the presence of nampt .
the present study demonstrates for the first time that regeneration - promotive actions of emd on a great number of pdl cell functions critical for periodontal regeneration are jeopardized by nampt .
the findings of this study suggest that increased levels of nampt , as found in obesity and periodontal inflammation , may compromise the regenerative capacity of pdl cells and , thereby , periodontal healing in the presence of emd .
nampt abrogated the stimulatory effects of emd on vegf and tgf1 , col1 , in vitro wound healing , and osteogenic differentiation .
vegf is an essential growth factor , which supports wound healing by its regulatory effects on vascular permeability , influx of inflammatory cells into the site of injury , migration and proliferation of preexisting endothelial cells , and the recruitment of marrow - derived endothelial progenitor cells to the local wound site .
in addition , vegf seems to play an important role in the modulation of bone remodeling by attracting endothelial cells and osteoclasts and by stimulating osteoblast differentiation .
tgf , another important growth factor , comprises three isoforms and also promotes wound healing like vegf .
moreover , it induces fibroblasts to deposit new extracellular matrix proteins , which promotes cell and vascular in - growth .
in addition to growth factors , matrix molecules , such as col1 and postn , are also critical for periodontal homeostasis and healing . like col1 ,
postn is also strongly expressed in the human pdl and regulates cell - matrix interactions as well as cell adhesion , proliferation , and differentiation [ 49 , 50 ] .
furthermore , periostin also aids to disperse mechanical forces applied to the pdl [ 50 , 51 ] .
interestingly , nampt also counteracted the stimulatory effects of emd on the in vitro wound healing .
following periodontal treatment , periodontal wounds need to be repopulated with cells to achieve periodontal healing . when emd - treated cells were exposed to nampt , the wound closure was dose - dependently delayed , indicating that nampt may also inhibit critical cell functions , such as proliferation and migration , under regenerative conditions .
pdl cells can acquire an osteoblastic phenotype , and a number of studies have proven that emd stimulates expression of osteogenesis - associated factors , such as runx2 , and calcium deposition , an early marker of matrix mineralization , from pdl cells . as expected , emd upregulated runx2 and induced calcium deposition in the present study . in the presence of nampt , the stimulatory effects of emd on these osteogenesis - related processes were reduced .
although nampt inhibited significantly the emd - induced runx2 and collagen expressions at 1 day , the inhibitory effects of nampt did not reach significance at 3 days due to the pronounced standard deviations .
however , including a higher number of donors in these experiments might have resulted in statistically significant changes also at 3 days .
nevertheless , our findings suggest that nampt interferes with both the emd - induced effects on both periodontal soft and hard tissue regeneration .
we also sought to unravel the mechanisms , whereby nampt modulates the actions of emd .
fractions of emd contain bmp- and tgf-like activity and emd also upregulates bmp and tgf in periodontal cells [ 1619 ] .
therefore , it is thought that beneficial effects of emd on periodontal regeneration are mediated , at least in part , by these factors .
we therefore studied whether nampt regulates the expression of their receptors as a possible mechanism , whereby nampt may modulate the actions of emd .
bmp binds to bmpr1 , upon which bmpr2 is recruited into the complex , or binds to a preformed complex of bmpr1 and bmpr2 , which triggers the activation of smad and non - smad pathways . following binding of tgf to tgfr2 , tgfr1 is recruited into a heterotetrameric receptor complex and then phosphorylated on serine residues by tgfr2 , which also finally results in the activation of the smad signaling pathway . as shown in the present and our previous studies ,
emd increased the constitutive expression of bmprs and tgfrs , and this emd - stimulated receptor upregulation was inhibited by nampt .
these findings suggest that nampt can regulate actions of emd also at receptor level , as it has recently been shown for interleukin-1 and biomechanical forces [ 2426 ] .
furthermore , we sought to identify intracellular mechanisms , whereby the stimulatory effects of emd are modulated by nampt .
our experiments revealed that the inhibition of the emd - induced vegf and tgf1 upregulation by nampt was jnk - dependent .
moreover , nampt inhibited the emd - stimulated phosphorylation of smads and , additionally , inhibited their nuclear translocation .
further experiments are needed to clarify how jnk interferes with smad signaling and whether additional signaling pathways are involved .
the present study also confirms our previous studies on the harmful effects of inflammatory signals on regenerative periodontal healing [ 2426 ] .
moreover , in the present study , we provide original evidence that also systemic factors , such as nampt , whose levels are increased in obesity , metabolic syndrome , and diabetes mellitus , may interfere with periodontal healing . although pdl cells are of utmost importance in periodontal regenerative healing , in a clinical setting , additional cells , such as inflammatory cells , keratinocytes , gingival fibroblasts , and osteo- and cementoblasts , are involved .
further studies should examine whether nampt also affects these cells under normal and regenerative conditions .
moreover , in addition to nampt , the levels of other adipokines , such as leptin , resistin , and adiponectin , are altered in obesity and periodontal inflammation [ 5356 ] .
future studies should therefore focus on the regulation of periodontal cells and their regenerative capacity by these adipokines . in summary ,
the present study shows for the first time that beneficial effects of emd on a number of pdl cell functions critical for periodontal regeneration are counteracted by nampt .
enhanced levels of nampt , as found in obesity and periodontal inflammation , may compromise the regenerative capacity of pdl cells and , thereby , regenerative periodontal healing in the presence of emd .
Output:
| periodontitis is an inflammatory disease characterized by destruction of the tooth - supporting tissues .
obese individuals have an increased risk of periodontitis , and elevated circulating levels of nicotinamide phosphoribosyltransferase ( nampt ) may be a pathomechanistic link between both diseases .
recently , increased levels of nampt have also been found in patients with periodontitis , irrespective of the presence of obesity .
this in vitro study sought to examine the effects of nampt on the regenerative capacity of human periodontal ligament ( pdl ) cells and , thereby , periodontal healing .
pdl cells treated with enamel matrix derivative ( emd ) , which was used to mimic regenerative healing conditions in vitro , were grown in the presence and absence of nampt for up to 14 d. emd stimulated significantly ( p < 0.05 ) the expression of growth factors and their receptors , matrix molecules , osteogenesis - associated factors , and wound closure and calcium accumulation . in the presence of nampt , all these stimulatory effects were significantly ( p < 0.05 ) reduced . in conclusion ,
the beneficial effects of emd on a number of pdl cell functions critical for periodontal regeneration are counteracted by nampt .
enhanced levels of nampt , as found in obesity and periodontal inflammation , may compromise the regenerative capacity of pdl cells and , thereby , periodontal healing in the presence of emd . |
PubmedSumm118204 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: intubation and mechanical ventilation ( mv ) are frequently necessary to treat the critically ill infant or after long surgical interventions . however , prolonged mv predisposes to nosocomial infection , tracheal injury , or difficulties with sedation of intubated children and should be discontinued at the earliest possible time .
the reported extubation failure of mechanical ventilation in infants ranges from 4.9% to 29% . a spontaneous breathing trial for weaning mechanically ventilated children using either a t - piece or pressure support showed that children could be successfully weaned from mv .
however , 1215% of these patients required reintubation within 48 h. to this way chavez et al . described the utilization of a mapleson c circuit as a spontaneous breathing trial ( sbt ) to predict successful extubation , with a high percentage of patients ( 92% ) extubated after a 15 min sbt using a flow inflating anesthesia bag .
noninvasive positive airway pressure ventilation has been described as safe and effective in infants with mild to moderate hypoxemic respiratory insufficiency , upper airway obstruction , and postextubation respiratory distress . however
, more evidence is necessary to define the mode of ventilation support to be used for specific cases , the adequate type of interface , and the length of use and weaning . over the last years
, we have used a flow - inflating bag circuit with a nasotracheal or nasopharyngeal tube as an interface to deliver effective cpap support in children ( mapleson d cpap system ) with acute respiratory insufficiency , for weaning of mv and to provide cpap outside the intensive care unit ( icu ) .
the primary goal of this study was to analyze the usefulness of the flow - inflating bag circuit with a nasotracheal or nasopharyngeal tube as an interface ( mapleson d cpap system ) for weaning of mv in fifty infants who received mv for more than 24 h.
la paz hospital human research ethics committee approved this retrospective , observational study . all infants and children who received prolonged mv for more than 72 h during 4 years and
were judged by the attending physician to be ready to undergo extubation were eligible for the study .
patients were enrolled if they met the following criteria : ( a ) full term infants to 16 years of age ; ( b ) improvement or resolution of the underlying cause of mv ; and ( c ) adequate gas exchange as indicated by arterial oxygen saturation 92% whereas breathing an fio2 of 0.40 ; level of consciousness acceptable for extubation ; ( d ) no clinical need for increased ventilator support in the last 12 h ; and ( e ) no need for vasoactive agents except for low dose of dopamine .
patients with tracheostomy , unrepaired congenital heart disease , neuromuscular disease , and estimated gestational age 37 weeks were excluded .
the physicians determined extubation readiness using the standard clinical practice of our unit , including assessment of physical exam , blood gasses , chest radiographs , and ventilator settings .
once , the team has identified a patient who was ready for extubation , in a first step patient ventilator was disconnected allowing the patient to breathe spontaneously with the mapleson d cpap system and a nasotracheal tube as interface [ figure 1 ] .
this step was made by a nurse in the absence of the attending or other physician staff to blind the medical team of the results .
the patient was reconnected to the ventilator if the patient experienced ( a ) signs of increased respiratory work , as the use of accessory respiratory muscles , paradoxical breathing ; ( b ) pulse oxygen saturation < 90% ; and ( c ) increase in systolic blood pressure > 20% baseline . in a second step ,
if the nasotracheal mapleson d cpap system was well tolerated , the patient was extubated to nasal prongs or to the nasopharyngeal mapleson d cpap system by a nurse in the absence of the attending or other physician staff to blind the medical team of the results , but according of the criteria of the medical team .
extubation failure was defined as respiratory distress requiring reintubation within 48 h of extubation or patients which were not able to maintain 6 h continuous spontaneous ventilation with the nasotracheal mapleson d cpap system .
the mapleson d cpap system was made by a mapleson d system ( intersurgical , wokingham , england ) with a 0.5 or 1 l reservoir bag and a 20 mm corrugated tubing that was connected to a lubricated uncuffed endotracheal # 3.5 to # 5.0 portex tube , as nasopharyngeal or nasotracheal airway .
airway pressure was measured at the proximal end of the system with a manometer ( vygon , ecouen , france ) [ figure 2 ] .
fresh gas was enriched with a siemens o2 -air mixer and was warmed and humidified using a bennett cascade ( bennett , london , uk ) humidifier .
we used a fresh gas flow rate of 23 times total ventilation at least to prevent rebreathing of co2 .
the mapleson d cpap system demographic data included age , gender , weight , and admission diagnosis .
laboratory results were obtained from data collected within 2 h before spontaneous ventilation , 2 h after the nasotracheal mapleson d cpap system , and 2 h after extubation , with the patient breathing spontaneously with nasal prongs or with the nasopharyngeal mapleson d cpap system [ figure 1 ] .
oxygenation data were evaluated only from patients who had arterial blood gas determinations performed both before and after initiation of this modality .
the following variables were measured during mv , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation , with the patient breathing spontaneously with nasal prongs or with the nasopharyngeal mapleson d cpap system : heart rate , respiratory rate , blood pressure , and oxygen saturation . recorded clinical information included the duration of mv , duration of spontaneous ventilation with the nasotracheal mapleson d cpap system and duration of spontaneous ventilation with or without the nasopharyngeal mapleson d cpap system or nasal prongs .
patients were classified into two groups according to the length of mv : patients with acute respiratory failure with mv for more than 48 h ( mv > 48 h ) , and patients with mv fewer than 48 h ( mv < 48 h ) .
statistical analysis consultation was provided by the biostatistics department at the la paz university hospital .
changes in the mean response of measured vital signs were explored 2 h before spontaneous ventilation , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation using analysis of variance .
la paz hospital human research ethics committee approved this retrospective , observational study . all infants and children who received prolonged mv for more than 72 h during 4 years and
were judged by the attending physician to be ready to undergo extubation were eligible for the study .
patients were enrolled if they met the following criteria : ( a ) full term infants to 16 years of age ; ( b ) improvement or resolution of the underlying cause of mv ; and ( c ) adequate gas exchange as indicated by arterial oxygen saturation 92% whereas breathing an fio2 of 0.40 ; level of consciousness acceptable for extubation ; ( d ) no clinical need for increased ventilator support in the last 12 h ; and ( e ) no need for vasoactive agents except for low dose of dopamine .
patients with tracheostomy , unrepaired congenital heart disease , neuromuscular disease , and estimated gestational age 37 weeks were excluded .
the physicians determined extubation readiness using the standard clinical practice of our unit , including assessment of physical exam , blood gasses , chest radiographs , and ventilator settings .
once , the team has identified a patient who was ready for extubation , in a first step patient ventilator was disconnected allowing the patient to breathe spontaneously with the mapleson d cpap system and a nasotracheal tube as interface [ figure 1 ] .
this step was made by a nurse in the absence of the attending or other physician staff to blind the medical team of the results .
the patient was reconnected to the ventilator if the patient experienced ( a ) signs of increased respiratory work , as the use of accessory respiratory muscles , paradoxical breathing ; ( b ) pulse oxygen saturation < 90% ; and ( c ) increase in systolic blood pressure > 20% baseline . in a second step ,
if the nasotracheal mapleson d cpap system was well tolerated , the patient was extubated to nasal prongs or to the nasopharyngeal mapleson d cpap system by a nurse in the absence of the attending or other physician staff to blind the medical team of the results , but according of the criteria of the medical team .
extubation failure was defined as respiratory distress requiring reintubation within 48 h of extubation or patients which were not able to maintain 6 h continuous spontaneous ventilation with the nasotracheal mapleson d cpap system .
the mapleson d cpap system was made by a mapleson d system ( intersurgical , wokingham , england ) with a 0.5 or 1 l reservoir bag and a 20 mm corrugated tubing that was connected to a lubricated uncuffed endotracheal # 3.5 to # 5.0 portex tube , as nasopharyngeal or nasotracheal airway .
airway pressure was measured at the proximal end of the system with a manometer ( vygon , ecouen , france ) [ figure 2 ] .
fresh gas was enriched with a siemens o2 -air mixer and was warmed and humidified using a bennett cascade ( bennett , london , uk ) humidifier .
we used a fresh gas flow rate of 23 times total ventilation at least to prevent rebreathing of co2 .
laboratory results were obtained from data collected within 2 h before spontaneous ventilation , 2 h after the nasotracheal mapleson d cpap system , and 2 h after extubation , with the patient breathing spontaneously with nasal prongs or with the nasopharyngeal mapleson d cpap system [ figure 1 ] .
oxygenation data were evaluated only from patients who had arterial blood gas determinations performed both before and after initiation of this modality .
the following variables were measured during mv , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation , with the patient breathing spontaneously with nasal prongs or with the nasopharyngeal mapleson d cpap system : heart rate , respiratory rate , blood pressure , and oxygen saturation . recorded clinical information included the duration of mv , duration of spontaneous ventilation with the nasotracheal mapleson d cpap system and duration of spontaneous ventilation with or without the nasopharyngeal mapleson d cpap system or nasal prongs .
patients were classified into two groups according to the length of mv : patients with acute respiratory failure with mv for more than 48 h ( mv > 48 h ) , and patients with mv fewer than 48 h ( mv < 48 h ) .
statistical analysis consultation was provided by the biostatistics department at the la paz university hospital .
changes in the mean response of measured vital signs were explored 2 h before spontaneous ventilation , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation using analysis of variance .
their median age was 34 45 months ( range , 159 months ) and median weight was 11.98 9.31 kg ( range , 148 kg ) . nearly 44% were female ( n = 22 ) and 56 were male ( n = 28 ) .
about 26% of the patients were intubated and ventilated for more than 48 h , and 11 required mv fewer than 48 h , due to prolonged surgery .
median duration of mv was 480 h ( range , 2570 ) . selected specific features of the study population are summarized in table 1 . there were no significant differences in respiratory rate , heart rate , oxygen saturation , systolic blood pressure , and diastolic blood pressure among baseline , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation [ table 2 ] .
twenty - five patients have oxygenation data from arterial line . there were no significant differences in pao2 , paco2 , and ph among mv , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation and spontaneous ventilation with the nasopharyngeal mapleson d cpap system or with nasal prongs [ figure 3 ] .
characteristics of the study population respiratory rate , heart rate , oxygen saturation , systolic blood pressure and diastolic blood pressure during the study po , pco and ph during the study the overall extubation failure rate was 26% ( n = 13 ) .
of these , 3 required reintubation and 10 patients were not able to maintain proper spontaneous ventilation with the nasotracheal mapleson d cpap system .
the reasons included fatigue ( 8) , hypoxemia ( 2 ) , and upper airway obstruction ( 3 ) . weight and age were significantly associated with extubation failure [ table 3 ] .
we did not found significant differences in heart rate , oxygen saturation , and systolic blood pressure among baseline and 2 h after the nasotracheal mapleson d cpap system in patients where nasotracheal mapleson d cpap system failed .
this study has a major finding by applying the mapleson d cpap system to the nasotracheal tube and successively withdrawing the tube from trachea to pharynx ; we provided cpap both before and after extubation . by this simple technique , we were able to predict successful extubation as well as to minimize extubation failure
unnecessary delays in extubation increase costs and the complication rate associated with mv ; however , aggressive discontinuation of ventilator support must be balanced against the possibility of extubation failure .
this , added to the longer duration of intubation in the success group , may indicate that our current practice of extubation children with the mapleson d cpap system was aggressive .
pediatric studies have shown that patients with a longer duration of intubation , younger age , and chronic respiratory and neurologic disorders have higher extubation failure rates .
showed that patients recovering from acute lung injury create an intratracheal positive end - expiratory pressure by breaking the expiratory airflow , probably by glottis narrowing . despite compensatory glottis narrowing , extubated patients with reduced lung function may benefit from higher levels of continuous positive airway pressure .
this is in aligned with ishaaya et al . , who showed that neither tracheal nor laryngeal disease caused the increase in work of breathing after extubation .
chavez et al . described the utilization of a mapleson c circuit as an sbt to predict successful extubation .
according to these authors , an important advantage of this method over the t - piece is that it could readily provide cpap to maintain functional residual capacity .
in contrast to our study , chavez et al . extubated their patients directly to nasal prongs .
one of the advantages of mapleson d cpap system is the possibility of withdraw the tube from trachea to pharynx , providing cpap after extubation with the use of a nasopharyngeal tube as an interface . in pediatric patients problems with
mask leaks and inability to attain the adjusted peak inspiratory pressure are common with nasal and facial masks in the acute setting .
in addition , the volume of the mask itself leads to increased dead space , especially in young children , thus limiting the benefit of noninvasive mv .
moreover , children 's natural fear of any device that covers their nose or mouth represents a major limitation of using face masks . the use of a nasopharyngeal tube as an interface avoids discomfort and facial bruising as well as the increase in dead space secondary to the use of nasal or face masks .
potential disadvantages of the nasopharyngeal tube are nasal trauma and the leaks through an open mouth , which we minimized using a dummy .
other advantage of the mapleson d cpap system is the needlessness of a ventilator .
currently , available bipap ventilators were primarily designed to treat adults and their often inefficient inspiratory triggering systems , expiratory valve mechanics , and flow delivery pattern may increase respiratory workload , especially in young children .
the absence of a ventilator would reduce the additional work of breathing and avoid asynchrony events due to inspiratory and expiratory triggers .
moreover , the utilization of a reservoir bag and an airway pressure limiting valve minimize the inspiratory workload and may be useful as defensive mechanism against barotrauma .
however , elevated gas consumption due to higher fresh gas flow rates must be taken into account .
the mapleson d cpap system , in our opinion , is a usefulness and safe alternative to more complex and expensive noninvasive cpap and bipap weaning from mv in infants .
Output:
| background : over the last years , we have used a flow - inflating bag circuit with a nasotracheal or nasopharyngeal tube as an interface to deliver effective cpap support in infants ( mapleson d cpap system ) . the primary goal of this study was to assess the usefulness of the mapleson d cpap system for weaning of mechanical ventilation ( mv ) in infants who received mv over 24 h.materials and methods : all infants who received mv for more than 24 h in the last year were enrolled in the study .
demographic data included age , gender , weight , and admission diagnosis .
heart rate , respiratory rate , blood pressure , and oxygen saturation were measured during mv , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation .
patients were classified into two groups : patients mv more than 48 h , and patients with mv fewer than 48 h. p < 0.05 was considered statistically significant.results:a total of 50 children were enrolled in the study , with a median age was 34 45 months ( range , 159 months ) and median weight was 11.98 9.31 kg ( range , 148 kg ) .
median duration of mv was 480 h ( range , 2570 ) .
there were no significant differences in pao2 , paco2 , and ph among mv , 2 h after the nasotracheal mapleson d cpap system and 2 h after extubation and spontaneous ventilation with the nasopharyngeal mapleson d cpap system or with nasal prongs .
the overall extubation failure rate was 26% ( n = 13 ) .
weight and age were significantly associated with extubation failure ( p < 0.05).conclusions : the mapleson d cpap system , in our opinion , is a useful and safe alternative to more complex and expensive noninvasive cpap and bipap weaning from mv in infants . |
PubmedSumm118205 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: fractures of the jaw bones render not only physical trauma but al so makes the person miss out on work productivity and other social obligations for a period ranging from four to eight weeks on an average .
fractures of the jaw bones , like other bones of the body take a reasonably long time to heal .
attempts have been made through the centuries to be able to reduce this period of six to eight weeks , either by means of improved surgical technology or by interfering with the physiological mechanism of bone healing .
ayurveda the ancient science of medicine describes various herb preparations that achieve the hastening of bone healing . in ayurveda
most of the names of the plants have been given according to their medicinal values .
harjor means that which joins the bones ( har is bone , jor the one which joins ) .
patients with jaw fracture were selected randomly from the outpatient department of the oral and maxillofacial surgery and trauma center .
patients with mandible fracture and associated undisplaced maxilla , zygomatic complex fracture were also included .
patients on steroid therapy or immunosuppressants and suffering from any other chronic debilitating diseases were not included in this study .
a total of 44 patients were included in this study and divided into four groups [ tables 14 ] .
osteoseal ( group 1 ) analysis of clinical variables at different time intervals moringa olifera ( group 2 ) analysis of clinical variables at different follow - ups placebo ( group 4 ) comparison of clinical variables at different follow - up group 3 : harjor ( cissus quadrangularis ) group 2 : moringa ( moringa oleifera ) the capsules were provided by the international institute of herbal medicine and they were certified organic , they were free from any pesticides and chemicals and heavy metals .
these were freshly powdered whole herb part dried to low moisture content of 6 - 7% and then grinded with slow grinders at low temperature .
this specific limit of moisture prevents the degradation of the phyto chemicals and also the chemical reaction between different in poly - herbal formulations .
this is the only way which can provide at least 90% of the prana of the whole herb intact . in this method
most of the active constituents are maintained for a long period and are highly bio - available to the human system through the gastrointestinal tract .
the consent of the patients was obtained after the explaining the nature of the study .
pre- and post - treatment serum calcium , total and ionic , and phosphorus were also investigated .
patients were called at the first , fourth , and sixth week for examination pain , swelling , tenderness , and mobility of the fractured segment were recorded .
radiograhic interpretation was done which showed there was significant radiographic evidence of the early healing of the fracture in the cases treated with osteoseal , harjor followed by moringa and at last placebo [ tables 15 ] .
pain , swelling , tenderness , mobility reduction in maximum in osteoseal group and minimum in placebo at different follow - ups ca , ca , p increase is maximum .
the most common cause of trauma was found to be rta , followed by fall from height as described in table 1 .
the most common site of fracture was parasymphysis ( 45.4% ) followed by body fracture ( 34.9% ) , and the least common site was ramus fracture [ table 2 ] .
the increased number of automobiles on the road and lack of traffic sense , coupled with high speed are the main causes of rtas .
pain , swelling , tenderness , mobility reduction is maximum in osteoseal group and minimum in placebo .
there was an increase in the serum calcium and phosphorus level at different follow - ups in each groups but there was a decrease in the placebo group .
suitable , antibiotic , analgesic , and anti - inflammatory drugs were given for five days [ tables 6 and 7 ] .
pain , swelling , tenderness , mobility reduction in maximum in osteoseal group and minimum in placebo at different follow - ups ca , ca , p increase is maximum .
the most common cause of trauma was found to be rta , followed by fall from height as described in table 1 .
the most common site of fracture was parasymphysis ( 45.4% ) followed by body fracture ( 34.9% ) , and the least common site was ramus fracture [ table 2 ] .
the increased number of automobiles on the road and lack of traffic sense , coupled with high speed are the main causes of rtas .
pain , swelling , tenderness , mobility reduction is maximum in osteoseal group and minimum in placebo .
there was an increase in the serum calcium and phosphorus level at different follow - ups in each groups but there was a decrease in the placebo group .
suitable , antibiotic , analgesic , and anti - inflammatory drugs were given for five days [ tables 6 and 7 ] .
cissus quandrangularis contains vitamins and steroid which are found to have a specific effect on bone fracture healing .
the anabolic steroidal principle from cissus quandrangularis shows a marked influence on the rate of fracture healing by influencing early regeneration of all connective tissues involved in the healing and quicker mineralization of callus .
the hastening in the fracture healing was attributed to the stimulation of all cells of mesenchymal origin , namely , the fibroblasts , chondroblasts and osteoblasts , by cissus quandrangularis .
thus cissus quandrangularis builds up the chemical composition of the fractured bone namely mucopolysachrides , collagen calcium phosphorus and others as well as its functional efficiency . in our study
intermaxillary fixation was removed at the third or fourth week in cases which were treated by harjor and osteoseal , there was no mobility no tenderness . at the sixth week
there was a significance rise in serum calcium both ionic and total , and serum phosphorus also . in another study
radioactive ca64 bone uptake decreased in the first week , followed by a gradual increase in subsequent weeks , and came to normal in six to eight weeks .
it seems that harjor increases the efficacy of the fracture healing mechanism which functions under the rule of maximum economy deposition of calcium is just enough safe joining of the broken parts of bone and entire remodeling process comes to end faster.[46 ] in another study the early radiographic evidence of periosteal reactin and bony dissolution in the harjor - treated group indicates a faster healing process .
active constituents of cissus quandrangularis may stimulate the proliferation and differentiation of mesenchymal cells ( mscs ) and promote new bone formation through the wntlrp5-b - creatnin signaling pathway of pre - osteoblast formation .
it can be used to treat various bone disorders and can also be used as a preventive measure for disorders that lead to decreased bone mineral density .
the role of nutrition in bone healing is the most important factor which influences bone healing , calcium is effective but can not be utilized just by increasing the uptake the ability of absorption of the calcium also has to be increased .
lysine is an amino acid that helps in the absorption of calcium , vitamin c is essential nutritionally to make the collagen that helps the body form healthy bones .
the damaged cells in the fractured area release a large amount of prostaglandin these are important in first stage of tissue repair , and as so causes pain , and if blocked by pain killers for longer duration can affect n bone healing .
the plant extract serves as a rich source of calcium ion , when reacted with co2 lead to formation of calcite crystals of highly irregular morphology indicating that bioorganic molecules present in extract modulate the crystals morphology .
the leaves and stems of moringa olifera are known to have a large amount of their calcium bound in calcium oxalate crystals more vitamin than carrot , more calcium than milk more iron than spinach more vitamin c than orange and more potassium than in banana .
one tablespoon of ( 8 g ) of leaf powder will satisfy about 14% of protein , 40% of calcium , 23% of iron , and all the vitamin a needs of a child aged one to three years .
six teaspoons full of powder will satisfy nearly all the women , daily need of iron and calcium needs during pregnancy and breast feeding .
it also has potent antibacterial , antifungal , antiviral , and anti - inflammatory activity analgesic antipyretic and muscle relaxant actions .
osteoseal is a formula with the highest natural bio - available calcium , phosphorus , vitamins and amino acids .
it helps prevent bone density loss , supplies natural , herbal calcium and minerals for strong bones and teeth , speeds healing of fractured bones , promotes healthy bone growth and increases bone mineral density in osteoporosis .
osteoseal should be avoided during the first three months of pregnancy and should not be recommended in higher doses for the rest of the pregnancy due to its neem content which has some anti - fertility and abortive properties .
neem is to prevent infection in the fractured bone joint and surrounding tissues as well as to support the analgesic anti - inflammatory action of these two herbs .
harjor showed clinical efficacy in the treatment of fractures , our study also showed reduction in intermaxillary fixation time from six weeks to three to four weeks with ostoeseal , followed by harjor , followed by moringa , and in cases of placebo there was no reduction in time of intermaxillary fixation [ figure 1 ] .
serum ca level , both ionic and total , and serum phosphorus level were significantly increased in the other three groups but decreased in the placebo group [ figure 2 ] . comparative clinical evaluation comparative biochemical evaluation
Output:
| background : ayurveda the ancient science of medicine describes various herb preparations that achieve the hastening of bone healing .
harjor showed clinical efficacy in the treatment of fractures.objectives:the comparative evaluation of herbal agents as osteogenic agents in mandibular fractures.study design : the patients were divided into four groups .
group 1 : osteoseal ; group 3 : harjor ( cissus quadrangularis ) ; group 2 : moringa ( moringa oleifera ) ; group 4 : placebo.result and conclusion : pain , swelling , tenderness , mobility reduction is maximum in osteoseal group and minimum in placebo .
there was an increase in the serum calcium and phosphorus level at different follow - ups in each groups but there was a decrease in the placebo group .
ca , ca+ , phosphrous increase was maximum in the group 1 . |
PubmedSumm118206 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: she underwent nephrectomy , and the histology revealed a renal cell carcinoma ( rcc ) of chromophobe type , eosinophilic variant .
maximum tumor diameter was 12 cm , with extensive necrosis , grade iv according to fuhrman 's nuclear grading system .
pn1 cm0 . neither the renal vein nor the adrenal gland was infiltrated . in august 2007 ,
treatment with sunitinib 50 mg on a 4 weeks on/2 weeks off schedule was initiated , resulting in stable disease . however , the doses had to be reduced due to grade 3 palmar and plantar toxicity . at the end of march 2009 , after 20 months of treatment , an mri showed progressive liver disease as well as local recurrence and mesenteric lymph node metastases .
the initial dose of 800 mg daily had to be reduced to 600 mg due to a hematologic toxicity .
no objective response was achieved , and the performance status decreased from 0 to 2 , with a 7-kg weight loss .
after 5 months of sorafenib therapy , an mri revealed further progression at all sites ( fig . 1 ; online suppl . video 1 ; see www.karger.com/doi/10.1159/000323804 ) .
at the end of august 2009 , temsirolimus was started as a third - line treatment at a dose of 25 mg intravenously every week . in november 2009 ,
disease stabilization was observed on ct . in february 2009 , a further mri showed a partial remission according to the recist criteria .
clinically , the patient had improved considerably ( ps 0 ) , and formerly elevated laboratory values normalized ( ldh from 1,400 u / l , alkaline phosphatase from 142 u / l , gt from 168
currently , the patient continues on weekly temsirolimus , is working full time , and is in excellent physical condition without experiencing any side effects .
this clinical observation of an impressive response to third - line temsirolimus in a case of chromophobe metastatic rcc leads us to raise the following questions : first , should the current practice of sequential therapy be revisited ? especially in chromophobe metastatic rcc , mtor inhibition may be considered earlier . in this patient ,
today , everolimus is the standard in second - line treatment , while temsirolimus is approved only for first - line treatment .
second , are all mtor inhibitors equal in terms of efficacy ? would this patient have responded equally well to everolimus ?
this question should be addressed by head - to - head comparisons of mtor inhibitors . since 2006 ,
six molecular targeted agents have been approved for the treatment of rcc ( sunitinib , sorafenib , bevacizumab / interferon , temsirolimus , everolimus , and pazopanib ) .
maybe more emphasis should be placed on the biology of rcc as reflected in its histology .
rare subtypes like chromophobe rcc or sarcomatoid dedifferentiated rcc may have to be considered separately .
current strategies are based on results obtained in the context of clear cell - type rcc .
separate trials for rare histologies seem unfeasible and are unlikely to be performed . for these cases ,
currently , the start trial is studying temsirolimus as first - line and second - line treatment .
patients in this trial are stratified by histological subtype , and the results may also answer the question raised by our observation : is chromophobe rcc particularly sensitive to mtor inhibition ?
Output:
| we report unexpectedly high efficacy of temsirolimus as third - line treatment in a patient with metastatic chromophobe renal cell carcinoma .
after failure of two sequentially administered tyrosine kinase inhibitors , treatment with temsirolimus resulted in a prolonged partial remission of 14 months , and the response is still continuing . up to now , no data from randomized clinical studies have been published addressing the question of efficacy of temsirolimus as third - line treatment after failure of tyrosine kinase inhibitors .
the case presented here implies that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma . |
PubmedSumm118207 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: restless legs syndrome ( rls ) is a common movement disorder that affects up to 5 - 10% of the general population.[13 ] rls is an important cause of sleep disruption and disability in several clinical and neurological disorders and can be identified on the basis of clinical criteria .
the four criteria for considering this diagnosis include , an urge to move the legs ( usually accompanied or caused by uncomfortable leg sensations ) , temporary relief with movement , onset or worsening of symptoms during rest , and worsening or onset of symptoms at evening and/or at night .
the diagnosis is further supported by the presence of periodic limb movements in sleep ( plms ) and positive response to dopaminergic treatment .
the majorities of rls cases is commonly classified as idiopathic and include sporadic and inherited forms .
refer to rls forms significantly related to physiological or pathological conditions , such as iron deficiency . among the neurological disorders , peripheral neuropathy , spinocerebellar ataxia , essential tremor , parkinson disease , and myelopathies
are reported to be associated with rls.[79 ] available studies suggest that rls prevalence among ms patients is higher compared with people without ms.[1012 ] however , ms has not been considered as a secondary cause for rls yet .
we sought to determine rls prevalence in iranian ms patient and the possible risk factors for the same .
a cross - sectional study was conducted at the university hospital of kashani , isfahan , iran , from september to december 2011 .
patients diagnosed with ms according to mcdonald criteria were recruited from ms outpatient clinic in kashani hospital ; the control group comprised of healthy volunteers , healthcare personnel , or companions of the patients . then all subjects were asked about rls symptoms .
the diagnosis of rls in patients was based on the four diagnostic criteria of rls according to the revised irlssg guidelines .
after the diagnosis of rls , the patients were divided into two groups : with and without rls .
the present study was approved by the ethical committee of isfahan university of medical sciences .
inclusion criteria for the study were patients with definite ms according to the standard diagnostic criteria for ms and with an age of 25 - 65 years .
there was no specific limitations regarding chronic ms treatments such as interferon , cyclophosphamide , or azatioprine .
exclusion criteria for the study were the usage of dopaminergic and antidopaminergic drugs , renal failure , pregnancy , sideropenic anemia , recent ms diagnosis ( < 6 months before the time of the interview ) , recent clinical ms relapse ( within 3 months of the interview ) , and history of alcohol or drug abuse .
patients who received a recent ( within 6 months from the time of the interview ) acute high - dose steroid treatment were excluded .
the diagnosis of rls in the patients was based on the four diagnostic criteria of rls according to the revised irlssg guidelines .
only those patients fulfilling all four criteria were assigned to the rls population . in both groups ,
the following variables were evaluated : age , sex , other underlying disease , duration of ms , ms course , family history of rls , history of anemia , and drug intakes ( related to ms ) .
neurological examination of all patients was carried out and their disability was defined according to expanded disability status scale score and by using points for functional systems .
parametric and nonparametric comparisons of categorical and continuous variables were performed using the chi - square test , student t - test , and correlation test , as suitable .
a cross - sectional study was conducted at the university hospital of kashani , isfahan , iran , from september to december 2011 .
patients diagnosed with ms according to mcdonald criteria were recruited from ms outpatient clinic in kashani hospital ; the control group comprised of healthy volunteers , healthcare personnel , or companions of the patients . then all subjects were asked about rls symptoms .
the diagnosis of rls in patients was based on the four diagnostic criteria of rls according to the revised irlssg guidelines .
after the diagnosis of rls , the patients were divided into two groups : with and without rls .
the present study was approved by the ethical committee of isfahan university of medical sciences .
inclusion criteria for the study were patients with definite ms according to the standard diagnostic criteria for ms and with an age of 25 - 65 years
. there was no specific limitations regarding chronic ms treatments such as interferon , cyclophosphamide , or azatioprine .
exclusion criteria for the study were the usage of dopaminergic and antidopaminergic drugs , renal failure , pregnancy , sideropenic anemia , recent ms diagnosis ( < 6 months before the time of the interview ) , recent clinical ms relapse ( within 3 months of the interview ) , and history of alcohol or drug abuse .
patients who received a recent ( within 6 months from the time of the interview ) acute high - dose steroid treatment were excluded .
the diagnosis of rls in the patients was based on the four diagnostic criteria of rls according to the revised irlssg guidelines .
only those patients fulfilling all four criteria were assigned to the rls population . in both groups ,
the following variables were evaluated : age , sex , other underlying disease , duration of ms , ms course , family history of rls , history of anemia , and drug intakes ( related to ms ) .
neurological examination of all patients was carried out and their disability was defined according to expanded disability status scale score and by using points for functional systems .
parametric and nonparametric comparisons of categorical and continuous variables were performed using the chi - square test , student t - test , and correlation test , as suitable .
a total of 126 patients in the ms group ( 96 females , 30 males , mean age 32.37 8.7 years ) and 126 healthy controls ( 96 females , 30 males , and mean age 33.34 8.3 years ) were included in the study .
there were no statistically significant differences between the 2 groups in terms of age and gender ( 33.34 8.3 ) .
mean edss score in ms groups was 1.8 1.74 ( range 0 - 7 ) .
mean edss score in women were 1.62 1.67 and , in men , it was 2.41 1.9 . according to statistical analysis
, there was significant difference in disability between two sex ( p < 0.035 ) [ figure 1 ] .
mean range and 25% , 75% of edss score demographic characteristics of patients in the case and control population ms duration was 43.2 33.4 months ( range 3 - 204 month ) . according to pierson correlation test , there was significant correlation between ms duration and edss score ( p < 0.001 ) . according to this test ,
correlation between ms duration and edss score in this study , 82 ( 65.1% ) in the ms group and 16 ( 12.7% ) in the control group had rls .
the frequency of rls in the ms patients was significantly higher than that in the control group ( p < 0.001 ) . among ms patients ,
60 male ( 73.2% ) and 22 female ( 26.8% ) had rls . in this study ,
patients with ms and higher edss score had more rls symptoms ( p < 0.005 ) .
mean rls score was 10.9 10.2 in the ms group and 17.9 6.6 in the control group .
according to t test , rls score was significantly higher in the control groups ( p = 0.008 ) [ figure 3 ] .
mean range and 25% , 75% of rls score table 2 showed characteristics of ms patients with and without rls .
rls is common in ms patients , and this has been investigated in several studies . in our study , the prevalence of rls was 65.1% . in other studies , the prevalence of rls in ms patients has been reported to be ranging from 13.3 to 57.5%.[1417 ] in our study , older ms patients had higher prevalence of rls symptoms ; similar findings were obtained in other studies . although the biological mechanism linking ms and rls is unknown , one study comparing mri parameters between ms patients with and without rls found no difference in brain mri scans , but did find more tissue damage in the cervical spinal cords of patients with ms with rls as compared with patients with ms without rls .
low iron levels in the brain and iron deficiency have been associated with rls . however , in this study , we did not find significant difference in the prevalence of iron deficiency anemia in ms patients with or without rls ( p < 0.29 ) .
an important aspect that differentiated patients with and without rls was clinical severity of ms according to the edss score .
the number of patients with higher edss score were significantly superior in the ms / rls positive group ( p < 0.005 ) .
the ms / rls positive phenotype may be the result of a particular lesion pattern , which eventually involves specific unknown nerve centers or their connection pathways important for the pathogenesis of rls . because inflammatory damages in ms are randomly disseminated in the central nervous system
, the higher likelihood of severe ms patients developing secondary rls might be simply due to a probabilistic reason . in patients with a higher number of lesions
, there are more chances of impaired specific neurological regions involved in the pathogenesis of rls than in patients with a milder ms course .
we determined that the difference in severity of rls between our ms group and controls was statistically significant ( the severity was greater in control group ) .
this is in contrast with a lot of studies that found that severity of rls was greater than in the ms group .
our hypothesis is that ms patients have other complaints like spasticity and weakness in their lower limbs , so may be their complaint of rls severity is less than in the normal subjects .
we found that ms patients and rls had higher family history of rls than ms patients without rls ( p 0.002 ) this finding is compatible with a few studies .
this finding show that rls in ms patients may be affected by primary rls . in the present study , no differences were found between groups with and without rls in their gender , ms duration , anemia , and antidepressant use .
current concepts of rls assume a dysfunction of the dopaminergic system ; this may involve the striatum , the spinal cord , and the hypothalamus .
damages including demyelization along this route may cause a dysfunction of the dopaminergic system manifesting as rls .
the high prevalence rate of rls in ms patients , the association between rls and more severe disability are the central aspects supporting the hypothesis of a new symptomatic form of rls secondary to the central nervous system damage . as for other neurological diseases , such as
parkinson 's disease , spinocerebellar atrophy , and peripheral neuropathies , ms should be considered as another risk factor for rls.[1518 ]
Output:
| background : restless legs syndrome ( rls ) is a common movement disorder .
the occurrence of this syndrome is due to genetic factors and lifestyle .
this study performed to determine restless legs syndrome ( rls ) prevalence in iranian multiple sclerosis ( ms ) patients and the possible risk factors.methods:this cross - sectional study was conducted with ms patients , and the age- and sex - matched control group comprised healthy persons .
then , all subjects were asked about rls symptoms .
after the diagnosis of rls , the patients were divided into two groups : with and without rls . in both groups ,
the following variables were evaluated : age , sex , other underlying disease , duration of ms , ms course , family history of rls , history of anemia , and drug intakes .
the severity of the disease in subjects diagnosed with rls was also evaluated.results:a total of 126 patients in the ms group and 126 healthy controls were included in the study , with no statistically significant differences between them in terms of age and gender . in ms group , 82 ( 65.1% ) and , in control group , 16 ( 12.7% ) had rls .
the frequency of rls in the ms patients was significantly higher than that in the control group . among ms patients ,
60 male ( 73.2% ) and 22 female ( 26.8% ) had rls .
mean age of ms patients with rls was significantly higher than that in ms patients without rls .
ms patients and higher edss score had more rls symptoms.conclusions:we suggest that rls always be considered during neurological examinations of ms patients . |
PubmedSumm118208 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: malignancies are an emerging public health problem in africa , especially with the increasing exposure to environmental carcinogens and change in lifestyles . to implement appropriate cancer awareness programs in these settings , early diagnosis and detection need to be widely introduced .
fundamental to this , however , is a reliable , quick , inexpensive , and accurate diagnosis .
surgical histopathology remains the gold standard for diagnosis , but is generally unavailable in most developing countries and comes with challenges of equipment , expertise , and cost to facilities and patients at large .
it involves obtaining tissue diagnosis of subcutaneous and other tumors with the aid of a special needle that with imaging techniques may allow its use in a wider scope .
the procedure is regarded as inexpensive , requiring simple equipment , less time consuming , and can be applied to a wide range of diseases .
detailed explanation of the procedure and how it can be applied throughout the body has been documented and has been adopted in clinical practices , especially for quick bedside diagnosis of various malignancies .
the dangers of false positives and the inevitability of false negatives can not be overemphasized because a negative cytology report is not definitive , especially when there is a mass .
a good cytopathology practice also requires access to surgical pathology to clarify cases for which cytopathology gives uncertain or no diagnosis and for validation and quality control purposes .
fine needle aspiration cytology ( fnac ) clinics and cytology practices have been running in the pathology department of our hospital since 2010 . after brief closure of the department in 2004 ,
much assistance in re - establishing the department to include a cytology unit came from the breast health global initiative .
there was also collaboration between our hospital and a teaching hospital in europe to train pathologists and technologists in 2005 . in this article
, we present a detailed retrospect of experience in running cytopathology services in kumasi , ghana after its establishment .
this will provide a clear picture on the performance with respect to this service as offered by the department .
this was a retrospective study conducted using reports on all cytology procedures performed in our department from january 2010 to december 2011 .
this retrospective study was approved and supervised by the research and development unit ( ethics committee ) of our institution with approval from the department .
participant informed consent was not obtained ; hence , patient records / information was anonymized and de - identified prior to analysis . in routine cytology practice in our centre , pathologists performed fine - needle aspirations with the assistance of biomedical scientists .
the method applies to various body sites and its interpretation was documented by a previous documented review of the methodology .
fluid specimens ( urine and pleural effusions ) are centrifuged to obtain the sediment , which is then used to prepare direct smears .
wet mounted smears are stained with papanicolaou stain , giemsa , and sometimes hematoxylin and eosin .
neelsen ( zn ) staining was performed on smears when tuberculosis was clinically suspected or if granulomatous inflammation was noted on the routine stains .
no gynecological smears were , however , received in the department during the period under review .
this was due in part to the unavailability of cyto - screeners to assist in the anticipated workload at the time .
data from the reports were entered into an excel spreadsheet and analyzed using the statistical package for social scientists , version 16.0 ( spss , il ) .
this was a retrospective study conducted using reports on all cytology procedures performed in our department from january 2010 to december 2011 .
this retrospective study was approved and supervised by the research and development unit ( ethics committee ) of our institution with approval from the department .
participant informed consent was not obtained ; hence , patient records / information was anonymized and de - identified prior to analysis .
in routine cytology practice in our centre , pathologists performed fine - needle aspirations with the assistance of biomedical scientists .
the method applies to various body sites and its interpretation was documented by a previous documented review of the methodology .
fluid specimens ( urine and pleural effusions ) are centrifuged to obtain the sediment , which is then used to prepare direct smears .
wet mounted smears are stained with papanicolaou stain , giemsa , and sometimes hematoxylin and eosin .
neelsen ( zn ) staining was performed on smears when tuberculosis was clinically suspected or if granulomatous inflammation was noted on the routine stains .
no gynecological smears were , however , received in the department during the period under review .
this was due in part to the unavailability of cyto - screeners to assist in the anticipated workload at the time .
data from the reports were entered into an excel spreadsheet and analyzed using the statistical package for social scientists , version 16.0 ( spss , il ) .
a total of 836 cases were reviewed , an average of approximately 418 cases were performed a year .
this accounted for approximately 5.7% of the total workload of the department including surgical pathology , cytopathology , and autopsy .
approximately one - fifth ( 19.4% ) of the cases reviewed , however , had no age specified .
more than half ( 58.0% ) of the cases received had no clinical diagnosis indicated on the forms .
although a number of cases had no indicated gender , this formed only 4.3% of the total cases [ table 1 ] .
characteristics of cytological cases received at the department relative to gender the most aspirated sites in decreasing order was the breast ( 20.2% ) , lymph nodes ( 20.0% ) , thyroid ( 12.0% ) , soft tissue ( 9.6% ) , salivary glands ( 4.7% ) , ascitic fluid ( 4.1% ) , pleura ( 5.1% ) , csf ( 0.7% ) , liver ( 0.6% ) , and other miscellaneous sites , which accounted for 23.0% of the total .
more females had samples aspirated from the breast ( 27.9% ) and thyroid ( 13.4% ) than males ( 5.6% and 8.8% , respectively ) .
there were more benign than malignant cases with respect to all sites aspirated except the breast ( 18.3% ) , lymph nodes ( 35.0% ) , and soft tissues ( 11.7% ) where the reverse occurred [ table 2 ] .
site distribution of cases according to age , sex , and nature of diagnosis in table 3 , the age and sex distribution of cases received relative to cytological diagnosis is shown .
there was an equal distribution ( 40.5% ) of reported benign and malignant cases among those aged 5 years and below .
there was an almost equal distribution of malignant ( 38.0% ) and benign ( 35.0% ) cases among males .
diagnosis , however , could not be ascertained in 28 ( 3.3% ) of the cases .
reasons for this included inadequate smear , inadequate cellular material , and no palpated lumps for aspiration .
cytopathology is a relatively inexpensive , quick , and reliable method of diagnosis in pathology settings , especially in developing countries .
, we sought to evaluate the frequency of cases , efficacy of diagnosis , its impact , and relevance to referring clinicians .
most of the fnacs performed were aspirates from the breast ( 20.2% ) , followed by that from the lymph nodes ( 20.0% ) .
our findings show that the use of cytopathology for the diagnosis of the abovementioned conditions is very important , in the triage of such patients and the provision of a quick diagnosis for prompt attention by referring clinicians .
in contrast to our findings , a study conducted in cameroon showed that lymphadenopathy was the most common indication for fnac followed by breast . in most of the cases under review , cytopathology was very useful in distinguishing benign and malignant cases .
benign cases were , however , more than malignant cases , a reassurance that with the right treatment patients are likely to have a very good prognosis .
this is contrary to a finding by spillane et al . , who found a high percentage of malignant lesions being diagnosed by fine - needle aspiration biopsy ( fnab ) .
however , this was of benefit by reducing the number of corresponding open biopsy rates .
the percentage of the total workload accounted for by cytopathology was relatively small . because pathology practice in ghana is still in its infancy with high rate of autopsy practice , cytopathology is usually not considered by clinicians , especially those in peripheral hospitals .
laboratory request forms , which provide detailed information about the patient and clinical history , were not properly filled or completed by referring clinicians .
approximately one - fifth of all the forms received did not specify sex , and more than half ( 58.0% ) of the cases did not have any clinical diagnosis indicated by referring clinicians .
this could lead to a possible delay in diagnosis as well as reliability of the diagnosis .
a similar finding was also reported in a study conducted in ghana on the evaluation of request forms received in a hematology laboratory , and seems to be the trend in most hospitals in ghana .
seventy - seven percent of the time , a working diagnosis was achieved with a definite diagnosis in 73.4% of cases
. however , there is a limitation in determining the specificity and sensitivity of diagnosis .
poor requests from referring clinicians , varied sampling techniques by pathologists and biomedical scientists may account for the high rate of nondiagnostic cases .
going forward , histology and cytopathology correlation may be necessary to reduce the high rate of non - diagnostic cases and to ascertain unclear cases .
it has been suggested that having a pathologist on site for fnac improves sampling and enables assessment of clinical signs and symptoms to enhance diagnostic accuracy .
this was a major advantage in this setting , as seen in the percentage of diagnosis obtained
. more work , however , needs to be done to improve efficiency and diagnosis rate .
cytopathology practice in our centre has improved and is promising . improving and expanding on the current practice will ensure that pathologists in practice sustain and improve diagnostic cytopathology , as well as provide materials for training young pathologists . as the number of pathologists on site increases , sub - specialization in cytopathology may be necessary to enhance the diagnostic capability of the department .
Output:
| aim : surgical pathology service is generally unavailable in most developing countries and comes with challenges .
cytopathology is a reliable , inexpensive adjunct to surgical histopathology .
we present a retrospective review of the various cytopathology cases received at the department.materials and methods : a retrospective review of 836 cytopathology cases from january 2010 to december 2011 at the department of pathology of our hospital was conducted .
all cytopathology reports and records from the department were retrieved and analyzed using the statistical package for the social sciences version 16 for windows.results:a total of 836 ( mean age 38.18 22.18 ) cases were reviewed , at an average of approximately 418 cases performed a year ( 5.7% of the total workload ) .
more than half ( 58.0% ) of the cases received had no clinical diagnosis indicated on request forms .
seventy - seven percent ( 77% ) of the cases were diagnosed as either definite or nondefinite .
the breast was the most aspirated specimen site ( 20.2% ) .
benign cases formed 45.0% of all the cases and 29.0% were malignant .
there were more benign than malignant cases with respect to all sites aspirated except the breast ( 18.3% ) , lymph nodes ( 35.0% ) , and soft tissues ( 11.7% ) where the reverse occurred.conclusion:patronage of cytopathology in kumasi is increasing and serves as a quick , cheap , and effective alternate means for diagnosis . improving and expanding on the current practice will ensure that pathologists in practice sustain and improve diagnostic cytopathology and provide material for training young pathologists . |
PubmedSumm118209 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the experiment site is located at a t. matsutake production pine stand at ssanggok valley in the sogri mt .
the site has two partly combined , partly circular colonies , each about 7 m diameter ( fig . 1 , fig
because the annual outward growth of t. matsutake colony was 11 to 14 cm , the age of the colony was approximately 30 years old .
from the 3/4 circular colony , samples at four points ( ahead of the colony , front edge , 20 cm back , 40 cm back ) each of 4 replicated colony locations ( ridge , down slope , upslope and contour ) were collected with a 3.2 cm diameter 10 cm long core sampler .
the samples were collected every two weeks from 31 august to 28 october 2005 , during t. matsutake fruiting season and stored in a ziplock bag at -79 until analysis .
samples from the ahead of colony did not have t. matsutake mycorrhizae , front edge ones include the most active t. matsutake mycorrhizae with white mycelia ( fig .
3 ) , 20 cm back ones have some decayed dark t. matsutake mycorrhizae and 40 cm back ones had powdered t. matsutake hyphae with black roots ( table 1 ) .
ergosterol analysis was done using the method by nylund and wallander ( 1992 ) , which we slightly modified .
five g of soil and 10 ml of 10% koh in 95% methanol were placed into 20 150 mm glass tubes and homogenized using a vortex mixer for ten seconds .
each tube was cooled , the 3 ml of deionized water plus 2 ml of n - hexane was added .
the sample was allowed to settle for 2 minutes , then approximately 1.5 ml of the supernatant ( n - hexane + ergosterol ) was removed with a 2 ml - syringe .
the dried sample was dissolved in 2 ml of methanol and filtered through a 0.2 m syringe filter tip ( millipore ) into a micro - centrifuge tube .
the tubes with the filtered sample solution were stored in a dark , 4 refrigerator . the extraction sample solution ( 20 l )
was injected into hplc ( waters 510 ) with c-18 nova - pak column at the pharmaceutical analysis lab in chungbuk national university .
the column was eluted with hplc grade 100% methanol at 1.5ml / min flow rate under 40 oven temperature and the ergosterol peak was detected at 280 nm at 6.5 min .
soil water content ( % by v / v ) was measured using a 15 cm long probe of a portable hydrosensor every 20 cm from 10 cm ahead of the colony to 250 cm back of the colony front edge at the four replicated colony locations ( ridge , down slope , upslope and contour ) in the 3/4 circular colony every month from may 2003 to june 2004 ( fig .
1 ) . during the t. matautake fruiting season from 31 august to 28 october 2005 ,
soil water using the hydrosensor and soil temperature using a 15 cm long probe of a portable testo 915 - 1 thermometer were measured at four sampling points ( ahead of colony , front edge , 20 cm back , 40 cm back ) in the same four replicated colony locations in the 3/4 circular colony every two weeks .
the experiment site is located at a t. matsutake production pine stand at ssanggok valley in the sogri mt .
the site has two partly combined , partly circular colonies , each about 7 m diameter ( fig . 1 , fig
because the annual outward growth of t. matsutake colony was 11 to 14 cm , the age of the colony was approximately 30 years old .
from the 3/4 circular colony , samples at four points ( ahead of the colony , front edge , 20 cm back , 40 cm back ) each of 4 replicated colony locations ( ridge , down slope , upslope and contour ) were collected with a 3.2 cm diameter 10 cm long core sampler .
the samples were collected every two weeks from 31 august to 28 october 2005 , during t. matsutake fruiting season and stored in a ziplock bag at -79 until analysis .
samples from the ahead of colony did not have t. matsutake mycorrhizae , front edge ones include the most active t. matsutake mycorrhizae with white mycelia ( fig .
3 ) , 20 cm back ones have some decayed dark t. matsutake mycorrhizae and 40 cm back ones had powdered t. matsutake hyphae with black roots ( table 1 ) .
ergosterol analysis was done using the method by nylund and wallander ( 1992 ) , which we slightly modified .
five g of soil and 10 ml of 10% koh in 95% methanol were placed into 20 150 mm glass tubes and homogenized using a vortex mixer for ten seconds .
each tube was cooled , the 3 ml of deionized water plus 2 ml of n - hexane was added .
the sample was allowed to settle for 2 minutes , then approximately 1.5 ml of the supernatant ( n - hexane + ergosterol ) was removed with a 2 ml - syringe .
the dried sample was dissolved in 2 ml of methanol and filtered through a 0.2 m syringe filter tip ( millipore ) into a micro - centrifuge tube .
the tubes with the filtered sample solution were stored in a dark , 4 refrigerator . the extraction sample solution ( 20 l )
was injected into hplc ( waters 510 ) with c-18 nova - pak column at the pharmaceutical analysis lab in chungbuk national university .
the column was eluted with hplc grade 100% methanol at 1.5ml / min flow rate under 40 oven temperature and the ergosterol peak was detected at 280 nm at 6.5 min .
soil water content ( % by v / v ) was measured using a 15 cm long probe of a portable hydrosensor every 20 cm from 10 cm ahead of the colony to 250 cm back of the colony front edge at the four replicated colony locations ( ridge , down slope , upslope and contour ) in the 3/4 circular colony every month from may 2003 to june 2004 ( fig .
1 ) . during the t. matautake fruiting season from 31 august to 28 october 2005 ,
soil water using the hydrosensor and soil temperature using a 15 cm long probe of a portable testo 915 - 1 thermometer were measured at four sampling points ( ahead of colony , front edge , 20 cm back , 40 cm back ) in the same four replicated colony locations in the 3/4 circular colony every two weeks .
the most active hyphal zone of the t. matsutake soil colony was only about 15 cm wide from the front .
the ergosterol content ranged from 2.5 to 4.8 g / g dried soil in the ahead of colony , active zone , versus 0 to 1.8 g / g dried soil in the other points ( fig .
the spatio - temporal changes of ergosterol contents in t. matsutake soil colony were related to the points within colony , but was not related to season or to water content . while the ergosterol concentrations were very low at the ahead where colony had not formed or at the 40 cm back where the colony was more than two years old , the content was very high at the front edge of the colony where the t. matsutake hyphae were most active .
the ergosterol content was 0.0 to 0.7 g / g dried soil at the ahead , 2.5 to 4.8 g / g dried soil at the front edge , 0.5 to 1.8 g / g dried soil at the 20 cm back and 0.3 to 0.8 g / g dried soil at the 40 cm back .
this observation supports the result that ergosterol content is high within 20 cm range from the colony front edge ( koo et al . , 2003 ) where t. matsutake colony is active .
this ergosterol change can explains ogawa 's finding ( 1975 ) that t. matsutake colony grows outwardly about 10 to 15 cm per year , and that the previous year colony content is used for the mushroom fruiting .
ogawa ( 1975 ) estimated that t. matsutake mushroom requires 100 to 200 cm surface area and 1500 to 2000 cm colony volume including soil , ectomycorrhizae and hyphae .
the average ergosterol concentration in the colony front edge was 3.8 g / g dried soil , and ranged from 1.4 to 6.7 g / g dried soil .
these values are quite low compared with other studies . when grown in a sterilized and nutrient enriched soil , the ergosterol content of t. matsutake hyphae was ca 50 g / g dried soil , but in natural t. matsutake soil colonies , it was 15.5 g / g dried soil ( bak et al . , 2006 ) .
ergosterol content in pure t. matsutake hyphae from liquid culture was about 0.85% and it was high at lag and stationary phases during the culture period ( lee et al . , 2003 ) .
in various ectomycorrhizal fungal hyphae , ergosterol contents ranged from 0.86 mg to 17.55 mg per gram fungal dry weight , with an average of 5.45 mg ( satomura et al . , 2006 ) .
this highly variable ergosterol content in the t. matsutake colony suggests that the hyphal distribution in the colony front edge is highly heterogenous . on the other hand
, the high ergosterol content can mean the hyphae in the front continuously grow and may not be related to current fruiting , while energy and nutrients from the hyphal tissues of the previous year are used for fruiting .
these lower ergosterol contents in older colony strongly support the conclusion of ekblad et al .
( 1998 ) that ergosterol as a component of membranes is considered to give a good measure of metabolic activity .
they found that aging had a marked effect on ergosterol concentration and that ergosterol content of 7 month - old brown , shrunken pine - paxillus ectomycorrhizas was only 10% of white turgid 1 to 4 month old specimens . during the fruiting season , the cumulative precipitation for the previous 10 days was 28.5 mm for the 31 august , 103.5 mm for the 17 september , 105.0 mm for the 1 october , 8.5 mm for the 14 october and 7.0 mm for the 28 october ( fig .
thus , soil water content was as high as 19% on 3 october with 105 mm rainfall within three days .
however , rainfall five days before did not seem to affect the soil water on steep slopes or in a dense tree stand .
the soil water content varied 12 to 19% at the ahead , 10 to 11% at the edge , 9 to 11% at the 20 cm back and 11 to 15% at the 40 cm back ( fig .
the soil water change due to rainfall was lower in the colony front edge and 20 cm back points than in the ahead and the 40 cm back points .
these changing patterns in ergosterol and water content in the t. matsutake colonies strongly support the hypothesis that active and dense t. matsutake colonies slowly absorb water and drain little , while the noncolonized soil and the decayed colonies absorb water little but drain more ( koo et al . , 2003 ) .
thus , for sustainable t. matsutake production we suggest that the front edge of t. matsutake soil colony be managed intensively in terms of irrigation and t. matsutake ectomycorrhizal root development , because the colony front is the only live and growing body .
generally , water content of t. matsutake soil colony changed depending on the rainfall , but the active colony portion was affected much less than the noncolony and the decayed portion of the colony .
water contents in the ahead and the 90 cm back ( estimated to be 6 to 8 years old ) were more variable , ranging from 7 to 32% , compared to the water contents in the 10 to 30 cm back ( 1 to 2 years old colony ) , which ranged from 8 to 23% ( fig .
when it rained in september , the water content differed by colony points , with 16% at colony front and 32% at the ahead and 90 cm back ( fig . 7 ) . in contrast , in the dry period in november , all the soil water contents ranged from 7 to 8% ( fig .
( 2004 ) , which showed that water content changed from 9.1 to 11.2% at the physiologically active t. matsutake hyphal zone , and from 11.7 to 19.5% at the noncolony during august to october .
on the other hand , soil water contents were highly variable among the four locations during the season ( fig .
the soil water within t. matsutake colony was lower at the front edge than at the other points .
these variable water contents may be due to the heterogeneous forest soils which may have varied by microtopography , slope , soil texture , soil organic matter array , coarse rock debris , etc .
soil temperature in the t. matsutake colony ranged from 20.4 to 21.1 on 31 august , and gradually decreased to 11.5 to 12.0 on the 28th october in 2005 ( data from koo et al . , 2007 ) .
the 19.0 , soil temperature that is known to form t. matsutake primordia ( owaga , 1991 ) arrived around mid september . generally , the temperatures in t. matsutake colonies were from 0.2 to 0.4 higher than in the ahead of colony .
this slightly higher temperature may mean that t. matsutake mycorrhizae and hyphae are actively respiring and consuming water in the soil . the front edge of t. matsutake colony is a specific point for high priority research .
the most active front edge of the circular t. matsutake colony is only about 20 cm wide , and we suggest that this active part should be managed most significantly in terms of irrigation and t. matsutake ectomycorrhizal development . understanding this narrow active zone in t. matsutake colony can improve irrigation efficiency and vegetation control effect .
the most active hyphal zone of the t. matsutake soil colony was only about 15 cm wide from the front .
the ergosterol content ranged from 2.5 to 4.8 g / g dried soil in the ahead of colony , active zone , versus 0 to 1.8 g / g dried soil in the other points ( fig .
the spatio - temporal changes of ergosterol contents in t. matsutake soil colony were related to the points within colony , but was not related to season or to water content . while the ergosterol concentrations were very low at the ahead where colony had not formed or at the 40 cm back where the colony was more than two years old , the content was very high at the front edge of the colony where the t. matsutake hyphae were most active .
the ergosterol content was 0.0 to 0.7 g / g dried soil at the ahead , 2.5 to 4.8 g / g dried soil at the front edge , 0.5 to 1.8 g / g dried soil at the 20 cm back and 0.3 to 0.8 g / g dried soil at the 40 cm back .
this observation supports the result that ergosterol content is high within 20 cm range from the colony front edge ( koo et al . , 2003 ) where t. matsutake colony is active .
this ergosterol change can explains ogawa 's finding ( 1975 ) that t. matsutake colony grows outwardly about 10 to 15 cm per year , and that the previous year colony content is used for the mushroom fruiting .
ogawa ( 1975 ) estimated that t. matsutake mushroom requires 100 to 200 cm surface area and 1500 to 2000 cm colony volume including soil , ectomycorrhizae and hyphae .
the average ergosterol concentration in the colony front edge was 3.8 g / g dried soil , and ranged from 1.4 to 6.7 g / g dried soil .
these values are quite low compared with other studies . when grown in a sterilized and nutrient enriched soil , the ergosterol content of t. matsutake hyphae was ca 50 g / g dried soil , but in natural t. matsutake soil colonies , it was 15.5 g / g dried soil ( bak et al . , 2006 ) .
ergosterol content in pure t. matsutake hyphae from liquid culture was about 0.85% and it was high at lag and stationary phases during the culture period ( lee et al . , 2003 ) .
in various ectomycorrhizal fungal hyphae , ergosterol contents ranged from 0.86 mg to 17.55 mg per gram fungal dry weight , with an average of 5.45 mg ( satomura et al . , 2006 ) .
this highly variable ergosterol content in the t. matsutake colony suggests that the hyphal distribution in the colony front edge is highly heterogenous . on the other hand
, the high ergosterol content can mean the hyphae in the front continuously grow and may not be related to current fruiting , while energy and nutrients from the hyphal tissues of the previous year are used for fruiting .
these lower ergosterol contents in older colony strongly support the conclusion of ekblad et al .
( 1998 ) that ergosterol as a component of membranes is considered to give a good measure of metabolic activity .
they found that aging had a marked effect on ergosterol concentration and that ergosterol content of 7 month - old brown , shrunken pine - paxillus ectomycorrhizas was only 10% of white turgid 1 to 4 month old specimens .
during the fruiting season , the cumulative precipitation for the previous 10 days was 28.5 mm for the 31 august , 103.5 mm for the 17 september , 105.0 mm for the 1 october , 8.5 mm for the 14 october and 7.0 mm for the 28 october ( fig .
the changes soil water content followed the previous rainfall amount closely . thus , soil water content was as high as 19% on 3 october with 105 mm rainfall within three days .
however , rainfall five days before did not seem to affect the soil water on steep slopes or in a dense tree stand .
the soil water content varied 12 to 19% at the ahead , 10 to 11% at the edge , 9 to 11% at the 20 cm back and 11 to 15% at the 40 cm back ( fig .
the soil water change due to rainfall was lower in the colony front edge and 20 cm back points than in the ahead and the 40 cm back points .
these changing patterns in ergosterol and water content in the t. matsutake colonies strongly support the hypothesis that active and dense t. matsutake colonies slowly absorb water and drain little , while the noncolonized soil and the decayed colonies absorb water little but drain more ( koo et al . , 2003 ) .
thus , for sustainable t. matsutake production we suggest that the front edge of t. matsutake soil colony be managed intensively in terms of irrigation and t. matsutake ectomycorrhizal root development , because the colony front is the only live and growing body .
generally , water content of t. matsutake soil colony changed depending on the rainfall , but the active colony portion was affected much less than the noncolony and the decayed portion of the colony .
water contents in the ahead and the 90 cm back ( estimated to be 6 to 8 years old ) were more variable , ranging from 7 to 32% , compared to the water contents in the 10 to 30 cm back ( 1 to 2 years old colony ) , which ranged from 8 to 23% ( fig .
when it rained in september , the water content differed by colony points , with 16% at colony front and 32% at the ahead and 90 cm back ( fig
in contrast , in the dry period in november , all the soil water contents ranged from 7 to 8% ( fig .
( 2004 ) , which showed that water content changed from 9.1 to 11.2% at the physiologically active t. matsutake hyphal zone , and from 11.7 to 19.5% at the noncolony during august to october . on the other hand ,
soil water contents were highly variable among the four locations during the season ( fig .
the soil water within t. matsutake colony was lower at the front edge than at the other points .
these variable water contents may be due to the heterogeneous forest soils which may have varied by microtopography , slope , soil texture , soil organic matter array , coarse rock debris , etc .
soil temperature in the t. matsutake colony ranged from 20.4 to 21.1 on 31 august , and gradually decreased to 11.5 to 12.0 on the 28th october in 2005 ( data from koo et al . , 2007 ) .
the 19.0 , soil temperature that is known to form t. matsutake primordia ( owaga , 1991 ) arrived around mid september . generally , the temperatures in t. matsutake colonies were from 0.2 to 0.4 higher than in the ahead of colony .
this slightly higher temperature may mean that t. matsutake mycorrhizae and hyphae are actively respiring and consuming water in the soil .
the front edge of t. matsutake colony is a specific point for high priority research .
the most active front edge of the circular t. matsutake colony is only about 20 cm wide , and we suggest that this active part should be managed most significantly in terms of irrigation and t. matsutake ectomycorrhizal development . understanding this narrow active zone in t. matsutake colony can improve irrigation efficiency and vegetation control effect .
Output:
| the purpose of this study is to understand spatio - temporal changes of active fungal biomass and water in tricholoma matsutake soil colonies during the mushroom fruiting season .
the active fungal biomass was estimated by analyzing ergosterol content at four different points within four replicated locations in a single circular t. matsutake colony at ssanggok valley in the sogri mt .
national park in korea during 2003 to 2005 .
the four points were the ahead of the colony , the front edge of the colony and 20 cm and 40 cm back from the front edge of the colony .
ergosterol content was 0.0 to 0.7 g per gram dried soil at the ahead , 2.5 to 4.8 g at the front edge , 0.5 to 1.8 g at the 20 cm back and 0.3 to 0.8 g at the 40 cm back .
the ergosterol content was very high at the front edge where the t. matsutake hyphae were most active .
however , ergosterol content did not significantly change during the fruiting season , september to october .
soil water contents were lower at the front edge and 20 cm back from the front edge of the colony than at the ahead and 40 cm back during the fruiting season .
soil water content ranged from 12 to 19% at the ahead , 10 to 11% at the edge , 9 to 11% at the 20 cm back and 11 to 15% at the 40 cm back .
our results suggest that the active front edge of the t. matsutake soil colony could be managed in terms of water relation and t. matsutake ectomycorrhizal root development . |
PubmedSumm118210 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the incidence of malignant neoplasms in poland in the past three decades has more than doubled , and , according to the prognosis put forward by didkowska , by 2025 the number of new cases in both men and women will continue to grow [ 1 , 2 ] . at the same time , advances in medicine tangibly contributed to improving overall efficacy of early cancer detection , as reflected in a steadily increasing number of successfully treated patients .
one of the widely applied methods of treatment of head and neck cancer consists in radiotherapy , be it used as a stand - alone , or a complementary method , following surgical intervention .
advances in the techniques of irradiation , as well as the establishment of new regional oncological centres , facilitate treatment of an increasing number of patients , which has already resulted in the emergence of a brand - new category of patients . following the radiotherapy treatment ,
it is essential that not only the dentists , but also the attending physicians pay due attention to the overall condition of the oral cavity and dentition in this group of patients .
the development of radiation - induced caries , also known as radiation caries , which is a late complication of radiotherapy , may even lead to a complete loss of teeth in patients who prior to the oncological treatment experienced no problems with their teeth whatsoever .
missing teeth can greatly affect overall quality of life , so greater awareness of the likely complications that might occur in the oral cavity after irradiation treatment is absolutely vital .
mucositis , hyposalivation , dysaesthesia , bacterial and fungal infections , osteoradionecrosis ( orn ) and trismus are the most common complications of direct irradiation in patients suffering from head and neck cancer [ 411 ] .
the incidence and severity of radiation - induced changes within the teeth individually vary , depending on the patient 's age , actual radiation dose , size of radiation exposure field ( position and actual size of the tumour ) , patient 's general condition and additional risk factors , e.g. alcoholism , smoking , malnutrition . during and after the radiotherapy some clinical symptoms may occur as an acute response to treatment . in the case of head and neck cancer radiotherapy ,
radiation caries is not a primary effect of radiotherapy , but develops as a secondary condition .
the main etiological factor in the development of caries is the bacteria encountered in the dental plaque . in the irradiated patients , however , it is the damage sustained by the serous cells of the salivary glands that is of essential importance , being the adverse side effect of the radiation therapy itself . as a result of the decreased amount of saliva flow and the changes in its properties , hyposalivation develops , which consequently impairs the self - cleaning of the teeth , with the resultant increased accumulation of dental plaque .
the population of cariogenic bacteria , i.e. lactobacillus and streptococcus mutans , increases in the saliva , and so does the level of immunoglobulin a ( igas ) . these changes may occur from the commencement of radiotherapy up to three months after its completion , and are believed to appreciably increase the risk of radiation caries .
their immediate effect consists in a limited re - mineralisation of the enamel , combined with severe demineralisation at the same time . during and immediately after the radiotherapy , patients often report increased sensitivity to thermal and chemical stimuli ( sweet , sour foods ) , which is associated with the lack of a protective layer of saliva and inflammation of the oral mucosa .
additional pain associated with tooth brushing often causes the patients to become negligent with regard to routine oral hygiene .
trismus and general malaise are also believed to be factors compromising oral hygiene [ 10 , 14 ] .
it usually has a rapid onset and quick progress , which in the most extreme cases may lead to total destruction of originally healthy dentition within a year .
radiation caries is characterised by the absence of acute pain even in the advanced changes .
histologically , the changes encountered in radiation caries are of the same character as the ones resulting from other causes [ 5 , 15 ] . in clinical terms , radiation caries
is located around the necks of the teeth , and typically affects more than one surface ; it is therefore called caries circularis ( fig .
it is most characteristic that radiation caries usually sets in on the smooth surfaces of the incisors , premolars and molars , which as a rule are most resistant to decay ( fig .
this is due to the reduced secretion of saliva and consequently the much impaired self - cleaning of the teeth .
the teeth located in the irradiated areas are discoloured , brownish , exhibit changes in translucency , and become brittle and prone to fracture ( figs . 3 , 4 ) .
incisors with typical signs of radiation - induced caries ( own research material ) multiple caries affecting the cervical region of the teeth in an irradiated patient ( own research material ) hard tissues of the teeth in an irradiated patient ( own research material ) pathological fracture of the crown ( own research material ) the article presents the specifics of dental care for patients after radiotherapy , with particular emphasis on prevention and treatment of radiation - induced caries .
thorough clinical dental examination combined with a detailed analysis of orthopantomograms prior to commencement of the radiation therapy allows one to effectively detect the potential focus of infection , and plan optimum pre - treatment of the oral cavity .
this appreciably reduces the risk of developing radiation caries , which may potentially lead to total destruction of dentition and , consequently , the need for extraction . fostering close co - operation between the oncologist and the dentist
is therefore deemed essential , especially at an early stage of preparing a patient for radiotherapy .
pre - treatment of the oral cavity , particularly any dental extractions due , should be completed two weeks before the scheduled commencement of radiotherapy [ 5 , 12 , 16 ] . with a view to reducing the likelihood of developing radiation caries ,
the patients are strongly advised to implement a preventive fluoride regimen before the radiotherapy commences . for this purpose ,
fluoride gels ( 1% naf ) are to be used at least every other day , or toothpaste with an increased fluoride content ( 3.0% naf ) twice a day , mouth rinses containing fluoride ( 0.05% naf ) , or ones containing chlorhexidine as an adjunct ( to be used for a maximum of 23 weeks ) . during the conservative treatment in this group of patients amalgam fillings
any treatment of the oral cavity , while the radiotherapy is already in progress , is of a symptomatic character only and applies in particular to ailments associated with mucositis , candidiasis , xerostomia , and opportunistic bacterial and viral infections . due to these conditions and weight loss during radiotherapy ,
the patients remain on a soft food diet rich in carbohydrates , thereby further aiding the development of caries [ 6 , 13 ] .
it is for this very reason that oral hygiene instructions combined with a preventive fluoride regimen are vital , and so is the dietary advice for the patients .
after the radiotherapy treatment has been concluded , it is essential to further motivate the patient to maintain adequate oral hygiene .
regular visits should be conducted every three months , as those are aimed at professional prophylaxis , symptomatic treatment of any ailments , as well as at the detection and treatment of any new cavities .
unfortunately , there are no specific guidelines for clinical management of radiation caries in this group of patients , so the actual treatment practices are based on the individual clinical experience of the attending dental surgeons rather than on any rigidly formulated regimen protocols .
recommend the use of composite materials and resin - modified glass ionomer cements , since no difference in the strength of binding to dentin was proven with regard to the adhesive materials in the irradiated teeth , in comparison with the control group .
the observations of hu et al . indicated that glass ionomer cements could be used in the treatment of radiation - induced , root surface carious lesions with good results .
if left untreated , caries leads to the development of pulp disease and periapical tissue disease , thereby necessitating endodontic treatment .
failure to carry out root canal treatment results in the necessity to have the inflamed teeth extracted , which in this group of patients is associated with an increased risk of osteoradionecrosis ( orn ) [ 1618 ] .
should it prove necessary to have the teeth extracted , any such extraction procedures should be carried out by specialists , effectively ensuring minimum trauma in the process , in conjunction with subsequent follow - up and adjuvant hyperbaric oxygenation .
the above notwithstanding , there is still orn risk that also needs to be addressed .
the incidence of orn is associated with ionizing radiation , which irreversibly damages the cells and vascular elements of the tissue , resulting in difficulties in healing of the post - extraction wound .
unfortunately , many dentists opt for excessively premature tooth extractions , although with quiet acquiescence of their patients .
it is estimated that post - extraction orn is encountered in 218% of patients who have previously undergone radiotherapy .
treatment of orn is rather long and drawn - out , and it can take up to 6 months , so before the decision of tooth extraction is ultimately made , the patients should be adequately advised about potential complications such as orn .
it should also be borne in mind that incomplete dentition should be remedied either by prosthodontic or implantology treatment .
in irradiated patients the risk of implant failure is higher than in patients in good general health [ 2022 ] .
therefore the option of endodontic treatment should always be considered in each case , with a view to effectively helping the patient to retain his own teeth .
evaluation of the quality of life in patients successfully treated for cancers of the head and neck includes their ability to chew in order to ensure proper nutrition .
this in turn may be achieved by enhancing the actual awareness of this issue in both the oncologists and the dentists , as they attend to and manage prophylaxis and treatment of radiation - induced dental caries . with a view to minimising the side effects of head and neck radiotherapy , fostering close co - operation between the oncologist and the dentist at an early stage of preparing a patient for radiotherapy
Output:
| overall improvement in the nationwide system of medical services has consequently boosted the number of successfully treated patients who suffer from head and neck cancer .
it is essential to effectively prevent development of radiation - induced caries as the late effect of radiation therapy .
incidence and severity of radiationinduced changes within the teeth individually vary depending on the patient 's age , actual radiation dose , size of radiation exposure field , patient 's general condition and additional risk factors . inadequately managed treatment of caries may lead to loss of teeth , as well as prove instrumental in tangibly diminishing individual quality of life in patients .
furthermore , the need to have the teeth deemed unyielding or unsuitable for the application of conservative methods of treatment duly extracted is fraught for a patient with an extra hazard of developing osteoradionecrosis ( orn ) , while also increasing all attendant therapeutic expenditures .
the present paper aims to offer some practical insights into currently available methods of preventing likely development of radiation - induced caries . |
PubmedSumm118211 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: myxoma occurs commonly in the left atrium ( la ) , but it can be found in any cardiac chamber .
this study reports a rare case of biatrial myxoma in a 28-year - old man who presented with left - sided heart failure symptoms . a 28-year - old male patient , a farmer , presented with exertional dyspnea and palpitation that had begun 10 months earlier .
he had never sought evaluation and treatment . on physical examination , he had an irregular heart rate with normal blood pressure .
cardiac auscultation demonstrated an s3 , a variable s1 , and a soft grade 2/6 systolic murmur over the left sternal border .
the 12-lead electrocardiogram demonstrated atrial flutter with variable atrioventricular conduction and the qrs complexes had an interventricular conduction delay .
chest x - ray showed pulmonary congestion and severe increase in the cardiothoracic ratio compatible with four - chamber enlargement .
transthoracic echocardiography ( tte ) examination revealed the enlargement of all chambers and severe lv dysfunction .
findings were in favor of cardiomyopathy . on color doppler imaging , there was moderate tricuspid regurgitation and mild mitral regurgitation .
it also demonstrated two lobulated hyper mobile masses in the atria , a larger one in the right atrium ( ra ) and a relatively small one in the la .
both of them were attached to the atrial septum in the fossa ovalis region opposing each other with a small stalk in between .
the masses prolapsed through the mitral / tricuspid valve during diastole ( figs . 1 , 2 ) .
in order to rule out secondary or metastatic tumors , computed tomography of the lung and abdomen were performed , which did not show any mass .
for his severe lv dysfunction , the patient underwent coronary angiography , which was normal . according to the findings , the patient underwent cardiac surgery with cardiopulmonary bypass . both masses and a small part of the interatrial septum ( ias )
the echocardiogram performed in the 6-month follow - up revealed significant improvement of the right and left ventricular function and reduction in the volume of the cardiac chambers .
there was no evidence of myxoma recurrence , and the patient showed a normal sinus rhythm .
he had long - term follow - up for the management of heart failure symptoms .
serial echocardiography was performed to assess tumor recurrence and the volume and function of cardiac chambers .
myxoma is the most common type of primary cardiac tumor , and the age at onset is usually between 30 and 50 years . up to 65% of the myxomas
the left atrium is the most common site of origin ( 83% ) , followed by the right atrium ( 12.7% ) ; 1.3% are biatrial .
only 1.7% and 0.6% of the myxomas occur in the lv and the right ventricle , respectively .
most cases occur sporadically , but in 7% of the cases , myxoma has a genetic origin presenting as the familial carney syndrome .
cardiac myxoma associated with the carney syndrome can occur as a single mass or multiple masses at any age , in any gender , and at any intracardiac location .
although the rate of recurrence is less than 5% after complete resection , patients should be evaluated on follow - up with serial echocardiography .
patients with cardiac myxoma have a variety of presentations , which are categorized into three groups : ( 1 ) constitutional and non - specific manifestations such as weight loss , fatigue , fever , and muscle weakness ; ( 2 ) embolization of the tumor , which can involve either pulmonary or systemic circulation depending on the myxoma location ; and ( 3 ) obstructive symptoms including dizziness , dyspnea , and syncope , which are the most frequent presenting features .
left - sided ventricular failure symptoms are seen in these patients and are commonly the result of the mechanical obstructive effect of the mitral valve by the tumor . electrocardiogram ( ecg ) abnormalities are seen in approximately 75% of the patients , demonstrating the evidence of la or ra enlargement and , rarely , atrial arrhythmia such as atrial fibrillation or flutter .
contrary to what we described for a typical presentation of cardiac myxoma , the present patient was a young man with biatrial myxoma with an unusual presentation of left - sided heart failure symptoms and atrial flutter on ecg .
according to our examinations and laboratory evaluation , the most probable cause for his cardiomyopathy seemed to be tachycardia - induced cardiomyopathy ( tic ) since the surgical removal of the mass and additional medical treatment improved the cardiac function dramatically .
tic is a reversible cause of heart failure in the absence of prior history of structural heart disease .
tic is characterized by atrial / ventricular tachycardia which induces atrial / ventricular systolic and diastolic dysfunctions .
the degree of cardiac dysfunction correlates with the duration and rate of tachyarrhythmia , and dysfunction presents earlier in higher cardiac rates . in many patients ,
once the heart rate or rhythm is controlled , the cardiac function and diameters normalize .
the diagnosis of tic is based on excluding other causes of heart failure and improving the ventricular / atrial performance after controlling the heart rate or rhythm . in summary ,
the typical presentation of cardiac myxoma is obstructive symptoms secondary to a single mass in the left atrium .
. however , the present case describes a young male with biatrial cardiac myxoma causing tic .
Output:
| this is a report of a biatrial cardiac myxoma in a young man with a 10-month history of exertional dyspnea and palpitation .
the echocardiogram revealed biatrial myxoma prolapsing through the mitral and tricuspid valves during diastole .
all cardiac chambers were enlarged and dysfunctional .
the electrocardiogram revealed a rapid ventricular response with atrial flutter rhythm .
the masses were resected and diagnosed as myxoma by a histological examination .
the follow - up echocardiogram revealed significant improvement in ventricular function and reduction in the cardiac chambers volume .
there was no evidence of myxoma recurrence .
the most probable cause of the patient s heart failure was considered to be tachycardia - induced cardiomyopathy . |
PubmedSumm118212 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: recently , international consensus for the histological diagnosis of hepatocellular carcinoma , especially of well - differentiated type of early stage ( early hcc ) , was published by the international consensus group for hepatocellular neoplasia ( icghn ) .
this was an epoch - making event for the early diagnosis and early treatment of hepatocellular carcinomas ( hccs ) . in this consensus paper ,
stromal invasion ( invasive growth of tumor tissue into portal tracts and fibrous septa ) was recognized as the most important finding for the diagnosis of early hccs .
unfortunately , however , this finding is not commonly known except among a small number of liver pathology experts . to present the correct histological diagnosis of early hccs , histological features of stromal invasion
it is also described how stromal invasion is closely related to characteristic image findings and histological features of early hccs .
stromal invasion , formerly called interstitial invasion of hcc , is defined as invasive growth of tumor tissue into fibrous septa , portal tracts , and/or blood vessels [ 27 ] .
stromal invasion by other tumors of other organs is a commonly recognized concept , and has long been important evidence for the definitive diagnosis of malignant tumor [ 8 , 9 ] .
this finding was first reported as a streak pattern in the fibrous septa of cirrhosis around an hcc nodule by kondo y. et al . .
kondo f. et al . then reported that this finding was frequently found within pre - existing portal tracts as well as fibrous septa , emphasizing that this finding was very useful for the diagnosis of well - differentiated hccs .
the invasion pattern was classified into 3 types crossing type , longitudinal type , and irregular type .
it was also reported that stromal invasion could be detected even by macroscopic view and by panoramic view of a histological specimen . at that time
. reported that the growth activity of well - differentiated hcc was rather suppressed with the stromal invasion .
divided stromal invasion into three types : ( 1 ) stromal invasion into fibrotic tissue and/or portal tracts , ( 2 ) blood vessel wall invasion of portal veins or hepatic veins , and ( 3 ) tumor thrombus .
described that hcc tissue in the state of stromal invasion was unaccompanied by reticulin frameworks and type iv collagen . in 1995 ,
an international working party ( iwp ) of the world congress of gastroenterology published a consensus nomenclature and diagnostic criteria for nodular hepatocellular lesions . in this article , stromal invasion was listed as a criterion for the histological diagnosis of well- and moderately differentiated hcc . even after publication of this article , however , this finding was still not well known especially among pathologists in western countries , possibly because related articles regarding stromal invasion were written by japanese pathologists .
this fact caused serious differences in criteria for the diagnosis of early hccs between eastern and western pathologists . in order to solve this serious problem , an international consensus group for hepatocellular neoplasia ( icghn )
this group met several times and discussed histological criteria for the diagnosis of early hccs subsequently , up to july 2007 . in these meetings ,
finally , all the participants including western pathologists generously accepted the importance and usefulness of this finding .
park et al . reported that ductular reaction confirmed by cytokeratin 7 ( ck7 ) is helpful in defining early stromal invasion , small hepatocellular carcinomas , and dysplastic nodules ( dns ) .
this was the first article of stromal invasion written by a non - japanese pathologist .
the authors consisted of 1 korean , 4 western , and 4 japanese pathologists . in 2009 , icghn published the consensus paper , which described that stromal invasion was the most helpful in differentiating early hcc from high - grade dns .
however , this finding was not sufficiently disseminated even after publication of the consensus paper . to achieve progress in the early diagnosis of many hcc patients in the world
stromal invasion is invasive growth of tumor tissue into stroma ( fibrous septa , portal tracts , and/or blood vessels ) .
it is histologically classified into 3 types crossing type , longitudinal type , and irregular type ( figures 1(a ) , 1(b ) , and 1(c ) . in the crossing type ,
hcc invades across fibrous septa of tumor nodules ( figure 1(a ) ) . in the longitudinal type ,
tumor cells grow longitudinally within fibrous septa ( figure 1(b ) ) . in the irregular type ,
the crossing type is usually observed in moderately or poorly differentiated hccs whereas the longitudinal and irregular types are usually found in well - differentiated hccs , although also at times in moderately or poorly differentiated hccs . in the evaluation of stromal invasion , comparison of cancer areas with noncancerous areas
pseudo - invasion means benign non - cancerous tissue in the fibrous stroma ( figure 1(e ) ) , and this does resemble stromal invasion . for the differentiation ,
stromal invasion can be identified even by a macroscopic and/or panoramic view of histological specimens . as is seen in figure 1(f ) ( macroscopic view of hcc ) , in the non - cancerous area without invasion ( area of ( a ) ) , the fibrous septa are clearly visible . however , in the area of tumor spread ( area of ( b ) ) , the septa are indistinct .
similarly , in a panoramic view of a histological specimen of hcc ( figure 1(g ) ) , distinct fibrous septa ( area of ( a ) ) and indistinct fibrous septa ( area of ( b ) ) can be clearly identified . in these indistinct septa , tumor invasion
the amount of the fibrous component is quite different between the invasive and noninvasive areas , an important point for the differentiation from pseudo - invasion .
the amount of the fibrous component was decreased as a result of the tumor invasion , and this decrease caused the indistinctness of the fibrous septa .
pseudo - invasion is usually caused by fibrosis around benign non - cancerous liver tissue .
when stromal invasion is very mild and fibrous components are minimally reduced , histological and macroscopic assessment of stromal invasion is difficult .
however , stromal invasion is severe enough , histological and macroscopic assessment is easy ( figures 1(f ) and 1(g ) ) . even in cases of hccs with minimal invasion and dns , proportion of fibrous stroma or portal tracts
are reduced to some extent as described later . therefore , macroscopic view is helpful for recognizing ehcc and dn .
the continuity to vascular invasion and destruction of the structure of portal tracts are also important findings ( figure 1(h ) ) .
although it is not a common finding , it can be detected in some early hccs .
tumor tissue first invades into fibrous septa , then into vascular walls , and finally into vascular lumina .
the connection among endothelial cells was most certainly destroyed by the mechanical force exerted by tumor growth .
, tumor cells have to survive within circulation , have to reach to remote areas , have to invade vascular walls from inside to outside , and have to proliferate outside the blood vessels .
however , it can be interpreted as blood space invasion after re - covering with endothelial cells .
destruction of the portal tract structure is more frequently found in stromal invasion while this feature is not seen in pseudo - invasion ( figure 1(e ) ) .
figures 1(i ) and 1(j ) show masson trichrome staining and silver staining of pseudo - invasion . and
magnification of figures 1(j ) and 1(l ) is a little higher than that of figures 1(i ) and 1(k ) .
the liver parenchyma is clearly surrounded by reticulin fibers in the pseudo - invasion ( figure 1(j ) ) . by contrast , the liver tissue of the true invasion lacks such surrounding reticulin fibers ( figure 1(l ) ) .
as described above , park et al . reported that ck7 immunostaining is useful for identifying stromal invasion .
ductular reaction confirmed by ck7 staining is frequently found in non - cancerous hepatocellular nodular lesions ( figure 1(m ) ) while it is less frequently found in hccs with true stromal invasion ( figure 1(n ) ) .
. they must have been invaded by well - differentiated hcc cells around the fibrous septa or by hcc cells from the fibrous septa . for the correct assessment of true stromal invasion ,
masson trichrome stain , azan - mallory stain , and victoria blue stain are also useful for clarifying the fibrous components .
next , some histological features that make the assessment of stromal invasion difficult must be shown ( figure 2 ) .
by contrast , figure 2(b ) shows pseudo - invasion consisting of very thin fibrous bundles within and around thick liver cell cords .
this pattern was not formed by the reduction of fibrous component but rather by dissection of liver parenchyma by very thin fibrous tissue . observing these two figures
reticulin fibers are lost in the case of true invasion but not in the case of pseudo - invasion . in cases like figure 2(a ) , i recommend pathologists to search for more severely invaded portal tracts that can easily be assessed as true invasion .
even very well - differentiated hccs sometimes include severely invaded portal tracts as well as minimally invaded portal tracts .
figure 2(d ) shows that reticulin fibers sometimes circumscribe cancer tissue even in the area of true invasion ( yellow arrow ) .
however , noncircumscribed cells are usually seen in the same fibrous septum ( green arrows ) .
by contrast , red arrows show ordinary tumor tissue with reticulin fibers outside the fibrous tissue .
in fact , reticulin fibers are sometimes observed within and around true invasive areas . after the invasive process is over ,
stromal invasion is closely related to the images and histological features of early hccs .
figure 3 shows the relationship between cancer development , vascularity , histological feature ( fatty change ) , and stromal invasion .
although there exists no direct evidence in a strict meaning , the possibility or hypothesis shown in figure 3 well explains the formation mechanism of vascularities and fatty change of hcc
. at least , previous studies [ 1218 ] can be good indirect evidence for the description in figure 3 .
well - differentiated hccs emerge from non - cancerous liver tissues ( normal liver , regenerative nodules , and dns ) , and then they progress into moderately or poorly differentiated hccs .
vascularity ( usually evaluated by contrast medium - enhanced images ) changes during this process .
this hypo - vascularity means a decrease in pre - existing arterial and portal venous blood supply caused by stromal invasion . during the process in which a well - differentiated hcc progresses into a moderately or poorly differentiated hcc , vascularity usually changes to become hypervascular [ 1217 ]
this vascular change is caused by proliferation of abnormal arteries ( neovascularization ) [ 1 , 17 ] . as a matter of fact
, abnormal arteries are found within dns [ 1 , 17 ] . however , the increase of arteries is not sufficient to cause hyper - vascularity .
this hypo - vascularity is attributed to a relative decrease of density of pre - existing portal tracts . because the parenchymal component increases within the dn nodule , the density of pre - existing portal tracts decreases .
after dns transforms into early hccs , the density may decrease more severely by stromal invasion .
this hypo - vascularity can also explain the formation mechanism of fatty change , a well - known feature of early hccs ( figure 3 ) .
although fatty change may be attributed to metabolic change of tumor cells with tumor development independent of hypoxic change , hypo - vascularity may cause fatty change as a hypoxic change . as mentioned above , knowledge of stromal invasion
stromal invasion can not always be assessed histologically , and it is very rarely assessed in the examination of thin - needle biopsy specimens .
for this reason , very well differentiated hccs lacking typical features of ordinary well - differentiated hccs are not diagnosed by biopsy . as histological criteria for the biopsy diagnosis of well - differentiated hccs , ( 1 ) nuclear crowding ( hypercellularity ) , ( 2 ) hyperstainability of cytoplasm ( basophilia or eosinophilia ) , and ( 3 ) microacinar formation have been used til now .
these criteria have been proved to be useful because ordinary well - differentiated hccs have considerable parenchymal atypia .
however , some very well - differentiated hccs are not diagnosed by biopsy and are definitively diagnosed after examination of stromal invasion in resected specimens . to make progress in the early diagnosis of hccs
, we have to develop new parenchymal tumor markers that can be used for biopsy diagnosis .
some attempts have been made recently to utilize immunohistochemical markers for the diagnosis of well - differentiated hccs [ 2025 ] .
heat shock protein 70 ( hsp70 ) [ 20 , 21 ] , glypican 3 ( gpc3 ) [ 20 , 22 , 23 ] , and glutamine synthetase ( gs ) [ 20 , 24 , 25 ] have been used independently or in combination . at present , these markers are used in a complementary manner to morphological criteria .
we are hopeful that excellent markers with high sensitivity and high specificity are developed in the future .
stromal invasion is a very important finding for the histological diagnosis of early hccs . for the correct assessment of stromal invasion ,
the following 5 items are useful : ( 1 ) macroscopic or panoramic views of the histological specimen , ( 2 ) amount of fibrous components of the stroma , ( 3 ) destruction of the structure of portal tracts , ( 4 ) loss of reticulin fibers around cancer cells , and ( 5 ) ck 7 immunostaining for ductular proliferation .
knowledge of stromal invasion is very useful to understand the formation mechanism of images ( vascularity ) and histological features ( fatty change ) of early hccs .
Output:
| stromal invasion ( invasive growth of tumor tissue into portal tracts and fibrous septa ) is now recognized as the most important finding in the diagnosis of the well - differentiated type of early hepatocellular carcinomas ( hccs ) . in differentiating stromal
invasion from pseudoinvasion ( benign hepatic tissue in fibrous stroma ) , the following 5 items are useful : ( 1 ) macroscopic or panoramic views of the histological specimen , ( 2 ) the amount of fibrous components of stroma , ( 3 ) destruction of the structure of portal tracts , ( 4 ) loss of reticulin fibers around cancer cells , and ( 5 ) cytokeratin 7 immunostaining for ductular proliferation
. knowledge of stromal invasion is also useful for a better understanding of the vasculature ( hypovascular hccs ) and histological features ( fatty change ) of early hccs .
invasion of preexisting arteries and portal veins causes hypo - vascularity of hccs .
further , hypovascularity causes fatty change as a hypoxic change of cancer tissues . |
PubmedSumm118213 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: patients with ulcerative colitis ( uc ) are at increased risk for colorectal cancer , a phenomenon with the largest fraction being attributed to chronic inflammation [ 1 , 2 ] .
growing evidence supports a role for proinflammatory mediators present in the tumor microenvironment in the pathogenesis of colitis associated colorectal cancer ( cac ) .
interleukin il-6 is a pleiotropic cytokine with potent functions in promoting inflammation and neoplastic transformation and is involved in the development of cac [ 47 ] .
it has been found that the expression of il-6 is increased and its expression level is correlated with the severity of disease in uc [ 810 ] .
the promoting effect of il-6 on the development of cac has also been studied [ 3 , 1113 ] .
grivennikov and colleagues have demonstrated that il-6 exerts a strong promoting effect on the development of cac in mice dosed with a low amount of chemical inflammation inducing regent dimethylhydrazine ( dss ) , whereas blocking of il-6 signal by injecting il-6 receptor antibody can successfully suppress the intestinal inflammation [ 14 , 15 ] and then cac [ 6 , 16 ] .
further evidence suggests that the genes that encode il-6 are under the control of transcriptional nuclear factor - kappa b ( nf-b ) [ 3 , 17 ] . in grivennikov 's study
, the authors have demonstrated that the activation of nf-b increases the production of il-6 by lamina propria myeloid cells , while the increase of il-6 protects the premalignant intestinal epithelial cell from apoptosis that is largely mediated by the transcription factor stat3 .
thus , it is proposed the nf-b - il-6-stat3 cascade is an essential stimulator for the proliferation and survival of precancerous cells in the context of chronic inflammation .
interestingly , a study has shown that the dss - evoked intestinal inflammation and cac are significantly inhibited by the inactivation of ikk ( a protein kinase responsible for nf-b activation ) in mice .
therefore , current evidence strongly suggests that nf-b / il-6 pathway is a key player in linking chronic inflammation to cac [ 19 , 20 ] .
however , dynamic of the nf-b / il-6 pathway during the procession of cac has not been well characterized . in view of these observations
, we therefore performed this study to evaluate the dynamic temporal changes of nf-b / il-6 pathway in relation to the procession of experimental cac in mice .
twenty - nine specific - pathogen - free icr male mice aged 5 weeks ( median weight of 35 g ) were purchased from shanghai super - b&k laboratory animal corp . , ltd . , china , and housed in a specific - pathogen - free environment and fed with commercial pellets .
cac in mice was inducedby 1.2-dimethylhydrazine ( dmh ) plus dextran sulfate sodium ( dss ) administration as previous reports [ 21 , 22 ] .
briefly , the mice were i.p . injected with 25 mg / kg dmh ( aladdin chemistry , shanghai , china , mw 133.02 ) once weekly and kept on regular diet and water for 7 days and then received 1% dss solution ( mp biomedicals llc , illkirch cedex , france , mw 50,000 ) for 7 days ; total 10 more dss treatment cycles were applied until the experimental terminal ( after induction for 22 weeks ) .
mice were sacrificed after induction for 14 , 16 , 18 , and 22 weeks .
large bowels were opened longitudinally , flushed with saline , and macroscopic tumors were counted .
then , bowel tissues were divided into two parts , one part for the protein ( western blotting ) study and another for the histological examination at the department of pathology .
embedded colorectal tissues were cut in 4 m thickened serial sections and stained with hematoxylin and eosin ( h&e ) staining sections .
severity of inflammation was graded as light , moderate , and high according to the inflammatory cell infiltration by experienced pathologists at the department of pathology , the 2nd affiliated university hospital of zhengzhou university , and reviewed by senior pathologist dr .
ihcs for il-6 and nf-b were performed with vectastain elite abc kit ( vector laboratories inc . ,
burlingame , ca , usa ) according to the manufacturer 's instructions and our published method .
the following primary antibodies were used : rabbit anti - il-6 polyclonal antibody ( working dilution 1 : 100 , santa cruz biotechnology inc . , santa cruz , ca , usa ) and rabbit anti - nf-b polyclonal antibody ( working dilution 1 : 100 , santa cruz biotechnology inc . , santa cruz , ca , usa ) .
3-amino-9-ethylcarbazole ( aec , vector laboratories , burlingame , ca , usa ) was used as chromogen and slides were slightly counterstained with mayer 's hematoxylin .
negative control slides for ihcs were performed routinely : ( 1 ) primary antibodies were substituted with the isotype - matched control antibodies ; ( 2 ) secondary antibody was substituted with phosphate buffered saline ( pbs ) . both h&e and ihc stained slides
were observed under light microscopy ( dm 2000 , leica microsystems , wetzlar , germany ) .
morphometric evaluation was performed in both the stroma and the epithelium in stained slide . in the stroma
the density of il-6 and nf-b positive cells in 3 fields with the most abundant positive cells was graded according to the method we published previously .
tissue samples were homogenized in a standard ripa buffer , unless stated otherwise , with a cocktail of protease and phosphatase inhibitors .
cytoplasmic and nuclear proteins were prepared using ne - per kit according to the manufacturer 's instructions .
lysates were separated on a 1015% sds - polyacrylamide gel and proteins were transferred to pvdv membrane .
membranes were blocked in pbst buffer containing 5% skim milk for 1 hour at room temperature and probed with primary antibodies and secondary hrp - conjugated antibodies .
results were expressed as mean sem ( standard error of the mean ) unless otherwise stated .
statistical significance was evaluated by the mann - whitney u test and the kruskal - wallis test .
the correlation coefficients between overall bowel tumor number and the densities of il-6 and nf-b positive cells were determined by spearman correlation analyses .
tumors were observed in the colorectal mucosa and the number of tumors was increased over observed times ( figure 1 ) .
the size of macroscopic tumors was gradually increased over times ( 14 weeks versus 16 weeks versus 18 weeks versus 22 weeks : 0.5 0.23 mm versus 3.13 1.5 mm versus 3.93 1.83 mm versus 4.42 1.20 mm , p < 0.01 , the kruskal - wallis test ) .
normal histological appearance was shown in the control ( figure 2(a ) ) ; dysplastic lesion was observed in cac mice .
dysplastic lesion in the colorectal mucosa after induction for 14 weeks was at a low grade ( figure 2(b ) ) and it was gradually increased over time ( figure 2(c ) for the 16 weeks , figure 2(d ) for the 18 weeks ) and finally became cancerous lesion after induction for 22 weeks ( figure 2(e ) ) .
the administration of dmh and dss also evoked a strong inflammation in the colorectal mucosa ; it was started after induction for 14 weeks and through the experimental terminal ( for 22 weeks ) .
the grading score of inflammation was increased after induction for 14 weeks and through the experimental terminal ( see figure 3 ) .
the expressions of il-6 and nf-b in dysplastic lesion during the procession of cac were examined with ihc over different time - points .
the results showed that il-6 immunoreactivity was observed both in the transformed epithelial cells ( arrow head pointed in figure 4(a ) ) and in the tumor stroma cells ( arrow pointed in figure 4(a ) ) .
after induction for 22 weeks , the cac neoplastic epithelium was strongly positive for il-6 ( arrow head pointed in figure 4(a ) ) .
when the density of il-6 positive cells was graded , it was shown that the increase of il-6 positive cell density was started after induction for 14 weeks , became even higher after induction for 16 and 18 weeks , and reached the highest level after induction for 22 weeks ( experimental terminal ) in both transformed epithelium ( figure 4(c ) ) and tumor stroma ( figure 4(d ) ) .
the expression of nf-b in the tumor tissues was in the same change pattern as il-6 .
nf-b immunoreactivity was detected both in the transformed cac cells ( arrow head pointed in figure 4(b ) ) and in the tumor stroma cells ( arrow pointed in figure 4(b ) ) .
the density of nf-b positive cells was also shown in an increased trend in both transformed epithelium ( figure 4(e ) ) and tumor stroma ( figure 4(f ) ) over the observed time - points .
the expression of il-6 and nf-b proteins in the tumor tissues was examined with western blotting .
the results confirmed the ihc observations and demonstrated increased expression of nf-b and il-6 proteins in the tumor tissues ( see figure 4(g ) ) that was started after induction for 14 weeks and became more significant in the experimental terminal ( after induction for 22 weeks ) . in order to further address the relationship between overall macroscopic tumor number in the bowel and the densities of nf-b and il-6 in the tumor tissues , we performed correlation analyses .
cac mice from all observed time - points were included in the correlation analyses . as results present in table 1
, the analysis data showed that both of nf-b and il-6 in the stroma and dysplastic epithelium were positively associated with the overall tumor number in the bowel ( p < 0.01 ~ 0.05 ; see table 1 ) .
there are growing evidences to support the view that the activation of nf-b / il-6 pathway is involved in the development of cac [ 12 , 17 , 18 , 20 , 26 ] .
this study used an cac mouse model to examine the dynamic temporal changes of nf-b / il-6 pathway in relation to the procession of experimental cac in mice .
our findings showed an elevation of nf-b / il-6 expression that occurs over the examined time - points ( after induction for 1422 weeks ) in association with the rapid increased macroscopic tumor number and dysplastic lesion degree in colitis mice .
these data contribute to the growing evidence on the association between intestinal inflammation and cac and provide new insights into the importance of nf-b / il-6 pathway in relation to colitis associated carcinogenesis .
the link between chronic inflammation and the development / progression of human cancers has been well recognized for several decades [ 2729 ] ; recent findings support the fact that nf-b - regulated inflammatory cytokines contribute to the pathogenesis of chronic inflammation and then to the development of crc [ 30 , 31 ] . in this study
, we have found that the expressions of nf-b and il-6 were synchronously increased in the tumor tissues and accompanied with the process of cac in mice over the examined time - points .
after induction for 14 weeks , inflammation characterization was observed ; the number of macroscopic tumors and the degree of dysplastic lesions in the bowel were gradually increased over the observed time - points .
furthermore , ihc analysis revealed that increased densities of il-6 and nf-b positive cells were observed in both the transformed epithelium and the tumor stroma , which are consistent with the findings in similar cac mouse models reported by other groups [ 4 , 12 , 18 ] . in this study , we have observed that the expression of both nf-b and il-6 was in the dysplastic epithelial cells ; this may suggest that nf-b expressed in the transformed cell also regulates the production of il-6 and contributes to the elevation of nf-b and il-6 in dysplastic lesions .
finally , our data showed a strong relationship between overall tumor number and nf-b / il-6 positive cells at all examined time - points and indicated that nf-b / il-6 pathway may contribute to the transformation of cac in this colitis mouse model .
the exact mechanisms behind the protumor effect of nf-b / il-6 in colitis associated carcinogenesis are not fully understood thus far .
il-6 , as an important proinflammatory cytokine , has been reported to be involved in both the tumor initiation and the promotion stages [ 12 , 32 ] . in the initiation stage of cac , il-6 acts as a tumor promoter by binding to its gp130-associated receptor and activated stat3 signal pathway , which is the major protumorigenic effector for il-6 .
then stat3 will further induce the expression of genes that are related to proliferation and antiapoptosis in transformed cells [ 12 , 20 , 33 ] .
besides its importance during early tumor promotion , il-6 can also accelerate tumor growth during late stages of cac via a direct stimulation effect on proliferation and growth of tumor cells [ 33 , 34 ] .
for instance , il-6 is one of the potential stimulators for the differentiation of th17 cell , while th17 cell has been demonstrated to be important in the pathogenesis of both uc and cac .
in addition , the promoting effect of il-6 on cancer growth can also be via an activation of nf-b in the cancer cells ; we have shown that increased nf-b was expressed in the transformed epithelial cells and tumor stromal cells over times and suggested that the interaction between nf-b and il-6 occurred during the procession of cac in colitis mice .
the effect of il-6 on cellular response is through a receptor complex consisting of at least one subunit of the signal - transducing glycoprotein gp130 .
the activation of gp130 is classically through il-6 binding to a membrane - bound cognate receptor ( il-6r ) .
however , il-6 induced biological activities are largely mediated via a natural formation of an agonistic complex with soluble il-6 receptor ( sil-6r ) ; this complex binds gp130 and then triggers cellular responses .
il-6 trans - signaling and plays a critical role in promoting chronic inflammation and inflammation related cancer [ 33 , 38 , 39 ] .
thus , it would be interesting to further investigate whether blockade of il-6 trans - signaling can prevent the development of cac in uc . indeed , a humanized anti - il-6 receptor monoclonal antibody ( tocilizumab ) that can block il-6-mediated signal transduction by inhibiting il-6 binding to both the transmembrane il-6r and the sil-6r has been developed .
the efficacy of tocilizumab has been confirmed in patients with chronic inflammatory diseases including castleman disease and rheumatoid arthritis [ 39 , 41 ] ; it would be interesting to investigate whether tocilizumab can inhibit the development of cac in the future . in conclusion ,
nf-b / il-6 pathway as a key protumorigenic player is dynamically increased throughout the pathological process of cac in murine model .
these findings indicate that nf-b / il-6 pathway may contribute to all the stages of initiation , promotion , and progression of cac in colitis mice .
future studies are necessary to fully evaluate the potential of anti - nf-b / il-6 pathway as a preventing approach ( i.e. , administered at early stage before dysplastic transformation ) to reduce dysplastic tumor number and as an intervention approach ( i.e. , administered after 14 weeks ) to suppress the progression of dysplastic degree in this model .
Output:
| nuclear factor - kappab ( nf-b)/interleukin ( il-6 ) pathway links chronic inflammation to colitis associated cancer ( cac ) . in this study , we examined the dynamic temporal changes of the nf-b / il-6 pathway during the procession of experimental cac mouse model .
mice were sacrificed after induction for 14 , 16 , 18 , and 22 weeks for the examination of tumor burden , inflammation degree , and protein level of nf-b and il-6 in bowel tissues .
the results showed that tumor burden and inflammation severity in the bowels were gradually increased over the observed time - points .
the expressions of il-6 and nf-b proteins were gradually increased after induction of dysplastic lesions over times .
these data provide new information on the dynamic temporal changes of nf-b / il-6 pathway in relation to cac development that may be relevant in the design of future investigations of therapeutic interventions to effectively target cac processes . |
PubmedSumm118214 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: nanotechnology can be defined as the techniques aimed at characterizing and producing materials on the nanometer scale ( < 100 nm ) which exhibit specific physical / chemical properties and functions .
the behavior of nanoparticles is a function of their size , shape and surface reactivity with the surrounding tissue . in principle
, a large number of particles could overload the body s phagocytes , cells that ingest and destroy foreign matter , thereby triggering stress reactions that lead to inflammation and weaken the body s defense against other pathogens .
in addition to questions about what happens if non - degradable or slowly degradable nanoparticles accumulate in body organs , another concern is their potential interaction or interference with biological processes inside the body . due to the importance of this size class of particles
, the term nanotoxicology has been coined that aims to establish the relationship between nanoparticle physicochemical properties ( e.g. size , surface properties and crystal phase ) and their toxic potential .
it addresses the toxicology of nanoparticles which appear to have toxicity effects that are unusual and not seen with larger particles . the smaller a particle , the greater it s surface area to volume ratio and the higher its chemical reactivity and biological activity . because of their large surface area , nanoparticles
will , on exposure to tissue and fluids , immediately adsorb onto their surface some of the macromolecules they encounter .
this may , for instance , affect the regulatory mechanisms of enzymes and other proteins .
genotoxic substances are known to be potentially mutagenic or carcinogenic , specifically those capable of causing genetic mutation .
nanoparticles are molecules which are sub-100 nm in range , which have specific physical , chemical and biological properties .
nanoparticles are widely used because of their desirable properties in industrial , medical and cosmetic fields .
the extremely small size of nanomaterials also means that they much more readily gain entry into the human body than larger sized particles .
how these nanoparticles behave inside the body is still a major question that needs to be resolved .
nanoscience and nanotechnology encompass a wide range of fields , including chemistry , physics , materials engineering , biology , medicine , and electronics .
there is also a notable rise in the number of publications discussing their toxicity , particularly in the past two years .
the total number of papers on toxicity , however , remains low compared to the total number of publications on nanomaterials .
there are several reviews addressing nanotoxicology aspects ; however , they are intended for a narrow , specialized audience .
several are comparatively general while others address selected aspects of nanoparticle toxicology , such as epidemiological reviews of exposure to particles and health affects ; targeted drug delivery ; particle characterization methods ; screening strategies and future directions of research ; and regulation of nanomaterials .
while the tremendous positive impacts of nanotechnology are widely publicized , potential threats or risks to human health and the environment are just beginning to emerge .
with limited information available for support , critics are presenting a number of concerns on the devastating effects of nanotoxicity on human health and the environment .
detailed studies on the long - term effects of nps are the need of the day to overcome or reduce possible threats .
simultaneous agglomeration , sedimentation and diffusion at physiologically relevant concentrations should be taken into account while conducting quantitative studies on the uptake of nps into biological systems , to assess the corresponding risks on human health .
a study suggests that inhaled carbon nps are capable of rapid translocation into the circulation . on the contrary
, a conflicting report suggests that inhaled carbon nps remain within the lung up to 6 h after inhalation , without passing to systemic circulation . in a recent study , suitability of mouse spermatogonial stem cell line as a model system to assess nanotoxicity
as nanomaterial - based products enter the market , there is an urgent need for related research in order to prevent dramatic consequences of any health - oriented issues caused by nanotechnology - driven products .
recent research has brought to light concerns over the safety of use of nanomaterials and also the long - term adverse effect of their use .
hence it is essential for us to establish the toxicity , safety and risks involved in the usage of these nanoparticles . during the last years
engineered nanoparticles ( nps ) have been extensively used in different technologies and consequently many questions have arisen about the risk and the impact on human health following exposure to nanoparticles . nevertheless , at present knowledge about the cytotoxicity induced by nps is still largely incomplete . in this context
, we try to show which types , sizes and concentrations of nanoparticles are safe for human use and this will help in developing diagnostic , prognostic and therapeutic models using nanoparticles .
nanogold , is a suspension of sub - micrometre - sized particles of gold in a fluid - usually water .
the liquid is usually either an intense red colour ( for particles less than 100 nm ) , or a dirty yellowish colour ( for larger particles ) . in recent days
uptake of gnps reaches a maximum when the size nears 50 nm and when the aspect ratio approaches unity .
nevertheless , most gnps can enter cells efficiently , and most studies indicate that they are nearly harmless to cultured cells in all , gold nanoparticles may not affect cell viability in short - term but affect cell proliferation and cause dna damage .
currently gold nanoparticles ( aunps ) are used in different biomedical applications , such as intracellular gene regulation , chemotherapy and drug delivery , as well as in optical and electronic applications .
a previous study revealed that gold - silica nanoshells release significant heat when exposed to near - infrared ( nir ) light ( 650950 nm ) and have been used to produce thermal cytotoxicity in vitro .
unfortunately , this treatment approach is mechanistically limited to use in superficial malignant tumors because of the minimal tissue penetration ( < 23 cm depth ) by nir wavelength light .
however , the gold - silica nanoshell study demonstrated that nanogold has potential clinical use as a thermal conductor of non - invasive energy sources .
gold , like most metals , is an excellent conductor of electrical and thermal energy .
silver nanoparticles are used as antibacterial / antifungal agents in a diverse range of applications : air sanitizer sprays , socks , pillows , slippers , face masks , wet wipes , detergent , soap , shampoo , toothpaste , air filters , coatings of refrigerators , vacuum cleaners , washing machines , food storage containers , cellular phones , and even in liquid condoms ( peter d , 2009 ) .
ingestion of ag can cause argyria , the benign condition characterized by the bluish - graying of the skin that occurs through the preferential deposition of ag in the basal lamina of soft tissues such as the skin , liver , and spleen and blood vessels , gastrointestinal tract , liver , and kidney ( fig 1 , table 1 ) .
carbon nanotubes ( cnts ; also known as buckytubes ) are allotropes of carbon with a cylindrical nanostructure .
these cylindrical carbon molecules have novel properties that make them potentially useful in many applications in nanotechnology .
determining the toxicity of carbon nanotubes has been one of the most pressing questions in nanotechnology .
unfortunately such research has only just begun and the data are still fragmentary and subject to criticism . under some conditions , nanotubes can cross membrane barriers , which suggest that if raw materials reach the organs they can induce harmful effects such as inflammatory and fibrotic reactions ( jelena k et al .
nanotechnology is a global cross - disciplinary undertaking that has extraordinary potential to change our lives by improving existing products and enabling new ones .
like most new technologies , the emphasis on benefits has been offset by considerable debate about the uses and safety of nanotechnologies .
occupational medicine is replete with examples of respirable dust particle exposures causing disease , and so matters of safety have been focused largely on nanoparticles ( np ) , which represent only one aspect of nanotechnology .
np , generally defined as particles less than 100 nm in any dimension and previously called ultrafine particles by inhalation toxicologists , are a concern because they may enter the body through the lungs , skin , or gut depending on the type of exposure .
several recent papers have highlighted this area of toxicology , its novelty , the gaps in research , and possible testing strategies for np and nanotubes .
there is sufficient ultrafine particle toxicology literature to consider that the large and diverse group of manufactured np arising from nanotechnology comprises an inhalation hazard of unknown potential .
most of the concern has flowed from this perception , enhanced by limited studies indicating that they may also be taken up through the skin or gut .
the notion , for which some limited support exists , that np may gain access to the blood poses a relatively new particle toxicological problem , i.e. , particle effects at sites other than the lungs ( fig 1 , table 1 ) .
this paper examines the toxicology issues relating to carbon nanotubes ( cnt ) , one of the major new np that are set to be produced in bulk for many diverse purposes .
global revenues from cnt in 2006 are estimated at ~ $ 230 million with a growth rate of ~ 170% .
this provides potential for workplace and even eventual general exposure , if there is attrition of materials that contain them .
concern has been raised over the safety of cnt because they have three properties that are clearly associated with pathogenicity in particles .
they are fiber shaped and so might behave like asbestos and other pathogenic fibers which have toxicity associated with their needle - like shape .
titanium dioxide ( tio2 ) particles with diameter larger than 100 nm are considered biologically inert in both humans and animals . based on this understanding ,
titanium dioxide nanoparticles have been widely used in many products , such as white pigment , food colorant , sunscreens , and cosmetic creams . however , adverse effects of tio2 nanoparticles have recently been uncovered .
new research is exploring the potential use of nanostructured tio2 photocatalyst materials for sterilizing equipment of environmental microorganisms in the health care facility .
exposure to nano - titanium dioxide showed dna and chromosome damage to a degree linked to all the big killers of man , namely cancer , heart disease , neurological disease and aging .
warheit and co - workers recently dosed the lungs of rats with 3 sizes of titanium dioxide nanoparticles and suggested that toxicity is not dependent upon particle size or surface area . a clear conclusion regarding particle size could not be reached as only 3 sizes were tested , of which one was of a different crystal phase , and the two of the same crystal phase ( rutile ) were of different shapes ( rods , ~200 nm 40 nm , and dots , ~10 - 20 nm ) . in a follow up study , these authors tested the pulmonary toxicity of 3 sizes ( hydrodynamic diameter : 136 nm , 149 nm and 382 nm ) of the rutile phase with alumina surface coating , and compared it to 25 nm tio2 particles ( of a different crystal phase ) . in a third study , they examined the toxic potential of 3 samples of different crystal phases , however , the sizes were also different .
oberdrster et al conducted pulmonary toxicity tests with 20 nm ( 80% anatase ) and 250 nm ( 100% anatase ) titanium dioxide particles and found that the total surface area was a metric that related to neutrophil lung inflammation in rats .
no clear trends with regard to the influence of tio2 crystallinity and particle size on biological activity could be seen in these different studies and contrasting concepts were proposed .
one major reason was the paucity of different well - characterized tio2 samples ( in terms of size and crystallinity ) that were used , thus precluding the development of convincing conclusions about the function of parameters such as particle size or crystal phase . in 1990 ,
the lipid nanoparticles were invented in the laboratories , the first patent filings took place in 1991 .
the lipid nanoparticles were developed as alternative to traditional carriers such as polymeric nanoparticles and leptosomes .
meanwhile many research groups are active worldwide , their results are reviewed which cover many different administration routes : dermal and mucosal , oral , intravenous / parenteral , pulmonary but also ocular ( fig 1 , table 1 ) .
the lipid nanoparticles are also used for peptide / protein delivery , in gene therapy and various miscellaneous applications ( e.g. vaccines ) .
although lipid nanoparticles represent potent drug carriers , for many formulations toxicity data are rare .
crucial for biological applications quantum dots must be covered with other materials allowing dispersion and preventing leaking of the toxic heavy metals .
polymers such as polysaccharide chitosan nanoparticles have been used for some time now as drug delivery systems .
polymer conjugation to proteins reduces immunogenicity , prolongs plasma half - life and enhances protein stability .
drug conjugation promotes tumour targeting through the enhanced permeability and retention effect and , at the cellular level following endocytic capture , allows lysosomotropic drug delivery ( fig 1 , table 1 ) .
the amphilic molecules used for the preparation of these compounds have similarities with biological membranes and have been used for improving the efficacy and safety of different drugs .
usually , liposomes are classified into three categories on the basis of their size and lamellarity ( number of bilayers ) : small unilamellar vesicles or oligolamellar , large unilamellar vesicles and multilamellar vesicles . the active compound can be located either in the aqueous spaces , if it is water - soluble , or in the lipid membrane , if it is lipid - soluble . recently , a new generation of liposomes called
stealth liposomes have the ability to evade the interception by the immune systems , and therefore , have longer half - life . like nanoorganisms ( viruses ) , nanoparticles are able to enter cells and interact with subcellular structures . cellular uptake , subcellular localization , and ability to catalyze oxidative products depend on nanoparticle chemistry , size , and shape .
the mechanism by which nanoparticles penetrate cells without specific receptors on their outer surface is assumed to be a passive uptake or adhesive interaction .
this uptake may be initiated by van der waals forces , electrostatic charges , steric interactions , or interfacial tension effects , and does not result in the formation of vesicles .
( steric interactions occur when nanoparticles have molecules with size , geometries , bonding , and charges optimized for the interaction with the receptors ) . after this type of uptake ,
the nanoparticles are not necessarily located within a phagosome ( which offers some protection to the rest of the cellular organelles from the chemical interaction with the nanoparticle ) .
for example , c60 molecules enter cells and can be found along the nuclear membrane and within the nucleus .
very small nanoparticles , such as c60 molecules with a diameter of 0.7 nm , are able to penetrate cells via a different mechanism than phagocytosis , probably through ion channels or via pores in the cell membrane .
this type of uptake and free movement within the cell makes them very dangerous by having direct access to cytoplasm proteins and organelles .
uptake location is likely to depend on material type ; however , current research does not provide sufficient information to drawing conclusions on this subject . upon nonphagocytic uptake , nano - particles can be found in various locations inside the cell , such as the outer - cell membrane , cytoplasm , mitochondria , lipid vesicles , along the nuclear membrane , or within the nucleus .
depending on their localization inside the cell , the nanoparticles can damage organelles or dna , or ultimately cause cell death .
recent studies have used a composite phenotype ( psychosis ) that includes bpd , scz , psychosis not otherwise specified , and schizoaffective disorder , to identify shared susceptibility loci .
several chromosomal regions are reported to be shared between these syndromes ( 18p , 6q , 10p , 13q , 22q ) .
nanoparticles are internalized not only by professional phagocytes such as alveolar macrophages , but by various types of cells , including endothelial cells , pulmonary epithelium , gastrointestinal epithelium , red blood cells , platelets , and nerve cells ( fig 1 ) .
for example , environmental particles with size between 2.5 and 10 m were found to collect in large cytoplasmic vacuoles , while smaller nanoparticles ( 100 nm ) localize in organelles , such as mitochondria , leading to disruption of mitochondrial architecture .
with very few exceptions , previous nanotoxicity studies implicitly involved the assumption that the techniques developed for risk assessment of hazardous chemical substances can be applied in unchanged form to explore cell response in np laden media .
this misleading approach has the consequence that the actual dose of exposure is ill defined or , more often , completely unknown .
pro - inflammatory cytokines such as interleukin- 6 ( il-6 ) and tumor necrosis factor alpha ( tnf- alpha ) are involved in the formation of toxic peroxynitrite by increasing the activity of nitric oxide synthase ( nos ) enzyme .
nitric oxide ( no ) is potent inflammatory mediator because of its strong reactivity with oxygen , superoxide and iron - containing compounds .
prostaglandins are well known as proinflammatory mediators , and inhibition of cyclooxygenase ( cox ) has long been used in the management of inflammation .
levels of prostaglandin e2 ( pge2 ) are increased in various states of inflammation . unlike larger particles , nanomaterials may be taken up by cell mitochondria and the cell nucleus .
studies demonstrate the potential for nanomaterials to cause dna mutation and induce major structural damage to mitochondria , even resulting in cell death .
the greater chemical reactivity of nanomaterials results in increased production of reactive oxygen species ( ros ) , including free radicals and it is one of the primary mechanisms of nanoparticle toxicity ; it may result in oxidative stress , inflammatory cytokines production and consequent damage to proteins , membranes , dna and cell death .
humanized nps , termed nano - proresolving medicines , are mimetics of endogenous resolving mechanisms , possess potent beneficial bioactions , can reduce nanotoxicity , and offer new therapeutic approaches .
nanotoxicology is an emerging new multidisciplinary field of science , and therefore there is a risk of change in its rapid development in the near future .
therefore , development of novel nanoparticles for pharmacology , therapeutics and diagnostics must proceed in tandem with assessment of any toxicological and environmental side effects of these particles . as the bioenvironment
is already polluted with nanoparticulates of particulate matter caution should be taken to prevent and contain any environmental effects of intentionally generated nanomaterials . in this review
we tried to put our effort to show the toxicity of various nanoparticles , which will be a very valuable reference source to students and investigators in this research field to guide them in their future work .
nanogold , is a suspension of sub - micrometre - sized particles of gold in a fluid - usually water .
the liquid is usually either an intense red colour ( for particles less than 100 nm ) , or a dirty yellowish colour ( for larger particles ) . in recent days
uptake of gnps reaches a maximum when the size nears 50 nm and when the aspect ratio approaches unity .
nevertheless , most gnps can enter cells efficiently , and most studies indicate that they are nearly harmless to cultured cells in all , gold nanoparticles may not affect cell viability in short - term but affect cell proliferation and cause dna damage .
its mechanism of action and involvement are yet to be elucidated . currently gold nanoparticles ( aunps ) are used in different biomedical applications , such as intracellular gene regulation , chemotherapy and drug delivery , as well as in optical and electronic applications .
a previous study revealed that gold - silica nanoshells release significant heat when exposed to near - infrared ( nir ) light ( 650950 nm ) and have been used to produce thermal cytotoxicity in vitro .
unfortunately , this treatment approach is mechanistically limited to use in superficial malignant tumors because of the minimal tissue penetration ( < 23 cm depth ) by nir wavelength light .
however , the gold - silica nanoshell study demonstrated that nanogold has potential clinical use as a thermal conductor of non - invasive energy sources .
gold , like most metals , is an excellent conductor of electrical and thermal energy .
silver nanoparticles are used as antibacterial / antifungal agents in a diverse range of applications : air sanitizer sprays , socks , pillows , slippers , face masks , wet wipes , detergent , soap , shampoo , toothpaste , air filters , coatings of refrigerators , vacuum cleaners , washing machines , food storage containers , cellular phones , and even in liquid condoms ( peter d , 2009 ) .
ingestion of ag can cause argyria , the benign condition characterized by the bluish - graying of the skin that occurs through the preferential deposition of ag in the basal lamina of soft tissues such as the skin , liver , and spleen and blood vessels , gastrointestinal tract , liver , and kidney ( fig 1 , table 1 ) .
carbon nanotubes ( cnts ; also known as buckytubes ) are allotropes of carbon with a cylindrical nanostructure .
these cylindrical carbon molecules have novel properties that make them potentially useful in many applications in nanotechnology .
determining the toxicity of carbon nanotubes has been one of the most pressing questions in nanotechnology .
unfortunately such research has only just begun and the data are still fragmentary and subject to criticism . under some conditions , nanotubes can cross membrane barriers , which suggest that if raw materials reach the organs they can induce harmful effects such as inflammatory and fibrotic reactions ( jelena k et al . 2007 ) ( fig 1 , table 1 ) .
nanotechnology is a global cross - disciplinary undertaking that has extraordinary potential to change our lives by improving existing products and enabling new ones .
like most new technologies , the emphasis on benefits has been offset by considerable debate about the uses and safety of nanotechnologies .
occupational medicine is replete with examples of respirable dust particle exposures causing disease , and so matters of safety have been focused largely on nanoparticles ( np ) , which represent only one aspect of nanotechnology .
np , generally defined as particles less than 100 nm in any dimension and previously called ultrafine particles by inhalation toxicologists , are a concern because they may enter the body through the lungs , skin , or gut depending on the type of exposure .
several recent papers have highlighted this area of toxicology , its novelty , the gaps in research , and possible testing strategies for np and nanotubes .
there is sufficient ultrafine particle toxicology literature to consider that the large and diverse group of manufactured np arising from nanotechnology comprises an inhalation hazard of unknown potential .
most of the concern has flowed from this perception , enhanced by limited studies indicating that they may also be taken up through the skin or gut .
the notion , for which some limited support exists , that np may gain access to the blood poses a relatively new particle toxicological problem , i.e. , particle effects at sites other than the lungs ( fig 1 , table 1 ) .
this paper examines the toxicology issues relating to carbon nanotubes ( cnt ) , one of the major new np that are set to be produced in bulk for many diverse purposes .
cntare discussed here exclusively as an inhalation hazard . global revenues from cnt in 2006 are estimated at ~ $ 230 million with a growth rate of ~ 170% .
this provides potential for workplace and even eventual general exposure , if there is attrition of materials that contain them .
concern has been raised over the safety of cnt because they have three properties that are clearly associated with pathogenicity in particles .
they are fiber shaped and so might behave like asbestos and other pathogenic fibers which have toxicity associated with their needle - like shape .
titanium dioxide ( tio2 ) particles with diameter larger than 100 nm are considered biologically inert in both humans and animals . based on this understanding ,
titanium dioxide nanoparticles have been widely used in many products , such as white pigment , food colorant , sunscreens , and cosmetic creams . however , adverse effects of tio2 nanoparticles have recently been uncovered .
new research is exploring the potential use of nanostructured tio2 photocatalyst materials for sterilizing equipment of environmental microorganisms in the health care facility .
exposure to nano - titanium dioxide showed dna and chromosome damage to a degree linked to all the big killers of man , namely cancer , heart disease , neurological disease and aging .
warheit and co - workers recently dosed the lungs of rats with 3 sizes of titanium dioxide nanoparticles and suggested that toxicity is not dependent upon particle size or surface area .
a clear conclusion regarding particle size could not be reached as only 3 sizes were tested , of which one was of a different crystal phase , and the two of the same crystal phase ( rutile ) were of different shapes ( rods , ~200 nm 40 nm , and dots , ~10 - 20 nm ) . in a follow up study , these authors tested the pulmonary toxicity of 3 sizes ( hydrodynamic diameter : 136 nm , 149 nm and 382 nm ) of the rutile phase with alumina surface coating , and compared it to 25 nm tio2 particles ( of a different crystal phase ) . in a third study , they examined the toxic potential of 3 samples of different crystal phases , however , the sizes were also different .
et al conducted pulmonary toxicity tests with 20 nm ( 80% anatase ) and 250 nm ( 100% anatase ) titanium dioxide particles and found that the total surface area was a metric that related to neutrophil lung inflammation in rats . no clear trends with regard to the influence of tio2 crystallinity and particle size on biological activity
one major reason was the paucity of different well - characterized tio2 samples ( in terms of size and crystallinity ) that were used , thus precluding the development of convincing conclusions about the function of parameters such as particle size or crystal phase . in 1990 ,
the lipid nanoparticles were invented in the laboratories , the first patent filings took place in 1991 .
the lipid nanoparticles were developed as alternative to traditional carriers such as polymeric nanoparticles and leptosomes .
meanwhile many research groups are active worldwide , their results are reviewed which cover many different administration routes : dermal and mucosal , oral , intravenous / parenteral , pulmonary but also ocular ( fig 1 , table 1 ) .
the lipid nanoparticles are also used for peptide / protein delivery , in gene therapy and various miscellaneous applications ( e.g. vaccines ) .
although lipid nanoparticles represent potent drug carriers , for many formulations toxicity data are rare .
crucial for biological applications quantum dots must be covered with other materials allowing dispersion and preventing leaking of the toxic heavy metals .
polymers such as polysaccharide chitosan nanoparticles have been used for some time now as drug delivery systems .
recently , water - soluble polymer hybrid constructs have been developed . these are polymer
polymer conjugation to proteins reduces immunogenicity , prolongs plasma half - life and enhances protein stability .
drug conjugation promotes tumour targeting through the enhanced permeability and retention effect and , at the cellular level following endocytic capture , allows lysosomotropic drug delivery ( fig 1 , table 1 ) .
the amphilic molecules used for the preparation of these compounds have similarities with biological membranes and have been used for improving the efficacy and safety of different drugs .
usually , liposomes are classified into three categories on the basis of their size and lamellarity ( number of bilayers ) : small unilamellar vesicles or oligolamellar , large unilamellar vesicles and multilamellar vesicles . the active compound can be located either in the aqueous spaces , if it is water - soluble , or in the lipid membrane , if it is lipid - soluble . recently , a new generation of liposomes called
stealth liposomes have the ability to evade the interception by the immune systems , and therefore , have longer half - life .
like nanoorganisms ( viruses ) , nanoparticles are able to enter cells and interact with subcellular structures . cellular uptake , subcellular localization , and ability to catalyze oxidative products depend on nanoparticle chemistry , size , and shape . the mechanism by which nanoparticles penetrate cells without specific receptors on their outer surface is assumed to be a passive uptake or adhesive interaction .
this uptake may be initiated by van der waals forces , electrostatic charges , steric interactions , or interfacial tension effects , and does not result in the formation of vesicles .
( steric interactions occur when nanoparticles have molecules with size , geometries , bonding , and charges optimized for the interaction with the receptors ) . after this type of uptake ,
the nanoparticles are not necessarily located within a phagosome ( which offers some protection to the rest of the cellular organelles from the chemical interaction with the nanoparticle ) .
for example , c60 molecules enter cells and can be found along the nuclear membrane and within the nucleus .
very small nanoparticles , such as c60 molecules with a diameter of 0.7 nm , are able to penetrate cells via a different mechanism than phagocytosis , probably through ion channels or via pores in the cell membrane .
this type of uptake and free movement within the cell makes them very dangerous by having direct access to cytoplasm proteins and organelles .
uptake location is likely to depend on material type ; however , current research does not provide sufficient information to drawing conclusions on this subject . upon nonphagocytic uptake , nano - particles can be found in various locations inside the cell , such as the outer - cell membrane , cytoplasm , mitochondria , lipid vesicles , along the nuclear membrane , or within the nucleus .
depending on their localization inside the cell , the nanoparticles can damage organelles or dna , or ultimately cause cell death .
recent studies have used a composite phenotype ( psychosis ) that includes bpd , scz , psychosis not otherwise specified , and schizoaffective disorder , to identify shared susceptibility loci .
several chromosomal regions are reported to be shared between these syndromes ( 18p , 6q , 10p , 13q , 22q ) .
nanoparticles are internalized not only by professional phagocytes such as alveolar macrophages , but by various types of cells , including endothelial cells , pulmonary epithelium , gastrointestinal epithelium , red blood cells , platelets , and nerve cells ( fig 1 ) .
for example , environmental particles with size between 2.5 and 10 m were found to collect in large cytoplasmic vacuoles , while smaller nanoparticles ( 100 nm ) localize in organelles , such as mitochondria , leading to disruption of mitochondrial architecture .
with very few exceptions , previous nanotoxicity studies implicitly involved the assumption that the techniques developed for risk assessment of hazardous chemical substances can be applied in unchanged form to explore cell response in np laden media .
this misleading approach has the consequence that the actual dose of exposure is ill defined or , more often , completely unknown .
pro - inflammatory cytokines such as interleukin- 6 ( il-6 ) and tumor necrosis factor alpha ( tnf- alpha ) are involved in the formation of toxic peroxynitrite by increasing the activity of nitric oxide synthase ( nos ) enzyme .
nitric oxide ( no ) is potent inflammatory mediator because of its strong reactivity with oxygen , superoxide and iron - containing compounds .
prostaglandins are well known as proinflammatory mediators , and inhibition of cyclooxygenase ( cox ) has long been used in the management of inflammation .
levels of prostaglandin e2 ( pge2 ) are increased in various states of inflammation . unlike larger particles , nanomaterials may be taken up by cell mitochondria and the cell nucleus .
studies demonstrate the potential for nanomaterials to cause dna mutation and induce major structural damage to mitochondria , even resulting in cell death .
the greater chemical reactivity of nanomaterials results in increased production of reactive oxygen species ( ros ) , including free radicals and it is one of the primary mechanisms of nanoparticle toxicity ; it may result in oxidative stress , inflammatory cytokines production and consequent damage to proteins , membranes , dna and cell death .
humanized nps , termed nano - proresolving medicines , are mimetics of endogenous resolving mechanisms , possess potent beneficial bioactions , can reduce nanotoxicity , and offer new therapeutic approaches .
nanotoxicology is an emerging new multidisciplinary field of science , and therefore there is a risk of change in its rapid development in the near future .
therefore , development of novel nanoparticles for pharmacology , therapeutics and diagnostics must proceed in tandem with assessment of any toxicological and environmental side effects of these particles . as the bioenvironment
is already polluted with nanoparticulates of particulate matter caution should be taken to prevent and contain any environmental effects of intentionally generated nanomaterials . in this review
we tried to put our effort to show the toxicity of various nanoparticles , which will be a very valuable reference source to students and investigators in this research field to guide them in their future work .
Output:
| nanotechnology involving manipulation of atoms and molecules at the nanoscale is one of the frontier areas of research in modern science . during the last few years
, nanotechnology has witnessed breakthroughs in the fields of medicine , environment , therapeutics , drug development and biotechnology .
this is due to the unique properties of nanomaterials ( e.g. chemical , mechanical , optical , magnetic , and biological ) which make them desirable for commercial and medical applications .
considering the theory and practice of using nanoparticles , nanotechnology has a great potential in improving treatment of various disorders and in vitro diagnostics . however , there is not much information available on the toxicity of nanoparticles in relation to human health .
toxic effect of nanomaterials on humans is the primary concern of the health industry .
nanomaterials are able to cross biological membranes and access cells , tissues and organs that larger - sized particles normally can not .
nanomaterials can gain access to the blood stream via inhalation or ingestion .
this may lead to both genotoxicity and biochemical toxicity . in this review
we try to show which types , sizes and concentrations of nanoparticles are safe for human use and this will help in developing diagnostic , prognostic and therapeutic models using nanoparticles . |
PubmedSumm118215 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a minority of the 8 million patients who present each year to us emergency departments ( eds ) with chest pain will be diagnosed with acute coronary syndromes ( acs).1 the purpose of the initial evaluation of these patients is to distinguish between those with and those without immediately lifethreatening conditions .
although not yet available in the united states , highsensitivity cardiac troponin ( hsctn ) assays have made it possible to rule out acute myocardial infarction ( mi ) rapidly on ed arrival.2 , 3 , 4 , 5 despite the increased sensitivity of ctn assays , there are still cases of biomarkernegative acs,6 and many patients without acute mi are observed or admitted for stress testing for additional risk stratification after initial exclusion of mi .
for that reason , ctn assays have been combined with the electrocardiogram ( ecg ) and clinical parameters to create accelerated diagnostic protocols ( adps ) that seek to identify patients for whom early discharge without further testing is safe .
one of the most evaluated adps is the rule studied in the 2hour accelerated diagnostic protocol to assess patients with chest pain using contemporary troponins as the only biomarker ( adapt ) trial .
the adapt study showed that patients with a thrombosis in myocardial infarction ( timi ) risk score ( trs ) of 0 , without ischemic ecg changes , and with sensitive ctn assays below the 99th percentile on 2 assessments 2 hours apart were at only a 0.3% risk of 30day major cardiac events.7 the adapt rule identified 20% of patients as low risk and potentially appropriate for ed discharge .
because the adapt study enrolled relatively young patients ( mean age 60 ) with few cardiac risk factors ( trs 1 in 44% of patients ) , it is unclear whether the adapt rule will be effective in older cohorts and/or those with more traditional cardiac risk factors and , if it is , whether it would identify a substantial number of patients at low risk .
thus , we tested a simple risk stratification strategy in a cohort of patients with multiple cardiac risk factors .
we hypothesized that patients older than 65 years and/or with traditional cardiac risk factors would have 30day event rates that were similar to those of patients identified as low risk by adapt if they had conventional ctn levels below the limit of detection ( lod ) of the assay on presentation and 4 to 14 hours later , no clear ischemic changes on ecg at presentation and no history of coronary artery disease ( cad ) .
we used the lod of the assay rather than the 99th percentile ( as used in adapt ) to augment the sensitivity of the ctn component of the rule and to offset the reduction in sensitivity that would come from including as low risk patients with traditional cardiac risk factors and concerning chest pain histories .
as proofofconcept for our risk classification scheme , we retrospectively applied it to our cohort and compared its performance to a modified adapt rule .
we performed a singlecenter , retrospective cohort study to assess operating characteristics of a simple risk stratification strategy that consisted of ( 1 ) no known history of cad , ( 2 ) a nonischemic ecg on presentation , and ( 3 ) ctn levels below the lod of the assay at presentation and 4 to 14 hours later .
the study was performed at the durham veterans affairs medical center ( vamc ) , a 271bed tertiary care hospital in durham , nc , serving 200 000 patients .
the research protocol was approved by the durham vamc institutional review board with a waiver of informed consent and health insurance portability and accountability act of 1996 authorization .
data were abstracted through chart review from 246 consecutive patient care episodes involving 231 individual patients between january 1 , 2012 , and december 31 , 2012 , during which a first ctn sample was drawn in the ed and a second ctn sample was drawn 4 to 14 hours later .
only a patient 's first presentation was included for analysis ; 15 patient care episodes were repeat presentations and were excluded .
the durham vamc uses a siemens dimension vista ctni assay , which has a lower lod of 0.015 ng / ml . the upper limit of normal ( 99th percentile ) is 0.045 ng / ml , and the % cardiovascular at the 99th percentile is 10% .
demographic data , including the presence or absence of cad and data related to the patient 's presenting chest pain episode , were collected through manual chart review from solely the ed documentation , to better approximate the conditions under which this risk stratification scheme would be used .
specific demographic data collected included preexisting cad , age , family history of premature cad , hypertension ( taking antihypertensive medications or having a diagnosis of hypertension ) , hyperlipidemia ( taking a statin or having a diagnosis of hyperlipidemia ) , active tobacco abuse , diabetes mellitus , obesity ( body mass index > 30
variables related to patient presentation included ctni value at presentation and 4 to 14 hours later , ecg at presentation ( scored as clearly ischemic , indeterminate , and normal ) , and chest pain history ( scored as clearly consistent with angina , somewhat consistent with angina , and inconsistent with angina ) .
followup data ( including mi , death , cause of death , percutaneous coronary intervention , coronary artery bypass graft surgery , and stress testing ) were collected at 30 days and 6 months through review of patient notes within the vamc medical record .
the vamc 's computerized records system has > 98% sensitivity for recording death , compared with the national death index.8 for all patients without a 30day event on vamc records , notes from subsequent visits were reviewed to identify any events that were treated at a facility outside the va within 30 days after the index visit .
this was a retrospective analysis of data collected in the context of routine clinical care .
treating physicians were given no guidance regarding care of the patients and no assistance in determining risk of acs .
the prespecified risk classification strategy we investigated consisted of ( 1 ) no known history of cad before presentation , ( 2 ) a nonischemic ecg , and ( 3 ) 2 ctn levels below the lod ( 0.015 ng / ml ) of the assay ( at baseline and at 4 to 14 hours ) . for a patient to be classified as low risk , all 3 criteria had to be negative .
history of cad was defined as prior mi , prior percutaneous intervention or coronary artery bypass graft surgery , or typical symptoms with positive noninvasive testing or invasive imaging for cad ; if none of these findings were documented in the ed provider 's note , the patient was classified as not having known cad .
a nonischemic ecg was defined by the absence of stsegment depression or elevation of 0.5 mv in 2 contiguous leads ; prior ecgs were not reviewed .
the adapt rule was applied to our cohort as described,7 but first and second ctn values were used , regardless of the time they were collected . for use in the adapt algorithm ,
a negative troponin was defined as < 0.05 ng / ml , the 99th percentile for the assay .
in addition to testing these schema , we performed a sensitivity analysis to determine the potential applicability of our risk stratification strategy to an adp .
in the sensitivity analysis , rather than testing a strategy that involved ctn samples drawn at presentation and 4 to 14 hours later , our strategy involved only ( 1 ) no known history of cad before presentation , ( 2 ) a normal ecg , and ( 3 ) presentation ctn level below the lod of the assay .
the primary end point was a composite of major adverse cardiac events that occurred within 30 days of ed presentation .
adverse events included death ( unless there was a clear noncardiac cause ) , any revascularization ( percutaneous coronary intervention or coronary artery bypass graft surgery ) , or acute mi . acute mi was defined consistent with the third universal definition of mi,9 requiring evidence of myocardial necrosis along with clinical evidence of myocardial ischemia .
consistent with the third universal definition of mi , necrosis was defined as 1 ctn value above the 99th percentile ( 0.05 ng / ml ) with evidence of a rising and/or falling pattern ( ctn > 20% ) ; clinical evidence of myocardial ischemia was defined as a typical or atypical chest pain syndrome , potentially ischemic ecg changes ( either on presentation or later ) , evidence of myocardial ischemia on stress testing , hemodynamically significant coronary artery stenosis , or a revascularization procedure .
a true positive stress test was defined as a positive stress test followed by cardiac catheterization revealing significant cad .
all other characteristics were recorded as categorical variables , and the raw percentages of patients with and without the characteristic are reported .
sensitivity , specificity , positive predictive value ( ppv ) , and negative predictive values ( npv ) were also calculated for each test .
sensitivity was calculated by dividing the number of patients with truepositive tests by the total number of patients with a cardiovascular event at 30 days ; specificity was calculated by dividing the number of patients with truenegative tests by the total number of patients without a cardiovascular event at 30 days .
npv was calculated by dividing the number of patients with truenegative tests from the total number of patients identified as low risk ; ppv was calculated by dividing the number of patients with truepositive tests from the total number of patients identified as high risk .
the cis for diagnostic test performance indices were calculated by using the exact method.10 the comparison of risk classification by adapt versus our new classification strategy in those who received a cardiac testing procedure was performed by using fisher 's exact test .
we performed a singlecenter , retrospective cohort study to assess operating characteristics of a simple risk stratification strategy that consisted of ( 1 ) no known history of cad , ( 2 ) a nonischemic ecg on presentation , and ( 3 ) ctn levels below the lod of the assay at presentation and 4 to 14 hours later .
the study was performed at the durham veterans affairs medical center ( vamc ) , a 271bed tertiary care hospital in durham , nc , serving 200 000 patients .
the research protocol was approved by the durham vamc institutional review board with a waiver of informed consent and health insurance portability and accountability act of 1996 authorization .
data were abstracted through chart review from 246 consecutive patient care episodes involving 231 individual patients between january 1 , 2012 , and december 31 , 2012 , during which a first ctn sample was drawn in the ed and a second ctn sample was drawn 4 to 14 hours later .
only a patient 's first presentation was included for analysis ; 15 patient care episodes were repeat presentations and were excluded .
the durham vamc uses a siemens dimension vista ctni assay , which has a lower lod of 0.015 ng / ml . the upper limit of normal ( 99th percentile ) is 0.045 ng / ml , and the % cardiovascular at the 99th percentile is 10% .
demographic data , including the presence or absence of cad and data related to the patient 's presenting chest pain episode , were collected through manual chart review from solely the ed documentation , to better approximate the conditions under which this risk stratification scheme would be used .
specific demographic data collected included preexisting cad , age , family history of premature cad , hypertension ( taking antihypertensive medications or having a diagnosis of hypertension ) , hyperlipidemia ( taking a statin or having a diagnosis of hyperlipidemia ) , active tobacco abuse , diabetes mellitus , obesity ( body mass index > 30 kg / m ) , and current aspirin use .
variables related to patient presentation included ctni value at presentation and 4 to 14 hours later , ecg at presentation ( scored as clearly ischemic , indeterminate , and normal ) , and chest pain history ( scored as clearly consistent with angina , somewhat consistent with angina , and inconsistent with angina ) .
followup data ( including mi , death , cause of death , percutaneous coronary intervention , coronary artery bypass graft surgery , and stress testing ) were collected at 30 days and 6 months through review of patient notes within the vamc medical record .
the vamc 's computerized records system has > 98% sensitivity for recording death , compared with the national death index.8 for all patients without a 30day event on vamc records , notes from subsequent visits were reviewed to identify any events that were treated at a facility outside the va within 30 days after the index visit .
this was a retrospective analysis of data collected in the context of routine clinical care .
treating physicians were given no guidance regarding care of the patients and no assistance in determining risk of acs .
the prespecified risk classification strategy we investigated consisted of ( 1 ) no known history of cad before presentation , ( 2 ) a nonischemic ecg , and ( 3 ) 2 ctn levels below the lod ( 0.015 ng / ml ) of the assay ( at baseline and at 4 to 14 hours ) . for a patient
history of cad was defined as prior mi , prior percutaneous intervention or coronary artery bypass graft surgery , or typical symptoms with positive noninvasive testing or invasive imaging for cad ; if none of these findings were documented in the ed provider 's note , the patient was classified as not having known cad .
a nonischemic ecg was defined by the absence of stsegment depression or elevation of 0.5 mv in 2 contiguous leads ; prior ecgs were not reviewed .
the adapt rule was applied to our cohort as described,7 but first and second ctn values were used , regardless of the time they were collected . for use in the adapt algorithm ,
a negative troponin was defined as < 0.05 ng / ml , the 99th percentile for the assay .
in addition to testing these schema , we performed a sensitivity analysis to determine the potential applicability of our risk stratification strategy to an adp . in the sensitivity analysis ,
rather than testing a strategy that involved ctn samples drawn at presentation and 4 to 14 hours later , our strategy involved only ( 1 ) no known history of cad before presentation , ( 2 ) a normal ecg , and ( 3 ) presentation ctn level below the lod of the assay .
the primary end point was a composite of major adverse cardiac events that occurred within 30 days of ed presentation .
adverse events included death ( unless there was a clear noncardiac cause ) , any revascularization ( percutaneous coronary intervention or coronary artery bypass graft surgery ) , or acute mi .
acute mi was defined consistent with the third universal definition of mi,9 requiring evidence of myocardial necrosis along with clinical evidence of myocardial ischemia .
consistent with the third universal definition of mi , necrosis was defined as 1 ctn value above the 99th percentile ( 0.05 ng / ml ) with evidence of a rising and/or falling pattern ( ctn > 20% ) ; clinical evidence of myocardial ischemia was defined as a typical or atypical chest pain syndrome , potentially ischemic ecg changes ( either on presentation or later ) , evidence of myocardial ischemia on stress testing , hemodynamically significant coronary artery stenosis , or a revascularization procedure .
a true positive stress test was defined as a positive stress test followed by cardiac catheterization revealing significant cad .
all other characteristics were recorded as categorical variables , and the raw percentages of patients with and without the characteristic are reported .
sensitivity , specificity , positive predictive value ( ppv ) , and negative predictive values ( npv ) were also calculated for each test .
sensitivity was calculated by dividing the number of patients with truepositive tests by the total number of patients with a cardiovascular event at 30 days ; specificity was calculated by dividing the number of patients with truenegative tests by the total number of patients without a cardiovascular event at 30 days .
npv was calculated by dividing the number of patients with truenegative tests from the total number of patients identified as low risk ; ppv was calculated by dividing the number of patients with truepositive tests from the total number of patients identified as high risk .
the cis for diagnostic test performance indices were calculated by using the exact method.10 the comparison of risk classification by adapt versus our new classification strategy in those who received a cardiac testing procedure was performed by using fisher 's exact test .
they had high rates of preexisting cardiovascular risk factors , and 52% had known cad at the time of ed presentation ( table 1 ) .
baseline characteristics of the cohort by low and high risk of cardiovascular disease bmi indicates body mass index ; cad , coronary artery disease ; ctn , cardiac troponin ; lod , limit of detection .
low risk is defined as ( 1 ) no known history of cad , ( 2 ) a nonischemic ecg on presentation , and ( 3 ) ctn levels below the lod of the assay at presentation and 4 to 14 hours later .
high risk is defined as either ( 1 ) known history of cad , ( 2 ) ischemic ecg on presentation , or ( 3 ) ctn level above the lod of the assay either at presentation or 414 hours later .
consistent with their advanced age and cardiovascular risk factors , the patients tended to have high trs ; only 10% ( n=23 ) had trs of 0 , and 25% ( n=58 ) had trs 1 ( figure 1 ) .
median timi risk score in the cohort was 3 ; 25% of patients had a timi risk score of 0 or 1 .
shown is percentage of patients at each trs strata ; error bars represent 95% ci .
a total of 47 ( 20% ) patients had a cardiovascular event in the 30 days after their ed visit ; 18 events were revascularization alone , 13 were mi alone , 9 were both , 2 were fatal mis , and 5 were other cardiovascular deaths .
the adapt rule ( modified to incorporate ctni on presentation and at 4 to 14 hours , rather than on presentation and at 2 hours ) identified 7.8% ( n=18 ) of patients as low risk , and our classification strategy ( no cad , a nonischemic ecg , and 2 ctni determinations below lod ) identified 22.9% ( n=53 ) of patients as low risk .
table 2 describes the performance of our expanded classification strategy and the modified adapt rule for predicting 30day events in our cohort .
of the 47 patients who developed a cardiovascular event , 46 ( sensitivity 98% , 95% ci 89% to 100% ) were correctly identified as high risk based on our classification scheme .
further , the classification scheme identified 53 patients as low risk , of whom 52 did not have an adverse cardiac event within 30 days ( npv 98% , 95% ci 90% to 100% ) .
the specificity was poor , with 132 ( 72% ) of the 184 patients without an event being labeled as high risk .
the modified adapt rule correctly identified all 47 patients who developed acs as high risk ( sensitivity 100% ) but identified only 18 patients as low risk , of whom none had an event ( npv 100% ) .
as with the expanded classification strategy , the specificity for adapt was poor , with 166 ( 90% ) of 184 eventfree patients being labeled as high risk .
our classification strategy concurred on 15 of the 18 patients adapt identified as low risk .
we identified an additional 38 patients as being low risk , of whom 1 patient experienced a revascularization procedure within 30 days of hospital admission .
comparison of a new classification strategy with troponins at 2 time points versus the adapt score adapt indicate 2hour accelerated diagnostic protocol to assess patients with chest pain using contemporary troponins as the only biomarker.the ideal score would identify all patients without an event as low risk and all patients with an event as high risk .
ctni indicates cardiac troponin i. identify the number of patients where the comparator score correctly identified patients but the new score did not .
identify the number of patients where the new risk score appropriately identified patients and the comparator did not . to examine the clinical relevance of our classification strategy
, we determined how many procedures might have been avoided in our cohort had all patients identified as low risk been discharged without further testing .
we found that many of the patients identified as low risk by our strategy ( 24/53 , 45% ) underwent stress testing or cardiac catheterization during the index hospitalization .
had every patient identified as low risk by our rule been discharged before further testing , 27% ( 24/89 ) of stress tests and left heart catheterizations performed in our cohort would not have been performed ( 9 patients underwent both stress testing and catheterization ) .
one patient identified by our strategy as low risk had a truepositive stress test and subsequently underwent revascularization ; no other patient had a truepositive stress test or left heart catheterization demonstrating significant cad .
no patient identified as low risk by our strategy had a positive stress test without further evaluation by cardiac catheterization . discharging all patients identified as low risk by adapt
would have prevented 4 ( 4.5% ) of the cardiac testing procedures , fewer than by using the new strategy ( p<0.0004 compared with our strategy by fisher 's exact test ) ( figure 2 ) .
universal application of the new risk assessment rule would have prevented 24 cardiac procedures had all patients identified as low risk been discharged prior to further testing , significantly more than would have been avoided by universal application of the adapt rule .
adapt indicate 2hour accelerated diagnostic protocol to assess patients with chest pain using contemporary troponins as the only biomarker . to determine whether our risk stratification strategy may have applicability as an adp , we performed a sensitivity analysis , adjusting our risk classification strategy to include only a single ctn level at presentation below the lod of the assay , along with no known history of cad prior to presentation and a nonischemic ecg .
this adjusted risk stratification strategy identified 25.5% ( n=59 ) of patients as low risk ( table 3 ) .
similar to the original risk stratification strategy , of the 47 patients who developed a cardiovascular event within 30 days , the adjusted strategy identified as high risk 46 patients ( sensitivity 98% , 95% ci 89% to 100% ) ; of the 59 lowrisk patients , 58 did not have an adverse cardiac event within 30 days ( npv 98% , 95% ci 91% to 100% ) . adjusting the adapt rule to include only troponin at presentation identified 14.3% ( n=33 ) of patients as low risk ; of these 33 lowrisk patients , 32
did not have an adverse cardiac event within 30 days ( npv 97% , 95% ci 84% to 100% ) .
comparison of the new classification strategy with troponins at 2 time points versus the new classification strategy with troponins at baseline only the ideal score would identify all patients without an event as low risk and all patients with an event as high risk .
ctni indicates cardiac troponin i. identify the number of patients where the new score using baseline ctni only correctly identified patients but the new score using 2 ctni measurements did not .
identify the number of patients where the new risk score using 2 ctni measurements correctly identified patients but the new risk score using baseline ctni only did not .
they had high rates of preexisting cardiovascular risk factors , and 52% had known cad at the time of ed presentation ( table 1 ) .
baseline characteristics of the cohort by low and high risk of cardiovascular disease bmi indicates body mass index ; cad , coronary artery disease ; ctn , cardiac troponin ; lod , limit of detection .
low risk is defined as ( 1 ) no known history of cad , ( 2 ) a nonischemic ecg on presentation , and ( 3 ) ctn levels below the lod of the assay at presentation and 4 to 14 hours later .
high risk is defined as either ( 1 ) known history of cad , ( 2 ) ischemic ecg on presentation , or ( 3 ) ctn level above the lod of the assay either at presentation or 414 hours later .
consistent with their advanced age and cardiovascular risk factors , the patients tended to have high trs ; only 10% ( n=23 ) had trs of 0 , and 25% ( n=58 ) had trs 1 ( figure 1 ) .
median timi risk score in the cohort was 3 ; 25% of patients had a timi risk score of 0 or 1 .
shown is percentage of patients at each trs strata ; error bars represent 95% ci .
a total of 47 ( 20% ) patients had a cardiovascular event in the 30 days after their ed visit ; 18 events were revascularization alone , 13 were mi alone , 9 were both , 2 were fatal mis , and 5 were other cardiovascular deaths .
the adapt rule ( modified to incorporate ctni on presentation and at 4 to 14 hours , rather than on presentation and at 2 hours ) identified 7.8% ( n=18 ) of patients as low risk , and our classification strategy ( no cad , a nonischemic ecg , and 2 ctni determinations below lod ) identified 22.9% ( n=53 ) of patients as low risk .
table 2 describes the performance of our expanded classification strategy and the modified adapt rule for predicting 30day events in our cohort . of the 47 patients who developed a cardiovascular event , 46 ( sensitivity 98% , 95% ci 89% to 100% )
further , the classification scheme identified 53 patients as low risk , of whom 52 did not have an adverse cardiac event within 30 days ( npv 98% , 95% ci 90% to 100% ) .
the specificity was poor , with 132 ( 72% ) of the 184 patients without an event being labeled as high risk .
the modified adapt rule correctly identified all 47 patients who developed acs as high risk ( sensitivity 100% ) but identified only 18 patients as low risk , of whom none had an event ( npv 100% ) .
as with the expanded classification strategy , the specificity for adapt was poor , with 166 ( 90% ) of 184 eventfree patients being labeled as high risk .
our classification strategy concurred on 15 of the 18 patients adapt identified as low risk .
we identified an additional 38 patients as being low risk , of whom 1 patient experienced a revascularization procedure within 30 days of hospital admission .
comparison of a new classification strategy with troponins at 2 time points versus the adapt score adapt indicate 2hour accelerated diagnostic protocol to assess patients with chest pain using contemporary troponins as the only biomarker.the ideal score would identify all patients without an event as low risk and all patients with an event as high risk .
ctni indicates cardiac troponin i. identify the number of patients where the comparator score correctly identified patients but the new score did not .
identify the number of patients where the new risk score appropriately identified patients and the comparator did not .
to examine the clinical relevance of our classification strategy , we determined how many procedures might have been avoided in our cohort had all patients identified as low risk been discharged without further testing .
we found that many of the patients identified as low risk by our strategy ( 24/53 , 45% ) underwent stress testing or cardiac catheterization during the index hospitalization .
had every patient identified as low risk by our rule been discharged before further testing , 27% ( 24/89 ) of stress tests and left heart catheterizations performed in our cohort would not have been performed ( 9 patients underwent both stress testing and catheterization ) .
one patient identified by our strategy as low risk had a truepositive stress test and subsequently underwent revascularization ; no other patient had a truepositive stress test or left heart catheterization demonstrating significant cad .
no patient identified as low risk by our strategy had a positive stress test without further evaluation by cardiac catheterization . discharging all patients identified as low risk by adapt
would have prevented 4 ( 4.5% ) of the cardiac testing procedures , fewer than by using the new strategy ( p<0.0004 compared with our strategy by fisher 's exact test ) ( figure 2 ) .
universal application of the new risk assessment rule would have prevented 24 cardiac procedures had all patients identified as low risk been discharged prior to further testing , significantly more than would have been avoided by universal application of the adapt rule .
adapt indicate 2hour accelerated diagnostic protocol to assess patients with chest pain using contemporary troponins as the only biomarker .
to determine whether our risk stratification strategy may have applicability as an adp , we performed a sensitivity analysis , adjusting our risk classification strategy to include only a single ctn level at presentation below the lod of the assay , along with no known history of cad prior to presentation and a nonischemic ecg . this adjusted risk stratification strategy identified 25.5% ( n=59 ) of patients as low risk ( table 3 ) .
similar to the original risk stratification strategy , of the 47 patients who developed a cardiovascular event within 30 days , the adjusted strategy identified as high risk 46 patients ( sensitivity 98% , 95% ci 89% to 100% ) ; of the 59 lowrisk patients , 58 did not have an adverse cardiac event within 30 days ( npv 98% , 95% ci 91% to 100% ) . adjusting the adapt rule to include only troponin at presentation identified 14.3% ( n=33 ) of patients as low risk ; of these 33 lowrisk patients , 32 did not have an adverse cardiac event within 30 days ( npv 97% , 95% ci 84% to 100% ) .
comparison of the new classification strategy with troponins at 2 time points versus the new classification strategy with troponins at baseline only the ideal score would identify all patients without an event as low risk and all patients with an event as high risk .
ctni indicates cardiac troponin i. identify the number of patients where the new score using baseline ctni only correctly identified patients but the new score using 2 ctni measurements did not .
identify the number of patients where the new risk score using 2 ctni measurements correctly identified patients but the new risk score using baseline ctni only did not .
in this retrospective cohort study performed in an older population ( mean age > 65 ) with multiple cardiac risk factors presenting to the ed with concern for acs , we found that a simple risk classification strategy that incorporated a ctn value below the lod at baseline and after 4 to 14 hours , ecg without ischemic changes , and no history of cad identified a substantial percentage ( 22.9% ) of patients at low risk for 30day cardiac events with high sensitivity and npv . applying this strategy to a patient population with a lower preexisting rate of cad
would likely enable even more patients to be categorized as low risk with similar sensitivity .
those patients identified as low risk by our study are potentially appropriate for discharge from the ed without admission for additional testing ; in our population , more than onefourth of all cardiac procedures performed potentially could have been avoided .
application of this strategy could have a substantial impact on health services utilization by decreasing the need for inpatient procedures . whether any risk stratification tool is sufficiently sensitive to be used in clinical practice
ed physicians display significant variability in their tolerance for missed diagnoses of acs , although a majority prefer a miss rate 1%.11 however , a miss rate this low may not be feasible in clinical practice : in a large , multicenter cohort of patients with acute chest pain receiving standard ed care , the miss rate for acs was 2.1%.12 there was no significant difference in unadjusted or adjusted mortality between patients with a missed diagnosis of mi or unstable angina and those correctly diagnosed ( adjusted risk ratio 1.9 , 95% ci 0.7 to 5.2 for mi ; adjusted risk ratio 1.7 , 95% ci 0.2 to 52 for unstable angina ) , although the point estimates suggested a signal toward higher mortality in those with a missed diagnosis and the 95% cis were wide.12 though there is potential harm associated with a missed diagnosis of acs and failure to institute prompt treatment , individual providers must balance this risk with the risks of overdiagnosis and further testing .
compared with a modified version of adapt , a highsensitivity rule validated in a population with fewer traditional cardiac risk factors and higher percentage of patients with low timi risk scores,7 our new rule identified a larger percentage of patients in our cohort as low risk with similar sensitivity and npv .
our rule differs from adapt and similar risk prediction rules in its elimination of cardiac risk factors and chest pain history from consideration in favor of an increased focus on ctn and ecg .
the sensitivity our strategy sacrifices in comparison to other risk classification schemes by enabling patients with cardiovascular risk factors and concerning chest pain histories to be categorized as low risk is offset by the increased sensitivity conferred by its more stringent limit on ctn values . using a lower cutoff for
a positive test may also allow earlypresenting patients with evolving mis to be appropriately characterized as high risk , even before ctn values rise above the 99th percentile .
further , among stable patients without cad , hsctn values increase in conjunction with an increasing burden of several cardiovascular risk factors,13 raising the possibility that setting a lower troponin threshold helps eliminate patients with these risk factors . as hsctn assays become widely available in clinical practice , the cutoffs chosen for a positive test will have important implications on test performance .
the performance of cardiac risk factors and chest pain history in diagnosing acs is limited in comparison to ctn and ecg,14 and these findings further reinforce their limitation .
in addition to enabling more patients to be classified as low risk , elimination of these variables from our rule allows a simplified stratification scheme that is easy to apply .
first , performance of the study at a single center with a single ctn assay may limit the broader applicability of our risk classification scheme .
however , despite coming from a single institution , our cohort was treated by a broad and varied group of physicians with different approaches to the management of patients presenting with concern for acs .
the ed is staffed by a combination of trained ed physicians , internists , and moonlighting subspecialty fellows .
the internal medicine service to which patients with chest pain are admitted is staffed by nearly 100 residents and interns supervised either by 1 of 10 hospitalists or by one of a number of internists with subspecialty training in fields such as infectious diseases or rheumatology .
second , our study population was 95% male and composed entirely of veterans , many of whom have a high burden of cardiac risk factors .
this population was chosen deliberately , as it is one that is not wellrepresented in studies of existing risk prediction tools that identify a large number of patients at low risk for coronary events in populations with a standard burden of cardiac risk factors .
still , before this risk classification scheme could be applied to women , a generally lowerrisk population , or a population at another center that uses a different ctn assay , it would need to be tested more broadly .
third , the study does not test an adp , as the second ctn test was drawn between 4 and 14 hours after patient presentation .
however , given the ability of modern ctn assays to detect lowlevel elevations in ctn , it is likely that collecting a second ctn sample 2 hours after presentation would not change the results , though this would need to be confirmed prospectively . indeed , in a sensitivity analysis , changing our classification strategy to require only a single ctn value at presentation below the lod of the assay ( an approach that would theoretically allow for acs to be ruled out immediately on ed arrival )
had no effect on sensitivity or negative predictive value and enabled 25% of patients to be characterized as low risk .
this suggests that an adp based on our risk classification scheme , with patients defined as low risk if they have no prior cad , a nonischemic ecg , and 2 ctn values below the lod of the assay at baseline and 2 hours after presentation , may have adequate sensitivity to rule out acs in a considerable cohort of patients with a high burden of cardiac risk factors .
last , the retrospective design could be problematic in a diagnostic study , as the information our risk assessment protocol used to determine risk was also available to the clinicians making care decisions . though the simplicity and availability of the elements of our rule allow for easy application in clinical practice , this simplicity and availability also may have allowed physicians treating the patients included in the study to intuitively assess the patients risk and avoid testing in lowrisk patients . patients
identified as low risk based on our rule may have been less likely to undergo stress testing or cardiac catheterization than were patients not identified as low risk ; thus , the ability to detect acs in these patients may have been reduced .
this is an unavoidable consequence of the design of our study , in which physicians treated patients according to their best clinical judgment and had access to the same clinical variables as were included in our risk prediction scheme .
moreover , without standardized troponin collection times , the adapt rule could not be applied to our cohort exactly as it was applied in its derivation study . for all of these reasons , our results
should be considered hypothesis generating and will need confirmation in prospective studies in which patients are treated according to a specific protocol , rather than according to their physician 's best clinical judgment .
this retrospective cohort study demonstrated that a predictive rule categorizing as low risk patients with no prior cad , a nonischemic ecg , and 2 ctn values below the lod of the assay identifies 23% of patients as low risk for 30day cardiac events and potentially appropriate for early ed discharge with > 98% npv .
if confirmed by prospective studies , this new risk assessment strategy could substantially reduce the number of stress tests performed , and an adp based on this strategy could potentially identify patients for early ed discharge , reducing ed lengths of stay and costs related to caring for patients with acute chest pain .
dr fanaroff was supported by a facultyresident research grant from the duke university department of medicine .
Output:
| backgroundit is unclear whether diagnostic protocols based on cardiac markers to identify lowrisk chest pain patients suitable for early release from the emergency department can be applied to patients older than 65 years or with traditional cardiac risk factors.methods and resultsin a singlecenter retrospective study of 231 consecutive patients with highrisk factor burden in which a first cardiac troponin ( ctn ) level was measured in the emergency department and a second ctn sample was drawn 4 to 14 hours later , we compared the performance of a modified 2hour accelerated diagnostic protocol to assess patients with chest pain using contemporary troponins as the only biomarker ( adapt ) rule to a new risk classification scheme that identifies patients as low risk if they have no known coronary artery disease , a nonischemic electrocardiogram , and 2 ctn levels below the assay 's limit of detection .
demographic and outcome data were abstracted through chart review .
the median age of our population was 64 years , and 75% had thrombosis in myocardial infarction risk score 2 . using our risk classification rule , 53 ( 23% ) patients were low risk with a negative predictive value for 30day cardiac events of 98% .
applying a modified adapt rule to our cohort , 18 ( 8% ) patients were identified as low risk with a negative predictive value of 100% . in a sensitivity analysis ,
the negative predictive value of our risk algorithm did not change when we relied only on undetectable baseline ctn and eliminated the second ctn assessment.conclusionsif confirmed in prospective studies , this lessrestrictive risk classification strategy could be used to safely identify chest pain patients with more traditional cardiac risk factors for early emergency department release . |
PubmedSumm118216 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a 77-year - old female with acute renal failure was transferred to our emergency department from an outside clinic . the patient had diabetes mellitus and had been on oral hypoglycemic agents .
three weeks before transfer to our hospital , tka of the left knee was performed under spinal anesthesia and 10 days before transfer , tka of the right knee was performed under spinal anesthesia . during the left knee tka ,
the patient had a huge blood loss and 4 pints of packed red blood cells ( prbcs ) were transfused .
after surgery , the patient 's hemoglobin ( hb ) levels continued to fall , and thus 5 pints of prbcs were transfused ( 2 pints , on the day of surgery ; 1 pint , one day after surgery ; and 2 pints , 1 week after surgery ) . at the time of the right knee tka
the patient 's postoperative hb level continued to fall gradually and 2 pints of prbcs were additionally transfused on the postoperative day 2 .
six days after the right knee tka , the volume of urine was decreased to less than 500 ml per day .
laboratory findings showed acute renal failure [ blood urea nitrogen ( bun ) , 35 mg / dl ( range , 6 to 22 mg / dl ) ; serum creatinine , 2.4 mg / dl ( range , 0.6 to 0.9 mg / dl ) ] , resulting in the transfer of the patient to our hospital .
after arrival in our emergency department , we conducted the same laboratory tests and confirmed that the patient was still in renal failure ( bun , 35 mg / dl ; serum creatinine , 2.2 mg / dl ) with a serum hb level of 7.9 g / dl ( range , 12 to 16 g / dl ) .
rhabdomyolysis was also diagnosed : myoglobin , 372.8 iu / l ( range , 11.1 to 57.5 iu / l ) ; creatine kinase , 1059 iu / l ( range , 35 to 215 iu / l ) ; and lactate dehydrogenase , 1375 iu / l ( range , 233 to 497 iu / l ) .
in addition , coagulation tests revealed a prothrombin time of 29.1 seconds ( range , 11.2 to 14.3 sec ) , an activated partial thromboplastin time of 47.6 seconds ( range , 29 to 43 sec ) , an international normalized ratio of 2.96 ( range , 0.84 to 1.16 sec ) , and a serum fibrinogen degradation products concentration of 82.5 g / ml ( range , 70 to 110 g / ml ) .
clinical examination of the right knee revealed that the operation wound had not yet healed .
the wound was erythematous and slightly warm , but it was not severe and other clinical findings were not consistent with surgical site infection such as pus discharge . compared to the left lower extremity , the right lower limb was more edematous with pitting edema ( fig .
severe pain evoked by passive stretching of toes was complained . below the right knee , the sensation was decreased to less than 50% of normal , and this paresthesia was not confined to a specific dermatome .
. the muscle power was grade zero for dorsiflexion and plantar flexion of the ankle and big toe .
color doppler ultrasonography did not show any abnormalities of the posterior tibial artery or dorsalis pedis artery .
the patient stated that when she recovered from spinal anesthesia on the operation day , severe pain was felt in the right foot with entire paresthesia below the right knee , and paralysis of the right ankle and foot developed .
an interview with the primary care doctor of the referring hospital revealed that he had known about the paresthesia and paralysis , but had judged these findings had been caused by postoperative peroneal nerve palsy .
therefore , he only performed symptomatic treatment , including the use of analgesics , for severe pain . in consideration of the clinical findings , such as severe pain and edema of the right lower limb , paralysis and paresthesia not confined to specific neurological areas , and laboratory findings indicating rhabdomyolysis , we suspected compartment syndrome of the right lower extremity following tka .
initially , we suspected a vascular injury and performed three - dimensional angiographic computerized tomography ( ct ) .
however , no vascular injuries or stenosis of the right lower limb were observed ; massive hematomas were observed in the vastus intermedius above the right knee joint , suprapatellar pouch and anterior and posterior compartments of the calf ( fig .
, we speculated that hematomas occurred after tka because of persistent bleeding and , as a result , caused compartment syndrome of the right lower limb .
to decompress the involved compartment and to remove necrotic tissue , we performed fasciotomy of the right lower extremity
. fasciotomy was performed on the anterior , lateral , and posterior compartments of the calf through two anterolateral and posteromedial incisions . during surgery
in particular , the hematoma of the posterior compartment extruded as soon as the fascial incision was made , indicating very high pressure in the posterior compartment ( fig .
3 ) . based on the color , consistency , contractility , and bleeding capacity of the posterior compartmental muscles
in contrast , the viability of the anterior compartmental muscles was relatively good compared to that of the posterior compartmental muscles .
we removed all hematomas from the anterior and posterior compartments of the calf and debrided the necrotic muscles .
following fasciotomy , we opened the wound of the prior operation and found a massive hematoma in the vastus intermedius and knee joint ( fig . 5 ) .
we also observed extensive dissection of the periosteum and surrounding soft tissues of the distal femur at the operation site .
we removed hematomas from the vastus intermedius and suprapatellar pouch of the knee joint cavity and performed massive irrigation of the entire operation site to prevent infection . and
the wound of the prior arthroplasty was securely sutured again . to maintain the decompression of compartmental pressure , the surgical wound of the calf was approximated with minimal tension for easy wound care ( fig .
pain in the ankle and foot disappeared immediately after surgery , and acute renal failure caused by myoglobinuria due to rhabdomyolysis improved within a week .
however , distal sensory and motor ability of the right lower extremity did not recover immediately .
we continued to administer antibiotics and sterilize the operation wound . at 3 weeks after surgery
, the operation wound had improved so we debrided the remaining necrotic tissue and closed the fasciotomy wound .
currently , 2 years after fasciotomy , the patient can walk with mild difficulty in ankle motion , though a severe injury of the common peroneal nerve and tibial nerve was confirmed by electromyography and nerve conduction velocity .
compartment syndrome after tka is extremely rare1,4,6 ) . it can occur in the calf and/or thigh compartments remote from tka sites : the blood from bones and soft tissue usually collects in the joint cavity or is drained outside through a drainage tube1,4,6,7 ) .
although the incidence of compartment syndrome after tka is very low , certain risk factors have been identified .
these risk factors include bleeding due to extensive soft tissue dissection and hematoma formation , postoperative venous insufficiency through thrombus or direct major vessel injury , iatrogenic coagulopathy resulting from an anticoagulant administration , unnecessarily high tourniquet pressure , a history of previous compartment syndrome , or previous surgery in the same leg1,4,5,8 ) . in our case ,
even though there was severe pain with neurological symptoms in the lower extremity that underwent surgery , these symptoms were mistaken for peroneal nerve palsy . as a result
, only symptomatic treatment was performed to control pain , and excessive analgesic administration made it difficult to diagnose compartment syndrome .
after transfer to our hospital , three - dimensional enhanced ct angiography did not show findings consistent with direct damage of the blood vessels .
however , the hb level of the patient decreased continuously after arthroplasties , indicating that blood vessel damage could not be completely ruled out .
in addition , after the left knee tka , massive blood transfusion was performed due to persistent bleeding before the right knee tka .
this may have resulted in postoperative consumptive coagulopathy in combination with other risk factors such as surgery . considering that an anti - thrombotic agent was not used after tkas , delayed blood clotting may have caused continuous bleeding and then compartment syndrome .
in addition , at the time of fasciotomy , we observed extensive dissection of the periosteum and surrounding soft tissue of the distal femur and suspected an extensive soft tissue injury .
if compartment syndrome is diagnosed in the lower extremities , surgical treatment to reduce the pressure of the involved compartment , such as fasciotomy , should be performed urgently .
generally , it has been known that fasciotomy within 6 to 8 hours after the onset of symptoms could result in a good prognosis2,3,4,5 ) .
little or no return of function can be expected if diagnosis and treatment are delayed3 ) . because of the possibility of severe infection of the necrotic soft tissue through the operation wound , fasciotomy is generally contraindicated 8 to 35 hours after the onset of symptoms2,3,5 ) .
if fasciotomy is not feasible , treatments that complement lost functions are recommended5 ) : use of an ankle brace , tendon transfer , and/or arthrodesis of the ankle joint may be considered as late treatment options . however ,
if there are medical complications related to compartment syndrome , for example , myoglobinuria due to rhabdomyolysis , late fasciotomy to debride necrotic tissue and salvage the compartment may be efficacious5,10 ) .
williams et al . demonstrated that late fasciotomy performed 36 hours after symptom onset could result in limb salvage with good functional outcome in spite of increased infection rates10 ) .
our patient had rhabdomyolysis and myoglobinuria due to the occurrence of compartment syndrome , which led to acute renal failure .
therefore , we performed late fasciotomy one week after symptom onset to relieve the medically compromised status .
after the surgery , laboratory and clinical features of rhabdomyolysis and acute renal failure were markedly improved .
this was because we performed fasciotomy rapidly after transfer of the patient to our hospital : considering the patient 's clinical symptoms , hematologic findings , and ct findings showing massive hematomas , compartment syndrome of the right lower leg , a condition that requires rapid surgical treatment , was strongly suspected .
surgical findings such as extrusion of the hematoma and muscle necrosis of the involved compartment supported our diagnosis .
second , we relied more on the medical records of the other hospital and interviews with the doctors that previously treated the patient than on direct observation to determine the patient 's clinical symptoms after the right knee tka . in summary ,
compartment syndrome after tka , albeit very rare , can significantly affect the prognosis of the patient .
therefore , it is important to be aware of the associated risk factors to prevent this potential complication , and , if it occurs , to ensure early diagnosis and prompt treatment to decompress the involved compartment and resolve the causative factor(s ) .
if compartment syndrome is accompanied by medical problems such myoglobinuria due to rhabdomyolysis and acute renal failure , late fasciotomy with debridement of necrotic tissue should be considered as a treatment option , regardless of the time elapsed since the onset of symptoms .
Output:
| compartment syndrome after total knee arthroplasty ( tka ) is a rare complication . because of its rarity
, it may be overlooked and misdiagnosed as peroneal nerve palsy or deep vein thrombosis .
this misdiagnosis could have a profound impact on the patient 's outcome .
we report a case of a 77-year - old female who developed unilateral compartment syndrome in the calf after staged bilateral tka at an outside clinic .
the patient presented with medical complications related to compartment syndrome : rhabdomyolysis and myoglobinuria , which caused acute renal failure .
thus , we performed late fasciotomy one week after symptom onset to debride necrotic tissue and salvage the compartment . in the discussion section , we will discuss risk factors for compartment syndrome after tka , results of late fasciotomy and other indications for surgical treatment of compartment syndrome . |
PubmedSumm118217 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: approximately 70% will undergo operative management and of those , about 40% will experience relapse .
presented is a case study of a patient with over 17 years long - term survival of multiply recurrent metastatic colon carcinoma . in these 17 years
, the patient has undergone four operations for tumor recurrence without any other adjuvant therapy besides the chemoradiation therapy completed after the time of initial diagnosis , with the latest recurrence being to the myocardium . in this case report
, we wish to emphasize the integral role of surgery for recurrent disease and the unusual nature of the cardiac recurrence , and explore the implications and limitations of these multiple surgical interventions .
in 1992 , a 60-year - old white female presented with hematochezia and change in bowel habits .
the patient underwent adjuvant therapy with 5-fluorouracil , levamisole and radiation therapy , completing therapy in 1993 . in july 1995 , a ct scan for persistently elevated cea demonstrated a lesion in the left lobe of her liver .
mri confirmed the left lobe lesion and was suspicious for a right lobe lesion as well .
an office visit physical exam revealed a palpable mass in her old incision site from the midepigastric region to the edge of the liver .
margins were negative and the patient had an uneventful recovery . in september 2006 , 16 years since her initial colon cancer diagnosis , a routine cea measurement was again slightly elevated .
repeat ct scan demonstrated areas of abnormality in what would be the falciform ligament and in the abdominal wall just right of midline .
the patient underwent en bloc wedge liver resection , partial diaphragm resection , partial gastrectomy and partial right chest wall resection .
no surgical margins were involved and the patient had an uneventful recovery . in april 2009 , the patient underwent reevaluation for elevated cea .
the heart border was abnormal on ct scan , and transesophageal echocardiogram showed a mass in the right atrioventricular groove .
repeat ct and pet scans at this time showed no other evidence of metastatic disease ( fig .
a follow - up pet / ct scan 6 months after her cardiac surgery showed evidence for extension of the neoplastic disease in her left and right atria , confirmed by mri .
last visit was november 2011 and she was on single agent bevacizumab without disease progression .
approximately 140,000 new cases of colorectal cancer are diagnosed annually in the united states . according to a study of the national cancer institute 's surveillance , epidemiology , and end results ( seer ) database of approximately 140,000 people with colon cancer between 1999 and 2006 ,
the patient described in this case is now a 78-year - old woman with long - term survival from 17 years of recurrent colon cancer , initially stage iii .
she underwent low anterior resection with adjuvant chemoradiation therapy completed by 1993 and she has since undergone four more operations for metastases and local recurrences , including two liver resections , right chest wall and right abdominal wall resections , and most recently , cardiac resection . in this case , surgery was the best means of therapy for the recurrent disease at each time point and we suggest that the multiple surgical interventions are the main reason for this patient 's long - term survival with metastatic colon adenocarcinoma .
the latest curative - intent surgery undergone by this long - term colon cancer survivor has been cardiac resection , and this has resulted in the shortest disease - free interval of all her resections ( 6 months ) . there appear to be a total of ten case reports in the literature since 1982 of colorectal cancer metastases to the heart [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ] .
indeed , the literature suggests cardiac metastasis from colorectal cancer to be extremely rare , probably less than 2% of all cases based on autopsy series [ 13 , 14 ] . currently , there are no studies investigating the role of surgery in colorectal cancer cardiac metastases .
our patient underwent one cardiac resection and at 6 months follow - up was shown to have recurrence and extension of disease on pet imaging .
one such factor is tumor biology , such as degree of differentiation , nodal involvement at presentation , cea level , and mutations in k - ras and p53 . although these tumor markers are not routinely tested and the exact biology of this tumor is unknown , the patient likely has a less aggressive type of colon adenocarcinoma .
if this tumor were more aggressive , recurrences would likely be widely metastatic , precluding further surgical intervention .
as is seen in this case , however , all of her recurrences were either isolated metastases or resectable local recurrences , deeming surgical intervention appropriate therapy .
this particular patient did not benefit from improved chemotherapy as she was diagnosed in 1992 and treated with levamisole , a drug no longer used .
she did , however , benefit from surgical intervention in 1995 , 1999 , 2006 , and 2009 .
the patient also received consistent follow - up with her surgeon and oncologist which included frequent cea measurements , as well as colonoscopies , ct , mri and pet imaging when necessary that proved essential in detecting early recurrence amenable to curative - intent salvage surgery .
the interesting surgical management in this case comes not at the onset of her disease , but throughout the multiple recurrences in the past 17 years , lastly the myocardial recurrence .
surgery remained the principal clinical intervention for this patient early on and she has benefited with long - term survival . survival for stage iv colorectal cancer has been improving dramatically since 1998 for many reasons , including improvements in chemotherapy and more aggressive surgical resections . at the times of this patient 's metastatic disease resections , adjuvant therapy after metastasectomy was not considered standard of care , and the issue remains controversial [ 17 , 18 ] . in the past 17 years , the patient has not undergone adjuvant chemotherapy after resection of recurrences .
however , with her current cardiac recurrence , the patient underwent folfox with bevacizumab and after being reevaluated for tumor sensitivity , bevacizumab only most recently .
this patient is an example of long - term metastatic colon cancer survival whose latest recurrence is in the heart , a very unusual place for colorectal metastatic disease .
we would like to suggest that with a nonaggressive tumor biology and only locally recurrent disease , surgery can provide long - term survival for other colon cancer patients .
proper follow - up and patient selection will further ensure survival benefit from repeated surgical interventions .
the role of new and active chemotherapy regimens in the adjuvant setting after resection of metastases remains an interesting area of future investigation .
Output:
| metastatic colorectal cancer represents a major health problem in the us and worldwide .
forty percent of patients undergoing resection of the primary tumor will experience relapse . in this brief review ,
we describe a case of a woman with metastatic disease and long - term survival culminating with an unusual myocardial recurrence . over three decades ,
a multimodality approach has evolved to allow for long - term survival in selected patients with metastatic colorectal cancer . in this case report , the role of multiple aggressive surgical resections is emphasized . |
PubmedSumm118218 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: acute poststreptococcal glomerulonephritis ( apsgn ) develops after streptococcal infection with the obvious latent period of around 10 days .
it is mostly accompanied by decrement in serum complement titer and glomerular deposition of c3 and igg . from these characteristic manifestations
, it has been widely accepted that the immunological reaction against streptococcus related antigens is engaged for the initiation of this disease .
the most popular theory of the pathogenic mechanism of apsgn has been the immune complex theory , which involves the glomerular deposition of nephritogenic streptococcal antigen and the subsequent formation of immune complexes in situ and/or the deposition of circulating antigen - antibody complexes [ 1 , 2 ] .
however , glomerular immunoglobulin deposition is not often prominent in this disease , and the reason for the difference in the site of glomerular cell infiltration and the site of immune complex deposition is unclear ; the major site of inflammation in this disease occurs on the inner side of the glomerular tufts ( endocapillary site ) , whereas the immune complex in early phase is localized to the outer side of the glomerular tufts ( subepithelial site ) .
indeed , another type of human glomerulonephritis with subepithelial immune complex deposition , membranous nephropathy , is rarely accompanied by endocapillary cell infiltration .
thus , the actual mechanism of how prominent glomerular endocapillary proliferation occurs in this disease is still unknown , and the most essential and critical issue ,
what is the causative entity / antigen , has remained a matter of debate [ 36 ] .
we recently isolated and characterized a nephritogenic antigen from group a streptococcus ( gas ) that we call the nephritis - associated plasmin receptor ( naplr ) and is homologous to the streptococcus plasmin(ogen ) receptor ( plr ) [ 7 , 8 ] .
the evidence for the important roles of naplr and the related plasmin activity in the development of glomerulonephritis associated with streptococcal infection are described .
we postulated that the nephritogenic antigen for apsgn should have affinity for the serum of convalescent apsgn patients .
so the fraction from the cytoplasmic proteins of gas that has high affinity for the igg of apsgn patients were collected by using affinity chromatography with apsgn patients ' igg - immobilized sepharose and then purified by ion exchange chromatography .
eventually the 43-kda protein , a potent nephritogenic antigen for apsgn , was isolated [ 7 , 8 ] . the amino acid and the nucleotide sequences of the antigen revealed to be highly identical to those of reported plr , or glyceraldehyde-3-phosphate dehydrogenase ( gapdh ) of gas [ 710 ] .
plr has been shown in vitro to bind plasmin and maintain its proteolytic activity by protecting it from physiologic inhibitors like 2-antiplasmin ( 2-ap ) .
naplr exhibited similar functions as plr , such as specific binding with plasmin(ogen ) , and expression of gapdh activity .
further analysis revealed the nephritogenic characteristics of the isolated antigen as described in the following sections .
we analyzed the anti - naplr antibody titers by western blotting in serum samples from 50 apsgn patients , 50 streptococcal infection ( si ) patients without nephritis , 50 young pediatric patients ( < 11 years old ) , 50 older pediatric patients ( 1120 years old ) , 50 young normal adults ( 2535 years old ) , and 50 older normal adults ( 5259 years old ) .
the percentage of those positive for anti - naplr antibody was high in apsgn patients , but was also quite high even in healthy older people ( table 1 ) .
apsgn patients , however , showed significantly higher antibody titers as demonstrated in figure 1(a ) than other groups , even si patients without nephritis .
anti - naplr antibody titer differed from aso titer in that the aso titer was similarly high in both apsgn and si patients ( figure 1(b ) ) .
direct immunofluorescence staining with rabbit anti - naplr antibody in renal biopsy tissue from apsgn patients revealed glomerular naplr deposition mainly on mesangial and endocapillary site as ring - like granular pattern ( figure 2 ) .
as shown by the values listed in table 2 , glomerular naplr deposition was observed in 100% ( 25/25 ) of apsgn patients within 2 weeks after disease onset or in 84% ( 36/43 ) of apsgn patients within 30 days after disease onset , but the percentage of tissue specimens showing naplr deposition decreased over time . on the other hand ,
no normal kidney was positive for naplr and only 4 out of 100 patients with other glomerulonephritis were positive for naplr .
it is worthy of notice that the glomerular distribution of naplr was essentially different from that of igg or c3 in the glomeruli of apsgn patients ( figures 3(a)3(c ) ) . in early - phase apsgn , c3 and/or igg deposits
are usually found at a subepithelial site ( on the outer side of the glomerular tufts ) , while naplr deposits are always found on the inner side of the glomerular tufts . using double immunofluorescence staining for more precise analysis
, we found naplr to be localized mainly on glomerular endocapillary neutrophils , mesangial area , and partially on endothelial cells or glomerular basement membrane .
naplr is a 43 kd protein with a pi of 4.7 , and its most characteristic feature in vitro is that it binds to plasmin and maintains the proteolytic activity of plasmin by protecting the enzyme from physiological inhibitors such as 2-ap .
actually , plasmin is engaged in many physiological phenomenon , such as , fibrinolysis , extracellular - matrix turnover , cell migration , wound healing , angiogenesis , and neoplasia [ 1316 ] , but because it is easily inhibited and tightly regulated by physiological inhibitors it is not normally found in an active form in vivo .
we found significant glomerular naplr deposition in the early phase of apsgn , which led us to speculate that deposited naplr would trap plasmin and cause glomerular damage by keeping it in an active condition in vivo . to evaluate this hypothesis
, we performed an in situ zymography with a plasmin - sensitive synthetic substrate ( p - toluenesulfonyl - l - lysine -naphthyl ester ) , and found prominent intraglomerular plasmin activity only in naplr - positive apsgn patients ( figure 3(e ) ) .
this activity was completely inhibited by aprotinin ( figure 3(f ) ) , a plamin inhibitor , but was resistant to 2-ap .
in contrast to the different distributions of naplr and c3 or igg ( figures 3(a)3(c ) ) , the glomerular distributions of plasmin activity and naplr are essentially identical ( figures 3(d ) and 3(e ) ) , suggesting that deposited naplr does indeed cause glomerular damage in apsgn by trapping plasmin and maintaining its activity .
plasmin might damage renal tissue directly by degrading extracellular matrix proteins such as fibronectin or laminin but might also exert an indirect effect on variety of extracellular matrix proteins by activating promatrix metalloproteases .
plasmin can also mediate inflammation by activating monocytes and neutrophils and causing their glomerular accumulation [ 18 , 19 ] .
thus we think that glomerular damage may initially be induced by deposited naplr , which can bind plasmin and maintain its proteolytic activity , rather than by subepithelial immune - complexes . in this respect ,
the finding that naplr is localized on the inner side of glomerular tufts ( endocapillary ) is consistent with the predominantly endocapillary glomerular inflammation in apsgn .
in other words , endocapillary localization of naplr might account for the different sites of glomerular inflammation and immune - complex deposition in apsgn .
naplr thus acts not only as a component of the immune complex but also as a plasmin receptor and might contribute to the pathogenesis of apsgn by maintaining proteolytic activity .
this is consistent with previous clinical findings that proteinuria and microscopic hematuria are occasionally found in the dormant phase of apsgn , when antibody against the nephritogenic antigen has not yet developed .
the incidence of apsgn in streptococcal infection patients with these manifestations ( proteinuria and hematuria in the dormant phase ) is higher than that in streptococcal infection patients without these symptoms . in keeping with these results , urinary plasmin activity assessed by chromogenic assay ( figure 4(a ) ) and casein gel zymography ( figure 4(b ) )
was upregulated in apsgn patients than that in the urine of healthy subjects and iga nephropathy patients , which support the pathogenic role of naplr and plasmin activity in apsgn .
as naplr was found to be localized mainly in neutrophils , we examined the plasmin activity of glomerular neutrophils and found that many were positive for plasmin activity in renal tissues from apsgn patients ( figures 5(a)5(c ) ) .
on the other hand , glomerular neutrophils were not positive for plasmin activity in renal tissues from rapidly progressive glomerulonephritis patients ( figures 5(d)5(f ) ) , which suggests disease specificity of the relationship between plasmin activity and neutrophils .
with respect to the pathogenic role of naplr on neutrophils , the hyperproteolytic state of naplr - positive neutrophils in the present study indicates a possible role of these neutrophils in the induction of proteolytic glomerular damage .
specifically , plasmin activity of naplr - positive neutrophils may damage mesangium and glomerular basement membranes from inner side of glomerular tufts by promoting plasmin - catalyzed proteolysis .
naplr may bind the urokinase - type plasminogen activator receptor expressed on neutrophils , which has recently been shown to be the receptor for streptococcal gapdh ( naplr ) .
despite the previously mentioned evidence that naplr is a potent nephritogenic antigen that could cause apsgn , batsford et al .
hypothesize that the nephritogenic antigen responsible for apsgn is streptococcal pyrogenic exotoxin b ( speb ) .
speb is a cationic cysteine protease secreted as a 42-kda zymogen that is subsequently cleaved to a 28-kda active proteinase .
it is a toxin in severe invasive streptococcal infections but has also been suggested by several groups [ 3 , 6 , 24 , 26 ] to be a potent nephritogenic antigen of apsgn . because of its cationic character , it is suspected to pass easily through the glomerular basement membrane and be deposited at a subepithelial site , where it would then induce immune complex formation .
cu et al . were able to demonstrate glomerular localization of speb in 67% of apsgn patients by indirect if staining with polyclonal anti - speb antibody .
batsford et al . recently compared naplr and speb in the renal biopsy tissues from a series of apsgn patients with anti - speb and antistreptococcal gapdh ( naplr ) antibodies that they generated .
in contrast to our previous findings [ 7 , 8 ] , they found rare glomerular positivity for streptococcal gapdh compared to those for speb .
it is important to note that they used an indirect immunofluorescence staining method with the antistreptococcal gapdh antibody that they generated , whereas we performed direct immunofluorescence staining with the anti - naplr antibody that we generated .
immunostaining results can vary with the use of different antibodies , so the comparison may be inappropriate .
nonetheless , we compared glomerular localization profiles of speb and naplr by using an speb antibody provided by dr .
batsford ( department of immunology , institute of medical microbiology , freiburg , germany ) and our naplr antibody .
double staining showed an extremely similar distribution of both antigens in the glomeruli of apsgn tissues , although naplr staining appeared to predominate ( figures 6(a)6(c ) ) [ 12 , 28 ] .
these results were surprising because many researchers , including us , have been assuming that apsgn is the result of a single nephritogenic streptococcal antigen .
therefore , we should consider the possibility that two or more antigens interact in the induction of this disease .
both bind plasmin , thereby protect it from physiological inhibitors , and thus might cause chemotaxis of inflammatory cells and degradation of glomerular basement membranes , due to the activity of plasmin [ 17 , 26 ] .
plasmin activity may be a common final pathway in apsgn , or those antigens may cooperate from different mechanisms for the development of apsgn as recently suggested by rodrguez - iturbe and batsford .
as described above , naplr is originally isolated as the putative nephritogenic antigen for apsgn .
indeed , glomerular naplr deposition can be found with extraordinary frequency in early - phase apsgn patients .
however , recent observation has revealed that glomerular naplr deposition and plasmin activity could be found in a similar fashion also in other glomerular diseases , such as dense deposit disease ( ddd ) [ 31 , 32 ] , henoch - schonlein purpura nephritis ( hspn ) [ 7 , 33 ] and membranoproliferative glomerulonephritis ( mpgn ) , in which recent streptococcal infection has been suggested by serological tests .
we believe that there is a subgroup of patients in these diseases ( ddd , mpgn , and hspn ) in which glomerulonephritis is induced by streptococcal infection and subsequent glomerular deposition of naplr and related plasmin activity .
we would like to refer to these diseases collectively as streptococcal - infection related nephritis ( sirn ) .
in light of our recent finding on nephritogenic antigen responsible for apsgn , we propose the following mechanisms for the development of apsgn ( figure 7 ) .
infection of the throat or skin with streptococcus induces the release of a nephritogenic antigen , such as naplr , into the circulation .
circulating naplr accumulates in the renal glomeruli on the mesangial matrix and glomerular basement membrane , probably by adhesion .
naplr then traps and maintains the activity of plasmin , which might induce glomerular damage by degrading the glomerular basement membrane by itself or by activating promatrix metalloproteases .
therefore we believe that an antibody - independent direct effect of the nephritogenic antigen is important for the initiation of the disease
. such glomerular damage may induce urine abnormalities during the latent period of the disease . the host immune reaction ( both humoral and cell - mediated ) against the nephritogenic antigen also develops during this latent period .
the circulating antibody forms immune complexes , either in situ or in the circulation that can readily pass through the altered glomerular basement membrane and accumulate in the subepithelial space as humps .
these final steps of immune cell accumulation and immune complex deposition are accompanied by the activation of complement and lead to the overt disease state .
the mechanisms localizing naplr specifically to the glomeruli and possible contributions and interactions of other nephritic antigens in apsgn must be elucidated in future studies .
glomerular naplr deposition and plasmin activity could be observed in a similar fashion in other glomerular diseases , such as ddd , hspn , and mpgn , in which recent streptococcal infection has been suggested .
we propose to refer to these diseases ( glomerulonephritis induced by streptococcal infection and subsequent glomerular deposition of naplr and plasmin activity ) collectively as sirn .
Output:
| it is well known that glomerulonephritis can occur after streptococcal infection , which is classically referred to as acute poststreptococcal glomerulonephritis ( apsgn ) .
the pathogenic mechanism of apsgn has been described by so - called immune complex theory , which involves glomerular deposition of nephritogenic streptococcal antigen and subsequent formation of immune complexes in situ and/or the deposition of circulating antigen - antibody complexes .
however , the exact entity of the causative antigen has remained a matter of debate .
we isolated a nephritogenic antigen for apsgn from the cytoplasmic fractions of group a streptococcus ( gas ) depending on the affinity for igg of apsgn patients .
the amino acid and the nucleotide sequences of the isolated protein revealed to be highly identical to those of reported plasmin(ogen ) receptor of gas .
thus , we termed this antigen nephritis - associated plasmin receptor ( naplr ) .
immunofluorescence staining of the renal biopsy tissues with anti - naplr antibody revealed glomerular naplr deposition in essentially all patients with early - phase apsgn . furthermore
, glomerular plasmin activity was detected by in situ zymography in the distribution almost identical to naplr deposition in renal biopsy tissues of apsgn patients .
these data suggest that naplr has a direct , nonimmunologic function as a plasmin receptor and may contribute to the pathogenesis of apsgn by maintaining plasmin activity . |
PubmedSumm118219 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: uterine septum is the known type of congenital uterine malformation , approximately with 8090% of uterine malformations .
it can be lead to infertility , miscarriage , abnormal fetal position , and premature birth .
hysteroscopic metroplasty is a simple and safe approach for the removal of the uterine septum ( 1 - 5 ) .
many studies represented the progression of spontaneous pregnancy rate after the hysteroscopic removal of septate uterus ( 6 - 23 ) .
in addition , some investigator suggested different treatment protocol after septum resection to impede asherman syndrome .
the postoperative hormone therapy using estrogen and terminal progesterone is controversial because their efficacy has not been demonstrated in well - designed , prospective , randomized studies .
they utilized hormone replacement therapy ( hrt ) and/ or temporary splints such as the intrauterine device ( iud ) to maintain the uterine cavity distended to denuding endometrial cavity to prevent septal fusion ( 24 - 28 ) .
nonetheless , they also suggested artificial stimulation of endometrial growth postoperatively may assist in the overall healing process by artificially enhancing endometrial growth by use of estrogen and subsequent shedding by use of terminal progesterone , paving the way to normal endometrial growth and subsequent spontaneous ovulation ( 5 , 29 , 30 ) . in spite of the comprehensive study of infertility , little data are available concerning the benefit of different treatment protocols after septum resection on fertility consequence .
our interest was to assess the efficacy of hysteroscopic septum resection on pregnancy rate and benefit of postoperative various methods in infertile women after septum resection .
a compilation sheet was developed for the present study after taking permission from the general director of the center to inspect the information existing in the medical records of infertile women .
the study was based on secondary data from fatemezahra infertility and reproductive health research center to inspect the information center that inclusion criteria for the study were infertile women who received different treatment protocols after hysteroscopic correction of the septet uterus between april 2005 and february 2014 .
a total of 106 patients was selected and reviewed based on inclusion criteria , 28 of these had male factor .
septet uterine and variable lengths ( class va : complete ; class vb : partial ) according the american fertility society classification of mullerian duct anomalies , who agreed to undergo hysteroscopic septoplasty in the infertility center , were included in the study ( 5 , 13 , 31 - 33 ) .
all patients were hospitalized and underwent surgery 2 to 5 days after menstruation period in the early proliferative phase .
patient was placed misoprostol suppository in the posterior vaginal fornix for cervical dilation to facilitate an easier and uncomplicated procedure prior night of surgery . after performing anesthesia , vaginal speculum placed after cleaning the external uterine ostium with a gauze soaked in iodine solution , surgeon used cervical dilator for dilatation of cervical os to 1010.5 cm
, a 3.5-mm mini - hysteroscope karl storz , germany for endoscopy , was administered to preserve hymen integrity ; normal saline was used as a factor of distending .
an endoscopic vaginal exploration presented the presence of one uterine cervix at the open vaginal side and the uterine distention pressure was set at 150 mm hg .
an electro resectoscope was inserted to corroborate the size , range of the septum and location .
then the septum by needle electrode was incised , and ultrasonography was applied for monitoring during the operation completely .
after hysteroscopy , different regimens were used postoperatively to decrease the formation of intrauterine adhesion in the denuded area of septal incision .
postoperatively , patients totally had an intrauterine device insertion ( iud ) to certify the potency of the uterine cavity and to prevent further adhesions .
all patients after receiving hormone therapy instruction and consciousness were discharged ( 26 , 29 , 33 - 40 ) . in 71 women , after septum resection alternate hormone order ( first protocol ) consist of conjugated estrogens ( premarin ; montreal postoperative canada , wyeth - ayerst ) at a dose of 1.25 mg daily was given for twenty five day after surgery and medroxyprogesterone acetate ( provera ; pharmacia and upjohnkalamazoo , usa ) at a dose of 10 mg twice per day was accomplished from day of sixteen in this time in combination with the conjugated estrogens a dose of 1.25 mg daily till 25th of cycle , after 25 days treatment will stop , then menstruation will occur and after menstruation period again we start this treatment process again for 2 month .
a total of 35 patients were received constant hormone ( second protocol ) includes ; conjugated oestrogen at a dose of 1.25 mg twice daily was given for 50 days .
medroxyprogesterone acetate at a dose of 10 mg twice daily was performed for the last 10 days of this time ( i.e. days 5460 ) in combination with the conjugated oestrogen . after a withdrawal bleeding , second day of menstruation ,
pregnancy and delivery follow - up for 12 months was done . if the pregnancy was not happening spontaneously after 6 month treatment , according to surgeon s idea art procedure
comparisons between the type of protocols after septum resection and characteristics of variables were made using t - test .
qualitative data are presented as number and percentage and comparison between groups are estimated by chi
comparisons between the type of protocols after septum resection and characteristics of variables were made using t - test .
qualitative data are presented as number and percentage and comparison between groups are estimated by chi
out of 106 infertile women with septate uterus who undergone hysteroscopy septum resection , 71 ( 67% ) of the patients received first protocol after septum resection and 35(33 % ) second protocol .
the bmi and menarche age the subjects were 274.3 kg / m and 12.91.0 years , respectively .
table 1 shows some of the characteristics for different treatment protocols after hysteroscopic septum resection .
there was no significant difference between age , menarche age , bmi , job of women , infertility type , and duration infertility types with treatment protocols of patients table 2 presented reproductive outcome and side effect after septum resection with different treatment protocol , showed a pregnancy rate after hystroscopic septum resection was enhanced .
44(62.0% ) of patients had a positive pregnancy rate with first treatment protocol , while 27(77.1% ) of patients with second treatment protocol had a positive pregnancy rate .
treatment following hysteroscopic septum resection , either the consistency or the alternate protocol is both adequate to improve rates of pregnancy .
27 ( 28.8% ) patient had a spontaneous pregnancy with first treatment protocol after hysteroscopic resection of uterine septum while 16 ( 45.7% ) with second treatment protocol had spontaneous pregnancy . after art , 17 ( 23.9% ) who had used first treatment protocol had a pregnancy and 11(31.4% ) with second treatment protocol had pregnancy after art while 27(38.0% ) patient had not pregnancy after using first treatment protocol and 8(22.9% ) patient had not pregnancy after using second treatment protocol .
live birth rate in patients with first and second treatment protocol was 37(52.1% ) and 24(68.6% ) , respectively .
abortion rate in patients with first and second treatment protocol was 3(4.2% ) and 2 ( 5.7% ) , respectively .
preterm deliveries in patients with first and second treatment protocol was 7(9.9% ) and 7 ( 20.0% ) , respectively .
term deliveries in patients with first and second treatment protocol was 34(47.9% ) and 18 ( 51.4% ) , respectively .
side effect of first and second treatment protocol was 20 ( 28.2% ) and 9 ( 25.7% ) , respectively .
chi - square test revealed no statistically significant difference in upper variables and two treatment protocols .
84 ( 79.2 % ) had no side effects during and after both treatments but 1 ( 9 % ) stopped treatment and 21 ( 19.8 % ) needed to add drug .
patients during treatment with first protocol 20 ( 28.2 % ) had a side effect but with second protocol 9 ( 25.7 % ) had side effect .
* independent t. test reproductive outcome and side effect after septum resection with different treatment protocol .
most of the researchers have shown a better reproductive outcome after hysteroscopic resection of uterine septum in woman with septate uterus , however , there is no evidence on the postoperative management of the hysteroscopic septum division ( 27)(48 ) .
most of authors also reported hysteroscopic metroplasty in patients with uterine septum improved pregnancy rate ( 10 , 42 ) . in this study ,
pregnancy rate and live birth rate after hystroscopic septum resection in women with septate uterus was high .
two studies found that the pregnancy rate after hysteroscopic metroplasty ( around 40% ) was lower compared with results ( 67.0% ) ( 3 , 15 , 43 , 49 ) .
other observational studies also have reported similar findings ( 50 ) . in a retrospective ,
matched , controlled study , the role of septet uterus in the reproductive performance of patients requiring in vitro fertilization ( ivf ) was evaluated .
the pregnancy rate before metroplasty was lower than after metroplasty , and the abortion rate was higher .
they suggest that the presence of septate uterus may be decreased the pregnancy rate and increased the abortion rate after the embryo transfers for ivf / icsi ( 51 ) . in the present study , in 63 patients who had hysteroscopic resection of uterine septum and did not conceive naturally pregnant , of these 28 ( 44.5% ) became pregnant by art .
many authors studied on pregnancy outcome after hystroscopic septum resection but they did not use hormonal postoperative therapy and concluded improved pregnancy rate after hystroscopic septum resection ( 9 , 11 , 15 , 18 , 20 , 21 , 38 , 52 - 60 ) .
nouri et al also agreed with these results and they represented an overall pregnancy rate of 60.1% and a live - birth rate of 45% after hysteroscopic metroplasty ( 20 ) .
other studies also have shown that neither iud placement , nor estrogen treatment , nor both prevent intrauterine adhesions or facilitate pregnancy after hysteroscopic uterine septum resection ( 29 ) .
another study also was agreed that a postoperative 3-month estrogen plus iud insertion or estrogen alone after hysteroscopic metroplasty are not necessary ( 61 ) .
this result showed that after hysteroscopic metroplasty without using postoperative therapy also we had improved reproductive outcome .
versus other authors also studied on pregnancy outcome after hystroscopic septum resection but they used hormonal postoperative therapy and concluded improved pregnancy rate after hystroscopic septum resection ( 13 , 62 - 70 ) . while some authors were used only estrogen after hystroscopic metroplasty but reproductive performance significantly improved ( 26 , 45 , 71 - 73 ) .
we found that both intrauterine device and estrogen plus progesterone ( hrt ) was same for effect on reproductive outcome and the was no significant difference between two protocols on pregnancy rate ( 41 ) . in our infertility center
we used two treatment protocols that mentioned upper and this was according to our surgeon s idea .
we were able to show that the different treatment after septum resection was elected according to surgeon s idea and the postoperative reproductive outcome was similar in both method and there were no significant differences on delivery rates .
the presenting findings showed that hysteroscopy for resection of uterine septa will increase the odds of clinical pregnancy in infertile women , but the evidence is not conclusive at present .
therefore , it is suggested that in women with septate uterus and a history of infertility , hysteroscopic septoplasty is a confident and efficient procedure resulting in a higher pregnancy rate .
but more randomized controlled trials and prospective studies with enough samples with no intervention and consistent follow - up data are needed to , which could provide the highest level of evidence and substantiate the effectiveness of the hysteroscopic removal of uterine septum in infertile women and various postoperative treatments .
further research studies should focus on specific populations with clear indications , to draw reasonable and meaningful conclusions about the outcomes of hysteroscopic metroplasty .
adequate time after the procedure should be allowed so that subjects have ample time to attempt conception and also to give birth , to allow for accurate live - birth rate calculations .
limitation : because of some limitations , we do nt have access to all surgical reports and therefore lacked detailed data on the diameter of cervical dilatation and intraoperative findings in some cases ; we were also not able to calculate the exact time interval between the hysteroscopic intervention and the beginning of the pregnancies .
a short interval between hysteroscopic intervention and conception might be an additional risk factor for preterm birth .
second , some of the infertile patients who underwent hysteroscopic septum resection in the course of infertility assessment at our clinic may have conceived naturally after the procedure , but were lost to follow - up or turned to another clinic for art .
treatment following hysteroscopic septum resection , either the consistent or the alternate protocol is both beneficial to improve pregnancy rate .
we have shown that hysteroscopic septum resection to remove a uterine septum in women with infertility is safe and may be an efficacious procedure .
however , the need remains for larger randomized controlled trials and prospective studies with enough samples with no intervention and consistent follow - up data to address the effectiveness and safety of adjunct therapy with hysteroscopic septum resection .
Output:
| background : septate uterus is the most common uterine anomaly and a cause for miscarriage and infertility . existing data suggested a better reproductive outcome of uterine septum following hysteroscopic septum resection.objective:current study was administered to share our experience in hystroscopic septum resection for reproductive outcome following hysteroscopic treatment of uterine septum and specifically focusing on different treatment protocols after hysteroscopic septum resection.methods & materials : this study was a cross - sectional study based on secondary data that was obtained from medical records of infertile women who had undergone transvaginal hysteroscopy and used different treatment protocols after hysteroscopic correction of uterine septum in infertility and reproductive health research center between april 2005 and february 2014.results:the total number of infertile women underwent hysteroscopy uterine septoplasty was 106 .
the hysteroscopy septoplasty resulted in an overall pregnancy rate of 67% and a live birth 57.5% .
pregnancy rate for patients who had not male infertility was 92.1% .
the chi - square test did not reveal any statistically significant difference in side affect , pregnancy , live birth , abortion , preterm deliveries , and term deliveries rate between these patients either with consistent hormone therapy plus iud insertion or with alternate hormone therapy plus iud after hysteroscopic metroplasty.conclusion:the findings of the present study indicated hysteroscopic septum resection to remove a uterine septum in women with infertility is safe and may be an efficacious procedure .
treatment following hysteroscopic septum resection , either the consistent or the alternate protocol is both beneficial to improve pregnancy rate . |
PubmedSumm118220 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: multiple sclerosis is an inflammatory and neurodegenerative disorder of the central nervous system that leads to a progressive axonal loss and degeneration of neurons . whereas a vast majority of ms patients present with a relapsing - remitting disease course ( rrms ) that may subsequently transforms into secondary progressive ms ( spms )
, a smaller portion of patients shows a progressive course ( ppms ) from the very beginning of the disease .
optical coherence tomography ( oct ) is an increasingly recognized , noninvasive tool in ms imaging that allows cost - effective investigation of the retina in a disease in which pathology of the anterior visual system is common . over the recent past ,
oct has emerged as a potential marker of axonal retinal degeneration in ms patients . of note ,
an increasing number of studies have consistently shown an association between oct measures of retinal atrophy and markers of degeneration derived from either structural magnetic resonance imaging or mr spectroscopy ( mrs ) studies [ 411 ] and between oct measures and functional visual parameters as well as physical disability and cognitive performance [ 1217 ] .
retinal nerve fibre layer ( rnfl ) thickness and total macular volume ( tmv ) are the most frequently investigated oct parameters .
they provide a unique opportunity to quantify the integrity of nonmyelinated axonal tissue ( rnfl ) as well as all retinal layers ( tmv ) , including cellular segments , by a noninvasive imaging technique .
rnfl and tmv reduction can be detected in eyes with ( ms - on ) or without a previous history of optic neuritis ( ms - non ) applying different oct devices [ 15 , 1829 ] .
data on distinct differences in oct findings between ms subtypes are scarce , and the results are at least in part conflicting . in general , cross - sectional studies show a more profound thinning of rnfl in progressive forms of ms compared to rrms patients .
however , it remains unresolved to date whether these differences are a genuine effect of the disease subtype per se or rather a function of disease duration , the number of optic neuritis ( on ) episodes in the patients ' history , or disease severity [ 3034 ] .
only very recently spectral - domain technology became available which enables imaging at substantially higher resolution without an increase in scanning time [ 16 , 22 , 3438 ] .
here we report results from the largest multicentre cohort of ms patients and healthy controls ( hc ) thus far , studied in three dedicated ms centres in germany , applying latest high - resolution spectral - domain oct ( sd - oct ) technology . in this large cohort ,
we reliably identified patterns of rnfl thinning and tmv reduction among different ms subtypes both with and without a history of on when controlling for disease duration and severity , age , and gender .
414 patients and 94 healthy controls were recruited in three dedicated ms units in the respective outpatient clinics at the charit university medicine berlin ( neurocure clinical research center ( ncrc ) ) , at the department of neurology of the heinrich - heine university dsseldorf ( ukd ) and in hamburg ( institute for neuroimmunology and clinical ms research ( inims ) ) .
inclusion criteria were age between 18 and 60 years and a definite diagnosis of ms according to the revised 2005 mcdonald criteria .
ms subtype classification in rrms , spms , or ppms was based on the clinical course as assessed by the treating physician using lublin criteria .
a history of on had to be clearly determinable either by existing medical records , a vep suggestive of optic neuritis , or by patient self - reports .
only eyes in which a history of on could either be confirmed by clinical records or ruled out were subsequently included in the analysis .
patients with a refractive error of 5.0 diopters or with a history of eye disease that may impact significantly on oct measures ( e.g. , glaucoma , retinal disease , retinal surgery , and diabetes ) were excluded .
other exclusion criteria were acute optic neuritis or any other acute relapse or steroid treatment less than six months prior to oct assessment as well as any other neurological disease with possible ocular manifestations .
participants were assessed in a clinical examination under supervision of board certified neurologists within 6 months of oct . extended disability status scale ( edss )
healthy control participants were recruited from the medical staff , patients ' relatives , and other volunteers .
a total of 937 eyes ( 754 ms eyes and 183 hc eyes ) were finally included , 79 eyes were excluded from the analysis either due to poor scan quality or incomplete clinical data , in detail missing data on history of on .
the study protocol was approved by the local ethics committee and was conducted in accordance with the declaration of helsinki ( 1964 ) in its currently applicable version , the guidelines of the international conference on harmonization of good clinical practice ( ich - gcp ) and applicable german laws .
participants underwent sd - oct examination using the heidelberg engineering spectralis sd - oct ( heidelberg engineering , heidelberg , germany ) .
for both eyes of each participant , rnfl thickness around the optic disc was acquired using the 3.4 mm circle scan with the eye tracker system ( truetrack ) activated and the maximum number of averaging frames in art - mean mode were tried to achieve . for assessing the macular volume two different scan protocols were used : the system built - in macula scan ( 25 b - scans , scanning angle = 15 15 , art = 9 ) was performed at the hamburg and dsseldorf sites , while for the macular volume determination at the ncrc a custom protocol ( 61 b - scans , scanning angle = 30 25 , art = 13 ) was used .
irrespective of the macular scan type , the tmv was calculated using the device 's software .
all scans were performed by trained operators and were reviewed for sufficient signal strength , correct centring , and beam placement as well as segmentation . only eyes that passed the quality review were included in the subsequent analysis .
group comparisons of demographic factors were analysed using mann - whitney u test ( for age and edss ) and pearson 's chi - square test ( for gender , alpha = 0.05 ) . within the ms cohort spearman 's rho analysis
was used for correlation of edss and disease duration . generalized estimation equation ( gee )
models accounting for within - subject intereye correlations were applied to test for differences of rnfl thickness and tmv between the study cohorts .
gee models were corrected for age and gender for the comparison of ms patients with hc and additionally for disease duration for ms subtype analysis .
associations of oct with edss and regression analysis of disease duration with rnfl thickness and tmv were investigated with gee models in a similar fashion . in all gee models oct measurements were included as the dependent variable .
all statistical analyses were performed with r ( r version 2.12.2 ) including the geepack package for gee models .
an overview of the demographic and basic clinical data including ms subtypes is given in table 1 .
healthy controls showed no significant gender differences to rrms ( chi - square : p = 0.452 ) and spms ( chi - square : p = 0.186 ) patients , while gender composition of ppms patients differed compared to hc ( chi - square : p = 0.010 ) .
mean age of hc was significantly lower compared to all ms patients and all subtypes ( mann - whitney u tests , p < 0.001 for all subtypes ) .
rrms patients were significantly younger than the progressive subtypes ( mann - whitney u tests , p < 0.001 for spms and ppms ) . as a consequence , age and gender were included as covariates in all gee models .
time since diagnosis of rrms and ppms was significantly shorter compared to spms ( mann - whitney u tests , p < 0.001 for both ) .
disease severity estimated by the edss was heterogeneous between ms subtypes as evaluated by mann - whitney u tests ( rrms versus spms : p < 0.001 ; rrms versus ppms : p <
0.001 ; spms versus ppms : p = 0.03 ) . for ms - non eyes , differences in rnfl thickness and tmv compared to hc are given in table 2 . in summary ,
average peripapillary rnfl thickness was reduced in the pooled cohort of all ms patients ' eyes and in all ms subtypes compared to hc ( figure 1(a ) ) .
likewise , tmv was reduced for the pooled cohort of all ms patients ' eyes and in all ms subtypes when compared to hc ( figure 1(b ) ) .
all alterations of rnfl and tmv in ms - non eyes compared to control eyes showed strong statistical significance based on gee models ( table 2 ) .
edss was inversely correlated with rnfl in case of all ms subtypes without a history of prior on ( rrms - non : p = 0.007 ; spms - non : p = 0.034 ; ppms - non : p = 0.006 ) .
in contrast , the tmv was only significantly correlated with the edss in rrms - non eyes ( p = 0.003 ) , but not in spms - non ( p = 0.321 ) or ppms - non ( p = 0.085 ) .
irrespective of the ms subtype , ms - on eyes were significantly different from hc eyes for rnfl thickness and tmv ( figure 2 ) and showed a more pronounced rnfl thinning and tmv reduction when compared to ms - non eyes ( table 3 ) .
rnfl thickness of rrms - on eyes and spms - on eyes was significantly thinner compared to rrms - non or spms - non eyes , respectively .
the same was true for the tmv of on - affected ms eyes , which was significantly reduced when compared to hc and to unaffected eyes of the same ms subtype ( table 3 , figure 2 ) .
the extent of rnfl thinning as well as tmv reduction was comparable between rrms - on and spms - on eyes ( rnfl gee : p = 0.369 ; tmv gee : p = 0.124 ) . rrms - on eyes showed a significant inverse correlation between edss and rnfl ( p = 0.012 ) while tmv did not reach significance ( p = 0.085 ) .
for spms - on eyes no significant correlation of edss with oct parameters was found ( rnfl : p = 0.169 ; tmv : p = 0.573 ) . among ms
subtypes , rrms patients showed less rnfl thinning when compared to progressive subtypes ( table 2 ) . when adjusting gee models for age , gender , and disease duration , the only significant difference based on the mean total rnfl thickness was found between rrms and spms patients , while patients with ppms did not differ from either rrms or spms ( table 4 , figure 1 ) . as opposed to rnfl thickness a different pattern was obtained for tmv measures , in which a significant reduction was found for spms and ppms when compared to rrms patients .
gee models in which we additionally corrected for edss to account for different stages of disease severity did not show differences in rnfl thickness or tmv between ms subtypes ( data not shown ) .
gee models were used to test for an association of disease duration and rnfl thickness or tmv in ms eyes .
ms - non eyes showed an association of rnfl thickness and tmv with disease duration in the pooled cohort of all ms subtypes ( table 5 , figure 3 ) .
this association was retained in rrms and spms eyes only for rnfl thickness and only in rrms eyes for tmv . in all ms
subtypes the correlation between rnfl thickness and tmv and disease duration was lost in on eyes ( data not shown ) . based on the effect size of the association of disease duration and rnfl thickness or tmv we estimated rnfl thinning and tmv reduction per year of ongoing disease in ms - non eyes only ( table 5 ) .
rrms - non eyes showed the strongest and highly significant yearly changes for rnfl thickness ( 0.495 m / year ) and tmv ( 0.0155 mm / year ) .
interestingly , the significant yearly rnfl thinning in spms - non eyes ( 0.464 m / year ) was not concomitantly associated with a significant correlation in tmv change ( 0.0016 mm / year , p = 0.838 ) .
in contrast , ppms - non eyes showed a less pronounced yearly rnfl thinning ( 0.105 m / year ) but in relation a distinct reduction of tmv ( 0.0111 mm / year ) .
however , correlations of rnfl and tmv with disease duration were not significant for ppms - non eyes .
here we present the largest ever performed cross - sectional study on retinal atrophy measures in ms subtypes applying latest sd - oct technology .
groups of disease subtypes in our study were sufficiently large to contrast findings in on versus on - free eyes within subgroups .
hereby we show that both rnfl and tmv are reduced in ms - non eyes versus hc when pooling all disease subtypes , but also when separately comparing disease subtypes ( rrms , spms , and ppms ) to hc . not surprisingly and in accordance with previous studies , ms - on eyes exhibited more severe rnfl and tmv damage than ms - non eyes .
both findings have been previously described in a similar way by various groups so that the nature of our study appears to be largely confirmatory at first glance .
however , our study has some methodological advances compared to previous works that have important implications for the interpretation of our and previous oct findings . the large sample size of our study enabled a statistically robust comparison of various disease subgroups with the inclusion of possible confounding factors such as age , disease duration , and gender in the statistical models .
in particular , we had larger numbers of patients in the progressive subgroups ( 65 spms , 41 ppms ) than any other previous study which allowed us to compare not only disease subtypes with hc but also with each other .
this is of special interest against the background of the ongoing scientific debate on distinct pathogenetic mechanisms in , for example , ppms versus rrms .
the subgroup comparisons revealed a significant reduction of rnfl thickness in spms patients versus rrms after correction for age , gender , and disease duration and a significant reduction of tmv in both spms and ppms patients versus rrms .
in contrast , most previous works had only small sample sizes , especially for progressive subtypes which may besides considerable differences in the statistical models at least partly explain the inconsistent findings .
( number of subjects : 135 rrms , 16 spms , 12 ppms , and 47 hc ) found only trends towards lower rnfl thickness values in progressive disease versus rrms and no difference in tmv in progressive ms versus rrms .
( number of subjects : 27 spms , 23 ppms , and 20 hc ) reported a significant reduction of rnfl and tmv versus hc only in non eyes from spms patients but not ppms patients and no difference between ppms and spms .
( number of subjects : 26 rrms , 10 spms , and 29 ppms ) could not detect differences between ppms - non eyes and the pooled rrms / spms - non eyes .
( number of subjects : 42 rrms , 17 spms , and 59 hc ) did not specifically address differences in oct measures between disease subtypes as did numerous other studies with highly heterogeneous patient populations ( gordon - lipkin et al .
, number of subjects : 20 rrms , 15 spms , 5 ppms , and 15 hc ; toledo et al .
, number of subjects : 7 cis , 36 rrms , 3 spms , 3 ppms , 4 progressive - relapsing , and 18 hc ; fisher et al . ,
number of subjects : 90 ms , 76 of whom rrms , and 36 hc ; sepulcre et al . ,
number of subjects : 22 cis , 28 rrms , 5 spms , 6 ppms , and 29 hc ) , either because of insufficient subgroup sample sizes or owing to the fact that the study had goals other than comparing disease subtypes . in line with several previous studies [ 16 , 30 , 31 , 42 , 43 ] we found higher rnfl measures in ppms as compared to spms ( 88.4 m versus 83.1 m ) , which is in striking accordance with another study that also reported a difference of approximately 5 m between ppms and spms - non eyes ( 93.9 m versus 88.4 m ) .
although these differences were not significant in both studies , these findings may point to a more severe rnfl damage in spms as compared to ppms , which is in line with the clinical features of ppms with a lower proportion of visual loss , less frequent on attacks , a predominant clinical involvement of the spinal cord , and smaller brain lesions as compared to spms [ 31 , 44 , 45 ] .
we found like in spms a significant reduction of tmv in non eyes of ppms patients versus rrms and hc , which may display the neurodegenerative component of ppms concomitantly reflected through brain atrophy measures . regarding the comparison of rnfl measures in rrms and spms patients
, differences between spms - non and rrms - non eyes were about twice that of differences between spms - on and rrms - on eyes ( ~20 m versus ~10 m in costello 's study , ~10 m versus ~5 m in our study ) .
costello et al . suggested that the impact of prior on may outweigh the effects of disease subtype .
further limitation of most of the previous studies is the utilization of time - domain oct devices ( td - oct ) that only allow for 2-dimensional retinal imaging , limiting its use especially in the demanding macular investigations .
the newer high - resolution spectral - domain oct allows spatial imaging of the retina thus potentially greatly increasing the accuracy and value of oct in ms [ 35 , 36 , 47 ] .
first studies have already applied sd - oct with intraretinal segmentation [ 16 , 22 , 26 , 29 ] .
interestingly , the recent work by saidha et al . supports the finding of a more severe neuroaxonal retinal damage in spms as compared to ppms ; a separate analysis of the combined ganglion cell layer and inner plexiform layer measured by cirrus sd - oct in different ms subtypes showed lowest values in spms .
in contrast , another study by albrecht et al . applying manual segmentation on spectralis sd - oct showed reduced measures in the deeper inner nuclear layer of ppms but not spms patients versus hc .
we presume that the ability of sd - oct to measure spatial scans ( earlier td - oct had to interpolate macular volume by using 6 radial linear scans ) will in future greatly increase the value of macular scans over the currently preferred peripapillary ring scans . in addition , spatial scans allow for correction of positioning errors after scan acquisition by limiting the analysed area to a subset of the actual scan .
for example , the cirrus sd - oct uses a spatial scan for the peripapillary ring scan , allowing for subsequent correction of alignment errors , whereas the heidelberg engineering spectralis facilitates an eye tracker function to correct for eye movements . in td - oct ,
incorrect placement of peripapillary ring scans accounts to a significant extent for a weaker inter - measurement reliability and can not be corrected after the scan has been acquired .
next to the ability to analyse all intraretinal layers , improved test / retest - reliability distinguishes sd - oct from td - oct and makes it an ideal instrument for the use in a longitudinal setting where inter - measurement reliability is crucial .
the time course of rnfl thinning and tmv reduction by atrophy of different retinal layers be it in the context of on or independent thereof is an essential characteristic in rating the usefulness of oct as a potential marker of axonal loss in longitudinal clinical trials . for ms - on eyes
it has previously been shown that rnfl thinning occurs within the first 6 months after the on attack [ 21 , 50 ] .
overall little is known about temporal dynamics of retinal thinning in ms - non eyes .
based on published data from cross - sectional studies in ms patients with different disease duration a rough estimate of the yearly atrophy rate appears to be around 1 m / year , which is ten times as much as what can be expected from normal ageing . in previous cross - sectional studies
significant inverse correlations of rnfl thickness and disease duration could be established by some authors [ 11 , 15 , 24 ] , while others did not find a significant correlation [ 20 , 31 ] . in ppms , an ms subtype in which frequency of clinical attacks of on is probably lowest , henderson et al . estimated an rnfl thinning of approximately 0.12 m ( tmv reduction : 0.01 mm ) per year of disease , which is in good agreement with our results in ppms eyes ( rnfl thinning 0.105 m / year ; tmv reduction : 0.011 mm / year ) .
correlations of oct measures of retinal atrophy and disease duration were not significant for ppms patients in both studies . in case of rrms and spms patients without on we estimated higher yearly rnfl changes than for ppms ( nearly 0.5 m / year ) .
it is , however , important to note that yearly atrophy rates are considerably lower than the optimized axial resolution of sd - oct devices , which is approximately 46 m [ 51 , 52 ] .
this is of relevance in case oct endpoints are taken into consideration for future clinical trials , for example , in proof - of - concept trials for neuroprotective agents .
depending on the disease subtypes , model timelines and sample sizes have to be planned accordingly . in a first longitudinal oct study by talman et al .
a thorough examination of the time course of rnfl thinning in a mixed cohort of different ms subtypes was performed with td - oct ( stratus ) revealing a yearly loss of approximately 2 m in ms - non eyes ( gee : p < 0.001 ) .
the study included a preliminary sample size calculation ( supplementary data of ) for future clinical trials that aimed to detect a 30% reduction in the proportion of eyes with an rnfl thinning greater than the test - retest variability of the stratus oct ( 6.6 m ) over a follow - up period of 2 - 3 years . with a power of 8090% and a type 1 error of 0.05 ,
the authors ' sample size calculation estimated roughly a number of 400600 patients per group .
oct is considerably higher than the yearly reduction of approximately 0.5 m calculated from our dataset .
discrepancies may derive from the differences in the devices applied ( td - oct versus sd - oct ) and the fact that our calculation is based on cross - sectional data only . in sum
, this study , based on a large sd - oct data set , confirms previous data on neuroaxonal retinal damage in ms subtypes . at the same time
, it extends previous findings by providing new insights into differences between ms - on and ms - non eyes in the various subgroups and in addition allowing for reliable correction for non - disease - related factors such as age , gender disease duration , and severity .
Output:
| background . optical coherence tomography ( oct ) has facilitated characterisation of retinal alterations in ms patients . only scarce and in part conflicting data exists on different ms subtypes . objective .
to analyse patterns of retinal changes in different subtypes of ms with latest spectral - domain technology . methods . in a three - centre cross - sectional study 414
ms patients and 94 healthy controls underwent spectral - domain oct examination .
results .
eyes of ms patients without a previous optic neuritis showed a significant reduction of both retinal nerve fibre layer ( rnfl ) thickness and total macular volume ( tmv ) compared to healthy controls independent of the ms subtype ( p < 0.001 for all subtypes ) .
rnfl thickness was lower in secondary progressive ms ( spms ) eyes compared to relapsing - remitting ms ( rrms ) eyes ( p = 0.007 ) , and tmv was reduced in spms and primary progressive ms ( ppms ) eyes compared to rrms eyes ( spms : p = 0.039 , ppms : p = 0.005 ) .
independent of the subtype a more pronounced rnfl thinning and tmv reduction were found in eyes with a previous optic neuritis compared to unaffected eyes .
conclusion .
analysis of this large - scale cross - sectional dataset of ms patients studied with spectral - domain oct confirmed and allows to generalize previous findings .
furthermore it carves out distinct patterns in different ms subtypes . |
PubmedSumm118221 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: gold and gold alloys , whose primary advantages are their resistance to corrosion and tarnishing and their biocompatibility , have long been used to fabricate dental prostheses . despite these advantages , base metal alloys such as nickel - chromium ( ni - cr ) and cobalt - chromium ( co - cr )
are commonly used instead of high noble and noble alloys because of cost . in addition , although base metal alloys have some advantages over high noble or noble alloys , such as high hardness ( exceeds 400 kg / mm if carbon is present ) , low density , high elastic moduli , high tensile strength , and the possibility of electrochemical etching for resin bonding , they can corrode in accordance with their elemental composition .
all dental alloys have a tendency to corrode in under intraoral conditions because of exposure to substances such as saliva , food , and beverages .
high noble and noble alloys are biocompatible because of their resistance to oxidation and corrosion , while the corrosion resistance of base metal alloys depends on the integrity of their passive oxide layer , which may be destroyed mechanically and chemically by acidic changes .
typically , the corrosion process takes place locally , but over time , this local process transforms to a gap corrosion , which causes several problems , such as gray discoloration at the margins of the fixed restorations close to the gingival sulcus .
recently , manufacturers have started adding some noble alloys to the composition of base metal alloys to improve their biocompatibility and minimize corrosion while still keeping their cost reasonably low .
another method , which is not commonly used , is the gold - hard - plating ( ghp ) of base metal alloys , also known as galvanic gold coating , layering application or gold plating - electrodeposition of gold .
the problem is that solid gold is expensive . to get the look of gold without the cost ,
gold plating has many applications , including uses in jewelry , scientific experiments , electronics , industry , and dentistry .
it is a technique that has been around for centuries and continues because it is effective .
the underlying metal is made negatively charged through chemical baths and/or electricity . once the metal has a charge
gold does not oxidize when exposed to air , so its electrical conductivity wo n't diminish over time .
gold plating acts as an anti - corrosive coating to the material to which it is applied .
the ghp technique used in dentistry involves the depositions of a 6 m to 8 m 24 k gold layer directly onto the cr - co cast prosthesis framework .
this method prevents oxidation of the metal surface , alters its conductivity and resistance , provides a surface seal , reduces surface hardness , and improves color .
according to the manufacturers instructions , the ghp technique is used primarily to coat cr - co alloys for removable dental prosthesis frameworks .
rogers studied cr - co alloy gold plating and reported of advantages of clasps and frameworks of removable partial dentures .
it was also reported that the strength of the gold plating is determined by the hardness and thickness of the gold deposition on the surface .
in addition , electroplating of gold was used to enhance porcelain to metal bond strength and to minimize the discoloration of enamel , which is frequently associated with perforated and etched - metal resin - bonded retainers alike .
this article describes the use of the ghp technique to gold - coat cr - co alloy used for the fabrication of a metal ceramic restoration ( mcr ) fabricated between mandibular right second premolar and second molar .
the use of such a technique has not been reported for fixed restorations in the literature .
the aim of the use of this technique for fixed partial dentures is to minimize gray discoloration at the margins of the restorations close to the gingival sulcus and enhance the esthetics .
fabricate the mcr with cr - co alloy ( heraenium p , heraeus kulzer gmbh , hanau , germany ) ; finalize the clinical and laboratory procedures ( glaze the porcelain and polish the metal ) [ figure 1].airborne - particle abrade ( basic classic ; renfert gmbh , hilzingen , germany ) the intaglio surface with 110 m aluminum oxide , when this surface is to be coated.clean the restoration in an ultrasonic cleaner ( emmevi spa , badia polesine , italy ) and then with a steam cleaner ( vap 6-a ; emmevi spa , badia polesine , italy ) .
make sure that no debris is left on the restoration surfaces.attach contact ligature wire ( 0.25 mm ) to the metal surface of the mcr to be gold - plated .
ensure all surfaces to be gold - plated have electric contact [ figure 2].use a ligature wire ( 0.25 mm ) attached to the surfaces to be coated to hang and stabilize the mcr on the hanging device ( gramm technic gmbh , ditzingen , germany ) .
stabilize the mcr horizontally with the wire so that the intaglio is placed vertically and that gas bubbles will not be trapped inside the framework.hang the hanging device ( gramm technic gmbh , ditzingen , germany ) in the gauging tool ( gramm technic gmbh , ditzingen , germany ) to verify correct distance to the anode [ figure 3].use the contact check ( gramm technic gmbh , ditzingen , germany ) to verify if all metal surfaces of the mcr are properly connected with ligature wire ( 0.25 mm ) [ figure 4].use galvano - wax ( gramm technic gmbh , ditzingen , germany ) or insulation lacquer ( protection lacquer , gramm technic gmbh , ditzingen , germany ) to isolate , and protect the surfaces which are not going to be coated with the ghp method [ figure 5].connect the mcr to the large plating head ( gramm technic gmbh , ditzingen , germany ) with the hanging device ( gramm technic gmbh , ditzingen , germany).determine the amount of gold solution ( gramm technic gmbh , ditzingen , germany ) required to gold - plate the surfaces , taking the manufacturer recommendations into consideration [ figure 6].perform the ghp procedures in the electrolysis device following the manufacturer 's instructions ( gammat optimo 2 , gramm technic gmbh , ditzingen , germany ) . fabricate the mcr with cr - co alloy ( heraenium p , heraeus kulzer gmbh , hanau , germany ) ; finalize the clinical and laboratory procedures ( glaze the porcelain and polish the metal ) [ figure 1 ] . airborne - particle abrade ( basic classic ; renfert gmbh , hilzingen , germany ) the intaglio surface with 110 m aluminum oxide , when this surface is to be coated .
clean the restoration in an ultrasonic cleaner ( emmevi spa , badia polesine , italy ) and then with a steam cleaner ( vap 6-a ; emmevi spa , badia polesine , italy ) .
attach contact ligature wire ( 0.25 mm ) to the metal surface of the mcr to be gold - plated .
ensure all surfaces to be gold - plated have electric contact [ figure 2 ] . use a ligature wire ( 0.25 mm ) attached to the surfaces to be coated to hang and stabilize the mcr on the hanging device ( gramm technic gmbh , ditzingen , germany ) . stabilize the mcr horizontally with the wire
so that the intaglio is placed vertically and that gas bubbles will not be trapped inside the framework .
hang the hanging device ( gramm technic gmbh , ditzingen , germany ) in the gauging tool ( gramm technic gmbh , ditzingen , germany ) to verify correct distance to the anode [ figure 3 ] . use the contact check ( gramm technic gmbh , ditzingen , germany ) to verify if all metal surfaces of the mcr are properly connected with ligature wire ( 0.25 mm ) [ figure 4 ] .
use galvano - wax ( gramm technic gmbh , ditzingen , germany ) or insulation lacquer ( protection lacquer , gramm technic gmbh , ditzingen , germany ) to isolate , and protect the surfaces which are not going to be coated with the ghp method [ figure 5 ] .
connect the mcr to the large plating head ( gramm technic gmbh , ditzingen , germany ) with the hanging device ( gramm technic gmbh , ditzingen , germany ) . determine the amount of gold solution ( gramm technic gmbh , ditzingen , germany ) required to gold - plate the surfaces , taking the manufacturer recommendations into consideration [ figure 6 ] .
perform the ghp procedures in the electrolysis device following the manufacturer 's instructions ( gammat optimo 2 , gramm technic gmbh , ditzingen , germany ) .
note intaglio surfaces of the restoration are facing upwards to prevent trapping air bubbles measurement of distance between plate and restoration attached to hanging device with gauging tool evaluation of electrical contacts with contact check restoration surfaces isolated with galvano wax restoration after gold - hard - plating
there have been several studies reporting the long - term survival rates and success of mcrs .
these reported restorations were mostly fabricated with noble alloys with the addition of base metal alloys for oxidation .
corrosion and the release of metal ions over time might have been responsible for reported discoloration and gingival problems . this modified ghp technique for mcrs may minimize corrosion of base metals and the concomitant gray discoloration of the soft tissues .
the outer , intaglio surfaces , as well as only metal bands of the mcrs can be coated with gold .
livaditis and tate investigated the effect of gold - plating on cementation and esthetics of adhesive bridges .
they recommended gold - plating technique as a viable solution for reducing the discoloration problem that results from the framework in etched - metal resin - bonded prostheses .
it has been observed that the number of clinical studies related with long - term success of gold - plating technique is limited . according to rogers ,
the durability of the plating depends upon the hardness of the gold deposited and its thickness .
a thickness of up to 0.0005 inch when applied to castings does not appear to have any effect on their fit .
also , it was reported that gold - plating technique is suitable for gold - plating cobalt - chromium castings and other chrome - containing alloys by surface activation .
disadvantages of the technique include additional equipment , need for experienced laboratory technicians , cost and the need for future research for long term predictability of the technique .
in addition , the long term efficacy of this technique should be established with clinical studies .
Output:
| metal ceramic partial fixed dental prostheses have been commonly used for the replacement of missing teeth for many years . because of an increase in the price of gold ,
base metal alloys have been the choice of alloy for the fabrication of metal ceramic restorations in many dental clinics .
some major disadvantages of base metals are their corrosion and the dark coloration they may cause at the crown margins .
this article describes a galvanic gold - plating technique , which is used to minimize corrosion and improve the esthetics of metal ceramic restorations fabricated with cr - co base metal alloys .
this technique involves the deposition of a 6 m to 8 m 24 k gold layer directly onto the cr - co cast prosthesis framework .
the technique improves metal surface properties , making them more biocompatible and usable , however , requires additional equipment and experienced laboratory technicians .
clinical studies should be performed to corroborate the long term success of this technique . |
PubmedSumm118222 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: renal transplant recipients have a higher risk for infection and malignancy due to immunosuppression than the general population .
kaposi sarcoma is classified in 4 types : 1 = classic kaposi sarcoma , 2 = iatrogenic ( immunosuppressive kaposi sarcoma ) , 3 = aids - associated ( epidemic ) kaposi sarcoma and 4 = endemic kaposi sarcoma .
it is well known that kaposi sarcoma is associated with human herpes virus 8 ( hhv-8 ) . in 0.5 - 5% of seropositive transplant recipients reactivated hhv-8 leads to kaposi sarcoma [ 1 , 2 ] . in northern europe
the seroprevalence of hhv-8 is 0 - 8% , whereas in the mediterranean area and in the middle east the seroprevalence is 10 - 25% .
kaposi sarcoma after renal transplantation is mainly found in patients of the mediterranean area and of middle eastern descent .
we report for the first time a case of a successful second renal transplantation using sirolimus in a patient with a history of kaposi sarcoma . the study by stallone et al
. showed a complete remission of kaposi sarcoma after conversion from calcineurin inhibitor to sirolimus within 6 months .
we report on a 42-year - old male patient who developed kaposi sarcoma with visceral involvement 38 months after living - related renal transplantation .
the patient originates from turkey and has been living in germany since he was born .
end - stage renal disease was due to chronic glomerulonephritis , and the patient was on hemodialysis for 6 months prior to transplantation .
subsequently , the patient lost his graft 30 months after diagnosis of kaposi sarcoma due to chronic rejection .
no signs of recurrent disease were present on physical examination and on ct scan 13 months after cessation of immunosuppression .
the patient was wait - listed after a period of 10 years and received a second transplant 5 weeks thereafter .
his immunosuppressive regimen includes sirolimus ( 2 mg / day ) , mycophenolate mofetil ( 1,000 mg / day ) and prednisone ( 4 mg / day ) .
after a follow - up of 4.5 years , the patient showed stable graft function with a serum creatinine of 1.2 mg / dl ( fig .
2 ) . recurrence of kaposi sarcoma is closely monitored by physical examination and ct scans .
to our knowledge , this is the first report on a renal transplant recipient with a previous history of transplant - related kaposi sarcoma undergoing de novo renal transplantation with favorable long - term graft function and tumor control .
. reported on 15 renal transplant recipients with kaposi sarcoma in whom cyclosporine was replaced by sirolimus to achieve tumor control .
a complete remission within several months was documented for the entire patient cohort , with no impact on graft function and no acute episodes of rejection .
previously , sirolimus - based immunosuppression has been shown to protect renal transplant recipients from de novo malignancies . in renal transplant recipients diagnosed with transplant - associated kaposi sarcoma , conversion to sirolimus - based immunosuppressive protocols
however , the use of less potent immunosuppressives bears the risk of early graft loss due to acute or chronic rejection .
an immunosuppressive protocol based on antiproliferative drugs , including sirolimus and mmf , has been shown to protect renal grafts from rejection and to provide reliable tumor control as compared to standard calcineurin - based immunosuppression .
our present case and recent literature suggest that de novo renal transplantation in recipients with a history of transplant - associated malignancy is feasible using an immunosuppressive protocol based on sirolimus and mmf .
Output:
| immunosuppressive treatment increases the risk of infection and malignancy in organ transplant recipients .
we report on a 42-year - old male renal transplant recipient who lost his first graft after reduction of immunosuppressive treatment due to kaposi sarcoma and who successfully underwent a second renal transplant 10 years later .
the patient 's current treatment consists of low - dose prednisone , and the two antiproliferative immunosuppressants mycophenolate mofetil and rapamycin .
4.5 years after his second transplant , the serum creatinine is 1 mg / dl and the patient has no signs of recurrent disease . |
PubmedSumm118223 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: in the past decade , rapid progress has been made on the origin and evolution of new genes thanks to the genomics revolution .
many cases of gene birth are now documented , and they have revealed that the mechanisms for new gene formation are surprisingly diverse . they include dna - based duplication , rna - based duplication ( retroposition or retroduplication ) , gene fusion ( chimerization ) , de novo gene origination , domestication of transposable elements , and horizontal gene transfer [ 1 , 2 ] . remarkably , many new genes show a male - biased expression and a majority of these are actually specifically expressed in the testis .
indeed , this organ seems to have a critical role in gene birth and evolution .
two of the first documented cases of gene origination , pgk2 in mammals and jingwei in drosophila , are both testis - specific [ 3 , 4 ] .
more recent work on retroduplication showed an overall propensity of young retrogenes to be testis specific [ 5 , 6 ] .
other types of new genes also tend to show testis - specificity or testis - biased transcription ( e.g , [ 712 ] ) .
several explanations have been proposed for this tendency of new genes to be testis specific [ 1 , 13 , 14 ] .
the first explanation relies on a peculiarity of sex chromosome biology called msci ( male sex chromosomes inactivation ) . in mammals and c. elegans ,
the sex chromosomes are inactivated during male meiosis , probably as a consequence of a general mechanism to avoid recombination between nonhomologous sequences [ 15 , 16 ] .
msci is expected to drive genes expressed during male meiosis out of the sex chromosomes .
this was observed by looking at retrogenes in mammals [ 1719 ] . in mice ,
in particular , it has been shown that the x parental genes are ubiquitously expressed except in testis , and this is complemented by a testis - specific expression of their daughter autosomal retrocopies in agreement with the escape from msci hypothesis . in drosophila ,
exodus of testis - specific genes out of x affects rna - based and possibly dna - based duplicates .
however , the actual contribution of msci to this phenomenon and even the very existence of msci in drosophila are actively debated issues [ 2126 ] .
another hypothesis has been proposed to explain this above - mentioned pattern , especially in drosophila where msci is controversial .
it involves the interaction between dosage compensation ( dc ) and sex - biased expression [ 24 , 27 , 28 ] . the massive y gene loss or silencing generates an imbalance of expression for x - linked genes compared to autosomal genes in males .
dc mechanisms have evolved to even x and autosomal gene expression . in mammals , where one x is inactivated in females ,
the x is hypertranscribed in both sexes , while in drosophila the x is hypertranscribed in males [ 29 , 30 ] . in drosophila
, male - biased genes have been shown to evolve mostly by hyperexpression in males only [ 28 , 31 ] .
however , such evolution of male - biased expression is difficult on the x chromosome because it is already hypertranscribed due to dc . in agreement with this model
, it has been shown that highly expressed male - biased genes are underrepresented on the x chromosome and that dosage - compensated x genes tend to have autosomal retrocopies with male - biased expression
. however , the escape from msci and escape from dc hypotheses can only explain the evolution of new testis - specific genes involving the relocation out of the sex chromosomes but not those involving autosomes only .
another more general explanation has been recently proposed [ 13 , 14 ] . in species with two sexes , mutations with sex antagonism ( beneficial for one sex ,
the presence of two sex - antagonistic alleles of a gene can cause an intralocus sexual antagonism . evolving sex - biased expression
however , this can not work for housekeeping genes that need to be expressed in both sexes . in this case
, duplication can resolve the intralocus sexual conflict , with the parental copy remaining expressed in both sexes and the new one being expressed only in one sex .
data in drosophila suggests that testis is the tissue where sex antagonism is by far the strongest , and most male - biased genes are indeed expressed in testis . in practice , solving intralocus sex conflict for housekeeping genes will imply getting a new copy expressed in testis [ 13 , 14 ] .
reported that 83% of the relocated copies of the mitochondrial genes found in the nuclear genome exhibit testis - specific expression .
importantly , about half of these relocation events involved autosomes only and could not be explained by the
dn / ds analysis of these genes suggested that the testis - specific copies tend to evolve under positive selection .
other examples of housekeeping genes show similar patterns , which fits well with the idea of resolving sexual conflict by duplication [ 13 , 14 , 36 ] .
finally , testis - specific new genes may be more common just because new genes arise more easily when expressed in the testis ( the out of testis hypothesis , see ) . in mammals , the chromatin in male germ cells is characterized by the presence of histone variants and histone marks favoring open chromatin , widespread demethylation of cpg - enriched promoters , and elevated levels of the transcription machinery components [ 37 , 38 ] .
similarly , in drosophila primary spermatocytes , very high level of transcriptional activity ensures the production of most mrnas required for the postmeiotic differentiation program of male germ cells [ 2 , 39 ] .
this highly permissive state of chromatin as well as other peculiar features of male germ cells may have facilitated the expression of newly arisen genes in testis during their early evolution .
we review the case of the hiphop / k81 telomere capping genes in drosophila , for which detailed functional studies are available .
we also present new results on the evolution of the hiphop / k81 genes and discuss functional and evolutionary data with respect to the hypotheses presented above .
telomeres are essential structures at the end of eukaryotic chromosomes that are generally composed of highly repetitive dna associated with specific proteins . the elongation of repetitive telomeric dna counteracts the slow erosion of chromosome arms caused by the incomplete replication of dna extremities at each s - phase .
telomere elongation is mediated in most eukaryotes by the conserved enzyme telomerase , a reverse transcriptase that adds small g - rich repeats , such as ( ttaggg)n , at the end of chromosomes .
in addition , telomeres function as protective caps that prevent the recognition of chromosome ends as dna double - strand breaks by the dna repair machinery and their irreversible and deleterious ligation [ 4143 ] . in most eukaryotes , this capping function is largely dependent on several dna binding proteins that specifically recognize the small repeats added by the telomerase complex .
drosophila represents an exception in telomere biology as this model organism lacks telomerase . in this species ,
the end replication problem is solved in an original manner , by the controlled insertion of specialized telomeric retrotransposons at chromosome extremities .
although repetitive by nature , drosophila telomeric dna thus lacks large arrays of small repeat motifs and associated binding proteins . instead , the capping function of drosophila telomeres is ensured by proteins that possess the remarkable ability to bind chromosome ends in a sequence - independent manner [ 4547 ] .
well - characterized drosophila capping proteins include hoap , hp1a , modigliani ( moi ) , verrocchio ( ver ) , and hiphop [ 4853 ] .
mutations affecting capping genes are all zygotic lethal and induce chromosome end - to - end fusions that are detectable in rapidly dividing cells .
telomere fusions form dicentric chromosomes that break in mitotic anaphase result in genomic instability . despite their critical role for the maintenance of genome integrity , drosophila capping proteins are rapidly evolving . with the exception of heterochromatin protein 1a ( hp1a ) , which has additional functions in the nucleus , and possibly the ob - fold containing protein ver
, other capping proteins do not seem to have any ortholog in yeasts , mammals , or plants .
the drosophila ms(3)k81 ( k81 ) gene was originally identified through a unique male sterile mutation found in a japanese population of d. melanogaster .
however , the resulting embryos invariably die before hatching , a phenotype which actually makes k81 one of the very rare paternal effect , embryonic lethal mutations .
furthermore , eggs fertilized by k81 mutant sperm develop as nonviable , aneuploid , or haploid embryos , after the loss of paternal chromosomes during the first zygotic nuclear division [ 5456 ] . despite the critical requirement of k81 for the integration of paternal chromosomes into the diploid zygote , its molecular identification unexpectedly revealed a small , intronless gene , encoding a nonconserved protein .
in fact , the k81 gene appeared restricted to the nine species comprising the melanogaster subgroup .
loppin et al . also identified another gene paralogous to k81 , now known as hiphop , which was present in species of the melanogaster subgroup as well as in the more distantly related d. pseudoobscura genome .
the conserved synteny around the hiphop locus in d. melanogaster and d. pseudoobscura strongly indicated that hiphop was the ancestor gene , while k81 appeared after the duplication of hiphop at the root of the melanogaster subgroup .
the hiphop gene is located in chromosome arm 3l and has a unique predicted intron immediately upstream its coding sequence .
hiphop is expressed in most tissues at low to moderate levels , but it is also strongly transcribed in adult ovaries , suggesting that the hiphop protein is required during early embryo development .
in contrast to hiphop , k81 expression is essentially restricted to the male germline , and adult flies homozygous for a k81 null allele are viable .
the k81 gene ( chromosome arm 3r ) has no intron and presumably shares its 5 regulatory sequences with its neighbor gene rb97d , which is also strongly expressed in the testis .
taken together , these features fit well with a retroposition event at the origin of k81 .
more recently , the independent findings that hiphop and k81 encoded telomere capping proteins [ 57 , 58 ] eventually provided the functional frame that was required to revisit the molecular evolution of these paralogs .
hiphop and k81 are small proteins ( 221 and 184 residues , resp . ) that do not display any known domain or motif .
hiphop was originally implicated in telomere biology through its physical interaction with the hoap and hp1a capping proteins .
furthermore , knocking down hiphop in somatic cells induces telomere fusions at high frequency indicating that hiphop is critical for the capping of chromosome ends .
finally , the hiphop protein is specifically enriched at telomeres and this localization occurs independently of the dna sequence .
similarly , k81 was demonstrated to associate with telomeres in the male germline , in a way similar to hiphop in somatic cells . indeed , functional gfp::k81 fusion protein was observed at telomeres in spermatocytes as well as in postmeiotic spermatids and in mature gametes [ 5759 ] . in spermatids
, gfp::k81 accumulates into a small number of foci ( that presumably correspond to clustered telomeres ) that also contain hoap and hp1a , but not hiphop . during the condensation of spermatid nuclei in drosophila as in many animals ,
histones are massively replaced by sperm - specific , nonhistone chromosomal proteins such as protamines .
interestingly , in the absence of k81 , hoap and hp1a are not maintained at telomeres after the histone - to - protamine transition , suggesting that k81 is required for the stability of the capping complex in the peculiar chromatin environment of condensing spermatid nuclei . using the gfp::k81 transgene allowed to demonstrate that the k81 capping protein remains associated with paternal telomeres until zygote formation , where it is required for the protection of paternally - transmitted telomeres .
accordingly , in eggs fertilized by k81 sperm , paternal chromatin bridges resulting from telomere fusions are observed during the first mitosis [ 55 , 57 , 58 ] .
after fertilization , maternally provided hiphop progressively replaces k81 at paternal telomeres , which is no longer detectable after two or three nuclear cycles
. why does drosophila melanogaster require a second hiphop - related protein to protect telomeres in postmeiotic germ cells when other species outside the melanogaster subgroup only have a single hiphop gene ?
first , experimental evidence clearly indicates that hiphop is not capable to functionally replace k81 in the male germline .
indeed , a transgene expressing hiphop in male germ cells using the k81 regulatory sequences can not restore the fertility of k81 mutant males [ 57 , 58 ] .
interestingly however , hiphop is nevertheless capable of restoring hoap and hp1a foci at telomeres in early spermatid nuclei , but all three capping proteins eventually disappear when histones are replaced with protamines .
thus , these observations support the idea that k81 has become specialized in protecting telomeres in the highly peculiar chromatin environment of condensing spermatid nuclei .
second , and quite remarkably , the single hiphop - related protein of d. virilis ( which lacks k81 ) was found associated with telomeres throughout spermiogenesis , strongly indicating that the ancestral hiphop gene in the melanogaster lineage was required to protect telomere in all cells , including male germ cells .
taken together , these studies suggest a reproductive subfunctionalization by duplication - degeneration - complementation ( ddc ) ( see ) , in which the ancestral hiphop lost its ability to protect telomeres in postmeiotic germ cells after the gene duplication event . meanwhile , the duplicated copy acquired male germline specific expression and specialized in the capping of telomeres in the peculiar sperm chromatin environment .
this scenario is actually supported by the analysis of nonsynonymous and synonymous nucleotide substitutions of hiphop and k81 sequences , which indicated that these genes evolved under purifying selection as in the typical ddc model .
based on the first available twelve drosophila sequenced genomes , the hiphop / k81 duplication appeared specific to the melanogaster subgroup of species . notably ,
the hiphop gene was found at the same genomic position in all species of the sophophora subgenus while k81 was restricted to the melanogaster subgroup .
this view , however , was biased by the absence of sequenced genomes belonging to the other subgroups comprising the melanogaster group .
indeed , this large and complex group includes at least ten subgroups with many species that can be partitioned into three main phylogenetic clades .
recently , the genome sequences of eight additional species representative of several other subgroups in all three clades were released by the modencode consortium ( modencode.org ) and were made available by flybase ( flybase.org ) .
interestingly , our combined blast analyses and microsynteny comparisons revealed an unsuspected diversification of the hiphop family in the melanogaster group ( figure 1 ) .
first , the k81 gene is also present in species from four other subgroups belonging to clade iii : ficusphila , eugracilis , takahashi , and suzukii ( represented by d. biarmipes ) .
conversely , within the melanogaster group , k81 is absent from the two available species from clade i ( d. ananassae and d. bipectinata ) and from the single representative species of clade ii ( d. kikkawai ) .
thus , k81 appears to have a broader phylogenetic distribution than initially thought , and the gene duplication event at the origin of this gene probably occurred at the base of clade iii ( figure 1 ) .
we have also noticed the absence of k81 in two species of clade iii ( d. elegans and d. rhopaloa ) where it is presumably replaced by a paralog at another genomic position ( k81-like , in orange in figure 1 ) .
interestingly , synteny block comparisons indicates that these two k81-like genes are apparently located on the x chromosome ( table 1 ) , in contrast to the general tendency of testis - specific retrogenes to avoid the x [ 5 , 20 ] .
finally , we observed that the original hiphop gene was independently lost or relocated at least at three occasions . in d. bipectinata and d. ananassae
( clade i ) , hiphop is apparently replaced by a single hiphop - like paralog . in d. ficusphila and d. takahashi ( clade iii ) ,
hiphop is absent but one or two additional paralogs are present , in addition to the original k81 gene .
interestingly , one of the new paralogs found in species of clade iii ( represented in light gray in figure 1 ) is conserved between d. ficusphila , d. elegans , and d. rhopaloa , but not in the d. eugracilis lineage .
thus , the repertoire of hiphop / k81 related genes in the drosophila group of species is extremely dynamic , with multiple gene gains and losses observed at several levels of this radiation .
some species have three members of this gene family in their genomes , while all other species have either one or two .
the fact that at least one hiphop - related capping gene is present in all drosophila genomes sampled so far underlines the essential role of these genes for telomere protection .
importantly , the tendency of hiphop to duplicate is not restricted to the melanogaster group since an independent duplication of this gene occurred in the lineage leading to d. willistoni ( willistoni group ) (; figure 1 ) .
based on a combination of k81/hiphop protein alignment and complementation tests with mutant proteins , gao and colleagues proposed that a small qfvh motif near the c - terminus of k81 is critical for the protection of telomeres in mature gametes .
interestingly , in hiphop proteins from the melanogaster subgroup , this motif is replaced with a ptv tripeptide which functions in somatic cells but not in mature male gametes . however , non - melanogaster species that harbor a single hiphop - related gene display a male germline - like motif which also begins with a glutamine residue as in qfvh .
the presence of such a motif is probably important for these proteins to fulfill their role in all cells , including postmeiotic male germ cells .
we have extended this analysis to the new available members of the family and found that this tendency is generally confirmed for the additional proteins .
for instance , the k81-like proteins from d. elegans and d. rhopaloa ( figure 1 and table 1 ) .
in addition , the single hiphop - like proteins from d. bipectinata ( clade i ) and d. kikkawai ( clade ii ) have also a motif of the male germline type ( qflv ) .
the only exception is d. ananassae where the single hiphop protein is apparently of the somatic type ( ptii ) .
the highly dynamic repertoire of k81/hiphop genes reported here is remarkable and suggests that a constant evolutionary pressure is forcing this gene diversification ( see below ) .
one can wonder whether other telomere capping genes display a comparable level of evolutionary instability and , notably , those that are known to functionally interact with hiphop and k81 . a great diversity of hp1 paralogs has already been documented in drosophila , but the situation is complicated by the fact that hp1a is associated with several other important functions not related to telomere capping . in contrast , the other k81/hiphop partner hoap is only required for telomere protection . in d. melanogaster
, the hoap protein is encoded by a unique and essential gene named caravaggio ( cav ) .
hoap is a fast evolving protein , which belongs to the drosophila terminin complex of telomere proteins [ 46 , 64 ] .
this complex also contains two other proteins , ver and moi , which are also rapidly evolving as demonstrated by dn / ds analyses of their respective genes .
interestingly , a recent study has reported the existence of three independent duplication of the cav gene outside the melanogaster group , in the d. willistoni , d. virilis , and d. pseudoobscura / d .
the presence of introns in these cav duplicates strongly suggests that these duplications occurred through a dna - based mechanism .
we found two additional independent duplication events in the recently released melanogaster group genomes ( d. ficusphila and d. elegans / d .
thus , although the presence of a syntenic cav gene in all drosophila genomes sequenced so far indicates that this gene is probably more ancient than hiphop , it is also subjected to recurrent duplication events .
if the functional partitioning of these paralogs is well established by experimental and phylogenetic analyses , we now face the challenge of understanding the nature of the evolutionary force responsible for the birth of k81 .
escape from msci and escape from dc can not explain the case of hiphop / k81 since both parental and daughter copies are autosomal , at least in the melanogaster subgroup . in the light of the duplication - degeneration - complementation classical model , the specialization of k81 in the capping of sperm telomeres as well as its restricted expression in the male germline
are interpreted as the result of differential loss of function ( i.e , subfunctionalization ) of the duplicated copies [ 5759 ] . in agreement with the ddc model
, hiphop performs both somatic tissues and sperm - telomere capping in species without duplicates while in d. melanogaster , hiphop has lost its ability to protect chromosome ends in spermatids . indeed
however , a simple subfunctionalization scenario does not predict the observed recurrent duplications of these capping genes that we have found here .
a possibility is that the expression of a gene in testis increases the chance to get a testis - specific duplicate for mechanistic reasons ( see the out of testis hypothesis in the introduction ) .
the high gene turnover observed within the hiphop / k81 gene family is more consistent with ongoing sexual conflicts , as recently proposed by gallach and betrn .
their model states that a preexisting sexual conflict between different alleles of a gene could be solved by a gene duplication event and the acquisition of testis - specific expression of the duplicate .
they propose that many testis - specific gene duplicates could have emerged under this scenario , including k81 .
this model implies that the ancestor gene plays an essential function in all cells ( housekeeping gene ) , which is indeed the case of hiphop , as demonstrated by its associated lethal mutant phenotype and its critical protection of chromosome ends .
in contrast , the duplicate gene k81 is specifically expressed in the male germline and is first detected in spermatocytes .
the k81 protein then decorates telomeres throughout spermiogenesis ( postmeiotic stages of spermatogenesis ) and after fertilization on paternal chromosomes [ 57 , 58 ] .
hiphop is actually also expressed in the male germline , but only in premeiotic cells . moreover , as previously mentioned , complementation analyses have demonstrated that hiphop and k81 have functionally diverged .
although this divergence could reflect an initial sexual conflict between different allelic variants of the ancestor protein , the gallach and betrn model states that acquisition of a testis - specific duplicate could also solve conflicting constraints on the expression of a ubiquitous parental gene .
indeed , genes that are specifically expressed in male germ cells are characterized by peculiar 5 ' regulatory elements and are often clustered in genome regions , suggesting the existence of higher order chromatin structure that favors transcription in spermatocytes or even in postmeiotic spermatids ( reviewed in ) . in this context , the existence of a duplicated copy could provide a more robust expression in the male germline than the ubiquitously expressed parental gene .
this prediction could be experimentally tested by comparing the expression of hiphop / k81-like genes in species where a duplication has occurred or not .
these features fit with the possible existence of an initial sexual antagonism at the ancestor locus , which has been resolved by duplication followed by the specialization of the new copy .
the fact that hiphop is actually expressed in the male germline is in apparent contradiction with this hypothesis .
however , the critical difference between hiphop and k81 is their differential expression in postmeiotic germ cells .
indeed , k81 regulatory sequences drive robust and specific expression of k81 in spermatids , while the ubiquitously expressed hiphop is essentially excluded from these differentiating cells .
thus , the birth of k81 may have removed this possible source of conflict at the ancestor locus . in this model , telomere capping genes that do not function in postmeiotic male germ cells are not expected to give rise to testis - specific duplicates .
it would thus be interesting to investigate the distribution and function of other essential telomere capping genes in the male germline , such as ver and moi , that do not show any duplicate in the species analyzed in the present study ( not shown ) .
interestingly , our phylogenetic analysis of the cav ( hoap ) gene revealed a rather different diversification pattern .
in contrast to hiphop , cav duplication events seem to occur only through a dna - based mechanism , and we did not observe any obvious correlation between the hiphop / k81 and the cav respective diversification patterns .
cav is notably characterized by the presence of a fixed parental gene throughout the analyzed genomes , which is not the case for hiphop .
observed that the d. willistoni cav - dup is specifically ( albeit weakly ) expressed in males , but the other cav duplicates are expressed in both sexes .
thus , despite their apparent close functional relationship , these telomere genes are probably not subjected to the same evolutionary constraints . in addition
the molecular identification of the k81 paternal effect gene about a decade ago was soon followed by the surprising observation that this essential male fertility gene in d. melanogaster was absent in the only other sequenced drosophila genome available at that time ( d. pseudoobscura ) .
we now know that the acquisition of essential functions by recently evolved genes is not exceptional .
a large - scale functional analysis of recently arisen genes in drosophila revealed that most of them rapidly acquire essential developmental functions .
the functional characterization of new genes is invaluable to approach the intimacy of the evolutionary forces responsible for their origination and selection .
our phylogenetic analysis of the hiphop / k81 gene family over twenty drosophila species has revealed a highly dynamic pattern of gene gains and losses . instead of our initial vision of a sporadic event specifically affecting the melanogaster subgroup ,
future work should aim at determining if this diversification is compatible with the resolution of a sexual antagonism or with the out of testis hypothesis .
Output:
| comparative genome analysis has allowed the identification of various mechanisms involved in gene birth . however , understanding the evolutionary forces driving new gene origination still represents a major challenge .
in particular , an intriguing and not yet fully understood trend has emerged from the study of new genes : many of them show a testis - specific expression pattern , which has remained poorly understood . here
we review the case of such a new gene , which involves a telomere - capping gene family in drosophila .
hiphop and its testis - specific paralog k81 are critical for the protection of chromosome ends in somatic cells and male gametes , respectively .
two independent functional studies recently proposed that these genes evolved under a reproductive - subfunctionalization regime .
the 2011 release of new drosophila genome sequences from the melanogaster group of species allowed us to deepen our phylogenetic analysis of the hiphop / k81 family .
this work reveals an unsuspected dynamic of gene birth and death within the group , with recurrent duplication events through retroposition mechanisms .
finally , we discuss the plausibility of different evolutionary scenarios that could explain the diversification of this gene family . |
PubmedSumm118224 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
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Input: gastric cancer remains one of the most frequently occurring malignancies , and ranks as the second leading cause of mortality next to lung cancer 1 .
although alterations in a large number of oncogenes and tumor suppressor genes have been reported in gastric carcinomas 2 , the molecular mechanisms underlying the pathogenesis of gastric carcinomas remain to be fully defined .
mirnas are small , noncoding , single - stranded rnas that bind to complementary sequences in the 3 ' untranslated region ( utr ) of their target mrnas and induce mrna degradation or translational repression 3 .
characteristic mirna signatures have been identified for human gastric cancer , which predict disease status and clinical outcome 4 - 9 . among them , mir-148a was one of the most frequently downregulated mirnas in mirna profiles of gastric cancers 4 , 7 , 8 , and correlated with tumor size 9 and node metastasis 7 .
previous studies have shown that mir-148a plays important roles in cancer cell proliferation , response to anti - cancer chemotherapy , and metastasis in some tumor types including cholangiocarcinoma , prostate , esophageal and colon cancers 10 - 15 .
for instance , downregulation of cytokine interleukin-6-regualted mir-148a contributes to cell proliferation by its target dnmt1 in malignant cholangiocytes 10 . in prostate cancer pc3 cells
, mir-148a could inhibit cell proliferation , migration and invasion , and increase the sensitivity to anti - cancer drug 11 .
however , the functional roles and target genes of mir-148a in gastric cancer remain unknown . in this study , we investigated the role of mir-148a in cell proliferation of gastric cancer cells .
conversely , transient and stable overexpression of mir-148a promoted cell proliferation and cell cycle progression .
moreover , p27 , a key inhibitor of cell cycle , was identified as the direct target of mir-148a , suggesting that mir-148a might exert its function through the downregulation of p27 .
finally , we confirmed that mir-148a expression was frequently downregulated in human advanced gastric cancer tissues , and observed a good inverse correlation between mir-148a and p27 expression in tumor samples . taken together
, our findings suggested that mir-148a downregulation might exert antagonistic function in gastric cancer cell proliferation during gastric tumorigenesis .
to explore the tissue - specific expression pattern of mir-148a , we detected mir-148a expression in different tissues of mouse by northern blot .
mir-148a expression was relatively high in stomach , heart , intestine , colon and liver ( fig .
1a ) . to visualize the spatial localization of mir-148a in whole - stomach tissue of mouse , we applied locked nucleic acid in situ hybridization . unlike with the mismatch control probe ( scrambled mirna ) , hybridization with mir-148a - specific probe revealed that mir-148a was expressed at the bottom half of glandular gastric epithelium , where parietal and chief cells resided ( fig .
several independent lines of evidence have shown that mir-148a was one of the most frequently downregulated micrornas in human gastric carcinomas 4 , 7 , 8 .
these studies led us to speculate that mir-148a dowregulation could contribute to gastric cell proliferation .
northern blot results showed that mir-148a expression in ags , bgc-823 and sgc-7901 cells was relatively higher than that in ges-1 , bgc-803 and snu-16 cells ( fig .
next , to evaluate the role of mir-148a downregulation in gastric cancer cells , we engineered mir-148a with antisense oligonucleotides ( mir-148a as ) to decrease the endogenous mir-148a expression in 3 human gastric cancer cell lines , ags , bgc-823 and sgc-7901 , respectively .
cellular proliferation assays were performed on the mir-148a - as - tranfected cells . to our surprise ,
mir-148a knockdown inhibited cell proliferation by 20 - 40% after 96 hours in ags , bgc-823 , and sgc-7901 cells ( fig .
2c , p<0.05 ) . to substantiate the function of mir-148a in gastric cell proliferation , we transfected ags cells with mir-148a mimic .
consistent with our prediction , the cell numbers of mir-148a - transfected ags cells at 72 and 96 hours were found to be increased by 42% and 48% , respectively , compared with that of scrambled - mirna - transfected cells ( fig .
2d , p<0.05 ) . moreover , we established a stable cell line ( ags - mir-148a ) in which mir-148a expression was significantly higher than that in ags stably transfected with empty vector ( ags - vector ) ( fig .
consistently , the cell numbers of ags - mir-148a at 48 and 72 hours were increased by 18% and 30% , respectively , compared with that in control cells ( fig .
the proportion of cells corresponding to s phase was higher in mir-148a - transfected ags ( 34%2.9% ) than that in control cells ( 26%2.1% , p<0.05 , fig .
these data suggested that mir-148a could promote cell proliferation by increasing the population of cells in s phase .
in addition , we checked the effect of mir-148a on apoptosis by facs analysis , and no obvious differences were observed between mir-148a - tansfected ags cells and control cells ( fig .
2h ) . to determine the mechanisms by which mir-148a promotes gastric cell proliferation , bioinformatics analysis was performed to search for mir-148a targets .
cdnk1b ( encoding p27 ) , a gene critical for cell cycle 15 , was predicted as a putative target of mir-148a ( fig .
p27 mrna 3'utr has a single predicted binding site that is highly conserved in mammals , and in chicken ( fig .
p27 mrna 3'utr encompassing the predicted binding site with or without mutation that would disrupt mirna interaction ( underlined in fig .
3a ) , were inserted to the downstream of luciferase open reading frame in pgl3-cm reporter vector . when introduced into sgc-7901 cells , the wild type p27 3'utr reporter showed a 39% reduction in luciferase activity in the mir-148a - transfected cells compared with that in scrambled - mirna - transfected cells ( fig .
mutation of mir-148a binding site abrogated the repression of luciferase activity caused by mir-148a overexpression ( fig .
next , we pursued the ability of mir-148a to regulate the expression of endongenous p27 .
conversely , mir-148a knockdown by as dramatically enhanced p27 expression in bgc-823 cells ( fig .
3c ) , indicating that endogenous mir-148a could regulate p27 abundance . to examine the functional interrelationship between mir-148a and p27
, ags cells was simultaneously transfected with mir-148a mimic and p27-expressing vector ( cmv - p27 ) .
as expected , overexpression of p27 dramatically rescued mir-148a - induced growth promotion ( fig .
3d , p<0.01 ) , indicating that mir-148a enhanced cell proliferation possibly by repressing p27 .
finally , we detected the expression of mir-148a and p27 in 10 advanced gastric primary tumors , each one paired with adjacent nontumor gastric tissue from the same patient ( fig . 4a and 4c ) .
northern blot assays showed that the reduced expression of mir-148a was found in 100% ( 10/10 ) of human advanced gastric tumor tissues as compared with adjacent normal counterparts ( fig . 4a and 4b , p=0.005 ) , indicating that mir-148a downregulation was a very common event in advanced gastric cancer .
furthermore , the inverse correlation was observed between mir-148a and p27 in tumor samples ( r=0.648 , fig .
4d ) , suggesting that mir-148a could negatively regulate p27 expression in human gastric cancer .
previous studies have shown that mir-148a could target its distinct targets to regulate cell proliferation in some cancer cells 10,12,16 .
dnmt1 , a direct target of mir-148a , plays important role to suppress cell proliferation in malignant cholangiocytes 10 .
mir-148a , also targets and suppresses microphthalmia associated transcription factor ( mitf ) , an important regulator involved in melanoma progression 16 . in the present study
, we identified a new target , p27 , possibly by which mir-148a could promote cell cycle progression and cell proliferation .
similarly , mir-148a could promote cell growth by repressing its target cand1 expression in prostate cancer lncap cells 12 .
these findings indicated that the different roles of mir-148a in regulating cell proliferation might depend on its distinct targets in different tumor cell types .
mir-148b , which has the same seed sequence as mir-148a , was downregulated in gastric cancer , and could inhibit cell proliferation by targeting cckbr 17 . although cckbr was a predicted target of mir-148a by bioinformatic analysis , it was not a real target of mir-148a by western blot and luciferase reporter assay in our experimental system ( data not shown ) , indicating that mir-148a and mir-148b , both belonging to the same microrna family , might exert opposite roles in one cell type possibly by regulating distinct targets .
in this study , we observed that mir-148a was frequently downregulated in human advanced gastric cancer samples .
we also showed that inhibition of mir-148a suppressed cell proliferation in different gastric cancer cell lines possibly by upregulating its target p27 , suggesting that mir-148a downregulation in human gastric cancer might inhibit but not promote gastric cancer cell proliferation during gastric tumorigenesis .
some evidence has shown that mir-148a is associated with migration , metastasis , and drug resistance in some tumor types 7,11,13,14 , indicating that mir-148a downregulation might contribute to these biological processes in gastric cancer .
in fact , we also found that mir-148a overexpression with mimic could promote gastric cell migration ( fig .
in this study , we investigated the role of mir-148a in regulating cell proliferation of gastric cancer cells .
we observed that mir-148a expression was frequently and dramatically downregulated in human advanced gastric cancer tissues compared with the matched adjacent normal tissues .
we further showed that transient and stable overexpression of mir-148a could promote cell proliferation and cell cycle progression .
moreover , p27 , a key inhibitor of cell cycle , was verified as a direct target of mir-148a , suggesting that mir-148a might promote gastric cell proliferation by depressing p27 expression .
collectively , our findings indicated that mir-148a downregulation might exert some sort of antagonistic function in gastric cancer cell proliferation during gastric tumorigenesis .
paired gastric cancer and adjacent non - tumor gastric tissues were obtained after review and approval by the general surgery department of pla general hospital of china .
tissue samples were immediately frozen in liquid nitrogen until rna extraction . cell culture and transfection .
the gastric cancer cell lines ags , ges-1 , snu-16 , mgc-803 , bgc-823 and sgc-7901 were cultured in dulbecco 's modified eagle medium supplemented with 2 mm l - glutamine , 1% penicillin / streptomycin , and 10% fetal bovine serum ( hyclone ) at 37 and 5% co2 .
ags , bgc-823 and sgc-7901 cells were individually plated onto tissue culture plates or dishes 24 hours before transfection .
transient transfection of mirna mimics or anti - sense ( as ) and control oligonucleotides ( genepharm ) at a final concentration of 50 nm was accomplished with lipofectmine 2000 reagent ( invitrogen ) . to establish stably transfected ags , pires2-egfp vector ( bd bioscience )
the primers for pcr amplification are : sense , 5'- aaaagatctgaacacacctgcaggaagaa-3 ' , anti - sense , 5'- aaaaaagcttctggcgtctggagcactg-3 ' .
cells were harvested and processed by standard methods by using propidium iodide staining of cell dna .
histograms were analyzed for cell cycle compartments using modfit version 2.0 ( verity software house ) .
210 cells were seeded into 24-well plate in triplicate , and the cell number was counted 48 , 72 or 96 hours later under microscope using a hemocytometer .
ags cells were treated with etoposide ( 30g / ml ) or a matched concentration of diluents for 48 hours .
after the treatment , cells were rinsed twice in cold pbs , and then analyzed for apoptosis by a pe - labeled annexin - v/7-aad assay .
cell samples ( 10,000 events ) were analysed in a facscan flow cytometer ( bd biosciences ) , and data were processed using facscan software .
the 3'utr region of human p27 mrna that containing mir-148a target site was amplified using specific primers : sense , 5'- ccgctcgaggtttatcagatacatcactgcttga-3 ' , anti - sense , 5'- ccgacgcgtttggctcagtatgcaacctttt-3 ' , and cloned into pgl3-cm to generate luciferase reporter vector .
reporter vectors were co - transfected with renilla luciferase expressing vector to normalize transfection efficiency .
luciferase activity assays were done at 48 hours after transfection using a dural - luciferase reporter assay system ( promega ) using lb 960 centro xs3 luminometer ( berthold technologies ) .
northern blot analysis was performed as described using 20 g total rna from each sample 18 .
probes were labeled with 32p -atp using t4 polynucleotide kinase ( new england biolabs ) .
mirna in situ hybridization was performed as previously described 19 using locked nucleic acid ( lna ) probes complementary to mouse mature mir-148a ( exiqon ) or scrambled control sequence ( exiqon ) .
proteins ( 25 ug ) were electrophoresed on sds - page and transferred onto pvdf membranes .
immunoblotting was done using human p27 ( cell signaling ) and gapdh ( zsgb - bio ) antibodys .
statistical analysis was performed by 2-tailed student 's t test , and results were considered statistically significant at p < 0.05 .
wilcoxon signed rank test was used to analyze the statistically significant downregulation of mir-148a expression in gastric cancers .
this work was supported by grants 2011cb504200 and 2011cb901601 from chinese national key program on basic research , grant 2009zx09501 - 027 from the chinese key program for drug invention , grant 2009zx10002 - 016 from the chinese key project for the infections disease , grants 31030040 , 30700423 and 30900863 from national natural science foundation of china , and grant 5082018 from beijing natural science foundation of china .
Output:
| accumulating evidence has shown that mirnas are aberrantly expressed in human gastric cancer and crucial to tumorigenesis .
herein , we identified the role of mir-148a in gastric cell proliferation .
mir-148a knockdown inhibited cell proliferation in gastric cancer cell lines .
conversely , mir-148a overexpression promoted cell proliferation and cell cycle progression .
p27 , a key inhibitor of cell cycle , was verified as the target of mir-148a , indicating mir-148a might downregulate p27 expression to promote gastric cell proliferation .
moreover , we confirmed that mir-148a expression was frequently and dramatically downregulated in human advanced gastric cancer tissues , and observed a good inverse correlation between mir-148a and p27 expression in tumor samples .
thus , our results demonstrated that mir-148a downregulation might exert some sort of antagonistic function in cell proliferation , rather than promote cell proliferation in gastric cancer . |
PubmedSumm118225 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: chronic subdural hematoma ( csdh ) is one of the predominant neurological diseases in the elderly patients .
csdh is defined as a cystic collection of old hematoma and blood breakdown products between the outer and inner membranes in the subdural space ; it usually develops 1 or 2 months after a minor head injury.2 ) in general , a high treatment success rate and good prognosis for csdh can be expected by a simple procedure of burr - hole trephination ( bht ) and closed - system drainage under local anesthesia.3 ) the incidence of post - operative seizure in patients who underwent bht for csdh is known to be about 5%.1 ) therefore , the use of prophylactic antiepileptic drug after bht for csdh has been controversial . here ,
we present a case of fatal status epilepticus with progressive respiratory complication following early discontinuation of prophylactic antiepileptic drug in an 84-year - old man who had undergone bilateral bht and closed - system drainage for bilateral csdh .
an 84-year - old man , experiencing dizziness and headache for 2 weeks , was admitted to our hospital . approximately 1 month before admission
seven years before the present admission , he had undergone radical nephrectomy surgery for renal cell carcinoma .
he had also been taking medications for hypertension and asthma for the past several years .
cranial computed tomography ( ct ) scans revealed csdh with mixed densities on the bilateral cerebral convexities with mass effects ( figure 1 ) .
prophylactic antiepileptic drug with intravenous valproic acid 1,200 mg was administered pre - operatively on the operation day .
he underwent bhts in the bilateral posterior parietal bone with closed - system drainage under local anesthesia .
postoperative skull x - ray revealed two fixed catheters through bilateral parietal burr - holes ( figure 2a ) .
cranial ct scans obtained 3 days after bht revealed a significant decrease in the bilateral csdh without mass effects ( figure 2b ) .
the postoperative course was uneventful , and the patient was discharged after 7 days with no neurological deficits .
he had been taking 900 mg of valproic acid daily until 12 days postoperatively , and then stopped the medications owing to increased levels of the enzymes , aspartate transaminase and alanine transaminase , in the liver blood test .
on postoperative day 16 ( 5 days after the discontinuation of the antiepileptic drug ) , the patient was admitted to the emergency room with status epilepticus after a generalized tonic - clonic convulsion for 80 minutes .
although his convulsion stopped after the management of status epilepticus in accordance with the guidelines , his consciousness did not recover , and deteriorated to a glasgow coma scale 4 score of ( e1 , v1 , m2 ) .
the patient 's condition continued to deteriorate until he died of pneumonia 1 month after the burr - hole craniotomy .
the risk factors include brain atrophy , coagulopathy , alcohol abuse , seizure disorders , shunts that drain excess cerebrospinal fluid from the brain , and head trauma.3 ) in the past , non - specific symptoms and signs of csdh were mistaken for cerebrovascular disease , brain tumor , and alzheimer 's disease , but recently , the frequency and identification of csdh has increased owing to the development of diagnostic techniques such as ct or magnetic resonance imaging , and extension of the average life span.1 ) the surgical treatments for csdh include several methods , such as , twist - drill drainage , bht and closed - system drainage , craniotomy and capsulectomy , and subduro - peritoneal shunt.3 ) although there have been some debates about the effects and safety of the various surgical methods , bht with closed - system drainage has been considered as a simple and effective method for the treatment of csdh.1 ) incidence of post - operative seizure after bht for csdh is known to be very low .
the effect of the prophylactic antiepileptic drug in reducing the development of new seizure after surgery is still unclear.156 ) sabo et al.6 ) reported that when using prophylactic anticonvulsants , seizure activity occurred in 2.4% of patients after surgery , while it occurred in 32% of patients when not using antiepileptic drug , and hence , they recommended the use of an antiepileptic drug with phenytoin .
however , rubin and rappaport5 ) reported that when using prophylactic antiepileptic drug , seizure occurred in 4.8% of patients , while it occurred in 3.4% when not using antiepileptic drug , and hence , they did not recommend the use of a prophylactic antiepileptic drug .
prophylactic administration of anticonvulsants is generally recommended when the occurrence risk of epilepsy exceeds 10% to 15%.1 ) thus , some authors recommended the use of a prophylactic antiepileptic drug , only in the case of csdh that shows mixed density lesions on pre - operative ct .
for example , in a study by chen et al.1 ) the incidence of early post - operative seizures was 13.7% in the mixed - density csdh group on pre - operative ct .
grobelny et al.4 ) suggested that the prophylactic anticonvulsants before surgery are likely associated with the reduction of post - operative seizure in patients with csdh treated with bht .
however , they noted no effect on discharge outcome , as determined by the modified rankin scale score , between the preoperative and postoperative initiation of the prophylactic antiepileptic drug .
additionally , in their study , the presence of neither preoperative nor postoperative seizures was found to have a significant effect on the outcome at discharge.4 ) sabo et al.6 ) demonstrated a significant increase in morbidity and mortality associated with respiratory complications and status epilepticus after surgery of csdh , including investigations of previous literature . because the elderly patients group is more vulnerable to and fatally affected by this complication
, they emphasized that the older patients may have the most to gain by seizure avoidance .
they also recommended the use of prophylactic anticonvulsants with phenytoin in patients treated surgically for csdh . in our case ,
after early discontinuation of the antiepileptic drug , he died with fatal status epilepticus and respiratory complications .
although the efficacy of the prophylactic anticonvulsants in bht for csdh has been controversial , the development of status epilepticus postoperatively seems to be strongly associated with an increased mortality rate in elderly patients .
therefore , prophylactic anticonvulsants should be administrated in elderly patients who undergo surgery for csdh , until a definitive clinical treatment guideline is suggested .
a larger prospective research is warranted in the future to further clarify the efficacy of this antiepileptic prophylaxis and avoid the fatal complication .
postoperative status epilepticus seems to be strongly associated with an increased mortality rate in aged patients .
therefore , prophylactic coverage of anticonvulsants should be carefully considered in aged patients who undergo surgery for csdh , until a definitive clinical treatment guideline is suggested .
Output:
| incidence of post - operative seizure after burr - hole trephination ( bht ) for chronic subdural hematoma ( csdh ) is known to be very low .
the effect of the prophylactic antiepileptic drug in reducing the development of new seizure after surgery is still unclear . here ,
we present a case of fatal status epilepticus with progressive respiratory complication following early discontinuation of prophylactic antiepileptic drug in an 84-year - old man who had undergone bilateral bht and closed - system drainage for bilateral csdh .
although the efficacy of the prophylactic anticonvulsants in bht for csdh has been controversial , the development of status epilepticus postoperatively seems to be strongly associated with an increased mortality rate in aged patients .
therefore , prophylactic anticonvulsants should be administrated in aged patients who undergo surgery for csdh , until a definitive clinical treatment guideline is suggested . |
PubmedSumm118226 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: gait initiation ( gi ) is the transition from an upright stance to a steady - state gait .
it is
a movement that can be completed in the absence of plantar surface feedback1 and is presumably preprogrammed2 . in quiet stance , the inhibition of the
soleus ( sol ) and the activation of the tibialis anterior ( ta ) result in a dorsiflexion
torque , forward propulsive force , and a backward movement of the center of pressure
( cop)3,4,5 . the cop and center of mass ( com ) become
decoupled , and a fall forward is initiated .
in addition , the stepping - limb hip abductors
create movement of the cop toward that limb6 . thus , muscle activity at the ankle and hip propels the com forward
and toward the intended stance limb to allow stepping - limb toe - off ( to ) and the first
step7,8,9 .
of interest has been the
modulation of ground reaction forces ( grfs ) and muscle activity before stepping - limb to with
changes in intended velocity . as would be expected ,
the posterior displacement of the cop
and the propulsive force have been shown to increase , and the time to this peak force
decrease , with an increase in the intended velocity of gi4 , 10,11,12,13 .
the duration of both stepping and stance ta activities increase
with the velocity of gi4 , 5 , 14 .
significant
correlations between kinetic events , time to stepping - limb to , amplitude and duration of ta ,
and intended velocity of gi have been reported5
. similar patterns of modulation seem to occur when stepping to a new
height15 or over an obstacle7 , 16,17,18,19,20,21 .
previous studies have described the velocity - dependent characteristics of gi . however , no
single study has reported electromyogram ( emg ) and grf data of both the stance and stepping
limbs and their relation to the intended velocity of gi .
one reason for this has been the
use of a single force plate12 , 13 , 22,23,24,25,26,27 and the other is that emg activity was not measured1 , 28,29,30,31,32,33,34,35,36,37 in many studies .
information on both the stepping and stance limbs is valuable in a rehabilitation setting
where accurate patient education and documentation of change is required .
this information
has uses when an asymmetrical lower - limb function is caused by injury or disease , and the
patient not only has to generate the required forces , but also strategize as to which limb
should be the stepping limb .
for example , time to stepping - limb to has been shown to be
slower in stroke patients when the hemiplegic limb is the stance limb28 , yet others have reported the initiation velocity to be
greater if the hemiplegic limb is the stance limb30 ,
35 .
tokuno and eng35 reported decreased anteroposterior ( a - p ) forces from the
hemiplegic limb , regardless of whether it was leading or trailing , and questioned whether
the hemiplegic limb should be the stepping or trailing stance limb .
those with a lower - limb
amputation tend to initiate gait with the prosthetic limb .
the force generated by this limb
is low , and a rescaling of the force of the sound limb is necessary for an adequate first
step length36 .
information on the interaction of the stance and stepping limbs during gi could help guide
rehabilitation decisions .
moreover , how this interaction changes with the velocity of gi is
also important , given that an increase in gait velocity is a positive indicator of
recovery38,39,40,41 . if the velocity and strategy employed to initiate gait is
important in rehabilitation , the collection of more comprehensive data from healthy subjects
is required .
the purpose of this study was , therefore , to investigate the effects of
accuracy constraints ( targets ) placed on the stepping - limb heel - strike ( hs ) on muscle
activities and grf during gi .
we hypothesized that the velocity of gi and stepping over an
obstacle would decrease when accuracy constraints were placed on the stepping - limb hs , and
our results show this decrease was the result of the modulation of grfs and muscle
activities of both the stance and stepping limbs before stepping - limb to .
the study sample consisted of twenty healthy participants ( ten males and ten females ; mean
age , 29.2 2.9 years ; range , 2434 years ) with no known neurological or orthopedic
deficits .
the study was approved by the university institutional review board , and all
participants signed an informed consent form . the study participants characteristics are
summarized in table 1table 1.subject characteristicsgendernumberage ( years)height ( cm)weight ( kg)male1030.2 ( 2.78)174.8 ( 5)71.2 ( 3.79)female1028 ( 2.69)164.6 ( 5.24)53.4 ( 3.09)total2029.2 ( 2.9)169.9 ( 7.3)62.8 ( 9.72 ) .
surface electrodes were applied to the center of the muscle bellies of the ta and sol of
the stance and stepping limbs . each recording electrode consisted of two silver - silver
chloride 1-cm - diameter electrodes , embedded in an epoxy - mounted preamplifier system ( 35 ) ,
and their centers were spaced 2 cm apart .
the emg signals were high - pass filtered ( 20 hz4 khz ) using a zero - lag
filter ( therapeutics unlimited , iowa city , ia , usa ) to remove movement artifacts and
full - wave rectified online .
the final amplification was 10 k. the collection and processing
of emg data followed seniams recommendations42 . two force platforms ( advanced mechanical technology , inc . ,
newton , ma , usa ) , embedded in a
level walkway ( 5 m length , 1.22 m width ) , measured the grfs of the stance and stepping
limbs .
the grfs ( kinetic data ) were collected at 1,000 hz and later filtered with a 4th
order , butterworth , zero lag filter , with a cutoff frequency of 50 hz .
foot switches ( b
& l engineering , los angeles , ca , usa ) were placed in the shoes to measure the hs of the
stepping limb .
the emg and foot switch signals were synchronized with the kinetic data to
simultaneously start both the emg and foot switch data capture .
both the emg and the force
platform data were recorded simultaneously on a personal computer at a sampling rate of
1,000 hz for 4 s ( biopac systems , goleta , ca , usa ) .
the test conditions included the use of
an obstacle ( 10 cm height , 10 cm depth , and 140 cm width ) made of wood .
for each trial , participants stood in a predetermined position with each foot on a force
platform .
participants were asked to begin walking or stepping over the obstacle , at a fast
speed , with the limb they naturally preferred to initiate gait with , after receiving the
verbal cue go , and to continue to walk a minimum of three steps . before the experimental
trials , the average position of the stepping hs was determined for each subject using a
video analysis . for half of the experimental trials ,
a 3-cm - diameter target was placed on
the ground to dictate the position and accuracy of the stepping - limb hs .
all participants
performed two practice trials to familiarize themselves with the experimental procedure .
participants completed 10 trials under each of the following four conditions : gi , gi to the
target , stepping over the obstacle , and stepping over the obstacle to the target .
all participants were required to wear flat - soled shoes normally used for everyday
walking or sports activities .
two - way analysis of variance ( initiation condition accuracy ) for repeated measures was
performed to determine the main and interaction effects of a - p grfs , muscle response , and
temporal events .
post hoc analysis using turkey s hsd was used to determine the
between - group mean differences if the analysis of variance found a significant main effect
or interaction of initiation condition accuracy
the independent variables were initiation condition ( gi and stepping over an obstacle ) and
accuracy ( target , no target ) .
the dependent measures included emg amplitude , slopes and peak
of the propulsive grf , and timing events of gi .
the amplitude of stance- and stepping - limb
ta emg was determined between the onset of movement and time to peak a - p grf of the stepping
limb ( taemg1 ) , and between time to stepping - limb peak a - p grf and stepping - limb to ( taemg2 ) .
the amplitude and duration of stepping - limb sol activity were also calculated . the onset and
offset of sol activity
time to stepping - limb to ,
stepping - limb hs , stance - limb heel - off , and stance limb to were also determined .
timing data
were referenced from the onset of movement , which was defined as the first detectable onset
of force platform activity .
an investigator blinded to the experimental trials performed all
determinations of muscle activity timing and change in grf .
the temporal events are shown in table
2table 2.means ( sd ) of temporal events ( ms)dependent variablesgait initiationsteppingno targettargetno targettargetstepping limb peak fx340 ( 49)423 ( 42)329 ( 47)368 ( 73)stepping limb toe - off511 ( 76)613 ( 81)475 ( 69)548 ( 91)stepping limb heel - strike890 ( 74)1008 ( 86)968 ( 71)1071 ( 108)stance limb toe - off1024 ( 76)1219 ( 156)1093 ( 85)1257 ( 153)values represent mean standard deviation ( sd ) . * significant main effect of target
( p<0.01 or p<0.05 )
. significant main effect of initiation condition
( p<0.01 or p<0.05 ) . significant interaction ( p < 0.05 ) .
significant difference between conditions ( p<0.01 or
p<0.05 ) .. although there was an interaction ( f(1 , 8) = 6.47 , p <
0.05 ) of the time to stepping - limb peak a - p grf ( the target condition for stepping over an
obstacle was greater than that for gi ) , the mean times to peak a - p grf in the target
conditions were significantly greater than in the no - target conditions .
the time to
stepping - limb to showed significant main effects of both the initiation and target
conditions ( f(1 , 8) = 10.87 , p
< 0.05 and f(1 , 8) =
19.29 , p < 0.01 , respectively ) .
time to stepping - limb to was longer in stepping to the
target but shorter in the obstacle condition .
the times to stepping - limb hs and stance - limb
to showed main effects of the initiation and target conditions ( f(1,7 ) =
7.83 to 18.24 , p < 0.01 to p < 0.05 ) . the times increased in both the target and
stepping conditions .
values represent mean standard deviation ( sd ) . * significant main effect of target
( p<0.01 or p<0.05 ) .
significant main effect of initiation condition
( p<0.01 or p<0.05 ) . significant interaction ( p < 0.05 ) .
the amplitude of the ta emg was determined from both the onset of force platform activity
to stepping - limb peak a - p grf ( taemg1 ) , and from stepping - limb peak a - p grf to to of the
stepping limb ( taemg2 ) .
there was a significant main effect of target on the stepping - limb
taemg1 ( f(1 , 8) = 7.75 , p < 0.05 ) which showed decreased amplitudes in
the target conditions ( table 3table 3.means ( se ) of emg dependent variables ( ms.v)dependent variablesgait initiationsteppingno targettargetno targettargetstance limb taemg1340 ( 49)423 ( 42)329 ( 47)368 ( 73)stance limb taemg2511 ( 76)613 ( 81)475 ( 69)548 ( 91)stepping limb taemg1890 ( 74)1008 ( 86)968 ( 71)1071 ( 108)stepping limb taemg21024 ( 76)1219 ( 156)1093 ( 85 ) 1257 ( 153)values represent mean standard deviation ( sd ) .
however , there was no significant effect on the taemg2 of the stepping
limb .
taemg : tibialis anterior
electromyogram . * significant main effect of target ( p<0.01 or p<0.05 ) .
significant interaction ( p<0.05 ) .
stance taemg1 showed a significant interaction ( f(1 , 8) = 12.12 , p <
0.05 ) ( table 3 ) .
stance taemg1 was greater in gi
than in the stepping over the obstacle with no target , but showed no difference between the
target conditions .
stance taemg2 was significantly greater in the no - target conditions than
in the target conditions ( f(1,8 ) = 13.31 , p < 0.01 ) ( table 3 ) .
the mean data show that except for taemg2 of the
stepping limb , the ta amplitude was clearly greater in the no - target conditions .
the
stepping - limb sol emg amplitude was similar in all the conditions ; however , its duration was
24 ms greater in the target conditions ( f(1 , 8) = 8.05 , p < 0.05 ) .
there was a significant main effect of target on both the stepping - limb peak a - p grf
( f(1 , 8) = 30.88 , p < 0.001 ) and the slope to stepping - limb peak a - p
grf ( f(l , 8) = 18.2 , p < 0.01 ) .
values were greater in the no - target
conditions ( table 4table 4.means ( sd ) of peak ( % bw ) and slope ( % bw / s ) force plate dependent
variablesdependent variablegait initiationsteppingno targettarget no targettargetstepping limb peak fx39.6 ( 6)26 ( 7.8)40.8 ( 9.6)25.7 ( 7.2)stepping limb slope fx125.2 ( 42)62 ( 22.5)120.6 ( 26.4)75.6 ( 32.3)stance limb peak fx81.8 ( 13)52.6 ( 12)66.3 ( 15)47.5 ( 13)stance limb slope fx318.2
( 63)208.2 ( 53)313.1 ( 87)192.5 ( 54)values represent mean standard deviation ( sd ) . fx : anteroposterior ground reaction
force ; % bw : percent body weight ; % bw / s : percent body weight per second .
there was no significant difference between the gi and stepping over the
obstacle conditions for either dependent variable .
although there was a significant
interaction of the stance - limb peak a - p grf ( f(1 , 8) = 13.64 , p < 0.01 ) ,
there were also main effects of the stepping ( f(1 , 8) = 30.07 , p < 0.01 )
and target ( f(1 , 8) = 24.80 , p < 0.01 ) conditions .
stance - limb peak a - p
grf was greater in the gi and no - target conditions ( table 4 ) .
the slope to peak a - p grf showed a main effect of target only and the
slope was greater in the no - target conditions ( f(1 , 8) = 22.27 , p <
fx : anteroposterior ground reaction
force ; % bw : percent body weight ; % bw / s : percent body weight per second . *
significant interaction
( p<0.05 ) . significant difference between conditions ( p<0.01 or
p<0.05 ) .
a unique relation exists between force profiles and muscle activity in different movement
strategies .
an increase in the degree of accuracy of a task causes a decrease in the
velocity of movement43,44,45 .
therefore ,
there must be a change in strategy with an accuracy constraint , but only if the accuracy
demands are sufficiently sensitive to dictate movement velocity46 .
furthermore , on the basis of previous studies of gi and
stepping7 , 8 , it could be concluded that by manipulating the limb trajectory , for
example , stepping over an obstacle as opposed to gi , forces would remain invariant . by
investigating
the component of gi thought to dictate the velocity of movement , better data
on how forces are modulated during voluntary movement from a quiet stance could be
provided .
the current study investigated both gi and stepping over an obstacle and the interaction of
the stance limb with the stepping limb , when target constraints were placed on the
stepping - limb hs .
the results show that the initiation velocity increase in no - target
conditions was due to the modulation of the stance- and stepping - limb grfs and the
corresponding increase of the ta activity in both limbs before stepping - limb to .
this was
achieved by significantly increasing the stepping- and stance - limb taemg1 in the no - target
conditions .
it seems , therefore , that taemg1 and the slope to stepping - limb peak a - p grf
contributed to the intended velocity of initiation ( gi or stepping over an obstacle ) . in the present study ,
stepping - limb to marks the first significant event , and in the no - target condition it
occurred approximately 90 ms earlier than in the target conditions .
this decrease in time
was , in part , due to a 15% ( 61 ms ) decrease in time to stepping - limb peak a - p grf of the
no - target conditions .
this decrease in time to peak a - p grf was due to a 78% increase in
slope to peak a - p grf that resulted in a 55% increase in peak a - p grf of the stepping limb .
given the relative changes in time and slope , it seems that subjects modulated the rate of
increase of force and kept the time to peak force relatively constant to achieve the
increase in the peak acceleration force of the stepping limb . as the ta controls the
backward movement of the cop3 , 4 , 10 , 47
, there was a significant increase in stepping - limb taemg1
in the no - target conditions .
the relation between the backward movement of the cop10 , 48
or ta activity and gait velocity has previously been recognized . of interest ,
the time from
stepping - limb to to stepping - limb hs remained invariant for both gi and stepping over the
obstacle , a finding supported by the earlier data of brenire and colleagues3 , 10 , 47 . in the present study , the mean difference
between the accuracy conditions was only 23 ms .
furthermore , there was no main effect of the
amplitude of stepping - limb taemg2 or sol , and it has been previously recognized that sol
creates heel rise in preparation for the first step but does not contribute toward gait
velocity48 .
the contribution of the
stepping limb to the velocity of initiation ( gi or stepping ) seems , therefore , to be
determined by taemg1 and the slope to stepping - limb peak a - p grf48 . for the stance limb , there was a significant target effect on both taemg1 and taemg2 . in
both stepping over the obstacle and gi ,
the amplitude of taemgi was far greater than that of
taemg2 , and only minimal acceleration force was generated until the slope to stance - limb a - p
grf appeared .
the onset of this slope coincided with the peak a - p grf of the stepping limb ,
our selected time division between taemg1 and taemg2 . during this phase of gi and stepping
over an obstacle ,
this transition
from unloading to loading occurs slightly before peak a - p grf of the stepping limb . given
the greater amplitude of taemg1 of the stance limb but smaller peak force
, we consider that
the smaller a - p grf is probably related to the unloading of the stance limb , and slope to
stance - limb peak a - p grf to the loading of that limb before stepping - limb to .
the slope to
stance - limb peak a - p grf was the same for gi and stepping over the obstacle , but peak a - p
grf was less when stepping over the obstacle .
peak a - p grf coincides with stepping - limb to ,
and the earlier to for stepping ( and therefore smaller peak a - p grf ) is thought to be
related to the trajectory of the stepping limb7 . because of the greater trajectory , the time to stepping - limb hs
from to was longer for stepping over the obstacle .
the slope to stance - limb peak a - p grf increased in the no - target condition .
there was an
increase of approximately 50% in the no - target condition , with only a 14% difference in time
to peak a - p grf .
the increase in the slope to peak a - p grf of the stepping limb was 78% . for
the stance limb
, these data differ from a previous report8 that used both a large and a small target .
however , it should be
noted that the target size used in the present study was 50% smaller than the small target
used in the previous study8 . in an
isometric plantar flexion task , the slopes to peak forces
were also found to be the same
once the target size had reached a critical level .
the fact
that an explicit instruction to increase the velocity of gi ( as opposed to accuracy
constraints ) resulted in an increase in the slope to stance - limb peak a - p grf supports this
interpretation7 .
because the experiment was
only conducted on a relatively small sample of healthy young adults ( gi in a
non - pathological setting ) , our findings can not be generalized to the population with a
pathological gi .
moreover , much of the pathological gi condition is asymmetrical , yet data
is only presented for right foot gait initiation .
furthermore , data was only collected at a
fast speed , and we used experimental manipulations such as a target and obstacle - crossing
instead of asking the participants to simply initiate their gait at slow , preferred , and
fast speeds . in conclusion , this study investigated changes in emg and grf responses during gi at
different intended velocities of initiation .
the velocity of gi and stepping over an
obstacle increased when no accuracy constraints were placed on the stepping - limb hs .
this
increase was due to the modulation of both the stance- and stepping - limb grfs before
stepping - limb to .
the time to these peak forces remained relatively constant ( 100-ms less in
the no - target conditions ) .
that is , the slope to the stepping- and stance - limb peak a - p grf
was modulated , whereas the time to peak a - p grf remained relatively constant .
this notion is
supported by the strong correlations between the slope to stepping - limb a - p grf and time to
stepping hs ( r = 0.84 ) , and the more modest correlation ( r
= 0.64 ) of the slope to stance - limb peak a - p grf .
furthermore , there were no differences in
the slopes to either stepping- or stance - limb peak a - p grf between gi and stepping over the
obstacle .
this concurs with upper - extremity studies showing that the distance moved does not
affect the rate of increase of force . on the basis of these data , gi and/or stepping over an
obstacle
this would be preferable in
upper - extremity experiments , for which the subject sits and the extremity is stabilized .
voluntary movement from an upright stance may be useful for assessing changes in performance
after rehabilitation .
hemiparetic patients show an asymmetric gait pattern and prefer initiating gait with the
affected leg to utilize the higher stability of the supporting limb .
however , hemiparetic
patients are encouraged to initiate gait with the intact limb to increase the weight - bearing
ability of the affected leg .
similarly , unilateral amputees in rehabilitation training are
also encouraged to lead with the intact limb when stepping up , and with their prosthetic
limb when stepping down49 .
however , a
recent study30 questions whether
initiating the gait of hemiplegic patients with the intact limb is related to a higher risk
of fall . the movement pattern of the cop and com is altered in patients with hemiparetic
stroke when initiating gait with the unaffected leg
. this difference may be attributable to
the higher incidence of falls when initiating gait with the unaffected leg due to the
altered movement pattern of the cop and com .
the present study provides insight into the
working mechanisms of the stepping and stance limbs and shows the clear need to further
investigate whether the intact or affected limb should be used to initiate gait during
rehabilitation and prosthetic training .
Output:
| [ purpose ] this study investigated the effects of accuracy constraints ( targets ) placed on
the stepping - limb heel - strike ( hs ) on the electromyogram ( emg ) and ground reaction forces
( grfs ) during gait initiation . [ subjects and methods ] twenty healthy subjects ( 29.2
2.9 years ) were asked to begin walking or stepping over a 10-cm - high obstacle at a fast
speed .
a 3-cm - diameter target was placed on the ground to dictate the position and
accuracy of the stepping - limb hs .
[ results ] the results showed that the initiation
velocity increase in the no - target conditions was due to modulation of the stance- and
stepping - limb grfs and a corresponding increase in the tibialis anterior ( ta ) activities
of both limbs before stepping - limb toe - off .
this was achieved by significantly increasing
the stepping- and stance - limb taemg1 ( determined between the onset of movement and time to
peak anteroposterior ( a - p ) grf of the stepping- and stance- limb ) for the no - target
conditions .
it seems , therefore , that taemg1 and the slope to stepping - limb peak a - p grf
contributed to the intended velocity of initiation .
[ conclusion ] these data indicate that
gait initiation and/or stepping over an obstacle may prove to be tasks by which motor
control can be measured .
the present study provides insight into the working mechanisms of
the stepping and stance limbs and shows a clear need to further investigate whether the
intact or affected limb should be used to initiate gait during rehabilitation and
prosthetic training . |
PubmedSumm118227 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: sepsis is a clinical syndrome related to severe infection and is characterized by systemic inflammation and injury to many organs and functional systems .
it is usually treated with antibiotics , surgical drainage of infected fluid collections , and fluid replacement .
appropriate support for organ dysfunction is provided by hemodialysis in kidney failure , mechanical ventilation in pulmonary dysfunction , transfusion of blood products , and drug and fluid therapy for circulatory failure .
however , loss of sympathetic nervous system autoregulation , systemic hypotension , direct renal vasoconstriction , release of cytokines , etc .
diuretics are frequently administered to augment renal salt and water excretion in the setting of extracellular volume of overload in arf patients .
the use of diuretics in arf due to sepsis may not always be beneficial to the patient .
we report a case of uremia , nonrecovery of renal function , and chronic renal failure ( crf ) caused by diuretics in a patient of sepsis with arf and undergoing dialysis .
a 61-year - old man with continuous high - grade intermittent fever associated with chills and rigor ( 8 days ) , hiccup ( 8 days ) , nausea ( 12 days ) , and breathlessness ( 1 day ) reported to the outpatient department ( opd ) of neelachal hospital pvt ltd , bhubaneswar . the patient was administered with arteether 150 mg i.v .
the patient was a known case of hypertension with cerebrovascular accident ( cva ) and right - sided hemiparesis since 13 years and was on atenolol 75 mg , amlodipine 7.5 mg , amiloride 40 mg , and aspirin 50 mg once daily . at the time of admission ,
the patient was confused with temperature 104f , pulse 110/min , blood pressure 130/80 mmhg , respiration rate 40/min , spo2 96% , pallor , and normal blood sugar and ultrasonography ( usg ) of whole abdomen .
an increase in serum urea ( 76 mg / dl ) , serum creatinine ( 3.2 mg / dl ) , serum glutamic oxaloacetic transaminase ( 40
iu / l ) , and total leukocytic count / tlc ( 10600 ) was observed .
tests for plasmodium vivax , plasmodium falciparum , hepatitis c virus ( hcv ) , and australian antigen were found to be negative .
the patient was diagnosed as a case of sepsis with arf and was administered with antibiotics such as ceftriaxone and tazobactam for 4 days
there was no relief in any of the symptoms and the serum urea and creatinine levels increased progressively daily .
hence , on the 5 day the two antibiotics were replaced by teicoplanin and meropenem .
on the 7 day , the symptoms start abated , but the serum urea ( 116 mg / dl ) and creatinine ( 4.3 mg / dl ) levels and the tlc ( 11900/cumm ) were raised . on the 10 day , there was an increase in serum urea ( 168 mg / dl ) and creatinine ( 4.34 mg / dl ) levels and tlc ( 21600/cumm ) .
hence , the two antibiotics and arteether were stopped and administration of three diuretics ( furosemide 40 mg twice daily , torsemide 20 mg twice daily , and metolazone 5 mg once daily ) and one antibiotic ( cefotaxime 1 g twice daily ) were started in addition to hemodialysis once in every 34 days .
the nephrologists administered three diuretics together with the objective that increased urination would decrease serum urea and creatinine . on the 12 day however , the tlc ( 31000 ) , serum urea ( 219 mg / dl ) , and creatinine ( 4.64 mg / dl ) increased further .
the day after hemodialysis , urea and creatinine levels decreased but again increased requiring another dialysis within 34 days .
hence , tigecycline 50 mg twice daily on the 17 day and caspofungin 50 mg once daily on the 24 day were added .
on the 29 day , the tlc decreased and another antibiotic ( doripenem 250 mg twice daily ) was added . on the 35 day , all the antibiotics were stopped as the tlc became almost normal ( 11000/cumm ) .
however , the serum urea ( 400 mg / dl ) and creatinine ( 3.6 mg / dl ) remained high .
the patient was diagnosed as a case of crf and dialysis at regular intervals was recommended .
after consultation with a nephrologist from another organization , on the 41 day , two diuretics ( torsemide 20 mg twice daily and metolazone 5 mg once daily ) were stopped . the next day ( 42 day )
urea and creatinine levels decreased to 208 mg / dl and 2.2 mg / dl , respectively . on the 43 day
the serum urea and creatinine levels started decreasing and by 60 day , they were normal ( tlc 7700/cumm , urea 27 mg / dl , and creatinine 1.1 mg / dl ) .
since its occurrence prominently affects the outcome , it is important to distinguish patients who eventually will develop arf , making it possible to correct the factors predisposing to arf .
it is important to prevent arf by careful monitoring and aggressive treatment of patients at risk .
diuretics are frequently given during arf in an effort to convert oliguric to nonoliguric arf , since oliguria has been recognized as a proxy for the severity of arf and the likelihood of requiring dialysis . despite the ubiquity of this practice
, there is scant evidence that diuretics provide any material benefit to patients with arf .
mehta et al . showed that the diuretic use in the intensive care unit ( icu ) patients with arf was associated with greater in - hospital mortality and nonrecovery of renal function .
infectious causes have consistently ranked second to cardiovascular disease in reported causes of death in patients on dialysis .
several studies suggest that septicemia rates in these patients are higher than in general population .
uremia is a classic state of hyper responsiveness , and infection rates are believed to be several times higher in dialysis populations than in the age - matched segments of the general population .
the increase in mortality and nonrecovery of renal function in arf patients may be due to a direct deleterious effect of diuretic agents , or a delay in the institution of renal support ( in effect , forestalling dialysis with volume overload or with anticipated reversal of azotemia ) , or other unknown factors .
therefore , uremia in this case may be caused by dialysis and/or use of diuretics .
an increase in tlc is a sign of infection and when it decreased to normal in this case , the patient was free from infection .
hence , all the antibiotics were stopped , but urea and creatinine levels remained high .
the renal function recovered after diuretics were stopped , and no dialysis was required . in the view of these findings
, it is suggested that physicians should be cautious in prescribing diuretics to patients with arf due to sepsis .
Output:
| sepsis is a clinical syndrome related to severe infection and is characterized by systemic inflammation and injury to multiple organs and functional systems .
sepsis is one of the main causes of acute renal failure ( arf ) .
diuretics are frequently administered during arf
. however , there is scant evidence that diuretics provide any benefit to the patients with arf .
this case report highlights the occurrence of uremia and nonrecovery of renal function after administration of diuretics in a patient with arf caused by sepsis .
it is suggested that physicians should be cautious in prescribing diuretics to patients with arf due to septicemia .
diuretics cause uremia and may lead to false diagnosis of chronic renal failure and nonrecovery of renal function .
the patient may unnecessarily require prolonged dialysis . |
PubmedSumm118228 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: abdominal aortic aneurysm ( aaa ) affects a high percentage of the aged population in industrialized countries and mortality rates associated with rupture of aaa are high .
the aetiology of aaa is essentially unknown , but it is generally accepted that environmental and genetic factors contribute substantially to the risk of aaa .
the major risk factors for aaa are increasing age , family history , male gender , hyperlipidemia ( hl ) , arterial hypertension ( htn ) , and smoking . of these , smoking seems to be the most relevant , with a considerably higher risk for aaa than for atherosclerosis .
diabetes mellitus ( dm ) is a well - established risk factor for atherosclerosis and has been reported to be protective for aaa . studying the influence of cardiovascular risk factors , particularly those that differentially influence aaa and atherosclerosis , could help to ascertain the causes of aaa .
human aaa is characterized by leukocyte infiltration into adventitia and media and depletion of vascular smooth muscle cells ( vsmc ) in the media .
another relevant feature of the disorder is a decrease in aaa wall strength caused by the breakdown of elastic fibres and the hypervascularization of aortic tissue .
pge2 induces expression of metalloproteinases and inhibits the production of macromolecules of the extracellular matrix [ 5 , 6 ] .
it acts as a signalling molecule in response to proangiogenic factors and also induces release of several angiogenic factors in a manner of positive loop [ 710 ] .
consequently , inhibition or deletion of the enzymes involved in the biosynthetic pathway of pge2 interferes in aaa development in animal models [ 1115 ] .
pge2 biosynthesis begins with the formation of pgh2 from arachidonic acid ( aac ) catalyzed by cyclooxygenase ( cox ) .
the microsomal isoform of pges , mpges-1 , is inducible by proinflammatory cytokines and it seems to be the essential pges isoenzyme involved in pge2 biosynthesis under inflammatory conditions [ 1719 ] .
cox-2/mpges-1 is widely regarded as the main contributing enzymatic tandem for pge2 biosynthesis under pathological conditions .
pge2 exerts its cellular effects by binding to four distinct e - prostanoid receptors ( ep14 ) .
eps belong to the family of seven transmembrane g protein - coupled rhodopsin - type receptors .
ep2 and ep4 are gs proteins - coupled receptors and they upregulate intracellular camp levels .
ep3 usually counteracts ep2- and ep4-mediated upregulation of camp by preferentially coupling to gi proteins . also , interventions on the pge2 receptor display benefits in experimental aaa [ 21 , 22 ] .
we recently reported that cox-2 , mpges-1 , ep-2 , and ep-4 are upregulated in aaa and that the cox-2/mpges-1/ep-4 axis could play a relevant role in aaa - associated hypervascularization from the early stages of aaa development .
however , information is lacking regarding the influence of cardiovascular risk factors on local levels of the cox-2/mpges-1/ep-4 axis in aaa . in this study , we aimed to evaluate the influence of major cardiovascular risk factors on the pge2 pathway in human abdominal aortic aneurysms .
the inclusion criteria for this study were patients who underwent open repair for aaa with an atherosclerotic aneurysm and in whom an infrarenal aorta biopsy was taken during the intervention .
the exclusion criteria were absence or inadequate aortic biopsy , pseudoaneurysms , and infectious or inflammatory aneurysms .
all patients underwent surgery at hospital de la santa creu i sant pau ( hscsp ) .
the study was approved by the local ethics committee , and informed consent was obtained from each patient .
samples were obtained from remaining midinfrarenal aortic wall after exclusion and prosthetic replacement of aaa . when luminal thrombus was present it was separated before the aorta biopsy was taken and aortic tissue was washed twice with cold phosphate buffered saline ( pbs ) .
a portion of each sample was placed in rnalater solution ( qiagen gmbh , hilden , germany ) and stored at 4c for 24 hours before long - term storage at 80c until further processing for rna isolation . when possible a portion was fixed in formalin solution 10% ( sigma - aldrich , inc . , st .
louis , mo ) for 24 h and included in paraffin for immunohistochemical studies .
the risk factors definitions used in this study were diabetes mellitus ( dm ) : glycated haemoglobin > 5.8% or use of oral antidiabetic drugs or insulin ; arterial hypertension ( htn ) : systolic blood pressure 140 mm hg , diastolic blood pressure 80 mm hg , or use of antihypertensive medication ; hyperlipidemia ( hl ) : a total cholesterol > 6.2 mmol / l , ldl cholesterol > 1.70 mmol / l , or triglycerides > 1.65
mmol / l ; smoking : categorized into 2 groups : current smoking ( cs ) : smokers and ex - smokers who stopped smoking < 1 year and noncurrent smoking ( n - cs ) : never - smokers and ex - smokers who stopped smoking > 1 year ; chronic occlusive pulmonary disease ( copd ) : fev1/fvc < 0.7 ; and renal insufficiency ( ri ) : estimated glomerular filtration rate ( egfr ) 60 ml / min/1.73 m calculated using the chronic kidney disease epidemiology collaboration ( ckd - epi ) equation .
tissues were homogenized in the fastprep-24 homogenizer and lysing matrix d tubes ( mp biomedicals , solon , oh ) .
rna was extracted using trizol ( invitrogen , carlsbad , ca ) following the manufacturer 's instructions .
cdna was prepared by reverse transcription of 1 g rna using high - capacity cdna archive kit with random hexamers ( applied biosystems , foster city , ca ) .
mrna expression of the selected genes was studied by real - time pcr in an abi prism 7900ht using predesigned validated assays ( taqman gene expression assays ; applied biosystems ) and universal thermal cycling parameters .
a sample of 10 ml of peripheral blood was collected in heparin - containing tubes .
pge2 and 13,14-dihydro-15-oxo - pge2 were determined using enzyme immunoassay ( eia ) kits ( cayman chemical , ann arbor , mi ) following the manufacturer 's instructions .
hpa045064 prestige antibodies , diluted 1 : 50 ) from sigma and a mouse monoclonal antibody anti - ep-4 ( ref .
ir613 , without further dilution ) from dako were used for von willebrand factor ( vwf , endothelial cell marker ) , cd45 ( pan - leukocyte marker ) , and cd68 immunostaining .
three - micrometer sections of paraffin - embedded tissue samples were stained in a dako autostainer link 48 using the dako envision flex kit .
all quantitative data in this study were nonnormally distributed and expressed as median ( 25th75th percentile ) .
the pearson product moment correlation was used to evaluate the association between continuous variables after log10 transformation of data with nonnormal distribution .
data were also analyzed using a multiple linear model including the effect of the identified risk factors and controlling possible confounding factors ; a logarithmic transformation was applied to those outcomes without a normal distribution .
from 2008 to 2012 , 225 elective aaa were performed in our center ( department of vascular and endovascular surgery of the hospital de la santa creu i sant pau in barcelona , spain ) .
none of the risk factors caused significant differences in either cox-1 or cox-2 levels between aaa samples ( table 2 ) .
regarding mpges-1 , only current smoking ( cs ) showed significant high transcript levels when compared with the noncurrent smokers ( n - cs ) group .
mpges-1 expression was higher in patients suffering copd than in those without copd , but the difference did not reach statistical significance .
following analysis , we identified copd and htn as variables likely related to cs .
as these two variables could act as confounding factors ( table 3 ) , we applied multiple linear regression analysis .
the relationship between cs and mpges-1 remained stable even in the presence of the confounding factors ( copd and htn ) in the statistics ( p = 0.03 ) .
we found that plasma levels of pge2 in aaa patients were significantly enhanced in the cs group when compared with the n - cs group ( table 4 ) .
none of the other risk factors analysed had statistically significant differences regarding circulating levels of pge2 .
when confounding variables were taken into account , multiple linear regression analysis showed statistically significant differences between cs and n - cs groups ( p = 0.012 ) .
microvessels were abundant in the adventitia and in the media . while major infiltrated leukocytes ( determined by cd45 immunostaining ) systematically accumulated in perivascular areas of microvessels , macrophages ( determined by cd68 immunostaining ) displayed a more scattered pattern .
immunohistochemistry study of mpges-1 was performed in aaa samples from 4 patients of each smoking group to localize the protein expression .
no differences were observed between cs and n - cs groups regarding mpges-1 protein location .
mpges-1 was located in mvec , vsmc , and infiltrating leukocytes ( figure 2(a ) ) . in an attempt to approach the origin of the differences of mpges-1 in our aaa samples
, we determined the statistical association of mpges-1 transcript levels with cell - characteristic markers as independent variables .
we analysed mrna levels of von willebrand factor ( vwf ) , -actin , and cd68 as markers of endothelial cell , vsmc , and macrophages , respectively .
no significant statistical association was found between mpges-1 and cd68 transcript levels ( not shown ) .
in contrast , mpges-1 levels significantly correlated with both -actin and vwf ( figure 2(b ) ) .
we then explored the influence of cs on the cell markers and no significant differences were found between cs and n - cs ( not shown ) .
regarding pge2 receptors , ep-1 was expressed only scarcely in aaa samples and therefore was not considered for the analysis of cardiovascular risk factors .
in contrast , significant differences between cs and n - cs groups were found regarding ep-4 , cs having the highest transcript levels when simple statistical analysis was applied ( table 5 ) .
moreover , when confounding variables ( copd and htn ) were introduced in statistics the relationship between cs and ep-4 remained stable ( p = 0.007 ) .
ep-4 was almost undetectable in vsmc in culture in terms of mrna ( 78-fold lower than in mvec , not shown ) .
no differences between cs and n - cs groups were observed regarding localization of ep-4 ( figure 3(a ) ) .
the association between ep-4 and cd68 transcript levels was poor ( figure 3(b ) ) , whereas the association with vwf was stronger .
this is the first study to describe the influence of cardiovascular risk factors on local levels of pge2 pathway in abdominal aortic aneurysm .
we found that current smoking was associated with increased local expression of transcript levels of mpges-1 in aaa . in accordance with other reports
additionally , we reported that mpges-1 was increased in aaa and that the upregulation of cox-2/mpges-1 precedes maximal leukocyte infiltration .
we found that ep-2 and ep-4 were upregulated in aaa , whereas ep-3 was significantly downregulated .
an interesting finding was that pge2-mediated in vitro angiogenesis was fully dependent on ep-4 . herein , we report the influence of the most relevant cardiovascular risk factors on the cox-2/mpges-1/ep-4 axis expression .
current smoking was the only cardiovascular risk factor that was significantly associated with increased local expression of mpges-1 in aneurysmatic aorta .
this observation is consistent with the fact that cox-2 and mpges-1 display different regulation in vitro [ 18 , 19 ] .
the increase in the expression of pge2 biosynthetic machinery was consistent with the higher levels of pge2 observed in the plasma of the smoker patients .
nevertheless , as aaa should be considered a systemic disease of the vasculature , other vascular territories may contribute to circulating levels of pge2 .
the presence of mpges-1 in a particular cell is necessary for pge2 biosynthesis [ 1719 , 25 ] .
all vascular cells [ 17 , 23 , 26 ] and leukocytes , likely mainly macrophages , express mpges-1 .
our present results show that the expression levels of mpges-1 correlate with the expression of vascular cell markers rather than with infiltrating macrophages markers suggesting that mpges-1 is expressed in vsmc and mvec as we reported before [ 17 , 18 , 26 ] .
the absence of statistically significant differences between the cs and n - cs groups regarding transcript levels of vascular cell markers , together with increased levels of mpges-1 in the cs group , strongly suggests that expression of mpges-1 is effectively upregulated in vascular cells in cs group .
nevertheless , vsmc tends to be reduced whereas mvec are substantially increased in aaa [ 1 , 4 , 26 ] .
altogether , our results heighten the role that mvec - associated mpges-1 and current smoking could have in aaa progression . of course
indeed , macrophage cox-2-derived pge2 has been found to be relevant in the pathogenesis and rupture of aaa [ 12 , 27 , 28 ] .
regarding pge2 receptors , only cs had an effect on the local levels of ep-4 .
ep-4 is the most abundant subtype of pge2 receptor in endothelial cells and it is a key receptor for pge2-induced angiogenesis .
it was expressed in leukocytes , but we found that variation of ep-4 expression correlated better with vwf mrna levels ( endothelial cell marker ) than with cd68 ( macrophage marker ) .
the statistical significance of the difference between cs and n - cs regarding mpges-1/ep-4 axis was maintained after the introduction of htn and copd as confounding variables in the statistics .
taken together , our results support the concept that smoking substantially affects aortic vascular cells and suggest that mvec are particularly affected .
it has been reported that the association between smoking and aaa is 2.5-fold higher than the association between smoking and coronary heart disease .
our data indicated that mpges-1/ep-4 is mainly linked to vascular cell state , whereas local levels of cox-2 depend on several factors such as the inflammatory infiltrate in the aortic wall .
therefore , it seems that smoking affects the state of the vascular cells more than the degree of leukocyte infiltration .
many reports provide evidence supporting the association between renal function and atherosclerosis , and egfr is an independent prognostic factor for cardiovascular disease .
we recently reported that egfr is an excellent predictor of vascular events in patients with peripheral arterial disease . since ri could indicate the atherosclerosis level of patients , our results suggest that the effect of smoking on local levels of mpges-1/ep-4 is independent of the atherosclerosis and copd states of patients with aaa .
these results support the lack of association of copd and aaa with smoking described in a previous report .
more research is needed to ascertain the molecular species and signalling pathways involved in the effect of tobacco smoke on the induction of mpges-1 and ep-4 expression in human aaa . in conclusion
, we show for the first time that current smoking increases mvec - associated mpges-1/ep-4 and provides further insight into the relevance of tobacco smoking in aaa development .
our data are consistent with reports showing that suppression of either mpges-1 or ep-4 expression reduces aaa development in animal models [ 15 , 21 , 22 ] and reinforce the potential of mpges-1 and ep-4 as alternative targets for therapy in aaa patients .
Output:
| background . the cyclooxygenase- ( cox- ) 2/microsomal pge - synthase- ( mpges- ) 1/pge - receptor- ( ep- ) 4 axis could play a key role in the physiopathology of abdominal aortic aneurysm ( aaa ) in humans . in this study , we investigated the influence of cardiovascular risk factors on the expression of the pge2 pathway in human aaa . methods .
aortic ( n = 89 ) and plasma ( n = 79 ) samples from patients who underwent aaa repair were collected .
patients were grouped according to risk factors .
cox - isoenzymes , mpges-1 , eps , -actin , and cd45 and cd68 transcripts levels were quantified by qrt - pcr and plasma pge2 metabolites by eia . results . current smoking ( cs )
patients compared to no - cs had significantly higher local levels of mpges-1 ( p = 0.009 ) , ep-4 ( p = 0.007 ) , and pge2 metabolites plasma levels ( p = 0.008 ) . in the multiple linear regression analysis ,
these parameters remained significantly enhanced in cs after adding confounding factors .
results from association studies with cell type markers suggested that the increased mpges-1/ep-4 levels were mainly associated with microvascular endothelial cells .
conclusions .
this study shows that elements of the pge2 pathway , which play an important role in aaa development , are increased in cs .
these results provide insight into the relevance of tobacco smoking in aaa development and reinforce the potential of mpges-1 and ep-4 as targets for therapy in aaa patients . |
PubmedSumm118229 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the forensic pathologist s task often consists of assisting the prosecuting and judicial authorities in determining whether the wounds sustained by the victim of the crime could have been inflicted with the instrument seized as material evidence . for this purpose , a careful inspection of bodily injuries and
the purpose of the examination is to search for characteristic features of the injuries which can be linked to the instrument . while examining the seized instrument , it is important to perform detailed descriptions and measurements of its parts such as the blade , hilt , and other characteristic elements such as projections or serrations .
sometimes , in order to define the marks left by a particular instrument , i.e. , in case of sharp , blunt , or gunshot wounds , it is helpful to perform an experiment using that instrument [ 19 ] .
although , in the case of sharp force traumas , it is possible to differentiate between injuries in bones or cartilages caused with serrated and non - serrated instruments ( i.e. , knives ) , the differentiation of the instrument in case of injuries to the skin and soft tissue is much more difficult [ 10 , 11 ] .
however , in some cases , conducting an experiment can make it possible to confirm or exclude the use of the examined instrument and avoid misidentification of an injury s origin . in the case described in this paper ,
doubt arose as to whether the injuries found on the body of the deceased could have been caused by the knife discovered near the crime scene .
the case concerns an incident during which a dozen or so attackers assaulted a man ( xy ) who died as a result of the injuries sustained .
the autopsy demonstrated that the cause of his death was exsanguination due to a massive hemorrhage as a result of numerous stab wounds to the chest and abdomen and damage to internal organs ( the heart , lungs , aorta , liver , and small intestine ) within the wound channels .
the character , extent , and location of the wounds indicated that they had been inflicted with great force , using a sharp instrument . during the investigation , after a thorough search of the vicinity of the scene of the crime and with the help of recordings of the surrounding area by municipal video surveillance ,
in the course of a subsequent police investigation it was established that the knife belonged to one of the assailants .
the post - mortem showed linear , regular , striated scratches on the integuments of the victim s abdomen , and also in the edge of one of the wounds , suggesting that the instrument used to inflict the wounds could have a serrated blade , while the knife found had a smooth one .
as a consequence , this led to doubts whether the knife in question was the only instrument of crime or another knife , with a serrated blade , was used too .
in view of the above , the public prosecutor examining the case ordered to carry out an experiment to verify whether it was possible to inflict injuries such as those found during the autopsy of the murder victim with the knife found in the pond .
the seized material evidence , provided by the public prosecutor , to be used in the experiment was a knife with a metal blade containing the inscription
the total length of the knife was 28 cm , of which the blade was 14 cm and the hilt was 14 cm long .
the maximum width of the blade at the hilt was 4 cm , narrowing to the front and attaining a width of 3 cm at 5 cm from the tip of the blade , and then it clearly narrowed forming a sharp ending . on the upper and lower edges of the knife , at the borderline with the hilt , there were single arched depressions with an arch 2.5 cm long each .
the arched depression in the upper edge had a chord of 2.4 cm and a height of 0.3 cm , and the one in the lower edge ( on the blade side ) had a chord of 2.2 cm and a height of 0.6 cm .
with nine slightly squared off serrations , each serration approximately 0.1 cm wide at the top , 0.2 cm apart from one another ( fig . 1 ) .
a blow - up of the serrated area of the hilt in the upper right hand corner the knife seized as material evidence .
a blow - up of the serrated area of the hilt in the upper right hand corner at the public prosecutor s order , an experiment was conducted to check whether it was possible to make the characteristic linear abrasions on the skin near the sharp edge of the wound found during the autopsy of xy s corpse ( fig .
2a ) , and a linearly shaped abrasion of the skin unrelated to these wounds ( fig . 3a ) , by using the knife found at the scene of the crime . after
the public prosecutor s consent had been given , the experiment was conducted on the body of a person who had died suddenly of natural causes , routinely directed by the prosecutor s office to the department of forensic medicine for autopsy .
such an experiment was the only possible way to imitate the real conditions of inflicting the characteristic injuries , as no other simulant material has properties similar enough to human skin , which could be valid in court .
2the wound found during the autopsy ( a ) and the one inflicted with the knife seized as material evidence ( b ) . in the edges of both wounds there are characteristic scratches looking alikefig .
3a characteristic striated abrasion of the skin of the abdomen , near navel , found during the autopsy ( a ) and marks originated during the experiment with the knife seized as material evidence made by the serrated area of the upper ( b ) and lower ( c ) edge of the hilt the wound found during the autopsy ( a ) and the one inflicted with the knife seized as material evidence ( b ) . in the edges of both wounds there are characteristic scratches looking alike a characteristic striated abrasion of the skin of the abdomen , near navel , found during the autopsy ( a ) and marks originated during the experiment with the knife seized as material evidence made by the serrated area of the upper ( b ) and lower ( c ) edge of the hilt during the experiment , red ink was applied onto the abovementioned serrations of the knife then the blade was plunged into the abdominal integuments up to the hilt and then turned left around its long axis and pushed deeper into the body , pressing the lower edge of the knife against the abdominal integuments .
moreover , the knife , plunged into the abdominal integuments up to the hilt with the red ink successively applied onto the serrations , was turned several times in different directions pressing its upper edge against the abdominal integuments , without the effect similar to the abrasion found during the autopsy of xy . subsequently , following the next application of red ink onto the serrations of the knife , it was struck at the abdominal integuments near the navel and as the serrated area of its upper edge touched the integuments the knife was moved tangentially to the integuments along a distance of approximately 3 cm , achieving the effect seen in fig .
then , the above action was repeated by striking the abdominal integuments with the serrated lower edge of the knife , achieving the effect illustrated in fig .
a comparison of the morphological features of the stab wound of the abdomen found during xy s autopsy ( fig .
2a ) and the morphological features of the wound of the abdomen resulting from the above experiment ( fig .
2b ) showed a similarity between their shapes and the location and size of the linear skin abrasions in the edges of both wounds .
what particularly weighed in favor of their origin in the same instrument was the identical width of the abrasions ( 0.1 cm ) and the distance between them ( 0.2 cm ) .
this shows that the characteristic striated abrasion of the skin near the wound in the abdominal integuments found during the autopsy could have resulted from the contact of the integuments in the immediate vicinity of the wound with the serrations of the depression at the border of the blade and the hilt of the seized knife located on the lower ( blade ) side .
hence , the outcome of the experiment suggests that the characteristic damage found in the vicinity of the wound most probably resulted from thrusting the knife deep into the abdomen and then rotating around its long axis to the left , simultaneously pressing the serrated edge to the abdominal integuments [ 4 , 14 ] .
a comparison of the characteristic striated skin abrasion found during xy s autopsy ( fig .
3a ) and the changes resulting from the experiment with the knife constituting material evidence ( fig .
3b and c ) indicates that the abrasion on the abdomen near the navel found during the post - mortem could have resulted from the contact of the integuments in this area of the body with the serrations located on the borderline of the knife s blade and hilt .
this is clearly evidenced by the same number and width of the linear abrasions of the integuments and the distance between them the same as for the abrasions in the edges of the wounds ( fig .
the striated abrasion in abdominal skin resulted from the tangential action of the above - described serrations on the knife on the abdominal integuments and it could have originated from the action of the serrations located both on the lower and upper edge of the knife seized as material evidence .
the experiment using the material evidence , conducted at the public prosecutor s order , led to the assumption that the injuries found during the autopsy could have originated from the action of the seized knife .
the experiment demonstrated that the striated marks found in the integuments of the body , at first glance suggesting their possible origin in a serrated knife blade , actually originated from the decorative rather than functional serrations discreetly located near the hilt of a knife with a smooth blade .
such conclusions could not be drawn in a different way , e.g. , based exclusively on a comparison between the appearance and features of the knife and the injuries to the body integuments .
thus , the present paper points to the usefulness of experiments using material evidence , such as alleged instruments of crime , to identify the origin of bodily injuries , if the need arises .
Output:
| this paper presents an experiment with a knife seized as material evidence in a homicide case .
the reason for the experiment was the necessity to determine whether the injuries of the deceased could have been inflicted with this instrument since in the course of the investigation doubt arose as to the origin of linear , parallel scratches around one of the wounds and on the abdominal integuments suggesting a serrated blade .
the knife found near the crime scene had a smooth blade and small serrations only on the borderline between its blade and hilt .
however , the performed experiment showed that if the knife is directed towards the integuments of the body in a special way , its serrations , even though not located on the blade itself , may leave such striated marks on the body , as those found during the autopsy , suggesting their origin from a serrated blade . |
PubmedSumm118230 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: in fact , cin is one of the most useful molecular markers to differentiate melanomas from benign nevi [ 1 , 2 ] .
found that 96.2% of melanomas demonstrated chromosomal aberrations while only 13.0% of benign nevi showed these same abnormalities , of which all were spitz nevi with stable 11p duplications .
the fact that melanomas have such unstable genomes comes as no surprise , as genomic instability is widely regarded as the hallmark of cancer [ 37 ] . while genomic instability decreases the viability of most cells , it may also permit a subpopulation of cells to acquire genetic changes that lead them to escape normal growth control mechanisms .
in addition , genomic instability allows established cancers to evolve and evade immunologic and pharmacologic destruction .
the extent to which different mechanisms play a role in genomic instability is controversial ; however three pathways are generally most accepted .
these are defective dna repair , telomere crisis , and mitotic spindle malfunction [ 3 , 912 ] .
an underappreciated but potentially important research area is the abnormal expression of germ cell proteins .
cancer / testis antigens ( ctas ) are a family of germ cell proteins expressed in a multitude of different histological tumor types [ 13 , 14 ] .
studies have shown that expression of specific ctas in melanoma can be used to predict tumor thickness , the presence of ulceration , and likelihood to undergo metastasis .
melanomas have also been shown to express meiosis specific proteins including scp1 ( homologous chromosome pairing ) , hormad1 ( meiotic synapse regulation ) , spo11 ( double stranded dna breaks ) , and rec8 ( meiosis cohesion protein ) .
we have also found three of these meiosis proteins , addition to a fourth not previously described , to be present in melanoma using western blot analysis ( figure 1 ) and immunofluorescence ( figure 2 ) . although the potential impact of the expression of meiotic proteins during mitosis in causing cin has been suggested [ 1721 ] and a role in reductional division in irradiated polyploid cells has been noted , thus far there has been no research directly evaluating the potential direct role of meiosis proteins in the creation of cin .
this review is focused on understanding meiosis pathways and explaining how the expression of these pathways during mitosis ( meiomitosis [ 19 , 20 ] ) may result in chromosomal instability .
mitosis in which a diploid cell ( 2n ) duplicates its dna once and divides to produce two genetically identical diploid cells ( 2n ) , in meiosis a diploid cell ( 2n ) duplicates its dna once and undergoes two distinct rounds of cell division to produce four genetically unique haploid ( 1n ) cells ( table 1 ) .
while mitosis occurs in all somatic cells of the human body , meiosis occurs naturally only in the male testis and female ovary .
the meiosis pathways are thought to have evolved from double - stranded dna repair pathways .
this occurs through recombination events , where corresponding sections of dna on the two homologous chromosomes are exchanged .
this ensures that dna damage is not passed on to progeny [ 24 , 25 ] , in addition to the obvious role of producing genetic diversity to facilitate species evolution [ 2527 ] .
the second division of meiosis ( meiosis ii ) has many aspects that are nearly identical to mitosis .
the first division , on the other hand , exhibits three major modifications : ( i ) meiotic pairing to allow recombination , ( ii ) kinetochore coorientation to allow for homologous chromosome segregation during anaphase i , and ( iii ) stepwise loss of cohesion to ensure that sister chromatids segregate together in meiosis i .
these unique meiosis i pathways are the ones most likely to interfere with normal mitosis and will be the primary focus of this review .
the switch to meiosis from mitosis occurs in germ cells when the decision is made to produce gametes . prior to this switch
, germ cells use mitotic divisions as a way of self - renewal to increase their numbers and ensure the cell line does not become depleted . the decision for cells to transition from a mitotic to meiotic cell cycle is complex and differs vastly among organisms . in most simple single - celled organisms that undergo asexual reproduction
nutrient deprivation triggers the dephosphorylation of the rna binding protein mei2 by pat1 kinase which initiates the switch from mitosis to meiosis . in caenorhabditis elegans germline cells , gld1 ( quaking ) , gld2 ( poly(a ) polymerase ) , and gld3 ( bicaudal c ) have been shown to be critical for this switch [ 31 , 32 ] . in mammals , the decision to transition from mitosis to meiosis is yet more complex and there are numerous regulatory molecules that govern this change .
stra8 is one of these proteins and is known to be imperative for the switch from mitosis to meiosis in both human male and female germ lines .
support this notion , showing that the spermatocytes in mice with depleted stra8 failed to enter meiosis .
the crucial point in the cell cycle by which the cell must decide to make the mitotic - to - meiotic shift is at the g1/s checkpoint .
this is because the cell must undergo meiotic - specific events during s phase to ensure the proper progression of meiosis .
the meiotic cohesin protein rec8 ( discussed further below ) must be incorporated into the newly replicated dna during the premeiotic s phase so that the kinetochores can orient appropriately to allow for reduction division during meiosis i. although meiosis follows mitosis in the production of gametes , it is important to note that in the fertilized egg , mitosis is reestablished after meiosis .
thus the mitosis - meiosis pathways can be switched on and off and are reversible .
the formation of crossover events lies at the heart of meiosis , as it allows for genetic recombination between homologous chromosomes and is necessary for the proper alignment of chromosomes during meiosis i. crossovers are initiated by the creation of double - stranded breaks ( dsbs ) by the protein spo11 .
spo11 creates dsbs using a catalytic tyrosine to attack the phosphodiester backbone of dna , creating a covalent bond between itself and the 5 end of the break .
each spo11 protein associates with only one strand of dna ; thus two spo11 molecules are needed for each dsb .
once the dsb is formed , spo11 is removed by polymerase with the help of the mre11 complex [ 36 , 38 ] and the 5 ends of the breaks are excised , leaving stretches of 3 ssdna .
this single stranded dna associates with dmc1 and rad51 , two proteins known to be involved in double - stranded dna repair , to form a filament .
this filament then begins the search for a location of homology on the opposite chromosome .
many of the factors which ensure that the single stranded dna correctly associates with a corresponding dna fragment on the homologous chromosome have yet to be elucidated .
it is clear that the meiosis specific kinase mek1 plays a role in ensuring interhomolog binding through its interaction with rad54 and rad51 [ 39 , 40 ] .
, dmc1 begins the crossover recombination event using one of the 3 ends to mediate a stable invasion of the homologous chromosome .
dna synthesis then extends the end of the invading strand . by recapture of this strand , a joint molecule
is generated that contains a holiday junction , which can then be resolved into either a noncrossover or crossover event .
hormad1 also plays a critical role in synapsis formation through its role in dsb formation .
independently , hormad1 also promotes the proper formation of the synaptonemal complex , a proteinaceous structure which stabilizes the tetrad and ensures proper homolog pairing .
together these factors cause dna strand breaks and create a controlled number of crossover events .
deregulation , or simply the presence , of these pathways in otherwise mitotic cells would be expected to cause translocations as well as insertions and deletions .
although there is no data specifically implicating these pathways in cancer , it is important to note that spo11 , dmc1 , and hormad1 have all been shown to be increased in cancer .
both spo11 and hormad1 have been specifically noted in melanoma [ 17 , 18 ] and we found them to be overexpressed in melanoma compared to nontransformed cell types using western blot analysis ( figure 1 ) and immunofluorescence ( figure 2 ) .
at least sixteen dna polymerases exist in eukaryotes , each with its own unique role in maintaining the integrity of the genome .
specific high fidelity dna polymerases function in replicating the genome during the s phase of the cell cycle .
more error - prone polymerases also exist and have specific functions including dna repair and cell recombination . while it is imperative that the cells employ methods to preserve the fidelity of dna replication , error - prone polymerases may play a role in producing variability which could provide a selective advantage . as such , in 1962 magni and von borstel observed that cells had a markedly higher rate of mutation during meiosis compared to mitosis .
dna polymerase ( pol ) is one of the more error prone polymerases found in eukaryotes and is required for base excision repair during dna replication and repair .
it has an error rate of one error per 10,000100,000 nucleotides incorporated , up to 100x higher than the more accurate polymerases which the cell routinely uses for chromosomal replication .
recently , pol has also been found to have a critical role during meiotic synapsis .
pol has been shown to localize to the synaptonemal complex during prophase i where it facilitates the removal of the spo11 complex from dna breakage ends , facilitating the creation of ssdna with which rad51 and dmc1 associate .
showed that pol knockdown spermatocytes were unable to undergo chromosome synapsis and , instead , underwent apoptosis during prophase i .
decreased pol expression has been detected in one fifth of tumors and this decrease has also been demonstrated to promote tumorigenesis presumably due to decreased dna repair .
conversely , increased levels of pol have been noted in approximately one - third of tumors studied , with one sample showing a 286-fold increase .
used mouse embryonic fibroblasts to study the effect of varying levels of pol on genomic instability by looking at three endpoints : dna strand breaks , chromosomal breakage , and gene mutation .
pol null cells showed a marked increase in genomic instability due to their inability to repair dna .
pol overexpressing cells showed a high frequency of mutations , but only after the introduction of dna damaging agents , most likely because pol was used to repair the dna damage instead of one of its higher fidelity counterparts .
servant et al . specifically studied the association between dna pol and melanoma and found that pol was markedly overexpressed in melanoma tissue when compared to normal skin .
mammalian cells which overexpressed pol had a 1.52-fold higher resistance to uv radiation , though the surviving cells had a 2.650-fold increase in mutations .
pol was able to repair both cyclobutane pyrimidine dimers ( cpd ) and pyrimidine - pyrimidone ( 64 ) photoproducts and had the ability to elongate the 3 strand after datp addition .
this is significant because this period of elongation serves as a potential source of dna point mutations due to pol 's markedly lower rate of fidelity than other polymerases .
although pol seems to be expressed at some level ubiquitously in all cells , it clearly plays an integral role in the meiotic pathways .
it would be anticipated that cells activating meiosis pathways may exhibit increased pol activity and increased mutations .
the decision is made to enter the meiotic cycle prior to replicating the dna . during the replication of dna for meiosis
, the newly duplicated strands are held together by a ring of proteins called cohesins .
the mitotic cohesin complex normally includes the structural maintenance ( smc ) proteins smc1 and smc2 , the kleisin protein scc1/rad21 , and an accessory subunit , scc3 [ 51 , 52 ] . in meiosis rad21
rec8 serves a number of functions including ( 1 ) acting within the synaptonemal complex to drive homologous recombination , ( 2 ) kinetochore orientation , and ( 3 ) sister chromatid adhesion .
the synaptonemal complex is a unique meiosis specific structure which is critical for chiasma ( locations of crossover ) formation , homologous chromosome binding , and chromosome segregation .
it bridges homologous chromosomes and is composed of three proteins : scp1 , 2 , and 3 .
rec8 is critical in this structure for driving chiasma formation between homologous chromosomes [ 55 , 56 ] .
as the chromosomes condense , rec8 is cleaved on the chromosome arms and the cohesin complex is replaced by the condensin complex . the crossover point remains to ensure proper alignment , tension , and segregation of the homologous chromosomes .
rec8 has also been shown to play a role in the monoorientation of sister kinetochores during meiosis i. when the mitotic cohesin protein rad21 is expressed instead of rec8 in yeast , sister chromatids undergo equational rather than reductional chromosomal segregation during meiosis i [ 55 , 57 ] .
this suggests that the coorientation of kinetochores is lost , allowing sister chromatids to be pulled towards opposite poles of the dividing cell .
studies performed in maize support this theory , demonstrating that , in the absence of rec8 , sister chromatids establish bioriented sister kinetochores in meiosis i .
while research suggests rec8 is required for monoorientation of sister kinetochores , its overexpression alone does not appear to always lead to chromosomal missegregation during mitosis [ 55 , 57 ] but instead requires the cooperation of other factors such as monopolins , as reviewed below .
rec8 is retained around the centromere until the start of anaphase ii ensuring that sister chromatids do not become prematurely separated .
two of the factors that prevent the cleavage of rec8 at the centromere are sgo1 and sgo2 .
although both of these proteins are ubiquitously expressed in mammals , sgo2 is found in higher concentrations in the testis , implying that it may play a more major role in meiosis .
studies have supported this theory , showing that mice with a deleted sgo2 gene show no failure to thrive but are infertile , suggesting that this protein is not as critical in mitosis as meiosis .
sgo2 protects rec8 from cleavage during meiosis i by ensuring its dephosphorylation at the centromeres .
this is accomplished through the recruitment of protein phosphatase 2a ( pp2a ) to centromere proximal cohesins .
pp2a localization to centromeres results in dephosphorylation of centromere proximal rec8 , inhibiting its cleavage by separase while allowing rec8 cleavage to occur along chromosome arms .
rec8 expression has been noted in melanoma and we found it to be overexpressed in melanoma using western blot analysis ( figure 1 ) and immunofluorescence ( figure 2 ) .
rec8 has also been noted in irradiated lymphoma cells . forced expression of rec8 during mitosis
compared with the wild type yeast cells , the strains with upregulated rec8 showed bridged nuclei which were not able to divide appropriately . thus it is possible that high levels of rec8 may play a role in nuclear division abnormalities .
it has also been postulated that rec8 may play a role in reducing chromosome number in polyploid cancer cells by driving reductional divisions .
interestingly , synaptonemal complex proteins scp1 and scp3 have been shown to be upregulated in cancer and are associated with tumor progression and survival [ 16 , 22 , 64 ] .
found that in melanoma , four of the 28 samples tested showed positive synaptonemal complex protein expression .
studies have demonstrated that when inserted into nongerm cells , these proteins are still able to produce a synaptonemal complex . thus it is possible that these proteins play a role in chromosomal missegregation and crossover events in cancer .
the kinetochore is a proteinaceous structure which forms on centromeres and serves as a spindle fiber attachment site used to pull chromosomes apart and to opposite poles of the nucleus during cell division .
every chromatid has its own kinetochore , thus after the duplication of genetic material each chromosome contains two kinetochores , one on each chromatid . during mitosis , the two kinetochores on each chromosome face in opposite directions so that spindle fibers from each pole attach to separate chromatids
the kinetochore works as a sensing mechanism , ensuring that the chromosomes are appropriately amphitelically attached .
it does this by detecting the tension produced from the counteracting pull from each spindle into the bidirectionally oriented sister kinetochores .
only when this tension is sensed does the cell proceed through the spindle assembly checkpoint ( sac ) and begin anaphase .
this process is more complicated in meiosis , as the cell must undergo two subsequent rounds of chromosome segregation without intervening dna duplication .
this is accomplished by a different orientation of the kinetochores in meiosis i through the use of rec8 , monopolin proteins , and aurora b kinase [ 58 , 65 ] . in meiosis
i , sister kinetochores are oriented on the same side of the chromosome ( monooriented ) and attach to spindle fibers in a syntelic fashion to ensure that sister chromatids are pulled towards the same pole of the dividing cell .
the tension necessary to proceed through the checkpoint is created by the crossovers between homologous chromosomes , which are pulled in opposite directions .
resolution of the chiasma allows for separation of the joined homologous pairs in anaphase i. meiosis ii then proceeds similarly to mitosis .
many of the details on kinetochore orientation and rotation in meiosis ii have yet to be determined .
condensins , proteins which play a major role in chromosome condensation and dsb repair during prophase i , are also known to play a role .
brito et al . showed that in the absence of condensins , a portion of kinetochores biorient during meiosis i .
a third group of proteins called monopolins also play a key role [ 6769 ] .
b kinase , monopolins help ensure that homologs are pulled towards opposite poles of the cell .
although rec8 plays a clear role in maintaining monooriented sister kinetochores , monopolins alone are able to hold together sister kinetochores independently [ 67 , 69 ] .
another critical part of this process is the spindle apparatus . in the female oocyte ,
the centrosome is destroyed before meiosis and the cell undergoes an acentrosomal spindle assembly [ 70 , 71 ] .
the spindle network is instead formed through the action of over 80 self - organized microtubule organized centers ( mtocs ) that develop from the cytoplasmic microtubule complex and eventually aggregate into a bipolar network .
very little is understood about acentrosomal spindle assembly and the differences between the mitotic and meiotic spindle , and further studies are needed . during meiosis
studies have shown that some sac proteins specifically interact with rec8 and shugoshin ( sgo1 and 2 ) .
bub1 is one of the sac proteins shown to be specifically involved with this process .
bub1 is required for the localization of the meiosis cohesion regulators sgo1 and sgo2 to protect rec8 during meiosis i .
for this reason , bub1 is thought to be essential for establishing proper kinetochore function [ 56 , 73 , 74 ] .
bub1 mutation results in chromosome fragmentation and missegregation in drosophila [ 56 , 73 ] and female specific germ cell aneuploidy in mice [ 56 , 75 ] .
bub1 has been noted to be abnormally expressed in several cancers including gastric , colon , esophageal , breast , and melanoma [ 7679 ] .
lewis et al . used qtpcr to identify molecular expression patterns in melanoma , benign nevi , and lymph nodes .
of the 20 melanoma - related genes tested , bub1 was one of the three genes found to have the highest discriminatory potential for distinguishing melanoma , benign nevi , and lymph nodes .
there is a delicate interplay between kinetochores , the spindle apparatus , and the sac which , when not functioning properly , would be expected to result in chromosomal segregation abnormalities .
it is possible that these two phenomena are related due to the collision of meiotic germ cell pathways with the normal mitotic cell cycle pathways ( meiomitosis ) .
as discussed , these pathways could impact genomic instability at many levels including double stranded dna breaks , crossover events , chromosomal cohesion , spindle defects , and direct introduction of point mutations ( table 3 ) .
chromosomal instability is a hallmark of human cancer , and we hypothesize that the aberrant expression of meiosis proteins will prove to be a critical step in this process .
expression of these pathways may serve a diagnostic role in identifying tumor with particular aggressive behavior due to their capacity to continuously evolve .
further , these pathways may serve as therapeutic targets . because meiosis proteins are largely limited to germ cells ,
targeted therapeutics could be designed to have very limited interactions with other cells in the body reducing potential adverse side effects .
meiomitosis is likely to play a critical role in cancer progression and we believe future research is needed to shed light on this promising field .
Output:
| melanomas demonstrate chromosomal instability ( cin ) .
in fact , cin can be used to differentiate melanoma from benign nevi .
the exact molecular mechanisms that drive cin in melanoma have yet to be fully elucidated .
cancer / testis antigens are a unique group of germ cell proteins that are found to be primarily expressed in melanoma as compared to benign nevi .
the abnormal expression of these germ cell proteins , normally expected only in the testis and ovaries , in somatic cells may lead to interference with normal cellular pathways .
germ cell proteins that may be particularly critical in cin are meiosis proteins . here
, we review pathways unique to meiosis with a focus on how the aberrant expression of meiosis proteins in normal mitotic cells meiomitosis could impact chromosomal instability in melanoma and other cancers . |
PubmedSumm118231 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: mouse models of chronic infection by t. cruzi - five to seven - week - old
female c3h / he ( h-2 ) and c57bl/6 ( h-2 ) mice obtained from the
animal facilities [ laboratory animals breeding center , oswaldo cruz foundation
( fiocruz ) , rio de janeiro , brazil ] were maintained under specific pathogen - free
conditions .
this study was carried out in strict accordance with the recommendations in
the guide for the care and use of laboratory animals of the brazilian national council
of animal experimentation ( cobea.org.br/ ) and the federal law
11.794 ( 8 october 2008 ) .
the institutional committee for animal ethics of fiocruz
( license 004/09 ) approved all of the procedures used in this study .
experimental infection - mice were infected intraperitoneally with 100
blood trypomastigotes of the colombian strain of t. cruzi , isolated
from a human patient in colombia ( federici et al .
1964 ) and genotypically characterised as a t. cruzi type i
strain ( zingales et al . 2009 ) .
parasitaemia was
estimated using 5 l of blood obtained from the tail vein , employed as a parameter to
establish the acute and chronic phases of infection ( dos santos et al .
three - five sex and
age - matched non - infected ( ni ) controls were analysed per time point in parallel with
five-10 infected mice at 70 days post - infection ( dpi ) , 120 dpi or 150 dpi , according to
the experimental protocol .
reagents and antibodies - for immunohistochemistry ( ihs ) , staining the
polyclonal antibody recognising t. cruzi antigens and the anti - mouse
cd8a ( 53 - 6.7 ) and anti - mouse cd4 ( gk1.5 ) supernatants were produced in our laboratory
( laboratory of biology of the interactions , oswaldo cruz institute , fiocruz ) .
the
anti - f4/80 polyclonal antibody recognising macrophages was purchased from caltag ( usa ) .
the polyclonal rabbit antibody recognising connexin 43 ( cx43 ) was purchased from sigma
( usa ) .
the polyclonal rabbit antibody recognising mouse fibronectin ( fn ) was obtained
from gibco - brl ( usa ) .
the biotinylated anti - rat immunoglobulin was obtained from dako
( denmark ) and the biotinylated anti - rabbit immunoglobulin and peroxidase - streptavidin
complex were purchased from amersham ( england ) . for ihs , appropriate controls were
prepared by replacing primary antibodies with rat immunoglobulin or normal rabbit serum .
histopathology and ihs - groups of five - eight infected and three - five
ni control mice were killed under anaesthesia at 120 dpi or 150 dpi , according to the
experimental protocols . in a series of experiments ,
the hearts of the mice were
collected , fixed in 10% formaldehyde , processed for histopathology , embedded in paraffin
and subjected to haematoxylin and eosin staining . in another set of experiments ,
the
hearts were removed , embedded in tissue - freezing medium ( tissue - tek , miles laboratories ,
usa ) and stored in liquid nitrogen until use .
serial cryostat sections , 3 m - thick , were
fixed in cold acetone and subjected to indirect immunoperoxidase staining for the
characterisation of inflammatory cells , as previously described ( dos santos et al .
the ihs assay for detection of
t. cruzi heart tissue parasitism was performed and analysed as
previously described ( silverio et al .
the
fn and cx43-positive areas in 25 fields ( 12.5 mm ) per section , in three
sections per heart , were evaluated with a digital morphometric apparatus .
images were
digitised using a colour view xs digital video camera adapted to a zeiss microscope .
the
images were analysed with analysis auto software ( soft imaging system , usa ) .
the areas
that expressed the molecule of interest were integrated with the areas that did not
express the molecule of interest and the data were presented as the percentage of the
positive area in the heart , as the distance ( m ) between stained gap junctions or as
parasite nests or cell numbers/100 microscopic fields ( 400x ) .
detection of cardiac muscle creatine - kinase isoform - the activity of
the creatine kinase cardiac mb isoenzyme ( ck - mb ) was measured using a commercial ck - mb
liquiform kit ( labtest , brazil ) in accordance with the manufacturer s recommendations
and has been previously adopted for an experimental approach in a murine model of
chronic infection ( medeiros et al .
.
electrocardiogram ( ecg ) registers - all mice were intraperitoneally
tranquilised with diazepam ( 10 mg / kg ) and transducers were carefully placed
subcutaneously according to the chosen preferential derivation ( dii ) .
two - minute long
traces were recorded using the digital system power lab 2/20 , which was connected to a
bio - amplifier at 2 mv for 1 s ( panlab instruments , spain ) .
filters were standardised to
between 0.1 - 100 hz and traces were analysed using the scope software for windows
v.3.6.10 ( panlab instruments , spain ) .
serum tnf determination - the tnf serum concentrations were evaluated
by elisa kits for the detection of mouse tnf ( r&d systems , usa ) according to the
manufacturer s protocols .
the colourimetric reaction was assessed using an elisa plate
reader at 490 nm ( asys hitech gmbh , austria ) .
in addition , a mouse cytometric bead array
( cba inflammation kit , becton & dickinson , usa ) was used to quantify tnf in the
serum according to the manufacturer s instructions .
the fluorescence produced by the cba
beads was measured on a facscalibur ( becton dickinson , usa ) and analysed using the fcap
array software .
no quantification - nitrate and nitrite ( nox ) were
determined in serum samples from ni and infected mice using the griess reagent and
vanadium chloride iii with a standard curve of 0.8 - 100 m nano2 and
nano3 ( carvalho et al . 2012 ) .
student s t , anova or other more appropriate tests
were used to analyse the statistical significance of the observed differences .
the
kaplan - meier method was used to compare the survival times of the studied groups .
t. cruzi - infected c3h / he mice present higher parasitaemia , inflammation and
heart parasitism than infected c57bl/6 mice - when female c57bl/6 and c3h / he
mice were infected with a low inoculum of the colombian t. cruzi type i
strain ( fig .
however , the c3h / he animals showed higher numbers of parasites at
the peak of parasitaemia , which occurs at 42 - 45 dpi in both mouse lineages ( fig .
furthermore , in both models of
parasitaemia , control occurs from 60 - 70 dpi .
approximately 70 - 85% of the c57bl/6 and
c3h / he mice survived ( fig .
1c ) without
trypanocidal treatment and developed a chronic infection when the rare blood
trypomastigote was found at 90 dpi . in all surviving animals , focal and diffuse
inflammatory infiltrates and remodelling of the cardiac tissue were detected in
chronically infected c57bl/6 and c3h / he mice , compared with age - matched ni controls
( fig .
the chronic myocarditis was mainly
composed of cd8 , cd4 lymphocytes and f4/80
macrophages were detected in the chronic phase of infection occurring at 120 dpi and 150
dpi ( data not shown ) in mice of both lineages , corroborating previous findings ( talvani et al . 2000 , dos santos et al .
importantly , total heart inflammation , representing the sum of
cd8 and cd4 t - cell subsets and macrophages , was more
pronounced in chronically t. cruzi - infected c3h / he mice compared to
infected c57bl/6 mice ( fig .
notably , heart
parasitism persisted during the chronic phase of infection , being more intense in c3h / he
mice compared to c57bl/6 mice ( fig .
. a : experimental design of the
article . c57bl/6 and c3h / he mice were infected with 100 blood trypomastigotes
( bt ) of the colombian t. cruzi type i strain and analysis at
70 days post - infection ( dpi ) , 120 dpi or 150 dpi , according experimental
protocol ; b : kinetics of parasitaemia ; c - d : quantitative data of the
immunohistochemistry for t. cruzi parasite nests ( c ) and total
inflammatory cells ( d ) in the heart tissue at 120 dpi ; # : p < 0.05 c57bl/6
mice compared to c3h / he mice .
data obtained from three independent experiments
[ 5 non - infected ( ni ) and eight-10 t. cruzi - infected mice per
experiment ] .
cardiac tissue injury is more severe in t. cruzi - infected c3h / he mice compared
to infected c57bl/6 mice - in six - month - old ni controls , the expression of
cx43 , a marker of cardiomyocyte connectivity ( orlic et
al .
however , in chronically ( 150 dpi ) t. cruzi - infected
mice , the expression of cx43 was reduced , disorganised and more disperse ( fig .
2a ) and was characterised by an increased
distance between the marks for cx43 in the intercalated disks of the cardiomyocytes
( fig .
in parallel experiments , the cx43
disorganisation was increased in six - month - old ni c3h / he mice compared to c57bl/6 mice
( fig .
furthermore , the cx43
disorganisation was more extensive in t. cruzi - infected c3h / he mice
compared to infected c57bl/6 mice ( fig .
2 : trypanosoma cruzi induces connexin 43 ( cx43 ) loss during
the chronic phase of infection .
a : representative sections of the heart tissue
of non - infected ( ni ) and infected c57bl/6 mice analysed by immunohistochemistry
for detection of cx43 at 150 days post - infection ; b : quantitative data of
cx43-containing gap junction distances in the heart tissue of ni and
t. cruzi - infected c57bl/6 and c3h / he mice ; * * : p < 0.01 ,
ni compared to t. cruzi - infected mice ; # : p < 0.05 , c57bl/6
compared to c3h / he lineage .
data obtained from three independent experiments ( 5
ni and 8 - 10 t. cruzi - infected mice per experiment ) .
when compared to ni controls , increase deposition of the extracellular matrix component
fn ( marino et al .
2003 ) was detected in the heart
tissue of c57bl/6 and c3h / he mice infected with the colombian t. cruzi
strain ( fig .
the fn expression was similar in six - month - old ni c57bl/6 and c3h / he
mice , the parallel controls of the infected mice ( fig .
3a ) . at 150 dpi , however , the fn deposition in the cardiac tissue was more
intense in t. cruzi - infected c3h / he mice compared to infected c57bl/6
mice ( fig .
3 : trypanosoma cruzi induces fibronectin ( fn ) deposition in
the cardiac tissue during the chronic phase of infection . a : representative
sections of the heart tissue of non - infected ( ni ) and infected c57bl/6 mice
analysed by immunohistochemistry for fn deposition ; b : quantitative data of
fn - stained area ( % ) in the heart tissue of ni and
t. cruzi - infected c57bl/6 and c3h / he mice ; * * * : p < 0.001 ,
ni compared to t. cruzi - infected mice ; # : p < 0.05 , c57bl/6
compared to c3h / he lineage .
data obtained from three independent experiments ( 3
ni and 5 t. cruzi - infected mice per experiment ) .
ck - mb activity , which is proportional to the concentration of the enzyme present in the
serum and assumed to be a marker of myocardial injury ( adams et al .
1993 ) , was increased in the serum of chronically ( 150 dpi )
t. cruzi - infected c3h / he and c57bl/6 mice compared with sex and
age - matched ni controls ( fig .
, the
levels of ck - mb activity were elevated in the serum of t.
cruzi - infected c3h / he mice compared to infected c57bl/6 mice ( fig .
enzymatic evaluation of creatine kinase cardiac
mb isoenzyme ( ck - mb ) activity in the serum of non - infected ( ni ) and t.
cruzi - infected c57bl/6 and c3h / he mice at 150 days post - infection .
data obtained from three independent experiments ( 3 - 5 ni and 6 - 8 t.
cruzi - infected mice per experiment ) .
od : optical density ; * : p <
0.05 ; * * : p < 0.01 , ni compared to t. cruzi - infected mice ;
# : p < 0.05 , c57bl/6 compared to c3h / he lineage .
electrocardiograph alterations are severe in t. cruzi - infected c3h / he mice
- disturbances in electrical conduction are striking features of chagas heart
disease ( rassi jr et al .
2010 ) . the normal p wave
and the qt complex register ( fig .
5a ) were altered
in chronically ( 150 dpi ) t. cruzi - infected mice compared with sex and
age - matched ni controls .
infected mice presented ecg abnormalities in the conduction
system , including a prolonged p wave , pr interval and qrst complex ( fig .
the duration of the qrs interval was similar in
six - month - old ni c57bl/6 and c3h / he control mice . at 150 dpi ,
significant alteration of
the qrs interval was detected in t. cruzi - infected c57bl/6 and c3h / he
mice compared with their ni controls ( fig .
5c ) .
additionally , the prolonged qrs interval was more pronounced in infected c3h / he mice
compared to c57bl/6 mice ( p < 0.01 ) . in both mouse lineages , t.
cruzi - infected mice frequently show ecg alterations such as arrhythmias
( arts ) and a second - degree atrioventricular block ( avb2 ) .
moreover , a low frequency of
infected c3h / he and c57bl/6 mice also presented with an avb1 , while fibrillation was
rarely ( < 5% ) detected in infected mice of either lineage .
therefore , t.
cruzi - infected mice frequently ( 80% for c57bl/6 and 100% for c3h / he ) showed
ecg abnormalities ( fig .
the ecg
abnormalities were more frequent and severe in t. cruzi - infected c3h / he
mice compared to infected c57bl/6 mice .
: trypanosoma cruzi induces electrocardiographic ( ecg )
abnormalities during the chronic phase of infection . a : schematic
representation of the p wave and qt complex segment of the ecg register of a
non - infected ( ni ) mice ;
b : representative ecg register segments of sex and
age - matched ni controls and t. cruzi - infected c3h / he mice at
150 days post - infection ; c : data for ecg records showing the duration ( ms ) of
the qrs interval ; d : summary of the group data for the frequency of ni and
t. cruzi - infected mice presenting arrhythmias ( arts ) ,
second - degree atrioventricular block ( avb2 ) and total ecg alterations ; * * : p
< 0.01 , ni compared to t. cruzi - infected mice ; # : p <
0.05 , c57bl/6 compared to c3h / he lineage .
data obtained from three independent
experiments ( 5 ni and 8 - 10 t. cruzi - infected mice per
experiment ) .
high tnf and no levels are detected in the serum of colombian - infected c3h / he
and c57bl/6 mice - compared with six - month - old matched ni controls , the
serum tnf levels of chronically ( 150 dpi ) t. cruzi - infected c57bl/6 and
c3h / he mice were significantly increased ( fig .
moreover , while the slight increase in the tnf levels in the serum of ni c3h / he mice
compared to ni c57bl/6 mice was not significant ( p > 0.05 ) , the tnf levels were
eight-12-fold higher in t. cruzi - infected c3h / he mice compared to
infected c57bl/6 mice ( p < 0.05 ) ( fig .
fig . 6 : trypanosoma cruzi induces increased tumour necrosis
factor ( tnf ) levels during the chronic phase of infection .
detection of tnf
concentrations in the serum of non - infected ( ni ) and
t. cruzi - infected c57bl/6 and c3h / he mice .
representative data
obtained from two independent experiments using elisa and cba inflammation kit
( 3 ni and 5 t. cruzi - infected mice per experiment ) . * : p <
0.05 , ni compared to t. cruzi - infected mice .
considering that no is proposed to control t. cruzi growth during acute
infection ( silva et al .
2003 ) , we measured the
serum nitrate / nox concentrations of mice after parasitaemia control , which
occurs at 60 - 70 dpi ( fig .
, nox
levels were increased in the serum of infected mice of either lineage in
comparison with their ni sex and age - matched controls ( fig .
furthermore , the nox levels in the serum of
t. cruzi - infected c3h / he mice were higher than in the serum of
infected c57bl/6 mice ( fig . 7 ) .
: trypanosoma cruzi infection increased nitric oxide ( no )
levels in the serum .
concentrations of nitrate / nitrite were measured in the
serum of non - infected ( ni ) and t. cruzi - infected c57bl/6 and
c3h / he mice at 70 days post - infection , using modified griess methodology . data
obtained from three independent experiments ( 3 ni and 3 - 5
t. cruzi - infected mice per experiment ) . * : p < 0.05 ; * * :
p < 0.01 , ni compared to t. cruzi - infected mice ; # : p <
0.05 , c57bl/6 compared to c3h / he lineage .
the severity of cardiac tissue injury and ecg abnormalities parallels the tnf
and no levels in the serum during t. cruzi infection - finally , all the
analysed parameters were comparatively scored for each of the four groups studied ( ni
and t. cruzi - infected c57bl/6 and c3h / he mice ) . as summarised in table ,
analysis of the different markers of heart injury and electrical abnormalities during
the chronic t. cruzi infection revealed that these alterations are more
intense in c3h / he mice compared with c57bl/6 mice .
importantly , the intensity of chronic
heart tissue injury and severity of ecg abnormalities paralleled the tnf and
nox levels in the serum of infected c57bl/6 and c3h / he mice ( table ) .
table comparative study of cardiac and immunological alterations in
trypanosoma cruzi - infected c57bl/6 and c3h / he mice parameters c57bl/6 c3h / he
ni
t. cruzi
ni
t. cruzi
parasitism
- + - + + + inflammation
- + - + + + cx43 loss
+ + + + + + + + + + fn deposition
+ + + + + + + + ck - mb activity
+ + + + + + + ecg alterations - + + - + + + tnf
+ + + + + + + + + + + no
+ + + + + + +
a : analysis of the heart tissue ; b :
analysis of biomarkers in the serum ; ck - mb : creatine kinase cardiac mb
isoenzyme ; cx43 : connexin 43 ; ecg : electrocardiogram ; fn : fibronectin ; ni :
non - infected ; no : nitric oxide ; tnf : tumour necrosis factor ; - : no detection
of the analysed parameter ; + : scores based on the relative expression of the
analysed parameter comparing the four groups of mice .
a : analysis of the heart tissue ; b :
analysis of biomarkers in the serum ; ck - mb : creatine kinase cardiac mb
isoenzyme ; cx43 : connexin 43 ; ecg : electrocardiogram ; fn : fibronectin ; ni :
non - infected ; no : nitric oxide ; tnf : tumour necrosis factor ; - : no detection
of the analysed parameter ; + : scores based on the relative expression of the
analysed parameter comparing the four groups of mice .
in the present study , we propose two reasonable experimental models with differing
degrees of t. cruzi - induced chronic cardiomyopathy that are supported
by parasitological , histopathological , biochemical and electrocardiographic findings .
furthermore , we show that the severity of experimental chagas heart disease parallels
the tnf and no levels in the serum . thus , these models reproduce , for the first time ,
the parallelism between the clinical severity and two relevant immunological features
described in chronic cardiopathic cd patients . the search for a suitable experimental animal model that reproduces the parasitological
and clinical aspects of cd
was initiated soon after the discovery of the disease ( chagas 1909 , torres
& villaa 1919 ) .
although several studies were carried out using different
animal models that reproduce aspects of the chronic disease ( laranja et al .
1956 , federici et al .
1964 , andrade & grimaud 1986 , figueiredo et al .
2012 ) , reasonable experimental models that
simultaneously reproduce relevant parasitological and clinical aspects of the chronic
chagas heart disease in association with immunological abnormalities are still
needed . in trying to prove a causal relationship of the parasite strain to the heart disease ,
federici et al .
( 1964 ) used a t.
cruzi strain ( colombian ) isolated from a human patient in colombia and the
inbred c3h / he mouse lineage . in this study
, parasitaemia peak occurred after 30 dpi and
parasite control occurred by 60 dpi , as corroborated by our results .
furthermore , loss
of cardiomyocytes and replacement by fibrosis in the presence of focal necrosis and
inflammation was observed during chronic infection ( federici et al .
1964 ) , resembling features of chagas heart disease ( higuchi et al . 2003 ) .
later , the model of
colombian - infected c3h / he mice was shown to reproduce the cd8-enriched chronic
t. cruzi - induced myocarditis ( dos santos et al .
2001 ) and was used to study the cellular and molecular
mechanisms of heart tissue colonisation by inflammatory cells ( marino et al .
the
infection of c57bl/6 mice with the colombian strain also reproduces the cd8-enriched
chronic myocarditis ( talvani et al .
2000 ) , as
well as important aspects of the cd electrocardiographic abnormalities ( silverio et al . 2012 ) .
this collection of data
showed that c3h / he and c57b/6 mice infected by the colombian strain reproduce relevant
features of ccc .
however , studies comparing these models with regards to the features of
ccc such as parasitism , inflammation , biomarkers of heart injury and electrical
abnormalities were not previously performed .
furthermore , a study of immunological
mediators associated with ccc in prior studies ( ferreira
et al . 2003 , prez - fuentes et al . 2003 ,
talvani et al . 2004 , carvalho et al .
mice of the
c57bl/6 and c3h / he lineages infected with a low inoculum of the colombian strain
survived the acute phase and developed chronic infections with persistent heart
parasitism and low grade cd8 t - cell - enriched inflammation , corroborating
previous findings ( talvani et al . 2000 , dos santos et al .
moreover , experiments performed in parallel showed that c3h / he mice
were more susceptible to the acute phase , with higher parasitaemia .
however , mice of
both lineages similarly survived and developed chronic infections , although c3h / he mice
presented higher cardiac parasitism and inflammation than their c57bl/6
counterparts .
next , we used biomarkers of heart injury to compare the extent of the tissue lesions in
the c3h / he and c57bl/6 models of chronic t. cruzi infection .
an intense
cx43 disorganisation in the heart tissue was detected in chronically infected c3h / he and
c57bl/6 mice compared with their ni controls .
furthermore , infected mice showed
distinguishable degrees of cx43 disorganisation , which was more intense in the c3h / he
lineage compared to c57bl/6 mice .
previous data showed that acute t.
cruzi infection induces cx43 disorganisation and remodelling , with
delocalisation of the connexin plaques from the intercalated discs and lateralisation
( kroll - palhares et al .
the cx43 lateralisation
accompanies electrical alterations in myocardial infarction and heart failure ( duffy 2012 ) .
moreover , there is an association
between disorganisation and loss of cx43 , the most abundant ventricular gap junction
protein and arrhythmogenic diseases ( orlic et al .
importantly , cx43 expression is down regulated in patients with ccc
( waghabi et al . 2009 ) and chronically
t. cruzi - infected monkeys ( carvalho
et al .
2012 ) , supporting the conservation of this feature in different species
subjected to t. cruzi infection .
thus , both experimental murine models
used in our study reproduce this relevant aspect of ccc . chagas heart disease may be considered a progressive fibrotic disorder ( higuchi et al .
2003 ) . enhanced deposition of
extracellular matrix components , including fn , characterises the cardiac tissue fibrosis
that develops during chronic t. cruzi infection in mice ( andrade et al .
1989a , dos santos et al . 2001 ) and patients ( higuchi et al .
furthermore , a higher frequency of cd patients with
heart failure present severe fibrosis , myocarditis and myocardial hypertrophy compared
to indeterminate - form patients ( higuchi et al .
our studies showed for the first time that it was possible to
discriminate between experimental models of chronic t. cruzi infection
having intense ( c3h / he ) and slight ( c57bl/6 ) fn deposition , which paralleled the degree
of heart inflammation and therefore resembled cd patients ( higuchi et al .
although fn expression was down regulated in
t. cruzi - bearing cardiomyocytes in vitro ( calvet et al .
2004 ) , the presence of the parasite and its antigens
triggered the production of fn in skeletal muscle cells ( pinho et al .
reduced heart parasitism is accompanied by
decreased fn deposition and fibrosis ( andrade et al .
furthermore , fn promotes t. cruzi adhesion to and uptake by macrophages
and fibroblasts ( ouaissi et al .
1985 , noisin & villalta 1989 ) and may perpetuate heart
parasitism . in this context , the differential degree of fn deposition detected in the
heart tissue of c3h / he and c57bl/6 mice paralleled the intensity of heart parasitism and
may reflect a causal relationship .
serum ck - mb activity is an important non - invasive biomarker of cardiomyocyte lesions in
both acute ( de souza et al .
2009 , carvalho et al . 2012 ) experimental chagasic cardiomyopathy . in our
current findings , the intensity of the cardiomyocyte lesion , as revealed by increased
levels of serum ck - mb activity , is more severe in infected c3h / he compared to c57bl/6
mice and is related to the degree of inflammation , fn deposition and cx43
disorganisation in the heart tissue . additionally , our data reinforce the applicability
of ck - mb activity as a biomarker for distinguishing between degrees of heart tissue
damage in chronic t. cruzi infection . both c3h / he and c57bl/6 ccc models reproduced the ecg abnormalities , primarily arts and
first and second - degree avbs , detected in chronically t. cruzi - infected
patients ( rassi jr et al .
furthermore , a
prolonged qrs interval was detected in chronically colombian - infected c57bl/6 and c3h / he
mice compared with their ni controls .
interestingly , the qrs score directly correlates
with cardiac fibrosis , as revealed by magnetic resonance myocardial scar size and
inversely correlated with left ventricular ejection fraction in chronic chagasic
patients ( strauss et al .
furthermore , in
colombian - infected rhesus monkeys with ccc , the intensity of fibrosis has been shown to
be related to the severity of electrical abnormalities ( carvalho et al .
when comparing chronically infected c57bl/6 and c3h / he
mice , the severity of the ecg abnormalities , particularly regarding the prolonged qrs
intervals , was directly related to the extent of fn deposition and cx43 disorganisation
in heart tissue and levels of ck - mb activity in the serum .
therefore , the non - invasive
ecg register should be further explored and validated as a tool reflecting the magnitude
of myocardial scar in chagas heart disease , as proposed by strauss et al .
moreover , the
colombian - infected c3h / he and c57bl/6 models may increase the understanding of the
pathophysiological causal relationship between myocardial scar and ecg alterations . there is a consensus that cd is a multifactorial disorder , in which t.
cruzi persistence and parasite - driven deregulated immune responses are key
players in the establishment of ccc ( lannes - vieira et
al .
2003 ) and the degree of cardiac dysfunction in
patients with ccc ( ferreira et al . 2003 , talvani et al . 2004 ) .
chronically t.
cruzi - infected c57bl/6 and c3h / he mice have increased expression of tnf mrna
and protein in the heart tissue ( talvani et al .
2000 , dos santos et al .
importantly , we show that
c57bl/6 and c3h / he mice present a range of tnf levels in the serum paralleling the
intensities of cardiac tissue injury and ecg abnormalities and thus mimicking features
of cd patients with different degrees of ccc severity ( ferreira et al .
2004 ) . increased tnf concentrations can directly damage myocardial cells and
may be responsible for the pathogenesis of advanced heart failure ( feldman & mcnamara 2000 ) . in t.
cruzi
infection , experiments using an anti - tnf blocking antibody have implicated tnf as
trigger of parasite - induced acute heart injury characterised by cx43 disorganisation ,
increased serum ck - mb activity ( kroll - palhares et al .
2008 ) and chronic cd8-enriched myocarditis ( prez et al . 2009 ) . altogether ,
these data reinforce the importance of the
colombian - infected c57bl/6 and c3h / he mouse models for the further exploration of the
pathophysiological role of tnf in ccc . according to prez - fuentes
et al . ( 2003 ) , the
pathophysiology of cd is associated with enhanced tnf and no production .
furthermore ,
high no levels in the serum are associated with the severity of heart injury and
electrical and echocardiographic alterations in chronically infected rhesus monkeys
( carvalho et al .
infection with
t. cruzi , especially occurring in a cytokine - enriched milieu ,
induces no expression by macrophages and cardiomyocytes ( aliberti et al .
however , the molecular mechanisms leading to exacerbated no production
in cd are not fully understood . in acute infection ,
conversely , no overproduction via inos / nos2 activity has been implicated in heart injury
in t. cruzi - infected monkeys and mice ( carvalho et al .
indeed , high no concentrations may be detrimental in
t. cruzi infection by depressing lymphocyte functions , which could
favour parasite survival and promoting heart denervation and myocardial cell dysfunction
( silva et al .
interestingly , our data support that
t. cruzi - infected c3h / he mice present higher serum no concentrations
than c57bl/6 mice , paralleling the severity of heart injury and electrical
abnormalities .
previous studies
did not ignore the influence of host factors , but supported the importance of the
parasite strain as a crucial factor in determining cardiac lesions in mice , particularly
with regards to a biological type iii strain ( andrade
1990 ) that is currently viewed as the genotypic t. cruzi type
i strain ( zingales et al .
our study
highlights a potential contribution of the immune response , as illustrated by the
variable degrees of tnf and no production in the colombian - infected c57bl/6 and c3h / he
mice , as determinant of ccc severity and therefore supporting the influence of host
factors in the fate of chagas heart disease .
however , the cause / consequence
relationship between tnf and no levels in the serum and heart tissue lesion and ecg
alterations is not settled .
furthermore , events surrounding the induction of elevated
tnf and no levels in the serum of chronically t. cruzi - infected
individuals remain to be identified .
one can not rule out the possibility that enhanced
levels of tnf and no and cardiac damage are all consequences of a more severe acute
phase in animals of the c3h / he lineage compared to c57bl/6 mice .
if this is true , high
levels of tnf and no would not lead to a more severe pathology , but would rather be a
consequence of the more severe pathology in the chronic infection .
altogether , cardiac tissue parasitism and inflammation , heart injury and ecg
abnormalities were less intense in the chronically colombian - infected c57bl/6 compared
to c3h / he mice , suggesting that they represent models of mild ( c57bl/6 ) and severe
( c3h / he ) ccc . moreover , in these models the ccc severity paralleled tnf and no levels in
the serum ( fig . 8) .
therefore , these reasonable
experimental models open a window of opportunity to ( i ) study the pathophysiology of cd
and biomarkers of ccc progression and ( ii ) test therapeutic agents for patients with
chagas heart disease .
fig . 8 : schematic synthesis of the proposal of experimental models for chronic
chagasic cardiomyopathy reproducing the mild ( c57bl/6 ) and severe ( c3h / he )
manifestations of chagas heart disease in association with tumour necrosis
factor ( tnf ) and nitric oxide ( no ) levels in the serum .
Output:
| heart tissue inflammation , progressive fibrosis and electrocardiographic alterations
occur in approximately 30% of patients infected by trypanosoma
cruzi , 10 - 30 years after infection . further
, plasma levels of tumour
necrosis factor ( tnf ) and nitric oxide ( no ) are associated with the degree of heart
dysfunction in chronic chagasic cardiomyopathy ( ccc ) .
thus , our aim was to establish
experimental models that mimic a range of parasitological , pathological and cardiac
alterations described in patients with chronic chagas heart disease and evaluate
whether heart disease severity was associated with increased tnf and no levels in the
serum .
our results show that c3h / he mice chronically infected with the colombian
t. cruzi strain have more severe cardiac parasitism and
inflammation than c57bl/6 mice .
in addition , connexin 43 disorganisation and
fibronectin deposition in the heart tissue , increased levels of creatine kinase
cardiac mb isoenzyme activity in the serum and more severe electrical abnormalities
were observed in t. cruzi - infected c3h / he mice compared to c57bl/6
mice .
therefore , t. cruzi - infected c3h / he and c57bl/6 mice represent
severe and mild models of ccc , respectively .
moreover , the ccc severity paralleled
the tnf and no levels in the serum .
therefore , these models are appropriate for
studying the pathophysiology and biomarkers of ccc progression , as well as for
testing therapeutic agents for patients with chagas heart disease . |
PubmedSumm118232 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the incidence of secondary neoplasms of the testis during autopsies is approximately 2.5% , including nonneoplastic deaths .
most secondary testicular metastases originate from distant primary sites , of which the lung , prostate , and gastrointestinal tract are common .
testicular metastases occur in up to 4% of all prostate cancer ( pca ) cases and are often detected incidentally after orchiectomy treatment for advanced disease .
generally , pca metastases to the pelvic lymph nodes , bones , lungs , and liver occur frequently in the advanced stages ; however , few of these patients have clinically manifested testicular metastasis .
we report the case of a patient with pca with testicular metastasis who was diagnosed based on the presence of a palpable mass in the right testis .
a 56-year - old japanese male presented to our hospital with an elevated serum prostate - specific antigen ( psa ) level of 137 ng / ml . on digital examination , the prostate was palpable with hard consistency on both lobes .
histological examination revealed adenocarcinoma of the prostate with a gleason score of 9 ( fig .
1 ) . computed tomography ( ct ) showed multiple lymph node enlargements from the pelvis to the bifurcation of the left renal artery .
bone scan imaging showed multiple skeletal metastases in the left ilium and ischium . written informed consent
was obtained from the patient for the publication of this case report and the use of the accompanying images .
a copy of the written consent is available for review by the editor - in - chief of this journal .
he received androgen deprivation therapy ( adt ) for 4 years , followed by luteinizing , hormone - releasing hormone and estramustine for 1 year .
his serum psa level was undetectable for 1 year , and no lymph node enlargement and no distant or skeletal metastases were visualized using imaging examinations .
ct revealed a heterogeneous mass of 5 4 cm in the right testis ( fig .
laboratory results for -fetoprotein , human chorionic gonadotropin , and lactate dehydrogenase were negative , and his serum psa level had increased to 4.94 ng / ml . a right high inguinal orchiectomy was performed .
macroscopic examination of the resected testis revealed a solid yellowish - white tumor of 5 4 cm .
histopathological analysis showed that the right testis was infiltrated by metastatic adenocarcinoma with a gleason score of 8 ( fig .
immunohistochemical examination revealed that tumor cells were diffusely positive for psa and -methylacyl coa racemase ( p504s ) .
the patient has been asymptomatic and disease - free with a serum psa level that decreased to an undetectable level 1 year after surgery .
with the exception of the infiltration of leukemia and lymphoma , secondary neoplasms of the testis are rare , with a reported incidence of 0.022.5% [ 1 , 2 , 5 , 6 ] .
the most common primary site of testicular metastases is the prostate ( 15% ) , followed by the lung , melanomas , skin , colon , and kidney .
however , most testicular metastases of pca were identified after the examination of large numbers of testes from patients with tumors who had undergone therapeutic orchiectomies [ 8 , 9 ] . nevertheless testicular metastases of pca are rare .
bubendorf et al . studied a cohort of 1,589 patients with pca and reported that 35% had hematogenous metastases most frequently involving bone ( 90% ) , lung ( 46% ) , and liver ( 25% ) ; metastases in the testes were found in 0.5% ( n = 3 ) .
the proposed mechanisms for the spread of pca to the testis include : ( i ) retrograde venous extension or embolism ; ( ii ) arterial embolism ; ( iii ) lymphatic extension , and ( iv ) endocanalicular spread [ 6 , 7 ] .
the involvement of the prostatic urethra in pca increases the risk of testicular metastases . in our case
, retrograde venous extension might have caused testicular metastasis due to embolism after radiation therapy .
most patients with pca with lymph node involvement or skeletal metastases undergo adt for several years . in previous studies , the interval from diagnosis of pca to testicular metastasis ranged from 2.5 to 15 years
therefore , the histological pattern of testicular metastasis might change to another subtype of pca such as small cell carcinoma .
tu et al . reported that the pathological features of testicular metastases resembled ductal or endometrioid adenocarcinoma of the prostate and that tumors contained tall columnar cells in a papillary , cribriform , and/or solid pattern .
therefore , a ductal prostate adenocarcinoma that metastasizes to the testis might be an admixture of different tumor types arising from specific prostatic stem cells . in patients with testicular
lu et al . found that the mean survival period after orchiectomy was 12.8 months in patients with pca and 7.4 months in those with other forms of cancer . nevertheless
, as in the current case , the patient 's serum psa can remain undetectable , but testicular metastasis can behave aggressively and further metastasize .
the authors declare that there are no conflicts of interest regarding the publication of this paper .
Output:
| the incidence of secondary neoplasms of the testis during autopsies is approximately 2.5% .
although most secondary testicular metastases are due to prostate cancer , only a few patients with prostate cancer have clinically manifested testicular metastasis .
we report the case of a prostate cancer patient with testicular metastasis who was diagnosed after the presence of a palpable mass in the right testis .
a 56-year - old japanese male presented to our hospital with an elevated serum prostate - specific antigen ( psa ) level of 137 ng / ml . he was diagnosed with stage iv ( t3n1m1b ) prostate cancer and received androgen deprivation therapy , followed by various hormonal manipulations .
his serum psa level was undetectable for 1 year .
no distant metastases were detected during imaging examinations .
he received radiation therapy ; however , his serum psa level increased gradually .
four months later , he presented with right testicular swelling .
computed tomography revealed a heterogenous mass in the right testis and a right high inguinal orchiectomy was performed .
histopathological analysis showed that the right testis was infiltrated with metastatic adenocarcinoma with a gleason score of 8 .
this is a rare case of right testicular metastasis in a patient with prostate cancer .
testicular metastasis of prostate cancer can be aggressive and metastasize . |
PubmedSumm118233 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the value of appropriate animal models to advance our understanding and treatment of human retinal disease processes that cause severe visual impairment or blindness can not be overemphasized .
animal models have led to the identification of disease genes , and elucidation of the molecular genetic and cellular mechanisms underlying retinal pathology . moreover
, they provide the basis for testing the efficacy of therapeutic approaches , including the use of drugs and gene replacement , novel genetic approaches ( sirna ) , stem cell therapy , surgical intervention , such as retinal transplantation , and the use of ocular or retinal prosthetics .
additionally , animal models can lead to the identification of novel genes underlying human retinal pathology .
though 157 genes have been identified as causative of nonsyndromic human retinitis pigmentosa ( rp ; http://www.sph.uth.tmc.edu/retnet/home.htm ) , over 50% of the genetic causality of rp still remains uncharacterized . though the mouse has been the classic animal model of retinal disease , the advent of comprehensive genetic maps of many mammals has led to the identification of a number of non - rodent animal models of human hereditary retinal disease .
the size of the rodent eye is restrictive for visualization using regular clinical ophthalmic instrumentation and also in conjunction with therapeutic intervention . even for detailed morphological studies
the small size of the mouse eye may be a problem . as a case in point
previously reported that in their research examining the trafficking of ciliary protein in photoreceptor cells , the physical limitations of the mouse retina led them to resort to the use of a bovid eye .
dog and cat populations offer a wealth of potential as large animal models of human retinal disease .
small effective population sizes , the use of popular sires and inbreeding have contributed to the load of inherited diseases , especially in dog breeds .
hereditary and primary photoreceptor diseases , or progressive retinal atrophies ( pra ) have been described in more than 100 dog breeds , many of which are likely to be caused by the same mutation which is observed across related breeds . this phenomenon has been observed in a number of gene - defining phenotypes in the dog [ 1012 ] .
thirteen genes have been mapped and characterized as causative of canine pra , including adam9 , ccdc66 , cngb3 , pde6 , pde6 , prcd , rd3 , rho , rpe65 , rphp4 , rpgr , rpgrip1 , and vmd2 .
cats have been considered to be affected less frequently by hereditary disease . however , the informative website online mendelian inheritance in animals ( http://omia.angis.org.au/ ) catalogues 288 distinctive pathologies with an inherited component in the cat , with cited references . only in recent years
have specific mutations been elucidated for hereditary retinal diseases in cats [ 26 , 27 ] , clinically similar to the pra complex in dogs .
domestic dogs and cats of today experience a level of medical surveillance second only to human kind , thus increasing the likelihood , that individuals with rare or unique mutations are identified .
report of two partial sequences ( 1.9x , 3x ) of the cat genome [ 29 , 30 ] has been invaluable in the initial mapping and characterization of feline hereditary diseases [ 26 , 27 , 31 ] .
a full genome sequence ( 14x ) of the cat has currently been completed ( wes warren , washington university , personal communication ) .
the identification of single - nucleotide polymorphisms ( snp ) in cat breeds , an integral part of the 14x full genome sequence project and the 3x sequencing of the cat genome is currently being utilized in development of a domestic cat snp chip . with the availability of these genomic resources
, the mapping and characterization of feline monogenic disorders will largely be dependent on obtaining an appropriate sample set . genome - wide association ( gwa ) studies in dog breeds are proving extremely successful in identifying genes associated with breed - defining phenotypes and monogenic disorders [ 13 , 32 , 33 ] . often this is accomplished with surprisingly small sample sizes .
the mapping of the canine cone - rod dystrophy 3 gene ( adams9 ) in the glen of imaal terrier breed was recently accomplished with as few as 22 unaffected and 19 affected individuals while awano et al .
reported identification of the gene causative of canine degenerative myelopathy ( sod1 ) in the pembroke welsh corgi with 38 affected and 17 control individuals . extended linkage disequilibrium ( ld ) in dog breeds [ 19 , 34 , 35 ] contributes to the success of gwa mapping in dogs and is an important factor underlying successful mapping with small sample sizes in the dog .
preliminary studies suggest that extended blocks of ld are also observed in cat breeds , though the length of ld appears to be abbreviated to that which is observed in dog breeds .
the female abyssinian cat ( cinnamon ) , subject of the feline whole genome sequencing efforts , is a member of a pedigree developed for genetic mapping of the gene defect for the rdac ( retinal degeneration in abyssinian cats ) model , first described in 1982 .
the autosomal recessive ( ar ) trait , rdac , has become an important model of human rp [ 37 , 38 ] . at birth ,
affected cats have normal vision , but , by 1.52 years of age they develop early changes that can be observed by ophthalmoscopy ( figures 1(a)1(c ) ) . by 7 months of age ,
affected cats demonstrate significantly reduced retinal function by electroretinography ( erg ; figure 1(d ) ) .
erg a - wave amplitudes are then reduced more than 50% as compared to normal individuals , with a parallel reduction in retinal oxygen tension .
rod photoreceptor outer segments exhibit the first morphological changes in individuals 58 months of age , observed as a disorganization and disruption of rod outer segment lamellar discs and the appearance of vacuoles near the connecting cilium .
progression of the disease results in further degeneration of the rods ( figures 2(a ) and 2(b ) ) , followed also by disruption of the cone photoreceptors . by 35 years of age
, the clinical end stage of the disease has been reached with generalized photoreceptor degeneration , and subsequently retinal atrophy leads to blindness .
a single - nucleotide polymorphism in an intron of the felid cep290 gene generates a novel strong canonical splice - donor site resulting in a 4-bp insertion , a frame shift , and the introduction of a premature stop codon ( figures 3(a ) and 3(b ) ) .
the protein is an important component of the intraflagellar transport ( ift ) system whereby specialized proteins critical for phototransduction are transferred from their site of synthesis in the inner segment of photoreceptors through the connecting cilium to the outer segment . as the rod photoreceptor discs are in a constant state of regeneration , a fully functional ift system is critical for the maintenance of the photoreceptors . in the rd16 mouse model , the phototransduction proteins opsin and rhodopsin
are found concentrated in the inner segment , which led chang et al . to propose a ciliary trafficking role for the cep290 protein .
mutations in cep290 have been reported in rp , leber 's congenital amaurosis ( lca ) , as well as the syndromic retinopathies , joubert , meckel - gruber , and bardet - biedl [ 4548 ] .
recently , it has been shown that rdac cats exhibit some degree of phenotypic variation , with end - stage blindness reached in individuals anywhere from three to seven years .
interestingly , it appears that the slow progression of disease may be one of the factors leading to the cat 's exceptional ability to adapt to decreasing retinal function .
the condition thus evaded detection by both owners and veterinarians in a highly popular cat breed , the siamese , which demonstrates a high frequency ( 33% ) for the rdac disease allele .
breeding practices have caused the cep290 mutation to spread to multiple cat breeds , and to exhibit a worldwide distribution .
a second feline model of human retinal dystrophy , the rdy cat , was first described in a single abyssinian cat , from which a pedigree was developed and extensively studied on a phenotypic level [ 5053 ] .
the disease is an early onset primary photoreceptor disorder with an autosomal dominant ( ad ) mode of inheritance in which affected individuals exhibit abnormal photoreceptor development at 22 days of age .
further characterization of the dystrophy has demonstrated that the photoreceptors never develop normally , and the disease has therefore been designated as a rod - cone dysplasia with early onset degeneration of both cones and rods .
a single - base deletion in the crx gene introduces a frameshift and a stop codon immediately downstream , truncating a region previously demonstrated as critical for gene function [ 26 , 54 ] ( figure 4 ) .
the crx gene product is critical in transcriptional activation of a number of genes involved in photoreceptor development and maintenance [ 55 , 56 ] . in humans , mutations in crx
are associated with human ad cone - rod dystrophy ( cord ) , and both ad and ar leber 's congenital amaurosis ( lca ) [ 54 , 5759 ] .
the rdy cat is the first large animal model for crx - linked spontaneous retinal disease .
a large screening of cat breeds has failed to detect any other domestic feline breeds with the disease allele .
the rdy model provides one of the very few large animal models of an autosomal dominant retinal disease .
causality of the disease can arise from haploinsufficiency of product , or in some circumstances from gain of function or competition from a truncated or aberrant protein product .
the presence of both mutant and wildtype rna in rdy individuals , initially suggestive that a truncated crx product might be generated has been supported by recent findings ( k. holland deckman , unpublished ) .
the truncated peptide would retain the crx motifs involved in nuclear localization and dna - binding , but lack the region critical for transcriptional activation of photoreceptor specific genes .
this truncated product could thus compete with the wildtype crx product and other transcription factors for promoter binding regions of target genes , which is currently under investigation .
in the late 1960s , a new feline breed , the bengal , which has gained huge popularity , was developed through hybridization of domestic cats and the asian leopard cat .
recently , a novel , early onset autosomal recessive disorder was described in this breed .
the disease is under investigation but appears to be an early onset primary photoreceptor disorder , leading to blindness within the first year of age .
affected individuals showed clinical signs of disease 2 - 3 weeks after birth and clinical blindness at 16 weeks of age .
the molecular genetic defect for both of these disorders has not as yet been elucidated .
it appears that the bengal cat retinal disease should become an important animal model for the research community in regards to the study of various treatment modalities .
the disease starts out from a mainly normal appearing retina but due to the fast progression of the disorder , retinal atrophy ensues comparatively early thus functioning as an effective model system for retinal research .
the retinas of large animal models more closely approximate that of humans , and are thus more easily amenable for visualization and imaging of the disease process , for surgical intervention , and for clinical evaluation of therapeutic effects .
dogs and cats also offer the potential of long - term followup studies in conjunction with treatment trials .
the rod and cone photoreceptors ( the latter ; short and middle wavelength sensitive cones ) of both species are distributed in the retina in a mosaic pattern comparable to that of the human retina .
however , in cats , in the same region as the human macula , there sre a cone - rich region called the area centralis where the concentration of cones in comparison to that of rods is higher than at any other location . along with the holangiotic configuration of the retinal vasculature ,
further , cats in particular , have historically been important models in neuroanatomy and neurophysiology , especially with respect to visual function .
successful therapeutic intervention is the ultimate goal of research using animal models for human retinal disease processes . in recent years
, groundbreaking research has been performed by independent groups in regards to gene therapy using dogs with spontaneous hereditary retinal disease .
proof of principle that the technology works was achieved by an in vivo study by acland et al . , using aav2/2 as a safe and effective vector .
the well - characterized rdac and rdy feline models of spontaneous hereditary retinal disease , now with known mutations , are excellent candidates for gene therapy - based approaches , especially for the late onset type of retinal degeneration ( jean bennett , personal communication , 2007 ) .
gene therapy approaches targeting the rdy model , which has been recently elucidated on the molecular genetic level , are currently under investigation .
novel therapeutic interventions have recently been developed to target aberrant rna species that survive nonsense mediated decay . short interfering rna ( shrna ) , short double stranded rna molecules , can be designed to degrade specific target mrnas , while ribozymes , which are small catalytic rnas , are designed to cleave complementary rna sequences .
rna interference - mediated suppression and replacement aims to remove both wildtype and aberrant rna copies of a targeted gene while replacing wildtype expression with a copy of the gene
experimentation in this regard includes the replacement of dying visual cells with healthy neuroblastic progenitor cells and retinal pigment epithelial ( rpe ) cells as sheets of normal tissue .
it has been demonstrated that retinal transplants in rats can morphologically reconstruct a damaged retina and restore retinal sensitivity . affected cats with the cep290 defect ( rdac )
surgeries have been successful as to graft survival in the retina , although cellular connectivity has not been shown and erg testing has not demonstrated improvement in retinal function . so far the cat model in regards to transplantation of large sheets of normal tissue has shown a comparatively high risk for complications .
the tight structures of the cat eye presents difficulties to manipulate the globe in the orbit in comparison to other large animal models ( such as dog , pig , and rabbits ) and the high frequency of hemorrhage from the deep venous plexus region of the domestic cat renders this surgery difficult even for experienced surgeons .
subretinal transplantation of neural progenitor cells in rats has shown evidence of cellular repopulation of damaged retinas and retardation of ongoing retinal degeneration [ 72 , 73 ] .
neural progenitor cells can also be engineered to secrete specific growth factors such as glial cell line - derived neurotrophic factor ( gdnf ) . when used for transplantation studies such cells contributed to enhanced cellular survival , neuronal differentiation , and improved host cognitive function following brain injury , in comparison to transplantation of nontransduced neuronal progenitor cells .
recent studies , using rdac animals have shown promising results when retinal progenitor cells from transgenic fluorescent red cats were transplanted to cats affected by the cep290 mutation ( rdac ) by subretinal injections of progenitor cell suspensions .
there was further development and migration of transplanted cells in the outer and inner retina , and development of donor progenitor cells specifically into mller - like cells observed by immunohistochemistry .
another modality under development using the feline species is intraocular implantation of retinal prosthesis .
the electrodes in the prosthesis may emit electrical currents and stimulate residual retinal cells , such as second- and third- order neurons , for example , bipolar and ganglion cells .
it appears that the cat eye , with the visual processes already thoroughly investigated , would be an optimal animal model for further development of research in regards to retinal prosthesis .
through discoveries of causative mutations and their detrimental effects on retinal cell function , new insights into retinal degenerative disease mechanisms have been gained .
it is now possible to aim therapies at correcting disease mutations in the eye directly or indirectly .
the cat species , with disease entities that are comparable to those of humans , and with large human - like eyes , is amenable to treatment using similar surgical techniques and instrumentation as those used for humans .
we now have an effective model system that can be used for cell replacement therapy , retinal transplantation using tissue from healthy retinas or retinal progenitor cells , artificial retinal prosthesis , or combinations of one or more of the above .
there definitely is some hope of further advancement in the field of spontaneously occurring hereditary retinal blinding disease using the cat as a valuable large animal model .
Output:
| large mammals , including canids and felids , are affected by spontaneously occurring hereditary retinal diseases with similarities to those of humans .
the large mammal models may be used for thorough clinical characterization of disease processes , understanding the effects of specific mutations , elucidation of disease mechanisms , and for development of therapeutic intervention .
two well - characterized feline models are addressed in this paper .
the first model is the autosomal recessive , slowly progressive , late - onset , rod - cone degenerative disease caused by a mutation in the cep290 gene .
the second model addressed in this paper is the autosomal dominant early onset rod cone dysplasia , putatively caused by the mutation found in the crx gene .
therapeutic trials have been performed mainly in the former type including stem cell therapy , retinal transplantation , and development of ocular prosthetics .
domestic cats , having large human - like eyes with comparable spontaneous retinal diseases , are also considered useful for gene replacement therapy , thus functioning as effective model systems for further research . |
PubmedSumm118234 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: wear following total hip replacement ( thr ) is well documented and often leads to revision surgery , which can be complex and demanding .
revision rates are reported to be 26% at 10 years , depending on the prosthesis used .
symptoms typically manifest following significant acetabular wear , at which point revision is usually considered .
if the wear leads to metal - on - metal articulation , metallosis may result with its associated complications .
metallosis is defined as the deposition of metal debris within periprosthetic soft tissue and bone .
this can cause chronic inflammation , accelerated wear , prosthetic loosening and in advanced cases osteolysis .
we present the second reported case of extreme wear through the metal - backed acetabular cup causing metallosis .
a 78-year - old gentleman with an uncemented left thr performed 20 years earlier for osteoarthritis was reviewed in clinic .
he was referred with increasing left hip pain , clicking on ambulation and worsening mobility over 3 years , having now become wheelchair dependent .
examination of the left hip revealed a fixed flexion deformity of 30 with a shortened wasted left leg of 2.5 cm .
the scar was well healed with no sinuses , normal skin temperature and no overlying skin changes or palpable soft tissue masses .
pelvic radiographs demonstrated that the femoral head had migrated superolaterally through the polyethylene ( pe ) liner and the acetabular cup with metallic fragments inferior to this , and was articulating with the superior wall of the acetabulum causing bony destruction .
there was no radiographic evidence of loosening to the stem ( fig . 1 ) .
figure 1:pelvic radiograph demonstrating superolateral migration of the femoral head , metallic fragments around the neck and bony destruction of the acetabular wall .
pelvic radiograph demonstrating superolateral migration of the femoral head , metallic fragments around the neck and bony destruction of the acetabular wall .
the pe liner remained engaged within the acetabular cup with significant wear through its back .
the femoral head had migrated superolaterally through the acetabular cup and was articulating with the superior acetabular wall causing bony destruction .
the acetabular cup remained well fixed within the acetabulum with good bony ingrowth ( figs 2 and 3 ) .
the acetabular component showing extreme wear - through and metallic fragments . the acetabular component and liner showing extreme wear .
structural porous titanium acetabular augment ( regenerex ) , reinforced with a cancellous allogeneic bone graft , was used to reconstruct the superior acetabular wall .
the cup was completely revised using a biomet regenerex ringloc multihole 56-mm acetabular cup and a hi - wall ringloc - x pe 54-mm liner .
the previous 32-mm femoral head was replaced with a bioball 36-mm metal head and a bioball adapter standard ( 0 mm ) taper 11/13 ( 4 3 ) , correcting the offset and achieving stability ( fig .
figure 4:a post - revision radiograph demonstrating a structural graft using the acetabular augment ( regenerex ) and revised cup in situ .
a post - revision radiograph demonstrating a structural graft using the acetabular augment ( regenerex ) and revised cup in situ .
postoperatively , the patient fell on the ward resulting in posterior dislocation ( fig .
subsequently , the patient developed a superficial surgical site infection , which resolved with antibiotic therapy .
three months following discharge , the patient was pain - free and could ambulate with a zimmer frame .
wear - through the pe liner and metal acetabular component is extremely rare . to our knowledge
the patient 's level of activity is the main factor affecting outcome , with prostheses inserted in younger , more active patients being associated with reduced longevity .
small metal particles can increase wear rates by interfering with smooth articulation , instigating an inflammatory response within the joint . when considering revision in metallosis , the following risk factors should be taken into account : ( i ) whether the patient is symptomatic , ( ii ) the size and shape of the particular prosthesis and ( iii ) if there is evidence of extreme wear or metallosis on plain radiographs .
characteristic features of metallosis on plain radiographs include eccentric alignment of the femoral head , suggesting extreme wear and radiolucency around the joint ( the bubble sign ) , suggesting deposited metallic debris .
however , plain radiographs alone have been shown to have poor sensitivity , with signs absent in over half the cases .
the imaging modality of choice is metal artefact reduction sequence of magnetic resonance imaging ( mars - mri ) .
it has been shown to reliably diagnose and confirm the extent of metallosis , identifying any pseudotumours following metal - on - metal hip replacements .
a review of the current literature suggests that a threshold > 4.5 ppb of cobalt / chromium should trigger further investigation with mars - mri .
it is necessary for patients to have regular clinical and radiological follow - up after a total hip arthroplasty .
when a severely worn acetabular shell is recognized , revision surgery should be performed early . if the damage to the metal shell is minimal , then it is acceptable to simply replace the liner . in the case of extreme metallic wear ,
extreme wear and associated metallosis of this kind are rare . the fact that our patient remained relatively asymptomatic until the wear was very severe highlights the importance of regular radiographs and follow - up . clinical suspicion of metallosis should lead to monitoring of blood metal ion levels , and an mars - mri scan if indicated .
if metallosis is detected , then revision surgery can be attempted at an earlier date , where the procedure is not as technically difficult .
Output:
| extreme wear through the metal - backed acetabular cup following total hip arthroplasty is rare , as symptoms such as pain and disability will usually manifest earlier .
we present the second reported case of extreme wear in a 78-year - old male patient , who presented 20 years following an uncemented total hip replacement with a 3-year history of hip pain , clicking on ambulation and worsening mobility .
radiographs demonstrated that the femoral head had migrated superolaterally through the polyethylene liner and the acetabular cup , and was articulating with the superior wall of the acetabulum causing bony destruction .
metallic fragments were also evident .
a review of the current literature on metallosis suggests that should there be any clinical suspicion , blood metal ion levels are monitored and an mars - mri scan performed if indicated .
if metallosis is detected , then revision surgery can be attempted at an earlier date , where the procedure is not as technically difficult . |
PubmedSumm118235 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: obstructive sleep apnea syndrome ( osas ) is characterized by collapse of the upper airway during sleep , recurring apnea , intermittent hypoxemia , and daytime sleepiness , associated with a decreased daytime performance and impaired quality of life .
it is a common disorder of middle - aged adults , affecting 4% of men and 2% of women .
osas is associated with several cardiovascular diseases , such as congestive heart failure , hypertension , atrial fibrillation , nocturnal arrhythmias , stroke , pulmonary hypertension , and atherosclerosis .
carotid intima - media thickness is a useful marker of early endothelial defect and atherosclerosis development .
there is increasing evidence that systemic inflammation markers such as high sensitive c - reactive protein , interleukin ( il)-6 , tumor necrosis factor- , and pentraxin-3 are increased in osa patients with cardiovascular complications .
red blood cell distribution width ( rdw ) is a numerical measure of the size variability of circulating erythrocytes .
disorders related to ineffective erythropoiesis or increased red blood cell destruction cause heterogeneity in size and a higher rdw .
rdw has been reported as an independent predictor of adverse outcomes in the general population and is believed to be associated with cardiovascular morbidity and mortality in patients with a previous myocardial infarction [ 1012 ] .
several studies have reported increased platelet activation and aggregation in patients with osas [ 1416 ] .
increased platelet activity is associated with increased platelet volume , which can be measured by larger mean platelet volume ( mpv ) and platelet distribution width ( pdw ) .
this increase in platelet volume increases the tendency for coronary thrombus formation in acute coronary syndrome patients .
a few studies have examined the relationship between rdw , pdw , mpv , and ahi in osas , but their relationship with cimt in osas is unclear . considering the association between osas and cardiovascular disease and the overlapping risk factors , we evaluated rdw , mpv , and pdw as a severity index in osas and the relationship of carotid intima media thickness as endothelial damage with ahi and other sleep parameters .
this prospective study consisted of 99 patients who were admitted to the sleep laboratory of our hospital with complaints of snoring , apnea , or daytime sleepiness and in whom polysomnography ( psg ) had been performed between january 2013 and august 2013 .
demographic and health behavior - related data , including age , sex , body mass index ( bmi ) , epworth sleepiness scale scores , and medical histories regarding sleep habits and cardiovascular disease were collected from patient records . a respiratory function test , posteroanterior chest x - ray , and electrocardiography performed before psg were evaluated , and complete blood counts were analyzed .
based on the ahi , patients were grouped into 3 osas severity categories : mild ( ahi 515 ) , moderate ( ahi 1530 ) , and severe ( ahi > 30 ) . as a control group ,
obesity , severity of ahi , and recurrent hypoxemia are the cardiovascular risk factors in the osas population .
the study protocol was approved by the local ethics committee and all patients gave written informed consent .
mpv , pdw , and rdw were measured in a blood sample collected in dipotassium edta tubes .
the biochemical analysis crp , ast , alt , urea , lipid parameters , and glucose were measured at the same time ( architect plus ci16200abbott illinois usa ) .
overnight polysomnography was performed with 16-channel embla ( medcare inc , iceland ) continuous sleep technician monitoring .
the system consists of 4 channels of eeg ( with electrode placements at c4-a1 , c3-a2 , o2-a1 , and o1-a2 ) , 2 channels of eog , submental emg , oronasal air flow , thoracic and abdominal movements , pulse oximeter oxygen saturation , tibial emg , body position detector , electrocardiogram , and tracheal sound .
hypopnea was defined as a > 30% reduction in airflow lasting more than 10 seconds accompanied by > 4% desaturation and/or arousal .
the average number of episodes of apnea and hypopnea per hour of sleep were measured as ahi .
the osas diagnosis was made on the basis of an apnea / hypopnea index ( ahi ) > 5 .
sleep stages were scored following standard criteria with 30-second epochs and were reviewed and verified by a certified sleep physician .
bilateral common carotid arteries of the patients were scanned longitudinally with a 7-mhz transducer attached to the available machine ( vivid 3 , general electric ) .
images were obtained from the distal portion of the common carotid artery , 12 cm proximal to the carotid bulb .
the 2 bright echogenic lines in the arterial wall were identified as the intima and media lines .
the intima media thickness was measured as the distance from the main edge of the first echogenic line to the main edge of the second .
images showing the maximum intima media thickness were digitally stored and cimt measurements were made offline .
the intima media thickness of the distal wall of the right common carotid artery on the lengthwise axis was calculated according to the method described by pignoli et al . .
each measurement was repeated 3 times and the mean of the left and right common carotid arteries was used for analysis .
plaques , defined as > 50% localized thickening of the intima compared to the rest of the wall or as an endoluminal protrusion of the arterial lumen of > 0.5 mm , were not included in the measurement of cimt .
analysis of variance followed by duncan s test was used to determine the different groups . to determine the relationships between these variables in each group separately , pearson s correlation coefficients were calculated .
pap , cimt , pdw , rdw , and mpv variables in patient and control groups were assessed and used in separating the cut - off value roc analysis .
this prospective study consisted of 99 patients who were admitted to the sleep laboratory of our hospital with complaints of snoring , apnea , or daytime sleepiness and in whom polysomnography ( psg ) had been performed between january 2013 and august 2013 .
demographic and health behavior - related data , including age , sex , body mass index ( bmi ) , epworth sleepiness scale scores , and medical histories regarding sleep habits and cardiovascular disease were collected from patient records . a respiratory function test , posteroanterior chest x - ray , and electrocardiography performed before psg were evaluated , and complete blood counts were analyzed .
based on the ahi , patients were grouped into 3 osas severity categories : mild ( ahi 515 ) , moderate ( ahi 1530 ) , and severe ( ahi > 30 ) . as a control group ,
obesity , severity of ahi , and recurrent hypoxemia are the cardiovascular risk factors in the osas population .
the study protocol was approved by the local ethics committee and all patients gave written informed consent .
mpv , pdw , and rdw were measured in a blood sample collected in dipotassium edta tubes .
the biochemical analysis crp , ast , alt , urea , lipid parameters , and glucose were measured at the same time ( architect plus ci16200abbott illinois usa ) .
overnight polysomnography was performed with 16-channel embla ( medcare inc , iceland ) continuous sleep technician monitoring .
the system consists of 4 channels of eeg ( with electrode placements at c4-a1 , c3-a2 , o2-a1 , and o1-a2 ) , 2 channels of eog , submental emg , oronasal air flow , thoracic and abdominal movements , pulse oximeter oxygen saturation , tibial emg , body position detector , electrocardiogram , and tracheal sound .
hypopnea was defined as a > 30% reduction in airflow lasting more than 10 seconds accompanied by > 4% desaturation and/or arousal .
the average number of episodes of apnea and hypopnea per hour of sleep were measured as ahi .
the osas diagnosis was made on the basis of an apnea / hypopnea index ( ahi ) > 5 .
sleep stages were scored following standard criteria with 30-second epochs and were reviewed and verified by a certified sleep physician .
bilateral common carotid arteries of the patients were scanned longitudinally with a 7-mhz transducer attached to the available machine ( vivid 3 , general electric ) .
images were obtained from the distal portion of the common carotid artery , 12 cm proximal to the carotid bulb .
the 2 bright echogenic lines in the arterial wall were identified as the intima and media lines .
the intima media thickness was measured as the distance from the main edge of the first echogenic line to the main edge of the second .
images showing the maximum intima media thickness were digitally stored and cimt measurements were made offline .
the intima media thickness of the distal wall of the right common carotid artery on the lengthwise axis was calculated according to the method described by pignoli et al . .
each measurement was repeated 3 times and the mean of the left and right common carotid arteries was used for analysis .
plaques , defined as > 50% localized thickening of the intima compared to the rest of the wall or as an endoluminal protrusion of the arterial lumen of > 0.5 mm , were not included in the measurement of cimt .
analysis of variance followed by duncan s test was used to determine the different groups . to determine the relationships between these variables in each group separately , pearson s correlation coefficients were calculated .
pap , cimt , pdw , rdw , and mpv variables in patient and control groups were assessed and used in separating the cut - off value roc analysis .
we included a total of 99 patients 73 with osas [ 5 patients 6.9% mild , 18 patients 24.7% moderate , and 50 patients 68.5% severe ] and 26 simple snoring control cases .
the mean age of the osas patients was 50.8411.0 years and 61.6% ( 45 ) were male .
there were statistically significant differences between the 2 groups regarding age , bmi , and epworth sleep score , but there was no statistically significant difference in sex distribution .
controls were overweight ( bmi 2530 ) and patients were obese ( bmi > 30 ) .
mean values of mpv , pdw , and rdw were similar in patients compared to simple snoring persons in the control group ( p>0.05 ) .
in the patient population , mean rdw was 14.4 ( 2.05 ) and rdw was not correlated with age or sex . among other hematological variables ,
body mass index , ahi , pulmonary artery pressure ( pap ) , and desaturation time under 90% were positively correlated with rdw .
pap had a positive correlation with rdw and negative correlation with the lowest saturation ( figure 1 ) .
we included a total of 99 patients 73 with osas [ 5 patients 6.9% mild , 18 patients 24.7% moderate , and 50 patients 68.5% severe ] and 26 simple snoring control cases .
the mean age of the osas patients was 50.8411.0 years and 61.6% ( 45 ) were male .
there were statistically significant differences between the 2 groups regarding age , bmi , and epworth sleep score , but there was no statistically significant difference in sex distribution .
controls were overweight ( bmi 2530 ) and patients were obese ( bmi > 30 ) .
mean values of mpv , pdw , and rdw were similar in patients compared to simple snoring persons in the control group ( p>0.05 ) .
in the patient population , mean rdw was 14.4 ( 2.05 ) and rdw was not correlated with age or sex . among other hematological variables ,
body mass index , ahi , pulmonary artery pressure ( pap ) , and desaturation time under 90% were positively correlated with rdw .
pap had a positive correlation with rdw and negative correlation with the lowest saturation ( figure 1 ) .
this prospective study is one of a few studies examining the relationship between rdw , pdw , mpv , and ahi in osas .
the main finding of the present study was that pdw , rdw , mpv , and cim were similar in the osas and simple snoring control group .
there was no statistically significant difference between control and osas groups . among the patients there was a correlation between rdw and the severity of osas and pulmonary hypertension .
our study demonstrates a relationship between severity of osas and rdw that is dependent on inflammation and intermittent hypoxia , and independent of anemia .
we also found a negative association of rdw with average minimum oxygen saturation and desaturation time under 90% during sleep , which could be explained by the effect of hypoxia on rdw .
a positive relationship between rdw and the oxygen desaturation index may also indicate the severity of osas .
found similar results about rdw and osas severity . in agreement with their results , we found a positive correlation between pulmonary artery pressure and rdw , and a relationship between osas severity and pulmonary hypertension .
rdw could be used in sleep laboratories as an indicator of pulmonary hypertension in further investigations .
varol et al . and nena et al . reported that levels of mpv were significantly greater in patients with severe osas than in patients in the control group and patients with mild - to - moderate osas .
in contrast , beyan et al . concluded that platelet markers should not be used alone as direct indicators of platelet activation . according to their results
, large platelets did not show stronger activation in the aggregometer . also , platelets shape and volume are variable , even in healthy persons .
our results indicate that patients with severe osas do not have significantly higher mpv values compared with controls and mild - to - moderate osas .
the lack of difference between osas groups reduces the importance of platelet markers . due to contradictory results on this subject ,
thickness of the common carotid intima media ( cimt ) has been used in the assessment of endothelial function [ 7,2527 ] .
increased cimt is correlated with cardiovascular risk factors and severity of coronary atherosclerosis and predicts cardiovascular events in populations . according to european society of cardiology ( esc ) comments ,
a common carotid artery imt > 0.9 mm can be considered as a measured estimate of actual abnormalities .
many hypotheses have been recommended to explain endothelial disfunction : oxidative stress seems to be a cause of endothelial deterioration in osas patients .
osas leads to sympathetic nervous system hyperactivity , a condition that can stimulate early alterations in the vascular morphology and countering the atherosclerotic process .
literature data suggest that carotis intima media thickness is evidence of early alterations in vascular morphology .
this is not synonymous with atherosclerosis , but because the underlying pathophysiological mechanisms are similar , the 2 conditions have been associated .
ciccone et al . found a positive relationship between imt and osas duration . in the present study we did not find any difference between patients and control groups regarding cimt , probably because the duration of osas symptoms was short .
a major cause of pht and cor pulmonale is chronic hypoxia , which leads to pulmonary arterial vasoconstriction and a cascade of molecular and biochemical events resulting in vascular smooth muscle hypertrophy , and intimal and adventitial thickening . in the present study ,
there is evidence that cv homeostatic mechanisms in subjects with osa are disrupted , as demonstrated by daytime abnormalities in sympathetic nervous system function and heart rate variability .
this means that at the lowest saturation , the sympathetic system is more active ; thus the length of desaturation is not as effective as the lowest saturation on pap .
there was no correlation with age and all parameters , so this condition did not affect the results .
one of the weaknesses of our study is that we did not have markers of inflammation , which could affect rdw values .
also , rdw could not be used as a screening tool in the general population according to our results because it could be affected by various independent variables .
our study showed a positive relationship between rdw and the ahi and systolic pulmonary hypertension in patients with osas .
the association between elevated rdw and the severity of osas in the study suggests the clinical utility of values .
we showed that average saturation and lowest saturation were negative correlated with pap , although the time under 90% saturation was no correlated with pap .
prospective , randomized , controlled studies are needed to assess the association between these parameters and osas .
Output:
| backgroundobstructive sleep apnea syndrome ( osas ) is characterized by repetitive collapse of the upper airway during sleep .
red blood cell distribution width ( rdw ) increases platelet activation and has been reported as an independent predictor of adverse outcomes in the general population and is believed to be associated with cardiovascular morbidity and mortality .
we evaluated rdw , mean platelet volume ( mpv ) , and platelet distribution width ( pdw ) as a severity index in osas and the relationship between carotid intima media thickness and pulmonary hypertension.material/methodsthe study population consisted of 99 patients who were admitted to the sleep laboratory .
based on the apnea - hypopnea index , patients were grouped into 3 osas severity categories .
morning blood samples were withdrawn from patients after a 12-hour fasting period .
mpv , pdw , and rdw were measured in a blood sample .
bilateral common carotid arteries of the patients were scanned.resultsninety-nine patients 73 with osas and 26 simple snoring control cases were included .
mean values of mpv , pdw , and rdw were similar in patients compared to simple snoring subjects in the control group ( p=0.162 , p=0.656 , p=0.091 ) .
rdw showed an inverse correlation with mean desaturation and lowest desaturation ( p<0.01 ) .
body mass index , apnea - hypopnea index , pulmonary artery pressure , and desaturation time under 90% were positively correlated with rdw ( p<0.05 ) .
mpv , pdw , and carotid intima media thickness had no correlation with any other parameters.conclusionsthe study showed a positive relationship between rdw and the apnea - hypopnea index and systolic pulmonary hypertension in patients with osas . |
PubmedSumm118236 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: set up a half - wave plate and a polarizer following the laser output to adjust the laser pulse energy . set up a beam splitter after the polarizer to split the laser pulse to two pulses : pump pulse and probe pulse .
use four reflecting mirrors and a manual translational stage to construct an optical delay device for the pump pulse . use another four reflecting mirrors to guide the pump pulse to reach the target surface vertically . set up a second harmonic generator ( shg ) to transform the laser pulse wavelength from 800 nm to 400 nm . use a harmonic separator to transmit the 800-nm pulse and reflect the 400-nm pulse . set up a beam reducer and a pair of focally lenses to adjust the size and convergence of the probe pulse .
set up another optical delay device , as mentioned in step 1.3 , for the probe pulse .
use an iris ring to adjust the area of the probe pulse and make sure the probe pulse pass the target surface horizontally and intersect with the pump pulse .
set up two objective lenses and several filters to generate the image of the plasma region to be received by the intensified charge - coupled device ( iccd ) camera .
connect the computer , the laser , the iccd camera and its controller using bnc cables or usb cables .
adjust the delay time of the camera controller till the camera captures an image of the probe pulse .
place a beam splitter at the intersection of the pump pulse and the probe pulse , and set up two photodiodes to receive these two pulses .
use an oscilloscope to receive the signals of these two photodiodes , and move the delay stage on the pump pulse beam path till the profiles of the pump pulse and the probe pulse overlap with each other on the oscilloscope screen .
an accuracy of 20 ps is achieved owing to the temporal resolution of the oscilloscope .
adjust the delay stage on the pump pulse beam path till the air breakdown region could just be observed on the iccd screen .
the time when the formation of air breakdown could be detected instead of a uniform background is determined as delay time zero . set up a lab - jack and two manual linear stages in order to move the sample with three degrees of freedom .
use a dial indicator and high precision shims to achieve a high flatness of the stages .
the height difference should be within 1 m per a distance of 25.4 mm . cut a square piece ( 30 mm 30 mm ) out of a cu sheet with a thickness of 0.8 mm using a milling machine .
polish a narrow side ( 30 mm 0.8 mm ) of the cu piece until the surface roughness is below 0.5 m .
fix the cu piece on the top manual stage with the polished narrow face up .
move the target by one manual stage as mentioned in step 3.1 ) while monitor its position via the iccd camera such that any tilt could be adjusted by inserting high precision shims below the target .
drill a dozen of holes on the target while vary the position of the focal lens by a third high accuracy manual stage .
the focal point location corresponds to the position of the focal lens where the smallest hole is drilled .
move the focal lens up to a distance of about 50 m away from the focal point .
move the delay stage on the probe pulse beam path with an interval of 0.3 mm to capture the image every 2 ps till 10 ps , or with an interval of 3 mm to capture the image every 20 ps till 480 ps .
move the focal lens down to a distance of about 50 m away from the focal point , and repeat step 4.3 .
3 , for the focal point slightly above and below the target surface , respectively .
the longitudinal expansions of these two cases in the first 100 ps are significantly different ; however , their longitudinal expansions in the following 400 ps and their radial expansions are similar . for the first case ,
the early plasma within 100 ps has a one - dimensional expansion structure consisting of multiple layers .
for the second case , the early plasma has a two - dimensional expansion structure that does not change very much within 100 ps .
time zero is defined as the time when the laser pulse peak reaches the target surface .
the simulated early plasma evolution processes agree well with the measured results for both of these two cases , as shown in fig .
the formation of the early plasma within 1 ps is also predicted for the first case using the simulation model and shown in fig .
the early plasma is found to have an air breakdown region and a cu plasma region .
the air breakdown is first caused by multi - photon ionization and then followed by avalanche ionization . for the second case , however , the focal point is below the target surface and no separate air breakdown region is formed . instead , air ionization occurs near the cu plasma front and is caused by impact ionization owing to the free electrons ejected from the cu target .
cu plasma expansion at successive delay times with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
cu plasma expansion at successive delay times with the focal point slightly below the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
plasma longitudinal and radial expansion positions at successive delay times with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
plasma longitudinal and radial expansion positions at successive delay times with the focal point slightly below the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
animation of measured and calculated plasma expansion within a delay time of 70 ps with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
animation of measured and calculated plasma expansion within a delay time of 70 ps with the focal point slightly below the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
animation of measured and calculated plasma expansion within a delay time of 1 ps with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
set up a half - wave plate and a polarizer following the laser output to adjust the laser pulse energy . set up a beam splitter after the polarizer to split the laser pulse to two pulses : pump pulse and probe pulse .
use four reflecting mirrors and a manual translational stage to construct an optical delay device for the pump pulse . use another four reflecting mirrors to guide the pump pulse to reach the target surface vertically . set up a second harmonic generator ( shg ) to transform the laser pulse wavelength from 800 nm to 400 nm . use a harmonic separator to transmit the 800-nm pulse and reflect the 400-nm pulse . set up a beam reducer and a pair of focally lenses to adjust the size and convergence of the probe pulse .
set up another optical delay device , as mentioned in step 1.3 , for the probe pulse .
use an iris ring to adjust the area of the probe pulse and make sure the probe pulse pass the target surface horizontally and intersect with the pump pulse .
set up two objective lenses and several filters to generate the image of the plasma region to be received by the intensified charge - coupled device ( iccd ) camera .
connect the computer , the laser , the iccd camera and its controller using bnc cables or usb cables .
adjust the delay time of the camera controller till the camera captures an image of the probe pulse .
place a beam splitter at the intersection of the pump pulse and the probe pulse , and set up two photodiodes to receive these two pulses .
use an oscilloscope to receive the signals of these two photodiodes , and move the delay stage on the pump pulse beam path till the profiles of the pump pulse and the probe pulse overlap with each other on the oscilloscope screen .
an accuracy of 20 ps is achieved owing to the temporal resolution of the oscilloscope .
adjust the delay stage on the pump pulse beam path till the air breakdown region could just be observed on the iccd screen .
the time when the formation of air breakdown could be detected instead of a uniform background is determined as delay time zero .
set up a lab - jack and two manual linear stages in order to move the sample with three degrees of freedom .
use a dial indicator and high precision shims to achieve a high flatness of the stages .
cut a square piece ( 30 mm 30 mm ) out of a cu sheet with a thickness of 0.8 mm using a milling machine .
polish a narrow side ( 30 mm 0.8 mm ) of the cu piece until the surface roughness is below 0.5 m .
fix the cu piece on the top manual stage with the polished narrow face up .
move the target by one manual stage as mentioned in step 3.1 ) while monitor its position via the iccd camera such that any tilt could be adjusted by inserting high precision shims below the target .
drill a dozen of holes on the target while vary the position of the focal lens by a third high accuracy manual stage .
the focal point location corresponds to the position of the focal lens where the smallest hole is drilled .
move the focal lens up to a distance of about 50 m away from the focal point .
move the delay stage on the probe pulse beam path with an interval of 0.3 mm to capture the image every 2 ps till 10 ps , or with an interval of 3 mm to capture the image every 20 ps till 480 ps .
move the focal lens down to a distance of about 50 m away from the focal point , and repeat step 4.3 .
3 , for the focal point slightly above and below the target surface , respectively .
5 . the longitudinal expansions of these two cases in the first 100 ps are significantly different ; however , their longitudinal expansions in the following 400 ps and their radial expansions are similar . for the first case ,
the early plasma within 100 ps has a one - dimensional expansion structure consisting of multiple layers . for the second case ,
the early plasma has a two - dimensional expansion structure that does not change very much within 100 ps .
time zero is defined as the time when the laser pulse peak reaches the target surface .
the simulated early plasma evolution processes agree well with the measured results for both of these two cases , as shown in fig .
the formation of the early plasma within 1 ps is also predicted for the first case using the simulation model and shown in fig .
the early plasma is found to have an air breakdown region and a cu plasma region .
the air breakdown is first caused by multi - photon ionization and then followed by avalanche ionization .
for the second case , however , the focal point is below the target surface and no separate air breakdown region is formed .
instead , air ionization occurs near the cu plasma front and is caused by impact ionization owing to the free electrons ejected from the cu target .
cu plasma expansion at successive delay times with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
cu plasma expansion at successive delay times with the focal point slightly below the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
plasma longitudinal and radial expansion positions at successive delay times with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
plasma longitudinal and radial expansion positions at successive delay times with the focal point slightly below the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
animation of measured and calculated plasma expansion within a delay time of 70 ps with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
animation of measured and calculated plasma expansion within a delay time of 70 ps with the focal point slightly below the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
animation of measured and calculated plasma expansion within a delay time of 1 ps with the focal point slightly above the surface .
laser wavelength : 800 nm ; pulse duration : 100 fs ; power density : 4.2 10 w / cm ; target : cu .
the measurement and simulation methods presented in this paper enable more accurate examinations of the early plasma dynamics and a better understanding of the ionization mechanisms for both air and cu .
high quality plasma structures are captured with a temporal resolution of 1 ps and a spatial resolution of 1 m .
the critical procedure is to align the beam very well and prepare a target surface with a high flatness as well as a low roughness .
the only limitation of the pump - probe shadowgraph method is a too low electron number density variation .
Output:
| early plasma is generated owing to high intensity laser irradiation of target and the subsequent target material ionization .
its dynamics plays a significant role in laser - material interaction , especially in the air environment1-11.early plasma evolution has been captured through pump - probe shadowgraphy1 - 3 and interferometry1,4 - 7 . however , the studied time frames and applied
laser parameter ranges are limited .
for example , direct examinations of plasma front locations and electron number densities within a delay time of 100 picosecond ( ps ) with respect to the laser pulse peak are still very few , especially for the ultrashort pulse of a duration around 100 femtosecond ( fs ) and a low power density around 1014 w / cm2 . early plasma generated under these conditions
has only been captured recently with high temporal and spatial resolutions12 .
the detailed setup strategy and procedures of this high precision measurement will be illustrated in this paper .
the rationale of the measurement is optical pump - probe shadowgraphy : one ultrashort laser pulse is split to a pump pulse and a probe pulse , while the delay time between them can be adjusted by changing their beam path lengths .
the pump pulse ablates the target and generates the early plasma , and the probe pulse propagates through the plasma region and detects the non - uniformity of electron number density .
in addition , animations are generated using the calculated results from the simulation model of ref .
12 to illustrate the plasma formation and evolution with a very high resolution ( 0.04 ~ 1 ps).both the experimental method and the simulation method can be applied to a broad range of time frames and laser parameters .
these methods can be used to examine the early plasma generated not only from metals , but also from semiconductors and insulators . |
PubmedSumm118237 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: three - dimensional visualization reconstruction refers to 3-d visualization model reconstructed by software using 2-d computed tomography ( ct ) images .
the iqqa - liver system developed by edda company is currently the most popular software for 3-d visualization , and xmqb - liver software with independent intellectual property rights has been developed by xiamen qiangben technology co. , ltd ( china ) . in recent years , although the 3-d visualization reconstruction technology has achieved better therapeutic effects when being applied in liver surgery , plastic surgery , and orthopedics , it has been rarely used in pancreaticoduodenectomy .
portal vein arterialization refers to the method of introducing arterial blood into portal veins to prevent liver damages caused by hepatic blood flow insufficiency due to various causes .
hepatic artery is very important for the liver , but it has to be removed when tumor invades it . therefore , portal vein arterialization has been used in clinic as a remedial measure , but there still is professional debate on portal vein arterialization .
we report here 1 case that underwent pancreaticoduodenectomy assisted by 3-d visualization reconstruction and portal vein arterialization .
all study methods were approved by ethics committee of the chenggong hospital affiliated to xiamen university . the patient gave written informed consent to participate in this study .
one 33-year - old female patient was admitted to hospital due to repeated onsets of right upper abdomen distension on april 4 , 2015 .
gastroscopy revealed a mass in duodenal bulb , histopathologic examination suggested poorly differentiated adenocarcinoma of the duodenum , and further immunohistochemistry was recommended in other hospital .
the patient has a 10-year history of viral hepatitis b , but no histories of hypertension or diabetes .
physical examinations on admission showed yellow sclera , flat and soft abdomen , tenderness in the epigastrium below xiphoid and in the right upper abdominal quadrant without rebound tenderness and palpable masses , and positive stomach water vibration .
liver and spleen were impalpable under ribs and there was no percussion pain in hepatic region and both renal regions .
mol / l , and blood routine examination and tumor - related markers were roughly normal .
ct scan showed that pylorus and duodenal bulb were thickened , and the boundary of them with hepatic portal , caput pancreatis , choledochus , and gallbladder was obscure with slightly dilated choledochus .
ct image data stored in the form of dicom were imported into xmqb - liver system for 3-d visualization reconstruction .
2 ) : location the tumor is located in the duodenal bulb and hepatic portal , and above pancreas ; relation with blood vessels
the tumor surrounds common hepatic artery , proper hepatic artery , gastroduodenal artery , and partial portal vein ; and relation with peripheral organs
the tumor completely invades the pylorus and duodenal bulb , and its boundary with the hepatic portal , caput pancreatis , choledochus , and gallbladder is obscure .
based on the 3-d reconstruction results combined with dynamic image and static model , we could understand the conditions that tumor invaded the caput pancreatis and it surrounded the hepatic portal .
abdominal ct , ( a ) ( arterial phase ) : the tumor invades the hepatic portal and gallbladder , and surrounds the proper hepatic artery , right hepatic arteria , and left hepatic artery .
( c ) ( arterial phase ) : the lower end of the tumor invades the caput pancreatis .
( d ) ( coronal view in arterial phase ) : the tumor invades the proper hepatic artery .
a : right hepatic arteria , b : enteric cavity of duodenum , c : tumor , d : proper hepatic artery , e : stomach , f : splenic artery , g : gallbladder , h : portal vein , i : duodenal bulb , and j : pancreas .
( a ) ( front view ) : the boundary between tumor and gallbladder is obscure , the tumor surrounds the duodenum and choledochus , but the liver is not invaded by the tumor .
( b ) ( dorsal view ) : both kidneys and stomach fail to be invaded by the tumor .
( c ) the caput pancreatic is severely invaded by the tumor and the portal vein and hepatic artery are surrounded by the tumor also .
( d ) ( vertical view ) : the portal vein and hepatic artery are surrounded by the tumor and the arrow indicates the common hepatic artery . a : stomach , b : liver , c : gallbladder , d : tumor , e : duodenum ,
f : both kidneys , g : portal vein , h : abdominal aorta , and i : pancreas .
preliminary diagnoses were poorly differentiated adenocarcinoma of the duodenum and viral hepatitis b. the surgical proposal included exploratory laparotomy and pancreaticoduodenectomy ( resection of the invaded vessels and revascularization ) .
a 20 cm - midline incision was made in the abdomen , and cholestatic liver and swollen gallbladder was seen .
one hard mass ( 7 cm 6 cm 6 cm ) , surrounding the portal vascular structure , could be palpable at duodenal bulb and hepatic portal ; and it was not sharply demarcated form the hepatic portal . enlarged lymph nodes could be palpable beside greater omentum and common hepatic artery .
after the 2nd and 3rd segments of duodenum as well as the caput pancreatis were separated from behind the peritoneum , we saw that the caput pancreatis was involved by the tumor .
the superior mesenteric artery and superior mesenteric vein were separated along pancreatic inferior border because they were not involved by tumor .
after the vascular structure in the hepatoduodenal ligament , celiac trunk , common hepatic artery , and splenic artery were exposed , we found that the proper hepatic artery and gastroduodenal artery were surrounded by tumor , and they could not be completely dissociated .
therefore , we decided to cut off the proper hepatic artery followed by end - to - side anastomosis between the proper hepatic artery and the portal vein .
pancreatic transection was performed through the upper and lower margins of the pancreas on the left side of superior mesenteric vein , and then the greater and lesser gastric curvatures were separated followed by gastric amputation .
after the gallbladder was removed and the common hepatic duct was cut off ; tumor removal , regional lymphadenectomy , and digestive tract reconstruction were performed ( figs . 3 and 4 ) .
the operation lasted for 6.5 hours , and intraoperative blood loss was about 1500 ml .
( d ) the liver after portal vein arterialization . a : inferior vena cava , b : portal vein , c : proper hepatic artery , d : splenic artery , e : splenic vein , f : superior mesenteric artery , g : common hepatic duct , h : liver , i : pancreas , and j : anastomotic stoma between portal vein and proper hepatic artery images obtained by 3-d visualization reconstruction .
liver function was dynamically monitored after operation , and it returned to normal limits 1 week later ( fig .
one week after operation , color doppler ultrasound showed portal vein patency , the signal of blood stream from proper hepatic artery into portal vein , 10 cm - inner diameter of the portal vein at the hepatic portal with a high flow velocity of 21 cm / s , and 12 cm - inner diameter at the midpiece of the portal vein with a high flow velocity of 94.8 cm / s ( fig .
one month after operation , color doppler ultrasound reexamination showed portal vein patency , no marked signal of blood stream in the proper hepatic artery , 8.5 cm - inner diameter of the portal vein at the hepatic portal with a high flow velocity of 22.52 cm / s , and 9.9 cm - inner diameter at the midpiece of the portal vein with a high flow velocity of 50.87 cm / s ( fig .
digital subtraction arteriography was performed through the celiac trunk 1 month after operation , and it showed clear shadow of splenic artery , a compensatory artery branch into the left liver , and no shadow in the proper hepatic artery .
angiography of superior mesenteric artery revealed clear shadow of mesenteric vessels and a compensatory artery branch into the right liver ( fig .
alb = albumin , alt = alanine aminotransferase , d - bil = direct bilirubin , t - bil = total bilirubin .
one week after operation , color doppler ultrasound shows the signal of blood stream from proper hepatic artery into portal vein .
a : portal vein , b : inferior vena cava , c : blood stream from proper hepatic artery into portal vein , and d : proper hepatic artery .
one month after operation , color doppler ultrasound shows no marked signal of blood stream in proper hepatic artery .
digital subtraction arteriography ( dsa ) performed through the celiac trunk shows a compensatory artery branch into the left liver and no shadow in the proper hepatic artery .
pancreaticoduodenectomy , mainly applied for surgical treatment of the tumors in caput pancreatis , is difficult with high risks .
it has been reported that the incidence of complications is 15% to 45% and perioperative fatality rate is less than 5% after pancreaticoduodenectomy . due to occult pathogenesy and special biological behaviors of tumors occurring in the caput pancreatic ,
they readily invade surrounding blood vessels and nerves , bringing difficulties to radical resection for these tumors .
therefore , it is critical to understand the tumor anatomy and evaluate resectability before operation . nowadays , preoperative assessment is mainly assisted by ct and mri imaging examinations .
ct examination , characterized by its high resolution and image clarity , is capable of showing the relation between tumor and surrounding organs and vessels , thus has been widely applied in clinic . with the development of medical imaging technology , 3-d visualization reconstruction has widely used in recent years .
the capability of 3-d visualization reconstruction , including arbitrarily rotating , zooming , combinatorially viewing , vitrification and concealing target organ model , makes it powerful in displaying the tumor 's volume and shape , anatomical relationship with organs and vessels , and the invasion condition .
tumors and vessels can not be stereoscopically shown in ct images , but the 3-d visualization reconstruction can greatly make up the limitation , and can provide more reliable preoperative assessment and more effective surgical proposal . for the tumors occurring in caput pancreatic and involving hepatic artery ,
it is difficult to obtain radical resection only by classical pancreatoduodenectomy , so simultaneous removal of the hepatic artery is necessary . because blood supply for the liver is mainly from portal vein ; if liver function is normal , liver artery ligation usually will not lead to liver ischemia or necrosis .
however , in extensive radical resection of tumor in porta hepatis , exposure of blood vessels in hepatoduodenal ligament often cut off the blood supply of collateral circulation for the remaining liver , so hepatic artery resection may cause severe biliary tract ischemia - related complications such as liver abscess , bilioenteric anastomotic leakage , and even hepatic failure .
based on the reduction of liver blood perfusion and increased incidence of hepatic encephalopathy after portacaval shunt for the treatment of portal hypertension , cohn ( 1952 ) and fisher ( 1954 ) conceived the idea of liver perfusion using arterial blood instead of portal vein blood .
portal vein arterialization could be performed by multiple ways such as complete or partial portal vein arterialization , direct or bridging anastomosis .
the blood supply could be from hepatic artery , right renal artery , splenic artery and right gastric artery , etc .
portal vein arterialization could effectively improve liver function , promote hepatic cell regeneration , prevent hepatic failure , and reduce biliary tract complications .
one case had acute hepatic failure and was not suitable for liver transplantation , this patient tried to receive portal vein arterialization and finally this patient was discharged from hospital because his liver function gradually recovered after operation .
tsivian et al performed a systematic review for literatures and found that portal vein arterialization was safe and reliable in prevention and treatment for acute liver failure .
however , it may also induce some adverse side effects such as increased portal vein pressure , hepatic cell apoptosis , and reduced hepatotrophic factors . to reduce the adverse side effects caused by portal vein arterialization , bonnet et
al adopted the method to limit portal vein flow , and kondo et al carried out anastomotic embolism after portal hypertension and collateral circulation were observed by angiography .
therefore , limiting blood flow and anastomotic embolism are the main methods to reduce or avoid the adverse side effects caused by portal vein arterialization .
chen et al believe that it is reasonable to block arterialization 1 to 6 months after operation . because the patient in this study had a 10-year medical history of viral hepatitis b and increased total bilirubin level before operation , and exposure of blood vessels in the hepatoduodenal ligament led to loss of hepatic blood supply from hepatic artery and most collateral circulation ; complications such as liver damage
, bilioenteric anastomotic leakage , liver abscess , and even liver failure would readily occur .
therefore , we adopted the anastomosis between portal vein and proper hepatic artery to increase portal vein blood flow and promote liver function recovery .
six days after operation , the liver function returned to normal limits , and no biliary tract complications occurred . to avoid side effects such as portal hypertension induce by long - term portal vein arterialization ,
digital subtraction arteriography angiography revealed anastomotic occlusion of portal vein arterialization and formation of liver compensatory arterial branches .
anastomotic occlusion might be caused by long proximal hepatic artery , end - to - side anastomosis , and small anastomotic stoma .
and the increase in portal pressure caused by artery blood perfusion decreased the pressure difference between arteries and veins , reducing blood flow rate at anastomotic stoma and finally resulting in thrombosis .
no biliary fistula or anastomotic leakage occurred in this case , suggesting that this surgical proposal was safe and effective .
in summary , 3-d visualization reconstruction can provide reliable basis and assistance for the accurate assessment and surgical design before pancreatoduodenectomy , and also is conducive to full preparation for extensive pancreatoduodenectomy and vessel reconstruction .
meanwhile , from the case of this study , we can see that it is certainly worth adopting portal vein arterialization when retention of hepatic artery is impossible or conventional arterial anastomosis is required during pancreatoduodenectomy .
although portal vein arterialization is used in clinic as an important remedial measure , its application still needs to be standardized .
the authors thank national natural science foundation of china ( no . 81272246 , 81101502 , 61271336 , 61327001 ) for the support .
Output:
| abstractbackground : three - dimensional visualization reconstruction , the 3-d visualization model reconstructed by software using 2-d ct images , has been widely applied in medicine ; but it has rarely been applied in pancreaticoduodenectomy . although the hepatic artery is very important for the liver , it has to be removed when tumor invades it .
therefore , portal vein arterialization has been used in clinic as a remedial measure , but there still is professional debate on portal vein arterialization.methods:here , we report 1 case that was diagnosed with poorly differentiated adenocarcinoma of the duodenum . the tumor had large size and invaded surrounding organs and vessels.results:preliminary diagnoses were poorly differentiated adenocarcinoma of the duodenum and viral hepatitis b. pancreaticoduodenectomy assisted by 3-d visualization reconstruction and portal vein arterialization were performed in this case .
the tumor was removed .
liver function returned to normal limits 1 week after operation .
digital subtraction arteriography showed compensatory artery branches within the liver 1 month after operation.conclusion:3-d visualization reconstruction can provide a reliable assistance for the accurate assessment and surgical design before pancreatoduodenectomy , and it is certainly worth adopting portal vein arterialization when retention of hepatic artery is impossible or conventional arterial anastomosis is required during pancreatoduodenectomy . |
PubmedSumm118238 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a new and large v. parahaemolyticus outbreak was detected in peru during the austral summer of 2009 . during february march 2009
, a total of 30 isolates were obtained from clinical samples of patients with symptoms of gastroenteritis .
initially illnesses were reported only in the northern cities of peru ( cajamarca , chiclayo , and piura ) , but subsequently the outbreak extended to lima .
thirty v. parahaemolyticus strains isolated from this outbreak were initially investigated for the presence of virulence - related genes , serotyped , and subtyped by using pulse - field gel electrophoresis ( pfge ) .
all strains belonged to serotype o3:k59 , a serotype not previously identified in peru ; moreover , all were tdh - positive , trh - negative , and carried genes for the variant of the type-3 secretion system 2 ( t3ss2 ) .
pfge analysis showed that all the clinical strains shared an indistinguishable pfge pattern ( technical appendix figure 1 ) .
environmental strains of v. parahaemolyticus isolated from shellfish collected at the central market in lima over the course of the outbreak were also investigated .
these strains ( n = 4 ) were tdh - positive , trh - negative , t3ss2-positive , and indistinguishable by pfge analysis from the outbreak strains .
the genomes of 20 of those strains ( 18 clinical and 2 environmental ) were sequenced by miseq ( illumina , san diego , ca , usa ) with 500 ( 2 250 ) cycles , 2 pair - end library with a minimum coverage of 40120 ; testing was carried out at the us food and drug administration s center for food safety and nutrition ( college park , md , usa ) .
libraries were prepared with the nextera xt dna sample preparation kit ( illumina ) , according to the manufacturer s instructions .
whole - genome sequence contigs for each strain were de novo assembled by using clc genomics workbench version 7.5.1 ( qiagen , valencia , ca , usa ) . in silico multilocus sequence typing ( mlst ) by eburst
( 13 ) identified all strains as belonging to a single sequence type profile , st-120 , which is the ancestral founder of clonal complex ( cc ) 120 ( technical appendix figure 2 ) .
all strains deposited in the v. parahaemolyticus mlst database belonging to cc120 originated from china .
whole - genome mlst analysis ( wgmlst ) using ridom seqsphere+ version 3.0.0 ( http://www.ridom.de/seqsphere ) identified 4,265 genes shared among all st-120 strains from peru .
ridom seqsphere+ does a gene - by - gene mapping of the shotgun genomes against the reference genome , identifies the core genes present in all genomes , identifies variants at sequence level ( single - nucleotide polymorphisms [ snps ] ) , and assigns alleles to each unique individual gene sequence .
snps identified in each allele for each locus were extracted and saved into a snp matrix to be used for further analysis .
then , nei s dna distance method ( 15 ) was used for calculating the genetic distance matrix by taking the number of same / different alleles scored for each loci in each genome . in some cases ,
values are not found in certain loci because that gene was either missing or truncated because of its position at either end of the de novo assembled contigs . with these genetic distances , we then built either a neighbor - joining tree or minimum - spanning tree . among those 4,265 core genes ,
a minimum - spanning tree of these strains showed genetic uniformity among all the outbreak strains , grouping all genomes within a single complex with a central group of 6 strains ( figure ) .
these 6 strains were indistinguishable , and the remaining strains showed minor differences ranging from 1 to 3 alleles and from 1 to 5 snps ( technical appendix figure 3 ) .
furthermore , environmental strains showed identical allelic profiles and sequences to the outbreak strains , which represent evidence supporting the domestic source of the seafood originating the infections .
the shellfish predominantly comprised bivalve mollusk species collected from warm areas of the north of the country where the outbreak originated and that are shipped daily to the central market in lima . v. parahaemolyticus outbreaks in peru , 2009 .
a ) minimum spanning tree showing the loci differences among peruvian sequence type ( st ) 120 strains .
ridom seqsphere+ version 3.0.0 ( http://www.ridom.de/seqsphere ) identified 4,265 loci shared among all st-120 v. parahaemolyticus strains .
a wgmlst analysis of the outbreak isolates with 236 v. parahaemolyticus genomes available in genbank grouped the st-120 isolates from peru in a single cluster that exclusively included isolates from china ( technical appendix figure 4 ) .
this finding constitutes additional support to the findings observed with the use of the available mlst data ( technical appendix figure 2 ) , which show genetically similar strains in very distant locations . by wgmlst analysis , st-120 isolates from peru differed from 2 isolates isolated in china in 1992 ( s016 ) and 1993 ( s018 ) by 48 and 259 alleles , respectively .
the fact that these 2 strains were isolated during the 1990s might explain why they are so different from the peru st-120 strains .
expanding the analysis to other genomes of st-120 recently isolated from china or southeast asia might identify more closely related strains .
taken together , our findings reveal another example of the emergence of an asian variant of v. parahaemolyticus in peru associated with seafood consumption . the arrival of st-120 strains in peru represents a third instance of an introduction of asian populations of pathogenic v. parahaemolyticus to the pacific coasts of south america , and , together with the arrival of strains of the seventh pandemic of cholera in 1991 , substantiates the existence of recurrent flux of pathogenic vibrio populations between both sides of the pacific ocean .
asian and peruvian coasts are intermittently interconnected through the movement of water displaced by el nio episodes .
these 4 introduction events of pathogenic vibrio strains in peru occurred just before the arrival of tropical el nio waters to the peruvian coasts , which suggests that the introduction of foreign populations of vibrio could be mediated by el nio events , as previously suggested ( 8) . in conclusion , this study stresses the importance of the application of genomic epidemiology for the routine investigation of outbreaks and surveillance as an efficient and high - resolution tool for tracing the dissemination of pathogens and diseases on a global scale .
this latter information is critical to detect the emergence of novel genetic variants , understand the colonization history of pathogens , and assess potential sources and scenarios contributing to the emergence of disease .
representative noti restriction patterns and clustering analysis of vibrio parahaemolyticus strains , eburst analysis showing clonal complex 120 , minimum - spanning tree of the peruvian strains showing single - nucleotide polymorphisms , and neighbor - joining tree showing the high diversity of v. parahaemolyticus strains isolated around the world .
Output:
| in 2009 , an outbreak of vibrio parahaemolyticus occurred in piura , cajamarca , lambayeque , and lima , peru .
whole - genome sequencing of clinical and environmental samples from the outbreak revealed a new v. parahaemolyticus clone .
all the isolates identified belonged to a single clonal complex described exclusively in asia before its emergence in peru . |
PubmedSumm118239 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: deficient formation of the embryonic atrioventricular canal by the endocardial cushions produces a spectrum of congenital cardiac malformations .
the ostium primum defect combines an atrial septal defect , contiguous with the atrioventricular valve annulus , with a cleft of the mitral valve 's anterior leaflet .
a few patients with ostium primum atrial septal defects have been reported in adulthood , as these patients frequently require medical attention at an earlier age .
we report the case of an adult patient with a recent onset of dyspnoea and decline of general condition , in whom noninvasive and invasive exams clarified the diagnosis of ostium primum defect ; surgical closure of the defect was then performed .
a 67-year - old male patient ( height 165 cm ; body weight 88 kg ) , without previous cardiological history , was admitted to our emergency room for paroxysmal nocturnal dyspnea .
the patient had reduction of functional capability and dyspnea ( new york heart association functional class iii ) in the preceding months .
electrocardiogram on admission showed atrial fibrillation with ventricular rate response of 100 beats / min , right bundle branch block and diffuse repolarization abnormalities .
physical examination revealed a 2/6 l holosystolic murmur over the aortic area , a fixed split of the second heartbeat and mild signs of pulmonary congestion .
transthoracic echocardiography showed normal size of the left ventricle , which was hypertrophic and with normal ejection fraction .
color - doppler evaluation revealed left to right shunt in the basal portion of the interatrial septum without the involvement of the interventricular septum [ figure 1 ] and moderate mitral valve regurgitation .
right atrium was dilated , right ventricle was hypertrophic and mildly dilated ( telediastolic diameter 49 mm ) with moderate to severe tricuspid regurgitation .
chest x - ray showed posterior bilateral pleural effusion , diffuse thickening of the interstitial peribronchial vascular tissue and enlargement of the cardiac shadow .
for further evaluation , a transesophageal echocardiography was performed , confirming an atrial septal defect , ostium primum type , with left - to - right shunt [ figure 2 ] .
mitral valve appeared dysmorphic , fibrocalcific ( compatible with a cleft of mitral valve 's anterior leaflet ) with moderate regurgitation .
the patient underwent surgical closure with autologous pericardium patch ( intraoperative measurement of the defect was 1,9 3 cm , localized in the caudal portion of the septum ) . during surgery ,
postoperative transthoracic echocardiography showed no residual atrial communication , with a slight reduction of the right sections dimensions and mild mitral regurgitation .
preoperative transthoracic echocardiography : apical four chambers view showing left to right shunt localized at the basal portion of the inter - atrial septum .
ra = right atrium , la = left atrium preoperative transesophageal echocardiography : on the left , mid - esophageal short axis view focused on interatrial septum showing morphological evaluation of the interatrial communication . on the right , mid - esophageal four chamber view : color - doppler evaluation showing left to right shunt .
during the development of the heart , failure of the septum primum to join with the fuses atrioventricular cushions leaves an opening , persistent ostium primum .
this defect is usually accompanied by abnormalities in the development of the endocardial cushions resulting in associated malformations of the mitral and tricuspid valves . while ostium secundum atrial septal defect is the most common congenital heart defect in the adults , few cases of ostium primum atrial septal defects
have been reported , as patients with such anomaly frequently require medical attention at an earlier age .
the estimated mean age at death of the patients with ostium primum septal atrial defect is about 36 years , and long - term survival without surgical therapy is very rare . since the positive impact of surgery on patient 's outcome and prognosis , when suspicion is founded
, both clinical cardiologists and echocardiographers should investigate for this uncommon disease in the adult . when ostium primum defect is associated with left atrioventricular valve regurgitation ,
longevity depends on the degree of valve incompetence ; if it remains mild to moderate , the appearance of symptoms may be delayed for decades .
somerville analyzed factors responsible for cardiac death or severe disability in 19 patients with ostium primum defect ( mean age 28.9 years ) : severe mitral regurgitation in 6 patients ( with age < 30 years ) , pulmonary hypertension in 2 , arrhythmias or heart block in 11 patients .
investigated the need for cardiac catheterization and angiography before surgical closure in 33 patients with ostium primum interatrial septum defect .
the authors performed a preoperative evaluation in patients ( mean age 4 , 3 years , range : 2 months to 23 years ) with both transthoracic echocardiography and cardiac catheterization and found that two - dimensional and doppler echocardiographic examination were equal or superior to cardiac catheterization and angiography for the morphologic evaluation of the defect .
our patient underwent coronary angiography because of the age and risk factors ( hypertensive , dyslipidemic , and smoker ) .
given the proximity of his bundle to the lower margin of the primum defect , perioperative heart block is a possible complication of surgery .
lukcs et al . evaluated early postoperative complications of surgical closure in 29 patients with ostium primum interatrial septal defect :
complications included supraventricular arrhythmias in 7 patients , transient complete heart block in 2 patients ( of these , one received permanent pacemaker implantation ) , and sternal dehiscence in one .
we believe our case report is interesting because of the age of the patient and the late appearance of the symptoms .
reported a case of a 75-year - old man , suffering congestive heart failure for several years , for whom autopsy evaluation showed a partial atrioventricular septal defect of 3 cm .
matsumoto et al . reported the case of a female patient with ostium primum type defect who died for refractory congestive heart failure at 82 years .
our patient was asymptomatic until the age of 67 years , despite the large dimensions of the defect ; probably the absence of severe mitral valve regurgitation and of severe pulmonary hypertension allowed him to have a satisfactory hemodynamic status for decades .
Output:
| ostium primum defect is a congenital malformation involving atrial septum contiguous with atrioventricular valve annulus ; it is accompanied by abnormalities in the development of the endocardial cushions , often resulting in associated atrioventricular valves malformations .
few cases have been reported in adulthood because these patients frequently come to medical attention at an earlier age when symptoms such as dyspnea , fatigue , cyanosis , and tendency to underweight occur .
various factors affect the timing of clinical presentation , but the most important is the degree of mitral / tricuspid insufficiency ; when valve regurgitation remains moderate , the appearance of symptoms may be delayed for decades . in adult patients ,
deterioration of clinical status and death are mainly due to the development of arrhythmias or heart block .
we present the case of a 67-year - old patient , without previous cardiovascular events , with a new onset of atrial fibrillation , who developed dyspnea and fatigue ; echocardiography showed a large interatrial defect localized in the basal portion of the septum , associated with anterior mitral valve cleft and moderate regurgitation .
the patient underwent surgical closure of the defect ( intraoperatory measures 1,9 3 cm ) with autologous pericardium patch ; a permanent epicardial pacemaker was implanted for the development of complete atrioventricular block in the early postoperative period . |
PubmedSumm118240 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: burkholderia pseudomallei is a pathogenic bacterium causing melioidosis disease , which is endemic predominantly in south eastern thailand and northern australia .
it has also been recognized as a b - type biological warfare agent possessing an ability for bioterrorism .
its sibling species b. mallei is the parasitic bacterial pathogen of glanders disease and was recognized for its destructive role during the world war i .
in contrast , another closely related species previously characterized as a b. pseudomallei strain with an ability of arabinose - positive assimilation , that is , b. thailandensis , is unable to invoke pathogenesis in human .
however , these bacterial species harbor genomic dna with high similarity in nucleotide as well as in amino acid sequences , suggesting that gain and/or loss of genes during evolution is a reason for differences in their behavior and pathogenicity [ 36 ] . for example
, an arabinose catabolic operon belonging to b. thailandensis , which is absent in both b. pseudomallei and b. mallei genomes , has a suppressive role in b. pseudomallei virulence identified by the operon overexpression analysis .
in addition , using a comparative proteomics of proteins expressed at prolonged stationary phase , we could identify protein - encoding genes that are lost in b. thailandensis genome compared with that of b. pseudomallei .
therefore , an establishment of a 2de dataset proteome reference map from one of these three species will be a valuable resource for comparing protein expression profile in order to study their pathogenesis differentially caused by b. pseudomallei and b. mallei comparing with b. thailandensis .
to this end , given the fact that b. pseudomallei has the most biomedical impact between these three bacterial species , the proteome reference map constructed from b. pseudomallei will eventually lead to the most effective effort , not only for interspecies comparative proteomic analysis but also for studying gene and environmental regulation in this bacterium [ 810 ] .
we previously reported an initiation of a partial proteome reference map of b. pseudomallei grown at prolonged stationary phase to apply for a proteomic comparison between this virulent species and the nonvirulent species b. thailandensis .
however , only 88 protein spots were identified at this growth phase limiting the application on further analysis of other growth conditions due to the spatial and temporal control of protein expression in this bacterium . to further expand the characterization of protein expression profile in b. pseudomallei
, we performed an extended proteome reference map of this bacterium grown at early stationary phase .
the early stationary stage of growth has been shown to be relevant to an adaptation phase in bacteria reflected by the gene regulatory pattern of the adaptive stress response rpos .
this proteome reference map will be an invaluable data for further analysis of pathogenesis and virulence factors of b. pseudomallei and its sibling species .
the clinical isolated b. pseudomallei strain 844 was grown in 100 ml luria bertani ( lb ) medium at 37c and 200 rpm .
bacterial cells were pelleted using the culture at the 12th h of growth ( od600 of about 9.0 ) corresponding to the early stationary phase by centrifugation at 10,000 g and 4c .
protein was extracted by resuspending the cell pellet in 500 l lysis buffer ( 8 m urea , 4% w / v chaps , 2 mm tbp , 1% v / v ipg buffer ph 47 ( amersham biosciences , uppsala , sweden ) and 1% v / v protease inhibitor cocktail set ii ( calbiochem , la jolla , ca ) ) .
cell debris was then removed by centrifugation at 13,000 g for 30 min at 20c .
protein concentrations were determined using rc dc protein assay kit ( biorad , hercules , calif , usa ) as previously described .
2de gels were fixed in fixing solution ( 50% v / v ethanol and 2% v / v phosphoric acid ) for 1 h. the gels were washed by soaking in distilled water for 10 min .
the proteins were then stained in the staining solution ( 20% v / v methanol , 10% v / v phosphoric acid , 10% w / v ammonium sulfate , and 0.1% cbbg-250 ) for an overnight staining .
image analysis was performed using the pdquest software version 7.1.1 ( biorad ) . a master gel used for spot - matching process
the master gel was then used to match corresponding protein spots between 2de gels from three different cultures .
approximately 300 protein spots were picked manually , and they were subjected to tryptic in - gel digestion .
protein spots were excised from a 2de gel and transferred into 1.5 ml microcentrifuge tubes . the in - gel digestion was carried out in 96-well microtiter plates by the ettan spot handling workstation ( amersham biosciences ) .
the gel pieces were washed in 200 l washing solution ( 50% v / v methanol and 5% acetic acid ) for 2 h at room temperature and were dehydrated by the addition of 200 l acetonitrile .
an incubation was performed for 5 min , and the gels were completely dried in a vacuum centrifuge .
protein disulfide bonds were reduced by adding 30 l of 10 mm dtt and incubating for 1 h at 56c .
they were then alkylated by adding 30 l 100 mm iodoacetamide and incubating for 1 h at room temperature .
the gel pieces were dehydrated in 200 l acetonitrile for 5 min to exchange the buffer .
two hundred l of 100 mm ammonium bicarbonate was added to rehydrate the gel pieces .
the gel pieces were dehydrated again in 200 l acetonitrile for 5 min and completely dried in a vacuum centrifuge for 3 min .
the tryptic digestion was carried out for overnight at 37c with 30 l of 20 ng/l ice - cold , sequencing - grade trypsin ( promega , madison , wis , usa ) .
peptides produced after digestion were collected by extraction with 30 l of 20 mm ammonium bicarbonate and 30 l of 50% acetonitrile with 5% formic acid .
the peptide extracts were then collected into 96-well microtiter plates for further analysis . for protein identification using the matrix - assisted laser desorption ionization time - of - flight mass spectrometry ( maldi - tof ms ) , peptide mass fingerprinting ( pmf )
was analyzed using the reflex iv maldi - tof mass spectrometer ( bruker daltonik , bremen , germany ) .
the matrix solution ( 10% w / v 2,5-dihydroxy benzoic acid ( sigma , st .
louis , mo , usa ) in 50% v / v acetonitrile with 0.05 v / v trifluoroacetic acid ( tfa ) ) was prepared prior to use .
peptide extracts were solubilized in 96-well microtiter plates by adding 2 l of 0.1% tfa .
one l of the solubilized peptides were mixed with an equal volume of the matrix solution on a 384-well anchorchip target plate ( bruker daltonik , bremen , germany ) .
the spots were dried at room temperature until crystal occurred , and the target plate was then subjected to the pmf analysis .
the mixture was irradiated with a 337 nm n2 laser and accelerated with 20 kv accelerating voltage in a two - stage gridless pulsed ion extraction source .
the resulting pmf of each protein spot was visualized by the flexanalysis software version 2.2 ( bruker daltonik ) .
protein identification from the tryptic fragment sizes was performed by using pmf searching against the bacterial subgroup of other proteobacteria using the entire ncbi'snr protein database from the mascot search engine ( http://www.matrixscience.com/ ) .
we set the assumption as monoisotopic peptides , a fixed modification at cysteine residues and a variable oxidation at methionine residues .
by using 2de coupled with maldi - tof ms , we have established an extended proteome reference map of b. pseudomallei .
pmfs of protein spots , which failed to be identified , showed only few peptide masses .
in addition , those low - quality pmfs also resulted in matching with proteins from bacterial genus other than burkholderia spp . rejecting the positive identification .
the failure to identify those protein spots might be due to a very low protein amount of the excised spots .
figure 1 shows the identified 282 protein spots , representing 220 open reading frames , within the analysis window of 1075 kda , and pi 47 .
the identified protein spots were categorized according to their biological processes and were listed ( see table s1 in supplementary material available online at doi : 10.1155/2011/530926 ) . based on a published genome of b. pseudomallei ,
the result shows that proteins involved in posttranslational modification and lipid metabolism represent more than 50% of predicted orfs .
in contrast , only 1 and 2% have been identified as cell envelope biogenesis and outer membrane proteins and hypothetical proteins , respectively ( figure s1 ) . within our proteome reference map ,
over 97 spots equivalent to 35% of the identified orfs are found to be involved in central metabolisms of the bacterium , of which energy , lipid , and carbohydrate metabolisms are the major pathways contributing to 28 , 18 , and 16% , respectively ( figure s2 ) .
this result suggests an essential role of those gene products for survival of b. pseudomallei at this growth phase .
approximately 20% of identified proteins presented in the reference map represent proteins functioning in posttranslational modification and stress responses . within these categories , chaperonin groel , heat shock hsp20-related protein , and phasin
are highly expressed at both early and late stationary phase when compared with our previously partial b. pseudomallei proteome map .
interestingly , up to 13% of the identified genes matched to hypothetical proteins highlighting the need for further functional characterization of these open reading frames , which might be important for the adaptation process upon entry into stationary phase .
we could also assign a new biological category of proteins identified in this extended proteome reference map , which we were unable to detect in the previous map .
this group is genes associated with cell motility and intracellular trafficking and secretion and comprises 6% of the identified orfs .
given the fact that the early stationary phase - associated adaptation involves expression of genes related to various processes of chemotaxis and that expression of genes involved in cell trafficking and motility is down - regulated in bacterial prolonged culture , this might be the reason why we could observe this gene category at the early but not late stationary phase . within this group ,
expression of genes involved in type iii secretion systems bsar , bsau , bipb , and bipd ( table s1 ) has been reported to be induced by osmotic stress through a transcriptome analysis .
similar to osmotic stress , a transcriptomic study has found that iron stress results in modulation of expression of atp synthase subunit epsilon and succinate dehydrogenases , two proteins identified in our proteome reference map .
these data show that our proteome reference map will be useful for studying comparative proteomics of b. pseudomallei grown under environmental stresses .
the b. pseudomallei genome consists of two chromosomes , in which the large chromosome ( chromosome 1 ) contains genes necessary for central metabolism whereas the small chromosome ( chromosome 2 ) harbors accessory genes important for bacterial response to the environment . to elucidate which biological processes of the gene ontology classification are dominant to which chromosome , we grouped all identified genes according to their encoding chromosome ( figure s3 ) .
we show that expressed proteins belonging to nucleotide metabolism , coenzyme metabolism , translation , and posttranslational modification categories are dominant for chromosome 1 . on the other hand ,
chromosome 2 favors proteins with secondary metabolism , cell motility , intracellular trafficking and secretion , and uncharacterized and hypothetical proteins .
since proteins are the functional output of genes , our result suggests a partitioning preference in functional expression of different cellular processes by the two chromosomes in b. pseudomallei .
because proteins involved in central metabolism represent the most abundant identified proteins of our proteome reference map , we then took the advantage of the kyoto encyclopedia of genes and genomes ( kegg ) database ( http://www.genome.jp/kegg/ ) to map metabolic pathways relating to these identified proteins .
pathways including glycolysis , krebs cycle , oxidative phosphorylation , pentose phosphate pathway , and fatty acid metabolism are summarized in figure s4 .
our extended proteome reference map also includes 34 genes whose expression is associated with protein isoforms ( table s2 ) in comparison with only 6 genes reported in our previous finding .
this finding is correlated with our previous work , which shows phasin as the major protein isoforms expressed in the late stationary phase b. pseudomallei proteome .
the abundance of phasin isoforms in the early and prolonged stationary phase cultures of b. pseudomallei suggests that the storage of polyhydroxy alkanoate , which is a form of carbon source associated with phasin , is a common feature between these growth phases .
however , in contrast to the previous reported , we find the majority of protein isoforms falling into the category of central metabolism .
for example , two enzyme isoforms encoded by glyceraldehyde 3-phosphate dehydrogenase ( gapa ) gene show a similar molecular weight , but their pis are 4.47 and 6.70
. this roughly 3-unit charge difference might be due to an intermediate transition , glyceraldehyde 3-phosphate - bound form of the enzyme localized at the acidic pi [ 16 , 17 ] .
thus , this result suggests that enzyme isoforms with charge difference might represent an intermediate of its catalytic step .
we have identified a number of genes , whose function has been reported to be implicated in bacterial pathogenesis , in the current proteome reference map of b. pseudomallei ( table s1 ) .
for instance , murf is an enzyme required for bacterial cell wall synthesis and antibiotic resistance .
ppk2 , a gene belonging to polyphosphate kinase family , functions in polyphosphate and atp / gtp biogenesis and signaling during stress response .
type iii secretion - related proteins are required for invasion of pathogenic bacteria into host cells .
expression of many of these proteins has been shown to be controlled by stress response sigma factors rpos and rpoe in b. pseudomallei [ 8 , 9 ] .
thus , translating our proteome reference map to other comparative proteome studies of b. pseudomallei grown at early stationary phase shall benefit the study of pathogenesis caused by b. pseudomallei , since expression of these pathogenesis - related proteins might be regulated by bacterial intrinsic factors and growth condition . with the very similarity in nucleotide and in amino acid sequences between b. pseudomallei , b. mallei , and b. thailandensis genomes [ 3 , 4 ] , we propose that our proteome reference map constructed from b. pseudomallei
can also be applied to the other two species and will be useful for comparing their proteome profiles .
to provide an example , we previously reported a comparative proteomic analysis in b. pseudomallei and the nonvirulent sibling b. thailandensis and identified a number of potential virulent factors and biomarkers for differentiating these two bacterial species .
this proteome reference map of proteins expressed at early stationary phase in b. pseudomallei will facilitate further studies on melioidomics , that is , the study of melioidosis - related global profile expressions .
the proteome reference map containing 282 protein spots , which represent 220 protein encoding genes , has been established for the melioidosis pathogen b. pseudomallei .
many of the identified proteins have been implicated in virulence of pathogenic bacteria and have been shown to be controlled by the stationary phase sigma factor rpos and a biofilm - associated sigma factor rpoe .
Output:
| burkholderia pseudomallei is the etiologic agent of melioidosis . using 2de and maldi - tof ms ,
we report here a proteome reference map constructed from early stationary phase , a bacterial adaptation process .
we identified 282 protein spots representing 220 orfs ; many of them have been implicated in bacterial pathogenesis .
up to 20% of identified orfs belong to post - translational modification and stress responses .
the proteome reference map will support future analysis of the bacterial gene and environmental regulation and facilitate comparative proteomics with its sibling species . |
PubmedSumm118241 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: for generations , the estrogen like or anti - androgen like environmental factors have been assumed to play an important role in the degeneration of men 's semen quality .
also correctable congenital factors such as cryptochidism , varicocele and uncorrectable acquired factors such as testicular and scrotal injury are known to have an influence on semen quality . with these , the hypothesis that makes a decision on men 's semen quality is suggested according to genetic information in the embryogenetic process .
it is based on the hox genes ( hoxa to hoxd ) which plays a role in the differentiation of genital buds and have an influence on the development of finger and prenatal androgen .
accordingly , many investigators tried to reveal the relationship between the index finger and ring finger ratio and the masculation aspect , sex role and semen quality [ 6 - 8 ] . manning et al
have compared the index finger to ring finger ratio ( 2d:4d ratio ) with semen quality and testosterone concentration , and they reported that the group of high 2d:4d ratio has low semen quality and testosterone concentration .
however , this has been refuted by a subsequent research performed by bang et al and firman et al who presented that it has no association with 2d:4d ratio and semen quality .
then , we conducted a study to confirm that the 2d:4d ratio can not be a predictable factor of semen quality of healthy young men .
from november 2008 to january 2009 , we measured the finger length of 264 male students majoring in various subjects in different departments at chosun university .
we found 31 students whose index finger is longer than the ring finger or of the same length .
out of the 31 students , two refused to participate and one had a medical disease .
experimental group consisted of 28 men while control group consisted of 33 volunteers out of 231 healthy young men .
the participants of both group were all single , healthy , and had no problems in ejaculation and sex life .
excleded candidates were those who had a history of cryptochidisms , varicoceles , or testicular injury which can have an influence on semen analysis as well as those who had burns or trauma on hands that can have an influence on finger length .
finger lengths were measured by physicians from department of rehabilitation . after putting ventral surface of right hand on the paper and drawing an outline of the hand , the length between basal crease and finger tip was measured with verniercalifers .
when the results were different , we used the means of the two measured values . with these results ,
we advised all participants to lead ascetic life more than 48 hours before semen sampling .
the semen samples were collected in a silent room that is away from the consultation room and these samples were collected for 3 days .
after semen was put in a sterile vial , it was sent to the department of clinical pathology and analyzed within 30 minutes of semen collection . in conformity with normal criteria of sperm count by who protocol , we defined the normal range of semen quality as follows : the concentration of spermatozoa is more than 2.010 , the normal motile sperm is rapid forward movement , ( grade a ) is more than 25 percent or the sum of rapid movement , and slow movement spermatozoa ( grade a+b ) is greater than 50 percent .
for the descriptive statistics , numerical value of semen index was indicated with meansd ( standard deviation ) and spss ( ver .
the variables such as finger ratio , semen volume , sperm count and quantity was analyzed by mann - whitney test , and spearman correlation analysis was done and p - value<0.05 was considered to indicate a statistical significance .
mean age of all subjects was 23.9 ( 21 - 28 ) , and the difference in age was not considerable between two groups ( 24.07 and 23.81 ) .
the average semen volume of group of 2d:4d ratio of more than 1 is 3.661.64 ml , and the group of 2d:4d ratio of less than 1 is 3.731.40 ml .
the semen volume of the group of 2d:4d<1 seemed to have a smaller amount , but it was not statistically significant ( p=0.82 ) . each total sperm count in semen was 98.6866.57 ( 10/ml ) and 94.3956.92 , respectively .
it seemed that the amount of motile sperm is greater in the group whose 2d:4d ratio is higher , but it also has no statistically significance ( p=0.43 ) ( table 1 ) .
each group had two oligospermias whose semen volume < 1 ml and a total sperm count < 110/ml where it did not make much difference between two groups .
spearman examination with a correlation analysis indicated that all semen volume , sperm count , and motile sperm ratio with finger ratio showed no statistical significance ( p=0.696 , p=0.749 , p=0.323 ) ( table 2 ) .
the scatter plot also showed there is no correlation between the finger ratio and the semen value ( fig .
many studies are attempting to identify the relationship between finger ratio and personal habitus , sex roles , sex hormone status and ability of fertility in conjunction with hox gene during fetal development .
these studies have been based on the hypothesis that a comparative study of the length of index finger and ring finger can predict personal habitus , sex roles , sex hormone status and ability of fertility in adulthood , and many studies have presented their correlations [ 8,9,14 - 16 ] .
however , many studies also rebutted these results by their respective findings [ 11,12,17 - 19 ] . manning et al
have found a significant negative relationship between digit ratio and semen quality for 52 men . however , the subject pool from which men were drawn was a non - random sample of the male population .
they suggested that a similar study conducted by baker et al who reported a comparable correlation between body asymmetry and sperm numbers , and a seemingly random population in regard to their fertility was based on a better representation of the general population .
the subject group used by baker et al consisted of 34 undergraduate university students , ranging in age from 19 to 22 years .
our study correctly identified the traits that were revealing of developmental instability through finger ratio , and showed that developmental instability may indeed be associated with poor semen quality in the general population .
previous studies about finger ratio , sex hormone , and semen quality had been carried out measuring finger ratio in randomized group and comparing dependent variables [ 9 - 12 ] .
but in our study , we first grouped the people by the finger ratio and analyzed the semen and comparing them with each group .
it may be the most direct way to find the difference in semen quality between two groups . manning et al
have presented the negative relationship between the 2d:4d ratio and sperm number , motility and testosterone concentrations .
in contrast , we have a comparable sample size and found no significant associations between 2d:4d ratio and semen quality such as the amount , number and motility of sperm .
these results are similar to the previous studies of bang et al and firman et al . manning et
al had a subset of oligospermic males , which reduced the overall mean sperm numbers and this may account for the significant relationship between sperm number and 2d:4d ratio in their study . on the other hand , our study has no meaningful oligospermic males and has no difference of sperm amount in each group .
although infertile men may have high 2d:4d ratios , our data show that men with high 2d:4d ratio do not necessarily have abnormal semen .
thus , the 2d:4d ratio is unlikely to be of general predictive value for men 's semen quality .
this study shows that the influence of finger ratio is minimal in the estimation of semen quality .
this means that a more influencing factor to the quality of semen may be found in the daily living , hormone like factor , surrounding environment and the way of sex life and so on .
furthermore , even under the condition of low semen quality , if the sperm 's shape and motility are good , a successful fertilization is possible . so it can be fallacious to predict infertility to males with a high 2d:4d ratio .
these findings led us to conclude that a large scale study will be helpful to demonstrate correlations between the finger ratio and semen quality .
also , a study with infertility groups is necessary to clarify the relation between the finger ratio and infertility .
in conclusion , this study demonstrated that there are no associations between 2d:4d ratio and the semen quality in healthy young adult men .
however , since the controversy is still afoot over this subject of relation between finger ratio and semen quality , we need a larger scale study that requires a greater comparative study design .
Output:
| purposethe purpose of this paper is to test the validity of hypothesis that the index finger and ring finger ratio ( 2d:4d ) is related with men 's semen quality.materials and methodswe set two groups of healthy young male student ( mean age 23.9 ) who have different 2d:4d ratio from different departments of chosun university .
one group consists of 26 men whose 2d:4d ratio is higher than 1 ( mean 1.06 ) , and the other group consists of 33 men whose 2d:4d ratio is lower than 1 ( mean 0.94 ) .
their semen was collected by masturbation and examined.resultsa comparative analysis revealed that there is no relation between semen quality and the 2d:4d ratio .
the group of 2d:4d1 showed a semen volume of 3.661.64 ml , on the other hand , the group of 2d:4d<1 showed a semen volume of 3.731.40 ml .
no statistical correlation was found ( p=0.82 ) .
the view of sperm count and motile sperm in single ejaculated semen also showed no statistically significance with 2d:4d ratio ( p=0.84 , p=0.43 , respectively).conclusionsthe 2d:4d ratio has no statistically significant correlation with the semen quality of health young male .
thus , measurements of finger length can not be a reliable indicator of semen quality and testicular function . |
PubmedSumm118242 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: vaginal atrophy is a common condition , with related symptoms affecting up to about half ( 45% ) of postmenopausal women1,2 and almost two - thirds ( 61.5% ) of postmenopausal breast cancer survivors.3 it is characterized by vaginal dryness , dyspareunia , vaginal itching , discharge , and pain.4 urinary symptoms , including frequent urinary tract infection and incontinence , are also commonly present ( table 1 ) . for many women ,
vaginal atrophy interferes with normal sexual functioning.57 vaginal atrophy may cause discomfort or pain during intercourse , difficulty in achieving orgasm , decreased sexual desire , embarrassing vaginal and urinary symptoms , and diminished perception of sexual attractiveness . these symptoms may reduce intercourse frequency ,
interfere with personal relationships , and decrease feelings of intimacy.6 despite the prevalence of vaginal atrophy among postmenopausal women , the topic of vaginal health is frequently absent in preventive health evaluations .
therefore , it is prudent to review the pathophysiology , current treatment recommendations , safety profile of low - dose local vaginal estrogen , and strategies to overcome barriers to the effective treatment of vaginal atrophy .
estrogen maintains vaginal health through interaction with estrogen receptors in the vagina.8 the north american menopause society ( nams ) notes that vaginal atrophy is most commonly associated with the diminished estrogen levels associated with menopause and aging.9 low levels of estrogen in the postmenopausal state lead to gradual changes in the urogenital system , including reduced collagen content and thinning of epithelium , altered appearance and function of smooth muscle cells , increased density of connective tissue , fewer blood vessels , decreased enervation and hyperplasia of terminal nociceptor nerve fibers.8,10 these changes can result in reduced flexibility of the vaginal vault , reduced vaginal blood flow , altered sensation , and increased ph .
additionally , cancer treatments ( surgery , pelvic radiation , chemotherapy , and endocrine therapy ) and chemoprevention therapies may cause or contribute to vaginal atrophy by modifying endocrine activity ( which particularly affects the vaginal epithelium ) , impairing vascular supply to the vaginal tissue or altering the anatomy of vaginal canal.9 symptoms of vaginal atrophy are commonly associated with endocrine breast cancer therapies , including tamoxifen ( when used in premenopausal women ) and aromatase inhibitors.11 symptoms may also arise in premenopausal women who undergo temporary induction of menopause for treatment of hormone - sensitive advanced breast cancer and in women at high risk for breast or ovarian cancer who undergo bilateral oophorectomy.11
nonhormonal therapies ( eg , vaginal moisturizers , lubricants , continued sexual activity ) are considered first - line therapies for women with vaginal atrophy ( figure 1).9 however , while these therapies may provide symptom relief , they do not address the underlying condition ( loss of vaginal integrity due to estrogen deficiency ) .
nams therefore recommends that nonhormonal therapies should be followed by a discussion of hormonal therapies , according to the patient s preference , with consultation from her oncologist.9 estrogen therapy , delivered systemically or locally ( to limit systemic absorption ) , may be considered for women in whom nonhormonal therapies are ineffective.9 if vasomotor symptom relief or osteoporosis prevention is desired and the patient has no contraindications or objections to systemic estrogen therapy , systemic estrogen therapy may be considered as a treatment for vaginal atrophy.12 these patients should be informed of the potential risks of therapy , including deep vein thrombosis , pulmonary embolism , coronary heart disease , and breast cancer .
low doses of orally administered conjugated equine estrogens ( 0.3 mg / day ) , ultra - low doses of continuous combined hormone - replacement therapy ( estradiol 0.5 mg / day plus norethisterone acetate 0.1 to 0.25 mg / day ) , and ultra - low - dose transdermal estradiol ( 0.0125 to 0.014 mg / day ) have shown safety and beneficial effects on both vasomotor symptoms and measures of vaginal atrophy ( eg , ph , maturation index , vaginal symptoms ) in studies of up to 2 years duration.1319 however , oral estradiol is less commonly prescribed because it undergoes significant first - pass metabolism through the liver , which leads to a large reduction in bioavailable drug.20 generally , for women with an intact uterus , concomitant progestogen therapy is recommended when receiving systemic estrogen therapy , to prevent endometrial hyperplasia and adenocarcinoma.12 in women with a history of hormone - dependent cancer , the potential risks associated with systemic estrogen therapy with or without progestogen may outweigh potential benefits ; therefore , systemic therapy is best avoided in this subgroup of patients with vaginal atrophy .
also , not all women experience complete relief of vaginal symptoms with systemic estrogen therapy and additional local estrogen therapy may be required for persistent vaginal symptoms.12 local estrogen therapy is commonly recommended for patients with primarily vaginal symptoms and moderate - to - severe vaginal atrophy . commercially available local estrogen therapies ( table 2 ) include an estradiol vaginal cream,21 a conjugated estrogen ( ce ) vaginal cream,22 an estradiol vaginal ring,23 and an estradiol vaginal tablet.24 these various formulations have shown comparable effectiveness25,26 for the relief of vaginal atrophy symptoms , including vaginal dryness , itching , discomfort , and dyspareunia ;
thus , therapy selection for individual patients is largely driven by provider and patient preference.9 the potential benefits and limitations of the available formulations are summarized in table 2 .
local estrogen therapy can provide sufficient estrogen to the vaginal tissues , with limited systemic absorption,9 so low - dose vaginal estrogen may achieve an effect in the tissue that is similar to the response obtained from oral or transdermal dosing regimens .
several large studies have provided evidence for the endometrial safety of various low - dose local vaginal estrogen formulations.2729 the lowest commercially available formulation , the 10 mcg estradiol biweekly vaginal tablet , was associated with no increased risk for endometrial hyperplasia or carcinoma in postmenopausal women treated for 52 weeks ( 0.52% incidence of endometrial hyperplasia or carcinoma in 386 evaluable biopsy samples , compared with 0% to 1% background incidence).27 in another study , the vaginal ring , which releases 7.5 mcg estradiol per day , was associated with endometrial thickening to > 7 mm in two of 126 women at 48 weeks , but evidence of proliferation was absent at biopsy.28 additionally , low - dose regimens of the ce cream ( 0.3 mg ce once daily [ 21 days on/7 days off ] or twice weekly ) did not result in endometrial hyperplasia or carcinoma in 155 biopsies evaluated at 52 weeks.29 the studies mentioned and others25 show that it is probable that low - dose local vaginal estrogen poses a minimal risk for endometrial hyperplasia and carcinoma .
therefore , nams advises that progestogen therapy is generally not needed when low - dose estrogen is administered locally for the treatment of vaginal atrophy.12 women living with breast cancer and breast cancer survivors comprise a population of particular interest with regard to the safety of vaginal estrogen preparations .
their numbers are growing because the overall incidence of breast cancer is increasing , while improved cancer treatments are improving survival times.30 the risks associated with vaginal estrogen use in women with a history of breast cancer have been addressed in the literature .
pruthi et al31 concluded that safety and risk of recurrence is undefined in this population ; however , the 10 mcg estradiol vaginal tablet or estradiol vaginal ring can be considered after appropriate disclosure to the patient .
dew et al32 evaluated the risk for breast cancer recurrence with the use of low - dose vaginal estrogen and were unable to show an increased risk .
however , a small study in which six women were using aromatase inhibitors and vaginal estrogen ( 25 mcg estradiol vaginal tablet , which has since been replaced with a 10 mcg estradiol vaginal tablet ) showed a short - term increase in serum estradiol that varied by individual.33 in two of the six women , serum estradiol levels did not return to baseline .
based on these results , kendall et al33 cautioned against using vaginal estrogen in patients using aromatase inhibitors because systemic absorption of the former could increase serum estradiol , thereby negating the effectiveness of the latter , which work by near - total suppression of estrogenic stimulation.33 health care providers ( hcps ) should counsel women who have a history of breast cancer regarding the risks and benefits of local vaginal estrogen for the treatment of vaginal atrophy .
quality of life issues , including sexual health , should also be addressed to help women make an informed decision regarding this therapy .
clinicians should also be aware that using local vaginal estrogen for women who have a history of breast cancer is considered off - label because of the black - box warning included in the package insert , which describes the increased risk for breast cancer associated with estrogen plus progestin therapy found in the women s health initiative study.24
multiple barriers prevent the treatment of vaginal atrophy with local estrogen therapy in women who may benefit from treatment ( table 3 ) . first , many women are uncomfortable discussing their vaginal health . results of one international survey indicated that the majority of women with vaginal discomfort ( 70% ) had not discussed it with their general practitioner or gynecologist.2 hcps can address vaginal atrophy by initiating a discussion about vaginal health during preventive health evaluations .
this discussion can be individually adapted to each patient s learning preferences and should reinforce that vaginal atrophy is common among peri- and postmenopausal women .
in addition , it should include an open conversation regarding improvement or exacerbation of symptoms with over - the - counter products .
if a patient reports vaginal discomfort , with or without self - treatment , a physical examination should be performed .
if evidence of vaginal atrophy is noted , a discussion about current treatment recommendations should follow . some women may be hesitant to use estrogen therapy , even if they have significant symptoms
. early termination of the women s health initiative randomized controlled trial34 and subsequent media coverage raised public awareness of the potential risks of standard - dose systemic hormone therapy .
adverse effects , such as uterine bleeding , breast tenderness , nausea , abdominal bloating , and fluid retention,35 may further hinder patient acceptance of systemic estrogen or estrogen plus progestogen therapy .
education regarding the risks and benefits of estrogen therapy , including the improved risk benefit profiles of less - than - standard - dose systemic therapies36 and the endometrial safety of low - dose local therapies,2729 can help facilitate acceptance among women for whom estrogen therapy is appropriate .
it may be helpful to mention to a patient that the amount of estradiol administered locally ( eg , by vaginal tablet or vaginal ring ) in a low dose is much less than that administered in a standard oral dose . while a standard oral dose of estradiol is considered 1 mg / day , the vaginal tablet regimen ( one 10 mcg tablet daily for 2 weeks followed by one tablet twice weekly thereafter24 ) exposes a patient to about 1.14 mg estradiol ( ie , roughly the same amount as the standard oral dose ) over an entire year of treatment .
for further comparison , patients using the ring are exposed to about 2.74 mg estradiol per year , while patients using the creams are generally exposed to more estrogen , depending on the regimen . closely following these total doses ,
systemic absorption of estrogen remains lowest with the vaginal tablet,37 followed by the ring38 and creams.39,40 barriers related to the use of local vaginal estrogen in particular might include its lack of effect on bone loss and vasomotor symptoms , the need for vaginal insertion , irregular treatment intervals , and concerns regarding the potential for improper dosing .
patients may also be apprehensive about potential discomforts associated with use of a vaginal medication ( eg , leakage with creams ) .
additionally , patients may be uncertain regarding the uterine safety of local vaginal estrogen ; therefore , hcps should counsel women effectively regarding the safety data of various formulations .
counseling should also include advising women that use of the lowest effective dose of local vaginal estrogen is recommended to minimize systemic absorption and associated risks.9 the decision for a woman to use a hormone medication depends on many individualized factors .
a patient s biological and psychological response to midlife and aging , tolerance for symptoms and side effects of the medication , and risk / benefit profile will influence both the hcp s recommendation for intervention and the woman s decision to implement the intervention .
the counseling and behavioral interventions work group of the united states preventive services task force recommends the 5 a s construct as a clinical counseling strategy41 : counseling using the 5 a s may be useful for overcoming the communication barriers between patients and their hcps .
routine assessment of vaginal health during preventive health evaluations should facilitate timely identification of vaginal atrophy .
hcps can then provide personalized advice regarding vaginal atrophy and help the patient understand the goals , benefits , and risks of treatment and agree to undergo treatment .
additional counseling about proper treatment administration and what to expect from therapy assists the patient in achieving her goals , while arranging appropriate follow - up appointments should facilitate long - term management of this chronic condition .
the decision for a woman to use a hormone medication depends on many individualized factors .
a patient s biological and psychological response to midlife and aging , tolerance for symptoms and side effects of the medication , and risk / benefit profile will influence both the hcp s recommendation for intervention and the woman s decision to implement the intervention .
the counseling and behavioral interventions work group of the united states preventive services task force recommends the 5 a s construct as a clinical counseling strategy41 : counseling using the 5 a s may be useful for overcoming the communication barriers between patients and their hcps .
routine assessment of vaginal health during preventive health evaluations should facilitate timely identification of vaginal atrophy .
hcps can then provide personalized advice regarding vaginal atrophy and help the patient understand the goals , benefits , and risks of treatment and agree to undergo treatment .
additional counseling about proper treatment administration and what to expect from therapy assists the patient in achieving her goals , while arranging appropriate follow - up appointments should facilitate long - term management of this chronic condition .
hcps such as gynecologists , primary care physicians , nurses , and nurse practitioners can play an essential role in reducing the barriers associated with discussion and treatment of vaginal atrophy .
a discussion of the pathophysiology of vaginal atrophy , treatment options ( including risks and benefits of treatment ) , and overall sexual health is pertinent to preventive health care .
additionally , a brief review of the safety profile of local vaginal estrogen may help women make informed decisions regarding their treatment .
counseling intervention using the 5 a s can empower women to manage their vaginal symptoms effectively in the long - term , potentially improving patient quality of life .
Output:
| the purpose of this review is to summarize current information regarding the pathophysiology and management of vaginal atrophy ( sometimes called atrophic vaginitis ) and to identify barriers to its treatment with local ( or topical ) vaginal estrogen therapy .
relevant clinical trials , meta - analyses , and reviews were identified through the pubmed database .
local estrogen therapy is effective and safe for treatment of vaginal atrophy ; however , barriers to treatment ( eg , patient reluctance to discuss the condition , misinformation , incomplete understanding of the effectiveness and safety of available therapies ) result in its underuse .
health care providers can help overcome barriers to effective treatment of vaginal atrophy by facilitating discussion with women about vaginal health .
discussions should occur at routine preventive health care examinations and during episodic visits when patients present with symptoms of vaginal atrophy .
education and counseling should include information on the importance of maintaining vaginal health and the benefits and risks of treatment , including the demonstrated effectiveness and safety profile of low - dose local estrogen therapy . |
PubmedSumm118243 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: in the past three decades , cochlear implantation has evolved from an experimental procedure to represent the standard of care for deaf patients .
advances in processing strategies , implant design , and patient selection criteria have significantly improved implant users ' performance . nowadays ,
the current frontiers in implantation involve strategies to preserve residual acoustic hearing and the development of algorithms to combine electrical and acoustic hearing .
moreover , it is important to keep in mind that , by preserving apical organ of corti structures , it is possible to take advantage of new technologies that may lead to regeneration of the inner ear in the future .
cochlear implantation with a standard - length electrode has been a reality in treating patients who have profound deafness .
however , the loss of residual acoustic hearing following cochlear implantation is an important clinical consideration when determining the most appropriate options for patients with severe hearing losses .
there are some patients with substantial low - frequency acoustic hearing up to 1500 hz and severe to profound high - frequency hearing loss that do poorly with bilateral amplification who have not been considered as candidates for implantation using standard criteria .
high frequencies report information about vocal vibration ( like the ability to distinguish between s and z ) , whereas lower frequencies apprise information regarding the vocal formants and spectral patterns ( such as the difference between b and g ) .
patients with high - frequency losses are able to distinguish loudness and speech pattern ( due to their low - frequency acoustic hearing ) , but they can not interpret spectral patterns well ( which erodes their capacity to distinguish between the different consonant sounds and thus their word discrimination scores ) .
the loss of low - frequency hearing during cochlear implantation is the result of the technique used to create the cochleostomy and its size combined with the characteristics of the electrode design ( diameter , stiffness , and length ) since it may induce substantial damage to the basilar membrane and cochlear hair cells as it advances into the scala tympani [ 1 , 2 ] .
it is known that cochlear implantation with a standard - length electrode and standard surgical technique in patients with some residual hearing results in complete loss of the remaining acoustic hearing [ 6 , 7 ] . nevertheless , since hodges et al . presented a series of patients who had undergone implantation and had preserved residual hearing ,
many studies have demonstrated the ability to retain residual low - frequency hearing in standard - length electrode implantation [ 9 , 10 ] .
the idea of acoustic plus electric hearing means a cochlear implant aided by an ipsilateral hearing aid , to benefit from the residual low - frequency hearing of an individual .
this idea of electric - acoustic stimulation ( eas ) first emerged from the work of two independent groups , one from iowa , usa , and the other from frankfurt , germany . in 1995 ,
the university of iowa cochlear implant research team along with the cochlear corporation ( lane cove , australia ) developed a shortened electrode array called the hybrid s. it was designed to be inserted only into the lower basal turn of the cochlea and thus stimulate the missing areas of high frequency for those specific patients with preserved low - frequency thresholds .
the hybrid s electrode has a smaller diameter than the standard electrode ( 0.2 mm 0.4 mm ) and initially , it was 6 mm in length and it contained 6 electrodes . because some patients reported a very high - pitched sound , it was then lengthened to 10 mm , still with 6 electrodes .
the ideal insertion depth is at approximately 195 of the basal turn of the cochlea . in 2003 ,
gantz and turner reported the first 6 patients implanted with the hybrid s electrode , three of which received the 6 mm electrode and the other three received the 10 mm electrode .
patients who received the 6 mm electrode improved their consonant recognition scores by 10% , whereas those who received the 10 mm electrode improved by 40% .
also , patients who received the 10 mm electrode did better in the combined mode ( cochlear implant + bilateral hearing aids ) than those who received the 6 mm electrode .
a larger multicenter phase 1 fda trial was conducted for the hybrid s 10 mm electrode with 87 patients from 13 centers , and preliminary data was published in 2009 .
two patients lost all residual hearing within 1 month of implantation ( initial hearing preservation rate ( ihpr ) of 98% ) . between 3 and 24 months after activation , 6 more patients lost residual hearing ( ihpr of 91% ) .
over time , 30% of the patients had a low - frequency threshold drop of more than 30 decibels ( db ) .
a duration of deafness of over 40 years and low preoperative consonant - nucleus - consonant ( cnc ) word scores were found to have a negative impact on functional outcomes .
another short electrode named hybrid l24 has been developed in conjunction with the cochlear corporation .
it contains 22 electrodes that are 16 mm long and its optimal insertion is 250 of the basal turn of the cochlea .
it would still preserve the residual hearing from the apical portions of the cochlea and if the low - frequency hearing is lost , it can be used as a traditional electric device since it has 22 electrodes , similar to a standard one .
the fda trial for the hybrid l has not been published yet , but the preliminary results from the european clinical trial demonstrated the ability to preserve residual hearing .
thirty - two patients were enrolled , 24 of whom were hybrid candidates and 8 long - electrode candidates . in 96% of the subjects ,
hearing was preserved within 30 db of preoperative thresholds and in 68% within 15 db .
these results were stable over time and there was a significant improvement in word scores between the 6-month and 12-month marks , demonstrating , as in the hybrid s trial , that there is a learning period for patients with short electrodes .
the med - el corporation has also developed a shortened electrode called m , which is 22 mm long with an ideal insertion of 360 from the basal turn of the cochlea .
it has a very flexible tip and a significantly reduced diameter in the distal portion .
gstoettner et al . in 2008 reported a series of 18 patients implanted with the m electrode .
twelve of the 18 ( 68% ) had low - frequency hearing preservation that could be usefully amplified .
three of the patients had some residual low - frequency hearing but did not find amplification useful .
interestingly , the loss of the residual hearing was not immediate , but delayed by 3 to 6 months after hybrid activation .
an alternative strategy for preserving the low - frequency hearing was developed with standard - length electrodes , but limiting the depth of insertion .
kiefer et al . implanted 14 patients with the med - el combi40 + electrode , limiting the length of insertion to less than 24 mm ( full insertion is 31.5 mm ) and using a soft insertion technique . in 12 out of the 14 patients ( 85% ) , useful low - frequency hearing ( less than 20 db drop in thresholds ) was maintained , with 2 patients losing all residual hearing . using a standard - length electrode and modified surgical techniques , other authors have reported rates from 67% to 89% of hearing preserved within 20 db of preoperative thresholds [ 7 , 1922 ] .
reported that although patients experienced only a 15 db drop in the low frequencies , the average acoustic cnc postoperative word score was 0% .
some authors defend this reason for its use , so if residual hearing is lost , the patient can have the full - length electrode to benefit from its electric - only listening mode , which would not happen with a short electrode .
since the short electrode is 10 mm long , it accesses only the 2800 to 4700 hz range according to the greenwood frequency placement map of the basilar membrane . even though this was thought to be a tonotopic mismatch , which could impair discrimination , hybrid s electrode users in electric - only mode showed similar performance as long - electrode users on consonant recognition tasks .
improved performance with the hybrid s electrode appears to require a longer time ( over 12 months ) than the long - electrode ( usually 6 to 12 months to adapt to electric hearing ) [ 16 , 23 ] .
one argument in favor of long electrode used to be the likelihood of progressive low - frequency hearing loss .
however , yao et al . demonstrated a loss of only 1.05 db in low - frequency hearing ( up to 2000 hz ) per year in hybrid s users , regardless of their age .
if it can be preserved at the time of implantation , it is likely that the patient will have minimal further hearing loss in the long term .
another concern regarding hybrid or eas studies is the progression of hearing loss after activation . at the time of implantation ,
very few patients lose all their residual low - frequency hearing . in the phase 1 hybrid s10 trial
, 2% of the patients lost their residual low - frequency hearing , and within 3 months of activation , 10% of the initial number of patients had a 30 db drop from their preoperative thresholds up to 500 hz .
the cause of this loss is still unknown ; some hypotheses suggest an immune reaction to the electrode , loss of afferent spiral ganglion neuron synapses at the hair cell related to the combination of acoustic amplification and electrical stimulation , or even an initial injury from noise - induced hearing loss .
steroids have been shown to reduce noise - induced cochlear damage and hearing loss and to increase recovery after noise trauma .
however , their efficacy has been controversially discussed due to a lack of adequate clinical trials .
also , there is controversy regarding drug application methods , be it systemic or local , either via diffusion from the middle ear space through the round window membrane or by direct instillation into the perilymphatic space .
a single - shot intracochlear glucocorticoid application appears to be a promising method for reducing progressive hearing loss caused by electrode insertion trauma due its long - term effects , such as reduction of inflammatory processes .
further in vitro studies with otoprotective drugs believed to bring new perspectives on an improved rate of hearing preservation are promising [ 1 , 26 , 27 ] .
in the initial studies , the indication was closer to standard cochlear implantation for thresholds above 65 db in the low frequencies between 125 and 500 hz .
after encouraging results from these studies , the criteria were gradually expanded to normal low - frequency hearing in the frequencies up to 1500 hz ( partial deafness cochlear implantation ) .
actual guidelines determine that pure tone audiometry scores for both ears have to be greater than 60 db between 125 and 500 hz and below 70 db at 1500 .
in addition , monosyllables tested at a 10 db signal - to - noise ratio ( snr ) should not exceed a score of 40% in the best aided condition .
further , these patients must have substantial cnc word scores in the best aided condition , with between 10% and 60% correct in the worse hearing ear and up to 80% correct in the best hearing ear .
wright and roland in 2005 first described a soft surgery technique , which was later modified by other authors [ 7 , 12 , 13 ] . when developing new strategies , the most import factors that contribute to possible cochlear damage during or after the surgery must be kept in mind : mechanical damage during electrode insertion ( fractures of the osseous spiral lamina , disruption of the basilar membrane , tearing of the lateral spiral ligament , and leakage of traumatized blood vessels),shock waves in the perilymph fluid due to implantation , acoustic trauma due to drilling , loss of perilymph and disruption of inner ear fluid homeostasis , potential bacterial infection , secondary intracochlear fibrous tissue formation .
mechanical damage during electrode insertion ( fractures of the osseous spiral lamina , disruption of the basilar membrane , tearing of the lateral spiral ligament , and leakage of traumatized blood vessels ) , shock waves in the perilymph fluid due to implantation , acoustic trauma due to drilling , loss of perilymph and disruption of inner ear fluid homeostasis , potential bacterial infection , secondary intracochlear fibrous tissue formation .
the technique used at the university of iowa for implantation of the cochlear hybrid s and l devices is described in this review .
a portion of the superior margin of the mastoid cortex is left in place and a suture is passed through the cortex to anchor the electrode before placing it in the cochlea .
the objective of this suture is to reduce the spring of the electrode and to prevent movement of the electrode during placement in the scala tympani ( st ) .
a bonny well for the internal processor is also created in the same manner used for a standard cochlear receiver / stimulator .
a ridge of bone between the mastoid cavity and the well is left so the implant does not later slide .
the facial recess is opened widely , and the round window niche is totally exposed by removing the bone overlying and anterior to the facial nerve . with a 1 mm diamond burr , the bony overhang of the round window niche is drilled away to expose the entire round window membrane . before creating the cochleostomy ,
the surgical field must be extensively irrigated and meticulous hemostasis must be done in order to prevent bone chips and blood debris from entering into the cochlea upon opening . the cochleostomy is created in the inferior - posterior quadrant of a box created by drawing a line at the superior margin of the round window and a perpendicular line at the inferior margin of the round window .
entering into the scala tympani in this specific location prevents damage to the basilar membrane and avoids injury to inner ear structures by facilitating insertion of the electrodes in the correct trajectory .
although in the united states a cochleostomy is the preferred strategy for placing the electrode , many european surgeons usually prefer the round window approach .
the round window technique may result in a conductive hearing loss and it predisposes to fracturing the osseous spiral lamina , according to some studies [ 30 , 31 ] .
a recent systematic review , however , did not show any benefit of one surgical approach over the other regarding the preservation of residual hearing .
the electrode and processor must be seated in position before opening the endosteum of the cochleostomy .
two holes are drilled into the tegmen tympani , which allow a 2 - 0 or 4 - 0 nylon suture to be passed through the bone in order to secure the hybrid s and l electrode array ( not the ground electrode ) . once the processor and electrode are seated and secured , a temporalis fascia washer with a 1.5 mm 1.5 mm diameter is harvested and flattened in a fascial tissue press .
it is then punctured with a straight needle and the electrode is inserted through the fascia up to the dacron collar in order to seal the scala tympani at the cochleostomy .
opening the endosteum into the scala tympani with a 0.2 mm footplate hook must be the final act of the procedure to reduce the time the cochlea is open .
the electrode is advanced slowly into the scala tympani ( over 1 to 2 minutes ) in order to minimize insertional trauma and to allow perilymph displacement .
there are some intraoperative tests described in order to further improve the safety of hearing preservation surgery , such as the measure of cochlear microphonics and auditory brainstem response ( abr ) during electrode insertion . likewise , oghalai et al . used auditory steady - state response audiometry to access hearing thresholds during regular cochlear implantation and draw the surgeon 's attention to the critical moments of the insertion procedure .
the surgeon must pause during the insertion to allow data for these tests to be collected .
the periosteum should then be closed completely over the receiver / stimulator and the electrode .
recently reported a series of 3 patients in whom revision surgery for cochlear implantation was required .
reimplantation was possible in these patients who had previously undergone eas surgery with the preservation of low - frequency hearing and without losing the residual hearing function .
also , a reduced insertion depth at the initial surgery could be followed by deeper insertion into the cochlea without any deterioration of residual hearing .
current literature has already reported several discrete advantages to both modalities , but the full benefits of an eas of the ipsilateral cochlea are still under investigation . patients with preserved low - frequency hearing show significant improvements in their discrimination scores .
hybrid s electrode users continue to improve on cnc scores over 1 to 2 years after activation . in the hybrid s trial , 48% of the patients showed improvement in both srt and cnc scores .
improvement on cnc testing ranged from 10% to 70% over preoperative scores for 73% of the patients with long - term followups .
for those implanted with the hybrid l24 , word recognition scores improved by 21% on average ; one single patient had improvement from 5% to 95% on the freiburg monosyllabic word test ( fmt ) .
exceptional improvement in speech understanding is possible for patients in the combined mode with all electrodes activated : some patients score more than 90% on the cnc monosyllabic word test .
flex users had preoperatively open - set sentence recognition of 24% and after 12 months of use , scores averaged 71% .
improvements in discrimination tasks have also been observed in long - electrode users with preserved acoustic hearing .
patients who received the med - el combi40 + with 19 to 24 mm of insertion scored 75% on monosyllabic tests after 1 year , an important improvement from the 9% preoperative scores .
distinguishing the correct words in a background of competing talkers is a challenging test for traditional cochlear implant users .
normal - hearing listeners have a signal - to - noise ratio ( snr ) of 30 db and 15 db for competing talkers .
the average snr of a long - electrode user is + 3 db for unmodulated background noise and + 8 for multitalker babble ( mtb ) , which means the talker has to speak 3 db louder than the competing noise or 8 db louder than mtb .
hybrid s users do better than traditional cochlear implant patients , but not as well as normal - hearing listeners in noisy backgrounds . in a subgroup of 27 hybrid s patients with at least 12 months of activation , snrs ranged from 12 to + 17 db ( average 9 db ) .
patients who had a drop greater than 30 db in their low - frequency hearing experienced a worse snr .
hybrid l electrode patients also improved their snr preoperatively from 12.1 db to 2.1 db postoperatively . those with the flex electrode changed their preoperative open - set sentence scores with a snr of + 10 db from 14% to 60% after 1 year of activation .
long - electrode users with preserved hearing in low frequencies also benefit when listening in noise .
med - el combi40 + users with a low - frequency threshold of < 80 db scored better than patients with a cochlear implant and no residual hearing with a snr of + 5 db .
gstoettner et al . showed an increase in understanding scores from 13.1% preoperatively to 75% in the electric - acoustic stimulation condition .
it is known that traditional cochlear implant users have difficulties identifying and enjoying music because of the extremely complex encoded spectral information .
they can usually distinguish lyrics to a certain degree but have significant trouble with pitch , timbre , and melody recognition [ 35 , 36 ] .
music appreciation has been a part of the research protocol for the hybrid s / l trials .
patients with preserved acoustic hearing have a distinct advantage over traditional cochlear implant users regarding pitch , lyrics , melody , and timbre of the instruments .
when hybrid users were provided with excerpts of easily recognizable american songs , they were able to correctly identify the songs 65%100% of the time , similar to normal - hearing listeners . in tasks regarding pitch recognition and melody without lyrics ,
the hybrid users still scored better than the traditional cochlear implant patients , but not as well as normal - hearing listeners did [ 36 , 37 ] .
studied music testing in eas patients with long - electrode insertion ( med - el combi40 + ) .
thirteen eas patients were compared with long - electrode users with no residual hearing and normal - hearing listeners .
eas patients did as well as normal - hearing listeners on pitch discrimination and better than traditional cochlear implant users .
however , eas patients ' scores in melody discrimination , instrument detection , and instrument identification were not significantly different from those of traditional cochlear implant users .
it is possible that treatments will emerge that require nave cochlear tissue ( i.e. , hair cell generation or tissue transfer ) .
this concern is relevant for families weighing the risks and benefits of bilateral cochlear implantation for deaf children .
the iowa ci research team has recently reported a series of 9 children with bilateral implants : one ear with a standard long electrode and the other with hybrid s12 research electrode .
the children were only 12 to 24 months old at the time of implantation and they scored an average of 80 in preschool language scale-3 ( pls-3 ) , whereas the average score in the same test for children with bilateral standard electrodes is 83 .
a long - term followup is necessary to determine whether the trends of the preliminary data are long - lasting ; a larger - scale study is being carried out .
although hearing preservation in cochlear implantation is technically challenging , the importance of preserving residual low - frequency hearing can not be underestimated in light of the added benefit of hearing in noisy atmospheres and music quality for eas users .
nowadays , patients undergoing hearing preservation surgery can expect a long - term low - frequency hearing preservation rate of 5070% . although surgeons have largely modified the initially described
few would have imagined the progress that has been made in the past 30 years regarding aiding deafened patients , and the future promises to be equally exciting .
the potential eas advantages highlight the value of the endeavors to preserve low - frequency hearing in the implanted ear and to continue amplification where appropriate .
further research is also needed to maximize outcomes for recipients with different degrees of hearing loss who use devices that combine electric and acoustic stimulation .
Output:
| in the past , it was thought that hearing loss patients with residual low - frequency hearing would not be good candidates for cochlear implantation since insertion was expected to induce inner ear trauma .
recent advances in electrode design and surgical techniques have made the preservation of residual low - frequency hearing achievable and desirable .
the importance of preserving residual low - frequency hearing can not be underestimated in light of the added benefit of hearing in noisy atmospheres and in music quality .
the concept of electrical and acoustic stimulation involves electrically stimulating the nonfunctional , high - frequency region of the cochlea with a cochlear implant and applying a hearing aid in the low - frequency range .
the principle of preserving low - frequency hearing by a soft surgery
cochlear implantation could also be useful to the population of children who might profit from regenerative hair cell therapy in the future .
main aspects of low - frequency hearing preservation surgery are discussed in this review : its brief history , electrode design , principles and advantages of electric - acoustic stimulation , surgical technique , and further implications of this new treatment possibility for hearing impaired patients . |
PubmedSumm118244 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: progress in new surgical techniques and medical management for congenital heart diseases ( chd ) has dramatically improved patient survival over the past decades . however , with many patients with chd surviving until adulthood , right ventricular ( rv ) failure has become a concern1 ) .
several types of chd are associated with rv failure , although surgical or interventional adjustments have been developed for chd1 ) .
rv outflow tract ( rvot ) obstruction after total correction of the tetralogy of fallot ( tof ) , pulmonary stenosis , atrial switch operation for transposition of the great arteries ( tga ) , congenitally corrected tga ( cctga ) , and systemic rv failure after the fontan operation are the causes of pressure - overload rv failure1,2 ) .
another problem is the volume - overload rv failure that may be caused by atrial septal defect ( asd ) , pulmonary regurgitation , and tricuspid regurgitation1,2 ) .
the development of rv failure associated with chd should be carefully monitored , and both optimal medical and surgical treatments should be considered . the aim of this review is to provide an update on the current understanding of rv failure in patients with chd .
in contrast to the ellipsoidal shape of the left ventricle ( lv ) , in the sideward view , the right ventricle appears triangular , and in the cross - sectional view , it appears crescent shaped3,4 ) .
the right ventricle can be divided into 3 components : 1 ) the inlet , 2 ) the trabeculated apical myocardium , and 3 ) the infundibulum or conus5 ) ( fig .
the specific morphological features of the anatomy of the right ventricle include the following : 1 ) the more apical attachment of the septal leaflet of the tricuspid valve relative to the anterior leaflet of the mitral valve , 2 ) the presence of a moderator band , 3 ) the presence of > 3 papillary muscles , 4 ) the trileaflet of the tricuspid valve with septal papillary attachments , and 5 ) the presence of prominent and coarse trabeculations3 ) . although the right ventricle appears smaller than the lv in the 4-chamber view , the volume of the right ventricle is more than that of the lv4,6 ) . in normal adults ,
rv mass is only approximately one - sixth that of the lv , and the right ventricle has a wall thickness 3 to 4 times less than that of the lv7 ) .
progressive regression of rv hypertrophy is observed as pulmonary vascular resistance ( pvr ) decreases during childhood4 ) .
the right ventricle is linked to the lv at several points such as a shared ventricular septal wall , mutually encircling epicardial fibers , attachment of the rv free wall to the anterior and posterior septum , and sharing the pericardial space2 ) .
the essential function of the right ventricle is to receive systemic venous blood and pump it into the pulmonary arteries . in the absence of
shunt physiology or significant valvular regurgitation , the right ventricle pumps the same stroke volume as the lv4 ) .
however , the stroke work of the right ventricle is only approximately 25% of that of the lv because of low vascular resistance and pulmonary artery distensibility .
therefore , the right ventircle is thinner walled and more compliant2 - 4 ) than the lv .
rv contraction starts with the inlet and trabeculated myocardium and ends with the infundibulum3 ) .
in contrast to the lv , twisting and rotational movements do not significantly contract the right ventricle , and rv shortening is greater longitudinally than radially3,8 ) .
rv performance is also influenced by heart rhythm , synchrony of ventricular contraction , rv force - interval relationship , and ventricular interdependence9 - 12 ) .
compared with the lv , the right ventricle demonstrates a heightened sensitivity to afterload change3,13,14 ) . in clinical practice
the pvr is influenced by hypoxia or hypercarbia , cardiac output , pulmonary volume and pressure , and specific molecular pathways such as the nitric oxide , prostaglandin , and endothelin pathways3,15,16 ) .
excessive rv volume can compress the lv and impair global lv function through the effects of ventricular interdependence14 ) .
the main structures for ventricular interdependence include the ventricular septum , pericardium , and continuity between myocardial fibers of the right ventricle and lv4 ) .
in acute rv pressure- or volume - overload states , dilatation of the right ventricle shifts the interventricular septum toward the left , altering lv geometry3 ) .
this leads to a decreased lv preload , an increased lv end - diastolic pressure , or low cardiac output12,15 ) .
when the right ventricle is exposed to pressure overload , progressive dilation follows a primary adaptive response that includes hypertrophy2 ) .
although some reports state that hypertrophy itself is beneficial for overcoming the increased backward pressure , it is well accepted that a persistent increase in the pressure of the right ventricle causes a loss of contractile force that is required for pumping out the blood17,18 ) .
pressure overload of the right ventricle also may lead to rv ischemia , which may further aggravate ventricular dysfunction14 ) .
compared with the volume - overload condition , histological changes are more common in the rv pressure - overload condition , in particular , increased myocardial fibrosis , which is seen in both animal and human studies19,20 ) .
two major conditions of pressure loading of the right ventricle are rvot obstruction and the right ventricle supporting the systemic circulation .
although the obstruction may also occur at the subvalvar or supravalvar levels , 80% to 90% of cases have valve level obstruction1 ) .
regardless of the level of obstruction , the right ventricle exerts a hypertrophic response according to the degree of obstruction21 ) .
the pressure gradient across the rvot can be estimated by continuous wave doppler echocardiography , which correlates well with catheter - based peak - to - peak gradient , obviating the need for cardiac catheterization1,22 ) . in patients with moderate - to - severe pulmonary valve stenosis ,
the right ventricle usually adapts well to pulmonary valve stenosis , even when the stenosis is severe .
longstanding untreated severe obstruction , however , may lead to rv failure and tricuspid regurgitation1,4 ) .
percutaneous valvuloplasty is considered in patients with moderate - to - severe pulmonary valve stenosis4 ) . in terms of physiology and anatomy
it is well suited to changes but is poorly tolerant to acute changes in afterload1,7 ) .
late rv failure usually occurs in patients with tga who have undergone an atrial switch surgery and in patients with cctga , because the anatomy of the right ventricle supports the systemic circulation1,23 ) .
however , myocardial perfusion defects , uncoordinated myocardial contraction , and systemic atrioventricular valve ( tricuspid valve ) regurgitation contribute to the progressive decline in rv function in patients who have undergone an atrial switch operation1,23,24 ) .
rv dilatation and impaired systolic function correlates inversely with rv systolic function25 ) . in patients with cctga ,
moderate - to - severe systemic atrioventricular valve ( tricuspid valve ) regurgitation and rv failure are associated with increased mortality1,4,26 ) .
rv dysfunction usually starts within 5 years from the onset of tr in cctga patients without associated lesions2 ) .
tricuspid valve replacement may slow the progression of rv failure18 ) . among the older patients with cctga , many
the right ventricle adapts better to volume overload than to pressure overload18 ) and may tolerate volume overload for a long time without significant systolic dysfunction1 ) .
recent studies , however , have demonstrated that chronic volume overload is associated with increased morbidity and mortality1 ) . a large asd results in left - to - right shunting and volume overload of the right ventricle18 ) .
large asds may remain minimally symptomatic during the high - volume phase , until and eisenmenger 's syndrome and pulmonary vasculopathy develop2 ) .
in contrast to patients with ventricular septal defects , only a small percentage of patients with asd develop eisenmenger 's syndrome in later life27 ) .
age older than 40 years at closure is associated with incomplete right ventricle , right atrial reverse remodeling , and increased risk of arrhythmias1,27 ) .
closure of the asd is contraindicated in patients with eisenmenger physiology , unless significant regression of pulmonary vascular disease occurs with pharmacological therapy3 ) .
severe pulmonary regurgitation is the most common cause of progressive rv dilatation and dysfunction in patients with repaired tof1 ) .
severe and progressive rv dilatation may be a primary sign of a rv dysfunction , an indication for pulmonary valve replacement .
pulmonary valve replacement generally results in ventricular reverse remodeling with a decrease in rv volume1 )
. advanced severe rv dilatation with an end - diastolic volume > 170 ml / m or an end - systolic volume > 85 ml / m before replacement , however , is associated with persistence of rv dilatation after surgery28 ) . in tof
, a " restrictive rv physiology " has been associated with worse outcome after repair of tof1 ) .
a restrictive rv physiology is characterized by the presence of forward and laminar late diastolic pulmonary flow throughout respiration1 ) .
early after tof repair , restrictive rv physiology is associated with a low cardiac output and longer intensive care unit stay1,29 ) .
late after tof repair , however , restrictive rv physiology counteracts the effects of chronic pulmonary regurgitation1,30 ) .
ebstein anomaly is characterized by an apical displacement of the septal and posterior tricuspid leaflets exceeding 8 mm / m1,31 ) , leading to an atrialized rv and moderate - to - severe tricuspid regurgitation .
rv failure in ebstein anomaly results from volume overload of the right ventricle and from a hypoplastic rv chamber unable to manage the systemic venous blood18 ) . in symptomatic patients ,
the size of the functional rv and tricuspid valve morphology determine the best surgical technique1 ) .
although the measurement of rv function is difficult , the right ventricle can be evaluated using several imaging and functional modalities2,18 ) . in clinical practice
compared with other modalities , it is versatile and available at all institutes18 ) . in addition ,
doppler - derived indices such as the myocardial performance index ( mpi ) and tricuspid annular isovolumic acceleration ( iva ) are emerging as promising parameters of rv function18 ) . cardiac magnetic resonance imaging ( mri )
mri may have an extending future role in assessing the physiological characteristics of pulmonary arterial flow18 ) .
radionuclide - based techniques provide reliable and geometrically independent assessments of rv ejection fraction ( rvef)18 ) .
cardiac catheterization provides direct hemodynamic data and allows accurate assessment of pvr . pulmonary angiography and coronary angiography
can further delineate important anatomic and functional characteristics18 ) . the simplest method for assessing rv volume includes linear dimensions and areas obtained from single tomographic echocardiographic planes18 ) . in an effort to be more accurate ,
three - dimensional echocardiography is a promising technique that could lead to more accurate measurement of rv volume18 ) .
the study of rv function comprises indices that reflect rv systolic function , rv diastolic function , and valvular function2,32 ) .
the most commonly used echocardiographic indices of rv systolic function are as follows : 1 ) geometric indices such as rv fractional area change , rvef , and tricuspid annular plane systolic excursion ( fig .
2 ) , which reflect the extent of contraction ; 2 ) myocardial velocity indices such as the tricuspid annular plane maximal systolic velocity and the iva ( fig .
3 ) ; 3 ) hemodynamic indices such as the first rv derivative of pressure and time ( rv dp / dt ) ; and 4 ) time interval indices such as the rv mpi ( fig .
4 ) or tei index , which reflect both systolic and diastolic parameters33 ) . right atrial pressure ( rap ) is a clinically useful diastolic variable of rv diastolic function34 ) . in patients who are not being mechanically ventilated ,
recent studies showed that serum levels of b - type natriuretic peptide may be useful in diagnosing rv failure associated with chd35,36 ) .
elevated troponin levels have also been associated with worse outcomes in pulmonary embolism and pulmonary hypertension37,38 ) .
for the management of rv failure , the cause and setting of the failure should be considered18 ) .
maintenance of sinus rhythm and atrioventricular synchrony is especially important in rv failure because atrial fibrillation and atrioventricular block may have profound hemodynamic effects18 ) . in patients with rv dysfunction and valvular heart disease or chd , corrective surgery or percutaneous intervention
if no hemodynamic improvement is observed with an initial fluid challenge of normal saline , volume loading should not be continued18 ) .
the hemodynamic improvement seen with nitric oxide is most likely secondary to selective pulmonary vasodilatation , resulting in a reduction in rv afterload and subsequent improvement in rv performance41 ) .
acute responsiveness to pulmonary vasodilators is associated with a better prognosis and survival in patients with advanced heart failure42,43 ) . in patients with
dobutamine is the most commonly used inotrope in cases of rv failure44 ) . in patients with pulmonary hypertension ,
dobutamine at doses of 2 - 5 g kg min increases cardiac output but decreases pvr44 ) .
the combination of dobutamine and nitric oxide in patients with pulmonary hypertension also has been shown to be beneficial44 ) .
dopamine is used in severely hypotensive patients , whereas milrinone is preferred in the presence of tachyarrhythmias induced by dopamine or in patients on -blockers18 ) .
digoxin therapy for rv failure has been studied in pulmonary hypertension and chronic pulmonary disease18 ) .
maintenance of sinus rhythm and heart rate control are important in rv failure . high - degree av block or atrial fibrillation may have profound hemodynamic consequences18 ) .
the rvef in patients with either systemic or pulmonic rv was improved by cardiac resynchronization therapy45 ) .
the effects of -blockade and angiotensin - converting enzyme inhibition have been studied mainly in lv heart failure . in patients with biventricular failure ,
angiotensin - converting enzyme inhibition has been shown to increase rvef and to reduce rv end - diastolic volume and filling pressures46 ) .
small studies also have demonstrated that -blockade with carvedilol or bisoprolol improves rv systolic function47 ) . clinical studies that assessed the role of angiotensin - converting enzyme inhibitors or angiotensin receptor blockers in the systemic right ventricle found that they do not improve exercise capacity or hemodynamics , although those studies may have been underpowered48 ) . in patients with acute rv failure that is refractory to medical treatment , mechanical support with an right ventricle assisting device may be used as a bridge to transplantation or recovery18 ) .
these new strategies might include cell - based or gene therapies , new drugs , or new combinations of existing drugs2 ) .
rv failure remains an important cause of morbidity and mortality in patients with chd both before and after cardiac surgery or intervention .
although recent advances in imaging including cardiac mri , echocardiography remains pivotal for the noninvasive assessment of the right ventricle .
a comprehensive evaluation of rv function may improve risk assessment and lead to early and optimal management of rv failure in patients with chd .
Output:
| despite developments in surgical techniques and other interventions , right ventricular ( rv ) failure remains an important clinical problem in several congenital heart diseases ( chd ) .
rv function is one of the most important predictors of mortality and morbidity in patients with chd .
rv failure is a progressive disorder that begins with myocardial injury or stress , neurohormonal activation , cytokine activation , altered gene expression , and ventricular remodeling .
pressure - overload rv failure caused by rv outflow tract obstruction after total correction of tetralogy of fallot , pulmonary stenosis , atrial switch operation for transposition of the great arteries , congenitally corrected transposition of the great arteries , and systemic rv failure after the fontan operation .
volume - overload rv failure may be caused by atrial septal defect , pulmonary regurgitation , or tricuspid regurgitation .
although the measurement of rv function is difficult because of many reasons , the right ventricle can be evaluated using both imaging and functional modalities . in clinical practice
, echocardiography is the primary mode for the evaluation of rv structure and function .
cardiac magnetic resonance imaging is increasingly used for evaluating rv structure and function .
a comprehensive evaluation of rv function may lead to early and optimal management of rv failure in patients with chd . |
PubmedSumm118245 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bioconjugation of magnetic nanoparticles is basically done to make it compatible for numerous biomedical applications such as mri contrast enhancement , drug delivery , detoxification of biological fluids , immunoassay , tissue repair , hyperthermia etc .
[ 1 - 6 ] . besides these , bioconjugate systems are also being applied in various large - scale bioprocesses such as nucleic acid detachment , protein separation , magnetic biosensor etc .
all these biorelated applications require the use of magnetic nanoparticles that should have size smaller than 10 nm with overall narrow particle size distribution , so that the particles have uniform and unique properties .
this is mainly because of the fact that particles at this size range have the advantage of showing well - established magnetic properties which reduces the possibility of particle aggregation upon magnetic attraction in a magnetic dispersion . for fabricating a bioconjugate
normally , these are synthesized by modifying the nanoparticle surface with some chemical linker molecule , so that it can further interact with next incoming bio molecular entity with the help of free functional group of linker molecule .
this procedure was already well established but supposed to be having some difficulty in the sense of stability of linker molecule due to various biochemical events .
this might occur mostly under in vivo condition when applying the bioconjugate system in the targeted delivery of neoplastic compounds to tumor cell . to overcome this difficulty , we proposed some biologically evolved linker moiety ( fatty acid binding domain ) to fabricate a novel bioconjugate in covalent fashion by utilizing the molecular recognition property of bio molecular system , such as bovine serum albumin ( bsa ) protein .
it is supposed to be an important substitute over the synthetic linker in designing the bioconjugate covalently so that it can be applied gently under preceding condition .
this can also be called as natural anchor molecule that is functional in several of its biological activities . here
, bsa is chosen as the material of interest for the bioconjugation purpose because of the fatty acid binding domain of bsa , which helps in the conjugation of stearic acid capped nanoparticle with the protein moiety . also , serum albumin is the major vehicle for transport of nonesterified fatty acids in the circulation .
magnetic bioconjugate of stearic acid capped ultrafine maghemite nanoparticle with bsa molecule is quite advantageous in case of stability because of the molecular recognition ability of the bsa molecule towards fatty acid itself and its well stability under physiological condition ( ph = 7.4 ) .
high purity ( > 99% ) iron ( iii ) nitrate [ fe(no3)3 9h2o ] , stearic acid [ c18h36o2 ] , and tetrahydrofuran ( thf ) were used for the synthesis of maghemite nanoparticle . the albumin protein required for the bioconjugation purpose
high purity iron ( iii ) nitrate [ fe(no3)3 9h2o ] and stearic acid [ c18h36o2 in the ratio of 1:2 were used as initial ingredients .
the homogeneous solution of molten mixture was then heated at 125 c for 1/2 h to form a reddish brown viscous mass which then subsequently treated with thf .
the powdery precipitates were collected through centrifugation and dried completely in an air oven at 70 c .
the dried precipitates were further subjected to heat treatment at 250 c for holding time of 30 min inside an electrically heating furnace to get the nanoparticles .
the synthesis of the conjugate of bovine serum albumin with maghemite nanoparticles ( -fe2o3 ) was carried out by transferring 3 mmol of bsa into pbs buffer .
the mixture was then kept at 4 c and allowed to stand for 12 h , so that protein sample gets completely soluble in the pbs buffer . after this , 1 mmol of maghemite nanoparticles ( -fe2o3 ) were mixed with the bsa containing buffer and the mixture was vortexed for 1 h at room temperature .
the vortexed mixture is again stored at 4 c for 2 h for the stabilization purpose .
this was basically done to control the covalent interaction taking place between stearic acid coated maghemite nanoparticles with that of protein molecule .
further , the mixture was centrifuged at high speed for 15 min to get the magnetic nanobioconjugate consisting of maghemite nanoparticles ( -fe2o3 ) and bsa .
the pellet portion is collected and allowed to vacuum dried and the supernatant being kept for further characterization .
the formation of maghemite bsa nanobioconjugate had been studied with the help of ft - ir spectrometer .
the dried samples of maghemite , bsa as well as the magnetic nanobioconjugate were grounded with kbr and the mixture was compressed into a pellet for characterization .
transmission electron microscopy ( tem ) study for the conjugate of bovine serum albumin with maghemite nanoparticle ( mnp / bsa ) as well as mnp itself was carried out using a jem-100cx model operated at 100 kv .
the magnetic properties of the resulting bioconjugate as well as maghemite nanoparticles had been studied with vibrating sample magnetometer ( vsm , lakeshore , 7410 ) for confirming the retaining of magnetic properties by the nanoparticles after the formation of nanobioconjugate .
in this work , we used a versatile technique for the synthesis of maghemite nanoparticle , which was quite advantageous in the sense of not forming large aggregates , occurrence of uncontrolled oxidation , and presence of matrix etc .
the procedure was characterized by a complete and homogeneous mixing of initial ingredients at molecular or atomic level .
this technique ensured the presence of uniform particle size distribution as evidenced from the saxs study .
we adopted the synthesis procedure for preparing magnetic nanobioconjugate system by taking the principle of covalent interaction of fatty acid binding domain of bsa molecule with stearic acid .
as the synthesized magnetic nanoparticle was capped with stearic acid molecule , it can effectively help in the formation of bioconjugate with protein molecule .
the reaction was carried out at 4 c by keeping the ph of the reaction medium constant at 7.4 .
the precaution was taken with a motivation to keep the structure of the albumin molecule in intact from .
this was primarily because of the fact that , at neutral ph(=7.4 ) , a net charge of 10 , 8 & 0 for domain i , ii & iii for bsa had been obtained .
so , to keep the various domains of the molecule stable , primarily the domain iii ; the reaction had been carried out at neutral ph in pbs buffer .
serum albumin also undergoes reversible conformational changes with the changes in ph . in this regard
, the % of helix transformation tends to be normal ( 55% ) at the ph range 4.38 .
though bioconjugation of bsa on nanosized magnetic nanoparticles ( fe3o4 ) as well as semiconductor nanocrystals ( cdte ) had already been done by different approaches , even using oleic acid coated magnetite nanoparticles .in these published reports , some of the surface functionalization reactions to conjugate bsa molecules onto the support particle surface were very complicated in comparison to the process described in this paper .
the conjugation scheme of maghemite nanoparticle with bovine serum albumin we performed the ftir study to primarily confirm the feasibility of the conjugation process .
the ftir spectra of maghemite / bsa nanobioconjuagte along with maghemite nanoparticle and bsa were shown in fig .
the ftir spectra exhibited strong bands in the low frequency region due to the iron oxide skeleton .
the presence of free carboxyl group on the nanoparticle surface was further confirmed from the c = o stretching band ( 1,704 cm ) as well as oh stretching band ( 2845.40 cm ) of the carboxyl group on the stearic acid capped magnetic nanoparticle .
due to very strong hydrophobic character of the hydrocarbon chain of stearic acid molecule , it is very difficult for it to be exposed to the aqueous solution .
so , the interaction of stearic acid molecule with the iron oxide skeleton took place through the hydrocarbon segment leaving the carboxyl group towards the aqueous solution . comparing the spectra of maghemite nanoparticles before and after conjugation with bsa , the strong absorption bands at 536.84 and 552.88 cmconfirmed the presence of maghemite as the main phase in both samples .
the characteristics band of the bsa protein at 1,650 and 1,530 cmare due to c = o stretching band of carboxyl functional group on the tryptophan moiety as well as carboxylate group .
the conjugation of bsa to nanoparticle surface was confirmed by the appearance of the new n h stretching band ( 3398.4 ~ 3,400 cm ) as well as vanishing of the c = o stretching band ( 1,704 cm ) of carboxyl functional group on stearic acid molecule .
this clearly signified the formation of the covalent bond between the amino & carboxyl functional groups of the protein molecule as well as stearic acid capped maghemite nanoparticle .
the new band ( 1655.02 cm ) appeared after the formation of the bioconjugate was due to c = o stretching pattern of the secondary amide linkage .
on the other hand , new bands appearing at around 1,100900 cmwere due to the c
n stretching ( 1080.49 cm ) from secondary amide linkage ; c h deformation out of plane ( 983.83 cm ) from stearic acid hydrocarbon chain as well as c h deformation of aromatic hydrocarbon ( 864.58 cm ) from tryptophan amino acid present over the protein molecule .
n stretching band at ( 1080.49 cm ) was a strong significance that the conjugation took place in covalent manner through amide linkage .
ft - ir spectra of maghemite nanoparticle before and after the conjugation with bsa further , to get the simplified view of the bioconjugate so prepared , we also carried out the tem studies of the maghemite nanoparticle as well as the resulting magnetic nanobioconjugate . from the tem micrographs
, the conjugation of the nanoparticles with the protein molecule can easily be visualized as shown in fig .
it clearly illustrates the ellipsoidal pattern of bsa molecule over which the nanoparticles were conjugated and formed an assembly pattern .
it is also evident that the nanoparticles are well separated from each other , i.e. aggregation has not taken place .
this has occurred as a result of the perturbation of electron cloud of the bimolecular environment during the conjugation process .
tem micrograph of the conjugate of maghemite nanoparticle with elongated bovine serum albumin molecule to understand the nature of interaction between magnetic nanoparticles with biomolecule , we had also studied the optical property of the resulting bioconjugate by carrying out the photoluminescence experiment . the photoluminescence pattern obtained for different samples were shown in fig .
, we calculated the binding constant of the magnetic nanoparticles with the bovine serum albumin by using the model put forward by lehrer and fashman . according to this method , the tryptophan residue fluorescence intensity ( f ) scaled with the maghemite / bsa concentration through the following equation : where f0 and f are the relative luminescence intensities of the protein alone and the protein conjugated with maghemite nanoparticles , respectively , n is the stoichiometry of the complex .
the intensity value ( f ) for the tryptophan residue was obtained from the area under the fluorescence spectra in the range of our investigation 300500 nm on calculation , the binding constant of the nanobioconjugate has been found out to be kb = 58.13 . from the figure , it became evident that the emission wavelength of the bare maghemite nanoparticles was 617 nm . while for the standard bsa sample it was found out to be 365.5 nm . for the maghemite / bsa nanobioconjugate colloidal solution
, it had been observed that there was significant shift in the emission wavelength ( 420.5 nm ) .
on the other hand , in case of standard maghemite / bsa mixture the emission wavelength was found out to be 343 nm which was strictly different from that of the optical effect shown by the bioconjugate .
the excitation wavelength applied in all the samples were : ex = 320 nm for bare maghemite nanoparticle , maghemite / bsa nanobioconjuage , & maghemite / bsa mixture.on the other hand , the excitation wavelength applied in case of bsa molecule was ex = 280 nm .
the pattern obtained for bare maghemite nanoparticle was due to the intrinsic property of the electronic transition in iron oxides such as the ligand to metal charge transfer transition .
this intensity was found to be low , due to the fast ( picosec ) overall decay as well as very efficient nonradiative relaxation raised from the dense band structure and a high density of trap states in the iron oxide skeleton as previously reported .
also we had assumed that there will be substantial improvement in pl yield as no quenching phenomenon occurring in pl pattern of the bare nanoparticle . on the other hand ,
the emission of bsa at 365.5 nm was due to luminescence originated from two aromatic tryptophan moieties present in bsa amino acid sequence : trp 134 and trp 214.this was further shifted to 420.5 nm after the formation of bioconjugate .
this shifting might be due to the increase in the nanoparticle size during the synthesis of bioconjuagte . also the produced bsa
np conjugate causes effective interaction between the excited states of the biological and inorganic parts .
this effect should be attributed to the spatial closeness of bsa and np in the tightly bound covalent system .
the photoluminescence spectra ofamaghemite nanoparticlebbsacmaghemite / bsa nanobioconjugatedmaghemite / bsa mixture for finally validating the magnetic properties of ultrafine maghemite nanoparticles before and after conjugation with bovine serum albumin molecule , we studied the same with vibrating sample magnetometer ( vsm ) .
we had mainly done it to ensure the existence of magnetic behavior of maghemite nanoparticle after the conjugation process .
nanoparticles assembly depends sensitively on the morphology and the size of the nanoparticles , where the dipole coupling between the nanoparticles governs the overall magnetic behavior .
in conjugate of maghemite nanoparticles with bsa , we observed a formation of unusual self - alignment of nanoparticles over bsa molecules .
figure 5a , b showed the room temperature magnetization of both maghemite and maghemite / bsa nanobioconjugate .
the bare maghemite nanoparticle had saturation magnetization 1.044 emu / g , whereas that of maghemite / bsa nanobioconjuagte was found to be 1.196 emu / g .
also , the retentivity ( mr ) and coercivity ( hc ) values ( 0.4016 emu / g as well as 25.860 oe , respectively ) of the bioconjugates were different in comparison to maghemite nanoparticles ( mr = 0.2851 emu / g ; hc = 23.083 oe ) .
the difference between these values could be attributed to the change in the microstructure of the particles due to covalent binding of bsa to the carboxyl group of stearic acid capped maghemite nanoparticle and the increase in the interparticle interactions during the bioconjugation process .
this microstructural variation occurred as a result of the drastic change in particle surface effect .
the particle surface effect hereby referred to the disordered alignment of surface atomic spins induced by reduced coordination and broken exchange bonds between surface spin .
the observed induction in saturation magnetization value could also be realized from the increase in the interparticle interactions during the bioconjugation process .
it had also been found out that the obtained saturation magnetization value ( 1.196 emu / g ) of the prepared bioconjuagte was close to the value ( 1.34 emu / g ) obtained by salgueirino - maceira et al . for the luminescent magnetic nanoparticle .
the other hysteretic parameter , the coercivity value , also increased due to the transition of domain boundary to multidomain regime .
in summary , we developed a simple technique for the synthesis of bioconjugate of maghemite nanoparticles with bsa molecule by using the covalent interaction between the fatty acid binding domains of bsa molecule with stearic acid capped nanoparticles .
this will lead to the development of non - toxic iron oxide nanoparticles using bsa as a biocompatible passivating agent .
we confirmed the formation of the same from the ft - ir spectra as well as tem micrograph .
we also established the well retaining of magnetic property of nanoparticles after the formation of bioconjugate from m h study .
it is worth mentioning here that , this is the first report on conjugation of nanoparticles with biomolecules by utilizing biologically evolved linker moiety in covalent fashion .
the designed magnetic bioconjugate seems to be applicable for targeted delivery purpose to a neoplastic cell due to the receptor action of the bsa molecule by binding to a wide variety of lipophilic compounds such as steroid present over cancer cell .
one of the author , pd , gratefully acknowledge the financial support by dae - brns , govt . of india ( vide project
the authors would like to extend sincere thanks to cif , iit guwhati , india and rsic nehu for vsm and tem facility .
Output:
| a novel bioconjugate of stearic acid capped maghemite nanoparticle ( -fe2o3 ) with bovine serum albumin ( bsa ) was developed by taking recourse to the fatty acid binding property of the protein . from ft - ir study
, it was found that conjugation took place covalently between the amine group of protein molecule and carboxyl group of stearic acid capped maghemite nanoparticle .
tem study further signified the morphology of the proposed nanobioconjuagte .
the binding constant of nanoparticle with protein molecule was evaluated from the optical property studies .
also , magnetic measurement ( m h ) showed retaining of magnetic property by significant values of saturation magnetization and other hysteretic parameters . |
PubmedSumm118246 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: vaginal practices ( vps ) include douching with water , detergent , or other substances , using fingers or cloth , and insertion of natural , household , or commercially available products to cleanse , dry , or
vps are commonly performed by women worldwide [ 14 ] and are undertaken for a range of purposes : for hygiene ( particularly during menstruation , prior to or following sex , or during pregnancy ) , for disease or pregnancy prevention , to meet expectations or preferences of sexual partners , or simply to follow traditional norms as learned from mothers or grandmothers in childhood [ 5 , 6 ] .
importantly , vps are frequently reported in areas of high hiv prevalence [ 3 , 4 , 7 , 8 ] .
vps may directly increase hiv risk by causing abrasions in the vaginal epithelium or mucosal inflammation that may lead to recruitment of hiv target cells [ 9 , 10 ] .
vps may also indirectly increase hiv risk by disrupting vaginal flora , leading to bacterial vaginosis ( bv ) ; bv is an established risk factor for hiv acquisition . in some analyses ,
vaginal practices have been directly associated with increased prevalence [ 3 , 8 , 12 ] and incidence of hiv , though other studies report no significant effect of vps on hiv risk [ 14 , 15 ] .
a recent meta - analysis of five longitudinal studies of african women presented a summary unadjusted effect of any kind of intravaginal practices ( including cleansing , drying , and tightening ) on incident hiv .
the authors report some evidence of an increased risk of hiv acquisition due to vaginal practices , but confidence intervals were wide and heterogeneity was high ( summary effect : 2.65 , 95% confidence interval ( ci ) : 0.95 , 7.36 , i 92.0% ) . if vaginal practices are associated with hiv risk , in - depth understanding of these behaviors is critical for the development of effective interventions aimed at changing them .
many previous studies of hiv risk which include vps as an exposure or confounding variable have considered it a single yes / no variable , without further exploration of important nuances in behaviors . using a large - scale ancillary study conducted alongside a prospective assessment of the effect of hormonal contraception on hiv risk , we aimed to evaluate the specific products , methods , and frequency of vaginal practices of hiv - negative zimbabwean women , particularly the timing of vps related to menses , sexual activity , and other behaviors .
we wished to consider changes in vaginal practices that occurred during women 's study participation and to examine whether specific vps were significantly correlated with other reproductive health factors , including condom use , contraception , symptoms of sexually transmitted infections ( stis ) , and laboratory - confirmed stis .
the hormonal contraception and the risk of hiv acquisition ( hc - hiv ) study was a multisite , prospective cohort study assessing the effect of hormonal contraception on hiv acquisition among women in zimbabwe , uganda , and thailand .
the data presented here were collected both through hc - hiv and through an ancillary study that explored in - depth the specific vaginal practices of hiv - negative zimbabwean women who participated in hc - hiv .
the project received ethical review and approval by the protection of human subjects committee at family health international ( durham , nc ) and the medical research council of zimbabwe .
these analyses are restricted to zimbabwean participants in the hc - hiv study who participated in the ancillary vp study .
eligible women were 1835 years of age , hiv - seronegative , sexually active ( three acts in the past three months ) , and using either combined oral contraceptive pills ( cocs ) , injectable depot medroxyprogesterone acetate ( dmpa ) , or a nonhormonal or no contraceptive method .
all zimbabwean participants were recruited from family planning and maternal - child health clinics . at enrollment and each followup visit , women in hc - hiv received structured interviews about their reproductive , contraceptive , and sexual behavior and physical exams with specimen collection .
first , hc - hiv participants were asked quarterly , since your last regular visit , did you ever use anything to dry or tighten your vagina for sex ? and since your last regular visit , did you use anything to clean the inside of your vagina , for instance , when you were bathing ? if women answered affirmatively , they were asked followup questions about the frequency of these behaviors and the products they used .
second , as part of the vp ancillary study , participants completed an additional four - page , interviewer - administered , structured survey that explored vps in greater detail , including timing related to contraception , sex , and menstruation , and the precise form and dose of commercial or traditional cleansing , drying , or tightening products ( survey available upon request ) .
importantly , the ancillary study asked questions about drying separately from tightening ; these concepts were combined in the hc - hiv questionnaire .
statistical analyses were performed using sas ( version 9.2 , sas institute , cary , nc ) .
we restricted the analysis to zimbabwean women who completed at least one followup visit with valid hiv results and provided information about their vaginal practices on the ancillary study questionnaire during at least one followup visit .
we excluded women who did not return to the clinic after enrollment or who never completed the vp ancillary study questionnaire .
because of hc - hiv 's primary aim , women were censored at the visit at which they were found to be hiv - infected .
women were considered hiv - infected if positive on a combination of two enzyme - linked immunosorbent assays ( elisa ) or rapid tests .
positive results were confirmed by western blot or hiv polymerase chain reaction ( pcr ) . at each visit ,
clinicians collected a single endocervical swab for pcr identification of both gonococcal and chlamydial infection ( amplicor ct / ng test , roche diagnostics , somerville , nj , usa ) .
trichomonal infection was diagnosed using wet mount with examination under low ( 10x ) and high ( 40x ) magnification .
we examined univariate and bivariate frequencies of vaginal practices reported by women both during their hc - hiv quarterly visits and on the vp ancillary study questionnaire .
we also ran unadjusted and adjusted multivariable logistic regression models to estimate the associations between various reproductive health factors ( frequency of unprotected sex , contraceptive use , sti symptoms in the last three months , and diagnosed chlamydial , gonococcal , or trichomonal infection at the current visit ) and reported vaginal practices .
we used generalized estimating equations ( gee ) to account for clustering from repeated visits by individual women [ 20 , 21 ] . for each of the three models ,
we adjusted for the reproductive health factors above as well as other fixed and time - varying variables that we hypothesized may be associated with vaginal practices , including age , years of education , cohabitation status , primary partner 's circumcision status , and sexual frequency in a typical month in the last three months .
we did not examine associations between vaginal practices and incident hiv ; a previous analysis of the hc - hiv data reported an adjusted hazard ratio of 0.81 for hiv acquisition ( 95% confidence interval , 0.59 to 1.10 ) for women who reported any vaginal practice in the last three months ( including vaginal drying , tightening , or cleansing ) .
the analysis dataset was comprised of 2,185 women , 95% of the 2,296 zimbabwean women enrolled in the parent hc - hiv study .
longitudinal analyses included 14,154 followup visits and 3,569 person - years ( pys ) of followup time .
the median number of visits per participant was 8 ( range : 2 to 11 ) and median followup time per participant was 21.4 months ( range : 1.9 to 42.7 months ) .
overall , participants ' median age at baseline was 26 years ( interquartile range ( iqr ) : 22 to 29 years ) , and they had a median of 11 years of education ( iqr : 911 ) ( table 1 ) .
women 's median sexual frequency was 14 acts per month ( iqr : 822 acts ) , and the median number of sex partners in the past three months was 1 ( iqr : 1 - 1 partners ) . almost all participants ( 93% ) were cohabitating with a husband or a boyfriend ( table 1 ) .
two - thirds of participants ( 66% ) reported any vp at baseline , including vaginal cleansing , drying , or tightening .
we observed few demographic differences between women engaging in vps and women who did not at baseline ( table 1 ) : cohabitation status , history of commercial sex , age , education , and sexual behaviors were similar between the two groups .
women who reported no vps in the previous three months were somewhat more likely to be users of combined oral contraceptives ( 41% versus 36% of women who did report vps at baseline ) . in the quarterly hc - hiv interviews , 1917 women ( 88% of participants ) reported at 10,402 followup visits ( 74% of visits ) that they ever cleaned inside the vagina in the last three months .
participants reported cleansing a median of 60 times per month ( iqr : 3060 times ) , the equivalent of roughly twice per day .
women reported at fewer visits ( n = 3,178 , 22% of visits ) that they had used something to dry or tighten the vagina ; 924 women ( 42% of participants ) ever gave this response during followup .
the frequency of drying / tightening ( among women reporting this behavior ) was also less than for cleansing : among those participants reporting drying or tightening , women dried or tightened the vagina a median of 20 times in the last month ( iqr : 630 times ) , less than once per day on average .
agreement on reported vaginal cleansing between the quarterly hc - hiv surveys and the vp ancillary study was good . in response to the general question for the ancillary study , do you wash inside your vagina ? 1,933 women ( 88% of participants ) reported cleansing inside the vagina at 10,598 followup visits ( 75% of all followup visits ) .
the majority had last cleansed on the same day as the visit ( 89% ) or one day previously ( 4% ) .
products used for cleansing included plain water only ( 86% of visits where cleansing was reported ) and water with soap ( 13% of visits ) .
women reported using disinfectants such as dettol ( a liquid , phenol - based household antiseptic product ) or betadine at 66 visits ( < 1% of visits where cleansing was reported ) .
cleansing with salt solution , vinegar , or lemon juice was very rare , reported at 18 , 3 , and 2 visits , respectively . the vp ancillary questionnaire next asked women about products they may have inserted into the vagina during menstruation in a typical month .
thirty - three percent of participants ( n = 723 ) ever reported inserting products during menstruation during the followup period .
insertion of products during menstruation was reported at 2,026 followup visits ( 14% ) , with the majority inserting cotton wool
. the ancillary study also explored practices related to vaginal drying . at 41% of followup visits ,
1,459 individual women ( 67% of participants ) reported that they used a towel , cloth , paper or , cotton wool to dry the vagina . at more than half of these visits ( 57% ) ,
the last time women dried the vagina was the same day as the visit , with an additional 17% last drying the vagina during the previous day .
most women reported moving their fingers in their vagina with the drying product ( 63% of visits where vaginal drying was reported ) . the median duration of time that the drying product was left in the vagina after insertion was 3 minutes ( iqr : 130 minutes ) .
the ancillary study survey further questioned women about products they may have inserted to tighten the vagina .
n = 272 ) ever answered yes to the general question , do you insert anything to tighten your vagina ? during followup .
most women who reported inserting products for vaginal tightening had last done so recently : 20% on the same day as the visit , 20% the day before the visit , and 34% between 2 and 7 days before the visit .
the median time that tightening products were left in the vagina was 75 minutes ( iqr : 30180 minutes ) .
women reported at 20 visits ( 3% of visits where tightening was reported ) that they left the product in place during sex .
the specific products which women inserted to tighten the vagina were extremely varied ( table 2 ) .
the most common included cloth ( 28% of visits where vaginal tightening was reported ) , lemon or lemon juice ( 21% ) , cotton wool ( 20% ) , natural substances including herbs , powders , and roots ( 16% ) , water ( 14% ) , and salt or salt solution ( 7% ) ( table 2 ) .
however , cloth and/or cotton wool were sometimes used in conjunction with lemon / lemon juice ( 38 of 120 reports of lemon juice also included use of cloth or cotton wool ) , salt / salt solution ( 12 of 40 reports of salt / salt solution also included cloth or cotton wool ) , and oil ( 5 of 14 reports of oil also included use of cloth or cotton wool ) .
we next explored whether women 's vaginal practices changed over time ( figure 1 ) .
cleansing , drying , and tightening behaviors reported during the vp ancillary study were fairly constant over the followup period , with the proportion reporting cleansing hovering around 75% , the proportion reporting drying fluctuating around 40% , and the proportion reporting tightening remaining around 4% ( figure 1 ) . among those reporting cleansing , the proportion that used water only and the proportion that used water with soap was also remarkably consistent over time ( figure 2 ) .
finally , we evaluated whether reported vaginal cleansing , drying , or tightening were associated with ( a ) the number of unprotected sex acts ( i.e. , sex acts where condoms were not used ) in a typical month in the last three months ; ( b ) current contraceptive use ( nonhormonal methods , cocs or dmpa ) ; ( c ) sti symptoms ( a composite variable capturing any vaginal discharge , genital itching , abdominal pain , pain during sex , and/or irregular bleeding in the last three months ) ; or ( d ) diagnosed sti ( laboratory - confirmed chlamydial , gonococcal , or trichomonal infection ) ( table 3 ) . in unadjusted analyses ,
women who reported at least 15 unprotected acts in a typical month in the last three months , compared to those reporting fewer than five unprotected acts , had higher odds of reporting vaginal cleansing ( or : 1.17 , 95% ci : 1.07 , 1.29 ) and vaginal drying ( or : 1.10 , 95% ci 1.00 , 1.20 ) .
coc users , compared to users of nonhormonal contraceptive methods , had higher odds of vaginal cleansing ( or : 1.22 , 95% ci : 1.07 , 1.40 ) , though contraceptive group was not significantly associated with odds of drying or tightening .
women who had sti symptoms in the last three months had significantly higher odds of reporting vaginal cleansing ( or : 1.13 , 95% ci : 1.04 , 1.23 ) and drying ( or : 1.09 , 95% ci : 1.00 , 1.19 ) , but not tightening .
finally , women with laboratory - confirmed chlamydial , gonococcal , or trichomonal infection did not have higher odds of vaginal cleansing or drying , but they did have increased odds of reporting vaginal tightening ( or : 1.42 , 95% ci : 1.07 , 1.88 ) . aside from slight reductions in precision ,
estimates changed very little following adjustment for fixed and time - varying covariables including age , years of education , cohabitation status , partner circumcision status , contraception , sexual frequency in a typical month in the last three months , sti symptoms in the last three months , and diagnosed sti at the current visit ( table 3 ) .
nearly 9 out of every 10 women in this sample of hiv - negative zimbabwean women reported vaginal cleansing ; about two - thirds reported vaginal drying and a smaller proportion , 12% , reported inserting products to tighten the vagina .
these frequencies are similar to behaviors reported in a cross - sectional evaluation of a cohort of south african women participating in a randomized trial for cervical cancer screening . in that study , all women reported some type of intravaginal practice , with 86% of women inserting water and much lower proportions inserting soap ( 18% ) , household antiseptics ( 12% ) , industrial detergents ( 5% ) , vinegar ( 4% ) , and salt water ( 2% ) .
vaginal practices in a prospective cohort of kenyan sex workers were also frequent , with 71% reporting using soap or other detergent / antiseptic substances for vaginal cleansing at baseline and 23% reporting vaginal cleansing with water only . in the methods for improving reproductive health in africa ( mira ) hiv prevention trial ,
vaginal practices were commonly reported at baseline by general population women in zimbabwe and south africa ; at enrollment , 83% of participants reported vaginal washing , 56% reported wiping out the vagina , and 21% reported inserting dry or absorbent materials into the vagina . reported vaginal practices were remarkably consistent over the followup period . at each visit
, clinicians briefly counseled women against using abrasive drying and tightening agents like powders and herbs ; some also instructed women not to cleanse inside the vagina using their fingers .
given the stability of reported behaviors , clinician counseling apparently had little impact on women 's decisions regarding vaginal practices .
several recent candidate vaginal microbicide trials instructed participants to abstain from cleansing and other vaginal practices during trial participation . whether women heeded this advice more frequently in those trials compared to this study
is not known , but frequent vaginal practices such as those reported in this population could affect microbicide retention in the vagina and consequent disease - prevention efficacy .
the adjusted results from multivariable models indicate that women with a higher absolute number of unprotected acts had higher odds of engaging in vaginal cleansing .
in addition , those with recent sti symptoms had higher odds of both cleansing and drying .
clean for themselves and their partners , and the presence of seminal fluid following sex may lead them to cleanse more than women who have sex less often . if they believe that cleansing provides protection from disease acquisition , they may also cleanse as a preemptive prevention measure or cure .
additionally , women with sti symptoms ( including bleeding , discharge , itching , and pain ) may be more likely to engage in more frequent vaginal cleansing and drying to relieve discomfort .
the associations between sti symptoms and both vaginal cleansing and vaginal drying persisted after adjustment for contraceptive use and other variables , suggesting that the increased vaginal bleeding sometimes associated with dmpa did not confound these associations .
the finding that women with laboratory - diagnosed sti had higher odds of vaginal tightening ( but not cleansing or drying ) bears further study , particularly in the very small group of women who reported leaving tightening products in the vagina during sex .
the temporal association of these variables that is , whether tightening increased susceptibility to sti , or whether prevalent sti led women to engage in tightening practices is not known because both of these measures were collected at the same time point .
women in our trial who reported inserting products to tighten the vagina used a range of kitchen , household , and traditional substances , including cotton wool , lemon juice , cloth , herbs , powder , roots , salt , disinfectant , oil , vicks , sugar , vinegar , baking soda , ice , and toothpaste .
these findings agree with several previous studies which investigated the prevalence and type of vaginal practices by women worldwide [ 2329 ] .
one of the most recent and comprehensive was a large qualitative study that conducted individual interviews with men and women in indonesia , mozambique , south africa , and thailand .
like the practices of participants in our analyses , women in these countries also reported using a range of substances for various cleansing , drying , and tightening functions , including traditional formulations of herbs , leaves , and bark , food ingredients ( lemon juice , vinegar ) , and commercially available products such as douching solutions , soaps and detergents , and vaginal creams .
the primary limitation of these analyses is that our vaginal practices assessment , like most measurements in sexual health , is self - reported and subject to courtesy and recall biases . in addition , as mentioned above , although the data were collected longitudinally , the interval between visits was long enough that it was not possible in multivariable models to assess the temporal association between various reproductive health factors and vaginal practices ; for example , it is not clear from our analysis whether sti symptoms preceded or followed vaginal drying . as such , our measures of effect should be interpreted as correlations only and without an inference of causality .
while these limitations must be noted , we believe our analyses make an important contribution to the literature on vaginal practices among african women due to the large size of our study , the comprehensive set of measures we captured on many aspects of vaginal practices , and the ability to adjust for many potential confounding factors collected as part of the parent hc - hiv study .
in this zimbabwean population , vaginal cleansing was commonly reported , whereas vaginal drying was less frequent and vaginal tightening was rare . because certain vaginal practices were associated with other hiv risk factors , synergism between vps and other risk factors for hiv / sti
Output:
| background . vaginal practices ( vps ) may increase hiv risk by injuring vaginal epithelium or by increasing risk of bacterial vaginosis , an established risk factor for hiv .
methods .
hiv - negative zimbabwean women ( n = 2,185 ) participating in a prospective study on hormonal contraception and hiv risk completed an ancillary questionnaire capturing detailed vp data at quarterly followup visits for two years . results .
most participants ( 84% ) reported ever cleansing inside the vagina , and at 40% of visits women reported drying the vagina using cloth or paper .
vaginal tightening using cloth / cotton wool , lemon juice , traditional herbs / powders , or other products was reported at 4% of visits .
women with 15 unprotected sex acts monthly had higher odds of cleansing ( adjusted odds ratio ( aor ) : 1.17 , 95% ci : 1.041.32 ) .
women with sexually transmitted infections had higher odds of tightening ( aor : 1.42 , 95% ci : 1.081.86 ) . conclusion . because certain vaginal practices were associated with other hiv risk factors , synergism between vps and other risk factors should be explored . |
PubmedSumm118247 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: parkinson disease ( pd ) is one of the most frequently seen neurodegenerative disorders affecting more than six million people worldwide .
although pd is primarily a movement disorder and its effects are prominent on neuromuscular system , cardiovascular disorders have also been widely investigated considering the risk of development of heart valve disease and heart failure especially in the patients using ergot - derived dopamine agonists ( edda). on the other hand , the corner stone therapy in pd , levodopa ( l - dopa ) , has been shown to increase serum homocysteine levels . , homocysteine is a well - established risk factor for cardiovascular disorders
. therefore , management of pd with l - dopa may render patients at increased risk of atherosclerosis and coronary artery disease . however , the knowledge about the association between use of l - dopa , homocystein levels and atherosclerotic disorders is quite limited .
the available data points an increased risk of vascular disease and this topic needs further evaluation .
propagation features of the pressure wave along the arterial tree reflect the intrinsic elasticity of the arterial wall .
the elastic properties of the vessels and especially the aorta are good predictors of adverse cardiovascular outcomes across many different patient groups as well as in the general population . beside being an index of total mortality ,
aortic stiffness is also an important determinant for vascular diseases including cardiac failure , myocardial infarction , renal disease and stroke. since the patients with pd are exposed to high doses of l - dopa which lead to an increase in serum homocystein levels , these patients are expected to have an increased cardiovascular risk .
herein , we designed this study to evaluate the cardiovascular risk profile of the patients with pd who are under l - dopa treatment by using aortic elastic parameters .
this study was designed with the collaboration of the cardiology clinic and movement disorders department of neurology clinic in ordu university .
the study population consisted of 65 patients with idiopathic pd who registered at our movement disorders outpatient clinic between june 2013 and january 2015 .
uncooperative patients and the subjects who did not want to participate were excluded from the study . also the patients with hypertension ,
diabetes mellitus , coronary artery disease , heart failure , chronic obstructive pulmonary disease , chronic kidney disease , atrial fibrillation , pacemaker or implantable cardioverter defibrillator , collagen vascular diseases , rheumatic heart valve disease , and heart valve prosthesis were excluded from the study in order to eliminate their effect on aortic stiffness .
all patients in this study were using only l - dopa / dopa decarboxylase inhibitor ( ddci ) .
use of an anti - parkinson drug except l - dopa / ddci was the other exclusion criteria .
the diagnosis of pd was confirmed by movement disorders specialists in neurology clinic , according to the uk parkinson 's disease society brain bank criteria .
, the severity of neurological impairment was assessed with the unified parkinson 's disease rating scale ( updrs scale , ranging from 0 to 147 ) and the hoehn - yahr scale ( hy scale , ranging from 0 to 5 ) .
, the control group included 32 age and gender matched individuals who had no cognitive decline .
baseline characteristics , echocardiographic measurements , serum homocysteine levels and elastic parameters of the aorta were compared between the patients with pd and controls .
all patients and their carers read the information sheet provided before giving verbal and written consent to participate in the study .
echocardiographic evaluation was performed in our cardiology department via a commercially available device ( philips , ie33 , xmatrix ultrasound , andover , usa ) using a 2.53.5 mhz transducer in the lateral decubitis position according to american society of echocardiography guidelines , with a simultaneously recorded electrocardiogram .
left ventricle end - systolic diameter , left ventricle end - diastolic diameter , posterior wall and interventricular septum thickness were measured on the m - mode tracing at the papillary muscle level in the parasternal long axis view while left atrium diameter and aortic diameter were measured at the level of sinus valsalva .
transmitral flow samples were obtained by placing the sample volume of posterior wall doppler to the edges of mitral leaflets in the apical four - chamber view .
mitral e , a waves , e / a ratio , isovolumetric relaxation time and dt were calculated from these tracings .
then , again in the apical four - chamber view , after appropriate gain settings were adjusted , lateral diastolic velocities ( lateral ea ) were measured by tissue doppler imaging .
the cursor was placed in tricuspid valve lateral ring in the standard apical four chamber view for measurements of tricuspid annular plane systolic displacement ( tapse ) in the m - mode tracing .
the scanning speed was kept as 75100 m / s in order to reduce the margin of error .
the diameter of the ascending aorta was measured in the parasternal long axis view by the m - mode tracing at a level of 3 cm above the aortic valve .
the systolic aortic diameter ( aos ) was measured at the maximal anterior motion of the aorta , while the diastolic aortic diameter ( aod ) was measured at the peak of the qrs complex on the simultaneously recorded electrocardiogram .
aortic elasticity parameters were calculated according to the following formulas : aortic strain = ( aosaod)/aod aortic stiffness ( ) index = ln ( systolic blood pressure / diastolic blood pressure)/aortic strain aortic distensibility = 2 aortic strain / pulse pressure analyses were performed using the statistical package for social science program ( spss for windows , version 16.0 ) .
comparisons between patients were made by using student 's independent t - test for normally distributed data and the mann - whitney u test for non - normal distributed data .
the data were expressed as the mean sd for normally distributed variables and as median ( minimum maximum ) for non - normally distributed variables .
pearson correlation coefficient was used to measure of the strength of the association between homocystein levels , aortic distensibility and aortic stiffness .
this study was designed with the collaboration of the cardiology clinic and movement disorders department of neurology clinic in ordu university .
the study population consisted of 65 patients with idiopathic pd who registered at our movement disorders outpatient clinic between june 2013 and january 2015 .
uncooperative patients and the subjects who did not want to participate were excluded from the study . also the patients with hypertension ,
diabetes mellitus , coronary artery disease , heart failure , chronic obstructive pulmonary disease , chronic kidney disease , atrial fibrillation , pacemaker or implantable cardioverter defibrillator , collagen vascular diseases , rheumatic heart valve disease , and heart valve prosthesis were excluded from the study in order to eliminate their effect on aortic stiffness .
all patients in this study were using only l - dopa / dopa decarboxylase inhibitor ( ddci ) .
use of an anti - parkinson drug except l - dopa / ddci was the other exclusion criteria .
the diagnosis of pd was confirmed by movement disorders specialists in neurology clinic , according to the uk parkinson 's disease society brain bank criteria .
, the severity of neurological impairment was assessed with the unified parkinson 's disease rating scale ( updrs scale , ranging from 0 to 147 ) and the hoehn - yahr scale ( hy scale , ranging from 0 to 5 ) .
, the control group included 32 age and gender matched individuals who had no cognitive decline .
baseline characteristics , echocardiographic measurements , serum homocysteine levels and elastic parameters of the aorta were compared between the patients with pd and controls .
all patients and their carers read the information sheet provided before giving verbal and written consent to participate in the study .
echocardiographic evaluation was performed in our cardiology department via a commercially available device ( philips , ie33 , xmatrix ultrasound , andover , usa ) using a 2.53.5 mhz transducer in the lateral decubitis position according to american society of echocardiography guidelines , with a simultaneously recorded electrocardiogram .
left ventricle end - systolic diameter , left ventricle end - diastolic diameter , posterior wall and interventricular septum thickness were measured on the m - mode tracing at the papillary muscle level in the parasternal long axis view while left atrium diameter and aortic diameter were measured at the level of sinus valsalva .
transmitral flow samples were obtained by placing the sample volume of posterior wall doppler to the edges of mitral leaflets in the apical four - chamber view .
mitral e , a waves , e / a ratio , isovolumetric relaxation time and dt were calculated from these tracings .
then , again in the apical four - chamber view , after appropriate gain settings were adjusted , lateral diastolic velocities ( lateral ea ) were measured by tissue doppler imaging . the cursor was placed in tricuspid valve lateral ring in the standard apical four chamber view for measurements of tricuspid annular plane systolic displacement ( tapse ) in the m - mode tracing .
the scanning speed was kept as 75100 m / s in order to reduce the margin of error .
the diameter of the ascending aorta was measured in the parasternal long axis view by the m - mode tracing at a level of 3 cm above the aortic valve .
the systolic aortic diameter ( aos ) was measured at the maximal anterior motion of the aorta , while the diastolic aortic diameter ( aod ) was measured at the peak of the qrs complex on the simultaneously recorded electrocardiogram .
aortic elasticity parameters were calculated according to the following formulas : aortic strain = ( aosaod)/aod aortic stiffness ( ) index = ln ( systolic blood pressure / diastolic blood pressure)/aortic strain aortic distensibility = 2 aortic strain / pulse pressure
analyses were performed using the statistical package for social science program ( spss for windows , version 16.0 ) .
comparisons between patients were made by using student 's independent t - test for normally distributed data and the mann - whitney u test for non - normal distributed data .
the data were expressed as the mean sd for normally distributed variables and as median ( minimum maximum ) for non - normally distributed variables .
pearson correlation coefficient was used to measure of the strength of the association between homocystein levels , aortic distensibility and aortic stiffness .
the mean age in the parkinson group was 70 9 years while it was 69 8 years in controls ( table 1 ) .
comparision of the baseline characteristics between the patients with pd and controls is given in table 2 .
there was no statistically significant difference between two groups in terms of smoking status , family history , body mass index ( bmi ) , high density lipoprotein cholesterol ( hdl - c ) and triglyceride levels ( p > 0.05 ) .
additional systolic blood pressure and heart rate did not differ significantly between the two groups ( p > 0.05 ) .
the parkinson group had significantly higher levels of low density lipoprotein cholesterol ( ldl - c ) as well as higher diastolic blood pressure ( p = 0.023 and p = 0.032 , respectively ) .
on the other hand , pulse pressure was significantly lower in parkinson group compared to controls ( p = 0.021 ) .
as an expected feature of l - dopa therapy , the parkinson group had significantly higher homocystein levels ( 15.1 3.9 mol
both parkinson and control groups had similar left ventricular ejection fraction , left ventricular end diastolic diameter , left ventricular end systolic diameter , left atrial diameter , left ventricular mass index , interventricular and posterior wall thickness ( p > 0.05 ) .
right ventricular function was also similar since tapse and estimated pulmonary artery systolic pressure values did not differ between the two groups ( p > 0.05 ) . beside
preserved systolic function in both parkinson and control groups , the prevalence of diastolic dysfunction was significantly higher in the patients with pd .
tissue doppler measurements revealed lower ea and higher e / ea values in the parkinson group ( 9.2 0.6 cm / s vs. 12.1 0.9 cm / s and 9.5 1.2 cm / s vs. 7.8 1.1 cm / s , p = 0.01 and p = 0.01 , respectively ) .
data are expressed as n ( % ) or mean sd ( min - max ) .
hys : hoehn - yahr scale ; pd : parkinson disease ; updrs : unified parkinson 's disease rating scale .
data are expressed as n ( % ) , mean sd , or median ( interquartile range ) .
bmi : body mass index ; dbp : diastolic blood pressure ; hdl - c : high density lipoprotein cholesterol ; hr : heart rate ; ldl - c : low density lipoprotein cholesterol ; sbp : systolic blood pressure .
when elastic parameters of the aorta were evaluated , aortic distensibility was significantly lower in patients with pd when compared to controls ( 6.2 1.9 dyn / cm
vs. 4.8 1.5 dyn / cm , p = 0.016 ) .
additionally , the patients with pd had higher aortic strain and aortic stiffness index ( 13.4% 6.4% vs. 7.4% 3.6% , p < 0.001 and 7.3 1.5 vs. 4.9 1.9 , p < 0.001 , respectively ) ( table 4 ) .
furthermore , serum homocysteine levels were found to be positively correlated with aortic stiffness index and there was a negative correlation between aortic distensibility and levels of serum homocysteine ( r = 0.67 , p < 0.001 , r = 0.60 , p < 0.001 , respectively ) .
data are expressed as mean sd . a : mitral late - diastolic velocity ; aa : late diastolic velocity of mitral annulus ; dt : decelaration time ; e : mitral early - diastolic velocity ; ea : early diastolic velocity of mitral annulus ; ef : ejection fraction ; epasp : estimated pulmonary artery systolic pressure ; ivrt : isovolumetric relaxation time ; ivs : interventricular septum ; la : left atrium ; lvedd : left ventricular end diastolic diameter ; lvesd : left ventricular end systolic diameter ; lvmi : left ventricular mass index ; pw : posterior wall ; tapse : tricuspid annular plane systolic displacement .
the results of our study demonstrated that the patients with pd under l - dopa therapy have impaired aortic elasticity and diastolic function .
elevated serum homocystein levels in this patient population was also another noteworthy finding of our study .
it can be hypothesized that increased aortic stiffness and impaired diastolic function may be secondary to elevated homocysteine levels .
pd is a neurodegenerative disorder and commonly seen in elder population. coronary heart disease also affects individuals in the same decades .
liang , et al . demonstrated a high risk of myocardial infarction in patients with pd when compared to healthy subjects .
another study found that pd was associated with an increased risk of ischemic heart disease
although these two studies revealed the fact that myocardial infarction and death secondary to ischemia are common in patients with pd , the underlying mechanism of this process has not been clearly identified . , orthostatic hypotension , oxidative stress and inflammation are thought to be the underlying mechanisms in the studies revealing increased frequency of coronary heart disease and mortality in patients with pd .
, oxidative stress and inflamation cause atherosclerosis secondary to endothelial dysfunction . on the other hand , ortostatic hypotension results in cardiac sympathetic denervation , extracardiac noradrenergic denervation , and baroreflex failure leading to
decreased diastolic perfusion pressure on myocardial blood flow., homocysteine has been identified as a risk factor for atherosclerotic vascular disease and hypercoagulability states since 1990 .
it is a sulphur - containing aminoacid and produced in the metabolism of the essential aminoacid methionine .
, , coagulation cascade activation , production of inflammatory mediators , ros generation and endothelial dysfunction have been proposed to explain the link between hyperhomocysteinemia and coronary artery disease .
the sulfhydryl group of homocysteine has redox potential and causes formation of reactive oxygen species resulting in substantial impairment of endothelial function and subsequent atherosclerosis .
, randomized and prospective studies have also demonstrated the association between hyperhomocysteinemia and increased aortic stifness as well as adverse cardiovascular events . , a moderately elevated homocysteine level indicates high risk of cvd ( coronary , heart , cerebrovascular and peripheral artery diseases ) .
, however , to settle the pure clinical effects of pd is tough since the anti - parkinson drugs have already been shown to have substantial effects on cardiovascular system .
the overlooked feature in pd is elevation of serum homocysteine levels resulting from use of l - dopa .
although its initial impressive therapeutic efficacy within a few years is typically interrupted due to development of motor complications such as fluctuations or abnormal movements and other neurological problems , l - dopa remains to be the first - line and gold - standard therapy in pd .
the pathophysiological mechanism is that o - methylation of l - dopa to 3-o - methyldopa is associated with conversion of s - adenosylmethionine to s - adenosylhomocysteine and subsequently homocysteine .
, , the knowledge about l - dopa therapy and homocysteine makes us speculate an increased risk of cardiovascular disorders in patients with pd under l - dopa treatment .
our study results demonstrated that patients with pd under l - dopa treatment had increased aortic stiffness .
the other prominent finding of our study was deterioration of diastolic function in patients with pd .
, also , in our study , elevated homocysteine levels may be the reason of impaired diastolic function .
consequently , we hypothesize that increased aortic stiffness and impaired diastolic function in patients with pd under l - dopa treatment may be secondary to elevated serum homocysteine levels
. lack of a more sophisticated method in assessment of aortic elastic parameters is a limitation of this study as we do not own the required equipment for oscillometric and tonometric measurement of arterial stiffness .
besides , evaluation of aortic stiffness through echocardiographic measurements is a well - established and commonly used method . on the other hand , in addition to increased aortic stiffness , high frequency of diastolic dysfunction was another indicator of increased cardiovascular risk in the parkinson group .
since pd patients were free of hypertension , use of l - dopa can be the reason for impaired diastolic function .
furthermore , the number of patients was relatively small and this cross - sectional study was not designed to establish causal relationship , which should be confirmed by longitudinal and interventional studies .
patients with pd under l - dopa treatment have increased aortic stiffness and impaired diastolic function compared to healthy individuals . elevated serum homocysteine levels may have played a role in the pathophysiological mechanism .
considering the cross - sectional design of the present study , the contributions of serum homocysteine measurement in impaired aortic elasticity and diastolic function in patients with pd under l - dopa treatment requires further investigation by prospective , interventional studies .
lack of a more sophisticated method in assessment of aortic elastic parameters is a limitation of this study as we do not own the required equipment for oscillometric and tonometric measurement of arterial stiffness . besides , evaluation of aortic stiffness through echocardiographic measurements is a well - established and commonly used method . on the other hand ,
in addition to increased aortic stiffness , high frequency of diastolic dysfunction was another indicator of increased cardiovascular risk in the parkinson group .
since pd patients were free of hypertension , use of l - dopa can be the reason for impaired diastolic function .
furthermore , the number of patients was relatively small and this cross - sectional study was not designed to establish causal relationship , which should be confirmed by longitudinal and interventional studies .
patients with pd under l - dopa treatment have increased aortic stiffness and impaired diastolic function compared to healthy individuals . elevated serum homocysteine levels may have played a role in the pathophysiological mechanism . considering the cross - sectional design of the present study , the contributions of serum homocysteine measurement in impaired aortic elasticity and diastolic function in patients with pd under l - dopa treatment requires further investigation by prospective , interventional studies .
Output:
| backgroundlevodopa is the indispensable choice of medial therapy in patients with parkinson disease ( pd ) .
since l - dopa treatment was shown to increase serum homocysteine levels , a well - known risk factor for cardiovascular disorders , the patients with pd under l - dopa treatment will be at increased risk for future cardiovascular events .
the objective of this study is to evaluate cardiovascular risk in patients with pd under levodopa treatment.methodsthe study population consisted of 65 patients with idiopathic pd under l - dopa treatment .
the control group included 32 age and gender matched individuals who had no cognitive decline .
echocardiographic measurements , serum homocysteine levels and elastic parameters of the aorta were compared between the patients with pd and controls.resultsas an expected feature of l - dopa therapy , the parkinson group had significantly higher homocystein levels ( 15.1 3.9 mol / l vs. 11.5
3.2 mol / l , p = 0.02 ) .
aortic distensibility was significantly lower in the patients with pd when compared to controls ( 4.8 1.5 dyn / cm2
vs. 6.2
1.9 dyn / cm2 , p = 0.016 ) . additionally , the patients with pd had higher aortic strain and aortic stiffness index ( 13.4% 6.4% vs. 7.4% 3.6% ,
p < 0.001 and 7.3 1.5 vs. 4.9 1.9 , p < 0.001 respectively ) .
furthermore , serum homocysteine levels were found to be positively correlated with aortic stiffness index and there was a negative correlation between aortic distensibility and levels of serum homocysteine ( r = 0.674 , p < 0.001 ; r = 0.602 , p < 0.001 , respectively).conclusionsthe patients with pd under l - dopa treatment have increased aortic stiffness and impaired diastolic function compared to healthy individuals .
elevated serum homocysteine levels may be a possible pathophysiological mechanism . |
PubmedSumm118248 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: musculoskeletal maladaptation in infants is defined as the failure of the motor system to respond , or to respond aberrantly to appropriate sensory stimuli due to biomechanical fault ( 1,2 ) .
normal response patterns are generated when the musculoskeletal system responds appropriately to the central nervous system , which mediates sensorimotor integration of the environment as well as physiological demands .
when the musculoskeletal system can not respond to normal signals due to biomechanical compromise , the infant 's response to signals may be inappropriate , inefficient , ineffective or aberrant .
these responses become characterised as functional problems of infancy and most commonly include excessive crying , inefficient sleep habits and sometimes ineffective feeding ( 3 ) .
musculoskeletal pain is the most common reason for the referral of children to rheumatologists ( 4 ) .
investigators suggested that spinally mediated reflexes caused by tactile stimulation causing pain sensations are heightened in neonates due to lower thresholds ( 5 ) . behavioral reaction to pain
is often used to evaluate the infant 's discomfort , however it can not be considered accurate primarily because facial reactions develop slowly , advancing over time and age .
therefore , neonate and young infants may demonstrate a reduced physical reaction to pain , despite having an exaggerated physiological response ( 5 ) .
infant pain is a specialised topic because infants are pre - verbal and because of clinical difficulty in assessing and measuring pain and acknowledging that infants experience pain without apparent or obvious injury ( 6 ) .
even physiological measurements such as heart , respiratory rates and blood pressure may not be useful in this age group , particularly in persistent pain or discomfort ( 7 ) .
observation of infant behaviors of facial expression , crying , body movements , sleep patterns and inconsolability have been found useful but may also be indicative of a stress response and not of pain .
understanding of infant pain is limited in part due to ethical issues that limit invasive investigations in children ( 8) , and prohibit study of the above concepts in human infants . the present review aimed to enlighten the management avenues available for the above chronic problem of young infants .
it has been suggested that infant colic can be treated by changes in feeding and is influenced by cow milk protein intolerance ( cmpi ) ( 9 ) . as such , there are cases of excessive crying that are indeed caused by an allergy or sensitivity to cow milk .
however , if that is the case , the aetiology and treatment are simple and clear , i.e. , remove the offending substance ( from the mother 's diet ) or , if formula fed , switch the child to a hydrolysed formula or an amino acid formula in order that the offending milk protein can not cause the irritation ( 10 ) .
however , if the cause and treatment are simple and clear , then the child 's affliction can be easily diagnosed as cmpi and , therefore , is not colic or inconsolable crying of infancy ( 11 ) .
further dietary changes , such as increased fibre or lactase , are not considered useful ( 12 ) .
although 70% of the adult population has primary lactase deficiency , this generally first occurs at the age of 56 years and is extremely unlikely in infancy ( 13 ) .
although dietary interventions such as the introduction of lactase are attempted , there is little evidence that any formulations have indicated any long - term positive effect on the condition ( 14 ) .
it is widely agreed that there is no association between method ( breast or bottle ) of feeding and infant colic ( 15 ) .
children with excessive crying should undergo complete assessment to be certain there is no disease process causing the problem .
however , since evidence indicates that < 5% have a medical problem that precipitates the crying ( 16 ) , this creates ambiguity , with an excessively crying infant , fearful parents , and an insufficient medical diagnosis .
the inconsolable crying starts at 814 days of age ( 17 ) and episodes of crying are most common at the end of the day ( 18 ) .
excessive crying was originally defined as that which lasted > 3 h / day , > 3 days / week for > 3 weeks .
diagnoses based on time of crying have little utility and more modern definitions accept that parents can report accurately whether or not their child suffers from colic , and this is known as the mother 's diagnosis ( 19 ) .
however , whether these are actual features of the disorder or of other aetiologies ( such as general pain ) remains to be clarified .
different types of therapy have been utilized to relieve this serious issue of musculoskeletal dysfunction including hospitalization , pharmacology , behavioral interventions , homeopathy , naturopathic interventions , herbal formulation , dietary interventions and manual medicine . however , those modalities resulted in expense but little relief for the families ( 20 ) .
although 1 of 6 children present to the hospital with a severe crying episode , hospitalization is not considered appropriate and may even lead to harmful or unnecessary interventions ( 21 ) .
similarly , pharmacological treatments , such as dicyclomine ( an anticholinergic drug ) are considered harmful ( 22 ) , with severe adverse effects including respiratory difficulties , seizure and death .
consequently this drug has been removed from the repertoire of treatments prior to 6 months of age .
the most common allopathic medication administered , simethicone , has been shown in three double - blind studies to have no effect ( 22 ) .
other medications , including gaviscon , proton - pump inhibitors and acid suppressants , routinely prescribed for gastroesophageal reflux disease are commonly given to this age group for excessive crying despite lack of evidence to support their use ( 23 ) .
emerging evidence suggests that probiotics used to modulate microbiotic intestinal flora in the child may be useful
. however , additional investigations are necessary to determine its actual efficacy in the pain syndrome of excessive crying ( 24 ) and for general health .
other ingested therapeutics such as herbal medicine , homeopathy , botanical supplements and teas have been subjected to few trials and have produced mixed results , raising concerns with regard to adverse effects ( 25 ) .
a wide variety of behavioral interventions including car ride simulation , enhanced carrying , uniform daily care and swaddling ( 27 ) have been investigated with insufficient evidence to recommend .
on the other hand , chiropractic manual therapy in the treatment of infant colic has shown some promise ( 28 ) .
additionally , there may be some , albeit limited , evidence for the use of massage in the first 6 months ( 29 ) .
the first time that manual medicine was reported as a treatment for infant colic was by still in 1910 ( 30 ) . since then , parents have preferred chiropractic care in increasing numbers ( 31 ) . although positive results from the manual treatment of infant colic have been reported , the exact mechanism responsible for such results remains to be elucidated ( 32 ) .
there is a potentially plausible biological mechanism by which chiropractic ( manual ) therapy may be successful .
it is known that pain sensations occur in infants and that the sensory system is intact well before birth and increases in ability to process sensations shortly after birth ( 33 ) .
pain sensations are most likely amplified in the extremely young ages and this affects short - term ( 8) and long - term functional movement patterns ( 34 ) . if the infant is subject to tense muscles and imbalances in the spine and ligaments , it is reasonable to postulate that chiropractic manual therapy may alleviate the imbalance , restore normal musculoskeletal function and relieve tension and pain .
the rationale for this type of care is the hypothesis that well - being is associated with connective tissues , including muscles and ligaments and fascia , working smoothly together with the skeletal structure along with the nervous system to integrate and relieve misalignments and decrease soft - tissue tensions in the body .
this process may enhance blood and nerve supply to any areas of dysfunction , thus decreasing pain sensations . in adults
chiropractic is manual medicine and is one of the most common types of manual therapies that include osteopathy and physiotherapy ( 36 ) .
chiropractors are musculoskeletalists who differ from the other types of manual therapists in that chiropractors are trained as primary contact clinicians and are responsible for diagnosis along with specific type of manual therapies ( 37 ) . as such , it is a profession dedicated to the prevention and treatment of musculoskeletal problems of humans of all ages .
chiropractors focus on the mechanical stress of the human body and this begins from the time of intra - uterine life and includes passage through the birth canal ( 38 ) as well as everyday life stresses that can manifest as pain , loss of function and even disability .
chiropractic therapy is demarcated by the use of manual treatment of joints and soft tissues intended to promote the health and well - being of the patient .
it may encompass a wide variety of techniques or modalities including chiropractic manual therapy , light touch ( hold and release ) , moderate touch or deeper pressure involving treatment of trigger points , myofascial release , neuromuscular techniques or massage ( 39 ) .
touch is the first sense to develop in humans and therapeutic touch therapy has been known and used in health care since the time of hippocrates or before ( ~460 to 370 bc ) and continues to be in use for pain control in modern medicine for even premature neonates ( 40 ) .
significant benefits of chiropractic manual therapy for pain control have been documented in at least one meta - analysis ( 41 ) . in europe , 52% of parents seek complementary and alternative medicine for their children ( 42 ) and many more seek conventional medical assistance worldwide .
although there are a limited number of studies focused on whether chiropractic therapy for infants is safe , current evidence has shown few adverse events from care of the paediatric patient , only transient irritability from infant care and one ( uncertain ) adverse event from colic treatment ( 43 ) . when placed into the context of 30 million chiropractic treatments of children annually in the usa alone , adverse events may be deemed extremely rare .
chiropractors in the united kingdom and most of the rest of europe adhere to the chiropractic reporting and learning system of adverse events or near miss reporting and no serious adverse events from infant or child treatment have occurred since its inception in 2006 ( 44 ) .
although it has been claimed that adverse effects resulting from the chiropractic care of paediatric patients may be under - reported ( 45 ) , it is unlikely that parents are to stand by and watch a child being injured or in pain without complaint .
any magnitude of the problem would certainly be associated with malpractice claims , which are virtually non - existent ( 46 ) .
there are no guidelines that systematise either the investigation or treatment of pain syndromes of infancy at this time .
a medical guideline is a protocol constructed to guide decision making around evidence - based criteria regarding diagnosis , management and treatment in specific areas of health care ( 47 ) .
these have been used throughout the history of health care , although in early times were based on tradition or authority opinion .
pain syndromes of infancy including the most common problem , excessive crying of infancy provide a window of opportunity into investigation of the musculoskeletal health of infants . in conclusion , based on the above literature
, it can be concluded that manual chiropractic therapy is the most successful option for the management of paediatric musculoskeletal health of infants .
in addition , few adverse effects have been reported , and these are negligible in comparison to the beneficial accounts of manual therapy
. however , additional investigations need to be performed to elucidate the core mechanisms responsible for existing results of manual therapy .
Output:
| excessive crying ( or infant colic ) is a common pain syndrome of infancy without any specific known aetiology or effective management .
many cases result in long - term poor sleep , behavioral problems and parental stress .
the biomechanical aspects of this condition lack adequate investigation despite its strong link with assisted and/or difficult births .
the present review focused on the current trends in the management of this mal - musculoskeletal health of infants associated with the condition of excessive crying .
in addition , the risk factors associated with therapeutic procedures used to manage the above conditions were also discussed . |
PubmedSumm118249 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: comparar os ndices de mortalidade por doenas respiratrias em idosos residentes no distrito federal ( df ) antes e aps a implantao da campanha nacional de vacinao contra influenza .
os dados referentes populao do df acima de 60 anos entre 1996 e 2009 foram obtidos de bancos de dados oficiais . as variveis estudadas foram o coeficiente
de mortalidade geral ( cmg ) , coeficiente de mortalidade por doenas respiratrias ( cmdr ) e ndice de mortalidade por causas respiratrias ( imr ) .
foi realizada uma anlise qualitativa dos dados referentes ao perodo antes e aps a implantao da campanha de vacinao ( 1996 - 1999 e 2000 - 2009 , respectivamente ) .
no decorrer do perodo do estudo , houve uma reduo no cmg em todas as faixas etrias , especialmente naquela com 80 anos ou mais .
houve reduo do cmdr em todos os grupos etrios , especialmente naqueles com mais de 80 anos . o imr mostrou uma reduo em todas as faixas etrias por todo o perodo estudado .
em 2000 , ano imediatamente subsequente primeira campanha vacinal , a reduo do imr foi mais pronunciada na faixa etria 70 anos ; em 2001 , houve um aumento do imr em todas as faixas etrias , apesar da maior adeso campanha de vacinao em relao a 2000 .
a vacinao contra a influenza parece influir positivamente na preveno da mortalidade por doenas respiratrias , particularmente nos idosos com 70 anos ou mais
influenza is an acute respiratory infection caused by myxovirus influenzae . worldwide , influenza causes greater morbidity than does any other infectious processes .
typically self - limiting , influenza is seen as having little relevance in its uncomplicated form and resolves spontaneously in approximately one week .
the typical clinical manifestations of the uncomplicated form include fever , odynophagia , cough , myalgia , rhinitis , headache , and asthenia . in the elderly population ,
influenza can lead to complications , primarily viral or bacterial pneumonia .
during influenza epidemics ,
the disease spreads rapidly and is responsible for high morbidity and mortality , especially in the elderly .
the complications of influenza are responsible for a significant number of hospitalizations in brazil . in 2009 , 851,044 hospitalizations for influenza and pneumonia were recorded by the hospital information service of the brazilian unified health care system , a figure that is 10% higher than was the average for the five years preceding that . of all hospitalizations ,
the elderly are the most vulnerable group to influenza , because advanced age is associated with a higher prevalence of chronic degenerative diseases and with immunological impairment .
the primary prevention measure is influenza vaccination , as has been recommended by the world health organization since 1963 . in brazil ,
influenza vaccination has been made available for free to the elderly throughout the country by the brazilian national ministry of health since 1999 .
the vaccination campaign for seniors in brazil represents a large public investment , involving an expenditure of about r$130 million per year in the purchase and application of the vaccine , as well as in dissemination campaigns .
various studies , especially those conducted in the northern hemisphere , have demonstrated that the influenza vaccine is effective in the elderly , reducing morbidity and mortality .
in brazil , one group of authors observed a reduction in mortality rates one year after the vaccine intervention in the state of so paulo .
however , another study observed that the rates of hospitalization and death for respiratory or circulatory diseases were not reduced by vaccination in the elderly population of the city of fortaleza , brazil .
the objective of the present study was to compare mortality rates for respiratory diseases among elderly individuals residing in the federal district of braslia , brazil , prior to and after the implementation of a national influenza vaccination campaign in 1999 .
this was an ecological time series analysis involving data from the mortality records for all - cause mortality and mortality from respiratory disease in residents of braslia who were over 60 years of age between 1996 and 2009 ; those data were obtained from the mortality database of the brazilian national ministry of health unified health care system .
estimates regarding the elderly population residing in braslia , by age , were obtained from the brazilian institute of geography and statistics .
in developing countries , the united nations considers individuals 60 years of age or older as elderly . in brazil ,
8.842/9 also classifies a person 60 years of age or older as elderly . in the present study , the elderly
were divided into three age groups : 60 - 69 years ; 70 - 79 years ; and 80 years . in order to determine the impact that influenza has on the community
, we used the diagnoses of the following respiratory complications of viral infection : pneumonia ; influenza ; bronchitis ; and chronic airway obstruction . for data collected up to 1997
, we used the ninth revision of the international classification of diseases ( icd-9 ) , and , for data collected from 1998 onward , we used the icd-10 . in the icd-9 , the codes assigned to the aforementioned diagnoses are 480 - 486 , 487 , 490 - 491 , and 495 - 496 , whereas those same diagnoses are coded as j10-j15 , j18 , j22 , j40-j42 , and j44 , respectively , in the icd-10 . because copd is prevalent in patients 60 years of age or older and is frequently complicated by viral infection , leading to hospitalization and eventually to death ,
it was included in the diagnoses .
we calculated the crude ( all - cause ) mortality rate ( cmr ) for each age group ( 60 - 69 years , 70 - 79 years , and 80 years ) .
in addition , we calculated the respiratory disease mortality rate ( rdmr ) , on the basis of the classification described above , also for each of the three age groups . subsequently , we calculated the proportional mortality ratio ( pmr ) for respiratory diseases , which is the ratio between the rdmr and the cmr .
data regarding vaccination coverage in the study population were obtained from the website of the department of information technology of the brazilian national ministry of health unified health care system and tabulated according to the area of interest ( i.e. , braslia ) in the specified period ( 1996 - 2009 ) .
considering 1996 as the beginning of the analysis period , we found that the cmr increased with advancing age , from 20/1,000 population in the 60- to 69-year age group to 200/1,000 in the 80-year age group ( figure 1 ) . over the study period ( 1996 - 2009 ) , the cmr remained mostly stable in the 60- to 69-year age group and showed a slight reduction in the 70- to 79-year age group after the implementation of the national vaccination campaign in 1999 .
however , in the 80-year age group , there were significant fluctuations in the cmr over that period .
for that age group , despite the decrease in the cmr that occurred in 2000 , the year following the implementation of the national vaccination campaign , the cmr increased gradually , reaching 200/1,000 population in 2006 .
it is of note that , in 2007 , the cmr again showed a considerable reduction , greater than that observed in 2000 , reaching approximately 150/1,000 population , and , in 2009 ( end of the analysis period ) , it reached 130/1,000 population .
therefore , as compared with the year immediately following the implementation of the national vaccination campaign , i.e. , 2000 , the cmr decreased in all three age groups , and the decrease was most pronounced in the 80-year age group .
figure 1crude ( all - cause ) mortality rate ( per 1,000 population ) between 1996 and 2009 in the federal district of braslia , brazil , by age group .
the analysis of the rdmr , as shown in figure 2 , indicates that this rate clearly decreased in all three age groups over the analysis period .
we found that the rdmr did not fluctuate significantly in the 60- to 69-year age group but that , in 2000 , one year after the implementation of the national vaccination campaign , it decreased in the 70- to 79-year age group , a decrease followed by transient rises and then by a steady and mild decline until 2009 . in the 80-year age group ,
the rdmr fluctuated after 2000 , with moderate increases in 2001 and 2002 , followed by a decrease in 2003 and marked increases in 2004 and 2005 . from 2007 to 2009
, there was a progressive reduction in the rdmr , which , in 2009 , reached a value similar to that recorded for 2000 .
figure 2respiratory disease mortality rate per 1,000 population between 1996 and 2009 in the federal district of braslia , brazil , by age group .
the analysis of the pmr curves revealed that there was a reduction in the pmr for respiratory diseases between 1996 and 2009 for all of the age groups evaluated .
however , in the 60- to 69-year age group , the pmr for respiratory diseases remained stable after 2000 , whereas it continued to oscillate in the other two age groups , with occasional decreases and tendencies toward an increase throughout the period , although never again reaching the high values observed in 1996 ( figure 3 ) .
figure 3proportional mortality ratio for respiratory diseases between 1996 and 2009 in the federal district of braslia , brazil , by age group .
table 1 shows that influenza vaccination coverage decreased significantly in 2000 as compared with 1999 , when the national vaccination campaign was implemented .
after that , between 2001 and 2009 , the level of coverage fluctuated , adherence increasing between 2001 and 2003 , after which there were additional fluctuations .
table 1influenza vaccination coverage ( brazilian national immunization campaign for seniors ) among individuals who were 60 years of age or older between 1999 and 2009 .
the brazilian population over 60 years of age has grown by 41.6% , and this growth was most significant in the 80-year age group , which increased by 60.2% .
individuals 80 years of age or older , designated as the very elderly , exhibit a higher prevalence of comorbidities and are at a greater risk of decompensation of their comorbidities in response to a stressor , such as influenza .
although there were fluctuations in the cmr and the rdmr , the results of the present study indicate that there was a reduction in mortality after the implementation of the national vaccination campaign .
there was a greater reduction in the pmr for respiratory diseases in those 70 years of age or older , and this can be attributed to greater vaccination coverage in this population , as has also been observed by a group of authors in the state of paran , brazil .
the greatest decline in the pmr for respiratory diseases , in all three age groups , occurred in 2000 , the first year after the implementation of the national vaccination campaign . in 2001 , however , the data suggest an increase in mortality from respiratory diseases in all groups . this behavior can be explained by the pattern of adherence to the influenza vaccination campaign , which was lower in 2000 . the non - participation of elderly individuals in immunization campaigns reflects their attitudes and beliefs about the risks and benefits of vaccination .
the target population was individuals 65 years of age or older , and 87.3% of the estimated population in this age group was vaccinated . in the subsequent year , vaccination was made available to all brazilians 60 years of age or older .
however , vaccination coverage decreased to 71.8% . in 2001 , a redoubling of efforts in the campaign resulted in nationwide vaccination coverage of 82.1% .
studies have shown that adherence to influenza vaccination campaigns is lowest among elderly individuals between 60 and 69 years of age , especially among those with a higher level of education .
in that age group ,
it is possible that the side effects of the vaccine , such as myalgia , low - grade fever , and malaise , can be mistaken for influenza , leading those individuals to believe that the vaccine does not protect them against influenza or even reinforcing the myth that the influenza vaccine can cause influenza .
a number of factors are involved in the behavior of influenza and affect the complexity of the data obtained .
the influenza virus exhibits antigenic variations that result in partial changes in its genetic structure .
this phenomenon enables the cyclical occurrence of the disease in the population ; this is possible because of the high genetic variability and adaptability of the virus .
the seasonality of influenza varies from region to region , seasonal differences in frequency being more marked in regions with well - defined seasons - higher frequencies being observed in the colder months in areas with a temperate climate and in the wetter months in areas with a tropical climate .
seasonal influenza can manifest in annual outbreaks of varying size , severity , and extent that complicate the accurate diagnosis of the condition and the accurate determination of the efficacy of prophylaxis .
in addition to the factors implicated in the difficulty in controlling influenza , another aspect that deserves attention is the increase in the circulation of other viruses with respiratory tropism .
in addition to the influenza virus , the viruses most commonly associated with pulmonary infections and their complications include respiratory syncytial virus , parainfluenza , adenovirus , rhinovirus , and metapneumovirus , the last having been identified most recently .
this could explain the fluctuations observed in the present study , particularly in the 80-year age group , because that group is more susceptible to infectious diseases .
the aging of the immune system , known as immunosenescence , is associated with the gradual deterioration of immune function , thereby increasing susceptibility to infections , autoimmune diseases , and cancer .
this deterioration of immune function is associated with changes that can occur in each phase of the development of the immune response .
the effectiveness of influenza vaccination in preventing disease is lower in elderly individuals than in younger adults , the effectiveness of vaccination ranging from 30% to 40% in the former group , compared with 70% to 90% in the latter .
an ecological analysis has limited ability to generate causal hypotheses . in the present study , it is relevant to consider the complexity of establishing respiratory infection as the cause of death in elderly individuals , who frequently have multiple comorbidities . underreporting or erroneous reporting of the cause of death occurs more often in the elderly population . in braslia , the cmr can be used reliably , since the death records in braslia cover almost all occurrences ( 95% ) .
the present study draws attention to the potential efficacy of the influenza vaccination campaign in reducing mortality from respiratory diseases among elderly individuals residing in braslia .
the investments made in health care , with regard to the vaccination campaign , appear to have had a positive impact on the health of this population segment .
Output:
| objective : to compare mortality rates due to respiratory diseases among elderly individuals residing in the federal district of braslia , brazil , prior to and after the implementation of a national influenza vaccination campaign .
methods : this was an ecological time series analysis .
data regarding the population of individuals who were over 60 years of age between 1996 and 2009 were obtained from official databases .
the variables of interest were the crude mortality rate ( cmr ) , the mortality rate due to the respiratory disease ( mrrd ) , and the proportional mortality ratio ( pmr ) for respiratory diseases .
we performed a qualitative analysis of the data for the period prior to and after the implementation of the vaccination campaign ( 1996 - 1999 and 2000 - 2009 , respectively ) .
results : the cmr increased with advancing age .
over the course of the study period , we observed reductions in the cmr in all of the age brackets studied , particularly among those aged 80 years or older .
reductions in the mrrd were also found in all of the age groups , especially in those aged 80 years or older .
in addition , there was a decrease in the pmr for respiratory diseases in all age groups throughout the study period .
the most pronounced decrease in the pmr for respiratory diseases in the 70 year age bracket occurred in 2000 ( immediately following the implementation of the national vaccination campaign ) ; in 2001 , that rate increased in all age groups , despite the greater adherence to the vaccination campaign in comparison with that recorded for 2000 .
conclusions : influenza vaccination appears to have a positive impact on the prevention of mortality due to respiratory diseases , particularly in the population aged 70 or over . |
PubmedSumm118250 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: hemophilia is an x - linked recessive hemorrhagic disease due to mutations in the f8 gene or f9 gene .
it affects one in 10,000 males , with hemophilia a representing 80% of all cases . in patients with hemophilia , intracranial hemorrhage ( ich ) is an important cause of morbidity and mortality with the overall incidence of 2.2 - 7.5% .
clotting factor concentrate replacement , neurosurgery and aggressive airway management is essential for comatose patients .
a multidisciplinary approach involving hematologist , neuro - intensivist , neurosurgeon , neurophysician and neuro - anesthesiologist is crucial for a successful outcome . to the best of our knowledge , there are a very few reports about ich in severe hemophilia in developing countries .
we are reporting the case series of this kind for the first time in nepal .
a 19-year - old male weighing around 50 kg , a diagnosed case of hemophilia a , presented with sudden onset of loss of consciousness .
patient had glasgow coma scale ( gcs ) score of 8 ( e2 v1 m5 ) with unequal pupils . computed tomography ( ct )
scan revealed left intracerebral hematoma with mass effect and midline shift of 1.23 cm . activated partial thromboplastin time ( aptt ) was 82 s. factor viii 2500 units and tranexamic
patient was endotracheally intubated , and anesthesia was maintained with oxygen , isoflurane and intermittent boluses of vecuronium .
factor viii was administered at the dose of 2000 units intravenously every 12 h for 3 days ; 1250 units intravenously every 12 h for next 4 days and then 750 units intravenously every 12 h for next 7 days .
he was discharged home on 9 post - operative day . a 12-year - old male patient , weighing around 30 kg , a diagnosed case of hemophilia b , presented with decrease in the level of consciousness and decreased movement in the left half of the body .
ct scan revealed right fronto - parietal hematoma with significant midline shift [ figure 1 ] .
his aptt was 86 s. right fronto - parietal intracerebral hematoma ( 4.68 5.17 cm ) with midline shift of 1.46 cm recombinant factor ix 3500 units and tranexamic acid 1 g were administered intravenously , and patient was transferred to the operating room for an emergency craniotomy .
endotracheal intubation was done and anesthesia was maintained with oxygen , isoflurane and intermittent boluses of vecuronium .
intraoperative blood loss was around 500 ml and one unit of crossmatched whole blood was transfused .
postoperative ct scan revealed some residual clots but with satisfactory resolution of midline shift and decrease in mass effect .
. he had persistent left sided weakness which improved during the subsequent days of hospital stay .
factor ix was administered at 3500 units daily for first 3 days followed by 2000 units daily for next 4 days and then 1500 units daily for another 7 days .
a 19-year - old male weighing around 50 kg , a diagnosed case of hemophilia a , presented with sudden onset of loss of consciousness .
patient had glasgow coma scale ( gcs ) score of 8 ( e2 v1 m5 ) with unequal pupils . computed tomography ( ct )
scan revealed left intracerebral hematoma with mass effect and midline shift of 1.23 cm . activated partial thromboplastin time ( aptt ) was 82 s. factor viii 2500 units and tranexamic
patient was endotracheally intubated , and anesthesia was maintained with oxygen , isoflurane and intermittent boluses of vecuronium .
factor viii was administered at the dose of 2000 units intravenously every 12 h for 3 days ; 1250 units intravenously every 12 h for next 4 days and then 750 units intravenously every 12 h for next 7 days .
he was discharged home on 9 post - operative day . a 12-year - old male patient , weighing around 30 kg , a diagnosed case of hemophilia b , presented with decrease in the level of consciousness and decreased movement in the left half of the body .
ct scan revealed right fronto - parietal hematoma with significant midline shift [ figure 1 ] .
his aptt was 86 s. right fronto - parietal intracerebral hematoma ( 4.68 5.17 cm ) with midline shift of 1.46 cm recombinant factor ix 3500 units and tranexamic acid 1 g were administered intravenously , and patient was transferred to the operating room for an emergency craniotomy .
endotracheal intubation was done and anesthesia was maintained with oxygen , isoflurane and intermittent boluses of vecuronium .
intraoperative blood loss was around 500 ml and one unit of crossmatched whole blood was transfused .
postoperative ct scan revealed some residual clots but with satisfactory resolution of midline shift and decrease in mass effect .
. he had persistent left sided weakness which improved during the subsequent days of hospital stay .
factor ix was administered at 3500 units daily for first 3 days followed by 2000 units daily for next 4 days and then 1500 units daily for another 7 days .
a 19-year - old male weighing around 50 kg , a diagnosed case of hemophilia a , presented with sudden onset of loss of consciousness .
patient had glasgow coma scale ( gcs ) score of 8 ( e2 v1 m5 ) with unequal pupils . computed tomography ( ct )
scan revealed left intracerebral hematoma with mass effect and midline shift of 1.23 cm . activated partial thromboplastin time ( aptt ) was 82 s. factor viii 2500 units and tranexamic
patient was endotracheally intubated , and anesthesia was maintained with oxygen , isoflurane and intermittent boluses of vecuronium .
factor viii was administered at the dose of 2000 units intravenously every 12 h for 3 days ; 1250 units intravenously every 12 h for next 4 days and then 750 units intravenously every 12 h for next 7 days .
a 12-year - old male patient , weighing around 30 kg , a diagnosed case of hemophilia b , presented with decrease in the level of consciousness and decreased movement in the left half of the body .
ct scan revealed right fronto - parietal hematoma with significant midline shift [ figure 1 ] .
his aptt was 86 s. right fronto - parietal intracerebral hematoma ( 4.68 5.17 cm ) with midline shift of 1.46 cm recombinant factor ix 3500 units and tranexamic acid 1 g were administered intravenously , and patient was transferred to the operating room for an emergency craniotomy .
endotracheal intubation was done and anesthesia was maintained with oxygen , isoflurane and intermittent boluses of vecuronium .
intraoperative blood loss was around 500 ml and one unit of crossmatched whole blood was transfused .
postoperative ct scan revealed some residual clots but with satisfactory resolution of midline shift and decrease in mass effect .
he had persistent left sided weakness which improved during the subsequent days of hospital stay .
factor ix was administered at 3500 units daily for first 3 days followed by 2000 units daily for next 4 days and then 1500 units daily for another 7 days .
patients with severe hemophilia can present with spontaneous bleeding , commonly into joints and muscles .
patients have high aptt , but platelet count , bleeding time and prothrombin time are normal . with
replacement of deficient factors is the mainstay of treatment for bleeding episodes in patients with hemophilia .
the knowledge related to replacement therapy should be mastered not only by hematologist , but also by the whole team involved in patient management . in patients with central nervous system bleeding , factor replacement
is recommended for 14 - 21 days , depending on resource constraints as mentioned in table 1 .
each unit of fviii per kilogram of body weight will raise the plasma level approximately 2 iu dl .
similarly , each unit of recombinant fix per kilogram of body weight will raise the plasma level approximately 0.7 iu dl in children under 15 years of age .
conservative factor replacement therapy coupled with antifibrinolytic agents was found to yield mortality similar to that of the western countries and with almost no morbidity . in both cases ,
clotting factor was administered as recommended for places with significant resource constraints and tranexamic acid was administered for 15 days .
factor level measurement and testing for inhibitor was not performed due to financial constraints and limited availability of tests . suggested plasma factor peak level and duration of administration patients with spontaneous ich with gcs score of 8 or less might be considered for intracranial pressure monitoring .
significant coagulopathy being contraindications for external ventricular drain placement , it was not performed in the first case . in a large trial ,
patients with hematomas extending to within 1 cm of the cortical surface , with gcs score of 9 - 12 had a trend towards more favorable outcome with early surgery .
craniotomy for supratentorial ich more than 30 ml , when performed early was associated with good outcome .
as both the patients had superficial clots with mass effect and a significant clot volume , emergency craniotomy with evaculation of clot was performed . during the perioperative period ,
supportive measures for prevention of secondary brain injury like management of blood pressure , glucose , temperature , antiepileptic drugs , hyperosmotic agents , optimization of oxygenation and ventilation and securing of the airway were considered in both cases by a neurointensivist .
introduction of neurointensivist coordinated neurocritical care team is associated with a significant reduction of in - hospital mortality and length of stay . to conclude , even in resource constrained places
, timely management of hemophilic patients with spontaneous intracerebral hemorrhage by a multidisciplinary team can improve the outcome .
Output:
| patients with hemophilia are prone to develop spontaneous intracranial hemorrhage .
it carries a significant risk of morbidity and mortality . in this case series , we report two cases of hemophilia who suffered spontaneous intracerebral hemorrhage with features of raised intracranial pressure and were successfully managed perioperatively . the patients were managed with early intensive care unit management , measures to reduce intracranial pressure , perioperative clotting factor administration , airway management and surgery to decrease the raised intracranial pressure .
both patients improved following surgery and were discharged home .
perioperative multidisciplinary management of hemophilia is discussed in this series . |
PubmedSumm118251 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: galli - galli disease ) is a rare genodermatosis which belongs to the spectrum of reticulate pigmentary disorders and is inherited in an autosomal - dominant manner .
it classically presents with reticulate pigmentation , usually hyperpigmented macules in combination with hyperkeratotic papules mainly of the flexures ; cases with disseminated monomorphous reddish - brown macules and papules have also been described .
recently , it has been shown that the most common mutation in the keratin 5 ( krt5 ) gene ( c. 418dupa ; p.ile140asnfsx39 ) is seen in galli - galli disease ( ggd ) as well as dowling - degos disease .
although the clinical picture of both forms is indistinguishable , detection of acantholysis on histopathological evaluation in ggd patients is believed to be the differentiating criterion between ggd and ddd .
however , acantholysis can also be found in patients with ddd , supporting the hypothesis that ggd is a variant of ddd .
there have been infrequent reports on a distinctive clinical picture in ddd presenting with hypopigmented macules in asian and african american patients , either with merely hypopigmentation or in combination with the aforementioned reticular pigmentation and erythematous erosive papules with the typical flexural focus .
guo et al . reported on a chinese family with ddd exhibiting hypopigmented macules along with the well - known typical clinical and histopathological features of ddd and identified a novel heterozygous nonsense mutation , c.10c > t , in exon 1 of krt5 .
wu and lin presented three patients from one family with clinical and histological ddd along with hypopigmented macules ; the histopathological evaluation in one of their patients in papules from the axillary region had features of galli - galli disease , however , they did not detect any mutation in krt5 .
however , recently , another gene was identified for ddd in two chinese families , called pofut1 , encoding protein o - fucosyltransferase 1 ( li et al .
we herein describe a family from india with clinical and histopathological features of ggd who exhibit hypopigmentation along with the typical reticular hyperpigmentation and erosive skin colored as well as erythematous papules pronounced on the trunk and flexural areas .
we performed molecular genetic analyses in several affected family members and identified the heterozygous nonsense mutation c.c10 t in the krt5 gene .
shyam verma in vadodara , india . the 57-year - old indian female patient ( patient 1 ) presented with extensive , confluent reticular hyperpigmentation in combination with erythematous macules and skin colored papules pronounced around the neck , decollet , sternal and submammary region and - to a lesser extent - in the axillary region .
hyperpigmentation was also seen on the extremities and the face . moreover , she had multiple hypopigmented macules between 3 and 10 mm size distributed symmetrically on her lower abdomen , legs and axillary region .
she gave a history of exacerbation of the lesions and itching when exposed to summer heat of her native town and dramatic relief from this in winters and when she went to visit her daughter in united states .
eroded hyperpigmented lesions of galli galli disease with accompanying hypopigmented macules in the index case the patient 's 32-year - old son ( patient 2 ) showed identical hyperpigmentation on the back of the hands , the face and the extremities ; sparse hyperpigmented papules were found in the axillary region .
in addition , sharply demarcated hypopigmented macules were symmetrically disseminated over chest , lower abdomen , back and groins [ figures 2 and 3 ] .
the patient 's 39-year - old daughter ( patient 3 ) and her 19-year - old granddaughter ( patient 4 ) displayed the same clinical findings as patient 2 [ figure 4 ] .
in addition , patient 3 showed some eroded papules on the lower back and lower abdomen with aggravation and itching during heat and summer .
further history revealed that the skin changes had started in all patients as asymptomatic hyperpigmented and hypopigmented macules after about 15 years of age .
subsequently many of the hyperpigmented macular lesions became raised and keratotic after 45 years of age in patient 1 , and after 34 years of age in patient 3 with erosions , burning and aggravation of symptoms occurring during hot and humid climate as well as by sweating .
predominantly hypopigmented macules scattered diffusely on the trunk in son hyperpigmented raised lesions in the axilla with hypopigmented macules on chest and hyperpigmented macules visible on neck of son multiple hypo and hyperpigmented macules diffusely scattered on extremities and trunk in daughter dermatohistopathological evaluation of skin biopsies from a hyperpigmented macule from abdomen from patient 1 and a hyperpigmented and hypopigmented macule from patient 2 revealed classic antler like rete ridges , lentiginous hyperplasia in all cases and formation of discrete cleft consistent with ggd in one [ figures 57 ] .
moreover , there was in part a very pronounced pigment incontinency [ figure 6 ] .
multiple antler like rete ridges with basal cell pigmentation fusing rete ridges with deeply pigmented basal cell layer and marked pigment incontinence mutational analysis for the krt5 gene for the molecular genetic analyses , dna was extracted from four affected individuals from peripheral blood leukocytes according to standard procedures .
all coding exons of the krt5 gene were amplified by pcr of an affected individual ( patient 1 ) .
the pcr products were purified with the gfx pcr dna purification kit ( ge healthcare ) and directly sequenced using the bigdye terminator v1.1 cycle sequencing kit ( applied biosystems ) on an abi 3100 genetic analyzer ( applied biosystems ) .
all patients provided written informed consent , and the investigation was approved by the ethics committee of the medical faculty of the university of dsseldorf .
shyam verma in vadodara , india . the 57-year - old indian female patient ( patient 1 ) presented with extensive , confluent reticular hyperpigmentation in combination with erythematous macules and skin colored papules pronounced around the neck , decollet , sternal and submammary region and - to a lesser extent - in the axillary region .
hyperpigmentation was also seen on the extremities and the face . moreover , she had multiple hypopigmented macules between 3 and 10 mm size distributed symmetrically on her lower abdomen , legs and axillary region .
she gave a history of exacerbation of the lesions and itching when exposed to summer heat of her native town and dramatic relief from this in winters and when she went to visit her daughter in united states .
eroded hyperpigmented lesions of galli galli disease with accompanying hypopigmented macules in the index case the patient 's 32-year - old son ( patient 2 ) showed identical hyperpigmentation on the back of the hands , the face and the extremities ; sparse hyperpigmented papules were found in the axillary region .
in addition , sharply demarcated hypopigmented macules were symmetrically disseminated over chest , lower abdomen , back and groins [ figures 2 and 3 ] .
the patient 's 39-year - old daughter ( patient 3 ) and her 19-year - old granddaughter ( patient 4 ) displayed the same clinical findings as patient 2 [ figure 4 ] .
in addition , patient 3 showed some eroded papules on the lower back and lower abdomen with aggravation and itching during heat and summer .
further history revealed that the skin changes had started in all patients as asymptomatic hyperpigmented and hypopigmented macules after about 15 years of age .
subsequently many of the hyperpigmented macular lesions became raised and keratotic after 45 years of age in patient 1 , and after 34 years of age in patient 3 with erosions , burning and aggravation of symptoms occurring during hot and humid climate as well as by sweating .
predominantly hypopigmented macules scattered diffusely on the trunk in son hyperpigmented raised lesions in the axilla with hypopigmented macules on chest and hyperpigmented macules visible on neck of son multiple hypo and hyperpigmented macules diffusely scattered on extremities and trunk in daughter
dermatohistopathological evaluation of skin biopsies from a hyperpigmented macule from abdomen from patient 1 and a hyperpigmented and hypopigmented macule from patient 2 revealed classic antler like rete ridges , lentiginous hyperplasia in all cases and formation of discrete cleft consistent with ggd in one [ figures 57 ] .
moreover , there was in part a very pronounced pigment incontinency [ figure 6 ] .
multiple antler like rete ridges with basal cell pigmentation fusing rete ridges with deeply pigmented basal cell layer and marked pigment incontinence mutational analysis for the krt5 gene
for the molecular genetic analyses , dna was extracted from four affected individuals from peripheral blood leukocytes according to standard procedures .
all coding exons of the krt5 gene were amplified by pcr of an affected individual ( patient 1 ) .
the pcr products were purified with the gfx pcr dna purification kit ( ge healthcare ) and directly sequenced using the bigdye terminator v1.1 cycle sequencing kit ( applied biosystems ) on an abi 3100 genetic analyzer ( applied biosystems ) .
all patients provided written informed consent , and the investigation was approved by the ethics committee of the medical faculty of the university of dsseldorf .
by sequencing analysis , we identified a heterozygous nonsense mutation , c.c10 t ( p.gln4x ) , in exon 1 of the krt5 gene in the index patient ( patient 1 ) .
further analyses revealed the same mutation in the son , the daughter and the granddaughter of the index patient ( patients 2 - 4 ) .
the heterozygous nonsense mutation c.10c > t in krt5 identified in this study was recently described in a chinese family with ddd with hypopigmented macules adjacent to the classic lesions showing histological features of ddd .
wu and lin published a family with reticular hyperpigmentation and hypopigmented macules with ddd with some biopsies showing features on histopathology in accordance with ggd , however , a mutation in krt5 could not be detected . upon review of the international dermatologic literature
our study seems to be the first mutation report on ggd in patients from india ; moreover , the mutation c. 10c > t has so far not been described in the literature for ggd ( acantholytic ddd ) .
the detection of this mutation not only in ddd but also in ggd patients gives further confirmation for our hypothesis that ggd is a variant of ddd .
in addition , so far there have not been any reports on ggd with hypopigmentation where detection of a mutation in the krt5 gene has been possible .
further studies have to show if there is a phenotypical correlation between the mutation c.10c > t of krt5 and ggd resp .
together with the mutation c.10c > t in ggd , five different mutations in krt5 underlying either ggg or ddd have been described so far , mostly in patients of european origin .
the understanding of the mechanisms leading to reticulate hyper- and/or hypopigmentation in ddd and ggd is rudimentary at the present time .
a single subtype of the hereditary bullous disorder , epidermolysis bullosa simplex ( ebs ) with hyper- and hypopigmentation , ebs with mottled pigmentation , has been described .
mutations in krt5 are the underlying cause of ebs with mottled pigmentation . in analogy and terms of a correct terminology , we propose that patients with ggd or ddd clinically displaying hyper and hypopigmentation have to be classified as ggd resp .
going by existing literature and from the author 's personal communications , the latter with mottled pigmentation seems to be a fairly commonly occurring phenotype in the asian population whereas in publications on caucasian patients the patients mainly exhibit the reticular phenotype .
keratin 5 constitutes an integral part of the basal cell layer of keratinocytes and thus dominant mutations in krt5 may play a significant role , besides cell adhesion , in uptake and distribution of melanosomes in keratinocytes .
it could be assumed that post - inflammatory hypopigmentation in patients with fitzpatrick type iv , v or vi leads to the phenotype of ggd or ddd with mottled pigmentation .
in addition , postinflammatory pigmentary changes usually regress over time if melanocytes are not destroyed .
permanent hypopigmentation in contrast can be due to the absence or diminution of melanocytes or aberrations in the complex process of melanin synthesis , transport and release to keratinocytes ; underlying causes comprise severe cutaneous inflammation or diverse genetic disorders .
future studies have to contribute to the understanding of hyper- and hypopigmentation in reticulate pigment disorders like ggd and ddd in general , as well as with special regard to patients with skin type iv , v and vi , appreciating and further elucidating the notion of a possibly genetically determined individual chromatic tendency. the idea that hypopigmentation can also be an expression of subclinical acantholysis was suggested in 1995 by rowley et al .
they studied hypopigmented lesions in two patients with dark skin diagnosed with the acantholytic dermatoses , darier 's and grover 's disease and detected acantholytic histopathological features , leading to the hypothesis that the associated leucoderma in those cases became apparent on surrounding dark skin .
this is what makes it an interesting hypothesis which could possibly be applied to our cases .
moreover , the mechanisms leading to acantholysis in ggd have to be explored further , especially the question whether acantholysis in ddd is indeed rare or is a disregarded or underobserved histopathological feature . in conclusion
, the analyses of our family from india further contribute to the broad and probably origin - related diverging spectrum of clinical symptoms and molecular genetic findings which is expanding steadily in ggd and ddd .
the correlation of hypopigmented macules with these genetically determined reticulate pigment disorders is uncommonly reported in literature and is worth studying further , especially with respect to patients with skin type iv , v and vi . a serious consideration needs to be given to the fact that hypopigmented lesions in the dowling - degos disease - spectrum may be underreported , a fact emerging from personal communications with several esteemed colleagues from india who have seen coexistence of hypo- and hyperpigmented macules in this disease spectrum .
this study also reiterates published observations and discussions suggesting that reticulate pigmentary disorders like ddd , ggd , acropigmentation of kitamura , acropigmentation of dohi and haber 's syndrome may have many overlaps clinically .
further studies will throw more light on whether there are true overlaps between these diseases or whether these entities are placed variably in a continuum under the broad rubric of reticulate pigmentary disorders .
mottled hypopigmentation in addition to the classic signs and symptoms of ddd and ggd may be well recognized over a period of time to be a distinct phenotype in individuals who have dark skin .
we have successfully detected the heterozygous mutation c.c10 t in krt5 in an indian family with acantholytic dowling - degos disease ( syn .
galli - galli disease ) with mottled pigmentation.we are highlighting the presence of mottled pigmentation in the reticulate pigmentary disorders of dowling - degos disease and galli galli disease in patients with fitzpatrick skin type iv and v. such reports are rather rare in literature .
it is also possible that there is under reporting of mottled pigmentation in this skin type with ddd / ggd .
we have successfully detected the heterozygous mutation c.c10 t in krt5 in an indian family with acantholytic dowling - degos disease ( syn .
we are highlighting the presence of mottled pigmentation in the reticulate pigmentary disorders of dowling - degos disease and galli galli disease in patients with fitzpatrick skin type iv and v. such reports are rather rare in literature .
it is also possible that there is under reporting of mottled pigmentation in this skin type with ddd / ggd .
Output:
| galli galli disease ( ggd ) is the name given to a rare form of acantholytic dowling - degos disease .
( ddd ) , the latter itself being a rare condition .
we believe we are describing for the first time in indian dermatologic literature a case of ggd in a family where 25 persons have ddd and have been able to document a krt5 mutation in four members of the family . whereas reticulate pigmentation is a hallmark of ddd
there are rare reports of mottled pigmentation with multiple asymptomatic hypopigmented macules scattered diffusely along with the pigmentation .
all the cases described here show a mottled pigmentation comprising hypo and hyperpigmented asymptomatic macules .
after the clinical diagnosis was made by one of the authors ( sv ) in india , the german authors repeated histological examination and successfully demonstrated a heterozygous nonsense mutation , c.c10 t ( p.gln4x ) , in exon 1 of the krt5 gene , from various centers in munich , bonn , dusseldorf and friedrichschafen in germany . |
PubmedSumm118252 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: colloidal nps with
excellent physical and chemical properties have
been employed in applications ranging from solar cells to light - emitting diodes and
photocatalysts . as biosensors , colloidal
nanoparticles , including quantum dots , gold nanoparticles , upconversion nanoparticles , and alloyed plasmonic nanoparticles ,
have attracted intense interest because of their
unique optical properties . however , despite success in the synthesis
of hydrophobic colloidal nps , the development of reproducible high - quality nanocrystal
biosensors remains challenging . to stabilize
the colloidal nps in organic media at high temperature ,
a layer of
hydrophobic surfactant is often needed , thus resulting in poor solubility in aqueous phases . to improve
the application of hydrophobic colloidal nps in biochemical
and biomedical research , most current methods use ligand exchange or amphiphilic ligand encapsulation to transfer the hydrophobic colloidal nps to
an aqueous phase .
typically , ligand exchange has been conducted in
a two - phase system with hydrophobic colloidal nps in a nonpolar phase
and the reacting ligands in a polar phase , but this leads to serious
aggregation and poor solubility .
amphiphilic ligand encapsulation
has been performed at high temperature and requires extra washing
steps , thus leading to low transfer efficiency and poor long - term
stability .
although molecular metal chalcogenide complexes provide
stable hydrophilic nps , their biocompatibility
and toxicity are concerns in biosensor applications . in previous
work
, we described a facile method to transfer hydrophobic
magnetic nanoparticles to hydrophilic phase .
however , that method could not be generalized to other hydrophobic
nanocrystals , such as quantum dots . to solve these solubility and
cytotoxicity problems ,
we have designed a simple model system to transfer
hydrophobic colloidal nps to an aqueous phase via ligand exchange
and ionization .
the process is conducted in a single phase ( thf solvent )
with gentle heating .
four different compounds , including 4-aminothiophenol
( 4-atp ) , 4-mercaptobenzoic acid ( 4-mcba ) , dopamine , and 3,4-dihydroxyhydrocinnamic
acid ( 3,4-dhca ) , were all tested in separate experiments to replace
the long hydrocarbon chain ligands on colloidal np surfaces , as shown
in figure 1a , b .
after
ligand exchange , aqueous hcl was added to the ligand exchange solutions
containing either 4-atp or dopamine to protonate the nh2 groups . likewise , aqueous naoh was added to ligand exchange
solutions containing either 4-mcba or 3,4-dhca to deprotonate the
cooh groups .
thus , the neutral hydrophobic np surfaces were
converted to multicharged ions , called ionic nps ( inps ) , which were
collected by centrifugation and redispersed in water .
( a ) schematic
representation of ionization of alloy metal ( fept ) and metal oxide
( fe3o4 ) nps with dopamine and 3,4-dhca . ( b )
schematic representation of ionization of noble metal ( pd ) nps and
quantum dots ( cdse ) with 4-atp and 4-mcba
. tem images of ( c ) ionic
fept , ( g ) cubic fe3o4 , ( k ) pd , and ( o ) cdse
nanoparticles with 3,4-dhca and 4-mcba in water , respectively .
tem
images of ( d ) fept , ( h ) cubic fe3o4 , ( l ) pd ,
and ( p ) cdse nanoparticles in hexane .
tem images of ( e ) ionic fept ,
( i ) cubic fe3o4 , ( m ) pd , and ( q ) cdse nanoparticles
with dopamine and 4-atp in water , respectively . corresponding photographic
images of ( f ) fept , ( j ) cubic fe3o4 , ( n ) pd ,
and ( r ) cdse nanoparticles in hexane and water after ligand exchange
and ionization .
compared with previously reported phase transfer methods
of hydrophobic
nanoparticles , the method we developed here has the following advantages :
( 1 ) unlike traditional ligand exchange , in which nanoparticles are
dissolved in nonpolar solvents and replacement ligands are dissolved
in polar solvents to form a two - phase ligand exchange environment ,
tetrahydrofuran as solvent can dissolve both hydrophobic nanoparticles
and the replacement ligands to provide a single - phase environment
to facilitate ligand exchange .
( 2 ) ionization of nanoparticles by
adding a small amount of naoh or hcl can precipitate the nanoparticles
immediately in tetrahydrofuran , and the precipitated nanoparticles
can be easily dispersed in water without any further surface modification ,
such as adding peg . (
3 ) for each kind of np , two replacement ligands
with the same binding groups but different terminal groups were selected
for ligand exchange .
after ligand exchange , each kind of np can be
ionized using either naoh or hcl to form negatively or positively
charged hydrophilic nps , respectively .
the ionized nps , whether positively
or negatively charged , can be dispersed in water very well because
of their mutual electronic repulsion .
these nps were synthesized
in a manner similar to previously reported procedures . in a typical synthesis of fept ,
platinum acetylacetonate
( 0.5 mmol ) , 1,2-hexadecanediol ( 1.5 mmol ) , and dioctyl ether ( 20 ml )
were mixed and degassed three times before heating to 100 c .
oleic acid ( 0.16 ml ) , oleylamine ( 0.17 ml ) , and fe(co)5 ( 0.13 ml ) were added .
then the mixture was heated to 300 c
and refluxed for 30 min under argon flow .
fept nanoparticles
were washed with ethanol and hexane and finally redispersed in tetrahydrofuran
( thf ) .
10.8 g of iron chloride ( fecl36h20 , 40 mmol ) and 36.5 g of sodium oleate
( 120 mmol ) were dissolved in a solvent mixture composed of 80 ml of
ethanol , 60 ml of distilled water , and 140 ml of hexane .
the resulting
solution was heated to 60 c and refluxed for 4 h. when the reaction
was finished and cooled to room temperature , the upper organic layer
containing the iron oleate complex was washed three times with distilled
water using a separatory funnel .
after removal of hexane , the resulting
iron oleate complex was in a waxy solid form . to synthesize fe3o4 nanocubes , iron
oleate
( 0.9 g , 1 mmol ) and sodium oleate ( 0.32 g , 1.05 mmol ) were
added to a three - necked flask ( 25 ml ) with a solvent of 1-octadecene
( 5 g ) .
the reaction mixture was heated to 200 c and maintained
for 1 h , followed by heating the mixture to 320 c .
after 40
min , the reaction solution was quickly cooled to room temperature
by blowing air across the reaction flask .
these nps were synthesized on the
basis of reported procedures . in a typical
synthesis ,
pd(acac)2 ( 0.1 g ) was added to 1 ml of trioctylphosphine
to form an orange solution .
then 10 ml of oleylamine was introduced
and the mixture was degassed for 10 min .
the resulting solution was
slowly heated to 250 c ( 5 c / min ) .
after 30 min , the reaction
system was cooled quickly , washed with ethanol and hexane , and finally
redispersed in thf .
precursor cadmium myristate was first prepared
using the following procedure : to a solution of sodium myristate in
methanol ( 0.025 m , 240 ml ) was added cadmium nitrate in methanol ( 0.05
m , 40 ml ) dropwise to form a white precipitate , which was washed twice
with methanol and dried under vacuum overnight . to synthesize cdse
nanocrystals , selenium powder ( 0.05 mmol ) and cadmium myristate ( 0.1
mmol )
the
cdse nanoparticles were washed with ethanol and toluene and redispersed
in tetrahydrofuran ( thf ) .
nayf4 ( yb 30% ,
er 2% , nd 1% ) nps were synthesized in a manner similar to previously
reported procedures . typically , y(ch3co2)3 ( 0.67 mmol ) , yb(ch3co2)3 ( 0.3 mmol ) , er(ch3co2)3 ( 0.02 mmol ) , and nd(ch3co2)3 ( 0.01 mmol ) were added to a 50 ml flask containing oleic
acid ( 7.5 ml ) and 1-octadecene ( 17.5 ml ) .
the resulting mixture was
heated to 150 c , maintained there for 0.5 h , and then cooled
to room temperature .
subsequently , a methanol solution ( 6 ml ) containing
nh4f ( 4 mmol ) and naoh ( 2.5 mmol ) was added and stirred
at 50 c for 0.5 h. the reaction mixture was then heated to 100
c to remove the methanol .
finally , the reaction solution was
heated to 290 c and maintained for 2 h under argon flow .
the
resulting nanoparticles were washed with hexane and ethanol and redispersed
in thf .
dopamine ( 50 mg ) was
first dissolved in 300 l of deionized water , followed by adding
4.7 ml of thf .
the mixture was transferred to a 25 ml three - necked
flask and heated to 50 c under argon flow . to the 25 ml three - necked
flask
were added fept ( 15 mg ) nanoparticles in thf ( 2 ml ) and the
mixture was incubated for 5 h at 50 c .
after incubation , 100
l of hcl ( 1 m ) was added to the mixture to form a precipitate ,
which was collected by centrifugation and redispersed in ultrapure
millipore water ( 18.2 ) . to a 25 ml three - necked
flask
was added 3,4-dihydroxyhydrocinnamic
acid ( 50 mg ) dissolved in 5 ml of thf .
then 15 mg of fept nanoparticles dissolved in 2 ml of thf
was added to the flask and the mixture was incubated for 5 h. after
incubation , 200 l of naoh ( 0.5 m ) was added to the mixture
to form a precipitate , which was collected by centrifugation and redispersed
in ultrapure millipore water ( 18.2 ) .
replacement
ligand 4-aminothiophenol ( 40 mg ) was dissolved in 5 ml of thf in a
25 ml three - necked flask and heated to 50 c .
then 10 mg of pd
nanoparticles dissolved in 2 ml of thf was added to the flask and
the mixture was incubated for 5 h. after incubation , 100 l
of hcl ( 1 m ) was added to the mixture to form a precipitate , which
was collected by centrifugation and redispersed in ultrapure millipore
water ( 18.2 ) .
replacement ligand 4-mercaptobenzoic acid ( 40 mg )
was dissolved in
5 ml of thf in a 25 ml three - necked flask and heated to 50 c .
then , 10 mg of pd nanoparticles dissolved in 2 ml of thf was added
to the flask and the mixture was incubated for 5 h. after incubation ,
200 l of naoh ( 0.5 m ) was added to the mixture to form a precipitate ,
which was collected by centrifugation and redispersed in ultrapure
millipore water ( 18.2 ) .
dopamine ( 50 mg ) was
first dissolved in 300 l of deionized
water , followed by adding 4.7 ml of thf .
the above mixture was transferred
to a 25 ml three - necked flask and heated to 50 c under argon
flow . to the 25 ml three - necked flask
were added fe3o4 nanocubes ( 15 mg ) dissolved in thf ( 2 ml ) , and the mixture
was incubated for 5 h at 50 c .
after incubation , 100 l
of hcl ( 1 m ) was added to the mixture to form a precipitate , which
was collected by centrifugation and redispersed in ultrapure millipore
water ( 18.2 ) . to a 25 ml three - necked flask
was added 3,4-dihydroxyhydrocinnamic
acid ( 50 mg ) dissolved in 5 ml of thf .
then , 15 mg of fe3o4 nanocubes dissolved
in 2 ml of thf was added to the flask and the mixture was incubated
for 5 h. after incubation , 200 l of naoh ( 0.5 m ) was added
to the mixture to form a precipitate , which was collected by centrifugation
and redispersed in ultrapure millipore water ( 18.2 ) .
replacement
ligand 4-aminothiophenol ( 40 mg ) was dissolved in 5 ml of thf in a
25 ml three - necked flask and heated to 50 c .
then , 10 mg of
cdse nanoparticles dissolved in 2 ml of thf was added to the flask
and the mixture was incubated for 5 h. after incubation , 100 l
of hcl ( 1 m ) was added to the mixture to form a precipitate , which
was collected by centrifugation and redispersed in ultrapure millipore
water ( 18.2 ) .
replacement
ligand 4-mercaptobenzoic acid ( 40 mg ) was dissolved in 5 ml of thf
in a 25 ml three - necked flask and heated to 50 c .
then , 10 mg
of cdse nanoparticles dissolved in 2 ml of thf was added to the flask
and the mixture was incubated for 5 h. after incubation , 200 l
of naoh ( 0.5 m ) was added to the mixture to form a precipitate , which
was collected by centrifugation and redispersed in ultrapure millipore
water ( 18.2 ) .
dopamine ( 50 mg ) was first dissolved in 300
l of deionized water , followed by adding 4.7 ml of thf .
the
above mixture was transferred to a 25 ml three - necked flask and heated
to 50 c under argon flow . to the 25 ml three - necked flask
were
added ucnps ( 15 mg ) dissolved in thf ( 2 ml ) , and the mixture was incubated
for 5 h at 50 c .
after incubation , 100 l of hcl ( 1 m )
was added to the mixture to form a precipitate , which was collected
by centrifugation and redispersed in ultrapure millipore water ( 18.2 ) . to a 25 ml three - necked
flask
was added 3,4-dihydroxyhydrocinnamic acid ( 50 mg ) dissolved
in 5 ml of thf .
then 15 mg of
ucnps dissolved in 2 ml of thf was added to the flask and the mixture
was incubated for 5 h. after incubation , 200 l of naoh ( 0.5
m ) was added to the mixture to form a precipitate , which was collected
by centrifugation and redispersed in ultrapure millipore water ( 18.2
) .
imaging was
carried out using a hitachi h-7000 transmission electron microscope
at 100 kv .
five microliter samples of colloidal nanocrystals in hexane
or water were dropped onto a carbon - coated copper grid ( ted pella )
and then dried for tem .
-potentials
were determined
at room temperature using a zetasizer nano - zs ( malvern ) .
spectra were recorded with a near- and
mid - ir spectrometer ( a nicolet nexus 670 ) in kbr pellets .
nanocrystals were
dissolved in hexane or water for measurement . a millenia ev laser ( second
harmonic of nd : yag , 532 nm )
was used to pump a spectra - physics tsunami
femtosecond ti : sapphire laser with a repetition rate of 80 mhz .
the
output of the ti : sapphire laser was tuned to 980 nm , had pulse widths
of < 100 fs , and had a power of 375 mw .
steady - state emission spectra
were collected on a fluoromax-3 spectrophotometer . in a typical test , fept3,4-dhca
or fept dopamine ( 5 l , 3.5 mg / ml )
was added to 200 l
of tmb solution ( 1.5 mm , ph 3 ) in a quartz cuvette ( 200 l ) .
the kinetics of the peroxidase - like activity of fept was monitored
by monitoring the absorbance of oxidized tmb ( 652 nm ) on a shimadzu
uv-1800 .
the initial velocities were measured by adding 17.5 g
of ionic fept to 200 l of standard tmb solution ( ph 3 ) with
different concentrations at room temperature .
various colloidal nps , including alloyed metal , metal oxide , noble
metal , and semiconductor nanoparticles , were transferred to the aqueous
phase by this ionization process . in our model system , dopamine and
3,4-dhca were used for metal alloys and metal oxides , respectively ,
while 4-atp and 4-mcba were used for noble metals and quantum dots ,
respectively . in particular
, we selected fept , cubic fe3o4 , pd , and cdse as representative samples of a metal
alloy , metal oxide , noble metal , and semiconductor nps , respectively .
( i ) they are soluble in tetrahydrofuran with hydrophobic colloidal
nps forming a single - phase ligand - exchange environment .
( ii ) the nucleophilic
thiol groups in 4-atp and 4-mcba form stable complexes with the surfaces
of pd and cdse nps to facilitate ligand exchange .
stable metallocyclic chelates are formed between the ligands
and the undercoordinated metal atoms on the colloidal np surface ( fept
and fe3o4 ) ; meanwhile , the two phenolic hydroxyl
groups of dopamine and 3,4-dhca also promote ligand exchange .
( iii ) they have either acidic ( cooh ) or basic
( nh2 ) groups , which can be neutralized by naoh or hcl to
form ionic nps . transmission electron microscopy ( tem ) revealed
that the monodisperse
inps retain their shape and size in the aqueous phase ( figure 1c e , g
.
infrared ( ir ) spectra [ figures s1s4 , supporting information ( si ) ] show characteristic c
h stretching
peaks from oleic acid ( oa)/oleylamine ( oam ) or myristic acid ( ma )
stabilizers before ligand exchange .
however , these peaks disappeared
after replacement with dopamine and 3,4-dhca , or 4-atp and 4-mcba ,
indicating successful exchange of the original ligands .
to further
determine the degree of ligand exchange , we used nmr to characterize
the ligands before and after ligand exchange .
fe3o4 nps were used as an example , because they can be dissolved
by hcl easily to release the surface ligands . from the nmr results
( figure s7 , si ) ,
a near quantitative ligand
exchange was achieved , demonstrating a high degree of ligand exchange .
as support ,
the photographs in figure 1 ( panels f , j , n , and r ) show that fept , cubic fe3o4 , pd , and cdse nps were transferred to the aqueous
phase from the organic phase after ligand exchange and ionization .
regarding the stability of inps , carboxyl terminal inps can be stable
in buffers over a period of 3 months without obvious aggregation .
amino - terminal inps aggregated immediately when buffers were introduced .
under high temperature , both inps aggregated when the temperature
exceeded 80 c .
after ligand exchange , -potentials
were measured for surface
characterization of inps in the aqueous phase .
the ionic colloidal
nps , whether using carboxylic acid- or amine - functionalized ligands ,
were redispersed in neutral ( ph 7 ) ultrapure millipore water ( 18.2
) . table 1 shows
that the inps modified by amine - functionalized ligands and neutralized
by hcl gave positive -potentials , while the inps modified by
carboxylic acid - functionalized ligands and neutralized by naoh gave
negative -potentials . when aqueous hcl or naoh was introduced
after ligand exchange , both amine and carboxyl groups were neutralized
to form salts , either np - nh3cl or np - coona , which aggregated
in tetrahydrofuran . in water , however , the positive or negative surface
charge prevented aggregation , thus maintaining the colloidal state
of inps .
the availability of
our inps led us to explore their catalytic
properties , especially because their ionic properties would commend
their use in aqueous solutions and because their thermal stability
may exceed that of most biological catalysts .
indeed , some nanozymes ,
which are nanomaterial - based enzyme mimics , offer high stability ,
low cost , and good catalytic efficiency , making them useful in immunoassays , biosensing , bioremediation ,
and cancer diagnostics . for greatest effectiveness ,
it is important to fabricate high - quality nanozymes of uniform size
and defined structure to best fulfill specific tasks . given that horseradish peroxidase is a heme
iron
protein that is widely used in bioanalytical chemistry , we examined
our fept , fe3o4 , pd , and cdse nanoparticles
for their ability to catalyze oxidation reactions . of these , ionic
fept and cdse nps were found to catalyze the oxidation of the colorless
substrate 3,3,5,5-tetramethylbenzidine ( tmb ) , which
is blue in the absence of hydrogen peroxide , while pd and fe3o4 nps could catalyze the oxidation of tmb in the presence
of h2o2 .
( spectra of the colorless substrate
and blue product are shown in figure s8 , si . ) mindful that most nanoparticles lack the cardinal features
of enzymes
( e.g. , homogeneous composition , structurally defined active sites ,
substrate specificity , and high catalytic rate enhancements ) , we were
interested in determining whether inp catalysis could be modeled phenomenologically
by the michaelis menten equation ( v = kcat[etot}/{1 + ( km/[s ] } ) , where v is the initial velocity , kcat is the turnover number , [ etot ] is total catalyst concentration , km is the michaelis constant , and [ s ] is the substrate concentration .
in the absence of detailed information
about likely binding sites ,
we assumed that there was one catalytic center per nanoparticle , but
multiple independent centers on each particle would only affect the
true value of kcat .
( future work using
the langmuir equation with unreactive substrates should clarify the
actual number of sites per particle . )
reaction conditions were optimized
to ensure that initial velocity data were obtained , insofar as product
formation was linear with time and v was found to
be directly proportional to inp concentration .
the resulting rate
data are presented in figure 2 , and the derived rate parameters are presented in table 2 .
menten
kinetics { ( initial velocity ) versus
[ s ] } for the oxidation of tmb catalyzed by ionic fept , cubic fe3o4 , and pd nanoparticles .
the initial velocities
of parts a and b were measured by adding 17.5 g of ionic fept
to 200 l of standard tmb solution ( ph 3 ) with different concentrations
at room temperature .
the initial velocities of parts c f were
measured by adding 25 g of ionic fe3o4 or 20 g of ionic pd to 200 l of standard tmb solution
( ph 3 ) with 400 mm of h2o2 .
km is the michaelis constant , vmax is the
maximal reaction velocity , [ e ] is the ionic nanoparticle concentration ,
and kcat is the catalytic constant , where kcat = vmax/[e ] .
we found that
this peroxidase - like activities of the above nps
show different catalytic properties and ph dependencies . in the absence
of h2o2 , for example
, fept displays better catalytic
activity than cdse , which requires up to several hours ( figures s13s15 , si ) to realize an obvious
color change with tmb . in the presence of h2o2
, fe3o4 shows better catalytic activity than
pd nanoparticles . to study the effect of ph on peroxidase - like activity
all inps
showed the best catalytic activity at ph 3 ( figure s9 , si ) .
thus , ph 3 and room temperature were adopted as the
standard conditions for the steady - state kinetics assay .
menten
curves were observed for fept , fe3o4 , and pd
with several replacement ligands ( figure 2 ) , and the parameters ( table 2 and si ) were
determined according to the fitted michaelis menten model and
lineweaver
the km values of amino - terminal inps were lower than those
of the carboxyl - terminal inps , suggesting that inps with terminal
nh3 have higher affinity for substrate than
the inps with terminal coo .
this can be attributed
to the surface charges of the inps and the aromatic amine structure
of tmb .
nh3 can easily attract and template the nucleophilic
aromatic tmb . in the kinetic studies presented here , we treated
the catalytic
process as a one - substrate reaction , where molecular oxygen was kept
at oxygen - saturated conditions or where hydrogen peroxide h2o2 is present in sufficient excess . further investigation
will be required to determine how metal ions on the nanoparticle surface
facilitate catalysis by acting as lewis acids and/or substrate templates . a control experiment was conducted using ionic cdse in the absence
of h2o2 , both in the dark and in visible light ,
and no oxidized tmb
however ,
the amino - terminal ionic cdse catalyzed tmb slowly under illumination
( medium bipin base bulb , 32 w ) .
the uv vis spectra showed no obvious wavelength
shift , either before or after ligand exchange ( figure s12 , si ) . under visible light irradiation ,
the excited
electrons in the valence band were transferred to the conduction band
with holes induced in the valence band .
valence band holes are powerful
oxidants and could directly react with the electron donor tmb to form
tmb radical cations and finally yield the oxidized product .
this process
indicates that the peroxidase - like activity of ionic cdse could be
attributed to its photocatalytic property .
ionic fe3o4 nanocubes and pd nps do
not catalyze
tmb oxidation in the absence of h2o2 .
fe3o4 synthesized in aqueous phase displayed peroxidase - like
activity by the presence of rich fe on the surface .
it has been reported that porous pd np assemblies
can be used as horseradish peroxidase substitutes .
ionic fe3o4 nanocubes and pd nps ,
which were synthesized in the organic phase , also exhibited excellent
peroxidase - like activity , indicating that the peroxidase - like activity
of fe3o4 and pd nps originates from the nps
themselves .
ligand exchange and ionization transfer hydrophobic colloidal
nps to the aqueous phase , but without affecting their peroxidase - like
activity .
ionic functionalization of colloidal nps via ligand
exchange in
a single phase provides a facile method to transfer the highly crystalline
nps synthesized through pyrolysis to an aqueous phase .
notably , ligand
exchange and ionization can be generalized to other nanoparticle systems ,
such as upconversion nanoparticles ( ucnps ) , which are used extensively
in bioimaging and photodynamic therapy . as a representative ,
nayf4 ( yb 30% , er 2% , nd 1% ) was selected and synthesized in order to study optical properties before
and after ligand exchange and ionization .
tem indicated that both
shape and size were maintained ( figure 3a c ) , and no obvious change was observed in
the photoluminescence spectra ( figure 3d ) .
-potential measurements ( figure 3e ) showed that dopamine - modified
ionic nayf4 has a positive surface charge and that the
3,4-dhca - modified ionic nayf4 has a negative surface charge .
tem and
photoluminescence spectra of nayf4 ( yb 30% ,
er 2% , nd 1% ) before and after ligand exchange and ionization .
tem
of ( a ) ionic nayf4 with 3,4-dhca in water , ( b ) nayf4 before ligand exchange in hexane , and ( c ) ionic nayf4 with dopamine in water . ( d ) photoluminescence spectra of
nayf4 before and after ligand exchange and ionization .
( e ) -potential measurement for nayf4dopamine
shows positive surface charge , and nayf43,4-dhca
shows negative surface charge in water . in conclusion ,
ionic functionalization of hydrophobic colloidal
nanoparticles to form hydrophilic ionic nps via ligand exchange offers
the opportunity to develop reproducible high - quality nanoparticle
biosensors with maximal performance under physiological conditions
and to achieve large - scale application and impact .
advanced nanoparticle
biosensors can be engineered for visualization and detection on the
basis of the ionic nps .
future work can also benefit from the rational
design of nanozymes , allowing natural horseradish peroxidase to be
replaced by nanozymes , which are cheaper and more stable .
Output:
| inorganic colloidal nanoparticles
( nps ) stabilized by a layer of
hydrophobic surfactant on their surfaces have poor solubility in the
aqueous phase , thus limiting their application as biosensors under
physiological conditions . here
we report a simple model to ionize
various types of hydrophobic colloidal nps , including fept , cubic
fe3o4 , pd , cdse , and nayf4 ( yb 30% ,
er 2% , nd 1% ) nps , to multicharged ( positive and negative ) nps via
ligand exchange .
surfaces of neutral hydrophobic nps were converted
to multicharged ions , thus making them soluble in water .
furthermore ,
peroxidase - like activity was observed for ionic fept , fe3o4 , pd , and cdse nps , of which fept and cdse catalyzed
the oxidation of the colorless substrate 3,3,5,5-tetramethylbenzidine
( tmb ) to the blue - colored product in the absence of h2o2 , while pd and fe3o4 catalyzed the oxidization
of tmb in the presence of h2o2 .
with the benefit
of the ionic functionalization protocols described herein , colloidal
nps should gain wider use as biomarkers , nanozymes , and biosensors . |
PubmedSumm118253 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bovine colostrum is an opaque white liquid which is a natural source of nutrition . five main components in bovine colostrum are water , fats , proteins ( e.g. , caseins , albumins , and globulins ) , sugars ( essentially lactose ) , and mineral salts . since bovine colostrum spoils easily , it is sometimes processed into dairy products .
the most durable form of bovine colostrum is bovine colostrum powder , which is produced by the dehydration of raw bovine colostrum . in developing countries ,
casein is the major protein in cow 's milk , and comprises about 80% of the total protein content of which the rest , 20% , are the whey or serum protein [ 1 , 2 ] .
whey proteins contain alphalactalbumin ( -la ) , betalactoglobulin ( -lg ) , immunoglobulin , lactoferrin , and bovine serum albumin .
alphalactalbumin ( -la ) and betalactoglobulin ( -lg ) are two kinds of whey protein in bovine colostrum and specifically produced in the mammary epithelial cells only during lactation . as a monomer , alphalactalbumin ( -la ) and betalactoglobulin ( -lg ) strongly bind calcium and zinc ions and may possess bactericidal or antitumor activity . high - effect capillary electrophoresis ( hpce ) ,
this technology already has applied to protein and aminofacid broadly for many years . due to the appealing advantages in separation efficiency and resolution , small amounts of solvent and sample , ce
have rapidly been applied for the assay in the protein separation field . for a long time , the capabilities of matrix - assisted laser desorption / ionization ( maldi ) mass spectrometry for the rapid evaluation of proteins have been proved .
furthermore , it has also been tested to be a valid tool in the dairy industry .
although the technique does not determine the exact concentrations of bovine colostrum proteins , the relative proportions of several main bovine colostrum proteins can be identified . in this experiment ,
another portion was separated with cpe method and detectable differences in their maldi spectra were found .
the present work describes alphalactalbumin ( -la ) and betalactoglobulin ( -lg ) in the rehydration of bovine colostrum powder were successfully separated by cloud point extraction using a nonionic surfactant triton x-114 .
the separation was mainly based on their contrasting hydrophobicities , and our main goal was to achieve the highest concentration of alphalactalbumin ( -la ) and betalactoglobulin ( -lg ) in the surfactant - poor phase obtaining high efficiency of cpe method .
since separation of these proteins using cpe depends on several variables , such as type and concentration of surfactant , ph , net charge , size and sample volume [ 6 , 7 ] , the optimization design was concluded in .
the matrix - assisted laser desorption ionization - time of flight mass spectrometry ( maldi - tof ms ) was used to confirm the separation of alphalactalbumin ( -la ) and betalactoglobulin ( -lg ) from the rehydration of bovine colostrum powder .
bovine colostrum powder ( sunlife bovine colostrum powder ) was purchased in a local chinese market . all the water used in
the experiment was milli - q deionized water ( millipore , billerica , ma , usa . ) .
acetonitrile ( hplc grade ) was obtained from sk chemicals ( ulsan , korea ) .
the -cyano-4-hydroxycinnamic acid ( chca ) was obtained from applied biosystems ( foster city , ca , usa ) .
trifluoroacetic acid ( tfa ) was obtained from sigma - aldrich ( steinheim , germany ) .
nacl , isooctylphenyl ether ( triton x-114 ) , and sucrose were obtained from sigma - aldrich ( steinheim , germany ) .
the factors were triton x-114 concentration , sample volume , nacl and sucrose concentration , and ph . the surfactant solution was prepared with 10 mmol / l tris - hcl ( ph 7.4 ) , 150 mmol / l nacl , and 6% ( w / v ) sucrose .
200 l bovine colostrum sample was added to the surfactant solution , and the solution was homogenized again .
the ce was performed using a p / ace mdq capillary electrophoresis system ( beckman coulter , fullerton , ca , usa ) under a normal polarity separation mode . a capillary ( beckman coulter , fullerton , ca , usa ) with 50 cm effective length ( 60 cm total ) and
an inner diameter ( i.d . ) of 75 m was used with an applied voltage of 25 kv at 20c .
prior to use the capillary for the first time , a rinse for 1 min ( 30 psi ) with 0.1 mol / l hcl was performed .
a rinse for 10 min ( 30 psi ) with the running buffer was performed then equilibrate the capillary for 10 min ( 25 kv ) .
finally a rinse for 10 min ( 30 psi ) was performed the temperature of the separation capillary column was thermostated at 20 c. among each runs , the capillary was rinsed with 0.1 mol / l hcl for 0.5 min and then with the electrophoresis buffer for 1.5 min .
the separation buffer was 50 mm citrate buffer ( ph 3.0 ) , and the applied voltage is 25 kv . the electrophoresis buffers were filtered through 0.22 m filter before use .
the samples were dissolved in 1 ml of buffer and filtered [ 0.22 m ( millipore ) ] for ce analysis .
samples were injected into the capillary using pressure at 0.5 psi for 10 s. the absorbance was measured at a wavelength of 214 nm for the detection of protein . to prepare a saturated solution of chca matrix : 10 mg of the dry chca matrix
was added to a tube containing 1 ml solution of water / acetonitrile/0.1% tfa ( 4/5/1 , v / v / v ) .
0.5 l of the sample / matrix ( 1/5 , v / v ) mixture was spotted per well on a stainless steel maldi sample plate .
all the maldi measurements were performed on a 4700 proteomics analyzer ( applied biosystems , foster city , ca , usa ) equipped with a nd : yag laser ( 355 nm ) operating at 200 hz .
ions formed by a pulsed laser beam were accelerated to 20 kilo volts in positive ion linear mode with a 740 ns delay times .
the acquisition method was set as follows : 60 subspectra were acquired on one spot and 25 shots were averaged per subspectrum , so one maldi spectrum was the accumulated spectra of a total of 1500 shots per spot . for each sample ,
five spots were equally spotted and examined , and the acquisition method ran three times per spot .
the final data were the trimmed means of the results of these 15 parallel tests as a whole .
this instrument operating parameters were optimized for ion peaks corresponding to apomyoglbin ( horse , m / z 16952 ) , thioredoxin ( e. coli , m / z 11674 ) , and insulin ( bovine , m / z 5734 ) .
to highlight the extraction of whey proteins from bovine colostrum and their separation from casein proteins by cloud point extraction , ce was used to identify -lactalbumin and -lactoglobulin extracted from the rehydration of bovine colostrum powder .
the electropherograms of standard and cloud point extraction sample from the rehydration of bovine colostrum powder were shown in figures 1(a ) and 1(b ) and figure 1(c ) , respectively .
the retention time of -lactalbumin and -lactoglobulin was about 10 and 15 min under the optimal separation condition . in figure 1(c ) , there were only two whey protein peaks ( -lactalbumin and -lactoglobulin ) .
it was proved right with maldi - tof ms in the next experiment . from figure 1(c ) , it is also proved the efficiency of the extraction procedure is successful . to highlight the extraction of whey proteins from bovine colostrum and their separation from casein proteins by cpe , maldi - tof ms to
intact samples of the two protein fractions was applied . a simple sample treatment that only involved dilution of precipitated proteins was performed . figure
2(a ) displays the mass spectra obtained , and it summarizes different proteins identified in the surfactant poor and water phases .
the theoretical molar masses are in agreement with those previously described for whole cow bovine colostrum protein analyses by maldi - tof ms .
the mass spectra of figure 2(a ) show ions of ca.m / z11958 and 23919 corresponding to the -casein and -casein , respectively .
those ions in figure 2(b ) of higher m / z values correspond to -lactalbumin ( m / z14152 ) and -lactoglobulin ( m / z18318 ) .
finally , the ion of ca.m / z 14152 in figure 2(b ) probably corresponds to species originating from lactose addition to -lactalbumin .
the main proteins identified in the surfactant poor phase ( figure 2(b ) ) were -lactalbumin and -lactoglobulin , which are fractions of the whey proteins . besides such proteins , -casein and -casein were also detected in the water phase .
in fact , both last proteins also present amphiphilic character [ 4 , 5 ] , corroborating their presence in the surfactant poor phase .
cpe was efficiently employed to cow bovine colostrum samples being able to extract and separate whey from casein proteins using only 200 l of sample volume , sample volume without any sample pretreatment .
( 1% , w / v ) , 150 mmol / l nacl , and sucrose ( 6% , w / v ) were used at ph 7.0 for protein separations . at such conditions ,
good partition coefficient was obtained , allowing the separation of -lactalbumin and -lactoglobulin ( present in the surfactant poor phase ) from casein proteins ( present in the water phase ) in only 15 min and with minimum costs , indicating that the proposed factorial design was successfully applied in the experimental domain employed and the main objective of this work attained .
although the partition coefficient was obtained , it is important to comment that some hydrophobic proteins were achieved in the surfactant poor phase and vice versa , as demonstrated through maldi - tof ms analysis .
after cloud point extraction , the capillary electrophoresis was used to check the efficiency of the extraction procedure .
the results had been effectively confirmed by the characterization with matrix - assisted laser desorption ionization time of flight mass spectrometry ( maldi - tof ms ) . finally , the adopted strategy could also be used for separating those low - abundant proteins in bovine colostrum after properly optimizing the cpe method for such task .
Output:
| alphalactalbumin ( -la ) and betalactoglobulin ( -lg ) in the rehydration of bovine colostrum powder were successfully separated by cloud point extraction using a nonionic surfactant triton x-114 .
the effects of different factors , including the surfactant concentration , sample volume , electrolyte , and ph were discussed . the optimized conditions for cloud point extraction of alphalactalbumin ( -la ) and betalactoglobulin ( -lg )
can be concluded that the best surfactant is 1% ( w / v ) triton x-114 , 200 l of sample volume , 150 mmol / l nacl , and 6% ( w / v ) sucrose .
after cloud point extraction , the capillary electrophoresis is used to check the efficiency of the extraction procedure .
the results had been effectively confirmed by the characterization with matrix - assisted laser desorption ionization time of flight mass spectrometry ( maldi - tof ms ) . |
PubmedSumm118254 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the incidence of acetabular fracture is gradually rising due to the increased incidence of high - energy injuries .
therefore , as an intra - articular fracture with deep anatomical position and complex types , acetabular fracture should be treated with accurate anatomic reduction , firm fixation , and early rehabilitation , which can obtain optimal results as soon as possible .
usually , acetabular fractures are managed with surgical fixation unless criteria for conservative treatment are fulfilled . however , the treatment of acetabular fractures is a major challenge for most orthopedists , not only due to combined multiple organ injuries , but also due to the complicated fracture type and complexity of surgical reconstruction .
most authors agree that positive open reduction and internal fixation ( orif ) during the early stage of complex acetabular fracture helps to restore hip joint function postoperatively [ 69 ] .
however , in recent years many have advocated ileo - inguinal and kocher - langenbeck approaches combined with the procedure above , which can develop a bottleneck when performing reduction . moreover
, the complications with this fracture , including severe soft tissue injury , intractable reduction , vulnerability of nerve and blood vessels , serious hemorrhage , and unclear exposure of the operative field , might result in difficult reduction , prolonged operation time , and poor functional recovery .
therefore , limiting intraoperative blood loss in orthopedic trauma surgery remains challenging for orthopedic surgeons . in recent years
, the use of an abdominal aortic occlusion balloon catheter to control excessive blood loss during surgery has been developed , including use in cesarean hysterectomy and other pelvic and sacral operations .
therefore , the purpose of this study was to investigate the efficacy of temporary balloon occlusion of the abdominal aorta in orif of complex acetabular fractures .
this retrospective study was approved by the affiliated shandong provincial hospital of shandong university institutional review board .
a total of 41 patients , who were treated for acetabular fractures at the affiliated shandong provincial hospital of shandong university from november 2000 to november 2010 , were enrolled in this study .
the inclusion criteria of this study were : 1 ) subjects with complex acetabular fracture ; 2 ) all patients aged no more than 60 years ; and 3 ) individuals diagnosed with the following types of fractures : anterior column with posterior hemi - transverse fracture , transverse with posterior wall fracture , t - shaped fracture , and both - column fracture .
exclusion criteria were : 1 ) age over 60 years ; 2 ) pathological fracture or other fractures ; 3 ) cardiac disease , diabetes , vascular disease of lower extremities , cancer , or immunodeficiency ; and 4 ) absence of follow - up information .
all data , including patient demographics and operative data , were collected from the hospital records .
all patients received a routine x - ray radiograph , computed tomography ( ct ) scan , and 3d ct reconstruction before surgery .
all operations were performed by the same fellowship - trained surgeon . under general anesthesia ,
then , the temporary balloon occlusion of the abdominal aorta was performed ; it should be used on patients if they have obvious displacement of acetabular fracture , broad dissection area , difficult reduction , or anticipation of severe hemorrhage .
the kocher - langenbeck approach , as previously described , was used to assist intraoperative orif .
all patients received reconstructive plate fixation of antero - posterior columns of the acetabulum ( figure 1 ) .
recovery status of patients was recorded . a routine , broad - spectrum antibiotic and non - steroidal anti - inflammatory drug ( nsaid )
after partial weight - bearing at 6~8 weeks postoperatively , we gradually added weight to full weight - bearing , according to the individual state of the patient . during regular follow - up , we performed x - ray radiography to evaluate the position of screws .
the operation time , intraoperative blood loss , and transfusion volume during the operation were recorded .
the reduction was assessed according to modified matta reduction criteria : excellent : anatomical reduction of the fracture ; good : 0~1 mm displacement unresolved ; medium : 2~3 mm displacement unresolved ; and poor : > 3 mm displacement unresolved .
the hip function was determined based on the modified merle daubign and postel hip scoring system : pain : 6 points , walking : 6 points , range of motion of hip joint : 6 points ( 18 points in total ) .
an excellent score is 18 points ; good is 15~17 points ; medium is 13~14 points ; and poor is < 13 points .
independent - samples t tests and mann - whitney u test were used for comparisons between groups .
there were 18 patients who underwent orif combined with temporary balloon occlusion of the abdominal aorta ( group a ) and 23 patients who only received normal orif .
the follow - up ranged from 12 to 30 months ( mean , 7.5 ) .
the mean time for performing temporary balloon occlusion of the abdominal aorta was 50.517.6 min .
the mean operative time was 213.38.9 min in group a and 248.37.0 min in group b. we observed a significant difference between the 2 groups in operative time ( p=0.003 ) . for intraoperative blood loss and blood transfusion , orif combined with temporary balloon occlusion of
the abdominal aorta appeared to be superior to normal orif ( blood loss : p=0.007 ; and blood transfusion : p=0.019 ) .
however , no differences were observed in postoperative blood loss or transfusion ( p>0.05 ) . in group
a , we did not observe any complications associated with occlusion of the abdominal aorta , including arterial puncture , renal impairment , spinal cord ischemic injury , ischemic necrosis of abdominal or pelvic organs , and vascular intimal injury . according to assessment of the reduction described by the matta reduction criteria , in group a 10 cases
were identified as excellent , 5 as good , 2 as medium , and 1 as poor , with a good - to - excellent rate of 83.3% . in group
b , there were 12 cases identified as excellent , 7 as good , 2 as medium , and 2 as poor , with a good - to - excellent rate of 82.6% .
the good - to - excellent rates in both groups were comparable ( p>0.05 ) .
based on the modified merle daubign and postel system , in group a hip function was excellent in 9 cases , good in 5 , medium in 3 , and poor in 1 , with a good - to - excellent rate of 77.8% .
in group b hip function was excellent in 11 , good in 7 , medium in 3 , and poor in 2 , with a good - to - excellent rate of 78.3% .
this suggests that hip function in the 2 groups was equivalent ( p>0.05 ) . with regard to postoperative complications , in group
a we observed 2 cases with incision fat liquefaction and 3 cases in group b. deep venous thrombosis of lower extremities was present in 1 case in group a , 2 in group b , cured by anticoagulant therapy .
there was 1 osteonecrosis of the femoral head in group a and 1 in group b , stabilized by conservative treatment .
there were 3 heterotopic ossifications in group a and 4 in group b , treated by indomethacin .
there were 2 transient paralysis of the sciatic nerve in group a and 1 in group b. there were no significant differences in the incidence of complications between the 2 groups ( group a : 9/18 ; group b : 11/23 ; p=0.890 ) .
it is difficult to perform a surgical approach to the acetabulum and to conduct an accurate orif due to the complicated anatomical structure and deep location of the acetabulum , as well as the risk of serious hemorrhage .
therefore , a thorough preoperative diagnosis and treatment plan , including the order of reduction and method of fixation , are necessary . a sufficient surgical field must be secured during the actual surgical procedure ; therefore , it is important to control bleeding using temporary balloon occlusion of the abdominal aorta . according to the letournel classification , complex acetabular fractures are usually classified into 4 types : anterior column with posterior hemi - transverse fracture , transverse with posterior wall fracture , t - shaped fracture , and both column fracture .
acetabular fractures are usually caused by high - energy injury with severe associated or multiple injury , including life - threatening head injury and organ injury in the thoracic and abdominal cavities , with severe hemorrhage . due to the deep anatomical position of the acetabulum , damage to major nerves and blood vessels
should be avoided during the operation ; therefore , it is necessary to ensure adequate exposure of the operative field to avoid this risk .
several combined approaches for complex acetabular fracture have been developed to control hemorrhage risk ; however , outcomes were not satisfactory .
the balloon catheter was first used in vascular interventional treatment , including angioplasty and perfusion therapy , as well as embolization therapy , to prevent flux and reflux , especially for those who may have an increased risk of severe blood loss during the operation .
crawford et al . first inserted a fogarty balloon catheter into organ arteries to preclude the blood flux , and then clasped the abdominal aorta and removed the aneurysm .
after that , abdominal aorta occlusion was gradually used more in various operations , including removal of gynecological , pelvic , and sacral tumors .
given the severe intraoperative hemorrhage in complex acetabular fractures , we hypothesized that using temporary balloon occlusion of the abdominal aorta might decrease intraoperative blood loss and improve the operative field . the decision to start occlusion
should be based on the intraoperative blood loss volume after the exposure of fracture ends .
the occlusion time should be limited to no more than 60 min so that there is less damage from complete ischemia .
if occlusion time is over 60 min , the occlusion should be paused ( the incision should be staunched using gauze ) and resumed 15 min later . in this study , we did not observe any complications caused by occlusion .
first , this was a study based on retrospective analysis , not a randomized controlled trial , which might have resulted in selection bias .
second , the sample size in this study was relatively small ; therefore , a randomized control study with larger sample size is needed to provide stronger conclusions .
finally , the follow - up period could be considered as being relatively short since it was only 30 months .
use of temporary balloon occlusion of the abdominal aorta assisting orif in treatment of complex acetabular fractures can effectively prevent excessive blood loss . this new technique can help create a clear operative field by reducing blood flux , thereby making reduction and fixation easier , and shortening the operation time , which improve its effectiveness in treating complex acetabular fractures .
Output:
| backgroundthe aim of this study was to explore the efficacy of temporary balloon occlusion of the abdominal aorta assisting open reduction and internal fixation ( orif ) in the treatment of complex acetabular fracture.material/methodsfrom august 2000 to october 2011 , a total of 48 patients with complex acetabular fracture were enrolled in this study .
average operative time , intraoperative blood loss volume , blood transfusion volume , satisfactory reduction , and postoperative functional recovery rate were recorded and compared between the 2 groups.resultsa significant difference was observed between the 2 groups in operative time ( p=0.003 ) . for intraoperative blood loss and blood transfusion , orif combined with temporary balloon occlusion of abdominal aorta techniques appeared to be superior to normal orif ( blood loss : p=0.007 ; and blood transfusion : p=0.019 , respectively ) .
however , no differences were observed in postoperative blood loss or transfusion ( p>0.05 ) .
patients in group a showed better hip function than those in group b ( group a : a good - to - excellent rate of 77.8% ; group b : a good - to - excellent rate of 78.3% ; p>0.05 ) . with regard to the incidence of postoperative complications , there were no significant differences between the 2 groups ( group a : 9/18 ; group b : 11/23 ; p=0.890).conclusionsin the treatment of complex acetabular fracture , temporary balloon occlusion of the abdominal aorta is a reliable technique to assist orif surgery to staunch the flow of blood . |
PubmedSumm118255 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: alterations in salivary function may lead to impairment of oral tissues , and risk of patients developing dental caries , oral discomfort , and candidiasis is increased . decreased salivary flow rates can have a large impact on patient 's quality of life .
menopause is the time of life when menstrual cycles cease and is caused by reduced secretion of the ovarian hormones estrogen and progesterone .
natural menopause is diagnosed after 12 months of amenorrhea not associated with a pathological cause .
the prevalence of oral symptoms was found to be significantly greater in menopausal women ( 43% ) than in premenopausal females ( 6% ) . increased incidences of xerostomia , lichen planus , pemphigoid ,
sjogren 's syndrome , burning mouth syndrome , and periodontal disease are observed during menopause .
estrogen can affect oral mucosa directly or through neural mechanism , thus altering the periodontal health in menopausal women .
this is associated with qualitative and quantitative changes of the saliva , which needs to be objectively assessed referred to as salivary hypofunction .
estimation of quantitative and qualitative salivary changes is challenging in a clinical setup owing to the lack of standardization in saliva collection methods .
the qualitative or quantitative salivary changes vary considerably , which can be attributed to differences in whole versus glandular saliva and unstimulated versus stimulated methods of collection
. the challacombe scale of clinical oral dryness could be used routinely and effectively by the general dental practitioner and specialist to assess and semiquantify the severity of oral dryness owing to its simplicity .
we hypothesize that salivary flow rate measured by sialometry correlates with clinical oral dryness score ( cods ) , and hence , the latter could be used to assess oral dryness .
we also hypothesize that xerostomia is distinct from unstimulated salivary flow rates and visual assessment of a dry mouth .
this study was carried out to assess the oral dryness in postmenopausal women and to correlate the salivary flow rate determined by sialometry with the cods obtained from challacombe scale .
in addition , the correlation between subjective and objective oral dryness and relationship of salivary flow rate with duration of menopause was evaluated .
a cross - sectional , descriptive study was conducted on sixty postmenopausal women attending the department of oral medicine and radiology , coorg institute of dental sciences , who had not had a menstrual cycle for at least 12 months .
patients on known xerogenic drugs such as cytotoxic drugs , anticholinergic drugs , centrally acting psychoactive agents , opioids , sympathomimetic drugs , and diuretics were excluded from the study .
patients with certain systemic diseases such as diabetes mellitus , sjogren 's syndrome , patients under corticosteroid or hormone replacement therapy , and patients with poor gingival and periodontal health were excluded .
gingival status of the patients was assessed using gingival index of loe and silness ( 1963 ) .
the presence of xerostomia was assessed by questioning the patient about the subjective perception of oral dryness .
of 60 patients , based on the response , 23 patients with xerostomia formed the case group and remaining 37 patients without xerostomia formed the control group .
the signs of dryness in the mouth were examined using a scoring system ( cods ) which is composed of ten features : ( 1 ) mirror sticks to buccal mucosa , ( 2 ) mirror sticks to tongue , ( 3 ) saliva frothy , ( 4 ) no saliva pooling in floor of mouth , ( 5 ) tongue shows loss of papillae , ( 6 ) altered gingival architecture / smooth ( especially anterior ) , ( 7 ) glassy appearance to oral mucosa ( especially palate ) , ( 8) tongue lobulated / deeply fissured , ( 9 ) cervical caries ( more than two teeth ) , and ( 10 ) mucosal debris on palate ( excluding under dentures ) .
the evaluator made use of a pro forma with illustrations of dry mouth features for scoring oral dryness .
unstimulated whole saliva ( uws ) was collected under resting conditions between 9 am and 12 pm at least 2 h after the last intake of food or drink .
subsequently , resting uws samples were collected using the spit method over a period of 5 min .
the patients were asked to spit into a dry , disposable plastic preweighted cup for 5 min at 1 min intervals .
the volume of saliva was determined and flow rate expressed as ml / min , where 1 g saliva = 1 ml . the uws flow rates were categorized as very low ( < 0.1 ml / min ) , low ( 0.10.25 ml / min ) , and normal ( > 0.25 ml / min ) , as per the classification of whole saliva flow rate proposed by ericsson and hardwick .
two observers were recruited for the assessment of cods and sialometry . to avoid bias ,
the study was approved by the institutional review board and the ethics committee of the institution .
pearson 's orrelation coefficient was used to analyze the relationship between uws flow rates and cods and also to determine the relationship between duration of menopause and uws flow rates .
independent sample t - test assessed the relationship of subjective oral dryness with that of cods and uws flow rates .
all the analyses were carried out with the use of statistical package for the social sciences ( spss ) ibm corp . released 2011 .
pearson 's orrelation coefficient was used to analyze the relationship between uws flow rates and cods and also to determine the relationship between duration of menopause and uws flow rates .
independent sample t - test assessed the relationship of subjective oral dryness with that of cods and uws flow rates .
all the analyses were carried out with the use of statistical package for the social sciences ( spss ) ibm corp . released 2011 .
the age range of patients was between 42 and 66 years with a mean age of 54.45 years .
the mean unstimulated salivary flow rate was 0.28 ml / min and mean cods was 4.2 .
13.3% patients had very low uws flow rate , 23.3% patients had low uws flow rate , and 63.3% patients had normal uws flow rate [ figure 1 ] .
percentage of unstimulated salivary flow rates among sixty postmenopausal women the results of the pearson 's orrelation coefficient showed highly significant negative correlation between uws and cods ( r = 0.651 ) , i.e. cases with low salivary flow rates had higher cods [ figure 2 ] .
scatter plot of correlation between unstimulated whole saliva flow and clinical oral dryness score ( pearson 's r = 0.651 ) the duration of menopause [ table 1 ] ranged from 1 to 26 years among the study population .
number of years since menopause ranged from 1 to 26 years a low negative correlation was observed between the duration of menopause and uws flow rates ( r = 0.159 ) . among 23 cases who reported with subjective oral dryness
of 37 cases who did not report having xerostomia , 11 had very low and low unstimulated salivary flow rates [ table 2 ] .
twenty - three cases reported having xerostomia , of which 11 had very low and low unstimulated whole saliva and 12 had normal unstimulated whole saliva .
thirty - seven cases did not report having xerostomia , of which 11 had very low and low unstimulated whole saliva and 26 had normal unstimulated whole saliva the independent sample t - test showed no significant correlation between subjective oral dryness with that of uws flow rates ( p = 0.0964 ) .
independent t - test showed no statistically significant difference between the case group and control group with regard to the cods score ( p = 0.525 ) [ table 3 ] .
mean clinical oral dryness score for cases with xerostomia ( n=23 ) is 4.5652 ; mean clinical oral dryness score for cases without xerostomia ( n=37 ) is 4.0811
the age range of patients was between 42 and 66 years with a mean age of 54.45 years .
the mean unstimulated salivary flow rate was 0.28 ml / min and mean cods was 4.2 .
13.3% patients had very low uws flow rate , 23.3% patients had low uws flow rate , and 63.3% patients had normal uws flow rate [ figure 1 ] .
the results of the pearson 's orrelation coefficient showed highly significant negative correlation between uws and cods ( r = 0.651 ) , i.e. cases with low salivary flow rates had higher cods [ figure 2 ] .
scatter plot of correlation between unstimulated whole saliva flow and clinical oral dryness score ( pearson 's r = 0.651 )
the duration of menopause [ table 1 ] ranged from 1 to 26 years among the study population .
number of years since menopause ranged from 1 to 26 years a low negative correlation was observed between the duration of menopause and uws flow rates ( r = 0.159 ) .
among 23 cases who reported with subjective oral dryness , only 11 had very low and low unstimulated salivary flow rates .
of 37 cases who did not report having xerostomia , 11 had very low and low unstimulated salivary flow rates [ table 2 ] .
twenty - three cases reported having xerostomia , of which 11 had very low and low unstimulated whole saliva and 12 had normal unstimulated whole saliva .
thirty - seven cases did not report having xerostomia , of which 11 had very low and low unstimulated whole saliva and 26 had normal unstimulated whole saliva the independent sample t - test showed no significant correlation between subjective oral dryness with that of uws flow rates ( p = 0.0964 ) .
independent t - test showed no statistically significant difference between the case group and control group with regard to the cods score ( p = 0.525 ) [ table 3 ] .
mean clinical oral dryness score for cases with xerostomia ( n=23 ) is 4.5652 ; mean clinical oral dryness score for cases without xerostomia ( n=37 ) is 4.0811
nederfors et al . interviewed 3,313 randomly selected individuals aged 2080 years in sweden and found that the prevalence of perceived xerostomia was 21.3% for men and 27.3% for women .
some studies demonstrated reduction while others have not found any change in the saliva of menopausal women .
along with the physiological aging of the oral tissues , the hormone changes that take place in menopausal women are responsible for the alterations observed within the oral cavity .
a weak negative correlation was observed between the duration of menopause and salivary flow rates in our study .
yalcin et al . have found a strong association of menopause with low saliva flow rate .
our study showed that only a small number of cases exhibited very low salivary flow rates .
food debris , microorganisms , and gingival crevicular fluid are other components of the whole saliva .
five minutes has been generally used collection time in the assessment of flow rate of unstimulated and stimulated saliva .
irrespective of the absence or presence of stimulation in the evaluation of salivary flow , whole saliva primarily reflects the functional status of the submandibular and sublingual glands , as these are mainly responsible for basal secretion .
determination of flow rates of glandular saliva requires special armamentarium and is essential for research purposes since whole saliva constitutes other components other than saliva . routinely performing these procedures in clinical settings in clinical assessment
other factors which affect salivary flow assessment are ambient temperature , air humidity , environmental noises , time of sampling , duration of collection , type of gustatory stimulation , consistency and size of the mechanical stimulus , fasting period , environment brightness , and season of the year .
hence , evaluation of xerostomia is intended to be done at specific time of the day , and standardization of sialometry collection techniques needs to be undertaken to avoid variations .
thomson have utilized visual analog scale questionnaire and xerostomia inventory , respectively , for the subjective assessment of salivary dysfunction and have found that the questionnaires are helpful in detecting changes in salivary flow over time .
xerostomia denotes the subjective sensation of dry mouth and may occur despite normal salivary gland activity .
xerostomia may also occur with the changes in the quality of saliva even when amount of saliva is unaffected .
this is the reason that people sometimes complain of dry mouth but have proper salivation .
therefore , a patient complaining of dry mouth can not automatically be assumed to have salivary dysfunction while oral dryness may have many causes .
fox et al . examined the intimate relationship between subjective reports of xerostomia and flow rates of parotid and submandibular / sublingual saliva in 93 cases .
they concluded that oral dryness and salivary hypofunction were not quantitatively related to each other which were similar to the findings of our study .
several semi - quantitative tests have been performed in the past for the clinical assessment of oral dryness .
snchez - guerrero et al . performed wafer test for screening of xerostomia . a high negative correlation ( 0.60 )
was found between the time of dissolution of wafer and unstimulated whole saliva flow rate .
a study was conducted by wiener et al . to investigate the association between three measures of oral dryness : hyposalivation ( low unstimulated salivary flow ) , self - reported xerostomia , and clinically assessed dry mouth in dentate older adults .
they have reported that visually inspecting oral tissues for dryness and asking a patient if his or her mouth is dry are insufficient measures for clinicians to use to determine whether the patient has hyposalivation .
our study , however , showed a highly significant negative correlation between cods and uws .
osailan et al . in their study have shown cods to be reliable and easy to use for routine assessment of the severity of dry mouth . apart from finding a general inverse relationship between cods and salivary flow rate , cods was higher in cases with lower mucosal wetness .
they also hypothesized that cods could discriminate between those with moderate reductions in mucosal wetness even when the uws was within the accepted normal range .
in addition , a very good agreement between two examiners was found when comparisons were made of the scores as well as the features scored by each examiner .
since cods is unaffected by the time of the day and the ease involved in the use of cods , makes it effective to be used routinely in evaluation of oral dryness .
the shortcoming we came across during the study was inability to utilize cods for edentulous cases .
no statistically significant difference was observed when the relationship between subjective and objective oral dryness was assessed .
a low negative correlation was noted between the duration of menopause and uws flow rates .
oral dryness needs to be identified early so that suitable interventions can be carried out to augment patient 's quality of life .
cods is a semiquantitative measure of oral dryness which involves visually inspecting the oral cavity which is beneficial in assessing the effectiveness of treatment given for reduced salivation . since codss correlated well with sialometry
, cods can be utilized routinely by the dental practitioners for semiquantitative assessment of oral dryness .
Output:
| objective : the aim of this study was to assess the oral dryness in postmenopausal women and to correlate the salivary flow rate determined by sialometry with the clinical oral dryness score ( cods ) obtained from challacombe scale . to correlate between subjective and objective oral dryness and relationship of salivary flow rate with that of the duration of menopause.materials and methods : sixty postmenopausal women were questioned regarding their oral dryness status and the duration of menopause .
patients complaining of xerostomia formed the case group and rest formed the control group .
cods was assessed based on the 10 features of oral dryness .
unstimulated whole salivary ( uws ) flow rate was assessed by sialometry for 5 min.results:highly significant negative correlation was observed between uws and cods ( r = 0.651 ) , low negative correlation was noted between the duration of menopause and uws flow rates ( r = 0.159 ) , and no significant correlation was found between subjective oral dryness with that of uws flow rates ( p = 0.0964 ) .
there was no statistically significant difference between case and control group with regard to cods ( p = 0.525).conclusion : a good correlation of cods with sialometry scores indicates that cods can be utilized for semiquantitative assessment of oral dryness .
it appears that uws has poor correlation with duration of menopause .
xerostomia and uws were not significantly related . |
PubmedSumm118256 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: polychlorinated biphenyls ( pcbs ) are a class of environmental pollutants that have from one to 10 chlorines substituted on the phenyl rings .
pcbs have been widely used from the 1930s to the 1960s in diverse industrial applications , including cooling and insulating fluids for industrial transformers and capacitors , hydraulic fluids , and sealants ( 1,2 ) .
pcbs are known to elicit various adverse effects , including carcinogenicity , neuroendocrine disturbances , developmental and reproductive toxicity , and immunotoxicity ( 3,4 ) .
pcbs have been implicated in or related to cancer such as malignant melanoma , breast , and lung cancers in exposed populations ( 5 ) .
the production of pcbs was banned in the 1970s due to the high toxicity of most pcb congeners and mixtures . however , because of their physical and chemical properties , pcbs are quite stable ; thus , they remain as ubiquitous environmental contaminants , which are frequently found as complex mixtures of isomers and congeners in air , water , soil , and dust on surfaces in homes and in factories ( 6 ) .
lower halogenated pcbs have been shown to be metabolized by rat microsomes to phenol and dihydroxybiphenyl metabolites ( 79 ) .
robertson et al . have reported that the primary metabolites of 4-monochlorobiphenyl are 4-chloro-2-hydroxybiphenyl , 4-chloro-3-hydroxybiphenyl , and 4-chloro-4-hydroxybiphenyl ; these phenolic compounds can then subsequently undergo a second hydroxylation yielding 4-chloro-3,4-dihydroxybiphenyl , 4-chloro-2,3-dihydroxybiphenyl , and 4-chloro-2,5-dihydroxybiphenyl ( 10 ) .
these para - dihydroxy pcbs and catechol type ortho - dihydroxy pcbs can be further oxidized to reactive quinones .
early research suggests that the intracellular activation of hydroquinones and quinones producing relatively stable semiquinone free radicals is an important step to account for their cytotoxicity ( 11 ) .
radicals produced downstream , such as superoxide anion radical ( o2 ) , will lead to hydrogen peroxide and hydroxyl radical formation ( ho ) ; these active oxygen species will deplete antioxidants and potentially lead to an increase in oxidative stress ( 1215 ) .
these reactive oxygen species can oxidize lipids , proteins , and dna ( 1618 ) . in the work reported here , we used epr to examine the many routes that can lead to the formation of pcb - semiquinone radicals .
we also examined the different spectral patterns of these various semiquinone radicals and used the changes observed in the epr spectra to understand their chemistry .
caution : pcb derivatives should be handled as hazardous compounds in accordance with nih guidelines .
hypoxanthine ( hx),1 xanthine oxidase ( xo ) , horseradish peroxidase ( hrp ) , tyrosinase ( tyr ) , lactoperoxidase ( lpo ) , catalase ( cat ) , superoxide dismutase ( sod ) , and diethylenetriaminepentaacetic acid ( detapac or dtpa ) were from sigma ( st . louis , mo ) ; benzoquinone , hydroquinone , phenyl - quinone , sodium hydroxide , and h2o2 were from fisher ; and quinhydrone was from alfa aesar ( ward hill , ma ) .
stock solutions of hx ( 10 mm ) , hrp ( 0.2 u/l ) , tyr ( 1 u/l ) , h2o2 ( 20 mm ) , sod ( 100 u/l ) , and cat ( 20 u/l ) were prepared with nanopure water just before use ; xo ( 10.8 mu/l ) and lpo ( 208 mu/l ) were used as received .
all experiments were carried out in 100 mm phosphate buffer containing 250 m detapac . when needed , adjustment of the ph was done with 5 m sodium hydroxide solution .
epr spectroscopy was done using a bruker emx spectrometer equipped with a high - sensitivity cavity and an aqua - x sample holder .
typical epr parameters were as follows : 3511 g center field ; 15 or 80 g sweep width ( for the spin trapping experiments with dmpo ) ; 9.854 ghz microwave frequency ; 20 mw power ; 2 10 receiver gain ; modulation frequency of 100 khz ; modulation amplitude of 1 or 0.1 g ; with the conversion time and time constant both being 40.96 ms with 5 x - scans for each 1024 point spectrum .
alkaline solutions ( ph 10 ) were prepared by adjusting with 5 m sodium hydroxide solution .
spectral simulations of epr spectra were performed using the winsim program developed at the niehs by duling ( 22 ) .
1abbreviations : a ( 4 ) , hyperfine splitting constant due to four identical hydrogens ; a , hyperfine splitting due to the hydrogen on position 3 of the pcb phenyl ring ; bq , benzoquinone ; cat , catalase ; detapac , diethylenetriaminepentaacetic acid ; dmpo , 5,5-dimethylpyrroline-1-oxide ; h2q , hydroquinone ; hrp , horseradish peroxidase ; hx , hypoxanthine ; lpo , lactoperoxidase ; mnsod , manganese - containing superoxide dismutase ; pq , phenyl - quinone ; q , quinone ; qh , quinhydrone ; sod , superoxide dismutase ; sq , semiquinone ; tyr , tyrosinase ; xn , represents a generic number of chlorines , each at a position n on the secondary ring ; xo , xanthine oxidase .
abbreviations : a ( 4 ) , hyperfine splitting constant due to four identical hydrogens ; a , hyperfine splitting due to the hydrogen on position 3 of the pcb phenyl ring ; bq , benzoquinone ; cat , catalase ; detapac , diethylenetriaminepentaacetic acid ; dmpo , 5,5-dimethylpyrroline-1-oxide ; h2q , hydroquinone ; hrp , horseradish peroxidase ; hx , hypoxanthine ; lpo , lactoperoxidase ; mnsod , manganese - containing superoxide dismutase ; pq , phenyl - quinone ; q , quinone ; qh , quinhydrone ; sod , superoxide dismutase ; sq , semiquinone ; tyr , tyrosinase ; xn , represents a generic number of chlorines , each at a position n on the secondary ring ; xo , xanthine oxidase . oxygen uptake was determined with a clark type electrode using an ysi model 5300 biological oxygen monitor ( yellow springs instrument co. , yellow springs , oh ) .
all measurements were made at room temperature ; 3.00 ml of pbs buffer was loaded in the chamber of the oxygen monitor and aerated by stirring for 5 min , and then , the electrode was placed in contact with the solution , leaving no headspace for air and ensuring that all air bubbles were removed . after a 2 min equilibration , reagents were introduced through the access slot , and then , oxygen consumption was monitored .
all measurements were made at room temperature ; 1.00 ml of pbs buffer was loaded in the cuvette , stirring with a small stirring bar to ensure that the solution mixed well . using the kinetics setting , after the introduction of reagents , the change in absorbance at 249 nm
the generation of semiquinone radicals by oxidation / reduction of hydroquinones and quinones is well - documented ( 2325 ) .
polychlorinated biphenyls can be oxidized to hydroquinones ( h2q ) and quinones ( q ) .
these species can be converted to their corresponding semiquinone free radicals ( sq ) that will have a quite different reactivity than the parent quinone or hydroquinone . here
the one - electron reduction of a quinone will yield its corresponding semiquinone radical . to determine if typical reducing enzymes can facilitate such a reaction , we examined the potential formation of sq from quinones by the molybdoflavin enzyme xanthine oxidase .
xanthine oxidase has been shown to reduce by one - electron compounds , such as adriamycin , to their corresponding sq(26 ) ( scheme 1 ) . to demonstrate the usefulness of the hypoxanthine / xanthine oxidase system ( hx / xo ) in our experiments with pcb - derived quinones
as seen in the epr spectrum of figure 2a , the well - studied five - line semiquinone free radical ( 1:4:6:4:1 intensity ratio , a(4 ) = 2.37 g ) of 1,4-benzoquinone ( 27,28 ) was obtained immediately after the introduction of 1,4-benzoquinone to the hx / xo enzyme system .
this demonstrates the utility of hx / xo , a flavoenzyme , in studying the reductive formation of sqfrom q. high ph implies values greater than 8 or 9 , as seen in figure 7 .
semiquinone radical ( sq ) can be formed by many routes : ( a ) sq generated from bq reacted with hx / xo , [ hx ] = 50 m , [ xo ] = 20 mu / ml ; ( b ) sq generated from 2-cl-2,5-q reacted with hx / xo , [ hx ] = 50 m , [ xo ] = 20 mu / ml ; ( c ) sq generated from 2-cl-2,5-h2q reacted with hrp / h2o2 , [ hrp ] = 10 mu / ml , [ h2o2 ] = 10 m ; ( d ) sq generated from 2-cl-2,5-h2q reacted with lpo / h2o2 system , [ lpo ] = 0.1 u / ml , [ h2o2 ] = 10 m ; ( e ) sq generated from 4-cl-3,4-h2q reacted with tyrosinase , [ tyr ] = 2.5 u / ml ; ( f ) sq generated from 2-cl-2,5-h2q at ph 10 ; ( g ) sq generated from 2-cl-2,5-q at ph 10 ; and ( h ) sq generated from 2-cl-2,5-q and 2-cl-2,5-h2q mixed 1:1 , ph 7.4 .
the epr modulation amplitude was 1 g for spectra ae and h and 0.1 g for spectra f and g. pcb - quinones can be viewed as substituted benzoquinone ( figure 1 ) .
addition of the pcb - quinone 2-cl-2,5-q to the hx / xo system ( ph 7.4 ) resulted in a distinct four - line spectrum with a = a = 2.1 g and a = 2.5 g ( spectrum b of figure 2 ) .
the spectrum of this radical appeared rapidly upon mixing ( < 130 s ) ; its intensity decreased with time lasting for several minutes under our experimental conditions ( an observed half - life of about 6 min ) .
the winsim program provided the best fit when the hydrogens and chlorine on the second ring made a contribution to the simulated spectrum ( table 1 ) .
these splitting constants are all very small ; thus , their contribution is in essence only to the observed line width .
these hyperfine splittings ( in gauss ) are the results from simulations of the experimental spectra .
assignment of hyperfine splittings to particular hydrogens on the semiquinone ring followed examples of previously published work ( 3638 ) . on the secondary ring
the numbering pattern is for the structure :
horseradish peroxidase ( hrp ) and lactoperoxidase ( lpo ) are the enzymes known to catalyze h2o2-dependent one - electron oxidations ; these systems will oxidize hydroquinones to the corresponding sq . when 2-cl-2,5-h2q was introduced into these systems , the spectra observed were consistent with the formation of 2-cl-2,5-sq ( figure 2c , d ) .
when 3-cl-2,5-h2q or 4-cl-2,5-h2q was introduced , their corresponding sq radicals were observed ( not shown ) .
these spectra were identical ( except for intensity ) to those observed when their respective quinones were exposed to the hx / xo system .
thus , the same sq can be derived from either the hydroquinone or the quinone with appropriate one - electron oxidation or reduction .
tyrosinase ( tyr ) is a copper - containing enzyme present in plant and animal tissues .
it catalyzes the two - electron oxidation of ortho - hydroquinones ( not para - hydroquinones ) to their corresponding quinones ( 29,30 ) . in our reaction , tyrosinase will catalyze the oxidation of one molecule of pcb ortho - hydroquinone to its quinone with the reduction of 1/2 molecule of oxygen to form one h2o ( scheme 1 ) .
this introduction of quinone will allow the formation of sq via the comproportionation of hydroquinone and quinone .
in air - saturated buffer at ph 7.4 , 100 m ortho - hydroquinone 4-cl-3,4-h2q produced a small background epr signal of 4-cl-3,4-sq ( at the noise level ) , due to the slow oxidation of the hydroquinone ( not shown ) .
however , in the presence of tyr , a much stronger epr spectrum of sq from 4-cl-3,4-h2q was observed ( figure 2e ) .
when a para - hydroquinone was exposed to tyr , no increase in sq was observed ( not shown ) . in the epr experiments ,
if too much tyr was introduced into the incubation such that all of the hydroquinone was very rapidly oxidized to quinone , the epr signal of sq was quite weak or below the limit of detection .
if reaction mixtures identical to those used for epr were monitored for oxygen consumption , the predicted stoichiometric loss of oxygen was observed with ortho - hydroquinones , while no oxygen was lost with para - hydroquinones .
these results demonstrate that ortho - hydroquinone - pcbs have additional mechanisms for radical formation as compared to para - hydroquinone pcbs .
when the phenolic oh groups of hydroquinones ionize , the anions are prone to rapid autoxidation . indeed ,
the semiquinone radical of hydroquinone was observed by epr spectroscopy in the 1950s when it was introduced to oxygenated , alkaline media ( 31 ) .
we hypothesized that hydroquinone derivatives of pcbs would also undergo a parallel autoxidation reaction and generate corresponding pcb semiquinones ( scheme 2a ) . to examine this hypothesis
, we introduced 2-cl-2,5-h2q to an alkaline environment ( ph 10 ) ; we obtained the corresponding sq radical ( figure 2f and table 1 ) .
it has been suggested that the generation of sq in alkaline solution is only the first stage of the autoxidation of dihydroxy phenols ( 3234 ) .
the radical can continue to oxidize to quinone , and then , a comproportionation reaction will turn one molecule of hydroquinone and one molecule of quinone into two molecules of sq ( scheme 2b ) . increasing the ph from 7 to 12
dramatically increased the concentration of the initially formed sq ; this is because high [ oh ] increases the rate of autoxidation of hydroquinone and decreases the rate of decay of sq , principally by disproportionation ( scheme 1 ) , which is dependent on [ h](35 ) .
using the hx / xo system , we have shown above that pcb quinones can be reduced by one electron to corresponding pcb semiquinone radicals . in addition , h2q can be oxidized to form sq ; high ph can increase this rate .
however , a most surprising observation is that 2-cl-2,5-q in high ph solution also generates a strong sq signal ( figure 2 g ) . to generate sq from q
, we observed that the epr signal for the initial sq ( 1:3:3:1 ) radical gives way to a 1:2:1 spectrum , consistent with the formation of a secondary radical sq(ii ) .
the evolution of the epr spectrum from a 1:3:3:1 pattern to a 1:2:1 pattern indicates the loss of a hydrogen from the quinone ring ( figure 3 ) .
this suggests a base - catalyzed michael addition of an oh to the quinone ring ( oh can in principle substitute for any of the three hydrogens on the quinone ring ; only one possibility is shown ) ( scheme 2c ) . when quinone is introduced to an alkaline solution
, we initially see only the primary radical , sq ; the secondary radical sq(ii ) is observed after some time has passed , indicating that the reaction is somewhat slow and a significant amount of the trihydroxy compound must be formed before the 1:2:1 spectrum can be observed .
the addition of oh to the quinone ring provides the reducing equivalents to form the initial sq observed as well as sq(ii ) ( scheme 2c ) .
epr spectra from dihydroxyl and trihydroxyl pcb : changes in the epr spectra of 2-cl-2,5-h2q after introduction of naoh ( 15 l of 5 m naoh add into 2000 l of 100 m 2-cl-2,5-h2q in buffer ) : ( a ) before introduction of naoh and ( b ) 5 min after the introduction of naoh .
the epr modulation amplitude was 1 g. to demonstrate that sq can be formed by the comproportionation reaction of h2q and q , we examined by epr solutions containing both species ( scheme 2b ) .
we used quinhydrone , a charge transfer complex consisting of equal parts of hydroquinone interacting with benzoquinone through ring stacking , as a test system ; a strong epr spectrum for the benzosemiquinone radical was observed in neutral solution consistent with an equilibrium comproportionation reaction ( spectrum not shown ; it has the same characteristics as the spectrum of figure 2a ) .
when 2-cl-2,5-q and 2-cl-2,5-h2q were mixed ( 1:1 ratio , 50 m each ) in neutral solution , the corresponding sq radical was observed by epr ( figure 2h ) .
when the ratio of h2q : q was varied over the range of 1:9 to 9:1 ( keeping [ h2q ] + [ q ] = 100 m ) , sq was observed at all ratios with approximately the same intensity .
this is consistent with comproportionation and disproportionation reactions achieving equilibrium rapidly , on the time scale of the epr observations , with an accompanying autoxidation reaction removing the radical .
as expected , the intensity of the epr signal increased with increasing ph . at high ph ,
the hydroquinone will ionize , leading to a more rapid autoxidation ; in addition , the disproportionation reaction is slowed , as protons are needed , thus a higher epr signal intensity .
because semiquinone radicals are more stable in alkaline solution , we generated a series of pcb semiquinone radicals at ph 10 to investigate the influence of the chemical structure on the epr spectra ( figure 4 ) .
here , we focus on the initially formed , primary radicals that are observed upon raising the ph to 10 .
semiquinone radical generated from pcb with different substitution patterns at ph 10 and computer simulations .
hyperfine splittings and spectral line widths derived by simulation of experimental spectra are presented in table 1 .
( a ) semiquinone radicals generated from different 2,5-q at ph 10 : ( a ) sq generated from 4-cl-2,5-q ; ( b ) sq generated from 3-cl-2,5-q ; ( c ) sq generated from 3 , 4-cl-2,5-q ; and ( d ) sq generated from pq .
( b ) semiquinone radicals generated from different 2,5-h2q at ph 10 : ( a ) sq generated from 4-cl-2,5-h2q ; ( b ) simulation of 4-cl-2,5-sq ; and ( c ) sq generated from 3-cl-2,5-h2q .
( c ) semiquinone radicals generated from different 2,3-h2q at ph 10 : ( a ) sq generated from 4-cl-2,3-h2q ; ( b ) sq generated from 3,4-cl-2,3-h2q ; and ( c ) simulation of 3,4-cl-2,3- sq .
( d ) semiquinone radicals generated from different 3,4-h2q at ph 10 : ( a ) sq generated from 4-cl-3,4-h2q ; ( b ) simulation of 4-cl-3,4-sq ; ( c ) sq generated from 2,5-cl-3,4-h2q ; ( d ) simulation of 2,5-cl-3,4-sq ; ( e ) sq generated from 2,3-cl-3,4-h2q ; and ( f ) simulation of 2,3-cl-3,4-sq .
the epr spectra of the sq generated from different xn -cl-2,5-q and xn-cl-2,5-h2q are quite similar ( figure 4a , b ) ; starting with either the quinone or the hydroquinone of a specific xn -cl-2,5-q , the same semiquinone spectrum was observed .
hyperfine splitting constants , derived from simulation ( table 1 ) , showed three nearly identical hydrogens , which yield a 1:3:3:1 four - line spectrum .
these results show that the primary interactions are with the hydrogens on the semiquinone ring ; the other ring provides no unique splittings , perhaps only contributing to the line width .
when oxidized to their corresponding sq , each member of a family produced a similar epr spectral pattern ( figure 4c , d and table 1 ) .
successful simulations of spectra from 2,5-sq or 2,3-sq did not require any contributions of hyperfine splittings from the other phenyl ring .
however , for the 3,4-sq ( figure 4d ) , hyperfine splittings from the second phenyl ring contributed markedly .
definitive assignments of hyperfine splittings to specific h or cl atoms from the second phenyl ring ( the phenyl ring with cl ) have not been made ( table 1 ) .
we have used the literature ( 3638 ) to guide our assignment of the hyperfine splitting constants for the hydrogens on the semiquinone ring .
however , the xn-cl-3,4-sq radicals show considerable spin density on the secondary ring , especially 4-cl-3,4-sq .
superoxide can play a key role in the generation of oxidative damage under various pathophysiological conditions .
however , o2 is very short - lived , and in most cases , the sensitivity of epr spectroscopy is insufficient for direct detection . thus , we used epr spin trapping to probe for the formation of superoxide radicals ( 4042 ) .
a spin trap reacts with short - lived radicals to form much longer - lived spin adducts that accumulate to a level detectable by epr . in figure 5 ,
spectrum a is a control demonstrating the absence of artifactual signals from dmpo .
b represents the typical dmpo / ooh spin adduct generated from hx / xo system and trapped by dmpo ; some dmpo / ho spin adduct is also present . when 2-cl-2,5-q was added to dmpo in neutral solution , both sq and dmpo / ho
if sod was included , there was no significant change in the intensity of the spectrum of sq ( spectrum d ) , but the signal of the dmpo / ho radical increased . because no evidence for dmpo / ooh radical was observed in
c and sod did not decrease the dmpo / ho signal , there appears to be no significant superoxide formation from 2-cl-2,5-q .
( a ) epr spectrum by dmpo ( 50 mm ) in pbs with detapac ( 250 m ) ; ( b ) superoxide and hydroxyl adducts of dmpo ( 50 mm ) generated with hx / xo at ph 7.4 ( a = 14.1 g , a = 11.3 g with an additional hydrogen splitting of 1.3 g for dmpo / ooh , and a = a = 14.9 g for dmpo / oh ) ; ( c ) spectrum generated from 2-cl-2,5-q ( 1 mm ) and dmpo ( 100 mm ) at ph 7.4 ; ( d ) spectrum generated from 2-cl-2,5-q ( 1 mm ) , dmpo ( 100 mm ) , and 500 u sod / ml at ph 7.4 ; ( e ) spectrum generated from 2-cl-2,5- h2q ( 1 mm ) and dmpo ( 100 mm ) at ph 7.4 ; and ( f ) spectrum generated from 2-cl-2,5-h2q ( 1 mm ) , dmpo ( 100 mm ) , and 500 u sod / ml at ph 7.4 .
all experimental spectra were collected using a 1.0 g modulation amplitude . when 2-cl-2,5-h2q was substituted for 2-cl-2,5-q , the addition of sod stimulated the generation of sq ( figure 5e , f ) ; the intensity of the sq spectrum increased over time , reached a steady state , and then decreased ( data not shown ) .
cat had no effect on the generation of sq or dmpo / ho radical ( not shown ) .
these observations indicate that generation of superoxide from sq , reaction 1 , is not kinetically or thermodynamically favorable .
substituted quinones as references , the rate constant for the forward reaction will be approximately 1010 m s , while the rate constant for the reverse reaction is on the order of 10 m s. this rapid back reaction explains why our spin trapping experiment can not detect superoxide formation .
the increase in [ sq ] observed in figure 5f suggests that sod can catalyze the autoxidation of 2-cl-2,5-h2q to 2-cl-2,5-q . to observe if the rate of formation of 2-cl-2,5-q increases when sod is added to a near - neutral solution of 2-cl-2,5-h2q , we used uv spectroscopy to follow the rate of formation of 2-cl-2,5-q . in the absence of sod ,
the autoxidation of 2-cl-2,5-h2q ( 100 m ) to quinone is relatively slow ( figure 6a , b ) . when sod is present at time zero
, there is no change in the initial rate of autoxidation ; however , after about 10 min or so , autoxidation accelerates ( figure 6c ) .
if a trace of 2-cl-2,5-q ( 1 m ) is introduced at time zero along with sod , there is no lag time for a much more rapid rate of autoxidation .
these observations are parallel to those observed by eyer in a study of hydroquinone autoxidation ( 44 ) ; this same process appears to hold with coenzyme q semiquinone radical in mitochondria with changes in mnsod ( 45 ) .
superoxide is formed by reaction 1 ; however , the equilibrium lies far to the left .
sod pulls this equilibrium by removing superoxide before it enters the back reaction due to its very rapid dismutation of superoxide , reaction 2 .
in the experiment of figure 6c ,
the rate of autoxidation remains low until significant 2-cl-2,5-q is generated , allowing for the comproportionation reaction of 2-cl-2,5-q with 2-cl-2,5-h2q to form sq , reaction 3 .
however , if a trace of 2-cl-2,5-q is introduced at time zero ( figure 6d ) , no lag time is observed because all of the ingredients are present to make significant sq .
these observations suggest that oxygen will be consumed in the autoxidation reaction , giving rise to the formation of h2o2 , the net reaction being
sod accelerates the autoxidation of hydroquinone .
the formation of 2-cl-2,5-q during the autoxidation of 2-cl-2,5-h2q ( 0.1 mm ) was followed at 249 nm .
( a ) 2-cl-2,5-h2q ( 0.1 mm ) ; ( b ) 2-cl-2,5-h2q ( 0.1 mm ) mixed with 2-cl-2,5-q ( 1 m ) ; ( c ) 2-cl-2,5-h2q ( 0.1 mm ) with 100 u / ml sod ; and ( d ) 2-cl-2,5-h2q ( 0.1 mm ) mixed with 2-cl-2,5-q ( 1 m ) plus 100 u / ml sod .
if sod accelerates the rate of oxidation of 2-cl-2,5-h2q as seen by formation of quinone , then the rate of oxygen consumption should also increase .
indeed , when 2-cl-2,5-h2q ( 500 m ) was introduced into ph 7.4 pbs , the rate of oxygen consumption paralleled all of the results of figure 6 ( data not shown ) .
the introduction of cat to a partially oxidized solution of 2-cl-2,5-h2q demonstrated that nearly all of the oxygen consumed was present as h2o2 .
autoxidation of 2-cl-2,5-h2q in alkaline ph is accelerated due to ionization of the phenolic hydroxyls and subsequent one - electron oxidation to 2-cl-2,5-sq , followed by loss of a second electron yielding 2-cl-2,5-q .
one might predict that 1 equiv of h2q would consume 1 equiv of dioxygen , yielding 1 equiv of h2o2 ( reaction 4 ) .
interestingly , the amount of oxygen consumed is a function of ph ( figure 7 ) .
we observed a sharp increase in the amount of oxygen consumed as the ph was increased from ph 8 to ph 13 . at higher ph values
, we observed that h2q consumed almost 2 equiv of oxygen , rather than the 1 equiv anticipated ; unexpectedly , we observed that the quinone also consumed oxygen in a ph - dependent manner .
the amounts of oxygen consumed by h2q and q paralleled each other ; the quinone form always consumed one - half equiv less oxygen than h2q at a particular ph .
these observations are consistent with oxidation of hydroquinone to quinone , followed by the nucleophilic addition of oh to the quinone forming a trihydroxy compound that can be oxidized in the high ph environment ( scheme 2c ) .
when starting with the quinone , there would be no initial oxidation ; thus , less oxygen would be consumed .
2-cl-2,5-h2q ( 100 m ) or 2-cl-2,5-q ( 100 m ) was introduced into the closed chamber of the ysi biological oxygen monitor containing solutions having different ph values .
the data points are the means of three determinations ; standard errors are in general smaller than the symbols used to present the data .
the rate of consumption of oxygen is dramatically increased upon initiating a ph jump of a near - neutral solution of the oxygenated pcbs that we examined ( figure 7 ) .
cat disproportionates 2h2o2 into 2h2o and 1o2 ; thus , it can be used as a tool to examine the stoichiometry of the reduction o2 to h2o2 . in near - neutral solution , little or no oxygen
was consumed after introduction of 2-cl-2,5-h2q ( table 2 , exp 1 ) . however , if the ph is increased to 12 by the addition of naoh , a rapid loss of oxygen occurs ( 170 m ) ( table 2 , exp 2 ) .
if reaction 4 holds , we would have expected to lose only 100 m o2 .
most surprising was our observation that upon introduction of cat , little if any oxygen returned , indicating that there was no hydrogen peroxide in the system .
( although high ph inactivates enzymes , this high ph did not inactivate cat in the short time frame of an experiment ; data not shown . )
the actual loss of oxygen is less than or on the order of the drift of the instrument , which typically is less than 5 m per 15 min .
a blank cell indicates that there was no addition of this reagent and thus no change in [ o2 ] .
the addition of 20 l of 5 m naoh into 2 ml of buffer increases the ph of solution to over 12 .
expected return of oxygen assuming that the only important reaction upon introduction of naoh is reaction 2 when hydroquinone is reactant ; if quinone is the reactant , the expected return of oxygen assumes no reaction between the quinone and the h2o2 . to determine if the hydroquinone reacts directly with h2o2 , we introduced 100 m h2o2 into a neutral solution of 100 m 2-cl-2,5-h2q . after 15 min ,
all of the h2o2 was still present as the introduction of cat saw the return of 50 m o2 ( table 2 , exp 3 ) .
thus , there is no rapid direct reaction of hydroquinone with h2o2 . in exp 4
the addition of cat resulted in the return of 50 m o2 , demonstrating that there was no rapid direct reaction of h2o2 with the oxidation products of 2-cl-2,5-h2q .
interestingly , the introduction of h2o2 before the ph jump reduced oxygen consumption ( 170 to 90 m ; table 2 , exp 5 ) ; cat returned only 30 m oxygen , indicating that some of the h2o2 was lost .
experiments 15 of table 2 indicate that h2o2 must be reacting with intermediates in the oxidation reactions of 2-cl-2,5-h2q .
hydrogen peroxide has been shown to react with benzoquinone ( 46 ) and chlorinated benzoquinone ( 47 ) .
experiments 610 of table 2 examine the possible reaction of h2o2 with a typical pcb - quinone , 2-cl-2,5-q . at near - neutral ph
however , experiments 7 and 10 show a considerable loss of h2o2 upon a ph jump .
an explanation for this observation is that in ph 12 solution , some h2o2 will be deprotonated ( pk1 for h2o2 to form ooh is 11.7 , ( 48 ) ) .
the peroxide anion is a powerful nucleophile , much more reactive than hydroxide anion ( 47 )
. it will react with pcb quinone , similar to oh ; however , the reaction will likely be much faster ( scheme 2d ) .
thus , experiments 7 and 10 in table 2 with 2-cl-2,5-q are consistent with a rapid nucleophilic addition reaction of h2o2 , via ooh , to the quinone .
the same semiquinone radical is produced when a pcb - hydroquinone undergoes a one - electron oxidization or the quinone form undergoes a one - electron reduction .
this can be accomplished many different ways , including the following : xanthine oxidase can reduce quinone pcbs to the corresponding sq .
the heme - containing peroxidases ( horseradish and lactoperoxidase ) can oxidize hydroquinone pcbs to the corresponding sq .
sq is formed rapidly when hydroquinone - pcbs undergo air oxidation in high ph buffer ( >ph 8) .
the epr spectra of semiquinone radicals produced from structurally similar pcb hydroquinones and quinones had similar spectral patterns as characterized by hyperfine splittings .
the production of superoxide radicals could not be observed using dmpo as a spin trapping agent due to the rapid reaction of superoxide with quinone ; however , sod accelerates the autoxidation of hydroquinone indicating a role for superoxide . at
higher ph , hydroxide anion can add to the quinone ring of a pcb - quinone , leading to the formation of a new hydroquinone and rupture of the quinone ring . using oxygen consumption at higher ph ,
the autoxidation of both hydroquinone and quinone consumed oxygen this oxygen consumption could be greater than the 1:1 stoichiometry predicted by reaction 2 .
h2o2 does not accumulate when a pcb - hydroquinone autoxidizes at high ph ; h2o2 appears to react with intermediates formed during the oxidation process .
h2o2 accumulates when sod is present in an autoxidizing pcb - hydroquinone solution at near - neutral ph ; without sod , the reaction is too slow to observe any loss of o2 or accumulation of h2o2 .
Output:
| polychlorinated biphenyls ( pcbs ) can be oxygenated to form very reactive hydroquinone and quinone products .
a guiding hypothesis in the pcb research community is that some of the detrimental health effects of some pcbs are a consequence of these oxygenated forms undergoing one - electron oxidation or reduction , generating semiquinone radicals ( sq ) .
these radicals can enter into a futile redox cycle resulting in the formation of reactive oxygen species , that is , superoxide and hydrogen peroxide . here , we examine some of the properties and chemistry of these semiquinone free radicals . using electron paramagnetic resonance ( epr ) to detect sq formation , we observed that ( i ) xanthine oxidase can reduce quinone pcbs to the corresponding sq ; ( ii ) the heme - containing peroxidases ( horseradish and lactoperoxidase ) can oxidize hydroquinone pcbs to the corresponding sq ; ( iii ) tyrosinase acting on pcb ortho - hydroquinones leads to the formation of sq ; ( iv ) mixtures of pcb quinone and hydroquinone form sq via a comproportionation reaction ; ( v ) sq are formed when hydroquinone - pcbs undergo autoxidation in high ph buffer ( >ph 8) ; and , surprisingly , ( vi ) quinone - pcbs in high ph buffer can also form sq ; ( vii ) these observations along with epr suggest that hydroxide anion can add to the quinone ring ; ( viii ) h2o2 in basic solution reacts rapidly with pcb - quinones ; and ( ix ) at near - neutral ph sod can catalyze the oxidization of pcb - hydroquinone to quinone , yielding h2o2 .
however , using 5,5-dimethylpyrroline-1-oxide ( dmpo ) as a spin - trapping agent , we did not trap superoxide , indicating that generation of superoxide from sq is not kinetically favorable .
these observations demonstrate multiple routes for the formation of sq from pcb - quinones and hydroquinones .
our data also point to futile redox cycling as being one mechanism by which oxygenated pcbs can lead to the formation of reactive oxygen species , but this is most efficient in the presence of sod . |
PubmedSumm118257 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: it is recognized that teeth with furcation involvement may undergo a more extensive and
rapid clinical probing attachment loss and are lost with greater frequency than
single - rooted teeth .
although
regeneration of periodontal tissue is the ultimate goal of periodontal therapy ,
regeneration is not a predictable healing outcome after conventional treatment . with the advent of regenerative techniques ,
a new concept of periodontal treatment based
on the principle of cellular selection and guided tissue regeneration , permits the treatment of teeth with
furcation lesions by conservative surgical methods .
various studies reported gains in
horizontal and vertical clinical attachment , with complete closure of the furcation in
up to 67% of the cases using different types of mechanical barriers . despite positive results based on reports of substantial attachment
gain and bone fill of furcations , guided - tissue regeneration ( gtr ) is technique
sensitive and could be associated with increased postoperative problems . a major
drawback to expanded polytetrafluoroethylene
( eptfe ) and other non - resorbable membranes
is the need for their removal after 4 to 6 weeks , often with a surgical procedure that
adds to patient morbidity and may disturb the healing tissue .
bone replacement grafts have achieved similar results to gtr , demonstrating a 55%
overall improvement , with either complete or partial furcation fill compared to 52% for
gtr
. the use of bioactive glass
( bg ) when compared to an eptfe barrier may produce similar clinical results .
when used in a variety of periodontal
and oral surgical applications , bg has shown positive clinical and histological
outcomes . in the past decade ,
several cytokines , or growth factors , have received attention
because they can regulate migration , attachment , proliferation and/or differentiation of
periodontal ligament cells into hard tissue cells and have been shown to enhance
regeneration with in vivo experiments .
a convenient
technique to obtain transforming growth factor
( tgf ) and platelet - derived growth factor ( pdgf ) is by preparing
autologous platelet - rich plasma ( prp ) .
pdgf has shown to exert a favorable effect on periodontal
regeneration as measured by gain in clinical attachment and defect fill in
humans .
considering that the most favorable outcome of periodontal regenerative procedures in
furcations lesions has been achieved with a combination of graft material and
gtr , the goal of the present study was to investigate , histologically
and histometrically , the potential adjunctive benefits of prp when used with gtr and bg
in the treatment of class ii furcation lesions .
nine adult female mongrel dogs were included in the experiment ( mean weight=15 kg ) .
the
surgical procedures were performed under general anesthesia with intravenous injection
of a 3% sodium pentobarbital solution ( 0.5 ml / kg ) .
the maxillary and mandibular second
and fourth premolars had been bilaterally extracted previously and the extraction sites
had been allowed to heal for 2 months .
bilateral class ii furcation lesions were
surgically created at the buccal aspect of mandibular third premolars . in order to
create the defects
osteotomy was done in the furcation area with high - speed diamond burs with
constant irrigation and with nos . 1 and 2 oschenbein chisels
. the furcations lesions
were standardized with a millimeter probe and measured 5.0 mm in the apico - occlusal
direction and 2.0 mm in the buccolingual direction ( figure 1 ) , following a technique previously described .
clinical aspect of class ii furcation defect ( 5x 2 mm ) the defects were filled with gutta - percha to induce an inflammatory response due to
plaque accumulation for a period of one month ( figure
2 ) .
after this period , scaling and root planing was performed and a regimen of
daily brushing plus topical application of 0.1% chlorhexidine gluconate was instituted
for 7 days prior to the surgical procedures
. clinical aspect of class ii furcation defect filled with gutta - percha in the same day of the treatment of the mandibular defects , similar defects were created
at the buccal aspect of maxillary third premolars and were exposed to plaque
accumulation for 1 month .
forty - five days after this surgical intervention , the
maxillary defects were assigned to receive the same treatments .
three tubes
( 5 ml ) , containing 0.5 ml of 3.2% sodium citrate solution as an anticoagulant , were
drawn from each dog .
the blood was thus separated into 3 basic parts : red blood cells ( at the
bottom of the tube ) , platelet enriched plasma ( a discrete grey line in the middle of
the tube ) and platelet poor plasma ( at the top of the tube ) .
the portion
corresponding to the platelet poor plasma was discarded from each tube and the
remaining content was centrifuged again at 1,200 rpm for 15 min .
four hundred
microliter of the middle portion , corresponding to the platelet enriched plasma , were
pipetted from each tube . in order to obtain the gel ,
30 l of 10% calcium chloride
was added to prp and heated in a water bath at 37c .
mucoperiosteal flaps were carefully reflected on the buccal aspect of the
experimental sites , the granulation tissue was removed by curettage , and the exposed
root surface was instrumented . on the root surface ,
the base of the defect was marked
with curettes to establish a landmark for the histomorphometric analysis .
each
contralateral defect in each animal was randomly assigned to one of the following
treatments : gtr+bg ( perioglas , us biomaterials , alachua , fl , usa ) - control group : bg particles
were applied filling the defect and absorbable membrane ( resolut xt
gore - tex , gore associates , flagstaff , az , usa ) was adapted to the defect ; gtr+bg+prp - test group : bg was incorporated to the prp ( 1:1 ) and this assemblage was
immediately taken to a water bath at 37c what enabled the formation of a mixture of
the gel and the bg graft .
this mixture was applied filling the defect and an
absorbable membrane ( resolut xt gore - tex , gore associates ) was adapted to
the defect .
primary , tension - free wound closure was accomplished following defect treatment , with
the gingival flaps positioned and sutured with interrupted sutures ( vicryl , ethicon
inc , so jos dos campos , sp , brazil ) in order to cover the membranes . immediately
after the surgeries , an intramuscular injection of penicillin ( 1.5 ml - 150,000 iu )
was given to the animal .
forty five days after the mandibular treatment , the maxillary defects ( 2 defects/
animal ) were randomly assigned to receive the same treatments ( group a and group
b ) .
postoperative plaque control was performed by irrigation with a solution of 1%
chlorhexidine gluconate ( every other day ) .
dogs were sacrificed 90 days after the
first treatment , under general anesthesia , with a perfusion of 10% neutral formalin
solution .
they were decalcified in a solution of equal parts of 50%
formic acid and 20% sodium citrate for 5 months .
the decalcified specimens were
washed in running water , dehydrated and embedded in paraffin .
mesiodistal 7-m - thick
sections were obtained from the tissue blocks longitudinally , in a buccolingual
direction , in a way to obtain a panoramic view of the furcation area .
the sections
were stained with hematoxylin and eosin . for histometric and descriptive histological analyses , 5 sections
per site representing the middle portion of the defect ( 30 m
apart )
were used to obtain the mean for each parameter in each dog , measured with an
image analysis system ( image pro plus version 3.0 , media cybernetics , silver spring ,
md , usa ) .
the following linear measurements ( mm ) were obtained in the mesial and distal roots
under the furcation :
defect extension ( de ) : linear extension of the total root surface
between the two notches ;
new cementum ( nc ) : linear extension of the root surface covered by
new cementum ;
connective tissue adaptation ( ca ) : extension of the root surface
covered by connective tissue without cementum .
new bone ( nb ) : measured from a horizontal line connecting both
notches ( apical limit of the defect ) to the most coronal extent of new bone .
the following
parameters ( mm ) were obtained by the point counting technique :
mineralized bone area ( mba ) : portion of the defect area filled with
mineralized bone tissue ;
residual bg particle area ( rbg ) : portion of the defect area filled
with bg remaining particles ;
non - mineralized bone area ( nmba ) : portion of the defect area filled
with non - mineralized tissue ; the measurements were performed using a microscope ( zeiss axioskop 2 , carl zeiss
instruments , gottingen , lower saxony , germany ) with a 1.25/.035 objective associated
with a video camera / computer / software ( image pro plus version 3.0 , media
cybernetics ) .
the mean
values for all groups were determined using the individual means from the 9 dogs .
after testing the assumptions confirming normal distribution , two - way anova was
carried out to check any significance among the different treatment groups , any
significance among the different time periods and the interaction between them .
three tubes
( 5 ml ) , containing 0.5 ml of 3.2% sodium citrate solution as an anticoagulant , were
drawn from each dog .
the blood was thus separated into 3 basic parts : red blood cells ( at the
bottom of the tube ) , platelet enriched plasma ( a discrete grey line in the middle of
the tube ) and platelet poor plasma ( at the top of the tube ) .
the portion
corresponding to the platelet poor plasma was discarded from each tube and the
remaining content was centrifuged again at 1,200 rpm for 15 min .
four hundred
microliter of the middle portion , corresponding to the platelet enriched plasma , were
pipetted from each tube . in order to obtain the gel ,
30 l of 10% calcium chloride
was added to prp and heated in a water bath at 37c .
mucoperiosteal flaps were carefully reflected on the buccal aspect of the
experimental sites , the granulation tissue was removed by curettage , and the exposed
root surface was instrumented . on the root surface , the base of the defect was marked
with curettes to establish a landmark for the histomorphometric analysis . each
contralateral defect in each animal was randomly assigned to one of the following
treatments : gtr+bg ( perioglas , us biomaterials , alachua , fl , usa ) - control group : bg particles
were applied filling the defect and absorbable membrane ( resolut xt
gore - tex , gore associates , flagstaff , az , usa ) was adapted to the defect ; gtr+bg+prp - test group : bg was incorporated to the prp ( 1:1 ) and this assemblage was
immediately taken to a water bath at 37c what enabled the formation of a mixture of
the gel and the bg graft .
this mixture was applied filling the defect and an
absorbable membrane ( resolut xt gore - tex , gore associates ) was adapted to
the defect .
primary , tension - free wound closure was accomplished following defect treatment , with
the gingival flaps positioned and sutured with interrupted sutures ( vicryl , ethicon
inc , so jos dos campos , sp , brazil ) in order to cover the membranes . immediately
after the surgeries ,
an intramuscular injection of penicillin ( 1.5 ml - 150,000 iu )
was given to the animal .
forty five days after the mandibular treatment , the maxillary defects ( 2 defects/
animal ) were randomly assigned to receive the same treatments ( group a and group
b ) .
postoperative plaque control was performed by irrigation with a solution of 1%
chlorhexidine gluconate ( every other day ) .
dogs were sacrificed 90 days after the
first treatment , under general anesthesia , with a perfusion of 10% neutral formalin
solution .
they were decalcified in a solution of equal parts of 50%
formic acid and 20% sodium citrate for 5 months .
the decalcified specimens were
washed in running water , dehydrated and embedded in paraffin .
mesiodistal 7-m - thick
sections were obtained from the tissue blocks longitudinally , in a buccolingual
direction , in a way to obtain a panoramic view of the furcation area .
the sections
were stained with hematoxylin and eosin . for histometric and descriptive histological analyses , 5 sections
per site representing the middle portion of the defect ( 30 m
apart )
were used to obtain the mean for each parameter in each dog , measured with an
image analysis system ( image pro plus version 3.0 , media cybernetics , silver spring ,
md , usa ) .
the following linear measurements ( mm ) were obtained in the mesial and distal roots
under the furcation :
defect extension ( de ) : linear extension of the total root surface
between the two notches ;
new cementum ( nc ) : linear extension of the root surface covered by
new cementum ;
connective tissue adaptation ( ca ) : extension of the root surface
covered by connective tissue without cementum .
new bone ( nb ) : measured from a horizontal line connecting both
notches ( apical limit of the defect ) to the most coronal extent of new bone .
the following
parameters ( mm ) were obtained by the point counting technique :
mineralized bone area ( mba ) : portion of the defect area filled with
mineralized bone tissue ;
residual bg particle area ( rbg ) : portion of the defect area filled
with bg remaining particles ;
non - mineralized bone area ( nmba ) : portion of the defect area filled
with non - mineralized tissue ; the measurements were performed using a microscope ( zeiss axioskop 2 , carl zeiss
instruments , gottingen , lower saxony , germany ) with a 1.25/.035 objective associated
with a video camera / computer / software ( image pro plus version 3.0 , media
cybernetics ) .
the mean
values for all groups were determined using the individual means from the 9 dogs .
after testing the assumptions confirming normal distribution ,
two - way anova was
carried out to check any significance among the different treatment groups , any
significance among the different time periods and the interaction between them .
no suppuration or
abscess formation was observed during the 90 days and no exposure of membranes was
observed in both groups during the healing period .
a clinical examination performed
immediately before sacrifice , disclosed that the gingival margin of all sites was
clinically normal and positioned coronal to the fornix of the buccal furcation .
there were no cases of epithelial downgrowth , ankylosis or extensive root resorption
observed in all sites .
a similar healing pattern was observed in the two groups , in both
periods , regarding the filling of the defect ( figure
3 ) .
mesiodistal histologic section of class ii furcation lesion stained with
hematoxilyn and eosin ( h&e ) , ( original magnification x20 ) ; a ) site of the
control group guided - tissue regeneration + bioactive glass ( gtr+bg ) after 45
days ; b ) site of the test group guided - tissue regeneration + bioactive glass +
platelet - rich plasma ( gtr+bg+prp ) after 45 days ; c ) site of the control group
after 90 days ; d ) site of the test group after 90 days .
both treatments promote
defect filling in both periods however a greater mineralized bone area was
observed for test group in both periods when compare with the control group a continuous layer of new cementum had formed in the specimens of both groups
extending coronally from the apical notches to a varying degree .
however , in the
group b , a more evident layer of new cementum was observed in the fornix region
( coronal portion of the defect ) . in both groups ,
some small areas of the defects
presented a very dense connective tissue surrounding the remaining bg particles .
however , connective tissue adaptation with collagen fibers running parallel to the
root surface seemed to be more frequent in group a. various defects in all groups presented bone surrounding bg particles and bone in
direct contact with these graft particles ( figure
4 ) .
however , in group b the defects were filled by a higher density bone
with a more evident mineralized bone area with islands of highly cellular bone
marrow . in group a , the bone presented larger marrow spaces what could indicate a
more immature bone when compared to group b. a ) photomicrograph of a mesiodistal histologic section of class ii furcation
lesion platelet - rich plasma + bioactive glass + guided - tissue regeneration
( prp+bg+gtr ) 90 days after treatment defect ( masson trichrome staining ,
original magnification x40 ) .
remaining bg particles were observed surrounded by new bone ( nb ) ,
connective tissue ( ct ) and areas suggesting the presence of immature bone ( ib )
in contact with bg ; b ) histologic section of the prp+bg+gtr defect , 90 days
after staining with hematoxilyn and eosin ( h&e ) , ( original magnification
x100 ) .
some
areas indicated the new bone formation occurring around bg particles
( arrows ) the histometric results are shown in tables 1
and 2 .
data analysis showed a superior length
of new cementum for group b in both periods ( 45 days and 90 days ) ( p<0.05 ) .
no
statistically significant differences were observed between periods for the linear
parameters for the two groups .
the addition of prp provided a greater mineralized
bone area in both periods ( p<0.05 ) .
the non - mineralized bone area was greater in
the control group ( p<0.05 ) in both periods while no statistically significant
difference was observed in the area occupied by the remaining bg particles between
groups .
significant differences between periods were observed in the mineralized bone
area and non - mineralized bone area ( p<0.05 ) .
mean and standard deviation ( sd ) for the linear parameters evaluated after all
the treatments ( bioactive glass+guided - tissue regeneration and bioactive
glass+platelet - rich plasma+guided - tissue regeneration ) in both periods .
capital letters compare treatments within each time and non - capital letter
compare times within each treatment .
means followed by different letters are
statistically different mean and standard deviation ( sd ) for the area parameters evaluated after all
the treatments ( bioactive glass+guidedtissue regeneration and bioactive
glass+platelet - rich plasma+guided - tissue regeneration ) in both periods capital letters compare treatments within each time and non - capital letter
compare times within each treatment .
no suppuration or
abscess formation was observed during the 90 days and no exposure of membranes was
observed in both groups during the healing period .
a clinical examination performed
immediately before sacrifice , disclosed that the gingival margin of all sites was
clinically normal and positioned coronal to the fornix of the buccal furcation .
there were no cases of epithelial downgrowth , ankylosis or extensive root resorption
observed in all sites . no inflammation and foreign body reactions indicating toxicity
were observed .
a similar healing pattern was observed in the two groups , in both
periods , regarding the filling of the defect ( figure
3 ) .
mesiodistal histologic section of class ii furcation lesion stained with
hematoxilyn and eosin ( h&e ) , ( original magnification x20 ) ; a ) site of the
control group guided - tissue regeneration + bioactive glass ( gtr+bg ) after 45
days ; b ) site of the test group guided - tissue regeneration + bioactive glass +
platelet - rich plasma ( gtr+bg+prp ) after 45 days ; c ) site of the control group
after 90 days ; d ) site of the test group after 90 days .
both treatments promote
defect filling in both periods however a greater mineralized bone area was
observed for test group in both periods when compare with the control group a continuous layer of new cementum had formed in the specimens of both groups
extending coronally from the apical notches to a varying degree .
however , in the
group b , a more evident layer of new cementum was observed in the fornix region
( coronal portion of the defect ) . in both groups ,
some small areas of the defects
presented a very dense connective tissue surrounding the remaining bg particles .
however , connective tissue adaptation with collagen fibers running parallel to the
root surface seemed to be more frequent in group a. various defects in all groups presented bone surrounding bg particles and bone in
direct contact with these graft particles ( figure
4 ) .
however , in group b the defects were filled by a higher density bone
with a more evident mineralized bone area with islands of highly cellular bone
marrow . in group a , the bone presented larger marrow spaces what could indicate a
more immature bone when compared to group b. a ) photomicrograph of a mesiodistal histologic section of class ii furcation
lesion platelet - rich plasma + bioactive glass + guided - tissue regeneration
( prp+bg+gtr ) 90 days after treatment defect ( masson trichrome staining ,
original magnification x40 ) .
remaining bg particles were observed surrounded by new bone ( nb ) ,
connective tissue ( ct ) and areas suggesting the presence of immature bone ( ib )
in contact with bg ; b ) histologic section of the prp+bg+gtr defect , 90 days
after staining with hematoxilyn and eosin ( h&e ) , ( original magnification
x100 ) .
some
areas indicated the new bone formation occurring around bg particles
( arrows )
data analysis showed a superior length
of new cementum for group b in both periods ( 45 days and 90 days ) ( p<0.05 ) .
no
statistically significant differences were observed between periods for the linear
parameters for the two groups .
the addition of prp provided a greater mineralized
bone area in both periods ( p<0.05 ) .
the non - mineralized bone area was greater in
the control group ( p<0.05 ) in both periods while no statistically significant
difference was observed in the area occupied by the remaining bg particles between
groups .
significant differences between periods were observed in the mineralized bone
area and non - mineralized bone area ( p<0.05 ) .
mean and standard deviation ( sd ) for the linear parameters evaluated after all
the treatments ( bioactive glass+guided - tissue regeneration and bioactive
glass+platelet - rich plasma+guided - tissue regeneration ) in both periods .
capital letters compare treatments within each time and non - capital letter
compare times within each treatment .
means followed by different letters are
statistically different mean and standard deviation ( sd ) for the area parameters evaluated after all
the treatments ( bioactive glass+guidedtissue regeneration and bioactive
glass+platelet - rich plasma+guided - tissue regeneration ) in both periods capital letters compare treatments within each time and non - capital letter
compare times within each treatment .
the present study evaluated if the application of prp on class ii furcation lesions
would enhance periodontal regeneration when associated with gtr and bioactive glass
( bg ) .
clinical reports have demonstrated that the association of gtr , bone substitutes
and prp could provide good results in the treatment of intrabony defects and class ii
furcation lesions , as revealed by gain in clinical attachment , defect fill at reentry ,
reducing probing depth , vertical defect fill and horizontal defect fill .
however , to the best of our knowledge , this is the first study that
evaluated histologically the effect of the association of prp with gtr and bg on
periodontal regeneration of class ii furcation lesions in dogs .
it has been demonstrated that when a bone graft or substitute is combined with the gtr
procedure in furcation lesions , a greater amount of defect fill is observed .
this advantage can be explained by the
osteoconductive and/or osteoinductive properties of the graft materials .
one of the bone
substitutes that have been investigated is the bg , a material that has been suggested as
an osteoconductive graft .
the use of bg in the present study was not associated with any
foreign body reaction .
it was observed that some remaining bg granules showed
dissolution of their core with the formation of new bone , as described by vogel , et
al .
the sites treated with grt+bg ( group a ) showed new cementum formation and new bone
regeneration in both periods .
these results are in accordance with previous reports ,
which demonstrated a beneficial effect of the association of gtr and bone
substitutes .
however , clinical studies do not provide information
about the nature of the healing process after these procedures .
in contrast with previous studies , in the present investigation , there were no instances of epithelial
downgrowth in all sites .
( 2007 ) observed a correlation between the exposure of the
membrane and the epithelial migration .
the presence of epithelial tissue was observed in
all histological sections of the sites that shown a membrane exposure and was ascribed
to the degradation of the exposed portions of this material .
the use of prp for periodontal regeneration has been based on the idea that this
preparation contains polypeptide growth factors ( pgfs ) .
some specific pgfs , like pdgf
and tgf , could promote the growth and differentiation of the periodontal ligament and
alveolar bone cells and could be responsible for the clinical improvement observed in
experimental sites
. other interesting feature of prp is its sticky
consistency due to its high fibrin content .
the fibrin component of prp may work as a
hemostatic agent aiding in stabilizing the graft material and the blood clot .
blood clot immobilization has been
suggested as an important event in the early phases of wound healing of periodontal
regenerative procedures .
it has been previously shown that prp may stimulate pdl cells and fibroblastic cell
proliferation but may suppress epithelial cell division in
vitro .
consequently , by
ordering these cellular responses into a series of related events , prp may facilitate
wound - healing and tissue regeneration . in the present study ,
the sites in the group b
showed a superior cementum formation , in both observation periods , when compared with
the sites of group a ( p<0.05 ) . to the best of our knowledge ,
no study provided direct
evidence that the prp could stimulate the differentiation of cells from the periodontal
ligament to cementoblasts , inducing cementogenesis .
however , previous investigations
have suggested that the treatment with recombinant growth factors , such as pdgf and igf
may enhance the formation of cementum on denuded dentin surfaces .
in addition to it , a similar result was
observed when the prp was associated with a subepithelial connective tissue graft for
the treatment of gingival recessions created in dogs .
the positive effect of prp in the bone response was demonstrated by previous
studiesand could be evidenced in the present study by the
largest area of mineralized bone observed in group b. sites treated with prp showed a
superior mineralized bone area with a concomitant inferior non - mineralized bone area , in
both periods , when compared with group a ( p<0.05 ) . however , the difference between
treatments is more evident in the first period ( 45 days ) when the area of mineralized
bone in group b was almost twice the one observed in group a. this observation is in
agreement with an in vitro study that suggested that pdgf acts upon osteoblastic cell
proliferation , exerting most of its effects during the early phase of wound healing .
although the mineralized bone formation was superior in group b of the present study , it
should be noticed that recent animals studies could not demonstrate that prp increases
bone regeneration when used in peri - implant bone defects . to date
, there is insufficient information about growth factor interactions and how they
influence the activations of gene expression and protein production .
also , the ideal
platelet and growth factor concentrations to promote periodontal regeneration has not
been established .
( 2003 ) reported that growth factors may act at specific times and at appropriate
concentrations and this may be other explanation for the different results in studies
with prp . in the present study ,
the achieved percentage mean of platelet concentration
was 227.02 % ( mean of 463,015 platelets/l ) in relation to blood platelet count .
the technique to produce prp used in this study was previously described by suaid , et
al.(2008 ) .
this technique
enables to produce a platelet concentration generally four times greater than the whole
blood .
( 2003 )
performed a study that measured the concentrations of bfgf , vegf , pdgf - bb and tgf - b1
released from platelet concentrate and whole blood , before and after the addition of
calcium alone , thrombin alone and various concentrations of calcium and thrombin .
they
observed that calcium chloride , regardless of the use of thrombin , released platelet
growth factors . in this study ,
the concentration of growth factors that was released was
sufficient to promote endothelial cell proliferation in vitro .
since the use of thrombin in this type
of investigation is not allowed in our country , instead of thrombin , 10% calcium
chloride was added to prp and heated in a water bath at 37c .
within the limits of this animal study , it was concluded that prp in association with
gtr and bg may enhance the amount of new cementum and provide a more mineralized bone
( mature ) in a shorter period of time when applied to the treatment of class ii furcation
lesions in dogs .
future studies are required to clarify the mechanism of action of prp
in the periodontal regeneration process and the ideal platelet and growth factor
concentrations to adequately promote periodontal regeneration .
the authors thank the financial support of fapesp ( the state of so paulo research
foundation , # 04/12428 - 6 ) and cnpq ( national counsel of technological and scientific
development # 300817/2007 - 0 ) .
Output:
| objective this study was designed to evaluate the potential adjunctive benefits of
platelet - rich plasma ( prp ) when used with guided - tissue regeneration ( gtr ) and
bioactive glass ( bg ) in the treatment of class ii furcation lesions .
material and methods bilateral class ii furcation lesions were surgically created and allowed to
become chronic in the mandibular third premolars of 9 dogs .
the defects were
randomly assigned to : a ) gtr+bg and b ) gtr+bg+prp .
similar defects were created in
the maxillary third premolars and received the same treatments after 45 days .
dogs
were sacrificed 90 days after the first treatment .
the histometric parameters
evaluated were : connective tissue adaptation , new cementum , new bone , mineralized
bone area , non - mineralized bone area , and residual bg particle area .
results data analysis showed a superior length of new cementum and a greater mineralized
bone area for group b in both periods ( p<0.05 ) .
the non - mineralized bone area
was greater in the control group ( p<0.05 ) in both periods .
conclusion within the limits of this study , it can be concluded that the use of prp in the
treatment of class ii furcation defects may enhance the amount of new cementum and
provide a more mineralized bone in a shorter period of time . |
PubmedSumm118258 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: glioblastoma multiforme ( gbm ) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas . a subanalysis in an international randomized trial by the european organization for research and treatment of cancer / national cancer institute of canada ( eortc / ncic ) compared the results of radiotherapy ( rt ) alone with those of concomitant rt and temozolomide ( tmz ) and found that the addition of tmz to radiotherapy for newly diagnosed gbm resulted significant survival benefit , additionally the subgroup analysis of the 5-year survival data of the eortc / ncic trial also revealed its benefit .
since then , tmz has been the current first - line chemotherapeutic agent for gbm .
however , despite aggressive treatment including surgery , adjuvant tmz - based chemotherapy , and rt , gbm still has a dismal prognosis : the median survival is 14.6 months from diagnosis .
many studies aim to overcome several determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of gbm such as modifying tmz administration and combining tmz with other agents , developing novel molecular - targeting agents , and novel strategies targeting gscs . in this paper
, we review up - to - date clinical trials of gbm treatments in order to overcome determinants and to aim at more therapeutical effect than conventional therapy that are ongoing or are about to launch in clinical settings and discuss future perspectives .
furthermore , increased mgmt expression is well correlated with in vitro and in vivo glioma resistance to tmz [ 36 ] .
however , in this process , mgmt is rapidly degraded via the ubiquitin - proteasome pathway after receiving alkyl groups from dna ; the repletion of cellular mgmt pools also depends on the resynthesis of the molecule .
this makes mgmt a suitable target for intervention to improve the therapeutic efficacy of tmz .
additional treatment options are limited in cases of relapse after a standard - dose tmz treatment ( 150200 mg / m 5 days , q4weeks ) .
supported by the assumption that continuous treatment with alkylating agents induces the depletion and exhaustion of mgmt activity , many researchers have investigated the effects of different dose- and time - modified tmz schedules . this is a randomized phase iii trial comparing standard adjuvant tmz with a dose - dense schedule in newly diagnosed gbm .
this trial was based on a report indicating that dose - dense tmz prolongs mgmt depletion in blood mononuclear cells and possibly tumors ; the study aimed to determine if intensified tmz ( 75100 mg / m 21 days , q4weeks ) improves overall survival ( os ) or progression - free survival ( pfs ) compared to the standard arm ( 150200 mg / m 5 days , 4weeks ) after the standard concomitant rt+tmz ( figure 1 ) .
no significant difference was observed between the standard and experimental arms with respect to median os ( 16.6 versus 14.9 months , p = 0.63 ) , median pfs ( 5.5 versus 6.7 months , p = 0.06 ) , or mgmt methylation status .
in addition , the experimental arm significantly increased grade 3 toxicity including lymphopenia and fatigue .
this study did not demonstrate improved efficacy of dose - dense tmz for newly diagnosed gbm regardless of mgmt methylation .
there is no consensus on the optimal approach for patients with recurrent gbm , in which recurrence occurs after tmz is initially used followed by 12 or more cycles of adjuvant therapy .
in addition , protracted tmz dosing may inhibit endothelial cell recovery in the tumor and the activity of circulating endothelial precursors as well as upregulate thrombospondin-1 , leading to an antiangiogenic effect [ 912 ] .
ninety - one patients with gbm were prospectively divided into 3 groups according to the timing of progression during adjuvant therapy : early , extended , and rechallenge ( figure 2 ) .
all patients received 50 mg / m / day tmz on a continuous ( 28/28 ) basis for a maximum of 12 months or until progression occurred .
pfs6 was 27.3% , 7.4% , and 35.7% in the early , extended , and rechallenge groups , respectively ; 1-year survival from time of study entry was 27.3% , 14.8% , and 28.6% for the 3 groups , respectively .
the results of the rescue study suggest that patients who progress early compared with those who progress late or after a treatment - free interval may respond differently to the continuous dose - intense tmz re - treatment
. however , given that no consensus treatment option exists for patients with recurrent gbm , it would be of note that continuous dose - intense tmz serves as a useful platform for combination strategies .
both surgery and radiation therapy are less tolerated in elderly patients than in younger ones . to reevaluate the widespread therapeutic nihilism with malignant glioma in the elderly ( age > 65 ) ,
the neurooncology working group ( noa ) of the german cancer society conducted a randomized phase iii trial to compare a 1-week - on/1-week - off tmz schedule at 100 mg / m with dose modification in 25 mg steps in both directions and involved field rt ( 5460 gy ) in elderly patients with newly diagnosed anaplastic astrocytoma or gbm ( noa-08 ) .
the primary endpoint was the median os during follow - up in the 12 months after the operation .
patient characteristics were balanced between arms in the intention - to - treat population ( n = 373 ) except for more resections and more anaplastic astrocytomas in the rt arm .
however , patients in the tmz arm had an increased risk of death ( hr = 1.24 [ 95% ci : 0.941.63 ] ) compared with those in the rt arm .
the rates of adverse and serious adverse events were also higher in the tmz arm .
this trial failed to demonstrate the noninferiority of dose - intensified tmz alone compared with rt alone in the primary treatment of older patients with malignant gliomas .
whether rt plus tmz is superior to rt alone , is being addressed in an ongoing companion trial conducted by the ncic , eortc , and rtog . although tmz replaced nitrosoureas such as 1,3-bis ( 2-chloroethyl)-1-nitrosourea ( bcnu ) as the standard initial chemotherapy in the treatment of gbm , the dna damage induced by nitrosoureas and tmz is partially repaired by mgmt .
thus , combined administration of nitrosoureas and tmz might overcome mgmt - mediated resistance via mgmt depletion , yielding superior treatment results compared with the administration of tmz alone .
this study assessed the efficacy and safety of bcnu ( 150 mg / m , day 1 ) and tmz ( 110 mg / m , days 15 ) every 6 weeks for up to 6 cycles before conventional rt ( 60 gy/30 fr ) in 54 patients .
grade 3 - 4 toxicities included thrombopenia ( n = 20 ) , neutropenia ( n = 13 ) , and elevated transaminases ( n = 5 ) .
treatment was discontinued in 4 patients , and possible treatment - related deaths occurred in 3 patients .
o
-benzylguanine ( o - bg ) is a potent inhibitor that irreversibly inactivates mgmt by covalently transferring its benzyl group to the cysteine residues of mgmt 's active site . as a result
, o - bg enhances tmz cytotoxicity in mgmt - proficient glioma cells both in vitro and in vivo but not in mgmt - deficient cells . since patients with mgmt overexpression in tumors
respond more poorly to alkylating agents , co - administration of o - bg to deplete the tumor pools of mgmt to enhance drug cytotoxicity has been previously attempted in a clinical setting [ 18 , 19 ] . however , systemic delivery of o - bg increased the myelotoxicity caused by mgmt depletion in bone marrow cells .
therefore , the therapeutic potential of adding o - bg to enhance tmz cytotoxicity in tumor cells has been discouraging thus far .
cilengitide , a selective v3/5 integrin inhibitor , exhibits dose - dependent antitumor activity in patients with recurrent gbm . a randomized controlled phase ii trial ( core )
was designed as stepwise cilengitide intensification in subjects with newly diagnosed gbm and unmethylated mgmt promoter status .
a further phase trial testing the use of intensified cilengitide ( 2000 mg , 5 days / week ) in combination with concomitant rt with tmz is now recruiting patients with newly diagnosed gbm with unmethylated mgmt status .
interferon ( ifn)- exerts pleiotropic biological effects and is widely used either individually or in combination with other antitumor agents to treat malignant gliomas and melanomas . in the treatment of malignant gliomas , ifn- can act as a drug sensitizer by enhancing the toxicity of chemotherapeutic agents against various neoplasms when administered in combination with nitrosoureas .
combination therapy with ifn- and nitrosoureas is primarily used for the treatment of gliomas in japan . in a previous in vitro study in human glioma cells
, we found that ifn- markedly enhances chemosensitivity to tmz ; this finding suggests that one of the major mechanisms by which ifn- enhances chemosensitivity is the downregulation of mgmt transcription via p53 induction .
the results of these 2 studies suggest that compared with chemotherapy with tmz alone and concomitant rt , chemotherapy with ifn- and tmz with concomitant rt might further improve the clinical outcomes of malignant gliomas . to evaluate the safety , feasibility , and clinical effectiveness of combination therapy with ifn- and tmz , a phase i clinical study , the integrated japanese multicenter clinical trial : a phase i study of interferon- and tmz for glioma in combination with rt ( integra study ) , was conducted .
the study population comprised 16 patients with newly diagnosed gliomas and 7 with recurrent high - grade gliomas .
grade 3 - 4 leukocytopenia and neutropenia were observed in 6.7% and 13.3% of the patients , respectively .
in patients with newly diagnosed gbm , the median os time was 17.1 months and the rate of 1-year pfs was 50% .
this regimen is safe and well tolerated by the patients , and may prolong the survival of patients with gbm .
a randomized phase ii clinical trial in patients with newly diagnosed gbm is under way to compare the standard - of - care regimen with the addition of ifn- in the upfront settings ( figure 3 ) .
gbm is characterized by sustained angiogenesis the key regulator of which is vascular endothelial growth factor ( vegf ) .
bevacizumab ( avastin , bev ) is a humanized monoclonal antibody that binds to and inhibits the activity of vegf [ 2629 ] . in preclinical models
, bev has been shown to exhibit activity against gbm both alone and in combination with rt and tmz .
the benefit and safety profile of bev was confirmed in a randomized , noncomparative phase ii trial ( brain study ; avf3708 g ) in gbm patients who experienced first or second recurrence following standard - of - care with tmz . in both
the bev ( n = 85 ) and bev plus irinotecan ( n = 82 ) cohorts , objective response rate and pfs6 were significantly higher than those of the external historical controls .
it might be important to state that the addition of irinotecan to bevacizumab did not improve outcome , and pfs6 as a primary endpoint is a controversial particularly in patients treated with antiangiogenic therapies ( such as bevacizumab ) that can lead to improved imaging findings without actual tumor response ( a so - called pseudoresponse ) . in any case ,
in light of these results , studies were initiated to evaluate bev in combination with rt plus tmz as the upfront treatment for newly diagnosed gbm . in a noncomparative study in 70 newly diagnosed
gbm patients , bev in combination with rt plus tmz resulted in median os and pfs times of 19.6 and 13.6 months , respectively . in another nonrandomized phase ii study , the effects of rt plus tmz were compared with ( n = 25 ) and without ( n = 31 ) bev ; rt plus tmz with bev resulted in increased pfs6 ( 87% versus 52% ) , median pfs ( 12 versus 7 months , p = 0.0001 ) , 2-year os rate ( 50% versus 22% ) , and median os ( 24.0 versus 17.5 months , p = 0.09 ) . a large randomized double - blind placebo - controlled phase iii trial ( avaglio , bo21990 , nct00943826 ) is currently recruiting approximately 920 newly diagnosed gbm patients from 140 centers worldwide .
however , there is evidence suggesting that anti - vegf treatment increases tumor cell invasion in gbm . while bev strongly decreases contrast enhancement ,
this is accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma .
these data strongly suggest that vascular remodeling induced by anti - vegf treatment leads to a more hypoxic tumor microenvironment .
this favors a metabolic change in the tumor cells toward glycolysis , which leads to tumor cell invasion into normal brain tissue .
cediranib is another potent oral vegf signaling inhibitor that exhibits activity against all 3 vegf receptors .
regal ( nct00777153 ) is a randomized phase iii study comparing cediranib and lomustine ( ccnu ) in patients with recurrent gbm . between october 2008 and september 2009 ,
other clinical trials are under way to assess cediranib either as a monotherapy or in combination with other agents . to date , various genetic alterations are reported in gbms such as epidermal growth factor receptor ( egfr ) amplification , cdkn2a loss , phosphatase and tensin homolog ( pten ) loss , and so forth . among these various alterations ,
several alterations deregulate pathways involving the rtk / pi3k / akt / mtor pathway [ 36 , 37 ] , which is regarded as the most amenable pathway to pharmacologic intervention .
egfr and platelet - derived growth factor receptor ( pdgfr ) are receptor tyrosine kinases ( rtks ) . in gbm , 4060% of cases exhibit egfr amplification and high egfr protein expression levels [ 39 , 40 ] .
the phosphatidylinositol-3 kinases ( pi3ks ) are lipid kinases that are activated downstream of growth factor receptor signaling . activated pi3ks phosphorylate the lipid phosphatidylinositol ( 4 , 5)-bisphosphate ( pip2 ) to generate phosphatidylinositol ( 3 , 4 , 5)-triphosphate ( pip3 ) .
pip3 recruits akt , which is the major effector of this pathway , to the cell membrane .
activated akt enhances cell growth , survival , and proliferation and indirectly enhances the activity of mammalian target of rapamycin ( mtor ) , which controls cell growth by regulating various cellular processes .
pten suppresses akt phosphorylation by reversing pi3k - driven phosphorylation , resulting in the inhibition of the pip3 signal thus suppressing cell proliferation [ 36 , 41 , 42 ] .
considering that these various alterations affect cell survival and proliferation , many studies suggest a novel strategy targeting these small molecules to improve the dismal prognosis of gbm . to date , the small - molecule inhibitors of egfr that were introduced in clinical trial include gefitinib , erlotinib , and nimotuzumab [ 4446 ] .
gefitinib is an oral low - molecular - weight adenosine triphosphate mimetic of the anilinoquinazoline family .
gefitinib is an efficient therapeutic agent for a subset of patients with nonsmall - cell lung cancers ( nsclc ) , particularly the ones who harbor an activating egfr mutation .
however , several clinical trials evaluating the efficacy of gefitinib with or without tmz in gbm report disappointing efficacy .
report that patients who exhibit adverse reactions to gefitinib ( e.g. , rash and diarrhea ) have prolonged overall survival erlotinib is also an egfr tyrosine kinase inhibitor ( egfr - tki ) .
this egfr - tki exhibits clinical activity particularly in tumors that have mutations in the adenosine triphosphate binding pocket of the tyrosine kinase domain of the egfr gene .
although several clinical trials have evaluated the efficiency of erlotinib , almost all failed to demonstrate its efficiency or any additional benefit [ 45 , 48 ] .
nimotuzumab was tested in an open - label randomized phase iii trial in 150 patients with newly diagnosed gbm , but the interim analysis has failed to demonstrate efficacy .
egfr variant iii ( egfrviii ) is a constitutively activated mutation of egfr that is expressed in approximately 25% of gbm cases but not in normal tissues .
a randomized phase iib / iii actiii study was initiated ; the primary objective was to reject the null hypothesis that less than 53% of patients will be progression - free at 5.5 months from first vaccination .
since this vaccination was well tolerated and the null hypothesis was rejected , further study is warranted .
afatinib , an irreversible erbb family blocker , exhibits high in vitro activity in tumor cell lines resistant to reversible egfr inhibitors .
this study compared the afatinib alone and afatinib with tmz therapies with tmz alone therapy .
imatinib blocks the atp - binding site of tyrosine kinase proteins including pdgfr and inhibits the activity of pdgfr .
the clinical efficiency of imatinib against other cancers such as chronic myeloid leukemia ( cml ) and gastrointestinal stromal tumors ( gists ) has been demonstrated [ 5254 ] .
in addition , since imatinib is active in gbm cell lines and mouse models , several clinical trials have evaluated its efficiency in gbm patients [ 43 , 55 , 56 ] . however , most of these clinical trials were not able to demonstrate any advantage of imatinib .
it should be noted that most of these clinical trials to date enrolled unselected patients in whom the relative importance of each dysregulated molecule affecting tumor growth was largely unknown , which may be why these clinical trials demonstrate no advantage .
sunitinib is an orally available multitarget tki of fdr , pdgfr , and c - kit .
a phase ii trial with stratification of prior use of bev was designed for recurrent gbm to assess the safety and efficacy of 37.5 mg sunitinib administered on a continuous daily schedule .
twenty - eight and twenty - one patients have been enrolled in the bev - resistant and bev - nave arms , respectively .
the efficacy of dasatinib , a pdgf and src inhibitor , was evaluated retrospectively in recurrent malignant gliomas .
twenty patients were treated with dasatinib alone , and in combinations with bev and other anticancer drugs , or bev - nave .
dasatinib alone or in combination with bev did not exhibit activity because low central nervous system penetration may limit its activity .
following the activation of rtk , the activated pi3k / akt / mtor pathway induces cell growth and proliferation .
in addition to the rtk inhibitors described above , several studies suggest potential therapeutic targets of pi3k , akt , and mtor [ 38 , 59 , 60 ] .
because of toxic effects , poor pharmaceutical properties , and a lack of selectivity , the use of these agents was restricted in the preclinical study .
recently , the thienopyrimidine drug gdc-0941 was found to exhibit excellent oral anticancer activity in a preclinical study and is now undergoing a phase i clinical trial in cancer patients .
in addition , imidazopyridines , pyridopyrimidines , quinazolyne derivatives , thiazoles , azolepyrimidine derivatives , and other chemotypes are reported to inhibit the pi3k .
the phospholipid perifosine is suggested to interfere with the association of the akt ph domain with pip3 , thus blocking the membrane localization of the protein .
perifosine is currently undergoing phase ii clinical trials for prostate , head and neck , breast , and pancreatic cancers , melanomas , and sarcomas .
the mtor kinase is intimately linked to pi3k / akt signaling as well as the regulation of protein synthesis , cell growth , and survival .
in addition , rapamycin and its analogs inhibit mtor kinase via a rather indirect fashion .
at present , 2 rapamycin analogs , temsirolimus and everolimus , are approved for the treatment of metastatic renal cell cancer .
several clinical trials evaluating the efficiency of mtor inhibitors such as temsirolimus in gliomas have been performed .
the results of these trials suggest that monotherapy with temsirolimus does not prolong survival but combination therapy enhances its efficiency .
after it serves as neurotransmitter , it is rapidly took up at the plasma membrane of neurons , glial cells , and terminated .
glioma cells released glutamate in concentration , and glutamate reuptake is reduced due to reduction of glutamate transporter .
this increased glutamate influences the surrounding cells and the glutamatergic system is associated with the proliferation , survival and migration of gliomas .
the phase 2 trial of talampanel combined with conventional tmz and radiation for 72 newly diagnosed gbm patients showed median survival time of 18.3 months .
the other phase 2 trial evaluated the efficiency of talampanel as single agent for recurrent malignant glioma patients .
this trial shows no significant activity as single agent ( median os ; 13 weeks ) .
hdac acts on nucleosomal histones , leading to the tight coiling of chromatin and silencing of the expression of various genes .
hdac regulates cell survival , proliferation , tumor cell differentiation , cell cycle arrest , and apoptosis .
there is preclinical evidence that vorinostat has antitumor activity against malignant glioma cell lines in vitro and orthotopic xenografts in vivo .
animal experiments also support the conclusion that vorinostat crosses the blood - brain barrier . on the basis of these results , a phase i study of vorinostat in combination with tmz
was performed and revealed that this treatment is well tolerated ; a phase ii trial is under way .
several studies revealed that gliomas harbor a small population of cells termed glioma stem - like cells ( gscs ) [ 67 , 68 ] .
gbm forms extensively heterogeneous bulk tumors ; this heterogeneity may be crucial for treating this disease
. the presence of gscs may be an important clue in clarifying the details of this heterogeneity .
in addition , gscs are resistant to a wide variety of chemotherapeutic agents and possess a remarkable ability to recover from cytotoxic therapy .
furthermore , gscs play a crucial role in rt failure , as tumors surviving rt are enriched in gscs .
therefore , an alternative strategy involving selective targeting of this functionally distinct chemo- and radiation - resistant small group of gscs rather than the bulk of the tumor may be more successful in treating this deadly disease .
gscs exhibit various alterations to signaling pathway activity including pten , sonic hedgehog ( shh ) , notch , wingless - type mmtv integration site family member ( wnt ) , maternal embryonic leucine - zipper kinase ( melk ) , and b lymphoma mo - mlv insertion region 1 ( bmi1 ) , which are associated with self - renewal and neoplastic proliferation .
pten suppresses akt phosphorylation by reversing pi3k - driven phosphorylation , resulting in the inhibition of pip3 signaling and the suppression of cell proliferation .
pten deletions with retinoblastoma - associated protein ( prb ) inactivation or abcg2 transporter activation accelerate the formation of aggressive high - grade tumors and gsc - like neurosphere formation capacity in a transgenic mouse model of glioma [ 7175 ] .
although pten is one of the most remarkable targets involved in gsc activity , its status in gscs has yet to be elucidated .
the dysfunction of pten leads to the activation of the pi3k / akt / mtor pathway . therefore , therapy targeting the pi3k / akt / mtor pathway described above may be also effective against gscs exhibiting pten dysfunction .
shh ligand binding to its receptors , patched homolog ( ptch ) and smoothened homolog ( smo ) , leads to the activation of gliotactin ( gli ) transcription factors that are translocated into the nuclease to regulate various cellular activities , including the maintenance of cell stemness , survival , and proliferation .
demonstrate that shh signaling regulates the expression of stemness genes such as nanog homeobox ( nanog ) , sry - box containing gene 2 ( sox2 ) , and octamer - binding protein 4 ( oct4 ) .
in addition , they demonstrate that shh - gli signaling is required not only for sustained glioma growth and survival but also for gsc survival and proliferation . considering these reports , the inhibition of the shh signaling pathway may be a target of therapy .
the novel smo inhibitor , vismodegib ( gdc-0449 ) , exhibits antitumor activity in a mouse model of medulloblastoma and primary human tumor cell xenograft models including colorectal cancer and pancreatic carcinoma . a phase i clinical trial was initiated on the basis of these preclinical tests ; the results demonstrate that vismodegib is generally well tolerated with an acceptable safety profile in refractory locally advanced metastatic solid tumors , including basal cell carcinoma and medulloblastomas .
therefore , the shh signaling pathway may be a potential target for therapy against gscs .
the notch pathway is initiated by the binding of transmembrane ligands on one cell to the notch receptors on an adjacent cell .
this binding causes the -secretase - mediated proteolytic release of the notch intracellular domain ( nicd ) .
released nicd translocates into the nucleus and then turns csl ( a transcriptional factor ) from a repressor to an activator , causing various effects .
notch controls the specification , proliferation , and survival of nonneoplastic neural precursors and is aberrantly activated in embryonal brain tumors , suggesting a molecular link between neural stem cells and medulloblastomas .
previously , sullenger et al . demonstrated that gscs promote radioresistance compared with gbm tumor bulk because gscs preferentially activate the dna damage - response pathway .
notch signaling plays an important role in this dna damage response pathway via the activation of the pi3k / akt pathway and the pro - survival protein , mcl-1 . notch pathway inhibition using -secretase inhibitors ( gsis ; mk0752 ) impairs cell growth , clonogenic survival , and tumor formation ability and sensitizes gscs to radiation at clinically relevant doses [ 79 , 80 ] .
wnt signals are divided into 2 different pathways : the canonical , or wnt/-catenin pathway is involved in cell fate determination and the noncanonical pathway is involved in the control of cell movement and tissue polarity . following the binding of wnt protein to a receptor complex comprising frizzleds / low - density lipoprotein receptor - related protein ( fz / lrp ) , cytoplasmic disheveled ( dvl ) is phosphorylated .
the phosphorylation of dvl inhibits the activity of glycogen synthase kinase-3 ( gsk-3 ) , elevating nonphosphorylated -catenin levels in the cytoplasm .
-catenin translocates into the nucleus and forms a complex with members of the t - cell transcription factor ( tcf)/lymphoid enhancer - binding factor ( lef ) family of transcription factors .
epigenetic silencing and loss - of - function mutations of negative regulators of wnt signaling are observed in a variety of human cancers .
it is suggested that wnt signaling is also involved in the regulation of cancer stem cells because of the many similarities in the pathways that regulate normal and cancer stem cells .
therefore , the inhibition of wnt signaling may disrupt the maintenance of the stemness of gscs . although they include preclinical agents , several agents inhibiting the wnt pathway
are suggested for potential clinical use in a review by takahashi - yanaga and kahn . of these agents ,
those that are used clinically are nsaids such as aspirin , sulindac , and celecoxib ; celecoxib is the only nsaid approved by the food and drug administration ( fda ) for the treatment of familial adenomatous polyposis .
the inhibition of the wnt pathway by celecoxib has been shown by its ability to induce the degradation of tcf .
these various pathways altered in gbm or in the presence of gscs with altered signaling pathways may induce resistance to conventional therapy .
in addition , in other cancers , several studies suggest the efficiency of various small - molecule inhibitors .
although several clinical trials of these inhibitors in gbm have been performed , almost all failed to demonstrate the efficiency of these inhibitors compared with conventional therapy .
we expect that combinations of these agents may overcome resistance to treatment or change the definition of patients who should be treated by each agent to induce a more favorable response .
the blood - brain barrier blocks most molecules that are larger than ~500 da .
many drugs are denied access to the very regions where they would be effective , thus limiting the clinical application of most anticancer drugs for treating brain tumors .
each anticancer agent showed various permeability for bbb , although the relationship of its permeability to therapeutic efficacy is not clear .
although several local therapies are attempted to overcome this bbb or blood - tumor barrier , local therapies should be more developed to deliver therapeutic agents in more distant locations due to highly infiltrative nature of high - grade gliomas . a meta - analysis combining the results of the randomized phase iii trial published by westphal et al . and an earlier randomized phase iii study by valtonen et al
. demonstrates that the subgroup of gbm treatments with bcnu wafers increases mean survival to 13.1 months compared with 10.9 months for placebo patients ( p = 0.03 ) .
the results of the 2 trials led the fda to approve gliadel for the treatment of newly diagnosed gbm in 2003 .
a combination of local bcnu wafer treatment and concomitant radiochemotherapy with tmz is attractive not only because it may significantly reduce the toxicity of a systemic combination of bcnu and tmz as described above but also because it may take advantage of the sensitizing effect of tmz and bcnu on their respective resistance by mgmt .
however , several complications are associated with the implantation of bcnu wafers , including cerebral edema , healing abnormalities , cerebral spinal fluid leaks , intracranial infections , seizures , hydrocephalus , and cyst formation .
the rates for these adverse events were well established in 2 randomized phase iii trials that compared bcnu wafers with placebo ones .
therefore , the combined approach requires special attention . a direct intracerebral approach called convection - enhanced delivery ( ced ) may be used as a strategy to address these issues [ 8890 ] .
ced employs positive pressure that generates a local pressure gradient to distribute agents in the extracellular space . unlike diffusion delivery ,
ced is not significantly affected by the concentration , molecular weight , or particle size of the agent .
furthermore , ced ensures high concentrations and the homogenous distribution of a drug throughout a given target tissue .
interleukin ( il)-13 is a cytokine derived from type 2 t - helper cells and can bind to 2 receptor chains : il-13r1 and il-13r2 ; il-13 has low affinity for the il-13r1 chain and high affinity for the il-4r chain .
it forms a receptor complex with the il-4r chain , which is involved in il-13-induced signal transduction via either janus kinase / signal transducer and activator of transcription ( jak - stat ) or pi3k .
the il-13r2 chain binds to il-13 with high affinity and internalizes it after ligand binding without the involvement of other chains .
il-13r is overexpressed in a majority of glioma cell lines and resected gbm specimens . a chimeric fusion protein composed of human il-13 and mutated
forms of pseudomonas aeruginosa exotoxin a ( pe38qqr ) has been developed and shown to affect the specific cytotoxicity of glioma cell lines [ 92 , 93 ] .
il-13-pe is reported to be more active against glioma cell lines than il-4-targeted toxins in vitro . in a phase i trial ,
a phase iii study was conducted to compare the efficacy of il-13-pe to that of gliadel wafers in patients with malignant gliomas .
pfs was longer ( 17.7 versus 11.4 weeks ) in patients treated with il-13-pe than in patients treated with gliadel wafers ; however , there was no significant difference in the median survival time between the 2 groups .
overall , il-13-based toxins can be potentially used in adjuvant therapy for malignant gliomas , but their use requires further clinical studies . transforming growth factor - beta ( tgf- ) is a multifunctional regulatory polypeptide belonging to a ligand superfamily that includes the tgf-s , activins , and bone morphogenetic proteins ( bmps ) .
tgf- controls many aspects of cellular function including proliferation , differentiation , migration , apoptosis , adhesion , angiogenesis , immune surveillance , and survival .
increased tgf-2 levels are associated with advanced disease stage and cause immunodeficiencies in patients with gliomas .
tgf-2 not only inhibits lymphocyte proliferation but also has multiple effects on the immune system .
these effects include inhibition of immune cell activation , blockage of antitumor activity , shift in cytokine balance toward immunosuppression , and inhibition of antigen presentation .
thus , the targeted inhibition of tgf-2 should have an antitumor effect and allow an immune - mediated response .
several approaches to block tgf- function are currently being studied including the use of monoclonal antibodies against tgf- , recombinant fusion proteins containing the ectodomains of tgf- receptor ( tr)ii and triii to prevent the binding of tgf- ligands , atp competitive inhibitors at the atp - binding site of tri kinase , and antisense oligonucleotides specific for tgf-2 [ 96101 ] .
trabedersen ( ap-12009 ) is a synthetic antisense oligodeoxynucleotide designed to block tgf-2 production . in a randomized controlled phase iib trial involving patients with brain tumors , the survival rates of patients for whom trabedersen was intratumorally administered were higher than those of patients receiving standard chemotherapy .
an international clinical phase iii trial is currently recruiting patients with recurrent or refractory anaplastic astrocytoma . a randomized controlled dose - finding
phase iib study evaluated the efficacy and safety in 145 patients with recurrent or refractory high - grade gliomas .
the patients were randomly assigned to receive 10 or 80 m trabedersen or standard chemotherapy .
although this study failed to meet the primary end point , it could be due to the pseudoprogression that occurs with immune therapies .
a prescribed anaplastic astrocytoma subgroup analysis found a significant benefit for 10 m trabedersen with respect to the 14-month tumor control rate .
the 2-year survival rate for 10 m trabedersen tended to be superior to those of the other treatments .
an international clinical phase iii trial is currently recruiting patients with recurrent or refractory anaplastic astrocytomas with end points of 14-month progression rate and 2-year survival rate .
the cancer genome atlas ( tcga ) is a project that catalogs genomic abnormalities that are involved in the development of cancer [ 105 , 106 ] .
tcga published the results of its first study in a large gbm cohort consisting of 206 patient samples .
techniques that are currently used for detection of abnormalities include gene - expression profiling , copy - number variation profiling , single - nucleotide polymorphism ( snp ) genotyping , genome - wide methylation profiling , microrna profiling , and exon sequencing . since the publication of the first paper , several analysis groups within the tcga network have presented the results of highly detailed analyses of gbm .
recently subclassified gbm into proneural , neural , classical , and mesenchymal subtypes by integrating multi - dimensional data on gene expression , somatic mutations , and dna copy number .
the major features of the proneural class are focal amplification of pdfra , idh1 mutation , and tp53 mutation and/or loss of heterozygosity .
moreover , the group showed high expression of genes associated with oligodendrocyte development , such as pdgfra , nkx2 - 2 , and olig2 .
the neural subtype is characterized by the expression of neuron markers such as nefl , gabra1 , syt1 , and slc12a5 .
the classical subtype features high egfr expression associated with chromosome 7 amplification and low expression of p16ink4a and p14arf , resulting from focal 9p21.3 homozygous deletion .
neural stem cell markers such as nestin , as well as components of the notch and sonic hedgehog signaling pathways , are highly expressed in the classical type .
the mesenchymal subtype is characterized by focal hemizygous deletions at 17q11.2 that contains nf1 and high expression of ykl-40 ( chi3l1 ) , met , cd44 , and mertk .
genes in the tumor necrosis factor superfamily pathway and nf - kappab pathway , such as tradd , relb , and tnfrsf1a , are highly expressed in this subtype .
the classification of gbm may lead to establishment of personalized therapies for groups of patients with gbm .
however , the results of clinical studies of egfr and pdgfr inhibitors as monotherapy are disappointing thus far .
while research and development of more promising molecular - targeted agents are needed in the laboratory , molecular - targeted agents are likely to have synergistic antitumor effects in combination .
on the other hand , strategies of how to evaluate better ways to design early phase clinical trials , to choose better endopoints should avoid trials that will not provide helpful answers .
the discrepancy between pfs and os as endpoints are still controversial ; also the question when and how to integrate new therapies into the backbone of standard therapy still remains .
Output:
| glioblastoma multiforme ( gbm ) is one of the most frequently occurring tumors in the central nervous system and the most malignant tumor among gliomas . despite aggressive treatment including surgery , adjuvant tmz - based chemotherapy , and radiotherapy
, gbm still has a dismal prognosis : the median survival is 14.6 months from diagnosis . to date , many studies report several determinants of resistance to this aggressive therapy : ( 1 ) o6-methylguanine - dna methyltransferase ( mgmt ) , ( 2 ) the complexity of several altered signaling pathways in gbm , ( 3 ) the existence of glioma stem - like cells ( gscs ) , and ( 4 ) the blood - brain barrier .
many studies aim to overcome these determinants of resistance to conventional therapy by using various approaches to improve the dismal prognosis of gbm such as modifying tmz administration and combining tmz with other agents , developing novel molecular - targeting agents , and novel strategies targeting gscs . in this paper
, we review up - to - date clinical trials of gbm treatments in order to overcome these 4 hurdles and to aim at more therapeutical effect than conventional therapies that are ongoing or are about to launch in clinical settings and discuss future perspectives . |
PubmedSumm118259 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
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the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
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Input: studies of local recurrences in patients without adjuvant whole breast irradiation ( wbi ) demonstrated that the majority of in - breast tumor recurrences are within the tumor bed [ 14 ] .
these results support that apbi ( accelerated partial breast irradiation ) could be a possible option to deliver adjuvant radiation therapy after lumpectomy in patients undergoing breast - conserving therapy ( bct ) .
results from phase i / ii / iii studies have shown acceptable local control and cosmesis with apbi [ 57 ] . another socio - economic reason that makes apbi a popular choice is that the accelerated treatment , which is typically completed within a week , offers a convenient choice to patients with restricted access to radiation therapy facilities .
tangential beam irradiation of the whole breast is the traditional technique used to spare lung dose in wbi .
conversely , apbi needs to spare normal breast tissue as much as possible such that 3d conformal radiotherapy ( 3d crt ) instead of the tangential beam arrangement should be applied in external radiation .
apbi uses 3d crt as well as interstitial multicatheter brachytherapy ( imbt ) planned either to cover a 10 - 15 mm expansion on the excision cavity plus another 10 mm ptv margin ( 3d crt ) or to cover 10 - 20 mm of the surrounding breast tissue of the lumpectomy cavity .
apbi using imbt has the longest treatment history and has provided the most treatment outcome , which is still the standard in evaluating newer apbi technique .
bedford , ma , usa ) offers easier intracavitary implementation to the resection cavity by use of a single lumen balloon , and has been demonstrated as a mature apbi technique . the later developed multilumen balloon ( mlb ) combines the simplified balloon placement with more complex and flexible dosimetry of imbt technique .
the target volume for the balloon based apbi is to 10 mm ( less 5 mm from skin ) surrounding the inflated balloon .
due to a tighter margin , the variations from daily treatment should be closely monitored .
treatment uncertainties exist at each stage of the radiation therapy process . in general , patient - specific clinical uncertainties
are related to interfraction and interfraction movement of both target and adjacent organs at risk ( oars ) .
internal uncertainties are caused by potential displacement of the applicator , relative to the target and/or movement of oars during bt irradiation or in between imaging and dose delivery [ 12 , 13 ] .
aapm has proposed a task group to develop a consensus on a minimum set of initial qa procedures for clinical implementation of 3d ct - based intracavitary breast brachytherapy .
the proposed qa procedures ( revised february 13 , 2012 ) includes qa for applicator ( physical integrity , source - position accuracy on each lumen , and uncertainty of a catheter length ) and qa for ct - based treatment planning ( physical dimensions of applicator in ct datasets , applicator reconstruction accuracy , verify dvh , and optimal concentration of image contrast medium in the imaging of applicator ) .
this study aimed to investigate the integrity and variation of daily treatment with mlb . by utilizing ct image - guided bt technique in 4d , daily variations of the mlb implementation were analyzed .
a total of 42 ct images ( one simulation ct plus five daily cts for each patient ) scanned from 7 patients with implanted contura multilumen ballon ( senorx , c.r .
, murray hill , nj , usa ) were acquired and evaluated in this study .
each patient had at least five 5 mm titanium clips placed at the medial , lateral , superior , inferior , and deep cavity edge ( positioned in the center of the cavity ) at the time of breast - conserving surgery .
depending on the cavity size , different amount of water and 1.5 cm2 cm of contrast medium was infused into balloon .
each ct acquisition was done using the following procedures : 1 ) re - position patient with mold by using lasers against medial and lateral markers , which were marked during simulation ; 2 ) check the orientation of the balloon by aligning lumen # 1 with the skin marker drawn during simulation ; 3 ) check the conformance of the balloon to tumor bed by evaluating the air - fluid pocket in ct images ; 4 ) use the vacuum port to aspirate the air - fluid if it is significant and then rescan ; 5 ) measure and record the treatment length of each lumen of the balloon ; 6 ) reconstruct the 1 mm thickness ct images to 22 22 cm field of view ( fov ) before exporting ct images to the oncentra planning system ( nucletron , an elekta company , stockholm , sweden ) for planning .
after the balloon was contoured in each ct image , a ptv_eval was created using a 10 mm expansion from the balloon , then excluding the balloon volume , the chest wall , and 5 mm from the skin surface .
the volume of the 10 mm expansion from balloon was designated as target volume , where target points were generated on its surface for further dose point optimization .
an inner skin surface , which was the 2 mm inner distance from external surface [ 14 , 15 ] , and the rib closest to the balloon were delineated to measure the maximum skin dose , ( dskin ) , and maximum dose to rib , ( drib ) , respectively .
the maximum dose reported in this study was the 0.1 cm of the corresponding volume .
planning goals of the original ( reference ) plan were 95% prescription dose ( pd ) to more than 95% of the vptv_eval ( ptv_eval volume )
v95 > 95% , dskin < 125% pd , drib < 125% pd , the vptv_eval received 150% pd ( v150 ) < 50 cm , and the vptv_eval received 200% pd ( v200 ) < 10 cm . a plan with 90% pd to less than 90% of the vptv_eval
the plan was created using dose point optimization in a volume model and followed by manually adjusting the isodose lines ( graphic optimization ) to achieve the planning goals . in dose point optimization , each point dose
is calculated based on tg-43 with anisotropic correction ; the dwell time to each source position is the analytical solution solved with singular value decomposition ( svd ) such that each point receives the reference dose ( 3.4 gy / fraction ) . by interactively updating dose distribution in 3d and dvh
, the graphic optimization allows altering the dwell time weights by locally dragging the isodose lines to adjust the hotspot in the organ at risk and cold spot in target , until the best dhv coverage of ptv_eval is reached without jeopardizing the other planning goals .
this two - step optimization ( dose point optimization followed by graphic optimization ) has been tested and compared with another ipsa ( inverse planning with simulated annealing ) optimizations [ 16 , 17 ] .
since the results from ipsa were not optimum and needed further graphical adjustment to the iso - dose line , we decided to stay with dose optimization in 3d model for apbi brachytherapy with mld .
the approved plan generated from the simulation ct ( reference ct ) was saved as reference plan .
the treatment length of the mlb measured on the simulation date was recorded as reference length . before the am fraction of each treatment day , the entire ct acquisition above ( 1 - 5 ) was repeated . before the pm fraction of each treatment , procedures ( 1,2,5 )
there were total 42 ct image sets acquired ( includes 7 sets form simulation ) and 77 treatment lengths recorded ( includes 7 reference lengths ) . in each ct image
set , balloon size ( vballoon ) , diameters of the balloon in ap , and lat directions ( dap , dlat ) , the closest skin - to - balloon distance ( dskin ) , the closest balloon - to - rib distance ( drib ) , and the volume of air - fluid pocket ( vseroma ) , were measured and recorded .
daily internal variations were measured by comparing the differences between the vballoon , dap , dlat , dskin , drib , and vseroma in daily ct image with those in simulation ct image in terms of vballoon , dap , dlat , dskin , drib , and vseroma , respectively .
conformance of balloon to the resection cavity was ensured , as long as vseroma < 2% or 2 cm of the ptv_eval volume ( vptv_eval ) . its impact to v95 and v90
was accounted by subtracting its volume ( in% of vptv_eval , if more than 0.5 cm ) from the v95 and v90 .
due to the variations of the patient positions and the measured conditions between treatments , the reading of separate measured treatment lengths could be different .
each catheter length was measured and recorded for each fraction ( total of 70 fractions ) . since there are five lumens in a contura ( senorx , c.r .
, usa ) balloon , the deviation of the catheter length in each fraction is reported by the root of sum of square:1rsql=i=15li2
where li is the deviation of the length of catheter
i from its first measured length . by repopulating the time weight of each dwell position of the reference plan onto the corresponding dwell position reconstructed from each daily ct image , dose variations to ptv_eval ,
tumor bed ( surgical clips ) , skin , and rib were evaluated with and without daily catheter length corrections .
the deviation of the catheter length from the first measurement during simulation was corrected by rounding to the nearest millimeter then offsetting the dwell positions of the corresponding catheter in ct image acquired from treatment day .
the variation of catheter length measured from day to day was considered as random variation .
the impact of the systematic errors related to source poisoning , treatment length measuring tool , and reconstruction of the catheters in planning system were accounted and tested by systematically offsetting the entire dwell positions of each catheter with 1 mm , 2 mm , 3 mm , and 4 mm .
dosimetric impact was measured in terms of v90 , v95 , v150 , and v200 .
dose change in each surgical clip was measured as the minimum dose received by 50% volume of the contoured surgical clip .
v95 and v90 were compared with different type of variations , include daily internal variation from ct image only ( intr ) , plus daily treatment length variation ( geor ) , or plus systematic error with different entire treatment shift ( geos ) . both of geor and geos were measured from treatment ct , the results inherently included the effect of intr . to simulate the dosimetric impact of the plans that did not meet planning goals due to too small skin distance ( e.g. , dskin < 5 mm ) , each plan was relaxed to v95 = 90% by graphically dragging the iso - dose line of the original plan inner away from breast tissue .
the results from the original plans were grouped as a and the results from the relaxed plans were grouped as b. dosimetric impact due to daily variations on mlb was compared between group a and group b by two - sided paired sample t - test on the parameters of v95 , v90 , v150 , and v200 .
in each ct image set , balloon size ( vballoon ) , diameters of the balloon in ap , and lat directions ( dap , dlat ) , the closest skin - to - balloon distance ( dskin ) , the closest balloon - to - rib distance ( drib ) , and the volume of air - fluid pocket ( vseroma ) , were measured and recorded .
daily internal variations were measured by comparing the differences between the vballoon , dap , dlat , dskin , drib , and vseroma in daily ct image with those in simulation ct image in terms of vballoon , dap , dlat , dskin , drib , and vseroma , respectively .
conformance of balloon to the resection cavity was ensured , as long as vseroma < 2% or 2 cm of the ptv_eval volume ( vptv_eval ) .
its impact to v95 and v90 was accounted by subtracting its volume ( in% of vptv_eval , if more than 0.5 cm ) from the v95 and v90 .
due to the variations of the patient positions and the measured conditions between treatments , the reading of separate measured treatment lengths could be different .
each catheter length was measured and recorded for each fraction ( total of 70 fractions ) . since there are five lumens in a contura ( senorx , c.r .
, usa ) balloon , the deviation of the catheter length in each fraction is reported by the root of sum of square:1rsql=i=15li2
where li is the deviation of the length of catheter
i from its first measured length . by repopulating the time weight of each dwell position of the reference plan onto the corresponding dwell position reconstructed from each daily ct image , dose variations to ptv_eval ,
tumor bed ( surgical clips ) , skin , and rib were evaluated with and without daily catheter length corrections .
the deviation of the catheter length from the first measurement during simulation was corrected by rounding to the nearest millimeter then offsetting the dwell positions of the corresponding catheter in ct image acquired from treatment day .
the variation of catheter length measured from day to day was considered as random variation .
the impact of the systematic errors related to source poisoning , treatment length measuring tool , and reconstruction of the catheters in planning system were accounted and tested by systematically offsetting the entire dwell positions of each catheter with 1 mm , 2 mm , 3 mm , and 4 mm .
dosimetric impact was measured in terms of v90 , v95 , v150 , and v200 .
dose change in each surgical clip was measured as the minimum dose received by 50% volume of the contoured surgical clip .
were compared with different type of variations , include daily internal variation from ct image only ( intr ) , plus daily treatment length variation ( geor ) , or plus systematic error with different entire treatment shift ( geos ) .
both of geor and geos were measured from treatment ct , the results inherently included the effect of intr .
to simulate the dosimetric impact of the plans that did not meet planning goals due to too small skin distance ( e.g. , dskin < 5 mm ) , each plan was relaxed to v95 = 90% by graphically dragging the iso - dose line of the original plan inner away from breast tissue .
the results from the original plans were grouped as a and the results from the relaxed plans were grouped as b. dosimetric impact due to daily variations on mlb was compared between group a and group b by two - sided paired sample t - test on the parameters of v95 , v90 , v150 , and v200 .
table 1 lists the initial anatomic parameters from the simulation ct image set and its corresponding plan evaluated parameters . comparing 7 simulation ct image sets with 35 daily treatment ct image sets , dap and dlat of the balloon , which had initial mean values of 40.9
mm ap and 45.4 mm lat , had a mean decrease of 0.9 mm and 0.2 mm , respectively ; vballoon , which had an initial mean value of 41.8 cm , had a mean decrease of 0.4 cm ; vseroma , which had an initial mean value of 0.2 cm , had a mean increase of 0.2 cm ; dskin and drib , which had an initial mean values of 18.5 mm and 15.2 mm , had a mean decrease of 1.3 mm and a mean increase of 3.1 mm , respectively .
a larger variation of daily reading from the initial reading within patient 's treatments and between patient 's treatments was seen in dskin .
the variation of dskin from day to day for each patient and its corresponding dosimetric impact due to the variation were illustrated in figure 1 .
the changes of the relationship between balloon and anatomy making vptv_eval , which had an initial mean value 90.9 cm , had a mean decrease of 1.7 cm .
the overall dosimetric impact of these internal variations had a minor impact on v90 , v95 , v150 , and v200 with mean values of 0.3% , 0.1% , 0.8 cm and 0.7 cm , respectively .
scatterplot of the variation of dskin due to intr and the corresponding dskin , where % pd was the percentage of the prescription dose and the larger symbols were the intial values taken from reference ct summary of the initial anatomic parameters from the reference ct image set and its corresponding plan evaluated parameters ( group a ) for each patient in this study .
values within the parenthesis were plan parameters for group b unit : mm ; cm ; % .
in addition to intr , table 2 demonstrates the dosimetric impact of geor and geos on ptv_eval .
the variation of the treatment lengths of the five lumens in terms of rsql had a mean value of 2.7 mm .
on top of intr , this deviation caused further degradation of the ptv_eval coverage and an increase of the hot spot within ptv_eval for both of group a and group b. there were mean values of 1% , 1.2% , 0.8 cm , and 1.0 cm for v90 , v95 , v150 , and v200 of group a , respectively .
the impacts of intr & geor on the mean dose ( which is close to 50% dvh value ) of each surgical clip are displayed in figure 2 .
although the statistical normality test did not suggest the frequency distributions follow a normal distribution , which may be due to too small of a sample set , both distributions showed the impacts were random .
frequency distribution of the change of 50% dose of sugical clips due to intr and geor , in terms of the percentage of priscription dose summary of internal variations due to the change of balloon and anatomy , geometrical variations due to the change of catheter length , size of systematic error , and their dosimetric impact on ptv_eval unit : , mm ; , cm ; , % .
the lower half of table 2 summarizes the degradation of the ptv_eval coverage related to geos ( on top of intr ) . in terms of v90 for group a , they were 0.0% and 0.7% for 1 mm , 0.7% and 1.9% for 2 mm , 2.1% and 3.6% for 3 mm , and 4% and 5.6% for 4 mm . in terms of v95 for group a , they were 0.0% and 0.8% for 1 mm , 1.1% and 2.4% for 2 mm , 2.8% and 4.4% for 3 mm , and 5.2% and 6.7% for 4 mm .
the values of v90 and v95 in group b had similar mean and variance compared to those in group b. comparing original plans in group a , which has a mean v95 of 96.8% , and the relaxed plans in group b , which has a mean v95 of 90.4% , using the testing parameters intr , geor and geos ( 1 mm , 2 mm , 3 mm , and 4 mm ) , the p values ( median and range ) for v90 , v95 , v150 , and v200 were 0.25 [ 0.04 , 0.64 ] , 0.58 [ 0.10 , 0.93 ] , 0.04 [ 0.01 , 0.28 ] , and 0.29 [ 0.23 , 0.94 ] , respectively .
it indicated that only v150 ( on geos with 2 mm , 3 mm , and 4 mm ) showed a significant difference between these two groups . since the majority of differences were not significant
it showed that the intr had the least dosimetric impact , followed by geos-1 mm , geor , geos-2 mm , geos-3 mm , and geos-4 mm . in terms of the percentage of plans that became unacceptable plans ( v90 < 90% ) due to daily treatment variations in this study , in group a , the chance was less than 3% , even if there was a 3 mm systemetic error since its baseline ( mean v95 = 96.8% ) was high .
however , in group b , the chance was more than 14% and 34% if the systematic error was more than 2 mm and 3 mm , respectively .
boxplots of the dosimetric impacts ( v90 , v95 , v150 , v200 ) vs. different type of variations , where int is intr , geo is geor , s represents geos and is followed with different size of systematic errors
table 1 lists the initial anatomic parameters from the simulation ct image set and its corresponding plan evaluated parameters . comparing 7 simulation ct image sets with 35 daily treatment ct image sets , dap and dlat of the balloon , which had initial mean values of 40.9
mm ap and 45.4 mm lat , had a mean decrease of 0.9 mm and 0.2 mm , respectively ; vballoon , which had an initial mean value of 41.8 cm , had a mean decrease of 0.4 cm ; vseroma , which had an initial mean value of 0.2 cm , had a mean increase of 0.2 cm ; dskin and drib , which had an initial mean values of 18.5 mm and 15.2 mm , had a mean decrease of 1.3 mm and a mean increase of 3.1 mm , respectively .
a larger variation of daily reading from the initial reading within patient 's treatments and between patient 's treatments was seen in dskin .
the variation of dskin from day to day for each patient and its corresponding dosimetric impact due to the variation were illustrated in figure 1 .
the changes of the relationship between balloon and anatomy making vptv_eval , which had an initial mean value 90.9 cm , had a mean decrease of 1.7 cm .
the overall dosimetric impact of these internal variations had a minor impact on v90 , v95 , v150 , and v200 with mean values of 0.3% , 0.1% , 0.8 cm and 0.7 cm , respectively .
scatterplot of the variation of dskin due to intr and the corresponding dskin , where % pd was the percentage of the prescription dose and the larger symbols were the intial values taken from reference ct summary of the initial anatomic parameters from the reference ct image set and its corresponding plan evaluated parameters ( group a ) for each patient in this study .
values within the parenthesis were plan parameters for group b unit : mm ; cm ; % .
in addition to intr , table 2 demonstrates the dosimetric impact of geor and geos on ptv_eval .
the variation of the treatment lengths of the five lumens in terms of rsql had a mean value of 2.7 mm .
on top of intr , this deviation caused further degradation of the ptv_eval coverage and an increase of the hot spot within ptv_eval for both of group a and group b. there were mean values of 1% , 1.2% , 0.8 cm , and 1.0 cm for v90 , v95 , v150 , and v200 of group a , respectively .
the impacts of intr & geor on the mean dose ( which is close to 50% dvh value ) of each surgical clip are displayed in figure 2 .
although the statistical normality test did not suggest the frequency distributions follow a normal distribution , which may be due to too small of a sample set , both distributions showed the impacts were random .
frequency distribution of the change of 50% dose of sugical clips due to intr and geor , in terms of the percentage of priscription dose summary of internal variations due to the change of balloon and anatomy , geometrical variations due to the change of catheter length , size of systematic error , and their dosimetric impact on ptv_eval unit : , mm ; , cm ; , % .
the lower half of table 2 summarizes the degradation of the ptv_eval coverage related to geos ( on top of intr ) . in terms of v90 for group a , they were 0.0% and 0.7% for 1 mm , 0.7% and 1.9% for 2 mm , 2.1% and 3.6% for 3 mm , and 4% and 5.6% for 4 mm . in terms of v95 for group a , they were 0.0% and 0.8% for 1 mm , 1.1% and 2.4% for 2 mm , 2.8% and 4.4% for 3 mm , and 5.2% and 6.7% for 4 mm .
the values of v90 and v95 in group b had similar mean and variance compared to those in group b.
comparing original plans in group a , which has a mean v95 of 96.8% , and the relaxed plans in group b , which has a mean v95 of 90.4% , using the testing parameters intr , geor and geos ( 1 mm , 2 mm , 3 mm , and 4 mm ) , the p values ( median and range ) for v90 , v95 , v150 , and v200 were 0.25 [ 0.04 , 0.64 ] , 0.58 [ 0.10 , 0.93 ] , 0.04 [ 0.01 , 0.28 ] , and 0.29 [ 0.23 , 0.94 ] , respectively .
it indicated that only v150 ( on geos with 2 mm , 3 mm , and 4 mm ) showed a significant difference between these two groups . since the majority of differences were not significant ,
it showed that the intr had the least dosimetric impact , followed by geos-1 mm , geor , geos-2 mm , geos-3 mm , and geos-4 mm . in terms of the percentage of plans that became unacceptable plans (
v90 < 90% ) due to daily treatment variations in this study , in group a , the chance was less than 3% , even if there was a 3 mm systemetic error since its baseline ( mean v95 = 96.8% ) was high .
however , in group b , the chance was more than 14% and 34% if the systematic error was more than 2 mm and 3 mm , respectively .
boxplots of the dosimetric impacts ( v90 , v95 , v150 , v200 ) vs. different type of variations , where int is intr , geo is geor , s represents geos and is followed with different size of systematic errors
in an effort to analyze the day to day variation of apbi in patients implanted with mlb , this study used daily ct and pre - treatment catheter length measurements to demonstrate the possible variations due to internal variation and geometrical uncertainties .
the major variations of an intracavitary balloon implant include the conformance of the balloon to the resection cavity , shape of the balloon , distance of balloon to oars , and edema of the breast tissue around the tumor bed due to the implant .
it has been reported that a high percentage of implanted patients had balloons explanted due to poor cavity - balloon conformance , or inadequate skin spacing [ 18 , 19 ] .
, usa ) mlb has a vacuum port , which can be used to aspirate the air - fluid pocket if it is significant .
studies have shown that some patients are likely to produce seroma after surgery or implantation .
bhatt observed a trend for larger seroma accumulation if the volume drawn on the first day of treatment was more than 3 - 6 cm , comparing to those of 0 - 2 cm .
their data suggested that serial aspiration may benefit a subpopulation of patients in terms of tissue conformality and reproducibility .
two out of seven patients in this study needed to aspirate the air - fluid pocket a couple of times in five treatment days .
after aspiration , only in one ct image the air - fluid pocket had volume slightly more than 2 cm , which is less than 3% of the ptv_eval volume .
the variation of the balloon in terms of shape ( diameters ) and size ( volume ) were all small .
dskin was 1.4 mm smaller and drib was 3 mm larger than the distances measured in the reference ct .
edema due to implant of the balloon is difficult to identify with a ct image . with the trend of the increasing drib over time
for a plan with both of skin and rib distance smaller than 7 mm , the maximum degradation on d95 of the ptv_eavl was about 6.5% when there was a 120 rotation error .
they found that in a clinical situation , which had a rotation error smaller than 10 , the degradation on d95 and d90 of the ptv_eval were less than 1% ; the deviation of the skin and rib dose were less than 2.5% of the prescription dose .
the geometrical variation due to the orientation of the mlb within the cavity of the lumpectomy had been implicitly evaluated within the ct image .
it was first visually inspected by aligning the line on the shaft of contura ( senorx , c.r .
bard , inc . ) with the line drawn on patient at the time of initial ct .
ouhib confirmed that visual inspection with marker alignment is an effective way of verifying the orientation of the mlb before treatment .
our experiences showed that with the shaft of the balloon aligned to the external marker , it should still have minor misalignment internally compared to initial ct image , since both of the shaft of contura and breast tissue are non - rigid . including
this deviated balloon orientation with the other internal uncertainties between balloon and internal anatomy , the intr in our study showed minimal deviation from the initial plan whether comparing the impact on the tumor bed surrogate , the surgical clips , or directly on the ptv_eval .
the spatial variation of the surgical clips over treatment course has been presented and will be reported separately .
a 2.7 mm rsql was not small if compared to the 2 mm source position tolerance implemented in most hdr qa programs .
we have observed that the bending and rotation of the middle soft flexible tube caused variations in lumen length .
the length could have a deviation of up to 4 mm if the balloon was rotated by 90 and the lumen bent by 60 at the same time .
fortunately , the directions and magnitudes of the deviation varied between the five lumens and usually had an arithmetical mean of less than 1.5 mm . by comparing the overall effect of this geor with geos in figure 3 ,
the mean 1% degradation of the ptv coverage due to geor was close to geos of 1.5 mm .
the dosimetric impact caused by geor was slightly worse than the impact of intr , however , the range of the error induced was tolerable in this study .
the impact increased with the systematic error and the probability that the original plan became unacceptable was proportional to the size of the error .
if there were a systematic error of 3 mm , the mean degradation of v95 was 4% , which would make the majority of the plans in group a became minor deviation from the planning goal and turn more than 30% of the plans in group b into unacceptable plans .
the geometrical uncertainties analyzed in this study were applied to a ptv volume with a standard 10 mm margin from the implanted balloon , which was estimated to be equivalent to treatment thickness of 16 mm and 20 mm in dickler and weed 's studies , respectively [ 24 , 25 ] . in a different study , vicini et al . concluded that the effective volume expanded from the 10 mm mammosite ctv margin was significantly smaller than the 3d - crt ctv based on a 15 mm margin .
besides , definition of the ptv volume was done irrespective to the status of the surgical margin .
studies showed that the majority of the patterns of failure after apbi were out of field recurrence or elsewhere recurrence [ 2730 ] .
however , it was confirmed that close - margin or close / positive - margin have a significant increase in ibtr ( in breast tumor recurrence ) compared to negative - margin .
according to the statistics measured by husain , the number of bt cases increased nearly 10-fold from 2002 to 2007 , and more than 60% of the patients who received apbi via bt would fall into astro 's cautionary or unsuitable groupings .
there is no direct relationship between the patterns of failure and planning coverage , however , it is good practice to plan with objective to meet the goal of v95 > 95% , and to follow a proper qa procedure for a balloon - based apbi patient who is defined as a cautionary or unsuitable apbi bt patient by astro .
this study did not intent to evaluate the variation due to the delineation of the balloon and critical structures , however , efforts have been done to reduce the variation .
each balloon has been infused with about 2 cm contrast to increase the visibility of the balloon .
each ct was scanned with 1 mm thickness and reconstructed with 22 cm 22 cm field of view to increase the resolution of the ct image .
albeit , a small number of patients , this study increased the sample size by relaxing plans with 5% lower than planning goal such that both groups can be tested via day to day uncertainties . as well as small sample size , another limitation of this study is that the impact of day - to - day variations on dskin and drib was not intensively studied and documented , since both of dskin and drib in our study were not short enough to receive more than 125% pd after uncertainties were applied .
this preliminary study showed that drib tended to be increased from the initial value while dskin did not have similar trend .
the fitting curve in figure 1 indicated that small initial dskin had higher dosimetric impact than large initial dskin . a mean decrease of 2 mm dskin from the reference ct image could have a 20%40% dose increase in treatment ct image when the initial dskin is smaller than 12 mm .
this would greatly increase the risk of skin complication if the initial dskin were close to 125% of the prescription dose .
mlb implant , the conclusions can be applied to any balloon based implant including ms ( hologic inc . ) .
ms ( hologic inc . ) does not need to consider balloon orientation , however , there is no vacuum port , so the volume of the air - fluid pocket has to be monitored .
treatments have shown similar recurrence rates to imbt , but the late toxicity of ms ( hologic inc . )
mlb have no shortcomings in ms ( hologic inc . ) and have the advantages of both ms ( hologic inc . ) and imbt , making mlb much more applicable than ms ( hologic inc . ) for apbi .
however , the treatment history of mlb is still short and it takes 2 - 5 years for the incidence of recurrence and late toxicity .
it is the purpose of this study to have more understanding on the variation from mlb such that a proper qa procedure can be followed .
based on the results of this study , we suggest : 1 ) setup position should be reproduced and mlb orientation should be checked at each fraction ; 2 ) the measured condition applied to mlb should be as close as possible to the mlb status during treatment with minimal bending and twisting of the mlb ; 3 ) the reference treatment lengths measured during simulation should be confirmed at least before the first treatment ; 4 ) ultrasound or ct scan should be checked at least at the first fraction to confirm the integrity of the implanted balloon and no new major air - fluid formation ; 5 ) if serious air - fluid were found , use vacuum port to aspirate the air - fluid ; a ct scan needs to be repeated in the following day until no new air - fluid is formed ; 6 ) if air - fluid can not be eliminated and is more than 5% of vptv_eval , re - plan with new ct or explant the balloon if new plan is not acceptable .
for mlb - based apbi patients whose treatment positions are reproducible , the day to day variation on balloon size , skin distance , and rib distance has very minimal impact on v90 , v95 , v150 , and v200 .
deviation of measured catheter length from the first day measurement had a mean rsql of 2.7 mm . combining the measured deviation of catheter length and the variation from the internal position ,
v95 was degraded by 1.2 2.3% . if there were a systematic error of 3 mm , the mean degradation of v95 was about 4% .
it would turn the majority of plans , which has no deviation from the goal of v95 > 95% into minor deviation of 90% < v95 < 95% , and turn more than 30% of the plans with original v95 close to 90% into an unacceptable plan of v90 < 90% .
a 2 mm tolerance of a hdr qa program is reasonable for regular mlb implant technique for plans with no or minor deviation from the planning goals .
plans with major deviation ( e.g. v95 < 90% ) should consider to re - implant with different size of balloon or to treat patient with other technique .
Output:
| purposeto evaluate the variations of multi - lumen balloon ( mlb)-based brachytherapy from simulation day to treatment day and their dosimetric impacts during accelerated partial breast irradiation ( apbi).material and methodsa total of 42 ct images scanned from seven patients were evaluated with regards to daily variation due to of : 1 ) internal uncertainty : size and shape of balloon , seroma volume ; 2 ) geometrical uncertainty - random : length of each catheter was measured for each fraction ( total 70 ) ; 3 ) geometrical uncertainty - systematic : virtual systematic errors were tested by offsetting dwell positions .
the original plans ( as group a ) had a mean value of 96.8% on v95 of the ptv_eval .
plans were rerun ( as group b ) such that the mean value of the v95 was relaxed to 90.4% . by applying the reference plan to each daily ct image
, variations of target coverage under different sources of error were evaluated.resultsshape and size of the balloon had means of < 1 mm decreased in diameter and < 0.4 cm3 decreased in volume ; the mean seroma volume increased by 0.2 cm3 .
this internal variation has a mean of < 1% difference for both v90 and v95 . the geometrical uncertainty made a mean deviation of 2.7 mm per root of sum of square .
it caused the degradations of v90 and v95 by mean values of 1.0% and 1.2% , respectively .
a systematic error of 3 mm and 4 mm would degrade both of v90 and v95 by 4% and 6% , respectively .
the degradations on target coverage of the plans in group a were statistically the same as those in group b.conclusionsoverall , apbi treatments with mlb based brachytherapy are precise from day to day .
however , minor variation due to daily treatment uncertainties can still degrade tumor bed coverage to an unacceptable coverage when v95 of the original plan is close to 90% . |
PubmedSumm118260 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: on january 15 , 2012 , a 13-month - old girl enrolled in a childcare center in rockville , maryland , experienced 3 episodes of vomiting within 1 hour , after which she had diarrhea or loose stools for 1 week . within 24 hours after this child s onset of symptoms , 2 family members reported multiple episodes of vomiting and diarrhea that lasted > 3 days . because several children and teachers at the childcare center reported similar symptoms , parents of children enrolled at the childcare center were alerted to the possibility of a gastroenteritis outbreak .
the patient reported here was subsequently enrolled in national institutes of health clinical study nct01306084 , after receipt of informed consent from the mother .
fecal samples were collected from the child and examined for norovirus rna by reverse transcription pcr .
viral rna was detected for 4 weeks after the onset of symptoms , and viral rna quantification reached up to 1.7 10 genome copies / g feces .
sequence and phylogenetic analyses of vp1 from the virus ( designated norovirus hu / gii.4/rockvilled1/2012/u.s . ) showed that it grouped within the newly emerging virus gii.4 sydney_2012 cluster ( figure 1 , panel a ) ( 11 ) .
characterization of norovirus detected in stool samples and levels of local iga responses for each infection .
a ) phylogenetic tree of the major capsid protein ( vp1 ) region from representative norovirus strains from each of the 22 genotypes within strain gii .
representative strains from each gii.4 and gii.6 cluster were compared with the strains reported in this article ( boxed ) .
b ) levels of iga in feces collected during the first ( g11.4 ) and ( g11.6 ) second infections .
elisa plates were coated with 1 g / ml of each virus - like particle ( vlp ) .
fecal samples were collected daily ( d ) and weekly ( w ) , diluted to 1:500 in phosphate - buffered saline ( ph 7.4 ) , and tested for the presence of iga with a polyclonal anti - human iga conjugate .
, a gastroenteritis outbreak occurred in a different childcare center in bethesda , maryland , at which the same child ( now 24 months of age ) was enrolled .
the child experienced vomiting , diarrhea , and fatigue that lasted 2 days , and a similar disease pattern developed in a family member 24 hours after the onset of the child s symptoms .
fecal samples were again positive for norovirus with 5.3 10 genome copies / g of feces , and viral rna was detected up to 3 weeks after disease onset .
phylogenetic and sequence analyses revealed a gii.6 norovirus ( designated norovirus hu / gii.6/bethesdad1/2012/u.s . ) , most closely related to gii.6 noroviruses detected in miami ( florida , usa ) and texas ( usa ) in 1994 and 1997 , respectively ( figure 1 , panel a ) .
norovirus strains gii.4 and gii.6 differed by 38% in vp1 sequences ; most amino acid sequence variation occurred in the capsid protruding domain ( 29% ; 163/556 ) .
alignment of the vp1 sequences from the 2 strains in this study showed several gaps ; each strain bore discrete regions of amino acid insertions or deletions that differed from those in the other strain .
the gii.6 vp1 ( 547 aa long ) contained 3 insertions at positions 296 ( 11 residues ) , 310 ( 2 residues ) , and 344 ( 3 residues ) ; gii.4 vp1 ( 540 aa long ) did not contain these insertions .
the same alignment showed gii.4 vp1 insertions at positions 190 ( 1 residue ) , 373 ( 1 residue ) , and 390 ( 7 residues ) ( figure 2 , appendix ) .
of note , most gaps in the alignment of the vp1 sequences were present in or near recently described gii.4 epitopes ( 7,12 ) , thereby suggesting that these residues might play a role in defining the antigenic specificity of the 2 genotypes . appendix .
differences in the major capsid protein ( vp1 ) between norovirus strains gii.4 and gii.6 .
the shell ( s ) domain is highlighted with a dark line , and the protruding ( p ) domain is highlighted with a gray line .
b ) top and side views of the p domain of gii.4 norovirus showing the location of the epitopes and the carbohydrate ( represented as sticks and highlighted in green ) binding sites . to understand the absence of immunity to the second norovirus and to gain insight into the specificity of the mucosal immune response after sequential norovirus infections , we developed virus - like particles from both noroviruses .
we used the bac - to - bac baculovirus expression system ( invitrogen , carlsbad , ca , usa ) and baculovirus
infected sf-9 cells for virus - like particle production as described elsewhere ( 7 ) .
the corresponding virus - like particles were used to test for iga in feces with an elisa that used polyclonal goat anti - human iga conjugated with horseradish peroxidase ( 1:2,000 dilution ; kpl , gaithersburg , md , usa ) as the detector antibody and 2,2-azino - bis(3-ethylbenzthiazoline-6-sulfonic acid ) ( abts ; kpl ) as the substrate . during the child
s first infection with norovirus gii.4 , virus - specific iga was not detectable until 3 weeks after infection ( figure 1 , panel b ) . at the onset of symptoms during the second infection with norovirus gii.6 , a rapid anamnestic response specific for gii.4 virus - like particles developed .
the gii.6-specific iga response was detected at day 6 after infection , and iga was detectable in feces until the last daily collection at 4 weeks ( figure 1 , panel b ) .
examination of feces for norovirus - specific igg after the second infection showed a similar anamnestic response that endured throughout the period examined ( data not shown ) .
the child s clinical history , young age , and absence of early detectable norovirus - specific fecal iga suggest that she experienced a primary infection with gii.4 norovirus in the first childcare center outbreak . during the second infection with gii.6 norovirus , a rapid anamnestic gii.4-specific iga response developed and persisted up to 4 weeks as the slower primary gii.6-specific iga response developed 1 week after symptom onset .
follow - up fecal samples collected at 14 weeks after the second infection contained little or no detectable levels of either gii.6- or gii.4-specific iga , indicating an eventual decline in mucosal iga titers against each genotype ( data not shown ) .
previous data from human volunteer studies suggest that homologous immunity to norwalk virus ( genotype gi.1 ) lasts from 2 months to 2 years ( 13 ) and that a rapid and specific mucosal iga response ( likely anamnestic ) was a correlate of protection ( 14 ) .
the data presented here are consistent with the development of a genotype - specific , short - lived mucosal iga response to norovirus infection that , when stimulated anamnestically , might provide little or no protection against other norovirus genotypes .
this study shows that a young child can experience 2 episodes of acute gastroenteritis caused by distinct norovirus genotypes ( gii.4 and gii.6 ) within 1 year .
reinfection with distinct genotypes can commonly occur in younger persons , as recently demonstrated in a longitudinal study of norovirus infection in infants and young children in peru ( 15 ) .
the mechanisms of enduring norovirus immunity in the development of cross - protective and effective vaccines need to be elucidated .
Output:
| we investigated sequential episodes of acute norovirus gastroenteritis in a young child within an 11-month period .
the infections were caused by 2 distinct genotypes ( gii.4 and gii.6 ) .
failure to achieve cross - protective immunity was linked to absence of an enduring and cross - reactive mucosal immune response , a critical consideration for vaccine design . |
PubmedSumm118261 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: progressive developments in magnetic resonance imaging ( mri ) technologies allow us to better assess csf circulation . therefore , mri aids in the diagnosis of diseases that result from alterations of the csf circulation .
hydrocephalus , which constitutes a major csf - related disorder , is well demonstrated using mri .
the provided data are important for planning the management as well as follow - up of the patients .
mri is also effective in the diagnosis and treatment planning of other csf disorders such as csf leakage , arachnoid cysts , etc . [
the role of mri in the evaluation of hydrocephalus and other csf disorders with emphasis on the most recently used sequences in routine practice is covered .
the csf volume is approximately 150 ml in adults ; 125 ml is distributed in the cranial and spinal subarachnoid spaces and 25 ml is found in the ventricles .
a volume of 400500 ml is secreted and approximately 330380 ml of csf enters the venous circulation daily .
csf is produced in the choroid plexus , brain parenchyma , spinal cord , and ependymal lining of the ventricles .
most is secreted in the lateral ventricles and leaves the ventricles through the foramen of monro to enter the third ventricle .
it leaves the fourth ventricle by the foramen of magendie and foramina of luschka and enters the subarachnoid space .
however , multiple experiments indicate that movement along nerve roots and exiting vessels also plays a role [ 1 , 3 ] . in addition ,
dilatation of the ventricular system may lead to loss of brain cells resulting in a variety of neurological symptoms , stroke , and sometimes even death due to pressure applied on the brain parenchyma .
the causes of csf increase are often obstructive diseases such as cystic lesions , tumours or obstructive membranes [ 57 ] .
rarely , it may be the result of excessive csf production , which may be due to pathologies at the sites where csf production takes place .
more frequently , it is be due to an obstruction in the ventricular system ( obstructive or non - communicating type ) or interrupted csf absorption or flow ( communicating type ) . in young adults and children ,
obstructive - type hydrocephalus is the most common type [ 6 , 9 , 10 ] . in some instances , such as meningitis ,
both absorption and flow may be interrupted , which is defined as complex - type hydrocephalus .
although there are several theories regarding the pathophysiology of hydrocephalus , recently the most widely accepted one has been greitz s hyperdynamic flow theory , which divides hydrocephalus into two main groups , acute and hydrocephalus .
the theory proposes that chronic hydrocephalus is a result of decreased intracranial capillaries , which causes restricted arterial pulsations and increased capillary pulsations and decreased intracranial compliance [ 8 , 9 ] .
the most commonly used radiological criteria in the diagnosis of hydrocephalus are given below [ 12 , 13 ] ( figs . 1 and 2);fig .
the rest of the images from two different patients with aqueductal stenosis demonstrate enlargement of the ventricles proximal to the obstruction ( b , c ) , enlargement of the third ventricular recesses ( b , c ) , dilated ventricular horns ( d f ) and narrowed cortical sulci ( mip image , e ) , which are typical findings of obstructive hydrocephalusfig .
2axial flair images of three different patients with hydrocephalus . in the first patient with chronic compensated hydrocephalus , lack of periventricular csf resorption
is seen ( a ) . in the second patient , periventricular hyperintensity consistent with interstitial oedema due to acute decompansated hydrocephalus
periventricular caps seen in middle aged adults should be differentiated from decompansated hydrocephalus ( arrows , c)ventriculomegaly ( evans ' index > 0.3),enlargement of the third ventricular recesses and lateral ventricular horns , decreased mamillopontine distance and frontal horn angle , thinning and elevation of the corpus callosum , normal or narrowed cortical sulci , periventricular white matter hyperintensities ( interstitial oedema and acute hydrocephalus),aqueductal flow void phenomenon in t2w images ( a sign of communicating hydrocephalus )
the rest of the images from two different patients with aqueductal stenosis demonstrate enlargement of the ventricles proximal to the obstruction ( b , c ) , enlargement of the third ventricular recesses ( b , c ) , dilated ventricular horns ( d f ) and narrowed cortical sulci ( mip image , e ) , which are typical findings of obstructive hydrocephalus axial flair images of three different patients with hydrocephalus . in the first patient with chronic compensated hydrocephalus , lack of periventricular csf resorption is seen ( a ) . in the second patient , periventricular hyperintensity consistent with interstitial oedema due to acute decompansated hydrocephalus is demonstrated ( arrow , b ) .
periventricular caps seen in middle aged adults should be differentiated from decompansated hydrocephalus ( arrows , c ) ventriculomegaly ( evans ' index > 0.3 ) , enlargement of the third ventricular recesses and lateral ventricular horns , decreased mamillopontine distance and frontal horn angle , thinning and elevation of the corpus callosum , normal or narrowed cortical sulci , periventricular white matter hyperintensities ( interstitial oedema and acute hydrocephalus ) , aqueductal flow void phenomenon in t2w images ( a sign of communicating hydrocephalus ) .
the gold standard diagnostic method for hydrocephalus is ventriculographic studies . on the other hand , this is a highly invasive method and may lead to serious complications .
therefore , new mri techniques have been developed in order to determine the aetiology and treatment .
these techniques include phase - contrast mri ( pc - mri ) , three - dimensional ( 3d ) heavily t2w sequences and contrast - material - enhanced mr cisternography ( ce - mrc ) [ 14 , 15 ] .
pc - mri provides quantitative and qualitative data regarding csf circulation . on the other hand , in the presence of complex or turbulent flow
another drawback of the technique is that it is extremely sensitive to technical factors ; 3d heavily t2w sequences [ such as 3d - drive ( philips ) , 3d - ciss ( siemens ) or fiesta - c ( ge ) ] may provide accurate anatomical data . however , these techniques lack physiological information [ 57 ] .
ce - mrc is an invasive test and is highly dependent on radiologist experience . in recent years
, 3d sampling perfection with application - optimised contrast using the variable flip - angle evolution ( 3d - space ) technique has been developed and shown to be useful in the evaluation of patients with obstructive hydrocephalus .
the technique allows scanning of the whole cranium in an acceptable acquisition time using isotropic voxels ( with voxel size < 1 mm ) , which is useful in obtaining high - resolution multiplanar reformatted images without exceeding specific absorption rate ( sar ) limits .
other advantages are that the technique is a flexible one allowing employment of different sequence types such as t1w , t2w , fluid - attenuated inversion - recovery ( flair ) , proton - density weighted or variant flip - angle mode t2w images .
also , the 3d - space technique is non - invasive and less sensitive to artefacts [ 1719 ] .
our 3-t mri protocol for patients with hydrocephalus is given in table 1.table 1our 3-t mri protocol for patients with hydrocephalus .
pc - mri and 3d - heavily t2w images are optional3d - mprage3d - spacepc - mri ( qualitative)3d - heavily t2w ( 3d - space)pc - mri ( quantitative)tr / te ( ms)2,130/3.453,000/57934.9/9.83,000/52630/7.43ti ( ms)1,100 - ---slice thickness0.8 mm0.6 mm4 mm0.7 mm4 mmfov * ( mm)230 230240 240240 240240 240240
240acquisition time5.5 min6 min5 min5 min5 minvelocity encoding--6 cm / s-20 cm / snex12221number of slices24024012401flip angle8variable1012010imaging planesagittalsagittalaxial - sagittalsagittalaxialdistance factor50 % ----pat factor22none2nonepat modegrappagrappa - grappa - voxel size ( mm)0.8 0.8 0.80.6 0.6 0.6 - 0.7 0.7 0.7-fa mode - t2 variant - t2 constant - note : ti : time of inversion ; 3d - space : three - dimensional sampling perfection with application optimised contrasts using different flip angle evolutions ; 3d - mprage : three - dimensional t1w magnetisation prepared rapid acquisition gradient - echo ; pc - mri : phase - contrast cine mri ; nex : number of excitations ; fov : field of view ; pat : parallel acquisition technique ; grappa : generalised auto calibrating partially parallel acquisitions our 3-t mri protocol for patients with hydrocephalus .
pc - mri and 3d - heavily t2w images are optional note : ti : time of inversion ; 3d - space : three - dimensional sampling perfection with application optimised contrasts using different flip angle evolutions ; 3d - mprage : three - dimensional t1w magnetisation prepared rapid acquisition gradient - echo ; pc - mri : phase - contrast cine mri ; nex : number of excitations ; fov : field of view ; pat : parallel acquisition technique ; grappa : generalised auto calibrating partially parallel acquisitions below imaging findings in different types of hydrocephalus have been summarised .
the location , aetiology and severity of obstruction are crucial in order to plan the treatment procedure .
it should be taken into consideration that any space - occupying lesion with significant size that compresses the foramina from outside or any intraventricular lesions and haemorrhage may lead to obstructive hydrocephalus [ 6 , 7 , 9 ] .
unless the condition is urgently treated , it may lead to serious complications including persistent blindness , cerebral infarct , herniation or death .
the most significant finding on mri to discriminate between acute and chronic forms of hydrocephalus is periventricular hyperintensities on t2w or flair images , which is consistent with acute interstitial oedema ( fig . 2 ) .
below , the obstruction sited are evaluated regarding pathologies specific to that site and mri .
unlike the other sites of obstruction , obstruction of the foramen of monro may lead to unilateral ventriculomegaly .
tumours arising from adjacent tissues such as glial tumours , epandimomas and subepandymomas , intra- or periventricular cysts such as arachnoid , dermoid or epidermoid cysts , adhesions due to previous haemorrhage or ventriculitis may lead to hydrocephalus by obstructing the foramina [ 4 , 9 ] .
although there may be variations in signal characteristics on mri depending on the content of the cyst , it generally appears as a hyperintense lesion on t1w images and may be iso- to hyperintense on t2w images .
cysts with proteinaceous debris may show hypointensity on t2w or flair images ( fig .
axial noncontrast - material enhanced ct image demonstrates hyperdense lesions located in the foramen of monro sized 2 cm in diameter ( arrow , a ) .
the lesion is hypointense in flair images , which indicates the proteinous content of the cyst ( arrow , b ) a 46-year - old male patient with a colloid cyst .
axial noncontrast - material enhanced ct image demonstrates hyperdense lesions located in the foramen of monro sized 2 cm in diameter ( arrow , a ) .
the lesion is hypointense in flair images , which indicates the proteinous content of the cyst ( arrow , b ) aqueductal stenosis ( as ) can be classified as congenital or acquired [ 14 , 17 ] .
the most common lesions causing as are pineal gland tumours , gliomas in the tectum - tegmentum , tentorial meningiomas , galen vein aneurysm , web , synechia and cysticercosis [ 4 , 6 ] .
generally , advanced mri techniques are needed in order to diagnose and determine the aetiology of the stenosis .
axial plane images encode in the craniocaudal direction for flow quantification and sagittal plane images encode craniocaudal images for qualitative evaluation .
quantitative csf velocity and qualitative flow information can be obtained in an additional 810 min in connection with routine mri .
these sequences have also been reported to be useful in the assessment of the treatment response [ 4 , 14 ] .
recent studies have shown that 3d - space with the variant flip angle mode ( vfam ) technique alone is usually sufficient for the diagnosis of as by itself ( fig . 4 ) .
furthermore , a heavily t2w 3d - space sequence with constant flip - angle images is beneficial in demonstrating luminal morphology [ 17 , 19 ] .
the absence of hypointense signal from the third ventricle into the fourth ventricle ( also called the flow void sign ) from csf on 3d - space with variant flip - angle mode images indicates aqueduct stenosis .
compared to the other fully balanced techniques , such as 3d - ciss and other flow - compensated gradient echo sequences , the 3d - space technique is less sensitive to artefacts while providing images with similar contrast and geometric resolution [ 1719].fig .
4a 32-year - old female patient with partial aqueductal stenosis , partial empty sella and hydrocephalus . in the sagittal midline 3d - mprage image
no increase in third ventricle size and no aqueductal abnormalities are detected ( a ) .
however , axial and sagittal pc - mri images ( venc value : 6 cm / s ) demonstrate lack of csf flow in the aqueduct ( b , c ) .
sagittal 3d - space image demonstrates passage of csf from basal - prepontine cisterns into the sellar cavity through the diaphragm sella ( white arrows , d ) .
this finding explains why hydrocephalus may be associated with empty sella in most of the patients . in the midline sagittal 3d - space image , a narrowed but patent aqueduct is demonstrated ( black arrow , e ) a 32-year - old female patient with partial aqueductal stenosis , partial empty sella and hydrocephalus . in the sagittal midline 3d - mprage image no increase in third ventricle size and no aqueductal abnormalities are detected ( a ) .
however , axial and sagittal pc - mri images ( venc value : 6 cm / s ) demonstrate lack of csf flow in the aqueduct ( b , c ) .
sagittal 3d - space image demonstrates passage of csf from basal - prepontine cisterns into the sellar cavity through the diaphragm sella ( white arrows , d ) .
this finding explains why hydrocephalus may be associated with empty sella in most of the patients . in the midline sagittal 3d - space image ,
a narrowed but patent aqueduct is demonstrated ( black arrow , e ) unfortunately , there has been no systematic research or case series to evaluat the fvo .
heavily t2w 3d sequences or the 3d - space technique with vfam may be used in order to detect obstructions . on the other hand ,
the most common reasons that lead to obstruction of the foramina of luschka and magendie are bleeding , meningitis and extrinsically decompressing lesions such as neoplasms and cranio - cervical developmental malformations ( fig . 5 ) .
among the posterior fossa neoplasms the most commonly seen lesions in paediatric age patients are medulloblastomas , cerebellar astrocytomas and brain stem gliomas [ 4 , 9 ] .
rarely , posterior circulation infarctions may lead to fvo obstruction and acute hydrocephalus due to mass effect.fig .
5reformatted coronal ( a ) and sagittal ( b ) 3d - mprage images of a 50-year - old male patient with a left cerebello - pontine angle mass and hydrocephalus .
coronal image demonstrates the mass extending out of the internal acoustic canal , decompressing and displacing midbrain structures to the right ( arrow , a ) .
in sagittal images it is shown that the mass narrows the fourth ventricle and fourth ventricular outlet ( b ) reformatted coronal ( a ) and sagittal ( b ) 3d - mprage images of a 50-year - old male patient with a left cerebello - pontine angle mass and hydrocephalus .
coronal image demonstrates the mass extending out of the internal acoustic canal , decompressing and displacing midbrain structures to the right ( arrow , a ) .
in sagittal images it is shown that the mass narrows the fourth ventricle and fourth ventricular outlet ( b ) conditions that may lead to narrowing of the foramen magnum include osteochondrodysplasias , metabolic disorders , developmental abnormalities and chiari malformations .
a narrowed foramen magnum may often be followed by intracranial hypertension due to interruption of cerebral venous return at the level of the jugular foramen [ 12 , 22 ] . in these cases , although the techniques explained above are beneficial , we suggest implementing a 3d t1w sequence in that mri protocol that may be 3d t1w [ magnetisation - prepared 180 degree radio - frequency pulses and rapid gradient - echo ( mprage ) ] in addition to the t2w ( 3d - space ) sequences for an optimum morphological analysis ( fig .
although pc - mri has been shown to be useful in the evaluation of csf circulation at the level of the posterior fossa and foramen magnum , the need for this technique has gradually decreased with the use of 3d - space with the vfam technique .fig .
sagittal 3d - mprage ( a ) and heavily t2w 3d - space ( b ) images demonstrate cerebellar tonsils extending into the foramen magnum ( arrows ) .
3d - space with variant fa mode image shows the narrow foramen of magendi and foramen magnum ( arrow , c ) .
thinned hypointense signal in these foramina is due to decreased csf flow ( arrow , c ) . on coronal
curved reformatted 3d - mprage ( d ) and heavily t2w 3d - space ( e ) images , the patency of the foramina and position of the cerebellar tonsils are better evaluated .
the coronal curved reformatted images are obtained by drawing a line on sagittal images as in fig .
6a ( yellow line in a ) a 19-year = old female patient with chiari malformation .
sagittal 3d - mprage ( a ) and heavily t2w 3d - space ( b ) images demonstrate cerebellar tonsils extending into the foramen magnum ( arrows ) .
3d - space with variant fa mode image shows the narrow foramen of magendi and foramen magnum ( arrow , c ) .
thinned hypointense signal in these foramina is due to decreased csf flow ( arrow , c ) . on coronal
curved reformatted 3d - mprage ( d ) and heavily t2w 3d - space ( e ) images , the patency of the foramina and position of the cerebellar tonsils are better evaluated .
the coronal curved reformatted images are obtained by drawing a line on sagittal images as in fig .
6a ( yellow line in a ) the characteristic example in this group is normal pressure hydrocephalus ( nph ) , which manifests with gait disturbance , urinary incontinence and dementia [ 13 , 23 , 24 ] .
early and accurate diagnosis is critical in the management of nph since among all the conditions that cause dementia , nph , which is treated by csf diversion , is the only one that can be treated [ 2325 ] .
on the other hand , response to csf diversion treatment is 50 - 60 % .
it was reported that patients diagnosed and treated in the early stage respond better to treatment [ 24 , 26 ] .
although conventional mri sequences may reveal morphological findings , certain diagnoses require demonstration of hyperdynamic aqueductal flow on pc - mri [ 23 , 27 ] ( fig . 7 ) .
pc - mri parameters are useful for the diagnosis , but they are not sufficient to predict treatment response [ 23 , 27 ] .
recent studies have demonstrated that ct cisternography or ce - mrc provides additive data for the diagnosis of nph and predicting treatment response [ 6 , 26 , 28 ] . on the other hand ,
today there are no methods to predict treatment response with high sensitivity , specificity and accuracy [ 2428].fig .
coronal trufisp image shows enlarged sylvian cisterns , tight medial parietal sulci and ventriculomegaly ( a ) .
sagittal 3d - space image shows hypointense hyperdynamic csf flow in the aqueduct and fourth ventricle ( b ) .
axial pc - mri examination at another centre shows aqueductal roi placement ( broken arrow ) for determination of csf flow ( c ) .
aliasing seen in the flow chart occurred because the venc value was selected as less than what it should be ( venc : 10 cm / s ) ( arrow , d ) .
on axial phase images obtained in the pc - mri examination carried out by selecting a venc value of 20 cm / s , rois on the aqueduct ( long arrow ) and right occipital lobe ( reference roi , short arrow ) are seen ( e ) .
maximum aquaductal csf flow is calculated as 14.73 cm and stroke volume was calculated as 0.051 ml ( f ) a 62-year - old male with normal pressure hydrocephalus ( nph ) .
coronal trufisp image shows enlarged sylvian cisterns , tight medial parietal sulci and ventriculomegaly ( a ) .
sagittal 3d - space image shows hypointense hyperdynamic csf flow in the aqueduct and fourth ventricle ( b ) .
axial pc - mri examination at another centre shows aqueductal roi placement ( broken arrow ) for determination of csf flow ( c ) .
aliasing seen in the flow chart occurred because the venc value was selected as less than what it should be ( venc : 10 cm / s ) ( arrow , d ) .
on axial phase images obtained in the pc - mri examination carried out by selecting a venc value of 20 cm / s , rois on the aqueduct ( long arrow ) and right occipital lobe ( reference roi , short arrow ) are seen ( e ) .
maximum aquaductal csf flow is calculated as 14.73 cm and stroke volume was calculated as 0.051 ml ( f ) although the causes of hydrocephalus vary in a wide range , treatment procedures are basically alike ( ventriculostomy or ventriculo - peritoneal shunt ) .
it is still debated which group of patients would benefit more from which treatment . today , mainly two methods are used in the treatment of hydrocephalus .
the first one is the ventriculoperitoneal shunt ( vps ) including treatment with catheters that are placed proximal to the obstruction to take out excess csf .
mortality , morbidity and complication rates are high for vps and 50 % of patients face various problems within 2 years [ 4 , 6 , 9 ] .
the second one [ endoscopic third ventriculostomy ( etv ) ] is described as entering into the brain with an endoscopic procedure and opening a new drainage pathway that bypasses the obstruction inside of the brain .
with this method is bleeding due to injury to the basilar artery or one of its branches that courses near the surgery site , and this may lead to death .
the csf diversion procedures explained above are carried out according to previously determined anatomic landmarks without visualising the whole brain and intracranial structures . in some of the patients with hydrocephalus , deformation and displacement or asymmetric enlargement of ventricles can be seen , increasing the failure and complication rates in these procedures .
this makes preoperative evaluation critical in patients who will undergo etv and vps procedures ( especially etv ) .
the preoperative etv evaluation should include detailed assessment of landmarks that the endoscope will pass through such as the ventricular system , integrity of the third ventricle , patency of the liliequist membrane , and positions of basilar artery - mammillary bodies and basal cisterns [ 12 , 29 ] .
therefore , it should be investigated in the preoperative period [ 6 , 15 , 30 ] .
t2w 3d - space with the vfam technique is usually sufficient for the preoperative evaluation [ 5 , 18 ] .
after successful etv , expected findings on routine mri include regression in ventricle size , interstitial oedema and demonstration of the flow void sign in the stoma [ 12 , 29 ] .
all these findings are demonstrated effectively with t2w 3d - space with the vfam technique ( with isotropic voxels and voxel size < 1 mm ) within an acquisition time of approximately 5 min ( fig .
heavily 3d t2w , thin - section t2w tse , pc - mri and/or mrc images can be used as adjunctive techniques [ 4 , 5 ] . on the other hand ,
correlation with clinical findings and close follow - up are critical since the failure rate is 40 % on long - term follow - up and sudden death has been reported .fig .
8sagittal 3d - mprage ( a ) and 3d - space with variant fa mode ( b ) images of a 41-year - old male patient with aqueduct stenosis and a history of previous etv .
3d - space image demonstrates that the etv stoma is patent and csf flow is clearly seen ( arrow , b ) sagittal 3d - mprage ( a ) and 3d - space with variant fa mode ( b ) images of a 41-year - old male patient with aqueduct stenosis and a history of previous etv .
3d - space image demonstrates that the etv stoma is patent and csf flow is clearly seen ( arrow , b ) also , mri is a useful method for evaluating vps .
position and integrity of the vps catheter and other complications ( e.g. subdural effusions , damage to neuronal tissues ) can be easily evaluated by the 3d - space technique with small isotropic voxels ( fig .
9 ) . pc - mri and/or 3d - space with vfam techniques can also be used to assess vps patency .fig . 9reformatted 3d - space images of an 11-year - old girl with aqueduct stenosis and hydrocephalus .
axial images show right temporal - parietal subdural haematoma ( arrows in a and b ) and iatrogenic callosal injury ( asterisk in a ) .
on reformatted sagittal 3d - space images obtained at the level of the shunt catheter , as shown in fig . 6b , the position and integrity of the catheter and shunt reservoir can be precisely evaluated ( arrows in c and d ) .
distal end of the catheter is shown to be in the corpus callosum ( arrow in d ) . also , tectal glioma is well demarcated in sagittal images ( asterisks in c and d ) reformatted 3d - space images of an 11-year - old girl with aqueduct stenosis and hydrocephalus .
axial images show right temporal - parietal subdural haematoma ( arrows in a and b ) and iatrogenic callosal injury ( asterisk in a ) . on reformatted sagittal 3d - space images obtained at the level of the shunt catheter , as shown in fig . 6b , the position and integrity of the catheter and shunt reservoir can be precisely evaluated ( arrows in c and d ) .
distal end of the catheter is shown to be in the corpus callosum ( arrow in d ) .
also , tectal glioma is well demarcated in sagittal images ( asterisks in c and d )
similar pathologies may lead to obstruction in different locations . the location , aetiology and severity of obstruction are crucial in order to plan the treatment procedure .
it should be taken into consideration that any space - occupying lesion with significant size that compresses the foramina from outside or any intraventricular lesions and haemorrhage may lead to obstructive hydrocephalus [ 6 , 7 , 9 ] .
unless the condition is urgently treated , it may lead to serious complications including persistent blindness , cerebral infarct , herniation or death .
the most significant finding on mri to discriminate between acute and chronic forms of hydrocephalus is periventricular hyperintensities on t2w or flair images , which is consistent with acute interstitial oedema ( fig . 2 ) .
below , the obstruction sited are evaluated regarding pathologies specific to that site and mri . unlike the other sites of obstruction
tumours arising from adjacent tissues such as glial tumours , epandimomas and subepandymomas , intra- or periventricular cysts such as arachnoid , dermoid or epidermoid cysts , adhesions due to previous haemorrhage or ventriculitis may lead to hydrocephalus by obstructing the foramina [ 4 , 9 ] .
although there may be variations in signal characteristics on mri depending on the content of the cyst , it generally appears as a hyperintense lesion on t1w images and may be iso- to hyperintense on t2w images .
cysts with proteinaceous debris may show hypointensity on t2w or flair images ( fig .
axial noncontrast - material enhanced ct image demonstrates hyperdense lesions located in the foramen of monro sized 2 cm in diameter ( arrow , a ) .
the lesion is hypointense in flair images , which indicates the proteinous content of the cyst ( arrow , b ) a 46-year - old male patient with a colloid cyst .
axial noncontrast - material enhanced ct image demonstrates hyperdense lesions located in the foramen of monro sized 2 cm in diameter ( arrow , a ) .
the lesion is hypointense in flair images , which indicates the proteinous content of the cyst ( arrow , b ) aqueductal stenosis ( as ) can be classified as congenital or acquired [ 14 , 17 ] .
the most common lesions causing as are pineal gland tumours , gliomas in the tectum - tegmentum , tentorial meningiomas , galen vein aneurysm , web , synechia and cysticercosis [ 4 , 6 ] .
generally , advanced mri techniques are needed in order to diagnose and determine the aetiology of the stenosis .
axial plane images encode in the craniocaudal direction for flow quantification and sagittal plane images encode craniocaudal images for qualitative evaluation . quantitative csf velocity and qualitative flow information can be obtained in an additional 810 min in connection with routine mri .
these sequences have also been reported to be useful in the assessment of the treatment response [ 4 , 14 ] .
recent studies have shown that 3d - space with the variant flip angle mode ( vfam ) technique alone is usually sufficient for the diagnosis of as by itself ( fig . 4 ) .
furthermore , a heavily t2w 3d - space sequence with constant flip - angle images is beneficial in demonstrating luminal morphology [ 17 , 19 ] .
the absence of hypointense signal from the third ventricle into the fourth ventricle ( also called the flow void sign ) from csf on 3d - space with variant flip - angle mode images indicates aqueduct stenosis .
compared to the other fully balanced techniques , such as 3d - ciss and other flow - compensated gradient echo sequences , the 3d - space technique is less sensitive to artefacts while providing images with similar contrast and geometric resolution [ 1719].fig .
4a 32-year - old female patient with partial aqueductal stenosis , partial empty sella and hydrocephalus . in the sagittal midline 3d - mprage image
no increase in third ventricle size and no aqueductal abnormalities are detected ( a ) . however ,
axial and sagittal pc - mri images ( venc value : 6 cm / s ) demonstrate lack of csf flow in the aqueduct ( b , c ) .
sagittal 3d - space image demonstrates passage of csf from basal - prepontine cisterns into the sellar cavity through the diaphragm sella ( white arrows , d ) .
this finding explains why hydrocephalus may be associated with empty sella in most of the patients . in the midline sagittal 3d - space image , a narrowed but patent aqueduct is demonstrated ( black arrow , e ) a 32-year - old female patient with partial aqueductal stenosis , partial empty sella and hydrocephalus . in the sagittal midline 3d - mprage image
no increase in third ventricle size and no aqueductal abnormalities are detected ( a ) .
however , axial and sagittal pc - mri images ( venc value : 6 cm / s ) demonstrate lack of csf flow in the aqueduct ( b , c ) .
sagittal 3d - space image demonstrates passage of csf from basal - prepontine cisterns into the sellar cavity through the diaphragm sella ( white arrows , d ) .
this finding explains why hydrocephalus may be associated with empty sella in most of the patients . in the midline sagittal 3d - space image ,
a narrowed but patent aqueduct is demonstrated ( black arrow , e ) unfortunately , there has been no systematic research or case series to evaluat the fvo .
heavily t2w 3d sequences or the 3d - space technique with vfam may be used in order to detect obstructions . on the other hand ,
the most common reasons that lead to obstruction of the foramina of luschka and magendie are bleeding , meningitis and extrinsically decompressing lesions such as neoplasms and cranio - cervical developmental malformations ( fig . 5 ) .
among the posterior fossa neoplasms the most commonly seen lesions in paediatric age patients are medulloblastomas , cerebellar astrocytomas and brain stem gliomas [ 4 , 9 ] .
rarely , posterior circulation infarctions may lead to fvo obstruction and acute hydrocephalus due to mass effect.fig .
5reformatted coronal ( a ) and sagittal ( b ) 3d - mprage images of a 50-year - old male patient with a left cerebello - pontine angle mass and hydrocephalus .
coronal image demonstrates the mass extending out of the internal acoustic canal , decompressing and displacing midbrain structures to the right ( arrow , a ) . in sagittal images
it is shown that the mass narrows the fourth ventricle and fourth ventricular outlet ( b ) reformatted coronal ( a ) and sagittal ( b ) 3d - mprage images of a 50-year - old male patient with a left cerebello - pontine angle mass and hydrocephalus .
coronal image demonstrates the mass extending out of the internal acoustic canal , decompressing and displacing midbrain structures to the right ( arrow , a ) .
in sagittal images it is shown that the mass narrows the fourth ventricle and fourth ventricular outlet ( b ) conditions that may lead to narrowing of the foramen magnum include osteochondrodysplasias , metabolic disorders , developmental abnormalities and chiari malformations .
a narrowed foramen magnum may often be followed by intracranial hypertension due to interruption of cerebral venous return at the level of the jugular foramen [ 12 , 22 ] . in these cases , although the techniques explained above are beneficial , we suggest implementing a 3d t1w sequence in that mri protocol that may be 3d t1w [ magnetisation - prepared 180 degree radio - frequency pulses and rapid gradient - echo ( mprage ) ] in addition to the t2w ( 3d - space ) sequences for an optimum morphological analysis ( fig . 6 ) . although pc - mri has been shown to be useful in the evaluation of csf circulation at the level of the posterior fossa and foramen magnum , the need for this technique has gradually decreased with the use of 3d - space with the vfam technique .fig .
sagittal 3d - mprage ( a ) and heavily t2w 3d - space ( b ) images demonstrate cerebellar tonsils extending into the foramen magnum ( arrows ) .
3d - space with variant fa mode image shows the narrow foramen of magendi and foramen magnum ( arrow , c ) .
thinned hypointense signal in these foramina is due to decreased csf flow ( arrow , c ) . on coronal
curved reformatted 3d - mprage ( d ) and heavily t2w 3d - space ( e ) images , the patency of the foramina and position of the cerebellar tonsils are better evaluated .
the coronal curved reformatted images are obtained by drawing a line on sagittal images as in fig .
6a ( yellow line in a ) a 19-year = old female patient with chiari malformation .
sagittal 3d - mprage ( a ) and heavily t2w 3d - space ( b ) images demonstrate cerebellar tonsils extending into the foramen magnum ( arrows ) .
3d - space with variant fa mode image shows the narrow foramen of magendi and foramen magnum ( arrow , c ) .
thinned hypointense signal in these foramina is due to decreased csf flow ( arrow , c ) .
on coronal curved reformatted 3d - mprage ( d ) and heavily t2w 3d - space ( e ) images , the patency of the foramina and position of the cerebellar tonsils are better evaluated .
the coronal curved reformatted images are obtained by drawing a line on sagittal images as in fig .
the characteristic example in this group is normal pressure hydrocephalus ( nph ) , which manifests with gait disturbance , urinary incontinence and dementia [ 13 , 23 , 24 ] .
early and accurate diagnosis is critical in the management of nph since among all the conditions that cause dementia , nph , which is treated by csf diversion , is the only one that can be treated [ 2325 ] .
on the other hand , response to csf diversion treatment is 50 - 60 % .
it was reported that patients diagnosed and treated in the early stage respond better to treatment [ 24 , 26 ] .
although conventional mri sequences may reveal morphological findings , certain diagnoses require demonstration of hyperdynamic aqueductal flow on pc - mri [ 23 , 27 ] ( fig . 7 ) .
pc - mri parameters are useful for the diagnosis , but they are not sufficient to predict treatment response [ 23 , 27 ] .
recent studies have demonstrated that ct cisternography or ce - mrc provides additive data for the diagnosis of nph and predicting treatment response [ 6 , 26 , 28 ] . on the other hand ,
today there are no methods to predict treatment response with high sensitivity , specificity and accuracy [ 2428].fig .
coronal trufisp image shows enlarged sylvian cisterns , tight medial parietal sulci and ventriculomegaly ( a ) .
sagittal 3d - space image shows hypointense hyperdynamic csf flow in the aqueduct and fourth ventricle ( b ) .
axial pc - mri examination at another centre shows aqueductal roi placement ( broken arrow ) for determination of csf flow ( c ) .
aliasing seen in the flow chart occurred because the venc value was selected as less than what it should be ( venc : 10 cm / s ) ( arrow , d ) .
on axial phase images obtained in the pc - mri examination carried out by selecting a venc value of 20 cm / s , rois on the aqueduct ( long arrow ) and right occipital lobe ( reference roi , short arrow ) are seen ( e ) .
maximum aquaductal csf flow is calculated as 14.73 cm and stroke volume was calculated as 0.051 ml ( f ) a 62-year - old male with normal pressure hydrocephalus ( nph ) .
coronal trufisp image shows enlarged sylvian cisterns , tight medial parietal sulci and ventriculomegaly ( a ) .
sagittal 3d - space image shows hypointense hyperdynamic csf flow in the aqueduct and fourth ventricle ( b ) .
axial pc - mri examination at another centre shows aqueductal roi placement ( broken arrow ) for determination of csf flow ( c ) .
aliasing seen in the flow chart occurred because the venc value was selected as less than what it should be ( venc : 10 cm / s ) ( arrow , d ) .
on axial phase images obtained in the pc - mri examination carried out by selecting a venc value of 20 cm / s , rois on the aqueduct ( long arrow ) and right occipital lobe ( reference roi , short arrow ) are seen ( e ) .
maximum aquaductal csf flow is calculated as 14.73 cm and stroke volume was calculated as 0.051 ml ( f )
although the causes of hydrocephalus vary in a wide range , treatment procedures are basically alike ( ventriculostomy or ventriculo - peritoneal shunt ) .
the first one is the ventriculoperitoneal shunt ( vps ) including treatment with catheters that are placed proximal to the obstruction to take out excess csf .
mortality , morbidity and complication rates are high for vps and 50 % of patients face various problems within 2 years [ 4 , 6 , 9 ] .
thus , shunt revision is generally required for most of the patients . the second one [ endoscopic third ventriculostomy ( etv ) ] is described as entering into the brain with an endoscopic procedure and opening a new drainage pathway that bypasses the obstruction inside of the brain .
etv is a more physiological treatment than vps . the most important complication with this method is bleeding due to injury to the basilar artery or one of its branches that courses near the surgery site , and this may lead to death .
the csf diversion procedures explained above are carried out according to previously determined anatomic landmarks without visualising the whole brain and intracranial structures . in some of the patients with hydrocephalus , deformation and displacement or asymmetric enlargement of ventricles can be seen , increasing the failure and complication rates in these procedures .
this makes preoperative evaluation critical in patients who will undergo etv and vps procedures ( especially etv )
. the preoperative etv evaluation should include detailed assessment of landmarks that the endoscope will pass through such as the ventricular system , integrity of the third ventricle , patency of the liliequist membrane , and positions of basilar artery - mammillary bodies and basal cisterns [ 12 , 29 ] . in the presence of spontaneous third ventriculostomy ( stv )
therefore , it should be investigated in the preoperative period [ 6 , 15 , 30 ] .
t2w 3d - space with the vfam technique is usually sufficient for the preoperative evaluation [ 5 , 18 ] .
after successful etv , expected findings on routine mri include regression in ventricle size , interstitial oedema and demonstration of the flow void sign in the stoma [ 12 , 29 ] .
all these findings are demonstrated effectively with t2w 3d - space with the vfam technique ( with isotropic voxels and voxel size < 1 mm ) within an acquisition time of approximately 5 min ( fig .
in controversial cases heavily 3d t2w , thin - section t2w tse , pc - mri and/or mrc images can be used as adjunctive techniques [ 4 , 5 ] . on the other hand ,
correlation with clinical findings and close follow - up are critical since the failure rate is 40 % on long - term follow - up and sudden death has been reported .fig .
8sagittal 3d - mprage ( a ) and 3d - space with variant fa mode ( b ) images of a 41-year - old male patient with aqueduct stenosis and a history of previous etv .
3d - space image demonstrates that the etv stoma is patent and csf flow is clearly seen ( arrow , b ) sagittal 3d - mprage ( a ) and 3d - space with variant fa mode ( b ) images of a 41-year - old male patient with aqueduct stenosis and a history of previous etv .
3d - space image demonstrates that the etv stoma is patent and csf flow is clearly seen ( arrow , b ) also , mri is a useful method for evaluating vps .
position and integrity of the vps catheter and other complications ( e.g. subdural effusions , damage to neuronal tissues ) can be easily evaluated by the 3d - space technique with small isotropic voxels ( fig .
pc - mri and/or 3d - space with vfam techniques can also be used to assess vps patency .fig . 9reformatted 3d - space images of an 11-year - old girl with aqueduct stenosis and hydrocephalus .
axial images show right temporal - parietal subdural haematoma ( arrows in a and b ) and iatrogenic callosal injury ( asterisk in a ) . on reformatted sagittal 3d - space images obtained at the level of the shunt catheter , as shown in fig . 6b
, the position and integrity of the catheter and shunt reservoir can be precisely evaluated ( arrows in c and d ) .
distal end of the catheter is shown to be in the corpus callosum ( arrow in d ) . also , tectal glioma is well demarcated in sagittal images ( asterisks in c and d ) reformatted 3d - space images of an 11-year - old girl with aqueduct stenosis and hydrocephalus .
axial images show right temporal - parietal subdural haematoma ( arrows in a and b ) and iatrogenic callosal injury ( asterisk in a ) .
on reformatted sagittal 3d - space images obtained at the level of the shunt catheter , as shown in fig . 6b , the position and integrity of the catheter and shunt reservoir can be precisely evaluated ( arrows in c and d ) .
distal end of the catheter is shown to be in the corpus callosum ( arrow in d ) .
also , tectal glioma is well demarcated in sagittal images ( asterisks in c and d )
arachnoid cysts are mostly found in the temporal fossa and cerebellopontine angle , but they may also be located intra- or periventricularly . due to csf
secreted from the cyst wall or check - valve mechanism , which allows inflow of csf but prevents outflow , these lesions may grow larger and compress ventricles and foramina [ 6 , 9 , 31 ] ( fig .
acs appear as homogeneous cystic lesions with smooth margins , isointense to csf in all sequences .
conventional cranial mri sequences usually enable diagnosis of ac , but for those lesions that are controversial , diffusion - weighted and post - contrast t1w images are beneficial [ 6 , 21 ] . demonstrating the communication of acs with the ventricular and subarachnoid system is essential in order to plan the treatment .
pc - mri or ce - mrc may be useful to identify the presence of the communication [ 6 , 31].fig .
10a 34-year - old male patient with intraventicular arachnoid cyst ( ac ) and hydrocephalus .
sagittal 3d - mprage ( a ) and axial flair ( b ) images show ac extending from the right lateral ventricle into the third ventricle ( arrows ) .
sagittal heavily t2w 3d - space image clearly shows the morphology of the ac and third ventricle ( c ) .
sagittal 3d - space with variant fa mode ( d ) and pc - mri ( e , f ) images demonstrate the narrowed aqueduct and decreased aqueductal csf flow ( arrows ) a 34-year - old male patient with intraventicular arachnoid cyst ( ac ) and hydrocephalus .
sagittal 3d - mprage ( a ) and axial flair ( b ) images show ac extending from the right lateral ventricle into the third ventricle ( arrows ) .
sagittal heavily t2w 3d - space image clearly shows the morphology of the ac and third ventricle ( c ) .
sagittal 3d - space with variant fa mode ( d ) and pc - mri ( e , f ) images demonstrate the narrowed aqueduct and decreased aqueductal csf flow ( arrows ) csf leakage from the nose is defined as rhinorrhoea , while leakage from the ear is called otorrhoea .
csf leakages may be traumatic , non - traumatic or spontaneous in origin , but the evaluation algorithm is the same for all three subtypes . in all patients
the first step is identifying the presence of -2 transferrin in order to make a certain diagnosis ( fig .
however , ct is usually inadequate in cases with multiple fractures and intermittent - low flow fistulas .
ct or radionuclide cisternography are not sufficient for low - flow or hair - like leakages either [ 6 , 33 ] . the most important drawback of these methods is their invasive nature and radiation exposure .
these limitations are overcome in non - contrast mr cisternography ( nce - mrc ) .
nevertheless , false - positive result rates are high with these methods because of viscous secretions and susceptibility artefacts [ 6 , 7 ] .
electrophoresis study ( a ) shows no beta-2-transferrin in the blood sample assigned as no .
1 , whereas in the columns assigned as 2 ( csf ) and 3 ( nasal sample ) beta-2-transferrin is demonstrated ( arrows ) .
coronal precontrast fat - saturated t1w images can not precisely locate the level of csf leakage ( b ) .
after intrathecal gd - dtpa administration , postcontrast t1w image obtained with the same parameters clearly demonstrates the leakage into the left frontal sinus ( arrow , c ) a 32-year - old male patient with rhinorrhoea and a history of trauma .
electrophoresis study ( a ) shows no beta-2-transferrin in the blood sample assigned as no .
1 , whereas in the columns assigned as 2 ( csf ) and 3 ( nasal sample ) beta-2-transferrin is demonstrated ( arrows ) .
coronal precontrast fat - saturated t1w images can not precisely locate the level of csf leakage ( b ) .
after intrathecal gd - dtpa administration , postcontrast t1w image obtained with the same parameters clearly demonstrates the leakage into the left frontal sinus ( arrow , c ) intracranial hypotension is a disease characterised by orthostatic headaches .
characteristic mri findings are thickened pachymeninges with contrast enhancement , subdural fluid collections , engorged cerebral veins , rounded dural sinuses , brain sagging , disappearance of the csf space of the optic nerve sheath and an inferiorly displaced midbrain [ 35 , 36 ] .
these findings are also useful in the follow - up period after treatment . identifying the presence and location of the csf leakage
nce - mrc obtained with heavily t2w sequences showing the extra - arachnoid fluid may provide additive data by demonstrating meningeal diverticula , high - flow fistulas and/or engorgement of the epidural venous plexus .
in equivocal cases , ce - mrc is more sensitive than other methods in demonstrating the leakage location .
although ear trauma - related csf leakages mostly manifest with otorrhoea , in some patients a fistula between the inner ear and subarachnoid space may develop without associated otorrhoea .
this may lead to sensorineural hearing loss ( snhl ) , which may progress to being persistent unless treated accurately .
nce - mrc demonstrates a decreased fluid level of the inner air . on ce - mrc .
intrathecally admistered contrast material is shown to pass into and adjacent to the inner ear .
if these perivascular spaces filled with csf reach larger sizes , it may be challenging to differentiate them from other cystic lesions [ 21 , 39 ] .
heavily t2w sequences ( such as 3d - ciss or 3d - space with constant fa mode ) are useful in the morphological evaluation of these lesions and their extensions as well as in the differential diagnosis [ 35 , 39 ] .
mri is not only beneficial in the diagnosis of csf - related diseases , but also aids in therapy planning and post - surgery follow - up of the patients . with
the advances in mri systems , newly developed sequences and techniques allow precise evaluation of many csf - related disorders , the most important of which is hydrocephalus . in order to be able to better assess csf - related disorders
, radiologists should follow new technologies that enable better assessment of csf hydrodynamics and should apply them in routine use when needed .
the pc - mri and/or 3d - space methods are relatively simple for evaluating true csf flow and determining the obstruction level .
the 3d - space technique seems to be the most efficient and rapid for evaluating hydrocephalus , etv and the shunt catheter . in suspicious or complex cases , pc - mri , 3d - heavily - t2w and/or ce - mrc images
Output:
| mri is not only beneficial in the diagnosis of cerebrospinal fluid ( csf)-related diseases , but also aids in planning the management and post - surgery follow - up of the patients . with recent advances in mri systems
, there are many newly developed sequences and techniques that rapidly enable evaluation of csf - related disorders with greater accuracy . for a better assessment of this group of disorders
, radiologists should follow the developments closely and should be able to apply them when necessary . in this pictorial review ,
the role of mri in the evaluation of hydrocephalus , csf diversion techniques , and other csf disorders is illustrated.teaching points the 3d - space seems to be most efficient technique for evaluation of hydrocephalus and ventriculostomy. in complex cases , pc - mri , 3d - heavily t2w , and/or ce - mrc images may prevent false results of 3d - space. mri is beneficial in the diagnosis and management of hydrocephalus and other csf - related diseases . |
PubmedSumm118262 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: endoscopic ultrasonography ( eus)-guided fine - needle aspiration ( fna ) have a better accuracy for the detection of pancreatic tumors compared with others images modalities .
we assessed if the image criteria of elastography and contrast harmonic echo - endoscopic ultrasound could help in choosing the appropriate fna - needle in the evaluation of focal pancreatic mass in other to maximize the diagnostic yield .
this study prospectively included all new patients with focal pancreatic masses referred to be examined by eus from october to december/2013 .
a total of 21 patients performed eus with sequentially elastography and intravenous injection of a second - generation contrast agent ( 2.4 ml of sonovue , braco international , the netherlands ) .
the lesions which appear hipovascular were assessed with 22 gauge or 25 gauge fna - needles .
the topography of the lesions varied on 13 at the head , 4 at the body and 1 on the tail .
the cytological diagnosis was achieved in 81% ( 17/21 patients ) on the first biopsy .
the others four patients have reached the diagnosis on the second examination . of those four patients , in one
was used the procore 25 gauge ( lesion on the uncinatus process ) , and another one was used both 22 gauge and 25 gauge in the first examination .
a characterization of the pancreatic lesions with elastography and contrast agents might be useful for clinical decision of which needle is better to improve biopsy quality and minimize eus - fna negatives results .
Output:
| introduction : endoscopic ultrasonography ( eus)-guided fine - needle aspiration ( fna ) have a better accuracy for the detection of pancreatic tumors compared with others images modalities .
we assessed if the image criteria of elastography and contrast harmonic echo - endoscopic ultrasound could help in choosing the appropriate fna - needle in the evaluation of focal pancreatic mass in other to maximize the diagnostic yield .
this study prospectively included all new patients with focal pancreatic masses referred to be examined by eus from october to december/2013 .
a total of 21 patients performed eus with sequentially elastography and intravenous injection of a second - generation contrast agent ( 2.4 ml of sonovue , braco international , the netherlands ) .
the lesions which appear hipovascular were assessed with 22 gauge or 25 gauge fna - needles .
the hipervascular masses were biopsied with 19 gauge needles.results : the topography of the lesions varied on 13 at the head , 4 at the body and 1 on the tail .
the finding of a hypoenhanced mass was found in 57% ( 12/21 patients ) .
hyperenhanced was detected in 28% ( 6/21 patients ) .
there were 14% ( three patients ) which the data were not recorded .
the cytological diagnosis was achieved in 81% ( 17/21 patients ) on the first biopsy .
the others four patients have reached the diagnosis on the second examination . of those four patients , in one
was used the procore 25 gauge ( lesion on the uncinatus process ) , and another one was used both 22 gauge and 25 gauge in the first examination.conclusion:a characterization of the pancreatic lesions with elastography and contrast agents might be useful for clinical decision of which needle is better to improve biopsy quality and minimize eus - fna negatives results . |
PubmedSumm118263 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bleaching treatment is in high demand by patients , and it is considered as part of most esthetic dental treatments . despite the tooth whitening esthetic benefits , some side - effects have been reported , including : tooth sensitivity and structural changes such as microhardness ( mh ) reduction and increased roughness . for minimizing the side - effects of the bleaching treatment , the application of desensitizing and remineralizing agents before , during or after the bleaching procedure has been used , clinically .
these agents include fluoride , calcium , potassium nitrate , and recently bioactive materials have been used as well . despite the wide information available , there is still controversy about the use of desensitizing agents during and after bleaching treatment can significantly protect bleached enamel and dentin or not .
desensitizing products currently available in the market are not always capable of eliminating tooth sensitivity caused by tooth bleaching .
clinical trials have shown tooth sensitivity incidence even when these products are applied , this condition can be associated to structural changes on enamel and dentin .
bioactive glasses when in contact with biological fluids start a reaction that quickly culminates in the formation of hydroxyapatite on its surface .
bioactive glasses can obliterate exposed and opened dentinal tubules with hydroxyapatite , which is the main component of enamel and dentin . due to this property ,
bioactive glass materials have been incorporated into toothpastes and even into bleaching gels , as remineralizing agent , as well as desensitizing agent in tooth sensitivity treatment .
previous in vitro studies investigated the influence of these remineralizing agents on bleached dental tissues .
gjorgievska and nicholson showed that bioactive materials are able to increase the calcium and phosphate content on the enamel damaged by bleaching agents .
the investigation done by cunha et al . concluded that the application of casein phosphopeptide - amorphous calcium phosphate ( acp ) before and after high concentration of hydrogen peroxide ( hp ) and carbamide peroxide ( cp ) exposure was able to prevent negative structural changes .
however , de abreu et al . showed no beneficial effects of adding acp to bleaching formulas on enamel mh . in this context , two experimental formulations with a new bioactive material were being proposed in this study to treat dental tissues submitted to the bleaching gel .
the experimental proposal consists in to insert a bioactive nanoparticles powder named biosilicate in a dentifrice and a paste .
one in vitro study by tirapelli et al . showed that micron - sized particles of biosilicate were able to induce hydroxyl carbonate apatite deposition in open dentinal tubules . in a clinical study ,
tirapelli et al . evaluated experimental formulations containing biosilicate and different commercial desensitizing agents in dentin hypersensitivity treatment , showing biosilicate mixed with distilled water as the best and the fastest method to reduce dentin hypersensitivity , suggesting this biomaterial could be used as a desensitizing agent . in another laboratorial study , authors indicated that when biosilicate is used immediately after bleaching treatment it could reduce or even avoid the demineralization effect of bleaching products and prevent exposing dentinal tubules .
nevertheless , there is little information in the literature evaluating this novel bioglass - ceramic associated to bleaching agents .
therefore , this in vitro study considers the null hypothesis that there is no difference between experimental formulations containing biosilicate and other commercial desensitizing agents regarding roughness and mh of enamel and dentin bleached with 16% cp or 35% hp .
variables mh and surface roughness ( ra ) ( rg ) were studied under four levels : ( 1 ) tooth tissue ; ( 2 ) bleaching treatment type ; ( 3 ) desensitizing agent ; ( 4 ) time ( before and after ) .
materials used are listed in table 1 and the experimental design is illustrated in figure 1 .
products utilized in the study schematic arrangement of the experimental design this in vitro study utilized 320 samples ( 160 of enamel and 160 of dentin ) .
the teeth were cleaned with periodontal curette , and the crowns were separated from the root using carborundum disks in a low - speed dental handpiece ( dabi atlante , ribeirao preto , sao paulo , brazil ) under refrigeration .
square enamel sections ( 4 mm 4 mm 3 mm ) were obtained from the middle third of the crown and the dentin sections ( 4 mm 4 mm 3 mm ) from the cervical region of the root .
the samples were polished under water - cooling on a polishing device ( struers / denmark ) .
grit abrasive papers ( 200 , 500 , 600 and 800 ) were used to obtain parallel planar surfaces required for the mh and roughness tests and 1200 grit abrasive paper to obtain standard smoothness .
the thickness of the samples was measured with micrometer ( mitutoyo - pocket gage , japan ) .
samples were removed from the individual containers for applying the bleaching product and the desensitizing agent .
the same protocol was established for enamel and dentin , as follows : for the in - home bleaching treatment , the specimens were exposed to 16% cp ( t1 ) for 4 h a day ( according the manufacturer instructions ) for 14 consecutive days .
after 4 h of bleaching gel exposition , samples were gently washed using tap water for 30 s. then , they were treated with the desensitizing agents according to the experimental groups :
t1/d1 , t1/d2 , t1/d3 and t1/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively and tap water ( 20% wt / vol ) for 15 min ; during the 14 days of the bleaching proceduret1/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching proceduret1/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) . this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching proceduret1/d7 group : the same as t1/d5 , replacing d5 with d7t1/cg group : control for t1 , samples immersed in distilled water for 14 days .
t1/d1 , t1/d2 , t1/d3 and t1/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively and tap water ( 20% wt / vol ) for 15 min ; during the 14 days of the bleaching procedure t1/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching procedure t1/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) .
this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching procedure t1/d7 group : the same as t1/d5 , replacing d5 with d7 t1/cg group : control for t1 , samples immersed in distilled water for 14 days . for in - office bleaching treatment ,
samples were treated with 35% hp ( t2 ) for 45 min ( with three 15 min applications each ) according to manufacturer instructions .
when the time of exposure to t2 was finalized , samples were also washed with tap water for 30 s and they were followed by desensitizing products application :
t2/d1 , t2/d2 , t2/d3 and t2/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively , and tap water ( 20% wt / vol ) for 15 min during the 14 days of the bleaching proceduret2/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching proceduret2/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) .
this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching proceduret2/d7 group : the same of t2/d5 replacing d5 with d7t2/cg group : control for t2 , samples immersed in distilled water for 14 days .
t2/d1 , t2/d2 , t2/d3 and t2/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively , and tap water ( 20% wt / vol ) for 15 min during the 14 days of the bleaching procedure t2/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching procedure t2/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) .
this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching procedure t2/d7 group : the same of t2/d5 replacing d5 with d7 t2/cg group : control for t2 , samples immersed in distilled water for 14 days . after each treatment , samples were gently washed using tap water for 30 s and stored in distilled water , which was changed every day during the experiment period ( 14 days ) . immediately , after the treatment period , samples were evaluated regarding mh and surface roughness .
microhardness and surface roughness were assessed for all samples before ( t0 ) and after the study time ( t1 ) . to measure surface roughness ( ra ) , a contact profilometer device ( mitutoyo , sj-201p , japo ) was used .
the cut - off was 0.8 mm calibrated and determined previously , and three measurements were performed on surface of each sample in different directions with a distance of 0.5 mm between them , for baseline values and for the measurements after the application of the bleaching and the desensitizing agents .
knoop mh measurement was made using a mh tester ( shimadzu hmv 2000 , kyoto , japan ) at a load of 1n for 30 s. measurements were made before and after experimental period of treatment . for baseline measurement
, three indentations were performed in each sample , with 0.5 mm of distance between them , following the mark 1 . for the final measurement , we set a mark 2 on the opposite side ( considering the first one ) , and the three indentation was performed following it .
representative samples of each experimental group of enamel and dentin were dehydrated in a desiccator at 37c for 24 h and coated with a conductive layer of gold by evaporation under vacuum and analyzed by scanning electron microscope ( sem ) ( zeiss , evo 50 , cambridge instruments co. , uk ) .
sem was performed at the baseline ( t0 ) and at the end of treatment ( t1 ) .
each sample was measured 3 times for roughness and mh before and after the treatments proposed - a total of 1920 measurements were obtained for each variable . the rg or mh value for each sample was the average obtained from the three measurements .
the authors analyzed the data statistically with the software prism version 7.0 ( graphpad software , california , usa ) .
the factor before - after treatments were analyzed using student 's t - test to compare the means in each group . to analyze the factors desensitizers / bleaching agents , and the tooth tissues ( dentin and enamel ) , two - way analysis of variance ( anova )
was used comparing the mean of the differences between the measurements moments ( after minus before ) for each variable .
the tukey multiple comparison test post - hoc ( = 0.05 ) was performed .
the mean 's groups could assume positive values if mh and rg had increased or negative values if had decreased .
variables mh and surface roughness ( ra ) ( rg ) were studied under four levels : ( 1 ) tooth tissue ; ( 2 ) bleaching treatment type ; ( 3 ) desensitizing agent ; ( 4 ) time ( before and after ) .
materials used are listed in table 1 and the experimental design is illustrated in figure 1 .
this in vitro study utilized 320 samples ( 160 of enamel and 160 of dentin ) .
the teeth were cleaned with periodontal curette , and the crowns were separated from the root using carborundum disks in a low - speed dental handpiece ( dabi atlante , ribeirao preto , sao paulo , brazil ) under refrigeration .
square enamel sections ( 4 mm 4 mm 3 mm ) were obtained from the middle third of the crown and the dentin sections ( 4 mm 4 mm 3 mm ) from the cervical region of the root .
the samples were polished under water - cooling on a polishing device ( struers / denmark ) .
grit abrasive papers ( 200 , 500 , 600 and 800 ) were used to obtain parallel planar surfaces required for the mh and roughness tests and 1200 grit abrasive paper to obtain standard smoothness .
the thickness of the samples was measured with micrometer ( mitutoyo - pocket gage , japan ) .
samples were removed from the individual containers for applying the bleaching product and the desensitizing agent .
the same protocol was established for enamel and dentin , as follows : for the in - home bleaching treatment , the specimens were exposed to 16% cp ( t1 ) for 4 h a day ( according the manufacturer instructions ) for 14 consecutive days .
after 4 h of bleaching gel exposition , samples were gently washed using tap water for 30 s. then , they were treated with the desensitizing agents according to the experimental groups :
t1/d1 , t1/d2 , t1/d3 and t1/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively and tap water ( 20% wt / vol ) for 15 min ; during the 14 days of the bleaching proceduret1/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching proceduret1/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) . this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching proceduret1/d7 group : the same as t1/d5 , replacing d5 with d7t1/cg group : control for t1 , samples immersed in distilled water for 14 days .
t1/d1 , t1/d2 , t1/d3 and t1/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively and tap water ( 20% wt / vol ) for 15 min ; during the 14 days of the bleaching procedure t1/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching procedure t1/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) .
this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching procedure t1/d7 group : the same as t1/d5 , replacing d5 with d7 t1/cg group : control for t1 , samples immersed in distilled water for 14 days . for in - office bleaching treatment , samples were treated with 35% hp ( t2 ) for 45 min ( with three 15 min applications each ) according to manufacturer instructions .
when the time of exposure to t2 was finalized , samples were also washed with tap water for 30 s and they were followed by desensitizing products application :
t2/d1 , t2/d2 , t2/d3 and t2/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively , and tap water ( 20% wt / vol ) for 15 min during the 14 days of the bleaching proceduret2/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching proceduret2/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) . this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching proceduret2/d7 group : the same of t2/d5 replacing d5 with d7t2/cg group : control for t2 , samples immersed in distilled water for 14 days .
t2/d1 , t2/d2 , t2/d3 and t2/d4 groups : samples were immersed in desensitizing solution of d1 , d2 , d3 and d4 respectively , and tap water ( 20% wt / vol ) for 15 min during the 14 days of the bleaching procedure t2/d5 group : a paste obtained from micron - sized particles of biosilicate and distilled water ( 50% wt / vol ) was applied using a micro - applicator ( microbrush ) on the sample surface and stayed active for 15 min on days 1 , 3 , 7 and 10 of the bleaching procedure t2/d6 group : desensibilize nanop was applied on the sample surface using a micro - applicator ( microbrush ) , the product was rubbed for 10 s , and then it stayed active for 5 min ( according to the manufactures instruction ) .
this procedure was carried out on days 1 , 3 , 7 and 10 of the bleaching procedure t2/d7 group : the same of t2/d5 replacing d5 with d7 t2/cg group : control for t2 , samples immersed in distilled water for 14 days .
after each treatment , samples were gently washed using tap water for 30 s and stored in distilled water , which was changed every day during the experiment period ( 14 days ) .
immediately , after the treatment period , samples were evaluated regarding mh and surface roughness .
microhardness and surface roughness were assessed for all samples before ( t0 ) and after the study time ( t1 ) . to measure surface roughness ( ra ) ,
the cut - off was 0.8 mm calibrated and determined previously , and three measurements were performed on surface of each sample in different directions with a distance of 0.5 mm between them , for baseline values and for the measurements after the application of the bleaching and the desensitizing agents .
knoop mh measurement was made using a mh tester ( shimadzu hmv 2000 , kyoto , japan ) at a load of 1n for 30 s. measurements were made before and after experimental period of treatment . for baseline measurement
, three indentations were performed in each sample , with 0.5 mm of distance between them , following the mark 1 .
for the final measurement , we set a mark 2 on the opposite side ( considering the first one ) , and the three indentation was performed following it .
representative samples of each experimental group of enamel and dentin were dehydrated in a desiccator at 37c for 24 h and coated with a conductive layer of gold by evaporation under vacuum and analyzed by scanning electron microscope ( sem ) ( zeiss , evo 50 , cambridge instruments co. , uk ) .
sem was performed at the baseline ( t0 ) and at the end of treatment ( t1 ) .
to measure surface roughness ( ra ) , a contact profilometer device ( mitutoyo , sj-201p , japo ) was used .
the cut - off was 0.8 mm calibrated and determined previously , and three measurements were performed on surface of each sample in different directions with a distance of 0.5 mm between them , for baseline values and for the measurements after the application of the bleaching and the desensitizing agents .
knoop mh measurement was made using a mh tester ( shimadzu hmv 2000 , kyoto , japan ) at a load of 1n for 30 s. measurements were made before and after experimental period of treatment . for baseline measurement
, three indentations were performed in each sample , with 0.5 mm of distance between them , following the mark 1 . for the final measurement
, we set a mark 2 on the opposite side ( considering the first one ) , and the three indentation was performed following it .
representative samples of each experimental group of enamel and dentin were dehydrated in a desiccator at 37c for 24 h and coated with a conductive layer of gold by evaporation under vacuum and analyzed by scanning electron microscope ( sem ) ( zeiss , evo 50 , cambridge instruments co. , uk ) .
sem was performed at the baseline ( t0 ) and at the end of treatment ( t1 ) .
each sample was measured 3 times for roughness and mh before and after the treatments proposed - a total of 1920 measurements were obtained for each variable .
the rg or mh value for each sample was the average obtained from the three measurements .
the authors analyzed the data statistically with the software prism version 7.0 ( graphpad software , california , usa ) .
the factor before - after treatments were analyzed using student 's t - test to compare the means in each group . to analyze the factors desensitizers / bleaching agents , and the tooth tissues ( dentin and enamel ) , two - way analysis of variance ( anova )
was used comparing the mean of the differences between the measurements moments ( after minus before ) for each variable .
the tukey multiple comparison test post - hoc ( = 0.05 ) was performed .
the mean 's groups could assume positive values if mh and rg had increased or negative values if had decreased .
table 2 summarizes the results obtained for both variables . mean values and standard deviation of the difference between before and after appliance of desensitizing agents in bleached enamel and dentin samples student 's t - test showed to the factor before - after no statistical difference between the baseline and posttreatment means for roughness ( p > 0.05 ) at any group .
descriptive statistics presents the mean of the differences between the measurements moments ( after - before ) as positive ( ~70% ) or negative values ( ~30% ) indicating an increased or decreased surface roughness .
however , two - way anova showed that the interaction among the factors ( desensitizing , bleaching agents and tooth structure ) was no significant ( p = 0.6267 ) .
data analysis revealed that there was no statistical difference in surface roughness of enamel and dentin in the control group and experimental groups .
student 's t - test showed to the factor before - after statistical difference in enamel only in the group d1 when treated with 16% cp where mh increased and in dentin samples for the group d6 where mh decreased significantly .
regarding the desensitizing factors , in enamel , the mh of the control group after in - home bleaching treatment decreased ( showing a negative difference ) , and it was statistical different to d1 , d2 , d5 and d7 experimental groups , in which were observed the higher increase of mh .
after the in - office bleaching treatment , the control group showed an increase in mh that was no statically different to the other groups , but the mh of d7 group decreased , showing a statistical difference with d1 , d3 , d4 , d5 and d6 .
about dentin , statistical analysis revealed no differences among the groups for both bleaching agents .
however , descriptive statistic showed that the mh decreased for all groups after in - home bleaching and in d2 , d4 , d5 and d6 after in - office bleaching .
regarding the bleaching factor , tukey test revealed a significant difference between bleaching agents to d7 ( p < 0.0001 ) .
finally , considering the factor tooth structure , the desensitizing d1 , d2 , d5 and d7 after in - home bleaching treatment showed different action on substrates enamel and dentin .
after in - office bleaching treatment , only d1 showed different effect in enamel and dentin .
the sem micrographs [ figure 2a and b ] show both untreated tooth structure enamel and dentin as regular images from these tissues .
( b ) dentin additionally , figure 3 shows a compilation of sem images from specimens of enamel and dentin submitted to the bleaching treatments and the subsequent application of the desensitizing agents . in dentin control group , compared with untreated tooth tissue , it was observed a different pattern on sample surfaces treated with 16% cp , with darkened regions suggesting the attacked part of the tissues by the bleaching gel .
the images on the top correspond to control group where the bleaching products ( t1 or t2 ) were applied .
all other images are allocated in accordance with the subsequent desensitizing treatment in the groups treated with 45s5 ( d7 ) and biosilicate ( d5 ) , on samples bleached with t1 suggested the deposition of these materials is present on both dentin surfaces .
the dentinal tubules appeared to be completely obliterated when treated with biosilicate for samples bleached with t2 ; however , this pattern ( dentinal tubule occlusion ) is also observed in the control group .
student 's t - test showed to the factor before - after no statistical difference between the baseline and posttreatment means for roughness ( p > 0.05 ) at any group .
descriptive statistics presents the mean of the differences between the measurements moments ( after - before ) as positive ( ~70% ) or negative values ( ~30% ) indicating an increased or decreased surface roughness .
however , two - way anova showed that the interaction among the factors ( desensitizing , bleaching agents and tooth structure ) was no significant ( p = 0.6267 ) .
data analysis revealed that there was no statistical difference in surface roughness of enamel and dentin in the control group and experimental groups .
student 's t - test showed to the factor before - after statistical difference in enamel only in the group d1 when treated with 16% cp where mh increased and in dentin samples for the group d6 where mh decreased significantly .
the multiple comparison among the factors showed statistical difference ( p < 0.0001 ) . regarding the desensitizing factors , in enamel , the mh of the control group after in - home bleaching treatment decreased ( showing a negative difference ) , and it was statistical different to d1 , d2 , d5 and d7 experimental groups , in which were observed the higher increase of mh . after the in - office bleaching treatment
, the control group showed an increase in mh that was no statically different to the other groups , but the mh of d7 group decreased , showing a statistical difference with d1 , d3 , d4 , d5 and d6 .
about dentin , statistical analysis revealed no differences among the groups for both bleaching agents .
however , descriptive statistic showed that the mh decreased for all groups after in - home bleaching and in d2 , d4 , d5 and d6 after in - office bleaching . regarding the bleaching factor ,
tukey test revealed a significant difference between bleaching agents to d7 ( p < 0.0001 ) .
finally , considering the factor tooth structure , the desensitizing d1 , d2 , d5 and d7 after in - home bleaching treatment showed different action on substrates enamel and dentin .
after in - office bleaching treatment , only d1 showed different effect in enamel and dentin .
the sem micrographs [ figure 2a and b ] show both untreated tooth structure enamel and dentin as regular images from these tissues .
( b ) dentin additionally , figure 3 shows a compilation of sem images from specimens of enamel and dentin submitted to the bleaching treatments and the subsequent application of the desensitizing agents . in dentin control group ,
compared with untreated tooth tissue , it was observed a different pattern on sample surfaces treated with 16% cp , with darkened regions suggesting the attacked part of the tissues by the bleaching gel . scanning electron microscope micrographs of enamel and dentin bovine samples .
the images on the top correspond to control group where the bleaching products ( t1 or t2 ) were applied .
all other images are allocated in accordance with the subsequent desensitizing treatment in the groups treated with 45s5 ( d7 ) and biosilicate ( d5 ) , on samples bleached with t1 suggested the deposition of these materials is present on both dentin surfaces .
the dentinal tubules appeared to be completely obliterated when treated with biosilicate for samples bleached with t2 ; however , this pattern ( dentinal tubule occlusion ) is also observed in the control group .
adverse effects of tooth bleaching have been described in previous research indicating that this procedure can cause defects on enamel and dentin surfaces .
these effects include roughness increase , mh decrease and potential alteration of the chemical composition of these hard tissues .
enamel matrix is altered allowing the diffusion of peroxides from enamel to dentin , and thus could cause increase dentin permeability which is reported in clinical trials as tooth sensitivity .
thus , in an attempt to reduce the loss of mineral of the dental tissues different desensitizing and remineralizing agents were used before , during or after the bleaching phase and the investigations revealed that their use could be a contributing factor in preventing this damage .
this study analyzed the mh and surface roughness because it is possible to quantitatively determine changes on the dental structure that indicate loss or gain of mineral of the dental structure .
in addition , sem has been used for qualitative analyze of the surface morphology of enamel and dentin samples following bleaching therapy in several studies .
the findings of this study rejected the null hypothesis that there is no difference between experimental formulations containing biosilicate and other commercial desensitizing agents regarding mh of enamel bleached with 16% cp .
this is because data supported comparatively that the experimental dentifrice containing micro particles of biosilicate ( d2 ) and paste containing micro particles of biosilicate ( d5 ) increased enamel mh treated after in - home bleaching . on the other hand , considering the roughness results , we observed no significant difference among the desensitizing agents at any factor ( before - after , bleaching / desensitizing agents and tooth structure ) .
apparently , bleaching agents did not cause significant alteration on both tooth enamel and dentin surface roughness .
similarly , in vitro studies have been related no alteration in roughness on enamel and dentin bleached .
abouassi et al . found no significant changes on enamel roughness after cp or hp use ; pedreira de freitas et al .
, showed no statistically significant changes on enamel roughness after hp 38% exposure . de abreu et al . demonstrated that the surface roughness only is altered when hp is applied , but after immersion in artificial saliva the values get similar to the baseline .
( 2012 ) found no changes on enamel exposure even using a high concentration of hp .
in contrast , azrak et al . indicated roughness alteration on an enamel surface after 10 h of 35% hp bleaching ; the authors attributed that fact to the high concentration of peroxide or low ph on eroded enamel . in our study , both of the bleaching agents tested had neutral ph , and relatively lower cp concentration .
despite we used a high concentration of hp ( 35% ) ; the total exposure time was 45 min with 15 min - interleaved ( according the manufacturer instructions ) .
regarding mh evaluation , the results of this study showed that when comparing before ( t0 ) and after ( t1 ) enamel values for in - home bleaching , mh increased when desensitizing products were applied and reduced only in the control group ( no application of desensitizing agents ) .
the comparison among the desensitizing agents revealed that the control group was statistically different from d1 , d2 , d5 and d7 products ( mh higher values ) .
concerning mh reduction observed in the control group , one study has pointed that this condition is associated with the loss of mineral content because demineralization .
previous studies have reported that different concentrations of cp may influence the chemical composition of enamel and dentin substrates .
thus , the good performance shown specifically by d2 , d5 ( experimental desensitizing agents containing biosilicate ) and d7 ( bioglass 45s5 ) may have been because of they are capable of bonding chemically to hard dental tissues and their components may impart bioactivity , inducing hydroxycarbonate apatite deposition on dental surface . also for the enamel mh , treated by in - office bleaching agent
it may be explained due to 35% hp ( t2 ) did not cause alteration on enamel in our study .
similarly , abouassi et al . reported no difference on enamel mh after bleaching with different hp concentrations .
2012 ) indicated that in vitro conditions , enamel mh is not affected by bleaching agents containing high concentrations .
conversely , other studies have related that 35% hp is able to reduce enamel mh .
enamel mh reduction is attributed to contact time between hp gel and substrate or to acid ph of bleaching gel .
the difference in our results could be due to a shorter hp exposure time ( 45 min ) recommended by the manufacturer or to ph , which not was acid .
considering time factor , we observed a mh reduction in all groups treated by in - home bleaching although it was no significant , exceptionally to d6 .
this pattern of reduction could explain why multiple comparison did not find difference among the desensitizing products .
they were not able to recover the baseline values of mh , showing a similar effect on dentin . at this regard ,
it is important to consider that radicular dentin is a soluble tissue and thus is more susceptible to demineralization .
related that bleaching does not alter enamel mh and surface roughness , but in the root dentin is capable of reducing its mh .
studies that investigated the surface morphology using sem found no significant changes following bleaching and abouassi et al . reported that changes occurred in the surface morphology of the bleached enamel , but with no major changes to the enamel composition .
in contrast , other studies revealed alterations on the morphological surface of hard dental tissues in different degrees of severity , characterized by an increased surface porosity , depressions , and superficial irregularities . in our study , it is possible to observe that in sem image from dentin control group [ figure 3 ] there was not significant change , the dentinal tubules were obliterated , grinding grooves were evident and part of smear layer was still persisted .
in addition , particles can be observed on dentin surface for the group treated with dessensiblize nanop paste ; however , images from samples bleached with 16% cp and treated with bioglass and biosilicate suggested incorporation of the particles on dentin surfaces .
also , the dentinal tubules seemed to be completely obliterated when treated with biosilicate for samples bleached with 35% hp .
finally , it is important to consider that our study had some limitations . although some studies have used artificial saliva as storing solution in order to closely simulate intra - oral conditions , in our study samples were stored in distilled water to avoid the remineralizing effect of artificial saliva , and evaluate if the products tested are able to re - harden the surface softened enamel and dentin samples .
moreover , it is important to consider other evaluation methods to identifying morphological and chemical changes and further clinical studies will be needed to clarify these findings .
according to the results of this in vitro study , it was concluded that :
roughness was not affected by dental bleaching agents on enamel and dentin or when associated to desensitizing agentsmicrohardness was increased by both experimental formulations containing biosilicate , sensodyne dentifrice and paste of bioglass on enamel bleached with 16% cpdentin mh was affected differently than enamel when treated with in - home bleaching agents together with both experimental formulations containing biosilicate , sensodyne dentifrice and paste of bioglass .
roughness was not affected by dental bleaching agents on enamel and dentin or when associated to desensitizing agents microhardness was increased by both experimental formulations containing biosilicate , sensodyne dentifrice and paste of bioglass on enamel bleached with 16% cp dentin mh was affected differently than enamel when treated with in - home bleaching agents together with both experimental formulations containing biosilicate , sensodyne dentifrice and paste of bioglass .
Output:
| objective : this study aimed to evaluate in vitro the effect of formulations containing biosilicate to treat enamel and dentin bovine samples exposed to dental bleaching agents.materials and methods : on enamel and dentin bleached with commercial gels containing 16% carbamide peroxide ( cp ) ( 14 days/4 h ) or 35% hydrogen peroxide ( single session/45 min ) , desensitizing dentifrices ( sensodyne ; experimental dentifrice of biosilicate ; odontis rx ; sorriso ) were applied along 14 days and desensitizing pastes ( biosilicate/water 1:1 ; dessensebilize nanop ; bioglass type 45s5/water 1:1 ) were applied on days 1 , 3 , 7 , 10 and 14 .
distilled water was the control .
microhardness ( mh ) and roughness measurements were the variables measured on the samples before and after the treatments .
student 's t - test analyzed differences before and after the treatments .
two - way analysis of variance and post - hoc tukey test analyzed differences among the factors desensitizing , bleaching agents and substrate.results:tukey test showed no differences in roughness for both bleaching treatments and among the desensitizing agents ( p > 0.05 ) .
differences in mh appeared on enamel treated with in - home bleaching when control group ( lower values ) was compared with sensodyne , biosilicate dentifrice , biosilicate paste , and bioglass paste ( higher values ) .
comparisons between desensitizing agents on dentin treated with both bleaching gels showed no statistical differences.conclusions:the effect of formulations containing biosilicate ( biosilicate dentifrice and paste ) was significant in the mh of enamel bleached with 16% cp . |
PubmedSumm118264 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: exposure of ultraviolet ( uv ) irradiation to the skin causes acute and chronic detrimental cutaneous effects , which may result in photocarcinogenesis [ 17 ] .
native human melanin includes eumelanin and pheomelanin that contains sulfur , and eumelanin has been found in almost every type of human skin [ 8 , 9 ] .
the exact chemical structures of the two types of melanin have not been identified yet , probably because of the complication of polymerization and modifications of polymerization [ 10 , 11 ] .
melanin in the skin is suggested to play an important role for protecting skin from the harmful effects of uv irradiation .
more in detail , melanin acts as a safeguard against the uv - mediated effects on skin through protecting membrane and dna [ 12 , 13 ] .
photoprotection for the skin by melanin is due to its role as a uv filter , and other properties of melanin are still remained to be clarified [ 1416 ] .
it has been reported that uv light energetic photons exerts biological effects through series of biological reactions [ 17 , 18 ] .
one is direct absorption of uv via cellular chromophores that results in excited states formation and subsequent chemical reactions .
the other is photosensitization mechanism , where the uv light is absorbed by endogenous sensitizers that are excited to lead to formation of ros . as for the effects of melanin on ros as a photoprotection mechanism of melanin ,
having examined the reactivity of melanins with radicals from water radiolysis , oh exhibited the strongest reactivity with melanins . in the other study , o2 was found to react to produce melanin free radicals in a reaction inhibited by superoxide dismutase ( sod ) .
furthermore , the authors also suggested that xanthine - xanthine oxidase ( xod ) system is not suitable for studying the reaction of o2 with melanin , since the enzyme activity of xod is considerably inhibited by melanin as evidenced by the diminished production of uric acid and h2o2 .
recently , we applied the kinetic analysis to study if a substance directly scavenge o2 in hypoxanthine ( hpx)-xod system [ 21 , 22 ] . in the present study , we examined scavenging activity of melanin against o2 by using this kinetic analysis , and also quenching activity of melanin against singlet oxygen ( o2 ) .
o2 is known to be generated by physiological doses of uva irradiation , and cause skin damage due to detrimental effects on lipids and proteins [ 23 , 24 ] .
reagents were purchased from the following sources : melanin ( eumelanin prepared by oxidation of tyrosine with hydrogen peroxide ) , hpx , sod from bovine erythrocytes , allopurinol , 1,3-diphenyl - isobenzofuran ( dpibf ) , and astaxanthin from sigma - aldrich corp .
( st . louis , mo ) ; xod ( from cow milk ) from roche diagnostics ( basel switzerland ) ; 5,5-dimethyl-1-pyrroline - n - oxide ( dmpo ) from labotec ( tokyo , japan ) ; ( + ) -catechin from tokyo kasei kogyo ( tokyo , japan ) .
the assay used in this study was essentially identical to that described in our previous papers [ 21 , 22 ] . in brief , 50 l of 2 mm hpx , 50 l of 0.1 m phosphate buffer ( ph 7.4 ) , 20 l of 4.45 m dmpo , 25 l of dimethyl sulfoxide ( dmso ) , and 5 l of different concentrations of melanin dissolved in dmso , and 50 l of 0.4 u / ml of xod were placed in a test tube and mixed . in the reaction mixture , to eliminate the effect of oh , dmso was added as a oh - scavenger .
the mixture was transferred to an esr spectrometry cell , and the dmpo - ooh spin adduct was quantified 97 s after the addition of xod .
the signal intensities of dmpo - ooh were determined from the peak height of the first signal as described in our previous papers [ 23 , 24 ] .
the measurement conditions of esr ( jes - fa-100 , jeol , tokyo , japan ) were as follows : field sweep , 330.80340.80 mt ; field modulation frequency , 100 khz ; filed modulation width , 0.07 mt ; amplitude , 400 ; sweep time , 1 min ; time constant , 0.1 s ; microwave frequency , 9.430 ghz ; microwave power , 5 mw .
signal intensities were evaluated from the peak height of the first signal of dmpo - ooh spin adduct . in an experiment for kinetic analyses with melanin by double reciprocal plots , different concentrations of dmpo
were added to the system . instead of different concentrations of melanin , different concentrations of sod as a superoxide scavenger or of allopurinol as an xod inhibitor
were added to the system as described in our previous paper [ 21 , 22 ] . to confirm the results of kinetic analyses , the production of uric acid from hpx was determined by = 1.1 10 mcm .
o2 was generated by a peroxidase , h2o2 , and halide system , and o2 quenching activity was measured by the oxidation of dpbif at 420 nm [ 26 , 27 ] . in brief , the reaction mixture was prepared in 50 mm acetate buffer ( ph 4.5 ) to contain 1 unit of lactoperoxidase , 0.25 mm potassium bromide , 0.25 mm h2o2 , 0.1 mm dpibf solubilized in 0.05% triton x-100 , and the test substances in dmso .
the reaction was initiated by addition of h2o2 into a cuvette containing the reaction mixture at room temperature , and the decrease in absorbance at 420 nm was read at 10 s intervals for 1 min .
the quenching percent was calculated from the reduction in the presence and absence of test substances .
reagents were purchased from the following sources : melanin ( eumelanin prepared by oxidation of tyrosine with hydrogen peroxide ) , hpx , sod from bovine erythrocytes , allopurinol , 1,3-diphenyl - isobenzofuran ( dpibf ) , and astaxanthin from sigma - aldrich corp .
( st . louis , mo ) ; xod ( from cow milk ) from roche diagnostics ( basel switzerland ) ; 5,5-dimethyl-1-pyrroline - n - oxide ( dmpo ) from labotec ( tokyo , japan ) ; ( + ) -catechin from tokyo kasei kogyo ( tokyo , japan ) .
the assay used in this study was essentially identical to that described in our previous papers [ 21 , 22 ] . in brief , 50 l of 2 mm hpx , 50 l of 0.1 m phosphate buffer ( ph 7.4 ) , 20 l of 4.45 m dmpo , 25 l of dimethyl sulfoxide ( dmso ) , and 5 l of different concentrations of melanin dissolved in dmso , and 50 l of 0.4 u / ml of xod were placed in a test tube and mixed . in the reaction mixture , to eliminate the effect of oh , dmso was added as a oh - scavenger .
the mixture was transferred to an esr spectrometry cell , and the dmpo - ooh spin adduct was quantified 97 s after the addition of xod .
the signal intensities of dmpo - ooh were determined from the peak height of the first signal as described in our previous papers [ 23 , 24 ] .
the measurement conditions of esr ( jes - fa-100 , jeol , tokyo , japan ) were as follows : field sweep , 330.80340.80 mt ; field modulation frequency , 100 khz ; filed modulation width , 0.07 mt ; amplitude , 400 ; sweep time , 1 min ; time constant , 0.1 s ; microwave frequency , 9.430 ghz ; microwave power , 5 mw .
signal intensities were evaluated from the peak height of the first signal of dmpo - ooh spin adduct . in an experiment for kinetic analyses with melanin by double reciprocal plots , different concentrations of dmpo
were added to the system . instead of different concentrations of melanin , different concentrations of sod as a superoxide scavenger or of allopurinol as an xod inhibitor
were added to the system as described in our previous paper [ 21 , 22 ] . to confirm the results of kinetic analyses , the production of uric acid from hpx was determined by = 1.1 10 mcm .
o2 was generated by a peroxidase , h2o2 , and halide system , and o2 quenching activity was measured by the oxidation of dpbif at 420 nm [ 26 , 27 ] . in brief , the reaction mixture was prepared in 50 mm acetate buffer ( ph 4.5 ) to contain 1 unit of lactoperoxidase , 0.25 mm potassium bromide , 0.25 mm h2o2 , 0.1 mm dpibf solubilized in 0.05% triton x-100 , and the test substances in dmso .
the reaction was initiated by addition of h2o2 into a cuvette containing the reaction mixture at room temperature , and the decrease in absorbance at 420 nm was read at 10 s intervals for 1 min .
the quenching percent was calculated from the reduction in the presence and absence of test substances .
representative esr spectra of dmpo - ooh ( an adduct formed by dmpo and o2 ) obtained by the addition of solvent alone or different concentration of melanin are shown in fig . 1 , which indicates that the amount of o2 was reduced by melanin in a concentration dependent manner .
dmpo - cr ( an adduct of carbon - center radical derived from dmso and hydroxyl radical ) , which has six - line spectrum with the hyperfine coupling constant of a = 1.64 , a = 2.24 , was observed as in the previous study , and signal intensities of dmpo - cr were not changed by the addition of melanin .
2 shows an inhibition curb against dmpo - ooh formation in the esr - spin trapping method with the hpx - xod system obtained by the addition of different concentrations of melanin , and its linear transformation .
the ic50 ( concentration that inhibited the formation of the spin adduct by 50% ) for melanin was 0.012 mg / ml , which is equivalent to 0.9 u / ml of sod , and to 0.008 mg / ml of ( + ) -catechin ( data not shown ) . to determine whether melanin would interfere with the enzyme reaction of hpx - xod , the esr - spin trapping method was applied to evaluate the competitive reaction between dmpo and melanin or reference agents . fig .
3 shows double reciprocal plots for melanin , sod , an authentic superoxide scavenger , and for allopurinol , a xod inhibitor .
the linear and intersecting patterns of the double reciprocal plots indicate that sod acted as a competitive inhibitor of dmpo . on the other hand ,
the double reciprocal plots show that the inhibition of dmpo - ooh formation by allopurinol was uncompetitive with dmpo . as is the case with sod ,
the double reciprocal plots indicate that melanin acted as a competitive inhibitor of dmpo . in other words ,
melanin scavenges directly o2 without interference with hpx - xod reaction . in a previous study , however , it was suggested tat melanin synthesized from dopa by autoxidation likely inhibited the activity of xod . to confirm
if melanin inhibits the activity of xod , we further examined the production of uric acid that is an end product of hpx - xod reaction .
as shown in table 1 , uric acid levels were not changed by addition of melanin , and a xod inhibitor allopurinol diminished the level of uric acid .
thus we conclude that tyrosine - derived synthetic melanin used in this study dose not inhibit xod activity , and has an ability to scavenge directly o2 . as shown in fig . 4 ,
the o2 quenching activity of melanin was compared to that of astaxanthin , an authentic quencher of o2 .
melanin showed concentration dependent quenching activity against o2 , and 1.6 g / ml of melanin quenched 64% of o2 .
astaxanthin also showed potent quenching activity , and almost 85% of o2 was quenched at a concentration of 24 g / ml ( = 40 m ) .
uv light is absorbed by endogenous sensitizers that are excited to generate ros , which can interact with dna , proteins , and fatty acids to cause oxidative damage [ 17 , 18 ] .
our study showed that melanin has an ability to scavenge representative ros , especially o2 and o2 .
as for photoprotective effect of melanin , two underlying mechanisms are proposed , these are an efficient uv filter , and removal of uv - damaged cells .
in addition , interaction with ros such as o2 is suggested to be involved in the photoprotection mechanism of melanin [ 19 , 20 ] .
our study confirmed the idea that scavenging or quenching activity of melanin against o2 and o2 .
in contrast to photoprotective function , however , it was recently reported that melanin , especially phoemlanin , also acts as a potent uvb photosensitizer that generates ros upon uv irradiation . in other words , we can say that melanin is either beneficial or deleterious in terms of photobiological end point . thus , it is of our further interest how the balance between scavenging or quenching effect on ros and ros - generating photosensitization effect affects the sunlight sensitivity of individuals .
Output:
| although photoprotective properties of skin melanin have been well documented , a few studies on the effect of melanin on reactive oxygen species ( ros ) generated by ultraviolet ( uv ) irradiation have been reported . to study the interaction of melanin with ros , scavenging or quenching effect of melanin on o2 and
1o2 was examined by electron spin resonance ( esr)-spin trapping methods and a spectrophotometric method , respectively .
melanin potently interacted with o2 generated in a hypoxanthine ( hpx)-xanthine oxidase ( xod ) reaction , and with 1o2 generated from a peroxidase , h2o2 , and halide system . in the hpx - xod reaction
, it was proved that melanin doses not interfere with the enzyme reaction .
it is confirmed that one of the mechanisms by which melanin protects uv - induced skin damage is likely scavenging or quenching activity against ros such as o2 and 1o2 . |
PubmedSumm118265 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: hepatic encephalopathy ( he ) , as defined by the european association for the study of the liver ( easl ) clinical practice guidelines,1 is a brain dysfunction caused by liver insufficiency and/or portosystemic shunting ; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma .
alterations in patient consciousness , intellect , personality , and neuromuscular activity can be considered as the most important manifestations of episodes of overt he.2 he deeply affects hospitalization rates and the quality of life of patients and caregivers , both physically and mentally.37 the direct costs associated with liver diseases are extremely relevant.8 the american gastroenterological association , using data from the 1995 national health interview survey and adjusting them to 1998 , estimates that the annual economic burden of chronic liver disease , cirrhosis , and hepatitis c is over $ 2.1 billion and the indirect costs is > $ 272 million.9 hospitalizations represented the major cost driver in patients with advanced liver diseases , with an annual expenditure exceeding $ 1.4 billion .
the most relevant studies regarding resource consumption of patients with he , conducted in the us , found out that he has a relevant and increasing economic burden.10,11 the analysis of hospital discharges with principal diagnosis of he in 2004 ( he or unspecified encephalopathy ) , in particular , revealed a 180% increase since 1993.10 to our knowledge , there are no economic data regarding patients suffering from he in european countries , particularly in italy .
our objective , in line with the suggestion of easl , was to estimate direct healthcare costs and resource consumption , with particular focus on hospitalizations , for patients with overt he in italy .
in italy , citizens have access to the healthcare services provided by the italian national health service ( inhs ) .
information on all healthcare interventions covered by the inhs is collected in local / regional databases . for the purpose of the present study ,
cineca interuniversity consortium provided data from the arno observatory.12 the arno observatory is an online , multicenter , observational database collecting population - based healthcare - related data ( from several local health units across italy ) , in which for each patient the data were combined and aggregated through epidemiological methods .
these data include territorial drugs prescriptions , hospitalizations , diagnostic laboratory tests , and therapeutic procedures .
this information is linked to other sources of patient data ( including vital statistics and patient demographics ) in order to construct a tool that is useful to provide comprehensive tracking of clinical diagnoses and healthcare use trends throughout italy . in the present study
, we analyzed data starting from a population of 2,678,462 subjects , of whom 47.3% came from northern regions , 31% from central regions , and 21.7% from southern regions of the country .
this was a retrospective , observational , and noninterventional study , for which all patients undergoing at least one hospitalization due to he in the period of january 1 , 2011 , to december 31 , 2011 , were selected and observed for a period of 12 months following the hospitalization .
as data reported in the arno observatory database were analyzed anonymously , ethical consent was not required .
index hospitalizations for he were identified through the international classification of diseases , ninth revision , clinical modification ( icd9-cm ) code 572.2 ( hepatic coma : he , portal - systemic encephalopathy , hepatocerebral intoxication);13 hospitalizations related to he relapses occurred during the observational period were identified through the following icd9-cm codes : 572.2 ( hepatic coma : he , portal - systemic encephalopathy , hepatocerebral intoxication ) , 572.4 ( hepatorenal syndrome ) , and 39.1 ( transjugular intrahepatic portosystemic shunts tips ) . abovementioned icd9-cm codes were reported in the hospital discharge records available for all patients .
comorbidities were summarized by the charlson index.14 the following resource consumptions were evaluated : drugs reimbursed by inhs ( public prices reimbursed by inhs ) , diagnostic and therapeutic procedures ( italian national tariffs ) , and inpatient admissions and day hospitals ( italian national tariffs for the supply of hospital care ) . as only direct healthcare resources in charge to inhs
costs are expressed both in euros and in us dollars with an exchange rate of 1.00 = 1.1420 usd .
a nonparametric statistical hypothesis test ( wilcoxon mann whitney ) was used to compare the average yearly costs for female and male he populations and to compare patients with and without rehospitalization . another nonparametric test ( kruskal wallis )
was used to compare the average yearly costs for the different age classes of patients .
all statistical analyses were conducted using r software version 3.1 , with 5% of significance level .
a nonparametric statistical hypothesis test ( wilcoxon mann whitney ) was used to compare the average yearly costs for female and male he populations and to compare patients with and without rehospitalization . another nonparametric test ( kruskal wallis )
was used to compare the average yearly costs for the different age classes of patients .
all statistical analyses were conducted using r software version 3.1 , with 5% of significance level .
out of a total analyzed population of 2,678,462 subjects , 381 patients were hospitalized for an overt he episode ( 0.014% of the observed population ) .
the selected cohort of patients had a mean age of 6813 ( mean sd ) years , 34.4% were females with a mean age of 7213 years .
the charlson index calculated by age classes highlights the high severity level of the population analyzed , irrespective of age class ( table 1 ) . out of 381 patients with overt he , 82 ( 21.5% ) died during the index hospitalization and 22 ( 5.8% ) died in hospital during the 1-year follow - up , with a mean time to death of 3124 days .
the survival rate in the full observation period was 72.7% . among those patients who were discharged alive from hospital at the index event , 42.5% ( 28.4% females ) had at least one rehospitalization due to he during the follow - up and 57.5% ( 39.5% females ) did not exhibit recurrences .
the mean time to event for patients with at least one recurrence was 9694 days .
in detail , time to event was 9593 days for patients exhibiting a recurrence of he , 113103 days for patients with a relapse of hepatorenal syndrome , and 23957 days for patients undergoing tips .
about 92.9% of hospitalized patients had a recurrence of he , 15.7% had a recurrence of hepatorenal syndrome , and 1.6% of them underwent tips .
the mean direct healthcare costs of a single relapse requiring hospital admission for he was 3,3611,286 ( 3,838 usd 1,469 ) , for hepatorenal syndrome was 3,2421,382 ( 3,702 usd 1,578 ) , and for tips was 17,6796,627 ( 20,189 usd 7,568 ) .
the mean length of stay for each single hospitalization was 97 days for he , 129 days for hepatorenal syndrome , and 2115 days for tips .
the average yearly cost for each of the 381 selected patients was 13,39319,184 ( 15,295 usd 21,908 ) , of which 11,79118,134 ( 13,465 usd 20,709 ) ( 88% ) were spent for ordinary hospitalizations and day hospitals , 1,0751,728 ( 1,228 usd 1,973 ) ( 8% ) for drugs , and 5271,268 ( 602 usd 1,448 ) ( 4% ) for diagnostic and therapeutic procedures .
costs were higher for males than for females ( 13,98916,459 [ 15,975 usd 18,796 ] vs 12,246 24,227 [ 13,985 usd 27,667 ] ; p=0.081 ) .
the average cost per patient significantly decreased with the increasing of age ( from 32,291 [ 36,876 usd ] in patients < 39 years old to 8,025 [ 9,165 usd ] in patients > 80 years old ; p=0.035 ) ( figure 1 ) .
the huge expenditure differences among age classes could be explained by the fact that liver transplantation was performed only in younger patients ( hospitalizations for liver transplantation has a unitary cost of about 80,200 [ 91,588 usd ] ) and not performed in elderly .
patients with at least one rehospitalization for he had on average a nearly double annual cost of 21,272 ( 24,293 usd ) compared to that of patients without relapses ( 12,098 [ 13,816 usd ] ) ( p<0.001 ) .
patients undergoing tips had an average yearly cost of 36,471 ( 41,650 usd ) .
the most frequent causes of ordinary hospitalizations during the follow - up were mainly related to liver diseases and complications related to he progression and treatments ( table 3 ) ; the 20 most frequent diagnoses represented 69% of the total ordinary hospitalizations . with an average 35 days of hospital
stay per patient during the follow - up period , the most frequent diagnoses that represent > 50% of total hospitalization days were strictly related to liver diseases ( nonalcoholic hepatic cirrhosis , hepatic alcoholic cirrhosis , hepatic cancer , and hepatic coma ) . out of a total of 94 day - hospital admissions during the follow - up , the four most frequent diagnoses , which represented 30% of the total day hospitals , were strictly related to liver diseases ( cirrhosis of liver without mention of alcohol , alcoholic cirrhosis of liver , primary malignant neoplasm of liver , and hepatic coma ) .
most frequently prescribed drugs and average yearly expenditure per patient are reported in table 4 .
this analysis of data deriving from a large italian population highlights the relevance of the healthcare costs for the management of patients suffering from overt he ( 13,393/patient / year [ 15,295 usd / patient / year ] ) .
the relevance of such analysis was also highlighted by the easl clinical practice guidelines in the section
suggestions for future research in he , which indicates the importance of economic studies in order to demonstrate the effects of he on patients and society.15 the present analysis highlights also how the recurrence rate of overt he episodes generates a high need of hospitalizations ( 42.5% of total patients with overt he ) .
the difference in annual costs , if we compare patients with and without he episodes requiring hospitalization , is relevant ( 12,098 [ 13,816 usd ] vs 21,272 [ 24,293 usd ] , respectively ) .
moreover , the mortality rate linked to the considered disease is significant ( ~28% including patients died both at index hospitalization and during follow - up ) .
these data confirm those reported in the literature.11,16 as reported in the previously published studies,10,11 the costs of ordinary hospitalizations and day hospitals represent the most relevant cost driver for overt he patients .
a comparison between the results of the present analysis and those of other studies10,11 is not feasible , because healthcare services , settings , and coverages differ ; however , the present study confirms the importance of the costs of hospitalizations and high mortality rates . a high readmission rate related to he has been confirmed and is comparable to the results of other studies.17,18 major limitation of the analysis of administrative databases is represented by the absence of single additional clinical information on in - hospital mortality rates and on the severity of the disease ;
furthermore , the impossibility of calculation of indirect costs19 could have a possible impact on the global economic burden of the disease.20 moreover , the costs reported in the analysis represent the real total direct healthcare costs in charge to inhs for the treatment of patients hospitalized for overt he ; a sharing of the costs related to he and of those due to comorbidities or concomitant pathologies was not possible .
the relevant advantages deriving from the use of administrative databases are constituted by real - life data on treatment and procedures , with specific reference to costs of a large sample of patients in charge to inhs observed in a longitudinal way . the possibility offered by administrative databases to collect longitudinal data on each patient and to link individual records from different datasets make administrative databases as useful tools for those analyses focused on resource utilization and patterns of treatment and outcomes.21,22
the relevant direct healthcare costs of patients with overt he and the high in - hospital mortality and rehospitalization rates highlighted in our study underline the importance of effective treatments and prevention of he recurrences .
Output:
| purposehepatic encephalopathy ( he ) is a recurrent severe complication of progressive hepatic cirrhosis . the aim of this study is to evaluate the average annual direct healthcare costs for the treatment of patients with overt he in italy.patients and methodsthis retrospective , observational study analyzed information from the database of arno observatory .
patients with at least one hospitalization due to overt he in the period from january 1 , 2011 to december 31 , 2011 , were selected and observed during the year following the hospitalization .
costs for drugs , diagnostic and therapeutic procedures , and hospitalizations were estimated from the italian national health service perspective.resultsout of a population of 2,678,462 subjects , 381 patients were identified , of whom , 21.5% died during the first hospitalization and 5.8% during the follow - up ; the survival rate was 72.7% at the end of the observation period .
the direct healthcare costs per patient amounted to 13,393/year ( 15,295 usd ) ( 88% for hospitalizations , 8% for drugs , and 4% for diagnostic procedures ) . during the follow - up
, 42.5% of patients had at least one rehospitalization due to he .
patients readmitted for he had an average annual cost of 21,272 ( 24,293 usd ) , almost doubled if compared to patients without readmissions ( 12,098 [ 13,816 usd]).conclusionthis analysis showed that patients with he had relevant direct healthcare costs , in which hospitalizations were the most important cost drivers . |
PubmedSumm118266 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input:
Output:
| this study was undertaken to examine how the softness of poly(ethylene ) glycol ( peg)-based hydrogels , creating a three - dimensional ( 3d ) microenvironment , influences the in vitro growth of mouse ovarian follicles .
early secondary , preantral follicles of 2 week - old mice were cultured in a crosslinked four - arm peg hydrogel . the hydrogel swelling ratio , which relates to softness , was modified within the range 25.715.5 by increasing the reactive peg concentration in the precursor solution from 5% to 15% w / v , but it did not influence follicular growth to form the pseudoantrum ( 6080% ; p = 0.76 ) .
significant ( p < 0.04 ) model effects , however , were detected in the maturation and developmental competence of the follicle - derived oocytes .
a swelling ratio of > 21.4 yielded better oocyte maturation than other levels , while the highest competence to develop pronuclear and blastocyst formation was detected at 20.6 . in conclusion , gel softness , as reflected in swelling ratio , was one of the essential factors for supporting folliculogenesis in vivo within a hydrogel - based , 3d microenvironment .
2014 the authors .
journal of tissue engineering and regenerative medicine published by john wiley & sons , ltd . |
PubmedSumm118267 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: open surgery can be performed through a median sternotomy , a left thoracotomy or a supraclavicular approach , depending on the location of the aneurysms .
a less invasive endovascular treatment using stent - grafts has been recently reported , which requires acceptable proximal and distal landing zones . and according to the anatomic relation of the aneurysm with the carotid artery and vertebral artery , complex extra - anatomic bypass is needed .
we present here a case of hybrid surgery to treat a patient with a complex right subclavian artery aneurysm .
endovascular stent grafting of innominate to carotid artery was combined with carotid - subclavian and carotid - vertebral bypass .
a 70-year old woman with a history of hypertension presented with an aneurysm of the right subclavian artery .
she had suffered from dry cough and hoarseness for 1 year . computed tomography ( ct )
angiography revealed a 50 49 mm size , true aneurysm of the right subclavian artery .
the aneurysm developed from the innominate artery proximally and extended to the right subclavian artery distally .
the right vertebral artery was originated the aneurysm , while the left vertebral artery was occluded ( fig .
we planned to adopt a less invasive approach including a stent graft of innominate artery to carotid artery and extra - anatomic bypass as shown in fig .
2 . under general anesthesia , after harvest of the great saphenous vein ( gsv ) for carotid - vertebral bypass , a subclavicular incision was made and the axillary artery was isolated .
then an oblique skin incision was made along the anterior border of the sternocleidomastoid muscle , and the common carotid and vertebral arteries were exposed .
an 1 cm - long vertical incision was made below the carotid bifurcation . a pruitt - inahara carotid shunt ( lemaitre vascular inc .
, burlington , ma , usa ) was inserted through the arteriotomy to reduce the cerebral ischemic time .
an anastomosis was made between the common carotid artery below the arteriotomy and the vertebral artery using gsv ( fig .
the proximal anastomosis of the carotid - axillary bypass was made with a 7-mm reinforced polytetrafluoroethylene ( ptfe ) graft ( w.l .
newark , de , usa ) in an end - to - side fashion at the site where the carotid shunt was inserted ( fig .
the carotid shunt was maintained until the completion of the posterior wall suture and the beginning of the anterior wall suture of the anastomosis .
and then percutaneous access was obtained through the right groin and a 5-french pigtail catheter was advanced into the ascending thoracic aorta .
a 6-french sheath was introduced through the side of the ptfe graft in the right common carotid artery . a berenstein catheter ( terumo co. , tokyo , japan ) with a guide wire was inserted , with the tip of the catheter advanced into the ascending aorta .
the size and position of the stent graft were assessed on the angiography . the zenith stent graft with a diameter of 12 to 16 mm and a length of 72 mm ( cook medical inc . , bloomington , in , usa ) was reloaded in a reverse manner using umbilical tape ( fig
the stent graft was deployed from the innominate artery to the common carotid artery for excluding the origin of the subclavian artery ( fig .
, costocervical trunk and internal mammary artery were already occluded on the angiography , further embolization was not required .
finally , the graft was anastomosed to the axillary artery in end - to - side fashion with ligation of the axillary artery just distal to the aneurysm ( fig .
completion angiography of the aortic arch showed good flow through the stent - graft and bypasses with complete exclusion of the aneurysm .
a ct angiography showed complete exclusion of the aneurysm without any endoleaks , and the maximal diameter of aneurysm decreased to 40 mm from 50 mm ( fig .
subclavian artery aneurysm is the rarest peripheral artery aneurysm . up to one third of the patients with this aneurysm are asymptomatic , and intrathoracic aneurysms are more likely to be asymptomatic and they are very difficult to be found on a physical examination .
the symptoms of subclavian artery aneurysm are brachial plexipathy , horner 's syndrome , dysphagia and hemoptysis .
other symptoms can develop as the result of complications such as rupture , thrombosis or upper extremity embolism .
physicians dealing with these aneurysms have to be fully aware of the potential for multiple aneurysms that can be aortic , visceral or peripheral .
the natural history of subclavian artery aneurysms is not well known due to the limited number of cases and the high rate of surgical intervention .
no reports have documented any correlation between the absolute size of aneurysms and the potential risk for rupture .
but elective surgical repair is mandatory for subclavian aneurysms even when they are asymptomatic , because they tend to increase in size with an increased risk of rupture , thrombosis , embolization and compression of adjacent structures .
any complications such as thrombosis , embolism , rupture and rapid growth with increasing symptoms are absolute indications of surgery [ 1 - 3 ] .
open surgical repair of the subclavian artery necessitates an invasive approach with sternotomy or lateral thoracotomy . in a series of 13 patients who underwent open surgery for subclavian artery aneurysms ,
endovascular treatment of the subclavian artery with a variety of devices and approaches has been reported in the literature [ 6 - 8 ] .
but in our case , two separate incisions including a subclavicular incision and an oblique incision along the anterior border of the sternocleidomastoid muscle were made .
we think that the separate oblique incision is better for the exposure of the carotid and vertebral arteries .
second , the left vertebral artery was occluded in our case , so right vertebral artery bypass was inevitable and we tried to reduce the cerebral ischemic time during the anastomosis .
3b , and a carotid - vertebral bypass with a gsv graft was performed with a minimal cerebral ischemic time .
third , in the other reports , the costocervical and thyrocervical trunks were ligated , but we tried to embolize them with coils ( fig .
but on the angiography , the costocervical and thyrocervical trunks were already occluded by the thrombus in the aneurysm , and so we did n't perform coil embolization . in conclusion , we successfully treated a complex true intrathoracic right subclavian artery aneurysm by a stent - graft combined with extra - anatomic bypasses .
this hybrid operation can be a useful , less - invasive alternative to open surgical approaches via sternotomy or thoracotomy .
Output:
| we report a hybrid surgery including endovascular aneurysm repair and debranching procedures to treat a patient with a complex right subclavian artery aneurysm . the patient was a 70-year - old woman who presented with dry cough and hoarseness .
the aneurysm was characterized by the absence of a proximal neck , and involvement of the origin of the right vertebral artery .
she underwent carotid - vertebral artery bypass , stent graft from the innomiate artery to the common carotid artery and carotid - axillary artery bypass .
great saphenous vein was used for the carotid - vertebral artery bypass and 7 mm reinforced polytetrafluoroethylene graft was used for the carotid - axillary artery bypass .
the postoperative course was uneventful . |
PubmedSumm118268 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: ambulatory blood pressure monitoring ( abpm ) is the method of obtaining automated brachial blood pressure ( bp ) measurements at fixed time intervals , during a 24-hour period away from a medical environment .
this represents a more realistic approach to bp assessment since it involves bp measurement during the usual daily activities and sleep . in this sense , the overall haemodynamic load and bp variability is more accurately estimated .
numerous studies have shown that ambulatory bp compared to office bp is more reproducible and superior in predicting target organ damage and incidence of cardiovascular events in both the general hypertensive population and in subjects with chronic kidney disease [ 1 , 2 ] .
all these advantages of ambulatory bp in comparison to office bp , along with the ability to identify the white coat phenomenon , that is , the combination of increased office bp with normal ambulatory bp , and masked hypertension , that is , the combination of normal office bp with increased ambulatory bp , resulted in the transition of abpm from a research tool to a clinical modality .
the indications for abpm in the clinical management of hypertensives include among others the resistance to treatment .
this has been defined as bp above goal despite the use of three agents of different classes in optimal doses , ideally including a diuretic .
more recently hypertension controlled with four or more agents has been proposed to be included in the spectrum of resistant hypertension . although the prognosis of resistant hypertension ( rh ) is inadequately substantiated in the literature due to lack of sufficiently powered studies ,
there is plenty of evidence relating target organ damage and cardiovascular outcomes to bp levels .
uncontrolled bp along with a clustering of other risk factors is a harbinger of poor outcome in rh .
one of the crucial points in the identification of rh as a unique hypertension - related phenomenon that warrants special management is the distinction of true rh from pseudoresistance .
the latter term is used to describe clinical situations with increased bp readings because of improper bp measurement technique , heavily calcified arteries , white coat effect , and lack of compliance to the prescribed medication .
white coat rh , a phenomenon that is characterized by elevated office bp but normal ambulatory and home bp ranges from 25 to over 50% in subjects with apparent resistance to treatment [ 57 ] .
muxfeldt et al . , in a cohort of 286 hypertensive subjects with uncontrolled bp , found that 43.7% had white coat rh , ( office bp > 140/90 mmhg and daytime bp < 135/85 mmhg ) and less target organ damage compared to the true resistant hypertensives . in support , pierdomenico et al . in a cohort of 742
treated hypertensive subjects , 426 apparently responders and 276 apparently resistant , found that 126 subjects ( 29.5% of the apparently responders ) had masked hypertension and 146 ( 52.8% of the apparent resistant ) had white coat rh . in the same study ,
in the follow - up period cardiovascular risk was higher in masked hypertensives ( masked versus responder hypertensives , relative risk ( rr ) 2.28 , 95% confidence interval ( ci ) 1.14.7 , p < .05 ) and in true resistant hypertensives ( true resistant versus responder hypertensives , rr 2.94 , 95% ci 1.028.41 , p < .05 ) . according to the above
, a significant proportion of treated subjects with apparently controlled hypertension may actually mask their poor response to treatment and some of them could possibly be classified as subjects with resistant hypertension .
therefore , abpm identifies patients with white coat rh or masked hypertension contributing to avoiding overtreatment in the first case and achieving optimal management in the second one .
regarding bp measurement at home and at the office , the established guidelines are not always followed resulting in false bp readings .
consequently , the physician having confirmed the adherence to the prescribed therapy that includes three antihypertensive agents at full doses , including a diuretic , should use abpm in order to label the patient as truly resistant hypertensive .
since abpm is a fundamental tool to differentiate true rh from white - coat rh , it has been widely used in the identification of the bp pattern that characterizes patients with rh .
demonstrated that subjects with true rh compared to white coat rh had lower nocturnal systolic bp reductions ( 6.4 8.8 versus 9.8 7.5 mmhg , p = .0004 ) , lower nocturnal diastolic bp ( 10.4 9.6 versus 13.6 9.2 mmhg , p = .001 ) , and a higher percentage of nondippers ( i.e. , subjects nighttime bp fall
< 10% of the corresponding daytime bp values ) ( 68.7% versus 49.6% , p = .001 ) . similarly friedman and logan showed that the prevalence of nondipping among normotensive , controlled hypertensive , and resistant hypertensive subjects was 25.0% , 42.3% , and 61.5% , respectively , ( p = .006 ) .
it should be emphasized that in terms of pathophysiology , both rh and nondipping status have been linked to sympathetic overactivity , subclinical inflammation , and volume overload [ 1114 ] .
furthermore , the failure of the once daily administration of antihypertensive drugs to provide 24-hour coverage has been identified as a cause of high nighttime bp , nondipping pattern and true rh . by definition , subjects with true rh compared to those with white - coat effect present significantly higher ambulatory bp .
apart from this , certain studies demonstrate that patients with true rh have also increased ambulatory pulse pressure in comparison with those with white coat rh [ 6 , 16 ] .
interestingly ambulatory 24-hour , daytime , and nighttime heart rate is higher in true resistant hypertensives , supporting the notion that increased sympathetic activation may be present in true rh .
although it is well known that the risk for cardiovascular hard end points in hypertension disease rises as the bp levels rise , there is a lack of evidence on the cardiovascular prognosis of rh .
there is one study demonstrating the higher risk of patients with true rh compared to those with white - coat rh for fatal and nonfatal cardiovascular events . on the other hand ,
there are studies evaluating the prognostic role of abpm and its indices in patients with rh , highlighting its significance in the clinical management . in particular , salles et al . in a cohort of 556 subjects with
resistant hypertension demonstrated that 24-hour ( hr : 1.32 ; 95% ci : 1.081.60 ; p < .01 ) , daytime ( hr : 1.26 ; 95% ci : 1.041.53 ; p < .005 ) , and nighttime systolic bp ( hr : 1.38 ; 95% ci : 1.131.68 ; p < .01 ) , 24-hour ( hr : 1.33 ; 95% ci : 1.061.66 ; p < .01 ) , daytime ( hr : 1.31 ; 95% ci : 1.051.63 ; p < .01 ) , and nighttime ( hr : 1.36 ; 95% ci : 1.101.69 ; p < .05 ) diastolic bp , and 24-hour ( hr : 1.22 ; 95% ci : 1.001.48 ; p < .01 ) and nighttime ( hr : 1.27 ; 95% ci : 1.041.55 ; p < .01 ) pulse pressure were independent predictors of fatal and nonfatal cardiovascular events and of cardiovascular and total mortality irrespectively of the office bp values . of note , there was no difference between systolic and diastolic bp , while pulse pressure was a weaker predictor and nighttime bp was superior to daytime bp .
exhibited that in 86 subjects with rh daytime diastolic bp predicted cardiovascular events ( lower tertile versus higher tertile of daytime diastolic bp ; rr : 6.42 ; 95% ci : 1.3929.7 ; p = .017 ) , while office bp had no prognostic significance .
demonstrated that , in a cohort of 556 subjects with rh , bp nondipping predicted a composite end point of fatal and nonfatal cardiovascular events , cardiovascular and total mortality ( hr : 1.74 ; 95% ci : 1.122.71 , hr : 2.31 ; 95% ci : 1.094.92 , hr : 1.67 ; 95% ci : 0.952.94 , resp . ) above and beyond other traditional cardiovascular risk factors and mean ambulatory bp levels .
although there are scarce data on the comparative value of the aforementioned indices derived from abpm as potential prognostic markers in rh , in a study of magnanini et al . in women with rh ,
uncontrolled daytime bp was the stronger independent risk factor ( rr : 1.67 ; 95% ci 1.002.78 ) . adding to the cluster of components of abpm that carry valuable prognostic information , ambulatory arterial stiffness index ( aasi ) , which has been defined as the regression slope of diastolic on systolic bp , emerges as a potential predictor of cardiovascular morbidity and mortality in rh ( hr : 1.46 ; 95% ci : 1.121.92 ) , after adjustment for traditional risk factors and other abpm parameters .
abpm can be useful as the components derived from it have been associated with target organ damage surrogates in hypertension .
more specifically , high - pulse pressure and nondipping status in resistant hypertensives have been associated with a high - cardiovascular risk profile including greater age , higher prevalence of cerebrovascular disease and nephropathy , increased serum creatinine and microalbuminuria , and higher left ventricular mass index .
moreover , a blunted nocturnal reduction in bp , a widened 24-hour pulse pressure and aasi have been independently associated with increased aortic stiffness in resistant hypertensive patients [ 21 , 24 ] . finally , according to some studies 24-hour
pulse pressure presents a closer correlation to target organ damage compared to the other abpm indices [ 23 , 25 ] .
abpm emerges nowadays as a useful tool in the evaluation of the efficacy of antihypertensive treatment in clinical trials .
the conrtibution of abpm in the assessment of treatment effectiveness , could be more prominent in the setting of rh , where it has been shown to possess a pivotal role in haemodynamic load evaluation .
additionally , apart from just testing the efficacy of different drugs , abpm has been used in the evaluation of the implementation of certain therapeutic strategies in resistant hypertensives by evaluating patients ' compliance .
furthermore , as abpm reveals the unfavorable circadian bp pattern of patients with rh , namely , the nondipping profile , apbm has been used in the investigation of the efficacy of therapeutic strategies aiming at administration - time - dependent effects ( chronotherapy ) on the circadian bp pattern and on the degree of 24-hour bp control in rh . because a possible cause of the unfavorable bp pattern in rh is the short - acting antihypertensive treatment that is based on a single morning dosage , administration of one of the three drugs at bedtime may result in better clinic and ambulatory bp control as well as in lower prevalence of nondipping pattern [ 30 , 31 ] . some of the disadvantages of abpm such as cuff discomfort or procedure - related disturbed sleep
may be overcome with the use of home bp as a means of out of office assessment of bp .
however , evidence of the superiority of home bp over office bp , for the assessment of rh , is scarce while there are no data regarding any comparisons with abpm , which for the present represents the most reliable tool in this setting .
Output:
| abpm constitutes a valuable tool in the diagnosis of rh .
the identification of white coat rh and masked hypertension ( which may fulfill or not the definition of rh ) is of great importance in the clinical management of such patients .
moreover , the various abpm components such as average bp values , circadian bp variability patterns , and ambulatory bp - derived indices , such as ambulatory arterial stiffness index ( aasi ) , add significantly to the risk stratification of rh .
lastly , abpm may indicate the need for implementation of specific therapeutic strategies , such as chronotherapy , that is , administration - time dependent therapy , and the evaluation of their efficacy . |
PubmedSumm118269 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: cellular cytoplasm is the context for all intracellular activities that are not sequestered within membrane - bounded organelles , and thus its physical chemical properties influence key cellular functions , including protein folding , enzyme catalysis , intracellular signaling , intracellular transport , and localization of molecules and organelles , as well as the fate of nanoparticles and therapeutic agents targeted to cells . in 2000
, i published a review article in which i attempted to summarize the extensive literature bearing on the nature of the cell interior and in particular the extent to which it departs from the ideal dilute solution often assumed in classical biochemistry ( luby - phelps , 2000 ) .
the principal conclusions of the review were that the aqueous phase of the cytoplasm is not a bag of freely diffusing enzymes but is crowded with macromolecules and that diffusive transport and partitioning of macromolecules and organelles in cytoplasm is highly restricted by steric hindrance , as well as by unexpected binding interactions .
the purpose of this perspective is to review developments in the literature since 2000 and place them in context for the readership of molecular biology of the cell .
the high concentration of macromolecules and the extensive surface area presented by intracellular membranes in eukaryotic cells has led to proposals that association of intracellular water with surfaces leads to significant effects on its mobility and solvent properties compared with bulk water . if true , this would profoundly affect our understanding of such fundamental cellular processes as diffusion - limited biochemical interactions and protein folding .
experimental support for this view at the time of the previous review lacked direct measurement of water mobility in intact cells under physiological conditions . since then , such measurements have become available ( jasnin et al .
, 2008 ; persson and halle , 2008 ; stadler et al . , 2008 ) , including a study of water relaxation times in cubic micrometer
sized subvolumes within living cos-1 cells ( potma et al . , 2001 ) .
these studies suggest that at most 1015% of intracellular water has altered mobility , and that although water molecules in the first layer of hydration may have relaxation times 10- to 15-fold lower than bulk , this does not propagate to water molecules over any significant distance , as the measured overall viscosity of intracellular water is only 70% higher than that of bulk water .
furthermore , water molecules hydrating proteins and other surfaces appear to be readily exchangeable with the bulk .
based on the evidence , there is no reason to suppose that hydration and solvation in the cell cytoplasm are significantly different from what is found in bulk water or that either the rotational or the translational diffusion of solutes in cytoplasm is much affected by the anomalous viscosity of cellular water .
the recognition that the cell cytoplasm is a highly crowded medium has led to much study and theorizing about the effects of macromolecular crowding on cellular biochemistry ( for reviews see dix and verkman , 2008 ; zhou et al . , 2008 ) .
pure crowding effects typically are modeled as hard - sphere repulsive interactions that sterically exclude macromolecules in solution from the volume occupied by their neighbors . according to this excluded - volume model , at high number concentration of macromolecules in solution ,
open space between molecules is reduced to the point that the free energy cost of making room for an additional molecule is thermodynamically significant . in the absence of other attractive or repulsive interactions between the macromolecules ,
this free energy cost may promote intermolecular interactions that are energetically unfavorable in dilute solution , much as two people unknown to each other or with little in common may find themselves engaged in conversation at a crowded party .
excluded - volume effects may also stabilize the native conformation of ordered proteins by disfavoring more - extended conformations , much as large arm movements are restricted at a crowded party for fear of hitting other guests .
in addition , the crowding molecules present obstacles that may retard long - range translational movement , much as it takes longer to thread one 's way around the other guests to cross the room at a crowded party . in the extreme limit , macromolecular
crowding might result in confinement of macromolecules within subvolumes of the cytoplasm for significant lengths of time , much as the press of other guests , furniture in the way . and
a narrow doorway may temporarily prevent one from moving from one room to another at the crowded house party .
many of the predicted effects of macromolecular crowding have been demonstrated to occur in vitro in well - defined model systems .
several studies have shown that macromolecular crowding can promote protein folding ( e.g. , hong and gierasch , 2010 ; stagg et al . , 2011 ) and stabilize the compact conformation of isolated metaphase chromatin ( hancock , 2012 ) .
fewer results are available for the effects of crowding on reaction kinetics , but a temperature - dependent increase in kcat has been reported for glucose-6-phosphate dehydrogenase in well - defined crowded media ( norris and malys , 2011 ) .
it is now clear , however , that in the more complex intracellular environment , entropic excluded - volume effects are likely to be counteracted by enthalpic contributions from uncharacterized weak attractive or repulsive forces , with results that are not predictable a priori ( inomata et al . , 2009 ; elcock , 2010 ; schlesinger et al .
, 2011 ; wang et al . , 2012 ; zhang et al . , 2012 ) .
an additional complication is that in complex mixtures like cytoplasm , crowded with multiple species of macromolecules of differing size , shape , and flexibility , some species may spontaneously demix and condense into stable droplet phases dispersed in the bulk , with unpredictable effects on any particular component ( long et al . ,
thus it now seems that bottom - up approaches such as experiments in well - defined model systems in vitro or simulations in silico will provide only very general insight when considering the dynamics of a specific macromolecule in the cytoplasm of a specific cell .
a variety of experimental measurements suggest that long - range translational diffusion of macromolecules in the cytoplasm may not match the expectations of normal diffusion in dilute aqueous solution , for which mean - squared displacement ( msd ) is a linear function of elapsed time ( msd t , where x = 1 ) . over the past decade ,
a concept called anomalous diffusion has been adopted from the realm of physics to describe the diffusion of macromolecules in cells . in anomalous diffusion the relationship of msd with time is nonlinear : cases in which the measured diffusion coefficient appears to decrease with elapsed time are referred to as subdiffusion ( x < 1 ) , whereas cases in which the apparent diffusion coefficient increases with elapsed time are referred to as superdiffusion ( x > 1 ) .
although subdiffusion is more often applied to cytoplasm , a recent theoretical treatment proposes that superdiffusion is more likely ( goychuk , 2012 ) .
this is a very active area of research , modeling , and simulation that so far has generated more heat than light regarding whether intracellular diffusion is anomalous , what the value of its exponent is , and what the detailed mechanism might be .
experimental data from the various studies on diffusion in living cells are difficult to reconcile due to the nonoverlapping time and spatial scales of different methods of measurement , and the conclusions drawn from models and simulations often are difficult to test experimentally .
a recent article by saxton ( 2012 ) succinctly summarizes the state of play and calls for development of a set of reproducible standard samples as positive controls that could be used to exclude the contributions of differing experimental conditions , methodologies , and artifacts to the experimental data , as well as to test the predictions of various mechanistic models that have been proposed . although anomalous diffusion clearly has implications for understanding any cellular process that depends on sampling of the cytoplasmic volume by diffusive transport , it is difficult to predict its effects without a clearer understanding of the extent to which anomalous diffusion actually describes intracellular dynamics .
reaction kinetics may be either faster or slower , depending on the type of anomalous diffusion and the time and distance scale under consideration .
the idea of aqueous phase separation as a self - organizing force in the cell interior dates back to the father of modern cell biology , e. b. wilson , who proposed that non membrane - bound compartments such as p - granules and cajal bodies could be explained by the principles of colloid chemistry ( wilson , 1899 ) .
a colloid is a liquid with two phases : a microscopic droplet phase dispersed in a continuous phase .
since wilson 's time , the idea of phase separation as a mechanism for cellular microcompartmentation has gone in and out of vogue ( welch and clegg , 2010 ) .
currently its popularity is resurging , partly as a result of renewed appreciation for how crowded the cytoplasm is .
phase separation of immiscible proteins in a crowded solution typically leads to formation of liquid droplets enriched in one or a subset of interacting proteins ( weber and brangwynne , 2012 ) .
in crowded solutions with many different protein species , the total protein concentration in droplets is not necessarily higher than in the surrounding medium , and thus there may be no difference in refractive index to make them visible by microscopy .
liquid droplets tend to adopt a minimum - energy , spherical shape unless deformed by external forces .
they are dynamic in the sense that proteins readily exchange in and out of the droplet and that droplets encountering each other may coalesce .
examples of well - known intracellular inclusions that exhibit droplet behavior include p - bodies in germline cells of caenorhabditis elegans and cajal bodies in the nucleus ( hyman and simons , 2012 ) , as well as intracellular lipid droplets .
recent studies suggest that lipid droplets are not merely a trivial result of immiscibility between hydrophobic lipids and aqueous cytoplasm but instead may be the locus of lipid metabolism ( walther and farese , 2012 ) and also may serve as an intermediate compartment in the endoplasmic reticulum associated protein degradation pathway ( jo et al . , 2013 ) .
recent reports show that purified components of the n - wasp signaling pathway ( li et al . , 2012 ) and rna - binding proteins in a cell lysate ( kato et al . , 2012
overexpression of the protein interaction domains of two binding partners in the n - wasp signaling platform resulted in formation of similar liquid droplets in tissue culture cells ( li et al . ,
in these studies , phase separation was found to depend on multivalent weak interactions between low - complexity repeat domains and/or disordered hydrophobic domains .
further experimentation on living cells is required to decide whether and how these observations are relevant physiologically .
an intriguing area of emerging research is the structure and function of bacterial microcompartments that encapsulate several enzymes of a metabolic pathway and sequester their substrates and intermediates ( yeates et al . , 2011 ) .
small pores in the walls of the shell are postulated to permit gated exchange of small molecules between the shell interior and the cytoplasm .
no analogous structures have been reported for higher organisms , but several metabolic pathways have been reported to form supramolecular assemblies microscopically visible as foci or fibers ( o'connell et al . , 2012 ) .
regardless of the details of the physical chemistry of cytoplasm , certain general concepts are clear . anything targeted to the cell surface by receptor specific ligands or on nanoparticles
will enter the cell primarily by endocytosis , and their transport will reflect the behavior and fate of the endocytic vesicle containing them unless there is some mechanism of escape from the endocytic compartment .
overexpressed proteins and agents delivered directly into the cytoplasm by methods that bypass the endocytic pathway will be subject to the same constraints on diffusion as endogenous intracellular solutes . it is inaccurate and misleading to think of cytoplasm as a homogeneous medium like a dilute solution , with a single viscosity that characterizes the rotational mobility of small molecules , the long - range translational diffusion of solutes , and the consistency of the bulk .
the observed mobility of solutes in crowded , complex mixtures such as the cell interior will depend on the size of the solute and the time / space interval over which it is observed . in the absence of binding , the rotational and translational mobility of small molecules , such as ions and small organic solutes , will be unaffected by crowding or by obstruction due to fixed obstacles and should reflect the viscosity of intracellular water , which current evidence suggests is essentially like bulk water . even macromolecules the size of a typical globular protein ( 3 nm in radius ) may diffuse normally over extremely short distances or on very short time scales because the probability of encountering barriers to diffusion in this space - time regime is relatively low . thus reaction rates that depend on diffusion of the reactants over short distances will be relatively unaffected by excluded - volume effects on diffusion and will approximate those measured in dilute solution . for macromolecule - sized solutes on longer time and distance scales , it is necessary to consider the possible effects of crowding , obstruction by fixed obstacles , and transient confinement on solute mobility .
predicting these from first principles is very difficult , if not impossible , and for real biological molecules in the cytoplasm of living cells additionally depend on the specific size , shape , and deformability of the molecule under study , as well as on the effects of weak attractive or repulsive forces . to the extent that they experience transient binding interactions or partition into droplet phases ,
regard , two recent studies indicate that binding interactions are the dominant factors responsible for the extremely low mobility of globular proteins observed in escherichia coli ( nenninger et al . , 2010 ; wang et al . , 2011 ) .
randomly distributed local inhomogeneity driven stochastically by crowding and phase separation , nonrandom localization of intracellular vesicles , organelles , and supramolecular assemblies is a hallmark of eukaryotic cells .
it is becoming clear that in prokaryotes , as well as in eukaryotes , individual protein and rna molecules may also be nonrandomly localized within the cytoplasmic compartment ( nevo - dinur et al . , 2012 ) .
an extensive literature suggests that the concentrations of even small signaling molecules such as camp and ca may be locally regulated .
it is important to remember that reported values for the physical properties of cytoplasm are spatially and temporally averaged and thus may not well describe the conditions in any particular subvolume of the cell .
Output:
| from the point of view of intermolecular interactions , the cytoplasmic space is more like a crowded party in a house full of furniture than a game of tag in an empty field .
understanding the physical chemical properties of cytoplasm is thus of key importance for understanding cellular function .
this article attempts to provide an entre into the current literature on this subject and offers some general guidelines for thinking about intracellular biochemistry . |
PubmedSumm118270 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: posterior reversible encephalopathy syndrome ( pres ) , also known as reversible posterior leukoencephalopathy syndrome , is a distinct clinic - radiological entity that was initially described by hinchey et al . in 1996 .
it describes a neurological syndrome with presenting symptoms ranging from headache , altered mental state , seizures , and visual loss to loss of consciousness , coma or even death .
the term describes a potentially reversible imaging appearance and symptomatology that is shared by a diverse array of causes .
the mechanism is not exactly understood , but it is thought to be related to a hyperperfusion state with a blood - brain barrier breakdown .
this leads to the extravasation of fluid , potentially containing blood or macromolecules , resulting in cortical or subcortical edema .
alternatively , vasospasms may precipitate the reversible edema , leading to cytotoxic edema if left untreated .
it may also cause focal reversible vasogenic edema involving predominantly the parietal and occipital lobes .
the typical imaging findings of pres are most apparent as hyperintensity on fluid attenuated inversion recovery ( flair ) images in the parieto - occipital and posterior frontal cortical and subcortical white matter .
pres has been described in association with severe hypertension , preeclampsia , transplantation , and less frequently , following the administration of immunosuppressive agents and cytotoxic drugs .
the pathophysiology of pres implicates endothelial dysfunctions especially in cases associated with preeclampsia or cytotoxic therapies , which may have a direct toxicity on vascular endothelium leading to capillary leakage , the disruption of the blood - brain barrier as well as axonal swelling , which may then trigger a vasogenic edema [ 4 , 5 , 6 ] .
pres has also been reported in association with the antivascular endothelial growth factor monoclonal antibody bevacizumab ( bev ) .
bev is believed to decrease tumor perfusion , vascular density and interstitial fluid pressure [ 7 , 8 ] .
we herein present a case of pres secondary to bev therapy and discuss salient aspects in its diagnosis and management .
a 45-year - old female was diagnosed with high - grade serous ovarian cancer stage iiic with omental involvement and malignant ascites .
she received 3 cycles of paclitaxel and carboplatin as a neoadjuvant chemotherapy followed by debulking total abdominal hysterectomy and bilateral salpingo - oophorectomy .
after 2 months , the patient presented with a disease recurrence in the form of an increase in her ca125 tumor marker as well as evident intra - abdominal lymph nodes and malignant ascites .
she was started on the single non - carboplatin chemotherapeutic agent named gemcitabine with a dose of 700 mg / m on days 1 and 8 every 3 weeks ( plus bev 15 mg / kg every 3 weeks given for 2 cycles ) . on day 4 after her last cycle
two days later , she experienced seizures at home and was brought to urgent care .
she was found to have a systolic blood pressure in the range of 150180 mm hg and a diastolic blood pressure in the range of 120125 mm hg .
this progressed to non - compulsive seizures necessitating a prompt intravenous anticonvulsive medication , intubation and admission to the icu .
a ct of the brain showed a hypodense area in the temporal occipital lobes , therefore raising the possibility of ischemia .
the patient was thoroughly examined for other clinical possibilities such as septicemia , encephalitis , metabolic seizures as well as cerebrovascular insults .
the patient was kept intubated for 2 weeks in the icu with blood pressure control and supportive measures .
repeated mri images after 2 weeks showed a decrease in all white matter abnormal t2 signals .
after 4 weeks , another mri showed an almost complete resolution of the previously seen white matter t2-hyperintense patches with few residual foci of microhemorrhages in the cerebellum ( fig .
bev has been approved by the food and drug administration as well as the european society of medical oncology for the therapy for various solid tumor malignancies because it has shown to improve survival and the rate of tumor regression in colorectal cancer , non - small cell lung cancer , renal cell carcinoma , recurrent glioblastoma multiforme , and most recently , epithelial ovarian cancer .
she is considered to have carboplatin - resistant recurrences since this occurred within 6 months of the initial chemotherapy completion .
she was started on gemcitabine according to the guidelines of the european society of medical oncology and the national comprehensive cancer network ( nccn ) .
bev was added in hope of a better survival according to the recent aurelia trial .
although generally well tolerated , the use of bev - based combination chemotherapy is associated with a risk of grade 3 hypertension in up to 16%percnt ; of patients .
the disrupted blood - brain barrier caused a vasogenic edema of the posterior cerebral white matter and pres in 1%percnt ; of patients .
it is postulated that bev could induce vasospasms leading to pres without causing significant hypertension .
it is important to differentiate this syndrome from acute cerebral ischemia or thrombotic phenomena which are also associated with bev .
although this nucleoside analog antineoplastic agent is similar in structure to cytarabine , central nervous system toxicities have rarely been attributed to it .
however , we have used gemcitabine in a large number of patients over many years without such a case , and we therefore tend to believe that bev was probably the more likely cause of pres in our case .
nonetheless , it remains possible that bev alone might not cause pres , but does so when combined with other chemotherapeutic agents .
a high level of suspicion for pres is advisable in patients who develop headache , confusion , visual disturbance or seizure during its use , either as a monotherapy or in combination .
however , failure to recognize the syndrome and a withdrawal of the offending agent may result in catastrophic cns injury or death .
the increase in reported cases of pres warrants further investigations into its risk factors and pathophysiological mechanisms as well as further education of oncology health care providers .
Output:
| a 45-year - old female developed neurological symptoms and elevated diastolic blood pressure while on bevacizumab ( avastin ) and gemcitabine for recurrent carboplatin - resistant high - grade serous ovarian cancer .
a brain mri diagnosed our patient with posterior reversible encephalopathy syndrome .
we are discussing her presenting symptoms in this paper as well as the management and the outcome .
we emphasize the importance of keeping this rare but very serious complication in all patients receiving bevacizumab . |
PubmedSumm118271 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: it has been generally believed that the activity of retinal ganglion cells ( rgcs ) contributes little to shaping the corneal electroretinogram ( erg ) elicited by ganzfeld stimuli ( full - field erg ) .
however , a response has been newly identified to originate from rgcs that receive signals from cones .
this response was termed the photopic negative response ( phnr ) , and it consists of a negative - going wave that follows the photopic cone b - wave . the phnr is strongly attenuated in primate 's eyes with experimentally induced glaucoma and also in eyes intravitreally injected with tetrodotoxin , a blocker of the neural activity of retinal ganglion cells , their axons , and amacrine cells [ 3 , 4 ] .
in addition to this experimental evidence , it has been demonstrated that the phnr was reduced in patients with optic nerve and retinal diseases that affect mainly the rgcs and retinal nerve fiber layer [ 516 ] .
we have shown that the amplitudes of the phnr of the full - field cone erg ( full - field phnr ) were correlated with visual sensitivity , disc topography , and retinal nerve fiber layer thickness in eyes with open angle glaucoma ( oag ) .
these results indicate that the full - field phnr can be used as an objective functional measure of the rgcs in glaucomatous eyes . when the full - field phnr amplitude was used as a diagnostic tool , the sensitivity and specificity to discriminate glaucomatous from normal eyes were 77% and 90% , respectively .
however , at the early stage of glaucoma , the sensitivity was reduced to 57% , indicating that the full - field phnr is not suitable for diagnosing early glaucoma .
this is not surprising because the early glaucomatous changes begin with localized neuronal loss in the retina and optic nerve head that could not be detected by the full - field erg .
recently , we have recorded focal ergs from patients with glaucoma [ 1820 ] and optic nerve diseases .
we found that the phnr of the focal erg ( focal phnr ) was also selectively attenuated in patients with oag .
in addition , we investigated correlation between the focal phnr and corresponding retinal sensitivity obtained by standard automated perimetry ( sap ) .
a curvilinear relationship was found between the focal phnr amplitude and retinal sensitivity ( decibel ) , in which a reduction of the focal phnr amplitude was associated with a small decrease of retinal sensitivity at the early stage of glaucoma .
this suggests that the focal phnr may be used for detecting functional loss at the early stage of glaucoma .
this focal erg system allows us to record focal retinal responses from the paramacular regions of the retina that are preferentially affected at the early stage of glaucoma . in our recent study , we recorded focal ergs from three retinal loci including the macular region , the supero - temporal and infero - temporal areas of the macula .
the sensitivity and specificity of the focal phnr to discriminate early glaucoma were > 90% .
these findings were made with the combined criterion in which eyes were classified as being glaucomatous when the focal phnr amplitudes were less than the optimal cut - off values in either retinal locus . from these results
, it appeared that the focal phnr is better than the full - field phnr to discriminate glaucomatous from normal eyes .
however , a direct comparative study comparing the diagnostic values of full - field and focal phnrs obtained from the same eyes has not been reported although studies using different patient populations for the full - field and focal phnrs have been done [ 16 , 18 , 19 ] .
thus , the purpose of this study was to compare the ability of the full - field and focal phnrs to detect glaucomatous eyes at different stages .
importantly , the full - field and focal phnrs were recorded from the same eyes .
their ages ranged from 37 to 83 years with a mean standard deviation of 68.2 9.1 years .
the diagnosis of oag was based on the presence of a glaucomatous optic disc associated with visual field defects measured by sap .
the presence of glaucomatous optic disc was determined by the guideline of japanese society of glaucoma developed in 2005 ( http://www.nichigan.or.jp/member/guideline/glaucoma2.jsp ) . according to the diagnostic criterion for minimal abnormality of the visual field , the visual field defect was determined to be glaucomatous when it met one of three criteria .
( 1 ) the pattern deviation plot showed a cluster of three or more nonedge points that had lower sensitivities than those in 5% of the normal population ( p < .05 ) , and one of the points had a sensitivity that was lower than 1% of the population ( p < .01 ) , ( 2 ) the value of the corrected pattern standard deviation was lower than that of 5% of the normal visual field ( p < .05 ) , or ( 3 ) the glaucoma hemifield test showed that the field was outside the normal limits .
forty - two eyes of 42 age - matched normal volunteers , ranging in age from 53 to 78 years with a mean of 67.6 7.3 years , were studied .
we selected normal eyes from patients with macular hole in the fellow eye which was treated by vitrectomy .
they underwent comprehensive ophthalmological examinations including measuring visual acuity by a snellen chart and observing the ocular fundus by an indirect ophthalmoscope as well as a biomicroscopic slit lamp .
in addition , we performed optical coherence tomography and sap to rule out macular and optic nerve diseases .
this research was conducted in accordance with the institutional guidelines of iwate medical university , and the procedures conformed to the tenets of the declaration of helsinki .
an informed consent was obtained from all subjects after a full explanation of the nature of the experiments .
the pupils were maximally dilated to approximately 8 mm in diameter following topical application of a mixture of 0.5% tropicamide and 0.5% phenylephrine hcl .
the recordings of the full - field and focal ergs were made on the same eye on the same day .
the stimulus conditions for the recordings of the full - field cone ergs and focal ergs have been reported in detail [ 16 , 18 ] .
the full - field cone ergs were elicited by red stimuli of 1 600 cd / m ( max = 644 nm , half - amplitude bandwidth = 35 nm ) on a blue background of 40 cd / m ( max = 470 nm , half - amplitude bandwidth = 18 nm ) .
the stimulus and background lights were produced by light emitting diodes ( leds ) embedded in the contact lens .
focal ergs were recorded from the macular area and from the supero - temporal and infero - temporal areas of the macula .
responses from these areas are designated as the center , superior / temporal , and inferior / temporal responses , respectively ( figure 1 ) .
the stimulus system was integrated into the infrared fundus camera ( mayo co. , nagoya , japan ) , which had been developed by miyake et al . .
the stimulus spot was 15 degrees in diameter and was placed on the retinal area of interest , and the position was confirmed by viewing the ocular fundus on a monitor .
the intensity of the white stimulus and background lights was 165 cd / m and 6.9 cd / m , respectively .
the focal ergs were recorded with a burian - allen bipolar contact lens electrode ( hansen ophthalmic laboratories , iowa city , ia ) .
the responses were digitally band - pass filtered from 0.5 to 1000 hz for the full - field erg and from 5 to 500 hz for the focal erg .
it is often difficult to determine the negative trough of the phnr especially in cases with reduced phnr amplitudes .
we determined the time of the maximum amplitude of the phnr in normal subjects according to the method of rangaswamy et al . .
we found that the full - field and focal phnrs were the largest at 65 ms and 70 ms after the flash , respectively .
therefore , we measured phnr amplitudes at 65 ms for the full - field phnr and 70 ms for the focal phnr throughout the study ( figure 2 ) . the humphrey visual field analyzer ( model 750 , humphrey instruments , san leandro , ca , usa ) was used for sap .
the sita standard strategy was applied to program 24 - 2 . from the mean deviation ( md ) of the 24 - 2 program ,
we classified patients with glaucomatous visual fields into three groups : early ( md > 6 db ; n = 41 , mean age and sd : 68.6 9.8 years ) , intermediate ( 6 db md 12 db ; n = 28 , 69.5 8.1 years ) , and advanced ( md < 12 db ; n = 34 , 69.4 7.4 years ) defects of the visual field . there was no significant difference in the mean age among the three groups .
the intraocular pressures ( iops ) of all patients were controlled under 21 mmhg by eye drops , and there was no significant difference in the iops among the groups .
the averaged mds were 3.31 1.58 , 8.88 1.67 , and 17.37 4.46 db for the early , intermediate , and advanced groups , respectively .
when the fixation loss rate is higher than 20% , the field examination was determined to be unreliable and excluded from the analysis .
in addition , when the false - positive or false - negative error rates exceeded 33% , the visual field was not used for the analysis .
the interval between the visual field testing and erg recording was less than 1 month .
we used receiver operating characteristic ( roc ) curves to determine the optimal cut - off values that yielded the highest likelihood ratio .
the area under the curve ( auc ) was used to compare the roc curves .
the comparison between aucs was made according to the method reported by delong et al . .
the sensitivity and specificity of the focal phnr were compared to that of the phnr of the full - field ergs using fisher 's exact test .
unpaired t tests were used to compare data between groups with different degrees of the visual field defect .
one - way anova was used to determine the statistical significance of the erg changes in eyes with the stage of glaucoma .
these analyses were performed using commercial software medcalc 11.3.3 ( medcalc software , mariakerke , belgium ) and prism 5.1 ( graphpad software inc . , san diego , ca ) .
the full - field and focal ergs recorded from a normal control and a patient that had advanced glaucoma with a mean deviation 13.28 db are shown in figure 2 .
both the full - field and focal phnrs were reduced in the patient compared to the normal control although there was no change in the amplitudes of the a- and b - waves in the full - field and focal ergs ( figure 2 ) .
we have plotted the phnr amplitudes and phnr / b - wave amplitude ratios against stages of glaucoma in figures 3 and 4 , respectively . in both the full - field and focal ergs ,
the phnr amplitudes and the phnr / b - wave amplitude ratios were significantly and progressively reduced with an advance in the stage of glaucoma ( p < .0001 ) .
even at the early stage of glaucoma , the phnr amplitude and phnr / b - wave amplitude ratio were significantly reduced compared to that in the normal controls for the full - field ( phnr amplitude : p < .004 ) and focal ergs ( all retinal areas : p < .0001 )
. however , for the phnr / b - wave amplitude ratio of the full - field ergs , the data of the normal control considerably overlapped those from the early glaucoma group resulting in no significant differences ( figure 4(a ) ) .
the phnr amplitude and phnr / b - wave amplitude ratio of the full - field ergs gradually decreased as the stage of glaucoma advanced . on the other hand ,
the greatest loss of the phnr amplitude and phnr / b - wave amplitude ratio of the focal erg was seen at the early stage of glaucoma .
for example , the mean of the focal phnr amplitude recorded from the center was reduced from 1.24 v to 0.69 v at the early stage of glaucoma .
then , it slightly decreased to 0.50 v at the advanced stage of glaucoma despite considerable loss of the visual sensitivity of sap ( figure 3(b ) ) .
the full - field phnr amplitude fell outside the normal range in 29 , 48 , and 56% of patients of the early , intermediate , and advanced groups .
the focal phnr amplitudes of the central retinal area fell outside the normal range in 62 , 61 , and 76% of patients of the early , intermediate and advanced groups .
the corresponding percentages for the superior / temporal and inferior / temporal focal phnr amplitudes were 49 and 46% for the early , 59 and 57% for the intermediate , and 85 and 79% for the advanced groups , respectively .
thus , the focal phnr amplitude showed abnormal values in more patients at any stages than the full - field phnr amplitude .
the cut - off values were varied by 1.0 v steps for the full - field phnr amplitude , 0.1 v for the focal phnr amplitudes , and 0.01 for the focal phnr / b - wave amplitude ratio for the pooled data of glaucomatous and normal eyes .
the sensitivity and specificity were obtained for each cut - off value and plotted to determine the roc curves from which the auc was obtained ( figures 57 , table 1 ) . in early glaucoma ,
the focal phnr amplitude curves were always superior to the full - field phnr amplitude curves .
as a result , the auc of the focal phnr amplitude of the inferior / temporal area was significantly larger than that of the full - field phnr amplitude ( figure 5(a ) , p < .05 ) .
the aucs of the focal phnr / b - wave amplitude ratio obtained from all retinal areas were significantly larger than those of the full - field phnr / b - wave amplitude ratio ( figure 5(b ) , table 1 , p = .01 for the center , p = .001 for the superior / temporal area , and p < .001 for the inferior / temporal area ) . for eyes with intermediate glaucoma , most parts of the roc curves of the focal erg amplitudes overlapped the curve of the phnr amplitude of the full - field ergs . thus , there was no significant difference in the aucs between the focal and full - field phnr amplitudes ( figure 6(a ) ) .
for the phnr / b - wave amplitude ratio , the curves of the focal phnr / b - wave amplitude ratio were always higher than those of the full - field phnr / b - wave amplitude ratio , resulting in significantly larger aucs for the focal phnr / b - wave amplitude ratio than for the full - field phnr / b - wave amplitude ratio ( figure 6(b ) , p < .05 for the center , p < .01 for the inferior / temporal and superior / temporal areas ) . in eyes with advanced glaucoma ,
the roc curves for the phnr amplitude and phnr / b - wave amplitude ratio of the focal and full - field ergs were overlapped ( figure 7 ) .
the differences in the aucs between the full - field and focal phnrs for both the phnr amplitude and phnr / b - wave amplitude ratio were not significant .
the sensitivity and specificity were obtained with the optimal cut - off values for the phnr amplitude ( table 2 ) and the phnr / b - wave amplitude ratio ( table 3 ) .
because the likelihood ratio reveals the sensitivity / false positive rate , the highest likelihood ratio indicates high sensitivity and specificity .
eyes were classified as being glaucomatous when their focal phnr amplitudes or focal phnr / b - wave amplitude ratio were less than the cut - off values in either retinal areas ( combined criterion in tables 2 and 3 ) . in all patient groups with different degrees of visual field defects ,
no significant difference was found in the specificity between the full - field and focal phnrs obtained from all retinal areas including the combined criteria . in patients with mild defects of the visual field ,
the sensitivities of the focal phnr amplitudes were significantly higher than those of the full - field phnr amplitudes ( p < .01 ) except for the inferior / temporal area .
for the phnr / b - wave amplitude ratio , the sensitivities of the focal erg in both retinal areas were significantly higher than those of the full - field ergs ( p < .001 for the center , p < .00001 for the superior / temporal and inferior / temporal areas ) .
the sensitivities of the phnr amplitude and phnr / b - wave amplitude ratio increased to 88.1% and 97.6% , respectively , when the combined criterion was used , and they were significantly higher than the corresponding values of the full - field phnr ( p < .00001 ) . in intermediate and advanced glaucoma ,
the sensitivities of the focal phnrs were generally higher than those of the full - field phnrs .
a significant difference was found between the focal and full - field phnrs in the phnr / b - wave amplitude ratio obtained from the superior / temporal and inferior / temporal areas in intermediate glaucoma ( p < .01 for the superior / temporal retinal area , p < .05 for the inferior / temporal area ) .
the sensitivities of the focal phnr obtained by the combined criteria were significantly higher than those of the full - field phnr in intermediate glaucoma ( p < .05 for the phnr amplitude , p < .005 for the phnr / b - wave amplitude ratio ) . in advanced glaucoma
, there was no significant difference in the sensitivity between the full - field and focal phnrs .
we compared diagnostic abilities between the full - field and focal phnrs in detecting glaucomatous eyes .
our results demonstrated that the aucs and sensitivities were higher for the focal phnr than for the full - field phnr at the early and intermediate stages of glaucoma .
this suggests that the focal phnr is a good indicator to detect the functional loss in early and intermediate glaucoma .
the aucs of the focal phnrs were better for identifying eyes with early and intermediate glaucoma than those of the full - field phnrs .
on the other hand , there was no significant difference in the aucs between the focal and full - field phnrs in advanced glaucoma .
when the combined criterion for the focal phnr was used , the sensitivity increased to 88.1% and 97.6% for the focal phnr amplitude and phnr / b - wave amplitude ratio , respectively , even in early glaucoma , while the sensitivities for the phnr amplitude and amplitude ratio of the full - field erg were 38.1% and 23.8% .
these findings indicate that the focal phnr is a better indicator than the full - field phnr in detecting functional changes in early and intermediate glaucoma .
we selected the optimal cut - off value with the highest likelihood ratio which maximally reduces false positive cases .
the disadvantage of the combined criterion is that it lowers the specificity as reported although a high sensitivity was obtained .
however , the specificity of the phnr of the full - field and focal ergs could be kept over 90% by using this method to select the optimal cut - off values .
our results indicated that , even in early glaucoma , the focal phnr had high sensitivity and specificity attained by the combined criterion .
we have reported that a curvilinear relationship existed between the retinal sensitivity ( in decibels ) measured by perimetry and the focal phnr amplitude .
this indicated that 3 db loss in the retinal sensitivity is approximately associated with a fifty percent decrease in the focal phnr amplitude at the early stage of glaucoma .
in fact , the largest loss of the phnr amplitude was seen at the early stage of glaucoma in the focal ergs ( figures 3 and 4 ) . on the other hand ,
the full - field phnr amplitude gradually reduced with advance of glaucoma . taken together ,
these findings indicate that the focal phnr could be a better measure to detect functional abnormalities at the early stage of glaucoma than the full - field phnr .
it is essential that the ocular fundus is visible to be able to record the focal phnrs reliably because the stimulus areas stimulated must be monitored during the recordings using an infrared fundus camera .
it is impossible to record the focal erg in patients with dense opacities of the ocular media , such as cataracts and vitreous opacities .
furthermore , opacities of the ocular media can produce stray - light that makes the focal stimulus larger . therefore , we have excluded patients with clinically significant cataracts that affected vision . on the other hand ,
the stray - light effect is negligible for the full - field ergs . in cases with severe opacity of the ocular media ,
intersession variability is represented by the coefficients of variation ( cv = standard deviation / mean 100 ) , and it was higher for the focal phnr than for the full - field phnr [ 16 , 18 ] .
in addition , variations of the phnr amplitude among individuals were greater for the focal phnr amplitude than for the full - field phnr amplitude . however , this disadvantage of the focal phnr can be reduced by using the amplitude ratio of the phnr to the b - wave amplitude .
therefore , the phnr / b - wave amplitude ratio is recommended for measuring the effectiveness of the focal ergs .
the recording and stimulus conditions of the focal erg were different from those of full - field erg , which may explain why the focal phnr was better than the full - field phnr in diagnosing early or intermediate glaucoma .
first , we set the low cut filters at 0.5 hz and 5 hz for the full - field and focal ergs , respectively .
the higher cut - off frequency ( 5 hz ) used to record the focal phnr was necessary to eliminate the drifts in the baseline .
thus , some of the low frequency components of the phnr were reduced as shown in monkeys [ 24 , 25 ] .
second , the full - field ergs were elicited by red stimuli on a blue background ( r / b ) while the focal ergs were elicited by white stimuli on a white background ( w / w ) .
the r / b stimuli have been shown to be a very good combination to elicit large and reliable phnrs .
furthermore , the results of our preliminary study demonstrated that the sensitivity and specificity to discriminate glaucoma were higher for the r / b than for the w / w stimulus conditions ( machida et al .
thus , the stimulus conditions used in this study are more advantageous to eliciting full - field phnrs than focal phnrs . therefore
, the differences in the recording and stimulus conditions do not seem to be able to explain the current results in which the focal phnr was more sensitive than the full - field phnr in diagnosing early and intermediate glaucoma .
the results of this study indicate that the phnrs of the full - field and focal ergs represent functional loss of rgcs in glaucoma at different stages of glaucoma .
the focal erg has the diagnostic ability with high sensitivity and specificity in detecting glaucomatous eyes at the early and intermediate stages , especially when the combined criterion is used .
there was no difference in the diagnostic value between the full - field and focal phnrs in advanced glaucoma .
thus , the focal phnr can be a good functional parameter to detect early or intermediate glaucoma .
Output:
| purpose . to compare the photopic negative response ( phnr ) of the full - field electroretinogram ( erg ) to the phnr of the focal ergs in detecting glaucoma
. methods .
one hundred and three eyes with glaucoma and 42 normal eyes were studied .
full - field ergs were elicited by red stimuli on a blue background .
the focal ergs were elicited by a 15 white stimulus spot centered on the macula , the superotemporal or the inferotemporal areas of the macula .
results . in early glaucoma ,
the areas under the receiver operating characteristic curves ( aucs ) were significantly larger for the focal phnr ( 0.8630.924 ) than those for the full - field phnr ( 0.6660.748 ) ( p < .05 ) .
the sensitivity was significantly higher for the focal phnr than for the full - field phnr in early ( p < .01 ) and intermediate glaucoma ( p < .05 ) .
in advanced glaucoma , there was no difference in the aucs and sensitivities between the focal and full - field phnrs .
conclusions .
the focal erg has the diagnostic ability with higher sensitivity in detecting early and intermediate glaucoma than the full - field erg . |
PubmedSumm118272 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the clinical manifestations of malaria differ with the geographic distribution , plasmodium species , epidemiology , age and immunity . in areas where malaria is hyper endemic , youngers and adults
may develop a partial immunity after repeated contact with the parasite , and they are at relatively low risk of severe disease .
the incubation period varies between 12 and 15 days , whereas individuals are asymptomatic , but on patients with partial immunity this period can increase up to 30 days after returning from the malaria endemic area . the initial symptoms of malaria are nonspecific , , and may include fever , tachycardia , tachypnea , chills , anaemia , myalgia , malaise , and other unspecific symptoms , secondary to the red blood cells ( rbc ) lysis and the release of pro - inflammatory cytokines to the bloodstream .
infected - rbc to the endothellium of microvessels is thought to be the key mechanism involved in pathogenesis of severe malaria .
cytoadherence leads to microvascular sequestration of parasitized erythocytes in different vital organs , developing partial blood flow obstruction , endothelial barrier breakdown and finally multiorgan failure and death , . increasing parasitemia
is associated with increasing disease severity . the world health organization ( who ) establishes a cutoff of 5 percent of parazited - rbcs in low transmission areas , and 10 percent in hyper endemic areas to define hyperparasitemia for the diagnosis of severe malaria .
semi - immune patients may have substantial parasitemia with no clinical manifestations . nevertheless , individuals with higher risk of complicated malaria include young children , nonimmune patients , pregnant women , and immunocompromised patients . due to the high mortality rate associated to this disease ,
up to 1520 percent in complicated cases , early diagnosis and a prompt treatment implementation are essential .
the main problem lies in countries with a low prevalence of malaria , where the lack of clinic suspicion due to the unspecific symptoms can delay the diagnosis and treatment .
the next description is a case of a patient with a haematological neoplasm and associated immunodepression who was diagnosed with a severe infection by p. falciparum .
it reflects the complexity of the diagnosis due to the unspecific and overlapped symptoms with the patient 's leukaemia , reflecting the importance of a prompt initiating highly active treatment in a very severe immunodepressed patient .
a 38-year - old nigerian woman , living in spain 7 years , went back to nigeria . in nigeria , she attended to a regional hospital presenting leucocitosis and severe lymphocitosis compatible with an acute lymph proliferative syndrome .
in addition , the patient had severe anaemia ; therefore , she needed blood transfusions ( bt ) . due to the severity of the signs and symptoms ( fatigue for 35 months , weight loss , analgesic non - responsive headache and lumbar pain ) ,
the patient was admitted at hospital for further study . after obtaining a marrow biopsy and cytogenetic studies ,
the patient was diagnosed with myeloid chronic leukaemia ( mcl ) bcr / abl positive in novo blast crisis and she started a quimiotherapy treatment with a suitable response .
coincidently with the severe aplasic phase , the patient was febrile ( 39 c ) and had severe low rbc counts which required bt .
in the first place these symptoms were associated with febrile neutropenia and tumoral lysis syndrome . despite the antimicrobial and antifungal wide spectrum treatment ,
in addition , the patient suffered severe undernourishment , mucositis and mainly nocturnal anxiety , confusion , agitation and disorientation episodes which required tranquilizers and sedative treatment .
ten days after the hospital admission , the patient suffered a sudden loss on conciousness which was , in first place , associated with the sedatives . due to an acute respiratory distress syndrome with tachycardia , dysnea , taquipnea , hipoxemia and respiratory distress ,
the patient required endotracheal intubation and mechanic ventilation in the intensive care unit ( icu ) .
cardiovascular dysfunction , renal failure and hepatomegaly were also presented . during the first 24 h the patient also suffered a generalized tonic clonic seizure with horizontal nistagmus to the left . despite all the above signs , neuroimaging was normal .
the study of the cerebrospinal fluid ( csf ) showed a slight increase in glucose ( 87 mg / dl ) , proteins ( 47 mg / dl ) and cells ( 27 cells / m ) .
because a leukemic infiltration was suspected regarding the patients basal disease , an intrathecal triple chemotherapy ( itc ) was initiated .
after 1 month a routine blood frotis was performed and parasite p. falciparum forms were observed , and a 10 percent of parasitemia was detected . with these findings
the pharmacy department was consulted for a recommended antimalarial treatment . due to the high parasitemia percentage , the organic dysfunction , the severe immunodeficiency , the probable cloroquin resistance related to the geographic origin of the infection and the oral intolerance related with the mucositis ,
intravenous artesunate treatment was initiated ( 2.4 mg / kg 3 initial dosing every 12 h , completed with 2.4 mg / kg every 24 h until the 4th day of treatment ) .
after 24 h from the beginning of the treatment , the parasitic forms were almost eradicated with a major clinical improvement . the antimalarial treatment was completed with an oral combination of atovaquone and proguanil for 3 days which eradicated the infection completely . a close monitoring for artesunate haemolysis for 4 weeks after treatment was recommended .
finally the patient was discharged on the 29th day of the chemotherapy treatment with an increase in neutrophils count and the disappearance of the mucositis and the neurologic manifestations .
we have faced a severe case of malaria produced by p. falciparum with a high parasitemia in a context of severe immunodeficiency due to the myelosuppressor chemotherapy treatment .
additionally , the patient comes from an endemic area of malaria which provides a partial immunity against the parasite as a protective factor , .
regarding malaria transmission , although the mosquito bite is the main course of transmission , there are cases of vertical transmission , through bt and organ transplants , .
the malaria transmission through bt from asymptomatic carriers is a major problem in tropical africa ( the patient received bt in a country where safety and quality controls are uncertain ) . regarding the symptoms , the patient suffered febrile peaks reaching 39 c which were impossible to relate to a focus of infection .
moreover , the patient suffered a systemic dysfunction involving the main organs affected by the cytoadherence of p. falciparum
.
in the course of malaria , a regular fever pattern is not always present , especially the falciparum malaria .
nevertheless there was a clear overlapping between the febrile peaks and the acute haemoglobin reduction which could be related to the rbc cells when merozoites escape to the bloodstream ( fig .
1 ) . cerebral malaria should be considered in anyone with impaired consciousness who have recently travelled in a endemic area , especially people with no neurologic focus and with normal csf .
the main risk factors for cerebral malaria are : age , undernourishment , high parasitemia and immunosuppression ; most of these risk factors were present in our patient , in addition , her cerebral manifestations could not be associated with tumoral infiltration .
one of the main aspects of this case was the lack of suspicion and the delay on the diagnosis due to the overlapping between malaria and basal leukaemia symptoms .
the diagnosis was achieved by a routine blood control test a month after hospital admission .
this delay was possibly explained by the fact that the patient received several blood transfusions which could have cleared the parasitemia .
high effective treatment that could reduce the parasitemia as fast as possible was totally necessary .
this treatment consisted in the administration of intravenous anti - malaria drugs ; at present , there are two alternatives : quinine gluconate associated with tetracyclines / clindamicin or artesunate .
artesunate was the option chosen for our patient essentially because it has a more favourable risk / benefit profile and effectiveness than quinine when treating patients with high parasitemia . the superiority of artesunate is probably associated to its unique mechanism with an antiparasite activity based on the removal of immature trophozoites in the blood stream ( ring - shaped ) , reducing the parasitemia quickly and preventing cytoadherence , which is the main physiopathologic mechanism of severe malaria due to p. falciparum
.
the treatment was completed with oral administration of the combination of atovaquone with proguanil according to the north american institute for public health and the centers for disease control and prevention ( cdc ) .
the atovaquone and proguanil coformulation was chosen due to its excellent tolerance with a simple dosage and the clinical experience .
we concluded that it is mandatory to consider malaria in all febrile patients coming from endemic areas ( imported malaria ) , regardless of other comorbidities .
rapid diagnostic tests for malaria such as test binaxnow malaria allow accurate diagnosis and prompt and effective treatment .
Output:
| severe malaria is a life - threatening condition caused by plasmodium falciparum .
rupture of red blood cells when merozoites release to the bloodstream is responsible for the clinical manifestations , febrile fever reaching 39 c , and other unspecific symptoms .
p. falciparum is considered as the worst form of malaria . moreover ,
this species has cytoadherence to red blood cells .
this can lead to an organic dysfunction .
people coming from hyper endemic areas have developed a partial immunity , but immunodepressed people are a group with a greater risk . due to the high mortality rate associated to this disease , early diagnosis and a prompt treatment implementation
are essential .
however , the missed or delayed diagnosis is one of the major reasons of reaching a severe malaria disease .
this case reflects the complexity of the diagnosis in an immigrant and immunodepressed patient with a haematological neoplasm with a severe infection by p. falciparum due to the unspecified symptoms and the overlapping of the same . |
PubmedSumm118273 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: an ophthalmologist may see many cases of vascular occlusions and majority of the cases are due to the thromboembolic phenomena .
apart from hypertension , diabetes , advancing age , and hyper - lipidemia or genetic predisposition , the next most common predisposing factor , amongst the systemic factors , is the use of oral contraceptive pills .
other risk factors associated with central retinal vein occlusion are obesity , sedentary life style , smoking , dehydration , cardiovascular disorders , bleeding or clotting disorders , vasculitis , closed - head trauma , alcohol consumption , primary open - angle glaucoma or angle - closure glaucoma and autoimmune disorders e.g. , antiphospholipid antibody syndrome , lupus , sarcoidosis , dysproteinemia .
majority of gynecologists advocate the use of oral contraceptive pills ( ocp ) for contraception in females of reproductive age group , but nowadays , there is extended use of these drugs in regulating the menstrual cycles for the patients undergoing in vitro fertilization ( ivf ) , resulting ina rise in the usage of these drugs
. therefore , its role in causing various problems like retinal vascular occlusions is of concern . here
we present a two such cases that were given ocp undergoing ivf cycles in a tertiary center of western india . in these patients , after ruling out any family history of thromboembolic disorders , laboratory testing was directed towards identifying various systemic vascular problems .
the basic workup included complete blood cell count ( cbc ) , glucose tolerance test , lipid profile , coagulation profile , activated partial thromboplastin time ( aptt ) , venereal disease research laboratory ( vdrl ) , thrombophilia screening , testing for lupus anticoagulant and anticardiolipin antibodies .
in a tertiary center in western india , 987 patients underwent ivf cycles in two years ( from december 2009 to december 2011 ) .
as a routine , these patients were recruited in the long protocol for ivf and started with third generation monophasic combined ocp containing ethinylestradiol 0.03 mg and desogestrel 0.15 mg on day 2 of menstrual cycle , till midluteal phase ( day 21 ) along with folic acid . from day 21 of menstrual cycle , they were started on gonadotropic releasing hormone ( gnrh ) analogue inj .
luprolide acetate 0.5 mg subcutaneously daily for initial down regulation of ovaries . out of these 987 cases
a 31-year - old female having primary infertility was recruited for in vitro fertilization - intracytoplasmic sperm injection cycle ( ivf - icsi ) .
she was given oral contraceptive pills for persistent functional ovarian cyst of 3.5 cm 3.5 cm which persisted for two menstrual cycles prior to starting her ivf cycle .
after few weeks of treatment , she started complaining of painless blurring of vision in right eye associated with metamorphopsia without redness , discharge , or colored halos . on examination ,
her visual acuity in left eye was found to be 6/6 without glasses but in right eye it was 6/18 with correction and was not improving with pinhole .
all the anterior segment findings were found to be within normal limits in both eyes . on fundus examination , left eye was found to be within normal limits , but right eye showed dilated tortuous central vein with multiple dots and blot hemorrhages all over the fundus , along with macular edema which was confirmed on optical coherence tomogram [ figure 1 ] . in both the eyes , intraocular pressure was found to be within normal limits .
since all the work up done was within normal limits , it was diagnosed to be a case of crvo in right eye secondary to the ocp .
the patient was given intra - vitreal injection of bevacizumab ( avastin ) and was meticulously followed up for 6 months . after 6 months ,
her vision in right eye improved to 6/6 partial and the macular edema regressed as seen on optical coherence tomogram , but the patient is still complaining of metamorphopsia till her last follow up . a female patient aged 38 years who was a case of primary infertility
her three consecutive cycles of ivf had failed earlier prior to initiation of this fourth ivf cycle . at that time
also , she was given monophasic ocp for down regulation of ovaries as well as to make the ovaries silent after the failure of cycle .
after a few months of treatment , she complained of painless diminution of vision in right eye , which was not associated with any other complaint . on examination ,
her best corrected visual acuity was found to be 6/12 partial in right eye and 6/6 in left eye .
on fundus examination , the upper temporal vein was found to be dilated and congested , with cotton wool spots and dot and blot hemorrhages along the upper temporal branch of retinal vein .
the edema and hemorrhages resolved within 3 months and the visual acuity improved to 6/6 after 3 months .
fundus photograph of right eye showing central retinal vein occlusion and optical coherence tomography showing macular edema fundus photograph showing right eye having upper temporal branch retinal vein occlusion with optical coherence tomography showing macular edema
a 31-year - old female having primary infertility was recruited for in vitro fertilization - intracytoplasmic sperm injection cycle ( ivf - icsi ) .
she was given oral contraceptive pills for persistent functional ovarian cyst of 3.5 cm 3.5 cm which persisted for two menstrual cycles prior to starting her ivf cycle .
after few weeks of treatment , she started complaining of painless blurring of vision in right eye associated with metamorphopsia without redness , discharge , or colored halos . on examination ,
her visual acuity in left eye was found to be 6/6 without glasses but in right eye it was 6/18 with correction and was not improving with pinhole .
all the anterior segment findings were found to be within normal limits in both eyes . on fundus examination ,
left eye was found to be within normal limits , but right eye showed dilated tortuous central vein with multiple dots and blot hemorrhages all over the fundus , along with macular edema which was confirmed on optical coherence tomogram [ figure 1 ] . in both the eyes , intraocular pressure was found to be within normal limits .
since all the work up done was within normal limits , it was diagnosed to be a case of crvo in right eye secondary to the ocp .
the patient was given intra - vitreal injection of bevacizumab ( avastin ) and was meticulously followed up for 6 months . after 6 months ,
her vision in right eye improved to 6/6 partial and the macular edema regressed as seen on optical coherence tomogram , but the patient is still complaining of metamorphopsia till her last follow up .
a female patient aged 38 years who was a case of primary infertility was recruited for her fourth consecutive ivf cycle .
her three consecutive cycles of ivf had failed earlier prior to initiation of this fourth ivf cycle . at that time also , she was given monophasic ocp for down regulation of ovaries as well as to make the ovaries silent after the failure of cycle .
after a few months of treatment , she complained of painless diminution of vision in right eye , which was not associated with any other complaint . on examination ,
her best corrected visual acuity was found to be 6/12 partial in right eye and 6/6 in left eye .
on fundus examination , the upper temporal vein was found to be dilated and congested , with cotton wool spots and dot and blot hemorrhages along the upper temporal branch of retinal vein .
all the systemic and local causes investigated were within normal limits . it was diagnosed to be secondary to ocp .
the edema and hemorrhages resolved within 3 months and the visual acuity improved to 6/6 after 3 months .
fundus photograph of right eye showing central retinal vein occlusion and optical coherence tomography showing macular edema fundus photograph showing right eye having upper temporal branch retinal vein occlusion with optical coherence tomography showing macular edema
the exact pathogenesis of the thrombotic occlusion of the central retinal vein is not known .
various local and systemic factors play a role in the pathological closure of the central retinal vein .
thrombotic occlusion of the central retinal vein can occur as a result of various pathologic insults , including compression of the vein ( mechanical pressure due to structural changes in lamina cribrosa , e.g. , glaucomatous cupping , inflammatory swelling in optic nerve , orbital disorders ) , hemodynamic disturbances ( associated with hyperdynamic or sluggish circulation ) , vessel wall changes ( e.g. , vasculitis ) , and changes in the blood ( e.g. , deficiency of thrombolytic factors , increase in clotting factors ) .
occlusion of the central retinal vein leads to the backup of the blood in the retinal venous system and increased resistance to venous blood flow .
it has been postulated that ischemic damage to the retina stimulates increased production of vascular endothelial growth factor ( vegf ) in the vitreous cavity . increased levels of vegf stimulate neovascularization of the posterior and anterior segment ( responsible for secondary complications due to central retinal vein occlusion ) .
also , it has been shown that vegf causes capillary leakage leading to macular edema ( which is the leading cause of visual loss in both ischemic central retinal vein occlusion and non - ischemic central retinal vein occlusion ) .
the ocp are used for down regulation of ivf cycles , treatment of functional ovarian cysts , and regularization of periods in polycystic ovarian syndrome , dysfunctional uterine bleeding , and puberty menorrhagia and to schedule / postpone menstrual cycle .
besides their main effect on cardiovascular system that can lead to increased mortality , oral contraceptives have been previously implicated in central retinal vein occlusion .
the mechanisms for retinal vascular occlusion development , symptomatology , clinical features , and treatment modalities remain the same as with other predisposing factors for central retinal vein occlusion . in a cohort study by vessev et al . , the only eye disease for which there was consistent evidence of a notable increase in risk in oral contraceptives users was a retinal vascular problem .
similarly , the prevalence of retinal vein occlusion in female patients less than 35 years taking the ocp was 66.0% in a large series by kirwan et al .
in apopulation based study by scoditti et al .
, reported that the use of low estrogen oral contraceptives was associated with an increased risk of cerebral venous thrombosis and ischemic stroke , but not of retinal vein / artery thrombosis .
because of the rise in infertile population and advances in treatment modalities like ivf , there is rise in usage of the ocp , hence , the risk for retinal vascular catastrophes is also rising .
so the treating doctor should be aware and more conscious of this situation and should refer the cases for screening at the earliest .
Output:
| retinal vascular occlusion is the most common cause of retinopathy leading to severe visual loss in all age groups .
central retinal vein occlusion ( crvo ) is usually seen in older age group and is often associated with systemic vascular diseases . although the exact cause and effect relationship has not been proven , central retinal vein occlusion has been associated with various systemic pathological conditions , hence a direct review of systems toward the various systemic and local factors predisposing the central retinal vein occlusion is advocated .
we describe the development of central retinal venous occlusion with associated cystoid macular edema ( cme ) in two healthy infertile women who were recruited for in vitro fertilization cycle for infertility .
predisposing risk factors associated with central retinal vein occlusion are obesity , sedentary life style , smoking , and some systemic diseases such as hyperlipidemia , hypertension , associated autoimmune disorders e.g. , antiphospholipid antibody syndrome , lupus , diabetes mellitus , cardiovascular disorders , bleeding or clotting disorders , vasculitis , closed - head trauma , alcohol consumption , primary open - angle glaucoma or angle - closure glaucoma . in our patients , they were ruled out afterdoing allpertaining investigations .
the cases were managed with further avoidance of oral contraceptives and intra - vitreal injections of bevacizumab ( avastin ) , an anti - vascular endothelial growth factor ( anti - vegf drug ) and triamcinolone acetonide ( a long acting synthetic steroid ) .
hence , even if no systemic diseases are detected .
physical examinations are recommended periodically for young women on oral contraceptive pills . |
PubmedSumm118274 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: in general , speakers phonate in order to convey information ( linguistic or paralinguistic ; intentionally or unintentionally ) to a listener .
the stages of transmitting information in this way can be described by the well - known speech chain
we presently know a good deal about the individual steps along the chain , including motor planning , laryngeal innervation , tissue properties , the biomechanics of laryngeal vibrations , aeroacoustics , acoustics and resonance , and voice perception .
however , very few studies address the manner in which information is transmitted from one stage to the next , much less from one end of this chain to the other . as a result , two important questions about voice remain unanswered : 1 ) when voice quality changes in some way , what caused the change ? and
2 ) if a change occurs in voice production , what will be the resulting perceived change in quality ? in this paper , we motivate a model of voice that is designed to answer these questions , and describe our preliminary steps towards generating this model . in our view , these two questions define the primary goals of the study of voice . because voice production , acoustics , and perception are all parts of the same communicative process , understanding the communicative function of any of these aspects of voice
laryngeal / physiologic , acoustic , or perceptual requires knowledge of how each stage interacts with the others in the transmission of vocal information .
details of voice production , acoustics and quality may be misinterpreted without considering the other domains .
for example , dozens of different measures of acoustic jitter , shimmer , and harmonics - to - noise ratios ( hnrs ) have been proposed ( see buder , 2000 , for review ) , presumably because the authors assumed that jitter and shimmer were important vocal characteristics .
hundreds of research papers have examined the correlations between ratings of voice quality and these acoustic measures ( see e.g. maryn , roy , de bodt , van cauwenberge , & corthals , 2009 , for review ) , and many more examined correlations between measured perturbation and voice physiology or vocal diagnosis ( see e.g. roy et al . , 2013 , for review ) . however , acoustic perturbation measures are not individually informative about voice quality , because listeners can not hear even large differences in jitter or shimmer ( although they are sensitive to changes in the overall level of harmonic vs. inharmonic energy in the voice source ; kreiman & gerratt , 2005 ) .
further , jitter , shimmer , and noise tell us little about voice production , because they have multiple neurological , biomechanical , aerodynamic , and acoustic causes ( see titze , 1994 , for review ) .
thus , these studies have not resulted in any significant insight into voice production or perception , because questions about causation are difficult to answer without a model explicitly linking production to perception . in another example
, clinicians applying stroboscopy or high - speed video imaging often interpret asymmetric vocal fold motion as evidence of vocal pathology .
however , although asymmetries sometimes co - occur with abnormal voice qualities , asymmetrical vibration can also occur without any negative effect on the sound of the voice .
high - speed video and audio recordings demonstrating such an asymmetry in a normal speaker are presented in the supplemental material [ s1 ] accompanying this paper ( see also zhang , kreiman , gerratt , & garellek , 2013 ) . again , no theoretical model exists to predict which asymmetries have perceptual consequences , and which do not .
thus , apart from its basic science interest , a theory describing the links between voice production and perception would also have substantial clinical importance , because the clinical process used to diagnose and treat voice disorders involves a search for cause and effect from one system to another .
the primary measure of treatment outcome in voice therapy is perceived voice quality a patient is not well until their voice sounds better , no matter what the values of instrumental measures may be .
thus , identifying and treating the cause of a deviation in voice quality requires knowledge of which physiological change is responsible for the quality deviation , and predicting treatment outcome requires knowledge of the links between changes in laryngeal physiology and the resulting perceived changes in quality . because the acoustic signal links production to perception , our approach to understanding how speakers and listeners produce and perceive communicative changes in voice quality begins with these three steps :
link perception to acoustics by explaining quality in terms of perceptually valid acoustic measures that combine to fully determine voice quality.link voice production to acoustics and perception by determining which changes in the physiological voice source produce perceptible changes in the acoustic signal.iterate until the two sets of acoustic parameters align .
link perception to acoustics by explaining quality in terms of perceptually valid acoustic measures that combine to fully determine voice quality .
link voice production to acoustics and perception by determining which changes in the physiological voice source produce perceptible changes in the acoustic signal .
note that in this approach , quality the speaker s ultimate concerndrives the model .
important acoustic changes are identified by assessing their perceptual salience , after which the acoustic changes that account for what listeners hear can be used to generate hypotheses about what physical changes have important perceptual consequences . by identifying perceptually - important vocal attributes and then examining the glottal pulse shapes associated with these attributes
, we will be able to highlight the physical attributes that are important in communication , thus potentially providing data to focus physical modeling efforts towards the physiologic aspects of greatest perceptual importance to speakers and listeners .
like pitch and loudness , quality results from an interaction between a listener and a signal . a significant body of behavioral and neuropsychological data ( e.g. , andics et al . ,
2010 ; kreiman , gerratt , & ito , 2007b ; kreiman & sidtis , 2011 ; latinus , mcaleer , bestelmeyer , & belin , 2013 ; lavner , rosenhouse , and gath , 2001 ; li & pastore , 1995 ; melara & marks , 1990 ) shows that listeners perceive voice quality as an integral pattern , rather than as the sum of a number of separate features ( the view implied by use of rating scales ) .
for example , studies of voice recognition from synthetically - altered stimuli indicate that the perceptual importance of a given feature depends on the values of the other attributes of the pattern , and not solely on the value of the feature itself ( van lancker , kreiman , & emmorey , 1985 ; van lancker , kreiman , & wickens , 1985 ) .
similarly , in priming experiments , reaction times to famous voices were significantly faster when listeners had previously heard a different exemplar of the voice . because the priming effect was produced by different samples of each voice
, it appears that the benefit derives from the complete voice pattern , not from the specific details of a given sample , again consistent with the view that voices are processed as patterns , and not as bundles of features ( schweinberger , herholz , & stief , 1997 ) . in the same manner , listeners appear largely unable to isolate single dimensions in a voice pattern ( kreiman et al .
, 2007b ) . data also demonstrate that harmonic and inharmonic ( noise ) components of the voice source interact perceptually ( kreiman & gerratt , 2012 ) , so that listeners sensitivity to either acoustic attribute depends on the levels of energy in both ; and sensitivity to tremor rates depends on tremor amplitude ( kreiman , gabelman , & gerratt , 2003 ) .
thus , neither the perceptual meaning of a given quality dimension nor the perceptual significance of an acoustic measure can be assessed without knowledge of the context provided by the complete voice pattern in which the feature or measure functions .
it follows that partitioning the overall quality of a voice into separate factors like breathiness or roughness and asking listeners to isolate and rate qualities is unlikely to tell us enough about how a listener actually perceives either the specific quality or overall quality , so that the sum of a set of individual rating scale responses is not informative enough about how a voice sounds or how it compares to other voices .
if quality is integral , as these studies indicate , then valid measurement requires quantifying the entire voice pattern . to achieve this goal
, we apply analysis - by - synthesis to copy each voice sample with a speech synthesizer ( kreiman , antoanzas - barroso , & gerratt , 2010 ) .
because the acoustic synthesizer parameters combine to completely re - create the perceived voice pattern , they can be considered a psychoacoustic model of voice quality that parametrically represents an integral voice pattern and objectively quantifies a subjective percept .
the next step in model development is the selection of parameters to map between acoustics and perception .
an adequate voice source model should 1 ) include enough parameters that it can model any voice quality ; and 2 ) should only include parameters to which listeners are sensitive . in other words ,
the parameters in the set should be both necessary and sufficient to model voice quality .
development of our psychoacoustic model began with the assumptions that listeners are more likely to pay attention to those acoustic parameters that actually vary across voices ( so that they meet the necessary test ) , and that parameters that are constant across voices are less likely to be perceptually important .
( for example , if every speaker spoke with exactly the same range of f0 values , f0 would not be useful for distinguishing among speakers . ) to determine the parameters that actually do vary across speakers and thus may be perceptually salient we performed a principal components analysis of the spectra of 70 voices ( kreiman , gerratt , & antoanzas - barroso , 2007a ) .
fft spectra for these voices were calculated and normalized to the amplitude of the first harmonic .
spectral envelopes were estimated by connecting the harmonic peaks , and seventy equally - spaced points were chosen along each envelope .
results indicated that four factors accounted for most of the variance in source spectral shape across voices : the source spectral slope above 4 khz , the slope below 450 hz , and the slope from 1.5 khz to 4 khz ( two factors ) . similar analyses of a large set of acoustic measures showed significant variability across voices in the relative amplitudes of the first and second harmonics ( h1h2 ) , the relative amplitudes of the second and fourth harmonics ( h2h4 ) , overall spectral slope , and high frequency noise excitation .
to assess model sufficiency throughout the course of model development , we used the ucla voice synthesizer to copy - synthesize several hundred voices over a period of several years .
briefly , speakers with and without vocal pathology were selected at random from a large library of voices recorded with a brel & kjr " microphone during clinical evaluation .
voices ranged from normal to severely disordered in quality , and a very wide range of diagnoses were represented , including reflux , mass lesions , and functional and neurogenic disorders .
the harmonic part of the voice source was estimated by inverse filtering a representative cycle of phonation , and source spectra were fitted with the model ( figure 2 ) .
the inharmonic part of the source spectrum was estimated using a cepstral - domain analysis ( de krom , 1993 ) , and f0 and amplitude contours were tracked on the original voice sample
. finally , the voice was resynthesized by combining these parameters with a model of the vocal tract ( estimated by lpc ) , and all parameters were adjusted until the synthetic copy formed an acceptable match to the natural token .
examples of natural and modeled tokens are included in the supplemental material [ s2 ] accompanying this paper .
we then asked listeners to compare the synthesized tokens to the natural voice samples in a series of same / different ( ax ) tasks .
examination of cases in which the synthetic tokens were distinguished from the natural target stimuli at greater than chance levels suggested that more detail was needed in our modeling of the source spectrum above h4 ( e.g. , kreiman , garellek , & esposito , 2011 ; kreiman & gerratt , 2011 ) . as a result
, we removed the parameter h45 khz from the model and replaced it with two new parameters : the spectral slope from the fourth harmonic to the harmonic nearest 2 khz in frequency ( h4 - 2 khz ) and the spectral slope from that harmonic to the harmonic nearest 5 khz in frequency ( 2 khz-5 khz ) .
we then repeated the same / different task , with the result that listeners were unable to consistently distinguish synthetic from natural tokens ( d < 1 ) .
although evaluation is ongoing , we conclude for the present that the current model ( table 1 ) provides enough detail to describe the majority of normal and pathological voice qualities .
establishing the necessity of each parameter as part of the model requires a series of experiments to determine how sensitive listeners are to changes in that parameter . to that end
, we began by defining sensitivity as the ratio of the smallest difference in a parameter that listeners can consistently detect ( the just - noticeable difference , or jnd ) to the overall variability of that parameter across speakers ( kreiman & gerratt , 2010 ) .
we reasoned that the smaller the jnd was relative to variability , the more information that parameter potentially carried to listeners . to calculate these ratios , we first estimated the range of each model parameter across natural voices by modeling 144 voice samples ( 79 female , 65 male ) via analysis - by - synthesis , and then measuring each of the source model parameters from the modeled source spectra .
samples ranged from normal to severely disordered in quality , and were unselected with respect to diagnosis and the specific voice quality . h1h2 and h2h4 values generally ranged from 020 db , while spectral slopes for h42 khz and 2 khz-5 khz ranged more widely , from 0 db-40 db ( see kreiman , garellek , samlan , & gerratt , 2014 , for detailed results ) .
we next conducted a series of experiments using a one up , two down protocol ( levitt , 1971 ) to determine the smallest change in each parameter that listeners can reliably detect ( e.g. , garellek , samlan , kreiman , & gerratt , 2013 ; kreiman & gerratt , 2012 ) .
we synthesized series of stimuli in which a single source spectral parameter was varied in very small steps , and then played pairs of these stimuli to listeners in a same / different ( ax ) task .
when listeners correctly perceived a difference between the stimuli , the difference between stimuli in the next pair decreased ; when listeners incorrectly judged the stimuli to be the same , the difference was increased , with the pattern of trials iterating until results began to oscillate around a single difference value which was defined as the jnd .
results are summarized in table 2 . because the amount of change listeners can hear is small relative to the variability of the parameters across speakers ,
we tentatively conclude that these parameters are potentially informative to listeners , and that the set of parameters that constitutes the psychoacoustic source model meets the necessary test .
this psychoacoustic model makes implicit claims about voice production . first , if voice quality is described by a specific set of acoustic parameters , then speakers must be able to control these parameters or their physiological precursors in order to convey information to listeners .
conversely , aspects of voice production that speakers can easily manipulate should produce perceptible changes in voice quality , which should be measurable with the parameters in the psychoacoustic model .
some evidence from studies of linguistic uses of voice quality is consistent with the first of these claims , particularly with respect to h1h2 ( or h1*h2 * ) . in languages with
phonemic contrasts in voice quality , speakers must change source characteristics to distinguish meanings , and evidence that they do this in consistent ways supports the notion that they are able to control specific source spectral attributes . for example , in white hmong ( a language in which changes in voice quality accompany some tones ) , increases in both h1h2 and h2h4 ( especially in combination ) increased the likelihood of perceiving phonemic breathiness , consistent with the view that the percept of breathiness is influenced by a steep drop in harmonic energy in the lower frequencies ( garellek et al . , 2013 ) . speakers of a number of other languages , including gujarati , mazatec , chong , and green mong , also distinguish word meanings via differences in h1h2 ( e.g. , andruski & ratliff , 2000 ; blankenship , 2002 ; fischer - jrgensen , 1967 ; see dicanio , 2009 , and garellek & keating , 2011 , for review ) . more directly , esposito ( 2012 ) combined electroglottographic ( egg ) measures of laryngeal closing speed and closed quotient with simultaneously - gathered acoustic measures of the source spectrum to examine the physiological and acoustic determinates of the phonation contrast in white hmong , which has tones characterized by differences in both f0 and phonation type ( breathy , modal , and creaky ) . closed quotient was a good predictor of h1*h2 * ( r = 0.6 , p < .05 ) , which in turn reliably distinguished breathy voice from modal and creaky voice . additional evidence comes from a high - speed imaging study of changes in glottal configuration with changes in voice quality along a continuum from breathy to pressed ( kreiman et al . ,
2012 ) . in this study , six speakers produced steady - state vowels while varying f0 and voice quality .
measures of the glottal open quotient ( oq ) and the asymmetry quotient were made from the high - speed images , and h1*h2 * was measured synchronously from audio recordings of the same utterances . across speakers and voice qualities , oq , the asymmetry coefficient , and fundamental frequency accounted for an average of 74% of the variance in h1*h2*.
however , individual speakers used several strategies for varying voice quality , including manipulating glottal gap size , changing oq , varying f0 , and altering the skewness of glottal pulses .
thus , h1*h2 * can be predicted from glottal configuration with good overall accuracy , although its relationship to phonatory characteristics is complex and speaker dependent .
it is not surprising that speakers would have a variety of phonatory strategies available to them for manipulating h1h2 in speech .
listeners are highly sensitive to the relative amplitudes of the lowest harmonics ( kreiman & gerratt , 2010 ) , which convey both paralinguistic information about a variety of personal and interpersonal attributes ( see kreiman & sidtis , 2011 , for review ) and linguistic information , as just described .
the ability to use different movements to produce the same speech sound has been described for the oral articulators ( e.g. , guenther , 1994 ) , and a similar facility for phonation may arise from attempts to produce a particular quality , whether for linguistic or paralinguistic reasons , in the context of different combinations of simultaneous pitch and/or loudness goals .
the second claim implicit in our psychoacoustic model of voice quality is that aspects of voice production that speakers can easily manipulate should produce perceptible changes in voice quality ( which also should be quantifiable via the parameters in the psychoacoustic model ) .
this in turn implies that examining the perceptual consequence of changes in physiology will allow us to identify perceptually - relevant mechanical or behavioral manipulations that may be attempted in the clinic .
unfortunately , studies manipulating vocal physiology can not be conducted in humans , who lack the ability to consciously control individual laryngeal muscles , vocal fold stiffness , glottal gap size and location , and so on .
however , we can apply various physical , computational , and ex vivo models of phonation to study the cause - effect relationship between voice production and voice quality by varying parameters of voice production ( e.g. , vocal fold geometry , stiffness , muscle stimulation , subglottal pressure , etc . )
one at a time and observing the consequence on vocal fold vibration , voice acoustics , and voice quality .
laryngeal modeling has a long history ( e.g. , ishizaka and flanagan , 1972 ; titze & talkin , 1979 ; berry , herzel , titze , & krischer , 1994 ; steinecke & herzel , 1995 ; story & titze , 1995 ; zhang , neubauer , & berry , 2006 , 2007 ; mendelsohn & zhang , 2011 ; xue , mittal , zheng , & bielamowicz , 2012 ) , but most studies assess only the physical and/or acoustic results of model permutations , without evaluation of any perceptual consequences .
( 2013 ) , who investigated the acoustic and perceptual consequences of left - right stiffness mismatches in a mechanical self - oscillating vocal fold model .
it is generally assumed that left - right stiffness mismatches like those occurring in unilateral vocal fold paralysis or paresis lead to left - right asymmetry in vocal fold vibration , which is often an indication for surgical intervention .
however , it is unclear whether left - right stiffness mismatches and the resulting left - right vibrational asymmetry are always perceptually significant .
in other words , the consequences of variability in the material properties and geometry of vocal folds on voice quality are not well understood , so we do not know if vibrational asymmetry ( or other deviations from normal vocal fold movement ) leads to acoustic changes that people can hear . to address this question ,
a body - cover two - layer mechanical vocal fold model was used ( figure 3 ) .
a series of left - right asymmetric conditions with varying left - right mismatches in body stiffness were created by varying the body - layer stiffness of the left vocal fold model while the right vocal fold remained unchanged .
all vocal fold models had identical vocal fold geometry and cover - layer stiffness . for each asymmetric vocal fold model , phonation tests
were performed using a flow - ramp procedure in which the flow rate was increased in steps from zero to a value above onset of vibration .
the outside acoustic signals recorded at a subglottal pressure 10% above onset were used in subsequent acoustic analysis and perceptual tests .
measures of source spectral slope were extracted ( as discussed above ) for each asymmetric condition .
in addition , the number of harmonics below 8 khz in the sound spectrum was also measured . for perceptual tests ,
listeners were asked to evaluate the voice samples in a sort - and - rate task ( figure 4 ) , in which they sorted the voice samples along a straight line so that tokens that sounded similar were placed close together on the line ( granqvist , 2003 ; zhang et al . , 2013 ) .
this study revealed two regimes of distinct vibratory patterns with varying left - right stiffness mismatch .
for conditions with a large left - right stiffness mismatch , only the soft - body fold was excited while the stiff - body fold barely moved , which led to weak excitation of high - order harmonics . for small left - right stiffness mismatches ,
both folds were strongly excited but the stiff fold always led in phase in their motion .
perceptual tests also demonstrated two clusters , each corresponding to one of the two vibratory regimes .
this study showed that changes to the degree of left - right stiffness mismatch and the resulting left - right vibratory asymmetry did not produce perceptually significant differences in quality unless the stiffness mismatch was large enough to cause a qualitative change in vibratory mode ( a bifurcation ) .
this suggests that a vibration pattern with left - right asymmetry does not necessarily result in a salient deviation in voice quality , and thus may not always be of clinical significance .
perceptual changes were explicable with reference to the psychoacoustic model parameters , including spectral slopes and the noise - to - harmonics ratio , consistent with the general framework being developed here . a similar approach has also been used recently by samlan and colleagues ( samlan & story , 2011 ; samlan , story , & bunton , 2013 ) , who studied the relationship between kinematic , acoustic , and perceptual measures using voice samples generated with a computational vocal fold model coupled to a model of the vocal tract .
for example , samlan and story ( 2011 ) manipulated vocal process separation , vocal fold bulging , the nodal point ratio ( the ratio of the point at which mucosal fold motion begins to overall vocal fold thickness ) , and epilaryngeal area , and measured the effects on h1h2 and on the cepstral peak prominence ( cpp ; hillenbrand & houde , 1996 ) , a measure of the relative levels of harmonic and inharmonic energy in the voice .
2013 ) added measures of spectral slope and ratings of perceived breathiness to the mix .
they found a clear relationship between cpp , separation of the vocal processes , and ratings of breathiness ( presumably related to increases in turbulent noise with increasing glottal gaps ) , with additional variance explained by nodal point ratio , vocal fold bulging , and spectral slope .
the relationship between measures of spectral slope and model parameters depended on severity of rated breathiness : h1h2 was a better predictor of mild breathiness of the kind often associated with
vocal weakness , while overall spectral slope was a better predictor when significant high - frequency noise was present in the voice .
this finding reflects both the complexity of causation in vocal physiology and the perceptual multidimensionality of breathiness ( kreiman , gerratt , & berke , 1994 ) .
modeling studies like these are attractive because they allow simultaneous direct manipulation of many parameters in a well - controlled laboratory setting
. the limitations of this approach lie in the vocal fold model used , or specifically , how realistically these models ( the mechanical or computational model in the examples above ) reproduce the physiology and physics of human phonation . ideally , we would like to model phonation in a living human being , but direct manipulation and measurement of muscle activities and vocal fold properties ( geometry and stiffness ) are currently impossible in living human subjects , due to the great sensitivity and relative inaccessibility of the larynx . to overcome this problem ,
an ex - vivo perfused living model of human phonation has been developed ( berke , mendelsohn , howard , & zhang , 2013 ) . in this model , a human larynx and trachea are harvested from an organ donor post mortem and perfused with oxygenated blood .
the tissue remains viable for several hours , and because the laryngeal nerves and muscles are still living , they can be directly stimulated in a well - controlled laboratory setting , as opposed to mechanical manipulations in ex vivo models in which the material properties of the muscles and other tissues change post - mortem .
this model makes it possible to study the effects of known levels of actual human laryngeal muscle activation on vocal fold stiffness and geometry .
it also allows us to study interactions among muscles ( for example , the thyroarytenoid and cricothyroid ) in investigations of the control of pitch , loudness , and voice quality .
although use of this model is only beginning , when combined with perceptual testing and acoustical analysis , it promises to provide new data about the precursors and correlates of changes in voice quality .
the studies reviewed in this paper suggest that phonation is best viewed as part of a communicative process , the pieces of which are difficult to understand out of the context of the entire process .
thus , understanding and ultimately predicting how speakers produce the intended voice quality ( and how disorders disturb this process ) requires a unified model of voice that links production to perception .
many issues await resolution as we work towards this goal . because phonation takes place in the time domain while perception depends largely on spectral information , understanding the relationship between perception and production requires mapping between time and spectral domain representations , which has proven difficult ( e.g. , fant , 1995 ; ni chasaide & gobl , 1997 ) .
more than one physical configuration may produce the same voice quality ; conversely , large changes in configuration may not result in changes in quality .
variables in the current voice source model certainly interact : for example , we know that the perceptual salience of changes in high - frequency harmonics depends on the signal - to - noise ratio and on the shape of the noise spectrum ( kreiman & gerratt , 2012 ) . finally , the extreme complexity of the phonatory system ( and of human communication in general ) and the difficulty inherent in observing and measuring many aspects of phonation make it hard both to gather all the needed data regarding interactions among factors , and to model those data once they are gathered . despite these complications and complexities
, we argue that the systematic approach described in this paper will eventually make it possible to understand how features of the voice production system combine with attributes of the perceptual system to transmit voice information from speakers to listeners , but only if the research community considers this a primary goal for voice research .
Output:
| at present , two important questions about voice remain unanswered : when voice quality changes , what physiological alteration caused this change , and if a change to the voice production system occurs , what change in perceived quality can be expected ?
we argue that these questions can only be answered by an integrated model of voice linking production and perception , and we describe steps towards the development of such a model .
preliminary evidence in support of this approach is also presented .
we conclude that development of such a model should be a priority for scientists interested in voice , to explain what physical condition(s ) might underlie a given voice quality , or what voice quality might result from a specific physical configuration . |
PubmedSumm118275 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the introduction of imatinib mesylate a small - molecule tyrosine kinase inhibitor ( tki ) active against c - kit , bcrabl , and platelet - derived growth factor receptor alpha ( pdgfra)has led to dramatically improved clinical outcomes of gastrointestinal stromal tumor ( gist ) patients [ 1 - 5 ] .
although clinical benefits of other tkis , such as sunitinib and regorafenib , have also been demonstrated , imatinib remains the cornerstone of treatment for gist in both adjuvant and palliative settings [ 4 - 8 ] .
current treatment guidelines recommend long - term continuous imatinib therapy in advanced gist patients , as long as clinical benefits are maintained , because rapid disease progression often occurs following treatment interruption [ 9 - 11 ] .
likewise , adjuvant imatinib should be administered to high - risk gist patients for 36 months . for patients receiving long - term imatinib treatment , maintaining the continued administration at a sufficient dose
imatinib is generally well tolerated and most adverse events are mild and can be managed without dose reduction or treatment interruption [ 2 - 5 ] ; however , some patients experience severe toxicity which may result in reduced patient compliance and dose intensity . considering the importance of maintaining sufficient daily imatinib dosing in order to achieve optimal clinical outcomes ,
skin rash commonly presenting as erythematous and maculopapular lesions is one of the most troublesome toxicities , which may affect imatinib compliance or persistence .
it affects up to one - third of gist patients receiving imatinib with grade 3/4 up to 10% [ 2 - 4 ] .
the treatment options for imatinib - related rash described in the medical literature are based on case reports , case series , and reported personal experiences .
however there are few data on the effectiveness of these treatments or the clinical outcomes of patients with severe skin rash .
we thus conducted this retrospective study using data retrieved from our database between 2000 and 2012 to evaluate ( 1 ) the incidence of skin rash in gist patients administered imatinib , ( 2 ) therapeutic interventions for severe skin rash and outcomes , and ( 3 ) the impact of skin rash on imatinib treatment outcomes .
a total of 1,392 patients were entered into the gist prospective database at the asan medical center in korea between january 2000 and july 2012 . of these ,
620 adult patients were treated with imatinib in adjuvant or palliative settings for histologically proven gist ( entire cohort ) .
this analysis focused on a group of 42 patients who developed severe skin rash requiring major interventions defined as interruption or dose reduction of imatinib and/or systemic steroid use ( group 1 ) .
anti - histamine agents and/or topical steroids were also administered at the discretion of the attending physicians .
severity of skin rash was classified as mild to moderate , corresponding to grade 1 to 2 ( macular or popular eruption or erythema without associated symptoms and with pruritus covering < 50% of body surface area , respectively ) , or
severe , corresponding to grade 3 ( symptomatic generalized erythroderma or macular , papular , or vesicular eruption or desquamation covering > 50% of body surface area ) to 4 ( generalized exfoliative dermatitis or ulcerative dermatitis ) .
the success of each intervention for severe rash was defined as continuation of imatinib without the persistence or recurrence of severe rash requiring further intervention .
the overall success rate of the entire clinical course was analyzed regardless of the number of interventions , and patients who had to permanently discontinue imatinib due to rash at the first occurrence were also considered treatment failures . the clinical features and treatment outcomes of the patients with severe imatinib - associated skin rash ( group 1 ) were compared with those of two comparator groups from the entire cohort .
one was composed of 106 gist patients who received imatinib during the same time period as group 1 and developed mild to moderate skin rash not requiring major interventions ( group 2 ) , and the other consisted of 100 consecutive patients in the order of being recently diagnosed who had not developed skin rash and had available clinical data ( group 3 ) .
all patients from these three groups were included in the analysis for blood eosinophil counts during imatinib treatment , and only patients treated with imatinib 400 mg / day for unresectable or metastatic gist were included in the analysis for treatment outcomes .
patients administered palliative imatinib due to tumor perforation that occurred before or during surgery for localized disease were excluded from the progression - free survival ( pfs ) analysis .
pearson s chi - square and fisher exact tests were used for comparison of discrete data as required , and the mann - whitney u and kruskal - wallis one - way analysis of variance tests were used for comparison of non - parametric variables when two or three categories were included , respectively .
pfs was calculated from the date imatinib was started for advanced gist to the date of disease progression or death due to any cause , whichever occurred first .
survival was estimated using the kaplan - meier method , and the log - rank test was used to determine the significance of any differences in the survival curves .
all tests were two - sided , and p - value of < 0.05 was considered statistically significant .
a total of 1,392 patients were entered into the gist prospective database at the asan medical center in korea between january 2000 and july 2012 . of these ,
620 adult patients were treated with imatinib in adjuvant or palliative settings for histologically proven gist ( entire cohort ) .
this analysis focused on a group of 42 patients who developed severe skin rash requiring major interventions defined as interruption or dose reduction of imatinib and/or systemic steroid use ( group 1 ) .
anti - histamine agents and/or topical steroids were also administered at the discretion of the attending physicians .
severity of skin rash was classified as mild to moderate , corresponding to grade 1 to 2 ( macular or popular eruption or erythema without associated symptoms and with pruritus covering < 50% of body surface area , respectively ) , or
severe , corresponding to grade 3 ( symptomatic generalized erythroderma or macular , papular , or vesicular eruption or desquamation covering > 50% of body surface area ) to 4 ( generalized exfoliative dermatitis or ulcerative dermatitis ) .
the success of each intervention for severe rash was defined as continuation of imatinib without the persistence or recurrence of severe rash requiring further intervention .
the overall success rate of the entire clinical course was analyzed regardless of the number of interventions , and patients who had to permanently discontinue imatinib due to rash at the first occurrence were also considered treatment failures . the clinical features and treatment outcomes of the patients with severe imatinib - associated skin rash ( group 1 ) were compared with those of two comparator groups from the entire cohort .
one was composed of 106 gist patients who received imatinib during the same time period as group 1 and developed mild to moderate skin rash not requiring major interventions ( group 2 ) , and the other consisted of 100 consecutive patients in the order of being recently diagnosed who had not developed skin rash and had available clinical data ( group 3 ) .
all patients from these three groups were included in the analysis for blood eosinophil counts during imatinib treatment , and only patients treated with imatinib 400 mg / day for unresectable or metastatic gist were included in the analysis for treatment outcomes .
patients administered palliative imatinib due to tumor perforation that occurred before or during surgery for localized disease were excluded from the progression - free survival ( pfs ) analysis .
pearson s chi - square and fisher exact tests were used for comparison of discrete data as required , and the mann - whitney u and kruskal - wallis one - way analysis of variance tests were used for comparison of non - parametric variables when two or three categories were included , respectively .
pfs was calculated from the date imatinib was started for advanced gist to the date of disease progression or death due to any cause , whichever occurred first . survival was estimated using the kaplan - meier method , and the log - rank test was used to determine the significance of any differences in the survival curves .
all tests were two - sided , and p - value of < 0.05 was considered statistically significant .
of the 620 study patients treated with imatinib , 148 patients ( 23.9% ) developed skin rash during imatinib treatment with 42 patients ( 6.8% ) having a severe skin rash requiring major interventions .
imatinib was administered in the setting of neoadjuvant , adjuvant , and palliative treatment in eight patients ( 19.0% ) , 11 patients ( 26.2% ) , and 23 patients ( 54.8% ) , respectively .
the median time to development of severe skin rash requiring major interventions was 2.8 months ( range , 0.2 to 8.4 months ) .
two patients ( 4.8% ) had to permanently discontinue imatinib due to a grade 3 or 4 skin rash , respectively .
major interventions for skin rash were administered in the remaining 40 patients , including systemic steroids only ( n=17 , 40.5% ) , imatinib dose modification only ( dose reduction only [ n=6 , 14.3% ] , dose interruption only [ n=2 , 4.8% ] , dose reduction+ interruption [ n=6 , 14.3% ] ) , or the combined use of systemic steroids and imatinib dose modification ( steroids+dose reduction [ n=2 , 4.8% ] , steroids+interruption [ n=3 , 7.1% ] , steroids+dose reduction+interruption [ n=4 , 9.5% ] ) . the median dose and duration of initial steroid treatment before tapering were 20 mg / day prednisolone ( range , 5 to 60 mg / day ) and 7 days ( range , 4 to 28 days ) , respectively , then the treatment was tapered off with a median total duration of steroid of 28 days ( range , 7 to 204 days ) .
the first intervention was successful in 22 patients ( 55.0% ) , but it failed in 14 patients ( 35.0% ) .
four patients ( 10.0% ) who had discontinued imatinib early due to adverse events other than rash ( n=2 ) , disease progression ( n=1 ) , or gist resection ( n=1 ) could not be evaluated for interventional efficacy .
of 14 patients whose first intervention failed , three patients ( 21.4% ) discontinued imatinib due to uncontrolled severe rash and a second intervention was administered in the remaining 11 patients ( 78.6% ) ; only systemic steroids ( n=6 , 42.9% ) , imatinib dose modification ( n=2 , 14.3% ; dose reduction and interruption in each one ) , and systemic steroids+imatinib dose modification ( steroids+imatinib reduction [ n=1 , 7.1% ] , steroids+imatinib interruption [ n=2 , 14.3% ] ) .
second interventions were successful ( n=4 , 36.4% ) , failed ( n=6 , 54.5% ) , or not evaluable ( n=1 , 9.1% ) . of six patients whose second intervention failed , two patients ( 33.2% ) discontinued imatinib and a third intervention was administered in the remaining four patients : systemic steroids ( n=1 , 25.0% ) , imatinib dose reduction ( n=1 , 25.0% ) , or steroids imatinib dose reduction ( n=2 , 50.0% ) .
the third intervention was successful in two patients ( 50.0% ) and failed in the other two patients ( 50.0% ) .
one intervention for skin rash was administered in 29 patients ( 69.0% ) , two interventions in seven patients ( 16.7% ) , and three interventions in four patients ( 9.5% ) .
interventions were successful over the entire clinical course in 28 patients ( 66.8% ) who were able to maintain imatinib without permanent discontinuation due to skin rash with a dose of 800 mg / day ( n=1 ) , 400 mg / day ( n=19 ) , 300 mg / day ( n=5 ) , or 200 mg / day ( n=3 ) .
toxicity requiring medical treatment , which was possibly related to the administration of steroids as an intervention for skin rash consisted of hyperglycemia aggravation in patients with preexisting diabetes mellitus ( n=2 ) . of note , patients administered systemic steroids for rash tended to maintain a higher imatinib dose intensity than patients who did not ( median relative dose intensity at 6 months , 1.00 vs. 0.79 , respectively ; p=0.122 ) no association was observed between the outcomes of the first intervention and clinical factors ( e.g. , sex , age ) , and the nature of the interventions , including types of intervention ( e.g. , imatinib dose modification , systemic steroid use starting dose , duration of starting or tapering dose ) ( table 2 ) .
these factors were also not associated with the interventional outcomes of the overall clinical course ( data not shown ) . however , a significant association was observed between successful intervention and the blood eosinophil level at the time intervention was initiated . among 34 patients for whom the blood eosinophil level at the time of intervention was available ,
the first intervention was successful in 92.3% ( 12 of 13 ) of patients with eosinophils < 500/l , but was only successful in 47.6% ( 10 of 21 ) of patients with eosinophils 500/l ( p=0.011 ) ( table 2 ) .
in addition , the success rate was 93.8% ( 15 of 16 ) in patients with eosinophils < 1,000/l compared with 38.9% ( 7 of 18 ) in patients with 1,000/l ( p=0.001 ) .
the final success rates for the overall clinical course were 92.3% ( 12 of 13 ) in patients with eosinophils < 500/l vs. 60.9% ( 14 of 23 ) in patients with 500/l ( p=0.060 ) , and 93.8% ( 15 of 16 ) in patients with eosinophils < 1,000/l vs. 55.0% ( 11 of 20 ) in patients with 1,000/l ( p=0.022 ) .
lower eosinophil counts were observed in patients with successful interventions compared to patients whose treatments failed ; the median eosinophil count was 435/l vs. 2,095/l for the first intervention ( p=0.020 ) , and 616/l vs. 2,630/l for the overall clinical course ( p=0.014 ) ( fig .
2 ) . in addition , serial blood eosinophil levels during imatinib treatment showed association with the development of skin rash and its severity .
higher eosinophil levels in peripheral blood were significantly more likely to be shown in patients who developed imatinib - associated skin rash , particularly those with higher severity ( fig .
3 ) . to determine the influence of skin rash and interventions on imatinib treatment outcomes ,
pfs was compared among patients with unresectable or metastatic gist from three groups ( group 1 , skin rash requiring major intervention ; group 2 , skin rash not requiring major intervention ; group 3 , no skin rash ) .
there were no significant differences in the baseline characteristics between groups , including age , sex , site of the primary tumor and metastasis , tumor size , tumor mutational status in c - kit and pdgfra , and baseline laboratory values ( hemoglobin , granulocyte count , albumin , etc . )
the median follow - up period was 55.9 months ( range , 13.7 to 143.0 months ) for group 1 , 45.0 months ( range , 14.3 to 145.4 months ) for group 2 , and 52.0 months ( range , 14.3 to 80.8 months ) for group 3 .
group 1 tended to show a poorer pfs compared with groups 2 and 3 ( p=0.326 ) ( fig .
as expected , actual dose intensity was significantly lower in group 1 compared with the other two groups : median relative dose intensity at 6 months was 0.88 ( range , 0.61 to 1.00 ) for group 1 vs. 1.00 ( range , 0.50 to 1.00 ) for group 2 vs. 1.00 ( range , 0.78 to 1.00 ) for group 3 ( p=0.0002 ) .
of the 620 study patients treated with imatinib , 148 patients ( 23.9% ) developed skin rash during imatinib treatment with 42 patients ( 6.8% ) having a severe skin rash requiring major interventions .
imatinib was administered in the setting of neoadjuvant , adjuvant , and palliative treatment in eight patients ( 19.0% ) , 11 patients ( 26.2% ) , and 23 patients ( 54.8% ) , respectively .
the median time to development of severe skin rash requiring major interventions was 2.8 months ( range , 0.2 to 8.4 months ) .
two patients ( 4.8% ) had to permanently discontinue imatinib due to a grade 3 or 4 skin rash , respectively .
major interventions for skin rash were administered in the remaining 40 patients , including systemic steroids only ( n=17 , 40.5% ) , imatinib dose modification only ( dose reduction only [ n=6 , 14.3% ] , dose interruption only [ n=2 , 4.8% ] , dose reduction+ interruption [ n=6 , 14.3% ] ) , or the combined use of systemic steroids and imatinib dose modification ( steroids+dose reduction [ n=2 , 4.8% ] , steroids+interruption [ n=3 , 7.1% ] , steroids+dose reduction+interruption [ n=4 , 9.5% ] ) . the median dose and duration of initial steroid treatment before tapering were 20 mg / day prednisolone ( range , 5 to 60 mg / day ) and 7 days ( range , 4 to 28 days ) , respectively , then the treatment was tapered off with a median total duration of steroid of 28 days ( range , 7 to 204 days ) .
the first intervention was successful in 22 patients ( 55.0% ) , but it failed in 14 patients ( 35.0% ) .
four patients ( 10.0% ) who had discontinued imatinib early due to adverse events other than rash ( n=2 ) , disease progression ( n=1 ) , or gist resection ( n=1 ) could not be evaluated for interventional efficacy .
of 14 patients whose first intervention failed , three patients ( 21.4% ) discontinued imatinib due to uncontrolled severe rash and a second intervention was administered in the remaining 11 patients ( 78.6% ) ; only systemic steroids ( n=6 , 42.9% ) , imatinib dose modification ( n=2 , 14.3% ; dose reduction and interruption in each one ) , and systemic steroids+imatinib dose modification ( steroids+imatinib reduction [ n=1 , 7.1% ] , steroids+imatinib interruption [ n=2 , 14.3% ] ) .
second interventions were successful ( n=4 , 36.4% ) , failed ( n=6 , 54.5% ) , or not evaluable ( n=1 , 9.1% ) . of six patients whose second intervention failed ,
two patients ( 33.2% ) discontinued imatinib and a third intervention was administered in the remaining four patients : systemic steroids ( n=1 , 25.0% ) , imatinib dose reduction ( n=1 , 25.0% ) , or steroids imatinib dose reduction ( n=2 , 50.0% ) .
the third intervention was successful in two patients ( 50.0% ) and failed in the other two patients ( 50.0% ) .
one intervention for skin rash was administered in 29 patients ( 69.0% ) , two interventions in seven patients ( 16.7% ) , and three interventions in four patients ( 9.5% ) .
interventions were successful over the entire clinical course in 28 patients ( 66.8% ) who were able to maintain imatinib without permanent discontinuation due to skin rash with a dose of 800 mg / day ( n=1 ) , 400 mg / day ( n=19 ) , 300 mg / day ( n=5 ) , or 200 mg / day ( n=3 ) .
toxicity requiring medical treatment , which was possibly related to the administration of steroids as an intervention for skin rash consisted of hyperglycemia aggravation in patients with preexisting diabetes mellitus ( n=2 ) . of note , patients administered systemic steroids for rash tended to maintain a higher imatinib dose intensity than patients who did not ( median relative dose intensity at 6 months , 1.00 vs. 0.79 , respectively ; p=0.122 )
no association was observed between the outcomes of the first intervention and clinical factors ( e.g. , sex , age ) , and the nature of the interventions , including types of intervention ( e.g. , imatinib dose modification , systemic steroid use starting dose , duration of starting or tapering dose ) ( table 2 ) .
these factors were also not associated with the interventional outcomes of the overall clinical course ( data not shown ) . however , a significant association was observed between successful intervention and the blood eosinophil level at the time intervention was initiated . among 34 patients for whom the blood eosinophil level at the time of intervention was available , the first intervention was successful in 92.3% ( 12 of 13 ) of patients with eosinophils < 500/l , but was only successful in 47.6% ( 10 of 21 ) of patients with eosinophils 500/l ( p=0.011 ) ( table 2 ) .
in addition , the success rate was 93.8% ( 15 of 16 ) in patients with eosinophils < 1,000/l compared with 38.9% ( 7 of 18 ) in patients with 1,000/l ( p=0.001 ) .
the final success rates for the overall clinical course were 92.3% ( 12 of 13 ) in patients with eosinophils < 500/l vs. 60.9% ( 14 of 23 ) in patients with 500/l ( p=0.060 ) , and 93.8% ( 15 of 16 ) in patients with eosinophils < 1,000/l vs. 55.0% ( 11 of 20 ) in patients with 1,000/l ( p=0.022 ) .
lower eosinophil counts were observed in patients with successful interventions compared to patients whose treatments failed ; the median eosinophil count was 435/l vs. 2,095/l for the first intervention ( p=0.020 ) , and 616/l vs. 2,630/l for the overall clinical course ( p=0.014 ) ( fig .
2 ) . in addition , serial blood eosinophil levels during imatinib treatment showed association with the development of skin rash and its severity .
higher eosinophil levels in peripheral blood were significantly more likely to be shown in patients who developed imatinib - associated skin rash , particularly those with higher severity ( fig .
to determine the influence of skin rash and interventions on imatinib treatment outcomes , pfs was compared among patients with unresectable or metastatic gist from three groups ( group 1 , skin rash requiring major intervention ; group 2 , skin rash not requiring major intervention ; group 3 , no skin rash ) .
there were no significant differences in the baseline characteristics between groups , including age , sex , site of the primary tumor and metastasis , tumor size , tumor mutational status in c - kit and pdgfra , and baseline laboratory values ( hemoglobin , granulocyte count , albumin , etc . ) ( table 3 ) .
the median follow - up period was 55.9 months ( range , 13.7 to 143.0 months ) for group 1 , 45.0 months ( range , 14.3 to 145.4 months ) for group 2 , and 52.0 months ( range , 14.3 to 80.8 months ) for group 3 .
group 1 tended to show a poorer pfs compared with groups 2 and 3 ( p=0.326 ) ( fig .
as expected , actual dose intensity was significantly lower in group 1 compared with the other two groups : median relative dose intensity at 6 months was 0.88 ( range , 0.61 to 1.00 ) for group 1 vs. 1.00 ( range , 0.50 to 1.00 ) for group 2 vs. 1.00 ( range , 0.78 to 1.00 ) for group 3 ( p=0.0002 ) .
skin rash is a well - recognized side effect of imatinib ; however , insufficient evidence - based data are available for establishing treatment guidelines . in practice ,
antihistamines , topical lotions , and steroids are used in management of mild to moderate skin rash with imatinib , and for severe skin rash , the imatinib dose can be interrupted or reduced and short - term systemic steroids are frequently administered .
however , the effectiveness of these interventions for controlling severe skin rash is largely unknown , and the predictive factors for interventional outcomes remain unknown . in addition , given the critical role of imatinib dose intensity in long - term treatment outcomes and possible adverse impact of systemic steroid on antitumor immunity in patients with gist , further evaluations are needed to determine whether patients who receive these major interventions for severe skin rash show unfavorable clinical outcomes of imatinib . in the current study ,
the overall incidence of skin rash was 23.9% and 6.8% of patients developed grade 3/4 severe rash during imatinib treatment , which is consistent with previous studies [ 2 - 4 ] .
major interventions for severe skin rash , including dose interruption or reduction of imatinib , or systemic steroid were successful in 66.7% of patients who were able to continue imatinib without recurrence of severe skin rash .
most patients ( 89.3% , 25 of 28 ) were able to maintain 300 mg / day imatinib .
although study limitations , including the small number of patients and its retrospective design , preclude the determination of optimal interventions , we believe that the proper use of interventions enables the continued administration of imatinib in most patients who develop severe skin rash .
the continuation of therapeutic doses of imatinib has important implications regarding the efficacy of imatinib . along with clinical and genetic factors , including baseline hemoglobin and granulocyte counts , albumin level , sex , primary tumor site , tumor size , and c - kit and pdgfra mutational status , systemic exposure to imatinib reportedly influences clinical outcomes . in advanced gist patients , low plasma exposure ( plasma trough concentrations [ cmin ] <
1,100 ng / ml ) is associated with a worse objective benefit rate and time to progression , suggesting that low steady - state plasma imatinib levels might contribute to drug failure . because severe skin rash occurs very early in the imatinib treatment course , as reported here ( median , 2.8 months ) , reduction of imatinib dose due to severe rash may considerably decrease the overall dose intensity .
indeed , in advanced gist , patients with severe skin rash requiring major interventions showed lower imatinib dose intensity , and tended to show a poorer pfs than patients with rash not requiring major interventions or patients without skin rash . given
that patients administered systemic steroids for rash had higher imatinib dose intensity than patients who did not , further studies are required to determine whether more aggressive systemic steroids with an optimal dose and duration could minimize dose interruption or reduction of imatinib due to rash , and improve imatinib treatment outcomes .
the high prevalence and dose relationship suggest that skin rash may be related to the pharmacological effects of imatinibblockade of c - kit , which is normally present in the skin , rather than hypersensitivity .
however , the activation of immune mechanisms also seems to be involved in imatinib - associated skin rash .
the predominant infiltration of cd8 + t - lymphocytes and enhanced interleukin ( il)-18 and il-1 was reported in drug eruption caused by imatinib . of note , in our current analyses we found an association of the blood eosinophil level during imatinib treatment with skin rash , severity , and the outcomes of major interventions for severe rash .
eosinophils are important effector cells which promote tissue inflammation and induce tissue damage in a wide variety of disorders via the release of toxic granule proteins , lipid mediators , cytokines , and chemokines .
the increased number of eosinophils in patients with skin rash suggests that these cells may be involved in amplifying the underlying inflammatory and/or immune response in imatinib - induced rash .
because of the higher failure rate of interventions observed here , more aggressive interventions should be considered for patients with high levels of eosinophils at the time of severe rash .
in addition , monitoring eosinophil levels to direct interventions in terms of intensity and duration could be useful for reducing recurrence and the exacerbation of skin rash during or after interventions .
our current findings indicate that aggressive treatment of severe skin rash by dose interruption or reducing imatinib or systemic steroids can result in good clinical outcomes in terms of imatinib continuation in most gist patients .
there is now a need to establish a management strategy for skin rash including optimal steroid use for maintenance of imatinib dose intensity , and to validate the role of blood eosinophil levels in order to direct these treatments and ultimately achieve optimal clinical efficacy of imatinib .
Output:
| purposethis study evaluated the incidence of imatinib - associated skin rash , the interventional outcomes of severe rash , and impact of severe rash on the outcomes of imatinib treatment in gastrointestinal stromal tumor ( gist ) patients.materials and methodsa total of 620 patients were administered adjuvant or palliative imatinib for gist at asan medical center between january 2000 and july 2012 .
this analysis focused on a group of 42 patients who developed a severe rash requiring major interventions , defined as dose interruption or reduction of imatinib or systemic steroid use.resultsof the 620 patients treated with imatinib , 148 patients ( 23.9% ) developed an imatinib - associated skin rash ; 42 patients ( 6.8% ) developed a severe rash requiring major intervention .
of these , 28 patients ( 66.8% ) successfully continued imatinib with interventions .
serial blood eosinophil levels during imatinib treatment were associated with skin rash and severity .
a significant association was observed between successful intervention and blood eosinophil level at the time of intervention initiation . in metastatic settings ,
patients with severe rash requiring major interventions tended to show poorer progression - free survival than patients who did not require major intervention and patients with no rash , although this finding was not statistically significant ( p=0.326).conclusionby aggressive treatment of severe rash through modification of imatinib dose or use of systemic steroid , the majority of patients can continue on imatinib . in particular , imatinib dose intensity can be maintained with use of systemic steroid .
measuring the blood eosinophil levels may be helpful in guiding the management plan for skin rash regarding the intensity and duration of interventions . |
PubmedSumm118276 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: stroke medicine has developed dramatically in recent years with the emergence of new and effective treatment methods and increasing attention paid to implementation of clinical guidelines for treatment and rehabilitation of stroke patients.1,2 this development has led to the establishment of several stroke - specific registries , which are used for monitoring and improving the quality of stroke care and for research in a wide range of countries , eg , sweden , uk , germany , poland , austria , us , australia , china , and denmark.311 although the value of such registries is entirely dependent on the validity and completeness of data,12 few validation studies of stroke - specific registries have been conducted.13 in addition , studies that have directly compared the validity of the registration of patients in stroke - specific and hospital discharge registries are largely missing .
the aim of this study was to examine and compare the validity of the registration of acute stroke events leading to hospitalization in the danish stroke registry ( dsr ) and the danish national registry of patients ( dnrp ) .
the dsr was established in 2003 with the aim of documenting and improving the early treatment and care of acute stroke.11,14 it is mandatory for all 28 danish hospitals treating patients with acute stroke to report data on selected evidence - based performance measures , which are monitored by the dsr .
all patients aged 18 years or older who are admitted with an acute stroke to a danish hospital should be registered in the dsr .
data are reported to a central database after discharge of the patient , and detailed instructions on the reporting of data have been provided by the dsr in order to ensure the data validity and completeness ( case ascertainment ) of the database .
once a year , a structured audit is conducted where the completeness of the database is assessed ( ie , the number of persons in the database with stroke / the number of persons with stroke admitted to hospital ) .
acute stroke should be the primary condition in case the patient is admitted with multiple diagnoses .
data are prospectively collected using a standardized registration form in a multidisciplinary effort involving the entire staff of health professionals involved in the patients care , including physicians , nurses , physiotherapists , and occupational therapists .
the data are subsequently entered into a web - based database , usually by a nurse or a medical secretary .
the dnrp was established in 1977 as a national administrative registry containing data on all discharges from danish non - psychiatric hospitals .
reporting to the registry is mandatory and 99.4% of all discharges are registered therein.15 data include hospital and department codes , dates of admission and discharge , surgical procedures performed during the hospital stay , and up to 20 diagnosis codes at discharge , defined according to the international classification of diseases , 10th edition ( icd-10 ) since 1994.16 diagnosis codes are assigned at discharge by a physician involved in the care of the patient and reported to the registry by a medical secretary . in both the dsr and the dnrp ,
patients are identified by a unique civil registration number , which is assigned to all danish citizens at birth or at the time of immigration .
the aim of the first approach was to examine the validity of the registration of patients on a national level based on the assumption that all hospitalized patients diagnosed with an acute stroke in 2009 would most likely be registered in the dsr , dnrp , or both . for this purpose
, we identified 25 patients who were only registered in the dsr , 25 patients who were only registered in the dnrp , and 25 patients who were registered in both data sources .
the sample sizes were not based on a formal power analysis , but pragmatically determined based on a priori estimation of the expected precision associated with different sample sizes .
the patients were randomly identified in the data sources using a computer algorithm which specified that patients should be at least 18 years old , inpatients diagnosed at a danish hospital with an acute stroke as the primary diagnosis ( icd-10 codes i61 , intracerebral hemorrhage ; i63 , cerebral infarction ; and i64 , unspecified stroke ) , and discharged in the period january 1 , 2009 to december 31 , 2009 . the aim of the second approach was to examine the validity of the registration of patients on a local level , based on four major neurologic wards that had agreed to participate in a more comprehensive study on the feasibility of extending the use of administrative data for quality improvement activities .
these four wards were all characterized by a high volume of patients with stroke ( approximately 350950 patients with stroke / year ) and extensive experience with diagnostics and treatment of stroke .
we reviewed the medical summaries for all patients discharged from the four participating neurologic wards in the period january 4 , 2010 to january 10 , 2010 , focusing on patients with a potential stroke diagnosis , including patients registered with discharge diagnoses of cerebrovascular disease ( i60i69 ) , inflammatory diseases of the central nervous system ( g00g09 ) , episodic and paroxysmal disorders ( g40g47 ) , hemiplegia / paraplegia and tetraplegia / other paralytic syndromes ( g81g83 ) , symptoms and signs involving the nervous and musculoskeletal systems ( r25r29 ) , head injuries ( s062s069 ) , and care involving use of rehabilitation procedures ( z501 ) .
this initial sorting of medical summaries was performed in order to focus efforts most effectively on the potentially stroke - related medical records .
if the medical summary indicated that the patient had potentially been admitted to hospital due to stroke , we obtained the medical record in order to verify the stroke diagnosis . in all
the medical records , including descriptions of diagnostic imaging procedures ( magnetic resonance imaging [ mri ] and/or computed tomography [ ct ] scans ) , were retrieved .
all information was reviewed by a physician ( spj ) , and in the event of an uncertain diagnosis , the case was assessed independently by two consultants in neurology ( hki and kv ) , who made a final decision by consensus .
we defined stroke in accordance with the criteria proposed by the world health organization , ie , a condition with a presumed vascular etiology leading to a rapid progression of symptoms of loss of neurologic function lasting > 24 hours or causing death.17 although fulfilling the world health organization criteria , we excluded patients with subarachnoid hemorrhage because these patients are not included in the dsr .
patients with subdural hematoma or epidural hemorrhage , retinal infarct or infarct caused by trauma , infection , or an intracranial malignant process , as well as asymptomatic patients with infarct detected only by ct or mri scan were not confirmed as stroke cases in our study .
similarly , patients with purely diffuse symptoms ( eg , isolated vertigo or headache ) did not fulfill the diagnostic criteria .
a diagnosis of intracerebral hemorrhage was considered confirmed in the presence of clinical symptoms of stroke combined with verification of hemorrhage by ct or mri scan and the absence of evidence of a previous stroke in the same area .
a diagnosis of ischemic infarction was confirmed in the presence of clinical symptoms of stroke with no visualization of hemorrhage by ct or mri scan .
brain imaging is not required according to the world health organization definition ; however , all potential patients in our study did have a ct and/or mri scan .
we excluded one record ( 1.3% ) due to a missing civil registration number ( dsr sample ) and two records ( 2.7% ) because the available data did not allow a meaningful validation ( joint sample ) , leaving 72 medical records available for data analysis .
in the second approach , medical summaries for patients discharged from the participating neurologic wards in the study period were retrieved and reviewed ( by cw and spj ) . on suspected diagnosis of stroke or insufficient information in the summary
, we retrieved the medical record and descriptions of diagnostic imaging procedures , and reviewed the material in accordance with the same diagnostic criteria used in the first part of the study ( spj ) .
any uncertain diagnoses were settled by the two consultants in neurology . for two patients ( 1.3% )
there were no medical records available to confirm a suspected diagnosis of stroke , and two patients ( 1.3% ) did not have a civil registration number , leaving 156 medical summaries for data analysis .
permission to conduct the study was obtained from the danish data protection agency ( journal number 2007 - 58 - 0016 ) and the national board of health ( journal number 7 - 604 - 04 - 67/1/ehe ) . in the first approach of the study , we assessed the sensitivity and positive predictive value of the registered diagnosis of stroke in the dsr and the dnrp , respectively , using the medical record as the gold standard .
we calculated the positive predictive value of stroke in each sample and then , referring to the total number of patients registered with a diagnosis of stroke in the dsr , the dnrp , or in both data sources in 2009 , we extrapolated the positive predictive value to the number of patients with stroke on a national level in 2009 in each registry . using this approach
, we were able to estimate the number of verified patients with stroke , and the total number of patients with stroke by gold standard and registry .
the sensitivity of the diagnosis of stroke was calculated as the number of patients with a verified diagnosis registered in either the dsr or dnrp divided by the total number of patients with a verified diagnosis of stroke .
the positive predictive value was calculated as the number of patients with a verified diagnosis registered in either the dsr or dnrp divided by the total number of patients registered with a diagnosis of stroke in either the dsr or dnrp .
given that the basis of this approach was the assumption that all relevant patients would be registered in either or both of the registries , we were not able to estimate the specificity or the negative predictive value .
since it is complex and debatable how best to estimate the 95% confidence intervals ( cis ) accurately when extrapolating to the total stroke population , we did not estimate 95% cis when extrapolating .
instead , we examined the robustness of our findings by performing additional analyses ( best and worst case scenarios ) using the 95% cis from the positive predictive values of the samples presented above .
the best case scenario reflected the highest possible extrapolated sensitivity and positive predictive value , whereas the worst case scenario represented the opposite .
the data analyses in the first approach are described in further detail in the appendix . in the second approach
, we assessed the sensitivity , specificity , positive predictive value , and negative predictive value of the registered diagnosis of stroke in the dsr and the dnrp , using the medical record as the gold standard . according to the guidelines of the dsr
, a patient should not be registered as discharged if he or she is transferred to another hospital ward for further treatment . because patients are often transferred to other wards from the neurologic ward ,
the registered date of discharge in the dsr is not necessarily in agreement with the date of discharge from the neurologic ward .
we therefore identified patients registered in the dsr with a date of discharge that was within 30 days of our study period . given that we included patients according to whether they were discharged in the study period , both long - term and shorter - term hospitalizations were represented
the specificity was calculated as the number of patients verified not to have had a stroke divided by the total number of patients without a stroke according to their medical record .
the negative predictive value was calculated as the number of patients verified not to have had a stroke divided by the total number of patients not registered in the dsr or dnrp with a diagnosis of stroke .
the data were analyzed using sas software version 9.2 ( sas institute , cary , nc , usa ) .
the dsr was established in 2003 with the aim of documenting and improving the early treatment and care of acute stroke.11,14 it is mandatory for all 28 danish hospitals treating patients with acute stroke to report data on selected evidence - based performance measures , which are monitored by the dsr .
all patients aged 18 years or older who are admitted with an acute stroke to a danish hospital should be registered in the dsr .
data are reported to a central database after discharge of the patient , and detailed instructions on the reporting of data have been provided by the dsr in order to ensure the data validity and completeness ( case ascertainment ) of the database .
once a year , a structured audit is conducted where the completeness of the database is assessed ( ie , the number of persons in the database with stroke / the number of persons with stroke admitted to hospital ) .
acute stroke should be the primary condition in case the patient is admitted with multiple diagnoses .
data are prospectively collected using a standardized registration form in a multidisciplinary effort involving the entire staff of health professionals involved in the patients care , including physicians , nurses , physiotherapists , and occupational therapists .
the data are subsequently entered into a web - based database , usually by a nurse or a medical secretary .
the dnrp was established in 1977 as a national administrative registry containing data on all discharges from danish non - psychiatric hospitals .
reporting to the registry is mandatory and 99.4% of all discharges are registered therein.15 data include hospital and department codes , dates of admission and discharge , surgical procedures performed during the hospital stay , and up to 20 diagnosis codes at discharge , defined according to the international classification of diseases , 10th edition ( icd-10 ) since 1994.16 diagnosis codes are assigned at discharge by a physician involved in the care of the patient and reported to the registry by a medical secretary . in both the dsr and the dnrp ,
patients are identified by a unique civil registration number , which is assigned to all danish citizens at birth or at the time of immigration .
the aim of the first approach was to examine the validity of the registration of patients on a national level based on the assumption that all hospitalized patients diagnosed with an acute stroke in 2009 would most likely be registered in the dsr , dnrp , or both . for this purpose
, we identified 25 patients who were only registered in the dsr , 25 patients who were only registered in the dnrp , and 25 patients who were registered in both data sources .
the sample sizes were not based on a formal power analysis , but pragmatically determined based on a priori estimation of the expected precision associated with different sample sizes .
the patients were randomly identified in the data sources using a computer algorithm which specified that patients should be at least 18 years old , inpatients diagnosed at a danish hospital with an acute stroke as the primary diagnosis ( icd-10 codes i61 , intracerebral hemorrhage ; i63 , cerebral infarction ; and i64 , unspecified stroke ) , and discharged in the period january 1 , 2009 to december 31 , 2009 . the aim of the second approach was to examine the validity of the registration of patients on a local level , based on four major neurologic wards that had agreed to participate in a more comprehensive study on the feasibility of extending the use of administrative data for quality improvement activities .
these four wards were all characterized by a high volume of patients with stroke ( approximately 350950 patients with stroke / year ) and extensive experience with diagnostics and treatment of stroke .
we reviewed the medical summaries for all patients discharged from the four participating neurologic wards in the period january 4 , 2010 to january 10 , 2010 , focusing on patients with a potential stroke diagnosis , including patients registered with discharge diagnoses of cerebrovascular disease ( i60i69 ) , inflammatory diseases of the central nervous system ( g00g09 ) , episodic and paroxysmal disorders ( g40g47 ) , hemiplegia / paraplegia and tetraplegia / other paralytic syndromes ( g81g83 ) , symptoms and signs involving the nervous and musculoskeletal systems ( r25r29 ) , head injuries ( s062s069 ) , and care involving use of rehabilitation procedures ( z501 ) .
this initial sorting of medical summaries was performed in order to focus efforts most effectively on the potentially stroke - related medical records .
if the medical summary indicated that the patient had potentially been admitted to hospital due to stroke , we obtained the medical record in order to verify the stroke diagnosis . in all
in the first approach , the medical records , including descriptions of diagnostic imaging procedures ( magnetic resonance imaging [ mri ] and/or computed tomography [ ct ] scans ) , were retrieved .
all information was reviewed by a physician ( spj ) , and in the event of an uncertain diagnosis , the case was assessed independently by two consultants in neurology ( hki and kv ) , who made a final decision by consensus .
we defined stroke in accordance with the criteria proposed by the world health organization , ie , a condition with a presumed vascular etiology leading to a rapid progression of symptoms of loss of neurologic function lasting > 24 hours or causing death.17 although fulfilling the world health organization criteria , we excluded patients with subarachnoid hemorrhage because these patients are not included in the dsr .
patients with subdural hematoma or epidural hemorrhage , retinal infarct or infarct caused by trauma , infection , or an intracranial malignant process , as well as asymptomatic patients with infarct detected only by ct or mri scan were not confirmed as stroke cases in our study .
similarly , patients with purely diffuse symptoms ( eg , isolated vertigo or headache ) did not fulfill the diagnostic criteria .
a diagnosis of intracerebral hemorrhage was considered confirmed in the presence of clinical symptoms of stroke combined with verification of hemorrhage by ct or mri scan and the absence of evidence of a previous stroke in the same area .
a diagnosis of ischemic infarction was confirmed in the presence of clinical symptoms of stroke with no visualization of hemorrhage by ct or mri scan .
brain imaging is not required according to the world health organization definition ; however , all potential patients in our study did have a ct and/or mri scan .
we excluded one record ( 1.3% ) due to a missing civil registration number ( dsr sample ) and two records ( 2.7% ) because the available data did not allow a meaningful validation ( joint sample ) , leaving 72 medical records available for data analysis .
in the second approach , medical summaries for patients discharged from the participating neurologic wards in the study period were retrieved and reviewed ( by cw and spj ) . on suspected diagnosis of stroke or insufficient information in the summary
, we retrieved the medical record and descriptions of diagnostic imaging procedures , and reviewed the material in accordance with the same diagnostic criteria used in the first part of the study ( spj ) .
any uncertain diagnoses were settled by the two consultants in neurology . for two patients ( 1.3% )
there were no medical records available to confirm a suspected diagnosis of stroke , and two patients ( 1.3% ) did not have a civil registration number , leaving 156 medical summaries for data analysis .
permission to conduct the study was obtained from the danish data protection agency ( journal number 2007 - 58 - 0016 ) and the national board of health ( journal number 7 - 604 - 04 - 67/1/ehe ) .
in the first approach of the study , we assessed the sensitivity and positive predictive value of the registered diagnosis of stroke in the dsr and the dnrp , respectively , using the medical record as the gold standard .
we calculated the positive predictive value of stroke in each sample and then , referring to the total number of patients registered with a diagnosis of stroke in the dsr , the dnrp , or in both data sources in 2009 , we extrapolated the positive predictive value to the number of patients with stroke on a national level in 2009 in each registry . using this approach
, we were able to estimate the number of verified patients with stroke , and the total number of patients with stroke by gold standard and registry .
the sensitivity of the diagnosis of stroke was calculated as the number of patients with a verified diagnosis registered in either the dsr or dnrp divided by the total number of patients with a verified diagnosis of stroke .
the positive predictive value was calculated as the number of patients with a verified diagnosis registered in either the dsr or dnrp divided by the total number of patients registered with a diagnosis of stroke in either the dsr or dnrp .
given that the basis of this approach was the assumption that all relevant patients would be registered in either or both of the registries , we were not able to estimate the specificity or the negative predictive value . since it is complex and debatable how best to estimate the 95% confidence intervals ( cis ) accurately when extrapolating to the total stroke population , we did not estimate 95% cis when extrapolating .
instead , we examined the robustness of our findings by performing additional analyses ( best and worst case scenarios ) using the 95% cis from the positive predictive values of the samples presented above .
the best case scenario reflected the highest possible extrapolated sensitivity and positive predictive value , whereas the worst case scenario represented the opposite .
the data analyses in the first approach are described in further detail in the appendix . in the second approach
, we assessed the sensitivity , specificity , positive predictive value , and negative predictive value of the registered diagnosis of stroke in the dsr and the dnrp , using the medical record as the gold standard . according to the guidelines of the dsr
, a patient should not be registered as discharged if he or she is transferred to another hospital ward for further treatment . because patients are often transferred to other wards from the neurologic ward ,
the registered date of discharge in the dsr is not necessarily in agreement with the date of discharge from the neurologic ward .
we therefore identified patients registered in the dsr with a date of discharge that was within 30 days of our study period . given that we included patients according to whether they were discharged in the study period , both long - term and shorter - term hospitalizations were represented . the sensitivity and positive predictive value
the specificity was calculated as the number of patients verified not to have had a stroke divided by the total number of patients without a stroke according to their medical record .
the negative predictive value was calculated as the number of patients verified not to have had a stroke divided by the total number of patients not registered in the dsr or dnrp with a diagnosis of stroke .
the data were analyzed using sas software version 9.2 ( sas institute , cary , nc , usa ) .
in our sample of 72 patients registered in the dsr , dnrp , or both registries with a diagnosis of stroke in 2009 , we were able to verify the diagnosis for 47 patients .
twenty - five patients had not had a stroke as defined by the inclusion criteria for the dsr , of whom the majority were patients with old non - acute strokes and patients with transient ischemic attacks , whereas the rest were admitted with non - stroke related conditions ( including unspecified dizziness , migraine , and meningitis ) ; 20 of these unconfirmed patients originated from the dnrp sample , three from the dsr sample , and two from the joint sample . on the basis of these three samples , the positive predictive value in the dsr was calculated as 21/24=88% ( 95% ci 69%96% ) , in the dnrp as 5/25=20% ( 95% ci 9%39% ) , and in both registries as 21/23=91% ( 95% ci 73%98% ) . when extrapolating the positive predictive value to the number of patients with stroke on a national level in 2009 , we referred to the total number of patients registered with stroke in one or both of the registries in 2009 ( figure 1 and appendix ) .
we thus estimated the number of patients with true stroke to be 0.88 2,429=2,138 ( 95% ci 1,6762,332 ) in the dsr , 0.20 1,722=344 ( 95% ci 155672 ) in the dnrp , and 0.91 8,278=7,533 ( 95% ci 6,0438,112 ) in both registries ( figure 2 ) .
table 1 shows that based on these samples , the validity of the registration of patients was higher in the dsr than in the dnrp .
the sensitivity of the dsr was 97% in contrast to a sensitivity of 79% for the dnrp when using the entire population included in the dsr and dnrp .
the positive predictive value of the dsr was 90% compared with 79% in the dnrp .
based on the 95% cis obtained from the samples of patients included in the medical record review , worst and best case scenarios were assessed .
these supplementary analyses showed that the sensitivity of the dsr could in fact be as low as 92% and as high as 99% , whereas the positive predictive value could be as low as 72% and as high as 98% .
for the dnrp , the sensitivity could be as low as 73% and as high as 84% , whereas the positive predictive value could vary from 62% to 88% .
of the 156 medical summaries that were reviewed using the second approach , we identified 74 cases of acute stroke .
table 2 shows that based on data from the second approach , the difference in sensitivity between the two registries was even greater , ie , 91% ( 95% ci 81%96% ) in the dsr and 58% ( 95% ci 46%69% ) in the dnrp .
the negative predictive value was 91% ( 95% ci 83%96% ) in the dsr compared with 72% ( 95% ci 62%80% ) in the dnrp .
however , the specificity and positive predictive value did not appear to differ between the registries .
using two different approaches in this study , we found that the sensitivity appeared to be higher in the dsr than in the dnrp , while the positive predictive value was comparable in the two registries .
the study has some important methodologic strengths and limitations . using two alternative approaches to assess the validity of the registration of hospitalized patients
, we aimed to both ensure results that were representative for the entire country ( approach 1 ) and findings that were based on a thorough assessment of all of the hospitalized potential stroke cases , including patients who had not been captured by any of the registries ( approach 2 ) .
the study design allowed for an estimation of the negative predictive value as well as sensitivity and specificity , which is otherwise rarely assessed in validation studies due to lack of access to an independent reference data source.18 further , the medical records were reviewed by a physician , with independent reviews of all difficult cases by two consultants in neurology . only a negligible number of medical records could not be found or were excluded due to insufficient information .
it appeared from our review of medical records in approach 2 that 82 of 156 admissions to the four neurologic wards were not due to an acute stroke .
other diagnoses included transient ischemic attack , sequelae of stroke , subdural hematoma , and intracerebral tumors , implying that patients admitted to these wards did have neurologic symptoms potentially indicating a stroke , which warranted their admission to a neurologic ward
. the limitations of the approaches used in our study should , however , be noted . in approach 1 ,
we relied on the assumption that all hospitalized patients with acute stroke would be registered in the dsr and/or the dnrp , although it is evident that there will be exemptions .
hospitalized patients not registered with an acute stroke may include surgical patients with minor stroke or patients admitted with other serious underlying conditions such as cancer or hematologic illness , or they may be inadequately diagnosed and thus misclassified by the hospital ward where they were initially admitted .
further , the number of patients / records involved in approach 1 was relatively small , precluding us from making otherwise relevant subanalyses ( eg , according to type of stroke or patient age ) .
these wards were characterized by a high patient volume and had agreed to take active part in a larger project .
however , the overall high agreement between findings from the two approaches indicates that these limitations did not have any major impact on the study findings .
our data indicated a higher sensitivity in the dsr than in the dnrp , in addition to a slightly higher positive predictive value in the dsr .
this may , in part , be attributed to different ways of collecting and reporting data on acute stroke events to the two registries ; for the dsr , data collection and reporting relies on a standardized registration form prospectively filled out by the health professionals responsible for the treatment and care of the patient .
the collection of data is a multidisciplinary effort with multiple staff members , including physicians , nurses , physiotherapists , and occupational therapists , being involved with each patient and a detailed , large dataset is recorded for each patient . in addition ,
yearly audit reports are published by the dsr based on the performance of the individual wards , and these may enhance the commitment of the staff involved to ensure the validity of data reported to the dsr . in contrast , for the dnrp , only a physician is involved in coding of the diagnosis .
the physician has typically been involved in the treatment of the patient , but does not necessarily have detailed knowledge about the entire admission or disease history .
further , detailed instructions on the coding of diagnoses in the dnrp are not available , and the coding of diagnosis may potentially be influenced by economic incentives due to use of the diagnosis - related group system .
finally , the staff receive no direct feedback on the reported data , which may negatively influence the interest and sense of ownership of the data .
generally , previous studies are characterized by use of different gold standards in the assessment of the validity of registries , different definitions of relevant diagnosis codes to validate as well as varying use of diagnostic procedures ( such as ct or mri scans ) , all of which complicate direct comparisons of existing results .
however , several studies have reported a high positive predictive value of stroke in hospital discharge registries,1828 and a few studies have reported moderate positive predictive value.13,2932 fewer studies have examined the sensitivity of discharge registries ; a sensitivity of 76%82% was reported from an italian hospital discharge register,25 whereas a sensitivity of 88%93% was found in swedish and norwegian hospital discharge registers,13,28,31,33 85%97% in a finnish hospital discharge register,26,27 and 76% in an american hospital discharge register.32 to our knowledge , only one study has investigated the validity of patient registration in a stroke - specific registry ; using an estimated true number of stroke cases in the population as the gold standard , stegmayr and asplund reported a sensitivity of 96% and a positive predictive value of 100% in the northern sweden monica ( multinational monitoring of trends and determinants in cardiovascular disease ) registry compared with values of 93% and 68% , respectively , in hospital discharge registers.13 these results are in accordance with our findings , although the positive predictive value of the monica registry was slightly higher than that of the dsr ; this may be partly due to exclusion of patients over 74 years of age in the swedish study , for whom diagnosing of stroke may be less accurate .
this suggests that a greater validity of stroke - specific registries may also apply to registries in other countries . however , further studies are needed to confirm this assumption .
we recommend that further efforts are needed if dnrp is to be used for monitoring of stroke epidemiology and stroke care .
such efforts should probably both involve further refinement of the algorithms used for identifying stroke events in the dnrp ( eg , in line with recent experiences from sweden)28 and improvements in the registration practice with the registration of data becoming a more integrated part of the work flow during clinical work combined with more emphasis on training and instructions to staff involved in the coding of diagnoses to the dnrp .
the dsr currently appears to have better data validity than the dnrp and appears to be a useful data source , but continued attention is required in order to improve the positive predictive value further .
however , further efforts are warranted to improve the validity of the dnrp and precautions should be taken if using the registry for administrative , quality improvement , and research purposes .
in approach 1 , we sampled the patients / records to be reviewed not simply randomly among all patients in the registries ; rather , we randomly selected 25 patients who were registered in the dsr alone , 25 patients registered in the dnrp alone , and 25 patients registered in both data sources .
table 1 presents the distribution of the random samples according to whether the acute stroke diagnosis could be confirmed by medical record review .
based on these data , the ppv of an acute stroke diagnosis could be computed in the dsr only , the dnrp only , and the dsr + dnrp , respectively .
ppv among patients only registered in the dsr : 21/24=0.88 ( 95% ci 0.690.96 ) .
ppv among patients only registered in the dnrp : 5/25=0.20 ( 95% ci 0.090.39 ) .
ppv among patients registered in both the dsr and dnrp : 21/23=0.91 ( 95% ci 0.730.98 ) .
extrapolations based on the ppvs were made using the total number of patients registered with acute stroke in the different data sources in 2009 : 2,429 patients were only registered in the dsr .
it is complex to estimate the 95% cis accurately when extrapolating to the total stroke population ; however , it is possible to do sensitivity analyses using the 95% cis from the ppvs of the samples presented above .
best case scenario reflects the highest possible extrapolated sensitivity and ppv , whereas
an example : keeping in mind that in approach 1 , we assume that all stroke patients are registered in the dsr and/or the dnrp , the best case scenario for dsr will be a situation where the true ppvs from the random samples were equal to the upper limit of the 95% cis for registration only in the dsr , and for registration both in the dsr and the dnrp , whereas the ppv for registration only in the dnrp was equal to the lower limit of the estimated 95% ci .
true acute stroke among patients registered in both the dsr and dnrp : 0.91 * 8,278=7,533 .
the validity of the acute stroke diagnosis in the dsr ( table 2 ) and the dnrp ( table 3 ) were estimated .
distribution of random samples of acute stroke diagnoses according to data source and medical record review one patient was excluded due to lack of a civil registration number two patients were excluded due to lack of diagnostic information in the medical records .
distribution of patients registered with acute stroke according to the danish stroke registry and medical record review notes : sensitivity : 9,671/10,015=96.6% ; worst case scenario : 7,719/8,391=92.0% ; best case scenario : 10,444/10,599=98.5% .
positive predictive value : 9,671/10,707=90.3% ; worst case scenario : 7,719/10,707=72.1% ; best case scenario : 10,444/10,707=97.5% .
distribution of patients registered with acute stroke according to the danish national registry of patients and medical record review notes : sensitivity : 7,877/10,015=78.7% ; worst case scenario : 6,198/8,530=72.7% ; best case scenario : 8,784/10,460=84.0% .
positive predictive value : 7,877/10,000=78.8% ; worst case scenario : 6,198/10,000=62.0% ; best case scenario : 8,784/10,000=87.8% .
Output:
| backgroundthe validity of the registration of patients in stroke - specific registries has seldom been investigated , nor compared with administrative hospital discharge registries .
the objective of this study was to examine the validity of the registration of patients in a stroke - specific registry ( the danish stroke registry [ dsr ] ) and a hospital discharge registry ( the danish national patient registry [ dnrp]).methodsassuming that all patients with stroke were registered in either the dsr , dnrp or both , we first identified a sample of 75 patients registered with stroke in 2009 ; 25 patients in the dsr , 25 patients in the dnrp , and 25 patients registered in both data sources . using the medical record as a gold standard , we then estimated the sensitivity and positive predictive value of a stroke diagnosis in the dsr and the dnrp .
secondly , we reviewed 160 medical records for all potential stroke patients discharged from four major neurologic wards within a 7-day period in 2010 , and estimated the sensitivity , specificity , positive predictive value , and negative predictive value of the dsr and the dnrp.resultsusing the first approach , we found a sensitivity of 97% ( worst / best case scenario 92%99% ) in the dsr and 79% ( worst / best case scenario 73%84% ) in the dnrp .
the positive predictive value was 90% ( worst / best case scenario 72%98% ) in the dsr and 79% ( worst / best case scenario 62%88% ) in the dnrp . using the second approach
, we found a sensitivity of 91% ( 95% confidence interval [ ci ] 81%96% ) and 58% ( 95% ci 46%69% ) in the dsr and dnrp , respectively .
the negative predictive value was 91% ( 95% ci 83%96% ) in the dsr and 72% ( 95% ci 62%80% ) in the dnrp .
the specificity and positive predictive value did not differ among the registries.conclusionour data suggest a higher sensitivity in the dsr than the dnrp for acute stroke diagnoses , whereas the positive predictive value was comparable in the two data sources . |
PubmedSumm118277 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: untargeted metabolomics aims to describe living systems by the set of metabolites present in a cell at certain moment of time and under specific environmental constraints ( fiehn 2002 ; dettmer et al .
2007 ; oldiges et al . 2007 ) . since metabolites are the final link between the gene expression and the phenotype exhibited by the cell , metabolomics represents a valuable tool to achieve a better understanding of an organism s phenotype ( fiehn 2002 ; oldiges et al .
the study of the metabolome is complementary to the other omics sciences ( genomics , transcriptomics , proteomics , fluxomics ) and fits well with the general approach of systems biology ( arita 2009 ) .
important advances have been realized in the past years for untargeted metabolite profiling in different research fields , from human health to nutrition ( scalbert et al .
however , metabolomics is still an emerging field in the post - genomic arena . for example , due to the chemical diversity of cellular metabolites and the complexity of the cell extracts , there is no single method which can separate , detect and identify all small molecules present in a cell extract .
furthermore the achilles heel of metabolomics remains the identification and structure elucidation of metabolites ( kind and fiehn 2010 ) .
sometimes , fragmentation patterns of the molecules can be used for identification . for metabolomics data the detected fragment patterns
can , e.g. , be matched to online databases , like metlin ( smith et al . 2005 ) , and assigned to a quality score .
but in our experiments we have however observed that the scan time of the ltq - orbitrap is considerably affected by the inclusion of fragmentation steps , making the normal lc - ms data stream fragmentary and difficult to analyze automatically . as more convenient alternative , the orbitrap exactive platform ( without the linear iontrap but with faster scan speeds )
can be used to capture more data points using the positive negative polarity switch mode ( lu et al .
thus , currently matching on mass alone to databases is the most commonly used method .
unfortunately , this approach to metabolite identification is very seriously hampered by the fact that the vast majority of the signals in the data set can be caused by contaminants in the sample or lc - ms system ( keller et al .
( scheltema et al . 2009 ) . in many cases , several peaks or signals
share the same identifications , even if signals are detected with an accuracy of better than 2 ppm , as is routinely possible using , e.g. , modern fourier transform mass spectrometers , like the orbitrap ( scheltema et al .
such spurious peaks need to be checked manually and assigned to their real identification or discarded if the signal shows typical artefacts .
our goal was to develop an analytical method that would be able to eliminate a substantial part of the spurious signals from the data set .
this required the development of new approaches and the collection of an unusual type of data on biological samples and mixtures of analytical standards , to distinguish real effects from spurious fluctuations in lc - ms analyses and peak detection algorithms .
amino acids and related compounds are contained at a final concentration of 0.5 mol / ml 4% in 0.2 n lithium citrate buffer , ph 2.20 , containing thiodiglycol ( 2% w / v ) and phenol ( 0.1% w / v ) as antioxidant and preservative , respectively . the concentration in the injected diluted samples is described in table 1.table 1dilution factor and concentrations of the analysed samplesdilution factor1/81/161/321/641/1281/2561/5121/1024concentration ( mol / ml)0.06250.03130.01560.00780.00390.00200.00100.0005injected on column ( pmol)312.5000156.250078.125039.062519.53139.76564.88282.4414 dilution factor and concentrations of the analysed samples analytical samples were obtained from streptomyces coelicolor wild - type m145 strain ( bentley et al .
bacteria were grown in 50 ml liquid minimum medium ( nieselt et al . 2010 ) as described ( takano et al .
cells from 25 ml of culture were collected on a 0.45 m filter by vacuum filtration and washed twice with 25 ml of 2.63% nacl solution . for cell quenching ,
the filter with the collected cells was quickly moved into 60% methanol solution ( hplc - grade , boom , the netherlands ) pre - chilled at 20c and frozen in liquid nitrogen .
cells were thawed in an ethanol bath at 20c ( ~15 min ) , vortexed vigorously for 1 min and , right afterwards , frozen in liquid nitrogen for 5 min .
after the third cycle , the samples were centrifuged at 4500 rpm for 10 min at 9c .
the supernatant ( cell extract ) was collected and stored at 80c until lc - ms analysis . before analysis ,
obtained samples were diluted with the same dilution factor as for the analytical standards mixture , resulting in eight samples with different metabolite concentrations .
the analytical mixtures and cell extracts were analyzed by liquid chromatography coupled to a high - accuracy ltq orbitrap xl mass spectrometer ( thermo fisher scientific , germany ) .
two chromatographic columns were used : a reversed - phase shim - pack xr - ods c18 column ( achrom , belgium ) ( 3.0 75 mm , 2.2 m , shimadzu corp . ) and a zic - hilic column ( achrom , belgium ) ( 150 2.1 mm , 3.5 m , merck sequant ab ) fitted with a zic - hilic peek guard column ( achrom , belgium ) ( 15 1.0 mm ; 5 m , merck sequant ab ) .
for the c18 column , the flow rate was set to 0.6 ml / min ; the mobile phase consisted of ( a ) 0.1% formic acid in water and
the elution of solvent b started at 2% for the first 2 min and was increased to 95% within 8 min .
this composition was maintained for 2 min , after which the elution of b was decreased to 2% within 1 min .
to re - equilibrate the system , the elution of b was held at 2% for 5 min . for the zic - hilic column ,
the flow rate was set to 0.1 ml / min ; as buffers , ( a ) 0.1% formic acid in acetonitrile and ( b ) 0.1% formic acid in water were used .
the elution fraction of solvent b was increased to 40% within 6 min and maintained at 40% for 12 min , after which solvent b was increased to 90% in a 4 min - interval .
this composition was held for 2 min after which b was decreased to 20% in 2.5 min .
the gradient was held at 20% b for 13.5 min to re - equilibrate the system .
the sample volume injected was 5 l for both columns , and two technical replicates were recorded for the c18 analysis , and three replicates on the hilic column .
full - scan spectra were obtained over an m / z range of 501000 da .
ulc grade acetonitrile , formic acid and water were purchased at biosolve ( netherlands ) .
raw data files from the mass spectrometer were converted into the mzxml format by the readw.exe utility ( a tool of the trans - proteomic pipeline software collection , downloaded from http://tools.proteomecenter.org/wiki/index.php?title=software:readw ) .
the centwave ( tautenhahn et al.2008 ) feature detection algorithm from the xcms ( smith et al.2006 ) package was used on each individual data file .
further processing was handled by the flexible data processing pipeline mzmatch ( scheltema et al .
2011 ) , performing noise removal ( windig 2004 ) and several steps of signal filtering and peak matching . the first matching step involved aligning of the chromatographic features between technical replicates of a single sample .
peaks that were not detected in all technical replicates were discarded from further analysis . in the second matching step , the chromatographic peaks , which were combined in single files containing technical replicates in the previous matching step , were aligned to each other for all eight dilutions . after combining the eight measurements in a single file , there were still peak sets that did not include peaks from every sample .
such gaps were filled by extracting ion chromatograms within the retention time and mass window of the given peak set directly from the raw data files .
derivative signals ( isotopes , adducts , dimers and fragments ) were automatically annotated by correlation analysis on both signal shape and intensity pattern , as described ( scheltema et al .
these peaks were not discarded and their assigned annotations were taken into account in the subsequent analysis .
putative identifications were made by matching the detected masses to a database of streptomyces coelicolor ( scocyc ) metabolites , a contaminants database ( keller et al . 2008 ) , and the list of analytical standards in the standard mixture .
the metabolite database was obtained from a genome annotation file created by jonathan moore as part of the sysmo stream project ( https://www.wsbc.warwick.ac.uk/groups/sysmopublic/ ) , which is also available for download from the biocyc project page ( karp et al .
2009 ) as a flat - file in pathway tools format ( karp et al .
pearson s correlation of binary logarithm of the peak intensities was applied to evaluate dilution trends in the obtained data set .
samples for the 8 dilution points were ordered from highest to lowest concentration , so that metabolites matching the sample dilution trend would show high negative correlation values between intensity and sample number .
correlation values smaller than 0.85 were considered as indicating a significantly reproducible dilution trend . for low - abundance peaks , where signals for the highest dilutions were below the limit of detection , correlation values
were calculated for the detectable consecutive measurements ( at least 3 dilution points were required ) .
all statistical analyses and graphical routines were handled in r ( r development core team , r : a language and environment for statistical computing , austria : 2011 ; http://www.r-project.org ) .
raw data files in mzxml format , r code containing the complete data processing pipeline , as well final peak tables are available for download at http://mzmatch.sourceforge.net/metabolomics.html .
amino acids and related compounds are contained at a final concentration of 0.5 mol / ml 4% in 0.2 n lithium citrate buffer , ph 2.20 , containing thiodiglycol ( 2% w / v ) and phenol ( 0.1% w / v ) as antioxidant and preservative , respectively . the concentration in the injected diluted samples is described in table 1.table 1dilution factor and concentrations of the analysed samplesdilution factor1/81/161/321/641/1281/2561/5121/1024concentration ( mol / ml)0.06250.03130.01560.00780.00390.00200.00100.0005injected on column ( pmol)312.5000156.250078.125039.062519.53139.76564.88282.4414 dilution factor and concentrations of the analysed samples
analytical samples were obtained from streptomyces coelicolor wild - type m145 strain ( bentley et al .
bacteria were grown in 50 ml liquid minimum medium ( nieselt et al . 2010 ) as described ( takano et al .
cells from 25 ml of culture were collected on a 0.45 m filter by vacuum filtration and washed twice with 25 ml of 2.63% nacl solution . for cell quenching ,
the filter with the collected cells was quickly moved into 60% methanol solution ( hplc - grade , boom , the netherlands ) pre - chilled at 20c and frozen in liquid nitrogen .
cells were thawed in an ethanol bath at 20c ( ~15 min ) , vortexed vigorously for 1 min and , right afterwards , frozen in liquid nitrogen for 5 min .
, the samples were centrifuged at 4500 rpm for 10 min at 9c .
the supernatant ( cell extract ) was collected and stored at 80c until lc - ms analysis . before analysis ,
obtained samples were diluted with the same dilution factor as for the analytical standards mixture , resulting in eight samples with different metabolite concentrations .
the analytical mixtures and cell extracts were analyzed by liquid chromatography coupled to a high - accuracy ltq orbitrap xl mass spectrometer ( thermo fisher scientific , germany ) .
two chromatographic columns were used : a reversed - phase shim - pack xr - ods c18 column ( achrom , belgium ) ( 3.0 75 mm , 2.2 m , shimadzu corp . ) and a zic - hilic column ( achrom , belgium ) ( 150 2.1 mm , 3.5 m , merck sequant ab ) fitted with a zic - hilic peek guard column ( achrom , belgium ) ( 15 1.0 mm ; 5 m , merck sequant ab ) .
for the c18 column , the flow rate was set to 0.6 ml / min ; the mobile phase consisted of ( a ) 0.1% formic acid in water and
the elution of solvent b started at 2% for the first 2 min and was increased to 95% within 8 min .
this composition was maintained for 2 min , after which the elution of b was decreased to 2% within 1 min .
to re - equilibrate the system , the elution of b was held at 2% for 5 min .
for the zic - hilic column , the flow rate was set to 0.1 ml / min ; as buffers , ( a ) 0.1% formic acid in acetonitrile and ( b ) 0.1% formic acid in water were used .
the elution fraction of solvent b was increased to 40% within 6 min and maintained at 40% for 12 min , after which solvent b was increased to 90% in a 4 min - interval .
this composition was held for 2 min after which b was decreased to 20% in 2.5 min .
the gradient was held at 20% b for 13.5 min to re - equilibrate the system .
the sample volume injected was 5 l for both columns , and two technical replicates were recorded for the c18 analysis , and three replicates on the hilic column .
full - scan spectra were obtained over an m / z range of 501000 da .
ulc grade acetonitrile , formic acid and water were purchased at biosolve ( netherlands ) .
raw data files from the mass spectrometer were converted into the mzxml format by the readw.exe utility ( a tool of the trans - proteomic pipeline software collection , downloaded from http://tools.proteomecenter.org/wiki/index.php?title=software:readw ) .
the centwave ( tautenhahn et al.2008 ) feature detection algorithm from the xcms ( smith et al.2006 ) package was used on each individual data file .
further processing was handled by the flexible data processing pipeline mzmatch ( scheltema et al .
2011 ) , performing noise removal ( windig 2004 ) and several steps of signal filtering and peak matching .
the first matching step involved aligning of the chromatographic features between technical replicates of a single sample .
peaks that were not detected in all technical replicates were discarded from further analysis . in the second matching step , the chromatographic peaks , which were combined in single files containing technical replicates in the previous matching step , were aligned to each other for all eight dilutions . after combining the eight measurements in a single file
such gaps were filled by extracting ion chromatograms within the retention time and mass window of the given peak set directly from the raw data files .
derivative signals ( isotopes , adducts , dimers and fragments ) were automatically annotated by correlation analysis on both signal shape and intensity pattern , as described ( scheltema et al .
these peaks were not discarded and their assigned annotations were taken into account in the subsequent analysis .
putative identifications were made by matching the detected masses to a database of streptomyces coelicolor ( scocyc ) metabolites , a contaminants database ( keller et al .
the metabolite database was obtained from a genome annotation file created by jonathan moore as part of the sysmo stream project ( https://www.wsbc.warwick.ac.uk/groups/sysmopublic/ ) , which is also available for download from the biocyc project page ( karp et al .
2009 ) as a flat - file in pathway tools format ( karp et al .
pearson s correlation of binary logarithm of the peak intensities was applied to evaluate dilution trends in the obtained data set .
samples for the 8 dilution points were ordered from highest to lowest concentration , so that metabolites matching the sample dilution trend would show high negative correlation values between intensity and sample number .
correlation values smaller than 0.85 were considered as indicating a significantly reproducible dilution trend . for low - abundance peaks , where signals for the highest dilutions were below the limit of detection , correlation values
were calculated for the detectable consecutive measurements ( at least 3 dilution points were required ) .
all statistical analyses and graphical routines were handled in r ( r development core team , r : a language and environment for statistical computing , austria : 2011 ; http://www.r-project.org ) .
raw data files in mzxml format , r code containing the complete data processing pipeline , as well final peak tables are available for download at http://mzmatch.sourceforge.net/metabolomics.html .
first we wanted to validate our filtering method by applying it to the data sets of the mixtures of analytical standards .
data for both chromatographic columns are shown : even for relatively simple samples ( 39 compounds in the mix of standards ) a huge amount of the peaks were detected ( 2831 peak sets for c18 data , and 11169 for hilic ) . only about 2030% of these signals can be identified in chemical databases or assigned to known contaminants .
a significant amount of the uninformative signals could be removed after application of the dilution trend filter .
for example , in the unfiltered data set for hilic data 28 unique standard compounds were matching 409 features within 5 ppm mass accuracy window .
after application of the dilution trend filter , this number decreased to 91 features matching 26 unique standard compounds .
in other words , the number of detected compounds is not significantly changing , while the number of total peaks in the data set is decreasing by almost 5 times and the number of unambiguous matches is substantially increased ( fig .
manual inspection showed that the two putative standard compounds removed by application of the filter were artefacts , i.e. these two compounds were not really detectable .
also , a very large amount of the signals matching the scocyc database ( which should not be present in samples of analytical standards ) was removed by the trend filter , as were most of the unidentifiable compounds , which also do not match the expected composition of the samples .
overall the fraction of correctly identifiable compounds is dramatically increased.table 2comparison of number of the peaks extracted for the standard mixtures samplesc18hilicbefore filteringfilteredbefore filteringfiltered12121212detected as standards ( bp)49121110409289126detected as standards ( rp)30272020256309928detected as contaminants ( bp)69231122728138detected as contaminants ( rp)40175414722229detected in scocyc ( bp)941762516687029detected in scocyc ( rp)723724233839211558unidentified ( bp)13351064745493unidentified ( rp)114234844861337the fraction of features uniquely identified as standard compounds is significantly increased after application of trend filteringbp labelled as base peaks by mzmatch software , rp labelled as derivative peaks , 1 number of peaks , 2 number of unique identifiersfig .
compounds labelled as base peaks by the mzmatch software are shown . for the standards mixture ( a ) where only matches to the standard compounds are expected , a clear increase of the fraction of identified peaks can be seen after filtering .
importantly , the fraction of uniquely identified compounds ( lighter shade of the color ) is also strongly increasing .
in other words , after filtering more compounds with unambiguous , unique identifications are retained .
the same trend can be also seen in the data for the biological samples ( b ) , where matches to the standard compounds and the scocyc data base are expected .
matches to the contaminant compounds decrease in the filtered data , and the number of unique identifications increases substantially ( color figure online ) comparison of number of the peaks extracted for the standard mixtures samples the fraction of features uniquely identified as standard compounds is significantly increased after application of trend filtering bp labelled as base peaks by mzmatch software , rp labelled as derivative peaks , 1 number of peaks , 2 number of unique identifiers proportional relationship between identified compounds before and after filtering on dilution trend .
compounds labelled as base peaks by the mzmatch software are shown . for the standards mixture ( a ) where only matches to the standard compounds
are expected , a clear increase of the fraction of identified peaks can be seen after filtering .
importantly , the fraction of uniquely identified compounds ( lighter shade of the color ) is also strongly increasing .
in other words , after filtering more compounds with unambiguous , unique identifications are retained .
the same trend can be also seen in the data for the biological samples ( b ) , where matches to the standard compounds and the scocyc data base are expected .
matches to the contaminant compounds decrease in the filtered data , and the number of unique identifications increases substantially ( color figure online ) a list of the standard compounds detected on both c18 and hilic columns is shown in table 3 .
the following structural isomers could not be distinguished : l - alanine , l - sarcosine and -alanine ; -amino - n - butyric acid , d , l--aminoisobutryic acid and l--amino - n - butyric acid . for l - isoleucine / l - leucine and 1-methyl - l - histidine/3-methyl - l - histidine two peaks eluting close to each other
ammonium chloride was not detected on either column ( because of its low molecular weight ) , and l - ornithine was not detected on the hilic column .
almost no separation was achieved on the c18 column ( most of the signals eluted within the first minute of the analytical run ) .
surprisingly high quantification accuracy ( correlation value is close to 1 , i.e. a linear relationship between intensity and sample dilution ) can be observed for almost all analytical standards on both chromatographic columns.table 3identified compounds in the analytical mixturemetabolite ( kegg compound id)molecular formulamonoisotopic massc18hiliccorr.rtcorr.rturea ( c00086)ch4n2o60.032400.880 min 40 s0.998 min 33 sethanolamine ( c00189)c2h7no61.052800.940 min 32 s0.9920 min 56 sglycine ( c00037)c2h5no275.032000.890 min 35 s117 min 58 sl - alanine ( c00041)c3h7no289.047700.970 min 35 s0.9814 min 58 s-amino - n - butyric acid ( c00334)c4h9no2103.063300.910 min 37 s0.9013 min 56 sl - serine ( c00065)c3h7no3105.042600.880 min 35 s118 min 05 sl - creatinine ( c00791)c4h7n3o113.058900.970 min 34 s0.8514 min 44 sl - proline ( c00148)c5h9no2115.063300.920 min 38 s0.9814 min 26 sl - valine ( c00183)c5h11no2117.079000.990 min 48 s0.9213 min 18 sl - threonine ( c00188)c4h9no3119.058200.950 min 35 s0.8918 min 16 staurine ( c00245)c2h7no3s125.014700.860 min 36 s0.9915 min 01 shydroxy - l - proline ( c01157)c5h9no3131.058200.960 min 36 s0.8515 min 23 sl - isoleucine ( c00407)c6h13no2131.094600.991 min 34 s111 min 48 sl - ornithine ( c00077)c5h12n2o2132.089900.950 min 28 sl - aspartic acid ( c00049)c4h7no4133.037500.900 min 36 s116 min 39 sl - lysine ( c00047)c6h14n2o2146.105500.950 min 28 s130 min 7 sl - glutamic acid ( c00025)c5h9no4147.053200.920 min 36 s0.9015 min 41 sl - methionine ( c00073)c5h11no2s149.051000.991 min 02 s112 min 48 sl - histidine ( c00135)c6h9n3o2155.069500.890 min 29 s129 min 19 s-hydroxylysine ( c01211)c6h14n2o3162.187000.950 min 28 s130 min 18 sl - phenylalanine ( c00079)c9h11no2165.079000.993 min 42 s111 min 16 s1-methyl - l - histidine ( c01152)c7h11n3o2169.085100.910 min 31 s129 min 38 sl - arginine ( c00062)c6h14n4o2174.111700.950 min 32 s130 min 10 sl - citrulline ( c00327)c6h13n3o3175.095700.930 min 36 s118 min 35 sl - tyrosine ( c00082)c9h11no3181.073900.991 min 40 s113 min 42 sl - tryptophan ( c00078)c11h12n2o2204.089900.994 min 39 s0.9912 min 01 sl - cystathionine ( c02291)c7h14n2o4s222.067400.870 min 35 s126 min 00 sl - carnosine ( c00386)c9h14n4o3226.106600.880 min 28 s131 min 01 sl - cystine ( c00491)c6h12n2o4s2240.023800.880 min 35 s125 min 17 sl - anserine ( c01262)c10h16n4o3240.122200.980 min 30 s130 min 53 sl - homocystine ( c01817)c8h16n2o4s2268.0551010 min 44 s124 min 02 scorr .
pearson s correlation coefficient between sample number and the logarithm of the signal intensity , rt retention time identified compounds in the analytical mixture corr .
pearson s correlation coefficient between sample number and the logarithm of the signal intensity , rt retention time the resulting numbers of detected peaks after processing of biological samples are shown in table 4 .
surprisingly , the amount of detected peaks is comparable to the numbers seen for the analytical standards , both in the filtered and unfiltered data sets . for the hilic data set , 639 features were putatively identified in the scocyc database ( 78 unique compounds ) , but only 28 peaks ( 24 unique identifiers )
interesting compounds that were identified ( and expected ) only in the biological samples on both chromatographic columns are the osmoregulator compound ectoine and hypoxanthine . in fig . 2 , an example of dilution trends and chromatographic peaks for the biological sample ( fig .
a peak was identified as matching the mass of ectoine with an apparent mass error less than 1 ppm , but in the standard mixture ( which does not contain ectoine ) , this peak was successfully discarded by the trend filter , as the signal intensity patterns ( shown in the left panel of the plot ) are not following the sample dilution trend.table 4comparison of the number of the peaks extracted for the biological samples before and after trend filteringc18hilicbefore filteringfilteredbefore filteringfiltered12121212detected as standards ( bp)341355366223215detected as standards ( rp)161288208232010detected as contaminants ( bp)59203225428108detected as contaminants ( rp)291644129291612detected in scocyc ( bp)972544639782824detected in scocyc ( rp)362277362784633unidentified ( bp)1235194962146unidentified ( rp)6321233053359the fraction of compounds with putative identifications is significantly increased after application of the trend filterbp labelled as base peaks by mzmatch software , rp labelled as derivative peaks , 1 number of peaks , 2 number of unique identifiersfig .
( on the left ) and extracted mass chromatograms ( on the right ) for a metabolite putatively identified as ectoine . for the biological samples , which are expected to contain ectoine ( kol et al .
2010 ) , three technical replicates show clearly identifiable dilution trend ( trend correlation value 0.97 ) .
for the standard mixture , which does not contain ectoine , a random trend is seen in all replicates for the signal putatively identified as ectoine ( mass error 0.86 ppm ) ; this putative technical artefact can thus be removed by the trend filtering ( color figure online ) comparison of the number of the peaks extracted for the biological samples before and after trend filtering the fraction of compounds with putative identifications is significantly increased after application of the trend filter bp labelled as base peaks by mzmatch software , rp labelled as derivative peaks , 1 number of peaks , 2 number of unique identifiers example of the dilution trends ( on the left ) and extracted mass chromatograms ( on the right ) for a metabolite putatively identified as ectoine . for the biological samples , which are expected to contain ectoine ( kol et al .
2010 ) , three technical replicates show clearly identifiable dilution trend ( trend correlation value 0.97 ) . for the standard mixture , which does not contain ectoine ,
a random trend is seen in all replicates for the signal putatively identified as ectoine ( mass error 0.86 ppm ) ; this putative technical artefact can thus be removed by the trend filtering ( color figure online ) the biological samples used in this illustrative example are particularly challenging , due to a large number of peaks with low signal intensities .
our results show that even for such difficult data , the dilution trend filter can be applied with no real danger of losing information of interest .
it is also quite obvious that sample dilution factors should be adjusted according to the expected overall metabolite levels in the analysed samples , to avoid over - dilution and loss of signals of interest . to avoid the problem of large correlations occurring by chance when the number of observations is low
, the statistical significance of the observed correlation can be examined and the obtained p - values can be used to determine the threshold for peak selection .
this method can also be integrated with a quality control sample approach ( sangster et al .
2006 ) , where repeated injection of a pooled randomized sample throughout the analysis serves as a reference for quality control ; this approach is commonly used in large populations studies ( zelena et al . 2009 ) .
this control sample can be replaced with injections of pooled dilution samples in randomized order .
thereby , without increasing the number of injections for a typical analytical sample batch , it will be possible to simultaneously assess machine stability ( as the dilution trend should stay constant ) and do a filtering of the data set on highly reproducible signals .
the method suggested here is therefore a useful complement to the commonly used relative standard deviation ( rsd ) filters ( shah et al .
2000 ; scheltema et al . 2008 ) and the coda - dw filters , ( windig 2004 ) , allowing automatic retrieval of signals of interest , reducing the complexity of the data and consequently speeding up the interpretation process .
the dilution filtering approach can be easily integrated in a complete data processing pipeline ( based on mzmatch and xcms software tools ) and used in a semi - automated manner .
this is illustrated in the r script provided as supplementary material for this study ( http://mzmatch.sourceforge.net/metabolomics.html ) .
we have been able to demonstrate the effectiveness and reliability of a relatively simple data filtering strategy .
the proposed trend correlation filter significantly decreases the amount of non - informative signals in the data sets and makes metabolite identification much easier .
we could show that even very stringent filtering of the data is not causing a loss of informative signals .
our illustrative application to biological samples demonstrates that our approach can also be applied to assess the performance of metabolite extraction from the samples .
this allows a more reliable estimate of the true metabolomic complexity observed in a particular experiment .
Output:
| liquid chromatography mass spectrometry ( lc - ms ) is a powerful and widely applied method for the study of biological systems , biomarker discovery and pharmacological interventions .
lc - ms measurements are , however , significantly complicated by several technical challenges , including : ( 1 ) ionisation suppression / enhancement , disturbing the correct quantification of analytes , and ( 2 ) the detection of large amounts of separate derivative ions , increasing the complexity of the spectra , but not their information content . here
we introduce an experimental and analytical strategy that leads to robust metabolome profiles in the face of these challenges .
our method is based on rigorous filtering of the measured signals based on a series of sample dilutions .
such data sets have the additional characteristic that they allow a more robust assessment of detection signal quality for each metabolite . using our method
, almost 80% of the recorded signals can be discarded as uninformative , while important information is retained . as a consequence ,
we obtain a broader understanding of the information content of our analyses and a better assessment of the metabolites detected in the analyzed data sets .
we illustrate the applicability of this method using standard mixtures , as well as cell extracts from bacterial samples .
it is evident that this method can be applied in many types of lc - ms analyses and more specifically in untargeted metabolomics . |
PubmedSumm118278 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: henoch - schnlein purpura ( hsp ) is the most common systemic vasculitis in children and involves inflammation of the small vessels of the skin , joints , gut , and kidney .
renal involvement , known as henoch - schnlein purpura nephritis ( hspn ) , which most commonly presents with hematuria and/or proteinuria , is the most serious complication of hsp and often determines the prognosis of hsp .
it has been reported that approximately 3050% of children with hsp develop nephritis within 4 to 6 weeks after disease onset .
the extent of renal injury is important in evaluating hspn prognosis and early individualized therapeutic strategies .
the pathological findings of hspn include mesangial cell proliferation , crescent formation in epithelial cells , and mesangial iga deposition .
, we found high asic1a and asic3 expression in the vascular endothelium of hsp patients .
acid - sensing ion channels ( asics ) , which are cationic channels that belong to the degenerin / epithelial na channel ( deg / enac ) superfamily , are activated by extracellular acidosis .
tissue acidosis associated with ischemia is caused by an accumulation of lactate and local or systemic lactic acidosis , which is the common feature of the diseases , such as tumors , ischemic injury , and inflammation [ 810 ] .
renal tubular acidosis due to ischemic tubular injury has been observed in kidney transplant recipients , but whether asics might be involved in the development of hspn has not been reported .
the present study is the first to investigate asics expression in the kidneys of hspn patients and to explore the potential function of asics involved in the development of hspn .
we screened 13 hspn patients ( mean age 20.086.96 years , range 829 years ) undergoing renal biopsy at the first affiliated hospital of anhui medical university between january 2011 and june 2015 .
we also recruited 7 patients with minimal change nephrotic syndrome ( mean age 25.273.58 years , range 1031 years ) as normal controls when the pathological changes in their renal biopsies were normal .
hspn was diagnosed according to the criteria recommended by the nephrology group of the chinese medical society in november 2000 .
the diagnosis of hsp was based on the criteria defined by the european league against rheumatism , the pediatric rheumatology international trials organization , and the pediatric rheumatology european society ( uular / printo / pres ) in 2010 .
informed consents were obtained and the study was approved by hospital institutional review board ( quick - pj 2016 - 5 - 12 ) .
the asic1 , asic2 , and asic3 protein levels in kidney tissue of hspn patients were examined using immunohistochemical staining .
slides of the tissues were routinely prepared and the staining was performed according to a streptavidin - biotin complex ( sabc ) immunohistochemical assay ( santa cruz biotechnology , inc . , santa cruz , ca , usa ) . based on the sabc staining technique , brownish - yellow granules in the cytoplasm indicated positive cells .
we also performed an sabc immunohistochemical assay using rabbit anti - human asic1 , asic2 and asic3 antibodies ( santa cruz biotechnology , inc ) as the primary antibodies .
results were analyzed using the percentage of the positive area of asic1 , asic2 , and asic3 expression .
clinical classification in hspn patients included 13 patients with hematuria and proteinuria , 5 with acute nephritis , and 8 with chronic nephritis .
tissues from the renal biopsy were examined by light microscopy , glomerular lesions were classified using international society for kidney disease community ( iskdc ) guidelines , and hspn was classified into levels i vi .
pathological grading of kidney tissue showed 7 patients with iskdc and 6 with iskdc. human renal tubular epithelial cells were supplied by mdl biotech co. , ltd ( beijing , china ) and cultured in dulbecco s modified eagle s medium ( dmem , gibco ) supplemented with 20% fetal bovine serum ( fbs , gibco , grand island , ny , usa ) .
cells were treated with different ph levels ( ph 7.4 , ph 7.0 , ph 6.5 , ph 6.0 , ph 5.5 ) solution for 3 h. after treatment , the cells were kept in normal media for about 4 h and then collected for the analysis of asic1 , asic2 , and asic3 mrna expression and k7 and k18 protein expression .
subsequently , in another set of experiments , the cells were exposed to solutions with ph 7.4 , ph 6.0 , and ph 6.0+amiloride ( 100 , 50 , and 25
umol / l ) for 3 h and used to assess k7 and k18 protein expression .
quantitative rt - pcr analysis was performed to analyze asic1 , asic2 , and asic3 mrna expression .
gene expression was performed using the one - step rt - pcr kit with sybr green in the abi 7900 qpcr detection system .
pcr reactions were performed with reverse transcription at 50c for 15 min , denaturation and reverse transcriptase inactivation at 95c for 2 min , followed by 40 cycles ( 20 s each ) of denaturation at 94c , and annealing and extension at 65c for 20 s. melt curve analysis was performed to confirm the specificity of pcr products .
pcr amplification data of each gene were normalized to ct value of internal housekeeping gene ( -actin ) from the same sample and the fold - changes in gene expression were calculated using the delta - delta ct method . a list of forward and reverse primer sequences used for qrt - pcr analysis is given in table 1 .
the treated cells were harvested , and total cellular protein lysates were prepared using ripa lysis buffer .
protein samples ( 50 g ) were subjected to sds - page and transferred to pvdf membranes . after blocking with 5% non - fat milk in tbst for 1
h , the membranes were incubated overnight at 4c with the following primary antibodies : keratins k7 ( 1 : 500 ) and keratins18 ( 1 : 500 ) .
lastly , the membranes were incubated with an hrp - conjugated secondary antibody ( 1 : 1000 ) for 60 min at 37c , which were then detected by an ecl luminescent detection system .
the intensity of protein bands was analyzed using image j software and normalized to expression of -actin .
student s t - test was used to analyze the statistical significance in the differences between 2 groups .
the relationship of asic expression with keratins7 and keratins19 expression was analyzed using pearson correlations .
for all comparisons , a p - value less than 0.05 were considered statistically significant .
we screened 13 hspn patients ( mean age 20.086.96 years , range 829 years ) undergoing renal biopsy at the first affiliated hospital of anhui medical university between january 2011 and june 2015 .
we also recruited 7 patients with minimal change nephrotic syndrome ( mean age 25.273.58 years , range 1031 years ) as normal controls when the pathological changes in their renal biopsies were normal .
hspn was diagnosed according to the criteria recommended by the nephrology group of the chinese medical society in november 2000 .
the diagnosis of hsp was based on the criteria defined by the european league against rheumatism , the pediatric rheumatology international trials organization , and the pediatric rheumatology european society ( uular / printo / pres ) in 2010 .
informed consents were obtained and the study was approved by hospital institutional review board ( quick - pj 2016 - 5 - 12 ) .
the asic1 , asic2 , and asic3 protein levels in kidney tissue of hspn patients were examined using immunohistochemical staining .
slides of the tissues were routinely prepared and the staining was performed according to a streptavidin - biotin complex ( sabc ) immunohistochemical assay ( santa cruz biotechnology , inc . , santa cruz , ca , usa ) . based on the sabc staining technique , brownish - yellow granules in the cytoplasm indicated positive cells .
we also performed an sabc immunohistochemical assay using rabbit anti - human asic1 , asic2 and asic3 antibodies ( santa cruz biotechnology , inc ) as the primary antibodies .
results were analyzed using the percentage of the positive area of asic1 , asic2 , and asic3 expression .
clinical classification in hspn patients included 13 patients with hematuria and proteinuria , 5 with acute nephritis , and 8 with chronic nephritis .
tissues from the renal biopsy were examined by light microscopy , glomerular lesions were classified using international society for kidney disease community ( iskdc ) guidelines , and hspn was classified into levels i vi .
human renal tubular epithelial cells were supplied by mdl biotech co. , ltd ( beijing , china ) and cultured in dulbecco s modified eagle s medium ( dmem , gibco ) supplemented with 20% fetal bovine serum ( fbs , gibco , grand island , ny , usa ) .
cells were treated with different ph levels ( ph 7.4 , ph 7.0 , ph 6.5 , ph 6.0 , ph 5.5 ) solution for 3 h. after treatment , the cells were kept in normal media for about 4 h and then collected for the analysis of asic1 , asic2 , and asic3 mrna expression and k7 and k18 protein expression .
subsequently , in another set of experiments , the cells were exposed to solutions with ph 7.4 , ph 6.0 , and ph 6.0+amiloride ( 100 , 50 , and 25
umol / l ) for 3 h and used to assess k7 and k18 protein expression .
quantitative rt - pcr analysis was performed to analyze asic1 , asic2 , and asic3 mrna expression .
gene expression was performed using the one - step rt - pcr kit with sybr green in the abi 7900 qpcr detection system .
pcr reactions were performed with reverse transcription at 50c for 15 min , denaturation and reverse transcriptase inactivation at 95c for 2 min , followed by 40 cycles ( 20 s each ) of denaturation at 94c , and annealing and extension at 65c for 20 s. melt curve analysis was performed to confirm the specificity of pcr products .
pcr amplification data of each gene were normalized to ct value of internal housekeeping gene ( -actin ) from the same sample and the fold - changes in gene expression were calculated using the delta - delta ct method . a list of forward and reverse primer sequences used for qrt - pcr analysis is given in table 1 .
the treated cells were harvested , and total cellular protein lysates were prepared using ripa lysis buffer .
protein samples ( 50 g ) were subjected to sds - page and transferred to pvdf membranes . after blocking with 5% non - fat milk in tbst for 1 h
, the membranes were incubated overnight at 4c with the following primary antibodies : keratins k7 ( 1 : 500 ) and keratins18 ( 1 : 500 ) .
lastly , the membranes were incubated with an hrp - conjugated secondary antibody ( 1 : 1000 ) for 60 min at 37c , which were then detected by an ecl luminescent detection system .
the intensity of protein bands was analyzed using image j software and normalized to expression of -actin .
student s t - test was used to analyze the statistical significance in the differences between 2 groups .
the relationship of asic expression with keratins7 and keratins19 expression was analyzed using pearson correlations .
for all comparisons , a p - value less than 0.05 were considered statistically significant .
the asic1 , asic2 and asic3 expression , as brown or yellow granules , was clearly shown in the cell cytoplasm of renal tubular epithelial cells from hspn patients ( figure 1a , 1c , 1e ) , whereas asic1 , asic2 , and asic3 expression was rarely observed in normal kidneys ( figure 1b , 1d , 1f ) .
the image analysis of the positive area of asic1 , asic2 , and asic3 using semiquantitative methods confirmed that the protein expressions of asic2 and asic3 were significantly different between the normal controls and patients with hspn ( table 2 ) .
furthermore , we found that asic1 expression and 24-h urine protein level were higher in the pathological grades iskd iii group than that in the iskd ii group ( table 3 ) . to observe the effect of ph on asics expression in renal tubular epithelial cells , we measured asic1 , asic2 , and asic3 expression with real - time quantitative polymerase chain reaction .
figure 2 shows that asic1 , asic2 , and asic3 expression was significantly increased at lower extracellular ph , and the change in asic1 expression was most notable with ph fluctuations in vitro .
when extracellular ph only drops from 7.4 to 7.0 , asic1 expression had already reached the maximum level . to observe the effect of different ph on renal tubular epithelial cell injury
, we investigate the expression of keratins , which are sensitive markers of renal tubular cell stress .
moreover , extracellular ph transients ( varying from 7.4 to 7.0 ) in vitro significantly stimulated k7 and k18 protein expression , as shown in figure 3 .
in addition , k7 and k18 protein expression was closely related with asic1 expression ( r=0.53 , p<0.01 ; r=0.56 , p<0.01 , respectively ) . to determine
if asics are involved in renal tubular injury , we observed the effect of the asics blocker , amiloride , on acid - induced renal tubular epithelial cell injury .
figure 4 shows that keratins 7 and keratins 19 protein expression was significantly increased in ph 6.0 solution compared with that in ph 7.4 solution ( p<0.01 )
. however , amiloride obviously inhibits keratins 7 and keratins 19 protein expression induced by extracellular acidosis .
the asic1 , asic2 and asic3 expression , as brown or yellow granules , was clearly shown in the cell cytoplasm of renal tubular epithelial cells from hspn patients ( figure 1a , 1c , 1e ) , whereas asic1 , asic2 , and asic3 expression was rarely observed in normal kidneys ( figure 1b , 1d , 1f ) .
the image analysis of the positive area of asic1 , asic2 , and asic3 using semiquantitative methods confirmed that the protein expressions of asic2 and asic3 were significantly different between the normal controls and patients with hspn ( table 2 ) .
furthermore , we found that asic1 expression and 24-h urine protein level were higher in the pathological grades iskd iii group than that in the iskd ii group ( table 3 ) .
to observe the effect of ph on asics expression in renal tubular epithelial cells , we measured asic1 , asic2 , and asic3 expression with real - time quantitative polymerase chain reaction .
figure 2 shows that asic1 , asic2 , and asic3 expression was significantly increased at lower extracellular ph , and the change in asic1 expression was most notable with ph fluctuations in vitro .
when extracellular ph only drops from 7.4 to 7.0 , asic1 expression had already reached the maximum level .
to observe the effect of different ph on renal tubular epithelial cell injury , we investigate the expression of keratins , which are sensitive markers of renal tubular cell stress .
moreover , extracellular ph transients ( varying from 7.4 to 7.0 ) in vitro significantly stimulated k7 and k18 protein expression , as shown in figure 3 .
in addition , k7 and k18 protein expression was closely related with asic1 expression ( r=0.53 , p<0.01 ; r=0.56 , p<0.01 , respectively ) .
to determine if asics are involved in renal tubular injury , we observed the effect of the asics blocker , amiloride , on acid - induced renal tubular epithelial cell injury .
figure 4 shows that keratins 7 and keratins 19 protein expression was significantly increased in ph 6.0 solution compared with that in ph 7.4 solution ( p<0.01 )
. however , amiloride obviously inhibits keratins 7 and keratins 19 protein expression induced by extracellular acidosis .
henoch - schnlein purpura nephritis ( hspn ) , the most serious long - term complication of hsp , is one of the most common renal diseases in children and adults .
the present study is the first to show higher asic1 , asic2 , and asic3 expression in kidney tissue , predominately in renal tubular cells .
we also observed that the more severe renal pathological lesions are associated with higher asic1 expression in renal tubular cells was and higher urine protein level .
acid - sensing ion channels ( asics ) are known as proton - gated cation channels , which are activated in tissue acidosis conditions .
inflammation in hsp is often accompanied by acidosis due to the release of lactate in the small vessels or glomerular capillaries , which may lead to activation of asics .
this study also demonstrated that asic1 , asic2 , and asic3 expression was upregulated in cultured renal tubular epithelial cells in a low ph environment .
moreover , we found that extracellular ph fluctuates in a limited range ( dropping from 7.4 to 7.0 ) and obviously influenced asic1 expression of renal tubular epithelial cells .
metabolic acidosis is one of the most common complications of kidney diseases , and it is mostly caused by renal tubular acidosis ( rta ) . in patients with renal transplantation , rta was attributed to ischemic tubular injury in the early post - transplant period .
acidification disorder due to tubular ischemia in hspn patients appears to cause renal tubular injury .
the extent of tubular involvement in hsp is a key factor in determining the development and prognosis of hspn . to investigate the relationship between asics expression and renal tubular injury , we measured renal tubular epithelial cell injury by identification of keratins expression .
keratins , the intermediate filaments of the renal tubular epithelial cell cytoskeleton , are novel sensitive markers of renal tubular cell injury .
reports show that they can be upregulated and post - translationally modified in kidney diseases .
the upregulation became significant early after disease induction and increased with disease progression . in this study
, we found that extracellular acidosis stimulated the expression of keratins 7 and keratins 18 proteins .
furthermore , k7 and k18 expression was closely related to asic1 expression , and blocking asics by amiloride reduced keratins protein expression .
our data suggest that asics are involved in renal tubular cell injury induced by acidosis , and inhibiting asics had a protective effect on renal tubular cell injury .
this study is the first to show that asic1 , asic2 , and asic3 are expressed in kidney tissue from hspn patients , predominately in the renal tubular cells .
however , the role of asics activation in the development of hspn has not been fully elucidated , which will be done in the future .
Output:
| backgroundacid - sensing ion channels ( asics ) are ligand - gated cation channels activated by extracellular protons . however , the role of asics in kidney diseases remains uncertain .
this study investigated asics expression in kidney tissues and their role in the development of henoch - schnlein purpura nephritis ( hspn).material / methodsthe expression of asic subunits was examined by immunochemical techniques in the kidney tissue from hspn patients .
acid - induced asics expression in cultured renal tubular epithelial cells was determined by quantitative rt - pcr analysis .
the expression of k7 and k18 protein in renal tubular epithelial cells was used to evaluate acid - induced cell injury .
in addition , we observed the effect of blocking asics on acid - induced cell injury to assess the role of asics in renal tubular epithelial cell injury.resultsthe results showed that asic1 , asic2 , and asic3 proteins were obviously expressed in renal tubular cells from hspn patients .
asic1 expression and 24-h urine protein level were higher in the pathological grade iskd iii group than in the iskd ii group .
asic1 , asic2 , and asic3 mrna , and k7 and k18 protein expression in cultured renal tubular epithelial cells were increased when exposed to ph 6.5 .
k7 and k18 protein expression was closely related to asic1 expression , and asics blockers reduced k7 and k18 protein expression in tubular epithelial cells.conclusionsthese findings suggest asics are most highly expressed in renal tubular cells of hspn patients , which is closely related to renal tubular injury .
asics might be involved in the development of hspn . |
PubmedSumm118279 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: tennis is considered to be one of the most popular sports in the world today . increasing popularity and professionalism inspire sport scientists to carry out more research related to the factors affecting performance in tennis .
these factors include stroke production , physical fitness , on - court movement and mental fitness ( groppel , 1992 ) . according to elliott and collaborators ( 2003 ) , success in tennis
is related to the effective combination of tennis strokes and on - court movements . as mentioned in earlier studies ( bahamonde , 2000 ; girard et al . , 2005 ; knudson et al . , 2004 )
it is very difficult to excel in the serve motion as it requires both complex coordination of the upper and lower body ( bahamonde , 2000 ; wong et al . , 2014 ) and
according to elliott ( 2006 ) producing high speed tennis serve requires a proper kinetic chain which involves sequential activation and coordination of different body parts ( leg , trunk , shoulder , elbow , and wrist ) . during the last few decades , changes in racquet technology and
training methods have made tennis players and coaches at all competitive levels to pay more attention to the power and velocity of the ball ( abrams et al . , 2011 ) .
( 2013 ) claimed that producing high velocity , especially during the serve , played an important role in successful play .
therefore , regardless of the sports level , all tennis players need to strive for a higher serve speed ( elliott et al . , 1995 ) .
the improvements in technology have also stimulated changes in the physical performance of players ( snchez - muoz et al . , 2007 ) .
these changes have forced modern tennis players to focus on versatile physical fitness training , and thus , to become more athletic ( reid et al . , 2003 ) .
previous studies reported the relationship between physical fitness and motor competence ( cattuzzo et al . , 2016 ;
2011 ) , the latter of which was described as the proficiency of physical skills and movement patterns ( castelli and valley , 2007 ) . according to bardid et al .
( 2015 ) motor competence in childhood is an important factor in the determination of physical fitness characteristics in later life .
motor competence depends on motor coordination , which is defined as the dexterity to coordinate movements of multiple body parts while the body is in motion ( magill , 2003 ) .
it involves rapid body movement during the execution of various fundamental skills ( gallahue and ozmun , 1995 ) .
well - developed coordination not only allows tennis players to control their body parts in space and time , but also yields successive stroke production ( farrell and van de braam , 2015 ) .
although serve speed and motor coordination have been widely investigated in the scope of sports science literature , there is limited information on the discrepancies between tennis players from different performance levels . the present study aimed to fill this gap through analyzing the differences between elite and club level junior tennis players of both genders .
it was hypothesized that elite players would obtain better scores on serve speed and motor coordination than their club counterparts .
the elite group consisted of children who were intensively participating in tennis and fitness training and competed in both national and international tournaments .
the club group included children who were attending training moderately and competed irregularly in varied regional and national tournaments .
the anthropometric and training characteristics of the subjects a radar gun ( sr3600 ; sports - radar , homosassa , fl , usa ) was used to assess the serve speed of the participants .
gross motor coordination performance levels of the participants were determined using a revised version of the krperkoordinationstest fr kinder ( ktk ) .
the ktk ( kiphard and schilling , 2007 ) includes four subtests : walking backward ( ktkbeam ) , hopping ( ktkhop ) , moving sideways ( ktkboard ) , and jumping sideways ( ktkjump ) .
each subset of scores was converted to a motor quotient that was adjusted to age and gender .
total ktk motor quotient ( totaktkmq ) scores enable the classification of gross motor coordination performances into five levels ( table 2 ) .
classification of motor coordination levels ( adapted from kiphard and schilling , 2007 ) all measurements were performed at an indoor tennis court .
each participant was encouraged to serve with the highest speed from the deuce court in 30 s intervals .
eight successful serves were recorded and the one with highest speed was used for further analysis .
the ktk was administered according to the protocol described in the reference manual ( kiphard and schilling , 2007 ) .
the ktkbeam test involved three balance beams that were 3 m long with different widths ( 3 cm , 4.5 cm and 6 cm ) .
participants were asked to walk backward 3 times on each balance beam ; the maximum number of steps for each beam was 8 .
for the ktkhop test , the participants were required to hop on one leg over foam obstacles ( height ranging from 0 to 60 cm ) .
the maximum score was 78 . in the ktkboard test , participants moved their body sideways from one board to another for 20 s. the score was the sum of the two trials . in the ktkjump test , participants were asked to jump laterally over a wooden rod ( 2 cm in height ) for 15 s. the score was the sum of the two trials .
finally , the raw scores for each subtest were converted into motor quotient scores to determine the totalktkmq . since the normality and homogeneity of variance assumptions failed , the non - parametric mann - whitney u test was performed to analyze the possible serve speed and motor coordination performance differences between the groups of both genders .
the elite group consisted of children who were intensively participating in tennis and fitness training and competed in both national and international tournaments .
the club group included children who were attending training moderately and competed irregularly in varied regional and national tournaments .
the anthropometric and training characteristics of the subjects a radar gun ( sr3600 ; sports - radar , homosassa , fl , usa ) was used to assess the serve speed of the participants .
gross motor coordination performance levels of the participants were determined using a revised version of the krperkoordinationstest fr kinder ( ktk ) .
the ktk ( kiphard and schilling , 2007 ) includes four subtests : walking backward ( ktkbeam ) , hopping ( ktkhop ) , moving sideways ( ktkboard ) , and jumping sideways ( ktkjump ) .
each subset of scores was converted to a motor quotient that was adjusted to age and gender .
total ktk motor quotient ( totaktkmq ) scores enable the classification of gross motor coordination performances into five levels ( table 2 ) .
classification of motor coordination levels ( adapted from kiphard and schilling , 2007 ) all measurements were performed at an indoor tennis court .
each participant was encouraged to serve with the highest speed from the deuce court in 30 s intervals .
eight successful serves were recorded and the one with highest speed was used for further analysis .
the ktk was administered according to the protocol described in the reference manual ( kiphard and schilling , 2007 ) .
the ktkbeam test involved three balance beams that were 3 m long with different widths ( 3 cm , 4.5 cm and 6 cm ) .
participants were asked to walk backward 3 times on each balance beam ; the maximum number of steps for each beam was 8 .
for the ktkhop test , the participants were required to hop on one leg over foam obstacles ( height ranging from 0 to 60 cm ) .
the maximum score was 78 . in the ktkboard test , participants moved their body sideways from one board to another for 20 s. the score was the sum of the two trials . in the ktkjump test , participants were asked to jump laterally over a wooden rod ( 2 cm in height ) for 15 s. the score was the sum of the two trials .
finally , the raw scores for each subtest were converted into motor quotient scores to determine the totalktkmq . since the normality and homogeneity of variance assumptions failed , the non - parametric mann - whitney u test was performed to analyze the possible serve speed and motor coordination performance differences between the groups of both genders .
a radar gun ( sr3600 ; sports - radar , homosassa , fl , usa ) was used to assess the serve speed of the participants .
gross motor coordination performance levels of the participants were determined using a revised version of the krperkoordinationstest fr kinder ( ktk ) .
the ktk ( kiphard and schilling , 2007 ) includes four subtests : walking backward ( ktkbeam ) , hopping ( ktkhop ) , moving sideways ( ktkboard ) , and jumping sideways ( ktkjump ) .
each subset of scores was converted to a motor quotient that was adjusted to age and gender .
total ktk motor quotient ( totaktkmq ) scores enable the classification of gross motor coordination performances into five levels ( table 2 ) .
classification of motor coordination levels ( adapted from kiphard and schilling , 2007 ) all measurements were performed at an indoor tennis court .
each participant was encouraged to serve with the highest speed from the deuce court in 30 s intervals .
eight successful serves were recorded and the one with highest speed was used for further analysis .
the ktk was administered according to the protocol described in the reference manual ( kiphard and schilling , 2007 ) .
the ktkbeam test involved three balance beams that were 3 m long with different widths ( 3 cm , 4.5 cm and 6 cm ) .
participants were asked to walk backward 3 times on each balance beam ; the maximum number of steps for each beam was 8 .
for the ktkhop test , the participants were required to hop on one leg over foam obstacles ( height ranging from 0 to 60 cm ) .
participants moved their body sideways from one board to another for 20 s. the score was the sum of the two trials . in the ktkjump test , participants were asked to jump laterally over a wooden rod ( 2 cm in height ) for 15 s. the score was the sum of the two trials .
finally , the raw scores for each subtest were converted into motor quotient scores to determine the totalktkmq .
since the normality and homogeneity of variance assumptions failed , the non - parametric mann - whitney u test was performed to analyze the possible serve speed and motor coordination performance differences between the groups of both genders .
each participant was encouraged to serve with the highest speed from the deuce court in 30 s intervals .
eight successful serves were recorded and the one with highest speed was used for further analysis .
the ktk was administered according to the protocol described in the reference manual ( kiphard and schilling , 2007 ) .
the ktkbeam test involved three balance beams that were 3 m long with different widths ( 3 cm , 4.5 cm and 6 cm ) .
participants were asked to walk backward 3 times on each balance beam ; the maximum number of steps for each beam was 8 .
for the ktkhop test , the participants were required to hop on one leg over foam obstacles ( height ranging from 0 to 60 cm ) .
the maximum score was 78 . in the ktkboard test , participants moved their body sideways from one board to another for 20 s. the score was the sum of the two trials . in the ktkjump test , participants were asked to jump laterally over a wooden rod ( 2 cm in height ) for 15 s. the score was the sum of the two trials .
finally , the raw scores for each subtest were converted into motor quotient scores to determine the totalktkmq .
since the normality and homogeneity of variance assumptions failed , the non - parametric mann - whitney u test was performed to analyze the possible serve speed and motor coordination performance differences between the groups of both genders .
since the normality and homogeneity of variance assumptions failed , the non - parametric mann - whitney u test was performed to analyze the possible serve speed and motor coordination performance differences between the groups of both genders .
serve speed and motor coordination performance results of the participants are presented in table 3 .
the results showed that both male ( u = 14.00 , p < .05 ) and female ( u = 2.50 , p <
motor coordination performances of male ( u = 5.00 , p < .01 ) and female ( u = 4.50 , p <
.01 ) subjects from the elite group were also significantly better than those of the other group . considering the raw scores , only ktkhop ( u = 13.50 , p < .05 ) and ktkboard ( u = 5.50 , p <
.01 ) for elite boys and only ktkboard ( u = 13.00 , p < .05 ) and ktkjump ( u = 2.00 , p < .01 ) for elite girls were significantly different from those of their club counterparts among the subtests of the ktk . serve speed and motor coordination performance scores of participants the distribution of motor coordination levels of the participants is given in table 4 . according to the classification by kiphard and schilling ( 2007 ) , none of the participants scored under the normal level .
the purpose of this study was to compare the serve speed and motor coordination of junior tennis players from different performance levels .
it was hypothesized that both elite male and female players would attain higher scores on the tested parameters than their club counterparts .
the results of the study supported the hypothesis that elite players had significantly superior scores on both tasks compared with club players . considering the serve speed scores , the results are in accordance with the findings of girard et al .
( 2005 ) who analyzed the lower - limb activity during the power serve of male tennis players ( age = 21.5 3.8 ) .
they ranked and divided their participants into three sub - groups : beginners ( recreational players ) , intermediate ( good club players ) , and elite athletes ( national level players ) .
their results indicated that serve speed was higher in elite players ( 169.4 11.3 km / h ) compared to beginners ( 107.2 6.1 km / h ) and intermediate players ( 148.8 16.3 km / h ) .
( 1995 ) who compared three - dimensional analyses of serves between national and county level tennis players .
the mean post - impact ball speed of national players was found to be much faster than that of county players . according to girard et al .
( 2005 ) , preloaded muscles and the use of leg extensor muscles are the major determinants in the production of effective high speed tennis serves by skilled players .
additionally , results demonstrated that the mean serve speed score of female players was better compare to that of their male counterparts in both groups .
this finding might be explained considering the age disparity as female players are older than male players in both elite and club group . as revealed by the results , none of the participants in either group performed at lower than normal levels of motor coordination , which is in line with the findings of vandorpe et al .
( 2012 ) who evaluated motor coordination levels of elite ( n = 12 ) and sub - elite ( n = 11 ) female gymnasts using the ktk .
the mean motor quotient scores of the participants were found to be above normal levels for both groups ( elite = 133.7 4.3 and sub - elite = 129.4 5.3 ) .
it was suggested that a non - sport - specific motor coordination test might be valuable for the early identification of talent in gymnastics and other sports ( vandorpe et al . , 2012 ) .
motor coordination scores of players in the elite group were significantly higher than these of players in the club group . these results are supported by the findings of opstoel et al .
they compared motor coordination differences in 9-to 11-year - old children who had low , moderate and high training volumes .
subjects were selected from 25 different sports that were categorized as athletics , ball sports , dance , gymnastics , martial arts , racquet sports , swimming and other sports .
it was found that regardless of the type of sport , children who had a high volume of training demonstrated superior motor coordination performance . in support of these findings ,
2012 ) assessed motor coordination of 735 male children who participated in multiple or single sports in three age groups ( 6 - 8 years , 8 - 10 years , and 10 - 12 years ) .
the mean motor coordination scores of children participating in multiple sports were higher compared to children participating in a single sport for all age groups . regarding the raw scores of the subtests , generally elite players obtained better mean scores .
however , no significant difference was found in the walking backward test between elite and club groups of both genders .
( 2015 ) noted that the walking backward task did not depend on physical fitness , whereas the other three tests required strength , speed , endurance , and flexibility . in conclusion ,
the study highlighted the serve speed and motor coordination differences between elite and club level junior tennis players .
these findings can be explained by the sport specific experience and weekly training volume of players .
subjects in the elite group not only had more experience , but also had greater amounts of weekly tennis and conditioning training . it can be concluded that participating intensively in tennis training at an early age might play an important role in the enhancement of serve speed and motor coordination performance of a junior tennis player .
further studies that focus on the predictability of the ktk for long term success in tennis are recommended .
Output:
| abstractthe purpose of this study was to compare the serve speed and motor coordination of elite and club level junior tennis players aged 11 - 14 years .
participants ( n=35 ) were assigned to one of the two groups according to their experience , weekly training volume and competition level .
serve speed was assessed with a sports radar gun .
motor coordination was evaluated by means of the krperkoordinationstest fr kinder .
the main results revealed that serve speed and motor coordination performance levels of the elite group were significantly higher than those of the club group .
this study emphasized the importance of early participation and training intensity , which can play an important role in enhancement of serve speed and motor coordination . |
PubmedSumm118280 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: there is a growing interest in the role of tryptophan catabolites ( trycats ) , such as kynurenic acid ( kyna ) and quinolinic acid ( quin ) , in the etiology , course , and treatment of a wide array of central nervous system ( cns ) disorders , including alzheimer disease and parkinson disease , and psychiatric disorders , including depression and schizophrenia .
this work has been complemented by the appreciation of the influence of trycat induction on the levels of tryptophan available for serotonin synthesis and therefore for the synthesis and release of n - acetylserotonin ( nas ) and melatonin .
although primarily known for its release by the pineal gland in modulating circadian rhythms , accumulating data show that melatonin is produced by a host of different cells , including astrocytes , macrophages , t cells , gut enterochromaffin cells , and fibroblasts .
it has recently been proposed that melatonin may be produced by all mitochondria - containing cells , including within mitochondria .
such synchronized interactions of the trycat pathway with levels of serotonin and melatonin synthesis are likely to have significant consequences for an array of cns and psychiatric disorders , including via the regulation of glia and immune cell reactivity levels . given that melatonin modulates the levels and activity of the alpha 7 nicotinic acetylcholine receptor ( a7nachr ) and that the a7nachr may mediate some of melatonin s effects , it is likely that alterations in a7nachr levels and activity may also covary with trycat induction . in this article , the effects of pro - inflammatory cytokine induced indoleamine 2,3-dioxygenase ( ido ) and stress / cortisol - induced tryptophan 2,3-dioxygenease ( tdo ) , which drive tryptophan to trycat synthesis , are reviewed .
this is looked at in the context of coordinated alterations in levels and activation of serotonin and the melatonergic pathways .
the interactions of these pathways have significant consequences for the levels and activity of the a7nachr and aryl hydrocarbon receptor .
the interactions of these pathways and receptors may not only be by the regulation of intracellular neuronal , glia , and immune cell pathways and activity but also directly within mitochondria .
indoleamine 2,3-dioxygenase is induced by the pro - inflammatory cytokines , interleukin ( il)-1b , il-6 , il-18 , and tumor necrosis factor ( tnf- ) , but especially interferon-. stress , and the stress hormone cortisol , can also lead to trycat induction via tdo activation . by driving tryptophan down the trycat pathways , ido and tdo lead to the production of a number of neuroregulatory products , including kyna , which has protective effects via its inhibition of glutamatergic receptor activation , including the n - methyl - d - aspartate receptor .
as such , kyna induction has been proposed as a significant treatment target under conditions associated with excessive excitatory glutamatergic activity , including for epilepsy and multiple sclerosis ( ms ) .
another commonly researched trycat is quin , which is excitotoxic and increased in a number of cns and psychiatric conditions , where it contributes to neuronal and cognitive losses .
another frequently investigated trycat is 3-hydroxykunurenine ( 3-ohk ) , which is increased in alzheimer disease and major depressive disorder ( mdd ) , as well as other cns and psychiatric disorders .
as indicated in figure 1 , any inhibition of kynurenine aminotransferase ( kat ) will decrease kyna synthesis and drive an increased synthesis of 3-ohk , which may further be enzymatically converted to quin and oxidized nicotinamide adenine dinucleotide ( nad+ ) .
as such , any kat inhibition , by decreasing kyna and increasing 3-ohk and quin , will contribute to cellular damage and/or inflammatory processes .
the initial conversion of tryptophan by tryptophan hydroxylase leads to the synthesis of serotonin and melatonin .
when stress and pro - inflammatory cytokines are increased , inducing tdo and ido , respectively , tryptophan is driven down the kynurenine pathway leading to the increased synthesis of tryptophan catabolites .
recently , we showed that an increase in the kynurenine / kyna ratio is evident in mdd and chronic fatigue syndrome / myalgic encephalomyelitis , but only in association with the somatization that is dramatically increased under these conditions .
as to whether this is mediated by an increased availability of kynurenine for conversion to 3-ohk and quin requires further investigation .
however , it does indicate how the classical association of mdd with an array of different neurodegenerative conditions , such as alzheimer disease , ms , and parkinson disease , may be mediated by particular aspects of mdd , namely , somatization , that are intimately associated with trycat pathway alterations .
most cns and psychiatric conditions show an increase in the kynurenine / kyna ratio , with increased levels in the kynurenine / tryptophan ratio also evident in many neuropsychiatric conditions , including mdd , bipolar disorder , schizophrenia , alzheimer disease , and ms .
given that the biological underpinnings of mdd may act on processes that biologically prime or accelerate the pathophysiology of such cns disorders , it requires investigation as to whether it is the somatization aspect of mdd , via increased kynurenine / kyna ratio , that is mediating the mdd influence on the etiology and course of these cns and psychiatric conditions .
it is of note that more than 60% of central kynurenine is peripherally derived , indicating the influence that peripheral inflammatory processes may have on levels of neuroregulatory trycats .
overall , trycats may be significant effectors of how oxidative and nitrosative stress and pro - inflammatory cytokines mediate their influence on cns and psychiatric conditions .
however , in addition to increasing trycats , the activation of ido and tdo drives down serotonin levels and therefore melatonergic pathway activity .
the methoxyindole n - acetyl-5-methoxytryptamine ( melatonin ) is primarily known for its nighttime release by the pineal gland , by which means it has a significant role in circadian rhythm entrainment .
this is of some importance as circadian dysregulation is a significant clinical aspect of many cns and psychiatric conditions , including alzheimer disease and bipolar disorder .
however , accumulating data show melatonin to be released by many different cell types , including enterochromaffin cells of the gut , glia , and immune cells . in the gut ,
melatonin release can be up to 400-fold greater than its maximal pineal gland release levels , with gut melatonin contributing to the maintenance of the gut barrier . in immune cells , the autocrine effects of melatonin lead to an anti - inflammatory phenotype that acts to prevent excessive pro - inflammatory activity .
on the basis of a growing body of evidence , melatonin has been proposed to be released by all mitochondria - containing cells , including possibly from within mitochondria .
induced ido or stress - induced tdo , by increasing trycat and decreasing serotonin for the melatonergic pathways , may have significant consequences for a wide array of physiologic and pathophysiologic processes that melatonin acts to regulate .
alterations in the levels of melatonergic pathway activity may also have significant and direct impacts on mitochondrial functioning .
melatonin has powerful effects on many fundamental cellular processes , including being a powerful antioxidant and driver of nuclear factor erythroid 2 ( nf - e2)-related factor 2 ( nrf2)-induced endogenous antioxidants ; increasing sirtuin-1 , the longevity protein , which regulates mitochondrial functioning and aging - associated processes ; being an anti - inflammatory , including from its autocrine release by immune cells ; being a clinically relevant antinociceptive ; and being an optimizer of mitochondrial functioning and enhancing neurogenesis levels .
such an array of effects highlights the relevance of altered melatonergic pathway activation under conditions of trycat induction .
serotonin is enzymatically converted by arylalkylamine - n - acetyltransferase ( aanat ) to nas , with nas then enzymatically converted by hydroxyindole o - methyltransferase ( hiomt ) ( also known as acetylserotonin methyltransferase ) to melatonin .
melatonin synthesis is therefore highly dependent on the levels of tryptophan availability for serotonin production and on the levels of serotonin degradation by monoamine oxidase ( mao ) . as such , many of the protective and clinical effects of different types of antidepressants , such as selective serotonin reuptake inhibitors and mao inhibitors , may ultimately be mediated by their regulation of local melatonin synthesis .
notably , it is not only increased central melatonin and nas that is mediating such effects but also melatonergic pathway activation in a variety of systemic systems and peripheral processes , including in the regulation of gut microbiota and gut permeability .
it should also be noted that melatonergic pathway activation leads to the synthesis and efflux of both nas and melatonin .
nas and melatonin are amphiphilic , allowing their ready diffusion across cell membranes , as well as intercellularly .
although far less investigated than melatonin , nas has many similar effects , including as an antioxidant , neurogenesis inducer , and mitochondria regulator .
n - acetylserotonin also mimics the effects of brain - derived neurotrophic factor ( bdnf ) via the activation of tropomyosin receptor kinase b ( trkb ) , a bdnf receptor .
some melatonin is also converted back to nas , whereas other factors , such as increased adenosine triphosphate , may inactivate hiomt , leading to only nas synthesis and release .
consequently , an array of factors can modulate the nas / melatonin ratio , which may be of relevance to the cause and course of the pathophysiologic processes that underlie glioblastoma and bipolar disorder which may be primarily mediated by the differential effects of nas and melatonin on the activation of trkb and a7nachr , respectively .
it should also be noted that many of melatonin s metabolites , including n1-acetyl - n2-formyl-5-methoxykynuramine and n1-acetyl-5-methoxykynuramine , also have significant anti - inflammatory , antioxidant , and immune regulatory effects . as such
, melatonergic pathway activation leads to the synthesis of products with antioxidant and generally beneficial effects that are relevant to all cns and psychiatric disorders .
it is also clear that the products of the melatonergic pathway also have some quite specific effects that are likely to be of clinical relevance across different cns conditions , including via melatonin s regulation of the a7nachr and the nas activation of trkb .
it remains to be determined as to whether there are other differential effects of the various products of the melatonergic pathways that would be relevant to cns and psychiatric disorders .
although many of melatonin s effects can be via the activation of the melatonin receptors ( mt1 and mt2 ) , melatonin also has powerful nonreceptor effects , aided by its amphiphilic nature .
melatonin frequently accumulates around mitochondria , where it may have an important role in the regulation of membrane fluidity , as recent data indicate .
structural membrane regulation may be another aspect of how melatonin can act to modulate and synchronize wider cellular processes .
the 14 - 3 - 3 protein is a crucial determinant of pineal gland melatonergic pathway activity , due to its stabilization of aanat , indicating that alterations in 14 - 3 - 3 levels will significantly modulate nas and melatonin synthesis in other cell types .
this role of 14 - 3 - 3 is likely to have significance in a number of cns and psychiatric disorders . in motor neuron disease , for example , 14 - 3 - 3 levels are often increased .
however , in this medical condition , 14 - 3 - 3 is mostly in a complex with mutant superoxide dismutase , thereby preventing its stabilization of aanat .
this suggests that decreased nas and melatonin synthesis may be relevant to the array of pathophysiologic changes that are evident in a number of cell types in this poorly conceptualized and poorly managed condition .
it is also of note that antidepressants increase a number of 14 - 3 - 3 isoforms , suggesting that some of their efficacy is mediated via effects on melatonergic pathway regulation , as well as increasing serotonin availability .
tumor necrosis factor and other pro - inflammatory cytokines inhibit pineal gland nas and melatonin synthesis , whereas increased adenosine triphosphate prevents the conversion of nas to melatonin , suggesting a significant impact on the nas / melatonin ratio .
as such , the melatonergic pathways may be regulated by a variety of cellular and systemic processes , in turn acting to modulate the reactivity of glia and immune cells .
interestingly , the regulation of inflammatory processes may be intimately linked to the synchronized regulation of the pineal gland and immune / glia reactivity .
the work of regina markus and colleagues indicates the presence of an immune - pineal axis . by pro - inflammatory cytokines switching off pineal gland melatonin synthesis ,
the generally immune - dampening effects of pineal gland melatonin are prevented during the course of infection and inflammation , allowing an appropriate immune response to develop .
however , when the immune response is no longer required , the autocrine effects of melatonin on activated immune cells lead to a dampening of the immune response and therefore the reinstatement of pineal gland melatonin synthesis .
as such , alterations in melatonin synthesis , in the pineal gland and immune cells , may be intimately associated with consequences for alterations in circadian regulation and the temporal coordination of the immune response .
melatonergic pathway regulation is therefore intimately linked to an array of core cellular and systemic processes .
melatonin effects contrast with many trycat effects , including in the levels and activity of the a7nachr , when compared with kyna effects on this receptor .
the a7nachr is also expressed in many immune cells and gut cells , as well as in the vagal nerve and cells of the enteric nervous system .
activation of the neuronal presynaptic a7nachr increases the influx of calcium and sodium ions , increasing neurotransmitter release .
activation of the a7nachr also regulates endothelial cells , neurogenesis , macrophages , t cells , and immature dendritic cell maturation , indicating a wide array of non - neuronal effects .
the a7nachr also inhibits the immune - activating consequences arising from increases in gut permeability , possibly via the regulation of vagal nerve activity , as well as having analgesic and cognitive - enhancing effects .
given the wide expression of the a7nachr and the possibly ubiquitous expression of melatonin , it is likely that interactions of the a7nachr and melatonin will occur in many central and peripheral sites , including in immune cells , glia , and the gut - brain axis .
for example , melatonin s protection against rodent ischemia is a7nachr dependent . both melatonin and a7nachr activation
the interactions of melatonin and the a7nachr may therefore affect a number of processes , including glia reactivity , macrophage reactivity , autophagy , and gut - brain axis .
this will be looked at in more detail below , including in the context of interactions within mitochondria .
the aryl hydrocarbon receptor ( ahr ) , commonly referred to as the dioxin receptor , is widely expressed , both centrally and systemically .
investigations of ahr effects have widely used 2,3,7,8-tetrachlorodibenzo - p - dioxin ( tcdd ) . however
, different trycats can also activate the ahr , suggesting that this could be an important consequence of trycat induction .
the ahr is a ligand - activated receptor of the per - arnt - sim family of basic helix - loop - helix transcription factors .
in addition to cigarette smoke associated tcdd , a growing number of endogenous ahr ligands have emerged , including kynurenine , kyna , and formylindolo(3,2-b)carbazole .
exogenous ligands include an array of environmental toxins , such as many of the particulate matter components of air pollution , which can alter the gut microbiome and increase gut permeability .
when ligand bound , the ahr translocates to the nucleus , where it binds to the ahr nuclear translocator ( arnt ) , with this ahr - arnt heterodimer binding to dioxin - responsive elements in the promoters of target genes .
target genes include the cytochrome p450 family ( including cyp1a1 , cyp1a2 , and cyp1b1 ) , with these target genes then acting to regulate an array of factors , including many pharmaceuticals , but also melatonin , suggesting a role for the ahr in the modulation of the circadian rhythm , as well as levels of local melatonin availability in many cell types . a number of pathways can interact with the ahr , especially in the formation of the ahr - arnt complex .
the ahr has recently been reconceptualized , from a xenobiotic receptor to one where an array of endogenous ligands may have a variety of effects on ahr - induced genes .
the ahr can therefore have complex effects , with different ahr ligands seemingly having differential effects on the patterning of the specific genes induced .
the ahr activation , via increased ido , can induce the trycat pathway , as well as increase immune - suppressive regulatory t cells .
however , the ahr can also increase the levels of autoimmune - associated pro - inflammatory t - helper 17 cells .
consequently , the ahr has complex effects , seemingly determined by specific ligands and local microenvironmental conditions , in part via the differential regulation of xenobiotic or dioxin response elements ( x / dre ) as well as non - x / dre - mediated pathways . as the ahr repressor ( ahrr )
is induced by ahr binding to x / dre in the ahrr promoter , the ahr negatively feeds back on itself .
this also indicates that the non - x / dre effects of the ahr will not affect ahrr expression , suggesting that variations in ahrr induction may contribute to the complex effects and inductions of the ahr .
recent data support a role for the ahrr in the regulation of specific pro - inflammatory cytokines , including il-1b , but not all pro - inflammatory factors are induced by the ahr .
the ahr , via ido induction , can directly regulate trycat production , with kynurenine and kyna also activating the ahr , suggesting a possible positive feedback loop that would be inhibited by the ahrr .
ahr activation , via cyp1a2 , also degrades melatonin , with melatonin inhibiting some ahr effects , indicating interactions of the ahr with the melatonergic pathways .
such data indicate a role for the ahr in the interactions of the melatonergic and trycat pathways and therefore with the effects of the a7nachr .
although all of these factors may differentially interact in different cell types and local microenvironments , it is their expression and interactions directly in mitochondria that this article will now focus on .
recent data show that the ahr is expressed in mitochondria , including in the mitochondrial intermembrane space . with the a7nachr and
the melatonergic pathway synthesis enzyme ( aanat ) also expressed in mitochondria , coupled with the direct effects of the trycats , 3-ohk , and 3-hydroxyanthranillic acid ( 3-oh - ana ) , on mitochondrial functioning , mitochondria may be important sites for the interactions of these pathway and receptors .
we review the data pertaining to these receptors and pathways in mitochondria , before looking at how they may interact in this crucial organelle .
some of the effects of kynurenine and kyna are mediated via its activation of the ahr , although at physiologic levels kynurenine and kyna can have quite distinct effects . as to whether kynurenine or kyna can directly activate
the ahr in mitochondria is an area of current investigation , including in the gut where the ahr can modulate the iga mucosal response , indicating a possible ahr role in the gut that would be relevant to levels of mucosal immune - inflammatory activity that are increasingly appreciated as having a role in a host of cns and psychiatric conditions .
there is a growing appreciation of the role of early developmental processes in an array of cns and psychiatric conditions , as well as recognition of a role for suboptimal vascular functioning and cardiovascular disease in such classically conceived brain disorders . in this context , it is notable that the ahr has significant early developmental impacts in cardiomyocytes that increase cardiovascular disease ( cvd ) risk , with cardiomyocytes being densely packed within mitochondria . as such , alterations in the early developmental regulation of the ahr may play a role in a host of medical conditions that can modulate many cns and psychiatric disorders , as well as having direct impacts on cells classically linked to brain disorders .
it is also important to emphasize that trycat pathway activation may lead to other factors that directly modulate mitochondrial functioning , with 3-oh - kyn and 3-oh - ana directly affecting the respiratory control index of brain mitochondrial functioning .
these authors also showed that both of these trycats lowered the adenosine diphosphate / oxygen ratio in brain mitochondria , as well as having impacts on hepatic and cardiac mitochondria .
such data indicate that the classical role attributed to trycats in the regulation of synaptic activity of cns and psychiatric disorders may be overly simplistic .
rather , some trycats may more directly modulate mitochondrial functioning across a host of cell types .
tcdd , the classical ahr ligand , has a plethora of pathophysiologic effects in different cell types , including changes in mitochondrial functioning and increasing the risk of metabolic syndrome . as to whether changes in specific trycats , and their direct effects in mitochondria , are relevant to how metabolic syndrome increases the risk of cns and psychiatric disorders , such as alzheimer disease and mdd , requires further information . as to how such 3-ohk and 3-oh - ana effects in mitochondria would modulate levels of mitochondrial melatonergic pathway activity and melatonin production requires investigation .
as aanat needs to be stabilized by 14 - 3 - 3 , it may be of note that proteomic analysis of hippocampal cells of patients with schizophrenia indicates coordinated changes in the levels of 14 - 3 - 3 and the ahr .
inhibition of 14 - 3 - 3 is used as a preclinical model of schizophrenia .
desynchronization of 14 - 3 - 3 and the ahr may therefore be of some importance in psychiatric conditions .
it requires investigation as to whether the trycat pathway , including via direct effects in mitochondria , modulates the melatonergic pathway , including within mitochondria , and as to whether alterations in 14 - 3 - 3 levels are relevant to this . in addition to decreasing serotonin availability as a necessary precursor for the melatonergic pathways , trycat effects in mitochondria , including possibly in mitochondrial ahr , may also act to regulate the melatonergic pathways . as indicated above , emerging data now indicate melatonergic pathway activity in mitochondria , with levels of mitochondrial melatonin synthesis dependent on serotonin availability . as such
, the regulation of mao , which can bind to the mitochondrial membrane , may be another target for the regulation of melatonergic pathway activation in mitochondria .
alterations in mao function have been associated with most cns and psychiatric disorders , possibly as a consequence of chronic stress increasing mao and therefore decreasing the availability of monoamines , including serotonin .
these authors also showed that exogenous melatonin prevented chronic stress induced mao in preclinical models , implicating alterations in melatonin in the increase in mao that is induced by chronic stress .
activation of the ahr by tryptamine requires mao , being another route by which chronic stress may act to modulate ahr activity , including possibly in mitochondria , and thereby increase melatonin metabolism .
it is also of note that melatonin has impacts on the structural organization of the lipids that form the cell and organelle membranes , including mitochondrial membranes . as to whether alterations in mitochondrial melatonin synthesis have any impacts on wider mitochondrial functions via such membrane lipid changes requires further investigation .
overall , melatonin is a significant regulator of mitochondrial functioning , suggesting that factors that modulate melatonin synthesis in mitochondria are likely to affect an array of fundamental cellular processes .
mitochondria express the a7nachr , with the a7nachr acting to regulate ca accumulation and cytochrome c release in isolated mitochondria .
as noted , melatonin can increase the levels and activation of the a7nachr , suggesting that the interactions of the trycat and melatonergic pathways will affect the levels and activity of the a7nachr , including in mitochondria .
it also important to note that the specific trycats produced may be of some relevance , as kyna inhibits the a7nachr .
given that the a7nachr may mediate some of melatonin s effects , ido induction may not only decrease melatonergic pathway activity but also increase kyna , thereby inhibiting melatonin s effects via the a7nachr .
this indicates that there may be a number of means by which the trycat and melatonergic pathways engage in mutual inhibition .
however , this may be primarily under conditions when the kyna wing of the trycat pathway is predominantly activated , which is likely to be considerably different to the activation of the 3-ohk , 3-oh - ana , and quin wing .
the relevance of the a7nachr in mediating the interactions of wider trycats with the melatonergic pathways awaits investigation .
this is likely to be of some importance , given the role of the a7nachr in the regulation of reactivity levels in glia , macrophages , and other immune cells .
this also suggests that the biological underpinnings in the recent phase iii trials of a7nachr agonists may be considerably more complicated than simple alterations in synaptic activity .
such an array of data indicates that mitochondria may be a crucial hub for the interactions of the ahr and a7nachr with the trycat and melatonergic pathways .
the ahr activation , including when activated by kyna and kynurenine , can also decrease nad+ levels , thereby decreasing levels of sirtuins , as has been shown for sirtuin-3 in hepatic cells .
although sirtuin-1 is commonly referred to as the longevity protein , data in humans , to date , only show alleles in sirtuin-3 to modulate human longevity .
as such , the interacting pathways and receptors described herein , by acting on nad+ induced sirtuins , may affect aging processes .
this is of obvious relevance to almost all medical conditions , including cancers and cvd , as well as to cns and psychiatric disorders .
pro - inflammatory cytokines and chronic stress increase ido and tdo , respectively , leading to trycat induction , with differential effects on mitochondrial functioning . trycat activation and stress - induced mao , by decreasing serotonin availability ,
ahr activation , via ido induction , may positively feedback on trycat synthesis , as well as decrease the availability of melatonin by increasing its metabolism .
some data indicate that the ahr decreases sirtuins , which may also be mediated by decreased melatonin .
3-oh - ana indicates 3-hydroxyanthranillic acid ; 3-ohk , 3-hydroxykynurenine ; a7nachr , alpha 7 nicotinic receptor ; ahr , aryl hydrocarbon receptor ; ido , indoleamine 2,3-dioxygenase ; kyna , kynurenic acid ; mao , monoamine oxidase ; tdo , tryptophan 2,3-dioxygenase ; trycats , tryptophan catabolites .
the overlapping benefits of melatonin and the a7nachr over an array of diverse medical presentations and pathophysiologic processes have been primarily attributed to their antioxidant effects and neuronal regulation , respectively .
the trycats have been portrayed as neuroregulatory effectors of pro - inflammatory processes , whereas the ahr has primarily been viewed as a modulator of specific immune activators .
the data presented here suggest that these diverse processes and effects may be mediated by the interactions of these receptors and pathways directly in mitochondria .
such a perspective dramatically changes the understanding of the consequences of alterations in tryptophan utilization in the body and suggests readily achievable future experiments , with significant clinical implications .
mitochondria have long been recognized as important sites of pathophysiological change across most medical conditions , including cancers and cvd , as well as cns and psychiatric disorders .
the mitochondrial interactions of the receptors and pathways described above are likely to be important determinants of an array of medical pathophysiological processes , including via alterations in the levels of aging - associated sirtuins within mitochondria .
it should be noted that such mitochondrial interactions , which are relevant to the cause and course of cns and psychiatric disorders , will not all be occurring centrally , but also in systemic systems , including the immune system , and peripheral organs and tissues , including the gut and the gut - brain axis .
Output:
| recent work indicates an intimate interaction of the tryptophan catabolite ( trycat ) pathways with the melatonergic pathways , primarily via trycat pathway induction taking tryptophan away from the production of serotonin , which is a necessary precursor for the melatonergic pathways .
the alpha 7 nicotinic receptor may be significantly modulated by this interaction , given its inactivation by the trycat , kynurenic acid , and its induction by melatonin .
similarly , the aryl hydrocarbon receptor is activated by both kynurenic acid and kynurenine , leading to cyp1a2 and melatonin metabolism , whereas melatonin may act to inhibit the aryl hydrocarbon receptor .
these 2 receptors and pathways may therefore be intimately linked , with relevance to a host of intracellular processes of clinical relevance . in this article , these interactions are reviewed .
interestingly , mitochondria may be a site for direct interactions of these pathways and receptors , suggesting that their differential induction may not only be modulating neuronal , glia , and immune cell processes and activity but also be directly acting to regulate mitochondrial functioning .
this is likely to have significant consequences as to how an array of diverse central nervous system and psychiatric conditions are conceptualized and treated . |
PubmedSumm118281 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
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the input is a biomedical literature
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the output is the summary of an input biomedical literature in six sentences
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Input: the past few years have seen a call for interdisciplinary research on the brain , including decade of the mind ( dom ) , an international initiative for basic neuroscience research on the mind including mental health , high - level cognitive function , education , and intelligent machines ( albus et al . , 2007 ) . despite dom 's interest in moving brain research beyond the clinic , to date anthropological research
has not been well represented in such interdisciplinary discussions . at the same time , however , there has been growing interest in incorporating neuroscience perspectives into anthropology , as exemplified by the encultured brain conference , oct 8th 2009 at notre dame university .
biological anthropology , with its concern for human brain evolution ( falk , 2004 ; holloway , 2008 ) , has embraced the insights of neuroscience into the origins of human cultural capacities ( deacon , 1998 ; rilling , 2008 ) .
social anthropology , on the other hand , with its focus on cultural variation in human experience , has been a philosophical holdout against reductionist neuroscience
. however , recent research has made it clear that these three fields have much to offer one another in creating a holistic conception of the role of the evolved brain in human culture
we suggest that evolutionary neuroscience can be used to bridge knowledge obtained by social scientists with that obtained in the neurosciences for a more complete appreciation of the mind .
more specifically , neuroscience can bring information about neurological mechanisms , evolutionary processes and primate context to enrich more traditional anthropological perspectives on human experience . to demonstrate this point
, we provide an example of how our understanding of embodiment , a term used by anthropologists to denote the subjective experience of the body , can be complemented by evolutionary neuroscience . as shown below , far from reducing embodiment to neural processes , a neurological and evolutionary perspective on embodiment open up new vistas for neuroanthropologists to explore in studying cultural variation in human experience .
as defined by anthropologists , embodiment is the subjective experience of the body , but not the physiological body ( csordas , 1990 ) . as such , embodiment
is generally considered to represent a culturally generated experience of the body and has been approached ethnographically ( csordas , 1990 , 1994 ) , including its expression in ritual ( strathen and stewart , 2008 ) . however , because ethnography relies largely on verbal description , the term embodiment has traditionally been limited to philosophical and/or ethnographic discourse , and carries post - modern connotations for many neuroscientists . from the perspective of the neurosciences , the subjective experience of the body must logically be instantiated in the brain .
the neural questions underlying embodiment are clear : where is the subjective representation of body located and functionally processed in the brain ? and is such a representation highly integrative ? a highly integrative representation of subjective somatic experience would make the neurological contribution to embodiment more compelling , yet still require environmentally - specific explanation in terms of variable expression .
understanding embodiment in terms of its neurological correlates allows for more holistic investigation into both internal psychological and external socio - cultural factors .
thus , neuroanthropology becomes a truly consilient perspective by which to tackle the cultural context of our evolved human brain .
the infusion of evolutionary principles into areas of neuroscientific investigation have spurred intellectually rewarding theoretical and predictive study , as demonstrated by platek , et al .
( 2007 ) work on evolutionary cognitive neuroscience as a new and emerging field of inquiry .
similarly , neuroanthropology combines input from evolutionary biology , behavioral neuroscience , and cultural anthropology , to attempt a deeper appreciation of how the cultural context of the evolved brain can influence individual experience . to begin to appreciate the physiology of embodiment
, craig refers to embodiment in terms of recent findings demonstrating the integration of somatosensory , homeostatic , and emotional information within the insula suggesting a specific location for a global somatic representation ( craig , 2002 , 2009 ) .
the insula cortex is part of the cerebral cortex and lies deep within the lateral sulcus , overlain by the opercula .
the insula is at the base of the parietal lobe with important inputs from other sub - cortical structures including the thalamus , anterior cingulate cortex , and amygdala ( craig , 2002 ) .
such bodily representation is not to be confused with penfield 's famous homunculus map of the body represented in the cortex .
rather , embodiment may be best thought of as somatic mood , a feeling that is not closely tied to language , perhaps helping to account for the subjective and elusive nature of its linguistic description . in its positive form
we will use the term emotional embodiment to distinguish the insular representation from the use of embodiment in conjunction with language and cognition ( see for instance clark , 2006 ) .
the insula and anterior cingulate cortex have been implicated in recent studies of ritual spiritual practices , including meditation ( lazar et al . , 2005 ; lutz et al . ,
2009 ) , yoga ( kakigi et al . , 2005 ) , and shamanism ( riba et al . , 2006 ) .
thus the neural correlates of emotional embodiment not only reflect our evolutionary heritage , but have become an object of cultural practice .
in fact , findings showing that individuals who are more aware of their own heart beat exhibit greater activation in the insula and experience stronger emotions ( critchley et al . , 2004 ) , suggest that some individuals may be more intrinsically skilled at such practices than others .
recent findings indicate that the relationship between emotion , the insula , anterior cingulate cortex , and autonomic nervous system function is central to meditation .
for instance , experienced compassion meditators showed greater activation of the insula to negative sounds ( lutz et al . , 2008 ) and
such activation was more strongly tied to heartbeat relative to novices ( lutz et al . , 2009 ) .
( 2005 ) report increased thickness of the insula among meditators who focused on internal awareness , suggesting long - term internal awareness can lead to increased development of the neural structures of embodiment . in a more exotic example , kakigi et al .
( 2005 ) investigated brain activity in a japanese yoga master who claimed to be impervious to pain while meditating .
they report decreased activity in the insula and anterior cingulate cortex during meditation relative to a non - meditative state , regions already mentioned to be central to the emotional aspects of pain ( singer et al . , 2004 ;
more such studies are needed to see if such findings are common among yogis who claim similar powers .
the anterior cingulate and insula have been implicated in other ritual healing practices as well .
ayahausca , a south american psychoactive plant tea , is known to have dramatic effects on bodily and emotional perceptions ( riba et al . , 2001 ) .
( 2006 ) report that the ingestion of ayahausca is associated with increased brain activity in the right anterior insula and the anterior cingulate cortex , consistent with previous findings on the neural correlates of emotional embodiment , and empathy .
thus the ingestion of ayahausca by traditional shaman may be important in generating an empathetic state that allows them to experience the feelings of afflicted individuals during their spirit journey and facilitate healing ( dobkin de rios , 1984 ) .
interestingly , the involvement of the anterior cingulate cortex and insula in meditation , yoga , and shamanic practices appears to be mirrored by the activation of both structures in long - term romantic relationships .
this investigation is consistent with jankowiak and fischer 's landmark study showing that romantic love , although culturally and idiosyncratically variable , is a cross - cultural and human universal ( jankowiak and fischer , 1992 ) . among individuals who reported being romantically in love ,
the anterior cingulate cortex and insula cortex were not very active during the first 8 months ( aron et al . , 2005 ) , but become more active from 8 to 17 months ( aron et al .
further , bartels and zeki ( 2000 ) found that activation of the anterior cingulate and insula cortex were clearly involved in feelings of romantic love among individuals who reported being in love for an average of over 2 years .
alcorte and sosis ( 2005 ) argue that one defining experience of ritual is a feeling of intense joy ( ritual can also invoke powerful negative feelings as well ) , a feature they associate with dopaminergic neurotransmission .
given activation of insula and anterior cingulate cortex in meditation , yoga , ingestion of ayahausca , as well as romantic love , spiritual healing practices may , in fact , as many of them claim , draw on the positive neurological experience of love .
rilling ( 2008 ) has suggested that anthropologists might make their best contribution to a deeper understanding of the human brain by concentrating on the neural basis of behaviors uniquely developed in humans and critical to the evolution of the human brain , including language ( deacon , 1998 ) , tool making ( stout and chaminade , 2007 ; stout et al . , 2008 ) , mental perspective - taking ( amodio and frith , 2006 ) , and altruism ( moll et al . ,
we suggest that emotional embodiment , that is the global representation of bodily status as somatic mood , is also critical to the evolution of the human brain and deserves special focus from neuroscientists and anthropologists alike .
bodily awareness has been argued by numerous philosophers and neuroscientists , including william james and antonio damasio , as the basis of human consciousness ( see prinz , 2004 for a more recent example ) .
the insula and anterior cortex is not only central to elements of somatic awareness , such as pain ( singer et al . , 2004 ; jackson et al . , 2006 ) but also to empathy ( lamm et al . , 2009 ) , racial group identity ( xu et al . , 2009 ) , social norm violation ( king - casas et al . , 2008 ) , and moral intuitions ( woodward and allman , 2007 ) , thus linking somatic awareness to social emotions .
based on anatomical evidence , craig ( 2002 ) argues that the incorporation of c and a nerve fibers into the spinothalamic lamina i tract provides primates with an integrated representation of physiological status not found in other mammals .
such fibers arise from nearly every cell of the body , including some that respond to lactic acid in muscle and provide information about peripheral metabolism processes . furthermore , among primates , the termination of the tract in the posterior ventromedial nucleus with the thalamus ( vmpo ) means that all such information is integrated in a single location providing a global emotional representation of the body ( craig , 2002 ) .
compared to anthropoid primates however , the representation of somatic status appears to be elaborated in humans .
humans exhibit a relatively larger vmpo . while in non - human primates some of the spinothalamic lamina
i neurons go directly to the orbitofrontal cortex , in humans , they all pass through the insula , in particular the right anterior insula ( craig , 2002 ) .
this allows for a fuller representation of somatic status , which is then passed on to the orbital frontal cortex where it serves as an hedonic input for decision - making ( wallis , 2007 ) .
the social brain hypothesis holds that it is the demands of complex social interactions in groups that have spurred the adaptive increase in brain size across the biological order primates ( dunbar , 1998 , 2009 ) , a relationship not found in other mammalian orders ( shultz and dunbar , 2007 ) .
the importance of bonding among primates would explain why affiliation through physical touch initiates a neurochemical cascade , involving oxytocin and opiates , that is positively reinforcing and fundamental to effective social cohesion ( dunbar , 2010 ) .
while such neuroendocrine mechanisms remain important in human social interaction , they do not appear sufficient to explain group cohesion among humans for whom language and technology form the foundation for greatly expanded spheres of social interaction .
humans and the great apes ( hominidae ) , but not other primates , exhibit von economo neurons ( vens ) linking both the frontoinsular and anterior cingulate cortex ( acc ) to other areas of the prefrontal cortex ( nimchinsky et al . , 1999 ) .
the density of vens is related to the degree of sociality exhibited across the four genera of great apes orangutans ( pongo ) , gorillas ( gorilla ) , chimpanzees ( pan ) , and humans ( homo ) .
these findings suggest a potentially similar role for emotional embodiment in complex social behavior , together with similarities in the prefrontal cortex , between humans and the other great apes ( semendeferi et al . , 2002 ) .
in humans , the neural correlates of emotional embodiment appear to be particularly well developed . along with a large and well developed insula ( craig , 2009 ) , humans demonstrate both greater density of ven linking the acc and insula relative to the apes ( nimchinsky et al . , 1999 ) as well as the presence of ven in the dorsolateral prefrontal cortex ( fajardo et al . ,
, 2001 ; woodward and allman , 2007 ) suggest that limbic / cortical connections through vens provide a neural pathway for rapid processing of complex social information which they argue underlies so - called moral intuition ( woodward and allman , 2007 ) .
importantly , both the insula and acc are active in response to the perception of fairness in social interactions ( hsu et al .
2009 ) . while the notion of fairness may seem a long step from bodily awareness , it represents a logical extension of threats to bodily awareness into the social sphere , or social embodiment
( singer , 2007 ) . to the extent that others actions threaten bodily survival they are unlikely to be experienced as
, 2003 ) suggests that fairness may be linked to survival because group exclusion is perceived as potentially threatening to survival .
the salience of the neural correlates of emotional embodiment extends to vocalization , language , and music , all important elements in ritual .
recent studies indicate that the insula is active in the response to the prosody or emotional content of language ( dietrich et al . , 2008 ; quadflieg et al . , 2008 ; ethofer et al . ,
2009 ) , laughing and crying ( sander and scheich , 2005 ) , and music listening ( brown et al . , 2004 ) .
in fact , music and speech perception overlap in the insula ( brown et al .
2006 ) , and the dorsal anterior insula may be specific for processing language and auditory information ( mutschler et al . , 2009 ) .
while language may facilitate social communication among larger human groups , its role in social cohesion is linked to emotional elements of vocalization clearly expressed in laughing , crying , and music .
biological anthropologists are particularly attuned to substantial population variation in somatic growth based on energy balance ( the difference between consumption and output ) related to subsistence patterns and cultural consumption practices ( stinson , 2000 ) .
however , much less attention has been given to the potential impact of energetics for population variation specifically in terms of brain development .
this reflects an assumption that the brain is prioritized for energy ( fehm et al . , 2006 ) and hence should suffer little from variation in energy supply ( campbell , in press ) .
however , given that the development of the prefrontal cortex during the first 15 years of life is directly related to glucose utilization ( chugani , 1998 ) , and that cortical development is a sequential hierarchical process ( gogtay et al . , 2004 ; shaw et al . , 2008 ) , brain development may be more sensitive to fluctuations in energy availability than currently considered ( vaynman and gomez - pinilla , 2006 ) . more specifically , given that the insula and acc exhibit elevated glucose utilization relative to the prefrontal cortex from the age of 6 years into the 20 s ( van bogaert et al .
, 1998 ) , food availability may have important implications for the development of emotional embodiment and hence empathy , notions of fairness , and artistic development .
there is relatively little evidence linking chronic undernutrition to specific aspects of brain development in humans .
however , recent findings demonstrate altered insula activity in anorexia nervosa ( nunn et al .
altered insula activity is related not only to changes in the taste of food , but also distorted self - body perception ( sachdev et al . ,
in addition , the size of the acc is reduced in an ( mhlau et al .
, 2007 ; mccormick et al . , 2008 ) , an effect that appears to reflect the degree of weight loss ( mhlau et al . , 2007 ) and is reversible with weight gain ( mccormick et al . , 2008 )
importantly , both the ability to indentify emotions ( miyake et al . , 2009 ) , and impaired cognitive set shifting ( zastrow et al . , 2009 ) among individuals with an
together these findings implicate the acc and insula in body perception , emotion , and intellectual performance , a combination of traits suggestive of emotional embodiment .
an is a chronic pathological condition and hence represents an extreme case for the potential malleability of the insula and acc in brain development .
( 2008 ) recently reported that a small sample of chronically unnourished children aged 5 to 10 years from india show reduced cognitive function .
deficits included attention , working memory , learning and memory , and visuospatial ability but not motor speed and coordination .
furthermore , while attention scores increased with age among the malnourished children , those of design fluency , working memory , visual construction , learning and memory did not . the authors conclude that chronic malnutrition specifically underlies deficits in higher cognitive functions .
these results are especially important because the ages of 5 to 10 years coincide with middle childhood , a time of elevated glucose utilization and overall brain plasticity ( chugani , 1998 ) , as well as important changes in social , emotional , and intellectual skills ( piaget , 1963 ) , including the development of reason and responsibility ( white , 1996 ) . thus given the hierarchical and sequential nature of cortical maturation ( gogtay et al .
, 2004 ; shaw et al . , 2008 ) , alterations in brain development during this stage may have important consequences for the long - term maturation of emotion , social emotion , and morality .
surprisingly , the role of physical activity in brain development may be particularly relevant in our own society .
recent work pointing to the importance of motor activity in the early development of the brain ( diamond , 2001 ) as well as the impact of physical exercise on learning in both school age children and adults ( ploughman , 2008 ) are consistent with the continued importance of elevated levels of physical exercise thought to characterize our hunting and gathering ancestors ( vaynman and gomez - pinilla , 2006 ) .
thus the simple recognition of the importance of physical activity for learning and the detrimental effects of a sedentary lifestyle as associated with video games and heavy use of the internet may do more for reviving our education and health care systems than any other single brain based pedagogical programs .
cultural neuroscience is already revealing important dichotomies in the activation of brain regions for such basic behaviors as response to fear faces ( chaio et al . ,
2008 ) as well the valuation of dominant and subordinate behaviors ( freeman et al . , 2009 ) based on differences between western and eastern cultures .
such results demonstrate that cultural conditions can lead to discernable differences in the specific cues that activate fundamental brain structures such as the amygdala and mesolimbic reward pathways .
we expect that similar comparisons of western and eastern cultures directed toward understanding the role of the acc and insula in such topics , as ritual , group identity , and romantic love will reveal similar differences based on habitual experience . extending such studies directly to traditional societies in which undernutrition , habitual levels of physical exercise , and even parasitic infections may represent important inputs in somatic mood , is much more difficult , because of a lack of brain imaging techniques that can be used in the field .
thus much of the investigation of emotional embodiment in traditional societies will have to rely on indirect methods , including questionnaires , neuropsychological tests , genetic and hormonal markers , and inferences from laboratory based brain imaging studies .
for instance , among male arrial pastoralists from northern kenya , self - reported quality of life , which may be thought of as a measure of well - being , is predicted by the number of male supporters as well as amount of body fat ( campbell unpublished data ) .
other findings demonstrate that drd4 7r+ is positively related to bmi among nomadic ariaal males ( eisenberg et al .
2008 ) while salivary t is positively related to measures of body fat in the same men ( campbell et al . , 2007 ) .
whether such biomarkers are also related to quality of life through their association with somatic status deserves more a detailed investigation of health , well - being and subjective mood among ariaal men based on genetic variation in neurotransmitters and salivary steroids , as well as cultural ideals .
there is growing excitement among neuroscientists and social scientists alike about the possibility of investigating the brain processes underlying those capacities for culture that seem uniquely human .
we suggest here that an evolutionary framework for such a neurological perspective on the human brain highlights a pre - existing primate neural system of emotional embodiment as a key element in human sociality .
the phylogenetic elaboration of bodily awareness helps to suggest the elaboration of human romantic love into a wider set of positive social emotions and moral sentiments that act to maintain the cohesion of larger groups .
in addition , it suggests that practices such as meditation , yoga , and shamanism are based on activating the neurological mechanisms associated with such positive social emotions .
an evolutionary approach suggests that the role of culture in human neuroplasticity is not a recent event , but extends throughout human brain evolution ( deacon , 1998 ) .
2006 ) is crucial to an evolutionary understanding of the way in which empathy and other social emotions are linked to somatic states .
thus the investigation of traditional cultures with deeply engrained cultural practices , high levels of habitual physical activity , and low caloric intake , has a critical role to play in neuroanthropology .
however , the lack of suitable brain imaging methods for the field means that such investigations , for now , will have to rely on indirect methods and courageous attempts at interdisciplinarity .
the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
Output:
| the decade of the mind is a proposal for a research initiative focused on four areas of neuroscience , including mental health , high - level cognitive function , education , and computational applications .
organizing efforts to date have primarily included cognitive scientists , computer scientists , and engineers , as well as physicians . at the same time
anthropologists have started to explore the implications of neuroscience for understanding culture . here
we suggest that evolutionary neuroscience can be used to bridge knowledge obtained by social scientists with that obtained in the neurosciences for a more complete appreciation of the mind .
we consider such a perspective as neuroanthropology .
we use embodiment , an anthropological concept that has been substantiated by recent findings in neuroscience , to illustrate an integrative biocultural approach within neuroanthropology and suggest future possible directions for research . |
PubmedSumm118282 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: macromolecular structures are at the basis of much research in fields as diverse as drug design , bio - fuel engineering , molecular biology or force field design .
the number of new protein structures deposited in the pdb has remained stable for several years at around 20 per day .
the statistics on web servers listed in the special volumes of nar collected by brazas et al .
( 1 ) clearly show that protein structures remain an important topic , as the number of web servers and visualization tools relating to protein structures continues to grow steadily .
what if ( 2 ) is a widely distributed interactive software package for macromolecular analysis , visualization , modelling and structure validation . originally an interactive application driven either via a graphical user interface or from the command line , a decade ago we exposed the first three components of what if via human - accessible web interfaces ( 3 ) .
since then , the collection of functions accessible in this way has grown to around 80 , which are being used by a few hundred users each day .
more recently , the software has been successfully integrated with the coot crystallographic software ( 4 ) and the yasara ( http://www.yasara.org/ ) molecular modelling , simulation and drug design software ( 5 ) . encouraged by initiatives such as biosapiens ( http://www.biosapiens.info/ ) and embrace ( http://www.embracegrid.info/ ) , which have championed the use of web services in the life sciences , we have now developed and deployed a freely available web service version of what if . unlike the more traditional web server ( e.g. html / cgi ) interfaces that have become a popular way of providing remote human access to tools and resources , web services are straightforwardly accessible from within computer programs , allowing them to be used for large - scale batch processing tasks that would be inconceivable via manual cut - and - paste alternatives . acting as a subroutine or function that resides on a remote computer , web services
provide a number of benefits to bioinformatics software developers ( and thence directly or indirectly also to life scientist users of their tools ) :
reduction in the amount of code that is being re - invented and maintained;reduction in the cost of installing , managing and maintaining local installations of software packages;access to the latest version of algorithms and data without the need to upgrade local installations ; andaccess to enormous amounts of ( free ) cpu time .
a more extensive description of the advantages and disadvantages of the use of web services can be found in the article describing the embrace web service registry elsewhere in this volume .
the first what if - based web servers were launched in 1997 and were published in 1998 ( 3 ) and remain active to this day ( http://swift.cmbi.ru.nl/ ) .
reduction in the amount of code that is being re - invented and maintained ; reduction in the cost of installing , managing and maintaining local installations of software packages ; access to the latest version of algorithms and data without the need to upgrade local installations ; and access to enormous amounts of ( free ) cpu time .
what if , a fortran program conceived in 1987 ( 2 ) , is still actively maintained and developed .
its core of around a million lines of code represent a substantial collection of algorithms and heuristics that remain of significant utility to today s scientific community . in order to deploy the what if code as a web service
, we designed a special wrapper application that acts as an intermediate between the legacy architecture of the command - line - based what if system and the modern protocols required by web services .
this application , called wiws ( what if web services ) , listens on the network for incoming web service requests and translates these into what if commands that are injected into the interactive component of the system as though they had been typed by a user .
what if then executes these commands and produces its own bespoke format output , which in turn is then parsed by wiws , and translated back to the contemporary protocols ( e.g. soap and xml ) expected by web service software .
the wsdl ( web service description languagea formal description of the web service , required by client software in order to access the service ) and the documentation for the web services are generated automatically by wiws and are available at http://wiws.cmbi.ru.nl/wsdl/ and http://wiws.cmbi.ru.nl/help/ , respectively .
experienced what if users can freely obtain from us all software elements needed to set up their own what if - based web services .
what if has over 1600 different functions that can be invoked using a command line interface , and which in essence form a simple state - based programming language . rather than expose all of this complex fine - grained level of control as web services , we have instead developed a scripting language that allows more meaningful course - grained web services to be automatically generated by combining what if s low - level commands in a coherent manner
the architecture of the system ( figure 1 ) thus consists of two components : ( i ) the original what if core , acting as an engine responsible for executing the underlying algorithms ; ( ii ) the wiws system : this contains ( a ) an interpreter and scripts containing subroutines that map between sequences of low - level what if commands and meaningful web service - level operations , and ( b ) a bespoke http server that responds to incoming web service requests and invokes the high - level functions represented by individual subroutines .
the original what if system at the far left is augmented with a software layer that receives streams of automated commands , and sends them to what if as though they had been typed at the command line .
the wiws server ( centre ) receives web service invocations from users in either rest or soap format , and matches these with one of the scripted subroutines , which then calls what if in order to execute the appropriate sequence of instructions .
the original what if system at the far left is augmented with a software layer that receives streams of automated commands , and sends them to what if as though they had been typed at the command line .
the wiws server ( centre ) receives web service invocations from users in either rest or soap format , and matches these with one of the scripted subroutines , which then calls what if in order to execute the appropriate sequence of instructions . when the server is initialized , it parses the latest version of its script and automatically generates and advertises the wsdl descriptions of the subroutines described therein , as well as creating corresponding soap and rest endpoints .
the script language is based on the oberon-2 programming language and implements most of its syntax .
the xml and http handling code comes from the open source libzeep project ( http://libzeep.berlios.de/ ) .
to date , we have produced 84 web servers and 64 web services , all of which take pdb format molecular structure data as input .
the web servers mainly deal with options that produce two- and three - dimensional graphics and other what if options that produce human readable output .
the web services focus on what if options that would be useful for third - party protein structure - related software tools .
the web service operations broadly fall into one of two groups . in the first group are operations that categorize or otherwise annotate residues or atoms , for example to :
provide simple geometric parameters , such as accessibilities , torsion angles , etc.;list observables , such as disulphide bridges , salt bridges , etc.;provide tables of per - residue structure validation scores .
in the second group are operations that generate , or otherwise modify , the input s molecular structure , for example to :
correct and or complete coordinates;add and optimize protons ; andadd symmetry - related residues / molecules .
a representative selection of these services
table 1.selected what if web services ( of the 64 that are available to date)visualization optionswhat the web service returns : getsurfacedot(many ) points in space that visualize the surface.geometric calculations atomaccessibilitysolventsolvent - accessible surface area for each atom in ngstrm .
residueaccessibilityvacuumsolvent - accessible surface area in ngstrm , for the residue in vacuum , only including the backbone of its direct neighbours .
residuetorsionsfor each residue , its torsion angles : , , , 15 ( in degrees ) .
cysteinetorsionscys - cys bridge torsions over : ci - ci ci - si si - sj sj - cj cj - cjatomic contacts showbumpsatom pairs with a clash worse than 0.25 .
hasnucleiccontactslists protein residues that contact a nucleic acid.structure quality packingqualitypacking normality for amino acids . improperqualitymaxper residue , its worst improper dihedral z-score.protein engineering showlikelyrotamersshow rotamer likelihoods for rotamers for all amino acid types .
prolinemutationvaluelikelihood at each position that an introduced proline will be thermostabilizing.returning coordinates pdbasxmlthe input pdb file is returned in xml .
symshellfivexmlshell of symmetry - related residues , 5.0 thick , as xml.the full list and all descriptions are available at http://wiws.cmbi.ru.nl / help/. the algorithms underlying the web services are explained at the what if web site ( http://swift.cmbi.ru.nl/whatif/ ) .
correct and or complete coordinates ; add and optimize protons ; and add symmetry - related residues / molecules .
selected what if web services ( of the 64 that are available to date ) the full list and all descriptions are available at http://wiws.cmbi.ru.nl / help/. the algorithms underlying the web services are explained at the what if web site ( http://swift.cmbi.ru.nl/whatif/ ) .
all the what if web services are regularly tested by a script that exercises them against 10 valid pdb files that have been selected for their complexity ( from a what if point of view ) .
the services have also been entered into the embrace registry ( 6 ) , which regularly monitors and reports on their availability .
usage of the web services is free and essentially unlimited , but we request that users submit their web service calls sequentially . as a case study , 10 of the what if web service operations have been integrated with the utopia ( 7,8 ) visualization suite .
utopia has a flexible plug - in system that allows its graphical visualization components to be linked easily with online tools and databases .
relevant fragments of the python code necessary to use the what if web services in utopia are listed at the what if ( http://swift.cmbi.ru.nl/whatif/ ) web service documentation page ( http://swift.cmbi.ru.nl/webservices/ ) .
utopia is freely available from http://www.getutopia.com/. figures 2 and 3 show utopia screenshots that illustrate the utility of the web service - based virtual linkup of the two software packages .
the integrated perspectives shown in the figures provide at - a - glance overviews of biophysical characteristics both of the molecular structure and of individual amino acids , and how these interrelate : this facilitates , for example , analysis of crystal - packing contact residues relative to core secondary structures ( e.g. contact residues 2636 in figure 2 lie on the long projecting finger - like loop in the centre of the 3d structure ) ; identification of the locations and relative strength of salt - bridging residues , again in the context of the secondary structures in which they are located ; and so on ( figures 3 and 4 ) .
the all - atom dot surface is calculated by what if , and is colour coded by atom type .
the backbone ribbon , generated by utopia , is coloured according to residue physicochemical characteristics : green , polar neutral ; red , polar acidic ; blue , polar basic ; white , hydrophobic aliphatic ; purple , hydrophobic aromatic ; brown , special structural ( proline , glycine ) ; yellow , sulphur - containing , structural ( cysteine ) .
figure 3.here , the horizontal tracks show in order ( i ) the amino acid residue number in the sequence , ( ii ) the sequence itself ( colour code as above ) , ( iii ) residues with crystal - packing contacts ( indicated by red triangles ) ; ( iv ) the secondary structure of 3ebx determined by dssp ( 11 ) , filtered by what if and displayed by utopia here , red arrows denote -strands ; ( v ) vacuum accessibility in square ngstrms .
figure 4.pdb file 1a08 ( 12 ) displayed using utopia , having invoked 4 what if services .
tracks show in order : ( i ) amino acid residue number , ( ii ) the residue sequence ( colour code as in figure 3 ) ; ( iii ) residues involved in salt bridges ( height of the bar indicates the total enthalpy contribution of all salt bridges in which the residue is involved ) ; ( iv ) secondary structure ( blue zigzags indicate -helices , red arrows denote -strands ) ; ( v ) vacuum accessibility displayed using an alternative mode of utopia visualization relative to that in figure 3 ( the values at 25 , 28 , 40 and 52 are missing because their side chains are not complete in the pdb file ) ; ( vi ) red triangles indicate residues involved in crystal - packing contacts
the all - atom dot surface is calculated by what if , and is colour coded by atom type .
the backbone ribbon , generated by utopia , is coloured according to residue physicochemical characteristics : green , polar neutral ; red , polar acidic ; blue , polar basic ; white , hydrophobic aliphatic ; purple , hydrophobic aromatic ; brown , special structural ( proline , glycine ) ; yellow , sulphur - containing , structural ( cysteine ) . here ,
the horizontal tracks show in order ( i ) the amino acid residue number in the sequence , ( ii ) the sequence itself ( colour code as above ) , ( iii ) residues with crystal - packing contacts ( indicated by red triangles ) ; ( iv ) the secondary structure of 3ebx determined by dssp ( 11 ) , filtered by what if and displayed by utopia here , red arrows denote -strands ; ( v ) vacuum accessibility in square ngstrms .
pdb file 1a08 ( 12 ) displayed using utopia , having invoked 4 what if services .
tracks show in order : ( i ) amino acid residue number , ( ii ) the residue sequence ( colour code as in figure 3 ) ; ( iii ) residues involved in salt bridges ( height of the bar indicates the total enthalpy contribution of all salt bridges in which the residue is involved ) ; ( iv ) secondary structure ( blue zigzags indicate -helices , red arrows denote -strands ) ; ( v ) vacuum accessibility displayed using an alternative mode of utopia visualization relative to that in figure 3 ( the values at 25 , 28 , 40 and 52 are missing because their side chains are not complete in the pdb file ) ; ( vi ) red triangles indicate residues involved in crystal - packing contacts . the use of the what if web services is rather straightforward .
the wsdl will suffice for most experienced programmers , so we will list here only one small example , mainly to illustrate the ease of use of the what if web services .
the smallest python program we could think of that actually does something is listed below . the first line in this four - line program points at the python executable
. the second line imports the suds python module ( which you can download from http://python-suds.sourceforge.net/ ) .
the third line tells the program where the what if web services wsdl is located and the fourth line tells these services to print the results of the showbumps web service for the pdb file with identifier 1crn .
/usr / bin / pythonfrom suds import clientc = client.client(http://wiws.cmbi.ru.nl/wsdl)print c.service.showbumps(1crn ' ) from suds import client c = client.client(http://wiws.cmbi.ru.nl / wsdl ) print c.service.showbumps(1crn ' ) we have produced 64 web services that perform a wide variety of macromolecular structure - related tasks . while selecting and designing these web services , we especially kept in mind the many programmers who provide macromolecular software and/or web services for niche research areas and who thus could benefit most from easy access to some of what if s more advanced features , such as protein structure validation , structure correction and hydrogen bond- and symmetry application - related options .
the automatic generation of web services via our scripting language means that deploying new services is a relatively trivial task , and we welcome and encourage requests from the community for new services .
we have produced 64 web services that perform a wide variety of macromolecular structure - related tasks . while selecting and designing these web services , we especially kept in mind the many programmers who provide macromolecular software and/or web services for niche research areas and who thus could benefit most from easy access to some of what if s more advanced features , such as protein structure validation , structure correction and hydrogen bond- and symmetry application - related options .
the automatic generation of web services via our scripting language means that deploying new services is a relatively trivial task , and we welcome and encourage requests from the community for new services .
nbic , embrace and uk bbsrc ( grant number bbe0160651 ) ; embrace project is funded by the european commission within its fp6 programme , under the thematic area life sciences , genomics and biotechnology for health ( contract number lhsg - ct-2004 - 512092 ) .
Output:
| the what if molecular - modelling and drug design program is widely distributed in the world of protein structure bioinformatics .
although originally designed as an interactive application , its highly modular design and inbuilt control language have recently enabled its deployment as a collection of programmatically accessible web services .
we report here a collection of what if - based protein structure bioinformatics web services : these relate to structure quality , the use of symmetry in crystal structures , structure correction and optimization , adding hydrogens and optimizing hydrogen bonds and a series of geometric calculations .
the freely accessible web services are based on the industry standard ws - i profile and the embrace technical guidelines , and are available via both rest and soap paradigms .
the web services run on a dedicated computational cluster ; their function and availability is monitored daily . |
PubmedSumm118283 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: hydrometrocolpos ( hmc ) is a rare diagnosis and is even more rarely associated with polydactyly in neonates .
it is a common presentation of bardet biedl syndrome , mckusick kaufman syndrome ( mks ) , ellis van creveld ( evc ) syndrome , and pallister hall syndrome .
neonatal hmc is caused by blockage of the vagina leading to accumulation of mucoid secretions proximal to the obstruction.1 the mucous secretions are the result of both intrauterine and postnatal stimulation of uterine and cervical glands by maternal estrogens .
a triad of congenital hmc , polydactyly , and cardiac anomalies are the cardinal feature of mks , also addressed as hydrometrocolpos - polydactyly syndrome.2 this triad also occurs in bardet biedl syndrome ( bbs ) along with hypogonadism , obesity , renal dysplasia , retinal degeneration , and mental impairment and also in evc syndrome and pallister
the neonate was operated successfully and postoperative period was uneventful and is in regular follow - up today .
the objective of this case report is to highlight the importance of antenatal detection and postnatal management of a diagnosed case of hmc .
a late preterm , large for gestation , female infant was born to a g4p2a1l2 mother by caesarean section with a birth weight of 3.48 kg at 34 weeks of pregnancy .
baby cried immediately after birth and the apgar score was 8 at 1 and 5 minutes of life .
maternal antenatal history was uneventful except for subclinical hypothyroidism detected during gestation . on a routine antenatal scan at 30 weeks of gestation
1 ) , midline cystic mass measuring 49 32 mm with low - level internal echoes behind urinary bladder , distension of fallopian tube including the fimbrial end ( fig .
2 ) , and minimal quantity of free fluid in the hip . a tentative diagnosis of hmc was made .
hydronephrosis of both kidneys with left pelvic dilatation more than right , echogenic left cortex , and normal right cortex were observed .
examination after birth revealed normal vital organs , no dysmorphism , postaxial polydactyly on right upper limb ( fig .
4 ) , distended abdomen , and palpable left kidney . no protruding mass from external genitalia .
abdominal ct scan performed before surgery revealed a large cystic area measuring 11.7 6 cm , arising from pelvis posterior to the urinary bladder ( figs . 5 and 6 ) .
evaluation of other systems , including brain , heart , and skeletal survey , did not reveal any other malformations .
the infant was operated on day 7 of life and the operative findings confirmed vaginal atresia with gross hmc with dilated vagina extending up to the epigastrium and uterus palpable in the right side of epigastrium .
thick viscid secretions were drained from the vagina and drains were placed with suprapubic tube and other across the membrane per vaginum .
the diagnosis of mks was considered as post axial polydactyly and hmc ; however , there were no cardiac anomalies .
in view of the absence of features such as retinal degeneration and renal anomalies , which are most common in bbs during neonatal period , it was not considered ; also , obesity and mental retardation are usually seen in infancy .
secretory type : it is secondary to accumulated mucus secreted by the uterine and cervical glands stimulated in utero by maternal estrogen.urinary type : it is secondary to the accumulation of urine in the presence of a vaginal obstruction .
secretory type : it is secondary to accumulated mucus secreted by the uterine and cervical glands stimulated in utero by maternal estrogen .
urinary type : it is secondary to the accumulation of urine in the presence of a vaginal obstruction .
the incidence of congenital hmc varies from 0.0014 to 0.1% in full - term newborn females with almost 90% having polydactyly .
neonatal hmc frequently results from anatomical malformations of the genital tract such as vaginal atresia , transverse vaginal septum , and imperforate hymen ; which lead to blockage of drainage of the secretions , which in turn leads to hmc.5,6 neonatal hmc is an obstructive mullerian duct anomaly .
the type of mullerian duct anomaly is based on embryologic steps of lateral and vertical fusion during fetal life . during the process of lateral fusion ,
the mullerian ducts develop at 56 weeks of gestational age from the coelomic epithelium simultaneously with wolffian ( mesonephric ) ducts , which is placed lateral to coelomic epithelium .
they usually fuse at about 79 weeks of gestational age in the midline to form the uterovaginal canal . during the process of vertical fusion at 8 weeks of gestation , the uterovaginal canal fuses with urogenital sinus at the mullerian tubercle ; the urogenital sinus results from separation of the cloaca into the urogenital sinus and rectum .
hence , the vagina is formed by both the mullerian ducts ( upper two thirds ) and the urogenital sinus ( lower one third ) .
embryology reveals the different types of hmcs observed ; secretory type occurs secondary to defect in upper two thirds and urinary type occurs as a result of defect in lower one third.7 congenital hmc accounts for around 15% of intra - abdominal cystic masses in female infants .
it has also been associated with urinary or intestinal tract abnormalities.8 the clinical features are varied and usually seen as an abdominal mass that may compress the adjacent organs like bladder , ureters , bowel , or pelvic veins , resulting in urinary retention , constipation , ascites , lower limb edema , or rarely life threatening conditions.9 postnatally , it can be suspected when lower abdominal swelling persists in spite of urinary catheterization.10 antenatally , ultrasonography remains the most widely used diagnostic imaging technique for identification of hmc and it is suspected when the scan shows the presence of large cystic abdominopelvic mass with a fluid - debris level.11 mri can also be used as a useful complementary tool for assessing fetal urogenital anomalies when ultrasonography is inconclusive.12,13 postnatally diagnosis of hmc is confirmed by ultrasound abdomen echography and ct scan.14 the definitive treatment involves drainage of the accumulated fluid in the uterine cavity and establishing communication between the vaginal epithelium and the vulva . in the cases of hmc
treatment varies from the simple x - shaped hymenotomy for the isolated imperforate hymen to major surgery for complex urogenital abnormalities .
abdominoperineal approach is usually preferred in cases of high vaginal atresia.15,16 the mks is induced by variations in the mkks gene mapped onto chromosome 20p12 between d20s162 and d20s894 markers .
the diagnosis of mks in males is based on genital malformations ( most commonly hypospadias , cryptorchidism , and chordae ) , postaxial polydactyly , and congenital heart disease ( chd ) .
chd includes atrioventricular canal , ventricular septal defect ( vsd ) , or hypoplastic left heart , which is present in nearly 1020% of cases .
long - term cognition is normal.11 other associated findings include gastrointestinal abnormalities ( 28% ) : imperforate anus , rectovaginal or vesicovaginal fistula , hirschsprung s disease and malrotation , and abnormalities ( 5% ) of the eyes.17 hmc , polydactyly , and cardiac defects as well occur in bbs .
the characteristic combination of findings in bbs are rod cone dystrophy in eyes ( 93100% ) , polydactyly ( 5869% ) , obesity ( 7288% ) , learning disabilities ( 4162% ) , hypogonadism in males ( 8590% ) , and renal anomalies ( 25100% ) .
the secondary features include speech disorders or delays ; eye abnormalities , such as complex female genitourinary malformations , strabismus , cataract , and astigmatism ; brachydactyly or syndactyly ; developmental delays ; ataxia ; diabetes mellitus ; craniofacial dysmorphism ; nephrogenic diabetes insipidus ; hepatic fibrosis ; and congenital heart disease .
the bbs phenotype is seen in individuals with mutations in 14 different genes.18 other differential diagnosis includes evc syndrome that is characterized by polydactyly , acromelic growth retardation , ectodermal dysplasia with dystrophy of nails , and cardiac anomalies ( most common atrial septal defect ) , and pallister hall syndrome that is characterized by facial anomalies , postaxial polydactyly , imperforate anus , and cns anomalies like diencephalic hamartoblastoma.19,20 the limitation of our case report is that we were not able to perform the gene analysis of the infant to get the exact diagnosis of the syndrome .
the suspicion of bbs or mks is made based on the clinical features ; and evaluation of an infant with mks or bbs includes ultrasound study of pelvis , kidney and urinary bladder , skeletal radiographs , ekg , and echocardiogram .
the bbs is confirmed by genetic analysis of bbs genes ( bbs1bbs11 genes ) and the mks is confirmed by genetic analysis of mkks genes on chromosome 20p12 between d20s162 and d20s894 markers.21 the evc syndrome is confirmed by genetic analysis of evc1 and evc2 genes.19 pallister hall syndrome is confirmed by genetic analysis of gli3 gene.20
hmc is a rare condition in the neonate and should be suspected when a prenatal ultrasound identifies a midline abdomino - pelvic mass .
prenatal diagnosis and early newborn imaging lead to early detection and treatment of these cases .
Output:
| neonatal hydrometrocolpos ( hmc ) is a rare mullerian duct anomaly with an incidence of 0.006% .
it occurs due to blockage of the vagina with accumulation of mucus secretions proximal to the obstacle .
these secretions are secondary to intrauterine and postnatal stimulation of uterine and cervical glands by maternal estrogens .
a triad of congenital hmc , polydactyly , and cardiac anomalies are the cardinal features of mckusick kaufman syndrome , which is also known as hydrometrocolpos - polydactyly syndrome .
bardet
biedl syndrome is a well - known combination of hypogonadism , obesity , postaxial polydactyly , renal dysplasia , retinal degeneration , and mental impairment . in this case report , we describe a neonate with hmc , polydactyly , and hydronephrosis . |
PubmedSumm118284 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: recently , laparoscopic distal gastrectomy ( ldg ) became an acceptable treatment option for early - stage gastric cancer in korea and japan .
its short - term outcomes including improved cosmetic appearance , reduced postoperative pain , shorter hospital stay , and improved quality of life have been reported in various studies.12 in addition , some retrospective studies reported comparable long - term survival outcomes between ldg and open distal gastrectomy.34 soon , randomized controlled trials comparing long - term outcomes between laparoscopic and open distal gastrectomy are expected to establish the oncologic feasibility of ldg.5 as laparoscopic devices and skills continue to develop , there have been reports of experienced surgeons using single - incision laparoscopic distal gastrectomy ( sidg ) to treat early gastric cancer with the aim of reducing the invasiveness of ldg.678 despite the small number of cases , we previously reported that sidg is both safe and feasible for treating early gastric cancer , with similar operation times and better short - term outcomes as compared to conventional ldg .
a single - incision laparoscopic total gastrectomy ( sitg ) technique was also reported by seoul national university bundang hospital in 2013.9 however , sitg is not as widely performed as sidg for early gastric cancer , with only two published case reports to date.1011 the technical difficulty inherent in maintaining a stable field of view for an intracorporeal esophagojejunostomy is considered the primary reason for the lack of the technique 's wider acceptance . because of the limited field of view , the necessary special equipment , and the need for enhanced cooperation between the surgeon and scopist , single - port gastrectomy is more complex to perform than conventional laparoscopic surgery . at seoul national university bundang hospital , we aimed to overcome these technical difficulties by recently introducing a simple , easy to use , low profile laparoscopic manual scope holder for use in single - port gastrectomy .
we hypothesized that this scope holder would provide a field of view that was adequately stable for performing secure esophagojejunostomy using barbed sutures .
here , we report the technical details of the world 's first successful solo sitg with d1 + lymph node dissection ( lnd ) and intracorporeal esophagojejunostomy performed using a laparoscopic scope holder and a barbed suture in four patients with proximal early gastric cancer .
between october 2013 and july 2013 , four patients underwent solo sitg with d1 + lnd at seoul national university bundang hospital using a scope holder ( laparostat ; civco medical solutions , kalona , ia , usa ) without an assistant or scopist .
patient eligibility criteria were as follows : a preoperative diagnosis of stage i gastric cancer according to the american joint committee on cancer staging manual , 7th edition , with no lymph node enlargement ; an age between 20 and 80 years ; no history of other malignancies ; no previous chemotherapy or radiotherapy ; and no severe comorbidities .
this study was performed according to the ethical standards of the 1975 declaration of helsinki ( revised in 1983 ) and approved by an institutional review board .
usually , the laparoscopic scope holder was exclusively manipulated and cleaned by the surgeon 's right hand while the left hand 's instrument was kept within the single port to maintain the surgical field .
since we reported the details of sitg in a previous paper , the sitg with d1 + lnd is described briefly here.10 the only point of difference is that in the present case series , we used a laparoscopic scope holder ( laparostat ) instead of a scopist ( i.e. , solo surgery ) .
the patient was placed in the lithotomy position with reverse trendelenburg positioning . however , the hip and knee joints were straightened and not bent so as not to limit the instruments ' movements .
the scope holder was place on the left side rail of the operating table and covered by a sterile plastic bag ( fig .
1 ) . this scope holder has a low profile , providing more working space for the surgeon with no interference between surgeon and scopist and with minimal clashes between the instruments and scope near the single port , which is in contrast to the conditions associated with additional human scope manipulation .
a commercial 4-hole single port ( gloveport ; nelis , bucheon , korea ) was inserted into a longitudinal 2.5-cm long transumbilical incision .
the abdominal cavity was insufflated with carbon dioxide at a pressure of 11 to 13 mmhg .
we used a 10-mm flexible high - definition laparoscopic scope ( endoeye flexible hd camera system ; olympus medical systems corp . ,
the conventional laparoscopic grasper was used in nearly all procedures while the curved long grasper was used for single - port surgery ( olympus medical system corp . ) when operating on the lesser curvature side , including suprapancreatic lnd .
we used a laparoscopic automatic linear stapler ( i - drive 45 purple and 60 purple ; covidien , minneapolis , mn , usa ) .
we performed routine total gastrectomy with d1 + lnd ( 1 ; 2 ; 3 ; 4sa , sb , d ; 5 ; 6 ; 7 ; 8a ; 9 ; 11p , 11d ; and 12a ) , including partial omentectomy ( fig .
2 ) . after complete exposure of the esophagus by division of the anterior and posterior vagus nerves ,
after the specimen 's proximal resection margin was examined histopathologically , we used semi - loop reconstruction to create an intracorporeal anastomosis after sitg . after a jejunal loop located approximately 20 cm distal to the treitz ligament
was transected by a linear stapler ( i - drive 60 tan ; covidien ) , a side - to - side jejunojejunostomy was created using the i - drive 45 tan ( covidien ) to construct a 40 to 45 cm roux - en - y limb .
the common entry opening was then closed in double layers by barbed sutures ( v - loc ; covidien ) .
next , the roux - en - y limb was brought up via the antecolic route to form an esophagojejunostomy .
a stay suture made using 3 - 0 monofilament thread was passed from the anterior part of the mid - portion of the staple line and retracted through the single port .
an esophageal opening was created at the mid - portion of the esophagus using the hook in cutting mode ( fig .
3c ) , which allowed for easy access to the esophageal lumen with nasogastric tube guidance ( fig .
the opening of the jejunum was created in a similar manner using the hook in cutting mode .
first , the stapler side of a linear stapler was inserted into the jejunal opening with a motion similar to that of pulling up socks ; the stapler side could then easily enter the jejunum without separate human assistance .
the jaw of the linear stapler was partially closed to prevent the jejunum slipping from the stapler ( fig .
the anvil side of the linear stapler was finally inserted into the opening in the esophagus while the traction suture was controlled with the grasper . by maintaining friction between the two serosal surfaces , it is possible to pull either the esophagus or jejunum using the grasper to adjust the length as needed . in general , a first stapling with a 3-cm length is adequate for preventing stenosis ( fig .
the common entry opening was closed with a 23-cm barbed suture ( 3 - 0 v - loc suture on a v-20 needle ; covidien ) . before starting the v - loc suture ,
one stay suture was placed on the corner of the near side of the staple site ; this stay suture was used to visualize the blind corner while the common entry opening was sutured ( fig .
4c ) . using 23-cm 3 - 0 v - loc sutures for both layers , a full - thickness inner layer closure was made proceeding from the corner of the far side of the staple site to the near side using a continuous technique ( fig .
once the full - thickness layer was completed , the second seromuscular layer was closed by returning to the far side corner using the same barbed suture ( fig .
after the last stitch was made , the suture was simply cut without any knots or additional sutures ( fig .
4f ) . at this point , a flexible scope with a laparoscopic scope holder provided a stable field of view for carrying out intracorporeal suturing .
this is normally a difficult task because even a scopist'ws minute tremors are maximized due to the leverage effect along with trembling caused by the movements of the heart and diaphragm . in this case , the suturing of the common entry opening could be accomplished without much difficulty in the stable field of view provided by the laparoscopic scope holder .
between october 2013 and july 2013 , four patients underwent solo sitg with d1 + lnd at seoul national university bundang hospital using a scope holder ( laparostat ; civco medical solutions , kalona , ia , usa ) without an assistant or scopist .
patient eligibility criteria were as follows : a preoperative diagnosis of stage i gastric cancer according to the american joint committee on cancer staging manual , 7th edition , with no lymph node enlargement ; an age between 20 and 80 years ; no history of other malignancies ; no previous chemotherapy or radiotherapy ; and no severe comorbidities .
this study was performed according to the ethical standards of the 1975 declaration of helsinki ( revised in 1983 ) and approved by an institutional review board .
usually , the laparoscopic scope holder was exclusively manipulated and cleaned by the surgeon 's right hand while the left hand 's instrument was kept within the single port to maintain the surgical field .
since we reported the details of sitg in a previous paper , the sitg with d1 + lnd is described briefly here.10 the only point of difference is that in the present case series , we used a laparoscopic scope holder ( laparostat ) instead of a scopist ( i.e. , solo surgery ) .
the patient was placed in the lithotomy position with reverse trendelenburg positioning . however , the hip and knee joints were straightened and not bent so as not to limit the instruments ' movements .
the scope holder was place on the left side rail of the operating table and covered by a sterile plastic bag ( fig .
1 ) . this scope holder has a low profile , providing more working space for the surgeon with no interference between surgeon and scopist and with minimal clashes between the instruments and scope near the single port , which is in contrast to the conditions associated with additional human scope manipulation .
a commercial 4-hole single port ( gloveport ; nelis , bucheon , korea ) was inserted into a longitudinal 2.5-cm long transumbilical incision .
the abdominal cavity was insufflated with carbon dioxide at a pressure of 11 to 13 mmhg .
we used a 10-mm flexible high - definition laparoscopic scope ( endoeye flexible hd camera system ; olympus medical systems corp .
the conventional laparoscopic grasper was used in nearly all procedures while the curved long grasper was used for single - port surgery ( olympus medical system corp . ) when operating on the lesser curvature side , including suprapancreatic lnd .
we used a laparoscopic automatic linear stapler ( i - drive 45 purple and 60 purple ; covidien , minneapolis , mn , usa ) .
we performed routine total gastrectomy with d1 + lnd ( 1 ; 2 ; 3 ; 4sa , sb , d ; 5 ; 6 ; 7 ; 8a ; 9 ; 11p , 11d ; and 12a ) , including partial omentectomy ( fig .
2 ) . after complete exposure of the esophagus by division of the anterior and posterior vagus nerves ,
after the specimen 's proximal resection margin was examined histopathologically , we used semi - loop reconstruction to create an intracorporeal anastomosis after sitg . after a jejunal loop located approximately 20 cm distal to the treitz ligament
was transected by a linear stapler ( i - drive 60 tan ; covidien ) , a side - to - side jejunojejunostomy was created using the i - drive 45 tan ( covidien ) to construct a 40 to 45 cm roux - en - y limb .
the common entry opening was then closed in double layers by barbed sutures ( v - loc ; covidien ) .
next , the roux - en - y limb was brought up via the antecolic route to form an esophagojejunostomy .
a stay suture made using 3 - 0 monofilament thread was passed from the anterior part of the mid - portion of the staple line and retracted through the single port .
an esophageal opening was created at the mid - portion of the esophagus using the hook in cutting mode ( fig .
3c ) , which allowed for easy access to the esophageal lumen with nasogastric tube guidance ( fig .
the opening of the jejunum was created in a similar manner using the hook in cutting mode .
first , the stapler side of a linear stapler was inserted into the jejunal opening with a motion similar to that of pulling up socks ; the stapler side could then easily enter the jejunum without separate human assistance .
the jaw of the linear stapler was partially closed to prevent the jejunum slipping from the stapler ( fig .
the anvil side of the linear stapler was finally inserted into the opening in the esophagus while the traction suture was controlled with the grasper . by maintaining friction between the two serosal surfaces , it is possible to pull either the esophagus or jejunum using the grasper to adjust the length as needed . in general , a first stapling with a 3-cm length is adequate for preventing stenosis ( fig .
the common entry opening was closed with a 23-cm barbed suture ( 3 - 0 v - loc suture on a v-20 needle ; covidien ) . before starting the v - loc suture ,
one stay suture was placed on the corner of the near side of the staple site ; this stay suture was used to visualize the blind corner while the common entry opening was sutured ( fig .
4c ) . using 23-cm 3 - 0 v - loc sutures for both layers , a full - thickness inner layer closure was made proceeding from the corner of the far side of the staple site to the near side using a continuous technique ( fig .
once the full - thickness layer was completed , the second seromuscular layer was closed by returning to the far side corner using the same barbed suture ( fig .
after the last stitch was made , the suture was simply cut without any knots or additional sutures ( fig .
a flexible scope with a laparoscopic scope holder provided a stable field of view for carrying out intracorporeal suturing .
this is normally a difficult task because even a scopist'ws minute tremors are maximized due to the leverage effect along with trembling caused by the movements of the heart and diaphragm . in this case
, the suturing of the common entry opening could be accomplished without much difficulty in the stable field of view provided by the laparoscopic scope holder .
since we reported the details of sitg in a previous paper , the sitg with d1 + lnd is described briefly here.10 the only point of difference is that in the present case series , we used a laparoscopic scope holder ( laparostat ) instead of a scopist ( i.e. , solo surgery ) .
the patient was placed in the lithotomy position with reverse trendelenburg positioning . however , the hip and knee joints were straightened and not bent so as not to limit the instruments ' movements .
the scope holder was place on the left side rail of the operating table and covered by a sterile plastic bag ( fig .
1 ) . this scope holder has a low profile , providing more working space for the surgeon with no interference between surgeon and scopist and with minimal clashes between the instruments and scope near the single port , which is in contrast to the conditions associated with additional human scope manipulation .
a commercial 4-hole single port ( gloveport ; nelis , bucheon , korea ) was inserted into a longitudinal 2.5-cm long transumbilical incision .
the abdominal cavity was insufflated with carbon dioxide at a pressure of 11 to 13 mmhg .
we used a 10-mm flexible high - definition laparoscopic scope ( endoeye flexible hd camera system ; olympus medical systems corp .
the conventional laparoscopic grasper was used in nearly all procedures while the curved long grasper was used for single - port surgery ( olympus medical system corp . ) when operating on the lesser curvature side , including suprapancreatic lnd .
we used a laparoscopic automatic linear stapler ( i - drive 45 purple and 60 purple ; covidien , minneapolis , mn , usa ) .
we performed routine total gastrectomy with d1 + lnd ( 1 ; 2 ; 3 ; 4sa , sb , d ; 5 ; 6 ; 7 ; 8a ; 9 ; 11p , 11d ; and 12a ) , including partial omentectomy ( fig .
2 ) . after complete exposure of the esophagus by division of the anterior and posterior vagus nerves ,
after the specimen 's proximal resection margin was examined histopathologically , we used semi - loop reconstruction to create an intracorporeal anastomosis after sitg .
after a jejunal loop located approximately 20 cm distal to the treitz ligament was transected by a linear stapler ( i - drive 60 tan ; covidien ) , a side - to - side jejunojejunostomy was created using the i - drive 45 tan ( covidien ) to construct a 40 to 45 cm roux - en - y limb .
the common entry opening was then closed in double layers by barbed sutures ( v - loc ; covidien ) .
next , the roux - en - y limb was brought up via the antecolic route to form an esophagojejunostomy .
a stay suture made using 3 - 0 monofilament thread was passed from the anterior part of the mid - portion of the staple line and retracted through the single port .
an esophageal opening was created at the mid - portion of the esophagus using the hook in cutting mode ( fig .
3c ) , which allowed for easy access to the esophageal lumen with nasogastric tube guidance ( fig .
the opening of the jejunum was created in a similar manner using the hook in cutting mode .
first , the stapler side of a linear stapler was inserted into the jejunal opening with a motion similar to that of pulling up socks ; the stapler side could then easily enter the jejunum without separate human assistance .
the jaw of the linear stapler was partially closed to prevent the jejunum slipping from the stapler ( fig .
the anvil side of the linear stapler was finally inserted into the opening in the esophagus while the traction suture was controlled with the grasper . by maintaining friction between the two serosal surfaces ,
it is possible to pull either the esophagus or jejunum using the grasper to adjust the length as needed . in general , a first stapling with a 3-cm length is adequate for preventing stenosis ( fig .
the common entry opening was closed with a 23-cm barbed suture ( 3 - 0 v - loc suture on a v-20 needle ; covidien ) . before starting the v - loc suture ,
one stay suture was placed on the corner of the near side of the staple site ; this stay suture was used to visualize the blind corner while the common entry opening was sutured ( fig .
4c ) . using 23-cm 3 - 0 v - loc sutures for both layers , a full - thickness inner layer closure was made proceeding from the corner of the far side of the staple site to the near side using a continuous technique ( fig .
once the full - thickness layer was completed , the second seromuscular layer was closed by returning to the far side corner using the same barbed suture ( fig .
after the last stitch was made , the suture was simply cut without any knots or additional sutures ( fig .
at this point , a flexible scope with a laparoscopic scope holder provided a stable field of view for carrying out intracorporeal suturing .
this is normally a difficult task because even a scopist'ws minute tremors are maximized due to the leverage effect along with trembling caused by the movements of the heart and diaphragm . in this case
, the suturing of the common entry opening could be accomplished without much difficulty in the stable field of view provided by the laparoscopic scope holder .
at seoul national university bundang hospital , solo sitg with d1 + lnd using a laparoscopic scope holder has thus far been performed for four patients with clinical stage i gastric cancer .
no intraoperative events occurred ( conversion to conventional laparoscopy or open gastrectomy , uncontrolled bleeding , unexpected injury to the adjacent organ , or surgery - related complications ) .
they tolerated the consumption of a semi - fluid diet on the third postoperative day and a soft blended diet on the fourth postoperative day .
postoperative cholangitis was the only early postoperative complication , occurring in a 51-year - old man who had common bile duct stones ; his condition improved following percutaneous transhepatic biliary drainage .
the mean postoperative hospital stay duration was 9.03.2 days ( range , 6~13 days ) ( table 2 ) .
here , we described the world 's first solo semi - loop intracorporeal esophagojejunostomy performed using a manual scope holder without any assistance .
our findings demonstrate that with the use of a scope holder , intracorporeal semi - loop esophagojejunostomy after sitg is technically feasible as a solo surgery that offers a more stable field of view than a procedure performed with human scope assistance .
in addition , barbed suture closure of the common entry opening after linear stapling can also be performed for other types of bowel anastomosis without separate assistance . in single - incision laparoscopic gastrectomy ,
team cooperation is crucial since the surgeon 's laparoscopic field of view is highly limited and is manipulated by an assistant .
any mismatch or miscommunication between the surgeon and the assistant(s ) causes stress with consequent operative risk.12 the concept of solo surgery - frequently discussed over the past 30 years - is a potential solution to this problem that offers various advantages including enhanced precision , enhanced ergonomics , and reduced health costs via reduction in the required human resources . over the past 30 years ,
many trials , including randomized controlled trials , evaluated the feasibilities of different camera - holding systems.13 however , such solo systems have yet to be implemented into general clinical practice , and most of these camera - holding systems have already disappeared from the market . moreover according to some authors ,
such solo surgery is associated with loss of comfort and limitations in practice and application , with only marginal resource benefits .
it is recognized that compared with human assistance , using a camera holder in laparoscopic surgery provides an optimal and stable image of the operation field .
control of the laparoscope by the surgeon is also generally considered superior to control accomplished with a scopist 's assistance .
aiono et al.14 concluded that there was no difference in these respects between passive and active ( robotic ) camera holders ; however , the benefits of active holders are questionable in relation to the performance of the much simpler passive designs , which can be repositioned with one hand .
even with five ports , laparoscopic total gastrectomy is a technically demanding procedure because of the difficulty of performing esophagojejunostomy solely via laparoscopy.151617 among the various types of laparoscopic total gastrectomy techniques described thus far , sitg is considered the most technically demanding procedure . in 2013 , we published the first technical report describing sitg.10 however , we recognize that it is not a comfortable procedure , mainly due to the difficulty inherent in performing continuous intracorporeal esophagojejunostomy via a single port .
this difficulty results from an unstable field of view , which can occur when the scope is manipulated by a scopist .
typically , the instruments around the single port tend to clash , and narrow areas of movement lead to physical bumping between the surgeon and scopist . at seoul national university bundang hospital
, we aimed to overcome these technical difficulties by recently introducing a simple , easy to use , low profile laparoscopic manual scope holder for use in single - port gastrectomy .
this can provide the surgeon with a greater degree of freedom of movement in the narrow workspace ( between the patient 's legs ) along with a more stable field of view , which allows for precise dissection and suturing .
when the scope holder ( laparostat ) is used as described in this report , the surgeon must manually reposition the camera or instrument .
consequently , the surgeon has to release one or more laparoscopic instruments in order to reposition the camera or instrument . at first glance
, this may appear inconvenient ; however , using one hand ( the dominant one ) to reposition the camera and release an instrument is not an important limitation because the surgeon never dissects when the camera requires repositioning .
thus , a passive scope holder is expected to be more efficient and economical in such situations .
based on our experience , we found that the laparostat could be used in clinical practice for single - port surgery ; furthermore , its usage could also be extended to conventional laparoscopic surgery .
the handling of the scope holder by the surgeon proved to be a skill that was easy to acquire and did not prolong the operation time .
the per - operation cost of a scope holder is estimated to be united states dollar ( usd ) 10 to 20 after the initial purchase ( usd 8,000 for the laparostat ) .
finally , solo surgery performed using a laparoscopic holder would allow an experienced surgeon to operate at any time , independent of the scheduling requirements of other staff such as assistants and scopists .
however , it would not be easy to react quickly in the event of bleeding , and there is a possibility of greater surgeon fatigue consequent to the solo execution of all procedures from skin incision to closure .
however , further experience from other surgeons and planned , well - designed studies are required to confirm the safety and feasibility of this technique .
Output:
| single - incision laparoscopic total gastrectomy for gastric cancer has recently been reported by seoul national university bundang hospital . however
, this is not a popular procedure primarily because of the technical difficulties involved in achieving consistent intracorporeal esophagojejunostomy . at seoul national university bundang hospital
, we recently introduced a simple , easy - to - use , low - profile laparoscopic manual scope holder that enables the maintenance of a stable field of view , the most demanding condition in single - port gastrectomy . in this technical report , we describe in detail the world 's first solo single - incision laparoscopic total gastrectomy with d1 + lymph node dissection and intracorporeal esophagojejunostomy for proximal early gastric cancer . |
PubmedSumm118285 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: feet provide the foundation for static support for body and dynamic support during walking or running .
the deformity includes four components : metatarsus adductus , cavus , hindfoot varus and equinus .
the cause of clubfoot has long been debated by the medical community . according to the journal of children s orthopaedics ,
some scientific investigators concluded that the condition was caused by malformed bones , abnormalities of muscle , joint or vascular lesions and/or abnormal ligaments and tendons .
another opinion is that congenital clubfoot results when external forces put the foot or the feet in a faulty position while the fetus is developing .
nowadays , there are two main hypotheses that say that congenital clubfoot is caused by neurogenic disorders in neuromuscle balance or gene variations .
any feet deformation should be corrected as early as possible to provide physiological function of proprioceptors that gives good balance and helps learning to walk .
treatment for clubfoot has evolved from a minimal surgery to a casting technique and then to extensive surgery . within the years , the principles of surgical technique in treatment for congenital clubfoot were changed and modified many times .
the most popular types of surgical procedures that are used in treatment for congenital clubfoot are listed below.medial side incision ( evans , dega , turco)two skin incisions medial and lateral side ( carroll , sotirow , uglov)circumferential ( cincinnati ) ( mckay , crawford)semi - cincinnati medial side incision ( evans , dega , turco ) two skin incisions medial and lateral side ( carroll , sotirow , uglov ) circumferential ( cincinnati ) ( mckay , crawford ) ponseti described his method in late 1950s .
his method is an innovative , conservative treatment for clubfoot involving a gentle manipulation of the child s foot and the application of toe - to - groin plaster casts that is followed by bracing and tenotomy .
the procedure consists of manual redresions , started as early as possible , which corrects a longitudinal arc of the foot and an abduction of a forefoot . with this treatment ,
a plaster cast is applied after each weekly session to retain the degree of correction obtained and to soften the ligaments .
after 46 weeks of the treatment , when adduction and supination of the calcaneum bone is corrected , the tight achilles tendon is cut in a minor procedure ( tenotomy ) to perform correction of the equinal deformation .
the corrected foot is put in a holding cast for 3 weeks to allow the tendon to regenerate .
then , when the final cast is removed , a foot abduction brace a.k.a .
this device consists of a pair of shoes attached to an adjustable bar at a specific width and angle .
the main objective of this paper is to present the early results of treatment congenital clubfoot by ponseti method .
the paper is based on data for 35 children25 boys and 10 girls with 47 clubfeet treated during the period of 20072011 .
we monitored the deformation before each redresion and casting , and before and after the tenotomy . to evaluate the effects of treatment
, we used pirani s scale with its six main features concerning external edge , medial crease and covering of the head of the talus bone in the midfoot region and posterior crease , incorrective equinal deformation and empty heel in hindfoot region .
according to pirani s scale , a total score of 6 points represents a severe clubfoot with a score of 0 points representing a normal foot .
all 35 patients were newborns with 7 of them suffering from bilateral deformation . according to bensachel
dimeglio s classification , 40 feet represented stift type of deformation and most of the patients had a maximal or medium grade of equinal , varus and adduction deformation ( table 1).table 1angular deformation before treatment most of them were medium or maximal ( 4090)result after tenotomysagital planepassive dorsal flexionmaximal719025median417017minimalbelow 405 angular deformation before treatment most of them were medium or maximal ( 4090 ) we started treating the patients as early as possible . for 25 patients , redresions and
clubfeet were corrected with manipulations every 57 days followed by plaster - cast applications .
then , we measured the residual deformation for varus and adduction through passive correction ( table 2 ) . for all treated patients , we accomplished satisfactory results.table 2angular deformation for varus and adduction after redresions and casting treatment during passive correction
we reached 05 in all treated patientsdeformationgrade of varus and adduction deformationnumber of feetspontaneous correction152045passive correction0545full correction02 angular deformation for varus and adduction after redresions and casting treatment during passive correction
we reached 05 in all treated patients when the correction of adduction and supination of the calcaneum bone was completed , the tenotomy of achilles tendon was performed .
this minor surgical procedure , conducted under a light sedation , was applied to 34 children out of the total number of 35 treated children . for one child
, excellent results were achieved after redresions followed by bracing so that no surgery was required .
the remaining patients underwent the tenotomy followed by a 3-week - long holding cast period that allowed the tendon to regenerate longer . in 85% of treated feet , we achieved sufficient correction in sagittal plane and ability of passive dorsal flexion ( table 3 ) .
for the final correction in all treated cases , we used tibax or clubax device , which is a simple instrument to perform corrections in all three planes .
such orthosis helped to preserve the good results after surgery ( fig . 1 ) .
however , those four children did not use that device strictly according to our recommendation.table 3correction in sagittal plane and ability of passive dorsal flexion after tenotomy we reached good results in 85% of treated feetresult after tenotomysagital planepassive dorsal flexionnumber of feet ( % ) good051039 feet ( 85%)satisfactory103008 feet ( 15%)fig .
1tibax and clubax orthosis correction in sagittal plane and ability of passive dorsal flexion after tenotomy
we reached good results in 85% of treated feet tibax and clubax orthosis during the analysis of our final results , we presented data after follow - up of all patients ( median 21 months ) , together with a subanalysis of patients according to pirani s scale .
after the treatment , we accomplished a score of 0.51.5 points in all 46 treated feet ( table 4 ) .
we evaluated the results of treatment as good or very good for 75% of patients . for the remaining patients ,
the results were evaluated as satisfactory.table 4pirani scale before and after treatment we accomplished 0.51.5 point in all 33 treated feetbefore treatment by ponseti method842 months after achilles tenotomypointsnumber of feetpointsnumber of feet6101.5955.5281164.590.520 pirani scale before and after treatment we accomplished 0.51.5 point in all 33 treated feet
the main objective of treatment for congenital clubfoot is to obtain pain - free , plantigrade foot , with good mobility and without calluses . in general ,
children who suffer from such deformation undergo some type of surgery to complete the correction .
this can range from a percutaneous heelcord lengthening to a wide release of medial , posterior and lateral structures , with or without transfer of the anterior tibial tendon [ 7 , 8 ] .
this leads ponseti to develop his method in the 1950s , repopularized in the beginning of 2000 in the usa and europe .
currently , manipulation , redresions and casting according to ponseti method are the gold standard , and this method is endorsed by the american association of orthopedic surgeons .
napiontek in 2004 introduced and widely popularized ponseti method in poland , and since 2007 , we have been using it in our clinic .
treatment should be initiated as soon as possible , preferably within the first week of life .
the majority of clubfeet can be corrected in infancy in about 68 weeks with the proper gentle manipulations and plaster casts followed by tenotomy .
however , the technique requires a lot of training , experience and practice . in our study ,
nonoperative procedures took usually 58 weeks which is a similar period to ponseti standards and that what other author report [ 11 , 12 ] .
for the treatment performed at our clinic , tenotomy of the achilles tendom was crucial for the completion of a successful correction of the foot .
all of them consist of a bar with shoes that are attached at the ends of the bar in external rotation .
the device is worn 23 h a day for 34 months and then at nighttime for 24 years . in our clinic , we used tibax or clubax device which was similar to orthosis recommended by posna ( pediatric orthopaedic society of north america ) as : the dobbs dynamic abduction brace , the markell or mitchell abduction brace .
severity of the deformity at birth is not a reliable indicator of the odds for a relapse ; therefore , almost all clubfoot patients are held to the same bracing protocols in order to provide them with the best protection against regression [ 13 , 14 ] . in early results
, we noticed that all children who did not use the orthosis as it was prescribed experienced high recurrence rate .
we have to add that in some severe cases , more invasive surgery treatment is needed to correct the position of the clubfoot despite using ponseti method .
most often , a more invasive surgery is this is needed in cases when a child has other developmental problems as , e.g. , arthrogryposis .
we also want to point out that the time when the child begins treatment by ponseti method is an important factor .
most authors consider that a congenital clubfeet treatment has to start no more than a few months after birth .
however , some resent researches showed that the ponseti method is effective for children as old as ten , even in cases of a failed surgery [ 16 , 17 ] .
we agree with ponseti s thesis that the basic of deformity in the congenital clubfoot is fibrosis of the soft tissue .
therefore , soft tissue in infants is more responsive to redresions , casting and finally bracing .
in essence , our study supports the principles of ponseti s method , because in cases when these principles were strictly obeyed , all patients accomplished satisfactory results and there have been no recurrences that are known to us [ 5 , 18 ] .
therefore , we strongly recommend using this method to avoid more invasive surgery in the future .
this method is of the particular value for the initial treatment of congenital clubfoot deformity .
Output:
| the purpose of this study was to evaluate the early results of the ponseti method in reducing extensive corrective surgery rates for congenital idiopathic clubfoot in patients treated in children s orthopaedic clinic and rehabilitation department medical university of lublin between the years 20072011 .
thirty - five patients with 47 idiopathic clubfeet were followed prospectively while being managed with the ponseti method .
clubfoot severity was graded with use of the dimeglio system .
the initial correction was achieved , and early results were measured by using pirani scoring method . |
PubmedSumm118286 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: recent estimates indicate that more than one billion people , living in tropical and subtropical regions of developing countries , are at the risk of contracting diseases ( which are mostly endemic at these places ) caused by the protozoans leishmania major , trypanosoma brucei and trypanosoma cruzi [ 13 ] .
these three microorganisms , together known as the tritryps ( family trypanosomatidae , order kinetoplastida ) , also cause the death of thousands of people every year . despite all these facts , these infirmities
the control of the diseases caused by these parasites depends nowadays on chemicals , vaccines not being commercially available so far .
besides , there is a very limited set of pharmaceuticals available at this moment : most of them were discovered at approximately 50 years ago , and they also have disadvantages like high toxicity , low efficacy , or high costs ; the development of resistance is also a possibility [ 68 ] .
however , with the recent publication of the tritryps ' genomes [ 911 ] , new opportunities allowed a better understanding of several biological processes that , up to this point , were poorly understood or even unknown in these organisms [ 7 , 12 ] .
cellular functions are based on complex networks of chemical reactions that interact producing observable results .
the rapid development of dna sequencing techniques provided a huge amount of information leading to a new comprehension about the organization of cellular processes .
first , by using annotation data , genes are classified in groups in accordance with their functions .
part of the gene products are enzymes , proteins that catalyze cellular reactions , making part of complex biochemical pathways . in the postgenome era , the study of these processes is gaining an importance , to improve the comprehension of the dynamics and regulation of these pathways , as well as the discovery of previously unknown steps [ 13 , 14 ] .
the reconstruction of biochemical pathways is considered to be one essential step in the study of cellular processes .
applications of these reconstructions may vary from the drawing of the biological system to the generation of testable hypotheses about the structure and working of the pathway and from the elucidation of complex properties not inferred by the simple description of the individual components to the recognition of potential drug targets against pathogenic organisms via the identification of essential steps in these processes .
several methods and databases are available for the reconstruction of said pathways from genome information ; one of the main resources for this task is the kegg database [ 13 , 17 , 18 ] .
one way to link the biological processes to the genomic information is through the ec numbers , which represent the reaction each enzyme catalyzes .
there are other types of functional classifications , ( reviewed by ouzounis and collaborators ) , but the ec classification system is certainly one of the most used by the scientific community .
enzymes have a high degree of specificity for their substrates and are fundamental for any biochemical process .
they act in an organized sequence , catalyzing successive reactions in enzymatic pathways , guaranteeing the maintenance of life in all organisms .
a particular group of enzymes , the nonhomologous isofunctional enzymes ( nise or analogous enzymes ) , executes the same function in different organisms , but without detectable similarity between their primary structures and , possibly , between their tertiary structures as well .
once analogy is detected between a pathogen 's enzyme and its human counterpart , it may be possible to use this analog as a potential target for drug development , provided it belongs to an essential biochemical step of the pathogen .
however , only a few studies have been done to identify and annotate isofunctional nonhomologous enzymes as such [ 2125 ] .
maintenance of the genome depends on the efficiency and accuracy of dna replication , as well as the repairing systems . through a series of complex interactions , the genome is transcribed and in good part translated , in order to produce the rnas and proteins necessary for the organism .
these molecules form its structure or participate in important reactions . for these reasons , the pathways of dna replication and repair , transcription and translation ( some of the genetic information processing pathways ( gipps ) ) comprise some of the most important processes for the organism survival [ 26 , 27 ] and
analyses of genomic data from l. major , t. brucei , and t. cruzi have provided a global view of the protein - coding genes that produce enzymes belonging to important pathways through the identification of several processes in common between these parasites and other species . a thorough examination of all
this information may allow the identification of steps of the gipps that are particularly accessible to potential therapeutic interventions .
new drugs may be also developed from inhibitors of specific biochemical processes essential to the parasite but absent in their hosts . in this work
, we employed computational methods to identify not only specific but also nonhomologous isofunctional enzymes in the genetic information processing pathways of the tritryps , enzymes that could serve as interesting candidates for further studies aiming at their validation as drug targets .
the dataset of predicted proteins of leishmania major , trypanosoma brucei , and trypanosoma cruzi was obtained from tritrypdb ( http://tritrypdb.org/tritrypdb/ ) as shown in table 1 .
a set of pathways ( maps ) referring to the replication and repair , transcription and translation processes was obtained from kegg ( http://www.genome.jp/kegg/pathway.html#genetic ) .
this dataset contains a complete biochemical description of the pathways related to genetic information processing observed in different organisms .
functions comprising a certain pathway were extracted from these descriptions as a collection of ec numbers and were used as templates for the reconstruction of the correspondent pathways in tritryps . each pathway is associated with a set of proteins , usually a list of enzyme families with their ec numbers .
kegg has a total of 10 maps distributed among these pathways : 6 maps representing replication and repair ; 2 maps symbolizing the transcription , but only one with an associated ec number ; 2 translation maps of which only one has an associated ec number .
to group homologous enzymes with the same activity , we used the anenpi pipeline ( http://www.dbbm.fiocruz.br/anenpi/ ) , which was based on a previous study in which enzymes are considered analogous ( i.e. , with different evolutionary origins ) according to differences in their primary structures .
after clustering , enzymes within a given cluster are considered homologous , while enzymes in different clusters ( of the same function ) are considered analogous .
as the cut - off parameter used in anenpi is based on experimental data obtained from enzymes , other values should probably be employed for other types of proteins . using another module of anenpi
, we were able to infer function of the predicted proteins of trypanosomatids using the groups ( or clusters ) obtained after clustering . in this module ,
the ec number assignment is based on the sequence similarity report from a blastp procedure : predicted proteins of tritryps ( query ) against the sequences of each individual anenpi cluster ( subject ) , as described in detail in .
the cutoff employed for functional inference was the e - value of e. the reconstruction of the gipps was performed using the data inferred by the anenpi pipeline .
after functional inference , enzymatic activities shared by tritryps were disclosed using scripts written in perl language .
nise and specific enzymes were obtained through an examination of the groups ( or clusters ) produced after clustering , where sequences of tritryps and h. sapiens were considered analogous if allocated in different groups and specific if absent in h. sapiens .
the tritryps ' genomes were first sequenced in 2005 [ 911 ] , with all chromosomes well characterized ( with the exception of t. cruzi due to the high degree of repetitions in its genome ) . however , some of the gipps still present gaps .
the computational reconstruction of these processes , in this work , is an attempt to obtain a better representation of them , with emphasis on the analogous and specific enzymes .
these analogs are enzymes that , even with a small or no significant similarity between their primary structures ( which reflect in differences in their 3d structure ) , are able to catalyze the same reaction . for these reasons , recent efforts have been made to include this phenomenon in the functional annotations [ 21 , 22 , 30 ] .
inference of function , if based only on sequence similarity , may be insufficient since they are usually not able to detect nonhomologous isofunctional enzymes .
tritryps share a series of features , like the presence of subcellular structures such as the kinetoplast and glycosomes .
each trypanosomatid is transmitted by a different vector , possessing distinct life cycles , tissue specificity , and pathogenies in their mammal host [ 31 , 32 ] .
in addition , they are considered ancient from an evolutionary perspective ; in fact , they present peculiar mechanisms in some of the genetic information transmission processes . many of these still have gaps to be filled . in this context , we have compared the number of enzymatic activities shared among the three microorganisms ( taking into account all pathways ) and the unique activities based on the results obtained after clustering ( figure 1 ) .
it may be worth noticing that some activities found have the same isoform ( or , more precisely , analog form ) in the three microorganisms ; this may serve as a basis ( ideally and depending on several other factors ) for one unique drug for the three pathogens or ( much more likely ) a family of related / similar molecules as drugs .
kegg has its own annotation protocol , which to our knowledge is not described in detail anywhere ; only its general lines are known [ 17 , 34 ] .
we opted to make a functional inference from all the predicted proteins of tritryps , in order to have a unified and comparable data .
for this , we performed a blastp of the available predicted proteins in the tritrypdb against the obtained clusters . from this it was possible to infer functions not detected by kegg , in almost all pathways studied . even using a very restrictive cut - off (
e - value < 10 ) , more enzymes were identified ( data not shown ) , indicating the validity of this approach .
in fact , even after using more restrictive e - values , like 10 or 10 , results did not differ for several ecs ( data not shown ) . with these information ,
the description of the enzymatic activities found by anenpi for each tritryp is listed in table 2 .
figure 2 displays the computational reconstruction of the gipps using the map representing the aminoacyl - trna biosynthesis ( map 00970 ) as an example .
the other 7 maps , as well as the tables with the description of the enzymes highlighted in each map , are available in the supplementary material available online at doi:10.4061/2011/543912 . in this map ,
all enzymatic activities detected by kegg were also identified by anenpi for the tritryps , with the exception of seprs ( ec 6.1.1.27 ) .
this enzyme participates of the alternative formation of cys - trnacys linking o - phosphoserine , a precursor of the aminoacid cysteine , to trnacys .
then sepcyss ( sep - trna : cys - trna synthetase ec 2.5.1.73 ) converts o - phosphoseryl - trnacys in cysteinyl - trnacys .
this alternative formation of cys - trnacys has been only detected in methanogenic archaea so far , where in some species the enzyme cysteinyl - trna synthetase ( ec 6.1.1.16 ) , which catalyzes the direct production of cys - trnacys , is lacking [ 35 , 36 ] .
however , we could not identify the second enzyme which completes the alternative formation of cys - trnacys , sepcyss .
one possible explanation is that , while this pathway is essential to archaea ( that do not possess the direct pathway for cys - trnacys formation ) , it is not for the tritryps . or yet , this enzyme has a particular gene sequence or structure , not yet examined experimentally .
the enzymatic activity represented by ec 2.1.2.9 ( methyonyl - trna formyltransferase ) , which is also part of the aminoacyl - trna biosynthesis map , was identified by kegg only for l. major and t. brucei ; this activity was identified by anenpi in t. cruzi .
this enzyme is responsible for adding the formyl radical to trnamet , which serves as the trna initiator of the polypeptide chain during translation in bacteria .
since mitochondria have a bacterial evolutionary origin , their translational apparatus follow the bacterial model .
the occurrence of this enzyme in nuclear dna is in agreement with the observed absence of trna genes in the mitochondrial dna of tritryps ( kdna ) , which are imported from the cytoplasm [ 3739 ] .
dna in cells is often under attack by mutagens , oxygen radicals , and ionizing radiation , and even cellular processes can create mutagenic and cytotoxic dna lesions which can be lethal to the cell .
organisms possess broad mechanisms of dna repair to fix damaged dna and in order to keep viability and genomic stability . in this context
, we identified four enzymatic activities with complete ec numbers ( four digits ) from three dna repair pathways : base excision repair ( ec 3.1.11.2 ) , nucleotide excision repair ( ec 2.7.11.22 ) , and nonhomologous end - joining ( ec 2.7.11.1 and ec 2.7.7.7 ) ( table 2 ) .
the enzyme exodeoxyribonuclease iii ( 3.1.11.2figure s3 and table s4 ) is responsible to catalyze the degradation of double - stranded dna acting progressively in a 3 to 5 direction , releasing 5-phosphomononucleotides on base excision repair ( ber ) pathway .
the enzymes of this pathway are conserved from bacteria to man , but mammalian enzymes frequently add in , within a larger structural framework , the catalytic core domains of bacterial enzymes [ 40 , 41 ] .
cyclin - dependent kinase ( ec 2.7.11.22 ) from nucleotide excision repair ( ner ) is linked to a complex called holo - tfiih complex ( figure s4 and table s5 ) .
this is a multiprotein complex required not only for transcription but also for nucleotide excision repair .
this enzyme is responsible for the phosphorylation of the carboxy - terminal domain ( ctd ) of rna polymerase ii in the absence of promoter opening .
nonhomologous end - joining ( nhej ) is a kind of recombination that links the ends from broken nonhomologous chromosomes .
the core nhej components are conserved from yeast to mammals and consist of the xrcc4/dna - ligase iv complex and the ku70/ku80 heterodimer .
first , the catalytic subunit , formed by dn - apkcs ( ec 2.7.11.1nonspecific serine / threonine protein kinase ) and artemis , is recruited .
the dna - pkcs phosphorylate the ku heterodimer and also the artemis complex which corresponds to a nuclease .
another enzyme whose participation is essential in such complex is the dna - directed dna polymerase ( ec 2.7.7.7 ) which fills in the gaps when the ends are joined ( figure s6 and table
data produced by the genome projects of the tritryps allowed researchers to establish new strategies to solve the problems caused by these diseases , which affect a great percentage of the world 's population .
the majority of the proposed drugs so far were discovered many years ago and several of them are toxic , have low efficacy , and the risk of resistance development is also a possibility . to search for functional analogs that could serve as potential candidates as drug targets
, we looked for the presence of these enzymes between the tritryps and h. sapiens , by comparing their primary structures .
one case meeting these criteria was identified : the exodeoxyribonuclease iii ( ec 3.1.11.2 ) from ber pathway .
exodeoxyribonuclease iii is an exonuclease that cleaves the 5 side of an ap ( apurinic / apyrimidinic ) site , acting in the repair pathway by base excision . in escherichia
coli this enzyme is a dna - modifying enzyme , very frequently used in molecular biology , which degrades single - stranded dna as a substrate .
we searched for more information about the inhibitors of this enzyme in the brenda database ( http://www.brenda-enzymes.org/ ) . according to hoheisel
, double - stranded dna was found to be a competitive inhibitor of the enzyme activity .
other known inhibitors are edta ( ethylenediamine tetraacetic acid ) , mn at concentrations above 5 mm , nacl , p - chloromercuribenzoate , pna ( peptide nucleic acids ) , and zncl2 [ 51 , 53 ] .
these sites can be generated by normal aerobic metabolism , uv light , or h2o2 .
exodeoxyribonuclease iii ( xtha gene ) can be considered a relevant target for tritryps because it plays an essential role in the ber pathway , a key repair system to neutralize dna oxidative stress .
e. coli xtha mutant strains hold a residual ap endonucleolytic activity due to the protein encoded by the nfo gene , the endonuclease iv ( endo iv ) .
some authors pointed out that exo iii is involved in the protection of e.coli cells against the toxic effects of uv light , h2o2 [ 5457 ] and is necessary to induce dna damage repair .
moreover , we have also identified a potential therapeutic target unique for l. major , the dna 3-methyladenine glycosilase ii ( ec 3.2.2.21 ) .
this enzyme consists in a glycosilase which breaks the bond between alkylated nitrogenated bases and their phosphate group , removing it and leaving an ap site [ 59 , 60 ] .
o - phosphoseryl - trna synthetase ( ec 6.1.1.- ) , assigned to the aminoacyl - trna biosynthesis map , was identified as a specific activity in tritryps when compared with h. sapiens .
this enzyme , today designated by the ec number 6.1.1.27 , catalyzes the alternative formation of cys - trnacys , as previously described .
the tdr targets database ( http://tdrtargets.org/ ) integrates genetic and biochemical information to pharmacological data , all related to ( primarily ) tropical pathogens .
none of the two ecs identified ( ec 3.1.11.2 and ec 6.1.1.27 ) had any information related to the tritryps in this database .
this suggests that the approach used in this work may increase the number of possible drug targets .
however , exodeoxyribonuclease iii ( ec 3.1.11.2 ) is assigned as a potential target in this database , but for other organisms .
in addition , dna 3-methyladenine glycosilase ii ( ec 3.2.2.21 ) , which in this work was identified only in l. major , is also assigned as a potential target ( again , for other organisms , not for leishmania ) .
none of the enzymatic functions disclosed in this work has a resolved 3d structure in the pdb database for any of the tritryps .
use of resolved 3d structures , as well as other types of information like functional studies , is paramount to advance research on these enzymes , to ensure that they are indeed possible targets for drug development . in the present work ,
we have studied only a part of the pathways assigned to the gipps in kegg .
we have left aside other important pathways such as those related to protein folding , sorting , and degradation , consisting in about 7 additional maps with several enzymes . moreover , kegg has already integrated more information and maps to the gipps , since it is updated weekly . in the future ,
a thorough reevaluation of the available data may disclose new cases of analogy and/or new specific enzymes .
the utilization of computers is constantly increasing in the field of drug discovery , because of the great potential in speeding up the identification of suitable targets and useful compounds and also ( arguably the most important feature ) in reducing costs . in this work ,
the development and utilization of computational methods allowed us to identify , in the genetic information processing pathways of tritryps , specific and nonhomologous isofunctional enzymes ( nise ) .
the identification of nise allowed the construction of an enriched list of proteins ( containing not only organism - specific enzymes ) that must be further studied to be validated as drug targets . among these studies
, we can cite ( i ) the obtention of crystals of the selected proteins to allow the construction of 3d models by molecular modeling , ( ii ) molecular dynamics and docking studies , to obtain a refined representation of their structure , including movement and possibly other interacting molecules as well , and ( iii ) a series of functional studies to determine their kinetics , expression patterns , stability , essentiality , and so forth .
Output:
| leishmania major , trypanosoma brucei , and trypanosoma cruzi ( tritryps ) are unicellular protozoa that cause leishmaniasis , sleeping sickness and chagas ' disease , respectively .
most drugs against them were discovered through the screening of large numbers of compounds against whole parasites .
nonhomologous isofunctional enzymes ( nises ) may present good opportunities for the identification of new putative drug targets because , though sharing the same enzymatic activity , they possess different three - dimensional structures thus allowing the development of molecules against one or other isoform . from public data of the tritryps ' genomes
, we reconstructed the genetic information processing pathways ( gipps ) .
we then used anenpi to look for the presence of these enzymes between homo sapiens and tritryps , as well as specific enzymes of the parasites .
we identified three candidates ( ecs 3.1.11.2 and 6.1.1.- ) in these pathways that may be further studied as new therapeutic targets for drug development against these parasites . |
PubmedSumm118287 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: monoclonal antibodies ( mabs ) undoubtedly belong to the most prominent therapeutics of the last two decades .
since 1986 , more than 40 mabs have been approved by the food and drug administration ( fda ) for the use in various diseases , including cancer , immune disorders , and infectious diseases , and many more are in clinical trials , with fullsize igg still representing the majority of these approved mabs . however , based on the success of these drugs , several different antigenbinding formats such as antibody fragments or domains ( i.e. antibodybased scaffolds ) and nonantibody protein scaffolds have been investigated for their potential as binding molecules .
the postulated advantage of such molecules is the reduced size that potentially leads to enhanced tissue penetration and facilitated production .
for example , three fullsize antigenbinding fragments ( fab ) of igg have been approved by the fda for clinical use so far [ certolizumab pegol 1 , ranibizumab 2 , and abciximab 3 ] . at a considerable smaller size , singlechain variable fragments ( scfv )
comprise the variable domains of heavy and light chain connected by a polypeptide linker and therefore contain the complete binding sites of antibodies .
it has been reported that scfvs can be readily expressed in various hosts like bacteria , yeasts , and plants 4 , 5 , 6 .
an advancement of this technology was the construction of bispecific tcell engagers [ bites 7 ] , comprising two scfvs with specificities for cd3 and a target antigen expressed as one polypeptide chain .
dualaffinity retargeting molecules ( darts ) follow a similar principle : as a further development of the diabody technology 8 , a cterminal disulfide bond covalently links two scfvs that are expressed as separate polypeptides to generate a more stable bispecific molecule 9 .
reported the selection of molecules based on the isolated ch2 domain of igg1 binding to the hiv1 envelope glycoprotein 10 .
another concept uses nanobodies , i.e. the singledomain antigenbinding fragments of camelid heavy chain antibodies , which , for example , have the potential for application in oral immunotherapy due to the increased resistance to extreme ph and proteolytic digest as compared to conventional antibodies 11 , 12 .
darpins are small , singledomain proteins derived from natural repeat proteins that can be engineered to bind diverse antigens 13 . and finally , the immunoglobulinlike structure of the tenth type iii unit of human fibronectin ( fn3 ) has served as the basis for the engineering of one further novel binding scaffold 14 .
the potential therapeutic value of these formats is , however , largely reduced due to the absence of the crystallizable fragment ( fc ) and the resulting inability to trigger effector functions such as antibodydependent cellular cytotoxicity ( adcc ) or complementdependent cytotoxicity ( cdc ) .
accordingly , the in vivo halflife is limited due to the absence of the fclocated binding site of the neonatal fc receptor fcrn , and a lot of effort is necessary to overcome these drawbacks , which to some degree outweighs the advantage of the smaller size . in 2009 ,
rker and wozniakknopp 15 reported the engineering of the structural loops of immunoglobulin constant domains to generate novel binding sites ( modular antibody engineering ) . based on the observation that immunoglobulinlike domains are structurally conserved in the sandwich core regions while at the same time exhibiting high variability of the loops 16 ,
the three cterminal loops of the ch3 domain of igg1fc were engineered to bind diverse antigens in initial studies , yielding antigenbinding fc fragments termed
fcabs. in this review , the therapeutic potential of such fcabs and efforts in functional engineering as well as the engineering of biophysical properties will be discussed .
there will be no focus on the engineering of individual antibody domains like monomeric ch2 or ch3 domains as scaffolds for the design of novel binders , as this topic has been reviewed recently 17 .
the structure and function of human iggfc has been described extensively . however , it is necessary to provide the background for discussion in the present review .
immunoglobulins of isotype g are the predominant antibody class in circulation and comprise two identical light ( l ) and heavy ( h ) chains forming a yshaped structure 18 .
an igg molecule can be dissected into two distinct fragments ( fab , fc ) that are responsible for the in vivo properties ( fig .
1 ) : an antigenbinding fragment ( fab ) is a heterodimeric protein composed of one light chain and the nterminal half of one heavy chain .
it encompasses two variable ( v ) domains ( vh , vl ) whose complementaritydetermining regions ( cdrs ) form the antigenbinding site , and two constant ( c ) domains ( cl , ch1 ) ( fig .
1 ) .
by contrast , the crystallizable fragment ( fc ) is a homodimeric glycoprotein with one monomer consisting of two constant immunoglobulin domains ( ch2 , ch3 ) from the cterminal half of one heavy chain ( fig .
1 ) . through interaction with
its ligands [ fc receptors ( fcr ) , c1q and fcrn ] it mediates various immune effector functions and increases the halflife of the antibody molecule 19 .
the fc and the two fab fragments meet at a central flexible segment , the hinge region , which plays an important role in the mediation between antigen recognition and effector functions and forms interchain disulfide bonds between the two heavy chains .
1 ) normally reveals structure for residues 238443 , underlining that the hinge region is highly flexible 21 , 22 , 23 , 24 .
in addition , the conformation of the hinge proximal region of the ch2 domain is shown to be
soft , i.e. to be relatively mobile in comparison to the more defined structure observed at the ch2ch3 interface .
schematic representation of homodimeric human igg1fc ( pdbid 1oqo ) , generated using pymol , with the corresponding amino acid sequence .
igg1 is composed of two heavy and two light chains , with the fab region carrying the antigenbinding sites and the fc part mediating various effector functions .
the homodimeric fc part comprises the ch2 and ch3 domains , where strands are depicted in green , and helices and random coils are shown in gray .
the cterminal loops of the ch3 domain are colored in red ( ab loop ) , orange ( cd loop ) , and purple ( ef loop ) .
the asparagine at position 297 carries the glycan ( nanafbi ) , graphically represented according to anthony et al .
the amino acid sequence of the ch2 and ch3 domain of wildtype igg1fc is shown and numbered according to eu numbering system 20 .
on top of the sequence , the secondary structure elements of ch2 and ch3 according to the crystal structure ( pdbid 1oqo ) are shown .
four distinct igg subclasses differing in their heavy chains ( and consequently in their fc ) , exist in humans ( higg14 ) , and in mice ( migg1 , 2a , 2b , 3 ) .
this review will mainly focus on the structure function relationships of the fc of human igg1 as a basis for engineering strategies for the design of novel therapeutic proteins . in the following
, iggfc and igg1fc will always mean the basic homodimeric scaffold including two monomers , each being composed of the nterminal hinge region followed by ch2 and ch3 domains ( i.e. thr225 to lys446 ; for amino acid numbering and assignment of secondary structures , see fig .
1 ) .
a single nlinked glycan is attached to asparagine 297 ( ch2 domain ) of each heavy chain .
the glycan has a complex biantennary structure ( fig .
1 ) and can vary by the addition of sugar residues to specific parts of the core structure .
the latter is composed of nacetylglucosamine and mannose and can be modified by the addition of fucose , bisecting nacetylglucosamine , and two arms defined by 1,3 and 1,6 mannose linkages ( fig .
1 ) .
there is a tremendous heterogeneity in the iggfc glycan , with over 30 distinct glycans detected on circulating igg in healthy individuals 25 .
the two fc glycans are essential for the structural integrity of fc ( and igg ) by contributing mainly to the interface of the ch2 domains , where they face the center of the fc with the 1,3 arm protruding into the cavity between the heavy chains and the 1,6 arm extending along the heavy chain backbone 26 , 27 .
crystal structures of iggfc reveal a distinct conformation for the oligosaccharide resulting from multiple noncovalent interactions with the protein 23 .
this was confirmed by molecular dynamics ( md ) simulations demonstrating that the glycans form more hydrogen bonds with the individual protein chains at the cost of glycan glycan interactions 28 .
the thermodynamic parameters ( obtained by differential scanning calorimetry ) describing the unfolding of igg1fc reflect these interactions , with the thermal unfolding of the ch2 domains showing a progressive reduction in stability with loss of sugar interactions while the unfolding of the ch3 domain is unaffected 29 . typically , igg1fc exhibits two thermal transitions ( best modeled using two sequential twostate transitions ) with the lower temperature transition ( tm1 approximately 71c ) reflecting unfolding of the ch2 domain and the second transition ( t
m2 approximately 82c ) unfolding of the ch3 domain at ph 7.4 30 .
the latter underlines the importance of the extensive hydrophobic ch3ch3 interface for the stabilization of igg1fc . during unfolding ,
the ch2 domains behave as a single cooperative unit , and unfolding is reversible as long as the protein sample is taken to approximately 75c at maximum , whereas unfolding of the ch3 domains is irreversible .
typically , the thermal stability of the fc fragment decreases with decreasing ph as demonstrated experimentally 31 and by computational means 28 . based on the importance of glycosylation for the conformational and thermal stability of igg1fc ,
yeast surface display has been the method of choice to screen igg1fc libraries for variants with desired properties 32 .
the advantage of yeast display over phage , bacterial , and ribosome display is the existence of a eukaryotic protein production machinery that is necessary for posttranslational modifications ( including glycosylation ) and quality control of expressed proteins in the endoplasmic reticulum ( er ) and the golgi complex of eukaryotes 33 .
also , in contrast to phage and ribosome display , yeast display selections usually include one or more flow cytometric sorting steps , facilitating quantitative analysis during selection .
the most obvious advantage of iggfc over other antibodyderived or nonantibody binding scaffolds is its quality of combining all essential antibody functions except for antigen recognition , including binding to fcrs .
these may be expressed constitutively on hematopoietic cells ( e.g. macrophages , eosinophils , neutrophils , natural killer cells , lymphocytes ) and other tissues and may be induced or upregulated , differentially , on each cell type when exposed to cytokines or other activating agents 21 .
stimulation of cells through fcrs may result in the activation or deactivation of one or more of a variety of effector functions , including adcc , cdc , phagocytosis , oxidative burst , release of inflammatory mediators , etc .
35 . due to the high sequence homology between the fcr types and between the subclasses of igg , spatial homology for interaction sites is found . in general , binding sites are located at the lower hinge and adjacent regions in the ch2 domain 36 , 37 ( fig .
2 ) .
representation of secondary structural elements with transparent molecular surface of igg1fc and its binding ligands .
dashed arrows mark the binding site of the neonatal fc receptor [ pdbid 1i1a 50 ] ; fc gamma receptor i [ pdbid 4w4o 119 ] ; the miniz domain of protein a ( pdbid 1oqo ) ; a globular head of the complement system protein c1q [ pdbid 1pk6 47 ] ; the cterminal pryspry domain of trim21 [ pdbid 2iwg
120 ] ; and the antich2 antibody ( clone mk 1 a6 , abd serotec ) .
the epitope of c1q was obtained by docking studies combined with md simulations by schneider et al .
86 defined the binding site of the antich2 antibody to be located at the cterminal part of the ch2 domain .
the proportions regarding size of all shown crystal structures are true to scale . a dynamic model of fc
fcr recognition was proposed in which oligosaccharide / protein interactions within the fc protein generate an equilibrium population of conformers , with distinct structures that recognize and bind individual ligands 21 . besides contribution to the conformational and thermal stability , the two glycan chains of fc are an absolute requirement for binding of fc ( and igg ) to fcrs , as this interaction is lost after deglycosylation 27 .
the fc glycan apparently maintains an open conformation of the fc heavy chains required for interaction with fcrs as supported by the structure of aglycosylated fc 38 . in the latter ,
the two heavy chains arrange in a closed conformation and therefore lack the fcrbinding pocket .
however , it was demonstrated that mutations in the fc backbone can alter the overall structure of aglycosylated fc and restore binding to fcrs to some extent , suggesting that the fc glycan chains primarily affect protein protein interactions by altering the fc backbone conformation 39 .
the interplay between the primary and secondary nacetylglucosamine residues with the protein structure seems to be particularly critical for fcr recognition 40 .
the human fcri ( cd64 ) is expressed on monocytes and macrophages and a number of myeloid cell lines and binds to igg1 and igg3 with similar affinity at the lower hinge region around residues 234238 and residues in the hinge proximal region of the ch2 domain 41 , 42 . in humans ,
both are widely expressed on multiple cell types , constitutively and/or following induction or upregulation 43 and bind to igg1 and igg3 with similar affinity . while their external domains are highly homologous they transduce opposite signals ( activating versus inhibitory ) via their intracytoplasmatic domains .
the binding site at the fc is similar to that of fcri 21 . finally , fcriii ( cd16 ) is a lowaffinity receptor either expressed as an intrinsic ( fcriiia ) or glycosphingolipidlinked protein ( fcriiib ) .
binding of natural killer ( nk ) cellexpressed fcriiia to the lower hinge region activates adcc 37 . as mentioned above
there is some variation in composition of iggfc glycans in vivo and this may directly contribute to modulation of interaction ( and affinity ) with individual fcrs classes , thereby mediating activating , inhibitory , or antiinflammatory processes .
for example , increase in fucosylation and decrease in sialylation and galactosylation on the fc glycan were observed during inflammatory conditions 45 .
there is an ongoing discussion whether these modifications are related to the expression of glycanmodifying enzymes like glycosyltransferases or whether other regulatory mechanisms are involved .
further studies are necessary to dissect the regulation of antibodies in vivo and this knowledge will also lead to the design and production of more efficient ( glycoengineered ) therapeutics , i.e. fullsize mabs or fcabs , respectively .
fig .
2 illustrates that c1q , the recognition subunit of c1 ( i.e. the complex triggering activation of the classical pathway of complement ) also binds at the ntermini of the ch2 domains . similar to fcrs , binding depends on the presence and mode of glycosylation at asn297 .
it includes acidic and basic residues at ch2 but might also involve in vivo interaction with the cl domains of the fab arms 46 , 47 .
there are six heads on c1q , connected by collagenlike stems to a central stalk , and the isolated heads bind to the fc rather weakly .
recently , it has been shown that antigenbinding on cell surfaces can facilitate the formation of igghexamers and that these igghexamers engage the headgroups of c1q 48 .
the igghexamers are formed by noncovalent fc fc interactions involving residues i253 , h433 , and n434 .
moreover , the authors also defined mutations in the iggfc molecule that increased the formation of hexamers and thus resulted in improved activation of cdc . thus , this study not only defined the molecular mechanism that triggers the classical pathway of complement but it also enabled the construction of fcmutants that activate the complement system more potently .
as mentioned above , one of the advantages of iggfcbased therapeutic antibody fragments is the presence of a natural binding site for the neonatal fc receptor fcrn ( fig .
2 ) .
fcrn mediates the transport of maternal igg across the placenta in humans , thereby conferring humoral immunity to the fetus against antigens encountered by the mother 49 .
in addition , fcrn binds igg with nanomolar affinity at acidic ph ( 6.5 ) in intracellular vesicles and releases it upon encountering the basic ph of the bloodstream ( 7.4 ) .
the fcrn / fcbinding interface spans a large surface area at the ch2ch3 interdomain region .
the center of the fcrn / fc interface includes a hydrophobic core with surrounding salt bridges . at the fc
, the interface encompasses residues in the ab loop and the ef loop of the ch2 domain , as well as the gstrand of the ch3 domain 50 .
another highly specific receptor binding to the iggfc region via its cterminal pryspry domain ( fig .
this cytosolic receptor recognizes antibodyopsonized pathogens and targets them to the proteasome through autoubiquitylation of e3 ubiquitin ligase .
the neutralization mechanism of trim21 is thought to link the adaptive immune system with intracellular defense 51 , 52 .
the most prominent example is staphylococcus aureus protein a that binds with high affinity at the ch2ch3 interface of igg1 and igg2 and is used for purification of mab formats containing fc ( e.g. fcabs ) .
as outlined above , binding of ligands to iggfc involves the ntermini of the ch2 domains as well as the ch2ch3 interface ( fig .
each ch3 domain provides three cterminal ( structural ) loops that can be diversified for the generation of novel antigenbinding sites : residues 358 to 362 ( ab loop ) , residues 383 to 391 ( cd loop ) and residues 413 to 422 ( ef loop ) ( fig .
1 ) .
these loops correspond to regions with the most pronounced flexibility within igg1fc 28 . upon engineering the loops , fcabs , homodimeric
five residues in each the ab loop ( 358362 ) and the ef loop ( 413415 , 418419 ) of the ch3 domain ( compare with fig .
1 ) were randomized using nnb degenerate codons and five additional random residues were inserted at position 415 to enlarge the potential binding surface .
a 7.4 10 yeast surface display library was constructed and probed for binding to protein a and fcri for comparison with surfacedisplayed wildtype igg1fc .
it was shown that a considerable amount of clones retained the binding to these proteins , suggesting structural integrity of the displayed molecules .
fc fragments binding to the extracellular domain of her2 ( an oncoprotein of the erbb receptor family ) were selected by fluorescenceactivated cell sorting ( facs ) using decreasing concentrations of the antigen .
next , the fcab exhibiting the highest binding affinity was matured , yielding the final clone h10036 , for which specific binding to her2 at a k
d value of 8.6 nm could be determined by surface plasmon resonance ( spr ) spectroscopy .
moreover , h10036 was shown to elicit adcc in an experiment involving a her2expressing cell line and primary human nk cells to an extent that was approximately 20fold lower than for trastuzumab , a monoclonal antibody binding to her2 which is applied in the treatment of certain breast cancers 54 .
importantly , no adverse effect of loop engineering on the in vivo halflife of the molecule could be determined after injection of h10036 or wildtype igg1fc in balb / c mice .
the correlation of fcriiiabinding affinity and adcc in fcabs was further investigated by kainer et al . , who performed mutational studies to modulate adcc potency .
in a similar experiment as described above , her2 overexpressing cells and nk cells were mixed and treated with variants of a her2binding fc fragment carrying mutations that were previously reported to affect the affinity for fcriiia .
the authors concluded that known effects of the affinitypotency correlation can be assumed for the fcab format 55 .
a recently published study describes a more elaborate investigation of the in vivo and in vitro activity of h10036 with a special emphasis on the comparison with the clinically approved antiher2 antibody trastuzumab 56 . complementing the work described above
, the authors demonstrated the simultaneous binding of fcriiia and her2 to h10036 in an sprspectroscopic experiment as well as binding of fcriiia to h10036 on the surface of her2expressing skbr3 cells .
interestingly , a human tumor cell proliferation assay revealed that , in contrast to trastuzumab , h10036 is not able to inhibit proliferation in a dosedependent manner .
however , when a preclinical in vivo tumor xenotransplant model using human her2 expressing bt474 cells was used to confirm tumorkilling via adcc , a significant retardation of tumor growth could be determined which provided proof of the biological activity of the fcab despite its obvious differences in functionality compared to trastuzumab . a complementary study on the adcc potency of h10036
57 , who expressed the fcab in human cells as well as wildtype and glycoengineered plants to generate four different glycoforms of h10036 .
the authors describe the crucial importance of the glycosylation pattern on adcc activity , thereby confirming the applicability of concepts reported for fullsize igg to the fcab format .
recently , the discovery and preclinical activity of a novel her2targeting fcab , fs102 , was reported 58 .
residues 358362 and 413419 in the ab and ef loops , respectively , were randomized to construct a yeast surface display library , which was screened for binding to the extracellular domain of her2 .
the structural integrity of specific clones was confirmed by their uncompromised binding to antich2 , fcri , and protein a. one resulting fcab , fs102 , contained a total of nine amino acid substitutions in both loops ( compared to wildtype igg1fc ) but exhibited similar biophysical properties , meaning no major structural deviation between the two molecules .
fs102 binds her2 with high affinity comparable to that of trastuzumab and pertuzumab , but does not compete with either mab in binding to the receptor , suggesting that it is targeting a different epitope .
interestingly , fs102 induces profound her2 internalization and degradation and , finally , tumor cell apoptosis , which is an important mode of action for antibody therapeutics .
the antitumor effect of fs102 in patientderived xenografts correlated strongly with the her2 amplification status of the tumors . at gene copy numbers of > 10 her2 per cell , superior activity of fs102 over trastuzumab or the combination of trastuzumab and pertuzumab was observed both in vitro and in vivo , and fs102 induced complete and sustained tumor regression in a significant portion of her2high patientderived xenograft tumor models .
the mode of action of fs102 is still under discussion but might be related to the structure of the fcab and its two potential her2binding sites that are close together ( 2040 ) and relatively inflexible compared to the two typical igg antigenbinding sites ( 120170 ) .
it is possible that the fcab favors a more ordered and tightly packed interaction with the antigen and thereby initiates pronounced aggregation and internalization of the fcab / antigen complexes .
binding of the fcab might also favor a conformation of her2 that is more susceptible to degradation . aside from the successful introduction of novel binding sites into igg1fc
, it was demonstrated that the cterminal loops in the ch3 domains can also be engineered to generate phdependent binding between the fcab and the respective antigen . as serum halflife controlled by fcrn is a major parameter to be considered for the applicability of therapeutic antibodies , engineering phsensitivity into the interaction of antibodies with their targets may also increase the clinical potential of these molecules .
increasing the affinity to the antigen in the plasma ( ph 7.4 ) while simultaneously decreasing the interactions at acidic ph potentially reduces antigenmediated clearance in the lysosome and therefore allows for administration of therapeutic antibodies at lower frequencies and doses .
it was demonstrated that prolonged halflife of tocilizumab , a humanized antibody against il6 receptor , and antibodies binding to proprotein convertase subtilisin kexin type 9 can be engineered by subjecting several residues within the cdr loops to histidine scanning .
antigen complex dissociates at endosomal ph and the antibody is salvaged from degradation by binding to fcrn which recycles it back to the cell surface 59 , 60 . to apply this concept to igg1fc
, the her2binding variant h10036 was used as model fcab and a library was constructed by applying parsimonious mutagenesis to the regions coding for the binding loops of h10036 in order to generate phdependent binding sites .
the resulting yeast surface display library was subjected to alternating selections for binding at ph 7.4 and nonbinding at ph 6.0 61 .
fcab variants could be selected whose interaction with her2 was phdependent not only in the yeast display format but also when her2positive skbr3 cells were titrated with soluble fcabs .
importantly , this effect was not caused by conformational changes , as shown by dsc and md simulations .
only one variant contained a single hissubstitution , but all selected mutations were in the close proximity of existing histidines .
the application of a surface display method for selections of phdependent binders in order to circumvent the laborintensive histidine scanning approach was also demonstrated in a very recent study by bonvin et al .
62 . here , scfv variants binding to the chemokine cxcl10 and enriched in histidine residues in the cdrh3 were selected de novo from a phage library . based on the selected lead clone ,
when reformatted into human igg1 , the isolated antibody 1a4 inhibited cxcl10induced chemotaxis with an ic50 of 1.6 nm .
in addition , the strong phdependency was evidenced by performing a dose response elisa , where 1a4 exhibited a 167fold lower affinity to cxcl10 at ph 6.0 than at ph 7.4 .
of course , not only can igg1fc be engineered to obtain novel functionalities but also to improve existing functions .
63 combined algorithms for computational prediction and high throughput screening methods to selectively optimize the affinity and specificity for fcrs .
designed fc variants of the her2binding monoclonal antibody trastuzumab exhibited adcc enhancements over wildtype with the enhancement levels being proportional to the increase in affinity for fciiia .
importantly , adcc was observed for the engineered variants even with a cell line whose low surface levels of her2 did not allow for adcc detection after using wildtype trastuzumab .
the authors concluded that especially for antibodies that fail in inhibiting proliferation , enhanced engagement of the immune system by fc engineering and thus mediated killing , i.e. by adcc and cdc , could prove to be important .
another very promising and constantly growing field in which the engineering of igg1fc plays an important role is the generation of bispecific antibodies ( bsabs ) , which are able to simultaneously target two different antigens while at the same time maintaining important functions of a mab . a number of different bispecific formats are currently in clinical trials or already approved for cancer therapy , with catumaxomab ( fresenius biotech ) , a mouse igg2a and rat igg2b hybrid antibody combining binding to cd3 and epcam that was approved in 2009 , being a prominent example 64 .
two other bsabs include rg7221 ( roche , basel , switzerland ) , a clinical phase ii bsab designed to bind angiopoietin 2 and vegfa , and ly3164530 bsab ( eli lilly , indianapolis , in , usa ) , currently being evaluated in clinical phase i and comprising binding sites for her1 and cmet 65 , 66 , 67 , 68 .
the technologies proposed for the construction of the latter two molecules use different strategies to solve the light chain association problem .
the crossmabch1cl technology from roche ensures correct pairing of the light chains by rearranging the ch1 domain of one heavy chain with the cl domains of the corresponding light chain 69 , while bispecificity of the ly3164530 antibody is partly achieved by creating an orthogonal interface through mutations in v and l domains for the correct assembly of the different fab domains .
the second prerequisite for the generation of bispecific antibodies is the enforcement of the correct heavy chain heterodimerization over wrong homodimerization , which requires modification of the fc fragment .
the knobintoholes ( kih ) approach mimics a keylocks system by introducing a bulky residue in one ch3 domain that favors binding to a small residue in the other ch3 domain 70 .
71 extended the kih technology by construction of a phage library of ch3 hole mutants which were tested for binding to the t366w knob mutant and were able to select a heterodimer variant with improved thermal stability . to further stabilize and increase the purity of the heterodimeric fc , an artificial disulfide bond was introduced by merchant et al .
another approach represents the seedbody technology , which is based on the fact that the ch3 domains of human igg and iga do not dimerize 73 . by using molecular modeling
, the authors investigated interdigitating strand segments of igg and iga ch3 domains for the generation of complementary heterodimer contact surfaces .
one further technology to enforce correct dimerization includes mutations at the interface of the ch3 domains altering charge polarity of the heavy chain monomers .
two negatively charged residues in chain a pair with two positively charged residues that were introduced in chain b ( ddkk variant ) resulting in a high degree of heterodimer purity , but also a decrease in thermal stability of the ch3 domain 66 , 74 .
75 identified mutations in the hinge region of human igg1 and igg2 that produce stabilizing ionic interactions . by combining these changes of the amino acid sequence with an additional mutation at the canonical position 409 in the ch3 domain ,
however , in this case both homodimers were first produced separately and then purified by affinity chromatography using protein a. formation of heterodimers was induced by mixing both samples at equimolar ratios and incubating them under reducing conditions at 37c for 24 h , resulting in the most stably paired variant eeerrr for higg1 .
76 identified residues in the ch3 interface promoting fc heterodimerization by combining structural considerations with sequence information .
several variants were screened for the highest degree of heterodimerization , and an hatf variant was identified , where his and thr are stabilized through a hydrogen bond and ala and phe act as key and lock .
described the heterodimer format zw1 providing high thermal stability and 95% purity , with the residual 5% being present as monomeric , but not homodimeric ch2ch3 subunits . by combination of in silico design and experimental screening , variants with high degrees of heterodimerization but low thermal stabilities
based on these initial results , modifications of the selected heterodimeric variants were designed toward increasing purity and stability . the leading format zw1 carries four mutations on each ch3 domain located in the ch3ch3 interface and exhibits wildtypelike tm values 77 . in a very recent study , choi et al .
78 combined electrostatic with asymmetric hydrophobic interactions and generated the ewrvt fc heterodimer . by introducing a disulfide bond between the ch3 domains they could further improve purity and thermal stability 79 .
all of the abovementioned approaches to the heterodimerization of heavy chains and the correct pairing of light chains aim at the production of fullsize bsabs providing one distinct specificity at each of the two fab fragments .
by contrast , application of the modular antibody technology would allow for the combination of these fablocated binding sites with novel , artificial antigenbinding sites in the structural loops of constant domains .
for example , the fc of an existing mab could be replaced with an fcab to generate a socalled mab that bivalently binds to one antigen via its fab fragments and mono or bivalently to a second antigen via the fcab portion ( fig .
schematic representation of a hypothetical mab2 [ based on pdbid 1hzh (
122
) ] and one isolated ch3 domain thereof .
secondary structure elements of the antibody are colored in gray with the molecular surface of the cdr loops shown in green .
loop areas in the ch3 domains are displayed in red ( ab loop ) , orange ( cd loop ) , and purple ( ef loop ) .
the surface approximations of the three loops indicate the putative region for the generation of binding sites .
the correctness of the overall fold of igg1fc variants was confirmed in many cases . under some circumstances it was necessary to improve the biophysical properties of fcabs , either in advance by including stabilizing measures in the construction of libraries to make use of the full versatility of the scaffold or by
repairing functionalized , yet impaired , fc fragments , which were mainly selected from early generation combinatorial libraries .
also , even though the fc fragment is an intrinsically stable protein , the engineering of its properties could further accentuate the advantages over other nonantibodybased protein therapeutics .
a detailed systematic study on the effect that the engineering of the cterminal structural loops of the ch3 domain of igg1fc has on the biophysical properties of the fc fragment was published by traxlmayr et al .
this motif , in the context of the heptapeptide gcrgdcl , forms a cyclic and rather rigid structure as a consequence of disulfide bond formation by the flanking cysteines , resulting in increased interaction with integrins .
single , double , and tripleinsertion variants ( i.e. grafting of gcrgdcl into ab loop , cd loop , ef loop , ab+cd , ab+ef , or cd+ef ) were expressed in pichia pastoris and evaluated for the binding to soluble or cell surfaceexpressed v3 integrin as well as for the effect of the engineering efforts on the overall fold and the structural integrity of the protein .
expression levels determined for the variants did not differ significantly from those determined for the wildtype protein , except for the heavily mutated triplevariant , where grafting of the rigid circular motif into each of the cterminal loops apparently resulted in severe misfolding and degradation . aside from wildtypelike expression levels , all other constructs exhibited high purity and homogeneity and eluted as single peaks and at defined elution volumes in sizeexclusion chromatography , suggesting the correct folding of the proteins and the absence of aggregates . also , using electronic circular dichroism spectroscopy , the overall secondary structure content was determined for each variant .
no significant changes were observed for ab and cd loop variants , whereas engineering of the ef loop apparently affected the helical content of the protein .
this effect was also reflected in the strongly decreased stability of ef loop variants as determined by dsc .
in contrast to that , manipulation of ab and cd loop destabilized the protein to a lesser degree . as expected , simultaneous insertion in two loops had a more pronounced effect on protein stability than single insertions . furthermore , the interaction with natural ligands was analyzed by spr spectroscopy and biolayer interferometry : fcrn , protein a , and fcriiiabinding revealed to be wildtypelike , which again confirmed the structural integrity of the recombinant proteins .
the importance of biophysical properties of antibody fragments for largescale production and/or therapeutic efficacy has been demonstrated in various studies .
81 described the correction of an antiegp2 scfv fragment which , despite its high affinity , did not enrich at tumor xenografts . by grafting the binding residues of this scfv onto the framework of a more stable fragment and identification and introduction of stabilizing mutations
, a functionally improved variant could be generated for which tumor localization was observed . in a different study
, antibodies directed against the chemokine ccl17 were selected from a fab phage library designed by shi et al .
82 , many of them raised from the vh169 germline gene family abundant in the human immune repertoire 83 .
the authors suggested that the high hydrophobicity of the germline cdrh2 leads to these unfavorable properties . by generating a library with randomized surfaceexposed residues within cdrh1 and cdrh2 to a group of biochemically distinct amino acids ,
a panel of novel clones could be isolated comprising both high affinity and reduced nonspecific interactions .
surprisingly , the overall hydrophobicity of the selected clones was not significantly reduced , but three residues turned out to be critical in terms of undesired protein protein interaction . clones exhibiting a mutation at position i51 to polar or charged residues as well as at position f54 to small polar residues demonstrated higher solubility .
furthermore , mutation of p52 suggested a structural change to the loop associated with higher stability .
this study reveals the challenge in selecting for high affinity and good biophysical properties and demonstrates the importance of combinatorial library design , which we will discuss later in this review .
one further study describes a monoclonal antibody that neutralizes binding of angiopoietin 2 to its receptor in vitro and inhibits tumor growth in vivo
84 . even though the pharmacological activity could be demonstrated , production of the antibody coincided with heterogeneity of the preparations , rapid aggregation , and poor expression yields .
exchange of a susceptible surfaceexposed cysteine by all other 19 amino acids yielded a threoninevariant that exhibited reduced proneness to aggregation , improved homogeneity , largely increased expression levels , retained activity and , interestingly , the midpoint of denaturation shifted by 11c , corresponding to a strongly improved thermal stability .
the authors stated that the engineering process resulted in the fulfillment of requirements necessary for largescale production in order to provide amounts of material sufficient for clinical trials .
considering the conclusions from the abovementioned work , comparable efforts proved to be beneficial for the fc scaffold .
tool box that would help the correction of impaired fc fragments was published recently 85 . in this work ,
the authors implemented a novel method that allows screening for stabilizing mutations in proteins that exhibit an already high thermal stability and t
m values of up to 85c .
two libraries of igg1fc variants differing in their mutation rates were constructed by errorprone pcr targeting the entire gene .
these libraries were then expressed in the yeast surface display format and incubated at 79c in order to denature those variants displayed on yeast that were not stabilized by mutation .
variants that were still conformationally intact were stained with fluorescently labeled structurespecific markers , either fcri or antich2 antibody , and thereby tagged for sorting of the displaying yeast cell by facs . as a consequence of heat denaturation of the yeast cells , plasmid dna coding for the stabilized variants had to be isolated , followed by retransformation of s. cerevisiae and construction of novel libraries , now being enriched in variants carrying favorable mutations .
a total of four sorting rounds were performed to select for the most stabilized variants in the libraries which were eventually identified by sequencing of the isolated plasmid dna .
biophysical characterization of 17 single , double , and triple mutants expressed in p. pastoris revealed that all of the variants exhibited increased thermal stabilities and wildtypelike binding to relevant ligands , i.e. fcrn , fcriiia , and protein a. it was concluded that possible adverse effects of the artificial amino acid composition in the engineered loops might be counteracted by the introduction of the identified stabilizing mutations without negatively affecting the intrinsic functionality of the fc fragment .
in addition , this original igg1fc library pool generated by errorprone pcr and the selected libraries after one round of facs were analyzed by highthroughput sequencing 86 .
for each amino acid position , the change in the mutation rate during selection was determined , indicating the tolerance to mutation at the respective position .
as expected , selection for binding either to fcri or the antich2 antibody resulted in reduced mutation rates .
this was more pronounced in the ch3 domain reflecting the thermal denaturation pathway of igg1fc with the reversibility of unfolding of the ch2 domain , as long as the ch3 domain remains natively folded .
these data indicate a lower selection pressure for the ch2 domain , as only mutations either located in the binding site of the structurespecific markers or impeding the correct folding of the ch2 domain were eliminated . as both ligands that were used in this study bind to the ch2 domain , the changes in the mutation rates at positions in the ch3 domain were solely dependent on the impact of the respective side chain on foldability and/or stability , enabling the generation of a stability landscape of the ch3 domain .
importantly , positions that are evolutionarily conserved among different species were significantly less tolerant to mutation in these in vitro selections , validating the quality of the stability landscape .
furthermore , the experimentally derived tolerances to mutation correlated with the changes in the free energy of unfolding determined in silico . the results of this study not only revealed the sequencestability relationship of an entire protein at single residue resolution but also proved to be an important tool for protein engineering , because library randomizations can be focused on mutationtolerant regions of the protein .
in addition , comparison of two selection experiments with different ligands ( fcri and an antich2 antibody ) enabled the identification of their epitopes on igg1fc . in a followup project , this directed evolution protocol was applied to improve the biophysical properties of the her2binding fcab h10036 87 , which , even though the interaction with important effector molecules was wildtypelike , exhibited impaired biophysical properties in an initial characterization .
in contrast to the method described above , mutagenesis was directed to the engineered loops only in order to minimize the overall changes the fc fragment .
an initial experiment revealed that the binding of h10036 to her2 was decreased after heat incubation , leading to the assumption that a correct fold is necessary for molecular recognition and that combination of heat shock and selection for ligand binding could be applied to simultaneously screen for improved thermal stability and retained affinity to the antigen . after heat incubation
, the yeast displayedlibrary was either sorted for ( i ) binding to the antigen and to structurally specific ligands or ( ii ) binding to the antigen only .
enriched clones were expressed in p. pastoris and hek293 cells and their biophysical properties were analyzed by sec , ecd spectroscopy , and dsc . stabilized variants resulting from the combined staining strategy ( antigen and structurally specific ligand ) exhibited higher thermal stabilities , which led to the assumption that this selection strategy should be favored .
in addition , some stabilized fcabs were less prone to aggregation after long term storage , showed more wildtypelike sec elution profiles and the solubility of the fcab exhibiting the highest thermal stability was largely increased when compared to the parental clone h10036 .
the general applicability of this method to improve the biophysical properties of suitable proteins was concluded .
in addition , the differences in thermal stability of igg1fc and fcabs between the two expression systems , p. pastoris and hek293 , were analyzed .
generally , the high mannose glycan structures attached to asn297 of the p. pastorisproduced fc variants destabilizes the interface of the ch2 domains and therefore leads to lower t
m values . in a study by schaefer and pluckthun 88 ,
significant differences between fullsize iggs produced in both expression systems revealed not only different temperatures of unfolding but also indicated differences in terms of aggregation susceptibility .
antibodies produced in p. pastoris were less prone to aggregate formation due their mannoserich glycan structure and the nterminal residual eaea extension , remaining from the factor prepro secretion sequence .
although the thermal stability of p. pastorisproduced fc variants was lower , the corresponding sec elution profiles were highly comparable with the hekproduced counterparts 87 , as was the stabilityranking of fcabs in both expression systems .
this clearly underlined that p. pastorisproduced fc variants can be used to investigate the biophysical properties and binding characteristics of a panel of selected fcabs .
a different approach to stabilize igg1fc in order to provide a stable scaffold for the engineering of antigenbinding sites or other novel functionalities is based on the insertion of artificial disulfide bonds based on computational prediction 89 .
selected cysteinevariants were expressed in p. pastoris and their biophysical properties were characterized , revealing that the thermal stabilities of two variants bearing novel intradomain disulfide bonds were largely increased while the overall structure remained wildtypelike .
moreover , stabilization of the her2binding fcab h10036 could be achieved by the introduction of only one of the disulfide bonds . in a second study , the observation that the cterminus of the ch3dimer closely resembles the cterminus of the ch1cldimer of the fab fragment led to the assumption that the three cterminal amino acids of the ch3 domains could be replaced by those of the cl domain 90 .
the resulting variant exhibited a wildtypelike elution profile in sec , leading to the assumption that specific disulfide bonding was accomplished and no incorrect crossbridging occurred .
thermal denaturation of the protein occurred at significantly higher temperatures compared to wildtype igg1fc and this effect was observed to be further pronounced in a variant carrying both the stabilizing inter and intradomain disulfides .
interestingly , more detailed analysis by dsc revealed a strong stabilizing cooperative effect that the ch3located alterations had on the ch2 domain .
the introduction of both the computationally and rationally selected mutants into h10036 increased the thermal stability of the protein to be approximately wildtypelike while antigenbinding was retained .
those identified mutations could serve as a valuable tool for stabilization of single proteins or entire libraries . in a similar study , gong et al .
91 described the stabilization of a monomeric human igg1ch2 domain by the introduction of artificial , rationally designed disulfide bonds . for two variants
whose expression levels were comparable to the wildtype domain and which were highly soluble , increased thermal and conformational stabilities were determined in heat and chemical denaturation experiments
structural changes in this variant as a consequence of the cysteine mutations were analyzed by nmr , once again confirming the correct formation of the novel disulfide bond .
nuclear overhauser effect spectra were recorded and showed that the flexibility of both the wildtype ch2 domain and the stabilized variant were rigid in the framework but highly flexible in the loop regions .
based on these findings , it was suggested that the ch2 domain as well as its stabilized variant can be applied as scaffolds for engineering antigen binders . in summary , the methods described in this section can be applied in several ways : one possibility is the introduction of thus identified stabilizing mutations in nave libraries in order to
prestabilize the scaffold and thereby minimize the risk of selecting an fcab with impaired biophysical properties .
the combination of several beneficial mutations exhibiting additive stabilizing effects could not only compensate for destabilization upon mutation of the structural loops but also further improve the characteristics of the resulting binders .
moreover , starting from a stabilized protein scaffold has been shown to promote evolvability by tolerating a wider range of mutations 92 .
in other words , a library based on a stabilized protein contains a higher fraction of correctly folded and therefore functional protein mutants
. a more elaborate way of exploiting stabilizing effects of single or multiple point mutations would be the
repairing of existing binders as a reaction to negative effects of loop mutations , as was shown for the her2 binding fcab h10036 .
the previous chapters have clearly shown that igg1fc is a very attractive scaffold for the design of novel binding molecules that possess all antibody functions at only onethird of the size of a fullsize igg1 molecule .
like many other therapeutic antibodies , antibodybased and nonantibodybased molecules , fcabs are selected from combinatorial libraries that became an alternative to conventional methods , i.e. the hybridoma technology .
the selection of proteins with the desired binding properties from these libraries is in many cases accomplished by the application of various display technologies such as phage , ribosome or yeast surface display 93 .
therapeutic igg1 molecules are generated by selecting either scfv or fab from combinatorial phage libraries , or fullsize igg from yeast or mammalian display libraries .
the three main aspects of such libraries that are known to impact library quality are ( i ) design , ( ii ) the origin of sequence diversity , and ( iii ) the method of library generation , while library quality can be assigned to the library size , diversity , and the developability of the selected molecules , i.e. high affinity and good biophysical properties .
maximization of library diversity can be accomplished by increasing the functional size and improving the resulting molecules developability , which for example is achieved by restriction to one stable framework or a limited number of consensus frameworks .
the issue of immunogenicity is met by choosing framework and cdr compositions as close to the human germline as possible 93 .
the introduction of novel binding sites into noncomplementaritydetermingregion ( cdr ) loops in immunoglobulinlike domains of nonig proteins as well as immunoglobulin constant domains as already demonstrated in the context of fcabs requires more elaborate considerations with respect to library design .
while the lack of somatic hypermutation is , as is the case for cdr sequences of scfv or fab fragments selected from combinatorial libraries , met by different affinity maturation strategies , the design of libraries for nave selections is more challenging than in scfv or fab libraries .
first of all , there is little or no natural variation in the amino acid sequences of noncdr loops and loop lengths are , in contrast to some cdr loops , mostly conserved .
information on typical amino acid compositions that can be drawn from the large pool of existing cdr sequences is not available for alternative scaffolds . and lastly , the knowledge of canonical cdr loop conformations is a design advantage that can not be exploited in noncdr loops as yet
. therefore , these favorable properties that are intrinsic to cdr loops have to be systematically investigated for noncdr loops of igderived and alternative binding scaffolds . as the term
antibodybased is commonly used to describe formats that exploit the original binding site formed by the cdrs of either both or only one of the variable domains , antigenbinding igg1fc , albeit derived from igg1 , will be classified as an alternative binding scaffold. in this respect , the initial strategies that are pursued in order to provide a high degree of diversity , but also functionality , in libraries of different alternative binding scaffolds , are consistent . in this section , we will focus on these strategies and compare the library design efforts that have been made in the engineering of igg1fc and other formats , especially the fibronectin type iii scaffold , which , due to its immunoglobulinlike fold , is particularly interesting for comparison . as mentioned above , the generation of diversity in alternative binding scaffolds can not rely on the natural variation that is present in antibodies through somatic recombination and hypermutation during bcell development .
while in the course of this maturation process stable frameworks supporting diversity in variable domains are selected for , it is highly probable that diversification of one or several amino acid positions in alternative binding scaffolds impairs the overall protein fold to a certain degree .
as mentioned above , in the case of fcabs , it was shown that the introduction of an integrinbinding motif into each of the three cterminal loops of igg1ch3 is possible while retaining the binding to generic ligands 80 .
however , overall folds of the proteins as well as thermal stabilities were impaired to some degree .
the design of the first combinatorial libraries , i.e. the choice of amino acid positions in the cterminal loops to be randomized , was based on the degree of evolutionary conservation and visual evaluation of the crystal structure of igg1fc according to several criteria ( solvent accessibility and structural independence of the respective amino acid side chains ; generation of a coherentbinding surface ) 15 , and the applicability of this igg1fc variant library was proved by isolating fcabs binding to hen eggwhite lysozyme and cd20 .
later , using an advanced library , it was shown that randomization of five positions in each the ab loop and the ef loop of igg1ch3 as well as insertion of five additional random amino acids in the ef loop , construction of a yeast surface display library and selection of igg1fc variants binding to her2 yielded wellexpressing and biologically functional , yet slightly destabilized proteins 53 . to circumvent this minor drawback already on the level of nave libraries , two approaches
have successfully been followed , which resulted in the construction of superior next generation libraries : first , prior to selections , nave libraries can potentially be cleaned by isolating yeast cells that display igg1fc still binding to conformationally specific ligands ( e.g. protein a or fcri ) after diversification . depending on the applied threshold of residual binding to these ligands ,
optimized regions of diversification were identified for the generation of libraries of igg1fc in order to minimize detrimental effects on the ch3 framework and increase the number of productive clones in the library 94 .
for this purpose , yeast surface display model libraries were constructed with distinct or overlapping regions randomized in the ab , cd , or ef loop of igg1ch3 and subjected to a protocol that involves the incubation at increasing temperatures of yeast suspensions induced for surface display and subsequent flow cytometric recording of the residual binding to conformationally specific ligands .
library denaturation curves were derived from the resulting mean fluorescent intensities and used for the determination of temperatures of halfmaximal irreversible denaturation ( t
1/2 ) of entire yeast libraries , yielding a clear hierarchy of the distinct loop regions tolerance to randomization .
igg1fc libraries were redesigned based on these findings and are currently evaluated for their potential in the selection of fcabs .
an approach to library design similar to the basic strategy pursued for fcabs was published by koide et al .
14 , who identified the tenth type iii unit of human fibronectin ( fn3 ) , an immunoglobulinlike sandwich protein , as a potent binding scaffold .
similar to the involvement of the nterminal loops bc , fg , and c'e of igg1ch2 in the binding of the fc receptors 39 , fn3 binds to integrin via the rgd motif in its fg loop .
initially , fn3 library design was based on sequence analyses of several fibronectin type iii domains as well as structural evaluation of the loop architectures .
selections using a library with five residues randomized in each the bc and the fg loop yielded a fn3 variant binding to ubiquitin with an ic50 of 5 m .
however , this variant was less soluble at neutral ph than the wildtype fn3 protein and interacted with the column material in sizeexclusion chromatography . in a followup study , it was suggested though that this negative side effect of mutation could be counteracted by the removal of unfavorable electrostatic interactions on the protein surface 95 .
96 reported selections of fn3 variants binding to tnf. the master library applied in these selections consisted of an equimolar mixture of three sublibraries having either one , two , or all three of the nterminal fn3 loops randomized .
interestingly , all but one of the resulting tnfbinding fn3 variants stemmed from the sublibrary having all three loops randomized , indicating the importance of diversity for the isolation of highaffinity binders .
again , the stabilities reported for two representative variants were decreased . in a followup study , parker et al .
97 reported the significant loss of stability and solubility of vegfr2binding fn3 variants during affinity maturation , once more suggesting a tradeoff between stability and affinity .
the authors counteracted destabilization by structurebased sitedirected mutagenesis , which also included the systematic reversion of randomized positions to their respective wildtype amino acids .
also , it was suggested to apply alternative designs of the apparently crucial de loop of fn3 .
all of these findings were based on the biophysical characterization of a limited set of fn3 variants , which leads to the assumption that it would be possible to further enhance fn3 library design ( i.e. at which positions the nterminal loops can be randomized ) by applying the flow cytometrybased method developed for libraries of igg1fc to this scaffold as described above , even though it is focused on stability and does not take into account the effects library design will have on affinity 94 .
if , on the other hand , results from one further study on the fn3 scaffold by lipovsek et al .
98 are taken into consideration , it can be expected that a higher number of randomized residues will increase the affinity of selected fn3 variants while , as mentioned above , stability and solubility will be impaired . consequently ,
if information on the importance of distinct regions for the overall fold and stability of the scaffold is made available in a systematic manner , as was done for igg1fc , desired affinities can be approached by manipulating increasing numbers of distinct loop positions while at the same time being aware of the effect this will have on the biophysical properties of the scaffold . besides the application of modular antibody engineering to the cterminal loops of igg1fcch3
, various other studies have described the introduction of novel binding sites to immunoglobulin constant domains : xiao et al .
10 identified hiv1 inhibitors based on isolated igg1ch2 by randomizing the longest nterminal loops in the domain , i.e. bc and fg . an interesting design feature was the addition of a glycine residue at the cterminal end of each loop to provide flexibility and favor the accommodation of amino acid alterations necessary for stability and antigen recognition .
however , as the stability of native ch2 is relatively low , the solubilities of three hiv1binding
nanoantibodies selected from this library were reported to be poor . to overcome these issues ,
the isolated ch2 domain was stabilized by introducing an additional disulfide bond and removing seven nterminal residues 91 , 99 , 100 .
starting from this scaffold , a library was constructed that comprised randomized bc and de loops and a cdrh3 from the hiv1 gp120binding vh m36 grafted in place of the fg loop 101 .
while one of two clones selected from this library interacted noncompetitively with an hiv1 neutralizing epitope and fcrn , the second was not further characterized due to its aggregation proneness , leading to the authors conclusion that further improvements to the library design would be necessary to develop igg1ch2 as a scaffold for the development of novel therapeutics .
length variation of cdr loops is another important factor in the natural generation of diversity . among the six cdr loops ,
h3 is the most diverse , both in terms of sequence and length . in a study on the clustering of antibody cdr loop confirmations , north et al .
102 assigned between two and eight different loop lengths to l1 , l2 , l3 , h1 , and h2 , and 20 different lengths to h3 , ranging from 5 to 26 residues .
this length variability is introduced by imprecise joining during the combinatorial rearrangement of vh , dh , and jh genes in the course of bcell maturation 103 and is considered to be a main contributor to the recognition of diverse antigens , as h3 , given by its location in the center of the antigenbinding site , potentially controls the relative positions of vh and vl and affects the flexibility and cavity size of the paratope 104 .
consequently , in order to mimic this crucial aspect of the development of antigen specificity by the immune system , loop length variation in the antigenbinding sites of alternative scaffolds is an important factor in the generation of specific , highaffinity interactions . in the process of development of the fcab scaffold
, several steps have been made toward a loop elongation strategy that would allow for the selection of variants binding to diverse antigens while at the same time the intrinsic stability can be retained to a satisfactory degree .
as mentioned above , the initial design for variant libraries of igg1fc included the insertion of five additional residues at the nterminal part of the ef loop , with this loop elongation aiding in the selection of an fcab binding to her2 with a k
d value of 8.6 nm 53 .
however , mutation and insertion negatively affected the biophysical properties of this fcab 87 . therefore , one further aspect of the detailed analysis of the cterminal loops of igg1ch3 was the systematic insertion of five additional random residues at different loop positions according to a sliding window 94 .
t
1/2 values were determined for the resulting yeast surface display libraries as described above and used for the comparison of the tolerance of different loop positions to insertion .
the results from this study , as well as the identification of sites of natural insertion from phylogenetic analysis of igg1ch3 from different species , were also considered for the design of novel variant libraries of igg1fc . as mentioned above ,
furthermore , findings from a study that dealt with the identification of stabilizing point mutations in igg1ch3 by using a directed evolution approach were combined with rational considerations 85 , 105 . in order to generate stabilizing stem regions that would allow for loop elongation
the central part of this loop is constituted by an arginine residue forming a salt bridge with a glutamic acid in the cd loop , and a tryptophan residue that has been shown to be crucial for protein stability by contributing to the packing of the hydrophobic core . at the cterminus of this rw motif , a glutamine residue was replaced by a stabilizing leucin residue . at the nterminus of the adjacent fstrand , a serine between a phenylalanine also contributing to hydrophobic packing and a cysteine forming the intradomain disulfide bond was replaced by a stabilizing threonine .
yeast surface display libraries including or not including these stabilizing stem regions and carrying increasing numbers of additional residues in between them were constructed , and their stabilities were evaluated by using the yeast surface displaybased method described above 94 , showing that , indeed , a largely increased tolerance to loop elongation was achieved by this stabilization approach , with the potential of such libraries for the selection of fcabs binding to diverse antigens being yet to be looked into . while the work on the design of libraries of igg1fc to date has focused on the question of how enhanced diversification , both in terms of site or regionspecific randomization and loop elongation ,
affects the overall fold and the biophysical properties of the scaffold , the tradeoff between this focus and its effect on fcab affinity is still under investigation .
however , this has been addressed for other alternative formats , including the abovementioned immunoglobulinlike fn3 scaffold , which is why the results of the underlying studies should be of interest in this context and a link can be made to ongoing and future projects dealing with igg1fc .
106 performed basic experiments on the potential for elongation of all the loops in the fn3 domain , thereby providing some first information on the tolerance to insertion of alanines , which , of course , does not reveal the effect of full randomization .
107 , who diversified all three nterminal loops of fn3 both in length and composition .
four different lengths were chosen for each loop based on sequence analysis of fn3 from different species , and nnb degenerate codons were used to incorporate all 20 amino acids .
the output of this nave selection was diversified by loop shuffling and errorprone pcr and sorted twice , followed by another four rounds of this procedure , yielding fn3 variants of single digit picomolar affinity and high sequence diversity , having accumulated a considerable number of beneficial framework mutations .
interestingly , further mutational studies on the de loop of one particular highaffinity fn3 variant revealed that this loop can be either engineered to improve affinity or stability to a considerable degree .
these results underline once more that library design for scaffolds based on immunoglobulin and immunoglobulinlike domains must undergo adjustments based both on the systematic evaluation of nave libraries and selection outputs in order to efficiently approach an optimum balance of stability and affinity of relevant variant proteins .
the degree of cdr sequence diversification in combinatorial libraries of antibodybased alternative scaffolds , i.e. the usage of the amino acid repertoire , follows various different strategies .
while nave libraries provide natural diversity by combination of functional vgene segments isolated from the lymphoid tissues of nonimmunized donors [ e.g. cat 1.0 and cat 2.0 libraries of cambridge antibody technology 108 , 109 ] , synthetic libraries such as the hucals ( morphosys ) offer any desired amino acid compositions in the cdrs 110 , 111 . in general ,
it was observed that , despite the hypervariability of cdr sequences , there is a bias of functional cdrs to certain amino acid types , most of all tyrosine , glycine , and serine 112 .
showed that while scfv variants binding to some antigens at nanomolar affinities were selected from phage display libraries providing only a binary amino acid repertoire ( i.e. tyrosine and serine ) , selections of binders from the same libraries to other antigens yielded affinities only in the micromolar range 113 , 114 , 115 .
modifications of these libraries included an increased chemical diversity in cdrh3 and the consideration of nonparatope residues potentially important for cdr conformation 116 .
as mentioned above , morphosys hucal fab libraries are fully synthetic , and they were developed over the course of several years 110 , 111 .
the latest version , named hucal platinum , offers , among other features , length variation in cdrh2 and cdrh3 , and lengthdependent amino acid frequencies as observed in the analysis of rearranged sequences , which was realized by using a large set of different trinucleotide mixtures . in principle , a similar approach is potentially valid for the construction of variant libraries of igg1fc .
naturally , while the alignment of thousands of vh and vl sequences was used to generate information on the amino acid distributions in cdr loops , it can not be estimated how , for example , binary codes or natural distributions in cdrs would influence the efficient isolation of welldevelopable fcabs binding to diverse antigens at high affinities .
investigated the effect of full or restricted diversity in fn3 , which , again , can be a valuable source of information for the engineering of igg1fc due to its immunoglobulinlike fold 117 , 118 . in these studies , the sequencefunction landscape of the fn3 scaffold
was approached by comparing various amino acid compositions in the nterminal loops , leading to important conclusions : first , it was shown that maximal amino acid diversity is more beneficial for the selection of antigenbinding fn3 variants than a binary tyrosine / serine code as described above . and second , wildtype conservation at positions potentially important for structural integrity , as well as amino acid distribution biases toward the natural occurrence in cdrs made clear that both strategies were valuable for an efficient selection of binding fn3 variants . consequently , while the identification of positions in igg1fcch3 at which conservation of wildtype amino acids improves the biophysical properties of selected variants has been accomplished 86 , 94 , the application of tailored amino acid distributions as described above is a promising approach to be investigated in the future .
over the past 30 years , therapeutic monoclonal antibodies and antibodybased alternative formats have been successfully developed , first by using the hybridoma technology and later by selection from combinatorial libraries . in this review
, we introduced the potential of igg1fc as a promising scaffold for the generation of alternative protein therapeutics . by applying the modular antibody engineering technology , novel binding sites for
theoretically any desired antigen can be introduced in the cterminal loops of the ch3 domains to create fcabs , antigenbinding fcs . in this way ,
the fc is engineered to unite all important functions normally conveyed by fullsize iggs , i.e. ( i ) the mediation of effector functions through binding to fcrs ; ( ii ) contribution to a long halflife in serum through binding to fcrn , and ( iii ) ( novel ) binding to an antigen .
fs102 , a her2binding fcab that has recently entered the clinic , is believed to accelerate aggregation and internalization of the antigen / fcab complexes as a consequence of the distinct fcab structure , with pharmacokinetics not being impaired by the sequence changes in the ch3 domain . in some cases , as has been described for other alternative scaffolds , the engineering process might negatively affect the biophysical properties of igg1fc .
the current article summarizes a set of methods , mostly based on directed evolution and yeast surface display , which provide a
we also reviewed the various approaches to modifying iggfc for the production of bispecific antibodies and described the highly promising concept of constructing mabs , monoclonal antibodies with one specificity in the two antigenbinding sites of the fabs and one additional specificity at the cterminus of the fc , which again can be accomplished by modular antibody engineering .
loop position and loop regionspecific information has been obtained that will aid in the construction of libraries of high quality , and studies dealing with the modification of the architecture of the putative fcab binding sites by loop elongation have been performed .
many approaches that have proved successful in the context of other alternative scaffolds , especially those targeting tailored amino acid distributions , can be used as models for the future investigation of libraries of igg1fc , which will ultimately lead to a further accentuation of the intrinsically favorable properties of fcabs .
Output:
| summarythe crystallizable fragment ( fc ) of the immunoglobulin class g ( igg ) is a very attractive scaffold for the design of novel therapeutics due to its quality of uniting all essential antibody functions .
this article reviews the functionalization of this homodimeric glycoprotein by diversification of structural loops of ch3 domains for the design of fcabs , i.e. antigenbinding fc proteins .
it reports the design of libraries for the selection of nanomolar binders with wildtypelike in vivo halflife and correlation of fc receptor binding and adcc .
the in vitro and preclinical biological activity of selected fcabs is compared with that of clinically approved antibodies .
recently , the great potential of the scaffold for the development of therapeutics for clinical use has been shown when the her2binding fcab fs102 entered clinical phase i. furthermore , methods for the engineering of biophysical properties of fcabs applicable to proteins in general are presented as well as the different approaches in the design of heterodimeric fcbased scaffolds used in the generation of bispecific monoclonal antibodies .
finally , this work critically analyzes and compares the various efforts in the design of highly diverse and functional libraries that have been made in the engineering of igg1fc and structurally similar scaffolds . |
PubmedSumm118288 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: world health organization ( who ) describes obesity as one of the main public - health problem that threatens to overwhelm the entire world ( 1 ) .
obesity is a medical disorder that also leads to a large number of comorbidities including hypertension , type 2diabetes and cardiovascular disease ( 2 ) .
this association is profoundly important for the affected individuals , but the associated morbidity is also economically damaging for society ( 3 ) .
recently , who european region office has reported that overweight and obesity are responsible for about 80% of cases of type 2 diabetes , 35% of ischemic heart disease , and 55% of hypertensive disease among adults in the region , and cause more than one million deaths and 12 million life - years of ill health each year ( 4 ) .
like many other countries in the world , overweight and
a recent nationwide survey reported that age - adjusted prevalence of overweight or obesity ( bmi25 ) was 42.8% and 57.0% in men and women , respectively in 2004 - 2005 ( 5 ) . among these people ,
11.1% of men and 25.2% of women were obese ( bmi30 ) ( 5 ) .
urbanization and changes in life style including improper eating habits and physical inactivity are considered as main causes of increasing obesity in iran ( 6 , 7 ) .
it is expected that these changes are more common among population in tehran as capital of the country . while some previous studies examined the prevalence of overweight and obesity in tehran , but they either reported an overall rate ( 8) or estimate a rate for a specific district ( 9 ) .
the aims of the current study were to present an update estimate of overweight and obesity prevalence among tehranian adults and examining the distribution of these disorders across the 22 districts of tehran using data from a large population - based survey ( urban heart ) in 2011 .
urban health equity assessment and response tool ( urban heart ) is rather an approach for evidence - based practice and policy making at national and local levels to identify and analyze inequities in health between people living in various parts of cities , or belonging to different socioeconomic groups within and across cities .
it facilitates decisions on viable and effective strategies , interventions and actions that should be used to reduce inter- and intra - city health inequities ( 10 ) . in october 2011
, the second round of urban heart project was conducted to determine inequalities in physical , mental , social and environmental health components supported by municipality of tehran .
to collect data in 22 districts and 368 neighborhoods of tehran ,
comprehensive map of tehran in 2011 separated by the districts and neighborhoods was selected as the sampling frame .
22 districts of the municipality and 368 neighborhoods were considered as stratums in the first stage and the second stage respectively .
a two - dimensional systematic sampling method was used to select blocks in each neighborhood using gis maps .
then the houses were numbered in each block and 8 houses were selected in each block systematically based on an eight - box table including four age groups ( 15 - 24 , 25 - 44 , 45 - 64 , and 65 and over ) and both sexes .
the sample size was determined as 1535 households in each district based on a prevalence of 10% with a margin of error of 0.015% and a confidence interval ( ci ) of 95% .
then to facilitate the allocation of sample to the mentioned eight - box table that must be completed for the individual questionnaires expanded to 1600 households . for sample allocation at neighborhood level ,
the method of the probability proportional to size of each district was used .
in this project
, there were three types of questionnaires consisted of 20 parts that the first 14 parts were completed for all selected households in the blocks and the remaining six parts ( mental health , health - related quality of life , social capital , physical pain , physical activity and oral health ) were completed by a selected individual in each household .
the last type of questionnaire was special for nutrition and was completed for a selected household in each block . in urban heart-2
we have collected data about demographics , assets , children health , accidents , domestic violence , disabilities , smoking and addiction , chronic diseases , household costs , nutrition habits , food insecurity , health service utilization and also individual data about mental health , health - related quality of life , pain , physical activity , social capital and oral health , through a multi - stage cluster random sampling proportional to population size at neighborhood level .
further details have been published earlier ( 11 ) .
using self - reported data on height and weight , we calculated body mass index ( bmi ) as weight ( kg)/height ( m ) .
then , overweight and obesity were defined following who recommendation : overweight 25bmi < 30 ; obesity bmi 30 .
age - standardized prevalence ( asp ) was calculated using the who reference population ( 12 ) . in univariate analysis
, we used chi2 test to examine significant differences in prevalence of overweight and obesity across sociodemographic strata .
stata version 11 ( stata corp lp , college station , tx , usa ) was used for statistical analysis .
to collect data in 22 districts and 368 neighborhoods of tehran , a multistage sampling was applied . comprehensive map of tehran in 2011 separated by the districts and neighborhoods was selected as the sampling frame .
22 districts of the municipality and 368 neighborhoods were considered as stratums in the first stage and the second stage respectively .
a two - dimensional systematic sampling method was used to select blocks in each neighborhood using gis maps .
then the houses were numbered in each block and 8 houses were selected in each block systematically based on an eight - box table including four age groups ( 15 - 24 , 25 - 44 , 45 - 64 , and 65 and over ) and both sexes .
the sample size was determined as 1535 households in each district based on a prevalence of 10% with a margin of error of 0.015% and a confidence interval ( ci ) of 95% . then to facilitate the allocation of sample to the mentioned eight - box table that must be completed for the individual questionnaires
in this project , there were three types of questionnaires consisted of 20 parts that the first 14 parts were completed for all selected households in the blocks and the remaining six parts ( mental health , health - related quality of life , social capital , physical pain , physical activity and oral health ) were completed by a selected individual in each household .
the last type of questionnaire was special for nutrition and was completed for a selected household in each block . in urban heart-2
we have collected data about demographics , assets , children health , accidents , domestic violence , disabilities , smoking and addiction , chronic diseases , household costs , nutrition habits , food insecurity , health service utilization and also individual data about mental health , health - related quality of life , pain , physical activity , social capital and oral health , through a multi - stage cluster random sampling proportional to population size at neighborhood level .
using self - reported data on height and weight , we calculated body mass index ( bmi ) as weight ( kg)/height ( m ) .
then , overweight and obesity were defined following who recommendation : overweight 25bmi < 30 ; obesity bmi 30 .
age - standardized prevalence ( asp ) was calculated using the who reference population ( 12 ) . in univariate analysis , we used chi2 test to examine significant differences in prevalence of overweight and obesity across sociodemographic strata .
stata version 11 ( stata corp lp , college station , tx , usa ) was used for statistical analysis .
the study population included 94,931 individuals 15 years or older distributed in the 22 districts of tehran .
the mean bmi was 25.2 ( 4.5 ) for total sample . in total , 34.6% and 13.1% of the sample were overweight and obese , respectively .
1 displays crude prevalence of overweight and obesity across age groups by gender . among men ,
the highest prevalence of both overweight and obesity was observed in the age group of 45 - 54 . among women ,
the highest prevalence of overweight was observed in the age group of 55 - 64 while the highest prevalence of obesity was seen in the age group of 45 - 54 . in both gender groups , the lowest prevalence of overweight and obesity
the lowest and the highest prevalence of overweight and obesity were observed in people in the age groups of 15 - 24 and 45 - 54 years old , respectively .
it can be seen that prevalence of overweight and obesity rose with age up to the age of 54 years and decreased thereafter .
the univariate analysis showed an inverse association between education and prevalence of overweight and obesity . across marital groups , single people had the lowest prevalence of overweight and obesity .
students had the lowest prevalence of overweight and obesity across employment strata .
the results of logistic regression ( table 2 , columns 4 & 5 ) showed that females , the age group of 15 - 24 years old , bachelor and higher education , being single and student were associated with the lowest odds of being overweight .
after control for other covariates , there was no gender disparity in prevalence of obesity .
single people and students had the lower odds of being obese than other groups .
figs . 2 and 3 show the asp of overweight and obesity across the tehran s districts .
the districts 16 , 18 , 19 had the highest asp of both overweight and obesity . on the other hand ,
the districts 1 , 3 , 6 , and 7 had the lowest asp of both overweight and obesity .
table 3 shows the asp of overweight and obesity across tehran 's districts for both genders .
overall asp of overweight was 36.5% and 32.0% among men and women , respectively ( p<0.001 ) .
these figures for obesity were 10.7% and 15.3% among men and women , respectively ( p<0.001 ) .
the lowest asp of overweight was observed among females in district 3 ( 26.8% ) and the lowest asp of obesity was reported among males in district 6 ( 7.2% ) .
there were significant sex - disparities in asp of both overweight and obesity across the tehran s districts .
while the national estimate of overweight and obesity is an important tool for policy - making , examining the distribution of these conditions within- and between geographic areas are equally important for informed decision - making in resource allocation to preventive and therapeutic programs . in the current study ,
distribution of overweight and obesity across the 22 districts of tehran was examined using data from a large population - based survey .
the results of the study showed the high prevalence of overweight and obesity for all districts in tehran .
moreover , there were significant disparities in distribution of overweight and obesity across sociodemographic strata and the districts in tehran .
the high prevalence of overweight and obesity in tehran is consistent with previous national estimates in 2005 ( 5 , 13 ) .
one may expect a high prevalence of overweight and obesity for tehranian adults as it is most industrialized city of the country and experience rapid socioeconomic changes which are among main causes of overweight and obesity worldwide ( 14 ) .
this high prevalence means that overweight and obesity is a very serious health problem in iran and implies that a high rate of obesity - related disorders is expected among iranian population in coming years . using the same reference population as the current study , finucane et al .
( 15 ) reported a worldwide asp of obesity of 9.8% in men and 13.8% in women .
this implies that prevalence of obesity is worryingly higher than worldwide average among men and women in tehran .
we found significant variations in prevalence of overweight and obesity across the districts in tehran .
this difference maintained even after control for age differences between the districts . in a national survey
, significant regional differences in distribution of bmi categories were observed in iran ( 13 ) .
in addition , geographic variation in overweight and obesity levels for children and adults were also reported in other countries ( 16 - 20 ) .
there are some potential explanations for this geographic variation : first , it might be due to differences in individuals ' characteristics living in the districts such as attitudes , beliefs , socioeconomic status , and physical activity ; second , it might be due to differences in environmental features of the districts such as availability of places for physical activity , access to health care ; third , differences in implemented policies by health authorities or municipalities which support healthy life style .
while overweight was less common among females , they were more obese than males in all districts of tehran .
similar trend was observed among adults in the other regions of iran ( 21 , 22 ) and other countries ( 23 - 27 ) .
moreover , higher prevalence of obesity among females than males is a global phenomenon and has been widely examined ( 15 , 28 - 30 ) .
consistent with some previous studies in iran ( 5 , 13 ) , the results showed that overweight and obesity rose with age until age 54 and decrease later on .
this higher prevalence of overweight and obesity up to middle age and a decline thenceforth was also observed in other countries ( 2 , 31 ) .
this could be possibly explained by weight loss occurring in old age or / and higher risk of mortality for obese ( 32 , 33 ) .
while there is no consensus on association between overweight / obesity and marital status , our finding of lower prevalence of overweight / obesity among single people was in line with previous studies in iran and other countries ( 34 - 36 ) . less physical activity , changing of dietary pattern , less concern about being attractive and having more social support for married people constitute main explanations for this association ( 34 , 37 ) .
in line with previous studies ( 38 - 40 ) we found an inverse association between obesity and education in our study . it is argued that better education is associated with health literacy which might resulted in higher consumption of fruits and vegetables and lower consumption of fats ( 41 ) .
using data from a large population - based survey and providing update estimates of prevalence of overweight and obesity for the 22 districts of tehran are main advantages of the current study .
however , the results of this study should be interpreted in light of some limitations .
these are prone to bias ( downward bias for weight and upward bias for height ) ( 42 ) which might cause downward bias in our estimated prevalence here .
second , this is a descriptive cross - sectional study meaning that no casual inference from findings is possible .
third , cross - sectional design of the study limits us to examine changes in prevalence of overweight and obesity over time .
the results of this large population - based survey showed a high prevalence of overweight and obesity among tehranian adults .
moreover , there were significant disparities in distribution of overweight and obesity across sociodemographic strata in tehran .
a high incidence of obesity - related disorders is expected in coming years implying considerable economic burden for health system which needs to be considered by health authorities and policy - makers in iran .
Output:
| background : to estimate and compare prevalence of overweight and obesity among adult people
across the 22 districts of tehran in 2011 .
methods : this was a cross - sectional study using data on 47,406 women and 47,525 men aged 15
years from a large population - based survey ( urban heart-2 ) .
age - standardized prevalence ( asp )
of overweight ( 25bmi<30 ) and obesity ( bmi30 ) were estimated for the tehran s districts .
pearson
chi2 tests and logistic regression were used to examine any significant differences in prevalence
of these disorders across sociodemographic groups .
results : asps of overweight were 36.5% and 32.0 % among men and women , respectively
( p<0.001 ) .
these figures for obesity were 10.7% and 15.3% among men and women , respectively
( p<0.001 ) .
crude prevalence of overweight and obesity rose with age up to the age of 54 years and
decreased thereafter . across education groups , the lowest prevalence of overweight /
obesity was seen
among most educated people .
the results showed that being young , single and student were associated
with lower odds of overweight / obesity .
conclusion : this study showed a high prevalence of overweight and obesity among adult in tehran .
there were significant associations between sociodemographic characteristics and prevalence of
overweight / obesity among adults in tehran .
the results of this study might be used in identifying
high risk groups of overweight and obesity in tehran . |
PubmedSumm118289 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: central venous catheterization is a simple , relatively inexpensive method of assessing a patient 's circulating blood volume , cardiac status , and vasomotor tone and is an essential component of modern - day critical care .
although it is relatively safe , numerous complications are described both during placement and in the maintenance of the catheter .
however , the possibility of entering smaller tributaries of the central veins is often forgotten and only rarely reported .
there is only one incidence of misdirected catheter in the smaller tributary of 2104 central venous catheterizations according to muhm et al .
this report of two cases illustrates a rare malposition of a central venous catheter tip in a small tributary of left brachiocephalic vein .
a 38-year - old female was admitted to our critical care unit with a diagnosis of leptospirosis and complicated malaria .
the possibility of fluid overload was considered , and it was decided to place a central venous catheter for monitoring of central venous pressure after intubation .
a 7-french triple lumen central venous catheter was placed through the left internal jugular vein ( ijv ) due to failed right ijv cannulation with all aseptic precautions by using the seldinger technique .
the catheter was fixed at the 13-cm mark at the skin level after free aspiration of venous blood .
after flushing the catheter with heparinized saline , opening central venous pressure ( cvp ) was noted as 3 mmhg .
on connecting the transducer to the monitor , it was observed that a characteristic waveform was absent .
the central venous waveform could not be obtained despite the change of the transducer , the cable , flushing the unit , and repeated zeroing .
an anteroposterior chest radiograph , obtained to confirm the position of the catheter , revealed the left paramedian location of the catheter following the aortic knuckle and pointing medially [ figure 1 ] .
the catheter was removed , as it was considered to be in one of the small tributaries of left brachiocephalic vein and an alternate venous access was obtained subsequently via the right subclavian vein .
note the left paramedian location of the central venous catheter beside the aortic knuckle a 45-year - old male patient was brought to the emergency room with unconsciousness and hemodynamic instability with a background history of distal renal tubular acidosis . in view of the clinical condition of the patient and the need to know intravascular volume status ,
a 7-french triple lumen central venous catheter was inserted in the left ijv due to failed right ijv cannulation in the emergency room by using the seldinger technique .
all the three ports were checked for free flow of blood and the catheter was fixed at the 13-cm mark at the skin level .
opening cvp was 5 cm , but the central venous waveform could not be obtained despite the change of the transducer , the cable , flushing the unit , and repeated zeroing .
an anteroposterior chest radiograph , obtained subsequently to confirm the position of the catheter , revealed the left paramedian location of the catheter following the aortic knuckle and pointing laterally [ figure 2 ] .
the catheter was removed and an alternate venous access was obtained subsequently via the right subclavian vein .
a 38-year - old female was admitted to our critical care unit with a diagnosis of leptospirosis and complicated malaria .
the possibility of fluid overload was considered , and it was decided to place a central venous catheter for monitoring of central venous pressure after intubation .
a 7-french triple lumen central venous catheter was placed through the left internal jugular vein ( ijv ) due to failed right ijv cannulation with all aseptic precautions by using the seldinger technique .
the catheter was fixed at the 13-cm mark at the skin level after free aspiration of venous blood .
after flushing the catheter with heparinized saline , opening central venous pressure ( cvp ) was noted as 3 mmhg .
on connecting the transducer to the monitor , it was observed that a characteristic waveform was absent .
the central venous waveform could not be obtained despite the change of the transducer , the cable , flushing the unit , and repeated zeroing .
an anteroposterior chest radiograph , obtained to confirm the position of the catheter , revealed the left paramedian location of the catheter following the aortic knuckle and pointing medially [ figure 1 ] .
the catheter was removed , as it was considered to be in one of the small tributaries of left brachiocephalic vein and an alternate venous access was obtained subsequently via the right subclavian vein .
a 45-year - old male patient was brought to the emergency room with unconsciousness and hemodynamic instability with a background history of distal renal tubular acidosis . in view of the clinical condition of the patient and the need to know intravascular volume status ,
a 7-french triple lumen central venous catheter was inserted in the left ijv due to failed right ijv cannulation in the emergency room by using the seldinger technique .
all the three ports were checked for free flow of blood and the catheter was fixed at the 13-cm mark at the skin level .
opening cvp was 5 cm , but the central venous waveform could not be obtained despite the change of the transducer , the cable , flushing the unit , and repeated zeroing .
an anteroposterior chest radiograph , obtained subsequently to confirm the position of the catheter , revealed the left paramedian location of the catheter following the aortic knuckle and pointing laterally [ figure 2 ] .
the catheter was removed and an alternate venous access was obtained subsequently via the right subclavian vein .
the correct placement of the central venous catheter tip is an important factor in obtaining accurate cvp measurements .
inaccurate cvp measurements or inability to obtain an ideal wave from tracing are suggestive of an undesirable location of the catheter tip .
unusual tachycardia during infusion or flushing through central port may also suggest thoracic pain syndromes described by webb et al . due to inexperience ,
malposition of the catheter tip may occur at the time of insertion or later as a result of spontaneous migration due to anatomic positioning or pressure changes within the thoracic cavity . because of the longer course and more transverse lie of the left brachiocephalic and more frequent smaller tributaries , malposition of the venous catheter is commoner when cannulation attempt is made via the left brachiocephalic vein rather than its right - sided counterpart . in this report
both the cannulations were done through left internal jugular vein because there is failed right ijv cannulation . on lateral chest films ,
the internal mammary vein will lie in the anterior mediastinum and the pericardiophrenic vein in the middle mediastinum , while the superior intercostal vein will occupy the posterior mediastinal position .
the most common locations for the malposition of venous catheters while attempting to cannulate the internal jugular vein include the internal mammary vein and the pericardiophrenic vein . on posterior -- anterior or anterior -- posterior views , the internal mammary vein will be located more laterally , catheter in the superior intercostal vein will follow the aortic knob , and pericardiophrenic vein catheter will follow the left cardiac border . so in our case 1 , the catheter tip may be in pericardiophrenic vein , and in case 2 the small tributary may be the superior intercostal vein .
a lateral film would have been helpful in distinguishing these possibilities but was inconclusive in case 1 and could not be done in the second case as the patient was unstable .
a venogram could have established the exact location of the catheter beyond any doubt . but
both the patients were renally compromised , and so the use of dye was contraindicated .
so the take - home message is that when the central venous waveform could not be obtained despite the change of the transducer , the cable , flushing the unit , and repeated zeroing , a strong suspicion of misplacement of central venous catheter tip into a smaller tributary to be kept in mind .
the ability to aspirate blood freely from the catheter lumen after the placement of the catheter does not necessarily confirm a proper placement of the catheter tip .
the use of chest radiographs to establish the correct placement of central neck lines is to be routinely practiced .
it would be a good practice to have a lateral view to confirm the central neck line placement when the anteroposterior view is not reassuring .
we recommend a computed tomography scan of the thorax or venography to assess the position of the catheter in case of radiological dilemma .
Output:
| erroneous positioning of central venous catheters in small tributaries of large central veins is a rare occurrence .
we describe two such unusual incidents involving cannulation of the small tributaries of left brachiocephalic vein .
malposition was suspected when the central venous waveform could not be obtained despite all attempts .
unusual central venous waveforms may indicate central venous catheter malposition , and these waveforms have not previously been described . |
PubmedSumm118290 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: liver failure is a clinical syndrome characterized by jaundice , ascites , hepatic encephalopathy , and a bleeding tendency due to impairment of liver function ; the syndrome can be caused by conditions such as viral hepatitis , autoimmune hepatitis , drug - induced liver injuries , metabolic diseases , and circulatory disturbances .
liver failure has been classified into 2 types , depending on the clinical course ; namely , acute liver failure and chronic liver failure . in general ,
acute liver failure is diagnosed in patients in whom severe liver function impairment , as judged from the clinical symptoms , laboratory data , and imaging examinations , develops within 24 or 26 weeks ( 6 months ) following the onset of liver injury in a preexisting normal liver , while chronic liver failure is diagnosed in patients with persistent liver inflammation and injuries who show liver function impairment later than 6 months after the onset of the liver symptoms .
worldwide , the representative disease entity associated with chronic liver failure is liver cirrhosis due to persistent hepatitis virus infection , autoimmune hepatitis , or hepatitis of indeterminate etiology .
however , the demographic and clinical features of acute liver failure differ between japan and europe or the united states .
hepatitis viral infection is the most important and common cause of acute liver failure in japan , while drug - induced liver injury , including acetaminophen intoxication , is the major cause of acute liver failure in europe and the united states .
thus , acute liver failure is typically associated with fulminant viral hepatitis in japan , and the diagnostic criteria for fulminant hepatitis , which are different from those for
acute liver failure in europe and the united states , were first established at the inuyama symposium in 1981 . the therapeutic strategies for acute liver failure also differ between japan and europe and/or the united states .
cadaveric transplantation is considered as the first - line therapy for acute liver failure in europe and the united states , while in japan , artificial liver support , consisting of plasma exchange and hemodiafiltration , is usually provided first to patients with fulminant hepatitis , and liver transplantation , usually from living donors [ 46 ] , is only scheduled when no clinical improvement is achieved with this conventional medical treatment .
thus , the criteria for scheduling liver transplantation for patients with acute liver failure and/or fulminant hepatitis also differ between japan and other countries . in the present article , we discuss in detail the differences between japan and europe and/or the united states in the definitions , classifications , and diagnostic criteria for the disease subtypes of acute liver failure and/or fulminant hepatitis , and also the indications for liver transplantation in these patients .
also , we describe the clinical features of patients with acute liver failure in japan , which were analyzed through a nationwide survey conducted using the diagnostic criteria revised in 2011 in reference to those in europe and the united states .
epidemic hepatitis was a worldwide health problem in the early twentieth century , and it was already known , even in the 1920s , that differences existed in the clinical course even among patients with the fatal form of the disease , and that patients could be divided into those with fulminant , acute , or chronic forms .
although most patients with fatal disease exhibited a subacute clinical course , with the patients dying between 4 and 6 weeks after the onset of the hepatitis symptoms , a patient showing a more rapid course was first reported in the great swedish epidemic in 1927 .
this was the first case report of fulminant - type epidemic hepatitis although it was thought that such patients were seldom encountered elsewhere in the world .
however , the concept of epidemic hepatitis changed with the occurrence of world war ii ; epidemic hepatitis changed to a hepatitis pandemic during world war ii , with large outbreaks occurring in many parts of the world , especially in armies .
lucke and mallory reported on the outbreak of epidemic hepatitis in the united states army between august 1943 and april 1945 , in which 104 of 196 patients ( 53 % ) had a fatal course and died within 10 days of the onset of the hepatitis symptoms .
lucke and mallory named this form of hepatitis , which was probably caused by hepatitis a virus ( hav ) or hepatitis e virus ( hev ) infection , the fulminant form of hepatitis . by the end of world war ii , the hepatitis pandemic had not spread to any extent in europe or the united states , and the fulminant form of hepatitis was recognized as an infrequent , but intractable , disease in western countries .
also , advances in the field of virology in the 1970s enabled hepatologists to evaluate patients with fulminant hepatitis for serum markers of hav and hepatitis b virus ( hbv ) infection , and these two types of hepatitis viruses were found to account for a large proportion of the patients [ 911 ] . on the other hand , trey et al . reported that drugs such as halothane may also cause acute liver disease , similar in clinical course to fulminant hepatitis .
they evaluated the etiology in 150 patients enrolled from 73 centers , and revealed that the cause of the hepatitis was presumed viral hepatitis in 70 patients ( 46.7 % ) ( including serum hepatitis and epidemic hepatitis in 24 and 46 patients , respectively ) , and drug - induced liver disease in 48 patients ( 32.0 % ) ( including 36 with halothane exposure as the culprit ) .
these observations prompted hepatologists to use the nomenclature of fulminant hepatic failure instead of fulminant hepatitis for patients presenting with acute onset of massive liver necrosis .
then , in 1970 , trey and davidson proposed the now well - known diagnostic criteria for fulminant hepatic failure ; they defined the condition as a clinical syndrome characterized by massive liver necrosis associated with severe impairment of hepatic function , manifesting as progressive jaundice , hepatic coma , and liver atrophy developing within 8 weeks of the onset of the first symptoms of the disease in individuals with no previous history of hepatic disease .
moreover , in 1986 , gimson et al . suggested that patients showing hepatic encephalopathy as well as other evidence of hepatic decompensation developing more than 8 weeks but less than 24 weeks of the onset of the first symptoms be labeled as having late - onset hepatic failure ( lohf ) , a clinical syndrome related to fulminant hepatic failure .
in contrast , in france , bernuau et al . proposed the nomenclature of fulminant and subfulminant liver failure for patients with rapidly progressive hepatic failure ; patients developing hepatic encephalopathy less than 2 weeks after the onset of jaundice were diagnosed as having fulminant liver failure , while those with hepatic encephalopathy developing between 2 and 12 weeks after the onset of jaundice were labeled as having subfulminant liver failure .
also , the terminology of subacute liver failure was introduced in india in 1982 for patients showing progressive jaundice with ascites of 8 weeks duration , with otherwise typical features of acute viral hepatitis ; the presence of hepatic encephalopathy was not a necessary criterion for the diagnosis of this condition . while intense debate still continues on the definition and classification of patients showing rapid progression of hepatic failure , all hepatologists around the world , including those in japan ,
agree that patients showing the most rapid onset of hepatic encephalopathy have the best chance of recovery with conventional medical treatment .
although geographic heterogeneity was found in the etiology and clinical features of acute liver diseases , standardization of the nomenclature and diagnostic criteria for patients showing rapidly progressive hepatic failure is required for reliable comparisons of the efficacies of various treatments and of the resultant outcomes among different countries .
thus , in 1993 , ogrady et al . redefined such syndromes as acute liver failure prefixed with
hyper and sub to describe 2 cohorts at opposite ends of the clinical spectrum , based on the observation of a large series of patients treated at king s college hospital , london , between 1972 and 1985 . according to this proposed classification ,
patients with hepatic encephalopathy developing within 7 days of the onset of jaundice are diagnosed as having hyperacute liver failure , which is often caused by acetaminophen intoxication . in contrast , patients showing hepatic encephalopathy between 8 and 28 days and those with encephalopathy developing later than 28 days after the first onset of symptoms were diagnosed as having acute liver failure and subacute liver failure , respectively , with hav or hbv infection and drug - induced liver damage being more frequently seen in the former cohort , and liver disease of indeterminate etiology being seen more frequently in the latter cohort . it should be noted that patients with pre - existing symptomless chronic liver diseases were included in the disease entity of acute liver failure by ogrady et al .
, while such patients were excluded from the entity of fulminant hepatic failure by trey and davidson . criticisms were raised regarding the nomenclature and definition of acute liver failure proposed by the king college hospital group , especially in france and india .
thus , the subcommittee of the international association for the study of the liver ( iasl ) published revised recommendations on the nomenclature of acute and subacute hepatic failure in 1999 . in this recommendation , two distinct disease entities , but not subgroups of a syndrome , were established ; namely , acute hepatic failure and subacute hepatic failure .
patients without pre - existing liver disease developing hepatic encephalopathy within 4 weeks of the onset of the disease symptoms are diagnosed as having acute hepatic failure .
acute hepatic failure is a potentially reversible liver disease and is classified into hyperacute and fulminant forms , defined by the development of hepatic encephalopathy less than 10 days and between 10 and 30 days , respectively , after the first onset of the disease symptoms .
in contrast , patients developing hepatic encephalopathy between the 5th and 24th weeks after the first onset of symptoms are diagnosed as having subacute hepatic failure .
consequently , until the beginning of the twenty - first century , hepatitis showing rapid progression was referred to by various names , including fulminant hepatitis , fulminant hepatic failure , fulminant liver failure , acute liver failure , and acute hepatic failure ( table 1 ) .
however , acute liver failure came to be used predominantly as the most suitable umbrella term , because it can be assumed to include all of the other disease entities .
thus , the practice guideline committee of the american association for the study of liver diseases ( aasld ) published a position paper for the management of acute liver failure in 2005 .
liver diseases characterized by the development of hepatic encephalopathy and coagulation abnormalities , usually characterized by an international normalized ratio ( inr ) of 1.5 or more , in patients without preexisting cirrhosis , and an illness of less than 26 weeks duration . in this position paper , subgroups classified according to the interval between the onset of hepatic encephalopathy and the first onset of the disease symptoms ; namely , the hyperacute , acute , and subacute types , were shown to be not helpful to predict the outcomes of the patients . despite the publication of this position paper by the aasld , differences in the definitions are still seen in recent articles regarding acute liver failure , and these differences hamper the conduct of reliable meta-analyses.table 1definition and classification of acute liver failure and related diseasesyearnomenclature ( classification)parametersauthoraffiliation or countryreferencedevelopment of hepatic encephalopathyptpre - ld1930acute yellow liver dystrophyndbergstrandgermany1946fulminant form of epidemic hepatitisndlucke and malloryusa1970fulminant hepatic failurewithin 8 weeks after disease symptoms onset absenttrey and davidsonusa1981fulminant hepatitis ( acute & subacute)within 8 weeks after disease symptoms onset ( within 10 days and between 11 and 56 days , respectively)40 % absenttakahashi et al.japan1982subacute hepatitisnot necessarily presenttandon et al.india1986late onset hepatic failurebetween 8 and 24 or 26 weeks after disease symptoms onsetgimson et al.england1986fulminant liver failure and subfulminant liver failureless than 2 weeks and between 2 and 12 weeks , respectively , after jaundice onset absent or presentbernuau et al.france1993acute liver failure ( hyperacute , acute and subacute)within 7 days , between 8 and 28 days , and later than 28 days , respectively , after jaundice onset absent or presentogrady et al.england1999acute hepatic failure ( hyper - acute and fulminant ) and subacute hepatic failurewithin 4 weeks ( less than 10 days and between 10 and 30 days ) and between 5th and 24th weeks , respectively , after disease symptoms onsettandon et al.iasl2005acute liver failurepreexisting illness of less than 26 weeks durationusually inr 1.5absentpolson and leeaasld2011acute liver failure [ without or with coma ( acute and subacute)]without or with encephalopathy within 8 weeks of disease symptoms onset ( within 10 days and between 11 and 56 days , respectively)40 % or inr 1.5absentmochida et al.japanpt prothrombin time , pre - ld preexisting symptomless liver diseases , nd not described , iasl international association for the study of the liver , aasld american association for the study of liver diseases definition and classification of acute liver failure and related diseases pt prothrombin time , pre - ld preexisting symptomless liver diseases , nd not described , iasl international association for the study of the liver , aasld american association for the study of liver diseases
the definition and classification of fulminant hepatitis , the representative disease entity associated with acute liver failure in japan , were established at the inuyama symposium in 1981 . according to the inuyama symposium criteria ,
patients with hepatitis were diagnosed as having fulminant hepatitis when they developed grade ii or more severe hepatic encephalopathy due to severe liver damage , as represented by prothrombin time values of 40 % of the standardized value , within 8 weeks of the onset of the hepatitis symptoms .
fulminant hepatitis was further classified into 2 clinical types ; that is , the acute and subacute types , on the basis of the hepatic encephalopathy developing within 10 days or between 11 and 56 days , respectively , after the onset of the hepatitis symptoms .
fulminant hepatitis in japan is defined as histological evidence of hepatic inflammation , characterized by lymphocytic infiltration of the liver , associated with acute liver failure .
thus , the etiology of fulminant hepatitis comprises viral infections , including hbv carriers , autoimmune hepatitis , drug allergy - induced liver injuries , and hepatitis of indeterminate etiology .
the intractable liver diseases study group of japan , supported by the ministry of health , labour and welfare , last revised the diagnostic criteria for fulminant hepatitis in 2002 ( table 2 ) . in this revision
, 5 items clarifying the inclusion and exclusion criteria for the diagnosis of fulminant hepatitis were added as a footnote .
we clarified that patients with preexisting chronic liver diseases , such as those with alcoholic hepatitis , were excluded from the disease entity of fulminant hepatitis , whereas asymptomatic hbv carriers developing acute exacerbation of hepatitis were included as cases of fulminant hepatitis .
also , the significance of histological evidence of liver inflammation was emphasized , so that liver failure caused by drug or chemical intoxication , circulatory disturbances , acute fatty liver of pregnancy , reye s syndrome , or wilson disease were excluded from the diagnosis of fulminant hepatitis .
moreover , the definitions of subtypes of fulminant hepatitis were clarified ; hepatitis patients with no or grade i encephalopathy , but showing prothrombin time values of 40 % of the standardized value were diagnosed as having severe type of acute hepatitis , while those with grade ii or more severe hepatic encephalopathy developing between 8 and 24 weeks after the disease symptoms onset , with prothrombin time values of 40 % of the standardized value were diagnosed as having lohf .
thus , the disease entity of lohf in japan differed from that in europe and the united states , because patients with no histological evidence of hepatitis and/or prothrombin time values of > 40 % of the standardized value were excluded from the diagnosis of lohf in japan , even if they had grade ii or more severe hepatic encephalopathy.table 2diagnostic criteria for fulminant hepatitis in japan established by the intractable liver diseases study group of japan , supported by the ministry of health , welfare and labour ( 2003 ) ; from reference fulminant hepatitis is defined as hepatitis with hepatic encephalopathy of grade ii or more that develops in the patients within 8 weeks of the onset of disease symptoms , associated with severe derangement of liver function , including prothrombin time values of less than 40 % of the standardized value .
fulminant hepatitis is classified into 2 subtypes ; the acute type and the subacute type , according to whether the encephalopathy occurs within 10 days and later than 11 days , respectively , after the onset of the symptoms.note 1 : patients with chronic liver diseases are excluded from the disease entity of fulminant hepatitis , but asymptomatic hepatitis b virus ( hbv ) carriers developing acute exacerbation are included as cases of fulminant hepatitis.note 2 : acute liver failure with no histological evidence of liver inflammation , such as that caused by drug or chemical intoxication , circulatory disturbance , acute fatty liver of pregnancy , or reye s syndrome is excluded from the disease entity of fulminant hepatitis.note 3 : the grading of hepatic encephalopathy is based on the criteria presented at the inuyama symposium in 1972.note 4 : the etiology of fulminant hepatitis is based on the criteria established by the intractable liver diseases study group of japan in 2002.note 5 : patients with no or grade i encephalopathy , but showing prothrombin time values of less than 40 % of the standardized value are diagnosed as having acute hepatitis , severe type .
patients in whom the encephalopathy develops between 8 and 24 weeks after the disease onset , with prothrombin time values of less than 40 % of the standardized value are diagnosed as having late - onset hepatic failure ( lohf ) .
both are diseases related to fulminant hepatitis , but are regarded differently from fulminant hepatitis .
diagnostic criteria for fulminant hepatitis in japan established by the intractable liver diseases study group of japan , supported by the ministry of health , welfare and labour ( 2003 ) ; from reference in the revision conducted in 2002 , however , the definition and concept of fulminant hepatitis were not modified , because the diagnostic criteria established at the inuyama symposium were useful to characterize the clinical features of patients with acute liver failure in japan . according to the nationwide survey of fulminant hepatitis and lohf conducted by the intractable hepato - biliary diseases study group in japan ( formally the intractable liver diseases study group of japan ) , the clinical features of patients differed markedly when the disease types were defined based on the diagnostic criteria established in 1981 or based on the revised criteria established in 2002 . in this survey , 1,094 patients with fulminant hepatitis , consisting of 543 with the acute type and 551 with the subacute type of fulminant hepatitis were included , and 92 patients with lohf seen between 1998 and 2009 were enrolled [ 1 , 2429 ] . in regard to the etiology of hepatitis , viral infection accounted for 67.4 and 30.9 % of the patients with the acute and subacute types of fulminant hepatitis , respectively , and for 10.9 % of the patients with lohf .
in most patients with fulminant hepatitis caused by viral infection , irrespective of the disease type , the causative agent was hbv ; transient hbv infection was more frequent in patients with the acute type ( 39.2 % ) as compared to the subacute type ( 10.0 % ) of fulminant hepatitis , while the frequency of hbv carriers was greater in patients with the subacute type ( 17.9 % ) as compared to the acute type ( 7.2 % ) of fulminant hepatitis .
autoimmune hepatitis was found in 1.8 , 12.2 , and 19.6 % of patients with the acute and subacute types of fulminant hepatitis and lohf , respectively .
drug allergy - induced liver injury was seen in 9.0 , 13.1 , and 18.7 % of patients with the acute and subacute types of fulminant hepatitis and lohf , respectively .
it is noteworthy that the etiology was indeterminate in 19.0 , 40.8 , and 40.2 % of patients with the acute and subacute types of fulminant hepatitis and lohf , respectively .
the survival rates of patients receiving medical treatment without liver transplantation were 53.7 , 24.4 , and 11.5 % , respectively , in patients with the acute and subacute types of fulminant hepatitis and lohf seen between 1998 and 2003 , while these rates were 48.7 , 24.2 , and 13.0 % , respectively , in the corresponding categories of patients seen between 2004 and 2009 [ 2429 ] .
although the diagnostic criteria for fulminant hepatitis in japan [ 1 , 3 ] merit consideration in clinical practice for the diagnosis of acute liver failure patients , they do need to be revised to fit with the criteria for acute liver failure adopted in europe and the united states .
thus , in 2006 , the intractable hepato - biliary diseases study group in japan constituted a task force to establish novel diagnostic criteria for acute liver failure , which includes the disease entity fulminant hepatitis .
acute liver failure in japan , two types of nationwide surveys were performed ; a survey of the commercial kits used for the measurement of prothrombin time at institutions to which hepatology specialists were affiliated , and a survey of acute liver failure patients who were excluded from the disease entities of fulminant hepatitis and lohf .
consequently , acute liver failure in japan ( table 3 ) came to be defined as an acute liver disease associated with prolongation of the prothrombin time , with an inr of 1.5 or more . to confirm the correspondence between the present criteria ( table 3 ) and previous criteria ( table 2 ) ,
prothrombin time values of40 % of the standardized value was also employed as a cutoff to define patients with acute liver failure .
patients without hepatic encephalopathy were also included in the disease entity of acute liver failure , if they showed an inr of 1.5 or more .
thus , acute liver failure patients are classified into those with and without hepatic coma , and acute liver failure with hepatic coma is further subdivided into 2 disease types ; namely , the acute type and the subacute type , according to the interval from the onset of symptoms to the development of hepatic encephalopathy , similar to the case for fulminant hepatitis [ 1 , 3].table 3diagnostic criteria for acute liver failure in japan ( 2011 ) ; from reference patients showing prothrombin time values of 40 % or less of the standardized value , or international normalized ratios ( inrs ) of 1.5 or more due to severe liver damage within 8 weeks of the onset of disease symptoms are diagnosed as having acute liver failure , where the liver function prior to the current onset of liver damage is estimated to have been normal based on blood laboratory data and imaging examinations .
acute liver failure is classified into acute liver failure without hepatic coma and acute liver failure with hepatic coma ; no or grade i hepatic encephalopathy is present in the former type , while grade ii or more severe hepatic encephalopathy is found in the latter type .
acute liver failure with hepatic coma is further subclassified into 2 disease types ; the acute type and subacute type , with grade ii or more severe hepatic encephalopathy developing within 10 days or between 11 and 56 days after the onset of disease symptoms , respectively , in the two types.note 1 : hepatitis b virus ( hbv ) carriers and autoimmune hepatitis patients showing acute exacerbation of hepatitis in the normal liver are included under the disease entity of acute liver failure . in the case of indeterminate previous liver function , the patients who are hbv carriers and those with autoimmune hepatitis are diagnosed as having acute liver failure when no liver function impairment preceding the exacerbation of the liver injury can be confirmed.note 2 : in general , alcoholic hepatitis develops in patients with chronic liver diseases caused by habitual alcohol consumption .
thus , patients with alcoholic hepatitis are excluded from the disease entity of acute liver failure . however , patients with fatty liver caused by alcohol intake and those with metabolic syndrome , including obesity , are diagnosed as having acute liver failure if etiologies other than habitual alcohol consumption are responsible for the acute injury in the liver , in the absence of prior impairment of liver function.note 3 : patients without histological evidence of hepatitis , such as inflammatory lymphocytic infiltration , are included under the disease entity of acute liver failure .
thus , patients with liver damage caused by drug toxicity , circulatory disturbance , or metabolic disease and acute fatty liver of pregnancy are diagnosed as having acute liver failure , while they are excluded from the disease entity of fulminant hepatitis .
in contrast , patients with liver injury caused by viral infection , autoimmune hepatitis , and drug allergy - induced hepatitis are included under the disease entities of fulminant hepatitis and acute liver failure.note 4 : the severity of hepatic encephalopathy is diagnosed according to the classification presented at the inuyama symposium in 1972 ( table 4 ) .
also , hepatic encephalopathy developing in pediatric patients and infants is classified according to the criteria proposed by the 5th workshop on pediatric liver diseases in 1988 ( table 5).note 5 : the etiology of acute liver failure is classified according to the criteria proposed by the intractable liver diseases study group of japan in 2002 , with some modifications ( table 6).note 6 : patients showing prothrombin time values of less than 40 % of the standardized value or inrs of 1.5 or more and grade ii or more severe hepatic coma between 8 and 24 weeks of the onset of disease symptoms are diagnosed as having late - onset hepatic failure ( lohf ) , as a disease related to acute liver failure . diagnostic criteria for acute liver failure in japan ( 2011 ) ; from reference similar to the entity of acute liver failure in europe and the united states , in japan patients without histological evidence of inflammation in the liver , such as those with the disease caused by drug toxicity , circulatory disturbances , or metabolic diseases are also included in the disease entity of acute liver failure .
in contrast , patients showing impaired liver function due to underlying chronic liver diseases before the worsening of the liver damage are excluded from the disease entity of acute liver failure .
thus , alcoholic liver disease patients are excluded from this entity , because they show clinical features consistent with acute - on - chronic liver disease .
however , patients with underlying chronic liver diseases such as fatty liver and autoimmune hepatitis are included in the disease entity of acute liver failure , when the liver function impairment is retrospectively estimated to be minimal or absent prior to the current exacerbation of the liver damage .
also , the criteria for classification of hepatic encephalopathy and etiology of hepatitis have been added as footnotes to the present criteria ( tables 4 , 5 , 6 ) .
in addition , patients with lohf are defined as those showing prothrombin time values of 40 % of the standardized value or inrs of 1.5 or more and grade ii or more severe hepatic coma between 8 and 24 weeks of the onset of the disease symptoms , and those without histological evidence of hepatitis are also included in the disease entity of lohf , similar to the case of acute liver failure .
on the other hand , the disease entity of acute hepatitis severe type was excluded from the footnote of the present criteria , because patients classified under such a disease entity can also be diagnosed as having acute liver failure without hepatic encephalopathy.table 4classification of hepatic encephalopathy in adult patients according to the grade of hepatic coma proposed by the inuyama symposium in 1972 ; from reference grade of comapsychiatric disordersreference itemsiinversion of sleep patterneuphoria and/or occasional depressionnegligent attitude with shortened attention spanrecognized retrospectively in most casesiidisorientation of time or place and confusioninappropriate behaviors , such as throwing away money or discarding items of valueoccasional somnolent tendency ; able to open eyes and respond appropriately to questionsmakes impolite remarks , but follows doctors instructionsexcitation state and , urinary and fecal incontinence are absent , but flapping tremor is found on physical examinationiiistate of excitation and/or delirium , showing defiant behaviorsomnolent tendency ; sleeping most of the timeopens eyes in response to stimulation , but can not follow the instructions of doctors , except for simple ordersflapping tremor is observed , and the extent of disorientation is severeivcoma ; complete loss of consciousnessresponse to painful stimulibrushes off doctor s hands if touched and/or frowns in response to stimulivdeep comano response to painful stimulitable 5classification of hepatic encephalopathy in pediatric patients and infants according to the grade of hepatic coma as proposed at the 5th workshop on pediatric liver diseases in 1988 ; from reference grade of comapediatric patientsinfantsilow - spirited from before ( seems lethargic compared with previous physical activity level)does not laugh aloudiiobedient attitude with somnolent tendencydisorientation of time or placedoes not laugh even when being played withcannot maintain eye contact with the mother ( more than 3 months after birth)iiiopens eyes in response to loud voiceivdoes not wake up in response to painful stimuli , but frowns and/or brushes off the item producing the stimulus with his / her handsvno response to painful stimulitable 6classification of etiologies of acute liver failure modified from the criteria proposed by the intractable liver diseases study group of japan in 2002 ; from reference i.viral infection 1 hepatitis a virus ( hav ) 2 hepatitis b virus ( hbv ) ( 1 ) transient infection ( 2 ) acute exacerbation in hbv carrier i. inactive carrier , without drug exposure ii .
reactivation in transiently infected patients by immunosuppressant and/or anticancer drugs ( de - novo hepatitis ) ( 3 ) indeterminate infection patterns 3 hepatitis c virus ( hcv ) 4 hepatitis e virus ( hev ) 5 other virusesii.autoimmune hepatitisiii.drug-induced liver injuries 1 .
drug toxicity - induced liver injuryiv.circulatory disturbancev.infiltration of the liver by malignant cellsvi.metabolic diseasesvii.liver injuries after liver resection and transplantationviii.miscellaneous etiologiesix.indeterminate etiology despite sufficient examinationsx.unclassified due to insufficient examinationspatients with etiologies i , ii , and iii-1 are diagnosed as having fulminant hepatitis as well as acute liver failure , whereas those with etiologies iii-2 and iv to viii are diagnosed as having acute liver failure , but are excluded from the disease entity of fulminant hepatitis .
diagnostic criteria for the classification of etiology based on laboratory data should be established in the futureserum hepatitis b surface ( hbs ) antigen - negative patients following transient infection with hbv are classified as hbv carriers , in whom hbv reactivation can be induced by immunosuppressant and/or anticancer drugs ; however , the significance of this causative etiology needs to be evaluated further classification of hepatic encephalopathy in adult patients according to the grade of hepatic coma proposed by the inuyama symposium in 1972 ; from reference classification of hepatic encephalopathy in pediatric patients and infants according to the grade of hepatic coma as proposed at the 5th workshop on pediatric liver diseases in 1988 ; from reference classification of etiologies of acute liver failure modified from the criteria proposed by the intractable liver diseases study group of japan in 2002 ; from reference patients with etiologies i , ii , and iii-1 are diagnosed as having fulminant hepatitis as well as acute liver failure , whereas those with etiologies iii-2 and iv to viii are diagnosed as having acute liver failure , but are excluded from the disease entity of fulminant hepatitis .
diagnostic criteria for the classification of etiology based on laboratory data should be established in the future serum hepatitis b surface ( hbs ) antigen - negative patients following transient infection with hbv are classified as hbv carriers , in whom hbv reactivation can be induced by immunosuppressant and/or anticancer drugs ; however , the significance of this causative etiology needs to be evaluated further
recently , the intractable hepato - biliary diseases study group performed a nationwide survey of patients with acute liver failure seen in 2010 , in whom the diagnosis was made according to the criteria published in 2011 .
the 220 patients , consisting of 211 patients with acute liver failure and 9 patients with lohf , were enrolled from 742 institutions with specialists in the fields of hepatology , gastroenterology , and/or acute medicine .
the 211 acute liver failure patients were classified into 96 ( 45.5 % ) without hepatic coma and 115 patients ( 54.5 % ) with hepatic coma , with the latter group being further divided into 61 patients ( 28.9 % ) with the acute type and 54 patients ( 25.6 % ) with the subacute type ( fig . 1 ) .
also , the acute liver failure patients were classified into 188 patients ( 89.1 % ) with hepatitis and 23 patients ( 10.9 % ) without hepatitis .
the 188 patients with hepatitis consisted of 85 patients ( 45.2 % ) without hepatic coma , and 103 patients with hepatic coma ( 54.8 % ) , with 54 patients ( 28.7 % ) classified with the acute type and 49 patients ( 26.1 % ) classified with the subacute type .
the 23 patients without hepatitis were divided into 11 patients ( 47.8 % ) without hepatic coma and 12 patients ( 52.2 % ) with hepatic coma , including 7 ( 30.4 % ) patients with the acute type and 5 ( 21.7 % ) patients with the subacute type . in contrast , all patients with lohf presented with hepatic coma and were classified as having the histological features of hepatitis ( fig .
1).fig . 1classification of acute liver failure patients in japan enrolled in a nationwide survey performed by the intractable hepato - biliary diseases study group in japan .
alf acute liver failure , lohf late - onset hepatic failure classification of acute liver failure patients in japan enrolled in a nationwide survey performed by the intractable hepato - biliary diseases study group in japan .
alf acute liver failure , lohf late - onset hepatic failure the etiologies of liver damage in patients with acute liver failure are shown in fig . 2 .
viral infection was determined as the cause in 43 of 96 patients ( 44.8 % ) with acute liver failure without hepatic coma , 48 of 115 patients ( 41.7 % ) with acute liver failure with hepatic coma , including 29 of 61 patients ( 47.5 % ) with the acute type and 19 of 54 patients ( 35.2 % ) with the subacute type , and 3 of 9 patients ( 33.3 % ) with lohf .
the percentage of patients with liver injury caused by viral infections was smaller than that reported from the previous nationwide survey in japan , especially in patients with acute type of liver failure with hepatic coma [ 1 , 2429 ] .
in most of the cases of viral infection , the causative virus was hbv ; transient infection was predominant in patients without hepatic coma and in those with acute - type liver failure with coma , whereas the incidence of asymptomatic carriers showing acute exacerbation of hepatitis was frequent in patients with subacute - type liver failure with coma .
it is noteworthy that among the 25 asymptomatic carriers , there were 9 patients with de - novo hbv hepatitis , with negative test results for serum hepatitis b surface ( hbs ) antigen , who developed acute liver failure following therapy with immunosuppressive and/or anticancer drugs through an increase of the serum hbv - dna level.fig .
2etiology of acute liver failure in japanese patients enrolled in a nationwide survey performed by the intractable hepato - biliary diseases study group in japan .
lohf late - onset hepatic failure , hav hepatitis a virus , hbv hepatitis b virus etiology of acute liver failure in japanese patients enrolled in a nationwide survey performed by the intractable hepato - biliary diseases study group in japan .
lohf late - onset hepatic failure , hav hepatitis a virus , hbv hepatitis b virus although a small number of patients with autoimmune hepatitis and drug allergy - induced liver damage were found among patients with each disease type , the etiology of liver failure remained indeterminate in most of the remaining patients , including 27 of 96 patients ( 28.1 % ) with acute liver failure without hepatic coma , 39 of 115 patients ( 33.9 % ) with acute liver failure with coma ( including 17 of 61 patients [ 27.9 % ] with the acute type and 22 of 54 patients [ 40.7 % ] with the subacute type of liver failure ) , and 2 of 7 patients ( 22.2 % ) with lohf .
etiologies other than hepatitis that may have induced liver injury were found in 11 patients ( 11.5 % ) with acute liver failure without hepatic coma and in 12 patients ( 10.4 % ) with acute liver failure with hepatic coma ( including 7 patients [ 11.5 % ] with the acute type and 5 patients [ 9.3 % ] with the subacute type of acute liver failure ) , while hepatitis was the cause of the liver injury in all the patients with lohf .
the etiologies of liver damage other than hepatitis were circulatory disturbance in 6 patients , hepatic infiltration by malignant cells in 5 patients , postoperative liver injuries in 4 patients , metabolic disease in 3 patients , hemolytic - phagocytotic syndrome ( hps ) in 3 patients , and drug toxicity - induced liver injury in 2 patients . among the 220 patients with acute liver failure and lohf ,
29 ( 13.2 % ) underwent liver transplantation and the remaining 191 patients ( 86.8 % ) were given conservative medical treatment , including artificial liver support ( consisting of plasma exchange and hemodiafiltration ) .
liver transplantation was performed only in patients with hepatitis , while all of the patients without histological evidence of hepatitis received medical treatment alone .
the survival rate of the 191 patients managed by medical treatment alone was 51.3 % ( 98/191 ) , including 54.8 % ( 92/168 ) in patients with hepatitis and 26.1 % ( 6/23 ) in patients without hepatitis . in patients with hepatitis ,
the survival rate was 86.7 % ( 72/83 ) in the patients without hepatic coma , 31.7 % ( 13/41 ) in the patients with acute - type liver failure with coma , and 19.4 % ( 7/36 ) in the patients with subacute - type liver failure with coma , and 0 % ( 0/8 ) in those with lohf ; these values were greater than those in the patients without hepatitis:45.5 % ( 5/11 ) in the patients without hepatic coma , 14.3 % ( 1/7 ) in patients with acute - type liver failure with coma , and 0 % ( 0/5 ) in patients with subacute - type liver failure with coma .
in contrast , the survival rate in the patients treated by liver transplantation was 62.1 % ( 18/29 ) . the overall survival rate , including the patients treated by liver transplantation , was 52.7 % ( 116/220 ) .
among the 220 patients with acute liver failure seen in 2010 , 112 patients were diagnosed as having fulminant hepatitis or lohf with the histological features of hepatitis .
the outcomes of these patients were as follows ; 20 patients ( 17.9 % ) and 65 patients ( 58.0 % ) , respectively , survived and died with medical treatment alone , and 27 patients ( 24.1 % ) underwent liver transplantation .
liver transplantation is inevitable for the rescue of most patients with acute liver failure , even in japan , where artificial liver support , including plasma exchange , is provided for almost all patients .
thus , outcome prediction models with high sensitivity and specificity levels were required to determine the indications for liver transplantation .
liver transplantation has been recognized as the standard therapy for patients with acute liver failure in europe and the united states since the 1980s [ 32 , 33 ] .
bismuth et al . reported that liver transplantation should be considered in patients with grade iii or more severe hepatic encephalopathy , with plasma coagulation factor v activity levels of less than 20 % of the standardized values . also , emond et al . reported that patients with brain edema due to encephalopathy , with prolongation of the prothrombin time after 24 or 48 h of intensive medical care , were candidates for liver transplantation .
a similar outcome prediction model was published by bernuau et al . through multivariate analysis of the data of 115 patients with fulminant hepatitis due to hbv infection , in which plasma factor v activity levels , status of disappearance of hbs antigen , and the serum -fetoprotein concentration
were selected as independent predictors of survival . moreover , in 1989 , ogrady et al . published a guideline with selection criteria for liver transplantation in patients with acute liver failure , based on a multivariate analysis of the data of 588 patients seen between 1973 and 1985 . in this guideline
, the prognosis was estimated differently in patients with liver failure resulting from acetaminophen intoxication and in those with liver failure resulting from viral hepatitis or drug allergy - induced liver injury . in the former category of patients ,
the prognosis was estimated based on 3 parameters ; namely , the arterial blood ph , peak prothrombin time , and the serum creatinine level .
in contrast , in the latter category of patients , the prognosis was determined based on 5 parameters ; namely , etiology of the disease , age of the patient , duration of jaundice before the onset of hepatic encephalopathy , peak prothrombin time , and the serum bilirubin level .
this famous guideline , well known as the king s college hospital criteria , was widely used around the world to determine the indications for liver transplantation in patients with acute liver failure [ 3840 ] . also , the usefulness of the model for end - stage liver disease ( meld ) , which was originally established to evaluate the prognosis of chronic liver failure patients , was assessed in comparison with the predictive accuracy of the king s college hospital criteria in patients with acute liver failure [ 4245 ] .
however , the king s college hospital criteria were found to be of limited usefulness for patients with fulminant hepatitis in japan , and the predictive accuracy of these criteria adopted for patients seen between 1993 and 1995 was found to be only 55 % for the assessment conducted at the onset of hepatic encephalopathy , and 53 % for the assessment conducted on day 5 after the onset of encephalopathy .
thus , a new guideline that could be adopted for patients in japan was established by sugihara et al .
, based on the results of a project undertaken by the acute liver failure study group of japan in 1996 . according to this guideline , the prognosis of patients with fulminant hepatitis is estimated through a two - step procedure ( table 7 ) .
first , the estimated prognosis is determined at the onset of hepatic encephalopathy based on 5 parameters , with the parameters associated with a poor prognosis being : ( 1 ) age older than 45 years , ( 2 ) interval of 11 or more days from the onset of the initial disease symptoms to the development of grade ii or more severe hepatic encephalopathy , ( 3 ) prothrombin time less than 10 % of the standardized value , ( 4 ) serum bilirubin level of 18 mg / dl or more , and ( 5 ) ratio of the serum direct to total bilirubin levels of less than 0.67 .
patients fulfilling 2 or more of the above criteria , with the estimated prognosis of death , are enrolled as candidates for liver transplantation .
then , intensive therapy , including artificial liver support , is administered to these patients for 5 days if possible , and those showing improvement of both the prothrombin time and encephalopathy grade are excluded from the list of candidates for liver transplantation , with the estimated prognosis changed to alive . such reassessment after intensive treatment for 5 days seemed to improve the prognostic accuracy of the guideline in fulminant hepatitis patients in japan , where artificial liver support can be undertaken for more than 90 % of the patients [ 1 , 2429 ] .
according to a prospective study , in which the guideline was adopted for patients seen between 1993 and 1995 , the predictive accuracy of the guideline was 76 % for the first assessment and 82 % for the reassessment . on the other hand ,
when the guideline was adopted for patients seen between 1998 and 2003 , the predictive accuracy was even worse ; the accuracy values in the patients not receiving liver transplantation were 67 and 78 % among those with acute and subacute types of fulminant hepatitis , respectively , and the specificity of the guideline was extremely low , especially in patients with the subacute type of fulminant hepatitis .
thus , the guideline to determine the indications for liver transplantation in acute liver failure patients in japan needs to be updated.table 7guideline to determine the indications for liver transplantation for patients with fulminant hepatitis and lohf ( published by the acute liver failure study group of japan in 1996 ) ; from references [ 46 , 47]patients may be registered as potential recipients of liver transplantation when at least 2 of the following 5 criteria are satisfied at the time of the onset of grade ii or more severe hepatic encephalopathy1 .
interval from the appearance of the initial symptoms to the development of hepatic encephalopathy 11 days3 .
serum bilirubin concentration 18.0 mg / dl5 . ratio of the direct to total bilirubin concentration < 0.67if liver transplantation can not be performed within 5 days of the onset of hepatic encephalopathy and intensive medical therapy , including artificial liver support , is undertaken , the prognosis of the patients is evaluated again .
if both of the criteria listed below are positive at 5 days after the onset of hepatic encephalopathy , the prognosis is reassessed as alive and the patients are excluded from the candidate list for liver transplantation1 .
the hepatic encephalopathy shows improvement to grade i or less or attenuation by 2 or more grades2 .
prothrombin time improves to over 50 % of the standardized value guideline to determine the indications for liver transplantation for patients with fulminant hepatitis and lohf ( published by the acute liver failure study group of japan in 1996 ) ; from references [ 46 , 47 ] accordingly , the task force of the intractable hepato - biliary diseases study group established a novel scoring system for predicting the outcomes of patients with fulminant hepatitis and lohf in 2011 , through analysis of the data of 1,096 patients enrolled in a nationwide survey . in this system ,
6 parameters were identified and graded as 0 , 1 , or 2 ; the parameters were : the interval between disease onset and the development of hepatic encephalopathy , prothrombin time , total serum bilirubin concentration , ratio of direct to total bilirubin concentration in the serum , peripheral blood platelet count , and presence / absence of liver atrophy ( table 8) .
the predicted mortality was greater than 90 % in patients with a total score of 7 or more , with predicted mortalities of 8090 , 7080 , and 5060 % in those with a total score of 6 , 5 , and 4 , respectively , while the predicted mortality was less than 30 % in those with a total score of 3 or less .
when the prognosis of the patients with a total score of 5 or more was judged as death , the predictive accuracy was 0.80 , with sensitivity , specificity , positive predictive value ( ppv ) , and negative predictive value ( npv ) of greater than 0.70 even in the validation cohort .table 8scoring system to predict the mortality of patients with fulminant hepatitis and lohf established by the intractable hepato - biliary diseases study group in japan in 2010 ; from reference
score012o - c ( days)561011pt ( % ) 20<5 < , 205 tb ( mg / dl)<1010 , < 1515d / t ratio0.70.5 , < 0.7<0.5plt ( 10/l)10<5 < , 105liver atrophyabsentpresentpt prothrombin time , tb total bilirubin , d / t ratio ratio of direct to total bilirubin concentration , plt platelets , o - c the interval between hepatitis onset and hepatic encephalopathy development scoring system to predict the mortality of patients with fulminant hepatitis and lohf established by the intractable hepato - biliary diseases study group in japan in 2010 ; from reference pt prothrombin time , tb total bilirubin , d / t ratio ratio of direct to total bilirubin concentration , plt platelets , o - c the interval between hepatitis onset and hepatic encephalopathy development recently , we performed a cluster analysis of 1,022 patients with fulminant hepatitis and lohf who were enrolled in a nationwide survey between 1998 and 2007 , to evaluate the validity of the classification of acute liver failure in japan ; we used a self - organizing map ( som ) , a data mining method that has been shown to be suitable for analyses of complex multidimensional relationships .
the results of the analysis revealed that the patients could be classified into three clusters , independent of the interval between the disease symptoms onset and the development of hepatic encephalopathy , with the clinical outcomes differing markedly among the clusters .
this observation prompted us to postulate that data - mining methods may be useful to revise the outcome prediction system , and we established a decision - tree algorithm for prediction of the prognosis of acute liver failure patients .
the outcome of the patients at the onset of encephalopathy was predicted based on 5 items : the patients were classified into 6 categories , with mortality rates ranging between 89 and 23 % .
the outcome of the patients was also predicted based on 7 items at 5 days after the onset of encephalopathy ; the patients were classified into 8 categories with mortality rates ranging between 100 and 11 % .
also , we established outcome prediction models based on other data - mining methods , such as radial basis function ( rbf ) and back propagation ( bp ) ( unpublished data ) .
the usefulness of these models based on data - mining methods needs to be further investigated .
Output:
| acute liver failure is a clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to severe impairment of liver function caused by massive or submassive liver necrosis .
viral hepatitis is the most important and frequent cause of acute liver failure in japan .
the diagnostic criteria for fulminant hepatitis , including that caused by viral infections , autoimmune hepatitis , and drug allergy induced - liver damage , were first established in 1981 . considering the discrepancies between the definition of fulminant hepatitis in japan and the definitions of acute liver failure in the united states and europe , the intractable hepato - biliary disease study group established the diagnostic criteria for acute liver failure
for japan in 2011 , and performed a nationwide survey of patients seen in 2010 to clarify the demographic and clinical features and outcomes of these patients . according to the survey , the survival rates of patients receiving medical treatment alone were low , especially in those with hepatic encephalopathy , despite artificial liver support , consisting of plasma exchange and hemodiafiltration , being provided to almost all patients in japan . thus , liver transplantation is inevitable to rescue most patients with hepatic encephalopathy .
the indications for liver transplantation had , until recently , been determined according to the guideline published by the acute liver failure study group in 1996 .
recently , however , the intractable hepato - biliary disease study group established a scoring system to predict the outcomes of acute liver failure patients .
algorithms for outcome prediction have also been developed based on data - mining analyses .
these novel guidelines need further evaluation to determine their usefulness . |
PubmedSumm118291 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: bullous pemphigoid ( bp ) is an immunobullous disorder due to autoantibodies against the hemidesmosomes of the basal keratinocytes . at present date ,
31 reports of localized bp induced by radiotherapy and two of localized bp over areas of lymphedema have been described in the international literature .
we herein describe a patient with localized bp lesions sharply limited to the radiotherapy site on the oral mucosa , and to lymphedema over the hand and lower limb . to the best of our knowledge ,
this is the first report of localized bp induced by radiotherapy and lymphedema occurring simultaneously in the same patient .
a 68-year - old woman presented with recurrent episodes of mildly painful , grouped hemorrhagic bullae on the right hand , right leg , and ankle of three months duration , and painful oral ulcers of three years duration .
she had been diagnosed with poorly differentiated squamous cell carcinoma of the hypopharynx four years earlier ( t2 n1 m0 ) , and had been treated with radiotherapy in a dose of 60 gy for 26 days , with complete resolution of the lesion . in addition , she had filarial lymphedema of the right hand and the right lower limb , diagnosed 40 years earlier , and treated with diethylcarbamazine citrate .
her subsequent history was uneventful , except for rare episodes of cellulitis of the lymphedematous leg that subsided quickly with appropriate treatment .
there was non - pitting edema of the dorsum of the right hand and right lower limb .
multiple hemorrhagic bullae and erosions , with a few vesicles , were present on the dorsum of the right hand and fingers , and the anterior aspect of the right leg and ankle [ figures 1 and 2 ] .
there was a well defined erosion 1.2 0.7 cm in the oral cavity at the junction of the hard and soft palate [ figure 3 ] .
bullae on the lymphedematous hand bullae on the leg with lymphedema lesions of bullous pemphigoid on the palate at the site of radiotherapy results of laboratory investigations including total hemogram , blood sugar levels , liver and renal function tests , human immunodeficiency virus antibody test , chest radiograph and urinalysis were all within normal limits .
a tzanck smear from fresh oral and cutaneous vesicles revealed only a few neutrophils . a skin biopsy drawn from an intact vesicle showed a subepidermal plane of cleavage with a perivascular lymphocytic infiltrate .
a direct immunofluorescence ( dif ) study on a perilesional biopsy demonstrated linear deposits of immunoglobulin g ( igg ) and c3 along the dermoepidermal junction .
the blood vessels also showed c3 ( 2 + ) deposits . a repeat dif study using salt split skin revealed complete separation of the epidermis from the dermis , with linear staining of the basement membrane zone with igg and c3 .
the band was seen mainly on the epidermal side of the split ( roof pattern ) , diagnostic of bp .
an otolaryngology consultation showed no evidence of local recurrence of the carcinoma in the hypopharynx .
the patient was started on 1 mg of intravenous dexamethasone along with 100 mg of dapsone daily and topical fluticasone ointment thrice a day .
topical treatment for the oral lesions was not given as the patient had difficulty in applying medication over the posterior part of the palate .
within a week , significant healing of the lesions over both sites occurred , and the steroid was tapered to an oral dose of prednisolone 15 mg / day with continuation of dapsone .
after discharge , oral steroid was gradually tapered and stopped over a period of six months , when no further breakthrough lesions were noted .
after a year , the dose of dapsone was gradually reduced to 50 mg / day and stopped after a further period of six months .
the skin lesions healed with perifollicular pigmentation , simultaneously with the oral ulcers , with no relapse on follow up [ figure 4 ] .
the lymphedema may be primary , or acquired as a result of trauma or other causes .
slow circulation of the lymphatic vessels , increased capillary permeability with preferential localization of antibodies in the area , and potential cleavage of the epidermal junction due to increased hydrostatic pressure have all been postulated as possible causes .
the lesions of bp may be localized to the lymphedematous sites , or may be associated with generalized lesions .
paradoxically , generalized bp sparing an area of post - surgical lymphedema has also been reported , indicating that an unexplained mechanism may be involved .
however , linear binding of anti - igg and anti - c3 autoantibodies was observed in the spared area , which may be suggestive of subclinical involvement . with regard to bp induced by radiotherapy ,
a larger number of reports are available , mostly for carcinoma of the breast , and less frequently cancers of the thorax , cervix , vulva , squamous cell carcinoma and non - hodgkins lymphoma .
generalized bp , bp strictly confined to the irradiated area , as well as pre - existing bp exacerbated by irradiation have all been reported .
radiotherapy may lead to structural alteration of the basement membrane zone and auto - antibody induction .
in addition , matrix metallopeptidase-9 and vascular endothelial growth factor levels may also have an association with radiotherapy treatment .
radiotherapy paradoxically acting as a cure for bp has also been reported in one case , probably due to remission of the underlying mycosis fungoides .
our case is unique in that the bp occurred exclusively over the oral mucosa which had undergone radiation four years previously , as well as on hand and lower limb on lymphedema of separate etiology , of 40 years duration .
another unusual feature was that the oral lesions were of three years duration , and appeared one year after radiotherapy , while the lesions on the limbs were of only three months duration , although the lymphedema was of 40 years duration .
this suggests that there is no predictable time interval between the precipitating stimulus and the appearance of bp in a predisposed individual . though mucosal bp of the vulva after radiotherapy has been reported , there have been no previous reports of radiotherapy - induced bp on the oral mucosa .
a single case was reported of localized cicatricial pemphigoid which appeared nine years after radiotherapy for breast carcinoma and was preferentially localized to the lymphedematous site over the upper limb ; cicatricial pemphigoid was assumed to be solely due to the lymphedema , and not due to the radiotherapy , because of the long interval between the radiotherapy and the onset of pemphigoid .
we believe that ours is the only case where bp was separately induced by radiotherapy and lymphedema in the same patient at nearby time points .
it was noteworthy that the bullous lesions did not involve any other area at any time in the course of the disease .
immunological alterations occurring as a result of damage to the skin may be the triggering factors for autoantibody production and activation of lymphocytes in these situations .
Output:
| bullous pemphigoid ( bp ) is a blistering disorder due to autoantibodies to the epidermal basement membrane zone .
the triggering factor could be localized damage to the skin by physical or chemical agents .
we report a case of a 68-year - old woman with a three year history of oral lesions of bp following radiotherapy for carcinoma of the hypopharynx , and a three month history of bp over lymphedematous sites on the right hand and right lower limb .
localized bp induced by radiotherapy or lymphedema is rare ; both factors working simultaneously in the same patient is even rarer . |
PubmedSumm118292 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the number of deaths annually attributable to tobacco is expected to increase from 3 million in 1993 to 8.4 million in 2020 .
medical cost related to tobacco use has shown to range from 4% in developing countries to 15% in developed countries .
this fact is concerning as in certain regions of world cigarette smoking constitutes a smaller fraction of total tobacco use with up to 86% tobacco users being non - cigarette users .
epidemiological studies have found smoking rates among psychiatric patients to be twice that of general population .
additionally it has been found to be predictive of future suicidal behaviour among these patients .
moreover , smokers with anxiety disorders have more severe withdrawal symptoms during smoking cessation than smokers without anxiety disorders .
it has been recommended to establish specialised services to help patients with psychiatric illness who have associated substance dependence . by virtue of its impact on lives saved ,
quality of life , and cost efficacy , treating smoking is considered one of the most important clinical activity .
additionally , most of the literature on tobacco and psychiatric disorders is limited to smoking forms of tobacco .
also certain disorders such as somatoform disorders are under - represented/ unrepresented in these studies.[1621 ] in spite of its wide use , validity of self - reported tobacco use has been questioned in recent times .
however , the literature on reliability of self - reported tobacco use among psychiatric disorder patients is limited .
the current study aims at comparison of the use and reliability of self - reported tobacco use ( both smoked as well as smokeless ) among patients with bipolar disorder and somatoform disorders .
the study was conducted at psychiatry out - patient department of a tertiary care hospital .
subjects meeting diagnostic and statistical manual of mental disorders iv text revision ( dsm iv tr ) criteria for bipolar disorders and somatoform disorders were approached for participation and those providing consent were included in the study . in order to ensure subject participation in providing the relevant information , we selected the follow up clinic for the recruitment purpose .
those refusing to provide consent or those who were unable to cooperate for participation in the study due to a physical illness , were excluded from the study .
subsequently the subjects were asked about the use of tobacco products ( smoked as well as smokeless ) over the past one week period .
they were asked to respond to answer the question have you used xxx over the past 1 week ? the tobacco products asked in the questionnaire included smoking forms ( cigarettes , bidi ) as well as smokeless forms ( gutkha , khaini , tobacco powder ) .
those reporting affirmatively in response to the question on use of tobacco products were assessed using fagerstrom test for nicotine dependence ( ftnd ) ( smoking as well as smokeless ) .
ftnd- smoking is a widely used six - item questionnaire used to screen for severity of dependence on smoked tobacco .
ftnd- smokeless ( ftnd - st ) is a nine - item instrument used to evaluate the level of nicotine dependence for smokeless tobacco . immediately after routine clinical examination ,
50 ml of urine sample was collected from each subject under close supervision and were submitted for laboratory analysis .
quantitative urinary cotinine was done by using enzyme - linked immunosorbent assay ( elisa ) kits of calbiotech.inc , usa which uses solid phase competitive elisa .
the detection limit of cotinine assay was 2 ng / ml . the data was computed and analysed using statistical package for the social sciences ( spss ) version 17 .
independent sample t test was carried out to find the in between group differences for the bipolar disorders and somatoform disorder groups .
the concordance for self report and urinary cotinine levels was calculated using the cohen 's kappa for both the study groups .
pearson 's correlation coefficient was calculated to assess the correlation between the scores on ftnd ( smoking and smokeless ) and urinary cotinine levels .
keeping in mind the wide range of cut off value used for urinary cotinine levels across studies , we carried out analysis using two cut offs ; 50 ng / ml ( the lower limit of the recommended cut off across studies ) and 550 ng/ ml ( the upper limit of recommended cut - off across studies ) . conditions of anonymity and confidentiality as recommended in ethical approval were strictly adhered to during the study .
additionally , a valid informed consent was obtained from all the study subjects and care givers as required by the ethical committee .
immediately after routine clinical examination , 50 ml of urine sample was collected from each subject under close supervision and were submitted for laboratory analysis .
quantitative urinary cotinine was done by using enzyme - linked immunosorbent assay ( elisa ) kits of calbiotech.inc , usa which uses solid phase competitive elisa .
the detection limit of cotinine assay was 2 ng / ml . the data was computed and analysed using statistical package for the social sciences ( spss ) version 17 .
independent sample t test was carried out to find the in between group differences for the bipolar disorders and somatoform disorder groups .
the concordance for self report and urinary cotinine levels was calculated using the cohen 's kappa for both the study groups .
pearson 's correlation coefficient was calculated to assess the correlation between the scores on ftnd ( smoking and smokeless ) and urinary cotinine levels .
keeping in mind the wide range of cut off value used for urinary cotinine levels across studies , we carried out analysis using two cut offs ; 50 ng / ml ( the lower limit of the recommended cut off across studies ) and 550 ng/ ml ( the upper limit of recommended cut - off across studies ) . conditions of anonymity and confidentiality as recommended in ethical approval were strictly adhered to during the study .
additionally , a valid informed consent was obtained from all the study subjects and care givers as required by the ethical committee .
5 ( standard deviation , sd = 12.7 ) years and 29.4 ( sd = 8.2 ) years , respectively .
the two groups were comparable on different socio - demographic variables [ table 1 ] .
self - reported use of tobacco products ( both smoked as well as smokeless ) was also comparable between the two groups .
the two groups did not differ on mean ftnd scores ( both smoking and smokeless ) and urine cotinine levels [ table 2 ] .
self - reported use of tobacco products over the past one week was 10% ( smoking forms ) and 8% ( smokeless forms ) by the subjects in the bipolar group .
the rates were 10% ( smoking forms ) and 12% ( smokeless forms ) for the somatoform group .
socio - demographic and tobacco product use profi le of study subjects concordance between self - report of tobacco product use and urine cotinine levels using a cut - off value of urine cotinine > 550 ng / ml , 48% of the subjects in bipolar group were found to have biochemical evidence of use of smokeless tobacco products over the past one week and 52% were found to have smoked over the past one week . among the somatoform group , 48%
were found to have biochemical evidence of smoking and use of smokeless tobacco products . calculation of cohen 's kappa using cross tabulation revealed discordance between the self - reported use of smoked as well as smokeless tobacco products in both the groups .
analysis using the lower cut off of 50 ng/ ml also revealed discordance between the self - reported tobacco use ( smoked as well as smokeless ) for both the groups [ table 2 ] .
further in order to assess the reliability of the severity of tobacco dependence among those who reported use of these products , we calculated the pearson 's correlation coefficient for ftnd scores ( smoked as well as smokeless ) and the urinary cotinine levels .
in fact , ftnd ( smoking ) scores had a statistically significant negative correlation with the urine cotinine level for the bipolar group ( pearson 's coefficient= -0.999 , p=0.001 ) .
we aimed at comparison of the use and reliability of self - reported tobacco use ( both smoked as well as smokeless ) among patients with bipolar disorder and somatoform disorders .
concerns have been raised over the validity of the self - reported tobacco use in medical settings .
use of self - reported measures of tobacco use has shown to result in under reporting .
there is limited literature on the validity of self - report of tobacco use among patients with psychiatric illness . a recent systematic review of the relationship between self - reported and cotinine - assessed smoking status failed to find any relevant study involving patients with psychiatric disorders .
we chose subjects with bipolar disorders as a comparison group since high rate of tobacco use among these patients has been a consistent finding across studies.[3034 ] adverse impact of smoking on the long term course of bipolar disorders has been demonstrated in prospective cohort studies .
urinary cotinine estimation has been found to be a sensitive and specific biomarker for tobacco use .
its use is recommended for validation of self - report of tobacco use in medical settings for smoking as well as smokeless tobacco use . cut off value for cotinine levels to detect tobacco use has varied from 50 to 550 ng / ml across studies . to address the issue we analysed the data using the two extremes of this wide range
however , no concordance was observed between the self - report and urinary cotinine levels using either of these cut offs .
the findings point to a comparable profile with respect to tobacco use ( both smoking and smokeless forms ) for the bipolar disorder and somatoform disorder patients as reflected by comparable urinary cotinine levels .
additionally finding of discordance between the self - report and urinary cotinine levels for both smoking and smokeless forms of tobacco use , highlights the need for use of a confirmatory bio - assay for patients with bipolar disorders and somatoform disorders .
such an approach would help improve the detection rates for tobacco use among these individuals .
tobacco use problem is likely to be overshadowed and missed in these individuals because of the management plan being focused on the psychiatric disorder . patients with mental illness might not reveal their actual tobacco use status due to multiple reasons .
altered mental state during florid phases of illness and cognitive deficits associated with the psychiatric conditions are common illness related factors .
other factor such as fear of social and medical disapproval can also prevent them from self - revelation of the tobacco use status .
inadequate knowledge of the potential harms of tobacco use might also make them non - forthcoming with this important information . additionally , the prominent distress and dysfunction due to the primary psychiatric condition might pin hole the focus of the care givers as well .
we compared a consecutive sample of out - patients patients of somatoform disorders with those of bipolar disorder .
moreover , there are no comparative studies on reliability of self - report on tobacco use among psychiatric patients including bipolar disorders and somatoform disorders .
one prior study assessed the validity of the self - reported tobacco use among patients with schizophrenia .
the stratified data on the duration of schizophrenia indicated that the positive relationship between self - reported smoking and the carbon monoxide ( co ) concentration became less obvious with the increase in duration of schizophrenia .
the authors concluded that psychiatrists should use objective methods of measurement to assess the smoking status of chronic schizophrenia patients .
the findings of the current study provide important insights that could be of help while planning the management services for patients seeking treatment for bipolar disorders and somatoform disorders .
the misclassification rates in studies employing urine cotinine as a measure of tobacco use have ranged from 0.9% to 9.8% . in order to minimise any such classification ,
we have used a higher cut off value of 550 ng / ml for detecting tobacco use in the current study as recommended by zieliska - danch et al .
additionally we carried out analysis using a cut - off of 50 ng/ ml as well ( the lower limit of range used across studies ) .
there is a need to replicate the findings using bigger sample size and from different treatment settings and centres . due to logistic reasons
. it would be interesting to conduct future studies with a larger sample size including female subjects .
also , addition of a comparison arm of healthy individuals would also add to the validity of the findings .
additionally , the current study did not aim at exploring the possible causes for this discrepancy between the self - report and urinalysis findings .
self - reported use of tobacco products ( smoking as well as smokeless ) is comparable among patients with bipolar disorder and somatoform disorders .
additionally , the reliability of this self - report is questionable among both these groups for smoking as well as smokeless tobacco products .
there is a case for validation of self - reported tobacco use by urinary cotinine assessment among these patient groups .
there is a need for objective measures for detection of tobacco use among psychiatric patients .
the need to establish specialised clinics for psychiatric patients with substance abuse problem has also been emphasised previously .
however it might not be practical to assess each and every patient for tobacco use with the help of a bioassay in a developing country setting like ours .
this calls for a need for adequate training of the mental health professionals on these issues .
a more comprehensive evaluation including information from the care givers on tobacco use status of the patients can help corroborate the report by the patients .
moreover the bioassay tools such as urinalysis should be available as they can be used if the clinician suspects tobacco use as indicated by some physical signs like nicotine staining etc .
Output:
| objective : to compare the use and reliability of self - reported tobacco use ( both smoked and smokeless ) among patients with bipolar disorder and somatoform disorders.materials and methods : the study was conducted at psychiatry out - patient department of a tertiary care hospital . a total of 50 consecutive patients were recruited .
the subjects were asked about the use of tobacco products ( smoked as well as smokeless ) over the past one week .
those reporting affirmatively in response to the question were assessed using fagerstrom test for nicotine dependence ( ftnd ) scales .
quantitative urinary cotinine levels were assessed using enzyme - linked immunosorbent assay ( elisa).results : calculation of cohen 's kappa using cross tabulation revealed discordance between the self - reported use of smoked as well as smokeless tobacco products in both the groups .
analysis using the lower cut off of 50 ng/ ml also revealed discordance between the self - reported tobacco use ( smoked as well as smokeless ) for both the groups.conclusions:the reliability of self - report is questionable among both these groups for smoking as well as smokeless tobacco products . |
PubmedSumm118293 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: glucagon - like peptide-1
( glp-1 ) is an endogenous incretin and plays
a significant role in glucose homeostasis .
glp-1 is a 30 amino acid containing peptide secreted from intestinal
l - cells in response to food intake .
it is produced by post - translational
processing of preproglucagon , a precursor of many glucagon related
peptides .
it exists in two equipotent forms , glp-1(736)-nh2 and glp-1(737 ) , the former being more abundant .
it
binds to and activates the glp-1 receptor ( glp-1r ) belonging to class
b family of g - protein - coupled receptors ( gpcrs ) in order to exert
its regulatory functions . while glp-1r is found in many organs , including
pancreas , brain , heart , kidney , and gi tract , a
recent study revealed that it is exclusively expressed in the pancreatic
-cells and rarely in - and -cells , as shown by
colocalization experiments of glp-1r mrna and protein with islet cell
hormones in mice , rats , and humans .
activation
of the receptor on the -cells leads to a rapid increase in
the levels of camp and intracellular calcium followed by insulin exocytosis
in a glucose - dependent manner .
although glp-1r in the -cells
is < 0.2% of that in the -cells , glp-1 inhibits glucagon
secretion by 50% through modulation of calcium channel activity . since its discovery in the early 1980s
glp-1 therapy
demonstrated that the peptide potentiates insulin secretion in both
healthy and type 2 diabetic patients . unlike other diabetes drugs ,
the insulinotropic effect of glp-1 is self - limiting , as it subsides
once the plasma glucose level is lowered to normal range , reducing
the risk of hypoglycemia .
in addition , glp-1 regulates postprandial
glucose elevation through several other mechanisms , including promoting
insulin gene transcription , stimulating pancreatic -cell proliferation
and neogenesis , inhibiting -cell apoptosis , and blocking glucagon
release .
it also prevents gastric emptying and induces satiety , leading
to body weight decrease .
all of these physiological
effects underscore glp-1 as a promising
therapeutic agent for treating type 2 diabetes ( t2d ) .
however , the
endogenous glp-1 has a very short half - life , owing to rapid metabolic
degradation by proteases like dipeptidyl peptidase iv ( dpp - iv ) and
neutral endopeptidase 24.11 ( nep 24.11 ) .
dpp - iv cleaves the peptide bond in ala - glu , and the resulting metabolite glp-1(936)-nh2 is
found to have 100-fold lower binding affinity compared to the intact
peptide .
the metabolite also exhibits
negligible agonistic activity ( > 10000-fold decrease ) . as a result , biologically active glp-1 constitutes
only
approximately 1020% of total plasma glp-1 , as determined by
the combination of hplc , specific radioimmunoassays ( rias ) and sensitive
enzyme - linked immunosorbent assays ( elisa ) .
although the metabolite does not induce insulin release or glucose
metabolism , a potential role was suggested
for inhibiting hepatic glucose production in an insulin - resistant
state of obesity .
it also appears to
increase glucose disposal independent of insulin effects as well as stimulates myocardial glucose uptake
and improves systemic hemodynamics .
on
the other hand , nep 24.11 cleaves glp-1 at multiple sites , particularly
at the peptide bonds in asp - val , ser - tyr , tyr - leu , glu - phe , phe - ile , and
trp - leu .
although
the dpp - iv degradation is a major cause of glp-1 function loss , an
investigation with a specific nep 24.11 inhibitor candoxatril suggested
that endoproteolysis by nep 24.11 may contribute up to 50% of glp-1
degradation in vivo . to date , a
couple of stable glp-1 agonists have received fda approval
as a new class of diabetic drugs , exenatide ( 1 , glp-1r
agonist ) and liraglutide ( 2 , glp-1 analog ) . marketed
as byetta by astrazeneca , 1 is a synthetic version of
exendin-4 , a 39 amino acid containing peptide isolated from the saliva
of gila monster . marketed as victoza
by novo nordisk , 2 is a glp-1 analog prepared by substituting
lys for arg and attaching a c16 fatty acid to lys via a -glutamyl spacer .
marketed as bydureon ( astrazeneca ) , exenatide long - acting release
( lar ) is a slow releasing subcutaneous depot form of 1 .
in addition , dpp - iv inhibitors have
been developed to prolong the activity of the endogenous glp-1 . besides the therapeutic impact
, glp-1 analogs
demonstrated high potential as molecular imaging agents for noninvasively
assessing pancreatic -cell mass , as the glp-1 receptor is highly
localized in the -cells .
glp-1 ,
after binding to its receptor , triggers a conformational
change of the receptor , leading to activation of an associated gs protein by exchanging its bound gdp with a gtp .
this results
in dissociation of gs protein from the receptor and increases
secondary messengers like camp and ca . in order to investigate
the significance and function of amino acid residues in the sequence
of the peptide ,
adelhorst and co - workers have systematically replaced each residue
with ala and identified key amino acids strongly contributing to receptor
interaction .
it appears that his , gly , phe , thr , asp , phe , and ile play an important
role in receptor binding , as marked decrease in binding affinity was
caused by each ala substitution . on the other hand ,
his , gly , asp , and phe are critical
for receptor activation , as their ala substitutions resulted in a
substantial decrease in camp production . on the basis of these results
,
it is hypothesized that the n - terminal region of glp-1 is more critical
for activating the receptor , whereas the c - terminal region mainly
contributes to receptor binding ( figure 1 ) .
however , this concept should be taken cautiously , since many residues
in the n - terminal region are still found to be essential for maximal
receptor interaction .
his is
found to be a critical
residue for both receptor binding and activation , as evidenced by
the alanine scanning studies .
a histidine at the
first position is , in fact , highly conserved in the glucagon family
that interacts with class b gpcrs for their functions .
deletion of his resulted in a significant loss
of affinity ( kd = 33 nm compared to 0.3
nm of glp-1 ) , and the activity of the truncated peptide became 82%
lower than that of glp-1 .
to investigate
the significance of the positively charged side chain , his was replaced with arg and lys .
these
substitutions substantially reduced receptor binding ( 270- to 1300-fold )
and activation ( 5788% lower activity ) , suggesting a special
role of the imidazole ring in receptor interaction . when his was substituted for tyr , it resulted in a significant reduction
of binding affinity ( kd = 52 nm ) and biological
activity ( 66% of glp-1 response ) . however ,
replacement with phe was found to retain the biological activity close
to glp-1 , suggesting aromaticity is an important factor for receptor
interaction . taken together , it can be
summarized that both the aromatic character and the positive charge
of the imidazole ring strongly contribute to receptor recognition
and function . however ,
a bulky aromatic group like the indole ring
of trp reduced potency , indicating that a steric factor should be
also considered .
it was suspected
that the -amino group of his plays a role in dpp - iv
activity .
synthesized several glp-1 analogs containing
alterations at the n - terminus of his , such as n - methylation ,
-methylation , des - amination , and imidazolelactic acid substitution .
this study revealed that all of the glp-1 analogs
except the -methylated ones were hardly degraded by dpp - iv
in vitro .
these modified glp-1 analogues showed a marginal reduction
in receptor affinity ( 2- to 5-fold ) , except des - amino - glp-1 that lost
binding by 15-fold .
in addition , modification
of his with n - pyrogluatmylation and n - acetylation decreased
both receptor binding ( 18- to 89-fold ) and activation ( 3- to 6-fold ) .
despite such poor binding , both analogs exerted
a potent insulinotropic effect in vitro .
another studies showed that
a glp-1 analog containing a glucitol or mpeg2k attached
at the n - terminus of his showed outstanding dpp - iv stability . since ala is the target
of dpp - iv , much work has focused on this residue .
substitution of
ala for gly resulted in only a slight decrease in binding
affinity ( 3-fold ) with comparable agonist activity to glp-1 .
the introduction
of gly circumvented the dpp - iv degradation and led to
a longer half - life , as a single injection of 0.1 nmol of the peptide
to diabetic mice normalized fasting hyperglycemia and glucose intolerance
for several hours , whereas the activity of 1 nmol of the native glp-1
vanished in a few minutes .
deacon et al . investigated the substitution
of ala with thr , gly , ser , and 2-aminoisobutyric acid
( aib ) .
they found that only [ aib]- and [ gly]-glp-1(736)-nh2 exhibited comparable receptor binding to glp-1 ( ic50 of
0.45 and 2.8 nm , respectively , compared to 0.78 nm of glp-1 ) .
while
the other three analogs showed slow degradation , [ aib]-glp-1(736)-nh2 was found to be completely resistant to dpp - iv and exerted
the highest insulinotropic effect .
the stereochemical configuration
at position 8 appeared to have little effect on receptor recognition ,
as replacement with d - ala retained comparable receptor binding
( ic50 = 0.15 nm compared to 0.26 nm of glp-1 ) and biological
activity ( ec50 = 0.8 nm compared to 0.8 nm of glp-1 ) .
substitution of ala with ser
reduced receptor binding
affinity ( 11-fold ) and receptor stimulation potency ( 19-fold ) , presumably
resulting from the introduction of a polar side chain group .
the lack of tolerance of polar residues at this
position was supported by an experiment replacing ala with val and
led to only a marginal reduction in biological activity ( 3-fold ) .
however , steric factor becomes important when the size of the amino
acid at position 8 exceeds a certain threshold , as substitution with
leu lowered the potency by 220-fold .
this position is conserved for negatively
charged amino acids like glu and asp among the secretin family ( class
b gpcrs ) except glucagon .
this suggests
that the carboxylate side chain of glu is required for
receptor interaction , which was supported by glu being
substituted with asp without losing receptor binding affinity and
potency examined on rin t3 cells .
interestingly , xiao et al . reported
a contradicting result that substitution with asp led to a 30-fold
potency decrease , although the comparable binding affinity was determined
on cho cells . despite the speculation ,
hydrophobic amino acids like leu or met successfully replaced glu while retaining the same potency of glp-1 , suggesting that
the negatively charged side chain of glu may not form
an ion pair with a basic residue in the receptor or the peptide .
introduction of lys at position 9 showed
a significant loss of binding and potency ( 830- and 160-fold , respectively )
when the resulting peptide was tested on rin t3 cells . in another experiment ,
[ lys]-glp-1
led to no camp production on brin - bd11 cells , although a moderate
loss of binding affinity ( 17-fold decrease ) was observed on chl fibroblast
cells .
even though the peptide remained
intact when incubated with dpp - iv for 12 h , it showed no insulinotropic
action or glucose - lowering capability in ob / ob mice .
substitution
with ala , ser , and val resulted in reduced potency ( 30- , 4- , and 130-fold ,
respectively ) .
the stereochemical configuration
of glu appears to be crucial , since replacement with d - glu led to a 130-fold decrease in potency , whereas binding
affinity was moderately affected ( 33-fold decrease ) .
when pro ,
phe , and tyr were introduced in lieu of glu , the resulting
peptides exhibited a comparable or marginally increased
insulinotropic effect compared to glp-1 even though their binding
affinity and potency were compromised .
in particular , [ pro]-glp-1 showed a remarkable capability
of moderating plasma glucose excursion and enhancing the circulating
insulin level in severely insulin - resistant obese diabetic mice .
it
also substantially reduced the susceptibility to dpp - iv degradation
( t1/2 > 12 h compared to 5.2 h of glp-1 ) .
the alanine scanning studies indicate
that gly is important for receptor interaction , particularly
receptor activation .
placed a hexafluoroleucine in the
sequence of glp-1 , aiming to improve bioactivity and bioavailability .
however , the substitution at position 10 only
led to a dramatic decrease in binding affinity and potency ( 60- and
67-fold , respectively ) .
substitution of
asp for
arg was found to significantly damage receptor binding and activity
( 710- and 90-fold , respectively ) , indicating the importance of the
negatively charged residue at this position .
while a severe loss of activity ( 10000-fold ) was reported when it
was substituted for ala , replacement
with glu led to only a moderate loss in affinity ( 31-fold ) , confirming
the requirement of a negatively charged amino acid at position 15 .
the stereochemical configuration of this residue
appears to be critical , since replacement with d - asp resulted
in a substantial loss of binding affinity ( 570-fold ) .
it was found that val can be substituted
with a bulky
hydrophobic amino acid without significant impact on receptor interaction .
whereas
substitution of ser for ala did not affect receptor binding
and activation , replacement with a charged amino acid lys resulted
in a 4-fold decrease in binding affinity .
substitution of glu for ala moderately affected receptor
binding ( 15-fold decrease ) , but replacement with a smaller amino acid
gly severely reduced the affinity ( 60-fold decrease ) . as an amino acid
without any side
chain , gly at position 22 has been replaced with various amino acids
bearing side chain groups .
it appears that gly can be
substituted for aib with retention of comparable binding affinity
and potency to glp-1 .
used
this position to attach a bulky metal chelator dota through lys for -cell imaging .
two
analogs were prepared , lys - in - dota - glp-1(736 )
and lys - aeea - in - dota - glp-1(736 ) ; the latter showed
a moderate loss of binding affinity and potency ( 19- and 6-fold , respectively ) ,
remarkably tolerating such a bulky substituent placed in the middle
of the glp-1 sequence .
green and co - workers
attached a fatty
acid chain at the -amino group of lys to avoid
renal clearance for prolonging half - life and increasing stability
over dpp - iv . whereas [ lys(palmitoyl)]-glp-1 has a weak affinity and potency compared to glp-1
( 86- and 23-fold , respectively ) , all of the palmitoylated lys - containing peptides showed a marginal increase ( 1.3- to
3.4-fold ) in dose - dependent stimulation of insulin secretion on insulin - secreting
brin - bd11 cells .
a stable glp-1 receptor agonist , 2 ,
was created by attaching a palmitoyl group to lys through
a -glutamyl spacer together with substitution of lys for arg .
this peptide demonstrated
a potent agonist activity ( ec50 = 61 nm compared to 55
nm of glp-1 on bhk cells , ic50 = 0.11 nm ) and superior
stability against proteolytic degradation ( half - life of 13 h compared
to 2 min of glp-1 ) .
lys was also exploited to attach
bulky metal chelators like dota for constructing -cell imaging
agents . however , coupling dota either directly to
the side chain of lys or through a linker significantly diminished
binding affinity ( 200- and 500-fold , respectively ) . on the other hand ,
various carbohydrate moieties were introduced at position 26 in an
attempt to increase proteolytic stability and in vivo glucose - lowering
potency .
substitution of lys for asn bearing n - acetylglucosamine ( glcnac ) , n - acetyllactosamine ( lacnac ) , or -2,6-sialyl - n - acetyl - lactosamine ( sialyl lacnac ) resulted in a moderate
loss of binding affinity and potency ( 2- to 8-fold ) but higher resistance
to the dpp - iv degradation compared to glp-1 . similarly , pegylation
of lys with mpeg2k was found to have a negligible
effect on receptor activation .
alanine scanning studies suggested
that glu is not an important residue for receptor interaction .
in agreement with this , it was found that glu can be
even substituted with an oppositely charged lys without losing binding
affinity and potency ( 2-fold decrease ) .
substitution
for ala brought in greater than 1000-fold decrease in binding affinity
and potency .
while phe is essential
for affinity and activity , it is interesting that replacement with
a synthetic residue hexafluoroleucine resulted in only a moderate
loss in binding affinity and biological activity ( 10- and 5-fold ,
respectively ) .
the alanine scanning
studies revealed that ile is critical for receptor binding .
when a hexafluoroleucine was introduced at position 29 or 32 , a moderate
loss in binding affinity and biological activity was observed .
its substitution at position 29 showed a moderate
potency and affinity ( 4- and 7-fold decrease , respectively ) as well
as a marginal reduction in the rate of dpp - iv degradation .
similar
results were observed with the substitution at position 32 ( 2- and
28-fold decrease in potency and affinity , respectively ) .
connecting dota to lys directly or through
a linker was reported for imaging pancreatic
-cells . however , these bulky substituents
resulted in a substantial loss in binding affinity ( 50- to 100-fold ) .
replacement of lys with an n - glycosylated asn ( e.g. , glcnac , lacnac , and sialyl lacnac ) resulted in similar binding
affinity and potency to glp-1 .
additionally ,
pegylation on the side chain of lys with mpeg2k resulted in comparable potency to glp-1 .
this lys - peg - glp-1 displayed 93% insulinotropic effect
in rat pancreatic islets and higher glucose lowering effect as well
as high stability to dpp - iv .
compared to 2 , a 2-fold
decrease in potency was observed when lys was palmitoylated
with a -glutamyl spacer together with substitution of lys for arg .
substitution of gly for aib , together with
introduction of aib at position 8 , resulted
in a potent analog called taspoglutide ( 3 ) .
it showed outstanding resistance to dpp - iv ( half - life
of 13 h in human plasma upon subcutaneous administration ) .
it is interesting that the double aib substitutions
led to comparable receptor binding and potency ( ic50 =
1.1 nm , ec50 = 0.06 nm compared to glp-1 ( ic50 = 1.5 nm , ec50 = 0.08 nm ) ) , whereas a single aib at position
8 brought in a 4-fold decrease in potency and 2-fold increase in binding
affinity .
direct conjugation of dota to the c - terminus of glp-1
through lys resulted in a moderate loss of binding affinity
and potency ( 12- and 6-fold , respectively ) . among four positions that have been examined for dota conjugation ,
positions 22 and 37
appear to tolerate the bulky substituent with
only a moderate decrease in receptor interaction ( 5- to 10-fold ) compared
to positions 26 and 34 ( 50- to 500-fold ) .
conversely , glycosylated
asn was found to have little impact on receptor interaction . taken together
, conjugation of macromolecules
at the c - terminus of glp-1 appears to be well accepted by the receptor .
glp-1 appears to be quite sensitive
to peptide chain truncation , since most of truncated peptides suffer
from substantially low or negligible binding affinity .
it was found
that just one amino acid deletion from the n - terminus ( i.e. , his ) led to a 100-fold decrease in binding affinity and nearly
a complete loss of biological activity .
removal of a dipeptide unit ( i.e. , his - ala ) resulted in a complete loss of activity along with a 1000-fold
decrease in binding affinity , highlighting the significance of the
dpp - iv degradation .
truncation of more residues from the n - terminus
did not reinstate receptor binding or activation . on the other hand ,
truncation of two to three amino acids from the c - terminus
did not
abolish the biological activity , although binding affinity decreased
by 4- to 5-fold .
however , further deletion of val resulted
in a complete loss of binding affinity and potency . taken together ,
these results indicate that the full length of glp-1 seems to be required
for strong receptor interaction . because they do not activate
glp-1r , metabolites resulting from glp-1 degradation have been considered
as pharmacologically inactive . however ,
several metabolites , especially
glp-1(936)-nh2 , glp-1(2836)-nh2 , and glp-1(3236)-nh2 , were reported to exert
glp-1r independent biological activity , such as cardioprotective and
glucoregulatory effects .
while these metabolites present a new direction to the incretin
therapy , there is also a growing concern about pancreatitis and pancreas
and thyroid cancers as unwanted side effects .
they introduced two bulky unnatural
amino acids at the c - terminus of a nonapeptide glp-1(715 )
and demonstrated that receptor binding affinity of these short glp-1
analogs greatly depend on the structure of these two unnatural residues .
the most potent undecapeptide contains two substituted biphenylalanines
at the c - terminus and showed surprisingly high potency as a truncated
glp-1 analog ( 200-fold decrease ) .
subsequent optimization of the undecapeptide
by replacing ala and phe with other unnatural
phenylalanine analogs further increased potency , comparable to the
native glp-1 ( 3-fold decrease ) .
it is a small glp-1r agonist with
high potency in insulin secretion and glucose reduction in vivo .
the structure
of glp-1 was first reported by thornton and gorenstein
using 2d nmr in an aqueous solution containing perdeuterated dodecylphosphocholine
( dpc ) micelles that were used to provide a membrane - like environment .
bound to the dpc micelles , glp-1 was found to
adopt two helical segments ( residues 1320 and 2435 )
that were connected by a short linker region ( residues 2123 ) .
the c - terminal helix contains a larger number of hydrophobic residues
and is more stable than the amphiphilic n - terminal one , evidenced
by amide proton exchange experiments .
this study also suggested that
gly plays an important role in separating the two helices
and allows the peptide to present a single hydrophobic surface to
the membrane ; this may facilitate membrane association and receptor
binding .
however , the structure of the n - terminal region ( residues
713 ) that strongly contributes to receptor activation was
not clearly elucidated because of high conformational flexibility .
the predominant helical structure of glp-1 was also confirmed by chang
et al . using 2d nmr in 35% aqueous tfe . in this study
, glp-1 was found to adopt an extended helical structure
from thr to lys with a less well - defined
region around gly .
neidigh et al . compared structures
of glp-1 and exendin-4 in the
solution and micelle - bound states .
although
both peptides showed a helix spanning from thr to lys , glp-1 is less helical than exendin-4 because of gly at
position 22 .
in contrast , the micelle - bound exendin-4 adopts a single
helix between residues 1127 , presumably aided by a helix - favoring
glu at position 16 , the corresponding position 22 in glp-1 .
it is
interesting that the c - terminal region of exendin-4 forms a compact
tertiary fold called trp - cage in aqueous tfe or glycol , shielding
the side chain of trp from solvent exposure .
however ,
this tertiary structure disappeared when exendin-4 was bound to dpc
micelles , since the indole ring of trp is energetically more favored
to associate with the hydrophobic micelles .
agonist - induced
activation of the glp-1 receptor has been suggested
involving a two - step mechanism where the c - terminal region of the
peptide binds to the n - terminal domain ( ntd ) of the receptor while
the n - terminal part of the peptide interacts with the core region
of the receptor , triggering signal transduction .
receptor binding and activation of glp-1 appear to rely on interaction
with the ntd of the receptor as well as with the receptor core comprising
transmembrane ( tm ) domains and extracellular loops ( ecls ) .
this is also emphasized by the findings that
the ligand binding to the full length receptor is due to not only
autonomous binding to the ntd but also contacts with the juxtamembrane
part .
it is further supported by photoaffinity
labeling studies that determined spatial approximation between the
ligand and receptor residues ( vide infra ) .
exendin-4
displayed a higher binding affinity ( ic50 =
6 nm ) to the isolated ntd of glp-1r compared to glp-1 ( ic50 > 500 nm ) .
and glp-1 is more sensitive to truncation in the n - terminal
region compared to exendin-4 .
for instance , n - terminally truncated
glp-1 analogs showed a significantly higher loss in binding affinity
and potency compared to truncated exendin-4 analogs .
furthermore , mutagenesis studies at the tm domains of glp-1r
resulted in a decrease in receptor interaction .
x - ray crystal
structures of exendin-4 and glp-1 bound to the isolated ntd of glp-1r
confirmed the multidomain binding model in detail .
however , the interaction between the n - terminal segment of the peptide
and the core region of the receptor could not be explained by the
x - ray studies either . whereas both exendin-4 and glp-1 were found
to bind to the same site in the receptor , the crystal structures alone
did not adequately explain the reason why exendin-4 has a higher affinity
to the isolated ntd of glp-1r compared to glp-1 . however , a recent
biophysical study suggests that higher helical propensity of exendin-4
contributes to the high affinity of the peptide to the isolated ntd
of the receptor compared to glp-1 .
it
was found that binding of exendin-4 to glp-1r resulted in a small
increase of helical content , while a significant increase was observed
with glp-1 upon binding to the receptor .
this indicates that transition
from the solution to the receptor - bound state is more substantial
with glp-1 than exendin-4 .
the crystal structure of glp-1 bound
to the ntd of glp-1r revealed
that glp-1 becomes -helical when it interacts with the receptor
and the c - terminal part of the peptide associates to the ntd of the
receptor .
the crystal structure of glp-1
showed a continuous -helix from thr to val with a kink around gly .
the residues between
ala and val were found to interact with
the ntd of the receptor , such as ala , ala , lys , phe , ile , leu , and val .
the c - terminal helix appears to be amphiphilic
and has a hydrophilic surface containing polar residues like gin , lys , glu , and lys , while nonpolar residues like ala , ala , phe , ile , leu , and val constitute a hydrophobic one .
the crystal structure
of exendin-4(939)-nh2 in
complex with the isolated ntd of glp-1r showed that exendin-4 also
adopts an -helical conformation except the c - terminal trp - cage
part .
the trp - cage was assumed to account
for the superior binding affinity of exendin-4 compared to glp-1 .
however , the crystal structure of exendin-4 pointed out that the trp - cage
was not involved in binding to the ntd of the receptor .
it was suggested
that binding affinity of exendin-4 solely depends on its interaction
with the ntd of glp-1r , not with tm helices and ecls because the binding
affinity of exendin-4 did not alter when it bound to the isolated
ntd of glp-1r .
also , the n - terminally
truncated exendin-4 analogs still have very similar binding affinity
to the native exendin-4 .
the crystal structure of exendin-4(939)-nh2 showed a well - defined helix from leu to asn , and the residues between glu and ser were found to interact with the ntd of the receptor .
like glp-1 ,
the c - terminal segment of exendin-4 also adopts an amphiphilic helix
that presents a hydrophilic surface comprising glu , glu , arg , glu , and lys and a hydrophobic one containing ala , val , phe , ile , trp , leu , and pro .
understanding the interaction between
a ligand and its receptor
has been a topic of interest , as it can provide useful insights for
designing more effective drugs . to investigate how glp-1 interacts
with the receptor , miller and co - workers conducted spatial approximation
studies by using photolabile probes and molecular modeling .
it was found that the c - terminal residues ala and gly in the peptide were docked in a close proximity to glu and glu of the extracellular domain ( ecd )
of the receptor , respectively .
this supports a previous finding that
glp-1 binds to its receptor via an -helix formed by the sequence
spanning from thr to val with the residues
between ala and val directly interacting
with ecd .
this study also showed that phe and val are positioned near tyr and leu of ecd , respectively , yet leu landed near trp in ecl2 . to obtain a clue on less characterized n - terminal residues ,
a photolabile probe was placed at position 6 and it labeled tyr in ecl1 .
the structures of glp-1 have been studied by
2d nmr and found to have two -helical segments between
residues
1320 and 2435 that are connected by a short linker
region comprising residues 2123 .
however , these nmr structures
were determined without the presence of the glp-1 receptor and may
be different from the receptor - bound conformation , since micelles
and helix - stabilizing tfe can not mimic specific interactions between
the peptide and receptor . to investigate on the presence and
locations of -helical
structures in the receptor - bound conformation , ahn and co - workers
have designed and synthesized a series of conformationally constrained
glp-1 analogs . in this study ,
a lactam
bridge between lys / glu was introduced and stabilized a helical conformation at
various positions from the n- to c - terminus .
the receptor binding affinity and potency of the cyclic and linear
peptides were compared , and the results clearly suggest the presence
of two helical segments ( residues 1121 and 2334 ) in
the n- and c - terminal regions of the receptor - bound conformation .
for instance , a lactam bridge between lys and glu led to comparable receptor binding and activation to glp-1 ,
suggesting that a helical structure fixed at this position is a part
of the receptor - bound conformation .
the significance of this n - terminal
helix was further demonstrated by deliberately distorting the helical
structure by forming a smaller size ring via a disulfide bridge between
cys , leading to a substantial loss in receptor interaction .
in the same manner
, the c - terminal helix was confirmed in the receptor - bound
conformation .
however , a helical structure fixed in the linker region
made the corresponding cyclic peptides lose binding affinity and potency
dramatically , clearly indicating the presence of a break between the
two helices in the bioactive conformation .
while this lactam
scanning study does not provide spatially well - defined
models like the nmr structures , this method is unique in elucidating
structural requirements in receptor - bound conformation of peptides .
the two helices in the n- and c - terminal regions in the nmr solution
structures appear to be critical binding determinants for receptor
interaction .
the c - terminal helix was later confirmed by the x - ray
structure of glp-1 cocrystallized with the ntd of the receptor .
however , the formation of the n - terminal helix
upon receptor binding was only confirmed by this lactam scanning study .
lactam - containing cyclic glp-1 analogs were also reported by miranda
and co - workers .
they placed a lactam
bridge between glu and lys at the c - terminal region and showed similar results .
in particular , the lactam bridges introduced between positions 1822 ,
2226 , and 2327 were well accepted by the receptor ,
showing comparable receptor binding and activation to glp-1 .
these
cyclic peptides have gly at position 8 and showed higher plasma stability .
the lactam bridge between position 1822 together with gly , aib , and c - terminal pegylation offered a sustained
in vivo efficacy in blood glucose reduction and body weight decrease . on the basis of these results , ahn et al . have designed and synthesized
highly constrained glp-1 analogs containing two or three lactam bridges
between glu and lys that were placed simultaneously to stabilize the both helical
structures in the n- and c - terminal regions .
these multiple lactam bridges not only improved potency ( up to 4-fold
increase ) by stabilizing the two helical binding determinants as evidenced
by cd spectroscopy but also enhanced resistance to proteolytic degradation .
whereas the dpp - iv degradation can be avoided by substituting ala with various amino acids like gly , ser , d - ala , and
aib , the degradation by nep 24.11 is hard to
address in a similar manner because of the multiple sites that nep
24.11 targets ( figure 1 ) .
it is remarkable
that these multiple lactam bridges offered outstanding protection
to the enzyme .
bicyclic and tricyclic glp-1 analogs , c[glu , lys]-c[glu , lys]-glp-1(736)-nh2 and c[glu , lys]-c[glu , lys]-c[glu , lys]-glp-1(736)-nh2 , respectively , showed 4.6- and 2.6-fold increase in potency ,
respectively , as well as half - life of greater than 96 h when incubated
with recombinant nep 24.11 .
this exceptionally high enzyme stability
of the bicyclic and tricyclic glp-1 analogs would be of interest in
achieving a long - acting in vivo activity and molecular imaging of
pancreatic -cells via the glp-1 receptor ( vide infra ) .
diabetes
mellitus is a chronic disease in which the body does not
either produce enough insulin or use it inadequately , leading to the
hallmarked symptom of high glucose level .
the former is classified
as type 1 diabetes ( t1d ) , also known as juvenile - onset diabetes , resulting
from an autoimmune attack on insulin - producing pancreatic -cells .
type 2 diabetes ( t2d ) , also called as adult - onset diabetes , is composed
of multiple metabolic abnormalities that lead to progressive hyperglycemia
caused by dysfunctional insulin secretion and impaired insulin utilization
( i.e. , insulin resistance ) .
in addition
to high glucose concentrations , diabetic patients are prone to develop
other complications , such as heart disease , stroke , hypertension ,
blindness and eye problems , kidney failure , nervous system related
diseases , amputations , and so on .
it was estimated that total costs
of diabetic treatment and care in the united states were $ 174 billion
in 2007 , and diabetes was the seventh leading cause of death based
on u.s .
treatment of t1d is centered on increasing insulin availability
mainly by direct insulin administration , whereas therapeutic interventions
for t2d are focused on improving insulin sensitivity along with improving
-cell function by use of oral hypoglycemics like sulfonylureas .
despite advances in options for treating diabetes
, optimal glycemic
control may often be difficult to achieve , and there is a growing
demand for novel therapeutic agents that not only lower plasma glucose
levels but also manage diabetic complications and prevent the disease
progression . an entirely new therapeutic option for treating t2d
became
available : incretin - based therapies that mainly involve in the glp-1
axis ( table 1 ) .
the major physiological
role of glp-1 is to connect the consumption
of nutrients with glucose metabolism through a network of regulatory
pathways .
since the insulinotropic
action of glp-1 depends on plasma glucose content , it is associated
with a reduced risk of hypoglycemia that often comes along with current
antidiabetic agents like sulfonylureas and glinides .
glp-1 has also shown superiority to thiazolidinedione ( e.g. , rosiglitazone )
because glp-1 therapy does not accompany side effects like peripheral
edema , weight gain , congestive heart failure , and osteoporosis , which
are common in thiazolidinedione therapy .
in addition , it has shown favorable cardiovascular benefits , such
as lowering blood pressure , beneficial effects on serum lipids , and
a potential to improve myocardial contractility and endothelial function .
furthermore , glp-1 is found to have effects
on -cell proliferation and regeneration , which may be of great
help in preventing the disease .
although there are
speculations of asymptomatic pancreatitis as a side effect to incretin
therapy , it is not clearly studied yet .
the
endogenous glp-1 is difficult agent for therapeutic use because
of the rapid cleavage of the dipeptide his - ala by dpp - iv , which leads to a loss of receptor interaction and insulinotropic
action .
this limitation can be overcome
by either metabolically stable glp-1 analogs or dpp - iv inhibitors .
a number of methods and strategies have been developed
for protecting peptides from proteolytic degradation .
these include
introduction of d - amino acids , ,-dialkylated
amino acids like aib , n - methylated amino acids , -amino acids ,
amide bond surrogates , pegylation , glycosylated amino acids , halogenated amino
acids , and conformational
restrictions .
as briefly described in
the structure activity studies ,
a variety of substitutions have been made in the n - terminal region ,
particularly ala , and examined on receptor interaction
and metabolic stability .
discovered in the saliva of the gila monster , exendin-4 is a 39 amino acid containing glp-1r
agonist with comparable binding affinity and potency to glp-1 .
it
possesses gly at position 2 instead of ala in glp-1 , offering
outstanding resistance to dpp - iv ( figure 2).1 is a synthetic form of exendin-4
and the first incretin - based therapeutic approved by fda . it is recommended to be administered subcutaneously
twice daily and found to lower plasma glucose and hba1c levels and
body weight . however , several side effects
were observed , such as accumulation of antibodies and acute pancreatitis ,
despite low incidences reported . on the other hand , lixisenatide ( 4 , lyxumia , formerly
known as ave0010 , sanofi - aventis )
is a 44-mer peptide and has a hexalysine
extension at the c - terminus of exendin-4 .
it reportedly binds to the receptor more tightly than glp-1 and
exendin-4 ( 4-fold increase ) .
it showed a median half - life ranging
from 2.7 to 4.3 h for a dose of 20 g , compared to 12
min for the native glp-1 .
it protects
pancreatic -cells from apoptosis and exhibited a higher insulinotropic
effect compared to glp-1 .
it has been approved in the european union ,
mexico , australia , and japan as a once - daily therapeutic ( 20 g )
to be used in combination with basal insulin . approved in 2009 ,
2 is a glp-1(737 ) analog
containing a palmitoyl chain at lys through a -glutamyl
spacer together with arg ( figure 2 ) .
this fatty acid chain facilitates
binding to albumin and consequently increases the half - life to 1115
h after parenteral administration in human . despite this modification
semaglutide
( 5 , nn9535 ) is an analog of 2 containing
aib and a different fatty acid chain connected to lys through a minipeg spacer ( figure 2 ) .
it is a once - weekly human glp-1 analog
currently being developed by novo nordisk .
another potent and stable
glp-1 analog 3 was developed by ipsen and roche by substituting
ala and gly for aib ( figure 2 ) .
it showed significantly higher
proteolytic resistance ( half - life of 165 h for a dose of 30 mg ) .
however , roche decided to halt the development
because of safety issues involving various gastrointestinal side effects
and allergic reactions .
academic laboratories have focused their
research on the quest
of more stable and potent glp-1r agonists as well as pharmaceutical
industries .
ahn and co - workers , for instance , have prepared a series
of conformationally constrained glp-1 analogs by introducing multiple
lactam bridges between glu and lys to stabilize two -helices at the
n- and c - terminal regions .
one of the
bicyclic peptides , [ d - ala]-c[glu , lys]-c[glu , lys]-glp-1(736)-nh2 ( 6 ) , was found to show outstanding metabolic
stability as well as higher potency compared to glp-1 ( figure 2 ) .
it is remarkable that
this highly constrained glp-1 analog demonstrated high in vivo efficacy
matching the gold standards ( 1 and 2 ) , as
examined by intraperitoneal glucose tolerance test ( unpublished results ) .
hexafluoroleucine
containing peptide ( 7 ) has glu replaced with
hexafluoroleucine and showed binding affinity and potency ( ic50 = 5.1 nm , ec50 = 2.0 nm ) comparable to glp-1
( ic50 = 1.9 nm , ec50 = 1.0 nm ) .
however , it displayed only 1.5-fold increase in stability
over dpp - iv compared to glp-1 .
lee and co - workers reported exendin-4
analogs ( 8) with a bile acid ( e.g. , cholic , deoxycholic ,
and lithocholic acid ) conjugated to lys.8 showed high binding affinity ( ic50 = 0.48 nm ) compared to exendin-4 ( ic50 = 0.14 nm ) without
loss of noticeable insulinotropic activity .
the increased hydrophobicity
resulting from the conjugation of the bile acid appeared to elevate
albumin - binding property .
these bile acid modified exendin-4 analogs
exhibited extended antidiabetic effect with prolonged restoration
of normoglycemia in t2d mice .
mapelli and co - workers developed 11 amino acid containing glp-1r agonists
( 9 ) that comprise structurally optimized n - terminal nine
residues of glp-1 and a substituted biphenylalanine ( bip ) dipeptide
at the c - terminus ( figure 2 ) . despite the significantly shortened length of the peptide , 9 showed a high potency ( ec50 = 0.087 nm ) compared
to glp-1 ( 0.034 nm ) and a longer pharmacokinetic half - life .
it was
also found to be highly selective to glp-1r over other class b gpcrs .
as another approach , schepartz and co - workers developed a 3-peptide
analog of glp-1 ( 10 ) .
it
was constructed by incorporating the epitopes of ala ,
phe , and trp in a 14-helical 3-peptide
and extending the sequence at the n - terminus with a short peg chain
followed by a short -peptide corresponding to the n - terminal
nine residues of exendin-4 .
the 3-peptide analog adopts a 14-helical
conformation that is stabilized by hydrogen bonds between an amide
proton of the ith residue and a carbonyl of the i
+ 2 residue .
however , 10 showed substantially weak potency
( ec50 = 1200 nm ) compared to glp-1 ( ec50 = 0.003
nm ) . as peptides are quickly cleared out of the body , fusion
proteins
have been developed to achieve longer plasma circulation .
albiglutide
( 11 , glaxosmithkline ) is a dimer of modified glp-1 sequence
linked to human serum albumin ( figure 2 ) .
it gained resistance to dpp - iv by both replacing
ala with gly and being a part of a macromolecule , allowing
5 days of plasma half - life , suitable for once - weekly dosing .
as a fusion protein , it showed a remarkably
high binding affinity ( ic50 = 0.61 nm compared to 0.02
nm of glp-1 ) .
it was recently approved by the european commission
under the name of eperzan and very recently ( april 2014 ) in the united
states as well .
it has
the sequence of exendin-4 and similarly showed a long circulation
half - life ( approximately 8 days ) as 11 .
another
long acting glp-1r agonist , dulaglutide ( ly2189265 , eli
lilly , structure not shown ) , is a recombinant fusion protein with
two analogs of glp-1(737 ) covalently linked by a synthetic
16 amino acid linker to a fc fragment of human igg4 .
conversely , langlenatide ( hm11260c , hanmi pharmaceuticals ,
structure not shown ) is a long acting exendin-4 analog conjugated
to a nonglycosylated fc region via a short peg linker .
vrs-859 ( exenatide - xten , diartis pharmaceuticals ,
structure not shown ) is a different kind of fusion protein comprising
exanatide and a long chain of all natural hydrophilic amino acids
referred to as xten .
structures of selected glp-1 receptor agonists . despite the striking similarity
between the two peptides , glp-1
and glucagon have opposing roles in glucose homeostasis .
glp-1 induces
glucose - dependent insulin secretion and reduces the plasma glucose
level , whereas glucagon triggers glycogenolysis and gluconeogesis
in the liver , increasing the glucose concentration .
since a glucagon
antagonist can inhibit hepatic glucose output , creating a bifunctional
molecule that is an agonist to the glp-1 receptor ( glp-1r ) and an
antagonist to the glucagon receptor ( gr ) simultaneously may be pharmacologically
significant for modulating the overall glucose in the body in multiple
ways .
developed a balanced glp-1 agonist / glucagon antagonist ,
anc7k2 ( structure not shown ; glp-1r , ic50 = 3.5 nm and
ec50 = 13 nm ; gr , ic50 = 120 nm and 36% inhibition
of the receptor activity ) .
in addition ,
a 43 kda peg chain was conjugated to position 31 , promoting a prolonged
glucose lowering activity .
conversely , dimarchi and co - workers
have reported bifunctional
molecules that are gr antagonist / glp-1r agonist and gr / glp-1r coagonist .
a glucagon antagonist [ pla , asp]-c[glu , lys]-glucagon(629 ) that has an ic50 value of 14 nm on gr showed a potent agonism on glp-1r ( ec50 = 11 nm ) .
they also investigated novel multifunctional ligands
that show coagonism on both gr and glp-1r in order to normalize glucose
and lipid metabolism . a glucagon - based
peptide comprising aib at position 2 , a lactam bridge between glu and lys , and a 40 kda peg chain at position
24 showed a potent agonistic activity on both receptors ( ec50 of 0.67 and 0.059 nm on gr and glp-1r , respectively ) .
this coagonist
resulted in a significant decrease in body weight and fat mass , demonstrating
that balanced simultaneous activation of the both receptors lowered
body adiposity and improved glucose tolerance . extending these works
further , dimarchi and
co - workers also developed a coagonist on glp-1r
and gastric inhibitory polypeptide ( gip ) receptor to achieve a greater
weight loss effect than glp-1 alone . in collaboration with boehringer ingelheim ,
zealand pharma
recently
developed a gr / glp-1r dual agonist ( zp2929 , structure not shown ) .
it is an oxyntomodulin - based peptide drug candidate
in preclinical development for the treatment of t2d and obesity .
tt401
( transition therapeutics , structure not shown ) is another dual agonist
on glp-1r and gr under development for once - weekly dosing .
ac164204 and ac164209 ( structures not shown )
( amylin pharmaceuticals ) are analogs of 1 covalently
linked to a second generation amylin analog , davalintide , another
example of coagonists .
both molecules
showed full agonism to their cognate receptors in vitro but with a
reduced potency to glp-1r .
another approach to prolong glp-1
action in vivo is dpp - iv inhibitors ,
since dpp - iv is one of the main causes of glp-1 degradation .
dpp - iv
inhibitors can be used either alone or as combination therapy for
reducing fasting and postprandial glucose levels with a low incidence
of hypoglycemia and weight gain . to date , many dpp - iv inhibitors have
been developed , including sitagliptin ( 13 ) , saxagliptin ,
vildagliptin , and linagliptin ( structures not shown ) . 13 ( januvia , merck ) reduces glucose and hba1c levels but has no effect
on body weight .
unlike stable glp-1 analogs ,
it can be orally administered once daily and has a half - life of 1214
h. dpp - iv inhibitors have been extensively reviewed elsewhere . despite low potency ,
nonpeptidic glp-1r agonists have been
reported
and showed a potential to achieve orally active glp-1 mimetics .
developing small molecules mimicking peptide
hormones is not a trivial task because peptides often have a large
surface area required for optimal receptor interaction .
in addition ,
residues important for receptor binding and activation are frequently
dispersed across their sequences and structures . whereas gpcrs have
been activated by nonpeptidic ligands ( e.g. , morphine activating opioid
receptors ) , they have been mainly limited to class a gpcrs that are
smaller and more extensively studied than class b receptors to which
glp-1r belongs .
however , small molecules have been reported of activating
glp-1r , offering a hope for this challenging quest . in 2007 ,
knudsen
reported substituted quinoxalines ( 14 )
discovered from an extensive screening campaign with 500 000-membered
library ( figure 3).14 compounds were found to be allosteric agonists selective
for human glp-1r . whereas these compounds showed toxicity at high
concentrations with an unusual bell - shaped dose
response curve ,
they induced glucose - dependent insulin release from normal mouse islets
but not from glp-1r knockout mice . on the other hand , chen and
co - workers
also reported their discovery of glp-1r agonists identified from screening
50 000 compounds .
two substituted
cyclobutanes ( 15 ) were found to be orthosteric agonists
with weak binding affinity and efficacy .
pyrimidine - based small molecules ( 16 ) were identified
as glp-1r agonists by cell - based screening and insulin secretion assays
with rodent and human islets ( figure 3).16 induced glp-1r - mediated camp
signaling and stimulated glucose - dependent insulin secretion both
in vitro and in vivo , although these molecules did not show competitive
binding to the receptor . sexton and co - workers developed a series
of quercetin - like flavonoids ( 17 ) with positive allosteric
modulator activity on glp-1r.17 selectively modulated ca responses induced
by the high - affinity agonists glp-1 and exendin-4 without altering
camp signaling .
similarly , gong and co - workers identified imidazopyridines
( 18 , 19 ) after screening 10 000 heterocyclic
small molecules by a functional assay on glp-1r overexpressed on hek293
cells .
researchers at dong - a pharmaceutical
developed 2-thioquinoxaline derivatives ( 20 ) as small
molecule agonists on glp-1r .
they were
found to have ec50 values ranging from 50 to 1000 nm in
camp response element ( cre ) luciferase reporter assays .
when orally
administered , 20 promoted glucose - stimulated insulin
secretion in a mouse intravenous glucose tolerance test . taking
a different approach , ahn and co - workers developed a new
strategy for rationally designing glp-1 peptidomimetics by using helix - mimicking
small molecules . as they demonstrated with a
series of conformationally constrained glp-1 analogs ,
the helical
segments at the n- and c - terminal regions of the peptide appear to
be important for receptor interaction . to mimic helical
peptides
, they designed a rigid and preorganized tris - benzamide scaffold
that placed three side chain groups of amino acids found at the i , i + 4 , and i + 7 positions
of a helix , reproducing one side of a helix .
they designed glp-1 peptidomimetics ( 21 ) by replacing
a helical peptide segment in glp-1 with a corresponding tris - benzamide - based
helix mimetic ( e.g. , sh3 ) , which showed promising receptor binding
and potency ( ec50 = 130 nm ; figure 3 ) . despite weak potency ,
these are
the first examples of rationally designed , not screened , glp-1 peptidomimetics
that are currently under investigation . structures of selected
non - peptide glp-1 receptor agonists . improving efficacy and pharmacokinetic profiles of natural
products
and therapeutics
can be achieved in many ways , including pharmaceutical
drug delivery systems and dosage forms .
one of the successful approaches
in the field of glp-1 is exenatide lar , a slow drug releasing subcutaneous
depot form of 1.1 is entrapped noncovalently into a biodegradable poly(d , l - lactide - co - glycolide ) ( plga ) microsphere
from which the drug is slowly released as the polymeric matrix breaks
down in vivo , increasing the half - life up to 6 days .
it is the first
once - weekly injectable formulation approved by the fda for the treatment
of t2d ( january 2012 ) . besides , other formulations are currently under
development for sustained release of glp-1r agonists as summarized
in table 2
noninvasive in vivo assessment
of pancreatic -cell mass
( bcm ) in humans has a tremendous potential as a clinical tool for
diagnosing and treating diabetes .
while sweet smell or taste of urine
is a classical and historical sign of diabetes , fasting plasma glucose
( fpg ) , oral glucose tolerance test ( ogtt ) , glycated hemoglobin a1c
( hba1c ) , insulin , and c - peptide levels are currently used to examine
functional pancreas . however
, these clinical manifestations detect the progress of the
disease too late , at which time the majority of the -cells
are destroyed and the disease is already too advanced for any preventive
measures to intervene .
for example ,
fasting plasma glucose ( fpg ) test and oral glucose tolerance test
( ogtt ) are two major methods for clinical diagnosis of diabetes .
if
either test indicates a positive result ( higher than 126 mg / dl ( fpg )
or 200 mg / dl ( ogtt ) of glucose levels ) , patients are diagnosed as
diabetic . at the time of diagnosis , t1d patients typically have their
bcm reduced by 7080% .
however ,
because the remaining -cells compensate the loss of insulin
production from -cell death , abnormalities in blood glucose
levels are unnoticed by these tests until bcm is diminished by more
than 50% .
thus , noninvasive imaging
of bcm would provide accurate and in - time status as well as useful
prediction .
such an approach can be used to monitor the disease progression ,
examine the loss of bcm , evaluate efficacy of therapies in preserving
and restoring bcm , and follow up -cell replacement therapies
like islet transplantation .
imaging
modalities , such as positron emission tomography ( pet ) ,
magnetic resonance imaging ( mri ) , other nuclear imaging techniques
like single - photon emission computed tomography ( spect ) , and optical
absorption or fluorescence spectroscopy and imaging have been promising
for visualizing and quantifying various molecular targets .
however , assessing bcm in vivo is still challenging ,
since the -cells exist in pancreatic islets that are small
( 50300 m in diameter ) , scarce ( 12% of pancreatic
mass ) , and scattered throughout the pancreas .
each islet is too small to be spatially resolved by current
noninvasive in vivo imaging techniques .
in addition , it is not trivial
to correlate signals from imaging experiments with changes in bcm .
a number of potential candidates for -cell imaging have been
reported , such as vesicular monoamine transporter ( vmat2 ) , glucagon - like
peptide-1 receptor ( glp-1r ) , sulfonylurea receptor ( sur1 ) , glucose
transporter 2 ( glut2 ) , glycogen , zinc transporters , fluorodithizone ,
and monoclonal antibodies .
however , many fell short because of either
low expression levels or insufficient -cell specificity . among them ,
c-
and f - labeled dihydrotetrabenazine ( dtbz ) derivatives
( structures not shown ) have demonstrated promising results . as a ligand to vmat2 that is
expressed at dopamine nerve ends in the central nerve system and pancreatic
-cells , they were identified from screening an extensive library
of radiotracers .
however , recent findings of nonspecific binding of
[ c]-dtbz in human pancreas overcasts its clinical applications .
compared to other -cell biomarkers ,
glp-1r shows a high
promise because of its specific expression in the -cells and
strong interaction with its ligands .
thus , glp-1 analogs are of great interest not only in treating diabetes
but also in determining bcm .
however , its endogenous ligand glp-1
can not be employed as an effective imaging agent because of its extremely
short half - life ( less than 5 min ) resulting from rapid metabolic degradation .
this indicates that -cell imaging via glp-1r as a biomarker
requires glp-1 analogs with high metabolic stability as well as strong
binding affinity . owing to inherent resistance to dpp - iv degradation ,
stable glp-1r agonists , exendin-3 and exendin-4 ,
on the other hand , bicyclic glp-1 analogs developed by ahn and co - workers
have also demonstrated a promising potential in determining bcm .
these stable glp-1 analogs were conjugated to a metal chelator like
dota , nota , and dtpa , which coordinates a radiotracer ( e.g. , cu , ga , tc , and in ) for pet and spect imaging modalities . [ lys(ahx - dtpa - in)nh2]-exendin-4
( 22 ) was reported as a spect probe to target glp-1r for
imaging insulinoma in rip1tag2 transgenic mice with high tumor uptake
( figure 4 ) . whereas ratios
of tumor to pancreas ( 9.71 at 48 h ) and other organs were high ,
a
low ratio of the tumor to kidney ( 1.27 at 48 h ) was observed . despite
such a high renal uptake ,
the potential of glp-1r in visualizing the
-cells has been demonstrated by pet and spect imaging of insulinoma
by using exendin-3 or exendin-4-based radioligands .
similarly , a cu - labeled
exendin-4 , [ lys(dota - cu)nh2]-exendin-4
( 23 ) showed high binding specificity to rodent -cells
by ex vivo autoradiography .
another cu - labeled exendin-4 analog , cu - do3a - vs - cys - exendin-4 ( 24 ) , demonstrated a feasibility
of in vivo imaging of intraportally transplanted islets in mice by
virtue of a high and specific uptake in ins-1 tumors despite high
renal uptake .
it is exciting that 22 was successfully used to highlight autologous islets that
have been transplanted into human muscle , proving a clinical potential
of human -cell imaging via glp-1r .
exendin-4 based near - infrared fluorescent imaging agent e412-vt750 ( structure not shown ) was reported as well .
in addition to the glp-1r agonists described above , antagonists
like exendin(939 ) were also employed as a -cell imaging
probe .
hunter
reagent at lysine residues , exendin(939 ) was examined for
receptor specificity in vitro and selectivity in vivo .
it showed radioactive
signals in pancreatic -cells although the resolution of the
imaging technique was low .
whereas the majority of -cell
imaging studies have been
carried out with exendin-4 analogs , ahn and co - workers have developed
outstanding glp-1 based pet imaging agents ( 25 , 26 ) to quantitate bcm .
as the endogenous peptide suffers from rapid metabolic degradation ,
they introduced multiple modifications , such as epimerization at position
8 and two lactam bridges , and produced highly constrained glp-1 analogs .
strategically placed two lactam bridges made the bicyclic peptides
resistant to the proteolytic cleavages by nep 24.11 , and d - ala protected them from the dpp - iv degradation , significantly
enhancing metabolic stability .
dynamic pet scans over 60 min showed
a high pancreatic uptake of a bicyclic glp-1 analog labeled with cu ( 26 ) as shown in figure 5 .
the pancreas uptake disappeared
in stz - induced type 1 diabetic mice or competitively displaced by
co - injection of unlabeled exendin-4 , indicating outstanding selectivity
to the -cells .
ex vivo pet scans and histology were also carried
out to confirm the in vivo pet imaging findings ( unpublished results ) .
this bicyclic glp-1 analog is currently under investigation with ossawbaw
mini - pigs for longitudinal pet imaging of bcm in the course of the
disease progression .
structures of selected
exendin-4 and glp-1 based imaging agents
for monitoring pancreatic -cells . in vivo pet / ct images of pancreas of healthy mice , healthy mice
co - injected with a blocking dose of cold exendin-4 , and stz - induced
diabetic mice . reproduced with permission from peptides across the pacific ,
proceedings of the 23rd american peptide symposium .
since its discovery , glp-1 has attracted tremendous attention because
of unique functions that are beneficial for managing diabetes .
it
not only stimulates insulin secretion in a glucose - dependent manner ,
preventing hypoglycemic episodes , but also restores pancreatic -cell
mass and functions .
intensive studies over the past decade revealed
elements required for strong receptor interaction and many players
in its metabolic degradation .
however , many fundamental
features of the peptide and its receptor interaction have not yet
been completely explained , although such discovery would be a vehicle
to design nonpeptidic glp-1 receptor agonists possessing long - pursued
oral activity . also , recent advances in molecular imaging have been
useful in monitoring changes of pancreatic -cells , playing
a significant role in diagnosing the disease and evaluating effectiveness
of therapeutic interventions and islet transplantation .
while promising
results have been reported , several issues like specific -cell
uptake and high accumulation in nearby organs need to be addressed
to become an effective clinical tool .
Output:
| glucagon - like peptide-1 ( glp-1 ) is
an incretin that plays important
physiological roles in glucose homeostasis .
produced from intestine
upon food intake , it stimulates insulin secretion and keeps pancreatic
-cells healthy and proliferating . because of these beneficial
effects , it has attracted a great deal of attention in the past decade ,
and an entirely new line of diabetic therapeutics has emerged based
on the peptide . in addition to the therapeutic applications , glp-1
analogs have demonstrated a potential in molecular imaging of pancreatic -cells ;
this may be useful in early detection of the disease and evaluation
of therapeutic interventions , including islet transplantation . in
this perspective
, we focus on glp-1 analogs for their studies on improvement
of biological activities , enhancement of metabolic stability , investigation
of receptor interaction , and visualization of the pancreatic islets . |
PubmedSumm118294 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: a large autopsy series has reported that 8.1% of patients with malignancy had pericardial involvement and 2.7% experienced pericardial effusion ( 1 ) .
malignant pericardial effusion can lead to various adverse events including , chest discomfort , dyspnea , tachycardia , hypotension and cardiogenic shock , although some patients remain undiagnosed until death . because the amount of pericardial fluid can only be semi - quantitatively estimated through imaging modalities , it is difficult to evaluate the relationship between pericardial fluid volume and its affect on the heart . the most effective method of managing malignant pericardial effusion with imminent or recurrent tamponade has not been determined , although repeated pericardiocentesis ( pcc ) and surgical drainage ( pericardiostomy or pericardial window operation ) have been widely used .
pericardial instillation of anti - cancer drugs has also been recommended ( 2 - 6 ) .
the selection of a management plan for these patients depends on the patient 's expected survival time and the probability of recurrence .
patients with pericardial effusion with imminent or recurrent tamponade have shown poor survival outcomes ( 7 - 9 ) .
however , recent improvement in systemic treatment , including chemotherapy and molecular - targeted therapy , has enabled us to re - evaluate clinical outcomes for patients with malignant pericardial effusion .
in addition , little is known about recurrence and survival after drainage , although a report has described practice patterns and outcomes for all types of pericardial effusion ( 10 ) .
in contrast to malignant pericardial effusion , other kinds of effusion , including those caused by surgery , infection and connective tissue disease are relatively uncommon , rarely recur , and can be relatively easily treated .
recent improvements in systemic treatment , including chemotherapy and molecular - targeted therapy , have allowed a re - evaluation of clinical outcomes for patients with malignant pericardial effusion .
we have therefore investigated clinical outcomes after drainage for malignant pericardial effusion with imminent or overt tamponade .
we retrospectively identified 100 consecutive patients who underwent successful pcc between august 2001 and june 2007 as initial treatment for hemodynamically significant or symptomatic malignant pericardial effusion .
hemodynamic significance was defined as diastolic right ventricular outflow collapse and exaggerated right atrial collapse during atrial systole ( 11 ) .
of the 100 patients , two were lost to follow up after pcc ; thus , 98 were included in this analysis .
malignant pericardial effusion was defined as the presence of malignant cells in pericardial effusion or the drainage of exudate effusion in patients with malignancy , in the absence of other causes , such as post - operative effusion or tuberculosis .
patients were classified by primary cancer type into four categories : adenocarcinoma of the lung ( adl - l ) , squamous cell carcinoma of the lung ( sq - l ) , breast cancer , and other cancers .
the study end points were recurrence of pericardial effusion after pcc and death from any cause .
recurrence was defined as a reaccumulation of pericardial effusion requiring another pericardial procedure , either pcc , pericardial window operation or surgical pericardiostomy .
information on patient vital status and survival was collected from medical records and death certificate data from the korea national statistical office .
we calculated the interval between the first pcc and the next drainage of pericardial effusion .
except for one patient who had adenocarcinoma of lung ( adc - l ) and poor performance status , all patients received chemotherapy after pcc .
chemotherapy responses were assessed after two or three treatment cycles using response evaluation criteria in solid tumors ( recist ) criteria ( 12 ) .
all pccs were performed in the medical intensive care unit under the guidance of two - dimensional echocardiography .
the point of minimal distance between the skin and maximal fluid accumulation was chosen as an entry site .
after insertion of a catheter ( 18f ) , using the standard seldinger technique , pericardial effusion was aspirated as much as possible on site and the drainage catheter was allowed to remain in place .
successful pcc , defined as adequate catheter positioning and effective drainage , was verified by echocardiography and chest radiography .
subsequently , the effusion was drained naturally ( without negative pressure ) for two days , and the catheter was removed when there was no significant pericardial effusion by echocardiography .
categorical variables , presented as counts and percentages , were compared using the chi - square test for equality of proportions .
recurrence - free survival and overall survival rates were assessed using the kaplan - meier method and between group differences in survival curves were assessed using the log - rank test .
predictors of recurrence - free survival and overall survival were investigated by fitting univariate and multivariable cox regression models .
variables , including age , sex , primary cancer type , response to subsequent chemotherapy , history of radiotherapy ( before and after pcc ) , signs of tamponade , drained effusion volume and results of effusion analysis , were entered into a backward and forward stepwise cox proportional - hazards model to identify predictors of recurrence .
stata / se 10.0 for windows ( stata corp lp , college station , tx ) was used for all statistical analyses .
we retrospectively identified 100 consecutive patients who underwent successful pcc between august 2001 and june 2007 as initial treatment for hemodynamically significant or symptomatic malignant pericardial effusion .
hemodynamic significance was defined as diastolic right ventricular outflow collapse and exaggerated right atrial collapse during atrial systole ( 11 ) .
of the 100 patients , two were lost to follow up after pcc ; thus , 98 were included in this analysis .
malignant pericardial effusion was defined as the presence of malignant cells in pericardial effusion or the drainage of exudate effusion in patients with malignancy , in the absence of other causes , such as post - operative effusion or tuberculosis .
patients were classified by primary cancer type into four categories : adenocarcinoma of the lung ( adl - l ) , squamous cell carcinoma of the lung ( sq - l ) , breast cancer , and other cancers .
the study end points were recurrence of pericardial effusion after pcc and death from any cause .
recurrence was defined as a reaccumulation of pericardial effusion requiring another pericardial procedure , either pcc , pericardial window operation or surgical pericardiostomy .
information on patient vital status and survival was collected from medical records and death certificate data from the korea national statistical office .
we calculated the interval between the first pcc and the next drainage of pericardial effusion .
except for one patient who had adenocarcinoma of lung ( adc - l ) and poor performance status , all patients received chemotherapy after pcc .
chemotherapy responses were assessed after two or three treatment cycles using response evaluation criteria in solid tumors ( recist ) criteria ( 12 ) .
all pccs were performed in the medical intensive care unit under the guidance of two - dimensional echocardiography .
the point of minimal distance between the skin and maximal fluid accumulation was chosen as an entry site .
after insertion of a catheter ( 18f ) , using the standard seldinger technique , pericardial effusion was aspirated as much as possible on site and the drainage catheter was allowed to remain in place .
successful pcc , defined as adequate catheter positioning and effective drainage , was verified by echocardiography and chest radiography .
subsequently , the effusion was drained naturally ( without negative pressure ) for two days , and the catheter was removed when there was no significant pericardial effusion by echocardiography .
categorical variables , presented as counts and percentages , were compared using the chi - square test for equality of proportions .
recurrence - free survival and overall survival rates were assessed using the kaplan - meier method and between group differences in survival curves were assessed using the log - rank test .
predictors of recurrence - free survival and overall survival were investigated by fitting univariate and multivariable cox regression models .
variables , including age , sex , primary cancer type , response to subsequent chemotherapy , history of radiotherapy ( before and after pcc ) , signs of tamponade , drained effusion volume and results of effusion analysis , were entered into a backward and forward stepwise cox proportional - hazards model to identify predictors of recurrence .
stata / se 10.0 for windows ( stata corp lp , college station , tx ) was used for all statistical analyses .
fifty seven patients had adc - l , 11 had sq - l , 10 had breast cancer , and 20 had other kinds of cancer ; including 3 with small cell carcinoma of the lung , 2 each with unspecified non - small cell lung cancer , uterine cancer , stomach cancer , and colon cancer , and 1 each with lymphoma , large cell carcinoma of the lung , mesothelioma , osteosarcoma , bladder cancer , prostate cancer , bile tract cancer , esophageal cancer and thymic cancer . therefore , the predominant tumor type was lung cancer , present in 74 of 98 ( 76% ) patients , including 57 with adc - l , 11 with sq - l , 3 with small cell lung cancer , 1 with large cell lung cancer and 2 with non - specified lung cancer .
although 23 patients ( 23% ) were negative for malignant cells , exudate effusion was drained from the patients with malignancy and without other causes , such as post - operative effusion or tuberculosis .
therefore , these patients were regarded as having malignant pericardial effusion . according to recist criteria , 74 patients had progressive disease after first chemotherapy , 2 had complete response , 10 had partial response and 12 had stable disease .
of the 75 patients with lung cancer , 13 ( 17% ) received targeted therapy .
including the 15 patients ( 15% ) who underwent pcc as the initial manifestation of cancer , the median time between cancer diagnosis and drainage of pericardial effusion was 10.2 months , and the mean volume of drained pericardial effusion was 1,148494 ml ( range , 370 to 2,300 ml ) .
the mean effusion to serum ratio of red blood cell ( rbc ) concentration was 0.30.3 ( range , 0 to 1.4 ) and was>0.5 in 17% ( 14/84 ) of patients . in 3/84 patients ( 3.6% ) , rbcs were more concentrated in the pericardial fluid than in the serum , but there was no evidence of pcc - related hemorrhage .
interestingly , effusion recurred only in patients with adc - l or adenocarcinoma of other organs ( prostate , stomach , and colon ) .
pericardial effusions recurred in 30 patients ( 31% ) ; of these , 12 underwent urgent surgical drainage , 11 underwent repeated pcc with subsequent pericardial window operations , and 7 underwent repeated pcc without subsequent pericardial window operations . the mean follow - up time in these 30 patients was 9.7 months .
univariate analysis showed that adc - l , progressive disease after chemotherapy , and a lower proportion of polynuclear cells in the effusion fluid were significantly associated with time to recurrence .
positive cytology and the effusion to serum ratio of rbc tended to show associations with recurrence , but these associations did not reach statistical significance ( table 2 ) .
although , some patients received radiotherapy before ( 19% ) and/or after ( 8% ) pcc , radiotherapy did not affect recurrence of pericardial effusion ( table 2 ) .
in multivariable analysis , adc - l ( hazard ratio [ hr ] , 6.6 ; 95% confidence interval [ ci ] , 1.9 to 22.3 ; p=0.003 ) and progressive disease ( hr , 4.3 ; 95% ci , 1.6 to 12.0 ; p=0.005 ) remained significant predictors for the recurrence of pericardial effusion . among lung cancer patients , those with adenocarcinomas were vulnerable to recurrence of effusion , whereas those with squamous cell carcinoma were not .
the probability of overall survival differed significantly by the type of primary cancer and response to chemotherapy .
breast cancer patients showed significantly better overall survival than did other groups ( vs. adl - l , p=0.02 ; vs. sq - l , p=0.002 ; vs. other cancers , p=0.02 ) ( fig .
2b ) , which may have been due to the lower rate of progressive disease in breast cancer patients ( 4/10 , 40% ) .
overall survival was better in patients with adc - l than those with sq - l or other cancers .
median survival after pcc was 6.8 months in patients with adc - l , 1.9 months in patients with sq - l , 16.5 months in patients with breast cancer , and 1.7 months in patients with other cancers .
the probabilities of survival 3 months after pcc in these 4 groups were 73% , 18% , 80% and 30% , respectively .
in addition , the survival rates 1 year after pcc were not so discouraging in patients with adc - l ( 26% ) and breast cancer ( 47% ) .
fifty seven patients had adc - l , 11 had sq - l , 10 had breast cancer , and 20 had other kinds of cancer ; including 3 with small cell carcinoma of the lung , 2 each with unspecified non - small cell lung cancer , uterine cancer , stomach cancer , and colon cancer , and 1 each with lymphoma , large cell carcinoma of the lung , mesothelioma , osteosarcoma , bladder cancer , prostate cancer , bile tract cancer , esophageal cancer and thymic cancer . therefore , the predominant tumor type was lung cancer , present in 74 of 98 ( 76% ) patients , including 57 with adc - l , 11 with sq - l , 3 with small cell lung cancer , 1 with large cell lung cancer and 2 with non - specified lung cancer .
although 23 patients ( 23% ) were negative for malignant cells , exudate effusion was drained from the patients with malignancy and without other causes , such as post - operative effusion or tuberculosis .
therefore , these patients were regarded as having malignant pericardial effusion . according to recist criteria , 74 patients had progressive disease after first chemotherapy , 2 had complete response , 10 had partial response and 12 had stable disease .
of the 75 patients with lung cancer , 13 ( 17% ) received targeted therapy .
including the 15 patients ( 15% ) who underwent pcc as the initial manifestation of cancer , the median time between cancer diagnosis and drainage of pericardial effusion was 10.2 months , and the mean volume of drained pericardial effusion was 1,148494 ml ( range , 370 to 2,300 ml ) .
the mean effusion to serum ratio of red blood cell ( rbc ) concentration was 0.30.3 ( range , 0 to 1.4 ) and was>0.5 in 17% ( 14/84 ) of patients . in 3/84 patients ( 3.6% ) , rbcs were more concentrated in the pericardial fluid than in the serum , but there was no evidence of pcc - related hemorrhage .
interestingly , effusion recurred only in patients with adc - l or adenocarcinoma of other organs ( prostate , stomach , and colon ) .
pericardial effusions recurred in 30 patients ( 31% ) ; of these , 12 underwent urgent surgical drainage , 11 underwent repeated pcc with subsequent pericardial window operations , and 7 underwent repeated pcc without subsequent pericardial window operations . the mean follow - up time in these 30 patients was 9.7 months .
univariate analysis showed that adc - l , progressive disease after chemotherapy , and a lower proportion of polynuclear cells in the effusion fluid were significantly associated with time to recurrence .
positive cytology and the effusion to serum ratio of rbc tended to show associations with recurrence , but these associations did not reach statistical significance ( table 2 ) .
although , some patients received radiotherapy before ( 19% ) and/or after ( 8% ) pcc , radiotherapy did not affect recurrence of pericardial effusion ( table 2 ) . in multivariable analysis , adc - l ( hazard ratio [ hr ] , 6.6 ; 95% confidence interval [ ci ] , 1.9 to 22.3 ; p=0.003 ) and progressive disease ( hr , 4.3 ; 95% ci , 1.6 to 12.0 ; p=0.005 ) remained significant predictors for the recurrence of pericardial effusion . among lung cancer patients ,
those with adenocarcinomas were vulnerable to recurrence of effusion , whereas those with squamous cell carcinoma were not .
deaths were observed in 89 patients ( 91% ) . the probability of overall survival was 45% at 6 months and 26% at 12 months ( fig .
the probability of overall survival differed significantly by the type of primary cancer and response to chemotherapy .
breast cancer patients showed significantly better overall survival than did other groups ( vs. adl - l , p=0.02 ; vs.
2b ) , which may have been due to the lower rate of progressive disease in breast cancer patients ( 4/10 , 40% ) .
overall survival was better in patients with adc - l than those with sq - l or other cancers .
median survival after pcc was 6.8 months in patients with adc - l , 1.9 months in patients with sq - l , 16.5 months in patients with breast cancer , and 1.7 months in patients with other cancers .
the probabilities of survival 3 months after pcc in these 4 groups were 73% , 18% , 80% and 30% , respectively .
in addition , the survival rates 1 year after pcc were not so discouraging in patients with adc - l ( 26% ) and breast cancer ( 47% ) .
pcc - related major complications , including chamber laceration , injury to intercostal vessels , pneumothorax , ventricular tachycardia and bacteremia have been reported to be rare ( 14/1,127 , 1.2% ) , as has pcc - related mortality ( 1/1,127 , 0.09% ) ( 10 ) .
pcc is considered safe for patients with significant pericardial effusion , although it requires experience and skill and is only a temporary resolution .
therefore , pcc is quite effective for patients with rarely recurrent pericardial effusion , including those with idiopathic effusion , heart failure , uremia , tuberculosis , myocardial infarction , connective tissue disease , or with pericardial effusion due to well controlled diseases such as hypothyroidism ( 13 ) .
in contrast , recurrent malignant pericardial effusion is common , and the life expectancy of these patients is limited due to advanced cancer ( table 3 ) .
we found that the recurrence rate after pcc differed according to the type of primary cancer and response to chemotherapy . to our knowledge ,
the present study is the largest to date to assess long - term outcomes in patients with malignant pericardial effusion , and to show that long - term outcome depends on the type of primary cancer .
patients with malignant pericardial effusion from breast cancer showed longer survival times and lower recurrence rates than did other patients , suggesting that pcc may be an effective solution for patients with malignant pericardial effusion from breast cancer .
patients with malignant pericardial effusion from sq - l had a poor survival rate ( 18% at 3 months ) and there may be little chance of recurrence .
however , patients with adc - l had better survival rates than those with sq - l or other cancers , and pericardial effusion recurred in many patients with adc - l .
l was significantly associated with both recurrence and higher survival rate , probably due to a better response to chemotherapy .
thus , patients with adc - l may be good candidates for surgical drainage to avoid repeated pcc .
although most surgical drainages are performed under general anesthesia , they are quite effective in avoiding the recurrence of pericardial effusion ( 14 ) . another independent predictor of recurrence was progressive disease .
therefore , response to chemotherapy should be considered when selecting a therapeutic option for pericardial effusion .
malignant cells were more frequently observed in patient with recurrent effusions than those with non - recurrent effusion , but the difference was not statistically significant .
abnormal cytology has been reported to predict poor prognosis ( 8) . in that study ,
however , cytology analyses were not performed for all patients , and the proportion of patients with lung cancer , which had the highest positive cytology rate , was lower than in our study
. a lower proportion of polynuclear cells is indicative of higher proportions of other cells , including malignant cells , but these findings also did not correlate with recurrence .
the effusion to serum ratio of rbc concentration varied considerably and was even greater than in some patients without evidence of hemorrhage .
therefore , unlike patients with hemothorax , it may not be appropriate to differentiate among patients with pericardial fluid by their effusion to serum rbc ratio .
the overall recurrence rate of malignant pericardial effusion was 31% and the median survival after first pcc was 5.0 months , although survival times varied considerably , from 0 to more than 10 years .
recurrences of pericardial effusion occurred exclusively in patients with adenocarcinoma ( lung , prostate , stomach and colon ) , with adc - l and progressive disease being significant predictors of recurrence .
median survival after first pcc in patients with adc - l was -6.8 months , and this may be increased due to recent advances in chemotherapy .
these findings highlight the importance of appropriate management of malignant pericardial effusion , along with active treatment of the primary cancer .
surgical interventions , such as pericardial window operation , may be warranted in selected patients , especially those with adc - l , to prevent recurrent pericardial tamponade .
although this study is retrospective in design and involves patients from a single center , our findings suggest that the approach to malignant pericardial effusion should be individualized based on the type of primary cancer and patient response to chemotherapy .
Output:
| purposewe evaluated clinical outcomes after drainage for malignant pericardial effusion with imminent or overt tamponade.materials and methodsbetween august 2001 and june 2007 , 100 patients underwent pericardiocentesis for malignant pericardial effusion .
adequate follow - up information on the recurrence of pericardial effusion and survival status was available for 98 patients.resultsrecurrence of effusion occurred in 30 patients ( 31% ) , all of whom were diagnosed with adenocarcinoma .
multivariate analysis indicated that adenocarcinoma of the lung ( hazard ratio [ hr ] , 6.6 ; 95% confidence interval [ ci ] , 1.9 to 22.3 ; p=0.003 ) and progressive disease despite chemotherapy ( hr , 4.3 ; 95% ci , 1.6 to 12.0 ; p=0.005 ) were independent predictors of recurrence .
survival rates three months after pericardiocentesis differed significantly with the type of primary cancer ; the rates were 73% , 18% , 90% and 30% in patients with adenocarcinoma of the lung , squamous cell carcinoma of the lung , breast cancer and other cancers , respectively.conclusionrecurrence and survival of patients with malignant pericardial effusion are dependent on the type of primary cancer and response to chemotherapy .
patients with adenocarcinoma of the lung may be good candidates for surgical drainage to avoid repeated pericardiocentesis , but pericardiocentesis is considered effective as palliative management in patients with other cancers . |
PubmedSumm118295 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: plaque is known to be the initiating factor in the development of gingivitis when in contact with the gingival tissues and , therefore , plaque control represents the cornerstone of good oral hygiene practice .
the tools most commonly used in mechanical supragingival plaque control are the toothbrush ( manual or electric ) , floss , woodsticks , and interdental brushes . despite the availability of these various oral hygiene devices ,
evidence indicates that the degree of motivation and skill required for the effective use of these oral hygiene products may be beyond the ability of the majority of patients .
there are also large groups of individuals , such as the handicapped and elderly , for whom maintaining adequate oral hygiene can be an insurmountable problem . for these patients ,
a chemical plaque control approach is desirable to deal with the potential deficiencies of daily self - performed oral hygiene .
chlorhexidine gluconate , a bisbiguanide , is considered to date the most effective anti - plaque agent , but it is not a magic bullet and it also comes with certain side - effects , notably tooth staining , taste disturbance , enhanced supragingival calculus formation and less commonly , desquamation of the oral mucosa.[57 ] today 's dentists are practicing in an era where the patients are more concerned about both their oral health and their overall medical wellbeing .
thus , in the midst of growing evidence of the connection between oral health and whole body health , herbal medicines with their naturally occurring active ingredients offer a gentle and enduring way for restoration of health by the most trustworthy and least harmful way .
it is a comprehensive system , which uses various remedies derived from plants and their extracts to treat disorders and to maintain good health .
natural herbs like triphala , tulsi patra , jyestiamadh , neem , clove oil , pudina , ajwain and many more used either as whole single herb or in combination have been scientifically proven to be safe and effective medicine against various oral health problems like bleeding gums , halitosis , mouth ulcers and preventing tooth decay .
the major strength of these natural herbs is that their use has not been reported with any side - effects till date .
apart from this , all herbal mouthrinses do not contain alcohol and/or sugar , two of the most common ingredients found in most other over - the - counter products .
the problem of these ingredients is that the microorganisms that cause bad breath and halitosis love to feed on these ingredients , and release byproducts that cause halitosis .
thus , by use of a herbal mouthrinse , we can avoid these ingredients , which itself is one step forward towards better oral hygiene and better health . in the present study , a commercially available herbal mouthrinse ( herboral ) , prepared from a combination of ten complex natural herbs
the aim of the study was to compare the effectiveness of this herbal mouthrinse with chlorhexidine gluconate , which is considered to be the gold standard .
the study population consisted of dental students ( undergraduates and postgraduates ) of the national dental college and hospital , derabassi .
fifty healthy individuals ( 27 females and 23 males ; age range 18 to 35 years ; mean age 23.5 years ) were selected for participation in the study .
inclusion criteria included : dentition with 20 evaluable teeth ( minimum of five teeth per quadrant ) , no oral lesions , no severe periodontal disease ( no probing depth 5 mm ) , no removable prosthesis or orthodontic bands or appliances worn at the time of study .
persons with any past history of systemic illness or allergy to components of mouthrinse were excluded from the study .
all subjects were explained the purpose of the study and were asked to sign an informed consent .
the study was conducted from 5 april to 22 may 2010 in the department of periodontology and oral implantology , national dental college and hospital , derabassi .
the study was approved by the institutional ethical committee and was carried out in accordance with the principles originating in the declaration of helsinki , and consistent with good clinical practices .
the study was a randomized , two - group , parallel experiment as a de novo plaque accumulation model . at baseline ,
plaque was disclosed with a disclosing solution ( containing 2% erythrosine ) , and all participants received a thorough supragingival scaling and root planing to remove all plaque , stains and calculus .
this was performed using hand instruments , mechanical scalers , and rotating brushes and polishing paste . to ensure that all deposits had been removed , a second disclosing session was carried out to remove any remaining plaque .
subjects were randomly assigned to group a ( test ) or group b ( control ) . during this three - day experimental non - brushing period ,
subjects in the test group used herbal mouthrinse ( herboral ) , whereas those in the control group used 0.2% chlorhexidine ( chx ) gluconate mouthrinse .
all participants were instructed to refrain from using any other means of oral hygiene during the experimental period . written instructions regarding the use of mouthrinse were provided to every participant .
they were instructed to rinse twice daily with 10 ml of the allocated mouthrinse ( undiluted ) for 60 sec , after which they could spit .
after three days , when subjects reported to the clinic for plaque assessments , the dentition was disclosed with the disclosing solution .
subsequently , the level of plaque was assessed at six sites per tooth using the quigley and hein index modified by turesky et al . and further modified by lobene et al .
all measurements were carried out under the same conditions by the same investigator who was unaware of the allocation of the mouthrinse to the participants . finally , after plaque scoring , all subjects received a questionnaire designed to evaluate their attitudes with regard to the product used using a visual analog scale ( vas ) .
subjects marked a point on a 10-cm - long uncalibrated line with the negative extreme response ( 0 ) at the left end and the positive extreme response ( 10 ) at the right end .
a non - parametric test ( mann - whitney test ) was used to compare the differences between the two groups .
the study population consisted of dental students ( undergraduates and postgraduates ) of the national dental college and hospital , derabassi .
fifty healthy individuals ( 27 females and 23 males ; age range 18 to 35 years ; mean age 23.5 years ) were selected for participation in the study .
inclusion criteria included : dentition with 20 evaluable teeth ( minimum of five teeth per quadrant ) , no oral lesions , no severe periodontal disease ( no probing depth 5 mm ) , no removable prosthesis or orthodontic bands or appliances worn at the time of study .
persons with any past history of systemic illness or allergy to components of mouthrinse were excluded from the study .
all subjects were explained the purpose of the study and were asked to sign an informed consent .
the study was conducted from 5 april to 22 may 2010 in the department of periodontology and oral implantology , national dental college and hospital , derabassi .
the study was approved by the institutional ethical committee and was carried out in accordance with the principles originating in the declaration of helsinki , and consistent with good clinical practices .
the study was a randomized , two - group , parallel experiment as a de novo plaque accumulation model . at baseline ,
plaque was disclosed with a disclosing solution ( containing 2% erythrosine ) , and all participants received a thorough supragingival scaling and root planing to remove all plaque , stains and calculus .
this was performed using hand instruments , mechanical scalers , and rotating brushes and polishing paste . to ensure that all deposits had been removed , a second disclosing session was carried out to remove any remaining plaque .
subjects were randomly assigned to group a ( test ) or group b ( control ) . during this three - day experimental non - brushing period ,
subjects in the test group used herbal mouthrinse ( herboral ) , whereas those in the control group used 0.2% chlorhexidine ( chx ) gluconate mouthrinse .
all participants were instructed to refrain from using any other means of oral hygiene during the experimental period . written instructions regarding the use of mouthrinse were provided to every participant .
they were instructed to rinse twice daily with 10 ml of the allocated mouthrinse ( undiluted ) for 60 sec , after which they could spit .
after three days , when subjects reported to the clinic for plaque assessments , the dentition was disclosed with the disclosing solution .
subsequently , the level of plaque was assessed at six sites per tooth using the quigley and hein index modified by turesky et al . and further modified by lobene et al .
all measurements were carried out under the same conditions by the same investigator who was unaware of the allocation of the mouthrinse to the participants . finally , after plaque scoring , all subjects received a questionnaire designed to evaluate their attitudes with regard to the product used using a visual analog scale ( vas ) .
subjects marked a point on a 10-cm - long uncalibrated line with the negative extreme response ( 0 ) at the left end and the positive extreme response ( 10 ) at the right end .
a non - parametric test ( mann - whitney test ) was used to compare the differences between the two groups .
the mean plaque scores for the test and control groups at the end of the experimental period are summarized in table 1 .
there was a significant difference in plaque levels between the two groups . in the test group , the mean overall mouth plaque index score was 1.650.96 , compared to 1.430.20 in the control group .
comparison of mean plaque scores for group a and b the results of the questionnaire are shown in table 2 . with regard to taste of the product , duration of taste and alteration of taste perception ,
with respect to perception of plaque reduction and convenience , the differences between the two groups were statistically significant ( p<0.001 ) .
more specifically , subjects preferred the taste of herboral mouthrinse ( vas 6.88 ) over the taste of chx ( vas 6.40 , p=0.173 ) .
they also experienced that taste duration ( aftertaste ) in their mouth after rinsing with herboral ( vas 5.80 ) was much less than after rinsing with chx ( vas 5.04 , p=0.132 ) .
also , subjects found herboral more convenient to use ( vas 8.12 ) as compared to chx ( vas 7.04 , p<0.001 ) .
however , they considered chx ( vas 7.56 ) to be more effective in reducing plaque in the mouth compared to herbal mouthrinse ( vas 6.12 , p<0.001 ) . also , with respect to alterations in taste perception , chx ( vas 1.68 )
the present study was designed to determine the efficacy of a herbal mouthrinse ( herboral ) with 0.2% chlorhexidine gluconate . in this study , we used a three - day non - brushing model that allowed for plaque accumulation .
this design was previously used to assess the effect of various mouthrinses ( dona et al .
it was a convenient model to assess the plaque - inhibitory capacity of the test product per se and to determine its relative activity in relation to the well established action of chx .
using such a three - day plaque accumulation model provides a general indication of how the product in question would perform under actual conditions , insofar as significant plaque reduction is a prerequisite for the reduction in gingivitis .
herboral is a herbal preparation , made from ten natural herbs i.e. triphala ( three myrobalans ) , khadir chaal ( acacia catechu ) , bakul chaal ( mimusops elengi ) , tulsi patra ( ocimum sanctum ) , jyestiamadh ( glycyrrhiza glabra ) , maypal ( quercus infectonia ) , neem paan ( azadirachta indica ) , clove oil ( caryophyllus aromaticus ) , pudina ke phool ( metha spicate ) and ajwain ke phool ( apium gravcolens ) . because of its unique combination of herbs herboral possesses various beneficial properties like antiseptic ( due to the presence of tulsi , neem ) , antibiotic ( due to the presence of khadir chaal ) , analgesic ( by virtue of tulsi , ajwain , clove oil ) , astringent ( by virtue of bakul chaal , khadir chaal ) , and anti - inflammatory and immunity booster ( due to the presence of triphala )
also , maypal present in herboral can be used to cure gum diseases and whiten teeth , and jyestiamadh at the same time can be used against mouth ulcers . apart from these ,
herboral is a non - alcoholic preparation , with no added sugar , no artificial preservatives , no artificial flavors and colors and absolutely no side - effects .
kaim et al . , in a study , investigated the anti - microbial activity of herbal mouthrinse with listerine and 0.12% chlorhexidine gluconate ( peridex ) against s. mutans , s. sanguis and a. viscosus .
it was found that herbal mouthrinse produced the largest zones of microbial inhibition when compared to listerine against all the three bacteria tested . however , when compared to peridex , herbal mouthrinse produced larger zones of microbial inhibition against two of three bacteria tested , and a similar zone of inhibition against the third bacteria tested .
similarly , haffajee et al . , compared the effectiveness of herbal mouthrinse ( the natural dentist , medford , mass ) with 0.12% chlorhexidine gluconate and an essential oil mouth rinse .
it was found that herbal mouthrinse ( though less potent than chx ) was effective in inhibiting oral bacteria , predominantly actinomyces sp .
, e. nodatum , p. intermedia , p. melaninogenica , p. nigrescens and t. forsythia .
herbal mouthrinse was found to be a more effective antimicrobial agent than essential oil mouth rinse . in the present study
but in comparison to chlorhexidine gluconate , it has proven to be less effective . in the questionnaire , with regard to the subjects rating about the plaque reduction efficacy and convenience of use , significant differences between the two groups were found .
subjects preferred herboral for its taste , convenience of use and taste duration ( aftertaste ) in their mouth after rinsing , which may be attributed to the presence of natural herbs like tulsi , pudina etc .
however , chx rinsing can cause a number of local side - effects including extrinsic tooth and tongue brown staining , taste disturbance , enhanced supragingival calculus formation and , less commonly , desquamation of the oral mucosa .
these side - effects limit its acceptability to users and the long - term use of chx - containing mouthrinses .
on the other hand , herboral due to its natural ingredients does not cause any side - effects and can serve as a good alternative to patients who wish to avoid alcohol ( e.g. xerostomics ) , sugar ( e.g. diabetics ) , any artificial preservatives and artificial colors in their mouthrinses .
further , more research is necessary to gain greater insight into the level of plaque inhibition achieved with this herbal mouthrinse .
studies of longer duration , in which the product in question is compared to other control ( positive or negative ) or placebo products and where safety and microbiological parameters will be assessed , are necessary to establish the effectiveness of this product and its place among the other agents used for chemical support of daily mechanical plaque removal .
herboral mouthrinse was found to be a potent plaque inhibitor , though less effective than chlorhexidine gluconate .
however , it was preferred by the patients for its taste , convenience of use and taste duration ( aftertaste ) in their mouth after rinsing .
moreover , it can serve as a good alternative for patients with special needs as in case of diabetics , xerostomics , etc .
Output:
| background : the key to good oral health is hidden in nature .
natural herbs like neem , tulsi , pudina , clove oil , ajwain , triphala and many more has been used since ages either as a whole single herb or as a combination against various oral health problems like bleeding gums , halitosis , mouth ulcers and preventing tooth decay .
the aim of the study was to compare the efficacy of a commercially available herbal mouthrinse ( herboral ) with that of chlorhexidine gluconate which is considered to be a gold standard as an anti - plaque agent.materials and methods : a randomized , two - group , parallel study as a de novo plaque accumulation model was carried out on 50 subjects ( 23 males and 27 females ) . at baseline ,
all participants received a professional prophylaxis and were randomly assigned to the test ( herbal mouthrinse ) and control ( chlorhexidine gluconate ) group . on the following three days , all subjects rinsed with 10 ml of the allocated mouthrinse twice daily for 1 min .
they were asked to refrain from use of any other oral hygiene measures during the study . at the end of the experimental period ,
plaque was assessed and a questionnaire was filled by all subjects.results:chlorhexidine ( mean plaque score=1.65 ) inhibited plaque growth significantly more than the herbal mouthrinse ( mean plaque score=1.43 , p<0.001 ) .
the results of the questionnaire showed that herboral was preferred by patients for its taste , its convenience of use and taste duration ( aftertaste ) .
however , chlorhexidine was considered to be more effective in reducing plaque as compared to herboral.conclusion:herbal mouthrinse was found to be a potent plaque inhibitor , though less effective than chlorhexidine gluconate .
however , it can serve as a good alternative for the patients with special needs as in case of diabetics , xerostomics , and so on . |
PubmedSumm118296 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: odontoma belongs to a group of dentigerous tumors developing in jaw bones in stages of odontogenesis .
however , most authorities accept the view today that the odontoma represents a hamartomatous malformation rather than a neoplasm . according to definition of who , it is a congenital developmental defect , resulting from growth of completely differentiated epithelial and mesenchymal cells , in which all kinds of dental tissues occur .
similar to teeth , once fully calcified , they do not develop further . according to who classification ( 1992 ) ,
two type of odontomas are acknowledged .
compound odontomas malformations with representation of all dental tissues and exhibiting an orderly distribution in which numerous tooth - like structures known as denticles are found.complex odontomas malformations in which all dental tissues are likewise represented , but showing a disorganized distribution .
compound odontomas malformations with representation of all dental tissues and exhibiting an orderly distribution in which numerous tooth - like structures known as denticles are found
. complex odontomas malformations in which all dental tissues are likewise represented , but showing a disorganized distribution .
this lesion is composed of more than one type of tissue , and for this reason , has been called a composite odontoma .
accordingly we have
complex composite odontomacompound composite odontoma
complex composite odontoma compound composite odontoma other types of odontomas are sometimes also seen , presenting combinations of the characteristics of compound and complex odontomas ( i.e. mixed odontomas ) , while in other cases the lesions can not be assigned to either of the two types ( cystic adenomas ) .
although the etiology of this malformation is not yet known , there is some evidence to show that there is a genetic basis for both complex and compound composite odontomas .
heredity is a possible factor and persistent lamina could be the hidden inherited developmental anomaly .
other theories have been proposed , including local trauma , infection , family history , and genetic mutation .
a 14-year - old , healthy female patient reported to the department of orthodontics , with the chief complaint of unerupted upper front tooth .
intraoral examination revealed unerupted maxillary right central incisor associated with a mild asymptomatic swelling which was slightly mobile on palpation , butwith no inflammation of the overlying mucosa [ figure 2 ] .
( a and b ) pre - treatment extraoral photographs pre - treatment intraoral photographs intra - oral periapical , occlusal , and panoramic radiographs revealed the presence of the right central incisor with a radiopaque mass present incisally , thereby obstructing its eruption [ figure 3 ] . on the basis of clinical and radiographic findings ,
( a , b and c ) pre - treatment radiographs complete excision of the odontoma under local anesthesia and orthodontic treatment for alignment of the impacted incisor was planned .
accordingly , an 0.018 mbt prescription preadjusted edgewise appliance was bonded on the upper arch .
there was adequate space for the alignment of the impacted central incisor in the arch .
after the initial leveling and aligning , surgical removal of the odontoma was done under local anesthesia . a mucoperiosteal flap extending from the labial surface of right canine to the left canine was reflected and the calcified mass was exposed [ figure 4 ] .
the calcified structure measured 13 mm mesiodistally and 6 mm incisocervically [ figure 5].the specimen was sent for histopathological examination which confirmed it as a complex composite odontoma with haphazardly arranged hard tissues of tooth like dentin and globules of cementum - like material [ figure 6 ] .
the layer of bone covering the labial surface of the impacted right central incisor was removed and the crown was exposed .
surgical exposure of the odontoma photomicrograph shows mixture of dental tissues arranged haphazardly [ h and e stain , 16 ] a begg 's bracket with a ligature wire extending was bonded onto the impacted incisor [ figure 7 ] .
the ligature wire extending from the bracket bonded on the impacted incisor was tied to the archwire thereby causing forced extrusion of the impacted incisor .
0.012 nickel titanium wire was engaged piggyback on the erupting incisor with a 0.016 0.022 stainless steel base archwire .
begg 's bracket with ligature wire extending bonded on the impacted incisor six weeks later the impacted tooth was properly aligned in the arch .
the begg 's bracket was replaced with a 0.018 mbt prescription bracket , and final finishing and detailing was achieved [ figure 8].the total active treatment duration was 18 months .
post - treatment intraoral photograph ( a and b ) post - treatment extraoral photographs ( a , b , and c ) post - treatment radiographs
the term odontoma , by definition alone , refers to any tumor of odontogenic origin . through usage ,
however , it has come to mean a growth in which both the epithelial and the mesenchymal cells exhibit complete differentiation , with the result that functional ameloblasts and odontoblasts form enamel and dentin .
paul broca was the first person to use the term odontoma in 1867 .
odontomas are hamartoma arising during normal tooth development , and they often reach a fixed size and are composed of mature enamel , dentin , cementum , and pulp tissues .
there is no gender predilection and an odontoma can occur at any age but most commonly occurs in the second decade of life .
of all the odontomas combined , 67% occurred in the maxilla and 33% in the mandible .
the compound odontoma has predilection toward the anterior maxilla ( 61% ) , whereas only 34% of complex odontomas occurred here .
in general , complex odontoma had a predilection for the posterior jaws ( 59% ) and lastly the premolar area ( 7% ) .
interestingly , both types of odontoma occurred more frequently on the right side of the jaw than on the left ( compound 62% , complex 68% ) .
the complex odontoma occurs predominantly in the second and third decades of life and the majority arises in the molar region of the mandible .
they are often associated with the crowns of unerupted teeth and occasionally may take the place of a tooth . for these reasons
they may be discovered , when small , as incidental findings when investigating a patient with a tooth missing from the dental arch .
as the lesion enlarges it usually presents as a painless , slow - growing expansion of the jaw , but may become infected and present with pain , particularly if it communicates with the mouth .
radiographically , a fully formed complex odontoma appears as a radiopaque lesion , sometimes with a radiating structure , but in the developing stages it shows as a well - defined radiolucent lesion in which there is progressive deposition of radiopaque material as calcification of the dental tissues proceeds .
the mature lesion is surrounded by a narrow radiolucent zone analogous to the pericoronal space around unerupted teeth .
histologically , the fully developed complex odontoma consists of a mass of disorderly arranged , but well - formed enamel , dentine , and cementum .
dentine forms the bulk of the lesion and , on surfaces not covered by enamel or cementum , is in contact with tissue resembling the normal pulp . in decalcified sections ,
the areas occupied by enamel appear as empty spaces except where enamel maturation is incomplete when the spaces contain remnants of enamel matrix with a fibrillar appearance .
the developing complex odontoma will contain varying amounts of soft tissue which include odontogenic epithelium and mesenchyme , and structures resembling enamel organs .
developing lesions show histological features of all stages in odontogenesis and may be difficult to differentiate from ameloblastic fibroma and ameloblastic fibro - odontoma .
, the prognosis of these tumors is very favorable , with a scant tendency toward relapse .
Output:
| odontomas are a heterogeneous group of jaw bone lesions , classified as odontogenic tumors which usually include well - diversified dental tissues .
odontomas are the most common type of odontogenic tumors and generally they are asymptomatic . two types of odontomas are described : compound and complex based on either the appearance of well - organized tooth - like structures ( compound odontomas ) or on a mass of disorganized odontogenic tissues ( complex odontomas ) .
compound odontomas have a predilection for the anterior maxilla , whereas complex odontomas have a predilection for the posterior mandible
. odontomas frequently interfere with eruption of teeth leading to their impaction .
this is a case report of a 14-year - old girl with an unerupted maxillary right central incisor due to a complex composite odontoma a rare occurrence in anterior maxilla
. surgical excision of the odontoma and orthodontic treatment to get the impacted maxillary right central incisor into alignment is discussed . |
PubmedSumm118297 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: preeclampsia is the leading cause of pregnancy - associated maternal and perinatal mortality and morbidity worldwide .
several mechanisms have been proposed in preeclampsia , including ( 1 ) genetics and epigenetic imprinting ; ( 2 ) increased uteroplacental ischemia / hypoxia ; ( 3 ) angiogenic imbalances characterized by an excess of antiangiogenic factors ; ( 4 ) increased trophoblast apoptosis / necrosis ; ( 5 ) an exaggerated maternal inflammatory response to injured trophoblast cells ; and ( 6 ) immune maladaptation .
shallow trophoblast invasion and inadequate artery remodeling early in pregnancy may underlie subsequent placental hypoperfusion , hypoxia , or ischemia , which are critical components in the pathogenesis of preeclampsia .
maternal responses are associated with release of placenta - derived circulating antiangiogenic molecules such as soluble fms - like tyrosine kinase 1 ( sflt-1 or the soluble vegf receptor-1 ) , soluble endoglin ( seng ) , the angiotensin ii type-1 receptor autoantibody ( at1-aa ) , and proinflammatory cytokines such as tumor necrosis factor- ( tnf- ) alpha and interleukin- ( il- ) 6 .
the loss of endothelial control of vascular development by these factors in turn acts in concert to cause hypertension and decrease renal function during pregnancy .
placenta - derived circulating factors could also stimulate proinflammatory cells to produce cytokines and chemokines , including il-1beta , il-2 , il-10 , il-12 , il-13 , il-18 , granulocyte - colony stimulating factor ( g - csf ) , interferon- ( ifn- ) gamma , monocyte chemoattractant protein-1 ( mcp-1 ) , and tnf - alpha , demonstrating that preeclampsia is associated with an overall proinflammatory systemic environment [ 46 ] .
although a normal pregnancy enhances a state of the t helper 2 ( th2 ) type anti - inflammatory responses , preeclampsia exhibits a shift towards th1 [ 4 , 7 ] and th17 type immunity .
the discovery of biologically functional numerous proinflammatory , anti - inflammatory , and immunomodulating proteins , cytokines , and chemokines in adipocytes emphasizes the role of the adipose tissue as a highly active immune response , endocrine and metabolically important organ that modulates energy expenditure , insulin resistance , and glucose homeostasis [ 9 , 10 ] .
adipose tissue is capable of contributing to this inflammation by its production of inflammatory mediators , which appears to be a key step in the development of the preeclampsia - associated inflammatory state . here
, we aim to investigate whether preeclampsia sera could modulate the inflammatory and adipogenic activities in visceral adipose tissue , using new method of the tissue culture .
our data suggest a revised paradigm for restoring host defense and preventing inflammatory sequelae in adipose tissue in women affected with preeclampsia .
the study was approved by the local ethics committee at nara medical university , and all participants provided written informed consent .
visceral fat ( omentum ) was taken from two women at reproductive age ( 36 years old and 40 years old ) who underwent prophylactic omentectomy on ovarian cancer operation .
the tissue was immediately suspended in cold sterile saline , transported to the laboratory , washed several times in sterile phosphate buffered saline to remove excess blood , and dissected to twenty pieces of approximately 1.5 g. next , we included severe preeclampsia ( pe ) patients of with a prepregnancy body mass index ( bmi ) before pregnancy was under less than 25 kg / m with gestational age - matched normal pregnant women at 28 weeks gestation or later .
all subjects of them were eastern asian origin , and none of the subjects were taking any medication or showed evidence of any metabolic disease or other complications beside pe .
severe pe was defined as new onset and diagnosed based on two consecutive measurements of diastolic and systolic blood pressure measurements , diastolic blood pressure greater than or equal to 110 mmhg , or systolic blood pressure 160 mmhg , respectively , with urine protein over 2 g / day , occurring diagnosed after 20 weeks of gestation .
all subjects had provided serum samples available for analysis and did not have gestational diabetes mellitus , thyroid malfunction , or other complications .
briefly , 5 women with severe preeclampsia with bmi ranging from 22.6 to 25.2 kg / m at test and 5 age- and bmi - matched control pregnant women were recruited .
characteristics of the subjects serum taken were shown in table 1 . in this study , we established new method for bottom culture of whole adipose tissue , not only adipocyte but other cells and connective tissue as well . dissected visceral fat was captured immediately on the bottom of the 24 well plastic plate ( becton , dickinson & co. , franklin lakes , nj ) with 99.5% medium - containing hydrogel ( puramatrix , becton , dickinson & co. ) after provider 's manual . after enough fiber construction , culture medium ( eagle 's minimal essential medium , sigma - aldrich co. , st .
louis , mo ) without any serum was added and changed for three times to adjust medium 's ph as homeostatic range .
next day , serum from pe or healthy pregnant subjects ( n = 5 each ) was added in 1 : 10 order in the wells in duplicate .
the human serum concentrations in the medium were decided from former report for bovine serum concentrations in the culture medium treating mice adipose tissue and separated cells .
after 24 hours of culture under incubator of 37c/21% o2/5% co2 condition , medium and the tissue were collected .
the purity of mrna was confirmed with od260/280 ( range : 2.072.11 ) and rna integrity number ( range : 7.58.3 ) .
and then , 370 genes in total mrna were analyzed with quantitative rt - pcr ( inflammatory response & autoimmunity gene set , rt2 profiler pcr array , qiagen inc .
results of the quantitative rt - pcr were shown as fold change on pe serum - added adipose tissue against normal serum added tissue after being normalized with internal control gene ( beta-2-microglobulin ( b2 m ) , hypoxanthine phosphoribosyltransferase 1 ( hprt1 ) , ribosomal protein l13a ( rpl13a ) , glyceraldehyde-3-phosphate dehydrogenase ( gapdh ) , actin , beta ( actb ) ) expression .
the criteria for selecting differentially expressed genes were preset as at least 2-fold difference in either direction or genes with statistical significance ( p < 0.05 , unpaired t - test ) .
japan ) on each gene with student 's t - test comparing pe and the normal ( n = 5 each ) , with p < 0.05 indicating a statistically significant difference .
thirty genes were identified with altered expression of at least 2-fold or statistical significance ( p < 0.05 , unpaired t test ) in adipose tissues treated with preeclampsia sera ( figure 1 , table 2 ) . among these genes ,
the greatest up- or downregulation was observed in genes involved in immune response , oxidative stress , and insulin and lipid metabolism , any of which may contribute to the molecular mechanisms underlying insulin resistance and adipogenesis in preeclampsia ( table 3 ) .
our results show that exposure of preeclampsia sera increased or decreased the expression of several genes and affected the functional pathways , including ( 1 ) energy balance , obesity , lipid metabolism , and adipogenesis , ( 2 ) insulin resistance and glucose tolerance , ( 3 ) host defense , redox balance , detoxification , and oxidative stress , and ( 4 ) inflammation , immune response , and th1/th2 type cytokine balance .
microarray analysis identified 11 upregulated and 2 downregulated immune response - related genes in preeclampsia sera - stimulated adipose tissue .
rt - qpcr confirmed changes in expression of th1 type cytokine - related genes ( il18 , cxcl10 , and ik ) and th2 type cytokine - related genes ( bcl6 , ccl28 , ltb4r , and il27 ) , with th2/th1 predominance .
differential expression of th17-related cytokine ( il36 g ) and other immune responsive genes ( mefv , ppbp , ccl23 , siglec1 , and cd97 ) was also confirmed by rt - qpcr and independently validated .
oxidative stress signaling genes were also differentially expressed . among oxidative stress - related genes , 7 genes
( prdx5 , mif , cd74 , nfe2l1 , csf3r , tlr4 , and tlr9 ) were induced while no genes were suppressed .
rt - qpcr confirmed aberrant expression of genes involved in inflammation and stress response ( tlr4 and tlr9 ) and also genes involved in host defense ( prdx5 , mif , cd74 , nfe2l1 , and csf3r ) , suggesting that preeclampsia sera suppress the tlr4/9-dependent excess oxidative stress in adipose tissue .
our results indicated that 6 upregulated genes ( ifngr2 , nfx1 , il10ra , sdcbp , epor , and csf2ra ) and 4 downregulated genes ( tlr3 , fos , prl , and osm ) were involved in glucose and lipid biosynthesis ( table 3 ) .
the amount of insulin resistance genes ( ifngr2 and nfx1 ) may correlate with the preeclampsia syndrome , which is regarded as a key feature of preeclampsia genesis .
in contrast , four genes such as il10ra , tlr3 , fos , and prl demonstrate strong inverse correlations with insulin resistance .
we also identified four genes associated with adipogenesis , indicating that the sdcbp and osm genes stimulate adipogenesis , while epor and csf2ra significantly reduce it .
adipose tissue produced several genes in the homeostasis of glucose and lipid metabolism as well as adipogenesis .
on the one hand , preeclampsia sera expectedly enhance inflammatory activities , including immune response , oxidative stress , insulin resistance , and adipogenesis , in adipose tissue .
on the other hand , they can also suppress inflammation through upregulation of th2 cytokine predominance , antioxidative stress , and insulin sensitivity .
these data collectively support that visceral fat in women affected with preeclampsia might promote and strongly suppress the inflammatory and adipogenic activities .
preeclampsia is strongly associated with abnormal placentation characterized by shallow trophoblast invasion and incomplete spiral artery remodeling , which causes elevated amounts of proinflammatory cytokines , chemokines , adhesion molecules , and growth factors .
chronic inflammation and endothelial injury might play a central role in the pathogenesis of preeclampsia , but the underlying pathophysiology is still unclear .
we demonstrate significant differences in gene expression of adipose tissue treated with sera from nonobese preeclampsia patients and age- and bmi - matched controls .
adipose tissue might be contributing to modulation of the potential functional genes for inflammation and immune response ( th1/th2 predominance ) , oxidative stress , insulin resistance , and adipogenesis ( table 3 ) .
the altered gene products in adipose tissue lead to suppression of preeclampsia - associated inflammation which in turn is responsible for excessive production of th2 type cytokines and host defense molecules , as well as modulation of adipogenesis and insulin resistance .
these data allow us to hypothesize that when chronic inflammation is consistently present , anti - inflammation remains active in adipose tissue . in an early event of placental dysfunction ,
newly synthesized inflammatory cytokines and chemokines drive association of inflammation and oxidative stress , leading to insulin resistance and adipogenesis .
the second wave of preeclampsia supports sustained expression of a subset of inhibition of oxidative stress , insulin resistance , and adipogenesis in adipose tissue , several of which play important roles in preeclampsia .
pregnancy is associated with th2 type cytokine predominance or downregulation of the th1 response , which is more pronounced at the maternal fetal interface .
th1 cells produce an array of proinflammatory cytokines including ifn - gamma , il-2 , and tnf - alpha .
the majority of publications report on aberrant th1/th2 balance and upregulation of the th17 immune response in preeclampsia .
we for the first time confirmed that preeclampsia sera could induce changes of th1/th2 cytokine balance with a predominance of th2 immunity in adipose tissue , suggesting the role of immunological mechanisms engaged in preeclampsia .
after the establishment of preeclampsia , predominance might be shifted from th1 cells to th2 cells in adipose tissue .
secondly , altered expression was observed in several defense and stress response genes associated with oxidative stress , which is involved in regulating host defense .
it appears that preeclampsia is a disease of exaggerated innate immunity that may be mediated by toll - like receptors ( tlrs ) .
previous studies have also identified immune - system alterations associated with the origin of preeclampsia as well as genetic associations between tlrs and preeclampsia : tlr2 and tlr4 snps appear to alter susceptibility to developing preeclampsia .
this study showed that preeclampsia sera stimulate expression of tlr4 and tlr9 in adipose tissue .
oxidative stress can in turn induce and maintain inflammatory responses mainly through a tlr4-dependent nuclear factor- ( nf- ) kappab pathway .
exaggerated placental cell injury and death result in the release of mitochondrial dna , which activates tlr9 to produce systemic maternal inflammation from adipocytes , and subsequent vascular dysfunction that may in turn lead to preeclampsia .
the tlr4 and tlr9 activation in adipose tissue may worsen the situation of patients with preeclampsia .
in contrast , we identified increased expression levels of 5 genes such as prdx5 , mif , cd74 , nfe2l1 , and csf3r , which play an essential role in the host immune response or the host defense against several pathogens or oxidative stress .
it is possible that increased expression of these genes in adipose tissue could strengthen host defense by protecting host cells from oxidative insults .
thirdly , genes involved in insulin resistance are differentially expressed in adipose tissue stimulated with preeclampsia sera .
it has been established that women with preeclampsia have an increased risk of developing diabetes .
our data demonstrated significant increases in the expression levels of several lipid metabolism - related genes , including ifngr2 and nfx1 , which modulate lipid metabolism to promote insulin resistance .
in contrast , we identified decreased expression of selected genes involved in insulin resistance in adipose tissue , including tlr3 , fos , and prl , which could induce insulin sensitivity .
thus , preeclampsia sera might contribute to insulin sensitivity by positive and negative regulation of the expression of diverse genes . finally , adipose tissue is a highly active endocrine and metabolically important organ , with the ability to modulate glucose homeostasis , energy expenditure , lipid metabolism , and peripheral inflammation .
our results identified increased expression of selected genes involved in lipid metabolism , including sdcbp , epor , and csf2ra .
increased expression of sdcbp in adipocytes likely contributes to adipogenesis , whereas epor and csf2ra are negatively involved in adipogenesis [ 2123 ] .
epor regulates energy homeostasis and mitigates adipogenesis via the metabolism coregulators peroxisome proliferator - activated receptor alpha ( pparalpha ) and sirtuin 1 ( sirt1 ) [ 2123 ] .
furthermore , csf2ra is a receptor for crf2 , also known as gm - csf , which is related to a central action to reduce food intake and body weight , since knockout mice are more obese and hyperphagic than wild - type mice .
osm inhibits the terminal differentiation of adipocytes through the ras / extracellular signal - regulated kinase ( erk ) and signal transducer and activator of transcription ( stat ) 5 signaling pathways [ 25 , 26 ] .
the last decade preeclampsia biology revealed that the early molecular changes affect inflammation , immune response , angiogenesis , oxidative stress , matrix remodeling , and lipid biosynthesis .
the tlr signaling pathway induces inflammation , which in turn modulates insulin resistance and adipogenesis [ 28 , 29 ] .
inflammation , oxidative stress , insulin resistance , and adipogenesis , secondary to the influx of proinflammatory cytokines and chemokines during placental dysfunction , are involved in the progression of preeclampsia .
preeclampsia serum priming in adipose tissue leads to enhanced th1 inflammation , oxidative stress , and insulin resistance , and simultaneously antiadipogenic induction may result in enhanced expression of th2 predominance , antioxidative stress , and insulin sensitivity .
this study limits the ability to ascribe causality to the association between adipocytes and their gene expression .
adipose tissue used in this study contains adipocytes , macrophages , t lymphocytes , other immune cells , vasculature , and stromal cells .
further study will be conducted to confirm the anti - inflammatory effects of preeclampsia serum and to elucidate its mechanism of action in adipocytes in culture . in conclusion , this study supports the hypothesis that there are at least two distinct phases of preeclampsia development : the initial wave of inflammatory activation in modulating immune response , oxidative stress , insulin resistance , and adipogenesis would be followed by the second big wave of anti - inflammation in adipose tissue .
finally , adipose tissue may have an ability to suppress inflammation , immune response , oxidative stress , and metabolic signals to protect host from excessive inflammation .
the primary event in the molecular sequence leading to chronic inflammation is placental dysfunction in preeclampsia .
increased inflammation likely contributes to adipokine dysregulation , adipogenesis , and insulin resistance in adipose tissue .
this initial wave of the systemic inflammation would be followed by the second big wave of subsequent production of anti - inflammatory mediators by adipose tissue , which then suppresses oxidative stress , insulin resistance , and metabolic dysfunction .
Output:
| objectives .
the pathophysiology of preeclampsia is characterized by abnormal placentation , an exaggerated inflammatory response , and generalized dysfunction of the maternal endothelium .
we investigated the effects of preeclampsia serum on the expression of inflammation - related genes by adipose tissue .
materials and methods .
visceral adipose tissue was obtained from the omentum of patients with early ovarian cancer without metastasis .
adipose tissue was incubated with sera obtained from either five women affected with severe preeclampsia or five women from control pregnant women at 37c in a humidified incubator at 5% co2 for 24 hours .
370 genes in total mrna were analyzed with quantitative rt - pcr ( inflammatory response & autoimmunity gene set ) .
results .
gene expression analysis revealed changes in the expression levels of 30 genes in adipose tissue treated with preeclampsia sera .
some genes are related to immune response , oxidative stress , insulin resistance , and adipogenesis , which plays a central role in excessive systemic inflammatory response of preeclampsia .
in contrast , other genes have shown beneficial effects in the regulation of th2 predominance , antioxidative stress , and insulin sensitivity . conclusion . in conclusion ,
visceral adipose tissue offers protection against inflammation , oxidative insults , and other forms of cellular stress that are central to the pathogenesis of preeclampsia . |
PubmedSumm118298 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: pituitary adenomas are one of the most common intracranial neoplasms . questions regarding their prevalence in the general population were recently addressed by a large cross - sectional study in the province of lige , belgium , which revealed 94 cases of pituitary adenomas per 100,000 inhabitants ( 1 ) .
similar findings were later confirmed in banbury , uk ( 2 ) . despite being generally benign , pituitary adenomas still exert significant influence as they combine symptoms of hormonal dysfunction with signs of local compression , and may require complex and costly management and long - term follow - up .
pituitary adenoma formation is generally considered to be the result of the clonal expansion of a single mutated cell ( 3 ) and molecular studies have identified a number of genetic and epigenetic abnormalities that may have a possible causative or facilitatory role in pituitary tumorigenesis .
these include somatic mutations in the gsp oncogene , overexpression of the pituitary tumor transforming gene ( pttg ) , disruptions in cell cycle regulation and intracellular signaling pathways and , rarely , mutations of classic oncogenes ( 4),(5 ) .
the vast majority of pituitary adenomas , however , arise sporadically , and inherited germline mutations in different genes are few in number , accounting for approximately 5% of all pituitary tumors ( 6 ) .
traditionally , familial pituitary adenomas have been associated with some multiple neoplasia syndromes , including multiple endocrine neoplasia type 1 ( men 1 ) , carney complex , and the newly defined multiple endocrine neoplasia type 4 . by the end of the 20th century , however , only occasional cases of non - syndromic familial pituitary tumors were reported , mostly acromegaly ( 7 ) .
the first single - center study to specifically scout for cases of familial pituitary adenomas unrelated to men 1 and carney complex was performed in lige , belgium in the 1990s , and led to the identification of an initial cohort of 27 patients ( 8) . reports from the same center confirmed the condition as a new clinical entity , and the term familial isolated pituitary adenomas ( fipa ) was adopted ( 9)(11 ) .
its definition expanded the search internationally , and by 2011 more than 200 affected families had been reported ( 12),(13 ) .
fipa is currently considered to account for around 23% of pituitary adenomas ( 14 ) .
the syndrome of fipa is defined as familial presentation of any type of pituitary adenoma in the absence of clinical and genetic evidence for men 1 and carney complex ( 9),(11),(14),(15 ) . following the initial description of the condition ,
the clinical characteristics of a large international cohort of 64 families comprising more than 140 patients from 22 tertiary referral centers were reported in 2006 ( 14 ) .
genealogical information suggested that fipa is inherited in an autosomal dominant pattern with variable penetrance .
based on the tumor phenotype in the individual families , fipa can be divided into two almost equal subgroups : homogeneous , when all affected family members experience the same adenoma type , and heterogeneous , with different pituitary tumors within the family .
prolactinomas and somatotropinomas comprise more than 70% of all tumors , and although in heterogeneous fipa all types of tumors can be seen , there is at least one prolactin- or growth hormone - secreting adenoma in almost all affected families .
females tend to be more frequently affected ( 62% ) , which is not unexpected given the fact that prolactinomas are the most common phenotype overall .
prolactin - secreting adenomas comprise 40% of all fipa tumors , and their characteristics principally match their sporadic counterparts in terms of sexual predisposition , age at presentation , and proportion of microadenomas . in heterogeneous fipa families , however , these tumors exhibit more aggressive behavior , with significantly higher rates of suprasellar expansion and cavernous sinus invasion compared with sporadic prolactinomas . growth hormone - secreting adenomas account for 30% of fipa tumors , and somatoprolactinomas are responsible for another 7% .
they are equally distributed between homogeneous and heterogeneous families but , unlike fipa prolactinomas , somatotropinomas are more aggressive when occurring in a homogeneous setting . in homogeneous fipa , acromegaly is usually diagnosed 10 years earlier , with tumors more frequently displaying extrasellar growth , compared with heterogeneous relatives and sporadic populations ( 14 ) .
acromegaly in patients with fipa also appears to respond poorly to somatostatin analog therapy ( 16 ) .
non - secreting adenomas , predominantly associated with heterogeneous families , arise in 13% of patients with fipa and are also characterized by more aggressive evolution , being diagnosed earlier and exhibiting more invasive properties than sporadic adenomas .
gonadotropinomas , corticotropinomas , and thyrotropinomas are rare , and account for 4% , 4% , and 1% of fipa tumors , respectively .
they are usually associated with other adenoma types in heterogeneous families , although individual families with homogeneous presentation have been reported ( 14 ) .
the descendants in fipa families with multiple affected generations are diagnosed considerably earlier than their parents / grandparents .
the elucidation of the responsible genetic causes of fipa started with the identification of loss of heterozygosity in locus 11q13 in relatives with familial acromegaly who lacked mutations in the men1 gene ( 17),(18 ) .
separate research for potential genes in a finnish cohort of patients with familial pituitary tumors revealed inactivating mutations in the gene for aryl - hydrocarbon receptor interacting protein ( aip ) ( 19 ) .
the causative role of aip in fipa was confirmed with the discovery of several new germline mutations in a large series of 73 families ( 20 ) .
loss of heterozygosity in tumor tissues suggests a tumor suppressor function for aip , but the exact molecular mechanisms leading to pituitary tumorigenesis are not known .
homozygous aip knockout mice die in the early embryonic period as a result of severe cardiovascular abnormalities , suggesting that aip may play a role in cardiovascular development ( 21 ) .
heterozygous aip animals , however , develop a phenotype that is very similar to human pituitary disease with the majority of the mice presenting with aggressive somatotropinomas ( 22 ) .
the aip gene consists of six exons and codes for a 330-amino - acid protein , the sequence of which is highly conserved between different species .
it shares a structural homology with immunophilin proteins because of the presence of a peptidyl - prolyl cis - trans isomerase - like domain , but does not function as such ( 23),(24 ) .
protein interactions , mediated through its c - terminal , which houses three tetratricopeptide repeats and a final -helix . among the first identified partners of aip is the aryl hydrocarbon receptor ( ahr ) , a ligand - inducible transcription factor that modulates cellular responses to various xenobiotic toxins , such as dioxins , as well as some endogenous compounds such as camp ( 25 ) . in the absence of ligands
, the ahr binds to two molecules of the 90-kda heat - shock protein , acting as chaperone , and to aip and p23 proteins , acting as co - chaperones , to form a multiprotein complex in the cytoplasm ( 26 ) .
the activation of this complex by its xenobiotic ligand results in nuclear translocation , where ahr binds to the aryl hydrocarbon receptor nuclear translocator and promotes the transcription of specific genes coding various drug metabolizing enzymes as well as other proteins ( 24 ) .
the effect of aip on the functional status of ahr is still a matter of debate because conflicting results have been reported , but it seems that it maintains the stability of the complex by protecting ahr from ubiquitin - dependent degradation ( 27 ) . reduced aip levels in aip - mutated pituitary adenomas are associated with a lack of nuclear ahr immunostaining , suggesting that down - regulation of ahr may be involved in pituitary tumorigenesis ( 28 ) .
consistent with this finding , overexpression of wild - type aip in pituitary and hepatic cell cultures slows down cell proliferation ( 16 ) .
aip is also thought to interact with two subtypes of phosophodiesterases : pde4a5 and pde2a ( 29),(30 ) .
these enzymes participate in the regulation of numerous signaling cascades that use camp as a second messenger , including the growth hormone - releasing hormone receptor pathway in pituitary cells .
disruptions in signal transduction , which lead to abnormally high camp concentrations , are associated with pituitary hyperplasia and adenoma formation in some conditions , such as carney complex and mccune albright syndrome ( 31 ) .
aip binding to pde4a5 reduces its catalytic activity , and it is not clear if this interaction plays a role in pituitary tumorigenesis , as loss of aip would presumably result in low camp levels .
the interaction with pde2a does not alter the enzyme activity , and the local reduction of camp may impede the nuclear translocation of the ahr complex ( 30 ) . recently ,
aip was shown to interact with the tyrosine kinase receptor , encoded by the ret proto - oncogene , and the inhibitor of apoptosis , survivin , and therefore to have a potential role in cell cycle regulation .
binding to survivin maintains its stability and promotes cell survival by elevating the anti - apoptotic threshold . on the other hand ,
the interaction with ret prevents the formation of the aip survivin complex , resulting in subsequent survivin degradation and increase in apoptosis ( 32 ) .
these effects , however , are contrary to the proposed tumor - suppressor role of aip . apart from stabilizing the ahr complex , aip may also bind to a set of nuclear receptors including peroxisome proliferator - activated receptor , the glucocorticoid receptor , and -thyroid hormone receptor 1 . furthermore , a role has been proposed for aip in virus - induced tumorigenesis as a potential partner of hepatitis b virus x antigen and epstein barr virus - encoded nuclear antigen 3 ( 24 ) . over 50 different mutations in the aip sequence have been identified in fipa families from all over the world , and these mutations are spread through the entire length of the gene ( 23),(33 ) .
most of them affect the c - terminal end and the tetratricopeptide repeat motifs supporting their essential role in aip function .
nonsense and frameshift mutations lead to premature stop codons with a resultant truncated protein , whereas missense mutations tend to affect the tetratricopeptide repeat domains and the terminal -helix .
whole gene deletions have also been identified , suggesting the use of a multiple ligation - dependent probe amplification method for patients with fipa in whom sequencing fails to identify abnormalities ( 34),(35),(36 ) .
, r271 , and r81 have been reported in independent families with fipa , indicating possible hotspots .
no genotype phenotype correlations have been observed to date in patients with aip - mutated fipa ( 37 ) .
mutations in the aip gene , however , are found in only approximately 25% of all patients with fipa , and in 4050% of patients in the subgroup with acromegaly from homogeneous fipa families ( 12 ) .
the genetic cause for the rest of the cases is still unknown , but several other loci , such as 2p16 , 3q28 , 4q32 , 8q12 , 19q13 , and 21q22 , may be involved in the development of the syndrome although no particular genes have been identified ( 38 ) . on the other hand ,
the penetrance of aip mutations is estimated to be approximately 30% in the largest reported families ( 15),(19),(35),(39 ) , suggesting the possible existence of genetic or environmental modifying factors ( figure 1 ) .
patients with aip - related pituitary adenomas have also been shown to exhibit some specific clinical features that differentiate them from patients with wild - type aip alleles ( 37 ) .
in contrast to the overall female predominance in fipa , male sex is significantly more common in the subgroup of patients harboring aip mutations .
all types of pituitary tumors may occur in association with mutated aip , but growth hormone - secreting adenomas largely predominate , arising in about 80% of patients , and co - secretion of prolactin is observed in more than 50% of these . a direct comparison of 75 patients with aip - mutated somatotropinomas with 232 genetically negative control subjects with acromegaly revealed that aip anomalies are associated with much earlier onset and more aggressive evolution of the disease ( table 1 ) .
invasive macroadenomas are manifested in childhood or adolescence in more than half of patients with aip mutations , and almost a third of patients with somatotropinomas present with gigantism .
disease control is also harder to achieve and maintain , because somatostatin analogs are less effective for lowering growth hormone and insulin - like growth factor levels and inducing tumor shrinkage in acromegaly caused by aip mutations .
moreover , these patients have significantly worse long - term therapeutic control although they frequently undergo multiple surgeries and radiotherapy .
patients with aip - mutated prolactinomas also present with large tumor size and invasive features .
resistance to dopamine agonists may be observed in 50% of these , raising the need for surgery and/or radiotherapy .
similar to the other familial presentations of pituitary tumors in men 1 and carney complex , the treatment of fipa does not differ substantially from the management of sporadic adenomas in terms of indications and therapeutic modalities . however , the aggressive nature of fipa tumors , especially in patients with aip mutations requires increased attention from medical specialists .
detailed physical examination should be performed for exclusion of extrapituitary pathology that may imply syndromic disease , and a comprehensive family history taken before referring patients to genetic screening .
genetic testing in relatives of patients with aip mutations can be especially beneficial in terms of early diagnosis , which may yield better outcomes from treatment .
although no consensus protocols for management of patients with aip - mutated fipa currently exist , it may be appropriate to start regular magnetic resonance imaging monitoring and hormonal evaluation from early childhood because macroadenomas and gigantism have been diagnosed in patients as young as 68 years ( 34),(36 ) .
widespread screening for aip mutations among apparently sporadic pituitary adenomas may not be warranted , as the prevalence of aip alterations is low in such populations .
however , aip mutations are discovered in approximately 12% of young patients ( aged < 30 years ) and in 20% of pediatric patients , most often presenting with growth hormone - secreting or prolactin - secreting macroadenomas , suggesting that focused screening in this patient group may provide valuable clinical information ( 33),(40 ) .
the definition of fipa has further widened the spectrum of familial pituitary pathology in addition to the well - known men 1 and carney complex .
the identification of the aip gene as a causative factor in a subset of patients with fipa has also provided some new insights into pituitary tumorigenesis .
genetic testing can now be offered to at - risk subjects in affected families , allowing for earlier diagnosis and more successful treatment .
consensus guidelines concerning the management and follow - up of patients with fipa will hopefully be developed with the accumulation of data from large international cohorts and long - term monitoring studies .
however , much remains to be done , as the low prevalence and the uncertain penetrance of aip mutations suggests that other predisposing or modifying genes are to be expected .
it is also unclear whether patients with fipa additionally have a predisposition for other endocrine or non - endocrine tumors , which could expand its definition beyond the pituitary .
further studies will help to clarify these issues and provide more information on the genetic and molecular basis for the development of pituitary adenomas .
albert beckers from the firs of the centre hospitalier universitaire de lige and from pfizer .
Output:
| pituitary adenomas represent a group of functionally diverse neoplasms with relatively high prevalence in the general population .
most occur sporadically , but inherited genetic predisposing factors are increasingly recognized .
familial isolated pituitary adenoma is a recently defined clinical entity , and is characterized by hereditary presentation of pituitary adenomas in the absence of clinical and genetic features of syndromic disease such as multiple endocrine neoplasia type 1 and carney complex .
familial isolated pituitary adenoma is inherited in an autosomal dominant manner and accounted for approximately 23% of pituitary tumors in some series .
germline mutations in the aryl - hydrocarbon interacting protein gene are identified in around 25% of familial isolated pituitary adenoma kindreds .
pituitary adenomas with mutations of the aryl - hydrocarbon interacting protein gene are predominantly somatotropinomas and prolactinomas , but non - functioning adenomas , cushing disease , and thyrotropinoma may also occur .
these tumors may present as macroadenomas in young patients and are often relatively difficult to control .
furthermore , recent evidence indicates that aryl - hydrocarbon interacting protein gene mutations occur in > 10% of patients with sporadic macroadenomas that occur before 30 years of age , and in > 20% of children with macroadenomas .
genetic screening for aryl - hydrocarbon interacting protein gene mutations is warranted in selected high - risk patients who may benefit from early recognition and follow - up . |
PubmedSumm118299 | ***TASK***
the task is to summarize an input biomedical literature in six sentences
***INPUT***
the input is a biomedical literature
***OUTPUT***
the output is the summary of an input biomedical literature in six sentences
***DOCUMENTATION***
***EXAMPLES***
Input: the mammalian cell cycle is controlled by cyclin - dependent kinases ( cdks ) and their related pathways ( fig . 1 ) [ 1 , 2 ] .
the cdks , particularly cdk1 , cdk2 , and cdk4/6 , are activated via binding to their selected cyclins , including cyclins a , b , d , and e , in specific phases of the cell cycle , following which they phosphorylate their target proteins to enable cell cycle progression .
the activities of the cdks are controlled not only by cyclins but also by phosphorylation or dephosphorylation by wee1 kinase or cdc25 phosphatase . moreover
, cdk inhibitors including p15 , p16 , p18 , p21 , p27 , and p57 specifically bind to their target cyclin
cdk complexes and inhibit their activities to negatively regulate the cell cycle [ 35].fig .
the mammalian cell cycle is controlled by cyclin - dependent kinases ( cdks ) and their related pathways .
cdks are activated via binding to their selected cyclins in specific phases of the cell cycle , following which they phosphorylate their target proteins .
the cdk inhibitors ( ckis ) negatively regulate the activities of cdks and control the cell cycle .
the p53 pathway plays a role in dna damage response as a gatekeeper of the genome .
several lncrnas control the expression of cyclins - cdks , ckis , prb and p53 , and participate in cell cycle regulation .
some of these lncrnas are induced by dna damage and inhibit cell cycle progression by regulating these cell cycle regulators outline of cell cycle control and involvement of lncrnas .
the mammalian cell cycle is controlled by cyclin - dependent kinases ( cdks ) and their related pathways .
cdks are activated via binding to their selected cyclins in specific phases of the cell cycle , following which they phosphorylate their target proteins .
the cdk inhibitors ( ckis ) negatively regulate the activities of cdks and control the cell cycle .
the p53 pathway plays a role in dna damage response as a gatekeeper of the genome .
several lncrnas control the expression of cyclins - cdks , ckis , prb and p53 , and participate in cell cycle regulation .
some of these lncrnas are induced by dna damage and inhibit cell cycle progression by regulating these cell cycle regulators cdks and their related pathways control the cell cycle by maintaining exit and entry to the different phases of the cell cycle . in the g1 phase ,
growth stimuli such as growth factors often activate the map kinase pathway , following which genes encoding the cyclin ds are transcribed .
cdk4/6 complexes phosphorylate retinoblastoma protein ( prb ) and its family members , p107 and p130 , in the late g1 phase and activate e2f - mediated transcription , which induces the expression of several growth - promoting genes [ 7 , 8 ] . at the g1/s transition point , cyclin e - cdk2 phosphorylates prb as well as several proteins involved in dna replication to promote g1/s progression .
cyclin b - cdk1 has many targets including apc / cyclosome , and promotes maturation of the g2 phase and critically participates in m phase events .
the cellular levels of cell cycle regulators such as cyclins , cdks , cdk inhibitors , cdc25 , rb , and e2f are critical for cell cycle regulation .
after the cell cycle regulators complete their functions , they are ubiquitylated by specific e3 ligases and eliminated via the ubiquitin
the level of cell cycle regulators is precisely controlled by not only post - translational but also translational mechanisms .
for example , several micro - rnas ( mirnas ) participate in cell cycle regulation through translational regulation .
mirnas are small non - coding rna molecules containing 22 nucleotides , and negatively regulate translation through binding of the untranslated region of its target mrnas .
the let-7 mirna family negatively regulates cyclins a and d , and cdk4/6 and cdc25a .
the mir-15 family also inhibits the translation of cyclin d , cdk4 , and cdc27 [ 17 , 18 ] .
interestingly , these let-7 and mir-15 family members may be involved in tumorigenesis since they are downregulated in various human cancers [ 1618 ] .
alternatively , cyclin d1 is a target for not only let-7 and mir-15 mirnas but also mir-19a , 26a , and 34a .
furthermore , p27 is targeted for regulation by the mir-181 family and the mir-221 family .
the roles of other mirnas in the expression of cell cycle regulators have also been reported .
thus , it has been shown that the cell cycle regulators are critically and precisely controlled by e3 ligases and mirnas both post - translationally and at the translational level . here , we focus on long non - coding rnas ( lncrnas ) involved in the regulation of the cell cycle through their various functions as epigenetic regulators , transcription factor regulators , post - transcription regulators and protein scaffolds [ 21 , 22 ] .
lncrnas are non - protein coding transcripts longer than 200 nucleotides , and can be divided into at least five categories based on their structural characteristics , including intergenic lncrnas ( lincrnas ) , intronic lncrnas , natural antisense transcripts , pseudogenes , and retrotransposons .
recent mass - scale transcriptome analysis has revealed that many kinds of lncrnas are transcribed in large amounts in the eukaryotic genome .
however , the question remains as to whether these lncrnas are merely by - products of the transcriptional units or have a critical function for biological processes .
however , it has become clear that some of these lncrnas participate in various biological processes such as genome imprinting , x - inactivation , development , differentiation , and cell cycle regulation [ 22 , 2426 ] .
for example , hotair , a well - investigated lncrna , is involved in correct development and tumorigenesis through recruiting the polycomb group ( pcg ) complex to its targeted hox genes for their repression [ 26 , 27 ] .
the pcg complex contributes to the epigenetic regulation of its target genes by forming polycomb repressive complex 1 ( prc1 ) and 2 ( prc2 ) .
prc2 participates in histone h3k27 methylation and , following histone h2ak119 monoubiquitination by prc1 , collaboratively represses target gene transcription .
in addition to hotair , several lncrnas such as xist , air , and kcnq1ot1 also recruit chromatin modifiers including pcg and h3k9 methyltransferase g9a to their target loci [ 25 , 2830 ] .
moreover , anril ( antisense non - coding rna in the ink4 locus ) directly binds to pcgs and recruits them to the ink4 locus to promote gene silencing [ 31 , 32 ] .
thus , hotair , xist , air , kcnq1ot1 , and anril function as epigenetic regulators by negatively regulating target gene transcription through recruitment of chromatin modifiers .
recently , several lncrnas that participate in the expression of several cell cycle regulators have been reported ( summarized in fig . 1 ; table 1 ) .
in this review , we introduce these lncrnas and discuss their functions in cell cycle regulation.table 1lncrnas involved in the cell cycle controllncrnahow it is inducedthe effects of the lncrna on its targets in cell cycle ( phase)references
ncrna
ccndi
dna damagesuppression of cyclin d1 transcription with tls ( g1)[33 , 34 ]
gadd7
dna damagedestabilization of cdk6 mrna ( g1)[35 , 36 ]
malat1
high expression in cancerpromotion of cell - cycle regulators such as cyclin a2 and b1 ( g1 and g2/m)[3739 ]
sra
?
cdt1 transcription ( g1 and g2/m)[40 , 41 ]
anril
dna damagesuppression of p15/p16 transcription with prc1/2 ( g1)[31 , 32 , 52 ]
lncrna - heih
high expression in hccsuppression of p16 .
p21 , p27 and p57 transcription with prc2(g0/g1 )
hulc
hbx - mediatedsuppression of p18 expression ( g1)[6062 ]
kcnq10t1
paternal expressionsuppression of p57 transcription with prc2 and g9a ( g1 ? }
h19 lncrna
e2f1-mediateddownregulation of rb mrna via mir675 ( g1)[6971 ]
lncrna - ror
p53-mediatedsuppression of p53 mrna translation ( g2/m )
p53-induced erna
p53-mediatedpromotion of p53 target genes transcription ( g1 ? )
loc285194
p53-mediatedgrowth inhibition by suppression of mir211 ( g1 ? )
lncrna - p21
p53-mediatedsuppression of transcription of the target genes involved in apoptosis and cell cycle with hnrna - k ( g1 ? ) suppression of -catenin and jun b mrna translation[77 , 78 ]
panda
dna damagesuppression of fas and bik transcription ( g1 ? ) lncrnas involved in the cell cycle control
cyclins and cdks are key players in cell cycle regulation ( fig . 1 ) .
ncrnaccnd1 , also called pncrna ( promoter - associated non - coding rna ) , is transcribed from the upstream region of the cyclin d1 gene , ccnd1 , and negatively regulates cyclin d1 .
it is induced in a dna damage - dependent manner , and associates with and recruits tls ( translocated in liposarcoma ) , an rna binding protein .
the ncrnaccnd1-tls complex is recruited to the ccnd1 promoter to inhibit the activity of the coactivator , cbp / p300 , thereby preventing ccnd1 transcription ( fig .
thus , suppression of cyclin d1 regulated by the ncrnaccnd1-tls complex may participate in g1 arrest in response to dna damage.fig .
2model showing the proposed mechanisms of lncrna - mediated regulation of cyclin d1 ( a ) and cdk6 ( b ) induced by dna damage .
a dna damage induces the transcription of ncrna
ccnd1 from the promoter region of the cyclin d1 gene .
ncrna
ccnd1 associates with and recruits tls , an rna binding protein , to the cyclin d1 promoter .
the ncrna
ccnd1tls complex inhibits the cbp / p300pcaf creb coactivator complex and thereby prevents cyclin d1 gene transcription .
b dna damage induces the expression of the lncrna , gadd7 , which dissociates tdp-43 from the cdk6 mrna to destabilize it , and cdk6 is thereby downregulated , inhibiting the g1/s transition .
the lncrnas gadd7 and ncrna
ccnd1 may collaboratively participate in the g1 checkpoint in response to dna damage model showing the proposed mechanisms of lncrna - mediated regulation of cyclin d1 ( a ) and cdk6 ( b ) induced by dna damage .
a dna damage induces the transcription of ncrna
ccnd1 from the promoter region of the cyclin d1 gene .
ncrna
ccnd1 associates with and recruits tls , an rna binding protein , to the cyclin d1 promoter .
the ncrna
ccnd1tls complex inhibits the cbp / p300pcaf creb coactivator complex and thereby prevents cyclin d1 gene transcription .
b dna damage induces the expression of the lncrna , gadd7 , which dissociates tdp-43 from the cdk6 mrna to destabilize it , and cdk6 is thereby downregulated , inhibiting the g1/s transition .
the lncrnas gadd7 and ncrna
ccnd1 may collaboratively participate in the g1 checkpoint in response to dna damage gadd7 is an lncrna involved in regulating cdk6 expression in a posttranscriptional manner .
tdp-43 ( tar dna binding protein ) binds to the 3 untranslated region of cdk6 mrna to stabilize it .
gadd7 is transcriptionally induced via dna damage mediated by uv and cisplatin [ 35 , 36 ] , and binds to tdp-43 and dissociates from cdk6 mrna .
the cdk6 mrna is then degraded , resulting in inhibition of the g1/s transition ( fig .
interestingly , gadd7 specifically controls mrna stability for cdk6 , but not cdk4 , cdk2 , or ccnd1 , by trapping tdp-43 .
gadd7 may be involved in the g1 checkpoint by collaborating with the lncrna , ncrnaccnd1 , to downregulate the cyclin d1cdk6 complex , thereby arresting cell cycle progression in response to dna damage ( fig .
malat1 , an mrna splicing mediator , is upregulated in several human cancers and contributes to cancer cell proliferation .
malat1 depletion results in arrest at g1 and promotes expression of p53 as well as p16 , p21 , and p27 in human fibroblasts ( table 1 ) .
in contrast , malat1 depletion suppresses various genes involved in cell cycle progression such as the genes encoding cyclin a2 and cdc25a , thereby arresting the cell cycle in g1 .
moreover , in g2/m progression , malat1 is required for expression of b - myb , which is involved in the expression of mitotic proteins such as cyclin b1 , cdk1 , foxom1 , and plk by controlling the splicing of b - myb mrna .
therefore , malat1 may contribute to cell cycle progression in each phase by coordinated control of cell cycle regulators .
steroid receptor rna activator ( sra ) was identified as an lncrna that binds to steroid receptors .
sra forms the src-1 complex to activate transcription , mediated by steroid receptors such as progesterone receptor and estrogen receptor .
it also binds to various other proteins such as myod , and has multiple cellular functions such as myogenesis .
sra also binds to ppar and coactivates gene expression mediated by ppar. as such , sra regulates adipogenesis and insulin sensitivity via ppar .
overexpression of sra in pre - adipocytes downregulates the expression of cell cycle - promoting genes such as those encoding the cyclins [ cyclins ( a2 , b1/2 ) ] , cdc20 , mcms ( 3 , 4 , 5 , 6 ) , and cdt1 .
conversely , these genes are upregulated by depletion of sra . however , it remains to be elucidated whether sra directly or indirectly suppresses the transcription of these genes , and further investigation into the mechanisms of sra - regulated gene expression is required .
the cdk inhibitory proteins , p16 and p15 ( hereafter p16 and p15 ) , bind to and inhibit cdk4 and 6 , respectively , via their ankyrin repeats [ 3 , 42 ] .
the p15 and p16 genes ( cdkn2b and cdkn2a , respectively ) are located at the ink4 locus together with the alternating reading frame gene , arf .
the ink4 proteins are relatively stable , and their ubiquitin - dependent proteolysis is not particularly important for controlling their cellular levels .
the participation of several transcription factors , including the ets family , foxo , and sp1 , has been reported . moreover ,
it has been suggested that pu.1 cooperates with dna methyltransferase and is involved in the ink4 locus via methylation of cpg islands .
moreover , pcg is recruited to the ink4 locus , thereby suppressing transcription via histone h3k27 methylation .
it has been suggested that antisense rna transcribed near the p15 gene controls transcription of p15 .
pasmant et al . identified an lncrna , anril , as an anti - sense transcript of the p15 gene in the ink4 locus .
both our study and other research have revealed that anril is involved in epigenetic repression of the transcription of the ink4 locus [ 31 , 32 ] ( table 1 ) .
we found that depletion of anril by short hairpin rna ( shrna ) decreased the recruitment of suz12 to the ink4 locus and promoted the expression of p15 gene dramatically and p16 gene moderately , but had no effect on arf .
in contrast , yap et al . demonstrated that anril binds to cbx7 , a component of the prc1 complex , in the chromatin fraction , and recruits prc1 to the ink4 locus to mediate transcriptional suppression .
therefore , anril binds to the prc2 complex to recruit it to the ink4 locus , and then histone h3k27 methylation is mediated by ezh2 in the prc2 complex .
next , prc2 with anril is recognized by cbx7 , and the prc1 complex is recruited to the region .
moreover , we demonstrated that depletion of anril promotes growth arrest and induces senescence - associated beta - galactosidase in wi38 human fibroblasts .
yap et al . also suggested that cbx7-mediated suppression of the ink4 locus is involved in regulating cellular senescence .
these reports strongly suggest that anril participates not only in cell proliferation but also in suppressing premature senescence via the recruitment of prc1 and prc2 to the ink4 locus ( fig .
3model showing the proposed mechanisms of anril - mediated regulation of the ink4 locus . a model of anril - mediated repression of the ink4 locus .
then , histone h3k27 methylation ( m ) is mediated by ezh2 in the prc2 complex with anril , which is recognized by cbx7 to recruit the prc1 complex to the region .
histone h2ak119 monoubiquitination ( ub ) is thereby induced to repress the transcription of ink4 .
overexpression of activated h - rasg12v in wi38 fibroblasts promotes excess ras signaling and suppresses anril expression .
then , p15 and p16 are induced and the cell cycle undergoes arrest , inducing a premature senescence - like phenotype model showing the proposed mechanisms of anril - mediated regulation of the ink4 locus . a model of anril - mediated repression of the ink4 locus .
then , histone h3k27 methylation ( m ) is mediated by ezh2 in the prc2 complex with anril , which is recognized by cbx7 to recruit the prc1 complex to the region .
histone h2ak119 monoubiquitination ( ub ) is thereby induced to repress the transcription of ink4 .
overexpression of activated h - rasg12v in wi38 fibroblasts promotes excess ras signaling and suppresses anril expression .
then , p15 and p16 are induced and the cell cycle undergoes arrest , inducing a premature senescence - like phenotype it is important to understand how anril expression is regulated .
we found that excess ras signaling promoted by the introduction of activated h - rasg12v into wi38 fibroblasts suppressed anril expression and induced p15 and p16 , thereby arresting the cell cycle and inducing senescence - associated beta - galactosidase ( fig .
reported that anril is induced by dna - damaging agents via the atm - e2f1 pathway , but p53 is not induced .
moreover , they suggested that depletion of anril decreases homologous recombination after dna double - strand breaks , although it is unclear whether anril promotes dna repair via the recruitment of prc1 and prc2 to the ink4 locus .
moreover , yang et al . found that lncrna - heih is highly expressed in hbv - related hepatocellular carcinoma .
it negatively regulates the expression of cdk inhibitors , such as p15 , p16 , p21 , and p57 , via interacting with ezh2 , and then plays an important role in g0/g1 arrest ( table 1 ) .
p18 ( hereafter p18 ) is another ink4 family cdk inhibitor that also inhibits both cdk4 and 6 [ 3 , 54 ] .
recently , ink4c/ mice have been shown to develop spontaneous pituitary adenomas , the frequency of which is enhanced by deletion of other cdk inhibitor genes .
the combined deletion of the p18 gene ( cdkn2c ) with the p16 gene is also found in human cancers .
moreover , the expression levels of p16 and p18 are often inversely correlated during the progression of senescence .
it has been reported that transcription of the p18 gene is regulated by menin - ret - signaling and the pi3k - akt pathway .
du et al . reported that the lncrna , hulc , negatively regulates the expression of p18 gene , which is located near the region containing hulc ( table 1 ) .
hulc was identified as an lncrna upregulated in human hepatocellular carcinoma ( hcc ) that is transcribed in a creb - dependent manner .
moreover , the expression of p18 is induced and suppressed by depletion and overexpression of hulc , respectively .
the expression of p18 is inversely correlated with the expression of hulc in human hcc tissue specimens .
furthermore , the hepatitis b virus oncogene product , hbx , activates the hulc promoter via creb to suppress the transcription of the p18 gene by upregulated hulc .
downregulation of the p18 gene by hbx via hulc induction may contribute to the development of hcc , although it is unknown how hulc suppresses the transcription of the p18 gene .
the transcription of p57 gene ( cdkn1c ) , which is located at the kcnq1 domain , is epigenetically suppressed as an imprinted gene on the paternal chromosome .
kcnq1ot1 is paternally expressed as an antisense rna of the kcnq1 domain containing kcnq1 and the p57 gene .
kcnq1ot1 functions as a recruiter that associates with the chromatin modifiers , prc2 and g9a , and recruits them to the kcnq1 domain to suppress the transcription of p57 gene ( table 1 ) .
as described above , lncrna - heih downregulates the expression of not only the ink4 family inhibitors , p15 and p16 , but also the cip / kip family inhibitors , p21 and p57 .
the cdk inhibitory proteins , p16 and p15 ( hereafter p16 and p15 ) , bind to and inhibit cdk4 and 6 , respectively , via their ankyrin repeats [ 3 , 42 ] .
the p15 and p16 genes ( cdkn2b and cdkn2a , respectively ) are located at the ink4 locus together with the alternating reading frame gene , arf .
the ink4 proteins are relatively stable , and their ubiquitin - dependent proteolysis is not particularly important for controlling their cellular levels .
the participation of several transcription factors , including the ets family , foxo , and sp1 , has been reported . moreover ,
it has been suggested that pu.1 cooperates with dna methyltransferase and is involved in the ink4 locus via methylation of cpg islands .
moreover , pcg is recruited to the ink4 locus , thereby suppressing transcription via histone h3k27 methylation .
it has been suggested that antisense rna transcribed near the p15 gene controls transcription of p15 .
pasmant et al . identified an lncrna , anril , as an anti - sense transcript of the p15 gene in the ink4 locus .
both our study and other research have revealed that anril is involved in epigenetic repression of the transcription of the ink4 locus [ 31 , 32 ] ( table 1 ) .
we found that depletion of anril by short hairpin rna ( shrna ) decreased the recruitment of suz12 to the ink4 locus and promoted the expression of p15 gene dramatically and p16 gene moderately , but had no effect on arf .
in contrast , yap et al . demonstrated that anril binds to cbx7 , a component of the prc1 complex , in the chromatin fraction , and recruits prc1 to the ink4 locus to mediate transcriptional suppression .
therefore , anril binds to the prc2 complex to recruit it to the ink4 locus , and then histone h3k27 methylation is mediated by ezh2 in the prc2 complex .
next , prc2 with anril is recognized by cbx7 , and the prc1 complex is recruited to the region .
moreover , we demonstrated that depletion of anril promotes growth arrest and induces senescence - associated beta - galactosidase in wi38 human fibroblasts .
yap et al . also suggested that cbx7-mediated suppression of the ink4 locus is involved in regulating cellular senescence .
these reports strongly suggest that anril participates not only in cell proliferation but also in suppressing premature senescence via the recruitment of prc1 and prc2 to the ink4 locus ( fig .
3model showing the proposed mechanisms of anril - mediated regulation of the ink4 locus . a model of anril - mediated repression of the ink4 locus .
then , histone h3k27 methylation ( m ) is mediated by ezh2 in the prc2 complex with anril , which is recognized by cbx7 to recruit the prc1 complex to the region .
histone h2ak119 monoubiquitination ( ub ) is thereby induced to repress the transcription of ink4 .
overexpression of activated h - rasg12v in wi38 fibroblasts promotes excess ras signaling and suppresses anril expression .
then , p15 and p16 are induced and the cell cycle undergoes arrest , inducing a premature senescence - like phenotype model showing the proposed mechanisms of anril - mediated regulation of the ink4 locus . a model of anril - mediated repression of the ink4 locus .
then , histone h3k27 methylation ( m ) is mediated by ezh2 in the prc2 complex with anril , which is recognized by cbx7 to recruit the prc1 complex to the region .
histone h2ak119 monoubiquitination ( ub ) is thereby induced to repress the transcription of ink4 .
overexpression of activated h - rasg12v in wi38 fibroblasts promotes excess ras signaling and suppresses anril expression .
then , p15 and p16 are induced and the cell cycle undergoes arrest , inducing a premature senescence - like phenotype it is important to understand how anril expression is regulated .
we found that excess ras signaling promoted by the introduction of activated h - rasg12v into wi38 fibroblasts suppressed anril expression and induced p15 and p16 , thereby arresting the cell cycle and inducing senescence - associated beta - galactosidase ( fig .
reported that anril is induced by dna - damaging agents via the atm - e2f1 pathway , but p53 is not induced .
moreover , they suggested that depletion of anril decreases homologous recombination after dna double - strand breaks , although it is unclear whether anril promotes dna repair via the recruitment of prc1 and prc2 to the ink4 locus .
moreover , yang et al . found that lncrna - heih is highly expressed in hbv - related hepatocellular carcinoma .
it negatively regulates the expression of cdk inhibitors , such as p15 , p16 , p21 , and p57 , via interacting with ezh2 , and then plays an important role in g0/g1 arrest ( table 1 ) .
p18 ( hereafter p18 ) is another ink4 family cdk inhibitor that also inhibits both cdk4 and 6 [ 3 , 54 ] .
recently , ink4c/ mice have been shown to develop spontaneous pituitary adenomas , the frequency of which is enhanced by deletion of other cdk inhibitor genes .
the combined deletion of the p18 gene ( cdkn2c ) with the p16 gene is also found in human cancers .
moreover , the expression levels of p16 and p18 are often inversely correlated during the progression of senescence .
it has been reported that transcription of the p18 gene is regulated by menin - ret - signaling and the pi3k - akt pathway .
du et al . reported that the lncrna , hulc , negatively regulates the expression of p18 gene , which is located near the region containing hulc ( table 1 ) .
hulc was identified as an lncrna upregulated in human hepatocellular carcinoma ( hcc ) that is transcribed in a creb - dependent manner .
moreover , the expression of p18 is induced and suppressed by depletion and overexpression of hulc , respectively .
the expression of p18 is inversely correlated with the expression of hulc in human hcc tissue specimens .
furthermore , the hepatitis b virus oncogene product , hbx , activates the hulc promoter via creb to suppress the transcription of the p18 gene by upregulated hulc .
downregulation of the p18 gene by hbx via hulc induction may contribute to the development of hcc , although it is unknown how hulc suppresses the transcription of the p18 gene .
the transcription of p57 gene ( cdkn1c ) , which is located at the kcnq1 domain , is epigenetically suppressed as an imprinted gene on the paternal chromosome .
kcnq1ot1 is paternally expressed as an antisense rna of the kcnq1 domain containing kcnq1 and the p57 gene .
kcnq1ot1 functions as a recruiter that associates with the chromatin modifiers , prc2 and g9a , and recruits them to the kcnq1 domain to suppress the transcription of p57 gene ( table 1 ) .
as described above , lncrna - heih downregulates the expression of not only the ink4 family inhibitors , p15 and p16 , but also the cip / kip family inhibitors , p21 and p57 .
as described above , the tumor suppressor prb is a critical regulator of g1/s progression [ 7 , 65 ] .
it is well known that the expression of the rb gene is epigenetically silenced by methylation of the promoter in some cancers , including retinoblastoma .
hypermethylation of the ctcf binding site in the rb promoter is mediated by the ctcf protein .
ctcf also regulates the expression balance between the igf2/h19 locus together with dna methylation of their promoters as an insulator of gene expression .
interestingly , the h19 gene encodes a 2.9-kb lncrna , and the h19 lncrna is a precursor of mir-675 .
the expression of h19 lncrna is mediated by e2f1 and promotes cell proliferation , but the mechanism is unknown .
tsang et al . reported that the h19 lncrna - derived mir-675 associates with the 3 untranslated region of rb mrna to negatively regulate prb expression ( fig . 4 ; table 1 ) . in human colorectal cancer , h19 lncrna / mir-675 expression
therefore , h19 lncrna / mir-675 may be a critical negative regulator of the rb tumor suppressor pathway ( fig .
, prb suppresses e2f - dependent transcription of h19 transcription via repression of the h19 promoter .
prb binds target transcription factors such as e2f and inhibits their activity in the g1 phase .
cyclin ds - cdk4/6 phosphorylate prb and activate e2f - mediated transcription in late g1 , which regulates the expression of several growth - promoting genes and s phase entry .
h19 lncrna is processed to generate mir-675 , which binds to rb mrna and inhibits its translation model showing the proposed mechanisms of lncrna - mediated regulation of the rb pathway .
prb binds target transcription factors such as e2f and inhibits their activity in the g1 phase .
cyclin ds - cdk4/6 phosphorylate prb and activate e2f - mediated transcription in late g1 , which regulates the expression of several growth - promoting genes and s phase entry .
h19 lncrna is processed to generate mir-675 , which binds to rb mrna and inhibits its translation another important tumor suppressor , p53 , functions as the gatekeeper of the genome to control cell cycle arrest and apoptosis in response to dna damage [ 65 , 72 ] .
although p53 is unstable , it is stabilized and activated via phosphorylation mediated by the atm / atr pathway in response to dna damage . moreover , p53 is also regulated via phosphorylation at various sites by specific kinases .
zang et al . reported that lncrna - ror negatively regulates p53 expression , thereby suppressing doxorubicin - induced g2/m arrest and apoptosis ( table 1 ) .
depletion of lncrna - ror leads to p53 accumulation , and overexpression of lncrna - ror suppresses p53 expression .
lncrna - ror binds to phosphorylated heterogeneous nuclear ribonucleoprotein i ( p - hnrnp - i ) in cytoplasm and thereby suppresses p53 translation .
additionally , wild - type p53 binds to the ror promoter to promote transcription of lncrna - ror , but mutant p53 does not bind to this promoter .
p53 controls cell cycle arrest , repair , and apoptosis in response to dna damage .
this is an autoregulatory feedback loop that controls p53 levels . in response to dna damage
, p53 is stabilized and activated via phosphorylation mediated by the atm / atr pathway .
p53 directly binds the target genes and regulates their expression to control cell cycle arrest , repair , and apoptosis .
p21 and lncrna - p21 , which is transcribed near the p21
gene , are p53-target genes .
p53 function is partially mediated by gene regulation via lncrna - p21
model showing the proposed mechanisms of lncrna - mediated regulation of the p53 pathway .
p53 controls cell cycle arrest , repair , and apoptosis in response to dna damage .
this is an autoregulatory feedback loop that controls p53 levels . in response to dna damage
, p53 is stabilized and activated via phosphorylation mediated by the atm / atr pathway .
p53 directly binds the target genes and regulates their expression to control cell cycle arrest , repair , and apoptosis .
p21 and lncrna - p21 , which is transcribed near the p21
gene , are p53-target genes .
p53 function is partially mediated by gene regulation via lncrna - p21
recently , melo et al .
reported that enhancer rnas ( ernas ) are required for coordinated promotion between p53 target genes and p53-bound enhancer regions distant from the target gene , and participate in p53-dependent cell cycle arrest ( table 1 ) .
lncrna loc285194 was suggested to have a tumor suppressor function , but its mechanism was unknown .
liu et al . found that loc285194 is induced by binding of p53 to its binding site in the promoter ( table 1 ) .
moreover , they indicated that loc285194 binds to and inhibits mir-211 , thereby downregulating mir-211-mediated cell proliferation .
loc285194 is downregulated in human colon cancer specimens , and thus may contribute to the tumor suppressive function of p53 to inhibit mir-211 .
identified lncrna - p21 , which is transcribed near the p21 gene ( cdkn1a ) as a p53-target gene .
depletion of lncrna - p21 alters the expression of some p53-target genes except for p21 gene and inhibits apoptosis ( fig . 5 ; table 1 ) .
lncrna - p21 binds to hnrnp - k and recruits it to the target genes , but the mechanism of target gene regulation is unknown .
moreover , yoon et al . proposed that lncrna - p21 functions as a modulator of translation .
lncrna - p21 associates with target mrnas such as -catenin and junb in collaboration with rck / p54 rna helicase , and thus the translation of the target mrnas is repressed .
therefore , lncrna - p21 regulates both transcription in the nucleus and translation in the cytoplasm .
panda ( p21-associated ncrna dna damage - activated ) was identified as a p21 promoter - derived transcript using ultra - high density tiling array of 56 cell - cycle genes .
it is induced by dna damage in a p53-dependent manner ( table 1 ) .
panda binds to and inhibits nf - ya transcription factor , which limits the expression of proapoptotic genes such as fas and bik and results in the repression of apoptosis .
the results suggest that abnormal overexpression of panda may suppress apoptosis induced by dna damage , which will accumulate and push the genome toward carcinogenesis .
another important tumor suppressor , p53 , functions as the gatekeeper of the genome to control cell cycle arrest and apoptosis in response to dna damage [ 65 , 72 ] .
although p53 is unstable , it is stabilized and activated via phosphorylation mediated by the atm / atr pathway in response to dna damage .
zang et al . reported that lncrna - ror negatively regulates p53 expression , thereby suppressing doxorubicin - induced g2/m arrest and apoptosis ( table 1 ) .
depletion of lncrna - ror leads to p53 accumulation , and overexpression of lncrna - ror suppresses p53 expression .
lncrna - ror binds to phosphorylated heterogeneous nuclear ribonucleoprotein i ( p - hnrnp - i ) in cytoplasm and thereby suppresses p53 translation .
additionally , wild - type p53 binds to the ror promoter to promote transcription of lncrna - ror , but mutant p53 does not bind to this promoter .
p53 controls cell cycle arrest , repair , and apoptosis in response to dna damage .
this is an autoregulatory feedback loop that controls p53 levels . in response to dna damage
, p53 is stabilized and activated via phosphorylation mediated by the atm / atr pathway .
p53 directly binds the target genes and regulates their expression to control cell cycle arrest , repair , and apoptosis .
p21 and lncrna - p21 , which is transcribed near the p21
gene , are p53-target genes .
p53 function is partially mediated by gene regulation via lncrna - p21
model showing the proposed mechanisms of lncrna - mediated regulation of the p53 pathway .
p53 controls cell cycle arrest , repair , and apoptosis in response to dna damage .
this is an autoregulatory feedback loop that controls p53 levels . in response to dna damage
, p53 is stabilized and activated via phosphorylation mediated by the atm / atr pathway .
p53 directly binds the target genes and regulates their expression to control cell cycle arrest , repair , and apoptosis .
p21 and lncrna - p21 , which is transcribed near the p21
gene , are p53-target genes .
p53 function is partially mediated by gene regulation via lncrna - p21
recently , melo et al . reported that enhancer rnas ( ernas ) are required for coordinated promotion between p53 target genes and p53-bound enhancer regions distant from the target gene , and participate in p53-dependent cell cycle arrest ( table 1 ) .
lncrna loc285194 was suggested to have a tumor suppressor function , but its mechanism was unknown .
liu et al . found that loc285194 is induced by binding of p53 to its binding site in the promoter ( table 1 ) .
moreover , they indicated that loc285194 binds to and inhibits mir-211 , thereby downregulating mir-211-mediated cell proliferation .
loc285194 is downregulated in human colon cancer specimens , and thus may contribute to the tumor suppressive function of p53 to inhibit mir-211 .
identified lncrna - p21 , which is transcribed near the p21 gene ( cdkn1a ) as a p53-target gene .
depletion of lncrna - p21 alters the expression of some p53-target genes except for p21 gene and inhibits apoptosis ( fig . 5 ; table 1 ) .
lncrna - p21 binds to hnrnp - k and recruits it to the target genes , but the mechanism of target gene regulation is unknown .
moreover , yoon et al . proposed that lncrna - p21 functions as a modulator of translation . lncrna - p21 associates with target mrnas such as -catenin and junb in collaboration with rck / p54 rna helicase , and thus the translation of the target mrnas
therefore , lncrna - p21 regulates both transcription in the nucleus and translation in the cytoplasm .
panda ( p21-associated ncrna dna damage - activated ) was identified as a p21 promoter - derived transcript using ultra - high density tiling array of 56 cell - cycle genes .
it is induced by dna damage in a p53-dependent manner ( table 1 ) .
panda binds to and inhibits nf - ya transcription factor , which limits the expression of proapoptotic genes such as fas and bik and results in the repression of apoptosis .
the results suggest that abnormal overexpression of panda may suppress apoptosis induced by dna damage , which will accumulate and push the genome toward carcinogenesis .
although the mechanisms of cell cycle regulation via cyclin cdk , the p53/rb pathway , and the checkpoint pathway have been described in detail , recent studies on lncrnas strongly suggest that lncrnas control the expression of cell cycle regulators .
however , it is unclear why lncrnas might be deployed to regulate the cell cycle .
as described in the introduction , lncrnas involved in cell cycle regulation are classified into four groups . as shown in table 1 , anril , lncrna - heih , and kcnq1ot1
are involved in epigenetic regulation of target gene transcription by collaborating with chromatin modifiers , which are classified as epigenetic regulators .
ncrnaccnd1 , sra , panda , and lncrna - p21 directly interact with the transcriptional machinery on the target genes and collaboratively regulate transcription as transcription factor regulators .
post - transcription regulators including gadd7 , malat1 , lncrna - ror , and loc285194 bind to their specific target mrna to suppress translation and/or to modulate mrna stability .
protein interactions and are classified as protein scaffolds . because the general cell cycle is closely associated with various cellular events as well as biological processes , it should be accurately regulated .
post - transcription regulators such as gadd7 , malat1 , h19 lncrna , and loc285194 can rapidly and transiently suppress translation of their target genes .
transcription factor regulators such as ncrnaccnd1 , sra , panda , and lncrna - p21 that directly interact with the transcription machinery on the target genes may also participate in transient regulation .
alternatively , epigenetic regulators such as anril , lncrna - heih , and kcnq1ot1 may have long - term effects on cellular senescence and imprinting because they mediate epigenetic regulation of cell cycle regulatory genes via chromatin modifiers . from this viewpoint , the cell cycle - regulated lncrnas mainly control cellular levels of cell cycle regulators via various mechanisms , and
as shown in table 1 , 4 of 14 lncrnas , lncrnaccnd1 , gadd7 , anril and panda , are induced by dna damage .
another 4 lncrnas , lncrna - ror , lncrnap21 , p53-induced erna , and loc285194 , are induced in a p53-dependent manner , suggesting that they are induced by dna damage .
therefore , these reported lncrnas may participate in cell cycle arrest or induction of apoptosis as non - canonical dna damage responses , whereas the atm / atr pathway is involved in a canonical dna damage response to inactivate cdk activity as a dna damage checkpoint .
lncrnas - mediated non - canonical pathways may ensure the response to dna damage is diverse and reliable depending on the cellular context .
considering the recent progress in lncrna research , many lncrnas that have a functional role in cell cycle regulation remain to be identified because the functions of only a small percentage of the total lncrna population are understood .
to clarify the roles of lncrnas in cell cycle regulation , it should be determined how they regulate the target cell cycle regulators and which signaling pathways induce these lncrnas . since abrogation of the cell cycle is closely associated with cancer development and growth , cell cycle regulatory lncrnas such as anril and panda may have oncogenic properties .
the importance of lncrnas in cell cycle regulation will be clarified by further pathological studies . moreover ,
these cell cycle regulatory lncrnas may be novel candidate molecular targets for cancer therapy or diagnosis .
Output:
| the mammalian cell cycle is precisely controlled by cyclin - dependent kinases ( cdks ) and related pathways such as the rb and p53 pathways
. recent research on long non - coding rnas ( lncrnas ) indicates that many lncrnas are involved in the regulation of critical cell cycle regulators such as the cyclins , cdks , cdk inhibitors , prb , and p53 . these lncrnas act as epigenetic regulators , transcription factor regulators , post - transcription regulators , and protein scaffolds .
these cell cycle - regulated lncrnas mainly control cellular levels of cell cycle regulators via various mechanisms , and may provide diversity and reliability to the general cell cycle .
interestingly , several lncrnas are induced by dna damage and participate in cell cycle arrest or induction of apoptosis as dna damage responses .
therefore , deregulations of these cell cycle regulatory lncrnas may be involved in tumorigenesis , and they are novel candidate molecular targets for cancer therapy and diagnosis . |
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