The Incidence of Adding-On or Distal Junctional Kyphosis in Adolescent Idiopathic Scoliosis Treated by Anterior Spinal Fusion to L3 Was Significantly Higher Than by Posterior Spinal Fusion to L3.
To compare and identify risk factors for distal adding-on (AO) or distal junctional kyphosis (DJK) in adolescent idiopathic scoliosis (AIS) treated by anterior- (ASF) and posterior spinal fusion (PSF) to L3. AIS patients undergoing ASF versus PSF to L3 from 2000-2010 were analyzed. Distal AO and DJK were deemed poor radiographic results. New stable (SV) and neutral vertebra (NV) scores were defined for this study. The total stability (TS) score was the sum of the SV and NV scores. Twenty of 42 (ASF group: 47.6%) and 8 of 72 patients (PSF group: 11.1%) showed poor radiographic outcome. Fused vertebrae, correction rate of main curve, coronal reduction rate of L3 were significantly higher in PSF group. Multiple logistic regression results indicated that preoperative SV-3 at L3 in standing and side benders (odds ratio [OR], 2.7 and 3.7, respectively), TS score -5, -6 at L3 (OR, 4.9), rigid disc at L3-4 (OR, 3.7), lowest instrumented vertebra (LIV) rotation > 15° (OR, 3.3), LIV deviation > 2 cm from center sacral vertical line (OR, 3.1) and ASF (OR, 13.4; p < 0.001) were independent predictive factors. There was significant improvement of the Scoliosis Research Society (SRS)-22 average scores only in PSF group. Furthermore, the ultimate scores of PSF group were significantly superior to ASF group. The prevalence of AO or DJK at ultimate follow-up for AIS with LIV at L3 was significantly higher in ASF group. Ultimate SRS-22 scores were significantly better in PSF group.


Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity: interactions with rolipram.
Forskolin, a direct activator of the catalytic subunit of adenylate cyclase (AC), and the cyclic nucleotide analogs dibutyryl cAMP (dBcAMP), 8-bromo cAMP (8-BrcAMP) and dibutyryl cGMP (dBcGMP) were tested for their ability to reverse the hypothermia or hypokinesia of mice depleted of presynaptic endogenous monoamines by pretreatment with reserpine, alpha-methyl-p-tyrosine and p-chlorophenylalanine. Forskolin and the cAMP analogs decreased the rectal temperature and inhibited locomotor activity in normal mice. In mice depleted of brain monoamines forskolin reversed the hypothermia and hypokinesia; dBcAMP and 8-BrcAMP antagonized the hypothermia but were only marginally effective in reversing the hypokinesia. DBcGMP was inactive. The antihypothermic action of forskolin or salbutamol was enhanced by the novel antidepressant and cAMP selective phosphodiesterase inhibitor rolipram (4RS-[3-cyclopentyloxy-4-methoxy-phenyl]-2-pyrrolidone). As an indirect effect via release of endogenous monoamines stimulating postsynaptic receptors was precluded by the monoamine-depleting pretreatment, forskolin and the cAMP analogs are thought to exert their antidepressant action by directly increasing brain cAMP availability. This is achieved by forskolin via activation of the catalytic subunit of AC and by the cAMP analogs via substitution for cAMP. These findings suggest that antidepressant activity is crucially linked to enhanced cAMP availability within brain effector cells. The successful treatment of endogenously depressed patients with rolipram supports this assumption.


Relation between conduction delay and ventricular fibrillation: characteristics of conduction of premature impulses during acute myocardial ischemia.
Critical conduction delay has been shown to be the important factor in reentrant arrhythmias. To determine the causal relation between conduction delay and spontaneous ischemic ventricular fibrillation, conduction delay of induced premature ventricular impulses in the ischemic and the border zones of ventricular myocardium was investigated in 23 dogs. There were 8 control dogs, 9 dogs that manifested ventricular fibrillation within 30 minutes of ligation of the distal left anterior descending coronary artery (group I), and 6 dogs that manifested ventricular fibrillation between 30 and 60 minutes of ligation of the proximal left anterior descending coronary artery (group II). Conduction delay was measured as the change of conduction time from preligation levels to postligation levels in epicardial and endocardial sites in both base to apex (anterograde) and apex to base (retrograde) directions. Conduction delay in all four directions was compared in the control group and groups I and II (ventricular fibrillation). By means of continuous recordings on tape, the origin of ventricular fibrillation was determined to be in the ischemic zone (13 of 15 dogs) or in the border zone (2 of 15 dogs). Conduction delay in all directions was greater in the group with ventricular fibrillation whether the fibrillation occurred after the first or second ligation. Specifically, epicardial anterograde conduction (in the border zone) and retrograde conduction (in the ischemic zone) were significantly delayed in group I. Conduction in group II was significantly delayed in both the ischemic and the border zones in three of four directions at 35 minutes. The rate of change of conduction time in all four directions was significantly greater in the group with ventricular fibrillation than in the control group. Pending further work, this model may provide a reliable marker for the development of spontaneous ventricular fibrillation during acute myocardial ischemia and may permit assessment of various interventions as specific therapy for acute reentrant ischemic tachyarrhythmias leading to ventricular fibrillation.


Involvement of class A calcium channels in the KCl induced Ca2+ influx in hippocampal synaptosomes.
Using Ca2+ channel toxins, we determined the types of voltage-sensitive calcium channels activated by two levels of KCl depolarization in hippocampal synaptosomes. The increase in the intracellular Ca2+ concentration ([Ca2+]i) induced by 30 mM KCl was equally sensitive to either omega-agatoxin IVA (omega-Aga IVA) or to omega-conotoxin MVIIC (omega-CgTx MVIIC), and the inhibition produced by these two peptides was not additive. The present results indicate that omega-Aga IVA and omega-CgTx MVIIC do not distinguish between two different VSCC in hippocampal synaptosomes and that they both inhibit a channel with the alpha 1A subunit which is present in the rat hippocampus.


Comparative metabolomics study on therapeutic mechanism of electro-acupuncture and moxibustion on rats with chronic atrophic gastritis (CAG).
Some studies have proved that both acupuncture and moxibustion are very effective for the treatment of CAG. However, little is known about therapeutic mechanism of electro-acupuncture and moxibustion on CAG as well as the difference between them. On the other hand, metabolomics is a 'top-down' approach to understand metabolic changes of organisms caused by disease or interventions in holistic context, which consists with the holistic thinking of electro-acupuncture and moxibustion treatment. In this study, the difference of therapeutic mechanism between electro-acupuncture and moxibustion on CAG rats was investigated by a 1H NMR-based metabolomics analysis of multiple biological samples (serum, stomach, cerebral cortex and medulla) coupled with pathological examination and molecular biological assay. For all sample types, both electro-acupuncture and moxibustion intervention showed beneficial effects by restoring many CAG-induced metabolic changes involved in membrane metabolism, energy metabolism and function of neurotransmitters. Notably, the moxibustion played an important role in CAG treatment mainly by regulating energy metabolism in serum, while main acting site of electro-acupuncture treatment was nervous system in stomach and brain. These findings are helpful to facilitate the therapeutic mechanism elucidating of electro-acupuncture and moxibustion on CAG rats. Metabolomics is promising in mechanisms study for traditional Chinese medicine (TCM).


In vitro mutagenicity of the soil nematicide 1,3-dichloropropene.
The cis- and trans-isomers of 1,3-dichloropropene have been tested in the Ames mutagenicity assay system on Salmonella typhimurium tester strain TA 1535. Both isomers have been found to be mutagenic even without microsomal activation.


Construction of high elastic artificial SEI for air-stable and long-life lithium metal anode.
Compared with other anode materials, Li metal anode has higher capacity density and lower electrode potential, which has been considered as one of the most promising anode materials. However, the unstable solid electrolyte interface (SEI) leads to Li dendrite growth and the infinite volumetric expansion of Li metal, which seriously hinders the stability and cycle life of Li metal batteries (LMBs). Here, a polyurethane elastomer (TPU) material with high elasticity and air stability is used as the artificial SEI of Li metal anode. Its designed synergistic effect of soft chain forging and hard chain segments not only gives TPU artificial SEI layer good electronic insulation, Li ion conductivity, Li dendrite growth inhibition, high elastic modulus and flexibility to adapt to Li volume expansion, but also has a significant air protection effect on the Li metal surface, so that the TPU coated Li foil will not occur obvious oxidation phenomenon after being placed in air for 45 min. The Li symmetric battery modified by TPU achieved a stable and long-term cycle performance of 1300 h at 1 mA/cm2, it can also cycle stably at a high current density of 10 mA/cm2. The Coulomb efficiency of the modified Li/Cu half-cell maintains at above 97% after 400 cycles. In addition, the full cell with LiFePO4 cathode also delivers a very excellent long cycle stability with 90% capacity retention after 1500 cycles at 5 C. This surface modification strategy of SEI on lithium anode has has great research value and will help to improve the widely application of LMBs.


Comparison of Adjuvant Chemotherapy for Upper Tract versus Lower Tract Urothelial Carcinoma: A Systematic Review and Meta-Analysis.
Principles of management for upper tract urothelial carcinoma (UTUC) are mostly derived from knowledge of lower tract urothelial carcinoma (LTUC), however recent research indicates that these may be disparate diseases. In this review, we sought to compare the responsiveness of these tumors to similar treatment, platinum-based chemotherapy used in the adjuvant setting. PubMed, EMBASE, and Web of Science were searched using a systematic search strategy. Disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) in patients with LTUC and UTUC treated with adjuvant chemotherapy were compared. Review Manager V 5.3 was used for meta-analyses. Adjuvant chemotherapy was associated with improved DFS (HR 0.41, 95%CI 0.31-0.54), CSS (HR 0.29, 95%CI 0.17-0.50) and OS (HR 0.51, 95%CI 0.38-0.70) rates in LTUC. The effectiveness of adjuvant chemotherapy in UTUC was less pronounced with respect to DFS (HR 0.61, 95%CI 0.1-0.93) and CSS (HR 0.70, 95%CI 0.56-0.90) rates, and there was no effect on OS (HR 0.87, 95%CI 0.69-1.10). Differences in CSS and OS were significant (p < 0.0001) in favor of adjuvant chemotherapy for LTUC versus UTUC. Despite similar histology, we found significant differences in responsiveness to adjuvant chemotherapy between LTUC and UTUC. This may add to the already growing knowledge that these are disparate diseases. Newer systemic treatments for urothelial carcinoma may prove more effective than platinum-based chemotherapy in the adjuvant setting for UTUC.


Increased Bacillus Calmette-Guérin Treatment Intensity Associated With Improved Outcomes in Elderly Patients With Non-Muscle-invasive Bladder Cancer in United States Clinical Practice.
To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC). Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group. Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease. We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population.


Nonsterile immunity to cryptosporidiosis in infants is associated with mucosal IgA against the sporozoite and protection from malnutrition.
We conducted a longitudinal study of cryptosporidiosis from birth to three years of age in an urban slum of Dhaka Bangladesh. Fecal DNA was extracted from monthly surveillance samples and diarrheal stool samples collected from 392 infants from birth to three years. A pan-Cryptosporidium qPCR assay was used to identify sub-clinical and symptomatic cryptosporidiosis. Anthropometric measurements were collected quarterly to assess child nutritional status. 31% (121/392) of children experienced a single and 57% (222/392) multiple infections with Cryptosporidium. Repeat infections had a lower burden of parasites in the stool (Cq slope = -1.85; p<0.0001) and were more likely to be sub-clinical (Chi square test for trend; p = 0.01). Repeat infections were associated with the development of growth faltering (Pearson correlation = -0.18; p = 0.0004). High levels of fecal IgA antibodies against the Cryptosporidium Cp23 sporozoite protein at one year of life were associated with a delay in reinfection and amelioration of growth faltering through three years of life (HAZ IgA high responders -1.323 ± 0.932 versus HAZ -1.731 ± 0.984 p = 0.0001). We concluded that nonsterile immunity to cryptosporidiosis in young children was associated with high levels of mucosal IgA anti-Cp23 and protection from diarrhea and growth faltering. Trial Registration: NCT02764918.


Highly efficient bioconversion of icariin to icaritin by whole-cell catalysis.
Icaritin is an aglycone of flavonoid glycosides from Herba Epimedii. It has good performance in the treatment of hepatocellular carcinoma in clinical trials. However, the natural icaritin content of Herba Epimedii is very low. At present, the icaritin is mainly prepared from flavonoid glycosides by α-L-rhamnosidases and β-glucosidases in two-step catalysis process. However, one-pot icaritin production required reported enzymes to be immobilized or bifunctional enzymes to hydrolyze substrate with long reaction time, which caused complicated operations and high costs. To improve the production efficiency and reduce costs, we explored α-L-rhamnosidase SPRHA2 and β-glucosidase PBGL to directly hydrolyze icariin to icaritin in one-pot, and developed the whole-cell catalytic method for efficient icaritin production. The SPRHA2 and PBGL were expressed in Escherichia coli, respectively. One-pot production of icaritin was achieved by co-catalysis of SPRHA2 and PBGL. Moreover, whole-cell catalysis was developed for icariin hydrolysis. The mixture of SPRHA2 cells and PBGL cells transformed 200 g/L icariin into 103.69 g/L icaritin (yield 95.23%) in 4 h in whole-cell catalysis under the optimized reaction conditions. In order to further increase the production efficiency and simplify operations, we also constructed recombinant E. coli strains that co-expressed SPRHA2 and PBGL. Crude icariin extracts were also efficiently hydrolyzed by the whole-cell catalytic system. Compared to previous reports on icaritin production, in this study, whole-cell catalysis showed higher production efficiency of icaritin. This study provides promising approach for industrial production of icaritin in the future.


Differentiation-associated expression of prostaglandin G/H synthase in monocytic cells.
Significant progress in the investigation of the regulation of prostanoid formation has recently been made by cloning a second gene coding for prostaglandin G/H synthase (PGHS; EC 188.8.131.52). In this study we examined the expression of the two PGHS isoforms during phorbol ester induced monocytic differentiation of human myeloid leukemia cells (U937). Murine and ovine PGHS-1 probes hybridized to 2.8- and 5.5-kb mRNA species, whereas the murine PGHS-2 probe hybridized to a 5.3-kb species. Western blot analysis using antisera to mouse PGHS-1 and to a synthetic peptide derived from a mouse PGHS-2-specific region revealed a band of 70 kDa for PGHS-1 and a doublet of about 85 kDa for PGHS-2. Unlike PGHS-2, which was not expressed in U937 control cells, both PGHS-1 protein and mRNA were detected in untreated U937 cells. TPA strongly induced PGHS-2 protein and also increased the amount of PGHS-1 protein. Correspondingly, a marked induction of PGHS-2 mRNA was found, but virtually no change in the expression of the PGHS-1 2.8-kb mRNA occurred. The induction of both PGHS isoforms turned out to be dexamethasone-sensitive. The suppression of PGHS-2 induction was more pronounced. These results suggest that both PGHS-1 and to a larger extent PGHS-2 contribute to the upregulation of prostanoid synthesis during monocytic differentiation.


Adherence of Uropathogenic Escherichia Coli in Dog Urine After Consumption of Food Supplemented with Cranberry (Vaccinium Macrocarpon).
Escherichia coli is the most common pathogen isolated from the urine of dogs with urinary tract infections (UTIs). While there are many studies in humans investigating the potential for the prevention of UTIs by dietary consumption of cranberry, few analogous studies have been carried out in dogs. Eight dogs, four male and four female, were successively fed two diets, first a control without cranberry, and then the second diet containing cranberry extracts. Naturally excreted urine was collected on the tenth day after the start of each diet for 24 h and used for bacterial growth. Madin-Darby canine kidney cell adherence by the uropathogenic E. coli G1473 strain expressing type 1 pili and positive for P pili and haemolysin gene markers was quantified after growth in urine samples. Significant reductions in bacterial adherence to MDCK cells (from -16.5 to -73.4%, P < 0.05) were observed in the four females but not in the males after consumption of the cranberry extracts compared to the same animals consuming the control diet. Dietary supplementation with cranberry may provide some degree of protection to female dogs against adhesion of uropathogenic E. coli to urinary epithelial cells.


B*39:60, a novel HLA-B*39 allele identified by sequence-based typing.
The new allele B*39:60 showed one nucleotide difference with B*39:01:01 at codon 152 (GTG/GCG).


Autologous connective tissue bars as vehicles for the administration of growth-influencing substances to the brain.
One of the main problems in the introduction of growth factors or other substances into the CNS is that most of these do not pass the blood-brain barrier, and so they have to be delivered directly to the target cells. Recently, different methods of intracerebral administration have been introduced such as release of drugs from polymer matrix or hollow polymer fibres, implantation of solution-soaked gel foam pieces or genetically modified cells secreting growth factors. In our studies on regeneration in CNS, the problem of introducing active substances into the brain arose. For this reason we elaborated a new method for the administration of soluble factor by means of autologous connective tissue chambers filled with fibrin. This method is particularly suitable in studies in which the visualization of the regrowth of nerve fibres is one of the main purposes. Presence of an active substance inside the chamber fibres to grow in the direction of the chamber and such fibres can be visualized here. Such visualization is impossible while using other methods of trophic substance delivery into the CNS, e.g. intraventricular steel cannula connected to an osmotic minipump, because there is neither space nor appropriate milieu to allow the fibres' ingrowth. Retrograde tracing methods allow to establish the cells of origin of these fibres. This method is inexpensive, simple and adaptable to histological procedures.


MicroRNA-196a and -196b as Potential Biomarkers for the Early Detection of Familial Pancreatic Cancer.
Screening programs are recommended for individuals at risk (IAR) from families with familial pancreatic cancer (FPC). However, reliable imaging methods or biomarkers for early diagnosis of pancreatic ductal adenocarcinoma (PC) or its precursor lesions are still lacking. The ability of circulating microRNAs (miRNAs) to discriminate multifocal high-grade precursor lesions or PC from normal was examined. The presence of miRNA-21, -155, -196a, -196b and -210 was analyzed in the serum of transgenic KPC mice to test their ability to distinguish mice with different grades of pancreatic intraepithelial neoplasia (mPanIN1-3) or PC from control mice. Serum levels of miR-196a and -196b were significantly higher in mice with PanIN2/3 lesions (n = 10) or PC (n = 8) as compared to control mice (n = 10) or mice with PanIN1 lesions (n = 10; P = .01). In humans, miR-196a and -196b were also diagnostic. Patients with PC, sporadic (n = 9) or hereditary (n = 10), and IAR with multifocal PanIN2/3 lesions (n = 5) had significantly higher serum levels than patients with neuroendocrine pancreatic tumors (n = 10) or chronic pancreatitis (n = 10), IAR with PanIN1 or no PanIN lesions (n = 5), and healthy controls (n = 10). The combination of both miR-196a and -196b reached a sensitivity of 1 and specificity of 0.9 (area under the curve = 0.99) to diagnose PC or high-grade PanIN lesions. In addition, preoperative elevated serum levels of miR-196a and -196b in patients with PC or multifocal PanIN2/3 lesions dropped to normal after potential curative resection. The combination of miR-196a and -196b may be a promising biomarker test for the screening of IAR for FPC.


Lifestyle factors increasing adiponectin synthesis and secretion.
Adiponectin is an anti-inflammatory adipokine released from adipose tissue that is known to exert insulin-sensitizing effects in skeletal muscle and liver. Given that the secretion of adiponectin is impaired in obesity and related pathologies, strategies to enhance its synthesis and secretion are of interest. There is evidence that several lifestyle factors, including consumption of dietary long-chain n-3 PUFA, TZD administration, and weight loss can increase adiponectin synthesis and secretion. The effect of chronic exercise, independent of weight loss, is variable and less convincing. Potential mechanisms by which such lifestyle factors exert their favorable effects on adiponectin include activation of PPARγ and AMPK, regulation of posttranslational modifications, and changes in adipose tissue morphology and macrophage infiltration. As a clear role for adiponectin in mitigating obesity-related impairments in lipid metabolism and insulin sensitivity is evident, further research investigating factors that enhance adiponectin synthesis and secretion is distinctly warranted.


Melatonin.
Melatonin is a neurohormone that is secreted by the pineal gland and known to impact the sleep-wake cycle. Melatonin is regarded to be a safe and natural sleep aid. Since many people with tinnitus suffer sleep disturbance, melatonin has been studied as a therapeutic agent for tinnitus. A review of the literature suggests that melatonin has a beneficial effect on tinnitus, especially for patients with sleep disturbance, but it does not seem to modify the strength or frequency of the tinnitus.


The role of the visual system in migraine: an update.
The visual system plays a prominent role in migraine headache, especially migraine with aura. Anatomical and functional studies in migraine are showing an increasing role linking the visual system to migraine and its multiple and complex clinical expressions. Recent research on photophobia highlights the progress of our understanding of these relationships. This review overviews a practicing neurologist's view of some of the roles of the visual system in migraine and how a clinical understanding of this relationship is enhanced by recent research and discovery in this in this important area.


Balloon aortic valvuloplasty as a bridge to aortic valve replacement in critically ill patients.
This report highlights our experience in 5 patients with severe aortic stenosis and multiple organ failure undergoing balloon aortic valvuloplasty as a bridge to conventional aortic valve replacement. Balloon aortic valvuloplasty successfully stabilized the condition of these patients, improved organ function, and decreased their baseline risk profile. Elective aortic valve replacement was then performed without complications. Short-term palliation with balloon aortic valvuloplasty should be considered as a bridge to aortic valve replacement in selected patients with critical aortic stenosis and multiple organ failure.


Suppurative Staphylococcus aureus thyroiditis.
Suppurative thyroiditis with septicaemia caused by Staphylococcus aureus in a 65-year-old male patient with diabetes mellitus was diagnosed by needle aspiration. Antibiotic treatment and surgical drainage cured the patient.


Quick Spreading of Populations of an Exotic Firefly throughout Spain and Their Recent Arrival in the French Pyrenees.
In August 2018, a firefly (Coleoptera: Lampyridae) of American origin was observed in several localities in Girona (Catalonia, Spain) and was described as Photinus immigrans by Zaragoza-Caballero and Vinolas, 2018. Here, we show that this species dispersed very quickly throughout northeastern Spain and was, in 2020, observed in the French Pyrenees. The animal's quick progress is documented, and part of its biology is described (dispersion speed, land use, phenology, identification of all life stages). An additional population was localized in Extremadura, and its special status is discussed. We were able to determine its Argentinian-Uruguayan origin and propose, therefore, to consider Photinus immigrans as a synonym of Photinus signaticollis (Blanchard, 1846) (=Photinus immigrans Zaragoza-Caballero and Viñolas, 2018, syn. nov.). Our data clearly show that at least the Catalan and French populations are spreading very quickly and are able to settle permanently if adequate ecosystems are found. The species is highly expansive and may well be invasive; our citizen science platforms are ideally suited to monitor their progress throughout Spain and France. This is important for avoiding future ecological problems with diverse native faunas, such as glow-worms, fireflies and earthworms. If no ways are found to stop the species' progression, the animals will quite probably invade substantial areas of France, Spain and the rest of Europe in the years to come.


Family history of cancer and risk of sporadic differentiated thyroid carcinoma.
Thyroid cancer incidence in the United States, particularly in women, has increased dramatically since the 1980s. Although the causes of thyroid cancer in most patients remain largely unknown, evidence suggests the existence of an inherited predisposition to development of differentiated thyroid carcinoma (DTC). Therefore, the authors explored the association between sporadic DTC and family history of cancer. In a retrospective hospital-based case-control study of prospectively recruited subjects who completed the study questionnaire upon enrollment, unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the DTC risk associated with first-degree family history of cancer. The study included 288 patients with sporadic DTC and 591 cancer-free controls. Family history of thyroid cancer in first-degree relatives was associated with increased DTC risk (adjusted OR, 4.1; 95% CI, 1.7-9.9). All DTC cases in patients with a first-degree family history of thyroid cancer were cases of papillary thyroid carcinoma (PTC) (adjusted OR, 4.6; 95% CI, 1.9-11.1). Notably, the risk of PTC was highest in subjects with a family history of thyroid cancer in siblings (OR, 7.4; 95% CI, 1.8-30.4). In addition, multifocal primary tumor was more common among PTC patients with first-degree family history of thyroid cancer than among PTC patients with no first-degree family history of thyroid cancer (68.8% vs 35.5%, P = .01). The study suggests that family history of thyroid cancer in first-degree relatives, particularly in siblings, is associated with an increased risk of sporadic PTC.


Straining puborectalis reflex: description and significance of a "new" reflex.
The present communication studies the technique and clinical significance of a new reflex, termed straining puborectalis reflex. Nineteen healthy volunteers with an average age of 38.2 years were studied, including ten males and nine females. The intravesical pressure, representative of intra-abdominal pressure, was measured by means of a balloon-tipped catheter introduced into the urinary bladder and connected to a pressure transducer. The electromyographic (EMG) activity of the puborectalis muscle was recorded using a concentric needle electrode inserted into the muscle. The EMG response of the puborectalis muscle to straining at different pressures was recorded. The response to two types of straining--sudden momentary and slow, sustained--was observed. The procedure was repeated in ten subjects after puborectalis infiltration with xylocaine or saline. Sudden straining evoked puborectalis contraction, whereas slow, sustained straining did not. Puborectalis contraction increased with the increase in straining intensity. These results were reproducible. The anesthetized puborectalis did not respond to straining, whereas the saline-infiltrated muscle did. The latency of the reflex was studied. Besides its role as a voluntary continent sphincter, the puborectalis seems to have a role also in the involuntary continence of the pelvic organs through the straining-puborectalis reflex. The muscle contracts on sudden straining, sealing the rectal and vesical necks and thereby preventing fecal or urinary leak. However, it is only on sudden straining that the puborectalis contracts. Slow, sustained straining as occurs during defecation and micturition does not evoke the reflex action. The straining puborectalis reflex is informative and may be incorporated as an investigative tool in patients with fecal and urinary control disorders.


Cerebrospinal fluid viral antibodies in obsessive-compulsive disorder in an Indian population.
Immunoglobulin G viral antibodies for herpes simplex virus type 1, varicella zoster virus, cytomegalovirus, measles, and mumps were studied in 76 subjects with obsessive-compulsive disorder and compared with a control population. There was a significantly higher titer for herpes simplex virus type 1 antibodies. Sera: cerebrospinal fluid ratios were suggestive of intrathecal synthesis.


Therapeutic effects of high molecular weight hyaluronan injections for tendinopathy in a rat model.
Tendinopathy is the most common tendon disorder. The etiology is still uncertain, and the disorder poses many therapeutic problems. In a few clinical studies, analgesic effects of high molecular weight hyaluronan (HMW HA) injections were observed, but the underlying mechanisms were not elucidated. In the present study, we analyzed the therapeutic effects of hyaluronan injections for tendinopathy in an animal model. We made the tendinopathy rat model using a rodent treadmill machine. Rats with tendinopathy were injected with HMW HA (HA group), normal saline (NS group), or nothing (control group) into the space between the patellar tendon and the fat pad bilaterally, or were injected with HMW HA into the right knees and with saline to the left knees (HA/NS group), 5 times every 4 days. To assess the pain-relieving effect of HA, the spontaneous locomotor activities at night (12 h) and weight bearing of hind paws were measured every day. Histological sections of the patellar tendon stained with hematoxylin-eosin or prepared by TdT-mediated dUTP nick end labeling were microscopically analyzed. The number of spontaneous locomotor activities in the HA group was significantly larger than those in NS or control groups, and in the HA group they recovered up to a healthy level. The percent weight distribution of the right hind paws was significantly increased along with the number of injections. On histologic examinations, the numbers of microtears, laminations, or apoptotic cells in the patellar tendons in the HA group were significantly lower than those in the NS or the control groups. The injections of HMW HA were effective for pain relief and for partial restoration of the patellar tendon in our tendinopathy rat model, and thus may become an effective therapeutic modality for the disease.


Distinct populations of corticotropin-releasing factor (CRF) neurons mediate divergent yet complementary defensive behaviors in response to a threat.
Defensive behaviors in response to a threat are shared across the animal kingdom. Active (fleeing, sheltering) or passive (freezing, avoiding) defensive responses are adaptive and facilitate survival. Selecting appropriate defensive strategy depends on intensity, proximity, temporal threat threshold, and past experiences. Hypothalamic corticotropin-releasing factor (CRF) is a major driver of an acute stress response, whereas extrahypothalamic CRF mediates stress-related affective behaviors. In this review, we shift the focus from a monolithic role of CRF as an anxiogenic peptide to comprehensively dissecting contributions of distinct populations of CRF neurons in mediating defensive behaviors. Direct interrogation of CRF neurons of the central amygdala (CeA) or the bed nucleus of the stria terminalis (BNST) show they drive unconditioned defensive responses, such as vigilance and avoidance of open spaces. Although both populations also contribute to learned fear responses in familiar, threatening contexts, CeA-CRF neurons are particularly attuned to the ever-changing environment. Depending on threat intensities, they facilitate discrimination of salient stimuli predicting manageable threats, and prevent their generalization. Finally, hypothalamic CRF neurons mediate initial threat assessment and active defense such as escape to shelter. Overall, these three major populations of CRF neurons demonstrate divergent, yet complementary contributions to the versatile defense system: heightened vigilance, discriminating salient threats, and active escape, representing three legs of the defense tripod. Despite the 'CRF exhaustion' in the field of affective neuroscience, understanding contributions of specific CRF neurons during adaptive defensive behaviors is needed in order to understand the implications of their dysregulation in fear- and anxiety-related psychiatric disorders. This article is part of the Special Issue on "Fear, Anxiety and PTSD".


Stable SERS substrate based on highly reflective metal liquid-like films wrapped hydrogels for direct determination of small molecules in a high protein matrix.
The study of the interaction between small molecules and proteins is important. Surface-enhanced Raman spectroscopy (SERS) is suitable for such applications since it has the power of detecting a molecule based on its intrinsic nature and without labeling. Herein, the MeLLFs@PAAG SERS substrate supporting highly reflective metal liquid-like films (MeLLFs) with polyacrylamide hydrogels (PAAG) has high-density "hot spots" to provide excellent SERS activity. The MeLLFs@PAAG formed by AgNPs only has less than 15% SERS activity loss when stored in the air for more than three weeks. By using rhodamine 6G (R6G) as a model analyte, the AgNPs based MeLLFs@PAAG SERS substrate exhibits an enhancement factor (EF) as high as 8.0 × 106, a limit of detection (LOD) of 76.8 pM (S/N = 3). Also, the formed PAAG provided a 3D molecular network to orderly secure the assembled nanoparticles (NPs), which not only improves the stability of NPs but also shields the Raman signal of proteins as high as 45 g/L allowing the direct determination of the binding rate of human serum albumin (HSA) and doxorubicin (DOX). A binding rate of about 70% was detected, which is consistent with previous reports. Thus, proposed the MeLLFs@PAAG SERS substrate can be used as a promising candidate for SERS measurement in complex biological samples.


[Chronic pain, pain disease, and satisfaction of patients with pain treatment in Germany. Results of a representative population survey].
There are only few data from representative samples of the general German population on the prevalence of a "pain disease" and on satisfaction with pain therapy of persons with chronic pain available. A cross-sectional survey with people aged ≥ 14 years representative for the German population was conducted in 2013. Measures were obtained for presence of chronic pain (based on the definition of the International Association for the Study of Pain) and for "pain disease" by the presence of disabling pain in the Chronic Pain Grade Questionnaire and increased psychological distress in the Patient Health Questionnaire 4. In case of chronic pain reports, the satisfaction with current pain treatment and current treatment by a pain specialist were assessed. Responses were received from 2508 (57.5 %) of the 4360 people contacted. The prevalence of chronic pain was 26.9 % [95 % confidence interval (CI) 25.2-28.6 %]. A total of 7.4 % (95 % CI 5.0-9.9 %) met the criteria for chronic disabling nonmalignant pain, while 2.8 % (95 % CI 2.2-3.4 %) of participants met the criteria of a pain disease. In all, 31.9 % of persons with disabling pain reported current treatment by a pain specialist and 33.1 % of persons with disabling pain were (very) dissatisfied with current pain treatment. Treatment by a pain specialist was associated with higher health care use and lower treatment satisfaction. There is a need to improve the care of persons with chronic disabling pain. Whether pain specialist treatment is (cost) effective in chronic disabling pain needs to be examined by longitudinal studies.


Complete Genome Sequence of Escherichia coli Strain M8, Isolated from ob/ob Mice.
Escherichia coli is one of the common inhabitants of the mammalian gastrointestinal track. We isolated a strain from an ob/ob mouse and performed whole-genome sequencing, which yielded a chromosome of ~5.1 Mb and three plasmids of ~160 kb, ~6 kb, and ~4 kb.


Pronounced short stature in a girl with tricho-rhino-phalangeal syndrome II (TRPS II, Langer-Giedion syndrome) and growth hormone deficiency.
We report on a 10-year-old girl with tricho-rhino-phalangeal syndrome type II (TRPS II) and pronounced short stature (-4.8 SD). The patient has an interstitial chromosome 8q24.1 deletion of 12-15 Mb. The deletion spans all genes from CSMD3 to at least ANXA13 including the TRPS1 and EXT1 genes, which are responsible for the TRPS II phenotype. In addition to the features of TRPS II, the patient had growth hormone (GH) deficiency with diminished response in three stimulation tests. Therapy with 0.2 mg GH/kg/week led to an increase of growth velocity from 2.5 to 6.6 cm/year. To our knowledge, such a combination of TRPS II and GH deficiency has not yet been described.


Activation of ERK mitogen-activated protein kinase in human cells by the mycotoxin patulin.
Patulin (PAT), a mycotoxin produced by certain species of Penicillium and Aspergillus, is often detectable in moldy fruits and their derivative products. PAT led to a concentration-dependent and time-dependent increase in phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human embryonic kidney (HEK293) cells, human peripheral blood mononuclear cells (PBMCs), and Madin-Darby canine kidney (MDCK) cells. Exposure of HEK293 cells to concentrations above 5 microM PAT for 30 min induced ERK1/2 phosphorylation; activation of ERK1/2 was also observed after 24 h incubation with 0.05 microM of PAT. Treatment of human PBMCs for 30 min with 30 microM PAT dramatically increased the phosphorylated ERK1/2 levels. Both MEK1/2 inhibitors, U0126 and PD98059, suppressed ERK1/2 activation in either HEK293 or MDCK cells. In HEK293 cells, U0126-mediated inhibition of PAT-induced ERK1/2 phosphorylation resulted in a significant decrease in levels of DNA damage, expressed as tail moment values, in the single cell gel electrophoresis assay. Conversely, U0126 did not affect cell viability, lactate dehydrogenase release, and the DNA synthesis rate in PAT-treated cultures. Exposure of HEK293 cells for 90 min to 15 microM PAT elevated the levels of early growth response gene-1 (egr-1) mRNA, but not of c-fos, fosB, and junB mRNAs. These results indicate that in human cells, PAT causes a rapid and persistent activation of ERK1/2 and this signaling pathway plays an important role in mediating PAT-induced DNA damage and egr-1 gene expression.


Protein conformational dynamics and phenotypic switching.
Intrinsically disordered proteins (IDPs) are proteins that lack rigid 3D structure but exist as conformational ensembles. Because of their structural plasticity, they can interact with multiple partners. The protein interactions between IDPs and their partners form scale-free protein interaction networks (PINs) that facilitate information flow in the cell. Because of their plasticity, IDPs typically occupy hub positions in cellular PINs. Furthermore, their conformational dynamics and propensity for post-translational modifications contribute to "conformational" noise which is distinct from the well-recognized transcriptional noise. Therefore, upregulation of IDPs in response to a specific input, such as stress, contributes to increased noise and, hence, an increase in stochastic, "promiscuous" interactions. These interactions lead to activation of latent pathways or can induce "rewiring" of the PIN to yield an optimal output underscoring the critical role of IDPs in regulating information flow. We have used PAGE4, a highly intrinsically disordered stress-response protein as a paradigm. Employing a variety of experimental and computational techniques, we have elucidated the role of PAGE4 in phenotypic switching of prostate cancer cells at a systems level. These cumulative studies over the past decade provide a conceptual framework to better understand how IDP conformational dynamics and conformational noise might facilitate cellular decision-making.


Resectable pancreatic adenocarcinoma: Role of CT quantitative imaging biomarkers for predicting pathology and patient outcomes.
Patients with a pancreatic cancer amenable to surgery still have a poor prognosis and high risk of post-operative recurrence. We aimed to assess the value of quantitative imaging biomarkers using computed-tomography (CT) texture analysis to evaluate the pathologic tumor aggressiveness and predict disease-free survival (DFS) in patients with resectable pancreatic adenocarcinoma. We retrospectively performed attenuation measurements and texture analysis on the portal-venous phase of the pre-operative CT scan of 99 patients that underwent resection of a pancreatic ductal adenocarcinoma in two university hospitals. Tumor attenuation parameters included: mean attenuation value of the whole tumor (WHOLE-AV), and of the most hypoattenuating area within the tumor (CENTRAL-AV). Tumor heterogeneity parameters included: standard deviation, entropy, skewness, and kurtosis. Tumor attenuation parameters showed significant association with the tumor differentiation grade (CENTRAL-AV, Odds ratio (OR) 0.968, 95% confidence interval (CI) 0.94-0.998) and lymph node invasion (WHOLE-AV, OR 0.886, CI 0.823-0.955). Variables associated with early-recurrence were: lymph node ratio (R2=0.15), kurtosis (R2=0.08), and CENTRAL-AV (R2=0.04). Lymph node ratio (Hazard ratio (HR) 1.02), and CENTRAL-AV (HR 0.98) were independently associated with shorter DFS. Patients with CENTRAL-AV<62 Hounsfield units had a shorter 1-year DFS (35% versus 68%, p=0.004). Tumors that are more hypoattenuating on the portal-venous phase on CT scan are potentially more aggressive with higher tumor grade, greater lymph node invasion, and shorter DFS.


Therapeutic applications of toll-like receptors (TLRs) agonists in AML.
Acute myeloid leukemia (AML) is an aggressive type of blood cancer affecting bone marrow (BM). In AML, hematopoietic precursors are arrested in the early stages of development and are defined as the presence of ≥ 20% blasts (leukemia cells) in the BM. Toll-like receptors (TLR) are major groups of pattern recognition receptors expressed by almost all innate immune cells that enable them to detect a wide range of pathogen-associated molecular patterns and damage-associated molecular patterns to prime immune responses toward adaptive immunity. Because TLRs are commonly expressed on transformed immune system cells (ranging from blasts to memory cells), they can be a potential option for developing efficient clinical alternatives in hematologic tumors. This is because several in vitro and in vivo investigations have demonstrated that TLR signaling increased the immunogenicity of AML cells, making them more vulnerable to T cell-mediated invasion. This study aimed to review the current knowledge in this field and provide some insight into the therapeutic potentials of TLRs in AML.


Emergency treatment of variceal haemorrhage.
For the initial control of haemorrhage from oesophageal varices, two methods of vasopressin administration have been compared--the conventional bolus of 20 units and a low dose infusion of 0.4 units per minute. Twenty patients bleeding from oesophageal varices, confirmed by endoscopy, were allocated into either treatment group (10 in each). Vasopressin infusion stopped bleeding in 86 per cent of the episodes in contrast to 12.5 per cent (P less than 0.01) with bolus doses. Balloon tamponade with a Sengstaken-Blakemore tube was used to control bleeding in only 2 episodes in patients on infusion and in 10 episodes in patients on bolus doses of vasopressin (P less than 0.05). Our study confirms that low dose vasopressin infusion in more effective in controlling bleeding from oesophageal varices than conventional bolus doses.


Allocation of scarce resources in a pandemic: rapid systematic review update of strategies for policymakers.
In pandemics like COVID-19, the need for medical resources quickly outpaces available supply. policymakers need strategies to inform decisions about allocating scarce resources. We updated a systematic review on evidence-based approaches and searched databases through May 2020 for evaluation of strategies for policymakers. The 201 identified studies evaluated reducing demand for healthcare, optimizing existing resources, augmenting resources, and adopting crisis standards of care. Most research exists to reduce demand (n = 149); 39 higher quality studies reported benefits of contact tracing, school closures, travel restrictions, and mass vaccination. Of 28 strategies to augment resources, 6 higher quality studies reported effectiveness of establishing temporary facilities, use of volunteers, and decision support software. Of 23 strategies to optimize existing resources, 12 higher quality studies reported successful scope of work expansions and building on existing interagency agreements. Of 15 COVID-19 studies, 5 higher quality studies reported on combinations of policies and benefits of community-wide mask policies. Despite the volume, the evidence base is limited; few strategies were empirically tested in robust study designs. The review provides a comprehensive overview of the effects of strategies to allocate resources and provides critical appraisal to identify the best available evidence.


Effect of water immersion on seminal stains on cotton cloth.
Reports on identification of seminal stains and spermatozoa on washed clothing are available. However, their detection on such clothing seems to depend on the washing material and the procedure adopted. It is reported here that prolonged immersion in water does not affect the detection of stains and spermatozoa. Results of experiments on water-immersed cotton clothing from 12 to 144 hours of water immersion are presented here. It is seen that intact human spermatozoa could be detected on such material even at 120 hours.


Treatment of chronic hepatitis due to hepatitis B and hepatitis delta virus coinfection.
An estimated 20-40 million individuals worldwide are infected with hepatitis delta virus (HDV), mostly with rapidly evolving liver disease. Therapy of chronic HDV infection remains an unmet need. To date, only interferon (IFN)-based therapy is recommended for HDV infection and response rates are unsatisfactory; in addition, many patients are intolerant to or ineligible for IFN treatment. In recent years, innovative approaches have been in development, including the following: targeting virus entry into hepatocytes; inhibition of the host enzyme farnesyltransferase by prenylation inhibitors, leading to inhibition of complete virion formation and release; blockade of hepatitis B surface antigen (HBsAg) secretion, inhibiting virus release; and IFN-lambda, which causes fewer adverse effects than IFN-alfa. Clinical trials are ongoing with encouraging preliminary results.


Greater variability in lipid measurements associated with kidney diseases in patients with type 2 diabetes mellitus in a 10-year diabetes cohort study.
This study aimed to evaluate the associations between variability of lipid parameters and the risk of kidney disease in patients with type 2 diabetes mellitus. Low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were specifically addressed in this study. This retrospective cohort study included 105,552 patients aged 45-84 with type 2 diabetes mellitus and normal kidney function who were managed under Hong Kong public primary care clinics during 2008-2012. Those with kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2 or urine albumin to creatinine ratio ≥ 3 mg/mmol) were excluded. Variabilities of low-density lipoprotein-cholesterol, total cholesterol to high-density lipoprotein-cholesterol ratio and triglyceride were determined using the standard deviation of the respective parameter obtained from a mixed effects model to minimize regression dilution bias. The associations between lipid variability and renal outcomes including incident kidney disease, renal function decline defined as ≥ 30% reduction in estimated glomerular filtration rate since baseline, and end-stage renal disease (estimated glomerular filtration rate < 15 mL/min/1.73 m2) were evaluated by multivariable Cox regression. After a median follow-up of 66.5 months (0.5 million person-years in total), 49,653 kidney disease, 29,358 renal function decline, and 1765 end-stage renal disease cases were recorded. Positive linear associations between low-density lipoprotein-cholesterol and total cholesterol to high-density lipoprotein-cholesterol ratio variabilities and the risk of all renal outcomes were demonstrated. However, no association between triglyceride variability and any outcome was found. Each mmol/L increase in low-density lipoprotein-cholesterol variability was associated with 20% (Hazard ratio 1.20 [95% CI 1.15-1.25]), 38% (Hazard ratio 1.37 [95% CI 1.30-1.45]), and 108% (Hazard ratio 2.08 [95% CI 1.74-2.50]) higher risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Similarly, each unit increase in total cholesterol to high-density lipoprotein-cholesterol ratio variability was associated with 35% (Hazard ratio 1.15 [95% CI 1.10-1.20]), 33% (Hazard ratio 1.33 [95% CI 1.26-1.40]), and 75% (Hazard ratio 1.75 [95% CI 1.46-2.09]) heightened risk in incident kidney disease, renal function decline and end-stage renal disease respectively. Cholesterol variability may potentially be a useful predictor of kidney diseases in patients with type 2 diabetes mellitus. Attention should be drawn to cholesterol variability when managing diabetic patients and further research is warranted to investigate the modifiable risk factors for lipid variability.


Distress and depression among patients with diabetes mellitus: prevalence and associated factors: a cross-sectional study.
This study aimed to validate the internal consistency of the Persian version of the diabetes distress scale-17 (DDS-17) and to investigate the prevalence of diabetes distress (DD), depression, and possible relevant factors. This was a cross-sectional study on 820 diabetes patients (62.4 % females) in Tehran, Iran between January and June 2017. The Ethics Committee of Shahid Beheshti University of Medical Sciences approved the protocol. Patients filled out a demographic and health survey, DDS-17, the Beck Depression Inventory Second Edition (BDI-II) and the Summary of Diabetes Self-Care Activities Measure (SDSCA). DDS-17 consist of emotional burden, and physician, regimen, and interpersonal related distress. The correlation between DDS subscales and association between DDS and BDI-II or SDSCA scores were assessed using SPSS. The mean age was 58.91 ± 12.35 years. Majority of patients had high DD (37.2 %) and severe depression (38.7 %). The general and specific diets got the highest score in six SDSCA subscales. The Persian version of DDS-17 had excellent internal consistency with Cronbach's alpha coefficient of 0.924. The DDS score had significant relationship with socioeconomic level (p < .001), type of DM (p < .001), type of treatment (p < .001), glycemic control status (p < .001), complication (p < .001) and depression level (p < .001). The level of hemoglobin A1c was the most useful predictor of DDS score (p < .001). High prevalence of depression and distress in patient with diabetes calls for greater emphasizes on the importance of enhanced physicians and patients' knowledge in these areas.


Activation of LIMK1 by binding to the BMP receptor, BMPRII, regulates BMP-dependent dendritogenesis.
The growth and morphological differentiation of dendrites are critical events in the establishment of proper neuronal connectivity and neural function. One extrinsic factor, BMP7, has been shown to specifically affect dendritic morphogenesis; however, the underlying mechanism by which this occurs is unknown. Here we show that LIM kinase 1 (LIMK1), a key downstream effector of Rho GTPases, colocalizes with the BMP receptor, BMPRII, in the tips of neurites and binds to BMPRII. This interaction is required for BMP-dependent induction of the dendritic arbor in cortical neurons. Furthermore, we demonstrate that the physical interaction of LIMK1 with BMPRII synergizes with the Rho GTPase, Cdc42, to activate LIMK1 catalytic activity. These studies thus define a Smad-independent pathway that directly links the BMP receptor to regulation of actin dynamics and provides insights into how extracellular signals modulate LIMK1 activity to permit fine spatial control over cytoskeletal remodelling during dendritogenesis.


Cytokine expression by peripheral blood neutrophils from heaves-affected horses before and after allergen challenge.
Heaves, also known as recurrent airway obstruction, is a common condition of horses characterised by pulmonary neutrophilia and reversible airway obstruction. This study evaluated the role of neutrophils in producing cytokines and chemokines that might be involved in the recruitment and activation of inflammatory cells in horses with heaves. Peripheral neutrophils were isolated from heaves-affected (n = 9) and control (n = 4) horses before and after 5 h of natural inhalation challenge. Expression of mRNA of two pro-inflammatory cytokines, tumour necrosis factor (TNF)-alpha and interleukin (IL)-1beta, along with two chemokines, IL-8 and macrophage inflammatory protein (MIP)-2, was evaluated. After exposure to mouldy hay, horses with heaves had significant airway obstruction and increased numbers of neutrophils in bronchoalveolar lavage samples, compared to control horses. However, there were no differences in the expression of mRNAs of TNF-alpha, IL-1beta, IL-8 and MIP-2 between the two groups, suggesting that the release of cytokines and chemokines by peripheral blood neutrophils is not necessary for the development of heaves.


Additional Expiratory Resistance Elevates Airway Pressure and Lung Volume during High-Flow Tracheal Oxygen via Tracheostomy.
The standard high-flow tracheal (HFT) interface was modified by adding a 5-cm H2O/L/s resistor to the expiratory port. First, in a test lung simulating spontaneous breathing, we found that the modified HFT caused an elevation in airway pressure as a power function of flow. Then, three tracheal oxygen treatments (T-piece oxygen at 10 L/min, HFT and modified HFT at 40 L/min) were delivered in a random crossover fashion to six tracheostomized pigs before and after the induction of lung injury. The modified HFT induced a significantly higher airway pressure compared with that in either T-piece or HFT (p < 0.001). Expiratory resistance significantly increased during modified HFT (p < 0.05) to a mean value of 4.9 to 6.7 cm H2O/L/s. The modified HFT induced significant augmentation in end-expiratory lung volume (p < 0.05) and improved oxygenation for lung injury model (p = 0.038) compared with the HFT and T-piece. There was no significant difference in esophageal pressure swings, transpulmonary driving pressure or pressure time product among the three treatments (p > 0.05). In conclusion, the modified HFT with additional expiratory resistance generated a clinically relevant elevation in airway pressure and lung volume. Although expiratory resistance increased, inspiratory effort, lung stress and work of breathing remained within an acceptable range.


Selectivity of the ubiquitin pathway for oxidatively modified proteins: relevance to protein precipitation diseases.
There is now consensus that the accumulation of oxidatively modified proteins is cytotoxic and causally related to several age-related diseases, including the amyloid diseases and age-related cataracts. There is also general agreement that proteolytic pathways provide a quality control mechanism to limit accumulation of damaged proteins. Although many researchers assume that the ubiquitin pathway is involved in recognition and proteolytic removal of oxidatively modified proteins, which are produced upon cellular stress, there has been no direct evidence to support this hypothesis. In this work, we used a novel proteolysis-resistant ubiquitin variant to demonstrate that ubiquitin conjugates isolated from oxidatively stressed mammalian cells are enriched 3.3-15-fold for oxidatively modified proteins and that failure to execute ubiquitin-dependent proteolysis renders various cell types more susceptible to oxidative stress-related cytotoxicity. These results were corroborated using several inhibitors of the ubiquitin proteasome pathway, including PS-341, an anticancer drug in clinical use. Taken together the data indicate that the ubiquitin proteolytic pathway recognizes and removes oxidatively modified proteins, and that failure of this system, as occurs upon aging or stress, may be involved in and exacerbate cytotoxicity and age-related syndromes in which accumulation of ubiquitinated and oxidatively modified proteins has an etiologic role.


Evidence that 5-HT2 receptors predominantly mediate the contraction of the rat basilar artery to 5-hydroxytryptamine.
We characterised the 5-hydroxytryptamine (5-HT) receptor subtype which mediates the contraction of the rat isolated basilar artery, mounted in a myograph, by using agonists and antagonists for 5-HT1-like, 5-HT2, 5-HT3 and 5-HT4 receptors. The rank order of potency for a range of selective agonists was: 5-HT > alpha-methyl-5-HT > 5-carboxamidotryptamine > 2-methyl-5-HT > sumatriptan. The maximum contractions for these agonists (Emax) was less than for 5-HT while 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was devoid of contractile activity. Ketanserin antagonised the contractile effect of 5-HT in the rat basilar artery with a provisional pA2 estimate of 9.3 +/- 0.2. A similar antagonism was observed against alpha-methyl-5-HT. Ergometrine (0.01-1 microM) was devoid of any agonist activity but antagonised the contractile effect of 5-HT on the rat basilar artery with a provisional pKB of 8.7 (7.8-9.8, 95% confidence limits). The 5-HT3 and 5-HT4 receptor antagonist ICS 205930 (10 microM) did not alter the response to 5-HT. The high potency and efficacy of alpha-methyl-5-HT, poor effect of sumatriptan and antagonism of 5-HT by ergometrine and ketanserin, support the conclusion that the 5-HT2 receptors are primarily responsible for the 5-HT-induced contraction of rat basilar artery.


Instrumental evaluation of gait smoothness and history of falling in older persons: results from an exploratory case-control study.
Gait smoothness, perceived when a person walks continuously and uninterruptedly, is associated with an undisrupted gait pattern, good sensorimotor control, and a lower risk of falling. The spectral arc length (SPARC) is a quantitative metric proposed for the evaluation of movement smoothness from the signal obtained by wearable sensors. In this small exploratory case-control study, older persons with and without a history of injurious falls underwent a turn-test while wearing an accelerometer: gait smoothness was estimated by calculating SPARC during the straight and turning phases. Cases seemed to exhibit lower SPARC values during the turning phase, in comparison with control.


Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response.
Little is known about either the basal or stimulated homeostatic mechanisms regulating nuclear tenure of Nf-e2-related factor 2 (Nrf2), a transcription factor that mediates expression of over 200 detoxification genes. Our data show that stress-induced nuclear Nrf2 accumulation is largely from de novo protein synthesis, rather than translocation from a pre-existing cytoplasmic pool. HepG2 cells were used to monitor nuclear Nrf2 24h following treatment with the dithiol micronutrient (R)-α-lipoic acid (LA; 50μM), or vehicle. LA caused a ≥2.5-fold increase in nuclear Nrf2 within 1h. However, pretreating cells with cycloheximide (50μg/ml) inhibited LA-induced Nrf2 nuclear accumulation by 94%. Providing cells with the mTOR inhibitor, rapamycin, decreased basal Nrf2 levels by 84% after 4h, but LA overcame this inhibition. LA-mediated de novo protein translation was confirmed using HepG2 cells transfected with a bicistronic construct containing an internal ribosome entry sequence (IRES) for Nrf2, with significant (P<0.05) increase in IRES use under LA treatment. These results suggest that a dithiol stimulus mediates Nrf2 nuclear tenure via cap-independent protein translation. Thus, translational control of Nrf2 synthesis, rather than reliance solely on pre-existing protein, may mediate the rapid burst of Nrf2 nuclear accumulation following stress stimuli.


[Relation between the carcinogenic activity of conjugated polycyclic hydrocarbons and the form of their localized molecular orbitals].
The carcinogenic activity of some compounds is linked to the electronic structure of their molecules. The authors calculate the localized molecular orbitals (LMO) by means of a topologic method they have developed, based in the electronic distribution of a single molecular region, that coincides or is next to the K region, instead of having to consider the two classical regions (K and L).


Combination of modified Broström procedure with ankle arthroscopy for chronic ankle instability accompanied by intra-articular symptoms.
To evaluate the effectiveness of the modified Broström procedure combined with ankle arthroscopy for chronic ankle instability (CAI) accompanied by intra-articular symptoms. We identified 85 consecutive patients with CAI (87 ankles). There were 58 male patients (58 ankles) and 27 female patients (29 ankles) with a mean age of 24.4 years (range, 14 to 36 years). All the patients had intra-articular symptoms. Ankle arthroscopic surgery was performed initially to manage any intra-articular lesions. This was followed by the modified Broström procedure, including shortening of the anterior talofibular ligament and/or calcaneofibular ligament, as well as extensor retinaculum augmentation. All the intra-articular lesions found during surgery were recorded. American Orthopaedic Foot & Ankle Society (AOFAS) scores were obtained before surgery and at follow-up. Intra-articular lesions were found in 79 ankles (90.8%), including 75 with synovitis and soft-tissue impingement, 33 with chondral injuries, 23 with anterior tibial osteophytes, 7 with loose bodies, and 6 with distal tibiofibular syndesmosis injuries. A total of 79 patients (92.9%) (81 ankles) were followed up for a mean of 29 months (range, 12 to 47 months). The mean AOFAS score improved from 46.6 +/- 8.1 preoperatively to 86.5 +/- 7.6 postoperatively (P < .05). Mean postoperative AOFAS scores were significantly higher in patients without chondral lesions than in those with chondral lesions (89.76 +/- 5.88 and 81.35 +/- 7.18, respectively; P < .05). Improvements in AOFAS scores after surgery were significantly greater in patients without chondral lesions than in those with chondral lesions (42.28 +/- 9.04 and 36.06 +/- 11.85, respectively; P < .05). The modified Broström procedure combined with ankle arthroscopy produced satisfactory surgical outcomes in patients with CAI and intra-articular symptoms. Accompanying chondral injuries were associated with poorer surgical outcomes. Level IV, therapeutic case series.


Clinical Profile and Outcome of Newborns Discharged Against Medical Advice From a Tertiary Care Centre.
To determine the clinical profile and outcome of neonates discharged against medical advice (DAMA) from the neonatal intensive care unit (NICU) of a tertiary care public hospital. We retrieved information from hospital records of infants who had been discharged against medical advice from the NICU between January, 2016 and December, 2020. This was followed by a telephonic interview to document the infant's outcome. Out of the 187 (7.7%) neonates that had left DAMA, 165 case records were available, and 65 (39%) families could be contacted telephonically. Congenital malformations accounted for 96 (58%) of the cases; cardiac malformations accounting for 42 (43.7%). 52 (80%) out of the 65 infants had died after median (IQR) 11 (5-35) days of DAMA, and 13 (20%) were alive at a median (IQR) age of 31 (18.5-31.5) months. Post-DAMA medical care was continued at another health facility in 12 (18%). One out of every five infants was alive for a median age of 31 months after having left DAMA. Mechanisms to ensure continuation of care after DAMA need to be explored.


Prevalence of dementia and distribution of ApoE alleles in Japanese centenarians: an almost-complete survey in Yamanashi Prefecture, Japan.
To determine the prevalence and types of dementia in centenarians and to examine whether the ApoE epsilon 4 allele has significant impact on the development of Alzheimer's disease (AD) in the population. Cross-sectional study and a 6-month prospective study. Yamanashi Prefecture, Japan. Forty-seven centenarians participated in the study to determine the prevalence and types of dementia. Thirty-three of the 47 participated in the study of ApoE genotyping. As controls, 224 demented older adults participated in the genetic study. Their age at onset was < 90 years. Prevalence of dementia based on DSM-III-R; types of dementia based on NINCDS-ADRDA and ICD-10; distribution on ApoE alleles in the centenarians and in the controls; and the 6-month mortality rate of the subjects. Of 47 centenarians, 70.2% had dementia, and AD accounted for the majority (75.8%) of the dementia cases. The distribution of ApoE alleles in all the subjects and the AD subjects was epsilon 2: 4.6% vs. 0%; epsilon 3: 90.1% vs. 94.1%; epsilon 4: 4.6% vs. 5.9%. The frequency of the epsilon 4 allele in the AD patients showed a tendency to decrease with increasing age, ranging from 38% for those with an age at onset of < 60 years to 22% for those with an age at onset of ranging from 80 to 89 years. The 6-month mortality rate was 27% (9/33) for the demented centenarians, whereas none of the 14 nondemented centenarians died. This almost-complete survey, conducted in a prefecture of Japan, revealed a high prevalence of dementia in centenarians. The ApoE epsilon 4 allele does not have an impact on the development of AD in centenarians.


Predicting suicidal and self-injurious events in a correctional setting using AI algorithms on unstructured medical notes and structured data.
Suicidal and self-injurious incidents in correctional settings deplete the institutional and healthcare resources, create disorder and stress for staff and other inmates. Traditional statistical analyses provide some guidance, but they can only be applied to structured data that are often difficult to collect and their recommendations are often expensive to act upon. This study aims to extract information from medical and mental health progress notes using AI algorithms to make actionable predictions of suicidal and self-injurious events to improve the efficiency of triage for health care services and prevent suicidal and injurious events from happening at California's Orange County Jails. The results showed that the notes data contain more information with respect to suicidal or injurious behaviors than the structured data available in the EHR database at the Orange County Jails. Using the notes data alone (under-sampled to 50%) in a Transformer Encoder model produced an AUC-ROC of 0.862, a Sensitivity of 0.816, and a Specificity of 0.738. Incorporating the information extracted from the notes data into traditional Machine Learning models as a feature alongside structured data (under-sampled to 50%) yielded better performance in terms of Sensitivity (AUC-ROC: 0.77, Sensitivity: 0.89, Specificity: 0.65). In addition, under-sampling is an effective approach to mitigating the impact of the extremely imbalanced classes.


Supramolecular salicylic acid ameliorates rosacea-like eruptions by suppressing NLRP3-mediated inflammasome activation in mice.
Rosacea is a chronic inflammatory skin disease with immunological dysfunction. Supramolecular salicylic acid (SSA) has the properties of keratolytic, antibacterial, and anti-inflammatory. However, the mechanism of SSA in the treatment of rosacea is still unclear. To investigate the efficiencies and molecular mechanisms of SSA in rosacea. Forty mice were randomly divided into four groups (10 in each group): control, LL-37, LL-37 + azelaic acid (AzA), and LL-37 + SSA. Forty μl LL-37 (320 μM) was administered intradermally into the dorsal skin of the mice in the latter 3 groups every 12 h and 4 times altogether (0 h, 12 h, 24 h, 36 h). Twenty % AzA was applied on the eruptions after the first and third LL-37 injection (0 h, 24 h) in LL-37 + AzA group, while 30 % SSA was applied after the first injection (0 h) in LL-37 + SSA group. The redness score and redness area were evaluated. The skin barrier function was measured by the transepidermal water loss (TEWL) and pH. The infiltration of inflammatory cells was evaluated by hematoxylin-eosin staining, and the inflammatory biomarkers were analyzed by RT-PCR and immunohistochemistry. SSA alleviated LL-37-induced rosacea-like inflammation. The increased TEWL and pH induced by LL-37 were also reversed by SSA. In addition, SSA reduced inflammatory cell infiltration and suppressed the production of Toll-like receptor 2, Matrix metallopeptidase 9, kallikrein 5, LL-37 associated with rosacea, and inhibited LL-37-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3)-mediated inflammasome activation in mice. Our findings indicated that SSA ameliorated LL-37-induced rosacea-like lesions by suppressing NLRP3-mediated inflammasome activation in mice.


Characterization of contrasting genotypes reveals general physiological and molecular mechanisms of heat-stress adaptation in maize (Zea mays L.).
In order to dissect the adaptation response of maize to heat-stress, we characterized and juxtaposed different physio-biochemical parameters for two contrasting genotypes, namely DTPYC9F119 (heat-stress tolerant) and K64R (heat-stress susceptible) under 6 days heat treatment (38/28 °C). Chlorophyll a and b content was found to be reduced under high temperature in both the genotypes, but, it was reduced more prominently in the susceptible genotype (K64R). Net photosynthetic rate was significantly reduced under high temperature in K64R but this reduction was relatively lower in case of DTPYC9F119. Stomatal conductance was increased under stress treatment in both the genotypes but the rate of increase was lower in tolerant one (DTPYC9F119). Activity of anti-oxidant enzymes (viz. catalase, peroxidase and superoxide dismutase) and their gene expression was increased in both the genotypes under heat-stress condition. Thus, the heat-stress tolerant genotype has evolved some strategies like modulation of anti-oxidant gene expression, lower transpiration rate, lower increase of internal CO2 concentration which could make sustain a basic level of photosynthesis even under high temperature stress, etc. that may contribute to its tolerance trait.


Deep Neural Network-based Video Processing to Obtain Upper-Extremity Motor Performance Toward Assessment of Cognitive and Motor Function.
Dementia is an increasing global health challenge. Motoric Cognitive Risk Syndrome (MCR) is a predementia stage that can be used to predict future occurrence of dementia. Traditionally, gait speed and subjective memory complaints are used to identify old adults with MCR. Our previous studies indicated that dual-task upper-extremity motor performance (DTUEMP) quantified by a single wrist-worn sensor was correlated with both motor and cognitive function. Therefore, the DTUEMP had a potential to be used in the diagnosis of MCR. Instead of using inertial sensors to capture kinematic data of upper-extremity movements, here we proposed a deep neural network-based video processing model to obtain DTUEMP metrics from a 20-second repetitive elbow flexion-extension test under dual-task condition. In details, we used a deep residual neural network to obtain joint coordinate set of the elbow and wrist in each frame, and then used optical flow method to correct the joint coordinates generated by the neural network. The coordinate sets of all frames in a video recording are used to generate angle sequence which represents rotation angle of the line between the wrist and elbow. Then, the DTUEMP metrics (the mean and SD of flexion and extension phase) are derived from angle sequence. Multi-task learning (MTL) is used to assess cognitive and motor function represented by MMSE and TUG scores based on DTUEMP metrics, with single-task learning (STL) linear model as a benchmark. The results showed a good agreement (r ≥ 0.80 and ICC ≥ 0.58) between the derived DTUEMP metrics from our proposed model and the ones from clinically validated sensor processing model. We also found that there were correlations with statistical significance (p < 0.05) between some of video-derived DTUEMP metrics (i.e. the mean of flexion time and extension time) and clinical cognitive scale (Mini-Mental State Examination, MMSE). Additionally, some of video-derived DTUEMP metrics (i.e. the mean and standard deviation of flexion time and extension time) was also associated with the scores of timed-up and go (TUG) which is a gold standard to measure functional mobility. Mean absolute percentage error (MAPE) of MTL surpassed that of STL (For MMSE, MTL: 18.63%, STL: 23.18%. For TUG, MTL: 17.88%, STL: 22.53%). The experiments with different light conditions and shot angles verified the robustness of our proposed video processing model to extract DTUEMP metrics in potentially various home environments (r ≥ 0.58 and ICC ≥ 0.71). This study shows possibility of replacing sensor processing model with video processing model for analyzing the DTUEMP and a promising future to adjuvant diagnosis of MCR via a mobile platform.


Hippocampal leptin signaling reduces food intake and modulates food-related memory processing.
The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 μg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 μg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.


A prospective evaluation of radiologic criteria for head injury patients in a community emergency department.
Several management strategies for radiographic evaluation of head-injury patients have been developed, most are based on retrospective analysis. The study attempted to prospectively evaluate the previously published Masters' criteria defining low-, medium-, and high-yield patients. A community hospital emergency department with a low prevalence of serious head injury was studied, and 1,000 consecutive patients 2 years of age presenting with historical or physical evidence of blunt head trauma were asked to participate; 967 consented. The patients were categorized by staff emergency physicians as low-, moderate-, and high-yield for intracranial injury on the basis of their initial history and physical examination. These categories guided imaging decisions in accordance with the guidelines of Masters. The patients were evaluated 6 weeks later by multiple questionnaire and/or telephone calls to determine whether or not undiagnosed head injuries had been missed. The 967 patients initially evaluated were classified according to their risk of intracranial injury as follows: 886 at low risk, 78 at moderate risk and 3 at high risk. Complete follow-up data were available for 895 of these patients (93%). Of the 895, 71 patients (7.9%) did report receiving follow-up medical care for their head injury; none had evidence of missed intracranial injury requiring intervention. Therefore, it can be inferred with a 95% confidence interval that 0.4% or less of patients who were diagnosed as not having intracranial injuries requiring intervention may actually have such injuries. The application of Masters' management strategy in low-risk populations permits clinicians to safely reduce the number of radiographs ordered for patients with head injury.


Discordant Bilateral Testicular Pathology Does not Affect Sperm Retrieval Rate in Bilateral Microdissection Testicular Sperm Extraction (mTESE).
To assess the incidence of discordant testicular pathology in men undergoing bilateral microdissection testicular sperm extraction (mTESE) and association with sperm retrieval rate. We performed a retrospective single-institutional review of all patients undergoing mTESE from 2007 to 2021 and aggregated clinical history, physical exam, semen analysis, and operative findings. Specimens with discordant pathology were re-reviewed by an experienced genitourinary.ßpathologist and categorized in a standardized fashion. Data were analyzed using SPSS. One hundred fourteen non-obstructive azoospermia.ßmen undergoing 132 mTESEs were identified within the study period. Eighty-five percent (112/132) of cases had pathology specimens available, and within this specific cohort the success rate was 41.9% (47/112). A total of 206 pathological reports resulted including 52.4% Sertoli cell only, 4.9% Leydig cell hyperplasia, 8.7% fibrosis, 16.5% maturation arrest, and 17.5% hypospermatogenesis. Twelve percent of testicles had more than 1 pathologic diagnosis. Sixty-six men had synchronous bilateral testicular pathology, and 11/66 (16.6%) had at least partially discordant pathology on initial review. Focused re-review by a genitourinary pathologist confirmed exclusively discordant pathology in 7/66 (10.6%) cases, with a sperm retrieval rate of 57% (4/7). The sperm retrieval rate.ßin men with discordant pathology was not significantly different from those with concordant pathology. Over 1 in 10 men undergoing mTESE may have discordant pathology between testicles, though this may not affect sperm retrieval rate.ßat the time of procedure. Clinicians should consider submitting bilateral testicular specimens for pathology to (1) clarify their outcomes data, and (2) assist with clinical decision-making and surgical planning if a repeat mTESE is indicated.


Effect of the biochemical state of the Ca-ATPase protein of scallop sarcoplasmic reticulum on its interaction with trans-parinaric acid.
The polyene fluorescent probe trans-parinaric acid (tPA) was used to compare lipid-protein interactions in the scallop fragmented sarcoplasmic reticulum (FSR) between biochemical states where the Ca-ATPase molecules were arranged differently in the membrane and had different tertiary conformations. The state of the bulk lipid phase was examined over the temperature range -3 to +32 degrees C by exciting the tPA directly at 320 nm. The state of the system close to the Ca-ATPase protein was followed over the same temperature range by indirectly exciting the tPA through resonance energy transfer from the Ca-ATPase protein, with approximately one twenty-fifth the quantum yield of the directly excited probe. Raising the tPA/lipid ratio in the membrane to high levels (approx. 1:9), caused the quantum yield of indirectly excited tPA to reach a maximum, which may reflect saturation of the annular lipid phase with the probe, or contribution to the fluorescence from indirectly excited tPA bound directly to the protein. In the presence of 0.1 M KCl, a thermal perturbation was observed at approx. 7 degrees C using indirect excitation when the Ca(2+)-binding sites on the Ca-ATPase were occupied, and the subunits were disorganized. This transition was not detected in the presence of 0.1 M KCl and EGTA, when the Ca(2+)-binding sites were empty, and the Ca-ATPase subunits were organized in dimeric arrays. The transition seen with the E1(Ca2+)2 form of the membrane may involve an event at the protein/lipid interface, or a change in the environment of tPA bound to the Ca-ATPase. The temperature at which the perturbation occurs is close to that of a discontinuity in the Arrhenius plot of the Ca-ATPase enzyme activity determined in the presence of 0.1 M KCl (Kalabokis, V.N. and Hardwicke, P.M.D. (1988) J. Biol. Chem. 263, 15184-15188). No perturbation was observed in the bulk properties of the lipid component of the membrane in either the E1(Ca2+)2 or E2 states.


Adenosine 3',5'cyclic monophosphate in adipose tissue of diabetic rats.
Normal male rats were made chronically diabetic by injection of alloxan or acutely diabetic by injection of anti-insulin serum. The concentration of cyclic AMP in epididymal adipose tissue was increased approximately 2 1/2-fold 24 h after alloxan administration and up to 7-fold 72 h post-alloxan. Treatment of alloxan-diabetic rats with insulin for 4 h completely suppressed lipolysis but only partially suppressed cyclic AMP levels; 6 h following insulin treatment cyclic AMP levels were normal. When segments of the epididymal fat bodies were incubated in vitro the high cyclic AMP levels were not maintained but instead decreased spontaneously. Addition of insulin to the incubation media decreased lipolysis in tissues of diabetic rats to levels measured in tissues of normal rats and accelerated the decline in cyclic AMP levels but did not return cyclic AMP levels to normal. Rats rendered acutely insulin deficient by injection of anti-insulin serum showed increased plasma glucose and free fatty acid levels and increased adipose tissue free fatty acid, and cyclic AMP levels 30 min following injection of the antiserum. Plasma glucagon levels increased but not until 2 h following anti-insulin serum, thereby excluding the possibility that an increment in plasma glucagon is the primary stimulus for the acceleration of lipolysis in diabetes. These data are consistent with the view that control of adipose tissue cyclic AMP levels in situ is an important physiologic action of insulin.


Some haemodynamic effects of compound AH 5158 compared with propranolol, propranolol plus hydrallazine, and diazoxide: the use of AH 5158 in the treatment of hypertension.
1. Intravenous administration of compound AH 5158, which possesses alpha- and beta-adrenergic receptor-blocking properties, produces haemodynamic effects similar to those seen from the combined effects of propranolol and hydrallazine. 2. Chronic oral administration has demonstrated that compound AH 5158 is an effective hypotensive agent capable of controlling the blood pressure in patients previously requiring large doses of drugs such as methyldopa. Some postural and exercise hypotension may be seen with larger doses.


Solubility of crystalline organic compounds in high and low molecular weight amorphous matrices above and below the glass transition by zero enthalpy extrapolation.
Pharmaceutical applications which require knowledge of the solubility of a crystalline compound in an amorphous matrix are abundant in the literature. Several methods that allow the determination of such data have been reported, but so far have only been applicable to amorphous polymers above the glass transition of the resulting composites. The current work presents, for the first time, a reliable method for the determination of the solubility of crystalline pharmaceutical compounds in high and low molecular weight amorphous matrices at the glass transition and at room temperature (i.e. below the glass transition temperature), respectively. The solubilities of mannitol and indomethacin in polyvinyl pyrrolidone (PVP) K15 and PVP K25, respectively were measured at different temperatures. Mixtures of undissolved crystalline solute and saturated amorphous phase were obtained by annealing at a given temperature. The solubility at this temperature was then obtained by measuring the melting enthalpy of the crystalline phase, plotting it as a function of composition and extrapolating to zero enthalpy. This new method yielded results in accordance with the predictions reported in the literature. The method was also adapted for the measurement of the solubility of crystalline low molecular weight excipients in amorphous active pharmaceutical ingredients (APIs). The solubility of mannitol, glutaric acid and adipic acid in both indomethacin and sulfadimidine was experimentally determined and successfully compared with the difference between their respective calculated Hildebrand solubility parameters. As expected from the calculations, the dicarboxylic acids exhibited a high solubility in both amorphous indomethacin and sulfadimidine, whereas mannitol was almost insoluble in the same amorphous phases at room temperature. This work constitutes the first report of the methodology for determining an experimentally measured solubility for a low molecular weight crystalline solute in a low molecular weight amorphous matrix.


Therapeutic failure in American cutaneous leishmaniasis is associated with gelatinase activity and cytokine expression.
Cutaneous lesions caused by Leishmania braziliensis infection occasionally heal spontaneously, but with antimonials therapy heal rapidly in approximately 3 weeks. However, about 15% of the cases require several courses of therapy. Matrix metalloproteinase-2 (MMP-2) and MMP-9 are gelatinases that have been implicated in other chronic cutaneous diseases and skin re-epithelialization. These enzymes are controlled by their natural inhibitors [tissue inhibitors of metalloproteinase (TIMPs)] and by some cytokines. Uncontrolled gelatinase activity may result in intense tissue degradation and, consequently, poorly healing wounds. The present study correlates gelatinase activity to therapeutic failure of cutaneous leishmaniasis (CL) lesions. Our results demonstrate an association between gelatinase activity and increased numbers of cells making interferon (IFN)-γ, interleukin (IL)-10 and transforming growth factor (TGF)-β in lesions from poor responders. Conversely, high levels of MMP-2 mRNA and enhanced MMP-2 : TIMP-2 ratios were associated with a satisfactory response to antimonials treatment. Additionally, high gelatinolytic activity was found in the wound beds, necrotic areas in the dermis and within some granulomatous infiltrates. These results indicate the importance of gelatinase activity in the skin lesions caused by CL. Thus, we hypothesize that the immune response profile may be responsible for the gelatinase activity pattern and may ultimately influence the persistence or cure of CL lesions.


Potential role of microRNAs as biomarkers in human glioblastoma: a mini systematic review from 2015 to 2020.
Glioblastoma (GBM) is the most common, aggressive and malignant type of glioma, with poor prognosis, despite advances in medical knowledge and technology. It's known that some microRNAs (miRNAs) can be dysregulated and associated with tumors. We aim to investigate miRNAs that may have a role as potential biomarkers in human glioblastoma. A search was performed using PubMed, LILACS and SCIELO databases to find papers from 2015 to 2020, related to human in vitro and ex vivo data. From 99 articles, 10 were eligible and 13 dysregulated miRNAs were found with description of regulation, target(s), pathway(s) and mechanism(s). The miRNAs of interest were found and seem to be involved in development and progression of glioblastoma and used as target therapies. Understanding the mechanisms in which those miRNAs are involved and their role in epigenetic pathways that lead to cancer, as well as their potential in clinical application, may improve GBM clinical outcome (CRD42020182706, 07/10/2020, retrospectively registered).


Peritoneal benign cystic mesothelioma.
A case of a benign cystic peritoneal mesothelioma is reported. A 25-year-old woman presented a 8-year history of recurrent tumor and five operations because of that. On the basis of this case and of 18 cases proved by electron microscopy reported by others, the clinicopathological features and the problems of differential diagnosis are discussed. The ultrastructural examination is essential for the diagnosis of cystic mesothelioma.


Review of dynamical models for external dose calculations based on Monte Carlo simulations in urbanised areas.
After an accidental release of radionuclides to the inhabited environment the external gamma irradiation from deposited radioactivity contributes significantly to the radiation exposure of the population for extended periods. For evaluating this exposure pathway, three main model requirements are needed: (i) to calculate the air kerma value per photon emitted per unit source area, based on Monte Carlo (MC) simulations; (ii) to describe the distribution and dynamics of radionuclides on the diverse urban surfaces; and (iii) to combine all these elements in a relevant urban model to calculate the resulting doses according to the actual scenario. This paper provides an overview about the different approaches to calculate photon transport in urban areas and about several dose calculation codes published. Two types of Monte Carlo simulations are presented using the global and the local approaches of photon transport. Moreover, two different philosophies of the dose calculation, the "location factor method" and a combination of relative contamination of surfaces with air kerma values are described. The main features of six codes (ECOSYS, EDEM2M, EXPURT, PARATI, TEMAS, URGENT) are highlighted together with a short model-model features intercomparison.


Studies on fd fragments of human immunoglobulins. III. Immunogenic properties of gamma chains, myeloma fd gamma, and myeloma fd1 alpha.
Earlier studies on antisera against Fab of pooled human IgG and IgA myeloma proteins disclosed the presence of class-specific Fd antibodies, the demonstration of which required interaction of heavy and light chains. To extend our knowledge about the antigenic structure of the Fd fragment of human immunoglobulins, antisera were prepared in rabbits against gamma chains of pooled IgG and of four IgG1 myeloma proteins, and Fd gamma fragment and a cyanogen bromide-produced CH1 preparation of an IgG1 myeloma protein, and an Fd' alpha fragment of an IgA1 myeloma protein. No antigenic determinants exclusively confined to the CH1 region of intact human IgG could be demonstrated with these antisera. The antigenic structure of CH1 intact immunoglobulins may thus only be defined by light-chain-dependent determinants.


Content validation and psychometric evaluation of the Angioedema Quality of Life Questionnaire for hereditary angioedema.
There is considerable burden of illness in hereditary angioedema (HAE). However, instruments to assess health-related quality of life (HRQoL) in HAE are limited. The Angioedema Quality of Life Questionnaire (AE-QoL) was developed to measure HRQoL in patients with recurrent angioedema; the validity of the AE-QoL in patients with HAE is described. To identify disease-related experiences with a focus on the impact of HAE on HRQoL, interviews were conducted with a group of clinician experts and patients with HAE from Canada, France, Germany, Spain, the United Kingdom, and the United States, along with a targeted literature review. Concepts were mapped to the AE-QoL to assess item relevance, interpretation, and conceptual coverage. Cognitive interviews assessed item clarity and relevance. A psychometric validation was performed using data from a phase 3 trial. Interviews were conducted with seven clinicians and 40 adult patients. Patients reported 35 unique impacts of HAE on their lives, the most frequent being on work/school, social relationships, physical activities, and emotions, particularly fear/worrying and anxiety. Saturation for these impacts was reached, and all concepts covered in the AE-QoL were reported during the interviews. Patients agreed that the questionnaire items and response options were clear and relevant, and the 4-week recall period was appropriate. The psychometric validation included data from 64 patients. For AE-QoL total scores, excellent internal consistency (Cronbach's alpha > 0.90), test-retest reliability (intraclass coefficient > 0.80), convergent validity with the Sheehan Disability Scale (r = 0.663), divergent validity with the EQ-5D-5L index (r = 0.292) and EQ-VAS (r = 0.337), and known-groups validity (p < 0.0001; ɳ2 = 0.56) were demonstrated. Qualitative and psychometric analyses showed that the AE-QoL is a reliable and valid instrument for measuring HRQoL in adult patients with HAE from six countries.


Effect of cell cycle on the regulation of the cell surface and secreted forms of type I and type II human tumor necrosis factor receptors.
The cell cycle has been shown to regulate the biological effects of human tumor necrosis factor (TNF), but to what extent that regulation is due to the modulation of TNF receptors is not clear. In the present report we investigated the effect of the cell cycle on the expression of surface and soluble TNF receptors in human histiocytic lymphoma U-937. Exposure to hydroxyurea, thymidine, etoposide, bisbensimide, and demecolcine lead to accumulation of cells primarily in G1/S, S, S/G2/M, G2/M, and M stages of the cell cycle, respectively. While no significant change in TNF receptors occurred in cells arrested in G1/S or S/G2 stages, about a 50% decrease was observed in cells at M phase of the cycle. Scatchard analysis showed a reduction in receptor number rather than affinity. In contrast, cells arrested at S phase (thymidine) showed an 80% increase in receptor number. The decrease in the TNF receptors was not due to changes in cell size or protein synthesis. The increase in receptors, however, correlated with an increase in total protein synthesis (to 3.8-fold of the control levels). A proportional change was observed in the p60 and p80 forms of the TNF receptors. A decrease in the surface receptors in cells arrested in M phase correlated with an increase in the amount of soluble receptors. The cellular response to TNF increased to 8- and 2-fold in cells arrested in G1 and S phase, respectively; but cells at G2/M phase showed about 6-fold decrease in response. In conclusion, our results demonstrate that the cell cycle plays an important role in regulation of cell-surface and soluble TNF receptors and also in the modulation of cellular response.