Lymphoedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema (Lymph-ICF-LL): reliability and validity.
Patients may develop primary (congenital) or secondary (acquired) lymphedema, causing significant physical and psychosocial problems. To plan treatment for lymphedema and monitor a patient's progress, swelling, and problems in functioning associated with lymphedema development should be assessed at baseline and follow-up. The purpose of this study was to investigate the reliability (test-retest, internal consistency, and measurement variability) and validity (content and construct) of data obtained with the Lymphoedema Functioning, Disability and Health Questionnaire for Lower Limb Lymphoedema (Lymph-ICF-LL). This was a multicenter, cross-sectional study. The Lymph-ICF-LL is a descriptive, evaluative tool containing 28 questions about impairments in function, activity limitations, and participation restrictions in patients with lower limb lymphedema. The questionnaire has 5 domains: physical function, mental function, general tasks/household activities, mobility activities, and life domains/social life. The reliability and validity of the Lymph-ICF-LL were examined in 30 participants with objective lower limb lymphedema. Intraclass correlation coefficients for test-retest reliability ranged from .69 to .94, and Cronbach alpha coefficients for internal consistency ranged from .82 to .97. Measurement variability was acceptable (standard error of measurement=5.9-12.6). Content validity was good because all questions were understandable for 93% of participants, the scoring system (visual analog scale) was clear, and the questionnaire was comprehensive for 90% of participants. Construct validity was good. All hypotheses for assessing convergent validity and divergent validity were accepted. The known-groups validity and responsiveness of the Dutch Lymph-ICF-LL and the cross-cultural validity of the English version of the Lymph-ICF-LL were not investigated. The Lymph-ICF-LL is a Dutch questionnaire with evidence of reliability and validity for assessing impairments in function, activity limitations, and participation restrictions in people with primary or secondary lower limb lymphedema.


Protective role of luteolin against bisphenol A-induced renal toxicity through suppressing oxidative stress, inflammation, and upregulating Nrf2/ARE/ HO-1 pathway.
For the development of renal diseases, oxidative stress (OS) is reasoned to be one of the risk factors. For the treatment or prevention of the renal disease, the use of antioxidants could be a hopeful therapeutic mediation as they retard or block the oxidative reaction along with the inflammatory process. Luteolin (Lut) is a plant flavonoid, a pharmacologically active component normally found in glycosylated forms in basic perilla leaf, green pepper, celery, seed, honeysuckle bloom, and chamomile blossom; it exhibits antioxidant activity. In this investigation, we explored the nephroprotective activity of Lut on bisphenol A (BPA)-induced nephron toxicity in rats. Orally administering Lut (100 and 200 mg/kg) diminished BPA-induced anomalies in the kidney, blood urea nitrogen, creatinine, and serum uric acid levels. Lut therapy reduced the BPA-influenced generation of inflammatory mediators, inclusive of tumor necrosis factor alpha, interleukin 6, and interleukin 1 beta. This was coupled with significant improvement in kidney histopathologic features. Lut enhanced the nuclear factor-like 2 (Nrf2) and heme oxygenase 1 (HO-1) expression, which showed protection against OS induced by BPA. The current outcomes of the study showed that Lut has a strong reactive oxygen species scavenging property and potentially decreases the lipid peroxidation as well as inhibits DNA damage in renal toxicity induced by BPA. In conclusion, the potential antioxidant effect of Lut may be because of its modulatory effect on the Nrf2/antioxidant response element (ARE)/HO-1 pathway, which means it protects the kidney from BPA-induced oxidative injury. © 2019 IUBMB Life, 2019.


Injection site effects on the pharmacokinetics and glucodynamics of insulin lispro and regular insulin.
The pharmacokinetics and glucodynamics of a new insulin analog, insulin lispro, and regular human insulin were compared and contrasted after subcutaneous administrations in femoral, deltoid, and abdominal injection sites. Single 0.2 U/kg doses of insulin lispro and regular insulin were administered to 12 healthy subjects in a six-way randomized crossover fashion. Each dose was given after an overnight fast in one of three injection sites: abdominal, deltoid, or femoral. Study drugs were given during a manual euglycemic glucose clamp. Blood samples were collected over the 12-h clamp for measurement of insulin-reactive components, with pharmacokinetic and glucodynamic measurements derived from these serum insulin and clamp measurements. Glucodynamic comparisons between insulin lispro and regular insulin showed a greater maximum infusion rate (Rmax) at an earlier time (TRmax), regardless of injection site. The total glucose infused (Gtot) showed nearly identical values between sites for insulin lispro. Regular insulin showed greater Gtot values from deltoid and femoral injections. When comparisons were made between drugs, regular insulin produced significantly greater Gtot, primarily driven by the increased Gtot from deltoid and femoral injections. Greater maximum serum insulin concentrations (Cmax) were experienced with insulin lispro at earlier times (tmax), regardless of the injection site (P < 0.001). Abdominal administrations produced the greatest Cmax values at the earliest tmax for both regular insulin and insulin lispro. Deltoid and femoral injections had lower Cmax values for both compounds. Shifts also occurred with tmax, although these shifts were much greater with regular insulin than with insulin lispro. Equivalent area under the curve (AUC) values were found when compared between compounds. Slower absorption from deltoid and femoral administrations resulted in an increased duration of action for both regular insulin and insulin lispro when compared to abdominal administration. However, notable increases in the onset of action were only apparent with regular insulin. The consistency with insulin lispro response from abdominal and extremity injection sites allows more potential sites for subcutaneous injection with an assured rapid response.


A multi-locus phylogeny suggests an ancient hybridization event between Campephilus and melanerpine woodpeckers (Aves: Picidae).
The ever increasing number of analysed loci in phylogenetics has not only allowed resolution of some parts of the Tree of Life but has also highlighted parts of the tree where incongruent signals among loci were detected. Previous molecular studies suggested conflicting relationships for the New World genus Campephilus, being either associated to the Megapicini or Dendropocini. Yet, the limited number of analysed loci and the use of the concatenation approach to reconstruct the phylogeny prevented the disentanglement of lineage sorting and introgression as causal explanation of this topological conflict. We sequenced four mitochondrial, nine autosomal and three Z-linked loci and used a method that incorporates population level processes into the phylogenetic framework to understand which process (lineage sorting of genetic polymorphism or hybridization/introgression) best explains this conflict. Our analyses revealed that the autosomal FGB intron-7 and to a lesser extent the Z-linked loci have a different phylogenetic history from the mitochondrial loci and some other nuclear loci we analysed. We suggest that this conflicting pattern is the result of introgression consecutive to a hybridization event at the time when members of the Campephilus and melanerpine (Melanerpes and Sphyrapicus) lineages colonized the New World. The case of Campephilus highlights that the mitochondrial genome does not always carry the 'wrong' phylogenetic signal after a past hybridization event. Indeed, we here emphasise that the signature of such event can also be detected in the nuclear genome. With the ongoing increase in the number of loci analysed in phylogenetic studies, it is very likely that further cases will be discovered. Our current results indicate that (1) the genus Campephilus is related to the Asian genera Blythipicus, Chrysocolaptes and Reinwardtipicus, in accordance with morphological data and (2) that the nuclear genome of Campephilus is likely the mixture of two unrelated lineages. Yet, further work with a denser sampling of loci is necessary to evaluate the extant of the Sphyrapicus/Melanerpes lineage nuclear genome that introgressed into the Campephilus genome.


Ventricular dyssynchrony index: comparison with two-dimensional and three-dimensional ejection fraction.
Left ventricular (LV) electromechanical coupling (synchrony) is important in the analysis of the systolic performance, especially for the indication of cardiac resynchronization therapy in patients with advanced CHF. To compare LV synchrony as analyzed by real-time three-dimensional (3D) echocardiography (ECHO) with LVEF measurements as obtained with 2D and 3D ECHO. Prospective study of 92 individuals (56 men, 47 +/- 10 years of age), of which 60 had normal heart structure (ECHO) and ECG (N group), and 32 had dilated cardiomyopathy (DCM group). Using 3D ECHO, LVEF, volumes and dyssynchrony index (%DI) for 16 LV segments were measured. Using 2D ECHO, LVEF (Simpson's method), and LV systolic and diastolic volumes were measured. Pearson's correlation coefficient, 95% CI, linear regression model, Bland & Altman analysis, p<0.05. %DI ranged from 0.2900 to 28.1000 (5.2014+/-6.3281), 3D LVEF ranged from 0.17 to 0.81 (0.52+/-0.17); and 2D LVEF ranged from 0.3 to 0.69 (0.49+/-0.11). The correlation between DI and 3D LVEF was (r): -0.7432, p<0.0001, CI: -0.8227 to -0.6350, the linear relation between DI (x) and 3D LVEF (y) was y = 19.8124 + (-27.9578) x, p<0.0001. The correlation between DI and 2D LVEF was (r): -0.7012, p<0.0001, CI: -0.7923 to -0.5797. In this case series, a good negative correlation was observed between LV electromechanical three-dimensional systolic coupling and LVEF as measured by echocardiography (3D and 2D).


Fire does not alter vegetation in infertile prairie.
The paradigm in prairie ecology is that fire is one of the key factors determining vegetation composition. Fire can impact grassland ecosystems in various ways, including changing plant species composition and inducing nitrogen loss. I found that 17 years of different burning frequencies in infertile grassland had only a minor impact on the vegetation composition and diversity. The only major impact from increasing the frequency of fires was a decrease of Poa pratensis abundance. However, other plant species did not respond to the change in Poa abundance. This result contrasts with previous studies in savannas and more productive grasslands, where the balance between trees, grasses, and the elimination of the litter layer can result in large vegetation changes. However, in this system primary productivity was low, litter did not accumulate and no major vegetation shifts occurred. Thus, the long-term vegetation impacts of burning in an infertile, low-productivity prairie were minimal.


Dependence of yeast pre-mRNA 3'-end processing on CFT1: a sequence homolog of the mammalian AAUAAA binding factor.
3'-End formation of pre-mRNA in yeast and mammals follows a similar but distinct pathway. In Saccharomyces cerevisiae, the cleavage reaction can be reconstituted by two activities called cleavage factor I and II (CFI and CFII). A CFII component, designated CFT1 (cleavage factor two) was identified by its sequence similarity to the AAUAAA-binding subunit of the mammalian cleavage and polyadenylation specificity factor (CPSF), even though the AAUAAA signal sequence appears to play no role in yeast pre-mRNA 3' processing. Depletion of a yeast whole-cell extract with antibodies to CFT1 protein abolished cleavage and polyadenylation of pre-mRNAs. Addition of CFII restored cleavage activity, but not polyadenylation. Polyadenylation required the further addition of poly(A) polymerase and polyadenylation factor I, suggesting a close but not necessarily direct association of these two factors with the CFT1 protein.


Hepatocyte polarity.
Hepatocytes, like other epithelia, are situated at the interface between the organism's exterior and the underlying internal milieu and organize the vectorial exchange of macromolecules between these two spaces. To mediate this function, epithelial cells, including hepatocytes, are polarized with distinct luminal domains that are separated by tight junctions from lateral domains engaged in cell-cell adhesion and from basal domains that interact with the underlying extracellular matrix. Despite these universal principles, hepatocytes distinguish themselves from other nonstriated epithelia by their multipolar organization. Each hepatocyte participates in multiple, narrow lumina, the bile canaliculi, and has multiple basal surfaces that face the endothelial lining. Hepatocytes also differ in the mechanism of luminal protein trafficking from other epithelia studied. They lack polarized protein secretion to the luminal domain and target single-spanning and glycosylphosphatidylinositol-anchored bile canalicular membrane proteins via transcytosis from the basolateral domain. We compare this unique hepatic polarity phenotype with that of the more common columnar epithelial organization and review our current knowledge of the signaling mechanisms and the organization of polarized protein trafficking that govern the establishment and maintenance of hepatic polarity. The serine/threonine kinase LKB1, which is activated by the bile acid taurocholate and, in turn, activates adenosine monophosphate kinase-related kinases including AMPK1/2 and Par1 paralogues has emerged as a key determinant of hepatic polarity. We propose that the absence of a hepatocyte basal lamina and differences in cell-cell adhesion signaling that determine the positioning of tight junctions are two crucial determinants for the distinct hepatic and columnar polarity phenotypes.


Enhancing the potency of chemotherapeutic agents by combination with bromelain and N-acetylcysteine - an in vitro study with pancreatic and hepatic cancer cells.
Current systemic dosages of chemotherapeutic drugs such as gemcitabine, 5-FU, cisplatin, doxorubicin are administered every 7 days over 4 cycles due to systemic toxicity. An increase in potency of the drugs will result in dosage reduction with more frequent administration and efficacy increase. Hence, we investigated how the drugs potency can be increased by combining with bromelain and N-acetylcysteine. Tumour cells (5,000/well) were seeded into a 96 well plate and treated 24 hrs later with either single agents or in combinations at various concentrations. Cell survival was assessed by the sulforhodamine B assay after 72 hours of exposure. LD 50 was determined for each treatment and the Combination Index (CI) was assessed to determine synergy using Tallarida's method. CI indicated that synergy was dependent on the concentration of the agents used and was cell line specific. For bromelain and N-acetylcysteine, certain ratio of the two agents gave very good synergy that was prevalent in almost all cell lines. Gemcitabine and 5-FU and doxorubicin reacted favourably with most concentrations of bromelain and NAC investigated. Cisplatin and oxaliplatin were not very compatible with NAC. A value of CI <0.5 indicated that the current clinical chemotherapeutic dosage can be dramatically reduced. Bromelain with NAC showed synergy in all tumour cell lines and acting synergistically with chemotherapeutic drugs. Synergistic combinations resulting in considerable dosage reduction of chemotherapeutic agents may enable more frequent treatment with higher efficacy.


Spatial disorientation in persons with early senile dementia of the Alzheimer type.
Although spatial disorientation is frequently observed in persons with Alzheimer disease, it is not well understood. A descriptive study was conducted to examine spatial skills associated with spatial orientation. Spatial tasks were selected and grouped into three types of spatial skills: perceptual, cognitive, and functional. These spatial tasks were administered to a group of 15 persons with senile dementia of the Alzheimer type (SDAT) (early Alzheimer disease) and a group of 15 control subjects. The results indicated that the subjects with SDAT were impaired on half of the perceptual spatial tasks and all of the cognitive spatial tasks. On the functional spatial tasks, however, the subjects with SDAT showed impaired skills in the new environment but intact skills in familiar environments. Spatial disorientation poses a danger and limits a person's ability to independently perform daily activities that require navigation outside of the home. Occupational therapy should therefore include the assessment of spatial orientation skills in persons who are in the early stages of dementia.


Esthetic preferences of European American, Hispanic American, Japanese, and African judges for soft-tissue profiles.
Our objectives were to determine whether observer and patient sex and race or ethnicity determine esthetic preferences for lip positions. Four independent panels each consisting of 30 lay judges viewed pretreatment silhouette profiles of 10 European American, 10 Japanese, and 10 African American Angle Class I and Class II orthodontic patients. The panels included European Americans, Hispanic Americans, Japanese, and Africans. Profiles were traced from lateral cephalograms and manipulated so that the lip profile lay on the Ricketts' E-line or at various distances from the E-line from -8 to +4 mm in 2-mm increments. The judges selected the profile that they considered the most attractive and then classified the remaining 6 profiles as either acceptable or unacceptable. The mean preferred lip positions (mean +/- SD) were -2.58 +/- 1.92 mm for European American, -3.28 +/- 2.26 mm for Hispanic American, -3.45 +/- 1.92 mm for Japanese, and -2.13 +/- 1.95 mm for African judges. The African judges preferred more protrusive profiles compared with the Hispanic American (P <0.01) and Japanese (P <0.001) judges. Patient race or ethnicity and sex also contributed significantly to the judgments of profile esthetics (P <0.001). Judge race or ethnicity and patient race or ethnicity and sex significantly influence laypersons' standards for lip profile esthetics.


NTP Toxicology and Carcinogenesis Studies of Amosite Asbestos (CAS No. 12172-73-5) in F344/N Rats (Feed Studies).
The term "asbestos" has a commercial/industrial derivation limited to naturally occurring fibrous minerals of the serpentine or amphibole series. Chrysotile is the only type of asbestos in the serpentine series, whereas the amphibole series is represented by actinolite, amosite, anthophyllite, crocidolite, and tremolite. The essential characteristic of asbestos minerals is their fibrous nature. Large portions of the population ingest asbestos through consumption of food and water. Asbestos or asbestos-like fibers may gain access to water supplies as a result of mining (Lake Superior), from the presence of natural serpentine or amphibole deposits in watersheds (Seattle, WA, and San Francisco, CA) or, under certain conditions, through the use of asbestos-cement pipes for municipal water supplies. For the latter, erosion of the pipe with release of fibers is associated with the "aggressiveness" of the water, a term representing a mathematical expression of pH, alkalinity, and calcium content. The EPA estimated that 68.5% of water systems in the United States utilize water that is potentially capable of eroding asbestos-cement pipe. Carcinogenesis studies of amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted in male and female rats. Amosite asbestos was administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. One group of amosite asbestos-exposed rats (amosite preweaning gavage) also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. Litter size was the same, but the offspring from mothers exposed to amosite asbestos were smaller at weaning than those from nonexposed mothers and remained smaller throughout their life. The DMH was administered by gavage at a dose of 7.5 mg/kg for males and 15 mg/kg for females every 14 days, starting at 8 weeks of age, for a total of five doses. The administration of DMH did not affect body weight gain either in amosite-exposed or nonexposed animals. The amosite-exposed rats showed enhanced survival compared with that of the nonexposed rats. DMH exposure reduced survival by approximately 1 year, although the survival of the amosite plus DMH groups was slightly greater than that of the DMH group alone. Significant increases in the incidences of C-cell carcinomas of the thyroid gland (untreated control, 11/117; amosite, 50/246, P<0.05; amosite preweaning gavage, 14/100) and of leukemia (38/117; 106/249, P<0.05; 49/100, P<0.01) in male rats were observed in amosite-exposed groups. However, the biologic significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and because the positive effect was not observed in the amosite preweaning gavage group. The biologic significance of an increased incidence of leukemia is questionable because of a lack of statistical significance in the amosite group when evaluated by life table analysis and because no toxic lesions were observed in the target organs, i.e., gastrointestinal tract and mesothelium. DMH caused a high incidence (62%-74%) of intestinal neoplasia in amosite-exposed and nonexposed groups. Neither an enhanced carcinogenic nor a protective effect was demonstrated by exposure to amosite asbestos. Conclusions: Under the conditions of these feed studies, amosite asbestos was not overtly toxic, did not affect survival, and was not carcinogenic when ingested at a concentration of 1% in the diet by male or female F344/N rats. The cocarcinogenic studies using DMH were considered inadequate because of the high incidence of DMH-induced intestinal neoplasia in both the amosite asbestos-exposed and nonexposed groups. Levels of Evidence of Carcinogenicity: Amosite Asbestos: Male Rats: Negative. Female Rats: Negative. Amosite Asbestos + DMH: Male Rats: Inadequate. Female Rats: Inadequate. Note: Amosite Asbestos was previously tested in Syrmosite Asbestos was previously tested in Syrian Golden Hamsters administered in feed (See TR-249, reported 1983).


Closed and open state dependent block of potassium channels cause opposing effects on excitability - a computational approach.
Block of voltage-gated potassium (Kv) channels has been demonstrated to affect neuronal activity described as increasing excitability. The effect has been associated with a closed-state dependent block. However, the block of Kv channels in e.g. local anesthetic and antiarrhythmics, is open state-dependent. Since the reduced excitability in this case mainly is due to sodium channel block, the role of the Kv channel block is concealed. The present investigation aims to analyse the specific role of state-dependent Kv channel block for excitability. Using a computational approach, with introduced blocked states in the Kv channel of the Frankenhaeuser-Huxley axon membrane model, we calculated the effects on threshold, firing and presynaptic Ca influx. The Ca influx was obtained from an N-type Cav channel model linked to the Frankenhaeuser-Huxley membrane. The results suggested that a selective block of open Kv channels decreased the rate of repetitive firing and the consequent Ca influx, thus challenging the traditional view. In contrast, presence of a closed-state block, increased the firing rate and the Ca influx. These findings propose that Kv channel block may either increase or decrease cellular excitability, thus highlighting the importance of further investigating the role of state-specific blocking mechanisms.


A longitudinal view of improved management strategies and outcomes after iatrogenic iliac artery rupture during endovascular aneurysm repair.
Intraoperative rupture of the iliac artery is a serious complication of endovascular aneurysm repair (EVAR), the outcomes of which have changed with increasing experience and improved endovascular tools over the past 2 decades. Over the past 15 years, the incidence and management of iliac rupture has changed as devices have improved and experience has grown. This study reviews our longitudinal experience with this complication. All cases of iliac artery rupture during EVAR from 1997 through 2011 were reviewed for presentation, treatment strategies, and outcomes. Iliac artery rupture complicated 20 (3%) of 707 EVARs performed. Sixteen (80%) common and four (20%) external iliac arteries were ruptured. Hypotension (systolic blood pressure: <90 mm Hg) was present in 11 (55%) cases. Five open bypasses were performed (25%), whereas 15 were repaired using an endovascular approach (75%). All open repairs (100%) were associated with postoperative morbidity (one wound infection, four multiorgan system failure), whereas three of the 15 patients (23%) repaired endovascularly experienced postoperative morbidity (cerebrovascular accident, myocardial infarction, line infection). There were no intraoperative deaths. There were four (20%) early deaths in the intensive care unit (<3 days postoperatively), all of which were associated with resection of bilateral hypogastric arteries and were due to complications of pelvic ischemia and/or multiorgan system failure. Iliac artery rupture remains relatively uncommon but can carry a high morbidity and mortality. As device technology, imaging quality for preoperative planning, and experience level have improved, iliac rupture has become less common, and outcomes in the setting of iliac rupture have significantly improved. Endoluminal management has evolved as the primary treatment strategy. Resection of both hypogastric arteries is associated with mortality from pelvic ischemia, a likely indicator of systemic disease.


Quantification of collagen organization in the peripheral human cornea at micron-scale resolution.
The collagen microstructure of the peripheral cornea is important in stabilizing corneal curvature and refractive status. However, the manner in which the predominantly orthogonal collagen fibrils of the central cornea integrate with the circumferential limbal collagen is unknown. We used microfocus wide-angle x-ray scattering to quantify the relative proportion and orientation of collagen fibrils over the human corneolimbal interface at intervals of 50 μm. Orthogonal fibrils changed direction 1-1.5 mm before the limbus to integrate with the circumferential limbal fibrils. Outside the central 6 mm, additional preferentially aligned collagen was found to reinforce the cornea and limbus. The manner of integration and degree of reinforcement varied significantly depending on the direction along which the limbus was approached. We also employed small-angle x-ray scattering to measure the average collagen fibril diameter from central cornea to limbus at 0.5 mm intervals. Fibril diameter was constant across the central 6 mm. More peripherally, fibril diameter increased, indicative of a merging of corneal and scleral collagen. The point of increase varied with direction, consistent with a scheme in which the oblique corneal periphery is reinforced by chords of scleral collagen. The results have implications for the cornea's biomechanical response to ocular surgeries involving peripheral incision.


Nocardia brasiliensis induces formation of foamy macrophages and dendritic cells in vitro and in vivo.
Foamy cells have been described in various infectious diseases, for example in actinomycetoma induced by Nocardia brasiliensis. These cells are generally considered to be macrophages, although they present dendritic cell (DC)-specific surface markers. In this study, we determined and confirmed the lineage of possible precursors of foamy cells in vitro and in vivo using an experimental actinomycetoma model in BALB/c mice. Bone marrow-derived macrophages (BMDM) or DC (BMDC) were infected in vitro with N. brasiliensis or labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE). Both, macrophages and DC, differentiated into foamy cells after in vitro infection. CFSE-labeled BMDM or BMDC were tested for phagocytosis and CD11c/CD11b receptors markers expression before being transferred into the actinomycetoma lesion site of infected mice. In vivo studies showed that BMDM and BMDC were traced at the site where foamy cells are present in the experimental actinomycetoma. Interestingly, many of the transferred BMDM and BMDC were stained with the lipid-droplet fluorophore Nile Red. In conclusion, macrophages and DC cells can be differentiated into foamy cells in vitro and in vivo during N. brasiliensis infection.


How reliably can we predict the reliability of protein structure predictions?
Comparative methods have been the standard techniques for in silico protein structure prediction. The prediction is based on a multiple alignment that contains both reference sequences with known structures and the sequence whose unknown structure is predicted. Intensive research has been made to improve the quality of multiple alignments, since misaligned parts of the multiple alignment yield misleading predictions. However, sometimes all methods fail to predict the correct alignment, because the evolutionary signal is too weak to find the homologous parts due to the large number of mutations that separate the sequences. Stochastic sequence alignment methods define a posterior distribution of possible multiple alignments. They can highlight the most likely alignment, and above that, they can give posterior probabilities for each alignment column. We made a comprehensive study on the HOMSTRAD database of structural alignments, predicting secondary structures in four different ways. We showed that alignment posterior probabilities correlate with the reliability of secondary structure predictions, though the strength of the correlation is different for different protocols. The correspondence between the reliability of secondary structure predictions and alignment posterior probabilities is the closest to the identity function when the secondary structure posterior probabilities are calculated from the posterior distribution of multiple alignments. The largest deviation from the identity function has been obtained in the case of predicting secondary structures from a single optimal pairwise alignment. We also showed that alignment posterior probabilities correlate with the 3D distances between C alpha amino acids in superimposed tertiary structures. Alignment posterior probabilities can be used to a priori detect errors in comparative models on the sequence alignment level.


Minilaparotomic incision for haemorrhagic corpus luteum: a case report.
Corpus luteum cyst rupture with consequent hemoperitoneum is a common cause of admission to the emergency room. This condition is frequently misdiagnosed because of overlapping of clinical findings in acute gynecologic diseases. However, an incorrect identification may lead to delay in surgical treatment, which can Romabe a life-threatening condition. Ultrasound (US) is the first technique used for diagnosis that can confirm or dismiss the presence of intraperitoneal fluid. Secondly, the contrast-enhanced computed tomography (CT) is the quickest way to identify the site of active bleeding and to establish the correct management of the clinical condition. Herein, we report a case of a 19-years-old girl with acute abdominal pain correctly identified by diagnostic images and treated with mini-invasive surgery techniques in order to quickly act without clinic and aesthetic sequelae.


Perioperative feeding management of neonates with CHD: analysis of the Pediatric Cardiac Critical Care Consortium (PC4) registry.
Introduction The optimal perioperative feeding strategies for neonates with CHD are unknown. In the present study, we describe the current feeding practices across a multi-institutional cohort. Inclusion criteria for this study were as follows: all neonates undergoing cardiac surgery admitted to the cardiac ICU for ⩾24 hours preoperatively between October, 2013 and July, 2014 in the Pediatric Cardiac Critical Care Consortium registry. The cohort included 251 patients from eight centres. The most common diagnoses included the following: hypoplastic left heart syndrome (17%), coarctation/aortic arch hypoplasia (18%), and transposition of the great arteries (22%); 14% of the patients were <37weeks of gestational age. The median total hospital length of stay was 21 days (interquartile range (IQR) 14-35) and overall mortality was 8%. Preoperative feeding occurred in 133 (53%) patients. The overall preoperative feeding rates across centres ranged from 29 to 79%. Postoperative feeds started on median day 2 (IQR 1-4); for patients with hypoplastic left heart syndrome postoperative feeds started on median day 4. Postoperative feeds were initiated in 89 (35%) patients before extubation (range across centres: 21-61%). The median cardiac ICU discharge feeding volume was 108 cc/kg/day, varying across centres. The mean discharge weight was 280 g above birth weight, ranging from +100 to 430 g across centres. A total of 110 (44%) patients had discharge feeding tubes, ranging from 6 to 80% across centres, and 40/110 patients had gastrostomy/enterostomy tubes placed. In addition, eight (3.2%) patients developed necrotising enterocolitis - three preoperatively and five postoperatively. In this cohort, neonatal feeding practices and outcomes appear to vary across diagnostic groups and institutions. Only half of the patients received preoperative enteral nutrition; almost half had discharge feeding tubes. Multi-institutional collaboration is necessary to determine feeding strategies associated with best clinical outcomes.


Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.
African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.


In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist.
S 38093, a novel histamine H3 receptor inverse agonist, was tested in a series of neurochemical and behavioral paradigms designed to evaluate its procognitive and arousal properties. In intracerebral microdialysis studies performed in rats, S 38093 dose-dependently increased histamine extracellular levels in the prefrontal cortex and facilitated cholinergic transmission in the prefrontal cortex and hippocampus of rats after acute and chronic administration (10mg/kg i.p.). Acute oral administration of S 38093 at 0.1mg/kg significantly improved spatial working memory in rats in the Morris water maze test. The compound also displayed cognition enhancing properties in the two-trial object recognition task in rats, in a natural forgetting paradigm at 0.3 and 1mg/kg p.o. and in a scopolamine-induced memory deficit situation at 3mg/kg p.o. The property of S 38093 to promote episodic memory was confirmed in a social recognition test in rats at 0.3 and 1mg/kg i.p. Arousal properties of S 38093 were assessed in freely moving rats by using electroencephalographic recordings: at 3 and 10mg/kg i.p., S 38093 significantly reduced slow wave sleep delta power and induced at the highest dose a delay in sleep latency. S 38093 at 10mg/kg p.o. also decreased the barbital-induced sleeping time in rats. Taken together these data indicate that S 38093, a novel H3 inverse agonist, displays cognition enhancing at low doses and arousal properties at higher doses in rodents.


Engaging First Nation and Inuit communities in asthma management and control: assessing cultural appropriateness of educational resources.
Asthma is a growing concern in First Nations and Inuit communities. As with many health indicators and outcomes, Aboriginal peoples living in remote areas experience greater disparities in respiratory health compared with non-Aboriginal Canadians. Therefore, it is critically important to take into account their unique needs when developing asthma educational materials and resources. The purpose of this study is to assess the cultural relevance of existing asthma education materials for First Nations and Inuit peoples. Five First Nations and Inuit communities from across Canada participated in the project. A combination of quantitative evaluations (eg surveys) and qualitative approaches (eg open discussion, live chats) were used to assess printed and web-based asthma education materials. Participants represented First Nations and Inuit communities from across Canada and were selected on the basis of age and role: 6 to 12 years old (children), 12 and over (youth), parents and grandparents, community leaders and teachers, and community advisory group members. In general, the results showed that although participants of all age categories liked the selection of asthma educational materials and resources, they identified pictures and images related to First Nations and Inuit people living and coping with asthma as ways of improving cultural relevance. This reinforces findings that tailoring materials to include Aboriginal languages, ceremonies and traditions would enhance their uptake. Our findings also demonstrate that visually based content in both printed and virtual form were the preferred style of learning of all participants, except young children who preferred to learn through play and interactive activities. Asthma is a growing concern in First Nations and Inuit communities. Given this concern, it is essential to understand cultural needs and preferences when developing asthma education materials and resources. The findings from this research emphasize the need to adapt existing asthma educational materials to better suit First Nations and Inuit cultures and the importance of directly engaging community members in the process.


Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults.
Observational studies have reported that higher plasma 25-hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations. Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%-18%) lower risk of diabetes in CKB. In a meta-analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%-23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: -1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes.


Systems Medicine: from molecular features and models to the clinic in COPD.
Chronic Obstructive Pulmonary Disease (COPD) patients are characterized by heterogeneous clinical manifestations and patterns of disease progression. Two major factors that can be used to identify COPD subtypes are muscle dysfunction/wasting and co-morbidity patterns. We hypothesized that COPD heterogeneity is in part the result of complex interactions between several genes and pathways. We explored the possibility of using a Systems Medicine approach to identify such pathways, as well as to generate predictive computational models that may be used in clinic practice. Our overarching goal is to generate clinically applicable predictive models that characterize COPD heterogeneity through a Systems Medicine approach. To this end we have developed a general framework, consisting of three steps/objectives: (1) feature identification, (2) model generation and statistical validation, and (3) application and validation of the predictive models in the clinical scenario. We used muscle dysfunction and co-morbidity as test cases for this framework. In the study of muscle wasting we identified relevant features (genes) by a network analysis and generated predictive models that integrate mechanistic and probabilistic models. This allowed us to characterize muscle wasting as a general de-regulation of pathway interactions. In the co-morbidity analysis we identified relevant features (genes/pathways) by the integration of gene-disease and disease-disease associations. We further present a detailed characterization of co-morbidities in COPD patients that was implemented into a predictive model. In both use cases we were able to achieve predictive modeling but we also identified several key challenges, the most pressing being the validation and implementation into actual clinical practice. The results confirm the potential of the Systems Medicine approach to study complex diseases and generate clinically relevant predictive models. Our study also highlights important obstacles and bottlenecks for such approaches (e.g. data availability and normalization of frameworks among others) and suggests specific proposals to overcome them.


Structure of the alpha beta tubulin dimer by electron crystallography.
The alphabeta tubulin heterodimer is the structural subunit of microtubules, which are cytoskeletal elements that are essential for intracellular transport and cell division in all eukaryotes. Each tubulin monomer binds a guanine nucleotide, which is nonexchangeable when it is bound in the alpha subunit, or N site, and exchangeable when bound in the beta subunit, or E site. The alpha- and beta-tubulins share 40% amino-acid sequence identity, both exist in several isotype forms, and both undergo a variety of posttranslational modifications. Limited sequence homology has been found with the proteins FtsZ and Misato, which are involved in cell division in bacteria and Drosophila, respectively. Here we present an atomic model of the alphabeta tubulin dimer fitted to a 3.7-A density map obtained by electron crystallography of zinc-induced tubulin sheets. The structures of alpha- and beta-tubulin are basically identical: each monomer is formed by a core of two beta-sheets surrounded by alpha-helices. The monomer structure is very compact, but can be divided into three functional domains: the amino-terminal domain containing the nucleotide-binding region, an intermediate domain containing the Taxol-binding site, and the carboxy-terminal domain, which probably constitutes the binding surface for motor proteins.


Diffusion tensor imaging of mild to moderate blast-related traumatic brain injury and its sequelae.
To evaluate the effects of mild to moderate blast-related traumatic brain injury (TBI) on the microstructure of brain white matter (WM) and neurobehavioral outcomes, we studied 37 veterans and service members (mean age 31.5 years, SD = 7.2; post-injury interval 871.5 days; SD = 343.1), whose report of acute neurological status was consistent with sustaining mild to moderate TBI due to blast while serving in Iraq or Afghanistan. Fifteen veterans without a history of TBI or exposure to blast (mean age 31.4 years, SD = 5.4) served as a comparison group, including seven subjects with extracranial injury (post-injury interval 919.5 days, SD = 455.1), and eight who were uninjured. Magnetic resonance imaging disclosed focal lesions in five TBI participants. Post-concussion symptoms (Neurobehavioral Symptom Inventory), post-traumatic stress disorder (PTSD) symptoms (PTSD Checklist-Civilian), and global distress and depression (Brief Symptom Inventory) were worse in the TBI participants than the comparison group, but no group differences were found in perceived physical or mental functioning (SF-12). Verbal memory (Selective Reminding) was less efficient in the TBI group, but there were no group differences in nonverbal memory (Selective Reminding) or decision making (Iowa Gambling Task). Verbal memory in the TBI group was unrelated to PTSD severity. Diffusion tensor imaging (DTI) using tractography, standard single-slice region-of-interest measurement, and voxel-based analysis disclosed no group differences in fractional anisotropy (FA) and apparent diffusion coefficient (ADC). However, FA of the left and right posterior internal capsule and left corticospinal tract was positively correlated with total words consistently recalled, whereas ADC for the left and right uncinate fasciculi and left posterior internal capsule was negatively correlated with this measure of verbal memory. Correlations of DTI variables with symptom measures were non-significant and inconsistent. Our data do not show WM injury in mild to moderate blast-related TBI in veterans despite their residual symptoms and difficulty in verbal memory. Limitations of the study and implications for future research are also discussed.


Premigratory and migratory neural crest cells are multipotent in vivo.
The neural crest (NC) is an embryonic stem/progenitor cell population that generates a diverse array of cell lineages, including peripheral neurons, myelinating Schwann cells, and melanocytes, among others. However, there is a long-standing controversy as to whether this broad developmental perspective reflects in vivo multipotency of individual NC cells or whether the NC is comprised of a heterogeneous mixture of lineage-restricted progenitors. Here, we resolve this controversy by performing in vivo fate mapping of single trunk NC cells both at premigratory and migratory stages using the R26R-Confetti mouse model. By combining quantitative clonal analyses with definitive markers of differentiation, we demonstrate that the vast majority of individual NC cells are multipotent, with only few clones contributing to single derivatives. Intriguingly, multipotency is maintained in migratory NC cells. Thus, our findings provide definitive evidence for the in vivo multipotency of both premigratory and migrating NC cells in the mouse.


The significance of patient participation in nursing care - a concept analysis.
The purpose of this study was to report on a concept analysis of the meaning of patients' participation. Participation is commonplace in many areas of health care and has become an important issue in healthcare services. Participation is essential when giving nursing care. Challenges exist throughout clinical practice to make the patient a participant in their own care. The study had a caring science perspective. A literature study based on Walker and Avant's method was used with eight steps. Data were collected using several databases covering the years 1995-2017. The analysis covered fifteen articles, dissertations, reports and textbooks. Patients' participation may be defined as a concept that relates to and includes the three caring science concepts: learning, caring relationship and reciprocity (defining attributes). Participation is a concept with vague meaning that is prevalent in nursing practice. Patients' participation is a complex concept. By using the attributes, it could be more visible in nursing care. The next question for research in this area is how these three attributes can best practically be achieved in a clinical context.


Environmental pollutants modulate RNA and DNA virus-activated miRNA-155 expression and innate immune system responses: Insights into new immunomodulative mechanisms.
Many persistent organic pollutants, such as polychlorinated biphenyls (PCBs), have high immunomodulating potentials. Exposure to them, in combination with virus infections, has been shown to aggravate outcomes of the infection, leading to increased viral titers and host mortality. Expression of immune-related microRNA (miR) signaling pathways (by host and/or virus) have been shown to be important in determining these outcomes; there is some evidence to suggest pollutants can cause dysregulation of miRNAs. It was thus hypothesized here that modulation of miRNAs (and associated cytokine genes) by pollutants exerts negative effects during viral infections. To test this, an in vitro study on chicken embryo fibroblasts (CEF) exposed to a PCB mixture (Aroclor 1260) and then stimulated with a synthetic RNA virus (poly(I:C)) or infected with a lymphoma-causing DNA virus (Gallid Herpes Virus 2 [GaHV-2]) was conducted. Using quantitative real-time PCR, expression patterns for mir-155, pro-inflammatory TNFα and IL-8, transcription factor NF-κB1, and anti-inflammatory IL-4 were investigated 8, 12, and 18 h after virus activation. The study showed that Aroclor1260 modulated mir-155 expression, such that a down-regulation of mir-155 in poly(I:C)-treated CEF was seen up to 12 h. Aroclor1260 exposure also increased the mRNA expression of pro-inflammatory genes after 8 h in poly(I:C)-treated cells, but levels in GaHV-2-infected cells were unaffected. In contrast to with Aroclor1260/poly(I:C), Aroclor1260/GaHV-2-infected cells displayed an increase in mir-155 levels after 12 h compared to levels seen with either individual treatment. While after 12 h expression of most evaluated genes was down-regulated (independent of treatment regimen), by 18 h, up-regulation was evident again. In conclusion, this study added evidence that mir-155 signaling represents a sensitive pathway to chemically-induced immunomodulation and indicated that PCBs can modulate highly-regulated innate immune system signaling pathways important in determining host immune response outcomes during viral infections.


The multi-service network: reaching the unserved multi-problem individual.
A small number of multi-problem, service-resistant individuals in every metropolitan community consume extraordinary amounts of human service at great cost to publicly-funded agencies with less than satisfactory benefit to the individual. This paper describes an innovative collaboration among mental health, alcohol/drug treatment, corrections, forensic, and social and housing agencies to provide more effective services at less cost. The theory of action was that (1) inter-agency communication and (2) external controls developed by core service agencies increase the efficacy of treatment and reduce the cost of caring for multi-problem clients. Agencies refer clients to the Multi-Service Network who are then screened for problematic multi-agency involvement. Case conferences result in individual service plans. Three illustrative cases are described and the results of two evaluative studies summarized. Cost of care for clients appears to have been reduced. Agencies appear to have benefited from improved information and communication. Clients' behavior was stabilized by external controls and more adequate attention to their needs.


Seedling establishment in a dynamic sedimentary environment: a conceptual framework using mangroves.
1. Vegetated biogeomorphic systems (e.g. mangroves, salt marshes, dunes, riparian vegetation) have been intensively studied for the impact of the biota on sediment transport processes and the resulting self-organization of such landscapes. However, there is a lack of understanding of physical disturbance mechanisms that limit primary colonization in active sedimentary environments. 2. This study elucidates the effect of sediment disturbance during the seedling stage of pioneer vegetation, using mangroves as a model system. We performed mesocosm experiments that mimicked sediment disturbance as (i) accretion/burial of plants and (ii) erosion/excavation of plants of different magnitudes and temporal distribution in combination with water movement and inundation stress. 3. Cumulative sediment disturbance reduced seedling survival, with the faster-growing Avicennia alba showing less mortality than the slower-growing Sonneratia alba. The presence of the additional stressors (inundation and water movement) predominantly reduced the survival of S. alba. 4. Non-lethal accretion treatments increased shoot biomass of the seedlings, whereas non-lethal erosion treatments increased root biomass allocation. This morphological plasticity in combination with the abiotic disturbance history determined how much maximum erosion the seedlings were able to withstand. 5.Synthesis and applications. Seedling survival in dynamic sedimentary environments is determined by the frequency and magnitude of sediment accretion or erosion events, with non-lethal events causing feedbacks to seedling stability. Managers attempting restoration of mangroves, salt marshes, dunes and riparian vegetation should recognize sediment dynamics as a main bottleneck to primary colonization. The temporal distribution of erosion and accretion events has to be evaluated against the ability of the seedlings to outgrow or adjust to disturbances. Our results suggest that selecting fast-growing pioneer species and measures to enhance seedling growth or temporary reduction in sediment dynamics at the restoration site can aid restoration success for vegetated biogeomorphic ecosystems.


Practice Bulletin No. 170 Summary: Critical Care in Pregnancy.
Critical care in pregnancy is a field that remains unevenly researched. Although there is a body of evidence to guide many recommendations in critical care, limited research specifically addresses obstetric critical care. The purpose of this document is to review the available evidence, propose strategies for care, and highlight the need for additional research. Much of the review will, of necessity, focus on general principles of critical care, extrapolating where possible to obstetric critical care.


Acupuncture Alters Expression of Insulin Signaling Related Molecules and Improves Insulin Resistance in OLETF Rats.
To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD) rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6), Zusanli (ST36), and Sanyinjiao (SP6); in contrast, acupuncture to Shenshu (BL23) was administered perpendicularly. For Neiguan (PC6) and Zusanli (ST36), needles were connected to an electroacupuncture (EA) apparatus. Fasting blood glucose (FPG) was measured by glucose oxidase method. Plasma fasting insulin (FINS) and serum C peptide (C-P) were determined by ELISA. Protein and mRNA expressions of insulin signaling molecules were determined by Western blot and real-time RT-PCR, respectively. OLETF rats exhibit increased levels of FPG, FINS, C-P, and homeostasis model assessment-estimated insulin resistance (HOMA-IR), which were effectively decreased by acupuncture treatment. mRNA expressions of several insulin signaling related molecules IRS1, IRS2, Akt2, aPKCζ, and GLUT4 were decreased in OLETF rats compared to SD controls. Expression of these molecules was restored back to normal levels upon acupuncture administration. PI3K-p85α was increased in OLETF rats; this increase was also reversed by acupuncture treatment. Acupuncture improves insulin resistance in OLETF rats, possibly via regulating expression of key insulin signaling related molecules.


Calculi and intracellular ochronosis in the submandibular tissues from a patient with alkaptonuria.
Alkaptonuria (AKU) is a rare autosomal recessive condition caused by deficiency of the enzyme homogentisate 1,2 dioxygenase, resulting in widespread deposition of oxidised homogentisic acid (HGA) polymer, primarily in joint tissues but also in other connective tissues. Macroscopic pigmentation of connective tissues in AKU is well documented and is the end point of a process that is not understood. Deposition in less common regions may provide clues to the pigment formation process. This is the first report of detection of ochronotic pigment in acinar cells and lumina in the submandibular gland of a patient with AKU. Deposition was noted in the apical region of the cells. A lobar duct presented a large calculus with unusual deposits possibly associated with calcium salts. This report highlights the effect that local and intracellular factors may have on converting HGA into polymeric derivatives in the absence of an extracellular matrix.


Survey of susceptibility to marbofloxacin in bacteria isolated from diseased pigs in Europe.
A monitoring programme of marbofloxacin susceptibility of bacteria from Europe causing respiratory tract infection and meningitis in pigs has been active since 1994 and 2002, respectively. Monitoring digestive, metritis and urinary tract infection (UTI) in pigs has been active since 2005 and susceptibility results until 2013 are presented. Minimum inhibitory concentration (MIC) was determined by broth microdilution. For MIC interpretation, Vétoquinol-evaluated breakpoints were applied. For digestive pathogens, Escherichia coli and Salmonella species (1717 and 300 isolates, respectively) exhibited 7.5 per cent resistance in E coli and no resistance in Salmonella species. Similarly, E coli from metritis (369 isolates) had 7.0 per cent resistance to marbofloxacin. However, E coli from UTI (633 isolates) had higher resistance (10.4 per cent). For Streptococcus suis causing meningitis (585 isolates), marbofloxacin susceptibility was very high with only 0.5 per cent resistance and 0.4 per cent resistance was observed with S suis causing respiratory disease (729 isolates). Other respiratory pathogens were also highly susceptible to marbofloxacin with no resistance in Actinobacillus pleuropneumoniae (647 isolates) or Bordetella bronchiseptica (504 isolates), 0.1 per cent resistance in Pasteurella multocida (1373 isolates) and 1.4 per cent resistance in Haemophilus parasuis (145 isolates). There was no apparent change in marbofloxacin MIC over time for any bacterial pathogen based on MIC50/90 These data confirm previously published MIC results from porcine and other animal infections.


Thymidylate synthetase (TS) genotype and TS/dihydropyrimidine dehydrogenase mRNA level as an indicator in determining chemosensitivity to 5-fluorouracil in advanced gastric carcinoma.
One of the target enzymes of 5-fluorouracil (5-FU) is thymidylate synthetase (TS). The DNA sequence of the TS gene includes either double or triple tandem 28-bp repeats within the promoter region, such that TS genotypes can be classified as homozygous 3R/3R heterozygous 2R/3R or homozygous 2R/2R Several recent studies have shown that TS genotype affects mRNA expression, with 3R/3R homozygotes showing higher TS mRNA expression compared to the other genotypes. We analyzed the TS genotype and TS and dihydropyrimidine dehydrogenase (DPD) mRNA expression levels in 22 advanced gastric carcinoma patients, and analyzed results with respect to patient 5-FU chemosensitivity, as detected by the tetrazolium-based colorimetric (MTT) assay and survival outcome. Between September 2001 and April 2002, 22 Japanese patients with advanced gastric carcinoma were evaluated. Informed written consent was obtained from all patients and the study was approved by the ethical committee at our University Hospital Fresh surgical specimens from carcinoma lesions were enzymatically dissociated and incubated with 5-FU at a concentration of 50 microg/ml for 48 hours to determine the inhibition rate as detected by MTT assay. Normal and tumor tissue and peripheral blood samples were collected and stored at -80 degrees C until assay for TS genotype and TS and DPD mRNA level The TS genotype was assessed by PCR assay using peripheral monocytes, since monocyte genotypes represent the genotype of normal and tumor tissues. Quantification of TS and DPD mRNA levels was performed using real-time PCRP Survival outcome was assessed according to the disease-free survival period in cases with similar clinical backgrounds. TS genotyping revealed 19 3R/3R homozygotes and 3 2R/3R heterozygotes. After analysis of normal and tumor tissues, samples from homozygote 3R/3R cases showed higher TS mRNA expression than heterozygote 2R/3R cases, which was statistically significant at p<0.05. We also observed a statistically significant correlation in TS mRNA levels between normal and tumor tissues, while no significant correlation was observed for DPD mRNA levels between normal and tumor tissues. While no relationship between 5-FU chemosensitivity and TS genotype or mRNA expression was observed, cases with high DPD mRNA expression were resistant to 5-FU and exhibited poor survival outcomes. While TS genotype affected TS mRNA expression in both normal and tumor tissues in advanced gastric cancer, there is no relationship between TS genotype or mRNA expression level and 5-FU chemosensitivity. Our finding, that DPD mRNA expression appears to be a factor in determining 5-FU chemosensitivity and the survival outcome of advanced gastric cancer patients, is comparable with previous reports.


Scavenging of reactive oxygen species in apoplastic and symplastic areas of rolled leaves in Ctenanthe setosa under drought stress.
The correspondence among apoplastic and symplastic antioxidant status, stomatal conductance and water potential was investigated during leaf rolling in Ctenanthe setosa (Rosc.) Eichler (Marantaceae) under drought stress. Apoplastic and symplastic extractions of leaf and petiole were performed at different visual leaf rolling scores from 1 to 4 (1 is unrolled, 4 is tightly rolled and the others are intermediate form). In the leaf symplast, the highest changes were found in catalase (CAT) and guaiacol peroxidase (GPX) activities when compared to score 1 during leaf rolling. No significant change was observed in superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities in the symplast of leaf during the rolling. The same phenomenon was also present in the symplast of petiole except APX activity. In the leaf apoplast, the highest increase occurred in APX and GPX activities, whilst a slight increase in CAT and SOD activities. In the apoplast of petiole, the highest increment was found only in GPX activity, while there were small increases in SOD, APX and CAT activities. Hydrogen peroxide content increased up to score 3 in the apoplast and symplast of leaf and petiole but then slightly decreased. Also, superoxide production increased in the leaf and petiole apoplast but its quantity in the apoplast was much more than that of the symplast. On the other hand, NAD(P)H oxidase activity increased in the leaf but no change was observed in the petiole. In conclusion, as a result of water deficit during leaf rolling antioxidant enzymes are induced to scavenging of ROS produced in symplast and apoplast.


The p11 subunit of annexin II heterotetramer is regulated by basic carboxypeptidase.
The Ca(2+)-dependent phospholipid-binding protein annexin II heterotetramer (AIIt) is composed of two copies of annexin II and a p11 dimer. The interaction of the carboxyl-terminal lysine residues of the p11 subunit of AIIt with the lysine-binding kringle domains of plasminogen is believed to play a key role in plasminogen binding and stimulation of the tPA-catalyzed cleavage of plasminogen to plasmin. In the current report, we show that AIIt-stimulated plasminogen activation is regulated by basic carboxypeptidases, in vitro. The incubation of AIIt with a 1/400 molar ratio of carboxypeptidase B for periods as short as 2 min resulted in a significant loss in AIIt-stimulated plasminogen activation. Carboxypeptidase B (CpB) as well as thrombin-activated fibrinolysis inhibitor (TAFIa) and carboxypeptidase N (CpN) rapidly reduced AIIt-stimulated plasminogen activation by 80%. The molar ratio of carboxypeptidase/AIIt for half-maximal inhibition of AIIt was 1/4700, 1/700, and 1/500 for CpB, TAFIa, and CpN, respectively. Treatment of AIIt with carboxypeptidase resulted in loss of both carboxyl-terminal lysine residues from the p11 subunit, which correlated with a decrease in the k(cat) and an increase in the K(m) for plasminogen activation. The data reveal a novel mechanism for the regulation of AIIt-stimulated plasminogen activation.


Dysregulation of the insulin/IGF binding protein-1 axis in transgenic mice is associated with hyperinsulinemia and glucose intolerance.
The insulin/IGF binding protein-1 (IGFBP-1) axis is important in coordinating insulin- and IGF-mediated regulation of glucose metabolism and glycemia. Dysregulation of the axis may play a role in the pathophysiology of disorders of insulin deficiency and resistance. We have investigated this hypothesis by generating transgenic mice that overexpress hIGFBP-1. To study the axis in its true physiological context, we used a human (h) IGFBP-1 cosmid clone so that transgene expression is responsive to normal hormonal stimuli. hIGFBP-1 mRNA is expressed in a tissue-specific fashion, and measurement of serum protein levels by specific immunoassay indicates normal physiological regulation in response to fasting/feeding and appropriate post-translational modification as indicated by the detection of phosphorylated and nonphosphorylated isoforms of the protein. The hypoglycemic response to exogenous IGF-I is attenuated in transgenic mice. Transgenic mice exhibit an enhanced insulin secretory response to a glucose challenge, although basal and stimulated blood glucose levels are similar to controls. There is a sexual dimorphism in phenotypic expression: male transgenic mice had higher stimulated glucose and insulin levels than did females. Transgenic mice exhibit fasting hyperglycemia and hyperinsulinemia and glucose intolerance in later life, indicating an age-related decline in glucocompetence. These findings demonstrate the importance of the normal inverse relationship between serum insulin and IGFBP-1 levels in glucoregulation and that sustained dysregulation of the insulin/IGF-I/IGFBP-1 axis is associated with impaired glucose tolerance and abnormalities of insulin action.


Assessing the use of contraceptives by female undergraduate students in a selected higher educational institution in Gauteng.
Unplanned pregnancies amongst students at higher education institutions are a major concern worldwide, including South Africa. Apart from various social and psychological challenges, unplanned pregnancies affect students' objectives of achieving academic success. Research undertaken in the United States of America (USA) indicates that around 80% of female students in institutions of higher education between ages 18 and 24 are sexually active. To assess and describe the use of contraceptives by undergraduate female students in a selected higher educational institution in Gauteng. A cross-sectional, descriptive, quantitative design was used. A total of 400 female undergraduate students were requested to respond to a self-administered questionnaire. Stratified random sampling was used to select the participants. They were selected systematically from two campuses. Data were entered using an excel sheet at the Department of Statistics, and analysed using the Statistical Analysis Software programme, (SAS version 9.3), of the Department of Statistics' higher educational institutions. A total of 74%females indicated they were sexually active, 79%of whom reported using contraceptives. The most common used methods were oral contraceptives at 38%, and 25% for male condoms. The most commonly known methods were condoms at 84%, and the oral contraceptive at 68%. The knowledge of condom use to prevent sexually transmitted diseases was high at 91%. Inadequate knowledge and awareness on some contraceptive methods was found. Thus, educational programmes to increase students' knowledge on the use of all contraceptive methods are urgently needed.


Universal Alternative Splicing of Noncoding Exons.
The human transcriptome is so large, diverse, and dynamic that, even after a decade of investigation by RNA sequencing (RNA-seq), we have yet to resolve its true dimensions. RNA-seq suffers from an expression-dependent bias that impedes characterization of low-abundance transcripts. We performed targeted single-molecule and short-read RNA-seq to survey the transcriptional landscape of a single human chromosome (Hsa21) at unprecedented resolution. Our analysis reaches the lower limits of the transcriptome, identifying a fundamental distinction between protein-coding and noncoding gene content: almost every noncoding exon undergoes alternative splicing, producing a seemingly limitless variety of isoforms. Analysis of syntenic regions of the mouse genome shows that few noncoding exons are shared between human and mouse, yet human splicing profiles are recapitulated on Hsa21 in mouse cells, indicative of regulation by a deeply conserved splicing code. We propose that noncoding exons are functionally modular, with alternative splicing generating an enormous repertoire of potential regulatory RNAs and a rich transcriptional reservoir for gene evolution.


Multidrug resistance proteins and folate supplementation: therapeutic implications for antifolates and other classes of drugs in cancer treatment.
Over the past decades, numerous reports have covered the crucial role of multidrug resistance (MDR) transporters in the efficacy of various chemotherapeutic drugs. Specific cell membrane-associated transporters mediate drug resistance by effluxing a wide spectrum of toxic agents. Although several excellent reviews have addressed general aspects of drug resistance, this current review aims to highlight implications for the efficacy of folate-based and other types of chemotherapeutic drugs. Folates are vitamins that are daily required for many biosynthetic processes. Folate supplementation in our diet may convey protective effects against several diseases, including cancers, but folate supplementation also makes up an essential part of several current cancer chemotherapeutic regimens. Traditionally, the folate leucovorin, for instance, is used to reduce antifolate toxicity in leukemia or to enhance the effect of the fluoropyrimidine 5-fluorouracil in some solid tumors. More recently, it has also been noted that folic acid has the ability to increase antitumor activity of several structurally unrelated regimens, such as alimta/pemetrexed and cisplatin. Moreover, studies from our laboratory demonstrated that folates could modulate the expression and activity of at least two members of the MDR transporters: MRP1/ABCC1, and the breast cancer resistance protein BCRP/ABCG2. Thus, folate supplementation may have differential effects on chemotherapy: (1) reduction of toxicity, (2) increase of antitumor activity, and (3) induction of MRP1 and BCRP associated cellular drug resistance. In this review the role of MDR proteins is discussed in further detail for each of these three items from the perspective to optimally exploit folate supplementation for enhanced chemotherapeutic efficacy of both antifolate-based chemotherapy and other classes of chemotherapeutic drugs.


Chocolate intake is associated with better cognitive function: The Maine-Syracuse Longitudinal Study.
Chocolate and cocoa flavanols have been associated with improvements in a range of health complaints dating from ancient times, and has established cardiovascular benefits. Less is known about the effects of chocolate on neurocognition and behaviour. The aim of this study was to investigate whether chocolate intake was associated with cognitive function, with adjustment for cardiovascular, lifestyle and dietary factors. Cross-sectional analyses were undertaken on 968 community-dwelling participants, aged 23-98 years, from the Maine-Syracuse Longitudinal Study (MSLS). Habitual chocolate intake was related to cognitive performance, measured with an extensive battery of neuropsychological tests. More frequent chocolate consumption was significantly associated with better performance on the Global Composite score, Visual-Spatial Memory and Organization, Working Memory, Scanning and Tracking, Abstract Reasoning, and the Mini-Mental State Examination. With the exception of Working Memory, these relations were not attenuated with statistical control for cardiovascular, lifestyle and dietary factors. Prospective analyses revealed no association between cognitive function and chocolate intake measured up to 18 years later. Further intervention trials and longitudinal studies are needed to explore relations between chocolate, cocoa flavanols and cognition, and the underlying causal mechanisms.


The Online Dissemination of Nature-Health Concepts: Lessons from Sentiment Analysis of Social Media Relating to "Nature-Deficit Disorder".
Evidence continues to grow supporting the idea that restorative environments, green exercise, and nature-based activities positively impact human health. Nature-deficit disorder, a journalistic term proposed to describe the ill effects of people's alienation from nature, is not yet formally recognized as a medical diagnosis. However, over the past decade, the phrase has been enthusiastically taken up by some segments of the lay public. Social media, such as Twitter, with its opportunities to gather "big data" related to public opinions, offers a medium for exploring the discourse and dissemination around nature-deficit disorder and other nature-health concepts. In this paper, we report our experience of collecting more than 175,000 tweets, applying sentiment analysis to measure positive, neutral or negative feelings, and preliminarily mapping the impact on dissemination. Sentiment analysis is currently used to investigate the repercussions of events in social networks, scrutinize opinions about products and services, and understand various aspects of the communication in Web-based communities. Based on a comparison of nature-deficit-disorder "hashtags" and more generic nature hashtags, we make recommendations for the better dissemination of public health messages through changes to the framing of messages. We show the potential of Twitter to aid in better understanding the impact of the natural environment on human health and wellbeing.


Early response assessment of palliative conventional radiotherapy for painful uncomplicated vertebral bone metastases.
Radiation therapy (RT) is the common treatment for painful vertebral bone metastases without paralysis by malignant spinal cord compression. However, no studies have focused on the time course of pain after RT. Then, we investigated the change of pain after RT for painful vertebral bone metastases without paralysis. Participants included 101 patients who received RT for painful vertebral bone metastases without paralysis in our institution between 2012 and 2016. All patients received RT and pain response was evaluated by Numeric Rating Scale (NRS). Follow-up assessments were performed just before the start of RT and every month for six months after RT. Pain response was classified as complete response (CR), partial response (PR), pain progression (PP), and indeterminate response (IR) based on the response criteria of International Bone Metastases Consensus Working Party. Responders were classified as either CR or PR, and non-responders as either PP or IR. Median NRS scores for pain were 5 before RT, decreasing to 0 by one month after RT and remaining zero until last follow-up, representing a significant decrease over time (P < 0.001). The rate of responders at each month from one to six months was 93, 96, 95, 100, 98, and 96%, respectively. Multivariate analysis revealed that Spinal Instability Neoplastic Score (SINS) was the only risk factor for response to RT at one month. At one month pain disappeared in 88% of the patients with spinal stability (SINS < 7), although pain disappeared 58% of the patients with spinal instability (SINS ≥ 7), which was significant (P = 0.002). Pain decreased significantly over time and 93% of patients were classified as responders as early as one month after RT in patients with painful vertebral bone metastases without paralysis. Pretreatment SINS could be a predictor of pain response to RT.


Case of chronic eosinophilic leukemia with deletion of chromosome 16 and hepatitis C.
Chronic eosinophilic leukemia is a rare entity, characterized by eosinophilia of >1.5 x 10(9)/L, persisting for >6 months after exclusion of other reactive and neoplastic causes of eosinophilia, and occurring in association with a clonal cytogenetic abnormality. Various chromosomal abnormalities have been associated with chronic eosinophilic leukemia. Partial deletion of the long arm of chromosome 16 is a cytogenetic abnormality first reported 20 years ago in patients with acute myeloid leukemia associated with bone marrow eosinophilia (AML-M4Eo). We report a case of a 45-year-old African-American male with hepatitis C and sustained peripheral blood eosinophilia who presented with gross hematuria, dyspnea on exertion, chills, decreased appetite and weight loss of 40 pounds associated with hepatosplenomegaly and lymphadenopathy. Bone marrow biopsy showed clonal cytogenetic abnormality consisting of deletion of the long arm of chromosome 16 (16q22). Philadelphia chromosome t (9;22) and polymerase chain reaction (PCR) analysis for C-kit and platelet-derived growth factor receptor-alpha (PDGFRA) mutations were negative. The patient was treated with imatinib at 400 mg/d with improvement of symptoms, reduction of lymphadenopathy and normalization of the eosinophil count. To our knowledge, this is the first case report of isolated del (16) (q22), a cytogenetic abnormality associated with AML-M4Eo, occurring in chronic eosinophilic leukemia. Whether this cytogenetic abnormality might represent a prodromal phase of AML-M4Eo is not known. In addition, the role of hepatitis C in inducing clonal proliferation of eosinophils is unclear.


Wine, beer or spirit drinking in relation to fatal and non-fatal cardiovascular events: a meta-analysis.
In previous studies evaluating whether different alcoholic beverages would protect against cardiovascular disease, a J-shaped relationship for increasing wine consumption and vascular risk was found; however a similar association for beer or spirits could not be established. An updated meta-analysis on the relationship between wine, beer or spirit consumption and vascular events was performed. Articles were retrieved through March 2011 by PubMed and EMBASE search and a weighed least-squares regression analysis pooled data derived from studies that gave quantitative estimation of the vascular risk associated with the alcoholic beverages. From 16 studies, evidence confirms a J-shaped relationship between wine intake and vascular risk. A significant maximal protection-average 31% (95% confidence interval (CI): 19-42%) was observed at 21 g/day of alcohol. Similarly, from 13 studies a J-shaped relationship was apparent for beer (maximal protection: 42% (95% CI: 19-58%) at 43 g/day of alcohol). From 12 studies reporting separate data on wine or beer consumption, two closely overlapping dose-response curves were obtained (maximal protection of 33% at 25 g/day of alcohol). This meta-analysis confirms the J-shaped association between wine consumption and vascular risk and provides, for the first time, evidence for a similar relationship between beer and vascular risk. In the meta-analysis of 10 studies on spirit consumption and vascular risk, no J-shaped relationship could be found.


Crystal structure of a complex between electron transfer partners, cytochrome c peroxidase and cytochrome c.
The crystal structure of a 1:1 complex between yeast cytochrome c peroxidase and yeast iso-1-cytochrome c was determined at 2.3 A resolution. This structure reveals a possible electron transfer pathway unlike any previously proposed for this extensively studied redox pair. The shortest straight line between the two hemes closely follows the peroxidase backbone chain of residues Ala194, Ala193, Gly192, and finally Trp191, the indole ring of which is perpendicular to, and in van der Waals contact with, the peroxidase heme. The crystal structure at 2.8 A of a complex between yeast cytochrome c peroxidase and horse heart cytochrome c was also determined. Although crystals of the two complexes (one with cytochrome c from yeast and the other with cytochrome c from horse) grew under very different conditions and belong to different space groups, the two complex structures are closely similar, suggesting that cytochrome c interacts with its redox partners in a highly specific manner.


Clinical and biological significance of vascular endothelial growth factor in endometrial cancer.
Vascular endothelial growth factor (VEGF) is critical for angiogenesis and tumor progression; however, its role in endometrial cancer is not fully known. Therefore, we examined the clinical and therapeutic significance of VEGF in endometrial carcinoma using patient samples and an endometrioid orthotopic mouse model. Following Institutional Review Board approval, VEGF expression and microvessel density (MVD) counts were evaluated using immunohistochemistry in 111 invasive endometrioid endometrial cancers by two independent investigators. Results were correlated with clinicopathologic characteristics. For the animal model, Ishikawa or Hec-1A cancer cell lines were injected directly into the uterine horn. Therapy experiments with bevacizumab alone or in combination with docetaxel were done and samples were analyzed for markers of angiogenesis and proliferation. Of 111 endometrial cancers, high expression of VEGF was seen in 56% of tumors. There was a strong correlation between VEGF expression and MVD (P < 0.001). On multivariate analysis, stage (P = 0.04), grade (P = 0.003), VEGF levels (P = 0.03), and MVD (P = 0.037) were independent predictors of shorter disease-specific survival. In the murine model, whereas docetaxel and bevacizumab alone resulted in 61% to 77% tumor growth inhibition over controls, combination therapy had the greatest efficacy (85-97% inhibition over controls; P < 0.01) in both models. In treated tumors, combination therapy significantly reduced MVD counts (50-70% reduction over controls; P < 0.01) and percent proliferation (39% reduction over controls; P < 0.001). Increased levels of VEGF and angiogenic markers are associated with poor outcome in endometrioid endometrial cancer patients. Using a novel orthotopic model of endometrioid endometrial cancer, we showed that combination of antivascular therapy with docetaxel is highly efficacious and should be considered for future clinical trials.


Effect of Interval and Continuous Aerobic Training on Basal Serum and Plasma Brain-Derived Neurotrophic Factor Values in Seniors: A Systematic Review of Intervention Studies.
The purpose of this systematic review was to provide a comprehensive analysis of the available clinical trials analyzing, in seniors, the effect of interval aerobic training (IAT) and continuous aerobic training (CAT) on peripheral brain-derived neurotrophic factor (BDNF) concentration. We identified 14 randomized or not-randomized intervention studies published up to January 2017 through a computer-assisted search (PUBMED, Pedro, and Science direct data bases). The five trials considering IAT and the nine considering CAT totalized 988 individuals (age range: 58.1-77 years). The parameters of aerobic training (AT) protocol in terms of frequency and intensity are the primary determinants of the BDNF response to AT. The interpretation of the relationship between AT and BDNF signaling pathway was very challenging when specific health conditions were taken into consideration. This was more particularly true with mild cognitive impairment or depressive symptoms. These findings argue in favor of a generalization of the practice of AT and show that the type of training is not the main determining factor of the increase in BDNF level, which results more from the combination of several factors such as intensity and frequency of sessions, duration of programs, and also some genetic determinant coding for BDNF protein. All these factors have to be carefully addressed in future researches in that field. Thus, further researches are still necessary to better the signaling pathway by which AT contributes to better health outcomes.


Directed growth of adult human white matter stem cell-derived neurons on aligned fibrillar collagen.
The nanoscale spatial organization of collagen fibrils as major constituents of extracellular matrices is believed to be crucial for neurite guidance in neural development and repair. To systematically study the influence of collagen fibril alignment, length, and density on human neuronal cell behavior, we used our novel technology to produce aligned collagen matrices by shear flow deposition using a microfluidic channel system and applied these surfaces to functional human neurons and glia derived from white matter neural stem cell cultures. Neurites on aligned collagen were highly oriented in the direction of the underlying fibrils, whereas neurites on nonaligned collagen or poly-d-lysine did not exhibit a preferred direction but formed a web-like morphology. Although the best alignment of collagen fibers in our study was seen using long fibrils at low density, the best neurite orientation was achieved on long fibrils at high density. Neurite outgrowth was enhanced on aligned collagen compared with nonaligned collagen or poly-d-lysine substrates, whereas neural differentiation and cell survival were not influenced by the type of substrate. Our data show that size and density of aligned collagen fibrils are crucial for axonal sprouting of human neural stem cell-derived neurons. The flexibility of our technology, allowing collagen matrix qualities to be adapted to the neuronal cell type of interest, is thus a major advantage for therapeutic reconstruction of axonal pathways in the central or peripheral nervous system.


C-reactive Protein Concentration Is Associated With a Higher Risk of Mortality in a Rural Korean Population.
C-reactive protein (CRP), an inflammatory biomarker, has been widely used as a preclinical marker predictive of morbidity and mortality. Although many studies have reported a positive association between CRP and mortality, uncertainty still remains about this association in various populations, especially in rural Korea. A total of 23 233 middle-aged participants (8862 men and 14 371 women) who were free from cardiovascular disease, cancer, and acute inflammation (defined by a CRP level ≥10 mg/L) were drawn from 11 rural communities in Korea between 2005 and 2011. Blood CRP concentration was analyzed as a categorical variable (low: 0.0-0.9 mg/L; intermediate: 1.0-3.0 mg/L; high: 3.1-9.9 mg/L) as well as a continuous variable. Each participant's vital status through December 2013 was confirmed by death statistics from the National Statistical Office. Cox proportional hazard models were used to assess the independent association between CRP and mortality after adjusting for other risk factors. The total quantity of observed person-years was 57 975 for men and 95 146 for women, and the number of deaths was 649 among men and 367 among women. Compared to the low-CRP group, the adjusted hazard ratio for all-cause mortality of the intermediate group was 1.17 (95% confidence interval [CI], 0.98 to 1.40) for men and 1.27 (95% CI, 1.01 to 1.61) for women, and the corresponding values for the high-CRP group were 1.98 (95% CI, 1.61 to 2.42) for men and 1.41 (95% CI, 1.03 to 1.95) for women. Similar trends were found for CRP evaluated as a continuous variable and for cardiovascular mortality. Higher CRP concentrations were associated with higher mortality in a rural Korean population, and this association was more prominent in men than in women.


Selection for early surgery in asymptomatic mitral regurgitation: a Markov model.
Current guidelines propose mitral valve repair in asymptomatic chronic mitral regurgitation (MR) when the likelihood of repair is 90% or more. As this figure is not evidence-based, we sought whether the results of a decision-analytic model could facilitate the selection between early surgery (ES) and watchful waiting (WW) based on current guidelines. A Markov model was developed to reflect the anticipated health states in MR (pre-operative, post-operative, post-complication and death). Risks and transitions were informed by the literature. Implications of the strategies for survival, quality-adjusted life years (QALYs), cost and cost-effectiveness were calculated from a US healthcare provider perspective. In the reference case (90% repair), QALY with ES was superior to WW (11.2 [0.4-21.3] vs 10.7 [95%CI: 1.0-21.3]) at an incremental cost-effectiveness of $54,659 ($45,030-$64,288) per QALY. Sensitivity analyses of health benefit showed the main variables influencing outcome were repair rate, operative mortality and risks of heart failure and death with medical management. At the registry repair rate (50%), outcomes of ES were worse than WW, and threshold analysis showed that a repair rate of 84% was required for ES to be superior. High medical risk (yearly heart failure risk 5.6 ± 6.6% and mortality 2.5 ± 4%) was the most favorable scenario for surgery; ES was more effective when mortality in the WW group was >3.5%/year. A Markov model might be used to guide the selection of asymptomatic patients for mitral repair, based on local variations in risk and complications as well as repair rate.


Place recognition using batlike sonar.
Echolocating bats have excellent spatial memory and are able to navigate to salient locations using bio-sonar. Navigating and route-following require animals to recognize places. Currently, it is mostly unknown how bats recognize places using echolocation. In this paper, we propose template based place recognition might underlie sonar-based navigation in bats. Under this hypothesis, bats recognize places by remembering their echo signature - rather than their 3D layout. Using a large body of ensonification data collected in three different habitats, we test the viability of this hypothesis assessing two critical properties of the proposed echo signatures: (1) they can be uniquely classified and (2) they vary continuously across space. Based on the results presented, we conclude that the proposed echo signatures satisfy both criteria. We discuss how these two properties of the echo signatures can support navigation and building a cognitive map.


Proximal and distal influences on hip and knee kinematics in runners with patellofemoral pain during a prolonged run.
Cross-sectional experimental laboratory study. To investigate the relationships between hip strength and hip kinematics, and between arch structure and knee kinematics during prolonged treadmill running in runners with and without patellofemoral pain syndrome (PFPS). Hip weakness can lead to excessive femoral motions that adversely affect patellofemoral joint mechanics. Similarly, foot mechanics, which are influenced by foot structure, are also known to influence patellofemoral joint mechanics. Thus, proximal and distal factors should be considered when studying individuals with PFPS. Twenty recreational runners with PFPS (5 male, 15 female) and 20 matched uninjured runners participated in the study. Hip abduction and hip external rotation isometric strength measurements were collected before and after a prolonged run, while the arch height index was recorded on all runners before the run. Lower extremity kinematic data were collected at the beginning and end of the run. Two-way repeated-measures analyses of variance (ANOVAs) were used for analysis. Both groups displayed decreases in hip abductor and external rotator strengths at the end of the run. The PFPS group displayed significantly lower hip abduction strength [(kg x cm)/body mass] compared to controls (PFPS group: begin 15.3, end 13.5; uninjured group: begin 17.3, end 15.4). At the end of the run, the level of association between hip abduction strength and the peak hip adduction angle for the PFPS group was statistically significant, indicating a strong relationship (r = -0.74). No other associations with hip strength were observed in either group. Arch height did not differ between groups and no significant association was observed between arch height and peak knee adduction angle during running. Runners with PFPS displayed weaker hip abductor muscles that were associated with an increase in hip adduction during running. This relationship became more pronounced at the end of the run. Therapy, level 5.


IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo.
To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNγ production, and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3, and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2, and patient survival.


Fetal exposure to high-avidity TCR ligand enhances expansion of peripheral T regulatory cells.
Lately, it has become clear that regulatory T cells (Tregs) play a major role in the maintenance of peripheral tolerance and control of autoimmunity. Despite these critical functions, the process underlying the development of Tregs remains largely undefined. Herein, altered peptide ligand (APL) variants derived from the proteolipid protein-1 (PLP1) epitope were expressed on immunoglobulins (Igs) and the resulting Ig-APLs were used to deliver the APLs from mother to fetus through the maternal placenta to influence thymic T cell selection. This delivery system was then adapted to the SJL/J mouse, a strain that expresses only the DM20 form of PLP, which lacks the dominant PLP1 epitope in the thymus during fetal and neonatal development. This model, which restores thymic T cell selection for PLP1, was then used to determine whether affinity plays a role in the development of Tregs. The findings show that fetal exposure to low-affinity peptide ligand was unable to drive development of Tregs while variants with higher affinity to the TCR resulted in significant seeding of the periphery with mature, naive Tregs. Thus, contrary to pathogenic T cells, Tregs require avid TCR-ligand interaction to undergo thymic development and maturation.