Clinical results of biologic prosthesis: A systematic review and meta-analysis of comparative studies.
Biologic prosthesis (BP) has been reported as a safe alternative to polytetrafluoroethylene (PTFE) in vascular reconstruction. However, efficacy of BP remains controversial. We, therefore, conducted a systematic review to summarize previous available evidences comparing the BP and PTFE in terms of clinical outcomes. A literature search of the MEDLINE and Scopus was performed to identify comparative studies reporting outcomes of BP, PTFE, and/or autologous veins graft (VG) in vascular access for hemodialysis or femoropopliteal bypass. The outcome of interest was graft patency. Two reviewers independently extracted data. Meta-analysis with a random-effect model was applied to pool a risk ratio (RR) across studies. Among 584 articles identified, 11 studies (4 randomized controlled trials (RCT) and 7 cohorts) comprising 2627 patients were eligible for pooling. Seven studies compared BP with PTFE and 3 studies compared PTFE with VG. Among BP vs PTFE, pooling based on 3 RCTs yielded the pooled RR of 1.54 (95% CI: 1.10, 2.16), indicating 54% higher graft patency in VG than PTFE. Adding the 7 cohorts in this pooling yield similar results with the pooled RR of 1.29 (95% CI: 1.15, 1.45). The pooled RR of graft patency for BP vs VG was 0.74 (95% CI, 0.55, 1.00), indicating 26% lower graft patency in BP than VG. Our first meta-analysis indicated that the biosynthetic prosthesis might be benefit over PTFE by increasing graft patency. An updated meta-analysis or a large scale randomized control trial is required to confirm this benefit.


Modulation of apoptosis sensitivity through the interplay with autophagic and proteasomal degradation pathways.
Autophagic and proteasomal degradation constitute the major cellular proteolysis pathways. Their physiological and pathophysiological adaptation and perturbation modulates the relative abundance of apoptosis-transducing proteins and thereby can positively or negatively adjust cell death susceptibility. In addition to balancing protein expression amounts, components of the autophagic and proteasomal degradation machineries directly interact with and co-regulate apoptosis signal transduction. The influence of autophagic and proteasomal activity on apoptosis susceptibility is now rapidly gaining more attention as a significant modulator of cell death signalling in the context of human health and disease. Here we present a concise and critical overview of the latest knowledge on the molecular interplay between apoptosis signalling, autophagy and proteasomal protein degradation. We highlight that these three pathways constitute an intricate signalling triangle that can govern and modulate cell fate decisions between death and survival. Owing to rapid research progress in recent years, it is now possible to provide detailed insight into the mechanisms of pathway crosstalk, common signalling nodes and the role of multi-functional proteins in co-regulating both protein degradation and cell death.


TLR7 influences germinal center selection in murine SLE.
TLR7 enhances germinal center maturation and migration of B cells to the dark zone where proliferation and somatic hypermutation occur. Our goal was to determine how Tlr7 dose influences selection of the autoreactive B cell repertoire in NZW/BXSB. Yaa mice bearing the site-directed heavy chain transgene 3H9 that encodes for the TLR7 regulated anti-CL response. To create a physiologic setting in which autoreactive B cells compete for survival with non-autoreactive B cells, we generated bone marrow chimeras in which disease onset occurred with similar kinetics and the transferred 3H9+ female non-Yaa, male Yaa or male TLR7(-/Yaa) cells could be easily identified by positivity for GFP. Deletion of 3H9 B cells occurred in the bone marrow and the remaining 3H9 follicular B cells manifested a decrease in surface IgM. Although there were differences in the naïve repertoire between the chimeras it was not possible to distinguish a clear pattern of selection against lupus related autoreactivity in TLR7(-/Yaa) or female chimeras. By contrast, preferential expansion of 3H9+ B cells occurred in the germinal centers of male Yaa chimeras. In addition, although all chimeras preferentially selected 3H9/Vκ5 encoded B cells into the germinal center and plasma cell compartments, 3H9 male Yaa chimeras had a more diverse repertoire and positively selected the 3H9/Vκ5-48/Jκ4 pair that confers high affinity anti-cardiolipin activity. We were unable to demonstrate a consistent effect of Tlr7 dose or Yaa on somatic mutations. Our data show that TLR7 excess influences the selection, expansion and diversification of B cells in the germinal center, independent of other genes in the Yaa locus.


Place of delivery and perinatal mortality in Kenya.
Increasing access to skilled birth attendants is a key goal in reducing perinatal mortality. In Kenya, where 40% of births occur at home, efforts toward this goal have focused on providing free maternity services in government facilities and discouraging home births. To identify trends in facility deliveries and determine the association between delivery location and PM in Kenya. We utilized data on 36,375 deliveries from the Kenya site of the Global Network for Women's and Children's Health Research, which maintains a prospective, population-based observational study of pregnancy and neonatal outcomes. We identified temporal trends in facility utilization and perinatal mortality. We then assessed associations between delivery location and PM using generalized linear mixed equations. The percentage of facility births increased from 38.4% in 2009 to 47.6% in 2013, with no change in perinatal mortality. Infants delivered in a facility had a higher risk of perinatal mortality than infants delivered at home (aOR = 1.41, p = 0.005). In stratified analyses, hospital deliveries had a higher adjusted odds of perinatal mortality than home and health center deliveries, with no difference between health center and home deliveries. The increase in facility deliveries between 2009 and 2013 was not associated with a decline in perinatal mortality. Infants born in facilities had a 41% greater risk of perinatal mortality than infants born at home. Further research is needed to assess possible explanations for this finding, including delays in referring and caring for complicated pregnancies, higher risk infants delivering at facilities, and poor quality of care in facilities.


Glut1-mediated glucose transport regulates HIV infection.
Cell cycle entry is commonly considered to positively regulate HIV-1 infection of CD4 T cells, raising the question as to how quiescent lymphocytes, representing a large portion of the viral reservoir, are infected in vivo. Factors such as the homeostatic cytokine IL-7 have been shown to render quiescent T cells permissive to HIV-1 infection, presumably by transiently stimulating their entry into the cell cycle. However, we show here that at physiological oxygen (O(2)) levels (2-5% O(2) tension in lymphoid organs), IL-7 stimulation generates an environment permissive to HIV-1 infection, despite a significantly attenuated level of cell cycle entry. We identify the IL-7-induced increase in Glut1 expression, resulting in augmented glucose uptake, as a key factor in rendering these T lymphocytes susceptible to HIV-1 infection. HIV-1 infection of human T cells is abrogated either by impairment of Glut1 signal transduction or by siRNA-mediated Glut1 down-regulation. Consistent with this, we show that the susceptibility of human thymocyte subsets to HIV-1 infection correlates with Glut1 expression; single-round infection is markedly higher in the Glut1-expressing double-positive thymocyte population than in any of the Glut1-negative subsets. Thus, our studies reveal the Glut1-mediated metabolic pathway as a critical regulator of HIV-1 infection in human CD4 T cells and thymocytes.


Differential Expression of Genes Involved in Host Recognition, Attachment, and Degradation in the Mycoparasite Tolypocladium ophioglossoides.
The ability of a fungus to infect novel hosts is dependent on changes in gene content, expression, or regulation. Examining gene expression under simulated host conditions can explore which genes may contribute to host jumping. Insect pathogenesis is the inferred ancestral character state for species of Tolypocladium, however several species are parasites of truffles, including Tolypocladium ophioglossoides. To identify potentially crucial genes in this interkingdom host switch, T. ophioglossoides was grown on four media conditions: media containing the inner and outer portions of its natural host (truffles of Elaphomyces), cuticles from an ancestral host (beetle), and a rich medium (Yeast Malt). Through high-throughput RNASeq of mRNA from these conditions, many differentially expressed genes were identified in the experiment. These included PTH11-related G-protein-coupled receptors (GPCRs) hypothesized to be involved in host recognition, and also found to be upregulated in insect pathogens. A divergent chitinase with a signal peptide was also found to be highly upregulated on media containing truffle tissue, suggesting an exogenous degradative activity in the presence of the truffle host. The adhesin gene, Mad1, was highly expressed on truffle media as well. A BiNGO analysis of overrepresented GO terms from genes expressed during each growth condition found that genes involved in redox reactions and transmembrane transport were the most overrepresented during T. ophioglossoides growth on truffle media, suggesting their importance in growth on fungal tissue as compared to other hosts and environments. Genes involved in secondary metabolism were most highly expressed during growth on insect tissue, suggesting that their products may not be necessary during parasitism of Elaphomyces. This study provides clues into understanding genetic mechanisms underlying the transition from insect to truffle parasitism.


Functional interaction of cytosolic hsp70 and a DnaJ-related protein, Ydj1p, in protein translocation in vivo.
In order to analyze the in vivo role of the SSA class of cytosolic 70-kDa heat shock proteins (hsps) of Saccharomyces cerevisiae, we isolated a temperature-sensitive mutant of SSA1. The effect of a shift of mutant cells (ssa1ts ssa2 ssa3 ssa4) from the permissive temperature of 23 degrees C to the nonpermissive temperature of 37 degrees C on the processing of several precursor proteins translocated into the endoplasmic reticulum or mitochondria was assessed. Of three mitochondrial proteins tested, the processing of only one, the beta subunit of the F1F0 ATPase, was dramatically affected. Of six proteins destined for the endoplasmic reticulum, the translocation of only prepro-alpha-factor and proteinase A was inhibited. The processing of prepro-alpha-factor was inhibited within 2 min of the shift to 37 degrees C, suggesting a direct effect of the hsp70 defect on translocation. More than 50% of radiolabeled alpha-factor accumulated in the precursor form, with the remainder rapidly reaching the mature form. However, the translocation block was complete, as the precursor form could not be chased through the translocation pathway. Since DnaJ-related proteins are known to interact with hsp70s and strains containing conditional mutations in a dnaJ-related gene, YDJ1, are defective in translocation of prepro-alpha-factor, we looked for a genetic interaction between SSA genes and YDJ1 in vivo. We found that a deletion mutation of YDJ1 was synthetically lethal in a ssa1ts ssa2 ssa3 ssa4 background. In addition, a strain containing a single functional SSA gene, SSA1, and a deletion of YDJ1 accumulated the precursor form of alpha-factor. However, no genetic interaction was observed between a YDJ1 mutation and mutations in the SSB genes, which encode a second class of cytosolic hsp70 chaperones. These results are consistent with SSA proteins and Ydj1p acting together in the translocation process.


Educational roles as a continuum of mentoring's role in medicine - a systematic review and thematic analysis of educational studies from 2000 to 2018.
Recent studies have gone to great lengths to differentiate mentoring from teaching, tutoring, role modelling, coaching and supervision in efforts to better understand mentoring processes. This review seeks to evaluate the notion that teaching, tutoring, role modelling, coaching and supervision may in fact all be part of the mentoring process. To evaluate this theory, this review scrutinizes current literature on teaching, tutoring, role modelling, coaching and supervision to evaluate their commonalities with prevailing concepts of novice mentoring. A three staged approach is adopted to evaluate this premise. Stage one involves four systematic reviews on one-to-one learning interactions in teaching, tutoring, role modelling, coaching and supervision within Internal Medicine, published between 1st January 2000 and 31st December 2018. Braun and Clarke's (2006) approach to thematic analysis was used to identify key elements within these approaches and facilitate comparisons between them. Stage two provides an updated view of one-to-one mentoring between a senior physician and a medical student or junior doctor to contextualise the discussion. Stage three infuses mentoring into the findings delineated in stage one. Seventeen thousand four hundred ninety-nine citations were reviewed, 235 full-text articles were reviewed, and 104 articles were thematically analysed. Four themes were identified - characteristics, processes, nature of relationship, and problems faced in each of the four educational roles. Role modelling, teaching and tutoring, coaching and supervision lie within a mentoring spectrum of increasingly structured interactions, assisted by assessments, feedback and personalised support that culminate with a mentoring approach. Still requiring validation, these findings necessitate a reconceptualization of mentoring and changes to mentor training programs and how mentoring is assessed and supported.


Functional Diversity of Diterpene Synthases in the Biofuel Crop Switchgrass.
Diterpenoids constitute a diverse class of metabolites with critical functions in plant development, defense, and ecological adaptation. Major monocot crops, such as maize (Zea mays) and rice (Oryza sativa), deploy diverse blends of specialized diterpenoids as core components of biotic and abiotic stress resilience. Here, we describe the genome-wide identification and functional characterization of stress-related diterpene synthases (diTPSs) in the dedicated bioenergy crop switchgrass (Panicum virgatum). Mining of the allotetraploid switchgrass genome identified an expansive diTPS family of 31 members, and biochemical analysis of 11 diTPSs revealed a modular metabolic network producing a diverse array of diterpenoid metabolites. In addition to ent-copalyl diphosphate (CPP) and ent-kaurene synthases predictably involved in gibberellin biosynthesis, we identified syn-CPP and ent-labda-13-en-8-ol diphosphate (LPP) synthases as well as two diTPSs forming (+)-labda-8,13E-dienyl diphosphate (8,13-CPP) and ent-neo-cis-trans-clerodienyl diphosphate (CT-CLPP) scaffolds not observed previously in plants. Structure-guided mutagenesis of the (+)-8,13-CPP and ent-neo-CT-CLPP synthases revealed residue substitutions in the active sites that altered product outcome, representing potential neofunctionalization events that occurred during diversification of the switchgrass diTPS family. The conversion of ent-CPP, ent-LPP, syn-CPP, and ent-neo-CT-CLPP by promiscuous diTPSs further yielded distinct labdane-type diterpene olefins and alcohols. Of these metabolites, the formation of 9β-hydroxy-syn-pimar-15-ene and the expression of the corresponding genes were induced in roots and leaves in response to oxidative stress and ultraviolet irradiation, indicating their possible roles in abiotic stress adaptation. Together, these findings expand the known chemical space of diterpenoid metabolism in monocot crops toward systematically investigating and ultimately improving stress resilience traits in crop species.


Control of polarized cell morphology and motility by adherens junctions.
Cell-cell interactions play a key role in tissue homeostasis. Intercellular adhesions share the complex task of establishing and maintaining tissue architecture while allowing tissue growth, renewal and repair. In particular, adherens junctions (AJs) have been implicated in the formation of diverse tissues and organs like epitheliums, blood vessels or the central nervous system. At the cellular level, AJs are well known for their essential role in epithelial cell differentiation and baso-apical polarity. They also contribute to the control of cell polarity to promote neuronal morphogenesis, growth cone guidance and directed migration in a variety of cell types during embryonic development. AJs based on classical cadherin- and nectin-mediated cell-cell interactions control local membrane dynamics to polarize cell morphology and motility at the single cell level and to coordinate cell shape changes and motile behaviour at the tissue level. I review here the molecular mechanisms allowing control of polarized cell morphology and motility by AJs.


Physical activity levels according to physical and social environmental factors in a sample of adults living in South Brazil.
To evaluate the association between the physical and social environment and physical activity (leisure-time and transport-related) in a population-based sample of adults. Cross-sectional study including 972 adults (20-69 years) living in the urban area of Pelotas, Brazil. Physical activity was measured using the long International Physical Activity Questionnaire. Environmental variables were assessed using a modified version of the Neighborhood Environment Walkability Scale. 69.8% (95% CI = 66.9-72.7) and 51.9% (95% CI = 48.8-55.1) of the subjects did not reach 150 min/wk on leisure-time and transport-related physical activity, respectively. Subjects living near green areas were more likely to be active in leisure-time, as well as those who reported to live in safe neighborhoods. Transport-related physical activity was higher among individuals living in areas with garbage accumulation, and was lower among those living in neighborhoods which are difficult to walk or cycle due to traffic. Social support was strongly associated with leisure-time physical activity. Safety investments, which are urgently required in Brazil, are likely to have a desirable side effect at increasing physical activity at the population level. Building enjoyable and safe public spaces for physical activity practice must be prioritized.


Visual mislocalization during saccade sequences.
Visual objects briefly presented around the time of saccadic eye movements are perceived compressed towards the saccade target. Here, we investigated perisaccadic mislocalization with a double-step saccade paradigm, measuring localization of small probe dots briefly flashed at various times around the sequence of the two saccades. At onset of the first saccade, probe dots were mislocalized towards the first and, to a lesser extent, also towards the second saccade target. However, there was very little mislocalization at the onset of the second saccade. When we increased the presentation duration of the saccade targets prior to onset of the saccade sequence, perisaccadic mislocalization did occur at the onset of the second saccade.


Activation of the Ah receptor by extracts of dietary herbal supplements, vegetables, and fruits.
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that can be activated by a structurally diverse range of synthetic and natural chemicals, and it mediates the toxic and biological effects of environmental contaminants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The spectrum of chemicals that bind to and activate the AhR signal transduction pathway and the identity of materials containing AhR active chemicals is only now being defined. Utilizing AhR-dependent gel retardation and reporter gene bioassays, the screening of extracts of 22 dietary herbal supplements and 21 food products (vegetables and fruits) was performed to identify those containing AhR agonists. Several herbal extracts (ginseng, Fo-Ti, white oak bark, licorice, ginkgo biloba, and black cohosh) stimulated AhR DNA binding and gene expression to levels between 20 and 60% of that produced by TCDD. Although some food extracts (corn, jalapeño pepper, green bell pepper, apple, Brussels sprout, and potato) were relatively potent activators of AhR DNA binding (30-50% of TCDD), only corn and jalapeño pepper extracts induced AhR-dependent luciferase reporter gene expression. However, dilution of corn, jalapeño pepper, bell pepper, and potato extracts dramatically increased their ability to induce luciferase activity, suggesting that these extracts contained AhR antagonists whose effectiveness was overcome by dilution. Overall, these results demonstrate that dietary products can be a major source of naturally occurring AhR ligands to which animals and humans are chronically exposed.


The mental health of Jehovah's Witnesses.
The function of religion in human society is complex. The part played by religion in psychiatric disorders is even more obscure. Previous literature and theories are divided into two groups: one school believes that intense religiosity is a symptom-complex indicative of psychiatric disorder, while the opposing view is that religious belief in some way acts as a defence mechanism protecting the individual and his psyche. The present study of 50 Jehovah's Witnesses admitted to the Mental Health Service facilities of Western Australia suggests that members of this section of the community are more likely to be admitted to a psychiatric hospital than the general population. Furthermore, followers of the sect are three times more likely to be diagnosed as suffering from schizophrenia and nearly four times more likely from paranoid schizophrenia than the rest of the population at risk. These findings suggest that being a member of the Jehovah's Witnesses faith may be a risk factor predisposing to a schizophrenic illness. Further studies would be interesting in investigating whether pre-psychotic people are more likely to join the sect than normal people and what part (if any) membership has in bringing about such a breakdown.


Molecular characterization and clonal diversity of methicillin-susceptible Staphylococcus aureus in milk of cows with mastitis in Brazil.
Mastitis is an important disease for the dairy industry worldwide, causing economic losses and reducing milk quality and production. Staphylococcus aureus is a worldwide agent of this intramammary infection, which also causes foodborne diseases. The objective of this study was to determine the frequency of methicillin-susceptible Staphylococcus aureus (MSSA) isolates in milk of mastitis cows in Brazil and to analyze the genetic lineages and the content of antimicrobial resistance genes and virulence factors among these isolates. Fifty-six MSSA isolates were recovered from 1,484 milk samples (positive for the California mastitis test) of 518 cows from 11 different farms in Brazil (representing 51% of total Staph. aureus obtained), and they were further characterized. Methicillin-susceptible Staphylococcus aureus were isolated from 3.7% of California mastitis test-positive tested milk samples and from 6.2% of tested mastitic cows. Methicillin-susceptible Staphylococcus aureus isolates were characterized by spa typing, agr typing, and multilocus sequence typing, and resistance and virulence traits were investigated by PCR. Seven spa types were identified among MSSA (% of isolates): t127 (44.6), t605 (37.5), t002, t1784, t2066 (1.8), and 2 new ones: t10856 (10.7) and t10852 (1.8). Five distinct sequence types (ST) were detected (% of isolates): ST1 (46.4), ST126 (37.5), ST133 (10.7), ST5 (3.6), and a novel ST registered as ST2493 (1.8). Resistances were detected for streptomycin, chloramphenicol, and tetracycline. One strain contained the chloramphenicol resistance gene (fexA; included within transposon Tn558) and 3 strains contained the tetracycline resistance gene [tet(K)]. Methicillin-susceptible Staphylococcus aureus strains were susceptible to most of the antibiotics studied and lacked the virulence genes of Panton-Valentine leukocidin (lukF/S-PV), toxic shock syndrome toxin 1 (tst), exfoliative toxin A (eta), and exfoliative toxin B (etb), as well as the genes of the immune evasion cluster. Methicillin-susceptible Staphylococcus aureus isolates were detected in a relatively low proportion of cows with mastitis (6.2%) and recovered isolates presented high diversity of genetic lineages, with CC1 and CC126 the predominant clonal complexes, and CC133 also being detected. Larger epidemiological studies with molecular characterization of isolates are required to deepen the knowledge on the circulating genetic lineages among the cow population with mastitis.


Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer.
Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti-tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed. High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI-positive MCF-7 cells and DNA fragmentation. Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities.


A pleurocidin analogue with greater conformational flexibility, enhanced antimicrobial potency and in vivo therapeutic efficacy.
Antimicrobial peptides (AMPs) are a potential alternative to classical antibiotics that are yet to achieve a therapeutic breakthrough for treatment of systemic infections. The antibacterial potency of pleurocidin, an AMP from Winter Flounder, is linked to its ability to cross bacterial plasma membranes and seek intracellular targets while also causing membrane damage. Here we describe modification strategies that generate pleurocidin analogues with substantially improved, broad spectrum, antibacterial properties, which are effective in murine models of bacterial lung infection. Increasing peptide-lipid intermolecular hydrogen bonding capabilities enhances conformational flexibility, associated with membrane translocation, but also membrane damage and potency, most notably against Gram-positive bacteria. This negates their ability to metabolically adapt to the AMP threat. An analogue comprising D-amino acids was well tolerated at an intravenous dose of 15 mg/kg and similarly effective as vancomycin in reducing EMRSA-15 lung CFU. This highlights the therapeutic potential of systemically delivered, bactericidal AMPs.


Aortic valve surgery and survival in patients with moderate or severe aortic stenosis and left ventricular dysfunction.
We aimed to determine the frequency of aortic valve surgery (AVR) with or without coronary artery bypass grafting (CABG), among patients with moderate/severe aortic stenosis (AS) and left ventricular systolic dysfunction (LVSD), and its relationship with survival. The Duke Echocardiographic Database (N = 132 804) was queried for patients with mean gradient ≥25 mmHg and/or peak velocity ≥3 m/s and LVSD (left ventricular ejection fraction ≤50%) from 1 January 1995-28 February 2014. For analyses purposes, AS was defined both by mean gradient and calculated aortic valve area (AVA) criteria. Time-dependent indicators of AVR in multivariable Cox models were used to assess the relationship of AVR and all-cause mortality. A total of 1634 patients had moderate (N = 1090, 67%) or severe (N = 544, 33%) AS by mean gradient criteria. Overall, 287 (26%) patients with moderate AS and 263 (48%) patients with severe AS underwent AVR within 5 years of the qualifying echo. There were 863 (53%) deaths observed up to 5 years following index echo. After multivariable adjustment in an inverse probability weighted regression model, AVR was associated with higher 5-year survival amongst patients with moderate AS and severe AS whether classified by AVA or mean gradient criteria. Over all, AVR ± CABG compared with medical therapy was associated with significantly lower mortality [hazard ratio, HR = 0.49 (0.38, 0.62), P < 0.0001]. Compared with CABG alone, CABG + AVR was associated with better survival [HR = 0.18 (0.12, 0.27), P < 0.0001]. In patients with moderate/severe AS and LVSD, mortality is substantial and amongst those selected for surgery, AVR with or without CABG is associated with higher survival. Research is required to understand factors contributing to current practice patterns and the possible utility of transcatheter approaches in this high-risk cohort.


Priority Needs for Conducting Pandemic-relevant Clinical Research With Children in Europe: A Consensus Study With Pediatric Clinician-researchers.
Infectious disease (ID) pandemics pose a considerable global threat and can disproportionately affect vulnerable populations including children. Pediatric clinical research in pandemics is essential to improve children's healthcare and minimize risks of harm by interventions that lack an adequate evidence base for this population. The unique features of ID pandemics require consideration of special processes to facilitate clinical research. We aimed to obtain consensus on pediatric clinician-researchers' perceptions of the priorities to feasibly conduct clinical pediatric pandemic research in Europe. Mixed method study in 2 stages, recruiting pediatric clinician-researchers with experience of conducting pediatric ID research in clinical settings in Europe. Stage 1 was an expert stakeholder workshop and interviews. Discussions focused on participant's experience of conducting pediatric ID research and processes to facilitate pandemic research. Information informed stage 2, an online consensus survey to identify pediatric inician-researchers priorities to enable ID pandemic research. Twenty-three pediatric clinician-researchers attended the workshop and 39 completed the survey. Priorities were primarily focused on structural and operational requirements of research design and regulation: (1) clarity within the European Clinical Trials Directive for pediatric pandemic research; (2) simplified regulatory processes for research involving clinical samples and data; and (3) improved relationships between regulatory bodies and researchers. Results suggest that changes need to be made to the current regulatory environment to facilitate and improve pediatric research in the pandemic context. These findings can provide expert evidence to research policy decision-makers and regulators and to develop a strategy to lobby for change.


Genome-wide meta-analysis reveals common splice site acceptor variant in CHRNA4 associated with nicotine dependence.
We conducted a 1000 Genomes-imputed genome-wide association study (GWAS) meta-analysis for nicotine dependence, defined by the Fagerström Test for Nicotine Dependence in 17 074 ever smokers from five European-ancestry samples. We followed up novel variants in 7469 ever smokers from five independent European-ancestry samples. We identified genome-wide significant association in the alpha-4 nicotinic receptor subunit (CHRNA4) gene on chromosome 20q13: lowest P=8.0 × 10(-9) across all the samples for rs2273500-C (frequency=0.15; odds ratio=1.12 and 95% confidence interval=1.08-1.17 for severe vs mild dependence). rs2273500-C, a splice site acceptor variant resulting in an alternate CHRNA4 transcript predicted to be targeted for nonsense-mediated decay, was associated with decreased CHRNA4 expression in physiologically normal human brains (lowest P=7.3 × 10(-4)). Importantly, rs2273500-C was associated with increased lung cancer risk (N=28 998, odds ratio=1.06 and 95% confidence interval=1.00-1.12), likely through its effect on smoking, as rs2273500-C was no longer associated with lung cancer after adjustment for smoking. Using criteria for smoking behavior that encompass more than the single 'cigarettes per day' item, we identified a common CHRNA4 variant with important regulatory properties that contributes to nicotine dependence and smoking-related consequences.


Bioreductive drugs: from concept to clinic.
One of the key issues for radiobiologists is the importance of hypoxia to the radiotherapy response. This review addresses the reasons for this and primarily focuses on one aspect, the development of bioreductive drugs that are specifically designed to target hypoxic tumour cells. Four classes of compound have been developed since this concept was first proposed: quinones, nitroaromatics, aliphatic and heteroaromatic N-oxides. All share two characteristics: (1) they require hypoxia for activation and (2) this activation is dependent on the presence of specific reductases. The most effective compounds have shown the ability to enhance the anti-tumour efficacy of agents that kill better-oxygenated cells, i.e. radiation and standard cytotoxic chemotherapy agents such as cisplatin and cyclophosphamide. Tirapazamine (TPZ) is the most widely studied of the lead compounds. After successful pre-clinical in vivo combination studies it entered clinical trial; over 20 trials have now been reported. Although TPZ has enhanced some standard regimens, the results are variable and in some combinations toxicity was enhanced. Banoxantrone (AQ4N) is another agent that is showing promise in early phase I/II clinical trials; the drug is well tolerated, is known to locate in the tumour and can be given in high doses without major toxicities. Mitomycin C (MMC), which shows some bioreductive activation in vitro, has been tested in combination trials. However, it is difficult to assign the enhancement of its effects to targeting of the hypoxic cells because of the significant level of its hypoxia-independent toxicity. More specific analogues of MMC, e.g. porfiromycin and apaziquone (EO9), have had variable success in the clinic. Other new drugs that have good pre-clinical profiles are PR 104 and NLCQ-1; data on their clinical safety/efficacy are not yet available. This paper reviews the pre-clinical data and discusses the clinical studies that have been reported.


A simplified sheathless cell separation approach using combined gravitational-sedimentation-based prefocusing and dielectrophoretic separation.
Prefocusing of the cell mixture is necessary for achieving a high-efficiency and continuous dielectrophoretic (DEP) cell separation. However, prefocusing through sheath flow requires a complex and tedious peripheral system for multi-channel fluid control, hindering the integration of DEP separation systems with other microfluidic functionalities for comprehensive clinical and biological tasks. This paper presented a simplified sheathless cell separation approach that combines gravitational-sedimentation-based sheathless prefocusing and DEP separation methods. Through gravitational sedimentation in a tubing, which was inserted into the inlet of a microfluidic chip with an adjustable steering angle, the cells were focused into a stream at the upstream region of a microchannel prior to separation. Then, a DEP force was applied at the downstream region of the microchannel for the active separation of the cells. Through this combined strategy, the peripheral system for the sheath flow was no longer required, and thus the integration of cell separation system with additional microfluidic functionalities was facilitated. The proposed sheathless scheme focused the mixture of cells with different sizes and dielectric properties into a stream in a wide range of flow rates without changing the design of the microfluidic chip. The DEP method is a label-free approach that can continuously separate cells on the basis of the sizes or dielectric properties of the cells and thus capable of greatly flexible cell separation. The efficiency of the proposed approach was experimentally assessed according to its performance in the separation of human acute monocytic leukemia THP-1 cells from yeast cells with respect to different sizes and THP-1 cells from human acute myelomonocytic leukemia OCI-AML3 cells with respect to different dielectric properties. The experimental results revealed that the separation efficiency of the method can surpass 90% and thus effective in separating cells on the basis of either size or dielectric property.


Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice.
Unrepaired or misrepaired DNA damage has been implicated as a causal factor in cancer and aging. Xpd(TTD) mice, harboring defects in nucleotide excision repair and transcription due to a mutation in the Xpd gene (R722W), display severe symptoms of premature aging but have a reduced incidence of cancer. To gain further insight into the molecular basis of the mutant-specific manifestation of age-related phenotypes, we used comparative microarray analysis of young and old female livers to discover gene expression signatures distinguishing Xpd(TTD) mice from their age-matched wild type controls. We found a transcription signature of increased apoptosis in the Xpd(TTD) mice, which was confirmed by in situ immunohistochemical analysis and found to be accompanied by increased proliferation. However, apoptosis rate exceeded the rate of proliferation, resulting in homeostatic imbalance. Interestingly, a metabolic response signature was observed involving decreased energy metabolism and reduced IGF-1 signaling, a major modulator of life span. We conclude that while the increased apoptotic response to endogenous DNA damage contributes to the accelerated aging phenotypes and the reduced cancer incidence observed in the Xpd(TTD) mice, the signature of reduced energy metabolism is likely to reflect a compensatory adjustment to limit the increased genotoxic stress in these mutants. These results support a general model for premature aging in DNA repair deficient mice based on cellular responses to DNA damage that impair normal tissue homeostasis.


Prevention of urinary and anal incontinence: role of elective cesarean delivery.
Currently, prophylactic elective cesarean to prevent incontinence is being promoted without robust evidence supporting it, this has created confusion among health personnel [corrected]. Past research centered on defining the damaging effect of vaginal birth on continence whilst the limited research on elective cesarean considered it protective. Cesarean delivery has economic, obstetric, gynecological and psychosocial consequences, but incontinence is not uncommon with a persistent morbidity. There is confusion among health personnel about advocating elective cesarean delivery to prevent incontinence. Reviewing current research would facilitate obstetric thinking. Multiplanar endosonography and three-dimensional magnetic resonance imaging scanning are reportedly better in delineating structural alterations in the continence mechanism following vaginal birth and could be applied to postcesarean incontinence. Incontinence can follow vaginal or elective cesarean delivery and the severity following either mode is comparable. Urinary incontinence can resolve, persist or start de novo and the primiparous prevalence is similar following cesarean or vaginal birth. Transient anal incontinence can manifest during pregnancy. Paradoxically, pelvic floor strengthening exercises are beneficial for pregnancy-related incontinence, yet urinary incontinence occurs in nulliparas notwithstanding a strong pelvic floor. Improved imaging techniques should promote a better understanding of postcesarean incontinence. Since severe incontinence can occur after elective cesarean, its reportedly preventative role deserves more scrutiny. When incontinence occurs without labor, it is transient or shows exercise-related improvement; the role of elective cesarean delivery seems tenuous and needs careful evaluation. Current evidence does not support the routine use of elective cesarean to prevent incontinence so the delivery mode should continue to be dictated by obstetric considerations.


Adenovirus-mediated HIF-1α gene transfer promotes repair of mouse airway allograft microvasculature and attenuates chronic rejection.
Chronic rejection, manifested as small airway fibrosis (obliterative bronchiolitis [OB]), is the main obstacle to long-term survival in lung transplantation. Recent studies demonstrate that the airways involved in a lung transplant are relatively hypoxic at baseline and that OB pathogenesis may be linked to ischemia induced by a transient loss of airway microvasculature. Here, we show that HIF-1α mediates airway microvascular repair in a model of orthotopic tracheal transplantation. Grafts with a conditional knockout of Hif1a demonstrated diminished recruitment of recipient-derived Tie2⁺ angiogenic cells to the allograft, impaired repair of damaged microvasculature, accelerated loss of microvascular perfusion, and hastened denudation of epithelial cells. In contrast, graft HIF-1α overexpression induced via an adenoviral vector prolonged airway microvascular perfusion, preserved epithelial integrity, extended the time window for the graft to be rescued from chronic rejection, and attenuated airway fibrotic remodeling. HIF-1α overexpression induced the expression of proangiogenic factors such as Sdf1, Plgf, and Vegf, and promoted the recruitment of vasoreparative Tie2⁺ cells. This study demonstrates that a therapy that enhances vascular integrity during acute rejection may promote graft health and prevent chronic rejection.


The role of deoxyribonucleic acid methylation in development, diagnosis, and prognosis of bladder cancer.
Alterations in global levels and regional patterns of deoxyribonucleic acid methylation are among the earliest and most common events known to occur in human cancer. The mutational and epigenetic effects of this covalent deoxyribonucleic acid modification to the development of bladder cancer are well recognized. The contribution of aberrant methylation to mutational hot spots located within genes, transcriptional silencing, and chromosomal instability is reviewed in the context of its relevance to bladder carcinogenesis. Understanding how such processes evolve during the progression of bladder cancer is essential for using these molecular changes in the clinical setting. The recent development of sensitive and specific techniques for quantifying methylation changes in urine specimens and bodily fluids underscores the potential use of this molecular marker for early detection and surveillance of bladder cancer. Further refinement of these molecular biological techniques holds much promise for the use of methylation markers for bladder cancer diagnosis, risk stratification, and disease prognostication.


Efficacy of LLLT in swelling and pain control after the extraction of lower impacted third molars.
Low Level Laser Therapy (LLLT) can facilitate wound healing stimulating a more rapid resolution and an earlier start for the proliferation phase. The purpose of this study is to evaluate the effects of LLLT on postoperative pain and oedema following the removal of impacted lower third molars. Fifty-nine patients, who were to undergo surgical removal of their lower third molars, were studied. Patients were randomly allocated to one of three groups: 17 patients LLLT + traditional drug treatment17 patients traditional drug treatment as control group25 patients treated with LLLT only on one side+traditional drug treatment. The laser we have used for this study is a diode laser, GaAs, which delivers both in the infrared band at the wavelength of 910 nanometers (pulsed and superpulsed source), and in the visible (continuous source) at the wavelength of 650 nanometers (red). LLLT was performed just after the intervention and approximately 12 hours after surgery delivering 240 J in 15 minutes with theoretical fluence values of 480 J/cm(2) and 31 J/cm(2) for every minute of irradiation. We considered and signed with a label constant landmarks on both sides of the face of each patient; measurements were taken: before the surgery, after the surgery right after the 1st laser treatment, after approximately 24 hours after the 2(nd) laser treatment. We collected all the values of the oedema measurements and the VAS reports and performed a statistical analysis by means One-way Analysis of Variance (ANOVA) test: for the evaluated values (X, Y, Z) an extremely significant difference was found with p values of 0.003 for Y at the first evaluation (pre-12 hours) and less than 0.001 for the other evaluations. A significant result was obtained for VAS recorded at hospital discharge (p<0.0001). This study demonstrates that LLLT is effective on postoperative pain and oedema accelerating healing time and reducing patients distress.


Sequence mining and transcript profiling to explore differentially expressed genes associated with lipid biosynthesis during soybean seed development.
Soybean (Glycine max L.) is one of the most important oil crops in the world. It is desirable to increase oil yields from soybean, and so this has been a major goal of oilseed engineering. However, it is still uncertain how many genes and which genes are involved in lipid biosynthesis. Here, we evaluated changes in gene expression over the course of seed development using Illumina (formerly Solexa) RNA-sequencing. Tissues at 15 days after flowering (DAF) served as the control, and a total of 11592, 16594, and 16255 differentially expressed unigenes were identified at 35, 55, and 65 DAF, respectively. Gene Ontology analyses detected 113 co-expressed unigenes associated with lipid biosynthesis. Of these, 15 showed significant changes in expression levels (log2fold values ≥ 1) during seed development. Pathway analysis revealed 24 co-expressed transcripts involved in lipid biosynthesis and fatty acid biosynthesis pathways. We selected 12 differentially expressed genes and analyzed their expressions using qRT-PCR. The results were consistent with those obtained from Solexa sequencing. These results provide a comprehensive molecular biology background for research on soybean seed development, particularly with respect to the process of oil accumulation. All of the genes identified in our research have significance for breeding soybeans with increased oil contents.


CXCR2 and its related ligands play a novel role in supporting the pluripotency and proliferation of human pluripotent stem cells.
Basic fibroblast growth factor (bFGF) is a crucial factor sustaining human pluripotent stem cells (hPSCs). We designed this study to search the substitutive factors other than bFGF for the maintenance of hPSCs by using human placenta-derived conditioned medium without exogenous bFGF (hPCCM-), containing chemokine (C-X-C motif) receptor 2 (CXCR2) ligands, including interleukin (IL)-8 and growth-related oncogene α (GROα), which were developed on the basis of our previous studies. First, we confirmed that IL-8 and/or GROα play independent roles to preserve the phenotype of hPSCs. Then, we tried CXCR2 blockage of hPSCs in hPCCM- and verified the significant decrease of pluripotency-associated genes expression and the proliferation of hPSCs. Interestingly, CXCR2 suppression of hPSCs in mTeSR™1 containing exogenous bFGF decreased the proliferation of hPSCs while maintaining pluripotency characteristics. Lastly, we found that hPSCs proliferated robustly for more than 35 passages in hPCCM- on a gelatin substratum. Higher CXCR2 expression of hPSCs cultured in hPCCM- than those in mTeSR™1 was observable. Our findings suggest that CXCR2 and its related ligands might be novel factors comparable to bFGF supporting the characteristics of hPSCs and hPCCM- might be useful for the maintenance of hPSCs as well as for the accurate evaluation of CXCR2 role in hPSCs without the confounding influence of exogenous bFGF.


Reducing the Discrepancy Between ASTER and MODIS Land Surface Temperature Products.
Human-induced global warming has significantly increased the importance ofsatellite monitoring of land surface temperature (LST) on a global scale. The MODerate-resolution Imaging Spectroradiometer (MODIS) provides a 1-km resolution LST productwith almost daily coverage of the Earth, invaluable to both local and global change studies.The Advanced Spaceborne Thermal Emission Reflection Radiometer (ASTER) provides aLST product with a high spatial resolution of 90-m and a 16-day recurrent cycle,simultaneously acquired at the same height and nadir view as MODIS. ASTER andMODIS are complementary in resolution, offering a unique opportunity for scale-relatedstudies. ASTER and MODIS LST have been widely used but the errors in LST were mostlydisregarded. Correction of ASTER-to-MODIS LST discrepancies is essential for studiesreliant upon the joint use of these sensors. In this study, we compared three correctionapproaches: the Wan et al.'s approach, the refined Wan et al.'s approach, and thegeneralized split window (GSW) algorithm based approach. The Wan et al.'s approachcorrects the MODIS 1-km LST using MODIS 5-km LST. The refined approach modifiesthe Wan et al.'s approach through incorporating ASTER emissivity and MODIS 5-km data.The GSW algorithm approach does not use MODIS 5-km but only ASTER emissivity data. We examined the case over a semi-arid terrain area for the part of the Loess Plateau of China. All the approaches reduced the ASTER-to-MODIS LST discrepancy effectively. With terrain correction, the original ASTER-to-MODIS LST difference reduced from 2.7±1.28 K to -0.1±1.87 K for the Wan et al.'s approach, 0.2±1.57 K for the refined approach, and 0.1±1.33 K for the GSW algorithm based approach. Among all the approaches, the GSW algorithm based approach performed best in terms of mean, standard deviation, root mean square root, and correlation coefficient.


Evaluation of on-road driving in people with hemianopia and quadrantanopia.
To examine whether some drivers with hemianopia or quadrantanopia display safe driving skills on the road compared with drivers with normal visual fields. An occupational therapist evaluated 22 people with hemianopia, 8 with quadrantanopia, and 30 with normal vision for driving skills during naturalistic driving using six rating scales. Of drivers with normal vision, > 90% drove flawlessly or had minor errors. Although drivers with hemianopia were more likely to receive poorer ratings for all skills, 59.1%-81.8% performed with no or minor errors. A skill commonly problematic for them was lane keeping (40.9%). Of 8 drivers with quadrantanopia, 7 (87.5%) exhibited no or minor errors. This study of people with hemianopia or quadrantanopia with no lateral spatial neglect highlights the need to provide individual opportunities for on-road driving evaluation under natural traffic conditions if a person is motivated to return to driving after brain injury.


Exploring the morphospace of communication efficiency in complex networks.
Graph theoretical analysis has played a key role in characterizing global features of the topology of complex networks, describing diverse systems such as protein interactions, food webs, social relations and brain connectivity. How system elements communicate with each other depends not only on the structure of the network, but also on the nature of the system's dynamics which are constrained by the amount of knowledge and resources available for communication processes. Complementing widely used measures that capture efficiency under the assumption that communication preferentially follows shortest paths across the network ("routing"), we define analytic measures directed at characterizing network communication when signals flow in a random walk process ("diffusion"). The two dimensions of routing and diffusion efficiency define a morphospace for complex networks, with different network topologies characterized by different combinations of efficiency measures and thus occupying different regions of this space. We explore the relation of network topologies and efficiency measures by examining canonical network models, by evolving networks using a multi-objective optimization strategy, and by investigating real-world network data sets. Within the efficiency morphospace, specific aspects of network topology that differentially favor efficient communication for routing and diffusion processes are identified. Charting regions of the morphospace that are occupied by canonical, evolved or real networks allows inferences about the limits of communication efficiency imposed by connectivity and dynamics, as well as the underlying selection pressures that have shaped network topology.


Assessment of electrocardiographic parameters in adult patients undergoing extracorporeal shockwave lithotripsy.
Extracorporeal shock wave lithotripsy (ESWL) is a safe and effective treatment for urinary tract calculi. While serious side effects are rare, transient cardiac arrhythmias may occur. New electrocardiographic (ECG) parameters, such as P wave dispersion (PWD), QT dispersion (QTd), T peak to T end (Tp-e) interval, Tp-e interval/QT ratio, and Tp-e interval/corrected QT ratio have been defined to help predict atrial and ventricular arrhythmias. However, effect of ESWL on these ECG parameters has not been previously investigated. The present study was an examination of the effect of ESWL on ECG parameters. Total of 40 consecutive patients who underwent ESWL were prospectively enrolled in the study. Pre-procedure ECG parameters were compared with post-procedure ECG parameters. PWD values were significantly longer on post-procedure ECG compared with pre-procedure ECG (p=0.017). Corrected QT duration and QTd were significantly longer on postprocedure ECG compared with pre-procedure ECG (p=0.046 and p=0.008, respectively). In addition, Tp-e interval, Tp-e interval/QT ratio, and Tp-e interval/QTc ratio were significantly longer post procedure (p=0.035, p=0.045, and p=0.022, respectively). In univariate correlation analysis, duration of procedure was significantly correlated with post-procedure PWD, QTc, and QTD values. Clinical use of ECG parameters may be helpful in monitoring of patients receiving ungated ESWL in order to detect cardiac dysrhythmia.


IDENTIFYING CANCER SPECIFIC METABOLIC SIGNATURES USING CONSTRAINT-BASED MODELS.
Cancer metabolism differs remarkably from the metabolism of healthy surrounding tissues, and it is extremely heterogeneous across cancer types. While these metabolic differences provide promising avenues for cancer treatments, much work remains to be done in understanding how metabolism is rewired in malignant tissues. To that end, constraint-based models provide a powerful computational tool for the study of metabolism at the genome scale. To generate meaningful predictions, however, these generalized human models must first be tailored for specific cell or tissue sub-types. Here we first present two improved algorithms for (1) the generation of these context-specific metabolic models based on omics data, and (2) Monte-Carlo sampling of the metabolic model ux space. By applying these methods to generate and analyze context-specific metabolic models of diverse solid cancer cell line data, and primary leukemia pediatric patient biopsies, we demonstrate how the methodology presented in this study can generate insights into the rewiring differences across solid tumors and blood cancers.


Tendon and Ligament Injuries in Elite Rugby: The Potential Genetic Influence.
This article reviews tendon and ligament injury incidence and severity within elite rugby union and rugby league. Furthermore, it discusses the biological makeup of tendons and ligaments and how genetic variation may influence this and predisposition to injury. Elite rugby has one of the highest reported injury incidences of any professional sport. This is likely due to a combination of well-established injury surveillance systems and the characteristics of the game, whereby high-impact body contact frequently occurs, in addition to the high intensity, multispeed and multidirectional nature of play. Some of the most severe of all these injuries are tendon and ligament/joint (non-bone), and therefore, potentially the most debilitating to a player and playing squad across a season or World Cup competition. The aetiology of these injuries is highly multi-factorial, with a growing body of evidence suggesting that some of the inter-individual variability in injury susceptibility may be due to genetic variation. However, little effort has been devoted to the study of genetic injury traits within rugby athletes. Due to a growing understanding of the molecular characteristics underpinning the aetiology of injury, investigating genetic variation within elite rugby is a viable and worthy proposition. Therefore, we propose several single nucleotide polymorphisms within candidate genes of interest; COL1A1, COL3A1, COL5A1, MIR608, MMP3, TIMP2, VEGFA, NID1 and COLGALT1 warrant further study within elite rugby and other invasion sports.


The clinical spectrum of the congenital myasthenic syndrome resulting from COL13A1 mutations.
Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.


Reduction of catheter-associated thrombosis in parenteral nutrition by intravenous heparin therapy.
A prospective trial was carried out to test the hypothesis that therapy with intravenous (IV) heparin sodium reduces the incidence of thrombotic complications related to the use of central venous catheters for parenteral nutrition. The patients studied were randomly allocated either to a group given heparin sodium, at a dosage of 5,000 IU/6 hr, or to a control group that received no heparin prophylaxis. The heparin group comprised 23 catheter periods (22 patients), and the control group 26 catheter periods (25 patients). In five of the 23 catheters in te heparin group and 14 of the 26 in the control group, catheter phlebography revealed thrombus formation in association with the catheter when this was removed. The results indicated that the use of IV heparin as prophylaxis against thrombosis reduced the risk of thrombus formation on the central venous catheter.


Allergy and sports in children.
Physical activity is beneficial for children with positive outcomes for mental and physical well-being. Allergic conditions unique to the sporting arena may serve as an impediment to participation in physical activity for allergic children. A common example is exercise-induced asthma; less common activity-related allergic conditions include food-dependent exercise-induced anaphylaxis, exercise-induced anaphylaxis, and exercise-induced urticaria. Allergic children may also be at risk of allergic reactions when exposed to allergens that are more commonly found in the sports environment, e.g., latex, sports drinks, and medications such as NSAIDs. Recent advances in our understanding of the patho-physiological and immunologic mechanisms that may account for these conditions have facilitated more effective and safer management strategies. There are also important immunologic lessons to be learnt with respect to specific physical factors that may result in diminished allergen tolerance; indeed, these lessons may facilitate safer allergen desensitisation regimens. The role of the immune system in exercise-induced immunoallergic syndromes, clinical aspects, and diagnostic and therapeutic approaches are discussed in this review.


LncRNA-H19 regulates cell proliferation and invasion of ectopic endometrium by targeting ITGB3 via modulating miR-124-3p.
Endometriosis, a common gynecological disease, is associated with pelvic pain and infertility. Endometriosis affects approximately 10% of women, but that number increases to 30-50% in symptomatic premenopausal women. Despite the prevalence of endometriosis, the cause has yet to be fully elucidated. Recent study of the molecular pathways of endometrial cancer has brought the long non-coding RNA (lncRNA) H19 to our attention. In this paper, we explored the role of lncRNA-H19 in endometrial tissue proliferation. We found that ectopic endometrial cells taken from women with endometriosis showed elevated levels of lncRNA-H19, with expression levels correlating to disease progression. Knockdown of H19 in ectopic endometrial cells inhibited cell proliferation and invasion. Coinciding with this change was an increase in microRNA-124-3p (miR-124-3p) and a decrease in integrin beta-3 (ITGB3) levels. The addition of a miR-124-3p inhibitor mitigated this decrease in ITGB3. Up-regulation of miR-124-3p markedly suppressed ITGB3 expression by binding to the 3' untranslated region (3' UTR), while inhibition of miR-124-3p had the opposite effect. ITGB3 overexpression potently counteracted the effects of miR-124-3p mimics on ectopic endometrial cells. From these results, we can infer that in endometriosis both miR-124-3p and ITGB3 operate as downstream effector proteins in the H19-signaling pathway. Down-regulation of lncRNA-H19 could inhibit ectopic endometrial cell proliferation and invasion by modulating miR-124-3p and ITGB3, offering a novel target for treatment.


Condensed tannin promotes the release of arachidonic acid from rabbit resident alveolar macrophages.
The condensed tannin present in cotton mill dust profoundly alters the functional capabilities of resident alveolar macrophages. Previous studies from this laboratory have shown that in vitro exposure of rabbit resident alveolar macrophages to condensed tannin significantly inhibits the ability of these cells to produce reactive oxygen intermediates or to ingest particles. In the present study, we demonstrate that condensed tannin also alters arachidonic acid (C20:4) metabolism in these cells. Exposure of rabbit resident alveolar macrophages to condensed tannin results in the time- and dose-dependent release of C20:4 from the membrane phospholipids. The release of C20:4 occurred only at tannin concentrations greater than 25 micrograms/ml and was maximal 90 min after the onset of exposure. The EC50 for release was 75 micrograms/ml. Exposure to 100 micrograms/ml tannin resulted in the release of 20 +/- 3% of the [14C]C20:4 incorporated in the cell membrane. In comparison, exposure to 160 micrograms/ml zymosan resulted in the release of 14 +/- 4% of the [14C]C20:4. For both tannin and zymosan, phosphatidylcholine and phosphatidylinositol were the principal sources of the released C20:4. Approximately 63% of the C20:4 released after zymosan stimulation was further metabolized, mainly via the cyclooxygenase pathway. The major metabolites were 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin E2. In contrast, only 24% of the C20:4 released by tannin was subsequently further metabolized. The metabolites formed were essentially evenly distributed between products of the cyclooxygenase pathway and the lipoxygenase pathway. Exposure of alveolar macrophages to 50 micrograms/ml tannin for 30 min reduced the ability of the cells to subsequently incorporate C20:4 by 50 to 70%. In contrast, exposure of the cells to 160 mg/ml zymosan for 30 min had only a minimal effect on the subsequent ability of these cells to incorporate C20:4. These results indicate that tannin promotes C20:4 release, at least in part, by inhibiting its reacylation back into phospholipids, a mechanism that differs from that of zymosan.


Plethora of transitions during breakup of liquid filaments.
Thinning and breakup of liquid filaments are central to dripping of leaky faucets, inkjet drop formation, and raindrop fragmentation. As the filament radius decreases, curvature and capillary pressure, both inversely proportional to radius, increase and fluid is expelled with increasing velocity from the neck. As the neck radius vanishes, the governing equations become singular and the filament breaks. In slightly viscous liquids, thinning initially occurs in an inertial regime where inertial and capillary forces balance. By contrast, in highly viscous liquids, initial thinning occurs in a viscous regime where viscous and capillary forces balance. As the filament thins, viscous forces in the former case and inertial forces in the latter become important, and theory shows that the filament approaches breakup in the final inertial-viscous regime where all three forces balance. However, previous simulations and experiments reveal that transition from an initial to the final regime either occurs at a value of filament radius well below that predicted by theory or is not observed. Here, we perform new simulations and experiments, and show that a thinning filament unexpectedly passes through a number of intermediate transient regimes, thereby delaying onset of the inertial-viscous regime. The new findings have practical implications regarding formation of undesirable satellite droplets and also raise the question as to whether similar dynamical transitions arise in other free-surface flows such as coalescence that also exhibit singularities.


Long-term effects of participation in a randomized trial of a low-fat, high-carbohydrate diet.
In 1982 we started a series of pilot studies to examine the feasibility of dietary intervention with a low-fat, high-carbohydrate diet in women with extensive mammographic densities. The purpose of the present paper is to examine the long-term effects of participation in these studies by assessing nutrient intake and other variables several years after active participation had stopped. Two hundred sixteen women were eligible for the follow-up study and were invited to attend and interview with a dietician. Data were collected by food frequency questionnaire from 157 subjects (73%), and blood was obtained from 115 subjects. Total energy intake was slightly lower in the intervention group. Total fat and percent energy from fat were significantly lower in the intervention group. The intake of all types of fat (saturated fat, linoleic acid, and oleic acid) and dietary cholesterol was lower in the in the intervention group; however, the polyunsaturated/saturated fat ratio did not differ between the groups. Total cholesterol and apoprotein B levels were lower in the intervention group compared to the control group. Follicle-stimulating hormone was 29% higher in postmenopausal members of the intervention group than in controls, but there was no difference in levels of estradiol. A total of 19 women enrolled in pilot studies had developed breast cancer, 5.7 times the number expected, confirming that the selection of women with extensive mammographic densities does identify a high-risk group. These data suggest that even quite short periods of intensive dietary counselling may have prolonged effects on diet, and that once subjects have adopted new dietary habits, the habits may persist even in the absence of continued counselling.


Engineering 3D degradable, pliable scaffolds toward adipose tissue regeneration; optimized printability, simulations and surface modification.
We present a solution to regenerate adipose tissue using degradable, soft, pliable 3D-printed scaffolds made of a medical-grade copolymer coated with polydopamine. The problem today is that while printing, the medical grade copolyesters degrade and the scaffolds become very stiff and brittle, being not optimal for adipose tissue defects. Herein, we have used high molar mass poly(L-lactide-co-trimethylene carbonate) (PLATMC) to engineer scaffolds using a direct extrusion-based 3D printer, the 3D Bioplotter®. Our approach was first focused on how the printing influences the polymer and scaffold's mechanical properties, then on exploring different printing designs and, in the end, on assessing surface functionalization. Finite element analysis revealed that scaffold's mechanical properties vary according to the gradual degradation of the polymer as a consequence of the molar mass decrease during printing. Considering this, we defined optimal printing parameters to minimize material's degradation and printed scaffolds with different designs. We subsequently functionalized one scaffold design with polydopamine coating and conducted in vitro cell studies. Results showed that polydopamine augmented stem cell proliferation and adipogenic differentiation owing to increased surface hydrophilicity. Thus, the present research show that the medical grade PLATMC based scaffolds are a potential candidate towards the development of implantable, resorbable, medical devices for adipose tissue regeneration.


Fetal macrosomia: risk factors, maternal, and perinatal outcome.
Macrosomia is defined as birth-weight over 4,000 g irrespective of gestational age and affects 3-15% of all pregnancies. Aim The present study aimed to determine the relationship between mother's characteristics and macrosomic births and also compare macrosomic and normal newborns regarding the maternal and offspring complications of diabetes during pregnancy. In this case control study, among the 420 consecutive births occurring in public and private hospitals of Shiraz, Iran from October 2006 to March 2007, the data of 32 macrosomic and 128 normal newborns were analyzed using t-test and chi square in bivariate and logistic regression in multivariate model. The mean (SD) of neonate weight, height, and head size was 3323.4 (709), 48.95 (3.2), and 34.9 (1.8), respectively. Regression analysis showed that gestational diabetes (Odds Ratio (OR): 11.9, Confidence Interval (CI): 4.6-30.3), preeclampsia in the pregnancy period due to diabetes (OR: 3.81, CI: 1.1-13.2), and macrosomic birth history (OR: 3.3, CI: 1.04-10.4) were the main predictors of macrosomia. Moreover, macrosomia increased neonate hypoglycemia (OR: 4.7, CI: 1.4-15.8) and section delivery (OR: 4.1, CI: 1.27-13.1). Gestational diabetes, preeclampsia due to diabetes, and history of macrosomic birth were the main predictors of macrosomia. Moreover, macrosomia increased some delivery complications for both mothers and newborns.


A Behavioral and Serological Survey on HIV Prevalence Among Prisoners in Benin.
Cases of HIV are common in Benin, with infection rates varying according to socioeconomic and cultural factors, and by region. Certain segments of the population, such as prison inmates, sex worker clients and truck drivers are at high risk for HIV/AIDS. The aim of this study is to identify which behavioral and serological indicators contribute to the spread of HIV among prisoners. A total of 496 inmates from prisons located in all major cities in Benin were surveyed. Data was collected through interview sessions carried out using a questionnaire and through blood samples. The results show that most inmates are Beninese (83.5%), and the average age is 33 years (range: 14-80 years). No prisoner reported using a condom the last time they engaged in sexual intercourse. Blood exposure was found in 14.6% of inmates and HIV was detected in 1.4% of cases. Our analysis indicates that the length of detention and gender are factors that influence HIV status. However, age, education, nationality and HIV awareness had no significant effect on HIV prevalence among inmates. The results highlight the need to raise awareness in prisons about HIV. This can be achieved by strengthening communication strategies and by organizing HIV and sexually transmitted diseases information sessions for both prison officers and inmates.


Spreading dilatation to luminal perfusion of ATP and UTP in rat isolated small mesenteric arteries.
Levels of ATP achieved within the lumen of vessels suggest a key autacoid role. P2Y receptors on the endothelium may represent the target for ATP, leading to hyperpolarization and associated relaxation of vascular smooth muscle through the endothelium-dependent hyperpolarizing factor (EDHF) pathway. EDHF signals radially from the endothelium to cause dilatation, and appears mechanistically distinct from the axial spread of dilatation, which we showed occurs independently of a change in endothelial cell Ca2+ in rat mesenteric arteries. Here we have investigated the potential of P2Y receptor stimulation to evoke spreading dilatation in rat resistance small arteries under physiological pressure and flow. Triple cannulation of isolated arteries enables focal application of purine and pyrimidine nucleotides to the endothelium, avoiding potential complicating actions of these agents on the smooth muscle. Nucleotides were locally infused through one branch of a bifurcation, causing near maximal local dilatation attributable to EDHF. Dilatation then spread rapidly into the adjacent feed artery and upstream against the direction of luminal flow, sufficient to increase flow into the feed artery. The rate of decay of this spreading dilatation was identical between nucleotides, and matched that to ACh, which acts only on the endothelium. In contrast, focal abluminal application of either ATP or UTP at the downstream end of cannulated arteries evoked constriction, which only in the case of ATP was also associated with modest spread of dilatation. The non-hydrolysable ADP analogue, ADPbetaS, acting at P2Y1 receptors, caused robust local and spreading dilatation responses whether applied to the luminal or abluminal surface of pressurized arteries. Dilatation to nucleotides was sensitive to inhibition with apamin and TRAM-34, selective blockers of small- and intermediate-conductance Ca2+-activated K+ channels, respectively. These data demonstrate that direct luminal stimulation of P2Y receptor on the endothelium of rat mesenteric arteries leads to marked spreading dilatation and thus suggests that circulating purines and pyrimidines may act as important regulators of blood flow.


Preclinical episodes of orofacial pain symptoms and their association with health care behaviors in the OPPERA prospective cohort study.
The course of preclinical pain symptoms sheds light on the etiology and prognosis of chronic pain. We aimed to quantify rates of developing initial and recurrent symptoms of painful temporomandibular disorder (TMD) and to evaluate associations with health behaviors. In the OPPERA prospective cohort study, 2,719 individuals aged 18 to 44years with lifetime absence of TMD when enrolled completed 25,103 quarterly (3-monthly) questionnaires during a median 2.3-year follow-up period. Questionnaires documented TMD symptom episodes, headache, other body pain, health care attendance, and analgesic use, and. Kaplan-Meier methods for clustered data estimated symptom-free survival time. Multivariable models assessed demographic variation in TMD symptom rates and evaluated associations with health care and analgesic use. One-third of the study subjects developed TMD symptoms and for a quarter of symptomatic episodes, pain intensity was severe. Initial TMD symptoms developed at an annual rate of 18.8 episodes per 100 persons. The annual rate more than doubled for first-recurrence and doubled again for second or subsequent recurrence such that, 1year after first recurrence, 71% of study subjects experienced a second recurrence. The overall rate increased with age and was greater in African Americans and lower in Asians relative to those of white race/ethnicity. The probability of TMD symptoms was strongly associated with concurrent episodes of headache and body pain and with past episodes of TMD symptoms. Episodes of TMD symptoms, headache, and body pain were associated with increases of ∼10% in probability of analgesic use and health care attendance. Yet, even when TMD, headache, and body pain occurred concurrently, 27% of study subjects neither attended health care nor used analgesics.


Learning to play it safe (or not): stable and evolving neural responses during adolescent risky decision-making.
Adolescent decision-making is a topic of great public and scientific interest. However, much of the neuroimaging research in this area contrasts only one facet of decision-making (e.g., neural responses to anticipation or receipt of monetary rewards). Few studies have directly examined the processes that occur immediately before making a decision between two options that have varied and unpredictable potential rewards and penalties. Understanding adolescent decision-making from this vantage point may prove critical to ameliorating risky behavior and improving developmental outcomes. In this study, participants aged 14-16 years engaged in a driving simulation game while undergoing fMRI. Results indicated activity in ventral striatum preceded risky decisions and activity in right inferior frontal gyrus (rIFG) preceded safe decisions. Furthermore, participants who reported higher sensation-seeking and sensitivity to reward and punishment demonstrated lower rIFG activity during safe decisions. Finally, over successive games, rIFG activity preceding risky decisions decreased, whereas thalamus and caudate activity increased during positive feedback (taking a risk without crashing). These results indicate that regions traditionally associated with reward processing and inhibition not only drive risky decision-making in the moment but also contribute to learning about risk tradeoffs during adolescence.


Less-tight versus tight control of hypertension in pregnancy.
The effects of less-tight versus tight control of hypertension on pregnancy complications are unclear. We performed an open, international, multicenter trial involving women at 14 weeks 0 days to 33 weeks 6 days of gestation who had nonproteinuric preexisting or gestational hypertension, office diastolic blood pressure of 90 to 105 mm Hg (or 85 to 105 mm Hg if the woman was taking antihypertensive medications), and a live fetus. Women were randomly assigned to less-tight control (target diastolic blood pressure, 100 mm Hg) or tight control (target diastolic blood pressure, 85 mm Hg). The composite primary outcome was pregnancy loss or high-level neonatal care for more than 48 hours during the first 28 postnatal days. The secondary outcome was serious maternal complications occurring up to 6 weeks post partum or until hospital discharge, whichever was later. Included in the analysis were 987 women; 74.6% had preexisting hypertension. The primary-outcome rates were similar among 493 women assigned to less-tight control and 488 women assigned to tight control (31.4% and 30.7%, respectively; adjusted odds ratio, 1.02; 95% confidence interval [CI], 0.77 to 1.35), as were the rates of serious maternal complications (3.7% and 2.0%, respectively; adjusted odds ratio, 1.74; 95% CI, 0.79 to 3.84), despite a mean diastolic blood pressure that was higher in the less-tight-control group by 4.6 mm Hg (95% CI, 3.7 to 5.4). Severe hypertension (≥160/110 mm Hg) developed in 40.6% of the women in the less-tight-control group and 27.5% of the women in the tight-control group (P<0.001). We found no significant between-group differences in the risk of pregnancy loss, high-level neonatal care, or overall maternal complications, although less-tight control was associated with a significantly higher frequency of severe maternal hypertension. (Funded by the Canadian Institutes of Health Research; CHIPS Current Controlled Trials number, ISRCTN71416914; ClinicalTrials.gov number, NCT01192412.).


Immunoparesis and monoclonal gammopathy of undetermined significance are disassociated in advanced age.
Immunoparesis and a skewed serum free light chain (FLC) ratio are indicators of immune dysfunction predictive of progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM). Previous studies have reported increased prevalence of MGUS by age, but no study has examined the relationship between immunoparesis and abnormal FLC ratios in the elderly. We screened 453 older adults (median age, 80 years; range, 65-96) to characterize the patterns of immunoparesis and abnormal FLC ratio in relation to MGUS. We defined MGUS in 4.4% of the subjects; the prevalence was 12.5% among individuals of >90 years. In MGUS (vs. non-MGUS) cases, immunoparesis and abnormal FLC ratios were detected in 70.0% (vs. 49.0%; P = 0.07) and 50.0% (vs. 12.9%; P = 0.0001), respectively. Based on small numbers, MGUS patients with abnormal FLC ratio were borderline (P = 0.07) more likely to have immunoparesis. Overall, the prevalence of immunoparesis varied in a nonlinear fashion, with lowest frequencies in the youngest and oldest groups. Our observed disassociation between MGUS prevalence and impaired immunoglobulin production suggests that separate mechanisms are involved in the development of MGUS and immunoparesis in advanced age. These findings emphasize the need for molecularly defined methods to characterize myeloma precursor states and better predict progression to MM.


Nfkb1 activation by the E26 transformation-specific transcription factors PU.1 and Spi-B promotes Toll-like receptor-mediated splenic B cell proliferation.
Generation of antibodies against T-independent and T-dependent antigens requires Toll-like receptor (TLR) engagement on B cells for efficient responses. However, the regulation of TLR expression and responses in B cells is not well understood. PU.1 and Spi-B (encoded by Sfpi1 and Spib, respectively) are transcription factors of the E26 transformation-specific (ETS) family and are important for B cell development and function. It was found that B cells from mice knocked out for Spi-B and heterozygous for PU.1 (Sfpi1(+/-) Spib(-/-) [PUB] mice) proliferated poorly in response to TLR ligands compared to wild-type (WT) B cells. The NF-κB family member p50 (encoded by Nfkb1) is required for lipopolysaccharide (LPS) responsiveness in mice. PUB B cells expressed reduced Nfkb1 mRNA transcripts and p50 protein. The Nfkb1 promoter was regulated directly by PU.1 and Spi-B, as shown by reporter assays and chromatin immunoprecipitation analysis. Occupancy of the Nfkb1 promoter by PU.1 was reduced in PUB B cells compared to that in WT B cells. Finally, infection of PUB B cells with a retroviral vector encoding p50 substantially restored proliferation in response to LPS. We conclude that Nfkb1 transcriptional activation by PU.1 and Spi-B promotes TLR-mediated B cell proliferation.


Refractory chronic cluster headache: a consensus statement on clinical definition from the European Headache Federation.
Chronic cluster headache (CCH) often resists to prophylactic pharmaceutical treatments resulting in patients' life damage. In this rare but pragmatic situation escalation to invasive management is needed but framing criteria are lacking. We aimed to reach a consensus for refractory CCH definition for clinical and research use. The preparation of the final consensus followed three stages. Internal between authors, a larger between all European Headache Federation members and finally an international one among all investigators that have published clinical studies on cluster headache the last five years. Eighty-five investigators reached by email. Proposed criteria were in the format of the International Classification of Headache Disorders III-beta (description, criteria, notes, comments and references). Following this evaluation eight drafts were prepared before the final. Twenty-four (28.2%) international investigators commented during two rounds. Refractory CCH is described in the present consensus as a situation that fulfills the criteria of ICHD-3 beta for CCH with at least three severe attacks per week despite at least three consecutive trials of adequate preventive treatments. The condition is rare, but difficult to manage and invasive treatments may be needed. The consensus addresses five specific clinical and paraclinical diagnostic criteria followed by three notes and specific comments. Although refractory CCH may be not a separate identity these specific diagnostic criteria should help clinicians and investigators to improve patient's quality of life.


Development of Cationic Quaternary Ammonium Sulfonamide Amino Lipids for Nucleic Acid Delivery.
Lipid nanoparticles (LNPs) currently comprise the most effective carrier class for the delivery of small RNAs. Among lipid carriers, charge-unbalanced lipids are relatively unexplored synthetically. Herein, we developed and evaluated a novel collection of compounds for small interfering RNA (siRNA) delivery, termed cationic quaternary ammonium sulfonamide amino lipids (CSALs). The formulated CSAL LNPs containing cholesterol, 1,2-distearoyl-sn-glycero-3-phosphocholine, and lipid poly(ethylene glycol) exhibited biophysical property trends directly related to the CSAL chemical structure. Lead CSAL LNPs were identified using an siRNA delivery screen. Further chemical synthesis using a rational structure-guided design showed that the head group structure could alter the pKa and other physical properties that modulated delivery efficacy. Shorter-chained dimethylamino head groups, acetate side chains, and higher tail carbon numbers were favorable for delivery. This led to a further study of A3-OAc-C2Me LNPs, which enabled in vivo delivery to normal mouse lungs and subcutaneous and orthotopic lung tumors. Incorporation of CSALs into liver-targeting formulations shifted the in vivo delivery of these carriers to the lungs. This study highlights the importance of the cationic lipid structure in LNPs and provides further design guidelines for nucleic acid carriers.


Evaluation of the effect of hydro alcoholic extract of cinnamon on herpes simplex virus-1.
Long-term treatments of herpes simplex with drugs such as acyclovir, the side effects to such drugs including limited usage during the lactation period, and concerns for the emergence of drug-resistant strains have given rise to a need for new medications with fewer complications. Nowadays, there is an increasing usage of herbal medicines throughout the world due to their higher effectiveness and safety. The present study aims to assess the effects of hydroalcoholic cinnamon extract on herpes simplex virus type 1 (HSV-1) in culture with vero cells. In this in vitro study Hydroalcoholic extract of cinnamon was extracted through percolation. To assess cell survival rates, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was employed, and the tissue culture infective dose 50 assay was used to quantify the virus. Effects of the extract were evaluated in three stages, including before, during, and after viral inoculation into the culture medium. Two-way ANOVA and Post hoc analysis the test was performed in 1, 0.5, and 0.25 mg/ml concentrations of cinnamon extract in every stage (P < 0.05). Over 50% of the cells survived in the 0.25 mg/ml extract concentration. Results of our viral quantification showed a viral load of 105. The cinnamon extract was able to reduce the viral titer in all concentrations under study. Hydroalcoholic extract of cinnamon was effective in reducing the viral titer of HSV-1. This effect could have been caused by prevention of viral attachment to cells; however, further research is required to determine the exact mechanisms at play.


Evaluating educators using a novel toolbox: applying rigorous criteria flexibly across institutions.
Valuing faculty as educators is essential for medical schools to fulfill their unique mission of educating physicians. The 2006 Consensus Conference on Educational Scholarship, sponsored by the Association of American Medical Colleges (AAMC) Group on Educational Affairs, provided educators seeking academic promotion with a portfolio-based format for documenting activities in five domains, using evidence of quantity, quality, a scholarly approach, and educational scholarship. Yet, the lack of a rigorous, widely accepted system to assess educator portfolio submissions during the promotion and tenure process continues to impede the ability to fully value educators and educational scholars.The AAMC Task Force on Educator Evaluation was formed in 2010 to establish consensus guidelines for use by those responsible for the rigorous evaluation of the educational contributions of faculty. The task force delineated the educational contributions currently valued by institutions and then fulfilled its charge by creating the Toolbox for Evaluating Educators, a resource which contains explicit evidence-based criteria to evaluate faculty in each of the five domains of educator activity. Adoption of such criteria is now the rate-limiting step in using a fair process to recognize educators through academic promotion. To inform institutional review and implementation of these criteria, this article describes the iterative, evidence- and stakeholder-based process to establish the criteria. The authors advocate institutional adoption of these criteria so that faculty seeking academic promotion as educators, like their researcher colleagues, can be judged and valued using established standards for the assessment of their work.


Long-term follow-up of study participants from prophylactic HIV vaccine clinical trials in Africa.
Long-term safety is critical for the development and later use of a vaccine to prevent HIV/AIDS. Likewise, the persistence of vaccine-induced antibodies and their impact on HIV testing must be established. IAVI has sponsored several Phase I and IIA HIV vaccine trials enrolling healthy, HIV-seronegative African volunteers. Plasmid DNA and viral vector based vaccines were tested. No vaccine-related serious adverse events were reported. After completion of vaccine trials conducted between 2001-2007, both vaccine and placebo recipients were offered enrolment into an observational long-term follow-up study (LTFU) to monitor potential late health effects and persistence of immune responses. At scheduled 6-monthly clinic visits, a health questionnaire was administered; clinical events were recorded and graded for severity. Blood was drawn for HIV testing and cellular immune assays. 287 volunteers were enrolled; total follow-up after last vaccination was 1463 person years (median: 5.2 years). Ninety-three (93)% of volunteers reported good health at their last LTFU visit. Infectious diseases and injuries accounted for almost 50% of the 175 reported clinical events, of which over 95% were mild or moderate in severity. There were 30 six pregnancies, six incident HIV infections and 14 volunteers reported cases of social harm. Persistence of immune responses was rare. No safety signal was identified. No potentially vaccine-related medical condition, no immune mediated disease, or malignancy was reported. HIV vaccines studied in these trials had a low potential of induction of persisting HIV antibodies.


Crosstalk in surface electromyography of the proximal forearm during gripping tasks.
Electromyographic (EMG) crosstalk was systematically analyzed to evaluate the magnitude of common signal present between electrode pairs around the forearm. Surface EMG was recorded and analyzed from seven electrode pairs placed circumferentially around the proximal forearm in six healthy individuals. The cross-correlation function was used to determine the amount of common signal, which was found to decrease as the distance between electrode pairs increased, but was not significantly altered by forearm posture (pronation, neutral, supination). Overall, approximately 40% common signal was detected between adjacent electrode pairs (3 cm apart), dropping to about 10% at 6 cm spacing and 2.5% at 9 cm. The magnitude of common signal approached 50% between adjacent electrode pairs over the extensor muscles, while over 60% was observed between neighbouring sites on the flexor aspect of the forearm. Although flexor and extensor EMG amplitude was similar, less than 2% common signal was present between flexor and extensor electrode pairs during both pinch and grasp tasks. Maximum grip force production was not affected by forearm rotation for pinch, but reduced 18% from neutral (mid-prone) to pronation during grasp (p=0.01). In spite of differences in grip force, mean muscle activity did not vary between the three forearm postures during maximum pinch or grasp trials. While this study improved our knowledge of crosstalk and electrode spacing issues, further examination of forearm EMG is required to improve understanding of muscle loading, EMG properties and motor control during gripping tasks.


The differential diagnosis of fetal alcohol spectrum disorder.
Fetal Alcohol Spectrum Disorder (FASD) affects an estimated 1% of all children born in North America. FASD is a chronic disorder impacting many systems of care. Only a minority of these children exhibit the pathognomonic facial features of Fetal alcohol syndrome (FAS) that include short palpebral fissures, smooth philtrum and thin upper lip. Hence, in the majority of affected individuals FASD is a diagnosis of exclusion. The differential diagnosis of both the dysmorphological and neurobehavioral aspects of FASD is wide. This review aims to provide the pediatrician with information concerning the differential diagnosis of FASD and to discuss genetic testing that might be relevant to the assessment.


The physiological action of gliclazide: beta-cell function and insulin resistance.
There is continuing debate about the physiological mechanisms of the action of sulphonylureas in man. In those patients taking sulphonylureas insulin secretion can be demonstrated to be higher, but there are also data which have been interpreted as evidence that these drugs may cause an alteration in peripheral insulin sensitivity. The physiological effects of the sulphonylurea gliclazide in diabetic subjects has been examined using a variety of experimental protocols to address this question: an intravenous gliclazide infusion, experiments using glucose clamping, mathematical modelling of the insulin and glucose data from subjects on and off gliclazide therapy, and the infusion of amino acids and glucose separately or in combination. The data from all these analyses suggest that the primary effect of gliclazide is on the beta-cell and that any effects on the peripheral insulin sensitivity are either slight or secondary to the improvement of the secretory capacity of the pancreatic islets.