Confidence in value-based choice.
Decisions are never perfect, with confidence in one's choices fluctuating over time. How subjective confidence and valuation of choice options interact at the level of brain and behavior is unknown. Using a dynamic model of the decision process, we show that confidence reflects the evolution of a decision variable over time, explaining the observed relation between confidence, value, accuracy and reaction time. As predicted by our dynamic model, we show that a functional magnetic resonance imaging signal in human ventromedial prefrontal cortex (vmPFC) reflects both value comparison and confidence in the value comparison process. Crucially, individuals varied in how they related confidence to accuracy, allowing us to show that this introspective ability is predicted by a measure of functional connectivity between vmPFC and rostrolateral prefrontal cortex. Our findings provide a mechanistic link between noise in value comparison and metacognitive awareness of choice, enabling us both to want and to express knowledge of what we want.


Lead in New York City community garden chicken eggs: influential factors and health implications.
Raising chickens for eggs in urban areas is becoming increasingly common. Urban chickens may be exposed to lead, a common urban soil contaminant. We measured lead concentrations in chicken eggs from New York City (NYC) community gardens and collected information on factors that might affect those concentrations. Lead was detected between 10 and 167 μg/kg in 48 % of NYC eggs. Measures of lead in eggs from a henhouse were significantly associated (p < 0.005) with lead concentrations in soil. The association between soil and egg lead has been evaluated only once before, by a study of a rural region in Belgium. In our study, the apparent lead soil-to-egg transfer efficiency was considerably lower than that found in Belgium, suggesting that there may be important geographic differences in this transfer. We developed models that suggested that, for sites like ours, lead concentrations in >50 % of eggs from a henhouse would exceed store-bought egg concentrations (<7-13 μg/kg; 3 % above detection limit) at soil lead concentrations >120 mg/kg and that the concentration in one of six eggs from a henhouse would exceed a 100 μg/kg guidance value at soil lead concentrations >410 mg/kg. Our models also suggested that the availability of dietary calcium supplements was another influential factor that reduced egg lead concentrations. Estimates of health risk from consuming eggs with the lead concentrations we measured generally were not significant. However, soil lead concentrations in this study were <600 mg/kg, and considerably higher concentrations are not uncommon. Efforts to reduce lead transfer to chicken eggs and associated exposure are recommended for urban chicken keepers.


Increasing burden of community-acquired pneumonia leading to hospitalisation, 1998-2014.
Community-acquired pneumonia (CAP) is a major cause of mortality and morbidity in many countries but few recent large-scale studies have examined trends in its incidence. Incidence of CAP leading to hospitalisation in one UK region (Oxfordshire) was calculated over calendar time using routinely collected diagnostic codes, and modelled using piecewise-linear Poisson regression. Further models considered other related diagnoses, typical administrative outcomes, and blood and microbiology test results at admission to determine whether CAP trends could be explained by changes in case-mix, coding practices or admission procedures. CAP increased by 4.2%/year (95% CI 3.6 to 4.8) from 1998 to 2008, and subsequently much faster at 8.8%/year (95% CI 7.8 to 9.7) from 2009 to 2014. Pneumonia-related conditions also increased significantly over this period. Length of stay and 30-day mortality decreased slightly in later years, but the proportions with abnormal neutrophils, urea and C reactive protein (CRP) did not change (p>0.2). The proportion with severely abnormal CRP (>100 mg/L) decreased slightly in later years. Trends were similar in all age groups. Streptococcus pneumoniae was the most common causative organism found; however other organisms, particularly Enterobacteriaceae, increased in incidence over the study period (p<0.001). Hospitalisations for CAP have been increasing rapidly in Oxfordshire, particularly since 2008. There is little evidence that this is due only to changes in pneumonia coding, an ageing population or patients with substantially less severe disease being admitted more frequently. Healthcare planning to address potential further increases in admissions and consequent antibiotic prescribing should be a priority.


Effects of Sensorimotor Rhythm Modulation on the Human Flexor Carpi Radialis H-Reflex.
People can learn over training sessions to increase or decrease sensorimotor rhythms (SMRs) in the electroencephalogram (EEG). Activity-dependent brain plasticity is thought to guide spinal plasticity during motor skill learning; thus, SMR training may affect spinal reflexes and thereby influence motor control. To test this hypothesis, we investigated the effects of learned mu (8-13 Hz) SMR modulation on the flexor carpi radialis (FCR) H-reflex in 6 subjects with no known neurological conditions and 2 subjects with chronic incomplete spinal cord injury (SCI). All subjects had learned and practiced over more than 10 < 30-min training sessions to increase (SMR-up trials) and decrease (SMR-down trials) mu-rhythm amplitude over the hand/arm area of left sensorimotor cortex with ≥80% accuracy. Right FCR H-reflexes were elicited at random times during SMR-up and SMR-down trials, and in between trials. SMR modulation affected H-reflex size. In all the neurologically normal subjects, the H-reflex was significantly larger [116% ± 6 (mean ± SE)] during SMR-up trials than between trials, and significantly smaller (92% ± 1) during SMR-down trials than between trials (p < 0.05 for both, paired t-test). One subject with SCI showed similar H-reflex size dependence (high for SMR-up trials, low for SMR-down trials): the other subject with SCI showed no dependence. These results support the hypothesis that SMR modulation has predictable effects on spinal reflex excitability in people who are neurologically normal; they also suggest that it might be used to enhance therapies that seek to improve functional recovery in some individuals with SCI or other CNS disorders.


Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios.
The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors with the capacity for lineage reprogramming, positive auto-regulation and mutual inhibition have been described as being expressed in uncommitted cell populations. This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors. However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses. Alternative models of lineage choice therefore cannot be excluded. Here we use novel reporter mouse lines and live imaging for continuous single-cell long-term quantification of the transcription factors GATA1 and PU.1 (also known as SPI1). We analyse individual haematopoietic stem cells throughout differentiation into megakaryocytic-erythroid and granulocytic-monocytic lineages. The observed expression dynamics are incompatible with the assumption that stochastic switching between PU.1 and GATA1 precedes and initiates megakaryocytic-erythroid versus granulocytic-monocytic lineage decision-making. Rather, our findings suggest that these transcription factors are only executing and reinforcing lineage choice once made. These results challenge the current prevailing model of early myeloid lineage choice.


SpineCor treatment for Juvenile Idiopathic Scoliosis: SOSORT award 2010 winner.
Juvenile idiopathic scoliosis is a condition used to describe patients who are least 4 years of age but younger than 10 when the deformity is first identified. In these patients, the condition is usually progressive and those that are diagnosed at five years or younger have a high chance of progression to a large curve, with additional pulmonary and cardiac complications. The main form of conservative treatment for juvenile scoliosis is the use of a bracing system. This prospective interventional study was conducted to evaluate the effectiveness of the Dynamic SpineCor orthosis for juvenile idiopathic scoliosis as well as to evaluate the stability of the spine after the weaning point. For this study, 150 juvenile patients were treated by the SpineCor orthosis between 1993 and 2009. Of these, 67 patients had a definite outcome and 83 are still actively being treated. To determine the effectiveness of the brace the OUTCOME criteria recommended by the SRS was used. The results from our study showed that of the 67 patients with a definite outcome, 32.9% corrected their Cobb angle by at least 5° and 10.5% had a stabilization of their Cobb angle. Within the patients with a definite outcome, 37.3% of patients where recommended for surgery before authorized end of treatment. For this group of patients, surgery was postponed. Looking at the stability of the curves 2 years after the end of the treatment, we found 12.5% of the patients continued their correction without the brace being used and 71.4% remained stable. From our study we can clearly see that the effectiveness of the SpineCor orthosis in obtaining and maintaining the neuromuscular integration of the corrective movement can be achieved effectively for juvenile patients. Over 75% of all patients that finished the treatment had remained stable with a few continuing to correct their Cobb angle after the use of the SpineCor orthosis was discontinued. Our conclusion from this study is that the SpineCor orthosis is a very effective method of treatment of juvenile idiopathic scoliosis. The results obtained also indicate that treatment outcomes are better with early bracing. Most encouraging perhaps is the fact that the positive outcome appears to be maintained in the long term, and that surgery can be avoided or at least postponed.


New Insights into the Genetics of Fetal Megacystis: ACTG2 Mutations, Encoding γ-2 Smooth Muscle Actin in Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (Berdon Syndrome).
To identify the molecular basis for prenatally suspected cases of megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) (MIM 249210) in 3 independent families with clinical and radiographic evidence of MMIHS. Whole-exome sequencing (WES) and Sanger sequencing of the ACTG2 gene. We identified a novel heterozygous de novo missense variant in ACTG2 c.770G>A (p.Arg257His) encoding x03B3;-2 smooth muscle actin (ACTG2) in 2 siblings with MMIHS, suggesting gonadal mosaicism of one of the parents. Two additional de novo missense variants (p.Arg257Cys and p.Arg178His) in ACTG2 were identified in 2 additional MMHIS patients. All of our patients had evidence of fetal megacystis and a normal or slightly increased amniotic fluid volume. Additional findings included bilateral renal hydronephrosis, an enlarged fetal stomach, and transient dilated bowel loops. ACTG2 immunostaining of the intestinal tissue showed an altered muscularis propria, a markedly thinned longitudinal muscle layer, and a reduced amount and abnormal distribution of ACTG2. Our study demonstrates that de novo mutations in ACTG2 are a cause of fetal megacystis in MMIHS and that gonadal mosaicism may be present in a subset of cases. These findings have implications for the counseling of families with a diagnosis of fetal megacystis with a preserved amniotic fluid volume and associated gastrointestinal findings.


Remission outcomes in severe eosinophilic asthma with mepolizumab therapy: Analysis of the REDES study.
Clinical remission as a multicomponent treatment goal in severe asthma is being explored in clinical practice. This post hoc analysis used data from the REDES study to assess the proportion of patients with severe eosinophilic asthma achieving our multicomponent definitions of clinical remission after 1 year of mepolizumab treatment. The real-world, retrospective observational REDES study enrolled patients with severe eosinophilic asthma who were newly prescribed mepolizumab and with ≥12 months of medical records pre-enrolment. Multicomponent clinical remission was defined as: oral corticosteroid (OCS)-free; exacerbation-free; asthma control test (ACT) score ≥20; and with or without post-bronchodilator forced expiratory volume in 1 second ≥80%. Baseline characteristics were also assessed in those who did/did not achieve clinical remission. 37% and 30% of patients with severe eosinophilic asthma met our proposed three- and four-component on-treatment clinical remission definitions; an increase from 2% and 3% at baseline. Most frequently achieved individual components of clinical remission were: OCS-free; ACT score ≥20. For patients fulfilling the multicomponent clinical remission definitions, at baseline we observed higher blood eosinophil counts, better ACT scores and lung function, lower maintenance OCS use, and a slightly lower rate of prior exacerbations versus those who did not. Clinical remission is a realistic target in clinical practice for a subset of patients with severe eosinophilic asthma receiving mepolizumab. Further studies are required to elucidate whether features linked to the underlying endotype can help predict treatment outcomes, increase rates of clinical remission, and potentially modify disease progression.


Calcium antagonists and islet function. I. Inhibition of insulin release by verapamil.
Verapamil is a potent calcium antagonist known to inhibit excitation-contraction coupling in both myocardium and myometrium. Its effect upon glucose- and sulfonylurea-induced insulin release was investigated in the isolated perfused rat pancreas. After twenty-five minutes' pretreatment and at concentrations ranging between 0.8 and 8.1 muM, verapamil caused a dose-related inhibition of glucose-induced insulin release during both the early and late phase of the secretory process. At a concentration of 0.8 muM, the degree of inhibition was more marked when the exposure time to verapamil prior to stimulation with glucose was increased to sixty minutes. Verapamil also inhibited gliclazide-induced insulin release. Infusion of verapamil during the late phase of the secretory response to glucose demonstrated that the inhibition of insulin release was an immediate and reversible phenomenon. The inhibitory effect of verapamil was enhanced at a subnormal calcium concentration and reduced at a high calcium concentration. These findings are consistent with the well-known calcium dependency of both glucose- and sulfonylurea-induced insulin release and suggest that verapamil might be a promising tool for further studies on the interactions between cations and secretagogues in the beta-cell secretory process.


Molecular cloning and characterization of the DNA adenine methyltransferase gene in Feldmannia sp. virus.
The genome of Feldmannia sp. virus (FsV), a marine brown alga virus, contains a putative DNA adenine methyltransferase (dam) gene of 1,245 bp that encodes a polypeptide of 45.8 kDa. A BLAST search with the FsV dam gene showed high amino acid identity to two putative methyltransferase genes, ORF B29 of Feldmannia irregularis virus (FirrV, 54%) and ORF129 of Ectocarpus siliculosus virus (EsV, 36%); and a PSI BLAST search revealed similarity to the N(6)-adenine methyltransferases (MTases) of other species. Most conserved motifs of beta-class MTases were observed in the FsV dam gene. However, neither of the highly conserved sequences in motifs I (FxGxG) or IV [(S/N/D)PP(Y/F/W)] perfectly matched those in the FsV dam gene. The highly conserved DPPY consensus sequence in motif IV was NTPW in the FsV dam gene, perfectly matching the sequences in ORF B29 of FirrV and ORF129 of EsV. Therefore, the dam genes in brown algae viruses may belong to a yet undiscovered group. The FsV Dam protein expressed from the cloned FsV dam gene methylated E. coli chromosomal DNA. This is the first report showing that a virus infecting marine filamentous brown algae encodes a functional Dam protein.


Uncontrolled combustion of shredded tires in a landfill -Part 2: Population exposure, public health response, and an air quality index for urban fires.
The Iowa City Landfill in eastern Iowa, United States, experienced a fire lasting 18 days in 2012, in which a drainage layer of over 1 million shredded tires burned, generating smoke that impacted the surrounding metropolitan area of 130,000 people. This emergency required air monitoring, risk assessment, dispersion modeling, and public notification. This paper quantifies the impact of the fire on local air quality and proposes a monitoring approach and an Air Quality Index (AQI) for use in future tire fires and other urban fires. Individual fire pollutants are ranked for acute and cancer relative risks using hazard ratios, with the highest acute hazard ratios attributed to SO2, particulate matter, and aldehydes. Using a dispersion model in conjunction with the new AQI, we estimate that smoke concentrations reached unhealthy outdoor levels for sensitive groups out to distances of 3.1 km and 18 km at 24-h and 1-h average times, respectively. Modeled and measured concentrations of PM2.5 from smoke and other compounds such as VOCs and benzo[a]pyrene are presented at a range of distances and averaging times, and the corresponding cancer risks are discussed. Through reflection on the air quality response to the event, consideration of cancer and acute risks, and comparison to other tire fires, we recommend that all landfills with shredded tire liners plan for hazmat fire emergencies. A companion paper presents emission factors and detailed smoke characterization.


Feminism, law, and bioethics.
Feminist legal theory provides a healthy skepticism toward legal doctrine and insists that we reexamine even formally gender-neutral rules to uncover problematic assumptions behind them. The article first outlines feminist legal theory from the perspectives of liberal, cultural, and radical feminism. Examples of how each theory influences legal practice, case law, and legislation are highlighted. Each perspective is then applied to a contemporary bioethical issue, egg donation. Following a brief discussion of the common themes shared by feminist jurisprudence, the article incorporates a narrative reflecting on the integration of the common feminist themes in the context of the passage of the Maryland Health Care Decisions Act. The article concludes that gender does matter and that an understanding of feminist legal theory and practice will enrich the analysis of contemporary bioethical issues.


Association of CD247 (CD3ζ) gene polymorphisms with T1D and AITD in the population of northern Sweden.
T1D and AITD are autoimmune disorders commonly occurring in the same family and even in the same individual. The genetic contribution to these disorders is complex making uncovering of susceptibility genes very challenging. The general aim of this study was to identify loci and genes contributing to T1D/AITD susceptibility. Our strategy was to perform linkage and association studies in the relatively genetically homogenous population of northern Sweden. We performed a GWLS to find genomic regions linked to T1D/AITD in families from northern Sweden and we performed an association study in the families to test for association between T1D/AITD and variants in previously published candidate genes as well as a novel candidate gene, CD247. DNA prepared from 459 individuals was used to perform a linkage and an association study. The ABI PRISM Linkage Mapping Set v2.5MD10 was employed for an initial 10-cM GWLS, and additional markers were added for fine mapping. Merlin was used for linkage calculations. For the association analysis, a GoldenGate Custom Panel from Illumina containing 79 SNPs of interest was used and FBAT was used for association calculations. Our study revealed linkage to two previously identified chromosomal regions, 4q25 and 6p22, as well as to a novel chromosomal region, 1q23. The association study replicated association to PTPN22, HLA-DRB1, INS, IFIH1, CTLA4 and C12orf30. Evidence in favor of association was also found for SNPs in the novel susceptibility gene CD247. Several risk loci for T1D/AITD identified in published association studies were replicated in a family material, of modest size, from northern Sweden. This provides evidence that these loci confer disease susceptibility in this population and emphasizes that small to intermediate sized family studies in this population can be used in a cost-effective manner for the search of genes involved in complex diseases. The linkage study revealed a chromosomal region in which a novel T1D/AITD susceptibility gene, CD247, is located. The association study showed association between T1D/AITD and several variants in this gene. These results suggests that common susceptibility genes act in concert with variants of CD247 to generate genetic risk for T1D/AITD in this population.


Does reduced oxygen delivery cause lactic acidosis in falciparum malaria? An observational study.
Lactic acidosis with an elevated lactate-pyruvate ratio suggesting anoxia is a common feature of severe falciparum malaria. High lactate levels are associated with parasitized erythrocyte sequestration in the microcirculation. To assess if there is an additional contribution to hyperlactataemia from relatively inadequate total oxygen delivery, oxygen consumption and delivery were investigated in patients with malaria. Adult Bangladeshi and Indian patients with uncomplicated (N = 50) or severe (N = 46) falciparum malaria or suspected bacterial sepsis (N = 27) and healthy participants as controls (N = 26) were recruited at Chittagong Medical College Hospital, Chittagong, Bangladesh and Ispat General Hospital, Rourkela, India. Oxygen delivery (DO2I) was estimated from pulse oximetry, echocardiographic estimates of cardiac index and haematocrit. Oxygen consumption (VO2I) was estimated by expired gas collection. VO2I was elevated in uncomplicated median (IQR) 185.1 ml/min/m2 (135-215.9) and severe malaria 192 ml/min/m2 (140.7-227.9) relative to healthy persons 107.9 ml/min/m2 (69.9-138.1) (both p < 0.001). Median DO2I was similar in uncomplicated 515 ml/min/m2 (432-612) and severe 487 ml/min/m2 (382-601) malaria and healthy persons 503 ml/min/m2 (447-517) (p = 0.27 and 0.89, respectively). The VO2/DO2 ratio was, therefore, increased by similar amounts in both uncomplicated 0.35 (0.28-0.44) and severe malaria 0.38 (0.29-0.48) relative to healthy participants 0.23 (0.17-0.28) (both p < 0.001). VO2I, DO2I and VO2/DO2 did not correlate with plasma lactate concentrations in severe malaria. Reduced total oxygen delivery is not a major contributor to lactic acidosis in severe falciparum malaria.


Oxidation potentials of phenols and anilines: correlation analysis of electrochemical and theoretical values.
Phenols and anilines have been studied extensively as reductants of environmental oxidants (such as manganese dioxide) and as reductates (e.g., model contaminants) that are transformed by environmental oxidants (ozone, triple organic matter, etc.). The thermodynamics and kinetics of these reactions have been interpreted using oxidation potentials for substituted phenols and anilines, often using a legacy experimental dataset that is of uncertain quality. Although there are many alternative oxidation potential data, there has been little systematic analysis of the relevance, reliability, and consistency of the data obtained by different methods. We have done this through an extensive correlation analysis of kinetic data for phenol or aniline oxidation by manganese oxide-compiled from multiple sources-and oxidation potentials obtained from (i) electrochemical measurements using cyclic and square wave voltammetry and (ii) theoretical calculations using density functional theory. Measured peak potentials (Ep) from different sources and experimental conditions correlate very strongly, with minimal root mean squared error (RMSE), slopes ≈ 1, and intercepts indicative of consistent absolute differences of 50-150 mV; whereas, one-electron oxidation potentials (E1) from different sources and theoretical conditions exhibit large RMSE, slopes, and intercepts vs. measured oxidation potentials. Calibration of calculated E1 data vs. measured Ep data gave corrected values of E1 with improved accuracy. For oxidation by manganese dioxide, normalization of rate constants (to the 4-chloro congener) allowed correlation of phenol and aniline data from multiple sources to give one, unified quantitative structure-activity relationship (QSAR). Comparison among these QSARs illustrates the principle of matching the observational vs. mechanistic character of the response and descriptor variables.


Tissue-specific alterations in thyroid hormone homeostasis in combined Mct10 and Mct8 deficiency.
The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.


Immunogenicity and safety of subunit influenza vaccines in pregnant women.
Pregnancy is a condition of modulated immune suppression, so this group of patients has increased risk of infectious diseases. Trivalent subunit vaccines, unadjusted Agrippal S1 (group I) and immunoadjuvant Grippol Plus (group II), containing 5 μg of actual influenza virus strains, were administered respectively to 37 and 42 women in the second and third trimester of physiological pregnancy. The administration of subunit influenza vaccines was accompanied by the development of local reactions in no more than 10% of patients, compared with 4.9% of the 41 pregnant women in the placebo group (group III). Systemic reactions were of a general somatic nature, did not differ between vaccinated and placebo groups, and were not associated with vaccination. Physiological births in groups I, II and III were 94.6%, 92.9% and 85.4%, respectively, and the birth rates of children without pathologies were 91.9%, 90.5% and 80.5%, respectively, and were comparable between groups. Vaccination stimulated the production of protective antibodies against influenza virus strains in 64.8-94.5% of patients after immunisation with an unadjusted vaccine and in 72.5-90.0% of patients after the administration of an immunoadjuvant vaccine. After 9 months, antibody levels were recorded in 51.3-72.9% in group I and 54.2-74.2% in group II. Immunisation against influenza in pregnant women provided a high level of seroprotection and seroconversion. Nevertheless, the level of seroprotection against the influenza strain A(H3N2, Victoria) was slightly lower in the group immunised with an unadjusted vaccine compared to those vaccinated with the immunoadjuvant vaccine.


The association between perceived provider discrimination, healthcare utilization and health status in racial and ethnic minorities.
A commonly cited explanation of how racial discrimination impacts health is the biopsychosocial model. However, the biopsychosocial model does not allow for the effects of perceived provider discrimination on health behavior and utilization. In fact, researchers have directed relatively little attention toward the direct and indirect effects of perceived provider discrimination on both healthcare utilization and health status. We, therefore, compared the extent to which perceived provider discrimination explains racial/ethnic differences in healthcare utilization and subsequently health status. The data came from the 2001 Survey on Disparities in Quality of Health Care. The final analytic sample was 5,642 adults living in the US. Structural equation modeling evaluated the relationship between perceived provider discrimination, healthcare utilization, and health status. African Americans, Hispanics and Asians reported significantly more perceived provider discrimination and poorer health compared to non-Hispanic whites. Poor health is significantly mediated by two paths: (1) by perceived provider discrimination and (2) by perceived provider discrimination through unmet need for healthcare utilization. Perceived provider discrimination contributes to health disparities in African Americans, Hispanics and Asians. Perceived provider discrimination has a direct effect on self-reported health status. Additionally, because minorities perceive more provider discrimination, they are more likely to delay health seeking. In turn, this delay is associated with poor health. This enriches our understanding of how racial/ethnic health disparities are created and sustained and provides a concrete mechanism on how to reduce health disparities.


phot1 inhibition of ABCB19 primes lateral auxin fluxes in the shoot apex required for phototropism.
It is well accepted that lateral redistribution of the phytohormone auxin underlies the bending of plant organs towards light. In monocots, photoreception occurs at the shoot tip above the region of differential growth. Despite more than a century of research, it is still unresolved how light regulates auxin distribution and where this occurs in dicots. Here, we establish a system in Arabidopsis thaliana to study hypocotyl phototropism in the absence of developmental events associated with seedling photomorphogenesis. We show that auxin redistribution to the epidermal sites of action occurs at and above the hypocotyl apex, not at the elongation zone. Within this region, we identify the auxin efflux transporter ATP-BINDING CASSETTE B19 (ABCB19) as a substrate target for the photoreceptor kinase PHOTOTROPIN 1 (phot1). Heterologous expression and physiological analyses indicate that phosphorylation of ABCB19 by phot1 inhibits its efflux activity, thereby increasing auxin levels in and above the hypocotyl apex to halt vertical growth and prime lateral fluxes that are subsequently channeled to the elongation zone by PIN-FORMED 3 (PIN3). Together, these results provide new insights into the roles of ABCB19 and PIN3 in establishing phototropic curvatures and demonstrate that the proximity of light perception and differential phototropic growth is conserved in angiosperms.


The changes in treatment strategies in ABOi living donor liver transplantation for acute liver failure.
Living donor liver transplantation (LDLT) using ABO-incompatible (ABOi) graft for acute liver failure (ALF) is a developing treatment modality. We reviewed the changes in our treatment strategies in applying ABOi LDLT for FH over our fourteen years of experience. Five patients with ALF received LDLT in adults using ABOi grafts, with different but gradually renewed protocols. The etiologies for acute liver failure included autoimmune hepatitis (n=3) and unknown (n=2). The desensitization protocol for ABOi barrier included Case #1; local infusion (portal vein)+plasma exchange (PE), Case #2; local infusion (hepatic artery)+rituximab+PE, Case #3 and #4; rituximab+PE, and Case #5; rituximab+PE under high-flow continuous hemodiafiltration. Local infusion was abandoned since Case #3, because Case #1 had portal vein thrombosis resulting in graft necrosis and Case #2 had hepatic artery dissection. The patients (Case #2 and #3), who received rituximab within 7 days before LDLT, experienced antibody-mediated rejection. Thus, the most recent protocol for ABOi-LDLT is that rituximab is given 2 weeks before LDLT, followed by high-flow continuous hemodiafiltration to obstacle hepatic encephalopathy until LDLT. The four patients except Case #1 are doing well with good graft function over 3.8±3.7 years. Rituximab-based ABOi-LDLT, most-recently under high-flow hemodiafiltration for treating encephalopathy, is a feasible option for applying LDLT for ALF.


OPTIMAL FALSE DISCOVERY RATE CONTROL FOR LARGE SCALE MULTIPLE TESTING WITH AUXILIARY INFORMATION.
Large-scale multiple testing is a fundamental problem in high dimensional statistical inference. It is increasingly common that various types of auxiliary information, reflecting the structural relationship among the hypotheses, are available. Exploiting such auxiliary information can boost statistical power. To this end, we propose a framework based on a two-group mixture model with varying probabilities of being null for different hypotheses a priori, where a shape-constrained relationship is imposed between the auxiliary information and the prior probabilities of being null. An optimal rejection rule is designed to maximize the expected number of true positives when average false discovery rate is controlled. Focusing on the ordered structure, we develop a robust EM algorithm to estimate the prior probabilities of being null and the distribution of p-values under the alternative hypothesis simultaneously. We show that the proposed method has better power than state-of-the-art competitors while controlling the false discovery rate, both empirically and theoretically. Extensive simulations demonstrate the advantage of the proposed method. Datasets from genome-wide association studies are used to illustrate the new methodology.


Evanescent-wave interactions in an optical wave-guiding structure.
Several types of waveguiding structures are known that can support the propagation of a finite number of bound electromagnetic modes. Two such structures are the dielectric slab and the optical fiber. In both structures the electromagnetic field associated with the bound modes extends beyond the central region; that part of the field that penetrates into the surrounding medium is termed evanescent. In this paper we use first-order perturbation theory to treat the effects caused by a surrounding medium with gain on the bound modes of the dielectric slab. A noteworthy effect is the amplification of these bound modes in accordance with formulas we present and which arises by evanescent-wave interaction with the surrounding medium.


Acupuncture on GB34 activates the precentral gyrus and prefrontal cortex in Parkinson's disease.
Acupuncture is increasingly used as an additional treatment for patients with Parkinson's disease (PD). In this functional magnetic resonance imaging study, brain activation in response to acupuncture in a group of 12 patients with PD was compared with a group of 12 healthy participants. Acupuncture was conducted on a specific acupoint, the right GB 34 (Yanglingquan), which is a frequently used acupoint for motor function treatment in the oriental medical field. Acupuncture stimulation on this acupoint activates the prefrontal cortex, precentral gyrus, and putamen in patients with PD; areas that are known to be impaired in patients with PD. Compared with healthy participants, patients with PD showed significantly higher brain activity in the prefrontal cortex and precentral gyrus, especially visible in the left hemisphere. The neuroimaging results of our study suggest that in future acupuncture research; the prefrontal cortex as well as the precentral gyrus should be treated for symptoms of Parkinson's disease and that GB 34 seems to be a suitable acupoint. Moreover, acupuncture evoked different brain activations in patients with Parkinson's disease than in healthy participants in our study, stressing the importance of conducting acupuncture studies on both healthy participants as well as patients within the same study, in order to detect acupuncture efficacy. KCT0001122 at cris.nih.go.kr (registration date: 20140530).


Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.
Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K(1) is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K(1) and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K(1) and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 mug/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.


Infertility with defective spermiogenesis in mice lacking AF5q31, the target of chromosomal translocation in human infant leukemia.
AF5q31 (also called MCEF) was identified by its involvement in chromosomal translocation with the gene MLL (mixed lineage leukemia), which is associated with infant acute lymphoblastic leukemia. Several potential roles have been proposed for AF5q31 and other family genes, but the specific requirements of AF5q31 during development remain unclear. Here, we show that AF5q31 is essential for spermatogenesis. Although most AF5q31-deficient mice died in utero and neonatally with impaired embryonic development and shrunken alveoli, respectively, 13% of AF5q31-deficient mice thrived as wild-type mice did. However, the male mice were sterile with azoospermia. Histological examinations revealed the arrest of germ cell development at the stage of spermiogenesis, and virtually no spermatozoa were seen in the epididymis. AF5q31 was found to be preferentially expressed in Sertoli cells. Furthermore, mutant mice displayed severely impaired expression of protamine 1, protamine 2, and transition protein 2, which are indispensable to compact the haploid genome within the sperm head, and an increase of apoptotic cells in seminiferous tubules. Thus, AF5q31 seems to function as a transcriptional regulator in testicular somatic cells and is essential for male germ cell differentiation and survival. These results may have clinical implications in the understanding of human male infertility.


The ability of optical coherence tomography to monitor percutaneous coronary intervention: detailed comparison with intravascular ultrasound.
We investigated the usefulness of optical coherence tomography (OCT) to evaluate vessel response after stent implantation by comparing with that of intravascular ultrasound (IVUS). Eighteen cases undergoing percutaneous coronary intervention (PCI) who provided consent for both IVUS and OCT usage pre- and post-PCI procedure were enrolled. The lumen area at the distal site of the culprit lesion was smaller on OCT images than on IVUS images due to proximal vessel occlusion, whereas the lumen area at the proximal site of the lesion did not differ between OCT and IVUS images (distal site: 4.6 ± 2.0 vs. 5.0 ± 1.8 mm²; p = 0.0004; proximal site: 5.5 ± 2.3 vs. 5.6 ± 2.3 mm²; p = 0.8160). Stent malapposition was more frequently observed by OCT (30%) than by IVUS (5%, p = 0.0381). Stent edge dissection was not detected by IVUS, but was detected in 10% by OCT. Tissue prolapse was identified in all stents by OCT and in 5% by IVUS. Thrombus was observed in 15% by OCT and in 5% by IVUS. Proximal coronary occlusion during OCT imaging was possibly related to underestimation of vessel sizing at distal reference. Our data suggested that OCT might provide more detailed information on the presence of tissue prolapse, thrombus formation and edge dissection than IVUS. Further study is warranted to assess its clinical utility.


Spinal Cord Stimulation: An Alternative Concept of Rehabilitation?
Chronic low back and leg pain is a disabling condition, affecting, in most cases, older patients with congenital or acquired spinal stenosis or patients with failed back surgery syndrome. Spinal cord stimulation has been introduced as an effective therapeutic option for those patients who have previously been operated without significant clinical benefits, or for all those patients who are ineligible for traditional surgery. We report our experience with ten patients treated with spinal cord stimulation plus medication and physical therapy between November 2014 and September 2015. Inclusion criteria were: previous surgical treatments for lumbar stenosis and metameric instability and persistent or ingravescent disabling low back and leg pain, with a mean duration of symptoms of at least 18 months. A visual analog scale (VAS) was employed for back and leg pain, and the Oswestry Disability Index (ODI) score was determined, and findings were analyzed after 6 months. No intra- or postoperative complication was recorded. The mean VAS score for back pain decreased from 7.5 to 2.9, while leg VAS decreased from 8.2 to 3.0. Analysis of ODI values showed evident improvement in daily life activities, ranging from a median value of 75.7% to 32.7 % after the stimulation. Spinal cord stimulation has a recognized impact on the pain and on the quality of life of patients with failed back surgery syndrome.


Can We Predict Oral Antibiotic Treatment Failure in Children with Fast-Breathing Pneumonia Managed at the Community Level? A Prospective Cohort Study in Malawi.
Pneumonia is the leading cause of infectious death amongst children globally, with the highest burden in Africa. Early identification of children at risk of treatment failure in the community and prompt referral could lower mortality. A number of clinical markers have been independently associated with oral antibiotic failure in childhood pneumonia. This study aimed to develop a prognostic model for fast-breathing pneumonia treatment failure in sub-Saharan Africa. We prospectively followed a cohort of children (2-59 months), diagnosed by community health workers with fast-breathing pneumonia using World Health Organisation (WHO) integrated community case management guidelines. Cases were followed at days 5 and 14 by study data collectors, who assessed a range of pre-determined clinical features for treatment outcome. We built the prognostic model using eight pre-defined parameters, using multivariable logistic regression, validated through bootstrapping. We assessed 1,542 cases of which 769 were included (32% ineligible; 19% defaulted). The treatment failure rate was 15% at day 5 and relapse was 4% at day 14. Concurrent malaria diagnosis (OR: 1.62; 95% CI: 1.06, 2.47) and moderate malnutrition (OR: 1.88; 95% CI: 1.09, 3.26) were associated with treatment failure. The model demonstrated poor calibration and discrimination (c-statistic: 0.56). This study suggests that it may be difficult to create a pragmatic community-level prognostic child pneumonia tool based solely on clinical markers and pulse oximetry in an HIV and malaria endemic setting. Further work is needed to identify more accurate and reliable referral algorithms that remain feasible for use by community health workers.


Modulation of movement-associated cortical activation by transcranial direct current stimulation.
Transcranial direct current stimulation (tDCS) is currently attracting increasing interest as a tool for neurorehabilitation. However, local and distant effects of tDCS on motor-related cortical activation patterns remain poorly defined, limiting the rationale for its use. Here we describe the results of a functional magnetic resonance imaging (MRI) experiment designed to characterize local and distant effects on cortical motor activity following excitatory anodal stimulation and inhibitory cathodal stimulation. Fifteen right-handed subjects performed a visually cued serial reaction time task with their right hand in a 3-T MRI scanner both before and after 10 min of 1-mA tDCS applied to the left primary motor cortex (M1). Relative to sham stimulation, anodal tDCS led to short-lived activation increases in the M1 and the supplementary motor area (SMA) within the stimulated hemisphere. The increase in activation in the SMA with anodal stimulation was found also when directly comparing anodal with cathodal stimulation. Relative to sham stimulation, cathodal tDCS led to an increase in activation in the contralateral M1 and dorsal premotor cortex (PMd), as well as an increase in functional connectivity between these areas and the stimulated left M1. These increases were also found when directly comparing cathodal with anodal stimulation. Significant within-session linear decreases in activation occurred in all scan sessions. The after-effects of anodal tDCS arose primarily from a change in the slope of these decreases. In addition, following sham stimulation compared with baseline, a between-session decrease in task-related activity was found. The effects of cathodal tDCS arose primarily from a reduction of this normal decrease.


Understanding Dyslexia Through Personalized Large-Scale Computational Models.
Learning to read is foundational for literacy development, yet many children in primary school fail to become efficient readers despite normal intelligence and schooling. This condition, referred to as developmental dyslexia, has been hypothesized to occur because of deficits in vision, attention, auditory and temporal processes, and phonology and language. Here, we used a developmentally plausible computational model of reading acquisition to investigate how the core deficits of dyslexia determined individual learning outcomes for 622 children (388 with dyslexia). We found that individual learning trajectories could be simulated on the basis of three component skills related to orthography, phonology, and vocabulary. In contrast, single-deficit models captured the means but not the distribution of reading scores, and a model with noise added to all representations could not even capture the means. These results show that heterogeneity and individual differences in dyslexia profiles can be simulated only with a personalized computational model that allows for multiple deficits.


The use of comorbidities among adults experiencing care transitions: a systematic review and evolutionary analysis of empirical literature.
To systematically review how comorbidities are employed in the empirical literature for adults coping with multiple chronic conditions during common episodes of acute illness that resulted in transition across health care setting. Evolutionary concept analysis inductively identifies current consensus regarding the usage of a concept and results in exploring attributes and clarification of the concept. Sixty studies from 1965 to 2009 identified from MEDLINE, CINAHL, PsychINFO, and ISI Web of Science databases were analysed. Comorbidities were used heterogeneously among reviewed studies with most controlling for their presence (n=33) and lacking robust measurement (n=37). The designation of index or principal condition was equally heterogeneous with approximately half (n=26) representing the main disease or diagnosis of interest to the researcher. In this study comorbidities were associated with personal, disease or system level antecedents and consequences. A conceptual framework is proposed. The impact of comorbidities on the care and outcomes of adults coping with multiple chronic conditions is limited by heterogeneous and ambiguous usage. While analytic techniques have become more sophisticated, continued lack of meaningful conceptualization and instrument use has limited maturation of this important concept for research, practice and policy purposes.


Pediatric multicenter cohort comparison of percutaneous endoscopic and non-endoscopic gastrostomy technique outcomes.
Enteral access is one of the mainstays of nutritional support. Several different modalities for gastrostomy placement are established. In pediatrics, however, there is a limited evidence base supporting the choice of 1 modality over the others. We retrospectively compared elective percutaneous endoscopically placed gastrostomy (PEG) with surgical and interventional radiology-placed gastrostomy outcomes using the Pediatric Hospital Inpatient Sample multicenter administrative database (Pediatric Health Information System). Pediatric patients (<18 years) undergoing planned elective gastrostomy (2010-2015) were included. Coded gastrostomy procedure subtype, patient demographic characteristics, chronic comorbidities and subsequent related outcomes, mortality, readmission, length of stay and total cost of admission were analyzed. Univariate analysis differentiated among gastrostomy techniques. The effect of gastrostomy on mortality and 30-day readmission were determined using a forward, stepwise, binary logistic regression. Generalized linear models were used to estimate the effect of gastrostomy type on length of stay and total cost. During the study period, 11,712 children underwent gastrostomy, including PEG (27%). Patients with chronic comorbidities were more, or as likely to undergo non-PEG procedures. Postoperatively, PEG patients were less likely to require mechanical ventilation and total parenteral nutrition (TPN). Gastrostomy type was not predictive of mortality; predictors included non-White race and need for mechanically assisted ventilation. Readmission following gastrostomy was common (29.5%), and more likely in PEG patients (OR 1.31). Predictors of readmission included earlier TPN (OR 1.39), cardiovascular (OR 1.17) and oncology (OR 4.17) comorbidities. Our study suggests that PEG placement entails similar length of stay and cost as in non-PEG gastrostomy. Patients undergoing PEG were less likely to require mechanical ventilation and TPN postoperatively. Mortality is similar in both groups although more likely with specific comorbidities. Racial background appeared to be associated with choice of gastrostomy, length of stay and mortality.


Possible Impact of RET Polymorphism and Its Haplotypic Association Modulates the Susceptibility to Thyroid Cancer.
Rearranged during Transfection (RET) gene polymorphisms act to influence thyroid cancer in a polygenic and low-penetrance manner and no study regarding RET alterations in thyroid cancer has undergone from this part of the world (North India). We evaluated RET G691S (rs1799939), L769L (rs1800861), and S904S (rs1800863) polymorphisms to elucidate their possible role as risk factors in papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Polymorphic analysis of RET gene was performed by polymerase chain reaction (PCR), followed by restriction fragment length polymorphism (RFLP). In RET G691S polymorphism, the overall distribution of variant alleles (GA + AA) in cases was 62.9% as against 44.5% in controls (P < 0.05) whereas frequency of RET L769L variant alleles (TG + GG) in cases was 70% versus 88% in controls (P < 0.05). In RET S904S, frequency of variant alleles (CG + GG) in cases was 56% versus 44% in controls (P < 0.05). Interestingly, G691S/L769L variant showed increased risk for the non-smokers (P < 0.05). RET S904S variant showed association with benign thyroid disease as against those with no history. The over-representation of homozygotes in G691S and L769L polymorphic variants was not observed, which suggest a "Dominant mode of inheritance." The S904S polymorphism heterozygote lies almost in the middle of the two homozygotes confirming an "Additive mode of inheritance." In conclusion, RET gene G691S/S904S polymorphisms were over-represented and L769L polymorphism was under-represented in PTC and FTC patients. RET polymorphic variants could act synergistically in the development or progression of PTC and FTC.


Clinical classification of deformational plagiocephaly according to Argenta: a reliability study.
The incidence of deformational plagiocephaly (DP) in primary health care is increasing. Patients are referred and treated by different practitioners. However, reliable and practical assessment tools in clinical practice are lacking. The clinical classification according to Argenta distinguishes 5 types of DP based on severity of asymmetry of the skull, ear position, and face. The aim of this study was to investigate the reliability of this clinical classification of DP. Twenty referred patients aged 0 to 1 year were classified for DP. Raters from 3 different professions (3 infant health care physicians, 3 pediatric physiotherapists, and 3 manual therapists) were used because these professionals are the first ones who see children with DP in clinical practise. Interrater and intrarater reliability was determined for the type of DP (I-V) and each characteristic clinical feature separately. There was a moderate overall interrater agreement for classifying DP (mean weighted kappa, 0.54), whereas intrarater agreement ranged from 0.60 to 0.85, indicating substantial to almost perfect agreement. Kappa scores of the first 4 clinical features of DP (occipital flattening, ear malposition, frontal bossing, and facial asymmetry) ranged from 0.45 to 0.57 for the interrater reliability and 0.47 to 1 for the intrarater reliability, except for 1 score of -0.14. Agreement for the fifth feature (vertical skull growth) was due to chance (kappa approximately 0). The classification according to Argenta is a moderately reliable method for classifying DP in clinical practice.


Measurement of b-Quark Fragmentation Fractions in pp[over ¯] Collisions at sqrt[s]=1.8 TeV.
We have studied the production of B hadrons in 1.8-TeV pp[over ¯] collisions. We present measurements of the fragmentation fractions, f_{u}, f_{d}, f_{s}, and f_{baryon}, of produced b quarks that yield B^{+}, B^{0}, B_{s}^{0}, and Λ[over ¯]_{b}^{0} hadrons. Reconstruction of five electron-charm final states yields f_{s}/( f_{u}+f_{d})=0.213±0.068 and f_{baryon}/( f_{u}+f_{d})=0.118±0.042, assuming f_{u}=f_{d}. If all B hadrons produced in pp[over ¯] collisions cascade to one of these four hadrons, we determine f_{u}=f_{d}=0.375±0.023, f_{s}=0.160±0.044, and f_{baryon}=0.090±0.029. If we do not assume f_{u}=f_{d}, we find f_{d}/f_{u}=0.84±0.16.


Dermatologic rituximab dosing: treatment of refractory pemphigus vulgaris in an adolescent male.
Rituximab is a chimeric monoclonal antibody against CD20 that mediates B-cell depletion. It has been shown to be effective in a variety of autoimmune-related diseases, including pemphigus vulgaris. Most reports of pemphigus treatment utilize the weekly dosing regimen designed for the treatment of B-cell malignancy. The authors report a case of successful treatment of refractory pemphigus vulgaris in an adolescent male using three infusions of rituximab spread over a four-month period of time. The authors also discuss recent updates in rituximab's mechanism of action in autoimmune disease. Rituximab acts to destroy auto-reactive B-cells prior to their development into auto-antibody producing plasma cells. More recent reports have shown that rituximab also indirectly leads to a decrease of autoreactive CD4+ T cells via depletion of B-cells that are necessary for antigen presentation. Monthly to bi-monthly rituximab infusion dosing may be a more appropriate dosing strategy for autoimmune disease that minimizes potential side effects while generating remission of disease. Dermatology continues to see an increase in use of medications designed for treatment of rheumatologic disease and malignancy. Additional studies should focus on the appropriate dosing of these medications for dermatologic conditions that limit the risk of adverse effects while preserving therapeutic benefit.


Urinary incontinence in women.
Urinary incontinence affects women of all ages. History, physical examination, and certain tests can guide specialists in diagnosing stress urinary incontinence, urgency urinary incontinence, and mixed urinary incontinence. First line management includes lifestyle and behavior modification, as well as pelvic floor strength and bladder training. Drug therapy is helpful in the treatment of urgency incontinence that does not respond to conservative measures. In addition, sacral neuromodulation, intravesical onabotulinumtoxinA injections, and posterior tibial nerve stimulation can be used in select patient populations with drug refractory urgency incontinence. Midurethral synthetic slings, including retropubic and transobturator approaches, are safe and efficacious surgical options for stress urinary incontinence and have replaced more invasive bladder neck slings that use autologous or cadaveric fascia. Despite controversy surrounding vaginal mesh for prolapse, synthetic slings for the treatment of stress urinary incontinence are considered safe and minimally invasive.


The role of sentrin-specific protease 2 substrate recognition in TGF-β-induced tumorigenesis.
Smad4, a common-mediator of Smads, plays a central role in forming complexes with receptor-phosphorylated Smads, and then transduces transforming growth factor (TGF)-β signals into the nuclei. Although many cellular factors are involved in TGF-β induced epithelial-to-mesenchymal transition (EMT) and cell migration, very little is known with the mechanism of Smad4 regulation on pro-oncogenes response by TGF-β. Herein, we demonstrate the interaction of Sentrin-specific protease 2 (SENP2) with Smad4 through SENP2 residue 363~400. The same segment is also important for desumoylation of Smad4, and able to relieve sumoylation-mediated TGF-β repression. The SENP2363~400 segment is critical for TGF-β-induced cell migration, which is correlated with SENP2363~400 deletion mutant failed to increase matrix metalloproteinase (MMP)-9 and EMT marker gene expression. Moreover, our results suggest that the interaction and desumoylation between SENP2 and Smad4 promote cell migration in triple-negative breast cancer cells. Altogether, our data show how SENP2 regulates its substrate for desumoylation, and also the role of SENP2 in TGF-β induced cancer cell migration.


Molecular Imaging of Platelet-Endothelial Interactions and Endothelial von Willebrand Factor in Early and Mid-Stage Atherosclerosis.
Nonthrombotic platelet-endothelial interactions may contribute to atherosclerotic plaque development, although in vivo studies examining mechanism without platelet preactivation are lacking. Using in vivo molecular imaging at various stages of atherosclerosis, we quantified platelet-endothelial interactions and evaluated the contribution of major adhesion pathways. Mice deficient for the low-density lipoprotein receptor and Apobec-1 were studied as an age-dependent model of atherosclerosis at 10, 20, 30, and 40 weeks of age, which provided progressive increase in stage from early fatty streak (10 weeks) to large complex plaques without rupture (40 weeks). Platelet-targeted contrast ultrasound molecular imaging of the thoracic aorta performed with microbubbles targeted to GPIbα demonstrated selective signal enhancement as early as 10 weeks of age. This signal increased progressively with age (almost 8-fold increase from 10 to 40 weeks, analysis of variance P<0.001). Specificity for platelet targeting was confirmed by the reduction in platelet-targeted signal commensurate with the decrease in platelet count after immunodepletion with anti-GPIb or anti-CD41 antibody. Inhibition of P-selectin in 20 and 40 weeks atherosclerotic mice resulted in a small (15% to 30%) reduction in platelet signal. Molecular imaging with microbubbles targeted to the A1 domain of von Willebrand factor demonstrated selective signal enhancement at all time points, which did not significantly increase with age. Treatment of 20 and 40 week mice with recombinant ADAMTS13 eliminated platelet and von Willebrand factor molecular imaging signal. Platelet-endothelial interactions occur in early atherosclerosis. These interactions are in part caused by endothelial von Willebrand factor large multimers, which can be reversed with exogenous ADAMTS13.


Committee opinion no. 466: ethical considerations for performing gynecologic surgery in low-resource settings abroad.
International humanitarian medical efforts provide essential services to patients who would not otherwise have access to specific health care services. The Committees on Ethics and Global Women's Health of the American College of Obstetricians and Gynecologists encourage College Fellows and other health care professionals to participate in international humanitarian medical efforts for this reason. However, such programs present Fellows with a unique set of practical and ethical challenges. It is important for health care providers to consider these challenges before participating in international surgical efforts in these settings. Health care professionals should ensure that they have the necessary surgical competence and training, including sufficient mentorship, prior to functioning as the primary surgeon abroad. Before they perform surgery, health care professionals should ensure that patients have access to adequate medical resources and preoperative and postoperative care. They should be willing and prepared to postpone or cancel surgery when the standards of ethical medical care cannot be met and the members of the surgical team believe that the best interest of the patient cannot be achieved with the current available resources. Health care professionals' efforts should contribute to the long-term well-being of the patients and the communities being served through the ethical practice of medicine, responsible conduct of research, and investment in the sustainability of services. The care of the patient should be the highest priority for those participating in these medical programs.


SEPARATION OF MICROSOMAL RNA INTO FIVE BANDS DURING AGAR ELECTROPHORESIS.
Microsomal RNA from rabbit livers and lymph nodes separate into five major bands during agar-gel electrophoresis. The electrophoretic method may be used either as an analytical or preparative tool. The 33S and 19S peaks of microsomal RNA from sucrose-gradient zone centrifugation divide into two bands each during simple agar electrophoresis.


Low physical performance determined by chair rising test muscle mechanography is associated with prevalent fragility fractures.
This study examined associations between physical performance assessed by chair rising test muscle mechanography and DXA T-score as well as body composition in a large patient cohort. Next to various significant interrelationships between these muscle and bone parameters, lower physical performance was associated with prevalent fragility fractures. Although the interaction between muscle and bone has been demonstrated in various aspects, the clinical focus in the diagnosis of musculoskeletal disorders mainly lies on the skeletal assessments. Accordingly, the association between muscle function, bone mineral density (BMD), and fragility fractures remains to be further elucidated with a feasible muscle assessment in a clinical setting. Patient data (2076 patients, 1538 women, 538 men) were evaluated retrospectively from a large dual energy X-ray absorptiometry (DXA) database as well as from chair rising test (CRT) that was performed on a muscle mechanograph. To determine potential predictors of the CRT time and maximum force, a multivariate regression analysis was performed including age, DXA T-score, and body composition indices. Furthermore, CRT results were compared between non-fracture and fracture cases. We determined independent predictors for CRT time such as age, femoral DXA T-score, and total fat mass, whereas CRT force was only influenced by total lean mass. Both women and men with previous fragility fractures displayed a longer CRT time (women p = 0.009, men p = 0.001) and lower CRT force (women p < 0.001, men p < 0.001) than those with no fractures, while no clear differences in CRT results could be detected between normal BMD, osteopenia, and osteoporosis based on DXA T-scores. Our study demonstrates that in addition to the associations between chair rising time and femoral T-score assessed by DXA, low muscle strength is associated with previous fragility fractures.


pH-dependent catabolic protein expression during anaerobic growth of Escherichia coli K-12.
During aerobic growth of Escherichia coli, expression of catabolic enzymes and envelope and periplasmic proteins is regulated by pH. Additional modes of pH regulation were revealed under anaerobiosis. E. coli K-12 strain W3110 was cultured anaerobically in broth medium buffered at pH 5.5 or 8.5 for protein identification on proteomic two-dimensional gels. A total of 32 proteins from anaerobic cultures show pH-dependent expression, and only four of these proteins (DsbA, TnaA, GatY, and HdeA) showed pH regulation in aerated cultures. The levels of 19 proteins were elevated at the high pH; these proteins included metabolic enzymes (DhaKLM, GapA, TnaA, HisC, and HisD), periplasmic proteins (ProX, OppA, DegQ, MalB, and MglB), and stress proteins (DsbA, Tig, and UspA). High-pH induction of the glycolytic enzymes DhaKLM and GapA suggested that there was increased fermentation to acids, which helped neutralize alkalinity. Reporter lac fusion constructs showed base induction of sdaA encoding serine deaminase under anaerobiosis; in addition, the glutamate decarboxylase genes gadA and gadB were induced at the high pH anaerobically but not with aeration. This result is consistent with the hypothesis that there is a connection between the gad system and GabT metabolism of 4-aminobutanoate. On the other hand, 13 other proteins were induced by acid; these proteins included metabolic enzymes (GatY and AckA), periplasmic proteins (TolC, HdeA, and OmpA), and redox enzymes (GuaB, HmpA, and Lpd). The acid induction of NikA (nickel transporter) is of interest because E. coli requires nickel for anaerobic fermentation. The position of the NikA spot coincided with the position of a small unidentified spot whose induction in aerobic cultures was reported previously; thus, NikA appeared to be induced slightly by acid during aeration but showed stronger induction under anaerobic conditions. Overall, anaerobic growth revealed several more pH-regulated proteins; in particular, anaerobiosis enabled induction of several additional catabolic enzymes and sugar transporters at the high pH, at which production of fermentation acids may be advantageous for the cell.


Impact of caring for people living with HIV on the psychosocial well-being of palliative caregivers.
Acquired immunodeficiency syndrome (AIDS) continues to be a serious public health issue, and it is often the caregivers who carry the brunt of the epidemic. Caregivers of people with AIDS face distinctive demands that could make them more prone to occupational stress, with serious consequences for their psychosocial well-being. The impact of caring for people living with HIV infection on the psychosocial well-being of palliative caregivers was investigated using in-depth interviews and questionnaires in 28 participants. The results indicated no burnout, but occupational stress was prevalent. Factors impacting negatively on well-being were stressors inherent in AIDS care, such as suffering and dying of the persons being cared for, work-related stressors such as heavy workload, lack of support and ineffective coping mechanisms. Positive aspects of caring such as job satisfaction, holistic palliative care, effective coping mechanisms and psychosocial support were identified. Recommendations to curb the negative effects of caregiving are provided.


Multiple annular linear diffractive axicons.
We propose a chromatic analysis of multiple annular linear diffractive axicons. Large aperture axicons are optical devices providing achromatic nondiffracting beams, with an extended depth of focus, when illuminated by a white light source, due to chromatic foci superimposition. Annular apertures introduce chromatic foci separation, and because chromatic aberrations result in focal segment axial shifts, polychromatic imaging properties are partially lost. We investigate here various design parameters that can be used to achieve color splitting, filtering, and combining using these properties. In order to improve the low-power efficiency of a single annular axicon, we suggest a spatial multiplexing of concentric annular axicons with different sizes and periods we call multiple annular aperture diffractive axicons (MALDAs). These are chosen to maintain focal depths while enabling color imaging with sufficient diffraction efficiency. Illustrations are given for binary phase diffractive axicons, considering technical aspects such as grating design wavelength and phase dependence due to the grating thickness.


Scientists' Warning on Climate Change and Medicinal Plants.
The recent publication of a World Scientists' Warning to Humanity highlighted the fact that climate change, absent strenuous mitigation or adaptation efforts, will have profound negative effects for humanity and other species, affecting numerous aspects of life. In this paper, we call attention to one of these aspects, the effects of climate change on medicinal plants. These plants provide many benefits for human health, particularly in communities where Western medicine is unavailable. As for other species, their populations may be threatened by changing temperature and precipitation regimes, disruption of commensal relationships, and increases in pests and pathogens, combined with anthropogenic habitat fragmentation that impedes migration. Additionally, medicinal species are often harvested unsustainably, and this combination of pressures may push many populations to extinction. A second issue is that some species may respond to increased environmental stresses not only with declines in biomass production but with changes in chemical content, potentially affecting quality or even safety of medicinal products. We therefore recommend actions including conservation and local cultivation of valued plants, sustainability training for harvesters and certification of commercial material, preservation of traditional knowledge, and programs to monitor raw material quality in addition to, of course, efforts to mitigate climate change.


ESCMID guideline for the diagnosis and treatment of biofilm infections 2014.
Biofilms cause chronic infections in tissues or by developing on the surfaces of medical devices. Biofilm infections persist despite both antibiotic therapy and the innate and adaptive defence mechanisms of the patient. Biofilm infections are characterized by persisting and progressive pathology due primarily to the inflammatory response surrounding the biofilm. For this reason, many biofilm infections may be difficult to diagnose and treat efficiently. It is the purpose of the guideline to bring the current knowledge of biofilm diagnosis and therapy to the attention of clinical microbiologists and infectious disease specialists. Selected hallmark biofilm infections in tissues (e.g. cystic fibrosis with chronic lung infection, patients with chronic wound infections) or associated with devices (e.g. orthopaedic alloplastic devices, endotracheal tubes, intravenous catheters, indwelling urinary catheters, tissue fillers) are the main focus of the guideline, but experience gained from the biofilm infections included in the guideline may inspire similar work in other biofilm infections. The clinical and laboratory parameters for diagnosing biofilm infections are outlined based on the patient's history, signs and symptoms, microscopic findings, culture-based or culture-independent diagnostic techniques and specific immune responses to identify microorganisms known to cause biofilm infections. First, recommendations are given for the collection of appropriate clinical samples, for reliable methods to specifically detect biofilms, for the evaluation of antibody responses to biofilms, for antibiotic susceptibility testing and for improvement of laboratory reports of biofilm findings in the clinical microbiology laboratory. Second, recommendations are given for the prevention and treatment of biofilm infections and for monitoring treatment effectiveness. Finally, suggestions for future research are given to improve diagnosis and treatment of biofilm infections.


Scandinavian women's experiences with abortions on request: a systematic review.
The objective of the review was to explore the experiences of Scandinavian women with abortions on request, that is, before, during and after the intervention. In Scandinavia, the primary issues surrounding the abortion debate to date have been women's legal rights to an abortion, and, to a lesser extent, how women experience an abortion on request and how society could and should support them. This systematic review investigated Scandinavian women's experiences in relation to this intervention. The current review included all studies that focused on adult women (aged 15 and over) living in Scandinavia (Denmark, Sweden and Norway) who have experienced an abortion on request (a medically or surgically induced abortion without a medical indication for the mother or child, described here as an "abortion on request"). The phenomena of interest were Scandinavian women's experiences in relation to an abortion on request, that is, before, during and after the intervention, and self-reported psychosocial or psychological health consequences following the abortion. This systematic review focused on Scandinavian hospital or clinical environments where authorized medical personnel performed abortions on request. This review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and feminist research. A three-step search strategy was used to identify published and unpublished studies from 1973 to June 2016. The comprehensive literature search identified nine studies that met the inclusion criteria. These nine studies were assessed by two independent reviewers using the standardized critical appraisal instruments from the Joanna Briggs Institute (JBI). Six of these studies were deemed to be of sufficient methodological quality for inclusion in this systematic review. Data were extracted from the six included studies using the standardized data extraction tool from JBI. A total of 24 qualitative research findings were pooled using JBI methodology. A total of six studies met the inclusion criteria, with a total of 80 participants. Twenty-four research findings were extracted and grouped into six categories that were synthesized into three synthesized findings: 1) Experiences in connection with the decision-making process; 2) Experiences in connection with the procedure; and 3) Experiences after abortion. The vast majority of participants were aged 15 to 24 years at the time of the abortion. Conclusions and recommendations for practice apply to Scandinavian women within this age group. This systematic review indicates that young Scandinavians consider it a woman's responsibility to obtain and use contraceptives and that young women seeking an abortion on request have little knowledge of their own bodies with respect to fertility and their menstrual cycles. Young Scandinavian women between the ages of 15 and 24 years seeking an abortion on request experience conflicted feelings. They feel both joy and shame about their pregnancies and, during the decision-making process, are torn between the possibility of motherhood and the reasonable and expected choice of abortion that is supported by their parents and friends. The majority of women experience worse-than-expected pain and discomfort in connection with the abortion procedure. The approach of healthcare staff to women's physical needs is described as good and professional, but there is little or no focus on the women's emotional and existential needs. After abortions on request, young women express ambivalence: relief that the pregnancy has been terminated, coupled with a feeling of loss. Some suffer from guilt and some express regret.


Potential Functional Benefit From Light Intensity Physical Activity in Knee Osteoarthritis.
Knee pain may preclude participation in higher intensity physical activity in people with knee osteoarthritis and benefits of light activity are unclear. The effect of replacing sedentary time with light intensity activity on incident functional limitation 2 years later was investigated. Included were people with or at high risk of knee osteoarthritis without baseline functional limitation using data from the Osteoarthritis Initiative collected between August 2008 and July 2010. Data were analyzed between May 2016 and August 2016 for time in sedentary, light, and moderate to vigorous physical activity from accelerometer monitoring. Incident functional limitation was defined as (1) slow gait speed <1.0 meters/second during a 20-meter walk, (2) Western Ontario and McMasters University Osteoarthritis Index physical function ≥28, or (3) Short Form 12 Physical Component scale <40. Inclusion criteria were met by 1,873 people (mean age=65.0 [SD=9.0] years, mean BMI=28.4 [SD=4.7] kg/m2). Replacing 60 minutes/day of sedentary time with 60 minutes/day of light activity was associated with a 17% reduced risk for incident slow gait speed 2 years later (Hazard Ratio=0.83, 95% CI=0.70, 0.99) after adjustment. Approximately 5 minutes/day of moderate to vigorous physical activity would be necessary to receive the equivalent benefit of 60 minutes/day of light activity. Effects in secondary patient-reported outcomes did not reach statistical significance. Replacing sedentary time with light activity may reduce the risk of performance-based functional limitation. As expected, moderate to vigorous physical activity rather than light provided stronger risk reduction. When moderate to vigorous physical activity is not an option, pursuing light activity may be a beneficial alternative to being sedentary.


T-lymphocyte responses to intestinally absorbed antigens can contribute to adipose tissue inflammation and glucose intolerance during high fat feeding.
Obesity is associated with inflammation of visceral adipose tissues, which increases the risk for insulin resistance. Animal models suggest that T-lymphocyte infiltration is an important early step, although it is unclear why these cells are attracted. We have recently demonstrated that dietary triglycerides, major components of high fat diets, promote intestinal absorption of a protein antigen (ovalbumin, "OVA"). The antigen was partly transported on chylomicrons, which are prominently cleared in adipose tissues. We hypothesized that intestinally absorbed gut antigens may cause T-lymphocyte associated inflammation in adipose tissue. Triglyceride absorption promoted intestinal absorption of OVA into adipose tissue, in a chylomicron-dependent manner. Absorption tended to be higher in mesenteric than subcutaneous adipose tissue, and was lowest in gonadal tissue. OVA immunoreactivity was detected in stromal vascular cells, including endothelial cells. In OVA-sensitized mice, OVA feeding caused marked accumulation of CD3+ and osteopontin+ cells in mesenteric adipose tissue. The accumulating T-lymphocytes were mainly CD4+. As expected, high-fat (60% kCal) diets promoted mesenteric adipose tissue inflammation compared to low-fat diets (10% Kcal), as reflected by increased expression of osteopontin and interferon-gamma. Immune responses to dietary OVA further increased diet-induced osteopontin and interferon-gamma expression in mesenteric adipose. Inflammatory gene expression in subcutaneous tissue did not respond significantly to OVA or dietary fat content. Lastly, whereas OVA responses did not significantly affect bodyweight or adiposity, they significantly impaired glucose tolerance. Our results suggest that loss or lack of immunological tolerance to intestinally absorbed T-lymphocyte antigens can contribute to mesenteric adipose tissue inflammation and defective glucose metabolism during high-fat dieting.


Two specific amino acid variations in colonization factor CS6 subtypes of enterotoxigenic Escherichia coli results in differential binding and pathogenicity.
CS6 is the predominant colonization factor of enterotoxigenic Escherichia coli (ETEC). We report the existence of multiple CS6 subtypes caused by natural point mutations in cssA and cssB, the structural genes for CS6. The subtype AIBI was mostly associated with ETEC isolated from diarrhoeal cases, whereas AIIBII was mostly found in asymptomatic controls. Here we explore the rationale behind this association. ETEC isolates expressing AIIBII showed weaker adherence to intestinal epithelial cells compared with ETEC expressing AIBI. AIIBII expression on the ETEC cell surface was threefold less than AIBI. We found that alanine at position 37 in CssAII, in conjunction with asparagine at position 97 in CssBII, was responsible for the decreased levels of AIIBII on the bacterial surface. In addition, purified AIIBII showed fourfold less mucin binding compared with AIBI. The asparagine at position 97 in CssBII was also accountable for the decreased mucin binding by AIIBII. Reduced fluid accumulation and colonization occurred during infection with ETEC expressing AIIBII in animal models. Together these results indicate that the differential adherence between AIBI and AIIBII was a cumulative effect of decreased surface-level expression and mucin binding of AIIBII due to two specific amino acid variations. As a consequence, ETEC expressing these two subtypes displayed differential pathogenicity. We speculate that this might explain the subjective association of AIBI with ETEC from diarrhoeal cases and AIIBII with asymptomatic controls.


2009 Melbourne metropolitan sewerage strategy: a portfolio of decentralised and on-site concept designs.
The bulk and retail water companies of the greater Melbourne area are developing the 2009 Metropolitan Sewerage Strategy to provide sustainable sewerage services to 2060. The objective of the strategy is to establish long term principles and near term actions to produce a robust sewage management system for Melbourne. Melbourne's existing sewerage system is largely centralised and discharges to two major treatment plants. Several small satellite treatment plants service local urban areas generally more distant from the centralised system. Decentralised and on-site wastewater systems are options for future sewage management and could play a role in local recycling. A portfolio of 18 on-site and decentralised concept designs was developed, applicable to the full range of urban development types in Melbourne. The concepts can be used in evaluation of metropolitan system configurations as part of future integrated water cycle planning. The options included secondary and tertiary treatment systems incorporating re-use of water for non potable uses, urine separation, black and greywater separation and composting toilets. On-site and cluster treatment systems were analysed. Each option is described by its indicative capital and operating costs, energy use and water and nutrient balances. This paper summarises and compares the portfolio mix of decentralized and on-site options in Melbourne's context.


The dimer interface of the membrane type 1 matrix metalloproteinase hemopexin domain: crystal structure and biological functions.
Homodimerization is an essential step for membrane type 1 matrix metalloproteinase (MT1-MMP) to activate proMMP-2 and to degrade collagen on the cell surface. To uncover the molecular basis of the hemopexin (Hpx) domain-driven dimerization of MT1-MMP, a crystal structure of the Hpx domain was solved at 1.7 Å resolution. Two interactions were identified as potential biological dimer interfaces in the crystal structure, and mutagenesis studies revealed that the biological dimer possesses a symmetrical interaction where blades II and III of molecule A interact with blades III and II of molecule B. The mutations of amino acids involved in the interaction weakened the dimer interaction of Hpx domains in solution, and incorporation of these mutations into the full-length enzyme significantly inhibited dimer-dependent functions on the cell surface, including proMMP-2 activation, collagen degradation, and invasion into the three-dimensional collagen matrix, whereas dimer-independent functions, including gelatin film degradation and two-dimensional cell migration, were not affected. These results shed light on the structural basis of MT1-MMP dimerization that is crucial to promote cellular invasion.


High-risk retrieval of adherent and chronically implanted IVC filters: techniques for removal and management of thrombotic complications.
To evaluate the safety and efficacy of aggressive techniques for retrieving adherent and chronically implanted inferior vena cava (IVC) filters. A single-center retrospective review was performed on all patients who underwent attempted filter retrieval from October 2007 through October 2008. Patients were included in the study if they had an adherent filter, refractory to standard retrieval techniques, and underwent high-risk retrieval after procedural risks were deemed lower than risks of long-term filter implantation. Fourteen patients were diagnosed with an adherent filter, 13 (93%) of whom were candidates for high-risk retrieval. These patients included seven men and six women (mean age, 40 years; age range, 18-71 years). Nine of the 13 patients (69%) were referred from an outside hospital. Filter retrieval was performed for the following indications: to avoid the risk of long-term thrombotic complications in a young patient (n= 6), to treat symptomatic filter-related IVC stenosis (n= 5), to treat symptomatic filter penetration (n= 1), and to avoid the need for lifelong anticoagulation (n= 1). There were eight Günther-Tulip filters (mean dwell time, 356 days; range 53-1,181 days), two Optease filters (mean dwell time, 62 days; range, 52-72 days), one G2 filter (dwell time, 420 days), and two Recovery filters (mean dwell time, 1,630 days; range, 1,429-1,830 days). Three IVC occlusions necessitated recanalization to facilitate retrieval. High-risk retrieval with use of various techniques with aggressive force was successful in all 13 patients (100%). Partial caval thrombosis occurred in the first four patients (31%) but did not occur after procedural modifications were implemented. There were no complications at clinical follow-up (mean, 221 days; range, 84-452 days). Alternative techniques can be used to retrieve adherent IVC filters implanted for up to 3-5 years. Although caval thrombosis was an observed complication, protocol modifications appeared to reduce this risk.


Improving the performance of the health service delivery system? Lessons from the Towards Unity for Health projects.
The World Health Organization developed the Towards Unity for Health (TUFH) strategy in 2000 for the improvement of health system performance. Twelve projects worldwide were supported to put this strategy into practice. A standard evaluation and monitoring framework was developed on the basis of which project coordinators prepared technical progress reports. To review the utility and effectiveness of the evaluation criteria recommended by TUFH and their application in four of the original twelve projects. We reviewed status reports provided by European project coordinators and developed a standardized reporting template to extract information using original TUFH evaluation criteria. The original TUFH evaluation framework is very comprehensive and has only partly been followed by the field projects. The evaluation strategies employed by the projects were insufficient to demonstrate the connections between the intervention and the desired process improvements, and few of the evaluation measures address outcomes. The evaluation strategies employed by the projects are limited in allowing us to associate the intervention with the desired process improvements. Few measures address outcomes. The evaluation of complex community interventions poses many challenges, however, tools are available to assess impact on structures and process, and selected outcome indicators may be identified to monitor progress in future projects. Based on the review of evaluation status of the TUFH projects and resources available we recommend moving away from uniform evaluation and towards monitoring minimal, context-specific performance indicators criteria.


Chondrodysplasia with multiple dislocations: comprehensive study of a series of 30 cases.
The group of chondrodysplasia with multiple dislocations includes several entities, characterized by short stature, dislocation of large joints, hand and/or vertebral anomalies. Other features, such as epiphyseal or metaphyseal changes, cleft palate, intellectual disability are also often part of the phenotype. In addition, several conditions with overlapping features are related to this group and broaden the spectrum. The majority of these disorders have been linked to pathogenic variants in genes encoding proteins implicated in the synthesis or sulfation of proteoglycans (PG). In a series of 30 patients with multiple dislocations, we have performed exome sequencing and subsequent targeted analysis of 15 genes, implicated in chondrodysplasia with multiple dislocations, and related conditions. We have identified causative pathogenic variants in 60% of patients (18/30); when a clinical diagnosis was suspected, this was molecularly confirmed in 53% of cases. Forty percent of patients remain without molecular etiology. Pathogenic variants in genes implicated in PG synthesis are of major importance in chondrodysplasia with multiple dislocations and related conditions. The combination of hand features, growth failure severity, radiological aspects of long bones and of vertebrae allowed discrimination among the different conditions. We propose key diagnostic clues to the clinician.


Cumulative exposure to organic pollutants of French children assessed by hair analysis.
Children represent one of the most vulnerable parts of the population regarding the effects of pollutants exposure on health. In this study, hair samples were collected between October 2013 and August 2015 from 142 French children originating from different geographical areas (urban and rural) and analysed with a GC/MS-MS method, allowing for the detection of 55 biomarkers for pesticides and metabolites both persistent and non-persistent from different families, including: organochlorines, organophosphates, pyrethroids, azoles, dinitroanilines, oxadiazines, phenylpyrazoles and carboxamidas; 4 polychlorobiphenyls (PCBs) and 5 polybromodiphenylethers (PBDEs). The number of compounds detected in each sample ranged from 9 up to 37 (21 on average), which clearly highlighted the cumulative exposure of the children. The results also showed a wide range of concentration of the pollutants in hair (often more than 100 times higher in the most exposed child compared to the less exposed), suggesting significant disparities in the exposure level, even in children living in the same area. In addition to the detection of currently used chemicals, the presence of persistent organic pollutants (POPs) in children also suggests that the French population is still exposed to POPs nowadays. PCP, DEP, PNP, 3Me4NP, trans-Cl2CA, 3PBA, fipronil and fipronil sulfone, presented statistically significant higher concentration in the hair of boys compared to girls. PCP, PNP and 3Me4NP presented statistically significant higher concentration in younger children. Finally, this study also suggests that local environmental contamination would not be the main source of exposure, and that individual specificities (habits, diet…) would be the main contributors to the exposure to the pollutants analysed here. The present study strongly supports the relevance of hair for the biomonitoring of exposure and provides the first values of organic pollutant concentration in the hair of French children.


Triptolide promotes spinal cord repair by inhibiting astrogliosis and inflammation.
Spinal cord injury (SCI) is a cause of major neurological disability, and no satisfactory treatment is currently available. Traumatic SCI directly damages the cell bodies and/or processes of neurons and triggers a series of endogenous processes, including neuroinflammatory response and reactive astrogliosis. In this study, we found that triptolide, one of the major active components of the traditional Chinese herb Tripterygium wilfordii Hook F, inhibited astrogliosis and inflammation and promoted spinal cord repair. Triptolide was shown to prevent astrocytes from reactive activation by blocking the JAK2/STAT3 pathway in vitro and in vivo. Furthermore, astrocytic gliosis and glial scar were greatly reduced in injured spinal cord treated with triptolide. Triptolide treatment was also shown to decrease the ED-1 or CD11b-positive inflammatory cells at the lesion site. Using neurofilament staining and anterograde tracing, a significantly greater number of regenerative axons were observed in the triptolide-treated rats. Importantly, behavioral tests revealed that injured rats receiving triptolide had improved functional recovery as assessed by the Basso, Beattie, and Bresnahan open-field scoring, grid-walk, and foot-print analysis. These results suggested that triptolide promoted axon regeneration and locomotor recovery by attenuating glial scaring and inflammation, and shed light on the potential therapeutic benefit for SCI.


Alfa 1 antitrypsin and protease levels in Puerto Rican asthmatics: a pilot study.
A cross-sectional pilot study was conducted on a population of 119 asthmatics who had been recruited from the Emergency Room Department of a major hospital in Ponce, Puerto Rico. The purpose of the study was to determine the frequency of the MM, MS, and SS a-i-antiprotease variants. Also, we analyzed the serum levels of the alpha-1-antiprotease inhibitor, quantified the levels of serine proteases in homes of the asthmatic volunteers, and determined whether environmental levels of proteases, regardless of their sources, had any association with either asthma symptoms or alpha-1-antiprotease inhibitor phenotypes. Our results do not support the role of the alpha-1-antiprotease as a risk factor for asthma in the study population as previously reported. Patients who had visited the ED due to asthma on 3 or more occasions had significantly higher trypsin levels than those who had done so 2 or fewer times. Of those asthmatic patients who had daily symptoms, 40% had been exposed to high levels of elastase, and 33.3% to trypsin. Similarly, 52.9% of the patients with 2 or more hospitalizations a year had been exposed to high elastase levels, and 40.5% of asthma patients who had nocturnal asthma more than 3 times a week had been exposed to high levels of elastase.


The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae.
Proteolysis mediated by the anaphase promoting complex (APC) has a crucial role in regulating the passage of cells through anaphase. Destruction of the anaphase inhibitor Pds1p is necessary for separation of sister chromatids, whereas destruction of the mitotic cyclin Clb2p is important for disassembly of the mitotic spindle, cytokinesis and re-replication of the genome. Pds1p proteolysis precedes that of Clb2p by at least 15 min, which helps to ensure that cells never re-replicate their genome before they have separated sister chromatids at the previous mitosis. What triggers Pds1p proteolysis and why does it not also trigger that of Clb2p? Apart from sharing a dependence on the APC, these two proteolytic events differ in their dependence on other cofactors. Pds1p proteolysis depends on a WD-repeat protein called Cdc20p, whereas Clb2p proteolysis depends on another, related WD protein called Hct1/Cdh1p. On the other hand, destruction of Clb2p, but not that of Pds1p, depends on the Polo-like kinase, Cdc5p. Cdc20p is essential for separation of sister chromatids, whereas Cdc5p is not. We show that both Cdc5p and Cdc20p are unstable proteins whose proteolysis is regulated by the APC. Both proteins accumulate during late G2/M phase and disappear at a late stage of anaphase. Accumulation of Cdc20p contributes to activation of Pds1p proteolysis in metaphase, whereas accumulation of Cdc5p facilitates the activation of Clb2p proteolysis.


Numerical methods for modeling photonic-crystal VCSELs.
We show comparison of four different numerical methods for simulating Photonic-Crystal (PC) VCSELs. We present the theoretical basis behind each method and analyze the differences by studying a benchmark VCSEL structure, where the PC structure penetrates all VCSEL layers, the entire top-mirror DBR, a fraction of the top-mirror DBR or just the VCSEL cavity. The different models are evaluated by comparing the predicted resonance wavelengths and threshold gains for different hole diameters and pitches of the PC. The agreement between the models is relatively good, except for one model, which corresponds to the effective index method. The simulation results elucidate the strength and weaknesses of the analyzed methods; and outline the limits of applicability of the different models.