Singlet molecular oxygen generation by light-activated DHN-melanin of the fungal pathogen Mycosphaerella fijiensis in black Sigatoka disease of bananas.
In pathogenic fungi, melanin contributes to virulence, allowing tissue invasion and inactivation of the plant defence system, but has never been implicated as a factor for host cell death, or as a light-activated phytotoxin. Our research shows that melanin synthesized by the fungal banana pathogen Mycosphaerella fijiensis acts as a virulence factor through the photogeneration of singlet molecular oxygen O2 (1Δg). Using analytical tools, including elemental analysis, ultraviolet/infrared absorption spectrophometry and MALDI-TOF mass spectrometry analysis, we characterized both pigment content in mycelia and secreted to the culture media as 1,8-dihydroxynaphthalene (DHN)-melanin type compound. This is sole melanin-type in M. fijiensis. Isolated melanins irradiated with a Nd:YAG laser at 532 nm produced monomol light emission at 1270 nm, confirming generation of O2 (1Δg), a highly reactive oxygen specie (ROS) that causes cellular death by reacting with all cellular macromolecules. Intermediary polyketides accumulated in culture media by using tricyclazole and pyroquilon (two inhibitors of DHN-melanin synthesis) were identified by ESI-HPLC-MS/MS. Additionally, irradiation at 532 nm of that mixture of compounds and whole melanized mycelium also generated O2 (1Δg). A pigmented-strain generated more O2 (1Δg) than a strain with low melanin content. Banana leaves of cultivar Cavendish, naturally infected with different stages of black Sigatoka disease, were collected from field. Direct staining of the naturally infected leaf tissues showed the presence of melanin that was positively correlated to the disease stage. We also found hydrogen peroxide (H2O2) but we cannot distinguish the source. Our results suggest that O2 (1Δg) photogenerated by DHN-melanin may be involved in the destructive effects of Mycosphaerella fijiensis on banana leaf tissues. Further studies are needed to fully evaluate contributions of melanin-mediated ROS to microbial pathogenesis.


The influence of environment on the shell structure of starch granules.
It is well known from light microscope studies of potato starch that the granules formed in a constant environment (of light and temperature) have a ring formation indistinguishable from that of granules formed under field conditions. Electron microscope studies have confirmed that normal potato starch granules have a fine shell structure not usually resolved by the light microscope, and also that shells do not develop in barley granules grown in a constant environment. The paper presented here reports a further study of the dependence of shell formation on environment. Potatoes were grown in a constant environment and starch granules from the newly formed tubers were examined in the light microscope, and in the electron microscope after corrosion by acid. No difference between these granules and normal granules was observed; both wide (light microscope) rings and fine lamellae developed in both granules. Parallel studies were made on wheat starch granules. In this case, shells were not differentiated in granules that developed in a constant environment, but they could be produced at will by imposing a dark period. Thus, shell formation in potato granules must be controlled by an endogenous rhythm, whereas in wheat granules it must be controlled by external environment.


Effect of semen characteristics on pregnancy rate in a gamete intrafallopian transfer program.
The aim of this study was to evaluate the influence of sperm morphology, swim-up concentration, and insemination volume on pregnancy outcome in patients undergoing gamete intrafallopian transfer (GIFT) treatment in whom the male partner had a morphology of less than 14%. Only patients who received four oocytes were entered into this study (n = 103). In all cases the swim-up procedure time was standardized to 1 h and the insemination concentration was standardized to 500,000 per oviduct. There was no significant difference in pregnancy rate when normal morphology, swim-up concentration, or insemination volume were used as predictors. In the P pattern group (< 4% normal forms) only four of the 28 (14%) patients had ongoing pregnancies, whereas in the G pattern group (5% to 14% normal forms) 16 out of 75 (21%) had ongoing pregnancies (P vs G, p > 0.05; not significant). The fertilization rate among excess oocytes in the P pattern group was 18% but was 39% (p < .0001) in the G pattern group. When an attempt was made to compensate for low morphology by increasing insemination concentration no significant difference in the pregnancy rate between the P and G pattern groups in the GIFT program was recorded. This was not the case when the in vitro fertilization rate was used as an endpoint. Insemination volume and swim-up concentration played no role in pregnancy rate.


Association of abdominal obesity, insulin resistance, and oxidative stress in adipose tissue in women with polycystic ovary syndrome.
To study the expression of insulin signaling-related genes and oxidative stress markers in the visceral adipose tissue obtained from polycystic ovary syndrome (PCOS) patients and healthy control subjects and to investigate the relationships among abdominal obesity, insulin resistance, and oxidative stress at the tissue level. Case-control study. University teaching hospital. In total, 30 PCOS patients and 30 healthy control subjects, who underwent laparoscopic surgery, were included in the study. Abdominal obesity was defined based on waist circumference (WC). The homeostasis model index was used to assess insulin resistance (HOMA-IR). Gene expression of glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS1) in visceral adipose tissue (VAT) and the parameters of oxidative stress, such as superoxide dismutase, enzyme glutathione reductase, and dimethylarginine, were measured, and the expression of protein oxidative damage product 3-nitro-tyrosine residues (nitrotyrosine) in VAT was identified with the use of immunohistochemistry. PCOS was associated with lower expression of GLUT4 and IRS1 and a higher level of oxidative stress in VAT, which was strongly correlated with WC and HOMA-IR. Presence of abdominal obesity further intensified the correlations observed in our measurements. The nitrotyrosine expression in VAT was stronger in PCOS patients. The strong correlation of insulin resistance with oxidative stress at the VAT level suggests that local oxidative stress and abnormalities of insulin signaling in adipose tissue play critical roles in the pathogenesis of PCOS.


[Validation of the Dutch Glasgow Anti- psychotic Side-Effect Scale for Clozapine].
To monitor the unique side effect pattern of clozapine, the Glasgow Antipsychotic Side-effect Scale for Clozapine (GASS-C) was developed in English and validated. This questionnaire was previously translated to Dutch, and revised, but not yet validated. The current study concerns the validation of the second revision of the GASS-C-NL-R2 for the Dutch language. Two Spearman correlation tests were conducted to compare GASS-C-NL-R2 with the Dutch version of the Liverpool University Neuroleptic Side-Effect Rating Scale (LUNSERS) at two time p´oints. There was one week between these two time points. The test-retest reliability was determined using a Spearman correlation test and Cronbach's alpha on the GASS-C-NL-R2 between the two time points. In addition, a factor analysis was performed. Spearman's correlation coefficient between the GASS-C-NL-R2 and the LUNSERS was 0.830 (p < 0.001, n = 72) at the first time point and 0.684 (p < 0.001, n = 50) at the second time point. GASS-C-NL-R2 also had a strong test-retest reliability: Spearman's correlation coefficient was 0.680 (p < 0.001; n = 46), and Cronbach's alpha was 0.847, n = 78. Factor analysis showed that all questions were relevant. The current study shows that GASS-C-NL-R2 is a valid and reliable questionnaire to monitor side effects related to clozapine with a relatively high prevalence. Future studies should focus on the practical utility of GASS-C-NL-R2 with a larger sample size.


Efficacy of glecaprevir and pibrentasvir treatment for genotype 1b hepatitis C virus drug resistance-associated variants in humanized mice.
Combination therapy with glecaprevir (GLE) and pibrentasvir (PIB) has high efficacy for pan-genotypic hepatitis C virus (HCV)-infected patients. However, the efficacy for patients who acquired potent NS5A inhibitor resistance-associated variants (RAVs) as a result of failure to respond to previous direct-acting antiviral (DAA) therapies is unclear. We investigated the efficacy of GLE/PIB treatment for genotype 1b HCV strains containing RAVs using subgenomic replicon systems and human hepatocyte transplanted mice. Mice were injected with serum samples obtained from a DAA-naïve patient or daclatasvir plus asunaprevir (DCV/ASV) treatment failures including NS5A-L31M/Y93H, -P58S/A92K or -P32 deletion (P32del) RAVs, then treated with GLE/PIB. HCV was eliminated by GLE/PIB treatment in mice with wild-type and NS5A-L31M/Y93H but relapsed in mice with NS5A-P58S/A92K, followed by emergence of additional NS5A mutations after cessation of the treatment. In NS5A-P32del-infected mice, serum HCV RNA remained positive during the GLE/PIB treatment. NS5A-P58S/A92K showed 1.5-fold resistance to PIB relative to wild-type based on analysis using HCV subgenomic replicon systems. When mice were administered various proportions of HCV wild-type and P32del strains and treated with GLE/PIB, serum HCV RNA remained positive in mice with high frequencies of P32del. In these mice, the P32del was undetectable by deep sequencing before GLE/PIB treatment, but P32del strains relapsed after cessation of the GLE/PIB treatment. GLE/PIB is effective for wild-type and NS5A-L31M/Y93H HCV strains, but the effect seems to be low for P58S/A92K and NS5A-P32del RAVs. Although NS5A-P32del was not detected, the mutation may be present at low frequency in DCV/ASV treatment failures.


A remarkable female cranium of the early Oligocene anthropoid Aegyptopithecus zeuxis (Catarrhini, Propliopithecidae).
The most complete and best-preserved cranium of a Paleogene anthropoid ever found, that of a small female of the early Oligocene ( approximately 29-30 Ma) stem catarrhine species Aegyptopithecus zeuxis, was recovered from the Jebel Qatrani Formation (Fayum Depression, Egypt) in 2004. The specimen is that of a subadult and, in craniodental dimensions, is the smallest Aegyptopithecus individual known. High-resolution computed tomographic (microCT) scanning of the specimen's well preserved cranial vault confirms that Aegyptopithecus had relatively unexpanded frontal lobes and a brain-to-body mass ratio lower than those of living anthropoids. MicroCT scans of a male cranium recovered in 1966 [Egyptian Geological Museum, Cairo (CGM) 40237] reveal that previous estimates of its endocranial volume were too large. Thus, some amount of encephalization evolved independently in platyrrhine and catarrhine anthropoids, and the relative brain size of the last common ancestor of crown Anthropoidea was probably strepsirrhine-like or smaller. A. zeuxis shows extreme sexual dimorphism in craniodental morphology (apparently to a degree otherwise seen only in some highly dimorphic Miocene catarrhines), and the crania of female Aegyptopithecus lack a number of morphological features seen in larger males that have been accorded phylogenetic significance in catarrhine systematics (e.g., a well developed rostrum, elongate sagittal crest, and frontal trigon). Although a unique pattern of craniofacial sexual dimorphism may have characterized advanced stem and basal crown catarrhines, expression of various allegedly "discrete" craniofacial features may have been intraspecifically variable in early catarrhine species due to high levels of dimorphism and so should be treated with caution in phylogenetic analyses.


Biomarkers of disease and treatment in murine and cynomolgus models of chronic asthma.
Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma. Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids. These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination.


Proximal aortic distensibility is an independent predictor of all-cause mortality and incident CV events: the MESA study.
The predictive value of ascending aortic distensibility (AAD) for mortality and hard cardiovascular disease (CVD) events has not been fully established. This study sought to assess the utility of AAD to predict mortality and incident CVD events beyond conventional risk factors in MESA (Multi-Ethnic Study of Atherosclerosis). AAD was measured with magnetic resonance imaging at baseline in 3,675 MESA participants free of overt CVD. Cox proportional hazards regression was used to evaluate risk of death, heart failure (HF), and incident CVD in relation to AAD, CVD risk factors, indexes of subclinical atherosclerosis, and Framingham risk score. There were 246 deaths, 171 hard CVD events (myocardial infarction, resuscitated cardiac arrest, stroke and CV death), and 88 HF events over a median 8.5-year follow-up. Decreased AAD was associated with increased all-cause mortality with a hazard ratio (HR) for the first versus fifth quintile of AAD of 2.7 (p = 0.008) independent of age, sex, ethnicity, other CVD risk factors, and indexes of subclinical atherosclerosis. Overall, patients with the lowest AAD had an independent 2-fold higher risk of hard CVD events. Decreased AAD was associated with CV events in low to intermediate- CVD risk individuals with an HR for the first quintile of AAD of 5.3 (p = 0.03) as well as with incident HF but not after full adjustment. Decreased proximal aorta distensibility significantly predicted all-cause mortality and hard CV events among individuals without overt CVD. AAD may help refine risk stratification, especially among asymptomatic, low- to intermediate-risk individuals.


Survey of transcripts expressed by the invasive juvenile stage of the liver fluke Fasciola hepatica.
The common liver fluke Fasciola hepatica is the agent of a zoonosis with significant economic consequences in livestock production worldwide, and increasing relevance to human health in developing countries. Although flukicidal drugs are available, re-infection and emerging resistance are demanding new efficient and inexpensive control strategies. Understanding the molecular mechanisms underlying the host-parasite interaction provide relevant clues in this search, while enlightening the physiological adaptations to parasitism. Genomics and transcriptomics are still in their infancy in F. hepatica, with very scarce information available from the invasive newly excysted juveniles (NEJ). Here we provide an initial glimpse to the transcriptomics of the NEJ, the first stage to interact with the mammalian host. We catalogued more than 500 clusters generated from the analysis of F. hepatica juvenile expressed sequence tags (EST), several of them not detected in the adult stage. A set of putative F. hepatica specific transcripts, and a group of sequences conserved exclusively in flatworms were identified. These novel sequences along with a set of parasite transcripts absent in the host genomes are putative new targets for future anti-parasitic drugs or vaccine development. Comparisons of the F. hepatica sequences with other metazoans genomes or EST databases were consistent with the basal positioning of flatworms in the bilaterian phylogeny. Notably, GC content, codon usage and amino acid frequencies are remarkably different in Schistosomes to F. hepatica and other trematodes. Functional annotation of predicted proteins showed a general representation of diverse biological functions. Besides proteases and antioxidant enzymes expected to participate in the early interaction with the host, various proteins involved in gene expression, protein synthesis, cell signaling and mitochondrial enzymes were identified. Differential expression of secreted protease gene family members between juvenile and adult stages may respond to different needs during host colonization. The knowledge of the genes expressed by the invasive stage of Fasciola hepatica is a starting point to unravel key aspects of this parasite's biology. The integration of the emerging transcriptomics, and proteomics data and the advent of functional genomics tools in this organism are positioning F. hepatica as an interesting model for trematode biology.


Antimony-Resistant Leishmania donovani Exploits miR-466i To Deactivate Host MyD88 for Regulating IL-10/IL-12 Levels during Early Hours of Infection.
Infection with antimony-resistant Leishmania donovani (Sb(R)LD) induces aggressive pathology in the mammalian hosts as compared with ones with antimony-sensitive L. donovani (Sb(S)LD) infection. Sb(R)LD, but not Sb(S)LD, interacts with TLR2/TLR6 to induce IL-10 by exploiting p50/c-Rel subunits of NF-κB in infected macrophages (Mϕs). Most of the TLRs exploit the universal adaptor protein MyD88 to activate NF-κB. We now show that infection of Mϕs from MyD88(-/-) mice with Sb(R)LD gave rise to significantly higher intracellular parasite number coupled with elevated IL-10/IL-12 ratio in the culture supernatant as compared with infection in wild type (WT) Mϕs. Τhese attributes were not seen with Sb(S)LD in similar experiments. Further, Sb(R)LD infection upregulated miR-466i, which binds with 3'-untranslated region, leading to the downregulation of MyD88. Infection of MyD88(-/-) Mϕ or IL-12(-/-) Mϕ with Sb(R)LD induced IL-10 surge at 4 h, whereas the same in WT Mϕ started from 12 h. Thus, absence of IL-12 in MyD88(-/-) mice favored early binding of NF-κB subunits to the IL-10 promoter, resulting in IL-10 surge. Infection of MyD88(-/-) mice with Sb(R)LD showed significantly higher organ parasites coupled with ill-defined and immature hepatic granulomas, whereas in WT mice there were less organ parasites and the granulomas were well defined. From the survival kinetics it was observed that Sb(R)LD-infected MyD88(-/-) mice died by 60 d postinfection, whereas the WT mice continued to survive. Our results demonstrate that Sb(R)LD has evolved a unique strategy to evade host antileishmanial immune repertoire by manipulating host MyD88 to its advantage.


The general L-amino acid permease of Rhizobium leguminosarum is an ABC uptake system that also influences efflux of solutes.
A general L-amino acid permease (Aap) from the ABC transporter family, encoded by four genes (aapJ, Q, M, P), has been cloned and characterized in Rhizobium leguminosarum. It transports a wide range of L-amino acids but has a preference for those with polar side-chains. A single binding protein of broad specificity (AapJ) is required for transport of all solutes. Unusually for an ABC transporter, Aap has both high affinity for and supports high rates of solute uptake. Genes for putative amino acid permeases with broad specificity for amino acids also exist in Escherichia coli and probably in Pseudomonas fluorescens, although the permease from E. coli does not appear to be expressed. Aap is an active uptake system that also affects the efflux of a broad range of amino acids. Efflux can be measured both as the loss of an intracellular amino acid after the addition of an excess of a homologous or heterologous amino acid, and as excretion of intracellularly synthesized glutamate. Mutation of Aap prevented efflux of intracellular amino acids caused by the addition of an extracellular heterologous amino acid, while overexpression increased the rates of such efflux. Furthermore, excretion of glutamate synthesized inside the cell was reduced by 76% in an aap strain. All four gene products, including the binding protein (AapJ), appear to be needed for efflux. Aap from R. leguminosarum expressed in E. coli also promoted efflux on addition of an extracellular heterologous amino acid. These results indicate either that Aap regulates an efflux channel/transporter or that solute has access to the translocation pathway of Aap from both sides of the membrane.


Electric-field control of single-molecule tautomerization.
The electric field is an important parameter to vary in a single-molecule experiment, because it can directly affect the charge distribution around the molecule. Yet, performing such an experiment with a well-defined electric field for a model chemical reaction at an interface has proven to be extremely difficult. Here, by combining a graphene field-effect transistor and a gate-tunable scanning tunneling microscope (STM), we reveal how this strategy enables the intramolecular H atom transfer of a metal-free macrocycle to be controlled with an external field. Experiments and theory both elucidate how the energetic barrier to tautomerization decreases with increasing electric field. The consistency between the two results demonstrates the potential in using electric fields to engineer molecular switching mechanisms that are ubiquitous in nanoscale electronic devices.


Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients.
BK polyomavirus (BKV or BKPyV) associated nephropathy affects up to 10% of kidney transplant recipients (KTRs). BKV isolates are categorized into four genotypes. It is currently unclear whether the four genotypes are also serotypes. To address this issue, we developed high-throughput serological assays based on antibody-mediated neutralization of BKV genotype I and IV reporter vectors (pseudoviruses). Neutralization-based testing of sera from mice immunized with BKV-I or BKV-IV virus-like particles (VLPs) or sera from naturally infected human subjects revealed that BKV-I specific serum antibodies are poorly neutralizing against BKV-IV and vice versa. The fact that BKV-I and BKV-IV are distinct serotypes was less evident in traditional VLP-based ELISAs. BKV-I and BKV-IV neutralization assays were used to examine BKV type-specific neutralizing antibody responses in KTRs at various time points after transplantation. At study entry, sera from 5% and 49% of KTRs showed no detectable neutralizing activity for BKV-I or BKV-IV neutralization, respectively. By one year after transplantation, all KTRs were neutralization seropositive for BKV-I, and 43% of the initially BKV-IV seronegative subjects showed evidence of acute seroconversion for BKV-IV neutralization. The results suggest a model in which BKV-IV-specific seroconversion reflects a de novo BKV-IV infection in KTRs who initially lack protective antibody responses capable of neutralizing genotype IV BKVs. If this model is correct, it suggests that pre-vaccinating prospective KTRs with a multivalent VLP-based vaccine against all BKV serotypes, or administration of BKV-neutralizing antibodies, might offer protection against graft loss or dysfunction due to BKV associated nephropathy.


Fellatio by fruit bats prolongs copulation time.
Oral sex is widely used in human foreplay, but rarely documented in other animals. Fellatio has been recorded in bonobos Pan paniscus, but even then functions largely as play behaviour among juvenile males. The short-nosed fruit bat Cynopterus sphinx exhibits resource defence polygyny and one sexually active male often roosts with groups of females in tents made from leaves. Female bats often lick their mate's penis during dorsoventral copulation. The female lowers her head to lick the shaft or the base of the male's penis but does not lick the glans penis which has already penetrated the vagina. Males never withdrew their penis when it was licked by the mating partner. A positive relationship exists between the length of time that the female licked the male's penis during copulation and the duration of copulation. Furthermore, mating pairs spent significantly more time in copulation if the female licked her mate's penis than if fellatio was absent. Males also show postcopulatory genital grooming after intromission. At present, we do not know why genital licking occurs, and we present four non-mutually exclusive hypotheses that may explain the function of fellatio in C. sphinx.


Search for monotop signatures in proton-proton collisions at √s=8 TeV.
Results are presented from a search for new decaying massive particles whose presence is inferred from an imbalance in transverse momentum and which are produced in association with a single top quark that decays into a bottom quark and two light quarks. The measurement is performed using 19.7 fb^{-1} of data from proton-proton collisions at a center-of-mass energy of 8 TeV, collected with the CMS detector at the CERN LHC. No deviations from the standard model predictions are observed and lower limits are set on the masses of new invisible bosons. In particular, scalar and vector particles, with masses below 330 and 650 GeV, respectively, are excluded at 95% confidence level, thereby substantially extending a previous limit published by the CDF Collaboration.


Hepatitis B infection among dental personnel in Pune & Bombay (India).
To assess the risk of hepatitis B infection among dental personnel, serum samples were collected from dentists of Pune and students, staff, auxiliary staff and class D staff of a dental college in Bombay. Dentists (32.02%), dental auxiliary staff (35.89%), clinical assistants and post-graduate students (19.56%) were found to have significantly higher prevalence of HBV infection as compared to undergraduate dental students (3.94%). The prevalence of HBV infection was high among the dentists as compared to voluntary donors. A positive linear association was observed in the positivity of HBV seromarkers with increasing age and number of years spent by the workers in the dental environment. The rate of increase in HBV seropositivity with age was higher (P less than 0.05) among dental personnel when compared to voluntary donors. Vaccination against hepatitis B is recommended for all the dental students before they start their clinical phase and for susceptible dentists and dental auxillary staff.


Brain glutamate concentration in men with early psychosis: a magnetic resonance spectroscopy case-control study at 7 T.
Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.


Interplay between DNA repair and inflammation, and the link to cancer.
DNA damage and repair are linked to cancer. DNA damage that is induced endogenously or from exogenous sources has the potential to result in mutations and genomic instability if not properly repaired, eventually leading to cancer. Inflammation is also linked to cancer. Reactive oxygen and nitrogen species (RONs) produced by inflammatory cells at sites of infection can induce DNA damage. RONs can also amplify inflammatory responses, leading to increased DNA damage. Here, we focus on the links between DNA damage, repair, and inflammation, as they relate to cancer. We examine the interplay between chronic inflammation, DNA damage and repair and review recent findings in this rapidly emerging field, including the links between DNA damage and the innate immune system, and the roles of inflammation in altering the microbiome, which subsequently leads to the induction of DNA damage in the colon. Mouse models of defective DNA repair and inflammatory control are extensively reviewed, including treatment of mouse models with pathogens, which leads to DNA damage. The roles of microRNAs in regulating inflammation and DNA repair are discussed. Importantly, DNA repair and inflammation are linked in many important ways, and in some cases balance each other to maintain homeostasis. The failure to repair DNA damage or to control inflammatory responses has the potential to lead to cancer.


BIX01294 suppresses osteoclast differentiation on mouse macrophage-like Raw264.7 cells.
Gene expressionis controlled by epigenetic mechanisms including histone methylation. Osteoclasts are bone-resorptive cells that differentiate from hematopoietic-precursor cells by receptor activator of nuclear factor-κB ligand (RANKL) stimulation. Although BIX01294, a specific inhibitor of G9a, which works as a histone H3 lysine 9 (H3K9) methyltransferase, reportedly changes cellular differentiational stage, its effect on osteoclast differentiation is unclear. In this study, the effects of BIX01294 on osteoclast differentiation were examined. Here, we showed that BIX01294 dose-dependently reduced RANKL-induced tartrate-resistant acid phosphatase positive multinuclear osteoclast-like cell differentiation from murine macrophage-like Raw264.7 cells. During differentiation, growth rates reduced only less than 14% of those of cells stimulated with RANKL alone by BIX01294 treatment. Moreover, western blot analysis showed that BIX01294 reduced RANKL-induced carbonic anhydrase II and cathepsin K production and decreased RANKL-induced nuclear factor of activated T-cell c1, a master regulatory transcription factor, production during osteoclast differentiation. These results suggest that BIX01294 suppresses RANKL-induced osteoclast differentiation. This is the first report about the effect of BIX01294 on osteoclast differentiation.


Fabrication and characterization of nanostructured porous silicon-silver composite layers by cyclic deposition: dip-coating vs spin-coating.
Composites of nanostructured porous silicon and silver (nPSi-Ag) have attracted great attention due to the wide spectrum of applications in fields such as microelectronics, photonics, photocatalysis and bioengineering, Among the different methods for the fabrication of nanostructured composite materials, dip and spin-coating are simple, versatile, and cost-effective bottom-up technologies to provide functional coatings. In that sense, we aimed at fabricating nPSi-Ag composite layers. Using nPSi layers with pore diameter of 30 nm, two types of thin-film techniques were systematically compared: cyclic dip-coating (CDC) and cyclic spin-coating (CSC). CDC technique formed a mix of granular and flake-like structures of metallic Ag, and CSC method favored the synthesis of flake-like structures with Ag and Ag2O phases. Flakes obtained by CDC and CSC presented a width of 110 nm and 70 nm, respectively. Particles also showed a nanostructure surface with features around 25 nm. According to the results of EDX and RBS, integration of Ag into nPSi was better achieved using the CDC technique. SERS peaks related to chitosan adsorbed on Ag nanostructures were enhanced, especially in the nPSi-Ag composite layers fabricated by CSC compared to CDC, which was confirmed by FTDT simulations. These results show that CDC and CSC produce different nPSi-Ag composite layers for potential applications in bioengineering and photonics.


Halofuginone stimulates adaptive remodeling and preserves re-endothelialization in balloon-injured rat carotid arteries.
Three major processes, constrictive vessel remodeling, intimal hyperplasia (IH), and retarded re-endothelialization, contribute to restenosis after vascular reconstructions. Clinically used drugs inhibit IH but delay re-endothelialization and also cause constrictive remodeling. Here we have examined halofuginone, an herbal derivative, for its beneficial effects on vessel remodeling and differential inhibition of IH versus re-endothelialization. Two weeks after perivascular application to balloon-injured rat common carotid arteries, halofuginone versus vehicle (n=6 animals) enlarged luminal area 2.14-fold by increasing vessel size (adaptive remodeling; 123%), reducing IH (74.3%) without inhibiting re-endothelialization. Consistent with its positive effect on vessel expansion, halofuginone reduced collagen type 1 (but not type 3) production in injured arteries as well as that from adventitial fibroblasts in vitro. In support of its differential effects on IH versus re-endothelialization, halofuginone produced greater inhibition of vascular smooth muscle cell versus endothelial cell proliferation at concentrations ≈50 nmol/L. Furthermore, halofuginone at 50 nmol/L effectively blocked Smad3 phosphorylation in smooth muscle cells, which is known to promote smooth muscle cell proliferation, migration, and IH, but halofuginone had no effect on phospho-Smad3 in endothelial cells. Periadventitial delivery of halofuginone dramatically increased lumen patency via adaptive remodeling and selective inhibition of IH without affecting endothelium recovery. Halofuginone is the first reported small molecule that has favorable effects on all 3 major processes involved in restenosis.


The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years.
We investigated the effects of head growth prenatally, during infancy, and during later periods of development on cognitive function at the ages of 4 and 8 years. We studied 633 term-born children from the Avon Longitudinal Study of Parents and Children cohort whose head circumference was measured at birth and at regular intervals thereafter. Their cognitive function was assessed with the Wechsler Preschool and Primary Scale of Intelligence at the age of 4 years and with the Wechsler Intelligence Scale for Children at the age of 8 years. Linear regression analysis was used to calculate postnatal head growth between successive time points, conditional on previous size, and to examine the relationship between head growth during different periods of development and later IQ. When the influence of head growth was distinguished for different periods, only prenatal growth and growth during infancy were associated with subsequent IQ. At 4 years, after adjustment for parental characteristics, full-scale IQ increased an average of 2.41 points for each 1-SD increase in head circumference at birth and 1.97 points for each 1-SD increase in head growth during infancy, conditional on head size at birth. At 8 years, head circumference at birth was no longer associated with IQ, but head growth during infancy remained a significant predictor, with full-scale IQ increasing an average of 1.56 points for each 1-SD increase in growth. The brain volume a child achieves by the age of 1 year helps determine later intelligence. Growth in brain volume after infancy may not compensate for poorer earlier growth.


Medical science, culture, and truth.
There is a fairly closed circle between culture, language, meaning, and truth such that the world of a given culture is a world understood in terms of the meanings produced in that culture. Medicine is, in fact, a subculture of a powerful type and has its own language and understanding of the range of illnesses that affect human beings. So how does medicine get at the truth of people and their ills in such a way as to escape its own limited constructions? There is a way out of the closed circle implicit in the idea of a praxis and the engagement with reality that is central to it and the further possibility introduced by Jacques Lacan that signification is never comprehensive in relation to the subject's encounter with the real. I will explore both of these so as to develop a conception of truth that is apt for the knowledge that arises in the clinic.


A combinational treatment of carotenoids decreases Aβ secretion in human neurons via β-secretase inhibition.
Alzheimer's disease (AD) is the most common cause of dementia and is characterized neuropathologically by the presence of amyloid plaques and neurofibrillary tangles. Amyloid-β (Aβ) peptides, major components of amyloid plaques and crucial pathogenic molecules in terms of the amyloid hypothesis, are derived from successive proteolytic processing of amyloid-β precursor protein (APP). In this study, we established a human neuronal culture system using induced pluripotent stem cells (iPSCs) to evaluate the possible effects of natural compounds on the amyloid phenotype. Unexpectedly, we found that combinational treatment of carotenoids, but not docosahexaenoic acid, significantly decreased Aβ secretion from iPSC-derived human cortical neurons. Importantly, the effects of the carotenoids resulted from specific inhibition of BACE1 activity and not from expression changes in APP or BACE1. Therefore, these results indicate a novel beneficial function of carotenoids in the anti-amyloidogenic processing of APP. Collectively, this study will shed light on neuronal protection by a novel mechanism during the pathogenesis of AD.


Inferior vena caval pressure increase contributes to sodium and water retention during PEEP in awake dogs.
This study compared the hemodynamic, renal, and hormonal effects of an experimentally induced increase in inferior vena caval pressure (IVCP) [to the same extent as during controlled mechanical ventilation (CMV) with positive end-expiratory pressure (PEEP)] with those of CMV with PEEP. Six volume-expanded conscious chronically tracheotomized dogs were studied under three conditions: 4 h of spontaneous breathing at 4 cmH2O continuous positive airway pressure (CPAP); CMV: CPAP for the 1st and 4th h and CMV with PEEP for the 2nd and 3rd h, resulting in a mean airway pressure of 20 cmH2O; and Increased IVCP: 4 h of CPAP, with IVCP increased during the 2nd and 3rd h by inflation of a chronically implanted cuff. Urine volume, sodium excretion, and fractional sodium excretion decreased during the 2nd and 3rd h of CMV and during increased IVCP compared with CONTROL. Glomerular filtration rate, mean arterial pressure, and antidiuretic hormone, atrial natriuretic peptide, and aldosterone plasma concentrations were not affected by CMV or Increased IVCP. Plasma renin activity decreased during CONTROL and Increased IVCP conditions but remained elevated during the 2nd and 3rd h of CMV. We conclude that, in conscious extracellular volume-expanded dogs, IVCP elevation contributes considerably to the water- and sodium-retaining effect of short-term CMV with PEEP.


Prevalence of caries among preschool-aged children in a northern Manitoba community.
Early childhood caries (ECC) is a devastating form of dental decay affecting many Canadian children, especially those from northern First Nations communities. ECC is multifactorial in origin, and the notion that the principal etiology is inappropriate feeding modalities is no longer tenable. This study was conducted in the community of Garden Hill First Nation, Manitoba, to assess the prevalence of dental decay in young children, to assess risk factors for ECC and to determine the influence of vitamin D supplementation (a modified form of stosstherapy using 100,000 IU vitamin D), both prenatally and at 6 weeks of age, on the oral health of children. The study involved a cross-sectional dental examination of children, an interview with mothers and a maternal chart review. A total of 98 children participated: their mean age was 46.4 +/- 6.3 months. The mean number of decayed, extracted and filled teeth (deft) was 13.7 +/- 3.2. Caries rates were significantly greater among children who had had sugar added to the feeding bottle. Behaviours typically associated with ECC and caries activity, such as poor oral hygiene and late weaning from the bottle, were also exhibited among residents. Although 50% of children had enamel hypoplasia, no statistically significant differences in the amount of enamel hypoplasia and caries were found between those who received modified stosstherapy and those who did not. Not receiving stosstherapy was associated with later eruption time of the first primary tooth (7.2 vs. 5.0 months). Interviews revealed that, during pregnancy, many of the mothers only infrequently consumed foods rich in calcium and vitamin D, elements that are essential to the development of strong bones and teeth. The mean deft for these First Nations preschoolers was high and 50% had enamel defects. Although daily vitamin D supplementation of 400 IU during pregnancy has been known to reduce primary tooth enamel defects, the supplementation previously administered to participants in this study was not found to result in reduced enamel defects or caries. The high caries burden among children from this community reveals the need for effective prevention methods. It is important for pediatricians, family physicians and other health service providers encountering very young children and expectant mothers to be cognizant of ECC and its ramifications, as their education efforts represent the first line of defence.


A mixed methods study to evaluate the feasibility of using the Adolescent Diabetes Needs Assessment Tool App in paediatric diabetes care in preparation for a longitudinal cohort study.
An evaluation study was carried out to determine the feasibility of integrating the Adolescent Diabetes Needs Assessment Tool (ADNAT) App into UK paediatric diabetes care, to ascertain best practice standards and to determine methodological recommendations for a future cohort study. A non-randomised, cohort, mixed methods study design was used to ensure equality of access to ADNAT for all participants at three sites in the North West of England. Following UK Medical Research Council guidance, the RE-AIM (reach, effectiveness (potential and perceived), adoption, implementation, maintenance) framework was used to guide study objectives and feasibility outcomes. Patients who completed ADNAT (completers) were compared with those who failed to complete (non-completers). Patients' glycaemic control (HbA1c) was accessed from their clinical data at baseline and at 6 months, alongside their ADNAT scores which were correlated with changes in HbA1c levels. The diabetes teams (respondents) completed a web-based survey and attended focus group interviews. Eighty-nine patients were recruited. Withdrawal rates were low at 4.5% (n = 4). Forty-four patients (49.4%) completed ADNAT, leaving 45 (50.6%) non-completers. There were large baseline differences in HbA1c and variable rates of change at 6 months. After adjusting for baseline HbA1C and site in an analysis of covariance, completers had a lower post-ADNAT mean HbA1C level than non-completers at 6 months (-5.42 mmol/mol, 95% CI -11.48, 0.64). Patients' glycaemic control (HbA1c) at 6 months correlated reasonably well with their ADNAT scores (Spearman's rho = 0.46). Survey and focus group data showed that ADNAT was judged to be an effective clinical tool by the diabetes teams. Value to patients was perceived by the teams to be linked to parental support, age and previous diabetes education. The combined data triangulated. It served to capture different dimensions which were used to define changes to achieve practice standards and methodological recommendations. The combined data showed that ADNAT has the potential to be a clinically viable tool. It has demonstrated the need for a randomised design that is tailored for a 'hard to reach' adolescent population. A cluster randomised controlled trial that involves sequential but random rollout of ADNAT over multiple time periods may be the most appropriate and is currently being considered for the larger study. NIHR Children's Clinical Research Network, UKCRN ID 6633.


High-intensity interval training versus moderate-intensity steady-state training in UK cardiac rehabilitation programmes (HIIT or MISS UK): study protocol for a multicentre randomised controlled trial and economic evaluation.
Current international guidelines for cardiac rehabilitation (CR) advocate moderate-intensity exercise training (MISS, moderate-intensity steady state). This recommendation predates significant advances in medical therapy for coronary heart disease (CHD) and may not be the most appropriate strategy for the 'modern' patient with CHD. High-intensity interval training (HIIT) appears to be a safe and effective alternative, resulting in greater improvements in peak oxygen uptake (VO2 peak). To date, HIIT trials have predominantly been proof-of-concept studies in the laboratory setting and conducted outside the UK. The purpose of this multicentre randomised controlled trial is to compare the effects of HIIT and MISS training in patients with CHD attending UK CR programmes. This pragmatic study will randomly allocate 510 patients with CHD to 8 weeks of twice weekly HIIT or MISS training at 3 centres in the UK. HIIT will consist of 10 high-intensity (85-90% peak power output (PPO)) and 10 low-intensity (20-25% PPO) intervals, each lasting 1 min. MISS training will follow usual care recommendations, adhering to currently accepted UK guidelines (ie, >20 min continuous exercise at 40-70% heart rate reserve). Outcome measures will be assessed at baseline, 8 weeks and 12 months. The primary outcome for the trial will be change in VO2 peak as determined by maximal cardiopulmonary exercise testing. Secondary measures will assess physiological, psychosocial and economic outcomes. The study protocol V.1.0, dated 1 February 2016, was approved by the NHS Health Research Authority, East Midlands-Leicester South Research Ethics Committee (16/EM/0079). Recruitment will start in August 2016 and will be completed in June 2018. Results will be published in peer-reviewed journals, presented at national and international scientific meetings and are expected to inform future national guidelines for exercise training in UK CR. NCT02784873; pre-results.


Routine Amoxicillin for Uncomplicated Severe Acute Malnutrition in Children.
High-quality evidence supporting a community-based treatment protocol for children with severe acute malnutrition, including routine antibiotic use at admission to a nutritional treatment program, remains limited. In view of the costs and consequences of emerging resistance associated with routine antibiotic use, more evidence is required to support this practice. In a double-blind, placebo-controlled trial in Niger, we randomly assigned children who were 6 to 59 months of age and had uncomplicated severe acute malnutrition to receive amoxicillin or placebo for 7 days. The primary outcome was nutritional recovery at or before week 8. A total of 2412 children underwent randomization, and 2399 children were included in the analysis. Nutritional recovery occurred in 65.9% of children in the amoxicillin group (790 of 1199) and in 62.7% of children in the placebo group (752 of 1200). There was no significant difference in the likelihood of nutritional recovery (risk ratio for amoxicillin vs. placebo, 1.05; 95% confidence interval [CI], 0.99 to 1.12; P=0.10). In secondary analyses, amoxicillin decreased the risk of transfer to inpatient care by 14% (26.4% in the amoxicillin group vs. 30.7% in the placebo group; risk ratio, 0.86; 95% CI, 0.76 to 0.98; P=0.02). We found no benefit of routine antibiotic use with respect to nutritional recovery from uncomplicated severe acute malnutrition in Niger. In regions with adequate infrastructure for surveillance and management of complications, health care facilities could consider eliminating the routine use of antibiotics in protocols for the treatment of uncomplicated severe acute malnutrition. (Funded by Médecins sans Frontières Operational Center Paris; ClinicalTrials.gov number, NCT01613547.).


Immunologic mechanisms in the pathogenesis of rheumatoid arthritis.
Although much is known about the etiology and pathogenesis of rheumatoid arthritis (RA), our understanding of the immune pathways remains incomplete. The observed clinical and pathologic manifestations result from activation of several interrelated immune pathways. Current concepts of RA pathogenesis, supported by animal models, laboratory studies, and clinical observation, have reestablished and revised some of the original views. Early proposals emphasized the importance of autoantibodies and immune complexes in the initiation of RA, suggested a role for T cells in the inflammatory response characteristic of RA, and based disease perpetuation on an imbalance in the cytokine networks. We now recognize that each of these interrelated mechanisms significantly contributes to RA pathogenesis, including T cells that can help initiate and perpetuate the disease. This article reviews the major components and immune pathways involved in RA and briefly discusses the animal models that contribute to our understanding. Although a unified theory of RA pathogenesis may not be possible at this time, a paradigm is presented that considers the immune pathways that contribute to disease progression and joint destruction. These pathways may have important implications for treatment, because their modulation by biologic response modifiers (BRMs) directed toward specific targets provides benefits to patients with RA. BRMs are a new class of therapeutic agents derived from biologically active molecules and designed to modulate specific immune or inflammatory pathways. Although currently approved BRMs still have limitations, choosing an appropriate target, possibly early rather than late in the immune response, might result in new and improved therapies for RA.


Association of anxiety and depression with physical and sensory functional difficulties in adults in five population-based surveys in low and middle-income countries.
The aim of this study was to assess the association between anxiety and depression with physical and sensory functional difficulties, among adults living in five low and middle-income countries (LMICs). A secondary data analysis was undertaken using population-based disability survey data from five LMICs, including two national surveys (Guatemala, Maldives) and 3 regional/district surveys (Nepal, India, Cameroon). 19,337 participants were sampled in total (range 1,617-7,604 in individual studies). Anxiety, depression, and physical and sensory functional difficulties were assessed using the Washington Group Extended Question Set on Functioning. Age-sex adjusted logistic regression analyses were undertaken to assess the association of anxiety and depression with hearing, visual or mobility functional difficulties. The findings demonstrated an increased adjusted odds of severe depression and severe anxiety among adults with mobility, hearing and visual functional difficulties in all settings (with ORs ranging from 2.0 to 14.2) except for in relation to hearing loss in India, the Maldives and Cameroon, where no clear association was found. For all settings and types of functional difficulties, there was a stronger association with severe anxiety and depression than with moderate. Both India and Cameroon had higher reported prevalences of physical and sensory functional difficulties compared with Nepal and Guatemala, and weaker associations with anxiety and depression. People with physical and sensory functional difficulties are more likely to report experiencing depression and anxiety. This evidence supports the need for ensuring a good awareness of mental health among those working with individuals with physical and sensory functional difficulties in LMICs. This implies that these practitioners must have the skills to identify anxiety and depression. Furthermore, mental health services must be available and accessible to patients with these conditions, which will likely require further programmatic scale-up in these LMIC settings.


Trends and inequalities in stunting in Nepal: a secondary data analysis of four Nepal demographic health surveys from 2001 to 2016.
The rate of stunting in Nepal is among the highest in the world, which is a major public health problem. The objective of this study was to present data on stunting prevalence according to socio-demographic and geographical circumstances and to determine the impact of those circumstances on the risk of stunting. Data from Nepal Demographic and Health Surveys were used with the study population of children under 5 years old. The prevalence of stunting was determined by descriptive analysis and logistic regression analysis was used to determine risk factors for stunting. The prevalence of stunting has declined in overall as well as in all groups and subgroups analysed. The percentage of stunted children from 2001 to 2016 decreased by 18 and 10.7% in the rural and urban areas respectively. The unadjusted analysis depicted association between stunting and children living in rural areas since children living in rural areas had higher odds of being stunted compared to their urban counterparts. However, the association was no longer observed when adjusted for other variables included in this study. Children born to mothers without any education had 2.27 (95% CI 1.70-3.05), 5.222 (95% CI 2.54-10.74), 1.81 (95% CI 0.92-3.55) and 1.92 (95% CI 1.28-2.89) odds of being stunted than those born to mothers with higher education for the year 2001, 2006, 2011 and 2016 respectively in the adjusted analysis. Similarly, children belonging to the poorest wealth quintile had 1.90 (95% CI 1.55-2.33), 1.87 (95% CI 1.36-2.58), 2.47 (95% CI 1.51-4.02) and 4.18 (95% CI 2.60-6.71) odds of being stunted than those belonging to the richest quintile in 2001, 2006, 2011 and 2016 respectively. The association between stunting and wealth quintile depicting children belonging to the poorest and poorer wealth quintile having higher odds of being stunted remain the same in both unadjusted and adjusted analysis. At national level, stunting is decreasing in Nepal; however, the prevalence of stunting is different between groups and subgroups analysed. The substantial inequalities in stunting have been preserved. Therefore, special emphasis should be given to vulnerable groups such as children belonging to the poorest and poorer wealth quintile instead of using blanket approach for delivering nutrition interventions. A balanced approach to nutritional inequalities prevalent across different regions and subgroups is required.


Impact of left ventricular function on health-related quality of life in coronary artery disease patients.
The aim of the study was to investigate the relation between health-related quality of life (HRQoL) and left ventricular systolic and diastolic function parameters in stable coronary artery disease (CAD) patients with mild and moderate heart failure. This study included 758 CAD patients. Left ventricular ejection fraction (LVEF) and ratio of peak velocities of early (E) and late (A) diastolic mitral inflow, ratio E/A, deceleration time, isovolumic relaxation time were assessed. Patients completed the SF-36 questionnaire. There were no strong and significant associations between echocardiographic measures and HRQoL in NYHA I-II class patients. In NYHA III class in univariate linear regression analyses significant associations were found between LVEF and physical functioning (β=0.230, P=0.009) and role limitations due to physical problems (β=0.230, P=0.009) and these associations remain significant after adjustment for age, gender, hypertension, angina pectoris class, nitrate, ACE inhibitors and diuretics use. E/A ratio was significantly associated only with mental health domain (β=0.188, P=0.048), and this association remains significant after all adjustments. In stable CAD patients with NYHA I-II functional class HRQoL was not strongly associated with left ventricular function; in NYHA III functional class patients' greater systolic function mainly was associated with better physical health and better diastolic function, with better mental health.


Optically tunable microcavity in a planar photonic crystal silicon waveguide buried in oxide.
We present all-optical tuning and switching of a microcavity inside a two-dimensional photonic crystal waveguide. The photonic crystal structure is fabricated in silicon-on-insulator using complementary metal-oxide semiconductor processing techniques based on deep ultraviolet lithography and is completely buried in a silicon dioxide cladding that provides protection from the environment. By focusing a laser onto the microcavity region, both a thermal and a plasma dispersion effect are generated, allowing tuning and fast modulation of the in-plane transmission. By means of the temporal characteristics of the in-plane transmission, we experimentally identify a slower thermal and a fast plasma dispersion effect with modulation bandwidths of the order of several 100 kHz and up to the gigahertz level, respectively.


The Effect of Age, Sex, Area Deprivation, and Living Arrangements on Total Knee Replacement Outcomes: A Study Involving the United Kingdom National Joint Registry Dataset.
Total knee replacement (TKR) is a common procedure for the treatment of osteoarthritis that provides a substantial reduction of knee pain and improved function in most patients. We investigated whether sociodemographic factors could explain variations in the benefit resulting from TKR. Data were collected from 3 sources: the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man; National Health Service (NHS) England Patient Reported Outcome Measures; and Hospital Episode Statistics. These 3 sources were linked for analysis. Pain and function of the knee were measured with use of the Oxford Knee Score (OKS). The risk factors of interest were age group, sex, deprivation, and social support. The outcomes of interest were sociodemographic differences in preoperative scores, 6-month postoperative scores, and change in scores. Ninety-one thousand nine hundred and thirty-six adults underwent primary TKR for the treatment of osteoarthritis in an NHS England unit from 2009 to 2012. Sixty-six thousand seven hundred and sixty-nine of those patients had complete knee score data and were included in the analyses for the present study. The preoperative knee scores were worst in female patients, younger patients, and patients from deprived areas. At 6 months postoperatively, the mean knee score had improved by 15.2 points. There were small sociodemographic differences in the benefit of surgery, with greater area deprivation (-0.71 per quintile of increase in deprivation; 95% confidence interval [CI], -0.76 to -0.66; p < 0.001) and younger age group (-3.51 for ≤50 years compared with 66 to 75 years; 95% CI, -4.00 to -3.02; p < 0.001) associated with less benefit. Cumulatively, sociodemographic factors explained <1% of the total variability in improvement. Sociodemographic factors have a small influence on the benefit resulting from TKR. However, as they are associated with the clinical threshold at which the procedure is performed, they do affect the eventual outcomes of TKR. Prognostic Level IV. See Instructions for Authors for a complete description of evidence.


The effects of prolonged wear of textured shoe insoles on gait, foot sensation and proprioception in people with multiple sclerosis: study protocol for a randomised controlled trial.
Many people with multiple sclerosis experience problems with walking, which can make daily activities difficult and often leads to falls. Foot sensation plays an important role in keeping the body balanced whilst walking; however, people with multiple sclerosis often have poor sensation on the soles of their feet. Wearing a specially designed shoe insole, which enhances plantar sensory information, could help people with multiple sclerosis to walk better. This study will explore whether long-term wear of a textured insole can improve walking in people with multiple sclerosis. A prospective randomised controlled trial with two parallel groups will be conducted aiming to recruit 176 people with multiple sclerosis living in the community (Brisbane, Australia). Adults with a clinical diagnosis of multiple sclerosis, Disease Steps score 1-4, who are ambulant over 100 m and who meet specific inclusion criteria will be recruited. Participants will be randomised to a smooth control insole (n = 88) or textured insole (n = 88) group. The allocated insole will be worn for 12-weeks within participants' own footwear, with self-report wear diaries and falls calendars being completed over this period. Blinded assessors will conduct two baseline assessments and one post-intervention assessment. Gait tasks will be completed barefoot, wearing standardised footwear only, and wearing standardised footwear with smooth and textured insoles. The primary outcome measure will be mediolateral base of support when walking over even and uneven surfaces. Secondary measures include spatiotemporal gait parameters (stride length, stride time variability, double-limb support time, velocity), gait kinematics (hip, knee, and ankle joint angles, toe clearance, trunk inclination, arm swing, mediolateral pelvis/head displacement), foot sensation (light touch-pressure, vibration, two-point discrimination) and proprioception (ankle joint position sense). Group allocation will be concealed and all analyses will be based on an intention-to-treat principle. This study will explore the effects of wearing textured insoles over 12-weeks on gait, foot sensation and proprioception in people with multiple sclerosis. The study has the potential to identify a new, evidence-based footwear intervention which has the capacity to enhance mobility and independent living in people with multiple sclerosis. Australian New Zealand Clinical Trials Registry ACTRN12615000421538 . Registered 4 May 2015.


Circulating Metabolic Biomarkers of Screen-Detected Prostate Cancer in the ProtecT Study.
Whether associations between circulating metabolites and prostate cancer are causal is unknown. We report on the largest study of metabolites and prostate cancer (2,291 cases and 2,661 controls) and appraise causality for a subset of the prostate cancer-metabolite associations using two-sample Mendelian randomization (MR). The case-control portion of the study was conducted in nine UK centers with men ages 50-69 years who underwent prostate-specific antigen screening for prostate cancer within the Prostate Testing for Cancer and Treatment (ProtecT) trial. Two data sources were used to appraise causality: a genome-wide association study (GWAS) of metabolites in 24,925 participants and a GWAS of prostate cancer in 44,825 cases and 27,904 controls within the Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Thirty-five metabolites were strongly associated with prostate cancer (P < 0.0014, multiple-testing threshold). These fell into four classes: (i) lipids and lipoprotein subclass characteristics (total cholesterol and ratios, cholesterol esters and ratios, free cholesterol and ratios, phospholipids and ratios, and triglyceride ratios); (ii) fatty acids and ratios; (iii) amino acids; (iv) and fluid balance. Fourteen top metabolites were proxied by genetic variables, but MR indicated these were not causal. We identified 35 circulating metabolites associated with prostate cancer presence, but found no evidence of causality for those 14 testable with MR. Thus, the 14 MR-tested metabolites are unlikely to be mechanistically important in prostate cancer risk. The metabolome provides a promising set of biomarkers that may aid prostate cancer classification.


Evaluation of quality of life/life satisfaction in women with breast cancer in complementary and conventional care.
The aim was to study the perceived quality of life/life satisfaction in a sample of women with breast cancer who were treated in a hospital with alternative/complementary care and the same variables in individually matched patients who received only conventional medical treatment. A non-randomized controlled trial design with repeated measurements was used. Sixty women with breast cancer treated with anthroposophic medicine (ABCW) and 60 with conventional medicine (CBCW) were included and 36 matched pairs took part on all occasions. The quality of life was measured by the EORTC QLQ-C30 and the Life Satisfaction Questionnaire (LSQ). The comparisons were calculated as effect sizes (ES). The women in the ABCW group reported small or moderate effects, expressed as ES, on their quality of life/life satisfaction compared to their matched "twins" in the CBCW group at the 1-year follow-up in 15 out of 21 scales/factors. It was concluded that the women who had chosen anthroposophic care increased their perceived quality of life/life satisfaction according to the methodology of the study.


The effects of whole body vibration on mobility and balance in Parkinson disease: a systematic review.
Whole body vibration (WBV) is a contemporary treatment modality that holds promise as an exercise training method in health-compromised individuals. A growing number of studies on individuals with Parkinson Disease are examining whether WBV improves balance and functional mobility. However, interpreting WBV studies is challenging since there is variability in the manner in which WBV intervention is conducted. The primary goal of this systematic review was to investigate the effect of WBV on improving mobility and balance as measured by a battery of clinical tests, in patients with Parkinson disease. Studies based on WBV parameters were characterized and a systematic search of peer-reviewed literature in five major databases was conducted. Randomized-controlled trials investigating the effects of WBV in patients with a Parkinson diagnosis and no cognitive impairment were included. A total of six publications met the inclusion criteria. Overall, studies demonstrated mixed results in favor of WBV for improving balance or mobility. The majority of studies seem to suggest a favorable benefit following WBV for mobility and balance, but not when compared to other active intervention or placebo. There was variability in the manner in which WBV intervention was applied. Variations among the six studies included: duration of intervention and rest, follow-up period, type of control groups, frequency of vibration, number of treatment sessions and sex distribution of subjects. Future research is needed to investigate the effects of different types of equipment and treatment dosage in individuals with Parkinson disease.


Inhibition of renal outer medullary 20-HETE production produces hypertension in Lewis rats.
Recent studies have indicated that a deficiency in the production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the outer medulla of the kidney may contribute to the abnormalities in the renal handling of sodium and the development of hypertension in Dahl salt-sensitive rats. To determine whether a reduction in 20-HETE production in the outer medulla is sufficient to induce hypertension, an inhibitor of the renal metabolism of arachidonic acid by P450 enzymes, 17-octadecenoic acid (17-ODYA), was chronically infused directly into the outer medulla of the left kidney of uninephrectomized Lewis rats fed a high salt diet. Renal medullary interstitial infusion of 17-ODYA (400 pmol/min) reduced the formation of 20-HETE in the outer medulla of the infused kidney by 70% compared with values seen in the right kidney collected when the rat was uninephrectomized, but it had no effect on the production of 20-HETE in the renal cortex. After 5 days, mean arterial pressure rose from 115 +/- 2 to 142 +/- 2 mm Hg (n = 6) in the rats infused with 17-ODYA, while mean arterial pressure was not significantly altered in the rats infused with vehicle alone (116 +/- 1 versus 117 +/- 2 mm Hg, n = 6). These results suggest that inhibition of the renal metabolism of arachidonic acid by P450 enzymes in the outer medulla of the kidney is sufficient to induce the development of hypertension in Lewis rats fed a high salt diet and support the view that P450 metabolites of arachidonic acid play an important role in the regulation of renal function and the long-term control of arterial pressure.


Systemic effects of epidural steroid injections.
The aim of this study was to review all the published articles in the English language literature regarding the systemic effects of epidural corticosteroid injections (ESIs) in humans. ESIs are among the procedures that are most commonly used to manage chronic back pain. However, there has been no conclusive review on the systemic effects of this popular procedure. Reports were searched for in MEDLINE and EMBASE using the terms 'epidural' and 'steroids', 'corticosteroids' or 'glucocorticosteroids' up to and including the year 2012. Reports were also located by examining the references in the identified articles. We concluded that even if epidural steroid injection is one of the most widely- -used techniques to treat radicular pain, it must be administered cautiously, with careful monitoring for systemic side effects. At the very least, a standardised protocol is necessary.


Comparison of radiography and computed tomography to evaluate fractures of the canine tarsus.
Detection and accurate classification of traumatic tarsal fractures are important for identifying cases requiring surgical intervention. The aim of this prospective, experimental, methods comparison study was to directly compare the accuracy, sensitivity, and specificity of tarsal computed tomography (CT), ten-view and two-view digital radiographs for detecting traumatic fractures of the canine tarsus. The working hypothesis was that tarsal fractures would be detected with higher accuracy, sensitivity, and specificity using CT imaging compared to radiography, and a ten-view would be superior to a two-view radiographic study. Ten cadaver hind limbs of medium to large dogs received a CT scan and ten-view radiographic study before and after induction of fractures with a hydraulic press. All bones included in the radiographic images were assessed for fractures by two observers and gross dissection was used as the gold standard. The two-view radiographic study (dorsoplantar, lateromedial) was created from the ten-view study and reviewed 2 years later. All limbs sustained fractures, the most common locations were the talus and calcaneus (n = 7). The sensitivity of CT was greater than ten-view radiographic study (77% vs. 57%), while the specificity was similar (97% vs. 98%). The sensitivity and specificity of the ten-view and two-view radiograph studies were similar (57% vs. 55%; both 98%). Computed tomography images were reassessed postdissection to determine if failure to identify fractures resulted from observer error. Overall, CT was better than radiography for detecting fractures of the canine tarsus, however there was little improvement with ten-view compared to two-view radiographic studies.


Antimicrobial resistance prediction and phylogenetic analysis of Neisseria gonorrhoeae isolates using the Oxford Nanopore MinION sequencer.
Antimicrobial resistance (AMR) in Neisseria gonorrhoeae is common, compromising gonorrhoea treatment internationally. Rapid characterisation of AMR strains could ensure appropriate and personalised treatment, and support identification and investigation of gonorrhoea outbreaks in nearly real-time. Whole-genome sequencing is ideal for investigation of emergence and dissemination of AMR determinants, predicting AMR, in the gonococcal population and spread of AMR strains in the human population. The novel, rapid and revolutionary long-read sequencer MinION is a small hand-held device that generates bacterial genomes within one day. However, accuracy of MinION reads has been suboptimal for many objectives and the MinION has not been evaluated for gonococci. In this first MinION study for gonococci, we show that MinION-derived sequences analysed with existing open-access, web-based sequence analysis tools are not sufficiently accurate to identify key gonococcal AMR determinants. Nevertheless, using an in house-developed CLC Genomics Workbench including de novo assembly and optimised BLAST algorithms, we show that 2D ONT-derived sequences can be used for accurate prediction of decreased susceptibility or resistance to recommended antimicrobials in gonococcal isolates. We also show that the 2D ONT-derived sequences are useful for rapid phylogenomic-based molecular epidemiological investigations, and, in hybrid assemblies with Illumina sequences, for producing contiguous assemblies and finished reference genomes.


The attentional demands of ambulating with an assistive device in older adults with Alzheimer's disease.
Ambulation with a mobility aid is a unique real-life situation of multi-tasking. These simultaneous motor tasks place increased demands on executive function in healthy young and older adults, but the demands have not been evaluated in people with Alzheimer's disease (AD). Mobility problems are common among adults with AD, leading to provision of a mobility aid to optimize independent activity. The study objectives were: (i) to determine the dual-task cost (DTC) associated with the use of a mobility aid in straight and complex path walking, and (ii) to evaluate the association between executive function and ambulation with a mobility aid in older adults with AD and age-sex matched cognitively normal controls. Fourteen people (mean age±SD, 72.6±9.9years) with a diagnosis of probable AD (MMSE range 12-25) and controls (mean age±SD, 72.9±9.5) walked at a self-selected pace and using a 4-wheeled walker in a 6m straight path and a Figure of 8 Test. Ambulation with the walker in a straight path produced a low DTC that was not different between the groups. Ambulation with the 4-wheeled walker in the complex path produced a significantly different DTC in the group with AD at -38.1±23.5% compared to -19.7±21.4% (p=0.041). Lower scores on executive function were associated with longer times across test conditions. Ambulation with a 4-wheeled walker, in particular maneuvering around obstacles, requires greater attentional costs in dementia. Future research should explore the timing for safely introducing mobility aids in AD and the role of improving executive function.


Menstrual hygiene management among adolescent schoolgirls in low- and middle-income countries: research priorities.
A lack of adequate guidance on menstrual management; water, disposal, and private changing facilities; and sanitary hygiene materials in low- and middle-income countries leaves schoolgirls with limited options for healthy personal hygiene during monthly menses. While a plethora of observational studies have described how menstrual hygiene management (MHM) barriers in school impact girls' dignity, well-being, and engagement in school activities, studies have yet to confirm if inadequate information and facilities for MHM significantly affects quantifiable school and health outcomes influencing girls' life chances. Evidence on these hard outcomes will take time to accrue; however, a current lack of standardized methods, tools, and research funding is hampering progress and must be addressed. Compile research priorities for MHM and types of research methods that can be used. In this article, we highlight the current knowledge gaps in school-aged girls' MHM research, and identify opportunities for addressing the dearth of hard evidence limiting the ability of governments, donors, and other agencies to appropriately target resources. We outline a series of research priorities and methodologies that were drawn from an expert panel to address global priorities for MHM in schools for the next 10 years. A strong evidence base for different settings, standardized definitions regarding MHM outcomes, improved study designs and methodologies, and the creation of an MHM research consortia to focus attention on this neglected global issue.


Neogenesis and maturation of transient Golgi-like cisternae in a simple eukaryote.
The highly reduced protozoan parasite Giardia lamblia has minimal machinery for cellular processes such as protein trafficking. Giardia trophozoites maintain diverse and regulated secretory pathways but lack an identifiable Golgi complex. During differentiation to cysts, however, they produce specialized compartments termed encystation-specific vesicles (ESVs). ESVs are hypothesized to be unique developmentally regulated Golgi-like organelles dedicated to maturation and export of pre-sorted cyst wall proteins. Here we present a functional analysis of this unusual compartment by direct interference with the functions of the small GTPases Sar1, Rab1 and Arf1. Conditional expression of dominant-negative variants revealed an essential role of Sar1 in early events of organelle neogenesis, whilst inhibition of Arf1 uncoupled morphological changes and cell cycle progression from extracellular matrix export. The latter led to development of ;naked cysts', which lacked water resistance and thus infectivity. Time-lapse microscopy and photobleaching experiments showed that putative Golgi-like cisternae in Giardia develop into a network capable of exchanging soluble cargo at a high rate via dynamic, tubular connections, presumably to synchronize maturation. The minimized and naturally pulsed trafficking machinery for export of the cyst wall biopolymer in Giardia is a simple model for investigating basic principles of neogenesis and maturation of Golgi compartments.


The immunoregulator soluble TACI is released by ADAM10 and reflects B cell activation in autoimmunity.
BAFF and a proliferation-inducing ligand (APRIL), which control B cell homeostasis, are therapeutic targets in autoimmune diseases. TACI-Fc (atacicept), a soluble fusion protein containing the extracellular domain of the BAFF-APRIL receptor TACI, was applied in clinical trials. However, disease activity in multiple sclerosis unexpectedly increased, whereas in systemic lupus erythematosus, atacicept was beneficial. In this study, we show that an endogenous soluble TACI (sTACI) exists in vivo. TACI proteolysis involved shedding by a disintegrin and metalloproteinase 10 releasing sTACI from activated B cells. The membrane-bound stub was subsequently cleaved by γ-secretase reducing ligand-independent signaling of the remaining C-terminal fragment. The shed ectodomain assembled ligand independently in a homotypic way. It functioned as a decoy receptor inhibiting BAFF- and APRIL-mediated B cell survival and NF-κB activation. We determined sTACI levels in autoimmune diseases with established hyperactivation of the BAFF-APRIL system. sTACI levels were elevated both in the cerebrospinal fluid of the brain-restricted autoimmune disease multiple sclerosis correlating with intrathecal IgG production, as well as in the serum of the systemic autoimmune disease systemic lupus erythematosus correlating with disease activity. Together, we show that TACI is sequentially processed by a disintegrin and metalloproteinase 10 and γ-secretase. The released sTACI is an immunoregulator that shares decoy functions with atacicept. It reflects systemic and compartmentalized B cell accumulation and activation.


Tunable supercurrent through semiconductor nanowires.
Nanoscale superconductor/semiconductor hybrid devices are assembled from indium arsenide semiconductor nanowires individually contacted by aluminum-based superconductor electrodes. Below 1 kelvin, the high transparency of the contacts gives rise to proximity-induced superconductivity. The nanowires form superconducting weak links operating as mesoscopic Josephson junctions with electrically tunable coupling. The supercurrent can be switched on/off by a gate voltage acting on the electron density in the nanowire. A variation in gate voltage induces universal fluctuations in the normal-state conductance, which are clearly correlated to critical current fluctuations. The alternating-current Josephson effect gives rise to Shapiro steps in the voltage-current characteristic under microwave irradiation.


The crystal structure of fragment double-D from cross-linked lamprey fibrin reveals isopeptide linkages across an unexpected D-D interface.
The crystal structure of fragment double-D from factor XIII-cross-linked lamprey fibrin has been determined at 2.9 A resolution. The 180 kDa covalent dimer was cocrystallized with the peptide Gly-His-Arg-Pro-amide, which in many fibrinogens, but not that of lamprey, corresponds to the B-knob exposed by thrombin. The structure was determined by molecular replacement, a recently determined structure of lamprey fragment D being used as a search model. GHRPam was found in both the gamma- and beta-chain holes. Unlike the situation with fragment D, the crystal packing of the cross-linked double-D structure exhibits two different D-D interfaces, each gamma-chain facing gamma-chains on two other molecules. One of these (interface I) involves the asymmetric interface observed in all other D fragments and related structures. The other (interface II) encompasses a completely different set of residues. The two abutments differ in that interface I results in an "in line" arrangement of abutting molecules and the interface II in a "zigzag" arrangement. So far as can be determined (the electron density could only be traced on one side of the cross-links), it is the gamma-chains of the newly observed zigzag units (interface II) that are joined by the reciprocal epsilon-amino-gamma-glutamyl cross-links. Auspiciously, the same novel D-D interface was observed in two lower-resolution crystal structures of human double-D preparations that had been crystallized under unusual circumstances. These observations show that double-D structures are linked in a way that is sufficiently flexible to accommodate different D-D interfaces under different circumstances.


Two distinct mechanisms target GAD67 to vesicular pathways and presynaptic clusters.
The inhibitory neurotransmitter gamma-amino butyric acid (GABA) is synthesized by two isoforms of the enzyme glutamic acid decarboxylase (GAD): GAD65 and GAD67. Whereas GAD67 is constitutively active and produces >90% of GABA in the central nervous system, GAD65 is transiently activated and augments GABA levels for rapid modulation of inhibitory neurotransmission. Hydrophobic lipid modifications of the GAD65 protein target it to Golgi membranes and synaptic vesicles in neuroendocrine cells. In contrast, the GAD67 protein remains hydrophilic but has been shown to acquire membrane association by heterodimerization with GAD65. Here, we identify a second mechanism that mediates robust membrane anchoring, axonal targeting, and presynaptic clustering of GAD67 but that is independent of GAD65. This mechanism is abolished by a leucine-103 to proline mutation that changes the conformation of the N-terminal domain but does not affect the GAD65-dependent membrane anchoring of GAD67. Thus two distinct mechanisms target the constitutively active GAD67 to presynaptic clusters to facilitate accumulation of GABA for rapid delivery into synapses.


Reaction intermediates in the heme degradation reaction by HutZ from Vibrio cholerae.
HutZ is a heme-degrading enzyme in Vibrio cholerae. It converts heme to biliverdin via verdoheme, suggesting that it follows the same reaction mechanism as that of mammalian heme oxygenase. However, none of the key intermediates have been identified. In this study, we applied steady-state and time-resolved UV-vis absorption and resonance Raman spectroscopy to study the reaction of the heme-HutZ complex with H2O2 or ascorbic acid. We characterized three intermediates: oxyferrous heme, meso-hydroxyheme, and verdoheme complexes. Our data support the view that HutZ degrades heme in a manner similar to mammalian heme oxygenase, despite their low sequence and structural homology.


First Report of Phytophthora taxon niederhauserii Causing Root and Stem Rot of Mimosa in Italy.
Mimosa [Acacia dealbata Link, syn. Acacia decurrens (Wendl. F.) Wild. var. dealbata (Link) F. Muell., Fabaceae] is an evergreen shrub native to southeastern Australia that is cultivated as an ornamental plant in warm temperate regions of the world. In spring 2010, in a commercial nursery in Liguria (northern Italy), 6- to 10-month-old potted plants of A. dealbata showed symptoms of sudden collapse, defoliation, and wilt associated with root and basal stem rot. An abundant gum exudate oozed from the basal stem. A Phytophthora species was consistently isolated from roots and stem on BNPRAH selective medium (4). On V8 agar (V8A), axenic cultures obtained by single hyphal transfers formed stellate to radiate colonies with aerial mycelium whereas on potato dextrose agar (PDA) the colonies grew more slowly than on V8A and showed stoloniform mycelium and irregular margins. Minimum and maximum growth temperatures on PDA were 10 and 35°C, with the optimum at 30°C. In water, all isolates produced catenulate or single fusiform hyphal swellings and ellipsoid, nonpapillate, persistent sporangia. Dimensions of sporangia were 46.1 to 65.4 × 23.1 to 30.8 μm (mean l/b ratio 2.1). All isolates were A1 mating type and produced spherical oogonia with amphyginous antheridia when paired with A2 mating type of P. drechsleri Tucker on V8A plus β-sytosterol (4). Internal transcribed spacer (ITS) regions of rDNA of the representative Phytophthora isolate IMI 500394 from A. dealbata were amplified and sequenced in both directions with primers ITS6/ITS4. The consensus sequence (GenBank Accession No. JF900371) was 99% similar to sequences of several isolates identified as Phytophthora taxon niederhauserii Z.G. Abad and J.A. Abad (e.g., GQ848201 and EU244850). Pathogenicity tests were performed on 1-year-old potted plants of A. dealbata with isolate IMI 500394. Twenty plants were transplanted into pots (12-cm-diameter) filled with soil infested (4% v/v) with the inoculum of IMI500394 produced on kernel seeds. Plants were kept in a greenhouse with natural light at 25 ± 2°C and watered to field capacity weekly. All inoculated plants showed symptoms of wilt, leaf chlorosis, and basal stem rot within 3 to 4 weeks. Twenty control plants transplanted in autoclaved soil mix remained healthy. P. taxon niederhauserii was reisolated solely from inoculated plants, thus fulfilling Koch's postulates. Since 2003, this pathogen has been found on bottlebrush and rock rose grown in a nursery in Sicily (southern Italy), as well as on Banksia in a nursery in Liguria (2,3). To our knowledge, this is the first report of P. taxon niederhauserii on A. dealbata. P. taxon niederhauserii, recently described as P. niederhauserii sp. nov. (1), is a polyphagous pathogen that was originally reported on arborvitae and ivy in North Carolina in 2001. References: (1) Z. G. Abad et al. Mycologia (in press), 2013. (2) S. O. Cacciola et al. Plant Dis. 93:1075, 2009. (3) S. O. Cacciola et al. Plant Dis. 93:1216, 2009. (4) D. C. Erwin and O. K. Ribeiro. Phytophthora Diseases Worldwide. The American Phytopathological Society, St. Paul, MN, 1996.


[Usefulness of QuantiFERON TB-2G in contact investigation of a tuberculosis outbreak in a university].
This study examined the usefulness of QuantiFERON TB-2G (QFT) i.e., a novel technique for detecting tuberculosis infection based on the whole blood interferon-gamma response to specific antigens, in the investigation of a tuberculosis outbreak among university students. One university student was diagnosed as smear-positive pulmonary tuberculosis. In order to determine the extent of tuberculosis infection among contact students, tuberculin skin tests and QFT were performed on the close-contact group (220 people), as well as on the non-close-contact group (242 people). Nine students were found to be TB either clinically or on the X-ray screening in the contact investigation. In the close-contact group, the QFT-positive rate was 32.7%. The proportion of those exhibiting tuberculin reactions with erythema diameters of 30 mm or larger was 57.7%. In the non-close-contact group, the QFT-positive rate was only 0.8 %, as expected from the current healthy Japanese youths of this age. In contrast, strong tuberculin reactions with erythema of 30 mm or larger were seen in 18.2% in the latter group, most likely due to the previous history of BCG vaccination. QFT was clearly demonstrated to be a useful method for diagnosing tuberculosis infection, especially among subjects who show tuberculin reactivity due to past BCG vaccination. At the same time, the current criteria for the indication of chemoprophylaxis based on the strong tuberculin reaction were considered to be unreliable, causing many subjects with strong reactions to be given unnecessary preventive medications.


Selection Sampling from Large Data Sets for Targeted Inference in Mixture Modeling.
One of the challenges in using Markov chain Monte Carlo for model analysis in studies with very large datasets is the need to scan through the whole data at each iteration of the sampler, which can be computationally prohibitive. Several approaches have been developed to address this, typically drawing computationally manageable subsamples of the data. Here we consider the specific case where most of the data from a mixture model provides little or no information about the parameters of interest, and we aim to select subsamples such that the information extracted is most relevant. The motivating application arises in flow cytometry, where several measurements from a vast number of cells are available. Interest lies in identifying specific rare cell subtypes and characterizing them according to their corresponding markers. We present a Markov chain Monte Carlo approach where an initial subsample of the full dataset is used to guide selection sampling of a further set of observations targeted at a scientifically interesting, low probability region. We define a Sequential Monte Carlo strategy in which the targeted subsample is augmented sequentially as estimates improve, and introduce a stopping rule for determining the size of the targeted subsample. An example from flow cytometry illustrates the ability of the approach to increase the resolution of inferences for rare cell subtypes.


Diet and physical activity in pregnancy and offspring's cardiovascular health: a systematic review.
There is increasing evidence linking maternal diet and physical activity before and during pregnancy with offspring's cardiovascular health. Although many studies examined this association, the evidence has not been reviewed systematically. We therefore undertook a systematic review to synthesize evidence examining the association of maternal diet and physical activity before and during pregnancy with offspring's blood pressure and vascular health. We systematically searched the databases MEDLINE and EMBASE from inception to June 30, 2017. Eligibility screening, data extraction and quality assessment were performed by two independent reviewers. A total of 19 articles were included comprising three randomized controlled trials and 16 observational studies. Of the studies that examined the association of interest, 60% (three out of five studies) showed that high maternal carbohydrate intake was associated with higher offspring's blood pressure. Maternal protein intake during pregnancy was negatively associated with offspring carotid intima-media thickness in two out of two studies. No consistent findings for maternal fatty acid intake were found. There were too few studies to draw conclusions on energy intake, fibre intake, protein/carbohydrate ratio, specific foods, dietary patterns and maternal physical activity. Heterogeneity in exposure and outcome assessment hampered pooling. Also, owing to the observational nature of most studies, causality cannot be established. Harmonization of valid exposure and outcome measurements, and the development of core outcome sets are needed to enable more robust conclusions.


Sequential quantitative trait locus mapping in experimental crosses.
The etiology of complex diseases is heterogeneous. The presence of risk alleles in one or more genetic loci affects the function of a variety of intermediate biological pathways, resulting in the overt expression of disease. Hence, there is an increasing focus on identifying the genetic basis of disease by systematically studying phenotypic traits pertaining to the underlying biological functions. In this paper we focus on identifying genetic loci linked to quantitative phenotypic traits in experimental crosses. Such genetic mapping methods often use a one stage design by genotyping all the markers of interest on the available subjects. A genome scan based on single locus or multi-locus models is used to identify the putative loci. Since the number of quantitative trait loci (QTLs) is very likely to be small relative to the number of markers genotyped, a one-stage selective genotyping approach is commonly used to reduce the genotyping burden, whereby markers are genotyped solely on individuals with extreme trait values. This approach is powerful in the presence of a single quantitative trait locus (QTL) but may result in substantial loss of information in the presence of multiple QTLs. Here we investigate the efficiency of sequential two stage designs to identify QTLs in experimental populations. Our investigations for backcross and F2 crosses suggest that genotyping all the markers on 60% of the subjects in Stage 1 and genotyping the chromosomes significant at 20% level using additional subjects in Stage 2 and testing using all the subjects provides an efficient approach to identify the QTLs and utilizes only 70% of the genotyping burden relative to a one stage design, regardless of the heritability and genotyping density. Complex traits are a consequence of multiple QTLs conferring main effects as well as epistatic interactions. We propose a two-stage analytic approach where a single-locus genome scan is conducted in Stage 1 to identify promising chromosomes, and interactions are examined using the loci on these chromosomes in Stage 2. We examine settings under which the two-stage analytic approach provides sufficient power to detect the putative QTLs.


Effects of angiotensin II on steroid metabolism and hepatic blood flow in man.
Metabolic clearance rates (MCR) of aldosterone, cortisol, 11-deoxycorticosterone (DOC), corticosterone, and progesterone were simultaneously measured by constant infusion in eight control subjects before and during angiotensin II infusion in subpressor (3 ng/min per kg) and pressor (22 ng/min per kg) doses. Plasma levels of aldosterone and cortisol, the heat-labile protein-bound fraction of aldosterone, and hepatic blood flow (HBF) (as estimated by the fractional clearance of indocyanine green) were determined concomitantly. Angiotensin II in a subpressor dose produced a significant decrease of the MCR of aldosterone (by 23%), cortisol (by 16%), DOC (by 26%), corticosterone (by 14%) and progesterone (by 33%). The pressor dose further decreased the respective MCR by 37%, 21%, 40%, 28%, and 42% of the baseline value. Plasma aldosterone levels rose by 317% with subpressor and by 434% with pressor doses. HBF decreased by 18% with subpressor and by 33% with pressor doses of angiotensin II. Furthermore, there were significant negative correlations between the MCR of each steroid and the respective values of the fractional clearance of indocyanine green. We conclude that angiotensin II, by its vasoconstrictive action on the splanchnic vascular bed, decreases the MCR of aldosterone, cortisol, DOC, corticosterone, and progesterone. This decrease has to be taken into account when considering the stimulatory effect of angiotensin II on various plasma steroid concentrations.