Household exposure to pesticides and bladder exstrophy in a newborn baby boy: a case report and review of the literature

© 2009 Martin et al; licensee Cases Network Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

Transcriptional Reprogramming of CD11b+Esamhi Dendritic Cell Identity and Function by Loss of Runx3

Classical dendritic cells (cDC) are specialized antigen-presenting cells mediating immunity and tolerance. cDC cell-lineage decisions are largely controlled by transcriptional factor regulatory cascades. Using an in vivo cell-specific targeting of Runx3 at various stages of DC lineage development we show that Runx3 is required for cell-identity, homeostasis and function of splenic Esamhi DC. Ablation of Runx3 in DC progenitors led to a substantial decrease in splenic CD4+/CD11b+ DC. Combined chromatin immunoprecipitation sequencing and gene expression analysis of purified DC-subsets revealed that Runx3 is a key gene expression regulator that facilitates specification and homeostasis of CD11b+Esamhi DC. Mechanistically, loss of Runx3 alters Esamhi DC gene expression to a signature characteristic of WT Esamlow DC. This transcriptional reprogramming caused a cellular change that diminished phagocytosis and hampered Runx3-/- Esamhi DC capacity to prime CD4+ T cells, attesting to the significant role of Runx3 in specifying Esamhi DC identity and function

Influences on gum feeding in primates

This chapter reviews the factors that may affect patterns of gum feeding by primates. These are then examined for mixed-species troops of saddleback (S. fuscicollis) and mustached (S. mystax) tamarins. An important distinction is made between gums produced by tree trunks and branches as a result of damage and those produced by seed pods as part of a dispersal strategy as these may be expected to differ in their biochemistry. Feeding on fruit and Parkia seed pod exudates was more prevalent in the morning whereas other exudates were eaten in the afternoon. This itinerary may represent a deliberate strategy to retain trunk gums in the gut overnight, thus maximising the potential for microbial fermentation of their β-linked oligosaccharides. Both types of exudates were eaten more in the dry than the wet season. Consumption was linked to seasonal changes in resource availability and not the tamarins’ reproductive status pro-viding no support for the suggestion that gums are eaten as a pri-mary calcium source in the later stages of gestation and lactation. The role of availability in determining patterns of consumption is further supported by the finding that dietary overlap for the trunk gums eaten was greater between species within mixed-species troops within years than it was within species between years. These data and those for pygmy marmosets (Cebuella pygmaea) suggest that patterns of primate gummivory may reflect the interaction of prefer-ence and availability for both those able to stimulate gum production and those not

TGFβR signalling determines CD103⁺CD11b⁺ dendritic cell development in the intestine

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFβR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103−CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1fl/fl mice reflects defective differentiation from CD103−CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFβR1-mediated signalling may explain the tissue-specific development of these unique DCs

Socio-demographic and lifestyle factors associated with overweight in a representative sample of 11-15 year olds in France: Results from the WHO-Collaborative Health Behaviour in School-aged Children (HBSC) cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The prevalence of overweight in children and adolescents is high and overweight is associated with poor health outcomes over short- and long-term. Lifestyle factors can interact to influence overweight. Comprehensive studies linking overweight concomitantly with several demographic and potentially-modifiable lifestyle factors and health-risk behaviours are limited in adolescents - an age-group characterized by changes in lifestyle behaviours and high prevalence of overweight. Thus, the objective of the current study was to examine the association of overweight with several socio-demographic and lifestyle variables simultaneously in a representative sample of adolescents.</p> <p>Methods</p> <p>A nationally representative sample of 11-15 year-olds (n = 7154) in France participated as part of the WHO-Collaborative Health Behaviour in School-aged Children (HBSC) study. Students reported data on their age, height, weight, socio-demographic variables, lifestyle factors including nutrition practices, physical activity at two levels of intensity (moderate and vigorous), sedentary behaviours, as well as smoking and alcohol consumption patterns using standardized HBSC protocols. Overweight (including obesity) was defined using the IOTF reference. The multivariate association of overweight with several socio-demographic and lifestyle factors was examined with logistic regression models.</p> <p>Results</p> <p>The adjusted odds ratios for the association with overweight were: 1.80 (95% CI: 1.37-2.36) for low family affluence; 0.73 (0.60-0.88) for eating breakfast daily; 0.69 (0.56-0.84) for moderate to vigorous physical activity (MVPA); and 0.71 (0.59-0.86) for vigorous physical activity (VPA). Significant interactions between age and gender as well as television (TV) viewing and gender were noted: for boys, overweight was not associated with age or TV viewing; in contrast, for girls overweight correlated negatively with age and positively with TV viewing. Fruit and vegetable intake, computer and video-games use, smoking and alcohol consumption were not associated with overweight.</p> <p>Conclusions</p> <p>In multivariate model, family affluence, breakfast consumption and moderate to vigorous as well as vigorous physical activity were negatively associated with overweight. These findings extend previous research to a setting where multiple risk and protective factors were simultaneously examined and highlight the importance of multi-faceted approaches promoting physical activity and healthy food choices such as breakfast consumption for overweight prevention in adolescents.</p

Associations of homelessness and residential mobility with length of stay after acute psychiatric admission

Background: A small number of patient-level variables have replicated associations with the length of stay (LOS) of psychiatric inpatients. Although need for housing has often been identified as a cause of delayed discharge, there has been little research into the associations between LOS and homelessness and residential mobility (moving to a new home), or the magnitude of these associations compared to other exposures. Methods: Cross-sectional study of 4885 acute psychiatric admissions to a mental health NHS Trust serving four South London boroughs. Data were taken from a comprehensive repository of anonymised electronic patient records. Analysis was performed using log-linear regression. Results: Residential mobility was associated with a 99% increase in LOS and homelessness with a 45% increase. Schizophrenia, other psychosis, the longest recent admission, residential mobility, and some items on the Health of the Nation Outcome Scales (HoNOS), especially ADL impairment, were also associated with increased LOS. Informal admission, drug and alcohol or other non-psychotic diagnosis and a high HoNOS self-harm score reduced LOS. Including residential mobility in the regression model produced the same increase in the variance explained as including diagnosis; only legal status was a stronger predictor. Conclusions: Homelessness and, especially, residential mobility account for a significant part of variation in LOS despite affecting a minority of psychiatric inpatients; for these people, the effect on LOS is marked. Appropriate policy responses may include attempts to avert the loss of housing in association with admission, efforts to increase housing supply and the speed at which it is made available, and reforms of payment systems to encourage this

Heterosubtypic Neutralizing Monoclonal Antibodies Cross-Protective against H5N1 and H1N1 Recovered from Human IgM+ Memory B Cells

Background: The hemagglutinin (HA) glycoprotein is the principal target of protective humoral immune responses to influenza virus infections but such antibody responses only provide efficient protection against a narrow spectrum of HA antigenic variants within a given virus subtype. Avian influenza viruses such as H5N1 are currently panzootic and pose a pandemic threat. These viruses are antigenically diverse and protective strategies need to cross protect against diverse viral clades. Furthermore, there are 16 different HA subtypes and no certainty the next pandemic will be caused by an H5 subtype, thus it is important to develop prophylactic and therapeutic interventions that provide heterosubtypic protection. Methods and Findings: Here we describe a panel of 13 monoclonal antibodies (mAbs) recovered from combinatorial display libraries that were constructed from human IgM+ memory B cells of recent (seasonal) influenza vaccinees. The mAbs have broad heterosubtypic neutralizing activity against antigenically diverse H1, H2, H5, H6, H8 and H9 influenza subtypes. Restriction to variable heavy chain gene IGHV1-69 in the high affinity mAb panel was associated with binding to a conserved hydrophobic pocket in the stem domain of HA. The most potent antibody (CR6261) was protective in mice when given before and after lethal H5N1 or H1N1 challenge. Conclusions: The human monoclonal CR6261 described in this study could be developed for use as a broad spectrum agent for prophylaxis or treatment of human or avian influenza infections without prior strain characterization. Moreover, the CR6261 epitope could be applied in targeted vaccine strategies or in the design of novel antivirals. Finally our approach of screening the IgM+ memory repertoire could be applied to identify conserved and functionally relevant targets on other rapidly evolving pathogens

Metformin Prevents Nigrostriatal Dopamine Degeneration Independent of AMPK Activation in Dopamine Neurons

Metformin is a widely prescribed drug used to treat type-2 diabetes, although recent studies show it has wide ranging effects to treat other diseases. Animal and retrospective human studies indicate that Metformin treatment is neuroprotective in Parkinson’s Disease (PD), although the neuroprotective mechanism is unknown, numerous studies suggest the beneficial effects on glucose homeostasis may be through AMPK activation. In this study we tested whether or not AMPK activation in dopamine neurons was required for the neuroprotective effects of Metformin in PD. We generated transgenic mice in which AMPK activity in dopamine neurons was ablated by removing AMPK beta 1 and beta 2 subunits from dopamine transporter expressing neurons. These AMPK WT and KO mice were then chronically exposed to Metformin in the drinking water then exposed to MPTP, the mouse model of PD. Chronic Metformin treatment significantly attenuated the MPTP-induced loss of Tyrosine Hydroxylase (TH) neuronal number and volume and TH protein concentration in the nigrostriatal pathway. Additionally, Metformin treatment prevented the MPTP-induced elevation of the DOPAC:DA ratio regardless of genotype. Metformin also prevented MPTP induced gliosis in the Substantia Nigra. These neuroprotective actions were independent of genotype and occurred in both AMPK WT and AMPK KO mice. Overall, our studies suggest that Metformin’s neuroprotective effects are not due to AMPK activation in dopaminergic neurons and that more research is required to determine how metformin acts to restrict the development of PD

Production of IFN-β during Listeria monocytogenes Infection Is Restricted to Monocyte/Macrophage Lineage

The family of type I interferons (IFN), which consists of several IFN-α and one IFN-β, are produced not only after stimulation by viruses, but also after infection with non-viral pathogens. In the course of bacterial infections, these cytokines could be beneficial or detrimental. IFN-β is the primary member of type I IFN that initiates a cascade of IFN-α production. Here we addressed the question which cells are responsible for IFN-β expression after infection with the intracellular pathogen Listeria monocytogenes by using a genetic approach. By means of newly established reporter mice, maximum of IFN-β expression was observed at 24 hours post infection in spleen and, surprisingly, 48 hours post infection in colonized cervical and inguinal lymph nodes. Colonization of lymph nodes was independent of the type I IFN signaling, as well as bacterial dose and strain. Using cell specific reporter function and conditional deletions we could define cells expressing LysM as the major IFN-β producers, with cells formerly defined as Tip-DCs being the highest. Neutrophilic granulocytes, dendritic cells and plasmacytoid dendritic cells did not significantly contribute to type I IFN production

Conditional Stat1 Ablation Reveals the Importance of Interferon Signaling for Immunity to Listeria monocytogenes Infection

Signal transducer and activator of transcription 1 (Stat1) is a key player in responses to interferons (IFN). Mutations of Stat1 cause severe immune deficiencies in humans and mice. Here we investigate the importance of Stat1 signaling for the innate and secondary immune response to the intracellular bacterial pathogen Listeria monocytogenes (Lm). Cell type-restricted ablation of the Stat1 gene in naïve animals revealed unique roles in three cell types: macrophage Stat1 signaling protected against lethal Lm infection, whereas Stat1 ablation in dendritic cells (DC) did not affect survival. T lymphocyte Stat1 reduced survival. Type I IFN (IFN-I) signaling in T lymphocytes reportedly weakens innate resistance to Lm. Surprisingly, the effect of Stat1 signaling was much more pronounced, indicating a contribution of Stat1 to pathways other than the IFN-I pathway. In stark contrast, Stat1 activity in both DC and T cells contributed positively to secondary immune responses against Lm in immunized animals, while macrophage Stat1 was dispensable. Our findings provide the first genetic evidence that Stat1 signaling in different cell types produces antagonistic effects on innate protection against Lm that are obscured in mice with complete Stat1 deficiency. They further demonstrate a drastic change in the cell type-dependent Stat1 requirement for memory responses to Lm infection