The effects of socioeconomic status and indices of physical environment on reduced birth weight and preterm births in Eastern Massachusetts

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Air pollution and social characteristics have been shown to affect indicators of health. While use of spatial methods to estimate exposure to air pollution has increased the power to detect effects, questions have been raised about potential for confounding by social factors.Methods: A study of singleton births in Eastern Massachusetts was conducted between 1996 and 2002 to examine the association between indicators of traffic, land use, individual and area-based socioeconomic measures (SEM), and birth outcomes ( birth weight, small for gestational age and preterm births), in a two-level hierarchical model.Results: We found effects of both individual ( education, race, prenatal care index) and area-based ( median household income) SEM with all birth outcomes. The associations for traffic and land use variables were mainly seen with birth weight, with an exception for an effect of cumulative traffic density on small for gestational age. Race/ethnicity of mother was an important predictor of birth outcomes and a strong confounder for both area-based SEM and indices of physical environment. The effects of traffic and land use differed by level of education and median household income.Conclusion: Overall, the findings of the study suggested greater likelihood of reduced birth weight and preterm births among the more socially disadvantaged, and a greater risk of reduced birth weight associated with traffic exposures. Results revealed the importance of controlling simultaneously for SEM and environmental exposures as the way to better understand determinants of health.This work is supported by the Harvard Environmental Protection Agency (EPA) Center, Grants R827353 and R-832416, and National Institute for Environmental Health Science (NIEHS) ES-0002

Neighborhood Socioeconomic Status and Use of Colonoscopy in an Insured Population – A Retrospective Cohort Study

Background: Low-socioeconomic status (SES) is associated with a higher colorectal cancer (CRC) incidence and mortality. Screening with colonoscopy, the most commonly used test in the US, has been shown to reduce the risk of death from CRC. This study examined if, among insured persons receiving care in integrated healthcare delivery systems, differences exist in colonoscopy use according to neighborhood SES. Methods We assembled a retrospective cohort of 100,566 men and women, 50–74 years old, who had been enrolled in one of three US health plans for $\geq$ 1 year on January 1, 2000. Subjects were followed until the date of first colonoscopy, date of disenrollment from the health plan, or December 31, 2007, whichever occurred first. We obtained data on colonoscopy use from administrative records. We defined screening colonoscopy as an examination that was not preceded by gastrointestinal conditions in the prior 6-month period. Neighborhood SES was measured using the percentage of households in each subject's census-tract with an income below 1999 federal poverty levels based on 2000 US census data. Analyses, adjusted for demographics and comorbidity index, were performed using Weibull regression models. Results: The average age of the cohort was 60 years and 52.7% were female. During 449,738 person-years of follow-up, fewer subjects in the lowest SES quartile (Q1) compared to the highest quartile (Q4) had any colonoscopy (26.7% vs. 37.1%) or a screening colonoscopy (7.6% vs. 13.3%). In regression analyses, compared to Q4, subjects in Q1 were 16% (adjusted HR = 0.84, 95% CI: 0.80–0.88) less likely to undergo any colonoscopy and 30%(adjusted HR = 0.70, CI: 0.65–0.75) less likely to undergo a screening colonoscopy. Conclusion: People in lower-SES neighborhoods are less likely to undergo a colonoscopy, even among insured subjects receiving care in integrated healthcare systems. Removing health insurance barriers alone is unlikely to eliminate disparities in colonoscopy use

Dengue virus neutralizing antibody levels associated with protection from infection in Thai cluster studies

BACKGROUND: Long-term homologous and temporary heterologous protection from dengue virus (DENV) infection may be mediated by neutralizing antibodies. However, neutralizing antibody titers (NTs) have not been clearly associated with protection from infection. METHODOLOGY/PRINCIPAL FINDINGS: Data from two geographic cluster studies conducted in Kamphaeng Phet, Thailand were used for this analysis. In the first study (2004-2007), cluster investigations of 100-meter radius were triggered by DENV-infected index cases from a concurrent prospective cohort. Subjects between 6 months and 15 years old were evaluated for DENV infection at days 0 and 15 by DENV PCR and IgM ELISA. In the second study (2009-2012), clusters of 200-meter radius were triggered by DENV-infected index cases admitted to the provincial hospital. Subjects of any age 6 months and older were evaluated for DENV infection at days 0 and 14. In both studies, subjects who were DENV PCR positive at day 14/15 were considered to have been susceptible on day 0. Comparison subjects from houses in which someone had documented DENV infection, but the subject remained DENV negative at days 0 and 14/15, were considered non-susceptible. Day 0 samples were presumed to be from just before virus exposure, and underwent plaque reduction neutralization testing (PRNT). Seventeen susceptible (six DENV-1, five DENV-2, and six DENV-4), and 32 non-susceptible (13 exposed to DENV-1, 10 DENV-2, and 9 DENV-4) subjects were evaluated. Comparing subjects exposed to the same serotype, receiver operating characteristic (ROC) curves identified homotypic PRNT titers of 11, 323 and 16 for DENV-1, -2 and -4, respectively, to differentiate susceptible from non-susceptible subjects. CONCLUSIONS/SIGNIFICANCE: PRNT titers were associated with protection from infection by DENV-1, -2 and -4. Protective NTs appeared to be serotype-dependent and may be higher for DENV-2 than other serotypes. These findings are relevant for both dengue epidemiology studies and vaccine development efforts

Baby Business: a randomised controlled trial of a universal parenting program that aims to prevent early infant sleep and cry problems and associated parental depression

<p>Abstract</p> <p>Background</p> <p>Infant crying and sleep problems (e.g. frequent night waking, difficulties settling to sleep) each affect up to 30% of infants and often co-exist. They are costly to manage and associated with adverse outcomes including postnatal depression symptoms, early weaning from breast milk, and later child behaviour problems. Preventing such problems could improve these adverse outcomes and reduce costs to families and the health care system. Anticipatory guidance-i.e. providing parents with information about normal infant sleep and cry patterns, ways to encourage self-settling in infants, and ways to develop feeding and settling routines <it>before </it>the onset of problems-could prevent such problems. This paper outlines the protocol for our study which aims to test an anticipatory guidance approach.</p> <p>Methods/Design</p> <p>750 families from four Local Government Areas in Melbourne, Australia have been randomised to receive the <it>Baby Business </it>program (intervention group) or usual care (control group) offered by health services. The <it>Baby Business </it>program provides parents with information about infant sleep and crying via a DVD and booklet (mailed soon after birth), telephone consultation (at infant age 6-8 weeks) and parent group session (at infant age 12 weeks). All English speaking parents of healthy newborn infants born at > 32 weeks gestation and referred by their maternal and child health nurse at their first post partum home visit (day 7-10 postpartum), are eligible. The primary outcome is parent report of infant night time sleep as a problem at four months of age and secondary outcomes include parent report of infant daytime sleep or crying as a problem, mean duration of infant sleep and crying/24 hours, parental depression symptoms, parent sleep quality and quantity and health service use. Data will be collected at two weeks (baseline), four months and six months of age. An economic evaluation using a cost-consequences approach will, from a societal perspective, compare costs and health outcomes between the intervention and control groups.</p> <p>Discussion</p> <p>To our knowledge this is the first randomised controlled trial of a program which aims to prevent both infant sleeping and crying problems and associated postnatal depression symptoms. If effective, it could offer an important public health prevention approach to these common, distressing problems.</p> <p>Trial registration number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN63834603">ISRCTN63834603</a></p

TNFAIP3 Maintains Intestinal Barrier Function and Supports Epithelial Cell Tight Junctions

Tight junctions between intestinal epithelial cells mediate the permeability of the intestinal barrier, and loss of intestinal barrier function mediated by TNF signaling is associated with the inflammatory pathophysiology observed in Crohn's disease and celiac disease. Thus, factors that modulate intestinal epithelial cell response to TNF may be critical for the maintenance of barrier function. TNF alpha-induced protein 3 (TNFAIP3) is a cytosolic protein that acts in a negative feedback loop to regulate cell signaling induced by Toll-like receptor ligands and TNF, suggesting that TNFAIP3 may play a role in regulating the intestinal barrier. To investigate the specific role of TNFAIP3 in intestinal barrier function we assessed barrier permeability in TNFAIP3−/− mice and LPS-treated villin-TNFAIP3 transgenic mice. TNFAIP3−/− mice had greater intestinal permeability compared to wild-type littermates, while villin-TNFAIP3 transgenic mice were protected from increases in permeability seen within LPS-treated wild-type littermates, indicating that barrier permeability is controlled by TNFAIP3. In cultured human intestinal epithelial cell lines, TNFAIP3 expression regulated both TNF-induced and myosin light chain kinase-regulated tight junction dynamics but did not affect myosin light chain kinase activity. Immunohistochemistry of mouse intestine revealed that TNFAIP3 expression inhibits LPS-induced loss of the tight junction protein occludin from the apical border of the intestinal epithelium. We also found that TNFAIP3 deubiquitinates polyubiquitinated occludin. These in vivo and in vitro studies support the role of TNFAIP3 in promoting intestinal epithelial barrier integrity and demonstrate its novel ability to maintain intestinal homeostasis through tight junction protein regulation

Conformational Targeting of Fibrillar Polyglutamine Proteins in Live Cells Escalates Aggregation and Cytotoxicity

Misfolding- and aggregation-prone proteins underlying Parkinson's, Huntington's and Machado-Joseph diseases, namely alpha-synuclein, huntingtin, and ataxin-3 respectively, adopt numerous intracellular conformations during pathogenesis, including globular intermediates and insoluble amyloid-like fibrils. Such conformational diversity has complicated research into amyloid-associated intracellular dysfunction and neurodegeneration. To this end, recombinant single-chain Fv antibodies (scFvs) are compelling molecular tools that can be selected against specific protein conformations, and expressed inside cells as intrabodies, for investigative and therapeutic purposes.Using atomic force microscopy (AFM) and live-cell fluorescence microscopy, we report that a human scFv selected against the fibrillar form of alpha-synuclein targets isomorphic conformations of misfolded polyglutamine proteins. When expressed in the cytoplasm of striatal cells, this conformation-specific intrabody co-localizes with intracellular aggregates of misfolded ataxin-3 and a pathological fragment of huntingtin, and enhances the aggregation propensity of both disease-linked polyglutamine proteins. Using this intrabody as a tool for modulating the kinetics of amyloidogenesis, we show that escalating aggregate formation of a pathologic huntingtin fragment is not cytoprotective in striatal cells, but rather heightens oxidative stress and cell death as detected by flow cytometry. Instead, cellular protection is achieved by suppressing aggregation using a previously described intrabody that binds to the amyloidogenic N-terminus of huntingtin. Analogous cytotoxic results are observed following conformational targeting of normal or polyglutamine-expanded human ataxin-3, which partially aggregate through non-polyglutamine domains.These findings validate that the rate of aggregation modulates polyglutamine-mediated intracellular dysfunction, and caution that molecules designed to specifically hasten aggregation may be detrimental as therapies for polyglutamine disorders. Moreover, our findings introduce a novel antibody-based tool that, as a consequence of its general specificity for fibrillar conformations and its ability to function intracellularly, offers broad research potential for a variety of human amyloid diseases

Left Bundle Branch Block, an Old–New Entity

Left bundle branch block (LBBB) is generally associated with a poorer prognosis in comparison to normal intraventricular conduction, but also in comparison to right bundle branch block which is generally considered to be benign in the absence of an underlying cardiac disorder like congenital heart disease. LBBB may be the first manifestation of a more diffuse myocardial disease. The typical surface ECG feature of LBBB is a prolongation of QRS above 0.11 s in combination with a delay of the intrinsic deflection in leads V5 and V6 of more than 60 ms and no septal q waves in leads I, V5, and V6 due to the abnormal septal activation from right to left. LBBB may induce abnormalities in left ventricular performance due to abnormal asynchronous contraction patterns which can be compensated by biventricular pacing (resynchronization therapy). Asynchronous electrical activation of the ventricles causes regional differences in workload which may lead to asymmetric hypertrophy and left ventricular dilatation, especially due to increased wall mass in late-activated regions, which may aggravate preexisting left ventricular pumping performance or even induce it. Of special interest are patients with LBBB and normal left ventricular dimensions and normal ejection fraction at rest but who may present with an abnormal increase in pulmonary artery pressure during exercise, production of lactate during high-rate pacing, signs of ischemia on myocardial scintigrams (but no coronary artery narrowing), and abnormal ultrastructural findings on myocardial biopsy. For this entity, the term latent cardiomyopathy had been suggested previously

Oxamniquine resistance alleles are widespread in Old World Schistosoma mansoni and predate drug deployment

Do mutations required for adaptation occur de novo, or are they segregating within populations as standing genetic variation? This question is key to understanding adaptive change in nature, and has important practical consequences for the evolution of drug resistance. We provide evidence that alleles conferring resistance to oxamniquine (OXA), an antischistosomal drug, are widespread in natural parasite populations under minimal drug pressure and predate OXA deployment. OXA has been used since the 1970s to treat Schistosoma mansoni infections in the New World where S. mansoni established during the slave trade. Recessive loss-of-function mutations within a parasite sulfotransferase (SmSULT-OR) underlie resistance, and several verified resistance mutations, including a deletion (p.E142del), have been identified in the New World. Here we investigate sequence variation in SmSULT-OR in S. mansoni from the Old World, where OXA has seen minimal usage. We sequenced exomes of 204 S. mansoni parasites from West Africa, East Africa and the Middle East, and scored variants in SmSULT-OR and flanking regions. We identified 39 non-synonymous SNPs, 4 deletions, 1 duplication and 1 premature stop codon in the SmSULT-OR coding sequence, including one confirmed resistance deletion (p.E142del). We expressed recombinant proteins and used an in vitro OXA activation assay to functionally validate the OXA-resistance phenotype for four predicted OXA-resistance mutations. Three aspects of the data are of particular interest: (i) segregating OXA-resistance alleles are widespread in Old World populations (4.29–14.91% frequency), despite minimal OXA usage, (ii) two OXA-resistance mutations (p.W120R, p.N171IfsX28) are particularly common (>5%) in East African and Middle-Eastern populations, (iii) the p.E142del allele has identical flanking SNPs in both West Africa and Puerto Rico, suggesting that parasites bearing this allele colonized the New World during the slave trade and therefore predate OXA deployment. We conclude that standing variation for OXA resistance is widespread in S. mansoni

Regulation of cytokine signaling through direct interaction between cytokine receptors and the ATG16L1 WD40 domain

ATG16L1, an autophagy mediator that specifies the site of LC3 lipidation, includes a C-terminal domain formed by 7 WD40-type repeats (WD40 domain, WDD), the function of which is unclear. Here we show that the WDD interacts with the intracellular domain of cytokine receptors to regulate their signaling output in response to ligand stimulation. Using a refined version of a previously described WDD-binding amino acid motif, here we show that this element is present in the intracellular domain of cytokine receptors. Two of these receptors, IL-10RB and IL-2Rγ, recognize the WDD through the motif and exhibit WDD-dependent LC3 lipidation activity. IL-10 promotes IL-10RB/ATG16L1 interaction through the WDD, and IL-10 signaling is suboptimal in cells lacking the WDD owing to delayed endocytosis and inefficient early trafficking of IL10/IL-10R complexes. Our data reveal WDD-dependent roles of ATG16L1 in the regulation of cytokine receptor trafficking and signaling, and provide a WDD-binding motif that might be used to identify additional WDD activators