Particulate air pollution, fetal growth and gestational length: The influence of residential mobility in pregnancy.

BACKGROUND: It remains unclear as to whether neglecting residential mobility during pregnancy introduces bias in studies investigating air pollution and adverse perinatal outcomes, as most studies assess exposure based on residence at birth. The aim of this study was to ascertain whether such bias can be observed in a study on the effects of PM10 on risk of preterm birth and fetal growth restriction. METHODS: This was a retrospective study using four pregnancy cohorts of women recruited in Connecticut, USA (N=10,025). We ascertained associations with PM10 exposure calculated using first recorded maternal address, last recorded address, and full address histories. We used a discrete time-to-event model for preterm birth, and logistic regression to investigate associations with small for gestational age (SGA) and term low birth weight (LBW). RESULTS: Pregnant women tended to move to areas with lower levels of PM10. For all outcomes, there was negligible difference between effect sizes corresponding to exposures calculated with first, last and full address histories. For LBW, associations were observed for exposure in second trimester (OR 1.09; 95% CI: 1.04-1.14 per 1µg/m(3) PM10) and whole pregnancy (OR 1.08; 95% CI: 1.02-1.14). For SGA, associations were observed for elevated exposure in second trimester (OR 1.02; 95% CI: 1.00-1.04) and whole pregnancy (OR 1.03; 95% CI: 1.01-1.05). There was insufficient evidence for association with preterm birth. CONCLUSION: PM10 was associated with both SGA and term LBW. However, there was negligible benefit in accounting for residential mobility in pregnancy in this study

Vaccine-Elicited Mucosal and Systemic Antibody Responses Are Associated with Reduced Simian Immunodeficiency Viremia in Infant Rhesus Macaques

ABSTRACT Despite significant progress in reducing peripartum mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) with antiretroviral therapy (ART), continued access to ART throughout the breastfeeding period is still a limiting factor, and breast milk exposure to HIV accounts for up to 44% of MTCT. As abstinence from breastfeeding is not recommended, alternative means are needed to prevent MTCT of HIV. We have previously shown that oral vaccination at birth with live attenuated Mycobacterium tuberculosis strains expressing simian immunodeficiency virus (SIV) genes safely induces persistent SIV-specific cellular and humoral immune responses both systemically and at the oral and intestinal mucosa. Here, we tested the ability of oral M. tuberculosis vaccine strains expressing SIV Env and Gag proteins, followed by systemic heterologous (MVA-SIV Env/Gag/Pol) boosting, to protect neonatal macaques against oral SIV challenge. While vaccination did not protect infant macaques against oral SIV acquisition, a subset of immunized animals had significantly lower peak viremia which inversely correlated with prechallenge SIV Env-specific salivary and intestinal IgA responses and higher-avidity SIV Env-specific IgG in plasma. These controller animals also maintained CD4 + T cell populations better and showed reduced tissue pathology compared to noncontroller animals. We show that infants vaccinated at birth can develop vaccine-induced SIV-specific IgA and IgG antibodies and cellular immune responses within weeks of life. Our data further suggest that affinity maturation of vaccine-induced plasma antibodies and induction of mucosal IgA responses at potential SIV entry sites are associated with better control of viral replication, thereby likely reducing SIV morbidity. IMPORTANCE Despite significant progress in reducing peripartum MTCT of HIV with ART, continued access to ART throughout the breastfeeding period is still a limiting factor. Breast milk exposure to HIV accounts for up to 44% of MTCT. Alternative measures, in addition to ART, are needed to achieve the goal of an AIDS-free generation. Pediatric HIV vaccines constitute a core component of such efforts. The results of our pediatric vaccine study highlight the potential importance of vaccine-elicited mucosal Env-specific IgA responses in combination with high-avidity systemic Env-specific IgG in protection against oral SIV transmission and control of viral replication in infant macaques. The induction of potent mucosal IgA antibodies by our vaccine is remarkable considering the age-dependent development of mucosal IgA responses postbirth. A deeper understanding of postnatal immune development may inform the design of improved vaccine strategies to enhance systemic and mucosal SIV/HIV antibody responses

A Recombinant Attenuated Mycobacterium tuberculosis Vaccine Strain Is Safe in Immunosuppressed Simian Immunodeficiency Virus-Infected Infant Macaques

ABSTRACT Many resource-poor countries are faced with concurrent epidemics of AIDS and tuberculosis (TB) caused by human immunodeficiency virus (HIV) and Mycobacterium tuberculosis , respectively. Dual infections with HIV and M. tuberculosis are especially severe in infants. There is, however, no effective HIV vaccine, and the only licensed TB vaccine, the Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine, can cause disseminated mycobacterial disease in HIV-infected children. Thus, a pediatric vaccine to prevent HIV and M. tuberculosis infections is urgently needed. We hypothesized that a highly attenuated M. tuberculosis strain containing HIV antigens could be safely administered at birth and induce mucosal and systemic immune responses to protect against HIV and TB infections, and we rationalized that vaccine safety could be most rigorously assessed in immunocompromised hosts. Of three vaccine candidates tested, the recombinant attenuated M. tuberculosis strain mc 2 6435 carrying a simian immunodeficiency virus (SIV) Gag expression plasmid and harboring attenuations of genes critical for replication ( panCD and leuCD ) and immune evasion ( secA2 ), was found to be safe for oral or intradermal administration to non-SIV-infected and SIV-infected infant macaques. Safety was defined as the absence of clinical symptoms, a lack of histopathological changes indicative of M. tuberculosis infection, and a lack of mycobacterial dissemination. These data represent an important step in the development of novel TB vaccines and suggest that a combination recombinant attenuated M. tuberculosis -HIV vaccine could be a safe alternative to BCG for the pediatric population as a whole and, more importantly, for the extreme at-risk group of HIV-infected infants

Maternal characteristics associated with the dietary intake of nitrates, nitrites, and nitrosamines in women of child-bearing age: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Multiple <it>N</it>-nitroso compounds have been observed in animal studies to be both mutagenic and teratogenic. Human exposure to <it>N</it>-nitroso compounds and their precursors, nitrates and nitrites, can occur through exogenous sources, such as diet, drinking water, occupation, or environmental exposures, and through endogenous exposures resulting from the formation of <it>N</it>-nitroso compounds in the body. Very little information is available on intake of nitrates, nitrites, and nitrosamines and factors related to increased consumption of these compounds.</p> <p>Methods</p> <p>Using survey and dietary intake information from control women (with deliveries of live births without major congenital malformations during 1997-2004) who participated in the National Birth Defects Prevention Study (NBDPS), we examined the relation between various maternal characteristics and intake of nitrates, nitrites, and nitrosamines from dietary sources. Estimated intake of these compounds was obtained from the Willet Food Frequency Questionnaire as adapted for the NBDPS. Multinomial logistic regression models were used to estimate odds ratios and 95% confidence intervals for the consumption of these compounds by self-reported race/ethnicity and other maternal characteristics.</p> <p>Results</p> <p>Median intake per day for nitrates, nitrites, total nitrites (nitrites + 5% nitrates), and nitrosamines was estimated at 40.48 mg, 1.53 mg, 3.69 mg, and 0.472 μg respectively. With the lowest quartile of intake as the referent category and controlling for daily caloric intake, factors predicting intake of these compounds included maternal race/ethnicity, education, body mass index, household income, area of residence, folate intake, and percent of daily calories from dietary fat. Non-Hispanic White participants were less likely to consume nitrates, nitrites, and total nitrites per day, but more likely to consume dietary nitrosamines than other participants that participated in the NBDPS. Primary food sources of these compounds also varied by maternal race/ethnicity.</p> <p>Conclusions</p> <p>Results of this study indicate that intake of nitrates, nitrites, and nitrosamines vary considerably by race/ethnicity, education, body mass index, and other characteristics. Further research is needed regarding how consumption of foods high in nitrosamines and <it>N</it>-nitroso precursors might relate to risk of adverse pregnancy outcomes and chronic diseases.</p

Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.Career Development Award: (#IK2 CX000538); U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH); U.S.Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML) Merit Award: (#I01 BX000533); American Lung Association: (RT-350058)

Association between Variants in Atopy-Related Immunologic Candidate Genes and Pancreatic Cancer Risk

<div><p>Background</p><p>Many epidemiology studies report that atopic conditions such as allergies are associated with reduced pancreas cancer risk. The reason for this relationship is not yet understood. This is the first study to comprehensively evaluate the association between variants in atopy-related candidate genes and pancreatic cancer risk.</p><p>Methods</p><p>A population-based case-control study of pancreas cancer cases diagnosed during 2011-2012 (via Ontario Cancer Registry), and controls recruited using random digit dialing utilized DNA from 179 cases and 566 controls. Following an exhaustive literature review, SNPs in 180 candidate genes were pre-screened using dbGaP pancreas cancer GWAS data; 147 SNPs in 56 allergy-related immunologic genes were retained and genotyped. Logistic regression was used to estimate age-adjusted odd ratio (AOR) for each variant and false discovery rate was used to adjust Wald p-values for multiple testing. Subsequently, a risk allele score was derived based on statistically significant variants.</p><p>Results</p><p>18 SNPs in 14 candidate genes (<i>CSF2</i>, <i>DENND1B</i>, <i>DPP10</i>, <i>FLG</i>, <i>IL13</i>, <i>IL13RA2</i>, <i>LRP1B</i>, <i>NOD1</i>, <i>NPSR1</i>, <i>ORMDL3</i>, <i>RORA</i>, <i>STAT4</i>, <i>TLR6</i>, <i>TRA</i>) were significantly associated with pancreas cancer risk. After adjustment for multiple comparisons, two <i>LRP1B</i> SNPs remained statistically significant; for example, <i>LRP1B</i> rs1449477 (AA vs. CC: AOR=0.37, 95% CI: 0.22-0.62; p (adjusted)=0.04). Furthermore, the risk allele score was associated with a significant reduction in pancreas cancer risk (p=0.0007).</p><p>Conclusions</p><p>Preliminary findings suggest certain atopy-related variants may be associated with pancreas cancer risk. Further studies are needed to replicate this, and to elucidate the biology behind the growing body of epidemiologic evidence suggesting allergies may reduce pancreatic cancer risk.</p></div

Effects of respiratory muscle training (RMT) in children with infantile-onset Pompe disease and respiratory muscle weakness

PURPOSE: Respiratory muscle weakness is a primary therapeutic challenge for patients with infantile Pompe disease. We previously described the clinical implementation of a respiratory muscle training (RMT) regimen in two adults with late-onset Pompe disease; both demonstrated marked increases in inspiratory and expiratory muscle strength in response to RMT. However, the use of RMT in pediatric survivors of infantile Pompe disease has not been previously reported. METHOD: We report the effects of an intensive RMT program on maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) using A-B-A (baseline-treatment-posttest) single subject experimental design in two pediatric survivors of infantile Pompe disease. Both subjects had persistent respiratory muscle weakness despite long-term treatment with alglucosidase alfa. RESULTS: Subject 1 demonstrated negligible to modest increases in MIP/MEP (6% increase in MIP, d=0.25; 19% increase in MEP, d=0.87), while Subject 2 demonstrated very large increases in MIP/MEP (45% increase in MIP, d=2.38; 81% increase in MEP, d=4.31). Following three-month RMT withdrawal, both subjects maintained these strength increases and demonstrated maximal MIP and MEP values at follow-up. CONCLUSION: Intensive RMT may be a beneficial treatment for respiratory muscle weakness in pediatric survivors of infantile Pompe disease

Systematic Review on Internet Support Groups (ISGs) and Depression (2): What Is Known About Depression ISGs?

BACKGROUND: Internet support groups (ISGs) are a popular means by which consumers with depression communicate online. A number of studies have evaluated the nature and impact of depression-specific ISGs. However, to date there have been no published systematic reviews of this evidence. OBJECTIVE: The aim was to systematically identify and summarize the available evidence concerning the scope and findings of studies of depression ISGs. METHODS: Three databases (PubMed, PsycINFO, Cochrane) were searched using over 150 search terms extracted from relevant papers, abstracts, and a thesaurus. Papers were included if they employed an online peer-to-peer depression-specific support group and reported either quantitative or qualitative empirical data. The objective of each study was coded according to a 20-category classification system, which included the effect on depression and other outcomes, including help seeking; user characteristics, activity, satisfaction, perceived benefits, perceived disadvantages; the reason for using the ISG; the nature of ISG posts; characteristics of depression ISGs compared to other ISG types, face-to-face groups, and face-to-face counseling; ISG structure and longitudinal changes; and predictors of ISG adherence. RESULTS: Thirteen papers satisfied the inclusion criteria from an initial pool of 12,692 abstracts. Of these, three collected data using survey questionnaires, nine analyzed samples of posts, and one both collected survey data and analyzed a sample of posts. The quality of most studies was not high, and little data were collected on most key aspects of depression ISGs. The most common objective of the studies was to analyze the nature of the posts (eight studies) and to describe site usage (six studies) and user characteristics (five studies). The most prevalent types of social support were emotional, informational, and social companionship. CONCLUSIONS: Given the popularity of depression ISGs and the paucity of available evidence about them, there is a need for high-quality, systematic studies of these groups, their impact, and the characteristics of their members and users. Such information is required to inform decision making by consumers, provider and educational organizations, guideline developers, policy makers, and funding bodies considering using, recommending, providing, or funding such groups

Cell surface translocation of MR1 in the presence of ligand.

<p>a) BEAS-2B or primary NHBE cells were transfected with pCI:MR1-GFP and incubated for 30 hours. Transfected cells were then incubated with 6-FP for 18 hours. For imaging, cells were fixed and surface stained with α-MR1 (26.5), then imaged. In NHBE cells, MR1 surface staining (red) in MR1-GFP-expressing cells (green) is denoted by the arrows in the enlarged insets. Images shown are representative of at least three independent experiments. b) BEAS-2B or NHBE cells were treated as described in a). Following 6-FP treatment cells were harvested and surface stained on ice with α-MR1 (26.5). After staining, cells were fixed and analyzed by flow cytometry. Data shown are representative of at least three independent experiments. Where indicated, cells were treated with 100ng/ml brefeldin A (BFA) for 2 hours prior to 6-FP addition. Shown is a representative histogram demonstrating BFA blockade of 6-FP-dependent surface stabilization and the geometric mean and SEM of from three independent experiments. c) BEAS-2B or NHBE cells were transfected with pCI:MR1-GFP and treated with 6-FP as described above. Where indicated, cells were treated with10ug/ml cycloheximide (CHX) for 2 hours prior to 6-FP addition. Cells were fixed, and where indicated, stained with α-β2M, and imaged. Shown are results from one of at least three independent experiments. The Mann-Whitney test was used to determine the statistical significance of CHX treatment. For all other statistical comparisons, a Student’s t-test was used, *p<0.01. d) MR1-GFP⁺ β2M⁺ EC were identified and quantified as described in the Materials and Methods. Each dot represents the number of endosomes in one cell for any of the conditions. Shown are results from one of at least three independent experiments, *p<0.01.</p

Identification of trafficking molecules involved in presentation of Mtb ligands on MR1.

<p>a) A lentiviral shRNA library of trafficking molecules was screened by IFNγ ELISPOT assay with MR1, HLA-E, and HLA-B45 restricted T cell clones as described. Each bar represents separate shRNA wells and each well was analyzed individually in relation to the mean and characterized as a hit if it was at least 25% below the mean. The mean was normalized to 100% and is represented by red line. Results from shRNA knockdown of Rab2b, Rab7L1, or Stx18 from three independent experiments are shown. Stars indicate gene specific shRNA wells that met the candidate selection criteria. Candidates were selected if at least 2 of 5 independent shRNAs resulted in reduced T cell response. b) BEAS-2B cells were treated with missense or Stx18 siRNA, infected with Mtb (MOI:5), and used as APC in an IFNγ ELISPOT assay with 1x10⁴ MR1, HLA-E, or HLA-B45 restricted T cells clones per well. Shown are the results using 5 x 10³ APC that have been normalized to the response to the Missense siRNA treated cells (100%). **p<0.01. Error bars represent the mean and SEM from four independent experiments. qRT-PCR was performed on cDNA synthesized from mRNA isolated from missense or Stx18 siRNA silenced BEAS-2B cells that were uninfected or infected with Mtb (MOI:5). Error bars represent the mean and SEM for three independent experiments. Mtb colony forming units (CFU) from 1x10⁵ infected cells were determined by lysing and plating serial dilutions on 7H10 agar plates. Error bars represent the mean and SEM from 3 independent experiments. c) NHBE cells were treated with missense or Stx18 siRNA and infected with Mtb (MOI:10). IFNγ ELISPOT and qRT-PCR analyses were performed as described for BEAS-2B cells. Error bars represent the mean and SEM from two independent experiments. d) BEAS-2B cells were treated with missense, VAMP4, or Rab6 siRNA and infected with Mtb (MOI:5). IFNγ ELISPOT and qRT-PCR analyses were performed as described above. Error bars represent the mean and SEM from at least three independent experiments, *p<0.01 compared to missense. e) BEAS-2B cells were treated with missense, Sec22b, BNIP1, or Use1 siRNA and infected with Mtb (MOI:5). IFNγ ELISPOT and qRT-PCR analyses were performed as described above. Error bars represent the mean and SEM from at least two independent experiments, *p<0.01 compared to missense.</p