TRPV6 modulates proliferation of human pancreatic neuroendocrine BON-1 tumour cells

Highly Ca2+ permeable receptor potential channel vanilloid type 6 (TRPV6) modulates a variety of biological functions including calcium-dependent cell growth and apoptosis. So far, the role of TRPV6 in controlling growth of pancreatic neuroendocrine tumour (NET) cells is unknown. In the present study, we characterize the expression of TRPV6 in pancreatic BON-1 and QGP-1 NET cells. Furthermore, we evaluate the impact of TRPV6 on intracellular calcium, the activity of nuclear factor of activated T-cells (NFAT) and proliferation of BON-1 cells. TRPV6 expression was assessed by real-time PCR and Western blot. TRPV6 mRNA expression and protein production were down-regulated by siRNA. Changes in intracellular calcium levels were detected by fluorescence calcium imaging (fura-2/AM). NFAT activity was studied by NFAT reporter assay; cell proliferation by bromodeoxyuridine (BrdU), MTT and propidium iodine staining. TRPV6 mRNA and protein are present in BON-1 and QGP-1 NET-cells. Down-regulation of TRPV6 attenuates BON-1 cell proliferation. TRPV6 down- regulation is associated with decreased Ca2+ response pattern and reduced NFAT activity. In conclusion, TRPV6 is expressed in pancreatic NETs and modulates cell proliferation via Ca2+-dependent mechanism, which is accompanied by NFAT activation

Hair Manganese and Hyperactive Behaviors: Pilot Study of School-Age Children Exposed through Tap Water

BACKGROUND: Neurotoxic effects are known to occur with inhalation of manganese particulates, but very few data are available on exposure to Mn in water. We undertook a pilot study in a community in Québec (Canada) where naturally occurring high Mn levels were present in the public water system. Our objective was to test the hypothesis that greater exposure to Mn via drinking water would be reflected in higher Mn content in hair which, in turn, would be associated with increased level of hyperactive behaviors. METHODS: Forty-six children participated in the study, 24 boys and 22 girls, 6–15 years of age (median, 11 years). Their homes received water from one of two wells (W) with different Mn concentrations: W1: mean 610 μg/L; W2: mean 160 μg/L. The Revised Conners’ Rating Scale for parents (CPRS-R) and for teachers (CTRS-R) were administered, providing T-scores on the following subscales: Oppositional, Hyperactivity, Cognitive Problems/Inattention, and ADHD Index. RESULTS: Children whose houses were supplied by W1 had higher hair Mn (MnH) than those supplied by W2 (mean 6.2 ± 4.7 μg/g vs. 3.3 ± 3.0 μg/g, p = 0.025). MnH was significantly associated with T-scores on the CTRS-R Oppositional (p = 0.020) and Hyperactivity (p = 0.002) subscales, after adjustment for age, sex, and income. All children with Oppositional and Hyperactivity T-scores ≥ 65 had MnH > 3.0 μg/g. CONCLUSIONS: The findings of this pilot study are sufficiently compelling to warrant more extensive investigations into the risks of Mn exposure in drinking water

Thyroid Hormones in Pregnancy in Relation to Environmental Exposure to Organochlorine Compounds and Mercury

Polychlorinated biphenyls (PCBs), chlorinated pesticides, and mercury are global environmental contaminants that can disrupt the endocrine system in animals and humans. However, there is little evidence that they can interfere with endocrine status in pregnant women and neonates at low levels of exposure. The aim of this study was to examine thyroid hormone levels during pregnancy and in cord blood in relation to blood concentrations of organochlorine compounds (OCs) and Hg in healthy women recruited during pregnancy. We found a significant negative correlation between maternal total triiodothyronine levels and three non-coplanar congeners (PCB-138, PCB-153, and PCB-180), three pesticides (p,p′-DDE, cis-nanochlor, and hexachlorobenzene), and inorganic Hg independently, without any other changes in thyroid status. No significant relationships were observed between OCs and cord serum thyroid hormones. Cord serum free thyroxin was negatively correlated with inorganic Hg. These results suggest that at even low levels of exposure, persistent environmental contaminants can interfere with thyroid status during pregnancy

Tetrachloroethylene (PCE, Perc) Levels in Residential Dry Cleaner Buildings in Diverse Communities in New York City

Fugitive tetrachloroethylene (PCE, perc) emissions from dry cleaners operating in apartment buildings can contaminate residential indoor air. In 1997, New York State and New York City adopted regulations to reduce and contain perc emissions from dry cleaners located in residential and other buildings. As part of a New York State Department of Health (NYSDOH) study, indoor air perc levels were determined in 65 apartments located in 24 buildings in New York City where dry cleaners used perc on site. Sampling occurred during 2001–2003, and sampled buildings were dispersed across minority and nonminority as well as low-income and higher income neighborhoods. For the entire study area, the mean apartment perc level was 34 μg/m(3), 10-fold lower than mean apartment levels of 340–360 μg/m(3) documented before 1997. The maximum detected perc level was 5,000 μg/m(3), 5-fold lower than the maximum of 25,000 μg/m(3) documented before 1997. Despite these accomplishments, perc levels in 17 sampled apartments still exceeded the NYSDOH residential air guideline of 100 μg/m(3), and perc levels in 4 sampled apartments exceeded 1,000 μg/m(3). Moreover, mean indoor air perc levels in minority neighborhoods (75 μg/m(3)) were four times higher than in nonminority households (19 μg/m(3)) and were > 10 times higher in low-income neighborhoods (256 μg/m(3)) than in higher income neighborhoods (23 μg/m(3)). Logistic regression suitable for clustered data (apartments within buildings) indicated that perc levels on floors 1–4 were significantly more likely to exceed 100 μg/m(3) in buildings located in minority neighborhoods (odds ratio = 6.7; 95% confidence interval, 1.5–30.5) than in nonminority neighborhoods. Factors that may be contributing to the elevated perc levels detected, especially in minority and low-income neighborhoods, are being explored

A discussion of key values to inform the design and delivery of services for HIV-affected women and couples attempting pregnancy in resource-constrained settings.

Introduction HIV‐affected women and couples often desire children and many accept HIV risk in order to attempt pregnancy and satisfy goals for a family. Risk reduction strategies to mitigate sexual and perinatal HIV transmission include biomedical and behavioural approaches. Current efforts to integrate HIV and reproductive health services offer prime opportunities to incorporate strategies for HIV risk reduction during pregnancy attempts. Key client and provider values about services to optimize pregnancy in the context of HIV risk provide insights for the design and implementation of large‐scale “safer conception” programmes. Discussion Through our collective experience and discussions at a multi‐disciplinary international World Health Organization–convened workshop to initiate the development of guidelines and an algorithm of care to support the delivery of services for HIV‐affected women and couples attempting pregnancy, we identified four values that are key to the implementation of these programmes: (1) understanding fertility care and an ability to identify potential fertility problems; (2) providing equity of access to resources enabling informed decision‐making about reproductive choices; (3) creating enabling environments that reduce stigma associated with HIV and infertility; and (4) creating enabling environments that encourage disclosure of HIV status and fertility status to partners. Based on these values, recommendations for programmes serving HIV‐affected women and couples attempting pregnancy include the following: incorporation of comprehensive reproductive health counselling; training to support the transfer and exchange of knowledge between providers and clients; care environments that reduce the stigma of childbearing among HIV‐affected women and couples; support for safe and voluntary disclosure of HIV and fertility status; and increased efforts to engage men in reproductive decision‐making at times that align with women's desires. Conclusions Programmes, policies and guidelines that integrate HIV treatment and prevention, sexual and reproductive health and fertility care services in a manner responsive to user values and preferences offer opportunities to maximize demand for and use of these services. For HIV‐affected women and couples attempting pregnancy, the provision of comprehensive services using available tools – and the development of new tools that are adaptable to many settings and follow consensus recommendations – is a public health imperative. The impetus now is to design and deliver value‐driven inclusive programming to achieve the greatest coverage and impact to reduce HIV transmission during pregnancy attempts

Associations of iron metabolism genes with blood manganese levels: a population-based study with validation data from animal models

<p>Abstract</p> <p>Background</p> <p>Given mounting evidence for adverse effects from excess manganese exposure, it is critical to understand host factors, such as genetics, that affect manganese metabolism.</p> <p>Methods</p> <p>Archived blood samples, collected from 332 Mexican women at delivery, were analyzed for manganese. We evaluated associations of manganese with functional variants in three candidate iron metabolism genes: <it>HFE </it>[hemochromatosis], <it>TF </it>[transferrin], and <it>ALAD </it>[δ-aminolevulinic acid dehydratase]. We used a knockout mouse model to parallel our significant results as a novel method of validating the observed associations between genotype and blood manganese in our epidemiologic data.</p> <p>Results</p> <p>Percentage of participants carrying at least one copy of <it>HFE C282Y</it>, <it>HFE H63D</it>, <it>TF P570S</it>, and <it>ALAD K59N </it>variant alleles was 2.4%, 17.7%, 20.1%, and 6.4%, respectively. Percentage carrying at least one copy of either <it>C282Y </it>or <it>H63D </it>allele in <it>HFE </it>gene was 19.6%. Geometric mean (geometric standard deviation) manganese concentrations were 17.0 (1.5) μg/l. Women with any <it>HFE </it>variant allele had 12% lower blood manganese concentrations than women with no variant alleles (β = -0.12 [95% CI = -0.23 to -0.01]). <it>TF </it>and <it>ALAD </it>variants were not significant predictors of blood manganese. In animal models, <it>Hfe</it>^-/-mice displayed a significant reduction in blood manganese compared with <it>Hfe</it>^+/+mice, replicating the altered manganese metabolism found in our human research.</p> <p>Conclusions</p> <p>Our study suggests that genetic variants in iron metabolism genes may contribute to variability in manganese exposure by affecting manganese absorption, distribution, or excretion. Genetic background may be critical to consider in studies that rely on environmental manganese measurements.</p