Polymorphisms in GSTT1, GSTM1, NAT1 and NAT2 genes and bladder cancer risk in men and women

Background: Cigarette smoking is an established risk factor for bladder cancer. Epidemiological and biological data suggest that genetic polymorphisms in activating and detoxifying enzymes may play a role in determining an individual's susceptibility to bladder cancer in particular when in combination with specific environmental exposures such as cigarette smoking. N-acetyltransferase (NAT) enzymes, NAT1 and NAT2, are involved in the activation and detoxification of tobacco smoke constituents. Polymorphisms in these genes alter the ability of these enzymes to metabolize carcinogens, as certain allelic combinations result in a slow or rapid acetylation phenotype. Glutathione S-transferases (GSTs) also detoxify tobacco smoke constituents, and polymorphisms within the GSTM1 and GSTT1 genes can result in a complete lack of enzyme activity. Methods: We assessed the association between common polymorphisms identified in the GSTM1, GSTT1, NAT1, and NAT2 genes and the risk of bladder cancer in two nested case-control studies within the Nurses' Health Study (n = 78 female cases, 234 female controls) and the Health Professionals' Follow-up Study (n = 139 male cases, 293 male controls). We also evaluated whether cigarette smoking modified the associations of the genotypes and bladder cancer risk in men and women. Results: Overall, we observed no statistically significant associations between the polymorphisms and bladder cancer risk among men and women, although given our sample size, we had limited power to detect small to moderate effects. There was however the suggestion of an increased risk among female ever smokers with the NAT2 slow genotype and an increased risk in male never smokers with the GSTM1 null genotype. Conclusion: In summary, these prospective results are consistent with previous literature supporting associations between bladder cancer and the NAT2 slow acetylation and the GSTM1 null genotypes

Constraints on the Petrogenesis of a Proterozoic Talc Deposit in Southwestern Montana: A Petrological and Geochemical study

Talc, a magnesium phyllosilicate, is used in many products, including paints, rubber, ceramics, cosmetics, and plastics. Talc mineralization generally occurs in low-grade metamorphic conditions and requires a significant source of magnesium. Large amounts of Al, Ca, or K in the formational environment limit talc mineralization in favor of other minerals such as chlorite, tremolite, and biotite. Formation processes, such as metamorphism or hydrothermal events, of the talc bodies, control the inherent compositions and can dictate which impurities are present. This study focuses on a talc deposit near Alder, Montana, one of a series of high purity Precambrian deposits within this region. Petrographic results indicate that dolomitic marble was pseudomorphically replaced by talc. This implies that sufficient magnesium was supplied from the host rock and silica was supplied by the hydrothermal fluid. Relatively pure (>90% by XRD) talc samples have only trace amounts of Al, Ca, and K, and are very low in rare earth elements (REE), with generally flat chondrite-normalized REE patterns by XRF and ICP-MS. For these samples, the most common accessory mineral is clinochlore. Acetic acid leachates from carbonate-rich units yield light REE enriched patterns and higher REE concentrations than the pure talc samples. Rare earth element patterns and concentrations suggest that the talc inherited its REEs from the carbonate during recrystallization from carbonate to talc. Sm-Nd isotope data from the carbonate samples define a linear trend corresponding to an age of 1.42±0.07 Ga, which is consistent with the inferred age of the hydrothermal event responsible for the talc formation

Transcriptional analysis of the mammalian heart with special reference to its endocrine function

<p>Abstract</p> <p>Background</p> <p>Pharmacological and gene ablation studies have demonstrated the crucial role of the endocrine function of the heart as mediated by the polypeptide hormones ANF and BNP in the maintenance of cardiovascular homeostasis. The importance of these studies lies on the fact that hypertension and chronic congestive heart failure are clinical entities that may be regarded as states of relative deficiency of ANF and BNP. These hormones are produced by the atrial muscle cells (cardiocytes), which display a dual secretory/muscle phenotype. In contrast, ventricular cardiocytes display mainly a muscle phenotype. Comparatively little information is available regarding the genetic background for this important phenotypic difference with particular reference to the endocrine function of the heart. We postulated that comparison of gene expression profiles between atrial and ventricular muscles would help identify gene transcripts that underlie the phenotypic differences associated with the endocrine function of the heart.</p> <p>Results</p> <p>Comparison of gene expression profiles in the rat heart revealed a total of 1415 differentially expressed genes between the atria and ventricles based on a 1.8 fold cut-off. The identification of numerous chamber specific transcripts, such as ANF for the atria and Irx4 for the ventricles among several others, support the soundness of the GeneChip data and demonstrates that the differences in gene expression profiles observed between the atrial and ventricular tissues were not spurious in nature. Pathway analysis revealed unique expression profiles in the atria for G protein signaling that included Gα_o1, Gγ₂and Gγ₃, AGS1, RGS2, and RGS6 and the related K⁺channels GIRK1 and GIRK4. Transcripts involved in vesicle trafficking, hormone secretion as well as mechanosensors (e.g. the potassium channel TREK-1) were identified in relationship to the synthesis, storage and secretion of hormones.</p> <p>Conclusion</p> <p>The data developed in this investigation describes for the first time data on gene expression particularly centred on the secretory function of the heart. This provides for a rational approach in the investigation of determinants of the endocrine of the heart in health and disease.</p

Long-term impact of sewage sludge application on soil microbial biomass: An evaluation using meta-analysis

The Long-Term Sludge Experiments (LTSE) began in 1994 as part of continuing research into the effects of sludge-borne heavy metals on soil fertility. The long-term effects of Zn, Cu, and Cd on soil microbial biomass carbon (Cmic) were monitored for 8 years (1997-2005) in sludge amended soils at nine UK field sites. To assess the statutory limits set by the UK Sludge (Use in Agriculture) Regulations the experimental data has been reviewed using the statistical methods of meta-analysis. Previous LTSE studies have focused predominantly on statistical significance rather than effect size, whereas meta-analysis focuses on the magnitude and direction of an effect, i.e. the practical significance, rather than its statistical significance. The results presented here show that significant decreases in Cmic have occurred in soils where the total concentrations of Zn and Cu fall below the current UK statutory limits. For soils receiving sewage sludge predominantly contaminated with Zn, decreases of approximately 7–11% were observed at concentrations below the UK statutory limit. The effect of Zn appeared to increase over time, with increasingly greater decreases in Cmic observed over a period of 8 years. This may be due to an interactive effect between Zn and confounding Cu contamination which has augmented the bioavailability of these metals over time. Similar decreases (7–12%) in Cmic were observed in soils receiving sewage sludge predominantly contaminated with Cu; however, Cmic appeared to show of recovery after a period of 6 years. Application of sewage sludge predominantly contaminated with Cd appeared to have no effect on Cmic at concentrations below the current UK statutory limit

The neurodevelopmental hypothesis of schizophrenia: Convergent clues from epidemiology and neuropathology

The neurodevelopmental hypothesis of schizophrenia suggests that the disruption of early brain development increases the risk of later developing schizophrenia. This hypothesis focuses attention on critical periods of early brain development. From an epidemiologic perspective, various prenatal and perinatal risk factors have been linked to schizophrenia, including exposures related to infection, nutrition, and obstetric complications. From a genetic perspective, candidate genes have also been linked to altered brain development. In recent decades evidence from neuropathology has provided support for the neurodevelopmental hypothesis. Animal models involving early life exposures have been linked to changes in these same brain systems, providing convergent evidence for this long-standing hypothesis

Pathogen-specifi c burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED)

Background Most studies of the causes of diarrhoea in low-income and middle-income countries have looked at severe disease in people presenting for care, and there are few estimates of pathogen-specifi c diarrhoea burdens in the community. Methods We undertook a birth cohort study with not only intensive community surveillance for diarrhoea but also routine collection of non-diarrhoeal stools from eight sites in South America, Africa, and Asia. We enrolled children within 17 days of birth, and diarrhoeal episodes (defi ned as maternal report of three or more loose stools in 24 h, or one loose stool with visible blood) were identifi ed through twice-weekly home visits by fi eldworkers over a follow-up period of 24 months. Non-diarrhoeal stool specimens were also collected for surveillance for months 1–12, 15, 18, 21, and 24. Stools were analysed for a broad range of enteropathogens using culture, enzyme immunoassay, and PCR. We used the adjusted attributable fraction (AF) to estimate pathogen-specifi c burdens of diarrhoea. Findings Between Nov 26, 2009, and Feb 25, 2014, we tested 7318 diarrhoeal and 24 310 non-diarrhoeal stools collected from 2145 children aged 0–24 months. Pathogen detection was common in non-diarrhoeal stools but was higher with diarrhoea. Norovirus GII (AF 5·2%, 95% CI 3·0–7·1), rotavirus (4·8%, 4·5–5·0), Campylobacter spp (3·5%, 0·4–6·3), astrovirus (2·7%, 2·2–3·1), and Cryptosporidium spp (2·0%, 1·3–2·6) exhibited the highest attributable burdens of diarrhoea in the fi rst year of life. The major pathogens associated with diarrhoea in the second year of life were Campylobacter spp (7·9%, 3·1–12·1), norovirus GII (5·4%, 2·1–7·8), rotavirus (4·9%, 4·4–5·2), astrovirus (4·2%, 3·5–4·7), and Shigella spp (4·0%, 3·6–4·3). Rotavirus had the highest AF for sites without rotavirus vaccination and the fi fth highest AF for sites with the vaccination. There was substantial variation in pathogens according to geography, diarrhoea severity, and season. Bloody diarrhoea was primarily associated with Campylobacter spp and Shigella spp, fever and vomiting with rotavirus, and vomiting with norovirus GII. Interpretation There was substantial heterogeneity in pathogen-specifi c burdens of diarrhoea, with important determinants including age, geography, season, rotavirus vaccine usage, and symptoms. These fi ndings suggest that although single-pathogen strategies have an important role in the reduction of the burden of severe diarrhoeal disease, the eff ect of such interventions on total diarrhoeal incidence at the community level might be limited

Transplastomic tobacco plants expressing a fatty acid desaturase gene exhibit altered fatty acid profiles and improved cold tolerance

The possibility of altering the unsaturation level of fatty acids in plant lipids by genetic transformation has implications for the stress tolerance of higher plants as well as for their nutritional value and industrial utilisation. While the integration and expression of transgenes in the plastome has several potential advantages over nuclear transformation, very few attempts have been made to manipulate fatty acid biosynthesis using plastid transformation. We produced transplastomic tobacco plants that express a Delta9 desaturase gene from either the wild potato species Solanum commersonii or the cyanobacterium Anacystis nidulans, using PEG-mediated DNA uptake by protoplasts. Incorporation of chloroplast antibioticinsensitive point mutations in the transforming DNA was used to select transformants. The presence of the transcript and the Delta9 desaturase protein in transplastomic plants was confirmed by northern and western blot analyses. In comparison with control plants, transplastomic plants showed altered fatty acid profiles and an increase in their unsaturation level both in leaves and seeds. The two transgenes produced comparable results. The results obtained demonstrate the feasibility of using plastid transformation to engineer lipid metabolic pathways in both vegetative and reproductive tissues and suggest an increase of cold tolerance in transplastomic plants showing altered leaf fatty acid profiles. This is the first example of transplastomic plants expressing an agronomically relevant gene produced with the ‘‘binding-type’’ vectors, which do not contain a heterologous marker gene. In fact, the transplastomic plants expressing the S. commersonii gene contain only plant-derived sequences, a clear attraction from a public acceptability perspective

Strengthening universal HIV 'test-and-treat' approaches with social science research.

Prevention, Population and Disease management (PrePoD

A prospective study of androgen levels, hormone-related genes and risk of rheumatoid arthritis

Introduction Rheumatoid arthritis (RA) is more common in females than males and sex steroid hormones may in part explain this difference. We conducted a case–control study nested within two prospective studies to determine the associations between plasma steroid hormones measured prior to RA onset and polymorphisms in the androgen receptor (AR), estrogen receptor 2 (ESR2), aromatase (CYP19) and progesterone receptor (PGR) genes and RA risk. Methods We genotyped AR, ESR2, CYP19, PGR SNPs and the AR CAG repeat in RA case–control studies nested within the Nurses\u27 Health Study (NHS), NHS II (449 RA cases, 449 controls) and the Women\u27s Health Study (72 cases, and 202 controls). All controls were matched on cohort, age, Caucasian race, menopausal status, and postmenopausal hormone use. We measured plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and sex hormone binding globulin in 132 pre-RA samples and 396 matched controls in the NHS cohorts. We used conditional logistic regression models adjusted for potential confounders to assess RA risk. Results Mean age of RA diagnosis was 55 years in both cohorts; 58% of cases were rheumatoid factor positive at diagnosis. There was no significant association between plasma DHEAS, total testosterone, or calculated free testosterone and risk of future RA. There was no association between individual variants or haplotypes in any of the genes and RA or seropositive RA, nor any association for the AR CAG repeat. Conclusions Steroid hormone levels measured at a single time point prior to RA onset were not associated with RA risk in this study. Our findings do not suggest that androgens or the AR, ESR2, PGR, and CYP19 genes are important to RA risk in women