Gene-by-gene interactions associated with the risk of conotruncal heart defects

BACKGROUND: The development of conotruncal heart defects (CTDs) involves a complex relationship among genetic variants and maternal lifestyle factors. In this article, we focused on the interactions between 13 candidate genes within folate, homocysteine, and transsulfuration pathways for potential association with CTD risk. METHODS: Targeted sequencing was used for 328 case-parental triads enrolled in the National Birth Defects Prevention Study (NBDPS). To evaluate the interaction of two genes, we applied a conditional logistic regression model for all possible SNP pairs within two respective genes by contrasting the affected infants with their pseudo-controls. The findings were replicated in an independent sample of 86 NBDPS case-parental triads genotyped by DNA microarrays. The results of two studies were further integrated by a fixed-effect meta-analysis. RESULTS: One SNP pair (i.e., rs4764267 and rs6556883) located in gene MGST1 and GLRX, respectively, was found to be associated with CTD risk after multiple testing adjustment using simpleM, a modified Bonferroni correction approach (nominal p-value of 4.62e-06; adjusted p-value of .04). Another SNP pair (i.e., rs11892646 and rs56219526) located in gene DNMT3A and MTRR, respectively, achieved marginal significance after multiple testing adjustment (adjusted p-value of .06). CONCLUSION: Further studies with larger sample sizes are needed to confirm and elucidate these potential interactions

Toll-like receptor gene variants and bacterial vaginosis among HIV-1 infected and uninfected African women.

Bacterial vaginosis (BV) is a common vaginal syndrome associated with altered microflora that increases the risk of preterm delivery and acquisition of sexually transmitted diseases. The cause of BV is unknown although toll-like receptors (TLRs), that are central to innate immune responses, may be important. We evaluated associations between TLR SNPs and BV among HIV-1 infected and uninfected African women. Logistic regression was used to assess associations between SNPs (N=99) in TLRs 2-4, 7-9 and BV (as classified by Nugent's criteria). Among HIV-1 uninfected women, TLR7 rs5743737 and TLR7 rs1634323 were associated with a decreased risk of BV, whereas TLR7 rs179012 was associated with an increased risk. TLR2 SNP rs3804099 was associated with a decreased risk of BV among HIV-1 infected women. Our findings indicate that there may be differences in TLR association with BV among HIV-1 infected and HIV-1 uninfected women

Glucose and C-Peptide Changes in the Perionset Period of Type 1 Diabetes in the Diabetes Prevention Trial–Type 1

OBJECTIVE—We examined metabolic changes in the period immediately after the diagnosis of type 1 diabetes and in the period leading up to its diagnosis in Diabetes Prevention Trial–Type 1 (DPT-1) participants

Reduction in Natural Death and Renal Failure From a Systematic Screening and Treatment Program in an Australian Aboriginal Community

BACKGROUND: Australian Aborigines in remote areas are experiencing an epidemic of renal and cardiovascular disease. In November 1995, we introduced a renal and cardiovascular treatment program into the Tiwi community, which has a three- to fivefold increase in death rates and a recent annual incidence of treated end-stage renal disease (ESRD) of 2760 per million. Our previous study described an estimated 50% reduction in renal failure and all-cause natural deaths in the treatment group through December 31, 1998. We now describe a reduction in these events through mid 2000. METHODS: People eligible for treatment were those with confirmed hypertension, diabetics with microalbuminuria or overt albuminuria, and people with overt albuminuria, regardless of blood pressure and diabetes. Treatment centered around the use of perindopril (Coversyl, Servier), with additional agents as needed to reach defined blood pressure goals, attempts at control of glucose and lipid levels, and health education. Two hundred and sixty-seven people, or 30% of the adult population, have been enrolled, with mean follow up of 3.39 years. Rates of terminal endpoints were compared on an intention-to-treat basis with those of 327 historical controls matched for baseline disease severity, who were followed for a mean of 3.18 years in the pre-treatment program era, against a background of no treatment or inconsistent changing treatment. RESULTS: Terminal events occurred in 38 controls and 23 people in the treatment group. The estimated rate of natural deaths in the treatment group was 50% that of the controls, (P=0.012); the rate of renal deaths was 47% (P=0.038) and the rate of non-renal deaths was 54% that of controls (P=0.085). Survival benefit in the treatment group was observed at all levels of overt albuminuria, in non-diabetics and diabetics, in normotensive as well as hypertensive people, and in people who had been taking angiotensin converting enzyme-inhibitors (ACEi) in the pre-program era, as well as those who had not. Benefit was absent among the low death rates of people without overt albuminuria, and questionable among people with glomerular filtration rates (GFRs

How can we get close to zero? The potential contribution of biomedical prevention and the investment framework towards an effective response to HIV.

BACKGROUND: In 2011 an Investment Framework was proposed that described how the scale-up of key HIV interventions could dramatically reduce new HIV infections and deaths in low and middle income countries by 2015. This framework included ambitious coverage goals for prevention and treatment services resulting in a reduction of new HIV infections by more than half. However, it also estimated a leveling in the number of new infections at about 1 million annually after 2015. METHODS: We modeled how the response to AIDS can be further expanded by scaling up antiretroviral treatment (ART) within the framework provided by the 2013 WHO treatment guidelines. We further explored the potential contributions of new prevention technologies: 'Test and Treat', pre-exposure prophylaxis and an HIV vaccine. FINDINGS: Immediate aggressive scale up of existing approaches including the 2013 WHO guidelines could reduce new infections by 80%. A 'Test and Treat' approach could further reduce new infections. This could be further enhanced by a future highly effective pre-exposure prophylaxis and an HIV vaccine, so that a combination of all four approaches could reduce new infections to as low as 80,000 per year by 2050 and annual AIDS deaths to 260,000. INTERPRETATION: In a set of ambitious scenarios, we find that immediate implementation of the 2013 WHO antiretroviral therapy guidelines could reduce new HIV infections by 80%. Further reductions may be achieved by moving to a 'Test and Treat' approach, and eventually by adding a highly effective pre-exposure prophylaxis and an HIV vaccine, if they become available