Investigating the relationship between alcohol consumption and type 2 diabetes: A longitudinal analysis of the Whitehall II cohort, 1985-2013

BACKGROUND: Although previous studies have reported a J-shaped association between the volume of alcohol consumption and incidence of type 2 diabetes (T2DM), a number of limitations weaken the validity of such findings. This thesis aims to systematically explore the effect of key methodological shortcomings. METHODS: Analyses were undertaken using Whitehall II data from 1985-2013. To examine the degree to which conventional survival analyses might be subject to misclassification error due to the use of a single baseline measure of drinking status, mixed effects models were used to plot the trajectory of alcohol intake according to baseline categories of consumption. Mixed effects models were also stratified by diagnosis status to shed light upon whether increases or decreases in risk are likely to accrue gradually over the life course or occur as a consequence of differences in intake specific to periods of heightened biological sensitivity. Finally, given changes in alcohol consumption across the life course, increasingly complex survival models were used to explore the relationship between different dimensions of the longitudinal trajectory and T2DM risk. RESULTS: Alcohol consumption within categories of baseline drinking converged over the adult life course toward moderate volumes, with moderate drinkers increasingly contaminated by participants defined at baseline as heavy or infrequent drinkers. Men who developed T2DM were found to increase their consumption up to their date of diagnosis, while drinking among women remained relatively stable up to diagnosis. Marked decreases in consumption were evident among both sexes following diagnosis. Reductions in the risk of T2DM were specific to or most pronounced among female current drinkers in middle age, with drinking in later life associated with an increased risk regardless of sex, after adjustment for prior consumption. CONCLUSIONS: Variations in alcohol consumption across the adult life course highlight the importance of considering drinking histories when defining alcohol consumption categories, with the risk of misclassification error appearing to increase with age. Although reductions in the risk of T2DM were most pronounced among middle-aged women, evidence concerning the determinants of such a sex-specific disparity is lacking. That risks are heightened in older age suggest that any benefits from drinking earlier in the life course may be countered by age-related deteriorations to the alcohol metabolism

All cause mortality and the case for age specific alcohol consumption guidelines: pooled analyses of up to 10 population based cohorts.

To examine the suitability of age specific limits for alcohol consumption and to explore the association between alcohol consumption and mortality in different age groups

Explanatory factors for health inequalities across different ethnic and gender groups: data from a national survey in England

BACKGROUND: The objective of this study was to examine the relative contribution of factors explaining ethnic health inequalities (EHI) in poor self-reported health (pSRH) and limiting long-standing illness (LLI) between Health Survey for England (HSE) participants. METHOD: Using HSE 2003-2006 data, the odds of reporting pSRH or of LLI in 8573 Bangladeshi, Black African, Black Caribbean, Chinese, Indian, Irish and Pakistani participants was compared with 28,470 White British participants. The effects of demographics, socioeconomic position (SEP), psychosocial variables, community characteristics and health behaviours were assessed using separate regression models. RESULTS: Compared with White British men, age-adjusted odds (OR, 95% CI) of pSRH were higher among Bangladeshi (2.05, 1.34 to 3.14), Pakistani (1.77, 1.34 to 2.33) and Black Caribbean (1.60, 1.18 to 2.18) men, but these became non-significant following adjustment for SEP and health behaviours. Unlike Black Caribbean men, Black African men exhibited a lower risk of age-adjusted pSRH (0.66, 0.43 to 1.00 (p=0.048)) and LLI (0.45, 0.28 to 0.72), which were significant in every model. Likewise, Chinese men had a lower risk of age-adjusted pSRH (0.51, 0.26 to 1.00 (p=0.048)) and LLI (0.22, 0.10 to 0.48). Except in Black Caribbean women, adjustment for SEP rendered raised age-adjusted associations for pSRH among Pakistani (2.51, 1.99 to 3.17), Bangladeshi (1.85, 1.08 to 3.16), Black Caribbean (1.78, 1.44 to 2.21) and Indian women (1.37, 1.13 to 1.66) insignificant. Adjustment for health behaviours had the largest effect for South Asian women. By contrast, Irish women reported better age-adjusted SRH (0.70, 1.51 to 0.96). CONCLUSIONS: SEP and health behaviours were major contributors explaining EHI. Policies to improve health equity need to monitor these pathways and be informed by them

Structural basis of dimerization and nucleic acid binding of human DBHS proteins NONO and PSPC1.

The Drosophila behaviour/human splicing (DBHS) proteins are a family of RNA/DNA binding cofactors liable for a range of cellular processes. DBHS proteins include the non-POU domain-containing octamer-binding protein (NONO) and paraspeckle protein component 1 (PSPC1), proteins capable of forming combinatorial dimers. Here, we describe the crystal structures of the human NONO and PSPC1 homodimers, representing uncharacterized DBHS dimerization states. The structures reveal a set of conserved contacts and structural plasticity within the dimerization interface that provide a rationale for dimer selectivity between DBHS paralogues. In addition, solution X-ray scattering and accompanying biochemical experiments describe a mechanism of cooperative RNA recognition by the NONO homodimer. Nucleic acid binding is reliant on RRM1, and appears to be affected by the orientation of RRM1, influenced by a newly identified 'β-clasp' structure. Our structures shed light on the molecular determinants for DBHS homo- and heterodimerization and provide a basis for understanding how DBHS proteins cooperatively recognize a broad spectrum of RNA targets

Quantitative trait loci for bone traits segregating independently of those for growth in an F-2 broiler X layer cross

An F broiler-layer cross was phenotyped for 18 skeletal traits at 6, 7 and 9 weeks of age and genotyped with 120 microsatellite markers. Interval mapping identified 61 suggestive and significant QTL on 16 of the 25 linkage groups for 16 traits. Thirty-six additional QTL were identified when the assumption that QTL were fixed in the grandparent lines was relaxed. QTL with large effects on the lengths of the tarsometatarsus, tibia and femur, and the weights of the tibia and femur were identified on GGA4 between 217 and 249 cM. Six QTL for skeletal traits were identified that did not co-locate with genome wide significant QTL for body weight and two body weight QTL did not coincide with skeletal trait QTL. Significant evidence of imprinting was found in ten of the QTL and QTL x sex interactions were identified for 22 traits. Six alleles from the broiler line for weight- and size-related skeletal QTL were positive. Negative alleles for bone quality traits such as tibial dyschondroplasia, leg bowing and tibia twisting generally originated from the layer line suggesting that the allele inherited from the broiler is more protective than the allele originating from the layer

Gene by environment QTL mapping through multiple trait analyses in blood pressure salt-sensitivity: identification of a novel QTL in rat chromosome 5

BACKGROUND: The genetic mechanisms underlying interindividual blood pressure variation reflect the complex interplay of both genetic and environmental variables. The current standard statistical methods for detecting genes involved in the regulation mechanisms of complex traits are based on univariate analysis. Few studies have focused on the search for and understanding of quantitative trait loci responsible for gene × environmental interactions or multiple trait analysis. Composite interval mapping has been extended to multiple traits and may be an interesting approach to such a problem. METHODS: We used multiple-trait analysis for quantitative trait locus mapping of loci having different effects on systolic blood pressure with NaCl exposure. Animals studied were 188 rats, the progenies of an F2 rat intercross between the hypertensive and normotensive strain, genotyped in 179 polymorphic markers across the rat genome. To accommodate the correlational structure from measurements taken in the same animals, we applied univariate and multivariate strategies for analyzing the data. RESULTS: We detected a new quantitative train locus on a region close to marker R589 in chromosome 5 of the rat genome, not previously identified through serial analysis of individual traits. In addition, we were able to justify analytically the parametric restrictions in terms of regression coefficients responsible for the gain in precision with the adopted analytical approach. CONCLUSION: Future work should focus on fine mapping and the identification of the causative variant responsible for this quantitative trait locus signal. The multivariable strategy might be valuable in the study of genetic determinants of interindividual variation of antihypertensive drug effectiveness

Eosinophils Are Important for Protection, Immunoregulation and Pathology during Infection with Nematode Microfilariae

Eosinophil responses typify both allergic and parasitic helminth disease. In helminthic disease, the role of eosinophils can be both protective in immune responses and destructive in pathological responses. To investigate whether eosinophils are involved in both protection and pathology during filarial nematode infection, we explored the role of eosinophils and their granule proteins, eosinophil peroxidase (EPO) and major basic protein-1 (MBP-1), during infection with Brugia malayi microfilariae. Using eosinophil-deficient mice (PHIL), we further clarify the role of eosinophils in clearance of microfilariae during primary, but not challenge infection in vivo. Deletion of EPO or MBP-1 alone was insufficient to abrogate parasite clearance suggesting that either these molecules are redundant or eosinophils act indirectly in parasite clearance via augmentation of other protective responses. Absence of eosinophils increased mast cell recruitment, but not other cell types, into the broncho-alveolar lavage fluid during challenge infection. In addition absence of eosinophils or EPO alone, augmented parasite-induced IgE responses, as measured by ELISA, demonstrating that eosinophils are involved in regulation of IgE. Whole body plethysmography indicated that nematode-induced changes in airway physiology were reduced in challenge infection in the absence of eosinophils and also during primary infection in the absence of EPO alone. However lack of eosinophils or MBP-1 actually increased goblet cell mucus production. We did not find any major differences in cytokine responses in the absence of eosinophils, EPO or MBP-1. These results reveal that eosinophils actively participate in regulation of IgE and goblet cell mucus production via granule secretion during nematode-induced pathology and highlight their importance both as effector cells, as damage-inducing cells and as supervisory cells that shape both innate and adaptive immunity

Transdermal fentanyl for the treatment of pain caused by osteoarthritis of the knee or hip: an open, multicentre study

BACKGROUND: This study was designed to evaluate the utility of transdermal fentanyl (TDF, Durogesic(®)) for the treatment of pain due to osteoarthritis (OA) of the knee or hip, which was not adequately controlled by non-opioid analgesics or weak opioids. The second part of the trial, investigating TDF in patients with rheumatoid arthritis (RA) is reported separately. METHODS: Current analgesia was optimised during a 1-week run-in. Patients then received 28 days treatment with TDF starting at 25 μg/hr, with the option to increase the dose until adequate pain control was achieved. Metoclopramide was taken during the first week and then as needed. RESULTS: Of the 159 patients recruited, 75 with OA knee and 44 with OA hip completed the treatment phase, 30 knee and 18 hip patients entered the one-week taper-off phase. The most frequently used maximum dose of TDF was 25 μg/hr. The number of patients with adequate pain control increased during the run-in period from 4% to 27%, and further increased during TDF treatment to 88% on day 28. From baseline to endpoint, there were significant reductions in pain (p < 0.001) and improvements in functioning (p < 0.001) and physical (p < 0.001) and mental (p < 0.05) health. Scores for 'pain right now' decreased significantly within 24 hours of starting TDF treatment. TDF was assessed favourably and 84% of patients would recommend it for OA-related pain. Nausea and vomiting were the most common adverse events (reported by 32% and 26% of patients respectively), despite prophylaxis with metoclopramide, which showed limited efficacy in this setting. CONCLUSION: TDF significantly increased pain control, and improved functioning and quality of life. Metoclopramide appeared to be of limited value in preventing nausea and vomiting; more effective anti-emetic treatment may enable more people to benefit from strong opioids such as TDF. This study suggests that four weeks is a reasonable period to test the benefit of adding TDF to improve pain control in OA patients and that discontinuing therapy in cases of limited benefit creates no major obstacles

A search for quantitative trait loci controlling within-individual variation of physical activity traits in mice

<p>Abstract</p> <p>Background</p> <p>In recent years it has become increasingly apparent that physical inactivity can predispose individuals to a host of health problems. While many studies have analyzed the effect of various environmental factors on activity, we know much less about the genetic control of physical activity. Some studies in mice have discovered quantitative trait loci (QTL) influencing various physical activity traits, but mostly have analyzed inter-individual variation rather than variation in activity within individuals over time. We conducted a genome scan to identify QTLs controlling the distance, duration, and time run by mice over seven consecutive three-day intervals in an F₂population created by crossing two inbred strains (C57L/J and C3H/HeJ) that differed widely (average of nearly 300%) in their activity levels. Our objectives were (a) to see if we would find QTLs not originally discovered in a previous investigation that assessed these traits over the entire 21-day period and (b) to see if some of these QTLs discovered might affect the activity traits only in the early or in the late time intervals.</p> <p>Results</p> <p>This analysis uncovered 39 different QTLs, over half of which were new. Some QTLs affected the activity traits only in the early time intervals and typically exhibited significant dominance effects whereas others affected activity only in the later age intervals and exhibited less dominance. We also analyzed the regression slopes of the activity traits over the intervals, and found several QTLs affecting these traits that generally mapped to unique genomic locations.</p> <p>Conclusions</p> <p>It was concluded that the genetic architecture of physical activity in mice is much more complicated than has previously been recognized, and may change considerably depending on the age at which various activity measures are assessed.</p