Linkage and Association Analysis of Radiation Damage Repair Genes XRCC3 and XRCC5 with Nevus Density in Adolescent Twins

Previous studies have shown that a deficiency in DNA damage repair is associated with increased cancer risk, and exposure to UV radiation is a major risk factor for the development of malignant melanoma. High density of common nevi (moles) is a major risk factor for cutaneous melanoma. A nevus may result from a mutation in a single UV-exposed melanocyte which failed to repair DNA damage in one or more critical genes. XRCC3 and XRCC5 may have an effect on nevus count through their function as components of DNA repair processes that may be involved directly or indirectly in the repair of DNA damage due to UV radiation. This study aims to test the hypothesis that the frequency of flat or raised moles is associated with polymorphism at or near these DNA repair genes, and that certain alleles are associated with less efficient DNA repair, and greater nevus density. Twins were recruited from schools in south eastern Queensland and were examined close to their 12th birthday. Nurses examined each individual and counted all moles on the entire body surface. A 10cM genome scan of 274 families (642 individuals) was performed and microsatellite polymorphisms in XRCC3 and adjacent to XRCC5 were also typed. Linkage and association of nevus count to these loci were tested simultaneously using a structural-equation modeling approach implemented in MX. There is weak evidence for linkage of XRCC5 to a QTL influencing raised mole count, and also weak association. There is also weak evidence for association between flat mole count and XRCC3. No tests were significant after correction for testing multiple alleles, nor were any of the tests for total association significant. If variation in XRCC3 or XRCC5 influences UV sensitivity, and indirectly affects nevus density, then the effects are small.

The evidence of conventional physiotherapeutic interventions after exercise-induced muscle damage: systematic review and meta-analysis

Abstract Introduction: Exhaustive and/or unaccustomed exercise, mainly those involving eccentric muscle actions, induces temporary muscle damage, evidenced by Delayed Onset Muscle Soreness. Different strategies to recover the signs and symptoms of this myogenic condition have been studied by researchers, as a result a significant number of articles on this issue have been published. Purpose: A systematic review was conducted to assess the evidence of the physiotherapeutic interventions of exercise-induced muscle damage. Methods: The electronic data bases were searched, including MEDLINE (1996-2011), CINHAL (1982- 2011), EMBASE (1988-2011), PEDro (1950-2011), and SPORTDiscus (1985-2011). Systematic review was limited to randomized control trials (RCTs) studies, written in English or Portuguese, which included physiotherapeutic interventions, namely massage, cryotherapy, stretching and low-intensity exercise, on adult human subjects (18-60 years old) of either gender. Studies were excluded when the intervention could not be assessed independently. The methodological quality of RCTs was independently assessed with the PEDro Scale by three reviewers. Results: Thirty-three studies were included in the systematic review; eight analyzed the effects of the massage, ten analyzed the effects of the cryotherapy, eight the effect of stretching and seventeen focused low-intensity exercise intervention. The results suggest that massage is the most effective intervention and that there is inconclusive evidence to support the use of cryotherapy; whereas the other conventional, namely stretching and low-intensity exercise, there is no evidence to prove their efficacy. Conclusion: The results allow the conclusion that massage is the physiotherapeutic intervention that demonstrated to be the most effective in the relief of symptoms and signs of exercise-induced muscle damage, as a result, massage should still be used in the muscular recovery after sports activities.

Molecular mobility, composition and structure analysis in glycerol plasticised chitosan films

This study was developed with the purpose to investigate the effect of polysaccharide/plasticiser concentration on the microstructure and molecular dynamics of polymeric film systems, using transmission electron microscope imaging (TEM) and nuclear magnetic resonance (NMR) techniques. Experiments were carried out in chitosan/glycerol films prepared with solutions of different composition. The films obtained after drying and equilibration were characterised in terms of composition, thickness and water activity. Results show that glycerol quantities used in film forming solutions were responsible for films composition; while polymer/total plasticiser ratio in the solution determined the thickness (and thus structure) of the films. These results were confirmed by TEM. NMR allowed understanding the films molecular rearrangement. Two different behaviours for the two components analysed, water and glycerol were observed: the first is predominantly moving free in the matrix, while glycerol is mainly bounded to the chitosan chain. (C) 2013 Elsevier Ltd. All rights reserved.

An uncertainty and sensitivity analysis applied to the prioritisation of pharmaceuticals as surface water contaminants from wastewater treatment plant direct emissions

In this study, the concentration probability distributions of 82 pharmaceutical compounds detected in the effluents of 179 European wastewater treatment plants were computed and inserted into a multimedia fate model. The comparative ecotoxicological impact of the direct emission of these compounds from wastewater treatment plants on freshwater ecosystems, based on a potentially affected fraction (PAF) of species approach, was assessed to rank compounds based on priority. As many pharmaceuticals are acids or bases, the multimedia fate model accounts for regressions to estimate pH-dependent fate parameters. An uncertainty analysis was performed by means of Monte Carlo analysis, which included the uncertainty of fate and ecotoxicity model input variables, as well as the spatial variability of landscape characteristics on the European continental scale. Several pharmaceutical compounds were identified as being of greatest concern, including 7 analgesics/anti-inflammatories, 3 β-blockers, 3 psychiatric drugs, and 1 each of 6 other therapeutic classes. The fate and impact modelling relied extensively on estimated data, given that most of these compounds have little or no experimental fate or ecotoxicity data available, as well as a limited reported occurrence in effluents. The contribution of estimated model input variables to the variance of freshwater ecotoxicity impact, as well as the lack of experimental abiotic degradation data for most compounds, helped in establishing priorities for further testing. Generally, the effluent concentration and the ecotoxicity effect factor were the model input variables with the most significant effect on the uncertainty of output results.

Strength and damage analysis of composite-aluminium adhesively-bonded single-lap joints

With the need to find an alternative way to mechanical and welding joints, and at the same time to overcome some limitations linked to these traditional techniques, adhesive bonds can be used. Adhesive bonding is a permanent joining process that uses an adhesive to bond the components of a structure. Composite materials reinforced with fibres are becoming increasingly popular in many applications as a result of a number of competitive advantages. In the manufacture of composite structures, although the fabrication techniques reduce to the minimum by means of advanced manufacturing techniques, the use of connections is still required due to the typical size limitations and design, technological and logistical aspects. Moreover, it is known that in many high performance structures, unions between composite materials with other light metals such as aluminium are required, for purposes of structural optimization. This work deals with the experimental and numerical study of single lap joints (SLJ), bonded with a brittle (Nagase Chemtex Denatite XNRH6823) and a ductile adhesive (Nagase Chemtex Denatite XNR6852). These are applied to hybrid joints between aluminium (AL6082-T651) and carbon fibre reinforced plastic (CFRP; Texipreg HS 160 RM) adherends in joints with different overlap lengths (LO) under a tensile loading. The Finite Element (FE) Method is used to perform detailed stress and damage analyses allowing to explain the joints’ behaviour and the use of cohesive zone models (CZM) enables predicting the joint strength and creating a simple and rapid design methodology. The use of numerical methods to simulate the behaviour of the joints can lead to savings of time and resources by optimizing the geometry and material parameters of the joints. The joints’ strength and failure modes were highly dependent on the adhesive, and this behaviour was successfully modelled numerically. Using a brittle adhesive resulted in a negligible maximum load (Pm) improvement with LO. The joints bonded with the ductile adhesive showed a nearly linear improvement of Pm with LO.

Compositional and functional analysis of polycomb target chromatin

Dissertation presented to obtain the Ph.D degree in Molecular Biology

Effect of environmental ageing on the numerical response of FRP-strengthened masonry walls

Recent durability studies have shown the susceptibility of bond in fiber-reinforced polymer (FRP) strengthened masonry components to hygrothermal exposures. However, it is not clear how this local material degradation affects the global behavior of FRP-strengthened masonry structures. This study addresses this issue by numerically investigating the nonlinear behavior of FRP-masonry walls after aging in two different environmental conditions. A numerical modeling strategy is adopted and validated with existing experimental tests on FRP-strengthened masonry panels. The model, once validated, is used for modeling of four hypothetical FRP-strengthened masonry walls with different boundary conditions, strengthening schemes, and reinforcement ratios. The nonlinear behavior of the walls is then simulated before and after aging in two different environmental conditions. The degradation data are taken from previous accelerated aging tests. The changes in the failure mode and nonlinear response of the walls after aging are presented and discussed.

Numerical and experimental analysis of full scale arches reinforced with GFRP materials

In this contribution, original limit analysis numerical results are presented dealing with some reinforced masonry arches tested at the University of Minho-UMinho, PT. Twelve in-scale circular masonry arches were considered, reinforced in various ways at the intrados or at the extrados. GFRP reinforcements were applied either on undamaged or on previously damaged elements, in order to assess the role of external reinforcements even in repairing interventions. The experimental results were critically discussed at the light of limit analysis predictions, based on a 3D FE heterogeneous upper bound approach. Satisfactory agreement was found between experimental evidences and the numerical results, in terms of failure mechanisms and peak load.

The influence of kaolin application on key metabolic pathways associated with grape berry quality: a molecular and biochemical analysis

Dissertação de mestrado em Biologia Molecular, Biotecnologia e Bioempreendedorismo em Plantas

Cholinergic stimulation with pyridostigmine, hemodynamic and echocardiographic analysis in healthy subjects

OBJECTIVE: Growing evidence suggests that sudden death after an acute myocardial infarction (AMI) correlates with autonomic nervous system imbalance. Parasympathomimetic drugs have been tested to reverse these changes. However, their effects on ventricular function need specific evaluation. Our objective was to analyze pyridostigmine's (PYR) effect on hemodynamic and echocardiographic variables of ventricular function. METHODS: Twenty healthy volunteers underwent Doppler echocardiographic evaluations, blood pressure (BP), and heart rate (HR) assessment at rest, before and 120 min after ingestion of 30 mg PYR or placebo, according to a double-blind, placebo-controlled, crossed and randomized protocol, on different days. RESULTS: PYR was well tolerated and did not cause alterations in BP or in ventricular systolic function. A reduction in HR of 10.9±1.3% occurred (p<0,00001). There was an A wave reduction in the mitral flow (p<0.01) and an E/A ratio increase (p<0.001) without changes in the other diastolic function parameters (p>0.05). CONCLUSION: PYR reduces HR and increases E/A ratio, without hemodynamic impairment or ventricular function change.

Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011.

BACKGROUND AND PURPOSE: Surgical clipping of unruptured intracranial aneurysms (UIAs) has recently been challenged by the emergence of endovascular treatment. We performed an updated systematic review and meta-analysis on the surgical treatment of UIAs, in an attempt to determine the aneurysm occlusion rates and safety of surgery in the modern era. METHODS: A detailed protocol was developed prior to conducting the review according to the Cochrane Collaboration guidelines. Electronic databases spanning January 1990-April 2011 were searched, complemented by hand searching. Heterogeneity was assessed using I(2), and publication bias with funnel plots. Surgical mortality and morbidity were analysed with weighted random effect models. RESULTS: 60 studies with 9845 patients harbouring 10 845 aneurysms were included. Mortality occurred in 157 patients (1.7%; 99% CI 0.9% to 3.0%; I(2)=82%). Unfavourable outcomes, including death, occurred in 692 patients (6.7%; 99% CI 4.9% to 9.0%; I(2)=85%). Morbidity rates were significantly greater in higher quality studies, and with large or posterior circulation aneurysms. Reported morbidity rates decreased over time. Studies were generally of poor quality; funnel plots showed heterogeneous results and publication bias, and data on aneurysm occlusion rates were scant. CONCLUSIONS: In studies published between 1990 and 2011, clipping of UIAs was associated with 1.7% mortality and 6.7% overall morbidity. The reputed durability of clipping has not been rigorously documented. Due to the quality of the included studies, the available literature cannot properly guide clinical decisions.

Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis.

PURPOSE: Investigation of the incidence and distribution of congenital structural cardiac malformations among the offspring of mothers with diabetes type 1 and of the influence of periconceptional glycemic control. METHODS: Multicenter retrospective clinical study, literature review, and meta-analysis. The incidence and pattern of congenital heart disease in the own study population and in the literature on the offspring of type 1 diabetic mothers were compared with the incidence and spectrum of the various cardiovascular defects in the offspring of nondiabetic mothers as registered by EUROCAT Northern Netherlands. Medical records were, in addition, reviewed for HbA(1c) during the 1st trimester. RESULTS: The distribution of congenital heart anomalies in the own diabetic study population was in accordance with the distribution encountered in the literature. This distribution differed considerably from that in the nondiabetic population. Approximately half the cardiovascular defects were conotruncal anomalies. The authors' study demonstrated a remarkable increase in the likelihood of visceral heterotaxia and variants of single ventricle among these patients. As expected, elevated HbA(1c) values during the 1st trimester were associated with offspring fetal cardiovascular defects. CONCLUSION: This study shows an increased likelihood of specific heart anomalies, namely transposition of the great arteries, persistent truncus arteriosus, visceral heterotaxia and single ventricle, among offspring of diabetic mothers. This suggests a profound teratogenic effect at a very early stage in cardiogenesis. The study emphasizes the frequency with which the offspring of diabetes-complicated pregnancies suffer from complex forms of congenital heart disease. Pregnancies with poor 1st-trimester glycemic control are more prone to the presence of fetal heart disease.

Political economics and normative analysis

The approaches and opinions of economists often dominate public policy discussion. Economists have gained this privileged position partly (or perhaps mainly) because of the obvious relevance of their subject matter, but also because of the unified methodology (neo-classical economics) that the vast majority of modern economists bring to their analysis of policy problems and proposed solutions. The idea of Pareto efficiency and its potential trade-off with equity is a central idea that is understood by all economists and this common language provides the economics profession with a powerful voice in public affairs. The purpose of this paper is to review and reflect upon the way in which economists find themselves analysing and providing suggestions for social improvements and how this role has changed over roughly the last 60 years. We focus on the fundamental split in the public economics tradition between those that adhere to public finance and those that adhere to public choice. A pure public finance perspective views failures in society as failures of the market. The solutions are technical, as might be enacted by a benevolent dictator. The pure public choice view accepts (sometimes grudgingly) that markets may fail, but so, it insists, does politics. This signals institutional reforms to constrain the potential for political failure. Certain policy recommendations may be viewed as compatible with both traditions, but other policy proposals will be the opposite of that proposed within the other tradition. In recent years a political economics synthesis emerged. This accepts that institutions are very important and governments require constraints, but that some degree of benevolence on the part of policy makers should not be assumed non-existent. The implications for public policy from this approach are, however, much less clear and perhaps more piecemeal. We also discuss analyses of systematic failure, not so much on the part of markets or politicians, but by voters. Most clearly this could lead to populism and relaxing the idea that voters necessarily choose their interests. The implications for public policy are addressed. Throughout the paper we will relate the discussion to the experience of UK government policy-making.

Reduction of alcohol consumption by brief alcohol intervention in primary care: systematic review and meta-analysis.

BACKGROUND: Numerous trials of the efficacy of brief alcohol intervention have been conducted in various settings among individuals with a wide range of alcohol disorders. Nevertheless, the efficacy of the intervention is likely to be influenced by the context. We evaluated the evidence of efficacy of brief alcohol interventions aimed at reducing long-term alcohol use and related harm in individuals attending primary care facilities but not seeking help for alcohol-related problems. METHODS: We selected randomized trials reporting at least 1 outcome related to alcohol consumption conducted in outpatients who were actively attending primary care centers or seeing providers. Data sources were the Cochrane Central Register of Controlled Trials, MEDLINE, PsycINFO, ISI Web of Science, ETOH database, and bibliographies of retrieved references and previous reviews. Study selection and data abstraction were performed independently and in duplicate. We assessed the validity of the studies and performed a meta-analysis of studies reporting alcohol consumption at 6 or 12 months of follow-up. RESULTS: We examined 19 trials that included 5639 individuals. Seventeen trials reported a measure of alcohol consumption, of which 8 reported a significant effect of intervention. The adjusted intention-to-treat analysis showed a mean pooled difference of -38 g of ethanol (approximately 4 drinks) per week (95% confidence interval, -51 to -24 g/wk) in favor of the brief alcohol intervention group. Evidence of other outcome measures was inconclusive. CONCLUSION: Focusing on patients in primary care, our systematic review and meta-analysis indicated that brief alcohol intervention is effective in reducing alcohol consumption at 6 and 12 months.

Fine mapping and functional analysis of the multiple sclerosis risk gene CD6.

CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2(nd) SRCR domain with susceptibility to MS (P max(T) permutation = 1×10(-4)). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. - CD4(+) naïve cells, P = 0.0001; CD8(+) naïve cells, P<0.0001; CD4(+) and CD8(+) central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells.