15 research outputs found
Meta-analysis combining new and existing data sets confirms that the TERT-CLPTM1L locus influences melanoma risk
No full textThe safety and effectiveness of different methods of ear wax removal: a systematic review and economic evaluation
No full textEar wax (cerumen) is a natural secretion produced to protect the inner ear from dirt and other fragments by moving these particles towards the outer ear. If this process does not happen properly, wax may build up causing blockage in the ear canal and the possibility of impaction. People with a build up of ear wax may suffer from hearing loss, discomfort and, on occasions, infection. It may present problems in assessing hearing, blocking the view of the ear drum during medical examination and interfering with the fitting or function of hearing aids. Although it is thought to affect between 2% and 6% of the population in the England and Wales, some groups may be at a higher risk, such as those using hearing aids or with small ear canals and/or skin conditions. Recurrence is thought to be high among some of these groups. The consequences of the build up of ear wax in the ear canal are thought to be a common reason for consultation and cost in general practice with over 2 million consultations per year in the NHS.Methods of removal of ear wax include drops, flushing with water in general practice, and removal with suction or probes in specialist clinics. The relative safety and benefits of these different methods of removal remains uncertain. This research will systematically review published and unpublished evidence on the clinical and cost effectiveness of different methods for the removal of ear wax. Where appropriate, it will develop an economic model using data from this systematic review and other relevant sources to estimate the relative costs and benefits of different methods. In addition, the project will provide recommendations for future research to try to help answer any remaining areas of uncertainty
Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.
No full textINTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified
The role of the Amygdala in the perception of reward
No full textThis study set out to examine the role of the amygdala in a number of appetitively motivated tasks. Experiment one was a position discrimination task with reversals, which in later reversals involved manipulation of some secondary reinforcers associated with a correct response, and the introduction of a magnitude of reward component. Rats with NMDA-induced amygdala lesions performed at a similar level to shams at the initial discrimination and first three reversals, proceeding to reverse faster than controls in the subsequent three reversals. Manipulation of secondary reinforcers led to an equal and significant decline in performance for both groups, with the lesioned animals retaining their significant superiority in reversal performance. Alteration of the task from a 2 vs 0 pellet discrimination to a 2 vs 1 led to a drastic increase in task difficulty, but both groups completed three reversals and did not differ significantly in performance. Experience of handling the lesioned animals led to the confirmation, in experiment two, that they were significantly more hostile/reactive to handling than shams (using die "blind" ratings of experienced animal handlers). Experiment three attempted to refine die picture of this behavioural change by measuring gross activity levels - no differences between groups were found. The finding of enhanced reversal performance and the absence of a magnitude of reward deficit amongst lesioned animals in experiment one were unanticipated, problematic and demand replication. No strong support was provided for either of the principal contemporary theories of amygdala involvement in secondary reinforcement. Increased reactivity to handling was found to be consistent with a minority of the past literature, and activity levels were as anticipated. It is argued that the notion of "stimulus-reward associations" as an amygdala function is incoherent and unhelpful, and that references to the functions of the amygdale as a whole rather than of subnuclei can be equally misleading
Genome-wide association study identifies novel loci predisposing to cutaneous melanoma
No full textWe performed a multistage genome-wide association study of melanoma. In a discovery cohort of 1804 melanoma cases and 1026 controls, we identified loci at chromosomes 15q13.1 (HERC2/OCA2 region) and 16q24.3 (MC1R) regions that reached genome-wide significance within this study and also found strong evidence for genetic effects on susceptibility to melanoma from markers on chromosome 9p21.3 in the p16/ARF region and on chromosome 1q21.3 (ARNT/LASS2/ANXA9 region). The most significant single-nucleotide polymorphisms (SNPs) in the 15q13.1 locus (rs1129038 and rs12913832) lie within a genomic region that has profound effects on eye and skin color; notably, 50% of variability in eye color is associated with variation in the SNP rs12913832. Because eye and skin colors vary across European populations, we further evaluated the associations of the significant SNPs after carefully adjusting for European substructure. We also evaluated the top 10 most significant SNPs by using data from three other genome-wide scans. Additional in silico data provided replication of the findings from the most significant region on chromosome 1q21.3 rs7412746 (P = 6 x 10(-10)). Together, these data identified several candidate genes for additional studies to identify causal variants predisposing to increased risk for developing melanoma
The effect on melanoma risk of genes previously associated with telomere length
No full textTelomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10-9, two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk
Avaliação do potencial efeito protetor do probucol em modelos experimentais da doença de Huntington
No full textDissertação (mestrado) - Universidade Federal de Santa Catarina, Centro de Ciências Biológicas. Programa de Pós-Graduação em BioquímicaA doença de Huntington (DH) é uma patologia neurodegenerativa, autossômica dominante caracterizada por sintomas atribuídos à morte de neurônios estriatais e corticais no cérebro. O mecanismo de neurodegeneração na DH parece estar relacionado com excitotoxicidade, disfunção mitocondrial e estresse oxidativo. O probucol (PB) é um composto fenólico antilipêmico, que apresenta propriedades anti-inflamatória e antioxidante em diferentes modelos experimentais de toxicidade/patologia. O objetivo deste estudo foi investigar o possível efeito protetor do PB sobre a neurotoxicidade e estresse oxidativo em modelos experimentais de DH in vitro e in vivo. Inicialmente, foi avaliada a relação entre prejuízo no metabolismo energético, excitotoxicidade e estresse oxidativo em fatias de estriado de ratos expostas ao ácido quinolínico (AQ), ácido 3-nitropropiônico (3-NP) e ao modelo combinado (AQ + 3-NP). Os dados sugerem que os modelos utilizados podem gerar um padrão complexo de dano, que envolve comprometimento metabólico, formação de espécies reativas de oxigênio (ERO) e estresse oxidativo. O PB preveniu o estresse oxidativo nas três condições experimentais e foi capaz de proteger contra disfunção mitocondrial induzida pelo AQ e AQ + 3-NP. Além disso, o potencial efeito protetor do probucol foi avaliado sobre a neurotoxicidade do 3-NP em ratos. O pré-tratamento com probucol (por 60 dias) aumentou a atividade da glutationa peroxidase (GPx) no estriado e no córtex e preveniu o prejuízo motor e o estresse oxidativo induzido pelo 3-NP em ratos. O efeito do PB sobre a GPx e suas propriedades antioxidantes estão provavelmente associados ao seu efeito benéfico neste modelo. Também foi verificado o possível efeito protetor do succinobucol, um análogo do PB, sobre a toxicidade induzida pelo 3-NP em preparações mitocondriais de cérebro de ratos in vitro. O probucol e o succinobucol preveniram o estresse oxidativo induzido pelo 3-NP, mas apenas o succinobucol foi capaz de prevenir a disfunção mitocondrial induzida pela toxina. Juntos este resultados sugerem um novo papel para o probucol e seu análogo succinobucol como potenciais agentes neuroprotetores em modelos de DH
Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.
No full textThirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology
A variant in FTO shows association with melanoma risk not due to BMI
No full textWe report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10−12, per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity
The pathophysiology of fluid removal during haemodialysis: implications for blood volume monitoring and determination of dry weight.
No full textThe aim of the research was to characterise the pathophysiology of ultrafiltration (UF) during haemodialysis (HD) using a range of assessment tools. The hypothesis was that objective monitoring would facilitate accurate estimation of dry weight (DW) and help optimise UF. Measurement timing, white-coat effect, UF prescription and volume status influenced blood pressure (BP) readings, particularly predialysis and immediate post- dialysis measurements. The 20-min post-dialysis BP best reflected interdialytic control. Extracellular volume measurements (ECF) using Bioimpedance spectroscopy (BIS) were reproducible, accurate, and confirmed the tight link between nutritional and volume status. The late increase in ECF and decline in nutritional status as end-stage approached, were only partially corrected by dialysis. Relative blood volume (RBV) characteristics were investigated using short UF pulses (perturbation analysis), at different hydration states, to identify predictors of hypotension and approaching DW. RBV change was greater as predicted DW approached. The critical level of RBV reduction leading to hypotension showed a wide inter-individual variation. The approach to linearity of RBV decay curve was a surrogate for plasma refill (PR) and predicted impending hypotension. The role of heat exchange on cardiovascular stability was also examined. Indocyanine green emerged as a suitable tracer for determining PV repeatedly during HD. The method was employed simultaneously with BIS to demonstrate abnormal proportional compartmental fluid distribution and assess fluid shifts and PR during UF. A significant relationship was demonstrated between ECF change, PR and haemodynamic stability. The dissociation between simultaneous absolute and RBV measurements was explained by a changing Fcell ratio, suggesting significant intravascular shifts within the microcirculation during UF. Objective monitoring has improved understanding of the pathophysiology of UF during HD. However, the main factors limiting fluid removal during HD are patient-specific responses to UF. Individualised prescriptions will require use of systems to characterise patient responses, and prompt appropriate adjustments. These studies may contribute
