Pancreatic and adrenal development and function in an ovine model of polycystic ovary syndrome.

Polycystic Ovary Syndrome (PCOS) is a complex disorder encompassing reproductive and metabolic dysfunction. Ovarian hyperandrogenism is an endocrine hallmark of human PCOS. In animal models, PCOS-like abnormalities can be recreated by in utero over-exposure to androgenic steroid hormones. This thesis investigated pancreatic and adrenal development and function in a unique model of PCOS. Fetal sheep were directly exposed (day 62 and day 82 of gestation) to steroidal excesses - androgen excess (testosterone propionate - TP), estrogen excess (diethylstilbestrol - DES) or glucocorticoid excess (dexamethasone - DEX). At d90 gestation there was elevated expression of genes involved in β- cell development and function: PDX-1 (P<0.001), and INS (P<0.05), INSR (P<0.05) driven by androgenic excess only in the female fetal pancreas. β- cell numbers (P<0.001) and in vitro insulin secretion (P<0.05) were also elevated in androgen exposed female fetuses. There was a significant increase in insulin secreting β-cell numbers (P<0.001) and in vivo insulin secretion (glucose stimulated) (P<0.01) in adult female offspring, specifically associated with prenatal androgen excess. At d90 gestation, female fetal adrenal gene expression was perturbed by fetal estrogenic exposure. Male fetal adrenal gene expression was altered more dramatically by fetal glucocorticoid exposure. In female adult offspring from androgen exposed pregnancies there was increased adrenal steroidogenic gene expression and in vivo testosterone secretion (P<0.01). This highlights that the adrenal glands may contribute towards excess androgen secretion in PCOS, but such effects might be secondary to other metabolic alterations driven by prenatal androgen exposure, such as excess insulin secretion Thus there may be dialogue between the pancreas and adrenal gland, programmed during early life, with implications for adult health Given both hyperinsulinaemia and hyperandrogenism are common features in PCOS, we suggest that their origins may be at least partially due to altered fetal steroidal environments, specifically excess androgenic stimulation

The total margin of exposure of ethanol and acetaldehyde for heavy drinkers consuming cider or vodka

Heavy drinkers in Scotland may consume 1600 g ethanol per week. Due to its low price, cider may be preferred over other beverages. Anecdotal evidence has linked cider to specific health hazards beyond other alcoholic beverages. To examine this hypothesis, nine apple and pear cider samples were chemically analysed for constituents and contaminants. None of the products exceeded regulatory or toxicological thresholds, but the regular occurrence of acetaldehyde in cider was detected. To provide a quantitative risk assessment, two collectives of exclusive drinkers of cider and vodka were compared and the intake of acetaldehyde was estimated using probabilistic MonteeCarlo type analysis. The cider consumers were found to ingest more than 200-times the amount of acetaldehyde consumed by vodka consumers. The margins of exposure (MOE) of acetaldehyde were 224 for the cider and over 220,000 for vodka consumers. However, if the effects of ethanol were considered in a cumulative assessment of the combined MOE, the effect of acetaldehyde was minor and the combined MOE for both groups was 0.3. We suggest that alcohol policy priority should be given on reducing ethanol intake by measures such as minimum pricing, rather than to focus on acetaldehyde.

Comprehensive assessment of alcohol-related brain damage (ARBD): gap or chasm in the evidence?

Alcohol-related brain damage (ARBD) is primarily caused by chronic alcohol misuse and thiamine deficiency, and results in a broad range of impairments. Despite the increasing incidence of ARBD in the UK in recent decades, it is currently underdiagnosed, managed inappropriately and treated inadequately. Moreover, information about assessments for individuals with ARBD is currently absent from clinical guidelines and policy documents. The aim of this paper was to review the evidence relating to the neurological, neuropsychological, psychosocial, physical and nutritional assessment of individuals with ARBD to identify appropriate assessment tools that could be used to measure and monitor the impact of ARBD over time. A systematic online database search revealed a total of 160 separate references, 133 of which were rejected and two of which could not be accessed. Twenty-five papers were included in the review, including six neuroimaging studies, 17 neuropsychological studies and two studies using psychosocial methods of assessment. A lack of evidence for nutritional and physical assessment of individuals with ARBD was found. The review findings are inconclusive; most instruments currently used in ARBD research have not specifically been validated for use within an ARBD context. Further research is required to identify comprehensive methods of ARBD assessment.