Supervised exercise training and increased physical activity to reduce cardiovascular disease risk in women with polycystic ovary syndrome: Study protocol for a randomized controlled feasibility trial

Background: Polycystic ovary syndrome (PCOS) affects up to 20% of women and is characterised by higher amounts of visceral fat, obesity, insulin resistance, dyslipidemia and reproductive and cardiometabolic complications. Increased oxidised low-density lipoprotein (LDL) concentrations have been associated with an increased risk of cardiovascular disease (CVD)-related events. Oxidised LDL is rarely used as a marker for CVD risk in PCOS-related studies despite its widely accepted role in atherogenesis and the increased risk factors associated with PCOS. Additionally, prolonged periods of sedentary behaviour can negatively affect metabolic health. No studies have specifically examined the effects of reducing sedentary behaviour on CVD risk in PCOS with a lifestyle physical activity intervention. The aim of the current study is to measure the feasibility of a randomised controlled trial (RCT) examining the effects of supervised exercise and reducing sedentary behaviour in women with PCOS on CVD risk. Methods/design: A feasibility, exploratory RCT will be conducted. Fifty-one pre-menopausal females will be randomly allocated between an exercise group (EG), a lifestyle physical activity group (LPAG) and a control group. Participants in the EG will undertake a 12-week supervised aerobic exercise programme. The LPAG will aim to increase daily physical activity and reduce sedentary behaviour for 12 weeks. The control group will not take part in any intervention. Primary outcomes are feasibility and acceptability of the intervention and procedures. Secondary outcomes are oxidised LDL, aerobic fitness, blood lipid profile, fasting glucose and insulin, testosterone and inflammatory markers. Discussion: PCOS is associated with various increased risk factors for CVD, including hypertension, dyslipidemia, abdominal obesity, insulin resistance, and inflammation. Whether oxidised LDL has a role in this increased risk is not yet known. The present study aims to measure the feasibility of implementing structured exercise training and/or increased lifestyle physical activity in women with PCOS, so that a subsequent adequately powered RCT can be designed. The results from the study will be used to refine the interventions and determine the acceptability of the study design. A limitation is that some self-monitoring in the lifestyle physical activity group may not be reliable or replicable, for example inputting information about time spent cleaning/gardening

Eating behaviours and food cravings; influence of age, sex, BMI and FTO genotype

Previous studies indicate that eating behaviours and food cravings are associated with increased BMI and obesity. However, the interaction between these behaviours and other variables such as age, sex, BMI and genetics is complex. This study aimed to investigate the relationships between eating behaviours and food cravings, and to examine the influence of age, sex, body mass index (BMI) and fat mass and obesity-associated (FTO) genotype on these relationships. A total of 475 participants (252 female, 223 male, BMI: 25.82 ± 6.14 kg/m², age: 30.65 ± 14.20 years) completed the revised 18-question version of the Three Factor Eating Questionnaire (TFEQ-R18) to assess cognitive restraint, uncontrolled eating and emotional eating, and the Food Cravings Inventory (FCI) to assess cravings for fatty food, sweet food, carbohydrates and fast food. DNA samples were genotyped for the rs9939609 polymorphism in the obesity-linked gene FTO. Questionnaire data was analysed for associations between the TFEQ-R18 and FCI subscales for the whole study group, and the group divided by sex, genotype and age (≤25 years versus >25 years). Finally, mediation analysis was used to explore the relationships between BMI, cognitive restraint and food cravings. FTO AA + AT genotype was associated with increased BMI, but not with differences in eating behavior scores or food craving scores; age was associated with increased BMI and decreases in food craving scores in which this effect was stronger in women compared to men. Increased cognitive restraint was associated with decreased food craving scores in the ≤25 years group. Mediation analysis demonstrated that in this group the association between BMI and reduced food cravings was mediated by cognitive restraint indicating that in this age group individuals use cognitive restraint to control their food cravings. The positive correlation between age and BMI confirms previous results but the findings of this study show that age, sex, FTO genotype and BMI have an influence on the relationships between eating behaviours and food cravings and that these variables interact

An acute bout of cycling does not induce compensatory responses in pre-menopausal women not using hormonal contraceptives

There is a clear need to improve understanding of the effects of physical activity and exercise on appetite control. Therefore, the acute and short-term effects (three days) of a single bout of cycling on energy intake and energy expenditure were examined in women not using hormonal contraceptives. Sixteen active (n = 8) and inactive (n = 8) healthy pre-menopausal women completed a randomised crossover design study with two conditions (exercise and control). The exercise day involved cycling for 1 h (50% of maximum oxygen uptake) and resting for 2 h, whilst the control day comprised 3 h of rest. On each experimental day participants arrived at the laboratory fasted, consumed a standardised breakfast and an ad libitum pasta lunch. Food diaries and combined heart rate-accelerometer monitors were used to assess free-living food intake and energy expenditure, respectively, over the subsequent three days. There were no main effects or condition (exercise vs control) by group (active vs inactive) interaction for absolute energy intake (P > 0.05) at the ad libitum laboratory lunch meal, but there was a condition effect for relative energy intake (P = 0.004, ηp2 = 0.46) that was lower in the exercise condition (1417 ± 926 kJ vs. 2120 ± 923 kJ). Furthermore, post-breakfast satiety was higher in the active than in the inactive group (P = 0.005, ηp2 = 0.44). There were no main effects or interactions (P > 0.05) for mean daily energy intake, but both active and inactive groups consumed less energy from protein (14 ± 3% vs. 16 ± 4%, P = 0.016, ηp2 = 0.37) and more from carbohydrate (53 ± 5% vs. 49 ± 7%, P = 0.031, ηp2 = 0.31) following the exercise condition. This study suggests that an acute bout of cycling does not induce compensatory responses in active and inactive women not using hormonal contraceptives, while the stronger satiety response to the standardised breakfast meal in active individuals adds to the growing literature that physical activity helps improve the sensitivity of short-term appetite control

An exploration of care-burden experienced by older caregivers of adults with intellectual disabilities, in Ireland.

Background: People with intellectual disabilities are experiencing increased longevity, and in parallel, their family caregivers are also ageing. The literature identifies that these caregivers are at risk of burden. The aim of this study was to measure the level of caregiver burden among older carers of adults with intellectual disabilities in an Irish sample and to analyse the effect of socio‐demographic factors upon experiences of caregiver burden. Materials and Methods: Thirty caregivers completed a survey questionnaire. Data were collected based upon participants’ self‐reports of burden using the Zarit Burden Interview (ZBI) and a socio‐demographic questionnaire. Data were analysed using SPSS version 24. Results: Over 57% of carers indicated a mild‐to‐moderate level of burden. Analysis indicated that younger caregivers experience significantly higher levels of burden, when compared to older caregivers. Conclusions: This study contributes to our understanding of burden among an Irish population of older caregivers supporting an adult with an intellectual disability. It identified that carers do experience burden. The importance of proactive assessments and supports for these caregivers was revealed. This study highlights a lack of Irish research in this area and may pave the way for future research which could build upon its findings

End-of-life care supports and decision-making practices in specialist intellectual disability residential services

Background: Over the past 50 years, the profile of people with intellectual disability (ID) has changed because they are living longer with a wide range of co-morbid conditions, which impact on both their cognitive and physical abilities to engage in conversations about end-of-life care. Coupled with this, people with an ID are being supported in community settings and are availing of supports from community and hospital services. In addition, the Assisted Decision Making (Capacity) Act (ADM) (2015) is changing the way these individuals will be included in decision making across all aspects of their lives into the future. These changes have led to an increased interest in the end-of-life care of people with an ID and how end- of-life decisions are made with this population. Aim: This study describes and analyses end-of-life care supports and decision making practices in specialist ID residential services. Methods: Case study methodology was used to develop a detailed account of how nine people with an ID were supported at the end of their lives. A multiple-embedded case study design was used, drawing on a range of data sources and multiple perspectives including those of family members and healthcare professionals, and the case files of nine decedents identified in this study. Qualitative content analysis techniques were used to analyse the data gleaned from documents, and interviews. Data identified from three questionnaires was also analysed qualitatively. Following the analysis of the nine individual case studies, cross case analysis was used to identify commonalities and differences between the cases. Findings: Analysis of these nine cases has identified a number of factors of importance to the end-of-life care of individuals with an ID from the perspectives of families and staff supporting them. Firstly, specialist ID services are committed to supporting people with an ID at end of life, and to providing services which allow them to “age and die in place”. Where this could not be achieved, supports were provided in external services such as hospitals and hospices, reflective of an ongoing commitment to the person at end of life. Secondly, this commitment is also reflected in the support provided to the decedents in this study by family members and ID staff who were involved in their care. Those individuals, who formed a circle of support around the decedents used their collective knowledge to promote the autonomy of people with an ID and actively advocated on their behalf. Thirdly, despite the evident commitment of all involved, issues arose in relation to the provision of end-of life care at organisational and individual levels. These issues included a lack of preparedness in both specialist ID residential services and acute hospital settings to support people with an ID at end of life. A culture of silence was also evident in specialist ID residential services: there was a lack of conversations about death and dying in general as well as discussions about end-of-life care in particular, with the decedents involved. This culture of silence prevented people with an ID from being informed that they were dying. Finally, this study also determined that people with an ID are not included in decision making about their end-of-life care, the responsibility for which was borne by family members and health professionals across a range of services. Conclusion: Given the changing age profile of people with an ID, the landscape in which health services are provided, and the legislative changes envisioned in the ADM (2015), issues relating to communication, capacity and decision making for people with an ID must be addressed. People with an ID and their families should be included in end- of-life care at a much earlier stage than is currently the case. The supports required by people with an ID, their families and staff need to be made explicit to ensure the autonomy of people with an ID is protected and promoted when making end-of-life decisions. There is potential for person centred planning processes, within specialist ID services, to be used to ensure conversations about death, dying and end-of-life care occur in a timely manner

Copper Binding and Subsequent Aggregation of α-Synuclein Are Modulated by N-Terminal Acetylation and Ablated by the H50Q Missense Mutation

The Parkinson’s disease-associated protein α-synuclein exhibits significant conformational heterogeneity. Bacterially expressed α-synuclein is known to bind to copper, resulting in the formation of aggregation-prone compact conformations. However, in vivo, α-synuclein undergoes acetylation at its N-terminus. Here the effect of this modification and the pathological H50Q mutation on copper binding and subsequent conformational transitions were investigated by electrospray ionization–ion mobility spectrometry–mass spectrometry. We demonstrate that acetylation perturbs the ability of α-synuclein to bind copper and that the H50Q missense mutation in the presence of N-terminal acetylation prevents copper binding. These modifications and mutations prevent the formation of the most compact conformations and inhibit copper-induced aggregatio

Neuromyelitis optica spectrum disorder in three generations of a Chinese family

© 2019 Neuromyelitis optica spectrum disorder is an inflammatory demyelinating disease that is largely sporadic. Familial disease has been reported in one or two generations, although its basis remains unknown. We report here three subjects meeting diagnostic criteria for NMOSD in one family: a father and son, and the maternal aunt of the father. Anticipation, of 27 years, was apparent in transmission from father to son. Aquaporin-4 antibodies were observed in the aunt but not the father and son, nor in other family members. A putative pathogenic mutation in the NECL2 gene was not found in this pedigree. This first report of NMOSD in three generations of one family underlines the heterogeneity of familial NMOSD

Lifestyle intervention in individuals with impaired glucose regulation affects Caveolin-1 expression and DNA methylation

© 2020, © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Aims: We investigated whether a lifestyle intervention could influence expression and DNA methylation of diabetes-related genes in patients with impaired glucose regulation (IGR), the results were compared to bariatric surgery, considering it an intensive change. Methods: Twenty participants with IGR had adipose tissue biopsy and blood collected pre- and post-lifestyle (6 months) intervention; 12 obese patients had subcutaneous fat taken before and after bariatric surgery. RNA/DNA was extracted from all samples and underwent qPCR. DNA was bisulphite converted and 12 CpG sites of Caveolin-1 (CAV1) promoter were pyrosequenced. Results: lifestyle intervention resulted in opposite direction changes in fat tissue and blood for CAV1 expression and DNA methylation and these changes were correlated between tissues, while no significative differences were found in CAV1 expression after bariatric surgery. Conclusions: Our findings suggest a role for CAV1 in modulating adipocyte function as a consequence of lifestyle changes, as exercises and diet. These results may provide insights into new therapeutic targets for diabetes prevention

An investigation into placental protein 14, a modulator of the immune response associated with human reproduction.

This thesis describes investigations into Placental Protein 14 (PP14), a immunomodulator involved in human reproduction. The studies included the development of a purification procedure and an investigation of the activity of the protein. In addition the cDNA coding for the protein was cloned and expressed as a recombinant fusion protein and the molecular structure of the protein was predicted and analysed using computer-assisted modelling. Finally the clinical significance of the protein was studied in a range of patient groups. The purification scheme consisted of ion exchange, hydrophobic interaction and gel filtration chromatography, and the pure protein obtained was analysed by SDS-PAGE and Western blotting. The results demonstrate that the purification procedure is a suitable method to obtain PP14 in large quantity and with high purity. PP14 purified by this method retained its activity and was shown to suppress, in a dose-dependent manner, the uptake of 3H-Thymidine by peripheral blood mononuclear cells stimulated with interleukin-2. Purified PP14 was also shown to suppress the uptake of 3H-Thymidine by the cell line U937, also in a dose-dependent manner. This suppression could be removed by the incubation of the PP14 sample with an immunoabsorbent gel linked to monoclonal antibodies against PP14, demonstrating that PP14 was the molecule responsible for the observed activity. Based on the suppression by PP14 of U937 cell growth a bioassay for PP14 was developed, this assay was used to express the specific activity of PPM in Units/ml. To obtain recombinant PP14, mRNA was purified from a tissue sample and reverse transcription used to prepare cDNA. Specific primers were used to amplify the portion of cDNA coding for PP14 which was then ligated into the plasmids pUC 18 and pGEX-KG. Recombinant PP14 was then expressed as a fusion protein with glutathione-S-transferase. The expression conditions were optimised and the fusion protein was purified using affinity chromatography. The structure of PPM was investigated using computer assisted modelling. PPM is a member of the lipocalin family of proteins which share the feature of binding small hydrophobic molecules. The X-ray coordinates of two lipocalins known to share sequence homology with PP14 were used as a basis to model a predicted structure for PP14. An analysis of the structural motifs of the protein was carried out, and it was established that PP14 shares many of the characteristic features of this family of proteins including the presence of a binding pocket. The model was then used to predict potential ligands for PP14.PP14 was measured by radioimmunoassay in uterine flushings from fertile women, women with unexplained infertility and women suffering from recurrent miscarriages, and in plasma samples from fertile and infertile women. The results from the uterine flushings from fertile women showed that PP14 levels rose during the second half of the menstrual cycle reaching ug/ml levels by the end of the cycle. These physiological concentrations are in the same range as the concentrations at which the immunomodulatory activity of PP14 was observed in vitro. The levels of PP14 measured in uterine flushings were lower in infertile women than in fertile women, indicating that a deficiency in PP14 may be associated with infertility. The levels measured in plasma samples from these two groups of women did not pick up this difference. These results suggests that the measurement of proteins such as PP14 in uterine flushings instead of plasma samples may be a more sensitive indicator of local uterine function. In women suffering from recurrent miscarriage a significant lack of secretion of PP14 was observed around the time of implantation. This may be conected with the failure of implantation in these patients. A correlation was observed between the PP14 levels measured in uterine flushings from recurrent miscarriage patients and the level of endometrial development

Distinct higher-order alpha-synuclein oligomers induce intracellular aggretation

Misfolding and aggregation of alpha-synuclein (α-syn) into Lewy bodies (LB) is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell to cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that preceded LB formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. Here we characterize, by electrospray ionisation - ion mobility spectrometry - mass spectrometry (ESI-IMS-MS), a specific population of α-syn oligomers. These mass spectrometry compatible oligomers were compared with oligomers with known seeding and pore forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain of function. Structurally the mass spectrometry compatible oligomers populated a range of species from dimers through to hexamers. Lower order oligomers were structurally diverse and consistent with unstructured assemblies. Higher order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases