Structure-based design and synthesis of antiparasitic pyrrolopyrimidines targeting pteridine reductase 1

The treatment of Human African Trypanosomiasis remains a major unmet health need in sub-Saharan Africa. Approaches involving new molecular targets are important and pteridine reductase 1 (PTR1), an enzyme that reduces dihydrobiopterin in Trypanosoma spp. has been identified as a candidate target and it has been shown previously that substituted pyrrolo[2,3-d]pyrimidines are inhibitors of PTR1 from T. brucei (J. Med. Chem. 2010, 53, 221-229). In this study, 61 new pyrrolo[2,3-d]pyrimidines have been prepared, designed with input from new crystal structures of 23 of these compounds complexed with PTR1, and evaluated in screens for enzyme inhibitory activity against PTR1 and in vitro antitrypanosomal activity. 8 compounds were sufficiently active in both screens to take forward to in vivo evaluation. Thus although evidence for trypanocidal activity in a stage I disease model in mice was obtained, the compounds were too toxic to mice for further development

Accessing HE for non-traditional students: 'Outside of my position'

Widening participation within higher education and increasing social mobility have been high on the agendas of former and current governments. This paper examines the admissions procedure of a Foundation degree in Early Years programme using Bourdieu's concept of capital as a vehicle for analysis. During the process of an admissions interview, the interviewer is required to make decisions regarding a student's suitability to fit into the existing field of the programme as they often feel it is outside of their position. The stories of three non-traditional students are explored to highlight existing capital and dispositions that they bring to the programme. Research findings showed that there are many variables that impact on a student's ability to gain entry and be successful on an HE programme, including accumulation of capital, emotional drivers and potential to acquire capital throughout the programme. © 2014 Further Education Research Association

Chronic administration of hydrolysed pine nut oil to mice improves insulin sensitivity and glucose tolerance and increases energy expenditure via a free fatty acid receptor 4-dependent mechanism

A healthy diet is at the forefront of measures to prevent type 2 diabetes. Certain vegetable and fish oils, such as pine nut oil (PNO), have been demonstrated to ameliorate the adverse metabolic effects of a high-fat diet. The present study study investigates the involvement of the free fatty acid receptors 1 (FFAR1) and 4 (FFAR4) in the chronic activity of hydrolysed PNO (hPNO) on high-fat diet-induced obesity and insulin resistance. Male C57BL/6J wild-type, FFAR1 knockout (-/-) and FFAR4-/- mice were placed on 60% high-fat diet for 3 months. Mice were then dosed hPNO for 24 days, during which time body composition, energy intake and expenditure, glucose tolerance and fasting plasma insulin, leptin and adiponectin were measured. hPNO improved glucose tolerance and decreased plasma insulin in the wild-type and FFAR1-/- mice, but not the FFAR4-/- mice. hPNO also decreased high-fat diet-induced bodyweight gain and fat mass, whilst increasing energy expenditure and plasma adiponectin. None of these effects on energy balance were statistically significant in FFAR4-/- mice but it was not shown that they were significantly less than in wild-type mice. In conclusion, chronic hPNO supplementation reduces the metabolically detrimental effects of high-fat diet on obesity and insulin resistance in a manner that is dependent on the presence of FFAR4

Impact of childhood and adulthood psychological health on labour force participation and exit in later life

Adulthood psychological health predicts labour force activity but few studies have examined childhood psychological health. We hypothesized that childhood psychological ill-health would be associated with labour force exit at 55 years. Data were from the 55-year follow-up of the National Child Development Study (n = 9137). Labour force participation and exit (unemployment, retirement, permanent sickness, homemaking/other) were self-reported at 55 years. Internalizing and externalizing problems in childhood (7, 11 and 16 years) and malaise in adulthood (23, 33, 42, 50 years) were assessed. Education, social class, periods of unemployment, partnership separations, number of children, and homemaking activity were measured throughout adulthood. Childhood internalizing and externalizing problems were associated with unemployment, permanent sickness and homemaking/other at 55 years, after adjustment for adulthood psychological health and education: one or two reports of internalizing was associated with increased risk for unemployment [relative risk (RR) 1.59, 95% confidence interval (CI) 1.12–2.25; RR 2.37, 95% CI 1.48–3.79] and permanent sickness (RR 1.32, 95% CI 1.00–1.74; RR, 1.48, 95% CI 1.00–2.17); three reports of externalizing was associated with increased risk for unemployment (RR 2.26, 95% CI 1.01–5.04), permanent sickness (RR 2.63, 95% CI 1.46–4.73) and homemaking/other (RR 1.95, 95% CI 1.00–3.78). Psychological ill-health across the lifecourse, including during childhood, reduces the likelihood of working in older age. Support for those with mental health problems at different life stages and for those with limited connections to the labour market, including homemakers, is an essential dimension of attempts to extend working lives

Identification of Multiple HPV Types on Spermatozoa from Human Sperm Donors

Human papillomaviruses (HPV) may cause sexually transmitted disease. High-risk types of HPV are involved in the development of cervical cell dysplasia, whereas low-risk types may cause genital condyloma. Despite the association between HPV and cancer, donor sperm need not be tested for HPV according to European regulations. Consequently, the potential health risk of HPV transmission by donor bank sperm has not been elucidated, nor is it known how HPV is associated with sperm. The presence of 35 types of HPV was examined on DNA from semen samples of 188 Danish sperm donors using a sensitive HPV array. To examine whether HPV was associated with the sperm, in situ hybridization were performed with HPV-6, HPV-16 and -18, and HPV-31-specific probes. The prevalence of HPV-positive sperm donors was 16.0% and in 66.7% of these individuals high-risk types of HPV were detected. In 5.3% of sperm donors, two or more HPV types were detected. Among all identified HPV types, 61.9% were high-risk types. In situ hybridization experiments identified HPV genomes particularly protruding from the equatorial segment and the tail of the sperm. Semen samples from more than one in seven healthy Danish donors contain HPV, most of them of high-risk types binding to the equatorial segment of the sperm cell. Most HPV-positive sperm showed decreased staining with DAPI, indicative of reduced content of DNA. Our data demonstrate that oncogenic HPV types are frequent in men

Social and occupational factors associated with psychological distress and disorder among disaster responders: a systematic review

BACKGROUND: When disasters occur, there are many different occupational groups involved in rescue, recovery and support efforts. This study aimed to conduct a systematic literature review to identify social and occupational factors affecting the psychological impact of disasters on responders. METHODS: Four electronic literature databases (MEDLINE®, Embase, PsycINFO® and Web of Science) were searched and hand searches of reference lists were carried out. Papers were screened against specific inclusion criteria (e.g. published in peer-reviewed journal in English; included a quantitative measure of wellbeing; participants were disaster responders). Data was extracted from relevant papers and thematic analysis was used to develop a list of key factors affecting the wellbeing of disaster responders. RESULTS: Eighteen thousand five papers were found and 111 included in the review. The psychological impact of disasters on responders appeared associated with pre-disaster factors (occupational factors; specialised training and preparedness; life events and health), during-disaster factors (exposure; duration on site and arrival time; emotional involvement; peri-traumatic distress/dissociation; role-related stressors; perceptions of safety, threat and risk; harm to self or close others; social support; professional support) and post-disaster factors (professional support; impact on life; life events; media; coping strategies). CONCLUSIONS: There are steps that can be taken at all stages of a disaster (before, during and after) which may minimise risks to responders and enhance resilience. Preparedness (for the demands of the role and the potential psychological impact) and support (particularly from the organisation) are essential. The findings of this review could potentially be used to develop training workshops for professionals involved in disaster response. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40359-016-0120-9) contains supplementary material, which is available to authorized users

Cohort Profile: COVIDMENT: COVID-19 cohorts on mental health across six nations

Why were the cohorts set up? With more than 218 million cases and 4.5 million deaths worldwide (Worldometers, 31 August 2021), the COVID-19 pandemic has had an unprecedented influence on the global economy and population health. As a potent global disaster, it is likely to significantly affect the incidence of adverse mental health symptoms and psychiatric disorders, particularly in vulnerable and highly affected populations. The World Health Organization and leading scientific journals have alerted concerning the potential adverse mental health impact of COVID-19 and emphasized the need for multinational research in this area, which additionally provides new insights into disease mechanisms

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)