Effect of androgen treatment during foetal and/or neonatal life on ovarian function in prepubertal and adult rats

We investigated the effects of different windows of testosterone propionate (TP) treatment during foetal and neonatal life in female rats to determine whether and when excess androgen exposure would cause disruption of adult reproductive function. Animals were killed prepubertally at d25 and as adults at d90. Plasma samples were taken for hormone analysis and ovaries serial sectioned for morphometric analyses. In prepubertal animals, only foetal+postnatal and late postnatal TP resulted in increased body weights, and an increase in transitory, but reduced antral follicle numbers without affecting total follicle populations. Treatment with TP during both foetal+postnatal life resulted in the development of streak ovaries with activated follicles containing oocytes that only progressed to a small antral (smA) stage and inactive uteri. TP exposure during foetal or late postnatal life had no effect upon adult reproductive function or the total follicle population, although there was a reduction in the primordial follicle pool. In contrast, TP treatment during full postnatal life (d1-25) resulted in anovulation in adults (d90). These animals were heavier, had a greater ovarian stromal compartment, no differences in follicle thecal cell area, but reduced numbers of anti-Mullerian hormone-positive smA follicles when compared with controls. Significantly reduced uterine weights lead reduced follicle oestradiol production. These results support the concept that androgen programming of adult female reproductive function occurs only during specific time windows in foetal and neonatal life with implications for the development of polycystic ovary syndrome in women

Hepatitis C virus reinfection after successful treatment with direct-acting antiviral therapy in a large population-based cohort.

BACKGROUND & AIMS: Direct-acting antiviral therapies (DAA) are an important tool for hepatitis C virus (HCV) elimination. However, reinfection among people who inject drugs (PWID) may hamper elimination targets. Therefore, we estimated HCV reinfection rates among DAA-treated individuals, including PWID. METHODS: We analyzed data from the British Columbia Hepatitis Testers Cohort which included ∼1.7 million individuals screened for HCV in British Columbia, Canada. We followed HCV-infected individuals treated with DAAs who achieved a sustained virologic response (SVR) and had ≥1 subsequent HCV RNA measurement to April 22nd, 2018. Reinfection was defined as a positive RNA measurement after SVR. PWID were identified using a validated algorithm and classified based on recent (<3 years) or former (≥3 years before SVR) use. Crude reinfection rates per 100 person-years (PYs) were calculated. Poisson regression was used to model adjusted incidence rate ratios (IRRs) and 95% CIs. RESULTS: Of 4,114 individuals who met the inclusion criteria, most were male (n = 2,692, 65%), born before 1965 (n = 3,411, 83%) and were either recent (n = 875, 21%) or former PWID (n = 1,793, 44%). Opioid-agonist therapy (OAT) was received by 19% of PWID. We identified 40 reinfections during 2,767 PYs. Reinfection rates were higher among recent (3.1/100 PYs; IRR 6.7; 95% CI 1.9-23.5) and former PWID (1.4/100 PYs; IRR 3.7; 95% CI 1.1-12.9) than non-PWID (0.3/100 PYs). Among recent PWID, reinfection rates were higher among individuals born after 1975 (10.2/100 PYs) and those co-infected with HIV (5.7/100 PYs). Only one PWID receiving daily OAT developed reinfection. CONCLUSIONS: Population-level reinfection rates remain elevated after DAA therapy among PWID because of ongoing exposure risk. Engagement of PWID in harm-reduction and support services is needed to prevent reinfections. LAY SUMMARY: Direct-acting antivirals are an effective tool for the treatment of hepatitis C virus, enabling the elimination of the virus. However, some patients who have been successfully treated with direct-acting antivirals are at risk of reinfection. Our findings showed that the risk of reinfection was highest among people with recent injection drug use. Among people who inject drugs, daily use of opioid-agonist therapy was associated with a lower risk of reinfection

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features

Deubiquitination is critical for the proper functioning of numerous biological pathways such as DNA repair, cell cycle progression, transcription, signal transduction, and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders (ND) and congenital abnormalities. ATXN7L3 is a component of the DUB module of the SAGA complex, and two other related DUB modules, and serves as an obligate adaptor protein of 3 ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and GeneMatching, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia, and distinctive facial characteristics including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set posteriorly rotated ears. In order to assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C&gt;T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic ND

Modifiable and Non-modifiable Risk Factors in Cognitive and Cerebrovascular Aging

For the first time in Canadian history, the number of Canadians over the age of 65 has surpassed those 14 years and younger making Canada an aging society. This trend is the same in all countries in the Developed World. With this increase of older adults in the world population, the study of modifiable and non-modifiable risk factors for healthy brain aging has become increasingly important. Normal brain aging is associated with a loss of some cognitive functions such as executive control, processing speed, learning, and memory functions. The trajectories of cognitive decline in older adults are influenced by modifiable risk factors such as hypertension and obesity, as well as non-modifiable risk genes (i.e., Apolipoprotein E) that potentially increase the risk of Alzheimer disease or related dementia. Physical activity has repeatedly been demonstrated to be effective in lowing cardiovascular risk factors while also protecting cerebrovascular reserve and cognitive functions. However, the potential relationship between multiple factors such as modifiable and non-modifiable risk factors, biomarkers, and physiological and psychological health in cognitive and cerebrovascular aging remains poorly understood. The Brain in Motion study was a quasi-experimental prospective cohort designed study which examined the effects of a six-month aerobic exercise intervention on cerebrovascular and cognitive function in healthy older adults. The study aimed to recruit 250 healthy, inactive, adults over the age of 55 years, and without mild cognitive impairment or dementia. Using pre-intervention data, Study I examined the effects of modifiable risk factors associated with Metabolic Syndrome and apolipoprotein E genotype on cerebrovascular function. Study II examined the contribution of genetic risk, subjective cognitive complaints, and vascular function during submaximal exercise on pre-intervention objective cognitive performance. Study III examined the influence of a six-month aerobic exercise intervention and exercise dose on cardiorespiratory fitness, cerebrovascular, and cognitive function. These results add to the growing literature suggesting that engagement of regular aerobic exercise improves cerebrovascular and cognitive functioning. In addition, these results provide insights on the influence of cerebrovascular mechanisms that are involved in promoting healthy brain aging

Stability dataset

N

The Function Acquisition Speed Test (FAST): A behavior-analytic implicit test for assessing stimulus relations

Subjects completed a baseline stimulus matching procedure designed to pro-duce two symmetrical stimulus relations; A1–B1 and A2–B2. Using A1, B1, and two novel stimuli, subjects were then trained to produce a common key-press response for two stimuli and a second key-press response for two fur-ther stimuli across two blocks of response training. During one block, the re-inforcement contingencies were consistent with baseline relations (i.e., A1 and B1 shared a response function), whereas during the other block they were not. Thirteen of 18 subjects who completed the procedure showed a response class acquisition rate differential across the two test blocks in the predicted direc-tion. It is suggested that this procedure may serve as a behavior analytic alter-native to popular implicit tests. It provides a nonrelative measure of stimulus association strength and may display superior procedural implicitness over other tests. There has been considerable recent interest in developing behavior analytic "implicit" tests for assessing histories of relational responding and stimulus relations generally. This interest can be traced to the finding that the stimulus relations formed during a subject's social history may interfere with the formation of novel stimulus relations, such as equivalence classes. Specifically, in what can now be surely described as a seminal study, Watt, Keenan, Barnes, and Cairns (1991) used a simple stimulu

Sex difference in cue strategy in a modified version of the Morris water task: correlations between brain and behaviour.

BACKGROUND: Sex differences in spatial memory function have been reported with mixed results in the literature, with some studies showing male advantages and others showing no differences. When considering estrus cycle in females, results are mixed at to whether high or low circulating estradiol results in an advantage in spatial navigation tasks. Research involving humans and rodents has demonstrated males preferentially employ Euclidean strategies and utilize geometric cues in order to spatially navigate, whereas females employ landmark strategies and cues in order to spatially navigate. METHODOLOGY/PRINCIPAL FINDINGS: This study used the water-based snowcone maze in order to assess male and female preference for landmark or geometric cues, with specific emphasis placed on the effects of estrus cycle phase for female rat. Performance and preference for the geometric cue was examined in relation to total hippocampal and hippocampal subregions (CA1&2, CA3 and dentate gyrus) volumes and entorhinal cortex thickness in order to determine the relation between strategy and spatial performance and brain area size. The study revealed that males outperformed females overall during training trials, relied on the geometric cue when the platform was moved and showed significant correlations between entorhinal cortex thickness and spatial memory performance. No gross differences in behavioural performance was observed within females when accounting for cyclicity, and only total hippocampal volume was correlated with performance during the learning trials. CONCLUSIONS/SIGNIFICANCE: This study demonstrates the sex-specific use of cues and brain areas in a spatial learning task

Grey literature in Australian education

The prevalence of informal publishing or grey literature in education appears to have increased as digital technologies have become main-stream, educators have become more proficient and policies have moved increasingly towards supporting its use. In addition, the take up of social networking technologies and innovative methods of digital publishing have encouraged educators to produce, distribute and share content and commentary. Grey literature may make a substantial contribution to education even though issues such as credibility, access and a lack of standards can pose problems for producers and users. This paper begins by providing a context for the discussion of grey literature within the broader policy and education environment in Australia. An overview of grey literature as it appears in education in Australia introducing evidence of its usage, dissemination and application in Australian education then follows. Evidence about the access, dissemination and use of grey literature is drawn from an examination of the characteristics of a leading social networking and digital publishing service that was used by educators in schools, training institutes and teacher education faculties. This evidence is discussed in the context of influential national, state and institutional policies that address the use of digital technologies in education. As the take up of digital technologies in education increases, there is an expectation that the access to, dissemination of and use of digital publishing by and for educators will increase and have an impact on online professional learning and awareness of education research and practices