Dynamics of IGF signalling during the ovulatory peak in women undergoing ovarian stimulation.

CONTEXT: IGF signalling is known to affect human ovarian follicular function during growth and development. However, the role of the IGF system is unknown during the ovulatory peak, which is characterized by profound changes in granulosa cell (GCs) mitosis and function. OBJECTIVE: How is the IGF system expressed and regulated during the midcycle surge in women? DESIGN: Follicular fluid (FF) and granulosa cells (GCs) were collected during the ovulatory peak from two specific time-points. One sample was obtained before oocyte pick up (OPU): before ovulation trigger (OT) (T = 0 h) or at 12, 17, or 32 h after OT, and one sample was obtained at OPU 36 h after OT. SETTING: University hospital. PATIENTS/PARTICIPANTS: Fifty women undergoing ovarian stimulation were included. MAIN OUTCOME MEASURE: Gene expression profiles were assessed by microarray analysis of GCs. IGF-related proteins in the FF were assessed by using immunoassays or by determination of activity with a proteinase assay. RESULTS: Expression of proteins promoting IGF activity (i.e., IGF2, PAPPA, and IRS1) together with proliferation markers were downregulated on a transcriptional level in GCs after OT, whereas proteins inhibiting the IGF signal (i.e., IGFBPs, IGF2R, and STC1) were upregulated. STC1 gene expression and protein levels were greatly upregulated after OT with a parallel steep downregulation of PAPP-A proteolytic activity. CONCLUSIONS: These data suggest that downregulation of IGF signalling mediated by increased STC1 expression is instrumental for the sudden cessation in GC proliferation and onset of differentiation during the ovulatory peak.

Confronting the dialectic between quality and access in early psychosis care in the United States: Finding the synthesis by leveraging psychological expertise.

Coordinated specialty care (CSC) is the dominant model for early psychosis care in the United States, representing a proactive recovery-oriented approach to serious mental illness in its early stages. CSC involves broad multidisciplinary support for participants, including from psychologists in some CSC teams, encompassing educational and vocational support, medication management, psychotherapy, case management, peer support, and family interventions. CSC programs have proliferated in the last 20 years, leading to a quality-access dialectic, where increasing access to treatment simultaneously prompts concerns about care quality, particularly in the context of staffing shortages and funding limits. Evidence-based psychosocial treatment, including psychotherapy, is an integral part of CSC, yet workforce training deficits, workforce turnover, and CSC financing pose threats to intervention fidelity and thus CSC participants' ability to access high-quality care. We propose an enhanced role for psychologists as a way of resolving the quality-access dialectic in the area of psychosocial treatment, specifically evidence-based therapy. We describe the potential of psychologists' skills in clinical supervision, formulation, evidence-based interventions and measurement-based care, drawing on practice examples. After considering possible limitations, we outline implementation models, for example, drawing on Early Psychosis Intervention Network and Project Extension for Community Healthcare Outcomes. We conclude with four recommendations: Psychologists should be placed in CSC team or network-leadership roles; psychological expertise should be made available to CSC teams for training, consultation, and technical assistance; psychological expertise should be used to address CSC implementation challenges; and research is needed to demonstrate psychologists' value to stakeholders. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Early-life stress affects Mongolian gerbil interactions with conspecific vocalizations in a sex-specific manner.

During development, early-life stress (ELS) impairs cognition, learning, and emotional regulation, in part by disrupting neural circuitry in regions underlying these higher-order functions. In addition, our recent work indicates that ELS also alters simple sensory perception: ELS impaired auditory perception and neural encoding of short gaps in sounds, which are essential for vocal communication. The combination of higher-order and basic sensory disruption suggests that ELS is likely to affect both the perception and interpretation of communication signals. We tested this hypothesis by measuring behavioral responses to conspecific vocalizations (those emitted by other gerbils) in ELS and untreated Mongolian gerbils. Because stress effects often differ by sex, we separately examined females and males. To induce ELS, pups were intermittently maternally separated and restrained from post-natal days (P) 9-24, a time window when the auditory cortex is most sensitive to external disruption. We measured the approach responses of juvenile (P31-32) gerbils to two types of conspecific vocalizations: an alarm call, which is emitted to alert other gerbils of a potential threat, and the prosocial contact call, which is emitted near familiar gerbils, especially after separation. Control males, Control females, and ELS females approached a speaker emitting pre-recorded alarm calls, while ELS males avoided this source, suggesting that ELS affects the response to alarm calls in male gerbils. During playback of the pre-recorded contact call, Control females and ELS males avoided the sound source, while Control males neither approached nor avoided, and ELS females approached the sound. These differences cannot be accounted for by changes in locomotion or baseline arousal. However, ELS gerbils slept more during playback, suggesting that ELS may reduce arousal during vocalization playback. Further, male gerbils made more errors than females on a measure of working memory, but the sex difference of cognition in this context may stem from novelty aversion rather than impaired memory. These data indicate that ELS influences behavioral responses to ethologically relevant communication sounds in a sex-specific manner, and are among the first to demonstrate an altered response to auditory stimuli following ELS. Such changes may arise from differences in auditory perception, cognition, or a combination of factors, and suggest that ELS may affect auditory communication in human adolescents.

Reductions in synaptic marker SV2A in early-course Schizophrenia.

Excess synaptic pruning during neurodevelopment has emerged as one of the leading hypotheses on the causal mechanism for schizophrenia. It proposes that excess synaptic elimination occurs during development before the formal onset of illness. Accordingly, synaptic deficits may be observable at all stages of illnesses, including in the early phases. The availability of [11C]UCB-J, the first-in-human in vivo synaptic marker, represents an opportunity for testing this hypothesis with a relatively high level of precision. The first two published [11C]UCB-J schizophrenia studies have documented significant, widespread reductions in binding in chronic patients. The present study tested the hypothesis that reductions are present in early-course patients. 18 subjects completed [11C]UCB-J PET scans, (nine with schizophrenia, average duration of illness of 3.36 years, and nine demographically-matched healthy individuals). We compared binding levels, quantified as non-displaceable specific binding (BPND), in a set of a priori-specified brain regions of interest (ROIs). Eight ROIs (left and right hippocampus, right superior temporal and Heschl's gyrus, left and right putamen, and right caudal and rostral middle frontal gyrus) showed large reductions meeting Bonferroni corrected significant levels, p < 0.0036. Exploratory, atlas-wide analyses confirmed widespread reductions in schizophrenia. We also observed significant positive correlations between binding levels and cognitive performance and a negative correlation with the severity of delusions. These results largely replicate findings from chronic patients, indicating that extensive [11C]UCB-J binding deficits are reliable and reproducible. Moreover, these results add to the growing evidence that excess synaptic pruning is a major disease mechanism for schizophrenia.

Follicle-Stimulating Hormone Glycosylation Variants Distinctly Modulate Pre-antral Follicle Growth and Survival.

Follicle-stimulating hormone (FSH) is a key endocrine regulator of ovarian function. FSH is secreted as 2 macroglycosylation variants: partially glycosylated FSH (FSH21/18) and fully glycosylated FSH (FSH24). FSH21/18 is more potent than FSH24 at binding to and activating the FSH receptor (R). The ratio of FSH21/18:FSH24 has been shown to change with age, with FSH21/18 predominant at reproductive prime, and FSH24 predominant during perimenopause/menopause. How these FSH glycosylation variants modulate ovarian follicle functions remains largely unknown. The aim of this study was to investigate the effect of FSH glycosylation variants of pre-antral follicle function. Pre-antral follicles were isolated from 3- to 5-week-old C57BL/6 mice and treated ±10 ng/mL FSH21/18, FSH24, a ratio of 80:20 FSH21/18:FSH24 (to mimic reproductive prime), 50:50 FSH21/18:FSH24 (perimenopause), or 20:80 FSH21/18:FSH24 (menopause) for up to 96 hours. FSH21/18 and 80:20 FSH21/18:FSH24 increased follicle growth, in comparison with control, contrasting with FSH24 and 20:80 FSH21/18:FSH24. Survival rates were decreased in follicles treated with FSH24 or 20:80 FSH21/18:FSH24, with follicles undergoing basement membrane rupture and oocyte extrusion, increased Caspase3 gene and protein expression, and decreased markers of cell proliferation in FSH24 or 20:80 FSH21/18:FSH24-treated follicles. Moreover, this correlated with differential regulation of key genes modulating follicular functions. Pharmacological inhibitors of key FSH signal pathways suggests FSH21/18 and FSH24 initiate different FSHR signal pathway activation, which may determine their differential effects on follicle growth and survival. These data suggest that the nature of FSH glycosylation modulates the follicular cellular environment to regulate follicle growth and survival and may underpin the increasing ovarian resistance to FSH observed during aging.

Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries.

CONTEXT: The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) play essential roles in follicle development and oocyte maturation, and aberrant regulation might contribute to the pathogenesis of polycystic ovary syndrome. OBJECTIVE: Are there measurable differences in concentrations of GDF9, BMP15, and the GDF9/BMP15 heterodimer in small antral follicle fluids from women with and without polycystic ovaries (PCO)? DESIGN AND SETTING: Follicle fluids (n = 356) were collected from 4- to 11-mm follicles in unstimulated ovaries of 87 women undergoing ovarian tissue cryopreservation for fertility preservation. PATIENTS: Twenty-seven women with PCO were identified and 60 women without PCO-like characteristics (non-PCO women) were matched according to age and follicle size. MAIN OUTCOME MEASURES: Intrafollicular concentrations of GDF9, BMP15, GDF9/BMP15 heterodimer, anti-Mullerian hormone (AMH), inhibin-A and -B, total inhibin, activin-B and -AB, and follistatin were measured using enzyme-linked immunosorbent assays. RESULTS: The detectability of GDF9, BMP15, and the GDF9/BMP15 heterodimer were 100%, 94.4%, and 91.5%, respectively, and concentrations were significantly negatively correlated with increasing follicle size (P < 0.0001). GDF9 was significantly higher in women with PCO (PCO: 4230 ±â€…189 pg/mL [mean ±â€…SEM], n = 188; non-PCO: 3498 ±â€…199 pg/mL, n = 168; P < 0.03), whereas BMP15 was lower in women with PCO (PCO: 431 ±â€…40 pg/mL, n = 125; non-PCO: 573 ±â€…55 pg/mL, n = 109; P = 0.10), leading to a significantly higher GDF9:BMP15 ratio in women with PCO (P < 0.01). Significant positive associations between BMP15 and AMH, activins, and inhibins in non-PCO women switched to negative associations in women with PCO. CONCLUSIONS: Intrafollicular concentrations of GDF9 and BMP15 varied inversely in women with PCO reflecting an aberrant endocrine environment. An increased GDF9:BMP15 ratio may be a new biomarker for PCO.

Micromechanical mapping of the intact ovary interior reveals contrasting mechanical roles for follicles and stroma.

Follicle development in the ovary must be tightly regulated to ensure cyclical release of oocytes (ovulation). Disruption of this process is a common cause of infertility, for example via polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Recent ex vivo studies suggest that follicle growth is mechanically regulated, however, crucially, the actual mechanical properties of the follicle microenvironment have remained unknown. Here we use atomic force microscopy (AFM) spherical probe indentation to map and quantify the mechanical microenvironment in the mouse ovary, at high resolution and across the entire width of the intact (bisected) ovarian interior. Averaging over the entire organ, we find the ovary to be a fairly soft tissue comparable to fat or kidney (mean Young's Modulus 3.3±2.5 kPa). This average, however, conceals substantial spatial variations, with the overall range of tissue stiffnesses from c. 0.5-10 kPa, challenging the concept that a single Young's Modulus can effectively summarize this complex organ. Considering the internal architecture of the ovary, we find that stiffness is low at the edge and centre which are dominated by stromal tissue, and highest in an intermediate zone that is dominated by large developmentally-advanced follicles, confirmed by comparison with immunohistology images. These results suggest that large follicles are mechanically dominant structures in the ovary, contrasting with previous expectations that collagen-rich stroma would dominate. Extending our study to the highest resolutions (c. 5 µm) showed substantial mechanical variations within the larger zones, even over very short (sub-100 µm) lengths, and especially within the stiffer regions of the ovary. Taken together, our results provide a new, physiologically accurate, framework for ovarian biomechanics and follicle tissue engineering.

Facilitating rapid access to addiction treatment: a randomized controlled trial.

BACKGROUND: Obtaining timely access to addiction medicine treatment for patients with substance use disorders is challenging and patients often have to navigate complex referral pathways. This randomized controlled trial examines the effect of providing an expedited pathway to addiction medicine treatment on initial treatment engagement and health care utilization. METHODS: Individuals with possible alcohol or opioid use disorder were recruited from three residential withdrawal management services (WMS). Subjects randomized to the Delayed Intervention (DI) group were given contact information for a nearby addiction medicine clinic; those randomized to the Rapid Intervention (RI) group were given an appointment at the clinic within 2 days and were accompanied to their first appointment. RESULTS: Of the 174 individuals who were screened, 106 were randomized to either the DI or RI group. The two groups were similar in demographics, housing status, and substance use in the last 30 days. In the 6-month period following randomization, 85% of the RI group attended at least one clinic appointment, compared to only 29% in the DI group (p < 0.0001). The RI group had a mean of 6.39 ED visits per subject in the 12 months after randomization, while the DI group had a mean of 13.02 ED visits per subject in the same 12-month period (p = 0.0469). Other health utilization measures did not differ between the two groups. CONCLUSION: Providing immediate facilitated access to an addiction medicine service resulted in greater initial engagement and reduced emergency department visits at 6 months. Trial registration This trial is registered at the National Institutes of Health (ClinicalTrials.gov) under identifier #NCT01934751.

Psychosis REACH: Effects of a Brief CBT-Informed Training for Family and Caregivers of Individuals With Psychosis.

OBJECTIVE: Psychosis Recovery by Enabling Adult Carers at Home (Psychosis REACH) is a training for families of individuals with psychosis that consists of recovery-oriented psychosis psychoeducation, caregiver self-care, and skills training informed by cognitive-behavioral therapy for psychosis (CBTp). The authors assessed the effects of a 1-day and a 4-day training on the natural supports (i.e., family and other caregivers) of individuals with psychotic disorders. METHODS: Attendees of a 1-day (N=168) and a 4-day (N=29) Psychosis REACH training were surveyed at three timepoints: pretraining, posttraining, and 4-month follow-up. Longitudinal changes across the full sample were evaluated by paired-sample t tests or a one-way repeated-measures analysis of variance (ANOVA). Two-way mixed ANOVAs were conducted with training condition, time, and the training condition × time interactions entered into the model. RESULTS: Reductions were noted in self-perceived depression, anxiety, negative aspects of the caregiving experience, and expressed emotion. Trainees also showed more prosocial attitudes toward psychosis immediately and at 4 months after the training. CONCLUSIONS: This evaluation of the launch of Psychosis REACH in the United States suggests that the training can improve the mental health, attitudinal, and relational outcomes of family and caregivers of individuals with psychosis. Given the dearth of CBTp and family interventions for psychosis in mental health services in the United States, short-term, intensive training that supplements clinical services has intuitive appeal as a means of surmounting the barriers that have plagued family interventions.

Brief report describing the integration of two psychotherapy evidence-based practices within coordinated specialty care services for early psychosis.

Individual psychotherapy is routinely offered within coordinated specialty care services for early psychosis. In the United States, 2 primary models have been implemented: cognitive-behavioral therapy for psychosis and individualized resiliency training. However, coordinated specialty care services have typically chosen between these approaches, thus limiting access to the unique aspects of each of the models, missing opportunities related to workforce development, and reducing consumer choice. Opportunities exist for integration of these 2 models. This brief report provides an overview of individualized resiliency training and cognitive-behavioral therapy for psychosis. In addition, elements of synergy between the 2 models are identified and opportunities for an integrated approach highlighted. Further study of the core elements of an integrated approach is required, and guidance for clinicians to support clinical decision making is needed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Training early psychosis community clinicians in CBT for psychosis: Implementation and feasibility.

OBJECTIVE: Cognitive behavioural therapy (CBT) has demonstrated efficacy for treating of psychotic symptoms and is recommended as an evidence-based practice (EBP) in early psychosis services. Despite this recommendation, there is limited information about the feasibility of training community clinicians, working in an early psychosis service, to competence in the delivery of this intervention. METHOD: Fifty clinicians working in an early psychosis service across five programs in Northern California were trained in CBT for psychosis (CBTp) between 2010 and 2014. Following the training, clinicians attended weekly group consultation and submitted taped sessions for review. Tapes were rated for competency using the Cognitive Therapy Scale-Revised (CTS-R). Clinicians who achieved competence were engaged in a train-the-trainer model to support ongoing sustainability of the training program. RESULTS: Data from 40 clinicians were reviewed for achievement of competence. Over the training period 18 clinicians achieved competence while 20 clinicians left the service before achieving competence and 12 were still in the process of achieving competence at the point of data analysis. It took on average 54 weeks (range 17-130 weeks) and an average of six tape reviews (range 3-18) to train clinicians to competency. CONCLUSIONS: Community clinicians working in an early psychosis program can be trained to competence in CBTp following an initial didactic period and ongoing weekly group consultation, although staff turnover hindered implementation. Challenges and opportunities for future implementation in community sites are presented in the context of further expansion of early psychosis services in the United States.

Androgen Reduces Mitochondrial Respiration in Mouse Brown Adipocytes: A Model for Disordered Energy Balance in Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including reduced postprandial thermogenesis. Although abnormalities in adipose tissue function have been widely reported in women with PCOS, less is known about direct effects of androgen on white and, particularly, brown adipocytes. The purpose of this study was to investigate the effect of the nonaromatizable androgen dihydrotestosterone (DHT) on (1) lipid accumulation and expression of adipogenic markers in immortalized mouse brown adipose cell lines (IMBATs), (2) mitochondrial respiration in IMBATs, (3) mitochondrial DNA content and gene expression, (4) expression of brown adipose tissue (BAT) markers and thermogenic activation. In addition, we profiled the relative levels of 38 adipokines secreted from BAT explants and looked at androgen effects on adipokine gene expression in both IMBATs and immortalized mouse white adipose (IMWATs) cell lines. Androgen treatment inhibited IMBAT differentiation in a dose-dependent manner, reduced markers of adipogenesis, and attenuated the ß-adrenoceptor-stimulated increase in uncoupling protein-1 (UCP1) expression. In explants of mouse interscapular BAT, androgen reduced expression of UCP1, peroxisome proliferator-activated receptor-γ coactivator-1 (PCG-1) and Cidea. Significantly, as well as affecting genes involved in thermogenesis in BAT, androgen treatment reduced mitochondrial respiration in IMBATs, as measured by the Seahorse XF method. The results of this study suggest a role for excess androgen in inhibiting brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in BAT. Together, these data provide a plausible molecular mechanism that may contribute to reduced postprandial thermogenesis and the tendency to obesity in women with PCOS.

Gene Expression in Granulosa Cells From Small Antral Follicles From Women With or Without Polycystic Ovaries.

CONTEXT: Polycystic ovary syndrome (PCOS) is the most common cause of anovulation. A key feature of PCOS is arrest of follicles at the small- to medium-sized antral stage. OBJECTIVE AND DESIGN: To provide further insight into the mechanism of follicle arrest in PCOS, we profiled (i) gonadotropin receptors; (ii) characteristics of aberrant steroidogenesis; and (iii) expression of anti-Müllerian hormone (AMH) and its receptor in granulosa cells (GCs) from unstimulated, human small antral follicles (hSAFs) and from granulosa lutein cells (GLCs). SETTING: GCs from hSAFs were collected at the time of cryopreservation of ovarian tissue for fertility preservation and GLCs collected during oocyte aspiration before in vitro fertilization/intracytoplasmic sperm injection. PARTICIPANTS: We collected hSAF GCs from 31 women (98 follicles): 10 with polycystic ovaries (PCO) and 21 without. GLCs were collected from 6 women with PCOS and 6 controls undergoing IVF. MAIN OUTCOME MEASURES: Expression of the following genes: LHCGR, FSHR, AR, INSR, HSD3B2, CYP11A1, CYP19, STAR, AMH, AMHR2, FST, INHBA, INHBB in GCs and GLCs were compared between women with PCO and controls. RESULTS: GCs in hSAFs from women with PCO showed higher expression of LHCGR in a subset (20%) of follicles. Expression of FSHR (P < 0.05), AR (P < 0.05), and CYP11A1 (P < 0.05) was lower, and expression of CYP19A1 (P < 0.05), STAR (P < 0.05), HSD3B2 (P = NS), and INHBA (P < 0.05) was higher in PCO GCs. Gene expression in GL cells differed between women with and without PCOS but also differed from that in GCs. CONCLUSIONS: Follicle arrest in PCO is characterized in GCs by differential regulation of key genes involved in follicle growth and function.

Quantitative Differences in TGF-ß Family Members Measured in Small Antral Follicle Fluids From Women With or Without PCO.

CONTEXT: Members of the TGF-ß family have been implicated in aberrant follicle development in women with polycystic ovaries (PCO). OBJECTIVE: Are there quantitative differences in the concentrations of TGF-ß family members in fluid from human small antral follicles (hSAFs) in women with or without PCO? DESIGN AND SETTING: Follicle fluids (FFs) were collected from 4- to 11-mm hSAFs obtained from women undergoing ovarian tissue cryopreservation for fertility preservation. PATIENTS: FFs from 16 women with PCO (FF = 93) and 33 women without PCO (FF = 92). MAIN OUTCOME MEASURES: Intrafollicular concentrations of growth differentiation factor-9 (GDF9); anti-Müllerian hormone (AMH); inhibin-A and inhibin-B; total inhibin; activin-A, activin-B, and activin-AB; follistatin; follistatin-like-3; estradiol; and testosterone. RESULTS: Activin-B concentrations were reported in hSAFs, and concentrations were 10 times higher than activin-A and activin-AB concentrations. Activin-B showed significant associations with other growth factors. Concentrations of inhibin-A and inhibin-B were significantly lower in FFs from women with PCO, especially in hSAFs <8 mm in diameter. AMH concentrations did not differ between the groups in hSAFs <8 mm; however, AMH remained high in hSAFs >8 mm in women with PCO but decreased in women without PCO. Estradiol was significantly lower in FFs from women with PCO and showed significant associations with AMH. Concentrations of GDF9 showed significantly higher concentrations in PCO FFs of follicles >6 mm. CONCLUSIONS: Altered concentrations of TGF-ß family members in hSAFs from women with PCO highlight altered growth factor signaling as a potential mechanism for follicle growth arrest.

SMAD3 directly regulates cell cycle genes to maintain arrest in granulosa cells of mouse primordial follicles.

Primordial follicles, consisting of granulosa cell (GC)-enveloped oocytes are maintained in a state of developmental arrest until activated to grow. The mechanism that operates to maintain this arrested state in GCs is currently unknown. Here, we show the TGFß-activated transcription factor SMAD3 is expressed in primordial GC nuclei alongside the cell cycle proteins, cyclin D2 (CCND2) and P27. Using neonatal C57/Bl6 mouse ovaries densely populated with primordial follicles, CCND2 protein co-localised and was detected in complex with P27 by immunofluorescence and co-immunoprecipitation, respectively. In the same tissue, SMAD3 co-precipitated with DNA sequences upstream of Ccnd2 and Myc transcription start sites implicating both as direct SMAD3 targets. In older ovaries follicle growth was associated with nuclear exclusion of SMAD3 and reduced P27 and CCND2 in GCs, alongside elevated Myc expression. Brief (2 H) exposure of neonatal ovaries to TGFß1 (10 ng/ml) in vitro led to immediate dissociation of SMAD3 from the Ccnd2 and Myc promoters. This coincided with elevated Myc and phospho-S6, an indicator of mTOR signalling, followed by a small increase in mean primordial GC number after 48 H. These findings highlight a concentration-dependent role for TGFß signalling in the maintenance and activation of primordial follicles, through SMAD-dependent and independent signalling pathways, respectively.

Nuclear exclusion of SMAD2/3 in granulosa cells is associated with primordial follicle activation in the mouse ovary.

Maintenance and activation of the limited supply of primordial follicles in the ovary are important determinants of reproductive lifespan. Currently, the molecular programme that maintains the primordial phenotype and the early events associated with follicle activation are not well defined. Here, we have systematically analysed these events using microscopy and detailed image analysis. Using the immature mouse ovary as a model, we demonstrate that the onset of granulosa cell (GC) proliferation results in increased packing density on the oocyte surface and consequent GC cuboidalization. These events precede oocyte growth and nuclear translocation of FOXO3a, a transcription factor important in follicle activation. Immunolabelling of the TGFß signalling mediators and transcription factors SMAD2/3 revealed a striking expression pattern specific to GCs of small follicles. SMAD2/3 were expressed in the nuclei of primordial GCs but were mostly excluded in early growing follicles. In activated follicles, GC nuclei lacking SMAD2/3 generally expressed Ki67. These findings suggest that the first phenotypic changes during follicle activation are observed in GCs, and that TGFß signalling is fundamental for regulating GC arrest and the onset of proliferation.

Androgen Action in the Ovary.

Androgen production by the ovary is an essential requirement for normal cyclical secretion of estradiol but its physiological role extends to important actions on both preantral and antral follicle development, including promotion of granulosa cell proliferation. It is likely only in mature antral follicles that androgens encourage apoptosis and consequent follicle atresia, and this may be an important mechanism to ensure mono-follicular ovulation in primates, including humans. Recent studies have provided new insight into the mechanism of androgen signaling in the ovary which involves both genomic and non-genomic effects that are complementary in effecting a cellular response. In polycystic ovary syndrome, a condition characterized by intra-ovarian androgen excess, aberrant development of both preantral and antral follicles is a salient feature. We present evidence that local action of androgens plays a part in such abnormalities. Finally, we review the role of androgens in follicle atresia and conclude that the effects are part of the normal physiology of follicle maturation.

Impact of age of onset of psychosis and engagement in higher education on duration of untreated psychosis.

BACKGROUND: The average age of onset of psychosis coincides with the age of college enrollment. Little is known about the impact of educational engagement on DUP in a college-aged population. AIMS: To determine DUP, and the impact of educational engagement, for college-aged participants of the RAISE study (n = 404). METHOD: We conducted secondary data analyses on the publicly available RAISE dataset. Subsamples were analyzed to determine the impact of age and educational engagement on DUP. RESULTS: DUP was significantly shorter (p < 0.02) for participants who were college-aged (18-22 years, n = 44) and engaged in post-secondary education (median = 12 weeks, mean = 29 weeks) compared with participants who were college-aged and not engaged in higher education (n = 92, median = 29 weeks, mean = 44 weeks). CONCLUSIONS: Educational engagement appears to be associated with a shorter DUP. This may be partially explained by the presence of on-site wellness centers in college settings. However, even among young people who engaged in post-secondary education DUP was still at, or beyond, the upper limit of WHO recommendations in this group. Future research exploring how colleges could improve their capacity to detect and refer at risk students for treatment at an earlier stage is recommended.