The Pleiotropic Role of Extracellular ATP in Myocardial Remodelling.

Myocardial remodelling is a molecular, cellular, and interstitial adaptation of the heart in response to altered environmental demands. The heart undergoes reversible physiological remodelling in response to changes in mechanical loading or irreversible pathological remodelling induced by neurohumoral factors and chronic stress, leading to heart failure. Adenosine triphosphate (ATP) is one of the potent mediators in cardiovascular signalling that act on the ligand-gated (P2X) and G-protein-coupled (P2Y) purinoceptors via the autocrine or paracrine manners. These activations mediate numerous intracellular communications by modulating the production of other messengers, including calcium, growth factors, cytokines, and nitric oxide. ATP is known to play a pleiotropic role in cardiovascular pathophysiology, making it a reliable biomarker for cardiac protection. This review outlines the sources of ATP released under physiological and pathological stress and its cell-specific mechanism of action. We further highlight a series of cardiovascular cell-to-cell communications of extracellular ATP signalling cascades in cardiac remodelling, which can be seen in hypertension, ischemia/reperfusion injury, fibrosis, hypertrophy, and atrophy. Finally, we summarize current pharmacological intervention using the ATP network as a target for cardiac protection. A better understanding of ATP communication in myocardial remodelling could be worthwhile for future drug development and repurposing and the management of cardiovascular diseases.

Initiating Cognitive Processing Therapy (CPT) in Community Settings: A Qualitative Investigation of Therapist Decision-Making.

Various organizations have provided treatment guidelines intended to aid therapists in deciding how to treat posttraumatic stress disorder (PTSD). Yet evidence-based psychotherapies (EBPs) for PTSD in the community may be difficult to obtain. Although strides have been made to implement EBPs for PTSD in institutional settings such as the United States Veterans Affairs, community uptake remains low. Factors surrounding clients' decisions to enroll in EBPs have been identified in some settings; however less is known regarding trained therapists' decisions related to offering trauma-focused therapies or alternative treatment options. Thus, the aim of the current study was to examine therapist motivations to initiate CPT in community settings. The present study utilizes data from a larger investigation aiming to support the sustained implementation of Cognitive Processing Therapy (CPT) in community mental health treatment settings. Enrolled therapists participated in phone interviews discussing their opinions of CPT, preferred treatments for PTSD, and process in assessing appropriate PTSD treatments for clients. Semi-structured interviews (N = 29) were transcribed and analyzed using a directed content analysis approach. Several themes emerged regarding therapists' decision-making in selecting PTSD treatments. Therapist motivations to use EBPs for PTSD, primarily CPT, were identified at the client (e.g., perceived compatibility with client-level characteristics), therapist (e.g., time limitations), and clinic levels (e.g., leadership support). The results provide insight into the complex array of factors that affect sustainability of EBPs for PTSD in community settings and inform future dissemination of EBPs, including training efforts in community settings.

Genotype-Phenotype Study of ß-Thalassemia Patients in Sabah.

ß-thalassemia is a serious public health problem in Sabah due to its high prevalence. This study aimed to investigate the effects of different types of ß-globin gene mutations, coinheritance with α-globin gene mutations, XmnI-Gγ, and rs368698783 polymorphisms on the ß-thalassemia phenotypes in Sabahan patients. A total of 111 patients were included in this study. The sociodemographic profile of the patients was collected using a semi-structured questionnaire, while clinical data were obtained from their medical records. Gap-PCR, ARMS-PCR, RFLP-PCR, and multiplex PCR were performed to detect ß- and α-globin gene mutations, as well as XmnI-Gγ and rs368698783 polymorphisms. Our data show that the high prevalence of ß-thalassemia in Sabah is not due to consanguineous marriages (5.4%). A total of six different ß-globin gene mutations were detected, with Filipino ß°-deletion being the most dominant (87.4%). There were 77.5% homozygous ß-thalassemia patients, 16.2% compound heterozygous ß-thalassemia patients, and 6.3% ß-thalassemia/Hb E patients. Further evaluation on compound heterozygous ß-thalassemia and ß-thalassemia/Hb E patients found no concomitant α-globin gene mutations and the rs368698783 polymorphism. Furthermore, the XmnI-Gγ (-/+) genotype did not demonstrate a strong impact on the disease phenotype, as only two of five patients in the compound heterozygous ß-thalassemia group and two of three patients in the ß-thalassemia/Hb E group had a moderate phenotype. Our findings indicate that the severity of the ß-thalassemia phenotypes is closely related to the type of ß-globin gene mutations but not to the XmnI-Gγ and rs368698783 polymorphisms.

Trauma-focused cognitive behavioral therapy for children and youth in low and middle-income countries: A systematic review.

BACKGROUND: Trauma-focused cognitive behavioral therapy (TF-CBT) has been identified as a gold standard treatment for childhood posttraumatic stress disorder (PTSD) in Western countries. More recently, TF-CBT has emerged in the literature as an area of interest for children and youth affected by conflict and war in low- and middle-income countries (LMIC). METHODS: The present systematic review assesses the current evidence base of TF-CBT for children and youth in LMIC, with a focus on conflict-affected countries. A total of 143 articles were identified, of which 11 articles, representing 1,354 participants, met the proposed inclusion criteria. RESULTS: Results showed that the majority of the studies identified were conducted in low-resource community settings in East or Central Africa (n = 8). It was also found that cultural considerations were taken into account in TF-CBT delivery to meet the needs of local populations. Additionally, measures were translated and validated for local use. CONCLUSIONS: Findings of outcome data indicated that TF-CBT was effective in treating trauma-related symptoms and improving psychosocial functioning in children and adolescents in LMICs. Given the limited number of published literature available in this area, further studies are needed to conclude when and for whom trauma-focused interventions are most relevant.

Acute upper gastrointestinal bleeding: a guide for nurses.

This article outlines latest evidence-based care for patients with acute upper gastrointestinal (GI) bleeding. It aims to help gastroenterology and general medical ward nurses plan nursing interventions and understand the diagnostic treatment options available. Acute upper GI bleeding can present as variceal or non-variceal bleeding and has a high death rate. Endoscopy is used for diagnosis and to provide therapy, prior to which the patient should be adequately resuscitated and assessed. Various therapies can be initiated at endoscopy, depending on the source of bleeding. If bleeding continues in spite of these therapies, further interventions such as the Sengstaken tube, oesophageal stents, radiological or surgical treatments may be required. After endoscopy, it is important to have a plan for ongoing treatment. Patients may require acid suppression treatment or eradication of Helicobacter pylori as part of their treatment plan. They may in additional require correction of their haemoglobin levels and follow-up endoscopy. It is essential that nurses caring for such patients are aware of the current UK guidance and help patients to adhere to agreed treatment plans.

Mental health and addictions capacity building for community health centres in Ontario.

PROBLEM ADDRESSED: In recent years, there has been increased recognition in Canada of the need to strengthen mental health services in primary health care (PHC). Collaborative models, including partnerships between PHC and specialized mental health care providers, have emerged as effective ways for improving access to mental health care and strengthening clinical capacity. Primary health care physicians and other health professionals are well positioned to facilitate the early detection of mental disorders and provide appropriate treatment and follow-up care, helping to tackle stigma toward mental health problems in the process. OBJECTIVE OF PROGRAM: This 4-year mental health and addiction capacity-building initiative for PHC addressed competency needs at the individual, interprofessional, and organizational levels. PROGRAM DESCRIPTION: The program included 5 key components: a needs assessment; interprofessional education; mentoring; development of organizational mental health and addiction action plans for each participating community health centre; and creation of an advanced resource manual to support holistic and culturally competent collaborative mental health care. A comprehensive evaluation framework using a mixed-methods approach was applied from the initiation of the program. A total of 184 health workers in 10 community health centres in Ontario participated in the program, including physicians, nurses, social workers, and administrative staff. CONCLUSION: Evaluation findings demonstrated high satisfaction with the training, improved competencies, and individual behavioural and organizational changes. By building capacity to integrate holistic and culturally appropriate care, this competency-based program is a promising model with strong potential to be adapted and scaled up for PHC organizations nationally and internationally.

Coping with the long-term impact of civil strife: A grief-centered analysis of Tamil Sri Lankan communities affected by ethnopolitical conflict.

Limited research has examined coping mechanisms in response to chronic war-related stressors, as opposed to war-exposure trauma. The current study sought to investigate the types of losses experienced by communities affected by the Sri Lankan conflict, how participants responded to their losses, and what coping mechanisms they employed. Data consisted of interviews from two independent investigations conducted following the end of the conflict in Northern Sri Lanka (total N = 103). Interview transcripts were analyzed using a directed content analysis approach. Participants most frequently described experiencing material loss and loss of loved ones. Relatedly, participants commonly reported experiencing ambiguous loss, that is, living with the uncertainty of their loved one's death. These losses were particularly pronounced by gender, with women experiencing higher rates of loss. Common coping strategies included support-seeking, including informal support from social networks and religion, and formal mental health services. Additionally, participants described a range of longer term coping strategies from establishing a future-oriented cognitive style to a sense of helplessness and resignation. The findings shed light on how conflict-affected groups cope with profound loss. We provide recommendations for how such findings can inform grief-related clinical interventions.

Multilevel factors in providers' decisions to utilize CPT in military- and veteran-serving treatment settings.

Numerous guidelines exist to inform decision-making regarding psychological treatment of patients with posttraumatic stress disorder (PTSD). While strides have been made in the implementation of evidence-based psychotherapies (EBPs) for PTSD in the United States. Department of Veterans Affairs (VA), a large population of veterans does not receive such services. Research has been conducted on veterans' decisions to enroll in EBPs; however, less is known about providers' perspectives related to offering trauma-focused therapies to the military and veteran population, particularly outside the United States. This study utilizes baseline data from a larger investigation aimed to support the sustained implementation of cognitive processing therapy (CPT) in U.S. VA and Canadian Operational Stress Injury (OSI) and Department of Defense settings. Providers who trained in CPT (N = 55) participated in interviews regarding their opinions of CPT, preferred treatments for PTSD, and their process in assessing appropriate PTSD treatments for each patient. A directed content analysis approach was used to identify themes for providers' decision-making to utilize CPT within the context of four Consolidated Framework for Implementation Research (CFIR) domains. In the outer setting domain, providers reported disconnect from policy and leadership as a barrier, and in the inner setting CFIR domain, providers reported multiple facilitators: available resources, leadership support, and compatibility with CPT. The CFIR domain for characteristics of the individuals aligned with a theme of theoretical orientation and training as a facilitator. The intervention characteristics domain aligned with facilitators and barriers; complexity of CPT was a barrier, but relative advantage and perceived strength of evidence were facilitators toward implementation. The systems surrounding and supporting EBP delivery within the U.S. VA, Canada OSI, and Canadian Forces clinics have more similarities than differences regarding barriers and facilitators to delivering CPT. Despite variability in funding and training, provider experiences across all three systems suggest similar themes. Further investigation is needed to determine whether these findings extend to community samples or sites not yet offering EBPs. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Modulation of POPDC1 Expression by Phenothiazine and Trifluoperazine Suppress Colon Cancer Growth and Migration.

OBJECTIVE: The aim of this study was to investigate the effects of CaM antagonist, PTZ, and TFP on cell proliferation and migration of colon cancer cells and its impact on POPDC protein expression. METHODS: The 50% inhibitory concentration (IC50) of PTZ and TFP in SW1116, SW480, HCT-15, and COLO205 colon cancer cell lines are measured using MTT. Western blot and immunocytochemistry were used to determine the expression of PCNA, cyclin D1 (CD1), and POPDC proteins. Cell migration was observed using a scratch wound-healing assay. RESULTS: Treatment with PTZ and TFP inhibited colon cancer cells growth in a dose-dependent manner. PTZ and TFP significantly inhibited the activation of proliferation markers, PCNA and CD1, and the migration of colon cancer cells. Furthermore, POPDC protein was significantly suppressed in all cell types of colon cancer, particularly in SW480. Finally, the CaM antagonist upregulates the POPDC1 expression in colon cancer cells. CONCLUSION: These findings suggest that CaM antagonists suppress colon cancer cells proliferation via downregulation of CD1 and PCNA. In addition, POPDC protein could be used as a biomarker in colon cancer, and CaM antagonist could be used to regulate POPDC1 expression. This study suggests that targeting POPDC1 with CaM inhibition could be a potential therapeutic strategy for colon cancer treatment. 
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Examining post-conflict stressors in northern Sri Lanka: A qualitative study.

Forcibly displaced individuals typically encounter daily stressors, which can negatively impact mental health above and beyond direct exposure to war-related violence, trauma and loss. Understanding the perspectives of war affected communities regarding daily stressors can enhance the integration of mental health into local primary care. The aim of the current study was to explore how daily stressors are conceptualized in a post-conflict setting. Data collection was completed with 53 adult participants who were recruited from primary healthcare clinics in Northern Province, Sri Lanka. Individual interviews were conducted in Tamil, audio-recorded, translated from Tamil to English, and transcribed. Themes emerging from the data were organized into an analytical framework based on iterative coding and grounded in the daily stressors framework. Stressors were conceptualized as chronic stressors and systemic stressors. Findings indicate that chronic stressors, such as loss of property, permeate daily life and have a profound impact on psychological wellbeing. Interviewees additionally reported that systemic stressors stemmed from unresolved grief for missing family members and limited support from institutions. The results of the current study complement existing literature, suggesting the value of multipronged approaches which identify and address symptoms of complicated bereavement while simultaneously alleviating financial hardship. An understanding of stressors experienced by conflict-affected populations in times of chronic adversity can be informative for the design and implementation of culturally-tailored interventions.

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis.

Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

Area deprivation, screen time and consumption of food and drink high in fat salt and sugar (HFSS) in young people: results from a cross-sectional study in the UK.

OBJECTIVES: To investigate associations between deprivation in young people and consumption of foods high in fat, salt and sugar (HFSS), screen time exposure and health knowledge. DESIGN: An online cross-sectional survey with people aged 11-19 years in the UK, where participants reported consumption behaviours across 13 HFSS and two non-HFSS groups; screen time for commercial television and streaming services; and knowledge of health conditions and their links to obesity. SETTING: UK PARTICIPANTS: A total of 3348 young people aged 11-19 years across the UK. MAIN OUTCOME MEASURES: The study assessed the consumption behaviours, commercial screen time exposure and the health knowledge of 3348 people aged 11-19 years. Multivariate binary regression analysis, controlling for age and gender, was performed. RESULTS: Deprivation level was associated with increases in consumption of six of the HFSS products including energy drinks (OR: 2.943, p<0.001) and sugary drinks (OR: 1.938, p<0.001) and a reduction in consumption in the two non-HFSS products included in the study, fruit (OR: 0.668, p=0.004) and vegetables (OR: 0.306, p<0.001). Deprivation was associated with high weekly screen time of both television (OR: 2.477, p<0.001) and streaming (OR: 1.679, p=0.001). Health knowledge was also associated with deprivation. There was lower awareness of the association of obesity and cancer (OR: 0.697, p=0.003), type 2 diabetes (OR: 0.64, p=0.004) and heart disease (OR: 0.519, p<0.001) in the most deprived. CONCLUSIONS: Young people from the more deprived areas of the UK were more likely to consume a range of HFSS products, report increased exposure to HFSS advertising and have a poorer awareness of health conditions associated with overweight and obesity. The findings suggest that population-level measures addressing childhood obesity should account for consumption patterns among different groups of children and young people and the factors that may influence these.

Thrombospondin-1 expression is increased during follicular atresia in the primate ovary.

Thrombospondin (TSP)-1 is an antiangiogenic extracellular matrix glycoprotein that modulates several aspects of cellular function. The aim of this study was to determine the pattern of TSP-1 mRNA and protein expression as well as expression of its receptor CD36 in the marmoset ovary and to investigate the effects of inhibition of gonadotropins or VEGF activity on TSP-1 and CD36 expression in vivo. GnRH antagonist or VEGF Trap, a soluble decoy receptor, was administered on d 0 of the follicular phase of the cycle, and ovaries were collected at the end of the follicular phase (d 10). TSP-1 mRNA and protein were present in granulosa cells of preantral and antral follicles, with the highest staining at the late secondary and tertiary stages. Moreover, expression of TSP-1 mRNA and protein was significantly increased in tertiary follicles undergoing atresia. CD36 protein was detected in granulosa cells of preantral and antral follicles as well as in endothelial cells of large vessels. Inhibition of gonadotropin secretion or VEGF activity had no effect on TSP-1 expression; however, expression of CD36 protein was inhibited by the VEGF Trap. In conclusion, TSP-1 may be involved in the cessation of angiogenesis in follicles undergoing atresia; alternatively, TSP-1 may act on granulosa and/or endothelial cells to promote follicular atresia in the ovary. Angiogenesis is likely to involve a balance between pro- and antiangiogenic factors. Our results suggest that loss of VEGF activity does not regulate TSP-1 expression directly but may influence TSP-1 activity via down-regulation of the CD36 receptor.

Expression of anti-Mullerian hormone protein during early follicular development in the primate ovary in vivo is influenced by suppression of gonadotropin secretion and inhibition of vascular endothelial growth factor.

Anti-Mullerian hormone (AMH) plays a role during early follicular development and selection. The aim of this study was to determine the pattern of AMH protein expression in the marmoset ovary and to investigate the effects of inhibition of gonadotropins or vascular endothelial growth factor (VEGF) activity on AMH expression in vivo. GnRH antagonist or VEGF Trap, a soluble decoy receptor, was administered on d 0 or 5 of the follicular phase of the cycle, and ovaries were collected at the end of the follicular phase (d 10). AMH protein was expressed in the marmoset ovary in granulosa cells from the primary stage, with the most abundant staining at the preantral and early antral stages. Inhibition of gonadotropin secretion or VEGF activity between d 0-10 of the cycle decreased AMH expression in early preantral follicles (P < 0.01), and AMH expression was decreased in late preantral follicles in the presence of the VEGF Trap (P < 0.01), compared with controls. There was significantly less AMH expression in early antral follicles with both treatments (P < 0.01), and a decrease in the ratio of oocyte-associated/basement-membrane-associated granulosa cell expression of AMH (P < 0.05). When treatments were administered from d 5-10 of the cycle, both VEGF Trap and GnRH antagonist decreased AMH expression in preantral follicles (P < 0.01) but had no significant effect on early antral follicles. In conclusion, VEGF and gonadotropins are involved in the regulation of expression of AMH in the marmoset. This AMH expression may be a marker of abnormal folliculogenesis in the absence of gonadotropin stimulation or functional angiogenesis.

Convening a conference--facilitating networking among delegates.

This article provides conference convenors and delegates with suggestions to enhance networking by delegates attending conferences. Our suggestions are based on a literature search (which revealed very little); what we have found to work well at the research conferences we have convened; conference evaluations; and our experiences at conferences we have attended.

New Zealand Healthline call data used to measure the effect of travel time on the use of the emergency department.

Telephone triage is a health tool increasingly used to connect geographically distant populations. Such services are also utilised to address issues of Emergency Department (ED) overuse. New Zealand's tele-triage service, Healthline, has existed since 2001 but is yet to be the focus of analysis. This research sought to understand the role that travel time to ED had upon Healthline users' compliance with telephone advice. Additionally, the role of deprivation in Healthline (as a determinant of caller behaviour) was examined. Travel time to ED was found to influence the impact of Healthline advice upon callers but this was not confounded by deprivation. Those living closest to the ED were more likely to attend when advised to, and less likely to stay away if told to avoid the ED. Different time brackets showed stronger trends, suggesting that callers at varying distances from EDs may be more or less influenced by both travel time and Healthline advice.

A Chemogenomic Screening Platform Used to Identify Chemotypes Perturbing HSP90 Pathways.

Compounds that modulate the heat shock protein (HSP) network have potential in a broad range of research applications and diseases. A yeast-based liquid culture assay that measured time-dependent turbidity enabled the high-throughput screening of different Saccharomyces cerevisae strains to identify HSP modulators with unique molecular mechanisms. A focused set of four strains, with differing sensitivities to Hsp90 inhibitors, was used to screen a compound library of 3680 compounds. Computed turbidity curve functions were used to classify strain responses and sensitivity to chemical effects across the compound library. Filtering based on single-strain selectivity identified nine compounds as potential heat shock modulators, including the known Hsp90 inhibitor macbecin. Haploid yeast deletion strains (360), mined from previous Hsp90 inhibitor yeast screens and heat shock protein interaction data, were screened for differential sensitivities to known N-terminal ATP site-directed Hsp90 inhibitors to reveal functional distinctions. Strains demonstrating differential sensitivity (13) to Hsp90 inhibitors were used to prioritize primary screen hit compounds, with NSC145366 emerging as the lead hit. Our follow-up biochemical and functional studies show that NSC145366 directly interacts and inhibits the C-terminus of Hsp90, validating the platform as a powerful approach for early-stage identification of bioactive modulators of heat shock-dependent pathways.

Oocyte-granulosa cell interactions during mouse follicular development: regulation of kit ligand expression and its role in oocyte growth.

Ovarian folliculogenesis is regulated by both endocrine and intraovarian mechanisms that coordinate the processes of oocyte growth and somatic cell proliferation and differentiation. Within the follicle, paracrine interactions between the oocyte and surrounding granulosa cells are critical for normal cell development and function. This review focuses on the role of paracrine interactions during early oocyte and follicular development that ensure proper coordination of oocyte and somatic cell function. Particular emphasis is given to granulosa cell-derived Kit Ligand (KitL), whose functional importance for oocyte growth has been demonstrated by a wide range of in vivo and in vitro studies. Reported interactions between KitL and oocyte-derived growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) suggest the molecular basis of oocyte-granulosa cell interactions, but also hint at the complexity of these communications. These paracrine interactions and the structure of the oocyte-granulosa cell interface are follicle stage-specific and regulated by FSH. Elucidation of the molecular mechanisms that promote the development of healthy oocytes with good developmental competence has potential applications for improving fertility and for in vitro growth systems for oocytes from domestic animals and humans.

Follicle-stimulating hormone regulates oocyte growth by modulation of expression of oocyte and granulosa cell factors.

Oocyte-granulosa cell communication is essential for oocyte development. The aims of this study were: 1) to determine the effect of FSH on expression of Kit ligand (KL), growth/differentiation factor-9, bone morphogenetic protein (BMP)-15, and Kit during growth of oocyte-granulosa cell complexes (OGCs) in vitro; 2) to investigate the role of BMP-15 in regulation of KL expression; and 3) to correlate mRNA expression with oocyte growth. OGCs from 12-d-old mice were cultured for up to 7 d in the presence of FSH [0.05 ng/ml (low), 5 ng/ml (high)] or BMP-15 (10 or 100 ng/ml). Transcripts were quantified using real-time RT-PCR, and oocyte and OGC diameters were measured. FSH regulated KL expression in a biphasic manner, with low FSH decreasing the KL-1/KL-2 ratio, and high FSH increasing the KL-1/KL-2 ratio, compared with controls (P < 0.05). The decrease in KL-1/KL-2 ratio with low FSH was due to increased KL-2 mRNA expression. Both FSH concentrations increased OGC diameter (P < 0.05), but only low FSH promoted oocyte growth (P < 0.05). High FSH also decreased BMP-15 expression (P < 0.05). FSH-stimulated oocyte growth was inhibited by Gleevec, an inhibitor of Kit activity. BMP-15 increased both KL-1 and KL-2 mRNA levels in a dose-dependent manner (P < 0.05) but did not alter the KL-1/KL-2 ratio or promote oocyte growth. When the KL-1/KL-2 ratio was increased by exogenous KL-1, FSH-stimulated oocyte growth was suppressed (P < 0.05), suggesting that lowered KL-1/KL-2 ratio is important for oocyte growth. In summary, the correct concentration of FSH is crucial for appropriate modulation of KL and BMP-15 to promote oocyte growth.

Activin promotes oocyte development in ovine preantral follicles in vitro.

Activins have been implicated as important regulating factors for many reproductive processes. The aim of this study was to determine the effect of activin A on the development of ovine preantral follicles in vitro. Mechanically isolated preantral follicles (161 +/- 2 microm) were cultured for 6 days in the presence of human recombinant activin A (0, 10 and 100 ng/ml). Half of the medium was replaced every second day and follicle diameters were measured. Conditioned medium was subsequently analysed for oestradiol content using a delayed enhancement lanthanide fluorometric immunoassay (DELFIA). At the end of the culture period, follicles were fixed and processed for histology, after which oocyte diameter and granulosa cell death were measured. There was significant follicle growth over 6 days in all groups (p < 0.001). Activin, at both concentrations, increased follicle growth over control levels by Day 6 (p < 0.05). Oocyte diameters were also significantly increased by Day 6 of culture in all groups (p < 0.05), with 100 ng/ml activin increasing oocyte diameter over control levels (p < 0.05). Activin, at both concentrations, increased oestradiol production on Day 2 of culture, but this increase was not sustained during the culture period. Moreover, activin did not have any effect on antrum formation or follicle survival. In conclusion, activin promoted ovine preantral follicle and oocyte growth in vitro, but did not accelerate follicle differentiation over a six-day culture period. These results support a paracrine role for activin A during early oocyte and follicular development.