Loss of function of male-specific lethal 3 (Msl3) does not affect spermatogenesis in rodents.

BACKGROUND: Male-specific lethal 3 (Msl3) is a member of the chromatin-associated male-specific lethal MSL complex, which is responsible for the transcriptional upregulation of genes on the X chromosome in males of Drosophila. Although the dosage complex operates differently in mammals, the Msl3 gene is conserved from flies to humans. Msl3 is required for meiotic entry during Drosophila oogenesis. Recent reports indicate that also in primates, Msl3 is expressed in undifferentiated germline cells before meiotic entry. However, if Msl3 plays a role in the meiotic entry of mammals has yet to be explored. RESULTS: To understand, if Msl3a plays a role in the meiotic entry of mammals, we used mouse spermatogenesis as a study model. Analyses of single-cell RNA-seq data revealed that, in mice, Msl3 is mostly expressed in meiotic cells. To test the role of Msl3 in meiosis, we used a male germline-specific Stra8-iCre driver and a newly generated Msl3flox conditional knock-out mouse line. Msl3 conditional loss-of-function in spermatogonia did not cause spermatogenesis defects or changes in the expression of genes related to meiosis. CONCLUSIONS: Our data suggest that, in mice, Msl3 exhibits delayed expression compared to Drosophila and primates, and loss-of-function mutations disrupting the chromodomain of Msl3 alone do not impede meiotic entry in rodents.

Optical diagnosis of colorectal polyps using novel blue light imaging classification among trainee endoscopists.

BACKGROUND: Blue light imaging (BLI) has been shown to improve the characterization of colorectal polyps among the endoscopy experts. We aimed to determine if this technology could be taught to endoscopy trainees while maintaining high accuracy and interobserver agreement. METHODS: Twenty-one gastroenterology trainees (fellows) from two academic institutions participated in this prospective study. Each trainee completed a web-based learning comprising four modules: pre-test, didactic videos explaining the BLI Adenoma Serrated International Classification (BASIC), interactive examples, and post-test assessment. The pre- and post-test modules consisted of reviewing video images of colon polyps in high definition white light imaging and BLI and then applying the BASIC classification to determine if the polyps were likely to be adenomatous. Confidence in adenoma identification (rated '1' to '5'), accuracy in polyp (adenoma vs. non-adenoma) identification, and agreement in characterization per BASIC criteria were derived. RESULTS: Trainee accuracy in the adenoma diagnosis improved from 74.7% (pre-test) to 85.4% (post-test) (P < 0.01). There was a trend towards higher accuracy in polyp characterization with subsequent years of training (1st year fellows 77.4%, 2nd year 88.5%, and final year 94.0%) with consistent improvements after the e-learning across years of trainees. Overall, trainees were able to identify adenoma with a high sensitivity of 86.9%, specificity 83.9%, positive predictive value of 84.4%, and negative predictive value of 86.5%. However, their interobserver agreement in adenoma diagnosis was moderate (k = 0.52). CONCLUSION: The novel BLI classification can be easily taught to gastroenterology trainees using an online module and accuracy improves with years of training reaching >90% for colorectal polyp characterization.

Artificial intelligence in the fertility clinic: status, pitfalls and possibilities.

In recent years, the amount of data produced in the field of ART has increased exponentially. The diversity of data is large, ranging from videos to tabular data. At the same time, artificial intelligence (AI) is progressively used in medical practice and may become a promising tool to improve success rates with ART. AI models may compensate for the lack of objectivity in several critical procedures in fertility clinics, especially embryo and sperm assessments. Various models have been developed, and even though several of them show promising performance, there are still many challenges to overcome. In this review, we present recent research on AI in the context of ART. We discuss the strengths and weaknesses of the presented methods, especially regarding clinical relevance. We also address the pitfalls hampering successful use of AI in the clinic and discuss future possibilities and important aspects to make AI truly useful for ART.

Evaluation of the self-directed format of Walk With Ease in patients with systemic lupus erythematosus: the Walk-SLE Pilot Study.

OBJECTIVE: To conduct a proof-of-concept pilot evaluation of the self-directed format of Walk With Ease (WWE), a 6-week walking program developed for adults with arthritis, in patients with systemic lupus erythematosus (SLE). METHODS: This was a single arm, 6-week pre- and post-evaluation of the self-directed WWE program to assess feasibility, tolerability, safety, acceptability, and effectiveness. Adult patients with physician-diagnosed SLE were recruited to participate during regularly scheduled visits to an academic rheumatology clinic. Self-reported outcomes of pain, stiffness, and fatigue were assessed by visual analog scales (VAS) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-fatigue) scale at baseline and at completion of the 6-week program. Patients also completed a satisfaction survey at the end of the program. Multivariate linear regression models were used to calculate mean changes between baseline and 6-week follow-up scores, adjusting for covariates. Mean change scores were used to estimate effect sizes (ES). RESULTS: At 6 weeks, 48 of the 75 recruited participants completed the WWE program. Participants experienced modest improvements in stiffness and fatigue (ES = 0.12 and ES = 0.23, respectively, for VAS scores; ES = 0.16 for FACIT-fatigue score) following the intervention. The majority of participants reported satisfaction with the program (98%) and benefitted from the workbook (96%). CONCLUSIONS: The self-directed format of WWE appears to reduce stiffness and fatigue in patients with SLE. It also seems to be a feasible and acceptable exercise program to patients with SLE. Larger studies are needed to confirm these findings.

Circular closure is associated with the lowest rate of surgical site infection following stoma reversal: a systematic review and multiple treatment meta-analysis.

AIM: Stoma reversal is frequently complicated by surgical site infection (SSI). To reduce SSI, several techniques for skin closure have been studied, with no agreement on which is best. The aim of this study was to identify the skin closure technique associated with the lowest rate of SSI following stoma reversal. METHOD: We systematically searched MEDLINE (PubMed and OvidSP), Scopus and clinical registries from 1 January 1980 to 24 March 2012, and included original reports on adult patients following stoma reversal. A network of treatments was created to map the comparisons between skin closure techniques, including primary closure, primary closure with a drain, secondary closure, delayed primary closure, loose primary closure and circular closure. Pairwise meta-analyses were performed for all available direct comparisons of closure types and heterogeneity was assessed. A multiple-treatments meta-analysis was conducted to estimate relative treatment effects between competing closure types (reported as an odds ratio with 95% credible interval, and a probability that each treatment is best). Several sensitivity analyses were performed. RESULTS: Fifteen studies were identified with a total of 2921 cases of stoma reversal. Overall, study quality was poor with observed low (one study), moderate (seven studies) and high (seven studies) risk of bias. Circular closure was associated with the lowest SSI risk (OR 0.12; 95% CI 0.02-0.40) and was the best of six skin closure techniques (probability of being best = 68.9%). Circular closure remained the best after sensitivity analyses. CONCLUSION: This study showed that circular closure is the best skin closure technique after stoma reversal in terms of SSI rate, but the quality of supporting evidence is limited, precluding definite conclusions.

Type II diabetes increases mitochondrial DNA mutations in the left ventricle of the Goto-Kakizaki diabetic rat.

Mitochondrial dysfunction has a significant role in the development of diabetic cardiomyopathy. Mitochondrial oxidant stress has been accepted as the singular cause of mitochondrial DNA (mtDNA) damage as an underlying cause of mitochondrial dysfunction. However, separate from a direct effect on mtDNA integrity, diabetic-induced increases in oxidant stress alter mitochondrial topoisomerase function to propagate mtDNA mutations as a contributor to mitochondrial dysfunction. Both glucose-challenged neonatal cardiomyocytes and the diabetic Goto-Kakizaki (GK) rat were studied. In both the GK left ventricle (LV) and in cardiomyocytes, chronically elevated glucose presentation induced a significant increase in mtDNA damage that was accompanied by decreased mitochondrial function. TTGE analysis revealed a number of base pair substitutions in the 3' end of COX3 from GK LV mtDNA that significantly altered the protein sequence. Mitochondrial topoisomerase DNA cleavage activity in isolated mitochondria was significantly increased in the GK LV compared with Wistar controls. Both hydroxycamptothecin, a topoisomerase type 1 inhibitor, and doxorubicin, a topoisomerase type 2 inhibitor, significantly exacerbated the DNA cleavage activity of isolated mitochondrial extracts indicating the presence of multiple functional topoisomerases in the mitochondria. Mitochondrial topoisomerase function was significantly altered in the presence of H2O2 suggesting that separate from a direct effect on mtDNA, oxidant stress mediated type II diabetes-induced alterations of mitochondrial topoisomerase function. These findings are significant in that the activation/inhibition state of the mitochondrial topoisomerases will have important consequences for mtDNA integrity and the well being of the diabetic myocardium.

Governance approval for multisite, non-interventional research: what can Harmonisation of Multi-Centre Ethical Review learn from the New South Wales experience?

BACKGROUND: In 2007, New South Wales Health mandated the separation of ethical and scientific review from research governance at all New South Wales public health sites based on their distinction in the National Health and Medical Research Council National Statement. This separation allowed for single-site ethical review of multicentre studies. AIMS: To investigate the time taken for governance approval of multicentre studies through the site-specific approval (SSA) process. METHODS: A retrospective audit of the SSA process for five non-interventional studies proposed by a university cancer research unit. RESULTS: The median total governance approval time for all submissions (n= 28) was 12 weeks (range 2.5-64); median time from starting the SSA to submission was 8 weeks (range 1-48) and median time for governance approval was 5 weeks (range 0.3-40). Approval times were shorter for public compared to private institutions. Reasons for delays in finalising submissions for approval were the absence of institutional governance officers, lack of clarity regarding signatories, the need to identify a principal investigator employed by the institution, and lack of recognition of ethical approval by private institutions. The need to develop legal agreements between the university and hospital was the main reason for lengthy delays in obtaining approval. CONCLUSIONS: The advantages of a harmonised single ethical review process were undermined by the coexistence of a fragmented, complex and lengthy governance approval process. This experience has implications for the success of the national Harmonisation of Multi-Centre Ethical Review (HoMER) model. A harmonised and fully supported national approach to research governance should be developed contemporaneously with HoMER.

Maturity-onset diabetes of the young (MODY): how many cases are we missing?

AIMS/HYPOTHESIS: Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence. METHODS: UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures. RESULTS: MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from <20 per million in Wales and Northern Ireland to >50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r = 0.96, p < 0.0001). The minimum prevalence of MODY was estimated to be 108 cases per million. CONCLUSIONS/INTERPRETATION: Assuming this minimal prevalence throughout the UK then >80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.

Preferential synthesis of ferritin and albumin by different populations of liver polysomes.

Free polysomes and a mixture of free and membrane-attached polysomes were isolated separately from rat liver, and each was added to a cell-free, protein-synthesizing system. The free polysomes showed a greater capacity than the mixed polysome population for incorporation of (14)C-leucine into ferritin, whereas the reverse was true for (14)C-leucine incorporation into albumin.

Alterations in L-glutamate binding in Alzheimer's and Huntington's diseases.

Brain sections from patients who had died with senile dementia of the Alzheimer's type (SDAT), Huntington's disease (HD), or no neurologic disease were studied by autoradiography to measure sodium-independent L-[3H]glutamate binding. In brain sections from SDAT patients, glutamate binding was normal in the caudate, putamen, and claustrum but was lower than normal in the cortex. The decreased cortical binding represented a reduction in numbers of binding sites, not a change in binding affinity, and appeared to be the result of a specific decrease in numbers of the low-affinity quisqualate binding site. No significant changes in cortical binding of other ligands were observed. In brains from Huntington's disease patients, glutamate binding was lower in the caudate and putamen than in the same regions of brains from control and SDAT patients but was normal in the cortex. It is possible that development of positron-emitting probes for glutamate receptors may permit diagnosis of SDAT in vivo by means of positron emission tomographic scanning.

Molecular Adsorbent Recirculating System as a Diagnostic and Therapeutic Modality.

Despite the many advancements in liver transplantation (LT), mortality in patients with hepatic failure remains high, and to date, many patients die while awaiting LT. The molecular adsorbent recirculating system (MARS®) is an extracorporeal liver support system intended to provide short-term metabolic detoxification, often as a vital bridge to LT. We report the case of a 41-year-old non-Hispanic White male who developed worsening multi-factorial encephalopathy in the setting of decompensated alcoholic cirrhosis. He continued to deteriorate despite supportive medical therapy, and extensive investigation for alternative causes of encephalopathy aside from hepatic was unrevealing; as a result, there was concern that his encephalopathy was due to irreversible causes from which he may not recover appropriately following LT. We herein: i) describe the implementation of MARS as a diagnostic intervention for encephalopathy of uncertain etiology in a patient with end stage liver disease who, on the basis of prompt psychomotor improvement, underwent LT 19 days post-MARS implementation with an excellent clinical outcome and thus ii) propose the use of extracorporeal liver support not only as a short-term bridge but also as a diagnostic (and potentially therapeutic) measure in cases of cryptogenic encephalopathy, particularly in the setting of advanced liver disease.

Immune modulator therapy for microscopic colitis in a case series of 73 patients.

BACKGROUND: Microscopic colitis (MC) is a common cause of chronic diarrhoea. Various treatment options have been described, but there are limited data describing outcomes of corticosteroid-sparing treatments. AIM: To evaluate the outcomes of patients with active MC treated with immune modulators. METHODS: All patients seen at Mayo Clinic, Rochester between January 1, 1997 and November 30, 2016 with a histological diagnosis of MC were identified. Patients treated with an immune modulator of interest were selected and clinical outcomes recorded. RESULTS: Seventy-three MC patients (50 collagenous colitis and 23 lymphocytic colitis) with a median disease duration of 24 months (range, 7-60) were included. The indications for treatment were budesonide-refractoriness in 66%, budesonide dependence in 29%, and budesonide intolerance in 5%. Median age was 51.8 years (range, 43.4-63.1) and 61 (84%) were female. Thiopurines were used in 49 patients (67%) for a median of 4 months (range, 1.5-15). Complete and partial response occurred in 43% and 22% respectively. Adverse effects resulting in therapy cessation occurred in 17 patients (35%). Twelve patients (16%) were treated with methotrexate for a median of 14 months (3-18.8). Complete and partial response occurred in 58% and 17%, respectively. Anti-TNF therapy was used in 10 patients (14%) for a median of 4 months (range, 2.3-5.5). Complete response occurred in four patients and partial response in four patients. CONCLUSIONS: The majority of patients with active MC responded to thiopurines, methotrexate, or anti-TNF therapy. Larger controlled studies are required to confirm the efficacy and safety of these medications in MC.

Higher Facebook use predicts greater body image dissatisfaction during pregnancy: The role of self-comparison.

OBJECTIVE: poor body image during pregnancy is a growing issue. Similarly, emerging evidence is suggesting that social media use may increase the risk of poor well-being e.g. depression, anxiety and body image concerns amongst users. Research has not examined how social media use may influence women during pregnancy. The aim of this study was to therefore to explore the relationship between body image during pregnancy and Facebook use. DESIGN: a cross sectional self-report questionnaire. PARTICIPANTS: two hundred and sixty nine pregnant women. SETTING: community groups and online forums. MEASUREMENTS: a self-report questionnaire exploring maternal body image, use of Facebook and how mothers perceived Facebook affected their body image. Descriptive statistics were used to explore body image perceptions. Partial correlations (controlling for maternal age, education, parity and gestation) were used to explore the association between Facebook use and body image during pregnancy. RESULTS: negative body image was common in the sample, increased with gestation and was unrelated to pre pregnancy weight. Mothers with a Facebook account had higher body image concerns than those without a Facebook account. Of those with an account, increased Facebook use was associated with increased body image dissatisfaction, particularly in terms of postnatal concerns for how their body would look with 56.5% reporting that they frequently compared their pregnant body to other pregnant women on the site. Facebook access was frequent with 85% of participants checking it at least once per day and the average participant spending over an hour per day on the site. KEY CONCLUSION: although causality cannot be fully explained, Facebook use may increase mother's risk of poor body image dissatisfaction during pregnancy. Mothers with already poor body image may also be drawn to the site in order to make comparisons of their appearance. IMPLICATIONS FOR PRACTICE: the potential impact of Facebook on increasing the risk of, or promoting existing poor body image is an important message for those working to support mothers during pregnancy and the postnatal period. Care should be taken when directing mothers to use the site.

Differential responses of two wetland graminoids to high ammonium at different pH values.

Enhanced soil ammonium (NH4+) concentrations in wetlands often lead to graminoid dominance, but species composition is highly variable. Although NH4+ is readily taken up as a nutrient, several wetland species are known to be sensitive to high NH4+ concentrations or even suffer toxicity, particularly at low soil pH. More knowledge about differential graminoid responses to high NH4+ availability in relation to soil pH can help to better understand vegetation changes. The responses of two wetland graminoids, Juncus acutiflorus and Carex disticha, to high (2 mmol·l(-1) ) versus control (20 µmol·l(-1) ) NH4+ concentrations were tested in a controlled hydroponic set up, at two pH values (4 and 6). A high NH4+ concentration did not change total biomass for these species at either pH, but increased C allocation to shoots and increased P uptake, leading to K and Ca limitation, depending on pH treatment. More than 50% of N taken up by C. disticha was invested in N-rich amino acids with decreasing C:N ratio, but only 10% for J. acutiflorus. Although both species appeared to be well adapted to high NH4+ loadings in the short term, C. disticha showed higher classic detoxifying responses that are early warning indicators for decreased tolerance in the long term. In general, the efficient aboveground biomass allocation, P uptake and N detoxification explain the competitive strength of wetland graminoids at the expense of overall biodiversity at high NH4+ loading. In addition, differential responses to enhanced NH4+ affect interspecific competition among graminoids and lead to a shift in vegetation composition.

An association of human congenital cardiac malformations and drinking water contaminants.

During an informal study in 1973 it was noted that approximately one third of patients with congenital heart disease lived in a small area in the Tucson Valley. In 1981 groundwater for a nearly identical area was found to be contaminated with trichloroethylene and to a lesser extent with dichloroethylene and chromium. Contamination probably began during the 1950s. Affected wells were closed after discovery of contamination. This sequence of events allowed investigation of the prevalence of congenital heart disease in children whose parents were exposed to the contaminated water area as compared with children whose parents were never exposed to the contaminated water area. The contaminated water area contained 8.8% of the Tucson Valley population and 4.5% of the labor force. Using their case registry, the authors interviewed parents of 707 children with congenital heart disease who, between 1969 and 1987, 1) conceived their child in the Tucson Valley, and 2) spent the month before the first trimester and the first trimester of the case pregnancy in the Tucson Valley. Two random dialing surveys showed that only 10.5% of the Tucson Valley population had ever had work or residence contact, or both, with the contaminated water area, whereas 35% of parents of children with congenital heart disease had had such contact (p less than 0.005). The prevalence of congenital cardiac disease (excluding syndromes, children with atrial tachycardia or premature infants with patent ductus arteriosus) in the Tucson Valley was 0.7% of live births and with syndromes was calculated to be 0.82%. The odds ratio for congenital heart disease for children of parents with contaminated water area contact during the period of active contamination was three times that for those without contact (p less than 0.005) and decreased to near unity for new arrivals in the contaminated water area after well closure. The proportion of infants with congenital heart disease as compared with the number of live births was significantly higher for resident mothers in the contaminated water area than for mothers with no exposure. No other environmental agent could be identified that was localized to the contaminated water area, but one could have been missed. The data show a significant association but not a cause and effect relation between parental exposure to the contaminated water area and an increased proportion of congenital heart disease among live births as compared with the proportion of congenital heart disease among live births for parents without contaminated water area contact.

Using Direct Instruction: Teaching Preposition Use to Students With Intellectual Disability.

PURPOSE: Students with intellectual disability often struggle with significant language delays or impairments and can require explicit instruction in language skills. The purpose of this study was to investigate the effects of direct instruction on the use of and response to prepositions by 3 elementary school students with intellectual disability. METHOD: A multiple-baseline design across prepositions was used in this study with replication across students. RESULTS: Results of this study found that students were able to use and respond to prepositions consistently after receiving direct instruction on each of the 3 target prepositions. Furthermore, all 3 students demonstrated maintenance and generalization of the prepositions. CONCLUSION: These results have implications for practice that could influence preposition acquisition for students with intellectual disability, providing educators with a simple, efficient instructional approach.

Facial and neuroepithelial abnormalities in a neurological mutant with congenital hydrocephalus. A scanning electron microscope study.

This investigation was carried out to determine the early structural abnormalities of the cephalic region in a genetic mutant of the rat characterized by prenatal aqueductal stenosis and hydrocephalus. The appearance of hydrocephalic and control embryos was examined on days 13-15 of gestation, and the structure and organization of the neuroepithelium and basal lamina were studied using scanning electron microscopy. In addition to some overall developmental delay, hydrocephalic embryos were characterized by abnormalities of forebrain and midbrain development, and eye and external ear anomalies. There were also associated defects of the midfacial region. The lateral cell surface of the neuroepithelium reflected the developmental delay of hydrocephalic embryos, and failed to undergo the morphogenetic cell-shaping changes seen in control embryos. There were also variations in the number of lateral cell-cell specializations as well as regions of neuroepithelial disorganization and occasional herniation into the mesenchymal compartment. The role of the neuroepithelial basal lamina and extracellular matrix in the development of these defects is considered.

Alterations in the neuroepithelial basal lamina in a neurological mutant with prenatal hydrocephalus.

The neuroepithelial basal lamina (BL) appears to be crucial in controlling cell-cell interactions during the early histogenesis of the nervous system. In this investigation we examined the changes in the BL in a neurological mutant of the rat previously characterized as having BL anomalies which progress to aqueductal stenosis and prenatal hydrocephalus. Embryos were obtained from matings of rats homozygous for the prenatal hydrocephalus gene or from controls, both originally derived from the same Wistar albino stock. On days 12 and 13 of development, embryos were processed for indirect immunofluorescence localization of BL components type IV collagen or laminin. Additional whole litters were processed for ultrastructural analysis of neuroepithelial and BL morphology. In control embryos, neuroepithelial BL components formed a smooth linear boundary to the basal surface of the neuroepithelium. This unbroken border was interrupted only in regions of active neural crest cell migration (day 12), and in areas of imminent vascularization (day 13). In hydrocephalic embryos on the 12th day there were gaps in the continuity of the BL and an apparent reduction in deposition of type IV collagen. By day 13, blood vessels had prematurely colonized the neuroepithelium, few BL breaks were observed, and deposition of type IV collagen appeared similar to that seen in control embryos. Ultrastructurally, a similar pattern of change was observed. The neuroepithelium of control embryos was uniformly bounded by an organized BL consisting of a lamina lucida subjacent to the plasma membrane, and a lamina densa which merged with scattered collagen fibrils in the mesenchymal compartment. On day 12, the BL of hydrocephalic embryos had large gaps through which neuroepithelial cells projected.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic prenatal aqueductal stenosis with hydrocephalus in rat.

A recessive mutation which arose in Wistar albino rats was variably expressed in the homozygous state as prenatal stenosis of the aqueduct with resultant hydrocephalus. The condition was often compatible with survival to adulthood and with successful reproduction. Mildly sparse hair was the constant gene marker. Eye defects and sometimes foot deformities occurred. The first observable ultrastructural alteration was a disruption of the integrity of the neuroepithelial basal lamina in the cephalic neural tube of affected embryos as early as the 11th fetal day (16-24 somite pairs). The hydrocephalic syndrome closely resembled that produced by giving folic acid analogs to, or producing vitamin B12 deficiency in, pregnant rats in the period including the 11th day. Neither vitamin B12 nor folate, nor certain metabolites closely related to their metabolism, prevented the gene's expression. Homozygote mutants mated with homozygote mutants produced 70% hydrocephalic (dome-shaped heads) offspring, but if the mother was heterozygote, there was a "protective" effect and the number of hydrocephalic young was disproportionately smaller.

Existence of somatotrope subpopulations which are differentially responsive to insulin-like growth factor I and somatostatin.

It is generally accepted that hypothalamic somatostatin and hepatic insulin-like growth factor I (IGF-I)/somatomedin-C act directly on the pituitary to inhibit GH release, but it is not known whether all somatotropes are responsive to these agents. In the present study, we used a reverse hemolytic plaque assay to compare the acute (8 h) effects of somatostatin and IGF-I on the release of GH from individual cells in 24-h cultures of male rat pituitaries. Treatment with these factors caused comparable dose-dependent decreases in both the rate of plaque formation and the percentage of cells which released GH. In 8-h incubations, maximal (10(-8) M) doses of IGF-I or somatostatin alone decreased the percentage of GH-releasing cells to approximately the same degree (from 34.4% in controls to 29.7% and 28.4%, respectively), yet the effects of these factors were additive when both agents were applied to the same cells (to 24.5%). When we analyzed the sizes of plaques (an index of the amount of hormone released per cell) which resulted from these treatments, we noted that somatostatin was a much greater suppressor (to 11% of control value) of GH release than IGF-I (60% of controls). Coincubation with 10(-8) M GH-releasing factor had no effect on the percentage of GH-releasing cells at 8 h but completely overrode the inhibitory effect of IGF-I on plaque size without affecting the somatostatin-induced decrease in this regard. Taken together, these data suggest that IGF-I and somatostatin act, at least in part, on separate subpopulations of rat somatotropes. Somatostatin is a much more effective inhibitor of total GH release than IGF-I and appears to affect most, if not all, somatotropes. In contrast, IGF-I acutely inhibits GH release (prevents plaque formation) from some somatotropes, but does not seem to affect the remaining GH cells.