Genome Wide Conditional Mouse Knockout Resources.

The International Knockout Mouse Consortium (IKMC) developed high throughput gene trapping and gene targeting pipelines that produced mostly conditional mutations of more than 18,500 genes in C57BL/6N mouse embryonic stem (ES) cells which have been archived and are freely available to the research community as a frozen resource. From this unprecedented resource more than 6,000 mutant mouse strains have been produced by the IKMC and mostly the International Mouse Phenotyping Consortium (IMPC). In addition, a cre-driver resource was established including 250 inducible cre-driver mouse strains in a C57BL/6 background. Complementing the cre-driver resource, a collection of comprising 27 cre-driver rAAVs has also been produced. The resources can be easily accessed at the IKMC/IMPC web portal (www.mousephenotype.org). The IKMC/IMPC resource is a standardized reference library of mouse models with defined genetic backgrounds that enables the analysis of gene-disease associations in mice of different genetic makeup and should therefore have a major impact on biomedical research.

Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa.

The autosomal dominant retinitis pigmentosa (RP) locus, designated RP1, has been mapped through linkage studies to a 4-cM interval at 8q11-13. Here we describe a new photoreceptor-specific gene that maps in this interval and whose expression is modulated by retinal oxygen levels in vivo. This gene consists of at least 4 exons that encode a predicted protein of 2,156 amino acids. A nonsense mutation at codon 677 of this gene is present in approximately 3% of cases of dominant RP in North America. We also detected two deletion mutations that cause frameshifts and introduce premature termination codons in three other families with dominant RP. Our data suggest that mutations in this gene cause dominant RP, and that the encoded protein has an important but unknown role in photoreceptor biology.

Dehiscence of the posterior and superior semicircular canal presenting in pregnancy.

OBJECTIVE: We present an interesting case of superior and posterior semicircular canal dehiscence in pregnancy. METHOD: We present a case report and a review of the world literature concerning semicircular canal dehiscence. CASE REPORT: A 34-year-old woman presented with sound and pressure induced vertigo at 22 weeks gestation. A thinly sliced computed tomography (CT) scan of the petrous temporal bones viewed with coronal reconstructions was performed post-partum. This showed the presence of both left superior canal and posterior canal dehiscence. CONCLUSION: To our knowledge this is the first reported case of semicircular canal dehiscence in pregnancy. The diagnosis of semicircular canal dehiscence should be suspected in pregnant patients with sound induced vertigo.

Successful outcome of cochlear implantation in a patient with superficial siderosis.

OBJECTIVE: To present the management of a rare case of progressive bilateral sensorineural hearing loss in a patient with superficial siderosis secondary to a cavernoma. METHOD: A case report and a review of the literature concerning superficial siderosis. RESULTS: The patient benefited significantly from a cochlear implantation. CONCLUSIONS: Careful assessment and adequate counselling is necessary to determine the best approach to hearing rehabilitation in patients with superficial siderosis of the central nervous system. Cochlear implantation in patients with superficial siderosis is controversial due to the retrocochlear origin of the hearing loss and, although the case presented had a successful outcome, the results might deteriorate with time.

Scaling of individual phosphorus flux by caterpillars of the whitemarked tussock moth, Orygia leucostigma.

We conducted a laboratory study to evaluate the effects of body mass, environmental temperature, and food quality on phosphorus (P) efflux by caterpillars of the whitemarked tussock moth, Orygia leucostigma, J. E. Smith (Lepidoptera: Lymantriidae). We found that individual phosphorus efflux rate (Q the rate at which excreted and unassimilated P was egested in frass, mgP/day) was related to larval mass (M, mg dry) and environmental temperature (T,K) as Q = e(14.69) M(1.00)e(-0.54/kT), where K is Boltzmann's constant (8.62 x 10(-5) eV/K, 1 eV = 1.60 x 10-19J). We also found that P efflux was not related to food phosphorous concentration, and suggest that this result was due to compensatory feeding by larvae eating low quality leaves. The P efflux model resulting from this analysis was simple and powerful. Thus, it appears that this type of model can be used to scale P flux from individual larvae to the population level and link species of insect herbivores to ecosystem processes.

Aggressive behaviour in the high-secure forensic setting: the perceptions of patients.

Twenty-seven patients undergoing treatment in a high-secure forensic facility participated in focus group interviews to elicit their perceptions of (1) the factors leading to aggressive behaviour; and (2) strategies to reduce the risk of such behaviour. The focus group interviews were audiotaped, transcribed and analysed using content analysis. The participants identified that a combination of patient, staff and environmental factors contributed to violence in the study wards. The cause of aggressive behaviour centred around five major themes: the environment; empty days; staff interactions; medication issues; and patient-centred factors. Potential strategies identified by patients to reduce aggressive behaviour included: early intervention; the provision of meaningful activities to reduce boredom; separation of acutely disturbed patients; improved staff attitudes; implementation of effective justice procedures; and a patient advocate to mediate during times of conflict. Findings suggested that social and organizational factors need to be addressed to change the punitive subculture inherent in forensic psychiatric facilities, and to ensure a balance between security and effective therapy.

Introduction of routine outcome measures: staff reactions and issues for consideration.

The aim of this study was to explore clinician reactions to (i) the introduction of routine outcome measures and (ii) the utility of outcomes data in clinical practice. Focus group discussions (n = 34) were conducted with mental health staff (n = 324) at approximately 8 months post implementation of routine outcome measures. A semi-structured interview schedule was used to collect data on two key issues; reactions to the introduction of outcome measures and factors influencing the utility of outcomes data in clinical practice. Data from the discussion groups were analysed using content analysis to isolate emerging themes. While the majority of participants endorsed the collection and utilization of outcomes data, many raised questions about the merits of the initiative. Ambivalence, competing work demands, lack of support from senior medical staff, questionable evidence to support the use of outcome measures, and fear of how outcomes data might be used emerged as key issues. At 8 months post implementation a significant number of clinical staff remained ambivalent about the benefits of outcome measurement and had not engaged in the process. The shift to a service model driven by outcomes and case-mix data will take time and resources to achieve. Implications for nursing staff are discussed.

Mental health nurses' views about antipsychotic medication side effects.

WHAT IS KNOWN ON THE SUBJECT?: The only previous quantitative study that examined nurses' use of assessment tools to identify antipsychotic medication side effects found that about 25% of mental health nurses were using assessment tools. No previous studies have examined factors that influence the manner in which mental health nurses assess antipsychotic medication side effects. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: One-third of the respondents were not aware of any antipsychotic medication side-effect assessment tool, and only one-quarter were currently using an assessment tool. 'Service responsibility' was significantly associated with ongoing use of antipsychotic medication assessment tools, indicating that respondents with more positive attitudes to their service were more likely to continue using antipsychotic medication assessment tools. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: The low level of awareness and use of antipsychotic medication side-effect assessment tools indicates that nursing educational institutions should incorporate more detail about these tools in course content, and emphasize in particular the benefits that result from the use of these tools in clinical practice. Service processes contributed significantly to the use of antipsychotic medication assessment tools, which indicates that managers need to foster workplace cultures that promote routine use of these tools. ABSTRACT: Introduction Limited evidence suggests that only a minority of mental health nurses regularly use standardized assessment tools to assess antipsychotic medication side effects, but the factors that contribute to the non-routine use of these tools remain unknown. Aim To examine Australian mental health nurses' awareness of, and attitudes towards, side-effect assessment tools, and also identify factors the influence the use of these tools. Methods A cross-sectional survey was undertaken through distributing an online questionnaire via email to members of the Australian College of Mental Health Nurses. Completed questionnaires were received from 171 respondents. Linear regression was used to examine the relationship between the 'service responsibility' and 'personal confidence' scale scores, and awareness, previous use and ongoing use of antipsychotic medication assessment tools. Results Only one-quarter of the respondents (26.5%) were currently using an assessment tool. 'Service responsibility' was significantly associated with ongoing use of antipsychotic medication assessment tools (Β = 3.26; 95% CI 0.83-5.69). 'Personal confidence' did not influence the ongoing use of assessment tools (Β = -0.05; 95% CI -1.06-1.50). Implications for clinical practice Stakeholders can incorporate 'service responsibility' processes to foster increased use of assessment tools, which may enhance the identification antipsychotic medication side effects and improve the quality of care for service users.

Fatty acid requirements and temperature dependence of monooxygenase activity in rat liver microsomes.

The effect of variation in the microsomal membrane fatty acid composition on Arrhenius plot phase transition temperatures for p-nitroanisole O-demethylation and benzo[a]pyrene hydroxylation has been investigated. In liver microsomes from normal-dieted rats, p-nitroanisole O-demethylase activity has a break temperature at 24 degrees C, while that of benzo[a]pyrene hydroxylase occurs at 29 degrees C indicating that these two enzymes may exist in different patches of membrane. The microsomal membrane fatty acid composition was altered by starving rats for 48 h and then refeeding them a fat-free diet for 4 or 5 days. In microsomes having diet-altered fatty acid compositions, benzo[a]pyrene hydroxylase has a break temperature at 33 degrees C, a value higher than that observed in normal-dieted rats. This observation correlates with the increase in saturation observed in the diet-altered fatty acid composition and thus may correspond to a phase transition roughly dependent on the fatty acid melting point. Induced and basal levels of cytochrome P-450 and P-448 in animals having different microsomal fatty acid composition are reported. Phenobarbital-induced levels of p-nitroanisole O-demethylase in normal microsomes were six times higher than those in microsomes having diet-altered composition, whereas 3-methylcholanthrene-induced levels of benzo[a]pyrene hydroxylase were similar regardless of diet. The low level of p-nitroanisole O-demethylase activity in membranes with altered fatty acid compositions suggests that a particular type(s) of fatty acid was not present in sufficient quantity to permit the induction of maximal enzyme activity. Since the induced benzo[a]pyrene hydroxylase activity was the same regardless of diet, there was presumably sufficient quantities of the appropriate fatty acids present in the membrane for induction of this activity. Therefore, particular fatty acids may be necessary for the induction of maximal activity of particular enzymes in the mixed function monooxygenase system.

Developmental regulation of the bcl-2 family during spermatogenesis: insights into the sterility of bcl-w-/- male mice.

Expression of bcl-w, a close relative of bcl-2 is essential for male fertility in mice. Although the initial wave of spermatogenesis in bcl-w -/- mice proceeds normally until 3-4 weeks of age, adults fail to produce sperm. To clarify why bcl-w is essential for adult but not juvenile spermatogenesis, we investigated the expression pattern of eight bcl-2 family members. We found that both the level and pattern of expression varied in different cell types during juvenile and adult spermatogenesis. Anti-apoptotic genes bcl-w, bcl-2 and bcl-xL were all expressed in spermatogonia during juvenile spermatogenesis, but only bcl-w was detected in spermatogonia of adult mice. A similar shift was evident in Sertoli cells. This developmental regulation may co-ordinate physiological germ cell apoptosis in wild type mice and account for the time of onset for pathological germ cell apoptosis in bcl-w -/- animals.

Use of binding site neighbor-effect parameters to evaluate the interactions between adjacent ligands on a linear lattice. Effects on ligand-lattice association.

A method using binding site "neighbor-effect" parameters (NEPs) is introduced to evaluate the effects of interaction between adjacent ligands on their binding to an infinite linear lattice. Binding site overlap is also taken into account. This enables the conditional probability approach of McGhee & von Hippel to be extended to more complex situations. The general equation for the isotherm is v/LF = SFKF, where v is the ratio of bound ligands to lattice residues, LF is the free ligand concentration, SF is the fraction of binding sites that are free, and KF is the average association constant of a free site. Solutions are derived for three cases: symmetric ligands, and asymmetric ligands on isotropic or anisotropic lattices. For symmetric ligands there is one NEP, E, which is the ratio of the average binding affinity of a free site if the status of the lattice residue neighboring one end of the site is unspecified (left to chance) to the affinity when this residue is free (holding the other neighbor constant). Thus KF is KE2, where K is the affinity of an isolated site. If a site is n residues long, SF is f ffn-1, where f = 1 - nv is the fraction of residues that are free and ff is the conditional probability that a free residue is bordered on a given side by another free residue. The expression for ff is 1/(1 + x/E), where x is v/f, E is (1 - x + [(1 - x)2 + 4x omega]1/2)/2, and omega is the co-operativity parameter. The binding of asymmetric ligands to an isotropic lattice is described by two NEPs; the last case involves four NEPs and a bound ligand orientation parameter. For each case, the expected length distribution of clusters of bound ligands can be calculated as a function of v. When Scatchard plots with the same intercepts and initial slope are compared, it is found that ligand asymmetry lowers the isotherm (relative to the corresponding symmetric ligand isotherm), whereas lattice anisotrophy raises it.

Evolution of duplications in the transferrin family of proteins.

The transferrin family is a group of proteins, defined by conserved amino acid motifs and putative function, found in both vertebrates and invertebrates. Included in this group are molecules known to bind iron, including serum transferrin, ovotransferrin, lactotransferrin, and melanotransferrin (MTF). Additional members of this family include inhibitor of carbonic anhydrase (ICA; mammals), major yolk protein (sea urchins), saxiphilin (frog), pacifastin (crayfish), and TTF-1 (algae). Most family members contain two lobes (N and C) of around 340 amino acids, the result of an ancient duplication event. In this article, we review the known functions of these proteins and speculate as to when the different homologs arose. From multiple-sequence alignments and neighbor-joining trees using 71 transferrin family sequences from 51 different species, including several novel sequences found in the Takifugu and Ciona genome databases, we conclude that melanotransferrins are much older (>670 MY) and more pervasive than previously thought, and the serum transferrin/melanotransferrin split may have occurred not long after lobe duplication. All subsequent duplication events diverged from the serum transferrin gene. The creation of such a large multiple-sequence alignment provides important information and could, in the future, highlight the role of specific residues in protein function.

Associations between initial antimicrobial therapy and medical outcomes for hospitalized elderly patients with pneumonia.

BACKGROUND: Although medical practice guidelines exist, there have been no large-scale studies assessing the relationship between initial antimicrobial therapy and medical outcomes for patients hospitalized with pneumonia. OBJECTIVE: To determine the associations between initial antimicrobial therapy and 30-day mortality for these patients. METHODS: Hospital records for 12945 Medicare inpatients (> or = 65 years of age) with pneumonia were reviewed. Associations between initial antimicrobial regimens and 30-day mortality were assessed with Cox proportional hazards models, adjusting for baseline differences in patient characteristics, illness severity, and processes of care. Comparisons were made with patients treated with a non-pseudomonal third-generation cephalosporin alone (the reference group). RESULTS: Initial treatment with a second-generation cephalosporin plus macrolide (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.52-0.96), a non-pseudomonal third-generation cephalosporin plus macrolide (HR, 0.74; 95% CI, 0.60-0.92), or a fluoroquinolone alone (HR, 0.64; 95% CI, 0.43-0.94) was independently associated with lower 30-day mortality. Adjusted mortality among patients initially treated with these 3 regimens became significantly lower than that in the reference group beginning 2, 3, and 7 days, respectively, after hospital admission. Use of a beta-lactam/beta-lactamase inhibitor plus macrolide (HR, 1.77; 95% CI, 1.28-2.46) and an aminoglycoside plus another agent (HR, 1.21; 95% CI, 1.02-1.43) were associated with an increased 30-day mortality. CONCLUSIONS: In this study of primarily community-dwelling elderly patients hospitalized with pneumonia, 3 initial empiric antimicrobial regimens were independently associated with a lower 30-day mortality. The more widespread use of these antimicrobial regimens is likely to improve the medical outcomes for elderly patients with pneumonia.

Temporal trends in outcomes of older patients with pneumonia.

BACKGROUND: It is unclear how outcomes of care for patients hospitalized for pneumonia have changed as patterns of health care delivery have changed during the 1990s. This study was performed to determine trends in outcomes of care for older patients hospitalized for pneumonia. METHODS: This retrospective analysis was based on Medicare claims and included most patients with pneumonia who were older than 65 years and admitted to acute care hospitals in Connecticut between October 1, 1991, and September 30, 1997 (fiscal years 1992-1997). We assessed the trends in hospital costs, discharge destination, hospital mortality rates, mortality rates within 30 days of discharge, and 30-day readmission rates for pneumonia. Multivariate logistic regression analyses were used to adjust for differences in patient characteristics. RESULTS: The mean (+/- SD) length of stay declined from 11.9 + 11.4 days to 7.7 + 7.2 days between 1992 and 1997. During this period, adjusted in-hospital mortality rates declined (P =.02), while the adjusted risk of discharge to a nursing facility increased (P<.001) and the adjusted risk of hospital readmission for pneumonia within 30 days of discharge increased (P =.05). The adjusted risk of death 30 days after discharge increased, although the difference was not statistically significant (P =.09). CONCLUSIONS: Between 1992 and 1997, the adjusted risks of mortality after discharge, placement in a nursing facility, and hospital readmission for pneumonia increased among older patients hospitalized for pneumonia, in association with a decline in mean hospital length of stay. These findings raise the question of whether the declining hospital length of stay has negatively affected patient outcomes. Arch Intern Med. 2000;160:3385-3391.

Sex differences in mortality after myocardial infarction: evidence for a sex-age interaction.

BACKGROUND: Studies of sex differences in mortality after myocardial infarction (MI) have shown conflicting results. OBJECTIVES: To test the hypothesis that sex differences in mortality after MI vary according to patients' age, with younger women, but not older women, having a higher mortality compared with men. METHODS: We performed a retrospective cohort study of 1025 consecutive patients who met accepted criteria for MI in 1992 and 1993 in 15 Connecticut hospitals. Data for the study were abstracted from medical records. RESULTS: Women had a 40% higher hospital mortality rate than men. Simple age adjustment eliminated the sex difference in mortality rate (odds ratio, 0.99; 95% confidence interval, 0.66-1.48). However, when the sample was subdivided into 2 age groups, women younger than 75 years showed twice as high a mortality rate as men in the same age group, while among older patients no difference in mortality was found. In multivariate analyses the interaction of sex with age was highly significant, even after adjusting for comorbid conditions, clinical severity, process of care, and hospital characteristics. In the fully adjusted model, this interaction indicated that among patients younger than 75 years women had 49% higher odds of hospital death than men, while in the age group 75 years or older women had 46% lower odds of death compared with men. CONCLUSIONS: A higher mortality of women compared with men after MI is confined to the younger age groups. The sex-age interaction should be considered when examining sex differences in mortality after MI.

Insect herbivory alters impact of atmospheric change on northern temperate forests.

Stimulation of forest productivity by elevated concentrations of CO2 is expected to partially offset continued increases in anthropogenic CO2 emissions. However, multiple factors can impair the capacity of forests to act as carbon sinks; prominent among these are tropospheric O3 and nutrient limitations(1,2). Herbivorous insects also influence carbon and nutrient dynamics in forest ecosystems, yet are often ignored in ecosystem models of forest productivity. Here we assess the effects of elevated levels of CO2 and O3 on insect-mediated canopy damage and organic matter deposition in aspen and birch stands at the Aspen FACE facility in northern Wisconsin, United States. Canopy damage was markedly higher in the elevated CO2 stands, as was the deposition of organic substrates and nitrogen. The opposite trends were apparent in the elevated O3 stands. Using a light-use efficiency model, we show that the negative impacts of herbivorous insects on net primary production more than doubled under elevated concentrations of CO2, but decreased under elevated concentrations of O3. We conclude that herbivorous insects may limit the capacity of forests to function as sinks for anthropogenic carbon emissions in a high CO2 world.

Tightly regulated and inducible expression of a yoked hormone-receptor complex in HEK 293 cells.

We have previously reported the construction of a constitutively active luteinizing hormone receptor by covalently linking a fused heterodimeric hormone to the extracellular domain of the G protein-coupled receptor. This yoked hormone-receptor complex (YHR) was found to produce high levels of cAMP in the absence of exogenous hormone. Stable lines expressing YHR were generated in HEK 293 cells to obtain lines with different expression levels; however, in a relatively short time of continued passage, it was found that YHR expression was greatly reduced. Herein, we describe the development of clonal lines of HEK 293 cells in which the expression of YHR is under the control of a tetracycline-regulated system. Characterization of clonal lines revealed tight control of YHR expression both by dose and time of incubation with doxycycline. These experiments demonstrated a good correlation between expression levels of the receptor and basal cAMP production. Moreover, the reduction in receptor expression following doxycycline removal revealed that YHR mRNA and protein decayed at similar rates, again suggesting a strong linkage between mRNA and protein levels. The controlled expression of YHR in this cell system will allow for a more detailed analysis of the signaling properties associated with constitutive receptor activation and may prove to be advantageous in developmental studies with transgenic animals.

A statewide initiative to improve the care of hospitalized pneumonia patients: The Connecticut Pneumonia Pathway Project.

PURPOSE: A statewide quality improvement initiative was conducted in Connecticut to improve process-of-care performance and to decrease length of stay for patients hospitalized with community-acquired pneumonia. SETTING AND METHODS: Data were collected on 1,242 elderly (> or =65 years) pneumonia patients hospitalized at 31 of 32 acute care hospitals between January 16, 1995, and March 15, 1996, and on 1,146 patients hospitalized between January 1, 1997, and June 30, 1997. Interventions included feedback of performance data (Qualidigm, the Connecticut Peer Review Organization), dissemination of an evidence-based pneumonia critical pathway (Connecticut Thoracic Society), and sharing of pathway implementation experiences (hospitals). Process and outcome measures included early antibiotic administration, blood culture collection, oxygenation assessment, length of stay, 30-day mortality, and 30-day readmission rates. Analyses were adjusted for severity of illness and hospital-specific practice patterns. RESULTS: After the statewide initiative, improvements were noted in antibiotic administration within 8 hours of hospital arrival (improvement from 83.4% to 88.8%, relative risk [RR] = 1.21; 95% confidence interval [CI]: 1.10 to 1.32), oxygenation assessment within 24 hours of hospital arrival (93.6% to 95.4%; RR = 1.23, 95% CI: 1.11 to 1.38), and length of stay (7 days to 5 days, P <0.001). There were no significant changes in blood culture collection within 24 hours of hospital arrival, blood culture collection before antibiotic administration, 30-day mortality, or 30-day readmission rates. CONCLUSIONS: Statewide improvements were demonstrated in the care of hospitalized pneumonia patients concurrent with a multifaceted quality improvement intervention. Further research is needed to separate the effects of the quality improvement interventions from secular trends.

Use of critical pathways to improve the care of patients with acute myocardial infarction.

PURPOSE: While critical pathways have become a popular strategy to improve the quality of care, their effectiveness is not well defined. The objective of this study was to investigate the effect of a critical pathway on processes of care and outcomes for Medicare patients admitted with acute myocardial infarction. SUBJECTS AND METHODS: A retrospective cross-sectional and longitudinal cohort study was made of Medicare patients aged 65 years and older hospitalized at 32 nonfederal Connecticut hospitals with a principal diagnosis of myocardial infarction during two periods: June 1, 1992, to February 28, 1993, and August 1, 1995, to November 30, 1995. The main endpoints of the cross-sectional analyses for the 1995 cohort were the proportion of patients without contraindications who received evidence-based medical therapies, length of stay, and 30-day mortality. Hospitals with specific critical pathways for patients with myocardial infarction were compared with hospitals without critical pathways. The main endpoints of the longitudinal analyses were change between 1992-93 and 1995 in the proportion of patients receiving evidence-based medical therapies, length of stay, and 30-day mortality. RESULTS: Ten hospitals developed critical pathways between 1992-93 and 1995. Eighteen of 22 nonpathway hospitals employed some combination of standard orders, multidisciplinary teams, or physician champions. Patients admitted to hospitals with critical pathways did not have greater use of aspirin within the first day, during hospitalization, or at discharge; beta-blockers within the first day or at discharge; reperfusion therapy; or use of angiotensin-converting enzyme inhibitors at discharge in 1995. The mean (+/- SD) length of stay in 1995 was not significantly different between pathway (7.8 +/- 4.6 days) versus nonpathway hospitals (8.0 +/- 4.2 days), and the change in length of stay between 1992-93 and 1995 was 2.2 days for pathway hospitals and 2.3 days for nonpathway hospitals. Patients admitted to critical pathway hospitals had lower 30-day mortality in 1995 (8.6% versus 11.6% for nonpathway hospitals, P = 0.10) and in 1992-93 (12.6% versus 13.8%, P = 0.39), but the differences were not statistically significant. CONCLUSIONS: Hospitals that instituted critical pathways did not have increased use of proven medical therapies, shorter lengths of stay, or reductions in mortality compared with other hospitals that commonly used alternative approaches to quality improvement among Medicare patients with myocardial infarction.

The roles of inhibin and related peptides in gonadal function.

Inhibin A and B are dimeric proteins capable of suppressing FSH both in vitro and in vivo. The principal form in the male is inhibin B which is produced in the testis and circulates to inhibit pituitary FSH secretion. Activin A, B and AB are dimeric proteins that share the same beta subunits with the inhibins but, in contrast, stimulate FSH secretion. Although activin A circulates, castration does not lead to a decrease in serum concentrations, indicating that the testis is not the major source of activin A. In the circulation, the activins are bound to a structurally unrelated binding protein, follistatin, that neutralizes the biological actions of these proteins. The subunits of the inhibins/activins as well as follistatin are also produced locally within the pituitary and their levels can be modulated by testosterone and gonadotrophin releasing hormone as well as by autocrine mechanisms. Consequently, the output of FSH is dependent of the balance between local processes and the circulating feedback exerted by testosterone and inhibin. There is increasing data to support the local gonadal production of not only inhibin but also activin and follistatin by both germ cells and somatic cells such as the Sertoli cells. Evidence is accumulating to support the concept that these proteins exert local regulatory mechanisms in the testis.