Regulation of the ovulation rate in female mammals : example of proliflcity genes in sheep

Sheep provides an interesting model to study ovulation rate control, as this species is associated with a wide genetic variability of its ovulation rate, and hence of the size of its litter. This variability has been shown in numerous cases to be due to the mutation of a single gene. To date, seven mutations have been identified in three different genes: BMP15, GDF9 and BMPR-IB. These three genes belong to the same regulatory pathway involving BMPs (Bone Morphogenetic Proteins), whose role in ovarian development was so far unsuspected. The analysis of these natural ovine mutants demonstrated that certain proteins of the BMP family play a dual role, first as key promoters of early ovarian folliculogenesis and afterwards as inhibitors of its hormone-dependent differentiation. Identifying all the mutations uncovered may confirm the exceptional role of the “BMP system”, or reveal new genes involved in ovulation rate control in female mammals.Le mouton peut être considéré comme une espèce modèle pour l'étude du contrôle du taux d'ovulation. En effet, cette espèce présente une grande variabilité génétique du taux d'ovulation et donc, de la taille des portées. Dans de nombreux cas, il a été montré que cette variabilité était due à la mutation d'un seul gène. À ce jour, sept de ces mutations ont été identifiées: elles affectent trois gènes, BMP15, GDF9 et BMPR-IB. Ces trois gènes font partie d'une même voie de régulation par les BMP (bone morphogenetic proteins) dont le rôle ovarien était insoupçonné. L'analyse de mutations naturelles a démontré que certaines protéines de la famille des BMP avaient une double action, étant d'abord indispensables au développement précoce du follicule ovarien et inhibant ensuite sa différenciation hormono-dépendante. L'identification de l'ensemble des mutations mises en évidence devrait permettre de vérifier le rôle exceptionnel de ce « système BMP » ou d'identifier d'autres gènes clés du contrôle de leur taux d'ovulation par les femelles des mammifères

Economic inequalities in the effectiveness of a primary care intervention for depression and suicidal ideation.

BACKGROUND: Economic disadvantage is associated with depression and suicide. We sought to determine whether economic disadvantage reduces the effectiveness of depression treatments received in primary care. METHODS: We conducted differential-effects analyses of the Prevention of Suicide in Primary Care Elderly: Collaborative Trial, a primary-care-based randomized, controlled trial for late-life depression and suicidal ideation conducted between 1999 and 2001, which included 514 patients with major depression or clinically significant minor depression. RESULTS: The intervention effect, defined as change in depressive symptoms from baseline, was stronger among persons reporting financial strain at baseline (differential effect size = -4.5 Hamilton Depression Rating Scale points across the study period [95% confidence interval = -8.6 to -0.3]). We found similar evidence for effect modification by neighborhood poverty, although the intervention effect weakened after the initial 4 months of the trial for participants residing in poor neighborhoods. There was no evidence of substantial differences in the effectiveness of the intervention on suicidal ideation and depression remission by economic disadvantage. CONCLUSIONS: Economic conditions moderated the effectiveness of primary-care-based treatment for late-life depression. Financially strained individuals benefited more from the intervention; we speculate this was because of the enhanced treatment management protocol, which led to a greater improvement in the care received by these persons. People living in poor neighborhoods experienced only temporary benefit from the intervention. Thus, multiple aspects of economic disadvantage affect depression treatment outcomes; additional work is needed to understand the underlying mechanisms

Are antipsychotic prescribing patterns different in older and younger adults? : a survey of 1357 psychiatric inpatients in Toronto

Objective: To compare antipsychotic prescribing patterns in younger (aged 59 years or younger) and older (aged 60 years or older) patients with psychotic or mood disorders. Method: Pharmacy records of all patients discharged from the Centre for Addiction and Mental Health over a 21-month period were reviewed. A total of 1357 patients who were prescribed an antipsychotic at the time of their discharge were included in the analysis (956 with a primary psychotic disorder and 401 with a primary mood disorder). World Health Organization-defined daily doses were used as the standardized dosing unit. Results: Both in patients with a primary psychotic disorder and in patients with a primary mood disorder, the prescribing patterns were similar in older and younger patients, with no statistical difference in the proportions receiving first-generation antipsychotics, second-generation antipsychotics (SGAs), multiple antipsychotics, or long-acting (depot) antipsychotics. Overall, the mean daily antipsychotic doses were lower only in the older group of patients with a primary mood disorder. However, the mean dose of SGAs was about 30% lower in older patients in both diagnostic groups. Regardless of age, patients with a mood disorder were prescribed lower doses of antipsychotics than those with a psychotic disorder. Conclusions: Our data suggest that older patients are prescribed lower antipsychotic dosages primarily when using SGAs. This finding emphasizes the need for dose-finding studies assessing both the efficacy and the safety of antipsychotics in older patients with a psychotic or mood disorder.peer-reviewe

The role of untreated psychosis in neurodegeneration: A review of hypothesized mechanisms of neurotoxicity in first-episode psychosis

For over 20 years, studies have tried to measure the association between the duration of untreated psychosis (DUP) and changes in brain morphology. A hypothesis that untreated psychosis is neurotoxic has been postulated, but the mechanisms of that toxicity have not been described. We re-analyzed papers collected for a systematic review to extract data on the hypotheses that have been generated on the potential mechanisms by which DUP could impact brain morphology in first-episode psychosis. Dopaminergic hyperactivity, prolonged hypothalamic-pituitary-adrenal activation, and persistent activity of catecholamines have been hypothesized as mechanisms to explain these associations. However, the question remains as to whether the observed structural changes are permanent or may be reversed via antipsychotic treatment

Neurobiology of delusions in Alzheimer’s disease

Alzheimer’s disease (AD) is associated with cognitive and functional impairment as well as neuropsychiatric sequelae, including psychotic symptoms such as delusions and hallucinations. Strong evidence supports the need to study delusions separate from hallucinations. Integrating the epidemiology, clinical correlates, and neuropathological and genetic literature for delusions in AD allows us to speculate on etiology and mechanisms. Plaque and tangle deposition in individuals with susceptible alleles of serotonergic, muscarinic, nicotinic, or Apoε4 genes appears to result in disruption of cortical circuitry, culminating in delusions. While delusions in AD correspond to a phenotype distinct from AD without delusions, subtypes of delusions may also define further distinct clinical entities. Persecutory delusions may occur earlier in the illness and have a more significant genetic component than misidentification delusions, which are associated with increased cognitive impairment and advanced dementia. Clearly distinguishing between these two syndromes is essential to making progress in the area of delusions in AD.peer-reviewe

Towards the development of new subtype-specific muscarinic receptor radiopharmaceuticals-radiosynthesis and ex vivo biodistribution of [18F] 3-(4-(2-(2-(2-fluoroethoxy) ethoxy) ethylthio)-1, 2, 5-thiadiazol-3-yl)-1-methyl-1, 2, 5, 6-tetrahydropyridine

Muscarinic receptors have been implicated in neurological disorders including Alzheimer’s disease, Parkinson’s disease, and schizophrenia. Nineteen derivatives of thiadiazolyltetrahydropyridine (TZTP), a core that has previously shown high affinities towards muscarinic receptor subtypes, were synthesized and evaluated via in vitro binding assays. The title compound, a fluoro-polyethyleneglycol analog of TZTP (4c), was subsequently labelled with fluorine-18. Fluorine-18-labelled 4c was produced, via an automated synthesis, in an average radiochemical yield of 36% (uncorrected for decay), with high radiochemical purity (>99%) and high specific activity (326 GBq/µmol; end-of-bombardment), within 40 min (n = 3). Ex vivo biodistribution studies following tail-vein injection of [18F]4c in conscious rats displayed sufficient brain uptake (0.4%–0.7% injected dose / gram of wet tissue in all brain regions at 5 min post injection); however, there were substantial polar metabolites present in the brain, thereby precluding future use of [18F]4c for imaging in the central nervous system.peer-reviewe

Regulation of ovulation rate in mammals: contribution of sheep genetic models

Ovarian folliculogenesis in mammals from the constitution of primordial follicles up to ovulation is a reasonably well understood mechanism. Nevertheless, underlying mechanisms that determine the number of ovulating follicles were enigmatic until the identification of the fecundity genes affecting ovulation rate in sheep, bone morphogenetic protein-15 (BMP-15), growth and differentiation factor-9 (GDF-9) and BMP receptor-1B (BMPR-1B). In this review, we focus on the use of these sheep genetic models for understanding the role of the BMP system as an intra-ovarian regulator of follicular growth and maturation, and finally, ovulation rate

Differentiating the Cognitive Profile of Schizophrenia from That of Alzheimer Disease and Depression in Late Life

To compare the cognitive profile of older patients with schizophrenia to those with other neuropsychiatric disorders assessed in a hospital-based memory clinic.Demographic, clinical, and cognitive data of all patients referred to the memory clinic at the Centre for Addiction and Mental Health between April 1, 2006 and August 15, 2008 were reviewed. We then identified four groups of older patients with: (1) late-life schizophrenia (LLS) and no dementia or depression (DEP); (2) Alzheimer's disease (AD); (3) DEP and no dementia or LLS; (4) normal cognition (NC) and no DEP or LLS.The four groups did not differ in demographic data except that patients with AD were about 12 years older than those with LLS. However, they differed on cognitive tests even after controlling for age. Patients with LLS were impaired on most cognitive tests in comparison with patients with NC but not on recalling newly learned verbal information at a short delay. They experienced equivalent performance on learning new verbal information in comparison with patients with AD, but better performance on all other tests of memory, including the ability to recall newly learned verbal information. Finally, they were more impaired than patients with DEP in overall memory.Patients with LLS have a different cognitive profile than patients with AD or DEP. Particularly, memory impairment in LLS seems to be more pronounced in learning than recall. These findings suggest that cognitive and psychosocial interventions designed to compensate for learning deficits may be beneficial in LLS

Physician-based availability of psychotherapy in Ontario : a population-based retrospective cohort study

BACKGROUND: Psychotherapy is recommended as a first-line treatment for the management of common psychiatric disorders. The objective of this study was to evaluate the availability of publicly funded psychotherapy provided by physicians in Ontario by describing primary care physicians (PCPs) and psychiatrists whose practices focus on psychotherapy and comparing them to PCPs and psychiatrists whose practices do not. METHODS: This was a population-based retrospective cohort study. We included all PCPs and psychiatrists in Ontario who submitted at least 1 billing claim to the Ontario Health Insurance Plan between Apr. 1, 2015, and Mar. 31, 2016, and categorized them as psychotherapists if at least 50% of their outpatient billings were related to the provision of psychotherapy. We measured practice characteristics such as total number of patients and new patients, and average visit frequency for 4 physician categories: PCP nonpsychotherapists, PCP psychotherapists, psychiatrist nonpsychotherapists and psychiatrist psychotherapists. We also measured access to care for people with urgent need for mental health services. RESULTS: Of 12 772 PCPs, 404 (3.2%) were PCP psychotherapists; of 2150 psychiatrists, 586 (27.3%) were psychotherapists. Primary care physician nonpsychotherapists had the highest number of patients and number of new patients, followed by psychiatrist nonpsychotherapists, PCP psychotherapists and psychiatrist psychotherapists. Primary care physician nonpsychotherapists had the lowest average annual number of visits per patient, whereas both types of psychotherapists had a much greater number of visits per patient. Primary care physician and psychiatrist nonpsychotherapists saw about 25% of patients with urgent needs for mental health services, whereas PCP and psychiatrist psychotherapists saw 1%-3% of these patients. INTERPRETATION: Physicians who provide publicly funded psychotherapy in Ontario see a small number of patients, and they see few of those with urgent need for mental health services. Our findings suggest that improving access to psychotherapy will require the development of alternative strategies