RESUMEN
OBJECTIVES: The objective was to assess the level of stigmatisation of psychiatric patients by medical interns specialising in general practice (GP), and to assess the influencing factors of stigmatisation. METHODS: A national survey was carried out among interns in general practice (GP) contacted through their local associations from December 10, 2019 to March 9, 2020. An online questionnaire was diffused. The validated French version of the Mental Illness Clinicians' Attitudes (MICA) was used to measure stigmatising attitudes towards psychiatry and persons with psychiatric disorder by the interns. This 16-item scale is designed to measure attitudes of health care professionals towards people with mental illness with scores ranging from 16 to 96 (the most stigmatizing). Several covariates were collected: socio-demographics, personal experiences with mental health, and mental health trainings during medical studies. All questionnaires were strictly anonymized. Comparative analyses of the MICA score by group were performed using Student's tests. RESULTS: A total of 389 interns responded. The majority of respondents were female (n=277; 71%) and the mean age was 27years [standard deviation (SD)±2.39]. The mean MICA rate was 40.64 (SD±8.09) for a neutral score of 56, reflecting low overall stigmatizing attitudes. MICA scores were significantly lower among female interns (40.11 vs. 41.95; P=0.042), those who had benefited from personal psychological or psychiatric support (38.70 vs. 41.61; P=0.001), and those who had completed a psychiatric externship (39.47 vs. 42.16; P=0.001). CONCLUSIONS: GP interns had an attitude that is generally not very stigmatizing even if its improvement should still be sought. This is particularly verified among those who have completed a psychiatric internship during their externship. This suggested association should be supported by other studies. The stakes are high for the future management of patients since stigmatisation by a physician is strongly implied in the worse healthcare management of patients with psychiatric disorders, leading them to a shorter lifespan.
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Medicina General , Trastornos Mentales , Estudiantes de Medicina , Humanos , Masculino , Femenino , Adulto , Actitud del Personal de Salud , Estereotipo , Trastornos Mentales/terapia , Trastornos Mentales/psicología , Salud Mental , Encuestas y Cuestionarios , Estudiantes de Medicina/psicologíaRESUMEN
BACKGROUND: Levodopa-carbidopa intestinal gel (LCIG) is an advanced therapy for patients with Parkinson Disease (PD). Weight loss has been pointed out as an adverse event of LCIG infusion. AIMS OF THE STUDY: To compare weight changes between three groups of PD patients: patients treated with LCIG, patients within the first year of subthalamic deep brain stimulation (STN-DBS) and patients treated exclusively with oral treatment during 1 year of follow up. METHODS: Patients treated with LCIG were retrospectively matched by age, gender, disease duration and Hoehn and Yahr to patients undergoing STN-DBS and to patients both receiving the standard of care treatment and unwilling advanced therapies (SOC). Clinical features and weight were collected at baseline, and 12 months after introducing the treatment (LCIG and STN-DBS groups) or for one year of treatment (SOC). RESULTS: Eighteen patients were included in each group. They had no differences in clinical and demographic features, except for cognitive impairment. There was a mean weight (-5.8kg ±6.8) and BMI (-2.1kg/m2±2.6) reduction in the LCIG group after 12 months, while there was a slight weight loss in the SOC (-1.4kg ±3.1) and a weight increase in the STN-DBS group (5.4kg ±4.7). Differences of weight were statistically different between, LCIG and STN-DBS (P<0.001), LCIG and SOC (P=0.002) and STN-DBS and SOC (P<0.001). CONCLUSIONS: The study shows a significant weight reduction after starting LCIG infusion compared to the other groups. Weight loss should be closely monitored in patients treated with LCIG.
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Estimulación Encefálica Profunda , Enfermedad de Parkinson , Núcleo Subtalámico , Antiparkinsonianos , Índice de Masa Corporal , Carbidopa , Estudios de Casos y Controles , Combinación de Medicamentos , Geles , Humanos , Levodopa/efectos adversos , Enfermedad de Parkinson/tratamiento farmacológico , Estudios Retrospectivos , Nivel de AtenciónRESUMEN
BACKGROUND: In France, consumption of antidepressant drugs by children and teenagers has been on the rise, even though recommendations for use are limited due to their association with serious adverse reactions. The objective of this study was to describe the patterns of antidepressant drug dispensing among children and adolescents in the French region of Midi-Pyrenees. METHOD: The data regarding the Midi-Pyrenees region were extracted from the French Health Insurance Database (SNDS) using their ATC codes. The reimbursements for antidepressants, benzodiazepines and neuroleptics dispensed to patients from 6 to 17 years old between January 2015 and June 2017 were analyzed, after which data on the antidepressants themselves were selected. The population was divided into sub-groups according to age (children : 6 to 11 years old, teenagers: 12 to 17 years old). RESULTS: During the 30 months analyzed, 12,783 antidepressants were dispensed to 3506 patients. The antidepressants were primarily issued (90%) to teenagers. In terms of prevalence, 24.7% of the teenagers had amitriptyline delivered at least once, while 31.2% of them received sertraline at least once. Regarding total amount of antidepressant issuances, sertraline was first in both the child (26.9%) and the teenage (40.7%) populations. Benzodiazepine with an antidepressant was issued to 35.1% of the children and teenagers. CONCLUSIONS: Amitriptyline was the most widely dispensed antidepressant among children, and sertraline among teenagers. However, fluoxetine is recommended as the first-line treatment for depression affecting this population. A psychotropic drug prescription assistance website such as psychotropes.fr addressed to general practitioners might improve the implementation of recommendations and guidelines.
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Antidepresivos/uso terapéutico , Prescripciones de Medicamentos/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Niño , Bases de Datos Factuales , Francia , HumanosRESUMEN
OBJECTIVE: To develop a practical guide for the management of child and adolescent depression for general practitioners (GPs), suited to their practice frame, that can be implemented on a website aimed to help GPs to manage the main mental disorders encountered in primary care. METHOD: A systematic meta-review was performed as recommended by the PRISMA statement. Each step, articles' selection, inclusion, methodological assessment and data extraction for the narrative synthesis was independently performed by two researchers. A study protocol was registered on PROSPERO (number CRD42016042710). The databases Pubmed, Cochrane and Web of Science were explored. Each step was performed independently by two researchers following PRISMA. Meta-analyses and systematic reviews (including guidelines based on a systematic review), published between 2002 and 2015, in English or French, dealing with the therapeutic management, in primary care, of patients aged 6 to 18 years old with a major depressive disorder (MDD) were included. Grey literature was explored searching the websites of national and international health agencies, learned societies, and article references. The methodological and report qualities were assessed using the AGREE II, PRISMA checklist and R-AMSTAR grid. A narrative synthesis was performed to produce the practical guide, prioritizing data from the best evaluated articles. An expert group of GPs' and one child psychiatrist validated the guide in its final form. RESULTS: Thirty-eight studies were included: 12 recommendations, 5 systematic reviews and 21 meta-analyses. The best evaluated guideline had an AGREE-II assessment of 81%, and the best evaluated meta-analysis had an assessment of 86% for R-AMSTAR and 96% for PRISMA. The average scores of the R-AMSTAR and PRISMA assessments were 65% and 72% respectively. The average score of the AGREE II grid assessment was 57%. The data were synthesized into a practical guide for the GPs' practice, corresponding to the different consultation times. MDD diagnosis should be done on the DSM or ICD basis. The Childrens' Depression Rating Scale-revised or the Revised Beck Depression Inventory are useful in primary care for MDD appraisal in children and adolescents. For mild MDD a supportive psychotherapy and surveillance for 4 to 6 weeks is preconized in primary care. In the absence of improvement, a specific and structured psychotherapy is recommended, and the patient should be addressed to a child psychiatrist. For moderate to severe MDD, the young patient should be addressed to a specialist in child psychiatry. A psychotherapy, which can be associated with fluoxetine, especially in adolescents, is indicated with a revaluation of the pharmacological treatment between 4 to 8 weeks. A weekly follow-up by the GP is recommended during the first month, especially after the initiation of an antidepressant to assess the suicidal risk. Beyond the first month, a consultation should be scheduled every two weeks. CONCLUSION: A clinical guide was created from the best evidence-based data to help GPs in the management of child and adolescent MDD. A French-language website, aimed to assist GPs in mental disease management and available during their consultation, will be created based on the compilation of this meta-review with other similar meta-reviews.
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Trastorno Depresivo/terapia , Atención Primaria de Salud , Adolescente , Niño , Preescolar , Trastorno Depresivo Mayor , Médicos Generales , Humanos , Psicología del Adolescente , Psicología Infantil , Adulto JovenRESUMEN
BACKGROUND: Subjective cognitive complaint (SCC) is a criterion recommended by the Movement Disorder Society (MDS) task force for the diagnosis of mild cognitive impairment (MCI). Until now there were few specific tools for detecting SCC in PD. We sought to develop a new tool to assess SCC specifically dedicated for PD. MATERIALS AND METHODS: We set a group of experts in movements disorders and neurocognition to develop an easy-to-use tool based on a visual analogue scale (VAS) for five cognitive domains: memory, executive functions, spatial orientation, attention, and language. We use it to assess SCC twice (at a one-month interval) in PD patients with disease duration of less than 5 years. Comprehensibility of the VAS was assessed. Controls were assessed with the same VAS. Patients with PD also underwent neuropsychological testing. RESULTS: VAS was easily understandable by the 70 patients with PD. We found significant SCC for the patients with PD vs controls in three cognitive domains: executive functions (1.7 ± 1.9 vs 0.8 ± 1.1; P < .001), language (2.3 ± 2.5 vs 1.0 ± 1.3, P < .001), and attention (2.1 ± 2.2 vs 1.2 ± 1.2; P < .01). Reproducibility between the two evaluations of patients with PD was good. There was no relationship between SCC and the results of neuropsychological testing. CONCLUSIONS: SCC seems to appear early in PD, in three cognitive domains (executive functions, language, and attention), and VAS might be a good way to detect SCC in PD, but need to be validated.
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Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Enfermedad de Parkinson/psicología , Escala Visual Analógica , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proyectos Piloto , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: In France, two vaccines are approved for prevention of papillomavirus infection: Cervarix(®) and Gardasil(®). The 17th of December 2010 the French High Committee of Public Hearth changed its recommendation about Cervarix(®) and decided that no scientific element justified a preference using Gardasil(®). This notification was published the 25th of January 2011. Our study aimed to determine whether this decision changed medical prescriptions. METHODS: An ecological study was performed with reimbursement data for the two vaccines. We performed a Chi(2) test for qualitative variables and Student's t test for quantitative variables. RESULTS: A significant difference was observed between the prescription of Cervarix(®) before and after the 25th January 2011. The difference favored increased prescription, compared to Gardasil(®) (P ≤ 0.05). CONCLUSION: This variation can be explained by the impact of recommendations for medical decisions. The strong involvement of pharmaceutical firms in medical education may explain why prescribers reacted so rapidly after the publication of the new recommendations.
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Directrices para la Planificación en Salud , Infecciones por Papillomavirus/prevención & control , Vacunas contra Papillomavirus/uso terapéutico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Administración en Salud Pública , Adolescente , Femenino , Francia/epidemiología , Adhesión a Directriz/estadística & datos numéricos , Humanos , Reembolso de Seguro de Salud/estadística & datos numéricos , Reembolso de Seguro de Salud/tendencias , Vacunas contra Papillomavirus/economía , Pautas de la Práctica en Medicina/tendencias , Administración en Salud Pública/legislación & jurisprudencia , Neoplasias del Cuello Uterino/prevención & control , Vacunación/economía , Vacunación/estadística & datos numéricos , Vacunación/tendencias , Displasia del Cuello del Útero/prevención & controlRESUMEN
INTRODUCTION: An acquired abnormality of haemoglobin is among the many causes of cyanosis, especially in patients with no identified cardiorespiratory cause. CASE REPORT: A 50-year-old woman, suffering from amyotrophic lateral sclerosis, was hospitalised for dyspnoea. Physical examination revealed cyanosis that persisted despite oxygen therapy. Discordance between the reduced arterial oxygen saturation and normal arterial oxygen tension led to a search for a dyshaemoglobinaemia as a possible cause. Use of co-oxymetry with spectrophotometry revealed sulphaemoglobinaemia. Sulphaemoglobinaemia is due to irreversible incorporation of a thiol radical into the porphyrin ring of a haem group. This decreases the affinity of haemoglobin for oxygen and thus reduces oxygen carrying capacity. A drug-induced cause is often identified. However, no previously described cause for sulphaemoglobinaemia was identified in our patient. The patient was currently being treated with thiocolchicoside (Miorel((R))). Thiocolchicoside was suspected as the cause because its chemical structure contains an easily hydrolysable thiol radical. Withdrawal of thiocolchicoside led to regression of the sulphaemoglobinaemia. CONCLUSIONS: This report underlines the importance of searching for an acquired abnormality of haemoglobin (methaemoglobinaemia or sulphaemoglobinaemia) in patients with cyanosis resistant to oxygen, in the absence of any cardiorespiratory abnormality. This case is the first to suspect thiocolchicoside as a possible cause of sulphaemoglobinaemia.
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Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Colchicina/análogos & derivados , Cianosis/inducido químicamente , Sulfohemoglobinemia/inducido químicamente , Compuestos de Sulfhidrilo/sangre , Tranquilizantes/toxicidad , Esclerosis Amiotrófica Lateral/sangre , Colchicina/farmacocinética , Colchicina/uso terapéutico , Colchicina/toxicidad , Cianosis/sangre , Diagnóstico Diferencial , Quimioterapia Combinada , Femenino , Radicales Libres , Humanos , Persona de Mediana Edad , Sulfohemoglobinemia/sangre , Tranquilizantes/farmacocinética , Tranquilizantes/uso terapéuticoRESUMEN
Dietary long-chain polyunsaturated fatty acids are known to influence brain levels of the endocannabinoid anandamide in newborn pigs and mice. Furthermore, endocannabinoids were shown to control pup suckling and body weight in mice, and food intake in adult rodents. Here we determined the effect of maternal under-nutrition during gestation, lactation, or both, on body weight, and on the levels of endocannabinoids and expression of cannabinoid CB1 receptors and fatty acid amide hydrolase in the hypothalamus of rat pups at weaning (21 days old) or adult rats (4 months old). Maternal under-nutrition resulted in a striking decrease in body weight of weaning rats, paralleled by a decrease in the hypothalamic levels of the endocannabinoid anandamide, but not of 2-arachidonoylglycerol. No significant change in the hypothalamic expression of either cannabinoid CB1 receptors or fatty acid amide hydrolase mRNA was detected in any of the three groups of weaned pups. The decrease in pup body weight and hypothalamic anandamide levels was not observable in 4-month-old rats from any of the three groups. These data suggest that maternal under-nutrition causes a decrease in hypothalamic anandamide levels and loss of body weight, and confirm a crucial role for endocannabinoid signalling in neonatal development.
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Animales Recién Nacidos , Peso Corporal , Ácidos Grasos Insaturados/metabolismo , Hipotálamo/metabolismo , Trastornos Nutricionales/complicaciones , Complicaciones del Embarazo , Preñez , Amidohidrolasas/metabolismo , Animales , Animales Lactantes , Moduladores de Receptores de Cannabinoides , Endocannabinoides , Femenino , Embarazo , Ratas , Ratas Wistar , Receptores de Cannabinoides , Receptores de Droga/metabolismoRESUMEN
The hypothalamic corticotropin-releasing hormone system and the sympathetic nervous system are anatomically and functionally interconnected and hormones of the hypothalamic-pituitary-adrenocortical axis contribute to the regulation of catecholaminergic systems. To investigate the role of glucocorticoids on activity of the adrenal gland, we analysed plasma and adrenal catecholamines, tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) mRNA expression in rats injected with metyrapone or dexamethasone. Metyrapone-treated rats had significantly lower epinephrine and higher norepinephrine production than control rats. Metyrapone increased TH protein synthesis and TH mRNA expression whereas its administration did not affect PNMT mRNA expression. Dexamethasone restored plasma and adrenal epinephrine concentrations and increased PNMT mRNA levels, which is consistent with an absolute requirement of glucocorticoids for PNMT expression. Adrenal denervation completely abolished the metyrapone-induced TH mRNA expression. Blockage of cholinergic neurotransmission by nicotinic or muscarinic receptor antagonists did not prevent the metyrapone-induced rise in TH mRNA. Finally, pituitary adenylate cyclase activating polypeptide (PACAP) adrenal content was not affected by metyrapone. These results provide evidence that metyrapone-induced corticosterone depletion elicits transsynaptic TH activation, implying noncholinergic neurotransmission. This may involve neuropeptides other than PACAP.
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Inhibidores Enzimáticos/farmacología , Glucocorticoides/metabolismo , Metirapona/farmacología , Feniletanolamina N-Metiltransferasa/genética , Tirosina 3-Monooxigenasa/genética , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/fisiología , Hormona Adrenocorticotrópica/sangre , Animales , Catecolaminas/sangre , Antagonistas Colinérgicos/farmacología , Corticosterona/sangre , Dexametasona/farmacología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Glucocorticoides/farmacología , Masculino , ARN Mensajero/análisis , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacosRESUMEN
Fetal intrauterine growth restriction (IUGR) is a frequently occurring and serious complication of pregnancy. Infants exposed to IUGR are at risk for numerous perinatal morbidities, including hypoglycemia in the neonatal period, as well as increased risk of later physical and/or mental impairments, cardiovascular disease and non-insulin-dependent diabetes mellitus. Fetal growth restriction most often results from uteroplacental dysfunction during the later stage of pregnancy. As glucose, which is the most abundant nutrient crossing the placenta, fulfills a large portion of the fetal energy requirements during gestational development, and since impaired placental glucose transport is thought to result in growth restriction, we investigated the effects of maternal 50% food restriction (FR50) during the last week of gestation on rat placental expression of glucose transporters, GLUT1, GLUT3 and GLUT4, and on plasma glucose content in both maternal and fetal compartments. Moreover, as maternal FR50 induces fetal overexposure to glucocorticoids and since these hormones are potent regulators of placental glucose transporter expression, we investigated whether putative alterations in placental GLUT expression correlate with changes in maternal and/or fetal corticosterone levels. At term (day 21 of pregnancy), plasma glucose content was significantly reduced (P<0.05) in mothers subjected to FR50, but was not affected in fetuses. Food restriction reduced maternal body weight (P<0.001) but did not affect placental weight. Plasma corticosterone concentration, at term, was increased (P<0.05) in FR50 mothers. Fetuses from FR50 mothers showed reduced body weight (P<0.001) but higher plasma corticosterone levels (P<0.05). Adrenalectomy (ADX) followed by corticosterone supplementation of the mother prevented the FR50-induced rise in maternal plasma corticosterone at term. Food restriction performed on either sham-ADX or ADX mothers induced a similar reduction in the body weight of the pups at term (P<0.01). Moreover, plasma corticosterone levels were increased in pups from sham-ADX FR50 mothers (P<0.01) and in pups from ADX control mothers (P<0.01). Western blot analysis of placental GLUT proteins showed that maternal FR50 decreased placental GLUT3 protein levels in all experimental groups at term (P<0.05 and P<0.01), but did not affect either GLUT1 or GLUT4 protein levels. Northern blot analysis of placental GLUT expression showed that both GLUT1 and GLUT3 mRNA were not affected by the maternal feeding regimen or surgery. We concluded that prolonged maternal malnutrition during late gestation decreases maternal plasma glucose content and placental GLUT3 glucose transporter expression, but does not obviously affect fetal plasma glucose concentration. Moreover, the present results are not compatible with a role of maternal corticosterone in the development of growth-restricted rat fetuses.
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Corticosterona/metabolismo , Retardo del Crecimiento Fetal/metabolismo , Proteínas de Transporte de Monosacáridos/metabolismo , Proteínas del Tejido Nervioso , Trastornos Nutricionales/metabolismo , Complicaciones del Embarazo/metabolismo , Preñez/metabolismo , Animales , Glucemia , Northern Blotting/métodos , Western Blotting/métodos , ADN Complementario/metabolismo , Electroforesis en Gel de Poliacrilamida/métodos , Femenino , Sangre Fetal/química , Transportador de Glucosa de Tipo 3 , Modelos Biológicos , Tamaño de los Órganos , Placenta/anatomía & histología , Placenta/metabolismo , Embarazo , ARN Mensajero/metabolismo , Radioinmunoensayo/métodos , Ratas , Ratas WistarRESUMEN
In humans, an altered control of cortisol secretion was reported in adult men born with a low birth weight making the hypothalamic-pituitary-adrenal (HPA) axis a possible primary target of early life programming. In rats, we have recently shown that maternal food restriction during late pregnancy induces both an intrauterine growth retardation and an overexposure of fetuses to maternal corticosterone, which disturb the development of the HPA axis in offspring. The first aim of this work was to investigate, in adult male rats, whether perinatal malnutrition has long-lasting effects on the HPA axis activity during both basal and stressful conditions. Moreover, as the HPA axis and sympathetic nervous system are both activated by stress, the second aim of this work was to investigate, in these rats, the adrenomedullary catecholaminergic system under basal and stressful conditions. This study was conducted on 4-month-old male rats malnourished during their perinatal life and on age-matched control animals. Under basal conditions, perinatal malnutrition reduced body weight and plasma corticosteroid-binding globulin (CBG) level but increased mineralocorticoid receptor (MR) gene expression in CA1 hippocampal area. After 30 min of restraint, perinatally malnourished (PM) rats showed increased plasma noradrenaline, adrenocorticotropin hormone (ACTH) and corticosterone concentrations similarly as controls, but calculated plasma-free corticosterone concentration was significantly higher and adrenaline level lower than controls. During the phase of recovery, PM rats showed a rapid return of plasma ACTH and corticosterone concentrations to baseline levels in comparison with controls. These data suggest that in PM rats, an elevation of basal concentrations of corticosterone, in face of reduced CBG and probably increased hippocampal MR lead to a much larger impact of corticosterone on target cells that mediate the negative-feedback mechanism on the activities of both the HPA axis and sympathoadrenal one.
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Sistema Hipotálamo-Hipofisario/fisiología , Trastornos Nutricionales/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiología , Estrés Fisiológico/fisiopatología , Glándulas Suprarrenales/química , Glándulas Suprarrenales/embriología , Glándulas Suprarrenales/fisiología , Hormona Adrenocorticotrópica/sangre , Factores de Edad , Animales , Corticosterona/sangre , Hormona Liberadora de Corticotropina/análisis , Hormona Liberadora de Corticotropina/genética , Epinefrina/análisis , Epinefrina/sangre , Femenino , Sistema Hipotálamo-Hipofisario/embriología , Masculino , Eminencia Media/química , Eminencia Media/fisiología , Norepinefrina/análisis , Norepinefrina/sangre , Tamaño de los Órganos , Núcleo Hipotalámico Paraventricular/química , Núcleo Hipotalámico Paraventricular/fisiología , Sistema Hipófiso-Suprarrenal/embriología , Embarazo , ARN Mensajero/análisis , Ratas , Ratas Wistar , Receptores de Glucocorticoides/genética , Receptores de Mineralocorticoides/genética , Restricción Física , Sistema Nervioso Simpático/embriología , Sistema Nervioso Simpático/fisiologíaRESUMEN
In rats, poor fetal growth due to maternal food restriction during pregnancy is associated with decreased beta-cell mass at birth and glucose intolerance in adulthood. Overexposure to glucocorticoids in utero can induce intrauterine growth retardation in humans and animals and subsequent glucose intolerance in rodents. The aims of this study were to investigate whether glucocorticoid overexposure mediates the effect of undernutrition on beta-cell mass and to study their potential role in normally nourished rats. Undernutrition significantly increased maternal and fetal corticosterone levels. Twenty-one-day-old fetuses with undernutrition showed growth retardation and decreased pancreatic insulin content; adrenalectomy and subcutaneous corticosterone implants in their dams prevented the maternal corticosterone increase and restored fetal beta-cell mass. In fetuses with normal nutrition, fetal corticosterone levels were negatively correlated to fetal weight and insulin content; fetal beta-cell mass increased from 355 +/- 48 microg in sham to 516 +/- 160 microg after maternal adrenalectomy; inhibition of steroid production by metyrapone induced a further increase to 757 +/- 125 microg. Our data support the new concept of a negative role of glucocorticoids in fetal beta-cell development.
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Glucocorticoides/fisiología , Islotes Pancreáticos/embriología , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/embriología , Adrenalectomía , Animales , Corticosterona/administración & dosificación , Corticosterona/biosíntesis , Corticosterona/sangre , Femenino , Sangre Fetal/química , Retardo del Crecimiento Fetal/etiología , Peso Fetal , Edad Gestacional , Insulina/análisis , Islotes Pancreáticos/efectos de los fármacos , Metirapona/farmacología , Trastornos Nutricionales/sangre , Trastornos Nutricionales/complicaciones , Páncreas/química , Páncreas/embriología , Embarazo , Ratas , Ratas WistarRESUMEN
The present investigation concerns 80-90-day-old female rats born from morphine-exposed mothers (2x10 mg/kg per day from day 11-18 of gestation) or saline-treated ones (controls). The former showed reduced size and activity of the adrenals at birth. At adult stage, they present: (1) higher increase of plasma adrenocorticotrophic hormone level on proestrus; (2) significant rise of plasma corticosterone level on diestrus morning and estrus evening; (3) adrenal atrophy which was significant only on diestrus and estrus morning; (4) more corticosterone binding sites of type I (mineralocorticoid receptors) on proestrus morning in the hippocampus; (5) more corticosterone binding sites of type II (glucocorticoid receptors) in the hippocampus on proestrus morning and in the hypothalamus on estrus morning. In both experimental groups, B(max) for hypothalamic mineralocorticoid receptors were drastically higher on estrus morning than on the other stages of the estrous cycle. The activity of the pituitary-gonadal axis is poorly affected by prenatal morphine-exposition. In both experimental groups drastic and comparable surges of both plasma progesterone and luteinizing hormone were observed during proestrus. Nevertheless morphine-exposed females showed higher levels of plasma estradiol on diestrus morning but lower levels on metestrus morning. In conclusion, prenatal exposition to morphine has long-term effects mainly on pituitary-adrenal axis as well as on binding sites for corticosterone in the hypothalamus and the hippocampus which are dependent on the estrous cycle stages in adult females.
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Glándulas Suprarrenales/anomalías , Estro/fisiología , Morfina/toxicidad , Sistema Hipófiso-Suprarrenal/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Hormona Adrenocorticotrópica/sangre , Animales , Corticosterona/sangre , Hormona Liberadora de Corticotropina/sangre , Hormona Liberadora de Corticotropina/genética , Femenino , Regulación de la Expresión Génica , Hipocampo/metabolismo , Hipotálamo/metabolismo , Hormona Luteinizante/sangre , Morfina/administración & dosificación , Proteínas del Tejido Nervioso/metabolismo , Ovario/fisiopatología , Embarazo , Progesterona/sangre , Ratas , Ratas Wistar , Receptores de Glucocorticoides/metabolismo , Receptores de Mineralocorticoides/metabolismo , Receptores de Esteroides/metabolismoRESUMEN
As fetal overexposure to glucocorticoids has been postulated to induce intrauterine growth retardation (IUGR) in humans, we investigated the effects of maternal 50% food restriction (FR50) in rats during the last week of gestation on the hypothalamo-pituitary adrenal (HPA) axis activity in both mothers and their fetuses. In mothers, FR50 increased both the plasma corticosterone (B) level from embryonic days 19-21 and the relative adrenal weight at term. FR50 decreased at term both the maternal plasma corticosteroid-binding globulin level and placental 11beta-hydroxysteroid dehydrogenase type 2 expression. In newborns, maternal FR50 reduced body and adrenal weights, glucocorticoid and mineralocorticoid receptor expressions in the hippocampus, corticoliberin expression in the hypothalamic paraventricular nucleus, and plasma ACTH. In FR50 newborns, the plasma B level was increased at birth and decreased 2 h later. When maternal circulating B was maintained at the basal level by adrenalectomy and B supply, FR50 induced IUGR in pups and decreased placental 11beta- hydroxysteroid dehydrogenase type 2 expression at term, but did not disturb the offspring's HPA axis. These results suggest that maternal undernutrition during late gestation induces both IUGR and an overexposure of fetuses to maternal B, which disturb the development of the HPA axis.
Asunto(s)
Corticosterona/farmacología , Retardo del Crecimiento Fetal/etiología , Feto/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiología , Trastornos Nutricionales/fisiopatología , Sistema Hipófiso-Suprarrenal/fisiología , Complicaciones del Embarazo/fisiopatología , 11-beta-Hidroxiesteroide Deshidrogenasas , Animales , Animales Recién Nacidos , Peso Corporal , Femenino , Hidroxiesteroide Deshidrogenasas , Tamaño de los Órganos , Embarazo , Ratas , Ratas WistarRESUMEN
OBJECTIVE: The first aim of the present study was to determine if morphine, a prototypic mu-opioid agonist drug, affects pituitary-adrenocortical activity in developing rat pups (first and second weeks of postnatal life). The second aim of this study was to explore, in vivo, if nitric oxide (NO) could be involved in the neurohormonal response to morphine in the early stages of postnatal life. METHODS: Plasma ACTH and corticosterone concentrations were determined by RIA in rat pups (n=5-14 rats/experimental group) after they had been killed by decapitation. In a first experiment, 1-day and 1- and 2-week-old rats were treated s.c. with morphine (20 mg/kg) or with vehicle (0.9% NaCl) and killed 5-90 min later. In a second experiment, 2-week-old pups were pretreated s.c. with naltrexone (NAL; 0.4 mg/kg or 10 mg/kg), and injected 1 h later with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Some pups injected with only NAL were killed 60 or 90 min later. On the other hand, pups injected with NAL (10 mg/kg) or NAL and morphine were killed 30 min later. In a third experiment, 2-week-old pups were pretreated s.c. with N-omega-nitro l arginine methyl-ester (L-NAME; 30 mg/kg or 100 mg/kg), and injected 1 h later with either morphine (20 mg/kg) or vehicle, and killed 30 min later. Moreover, some pups injected with L-NAME (100 mg/kg) or L-NAME with morphine were killed 30 min later. In a final experiment, pups were injected s.c. with either S-nitroso-N-acetylpenicillamine (SNAP; 5 mg/kg) or vehicle, and killed 60 or 90 min later. RESULTS: Morphine administered to rat pups elicited marked rises in both ACTH and corticosterone secretion. Moreover, these responses increased with advancing postnatal age. In 2-week-old rat pups, NAL, a competitive antagonist at mu-opioid receptors, administered alone increased both plasma ACTH and corticosterone concentrations 30 min later. L-NAME, a specific NO synthase inhibitor, did not affect plasma ACTH and corticosterone concentrations 30 min later when administered alone. NAL, when concomitantly administered with morphine, was unable to block morphine responses. In contrast, morphine responses were blocked by pretreatment (60 min before) with NAL or with L-NAME. Acute injection of SNAP increased both ACTH and corticosterone release. CONCLUSION: Our results suggest that opioids have controversial effects on pituitary-adrenocortical activity in the early postnatal period in the rat, and that endogenous NO is one of the major factors in the response of the pituitary-adrenocortical axis to morphine.
Asunto(s)
Analgésicos Opioides/farmacología , Animales Recién Nacidos/fisiología , Morfina/farmacología , Óxido Nítrico/fisiología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Animales , Corticosterona/sangre , Inhibidores Enzimáticos/farmacología , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Radioinmunoensayo , Ratas , Ratas Wistar , Estimulación QuímicaRESUMEN
The effects of the polypeptide hormone prolactin (PRL) in the development and regulation of benign prostate hyperplasia (BPH) and also in prostate cancer are not very well characterized. This study examines the action of PRL, either alone or in association with androgens [testosterone (T) or dihydrotestosterone (DHT)], in the rat prostate gland. The effects of PRL and androgens were investigated after 30 and 60 days in control, castrated, castrated with a substitutive implant of T or DHT, and sham-operated Wistar rats. To enhance PRL release, we induced hyperprolactinemia by administering chronic injections of sulpiride (40 mg. kg(-1). day(-1)). Chronic hyperprolactinemia induces enlargement and inflammation of the lateral rat prostate without any histological changes on ventral and dorsal lobes. We also demonstrate that hyperprolactinemia induces Bcl-2 overexpression in the lateral rat prostate and that this could inhibit the level of apoptosis. The in vivo model established here is a useful in vivo approach for studying the hormonal regulation of normal and pathological prostate development.
Asunto(s)
Hormonas Esteroides Gonadales/farmacología , Hiperprolactinemia/patología , Próstata/crecimiento & desarrollo , Próstata/patología , Testosterona/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Enfermedad Crónica , Dihidrotestosterona/sangre , Dihidrotestosterona/farmacología , Antagonistas de Dopamina/farmacología , Hormonas Esteroides Gonadales/sangre , Hiperprolactinemia/inducido químicamente , Masculino , Orquiectomía , Tamaño de los Órganos , Prolactina/sangre , Próstata/metabolismo , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/patología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Ratas , Ratas Wistar , Sulpirida/farmacología , Testosterona/sangreRESUMEN
RATIONALE: Gabolysat PC60 is a fish protein hydrolysate with anxiolytic properties commonly used as a nutritional supplement. OBJECTIVE: The diazepam-like effects of PC60 on stress responsiveness of the rat pituitary-adrenal system and on sympathoadrenal activity were studied. METHODS: The activity of the pituitary-adrenal axis, measured by plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (B) of the sympathoadrenal complex, measured by circulating levels of noradrenaline (NA) and adrenaline (A), and the gamma aminobutyric acid (GABA) content in the hippocampus and the hypothalamus were investigated in male rats which received daily, by an intragastric feeding tube, for 5 days running either diazepam (1 mg/kg) or PC60 (300 or 1,200 mg/kg). Controls received only solvent (carboxymethylcellulose 1%). Six hours after the last force-feeding, the rats were subjected to 3 min ether inhalation or 30 min restraint and killed by decapitation 30 min after ether stress or at the end of restraint. RESULTS: Baseline plasma levels of ACTH, B, NA and A were not affected by either diazepam or PC60. Both ether- and restraint-induced release of ACTH, but not B, were similarly and drastically reduced by diazepam and PC60 (1,200 mg/kg). Both diazepam and PC60 (1,200 mg/kg) deleted restraint-induced NA and A increases. Both treatments also reduced the ether-induced rise of A. Basal levels of GABA were significantly increased in both the hippocampus and the hypothalamus in PC60-treated rats and only in the hippocampus in diazepam-treated ones. In controls, ether inhalation as well as restraint increased GABA content of these two brain structures. In contrast, such stress procedures performed in PC60-treated rats reduced GABA content slightly in the hippocampus but significantly in the hypothalamus. In diazepam-treated rats, GABA content of the hypothalamus was unaffected by stresses but that of the hippocampus was slightly decreased. CONCLUSIONS: Present data suggest diazepam-like effects of PC60 on stress responsiveness of the rat pituitary adrenal axis and the sympathoadrenal activity as well as GABA content of the hippocampus and the hypothalamus under resting and stress conditions. These effects of PC60 agree with anxiolytic properties of this nutritional supplement, previously reported in both rats and humans.
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Diazepam/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hidrolisados de Proteína/farmacología , Estrés Fisiológico/fisiopatología , Estrés Psicológico/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Administración por Inhalación , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Peso Corporal/efectos de los fármacos , Catecolaminas/sangre , Corticosterona/sangre , Epinefrina/sangre , Éter/administración & dosificación , Peces/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Sistema Hipófiso-Suprarrenal/fisiología , Hidrolisados de Proteína/química , Ratas , Ratas Wistar , Restricción Física , Ácido gamma-Aminobutírico/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Exposure of pregnant rats to morphine, from day 11 to day 18 of gestation, was previously reported to induce both an adrenal atrophy and hypoactivity of the glucocorticoid function in newborns at term, but did not affect, in vitro, the responsiveness of those glands to adrenocorticotrophin hormone (ACTH) concerning corticosterone release. Moreover, these effects were mediated by maternal hormones from the adrenal glands. In the present work, we investigated the effects of a prenatal morphine exposure on the mineralocorticoid activity of the adrenals in neonates. The first aim of the present study was to determine in these newborns 1) the adrenal and plasma aldosterone concentrations at birth time and during the early postnatal period 2) the plasma levels of Na+ and K+ at birth time, 3) the in vitro responsiveness of the newborn adrenals to angiotensin II (A(II)) and ACTH. The second aim of our study was to investigate the mineralocorticoid activity of the adrenals in newborns from adrenalectomized mothers treated with morphine during gestation. According to present data morphine given to intact mothers induced in newborns a severe adrenal atrophy but increased adrenal aldosterone content and plasma aldosterone level. However, prenatal morphine was unable to affect significantly Na+/K+ ratio in both mothers and newborns. In vitro, the adrenals of neonates from morphine-treated mothers were unresponsive to An and ACTH for promoting aldosterone release; in contrast, aldosterone secretion was significantly stimulated by high potassium levels (55 mEq). Maternal adrenalectomy performed one day before the beginning of morphine treatment prevented morphine-induced adrenal atrophy but was unable to affect significantly the adrenal mineralocorticoid function of the offspring. Such data suggest that a prenatal morphine exposure stimulated both aldosterone synthesis and release in neonates. However, this basal hyperfunction did not appear to be coupled with an enhanced adrenal responsivity to AII or ACTH. Prenatal morphine-induced hyperactivity of the mineralocorticoid function of the newborn adrenals, which drastically contrast with hypoactivity of the glucocorticoid one, was independent of adrenal factors from maternal origin.
Asunto(s)
Glándulas Suprarrenales/metabolismo , Mineralocorticoides/sangre , Morfina/farmacología , Narcóticos/farmacología , Glándulas Suprarrenales/efectos de los fármacos , Adrenalectomía , Hormona Adrenocorticotrópica/sangre , Aldosterona/sangre , Angiotensina II/farmacología , Animales , Animales Recién Nacidos , Femenino , Tamaño de los Órganos/efectos de los fármacos , Potasio/sangre , Embarazo , Efectos Tardíos de la Exposición Prenatal , Ratas , Ratas Wistar , Sodio/sangreRESUMEN
BACKGROUND: The growth of the prostate gland is mainly dependent on androgens. Other hormones, like prolactin (PRL), also influence prostate development. Our purpose was to analyze and compare the effects of two drugs (5alpha-reductase inhibitor) used in the therapy of benign prostatic hyperplasia: lipidosterolic extract of Serenoa repens (LSESR), and finasteride in an in vivo model of rat prostate hyperplasia induced by hyperprolactinemia. METHODS: Hyperprolactinemia was induced by 30 daily injections of sulpiride. Wistar rats received daily gavages of LSESR or finasteride. We used the following groups: control, castrated, castrated with a substitute testosterone (T), or 5alpha-dihydrotestosterone (DHT) implant. RESULTS: Hyperprolactinemia increases the wet weight and induces hyperplasia in the lateral prostate (LP). Unlike finasteride, LSESR significantly reduced LP growth and hyperplasia in castrated, DHT-implanted, and sulpiride-treated rats. CONCLUSIONS: Finasteride was only capable of inhibiting the effect of androgens on rat prostate enlargement. LSESR inhibited not only the androgenic but also the trophic effect of PRL in rat LP hyperplasia.
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Antagonistas de Andrógenos/farmacología , Inhibidores Enzimáticos/farmacología , Finasterida/farmacología , Hiperprolactinemia/complicaciones , Extractos Vegetales/farmacología , Hiperplasia Prostática/etiología , Hiperplasia Prostática/patología , Animales , Masculino , Tamaño de los Órganos/efectos de los fármacos , Próstata/efectos de los fármacos , Próstata/patología , Ratas , Ratas Wistar , SerenoaRESUMEN
H19 is an imprinted and developmentally regulated gene whose product remains apparently untranslated. In a previous study on breast adenocarcinomas, we reported that overexpression of the H19 gene was significantly correlated with the presence of steroid receptors, suggesting the putative role of hormones in H19 transcription. To determine the mode of steroid action, we have detected levels of H19 RNA synthesis during mammary gland development by in situ hybridization (ISH): two peaks of H19 transcription occur during puberty and pregnancy. Furthermore, we demonstrated by ISH that in the uterus H19 RNA synthesis is high during estrus and metestrus phases. To test steroid control of H19 transcription, ovariectomized and adrenalectomized mice were supplemented, 1 week after surgery, with 17-beta-estradiol (E2, 20 microg/kg/day), progesterone (P, 1 mg/kg/day) or corticosterone (B, 0.3 mg/ kg/day) for 2 weeks. According to ISH data, E2 and to a lesser extent B stimulated H19 transcription in the uterus, whereas P inhibited it. To confirm the in vivo results, in vitro experiments were performed using cultures of MCF-7 cells (a hormone-sensitive mammary cell line). E2 stimulated the endogenous H19 gene of this cell line and tamoxifen inhibited this effect. Furthermore, we performed transient cotransfections in MCF-7, in HBL-100 (another hormone-sensitive mammary cell line) and in BT-20 (a hormone-insensitive mammary cell line) with various constructs of ERalpha (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERalpha up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any effect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERalpha-mediated promoter enhancement, but in HBL-100 this counteracting effect on the ERalpha up-regulation was not found. Interestingly, the same experiments performed in BT-20 cell line provided very similar results as those obtained in MCF-7 cells, with a clear down-regulation mediated by PR-A on the H19 promoter. All these in vitro data are in agreement with in vivo results. In addition, data obtained with ERalpha mutants indicate that H19 promoter activation is both ligand-dependent and ligand-independent. We have thus demonstrated that H19 gene expression is controlled by steroid hormones; furthermore, this gene is highly expressed in hormone-sensitive organs when the hormonal stimulation is accompanied with a morphological repair.