RESUMEN
OBJECTIVE: GH was used to counteract the catabolic metabolism in critically ill patients until it was demonstrated that administration of GH was associated with an increased morbidity due to uncontrolled infections and sepsis. The immunomodulatory effect of GH and its main mediator IGF-I during systemic inflammation remain to be established. We therefore investigated the effect of GH and IGF-I on cellular immune functions in a murine model of sepsis. DESIGN: Randomized animal study. Septic mice were treated with either saline, GH (1mg/kg/24h s.c.), IGF-I (4mg/kg/24h), or GH in combination with IGF-I over a 48h period. SETTING: Level 1 trauma center, university research laboratory. OBJECTS: Male NMRI mice. MEASUREMENTS: clinical parameters (survival rate, body weight, body temperature, fluid intake, food intake, blood glucose levels) and cellular immune functions (splenocyte proliferation by using a (3)H-thymidine incorporation assay, splenocyte apoptosis by determination of Annexin V binding capacity, splenocyte IL-2, IL-6, and TNF-alpha release by using ELISA, and distribution of circulating immune cell subsets by FACScan). RESULTS: Administration of GH did not affect clinical parameters or cellular immune functions in septic mice. In contrast, treatment with IGF-I alone or in combination with GH improved splenocyte proliferation and increased the ability of splenocytes to release IL-2 and IL-6 without affecting the survival rate or any other clinical parameter determined. CONCLUSION: GH did not affect cellular immune functions or the survival rate in our murine sepsis model. In contrast, IGF-I improved splenocyte proliferation and cytokine release independently of GH but did not affect the determined clinical parameters of septic mice.
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Hormona del Crecimiento/farmacología , Inmunidad Celular/efectos de los fármacos , Sepsis/inmunología , Somatomedinas/farmacología , Animales , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Citocinas/inmunología , Recuento de Leucocitos , Masculino , Ratones , Distribución Aleatoria , Bazo/citología , Bazo/efectos de los fármacos , Análisis de SupervivenciaRESUMEN
OBJECTIVE: To determine whether infusion of dopamine modulates cellular immune functions and survival during systemic inflammation. DESIGN AND SETTING: Randomized animal study, university research laboratory, Level I trauma center. SUBJECTS: Male NMRI mice. INTERVENTIONS: Mice were subjected to laparotomy (sham intervention, LAP) or polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice in each of these conditions received either an intraperitoneal infusion of 0.9% saline (CLP/saline; LAP/saline) or an intraperitoneal infusion of dopamine (1.0 microg/kg/min i.p., CLP/DOP; LAP/DOP). Metabolic data and survival were monitored 24 h and 48 h after onset of sepsis, and animals were terminated 48 h after induction of sepsis to determine splenocyte apoptosis (Annexin V binding capacity), splenocyte proliferation (3H-Thymidine incorporation assay), splenocyte IL-2, IL-6 and IFN-gamma release (ELISA) and leukocyte distribution (WBC; CD3, CD4, CD8, B220, F4/80, NK1.1). MEASUREMENTS AND RESULTS: Infusion of dopamine in septic mice increased splenocyte apoptosis and decreased splenocyte proliferation and IL-2 release of septic mice. Furthermore, an inhibitory effect of dopamine infusion on splenocyte proliferation and the release of the TH1-cytokines IL-2 and IFN-gamma was observed in sham operated control mice. These effects were paralleled by a decreased survival of dopamine-treated septic animals (47% vs. 67%). Treatment with DOP did not affect sepsis-induced changes of leukocyte distribution. CONCLUSIONS: We conclude that dopamine is capable of modulating cellular immune functions in a murine model of sepsis.
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Dopaminérgicos/farmacología , Dopamina/farmacología , Inmunidad Celular/efectos de los fármacos , Sepsis/inmunología , Animales , Dopamina/administración & dosificación , Dopaminérgicos/administración & dosificación , Alemania , Masculino , Ratones , Modelos Animales , Neuroinmunomodulación , Sepsis/microbiología , Análisis de SupervivenciaRESUMEN
Behavioral conditioned immunosuppression has been described in rodents as the most impressive demonstration of brain-to-immune system interaction. To analyze whether behavioral conditioned immunosuppression is possible in humans, healthy subjects in this double-blind, placebo-controlled study were conditioned in four sessions over 3 consecutive days, receiving the immunosuppressive drug cyclosporin A as an unconditioned stimulus paired with a distinctively flavored drink (conditioned stimulus) each 12 h. In the next week, re-exposure to the conditioned stimulus (drink), but now paired with placebo capsules, induced a suppression of immune functions as analyzed by the IL-2 and IFN-gamma mRNA expression, intracellular production, and in vitro release of IL-2 and IFN-gamma, as well as lymphocyte proliferation. These data demonstrate for the first time that immunosuppression can be behaviorally conditioned in humans.
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Condicionamiento Clásico , Terapia de Inmunosupresión , Adulto , Conducta , Células Cultivadas , Ciclosporina/farmacología , Método Doble Ciego , Humanos , Tolerancia Inmunológica , Inmunosupresores/farmacología , Interferón gamma/biosíntesis , Interferón gamma/genética , Interleucina-2/biosíntesis , Interleucina-2/genética , Activación de Linfocitos , Masculino , ARN Mensajero/biosíntesis , Linfocitos T/inmunologíaRESUMEN
Recent studies from our laboratory have investigated the hormonal response to various forms of sexual stimulation, including film, masturbation, and coitus in both men and women. This series of studies clearly demonstrated that plasma prolactin (PRL) concentrations are substantially increased for over 1h following orgasm (masturbation and coitus conditions) in both men and women, but unchanged following sexual arousal without orgasm. Here we discuss evidence suggesting that the PRL response to orgasm may play an important role in the control of acute sexual arousal following orgasm. Supporting this position, chronic elevations of PRL (hyperprolactinemia) produce pronounced reductions in animal sexual activity, and significant reduction of libido and gonadal function in both men and women. These data suggest that PRL may represent a peripheral regulatory factor for reproductive function, and/or a feedback mechanism that signals CNS centres controlling sexual arousal and behaviour. Thus, we propose a theoretical model of the role of PRL as a neuroendocrine reproductive reflex.
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Libido/fisiología , Orgasmo/fisiología , Prolactina/metabolismo , Conducta Sexual/fisiología , Animales , Retroalimentación/fisiología , Femenino , Humanos , MasculinoRESUMEN
Using Cyclosporin A (CsA) as an unconditioned stimulus has previously demonstrated that behaviorally conditioned inhibition of splenocyte proliferation and cytokine production is mediated via the splenic nerve. Therefore, we currently examined the adrenergic modulation of conditioned suppression of splenocyte function. Chemical sympathectomy via 6-OHDA completely blocked the conditioned suppression of splenocyte proliferation to mitogens and cytokine (IL-2, IFN-gamma) production. Furthermore, administration of beta-adrenoceptor antagonist propranolol abrogated the conditioned effect on splenocyte proliferation. Supporting the position that conditioning is beta-adrenergic-dependent, addition of beta-adrenoceptor agonist, but not alpha-adrenoceptor agonists, to splenocytes in vitro mimicked the conditioned suppression of splenocyte functions, with these effects blocked by propranolol. Therefore, these data indicate that behavioral conditioning of splenocyte function in the rat is regulated by the sympathetic nervous system, predominantly via beta-adrenergic mechanisms.
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Neuroinmunomodulación , Norepinefrina/fisiología , Receptores Adrenérgicos beta/fisiología , Bazo/inmunología , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Conducta Animal , División Celular , Células Cultivadas , Terapia de Inmunosupresión , Interferón gamma/biosíntesis , Interferón gamma/genética , Interleucina-2/biosíntesis , Interleucina-2/genética , Masculino , Oxidopamina/farmacología , Propranolol/farmacología , ARN Mensajero/biosíntesis , Ratas , Bazo/citología , Simpatectomía Química , Simpaticolíticos/farmacologíaRESUMEN
An immune-neuroendocrine interaction that is mediated via beta2-adrenergic receptors has been demonstrated previously. Dopexamine is a substance with strong beta2-adrenergic effects and is used in the treatment of critically ill patients. We therefore investigated the effect of dopexamine infusion on survival and cellular immune functions during systemic inflammation. Sepsis (CLP) was induced in male NMRI mice that received either 0.9% saline, dopexamine (0.05 mg/kg/hour ip, DPX), the selective beta2-adrenergic antagonist ICI 118.551 (0.5 mg/kg ip every 12 hours, ICI) or a combination of both drugs. 48 hours after onset of sepsis, survival rate, splenocyte apoptosis, splenocyte proliferation, splenocyte IL-2, IL-6 and IFN-gamma release, and leukocyte distribution were monitored. Dopexamine increased splenocyte apoptosis and normalized the distribution of circulating lymphocytes but did not affect sepsis-induced mortality. ICI 118.551 induced a dramatic increase of mortality paralleled by a decreased splenocyte proliferation and the strongest increase in splenocyte apoptosis. Co-administration of dopexamine abolished the ICI 118.551-induced alterations but this effect seemed to be mediated via a pathway other than adrenergic beta2-receptors. We conclude that dopexamine modulates cellular immune functions during systemic inflammation and that different receptor systems are involved in the mediation of this process. Furthermore, the immunomodulatory effect of beta2-adrenergic blockade was demonstrated.
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Antagonistas Adrenérgicos beta/farmacología , Dopamina/análogos & derivados , Dopamina/farmacología , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Animales , Citocinas/metabolismo , Inmunidad Celular/inmunología , Masculino , Ratones , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/metabolismo , SobrevidaRESUMEN
Recently, we have demonstrated that behavioral conditioning reduced splenocyte proliferation and IL-2 production in DA rats, and that these behaviorally conditioned immunosuppressive effects were completely abrogated by prior surgical denervation of the spleen. Since the splenic denervation significantly reduced catecholamine concentrations in the spleen, adrenergic mechanisms have been considered to play an important role in conditioned immunosuppression observed in this model. Thus, the current in vitro studies were designed to analyze the influence of adrenergic mechanisms on the proliferation of rat splenocytes, their IL-2 production, and IL-2 mRNA expression. The data demonstrate that beta-adrenoceptor agonist isoproterenol at concentrations of 10(-5) M diminished mitogen (ConA)-induced splenocyte proliferation by 75%, which was associated with a pronounced (50%) decrease in IL-2 production at both the protein and mRNA levels. The beta-adrenoceptor antagonist propranolol completely reversed the isoproterenol-mediated suppressive effects. Stimulation of splenocytes with the mitogen and either the alpha1-adrenoceptor agonist methoxamine or the alpha2-adrenoceptor agonist UK-14,304 did not affect splenocyte proliferation, IL-2 synthesis or IL-2 mRNA expression. These data demonstrate that catecholamines inhibit splenocyte proliferation and IL-2 production via a beta-adrenoceptor-induced regulation of IL-2 mRNA expression, indicating that beta-adrenoceptor mechanisms are responsible for behaviorally conditioned immunosuppression.
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Interleucina-2/genética , Receptores Adrenérgicos beta/metabolismo , Bazo/inmunología , Bazo/metabolismo , Agonistas alfa-Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Tartrato de Brimonidina , Concanavalina A/farmacología , Técnicas In Vitro , Interleucina-2/biosíntesis , Isoproterenol/farmacología , Activación de Linfocitos/efectos de los fármacos , Masculino , Metoxamina/farmacología , Quinoxalinas/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Bazo/efectos de los fármacos , Bazo/inervación , Transcripción Genética/efectos de los fármacosRESUMEN
Problematic gambling is thought to be influenced by neurobiological mechanisms. However, the neuroendocrine response to gambling is largely unknown. Therefore, the effect of casino gambling on the sympathoadrenal system, the HPA-axis, and pituitary hormones were analyzed. Fourteen male problem gamblers and 15 non-problem gamblers were examined in a balanced cross-over design. In the experimental session, participants played blackjack in a casino wagering their own money. During the control session, subjects played cards for accumulation of points. Heart rate and endocrine measures were recorded at baseline, at 30, 60 and 90 min during gambling/card playing, and after the game. Heart rate and norepinephrine levels increased with the onset of blackjack in both groups, with problem gamblers showing significantly higher levels across the entire gambling session. In addition, dopamine levels were significantly higher in problem gamblers during casino gambling compared to non-problem gamblers. Cortisol levels were transiently increased with the onset of blackjack in both groups. Casino gambling as a "real life" situation induces activation of the HPA-axis and the sympathoadrenergic system, with significantly more pronounced changes in problem gamblers. These findings may contribute to a better understanding of neuroendocrine disturbances in problem gambling.
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Hormona Adrenocorticotrópica/sangre , Conducta Adictiva/sangre , Catecolaminas/sangre , Juego de Azar , Hidrocortisona/sangre , Hormonas Hipofisarias/sangre , Adulto , Conducta Adictiva/fisiopatología , Dopamina/sangre , Epinefrina/sangre , Frecuencia Cardíaca/fisiología , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Masculino , Persona de Mediana Edad , Norepinefrina/sangre , Sistema Hipófiso-Suprarrenal/fisiología , Prolactina/fisiología , Valores de Referencia , Estadística como Asunto , betaendorfina/sangreRESUMEN
This study investigated the relationship between the G protein beta3 subunit 825T allele and depression in young, healthy subjects. 825T and 825C allele carriers were characterized among 190 healthy medical students. State depression was assessed by the Becks Depression Inventory, supplemented by subscales of the Freiburg Personality Inventory, and Questionnaire for Measuring Factors of Aggression which assess trait depression. Depression of homo- and heterozygous 825T allele carriers was compared to 825C allele carriers via multi-level statistical analysis. 825T allele carriers displayed higher levels of depression, as measured by each questionnaire. Regression analysis demonstrated that allele type was the single predictor of depression. The predictive capacity of the 825T allele in depression was further supported by odds-ratio analysis. We conclude that the G protein beta3 subunit 825T allele is predictive of depressive mood in a young, healthy population.
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Alelos , Depresión/genética , Proteínas de Unión al GTP Heterotriméricas/genética , Adulto , Agresión , Depresión/diagnóstico , Depresión/psicología , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Inventario de Personalidad , Valor Predictivo de las Pruebas , Valores de Referencia , Encuestas y CuestionariosRESUMEN
HYPOTHESIS: Splenic autotransplantation plays a role in preserving immune function of the spleen in patients with portal hypertension and liver cirrhosis. DESIGN: Prospective randomized study. SETTING: University hospital. PATIENTS: Twenty patients (19 men and 1 woman; aged 33-80 years) suffering from portal hypertension and liver cirrhosis were randomly allocated into 2 groups. Each group consisted of 10 patients. INTERVENTIONS: All patients underwent modified Sugiura operation. In the control group, splenectomy was performed, while partial splenic autotransplantation into the retroperitoneal space was additionally completed in the splenic autotransplantation group. MAIN OUTCOME MEASURES: Serum tuftsin and IgM were measured preoperatively and 2 months after surgery. Dynamic scintigraphy with technetium Tc 99m-labeled heat-damaged erythrocytes was performed at 2-month intervals during the 8-month follow-up. RESULTS: There was no statistical difference in the mortality of the groups. The preoperative levels of serum tuftsin and IgM showed no statistical difference between groups. However, although these measures had decreased remarkably in the control group 2 months after operation (P<.001 for serum tuftsin; P =.04 for serum IgM), they remained stable in the splenic autotransplantation group (P =.25 for serum tuftsin; P =.12 for serum IgM). Four patients within the splenic autotransplantation group showed positive scanning of the transplanted splenic fragment during follow-up, whereas there was no positive scanning in the control group. CONCLUSION: Our results suggest that partial splenic autotransplantation can preserve immune function of the spleen, as measured by serum levels of tuftsin and IgM, in patients with portal hypertension and liver cirrhosis.
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Hipertensión Portal/cirugía , Bazo/inmunología , Bazo/trasplante , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipertensión Portal/etiología , Inmunoglobulina M/sangre , Cirrosis Hepática/complicaciones , Cirrosis Hepática/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Cintigrafía , Bazo/diagnóstico por imagen , Trasplante Autólogo , Tuftsina/sangreRESUMEN
Neurologic soft signs (NSS) are considered a somatic feature associated with schizophrenia (DSM-IV) that are present in neuroleptic-treated, as well as untreated or first-episode patients. The aim of this study was to determine the incidence and severity of NSS in groups of schizophrenic patients treated with either a conventional neuroleptic medication, haloperidol (n = 37), or atypical antipsychotic medications, risperidone (n = 19), clozapine (n = 34), and olanzapine (n = 18). NSS were assessed with the Neurological Evaluation Scale (NES), whereas extrapyramidal symptoms (EPS), which occur more commonly with conventional neuroleptic treatment, were evaluated using the Simpson-Angus Scale. NES scores were not significantly different between groups. Slight differences were found for 2 items only. The haloperidol group showed higher scores for the "Romberg test," whereas the clozapine group showed higher scores for "short-term memory." There were significant correlations between EPS and NES total score in the haloperidol and risperidone groups. These results demonstrate an overall overlapping of NSS among the groups, confirming their substantial independence from neurologic implications of neuroleptic treatment.
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Antipsicóticos/efectos adversos , Enfermedades del Sistema Nervioso/etiología , Esquizofrenia/tratamiento farmacológico , Adulto , Benzodiazepinas/efectos adversos , Clozapina/efectos adversos , Haloperidol/efectos adversos , Humanos , Masculino , Pruebas Neuropsicológicas , Olanzapina , Risperidona/efectos adversos , Esquizofrenia/complicaciones , Índice de Severidad de la EnfermedadRESUMEN
Interferon-beta-1b (IFN-beta-1b) has been shown to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis (MS) and disease progression in patients with secondary progressive MS. While acute administration of IFN-beta-1b is known to cause flu-like symptoms, chronic medication has been suggested to cause mood alterations and anxiety attacks, and secondary to this neuropsychological deficits that may impair daily life. It is unknown, however, whether the latter symptoms are induced by acute IFN-beta-1b administration. Therefore, we examined the impact of a single subcutaneous injection of IFN-beta-1b in 8 healthy males. In a crossover design, each subject was injected subcutaneously with either 8 million IU IFN-beta-1b or placebo (NaCl) at 8:00 h. Flu-like symptoms (body temperature, heart rate, blood pressure), mood status ['profile of mood states', Befindlichkeitsskala (BFS)] and neuropsychological performance (trail marking test, verbal memory test, d2 attention test) and were assessed at baseline, 4, 8 and 24 h after injection. IFN-beta-1b increased body temperature, heart rate and fatigue. Nevertheless, acute IFN-beta-1b injection did not impair any parameters of neuropsychological performance. Thus, although IFN-beta-1b produces physiological symptoms indicative of sickness behavior, these data suggest that IFN-beta-1b administration does not have an impact on the cognitive capacity following acute administration.
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Afecto/efectos de los fármacos , Cognición/efectos de los fármacos , Factores Inmunológicos/efectos adversos , Interferón beta/efectos adversos , Adulto , Estudios Cruzados , Humanos , Factores Inmunológicos/administración & dosificación , Inyecciones Intravenosas , Interferón beta/administración & dosificación , Masculino , Desempeño Psicomotor/efectos de los fármacos , Valores de Referencia , Factores de TiempoRESUMEN
The most fascinating example of the bi-directional interaction between the central nervous system (CNS) and immune system is the behavioral conditioning of immune functions. We therefore investigated the behavioral conditioning of lipopolysaccharide (LPS)-induced endotoxin tolerance using the taste aversion paradigm. The conditioned stimulus (CS) saccharin was paired with the unconditioned stimulus (UCS) LPS over a five (CONDl) or four (COND2) days learning trial. Controls received drinking water with (SHAM) or without (UNT) LPS. Endotoxin tolerance was tested by determination of LPS-induced tumor necrosis factor (TNF)-alpha release. After the avoidance of the induced endotoxin-tolerance the CS saccharin was re-presented in all experimental groups. A the end of the re-exposure period a complete endotoxin tolerance was noticed in the CONDl- and COND2-group. In contrast, no effect of saccharin administration was observed in the SHAM- or UNT-group. Our data demonstrate for the first time the behavioral conditioning of endotoxin tolerance. Furthermore, these results contribute new aspects to the mechanisms underlying the development and modulation of endotoxin tolerance.
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Condicionamiento Clásico/fisiología , Endotoxinas/farmacología , Animales , Reacción de Prevención , Tolerancia a Medicamentos/fisiología , Lipopolisacáridos/farmacología , Masculino , Ratas , Ratas Endogámicas , Sacarina/farmacología , Gusto/fisiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVES: The goal of this study was to investigate behavioral (self-reported) and physiological sleep characteristics in irritable bowel syndrome (IBS) patients with and without concurrent dyspeptic symptoms, as compared to control subjects. METHODS: A total of 31 women with IBS were stratified into two groups: 15 with bowel symptoms only (IBS-only) and 16 with both lower and upper dyspeptic symptoms (IBS+D). In addition, 23 healthy women served as controls. For 4 consecutive days, subjective sleep quality, insomnia symptoms, alertness, state anxiety, perceived daytime stress, and daytime and nighttime GI symptoms were assessed. On night 4, subjects underwent polysomnographic (PSG) monitoring for an objective assessment of sleep quality including microarousals and respiratory parameters. Saliva samples were collected for cortisol analyses each morning and evening across the 4 days of the study. Psychological disturbances were assessed with the SCL. RESULTS: Patients reported significantly more dissatisfaction with their sleep quality and increased daytime fatigue as a result of both insomnia-type symptomatology and nonrestful sleep. These complaints were significantly greater in IBS+D compared to IBS-only for some measures. A significant proportion of patients, particularly IBS+D patients, reported nighttime GI symptoms. Patients reported significantly greater average anxiety across the 4 days, which was greatest in IBS+D. Although both patient subgroups showed normal levels and circadian changes in cortisol compared to controls, IBS+D had significantly increased morning salivary cortisol levels compared to IBS-only. PSG data showed no significant differences between the patient groups and controls. Significant correlations were found between psychological distress and retrospective subjective sleep complaints for patients. CONCLUSIONS: This study confirms the importance of sleep complaints and nighttime GI symptoms in women with IBS that are not substantiated by any objective, physiological evidence. Rather, there is a reporting bias regarding sleep disturbances, which appears to be related to symptom severity and psychological disturbances.
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Enfermedades Funcionales del Colon/fisiopatología , Enfermedades Funcionales del Colon/psicología , Dispepsia/fisiopatología , Dispepsia/psicología , Trastornos Mentales/fisiopatología , Trastornos Mentales/psicología , Trastornos del Sueño-Vigilia/fisiopatología , Trastornos del Sueño-Vigilia/psicología , Adulto , Enfermedades Funcionales del Colon/complicaciones , Dispepsia/complicaciones , Femenino , Humanos , Trastornos Mentales/complicaciones , Persona de Mediana Edad , Polisomnografía , Índice de Severidad de la Enfermedad , Factores Sexuales , Trastornos del Sueño-Vigilia/complicaciones , Factores de TiempoRESUMEN
BACKGROUND: The immunomodulatory properties of the pituitary hormone prolactin have been demonstrated. It was proposed that prolactin is important in maintaining normal immune response in several pathological states. We investigated the effect of prolactin administration on the survival and cellular immune functions during systemic inflammation. MATERIALS AND METHODS: Male NMRI mice were subjected to laparotomy (LAP) or sepsis induced by cecal ligation and puncture (CLP). Mice were treated with either saline (LAP/saline; CLP/saline) or prolactin (LAP/PRL, CLP/RPL; 4 mg/kg s.c.). Survival of septic mice was determined 24 and 48 h after CLP. Forty-eight hours after the septic challenge, the proliferative capacity, cytokine release (IL-2, IL-6, IFN-gamma) and apoptosis of splenocytes were determined. Additionally, monitoring of circulating leukocyte distribution was performed (WBC; CD3+, CD4+, CD8+, B220+, NK1.1+, F4/80+ cells by FASCan). RESULTS: CLP was accompanied by a mortality of 47% and induced a decrease in splenocyte proliferation and apoptosis rate. Administration of prolactin significantly increased the mortality of septic mice (81%). This was paralleled by a further decrease of splenocyte proliferation and an increased splenocyte apoptosis. In addition, administration of prolactin augmented the sepsis-induced inhibition of IL-2 release, attenuated the sepsis-induced inhibition of IFN-gamma release, and did not affect the release of IL-6. However, prolactin did not affect the sepsis-induced changes of circulating leukocyte subpopulations. CONCLUSIONS: We conclude that prolactin has profound immunomodulatory properties and that administration of prolactin in pharmacological doses is associated with a decreased survival and an inhibition of cellular immune functions in septic mice.
Asunto(s)
Inmunidad Celular/efectos de los fármacos , Hormonas Hipofisarias/farmacología , Prolactina/farmacología , Sepsis/inmunología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/fisiología , Ciego/cirugía , Citocinas/análisis , Obstrucción Intestinal , Perforación Intestinal , Ligadura , Masculino , Ratones , Modelos Animales , Hormonas Hipofisarias/inmunología , Prolactina/inmunología , Análisis de SupervivenciaRESUMEN
Although both alcohol intoxication and withdrawal have been demonstrated to produce significant endocrine alterations, no data exist on the effects of acute withdrawal on immune functions. Therefore, the current study investigated the effect of alcohol intoxication and acute withdrawal on plasma cortisol, prolactin and catecholamines, and blood leukocyte subset distribution in alcohol-dependent subjects. Nine male alcoholics admitted to the university clinic for alcohol dependence and 9 age-matched controls participated in the study. Blood was drawn from the alcohol-dependent subjects at 10:30 a.m. on day 0 (chronic alcohol intoxication), at the same time during acute alcohol withdrawal (day 1) and following the resolution of acute withdrawal (day 7). Blood was drawn from age- and gender-matched healthy control subjects at the corresponding time points. Plasma was then analyzed for hormone concentrations and blood examined for leukocyte subsets by flow cytometry. Alcohol-dependent patients displayed significantly elevated plasma cortisol during intoxication and withdrawal, which decreased to control levels following resolution of acute withdrawal. Small elevations of plasma prolactin and catecholamines were also observed during intoxication. Furthermore, alcohol-dependent subjects showed reduced absolute numbers of CD4(+) and CD8(+) T cells and natural killer cells compared with healthy controls across all time points. In contrast, although monocyte numbers were lower in alcohol-dependent patients during intoxication, acute alcohol withdrawal increased the number of monocytes in patients. Thus, alcohol dependence produces a general suppression of leukocyte subset populations in blood. However, resolution of acute alcohol withdrawal is associated with a return of plasma cortisol to control levels, and a concomitant increase in peripheral blood monocyte numbers.
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Intoxicación Alcohólica/sangre , Catecolaminas/sangre , Depresores del Sistema Nervioso Central/efectos adversos , Etanol/efectos adversos , Hidrocortisona/sangre , Leucocitos , Prolactina/sangre , Síndrome de Abstinencia a Sustancias/sangre , Intoxicación Alcohólica/inmunología , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Citometría de Flujo , Humanos , Células Asesinas Naturales , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Monocitos , Síndrome de Abstinencia a Sustancias/inmunología , Factores de TiempoRESUMEN
OBJECTIVE: An immunomodulatory effect of epinephrine has been reported that is supposed to be mediated via beta-adrenergic receptors. The effect of epinephrine and/or beta-adrenergic blockade on cellular immune functions during systemic inflammation has not yet been investigated. METHODS: Male NMRI mice were treated with either an infusion of epinephrine (0.05 mg/kg/h i.p.), administration of the nonselective beta-adrenoceptor antagonist propranolol (0.5 mg/kg s.c.), or a combination of epinephrine and propranolol after induction of a polymicrobial sepsis by cecal ligation and puncture. Forty-eight hours thereafter survival and cellular immune functions (splenocyte proliferation, splenocyte apoptosis and cytokine release, distribution of leukocyte subsets) were determined. RESULTS: Infusion of epinephrine did not affect lethality of septic mice but induced alterations of splenocyte apoptosis, splenocyte proliferation and IL-2 release and was associated with profound changes of circulating immune cell subpopulations. Treatment with propranolol augmented the epinephrine-induced increase of splenocyte apoptosis, did not affect the decrease of splenocyte proliferation and IL-2 release, augmented the release of IL-6 and antagonized the mobilization of natural killer cells observed in epinephrine-treated animals. Furthermore, these immunologic alterations were accompanied by a significant increase of sepsis-induced mortality. Coadministration of propranolol and epinephrine augmented the propranolol-induced changes of splenocyte apoptosis and IL-6 release and was associated with the highest mortality of septic mice. CONCLUSION: Epinephrine infusion modulated cellular immune functions during systemic inflammation without an impact on survival. A pharmacologic beta-adrenergic blockade partly augmented the epinephrine-induced immune alterations and was associated with a pronounced increase of mortality. This effect was further augmented by a combination of epinephrine infusion and beta-adrenergic blockade. These data indicate that adrenergic mechanisms modulate cellular immune functions and survival during sepsis, with these effects being mediated via alpha- and beta-adrenergic pathways.
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Epinefrina/inmunología , Inmunidad Celular/inmunología , Neuroinmunomodulación/inmunología , Receptores Adrenérgicos beta/inmunología , Sepsis/inmunología , Sistema Nervioso Simpático/inmunología , Antagonistas Adrenérgicos beta/farmacología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , División Celular/efectos de los fármacos , División Celular/inmunología , Citocinas/efectos de los fármacos , Citocinas/inmunología , Sinergismo Farmacológico , Epinefrina/sangre , Epinefrina/farmacología , Inmunidad Celular/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Ratones , Norepinefrina/sangre , Norepinefrina/inmunología , Propranolol/farmacología , Receptores Adrenérgicos beta/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/microbiología , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Tasa de SupervivenciaRESUMEN
BACKGROUND: Several pharmacotherapeutic approaches have confirmed the influence of neuroendocrine parameters on sexual desire, function, and fantasies in men; however, the relevance of acute neuroendocrine changes in mediating heightened sexual drive remains unknown. We recently demonstrated that plasma prolactin substantially increases following orgasm in healthy men, suggesting a feedback mechanism for peripheral prolactin in the control of acute sexual arousal. Because prolactin appears to play a regulatory role in acute sexual drive, we initiated this study to see whether sexual offenders with a high sexual drive have a different neuroendocrine response to sexual arousal. This study compares the prolactin response to orgasm of sexual offenders with high sexual drive and that of healthy subjects with average sexual drive. METHODS: From a subject pool of 150 inpatients held because of sexual crimes, we recruited 10 volunteers, based on their high sexual drive according to an intensive, semistructured clinical interview. We defined sexual drive by a short refractory period and strong sexualization, or a high frequency of sexual stimulation. We analyzed the acute psychoneuroendocrine response to sexual arousal and orgasm continuously before, during, and after masturbation-induced orgasm in patients and control subjects. RESULTS: Sexual offenders demonstrated higher sexual desire (P < 0.001) and function (P < 0.001) and a more positively perceived refractory period (P < 0.05). Both groups displayed a prolonged, significant increase in prolactin plasma levels after orgasm (P < 0.001). Sexual offenders did not differ from control subjects in neuroendocrine response to sexual arousal and orgasm. CONCLUSIONS: These data demonstrate that sexual offenders with a high sexual drive do not differ from control subjects in the postorgasmic neuroendocrine response, particularly in prolactin release. This study confirms that factors other than peripheral hormones influence deviant sexual behaviour.
Asunto(s)
Hormona Folículo Estimulante/metabolismo , Frecuencia Cardíaca/fisiología , Hidrocortisona/metabolismo , Hormona Luteinizante/metabolismo , Masturbación/psicología , Orgasmo/fisiología , Prolactina/metabolismo , Delitos Sexuales/psicología , Testosterona/metabolismo , Adulto , Hormona Folículo Estimulante/sangre , Humanos , Hidrocortisona/sangre , Libido , Hormona Luteinizante/sangre , Masculino , Prolactina/sangre , Testosterona/sangreRESUMEN
The study evaluates the expression and production of cytokines in peripheral blood mononuclear cells of patients with Alzheimer disease treated or not treated with acetylcholinesterase inhibitor, which enhances neuronal transmission. Cytokines associated with brain inflammation such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha have been implicated in the regulation of amyloid peptide protein synthesis. The anti-inflammatory cytokine, IL-4, may suppress the activity of IL-1beta. Patients were assessed for clinical and immunologic features at baseline and after 1 month of treatment with Donepezil, an acetylcholinesterase inhibitor. Peripheral blood mononuclear cells were cultured with and without phytohemagglutinin stimulation. IL-1beta and IL-4 levels were measured by enzyme-linked immunosorbent assay. Reverse transcriptase-polymerase chain reaction was used to determine the expression of cytokines in peripheral mononuclear cells. Compared with untreated patients and healthy control subjects, IL-1beta levels and expression decreased in Alzheimer disease patients treated with Donepezil (P < 0.001). In contrast, IL-4 levels and expression were significantly higher in Alzheimer patients treated with the acetylcholinesterase inhibitor. This increment was observed in both unstimulated and phytohemagglutinin-stimulated peripheral blood mononuclear cells.