RESUMO
BACKGROUND: Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins and enables uptake of lipolysis products for energy production or storage in tissues. Our aim was to study the localization of LPL and its endothelial anchoring protein glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in mouse pancreas, and effects of diet and leptin deficiency on their expression patterns. For this, immunofluorescence microscopy was used on pancreatic tissue from C57BL/6 mouse embryos (E18), adult mice on normal or high-fat diet, and adult ob/ob-mice treated or not with leptin. The distribution of LPL and GPIHBP1 was compared to insulin, glucagon and CD31. Heparin injections were used to discriminate between intracellular and extracellular LPL. RESULTS: In the exocrine pancreas LPL was found in capillaries, and was mostly co-localized with GPIHBP1. LPL was releasable by heparin, indicating localization on cell surfaces. Within the islets, most of the LPL was associated with beta cells and could not be released by heparin, indicating that the enzyme remained mostly within cells. Staining for LPL was found also in the glucagon-producing alpha cells, both in embryos (E18) and in adult mice. Only small amounts of LPL were found together with GPIHBP1 within the capillaries of islets. Neither a high fat diet nor fasting/re-feeding markedly altered the distribution pattern of LPL or GPIHBP1 in mouse pancreas. Islets from ob/ob mice appeared completely deficient of LPL in the beta cells, while LPL-staining was normal in alpha cells and in the exocrine pancreas. Leptin treatment of ob/ob mice for 12 days reversed this pattern, so that most of the islets expressed LPL in beta cells. CONCLUSIONS: We conclude that both LPL and GPIHBP1 are present in mouse pancreas, and that LPL expression in beta cells is dependent on leptin.
Assuntos
Leptina/deficiência , Leptina/metabolismo , Lipase Lipoproteica/metabolismo , Pâncreas/metabolismo , Receptores de Lipoproteínas/metabolismo , Animais , Capilares/metabolismo , Dieta Hiperlipídica/métodos , Células Endoteliais/metabolismo , Glucagon/metabolismo , Células Secretoras de Glucagon/metabolismo , Glicosilfosfatidilinositóis/metabolismo , Heparina/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismoRESUMO
Cerebral responses to putative pheromones and objects of sexual attraction were recently found to differ between homo- and heterosexual subjects. Although this observation may merely mirror perceptional differences, it raises the intriguing question as to whether certain sexually dimorphic features in the brain may differ between individuals of the same sex but different sexual orientation. We addressed this issue by studying hemispheric asymmetry and functional connectivity, two parameters that in previous publications have shown specific sex differences. Ninety subjects [25 heterosexual men (HeM) and women (HeW), and 20 homosexual men (HoM) and women (HoW)] were investigated with magnetic resonance volumetry of cerebral and cerebellar hemispheres. Fifty of them also participated in PET measurements of cerebral blood flow, used for analyses of functional connections from the right and left amygdalae. HeM and HoW showed a rightward cerebral asymmetry, whereas volumes of the cerebral hemispheres were symmetrical in HoM and HeW. No cerebellar asymmetries were found. Homosexual subjects also showed sex-atypical amygdala connections. In HoM, as in HeW, the connections were more widespread from the left amygdala; in HoW and HeM, on the other hand, from the right amygdala. Furthermore, in HoM and HeW the connections were primarily displayed with the contralateral amygdala and the anterior cingulate, in HeM and HoW with the caudate, putamen, and the prefrontal cortex. The present study shows sex-atypical cerebral asymmetry and functional connections in homosexual subjects. The results cannot be primarily ascribed to learned effects, and they suggest a linkage to neurobiological entities.
Assuntos
Cérebro/fisiologia , Heterossexualidade/fisiologia , Homossexualidade/fisiologia , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Adulto , Tonsila do Cerebelo/anatomia & histologia , Tonsila do Cerebelo/fisiologia , Cérebro/anatomia & histologia , Feminino , Lateralidade Funcional , Humanos , MasculinoRESUMO
Background: Robot-assisted ventral hernia repair, when performed correctly, may reduce the risk for pain and discomfort in the postoperative period thus enabling shorter hospital stay. The aim of the present study was to evaluate postoperative pain following robot-assisted laparoscopic repair. The approach was selected after an intraoperative decision to complete the repair as: (1). Transabdominal Preperitoneal Repair (TAPP); (2). Trans-Abdominal RetroMuscular (TARM) repair; or (3). Intraperitoneal Onlay Mesh (IPOM) repair depending on anatomical conditions. Methods: Twenty ventral hernia repairs, 8 primary and 12 incisional, were included between 18th Dec 2017 and 11th Nov 2019. There were 8 women, mean age was 60.3 years, and mean diameter of the defect was 3.8 cm. The repairs were performed at Södersjukhuset (Southern General Hospital, Stockholm) using the Da Vinci Si Surgical System®. Sixteen repairs were completed with the TAPP technique, 2 with the TARM technique, and 2 as IPOM repair. Results: Mean hospital stay was 1.05 days. No postoperative infection was seen, and no recurrence was seen at 1 year. At the 30-day follow-up, fifteen patients (75%) rated their pain as zero or pain that was easily ignored, according to the Ventral Hernia Pain Questionnaire. After 1 year no one had pain that was not easily ignored. Conclusion: The present study shows that robot-assisted laparoscopic ventral hernia is feasible and safe. More randomized controlled trials are needed to show that the potential benefits in terms of shorter operation times, earlier discharge, and less postoperative pain motivate the extra costs associated with the robot technique.
RESUMO
This review summarizes key aspects of what has been learned about the physiology of pancreatic islets and leptin deficiency from studies in obese ob/ob mice. ob/ob Mice lack functional leptin. They are grossly overweight and hyperphagic particularly at young ages and develop severe insulin resistance with hyperglycemia and hyperinsulinemia. ob/ob Mice have large pancreatic islets. The beta-cells respond adequately to most stimuli, and ob/ob mice have been used as a rich source of pancreatic islets with high insulin release capacity. ob/ob Mice can perhaps be described as a model for the prediabetic state. The large capacity for islet growth and insulin release makes ob/ob mice a good model for studies on how beta-cells can cope with prolonged functional stress.
Assuntos
Hiperglicemia/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/fisiologia , Camundongos Obesos/fisiologia , Animais , Modelos Animais de Doenças , Glucose/metabolismo , Hiperglicemia/genética , Incretinas/metabolismo , Insulina/metabolismo , Resistência à Insulina , Ilhotas Pancreáticas/citologia , Leptina/metabolismo , Camundongos , Camundongos Obesos/genética , Modelos Biológicos , Oscilometria/métodosAssuntos
Epilepsia/psicologia , Transtornos Psicofisiológicos/diagnóstico , Convulsões/psicologia , Diagnóstico Diferencial , Epilepsia/diagnóstico , Epilepsia/etiologia , Epilepsia/terapia , Humanos , Educação de Pacientes como Assunto , Transtornos Psicofisiológicos/etiologia , Transtornos Psicofisiológicos/terapia , Psicoterapia , Convulsões/diagnóstico , Convulsões/etiologia , Convulsões/terapiaRESUMO
OBJECTIVE: C-peptide replacement in animals results in amelioration of diabetes-induced functional and structural abnormalities in peripheral nerves. The present study was undertaken to examine whether C-peptide administration to patients with type 1 diabetes and peripheral neuropathy improves sensory nerve function. RESEARCH DESIGN AND METHODS: This was an exploratory, double-blinded, randomized, and placebo-controlled study with three study groups that was carried out at five centers in Sweden. C-peptide was given as a replacement dose (1.5 mg/day, divided into four subcutaneous doses) or a dose three times higher (4.5 mg/day) during 6 months. Neurological examination and neurophysiological measurements were performed before and after 6 months of treatment with C-peptide or placebo. RESULTS: The age of the 139 patients who completed the protocol was 44.2 +/- 0.6 (mean +/- SE) years and their duration of diabetes was 30.6 +/- 0.8 years. Clinical neurological impairment (NIA) (score >7 points) of the lower extremities was present in 86% of the patients at baseline. Sensory nerve conduction velocity (SCV) was 2.6 +/- 0.08 SD below body height-corrected normal values at baseline and improved similarly within the two C-peptide groups (P < 0.007). The number of patients responding with a SCV peak potential improvement >1.0 m/s was greater in C-peptide-treated patients than in those receiving placebo (P < 0.03). In the least severely affected patients (SCV < 2.5 SD below normal at baseline, n = 70) SCV improved by 1.0 m/s (P < 0.014 vs. placebo). NIA score and vibration perception both improved within the C-peptide-treated groups (P < 0.011 and P < 0.002). A1C levels (7.6 +/- 0.1% at baseline) decreased slightly but similarly in C-peptide-and placebo-treated patients during the study. CONCLUSIONS: C-peptide treatment for 6 months improves sensory nerve function in early-stage type 1 diabetic neuropathy.
Assuntos
Peptídeo C/uso terapêutico , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/tratamento farmacológico , Neuropatias Diabéticas/fisiopatologia , Condução Nervosa/fisiologia , Adulto , Idade de Início , Método Duplo-Cego , Humanos , Pessoa de Meia-Idade , Exame Neurológico , Seleção de Pacientes , Nervo Sural/fisiopatologia , SuéciaRESUMO
A decline in cognitive function has been reported in type 1 diabetes, but its relation to different disease factors such as hypoglycemic events and peripheral neuropathy is controversial. The objective of the present study was to identify factors that are important for cognitive impairment in type 1 diabetes. A cross-sectional study was performed in adult patients (N=150) with type 1 diabetes (duration 26.6+/-11.4 years). Function in different cognitive domains was evaluated by the same trained examiner, in order to eliminate inter-rater variability. Peripheral nerve function was tested quantitatively. Predictors of cognitive impairment were identified using multiple regression analysis. The major finding was that long diabetes duration and young age of diabetes onset were the strongest predictors of low scores in psychomotor speed, memory, processing speed, attention, working memory, verbal ability, general intelligence, executive functions and a low global score. The number of previous hypoglycemic events had no defined effect upon cognitive functioning. Other significant predictors were low compound muscle action potential (CMAP) (for visual perception-organization), old age (for visual-spatial ability), short stature, high BMI and hypertension. Presence of retinopathy and long-term metabolic control correlated with nerve conduction defects, but not with cognitive impairment. Although a history of hypoglycemic events was not a predictor of cognitive impairment, we cannot exclude the possibility that the influence of young age of diabetes onset depends on the effect of hypoglycemic events early in life. The clinical relationships of cognitive impairment differ from those of peripheral neuropathy, indicating a different pathogenesis. The influence of diabetes duration, BMI, height, age and CMAP may suggest that loss of the neuroprotective effects of insulin or insulin-like growth factors plays a role.
Assuntos
Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Diabetes Mellitus Tipo 1/complicações , Neuropatias Diabéticas/diagnóstico , Adulto , Transtornos Cognitivos/fisiopatologia , Estudos Transversais , Feminino , Humanos , Hipoglicemia/diagnóstico , Hipoglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Análise de RegressãoRESUMO
This review summarizes key aspects of what has been learned about the physiology of leptin deficiency as it can be observed in obese-hyperglycemic ob/ob mice. These mice lack functional leptin. They are grossly overweight and hyperphagic, particularly at young ages, and develop severe insulin resistance. They have been used as a model for obesity and as a rich source of pancreatic islets with high insulin release capacity. The leptin deficiency manifests also with regard to immune function, the cardiovascular system including angiogenesis, supportive tissue function, malignancies, and reproductive function. ob/ob Mice are well suited for studies on the interaction between leptin and insulin, and for studies on initial aspects of metabolic disturbances leading to type-2 diabetes.
Assuntos
Modelos Animais de Doenças , Hiperglicemia/patologia , Hiperglicemia/fisiopatologia , Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Leptina/deficiência , Obesidade/fisiopatologia , Animais , Humanos , Camundongos , Camundongos Obesos , Obesidade/patologiaRESUMO
We recently reported that the timing and magnitude of the nutrient-induced Ca(2+) response are specific and reproducible for each isolated beta-cell. We have now used tolbutamide and arginine to test if the cell specificity exists also for the response to non-nutrient stimulation of beta-cells and if so, whether it is disturbed in beta-cells from hyperglycemic ob/ob and db/db mice. Zn(2+) outflow measurements were used to study the correlation between Ca(2+) response and insulin secretion in individual beta-cells. Tolbutamide and arginine induced cell-specific Ca(2+) responses in lean mouse beta-cells both with regard to lag times for [Ca(2+)](i) rise and peak [Ca(2+)](i) heights. beta-Cells within intact islets also showed cell-specific timing of their Ca(2+) responses to tolbutamide. However, in tolbutamide- and arginine-stimulated single beta-cells from ob/ob and db/db mice only the magnitude of Ca(2+) response was cell-specific, not the timing. The lag time of tolbutamide-induced insulin secretion was cell-specific in lean mouse beta-cells but not in ob/ob mouse cells. Therefore, cell specificity seems to be a robust mechanism, and probably important for an adequate beta-cell function. The loss of temporal cell specificity for the response to tolbutamide in single beta-cells from hyperglycemic mice may be a sign of K(ATP)- or voltage-dependent calcium channel dysfunction.
Assuntos
Cálcio/metabolismo , Citoplasma/metabolismo , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Células Secretoras de Insulina/metabolismo , Tolbutamida/farmacologia , Animais , Cálcio/análise , Citoplasma/química , Feminino , Insulina/análise , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Camundongos , Camundongos Mutantes , Microscopia Confocal , Microscopia de FluorescênciaRESUMO
Obesity and development of the metabolic syndrome is related to an increased parasympathetic tone and hyperinsulinemia. We have now studied the effects of age and metabolic status on glucose-induced insulin release stimulated by the neuropeptides vasoactive intestinal polypeptide (VIP; 10 nM) and pituitary adenylate cyclase activating polypeptide (PACAP; 10 nM), that are constituents of the parasympathetic nerves in the islets, and the cholinergic agonists acetylcholine (ACh; 10 microM) and carbachol (10 microM), in isolated islets from female obese ob/ob mice and lean mice. Both VIP and PACAP enhanced insulin secretion in islets from 4-week-old hyperglycemic ob/ob mice. VIP did not increase 11.1 mM glucose-induced insulin release in islets from 4-week-old lean normoglycemic mice and neither did PACAP in the absence of bicarbonate. The neuropeptides increased insulin release in islets from 9 to 10-month-old mice but VIP and PACAP had no effect in islets from very old mice. ACh had no effect in islets from 9 to 10-months and older ob/ob mice in the absence of bicarbonate. The combination of VIP and cholinergic agonists had an additive effect in islets from ob/ob mice, and PACAP combined with carbachol potentiated insulin release in islets from 4-week-old lean mice. VIP increased early phase insulin release in perifused islets from young mice. A higher concentration of theophylline was needed to potentiate glucose-induced insulin release in islets from young lean mice than in islets from old lean mice and ob/ob mice. The present results demonstrate age-related dynamics in the effects of neuropeptides affecting cAMP in pancreatic islets. We suggest that VIP and PACAP contribute to the developing metabolic syndrome in ob/ob mice by aggravating hyperinsulinemia.
Assuntos
Envelhecimento/fisiologia , Metabolismo Energético , Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Peptídeo Intestinal Vasoativo/farmacologia , Animais , Carbacol/farmacologia , Feminino , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Obesos , Agonistas Muscarínicos/farmacologia , Técnicas de Cultura de TecidosRESUMO
The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in ß-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of ß-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet ß-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their ß-cell population. Unawareness of the characteristics of ß-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of ß-cell adaptation and function.
Assuntos
Ilhotas Pancreáticas/diagnóstico por imagem , Ilhotas Pancreáticas/patologia , Pâncreas/diagnóstico por imagem , Animais , Fibrina/metabolismo , Hipertrofia , Imageamento Tridimensional , Camundongos Obesos , Pâncreas/citologia , Pâncreas/patologia , Tomografia Óptica/métodosRESUMO
Studies have demonstrated that proinsulin C-peptide stimulates the activities of Na(+),K(+)-ATPase and endothelial nitric oxide synthase, both of which are enzyme systems of importance for nerve function and known to be deficient in type 1 diabetes. The aim of this randomized double-blind placebo-controlled study was to investigate whether C-peptide replacement improves nerve function in patients with type 1 diabetes. Forty-nine patients without symptoms of peripheral neuropathy were randomized to either 3 months of treatment with C-peptide (600 nmol/24 h, four doses s.c.) or placebo. Forty-six patients (15 women and 31 men, aged 29 years, diabetes duration 10 years, and HbA(1c) 7.0%) completed the study. Neurological and neurophysiological measurements were performed before and after 6 and 12 weeks of treatment. At baseline the patients showed reduced nerve conduction velocities in the sural nerve (sensory nerve conduction velocity [SCV]: 50.9 +/- 0.70 vs. 54.2 +/- 1.2 m/s, P < 0.05) and peroneal nerve (motor nerve conduction velocity: 45.7 +/- 0.55 vs. 53.5 +/- 1.1 m/s, P < 0.001) compared with age-, height-, and sex-matched control subjects. In the C-peptide treated group there was a significant improvement in SCV amounting to 2.7 +/- 0.85 m/s (P < 0.05 compared with placebo) after 3 months of treatment, representing 80% correction of the initial reduction in SCV. The change in SCV was accompanied by an improvement in vibration perception in the patients receiving C-peptide (P < 0.05 compared with placebo), whereas no significant change was detectable in cold or heat perception. In conclusion, C-peptide administered for 3 months as replacement therapy to patients with early signs of diabetic neuropathy ameliorates nerve dysfunction.
Assuntos
Peptídeo C/uso terapêutico , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Adulto , Idade de Início , Pressão Sanguínea , Peso Corporal , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Neuropatias Diabéticas/sangue , Neuropatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/uso terapêutico , Masculino , Condução Nervosa/efeitos dos fármacos , Exame Neurológico , Seleção de Pacientes , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Placebos , Fatores de TempoRESUMO
BACKGROUND: Juvenile myoclonic epilepsy (JME) is classified as primarily generalized epilepsy and as such is assumed to lack an anatomic substrate. Although neurochemical abnormalities are probable, few studies have investigated whether they exist in JME. Animal data and the high incidence of myoclonic seizures in serotonin-intoxicated patients suggest that the serotonin system may be disturbed in JME. OBJECTIVE: To test the hypothesis that JME is associated with a disturbed serotonin system and that this disturbance could be reflected in altered serotonin 1A receptor binding. DESIGN: The serotonin 1A receptor binding potential (BP) was measured with positron emission tomography and serotonin 1A receptor antagonist carbonyl-carbon 11-WAY-100635. The BP was calculated using a reference tissue model in several limbic and neocortical regions and the raphe nuclei. SETTING: Epilepsy clinics of the Karolinska University Hospital, Stockholm, Sweden. PATIENTS: Eleven patients with JME and 11 controls were studied. MAIN OUTCOME MEASURE: Serotonin 1A receptor BP calculated in a set of volumes of interest. RESULTS: The patients with JME showed a reduced BP in the dorsolateral prefrontal cortex, raphe nuclei, and hippocampus. CONCLUSIONS: The observed reductions in serotonin 1A receptor BP suggest that the serotonin system is affected in JME. Although the data give no definitive information about underlying mechanisms, they provide a strong argument for the view that not all brain regions are homogeneously involved in this condition, further questioning the current classification of primarily generalized epilepsy.
Assuntos
Encéfalo/metabolismo , Epilepsia Mioclônica Juvenil/metabolismo , Receptor 5-HT1A de Serotonina/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Regulação para Baixo , Feminino , Humanos , Masculino , Epilepsia Mioclônica Juvenil/diagnóstico por imagem , Piperazinas/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Ligação Proteica/fisiologia , Piridinas/metabolismoRESUMO
A rise in the cytoplasmic calcium concentration ([Ca(2+)](i)) is a key event for insulin exocytosis. We have recently found that the 'early [Ca(2+)](i) response' in single ob/ob mouse beta-cells is reproduced during consecutive glucose stimulations. It, therefore, appears that the response pattern is a characteristic of the individual beta-cell. We have now investigated if a cell-specific [Ca(2+)](i) response is a general phenomenon in rodent beta-cells, and if it can be observed when cells are functionally coupled. With the use of the fura-2 technique, we have studied the 'early [Ca(2+)](i) response' in single dispersed beta-cells, in beta-cell clusters of different size and in intact islets from the ob/ob mouse during repeated glucose stimulation (20mM). beta-Cells from lean mouse and rat, and intact islets from lean mouse were also investigated. Significant correlations between the first and second stimulation were found for the parameters lag-time for Ca(2+) rise (calculated as the time from start of stimulation of the cell until the first value above an extrapolated baseline), nadir of initial lowering (difference between the baseline and lowest [Ca(2+)](i) value), and peak height (difference between baseline and the highest [Ca(2+)](i) value of the first calcium peak) in single dispersed beta-cells, in 'single beta-cell within a small cluster', in clusters of medium and large size, and in single dispersed beta-cells from lean mouse and rat. The lag-times for Ca(2+) rise and peak heights were correlated within the pairs of stimulation also in intact ob/ob islets. In summary, despite a large heterogeneity of the 'early [Ca(2+)](i) response' among individual cells, the lag-time for [Ca(2+)](i) rise, the nadir of initial lowering and the height of the first peak response can be identified as cell-specific markers in beta-cells.
Assuntos
Cálcio/metabolismo , Glucose/farmacologia , Ilhotas Pancreáticas/metabolismo , Animais , Agregação Celular , Células Cultivadas , Fura-2 , Insulina/metabolismo , Camundongos , Camundongos Obesos , Família Multigênica , Ratos , Fatores de TempoRESUMO
Tocainide is a derivative of lidocaine with anti-arrhythmic action and, unlike lidocaine, can be used for oral treatment. Tocainide was alternatively with carbamazepine given to 12 patients with trigeminal neuralgia in a double-blind cross-over study for 2 weeks. The analgesic effect was estimated each day by the patients using a 0-10-point scale summarizing the frequency and severity of the attacks. The similarity in analgesic effect of the two drugs was striking. A possible analgesic mechanism could be that tocainide blocks the sodium channels in the hyperexcitable nerve membranes in the pain-producing foci in trigeminal neuralgia.
Assuntos
Carbamazepina/uso terapêutico , Lidocaína/análogos & derivados , Neuralgia do Trigêmeo/tratamento farmacológico , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Lidocaína/efeitos adversos , Lidocaína/uso terapêutico , Masculino , Pessoa de Meia-Idade , TocainideRESUMO
OBJECTIVE: GH causes insulin resistance, impairs glycemic control and increases the risk of vascular diabetic complications. Sulphonylureas stimulate GH secretion and this study was undertaken to investigate the possible stimulatory effect of repaglinide and nateglinide, two novel oral glucose regulators, on critical steps of the stimulus-secretion coupling in single rat somatotrophs. METHODS: Patch-clamp techniques were used to record whole-cell ATP-sensitive K(+) (K(ATP)) and delayed outward K(+) currents, membrane potential and Ca(2+)-dependent exocytosis. GH release was measured from perifused rat somatotrophs. RESULTS: Both nateglinide and repaglinide dose-dependently suppressed K(ATP) channel activity with half-maximal inhibition being observed at 413 nM and 13 nM respectively. Both compounds induced action potential firing in the somatotrophs irrespective of whether GH-releasing hormone was present or not. The stimulation of electrical activity by nateglinide, but not repaglinide, was associated with an increased mean duration of the action potentials. The latter effect correlated with a reduction of the delayed outward K(+) current, which accounts for action potential repolarization. The latter effect had a K(d) of 19 microM but was limited to 38% inhibition. When applied at concentrations similar to those required to block K(ATP) channels, nateglinide in addition potentiated Ca(2+)-evoked exocytosis 3.3-fold (K(d)=3 microM) and stimulated GH release 4.5-fold. The latter effect was not shared by repaglinide. The stimulation of exocytosis by nateglinide was mimicked by cAMP and antagonized by the protein kinase A inhibitor Rp-cAMPS. CONCLUSION: Nateglinide stimulates GH release by inhibition of plasma membrane K(+) channels, elevation of cytoplasmic cAMP levels and stimulation of Ca(2+)-dependent exocytosis. By contrast, the effect of repaglinide was confined to inhibition of the K(ATP) channels.
Assuntos
Cicloexanos/farmacologia , Hormônio do Crescimento/metabolismo , Hipoglicemiantes/farmacologia , Fenilalanina/análogos & derivados , Fenilalanina/farmacologia , Hipófise/efeitos dos fármacos , Bloqueadores dos Canais de Potássio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio , Animais , Cálcio/farmacologia , Carbamatos/farmacologia , AMP Cíclico/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Canais de Potássio de Retificação Tardia , Exocitose/efeitos dos fármacos , Hormônio Liberador de Hormônio do Crescimento/farmacologia , Masculino , Potenciais da Membrana/efeitos dos fármacos , Nateglinida , Técnicas de Patch-Clamp , Piperidinas/farmacologia , Hipófise/citologia , Hipófise/metabolismo , Potássio/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Although there is increasing evidence for microglial activation after an ischaemic stroke in the infarct core and the peri-infarct region, the "evolution" of the process in stroke patients is poorly known. Using PET and [((11))C]vinpocetine, we measured the regional changes of TSPO in the brain of nine ischaemic stroke patients up to 14weeks after the insult. Already a week after stroke there was an increased radioligand uptake, indicating the up-regulation of TSPO and the presence of activated microglia, in both the ischaemic core and the peri-infarct zone. This increased activation showed a steady decrease with post stroke time. The proportion between %SUV values in the peri-infarct zone and the ischaemic core increased with time. There were no time-dependent TSPO activity changes in other regions, not affected directly by the stroke. The present observations demonstrate that increased regional microglia activation, as a consequence of stroke, can be visualised with PET, using the TSPO molecular imaging biomarker [((11))C]vinpocetine. The evolution of this microglial activation shows a time dependent decrease the gradient of which is different between the peri-infarct zone and the ischaemic core. The findings indicate an increased microglial activation in the peri-stroke region for several weeks after the insult.
Assuntos
Isquemia Encefálica/metabolismo , Neuroimagem Funcional/métodos , Infarto/metabolismo , Microglia/metabolismo , Receptores de GABA/metabolismo , Acidente Vascular Cerebral/metabolismo , Alcaloides de Vinca , Adulto , Idoso , Biomarcadores/metabolismo , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Radioisótopos de Carbono , Neuroimagem Funcional/estatística & dados numéricos , Humanos , Infarto/complicações , Infarto/diagnóstico por imagem , Infarto/patologia , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Microglia/diagnóstico por imagem , Pessoa de Meia-Idade , Imagem Molecular/métodos , Imagem Molecular/estatística & dados numéricos , Tamanho do Órgão , Tomografia por Emissão de Pósitrons/métodos , Tomografia por Emissão de Pósitrons/estatística & dados numéricos , Ensaio Radioligante/métodos , Ensaio Radioligante/estatística & dados numéricos , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/patologia , Fatores de Tempo , Regulação para CimaRESUMO
Metabolic and neuro-receptor abnormalities within the extrafocal limbic circuits are established in mesial temporal lobe epilepsy (MTLE). However, very little is known about how these circuits process external stimuli. We tested whether odor activation can help delineate limbic functional disintegration in MTLE, and measured cerebral blood flow with PET during birhinal smelling of familiar and unfamiliar odors, using smelling of odorless air as the baseline condition. Patients with MTLE (13 left-sided, 10 right-sided) and 21 controls were investigated. In addition to odor activation, the analysis included functional connectivity, using right and left piriform cortex as seed regions. Healthy controls activated the amygdala, piriform, anterior insular, and cingulate cortices on both sides. Smelling of familiar odors engaged, in addition, the right parahippocampus, and the left Brodmann Area (BA) 44, 45, 47. Patients failed to activate the amygdala, piriform and the anterior insular cortex in the epileptogenic hemisphere. Furthermore, those with left MTLE did not activate the left BA 44, 45 and 47 with familiar odors, which they perceived as less familiar than controls. Congruent with the activation data each seed region was in patients functionally disconnected with the contralateral amygdala+piriform+insular cortex. The functional disintegration in patients exceeded the reduced activation, and included the contralateral temporal neocortex, and in subjects with right MTLE also the right orbitofrontal cortex. Imaging of odor perception may be used to delineate functional disintegration of the limbic networks in MTLE. It shows an altered response in several regions, which may underlie some interictal behavioral problems associated with this condition.
Assuntos
Epilepsia do Lobo Temporal/patologia , Epilepsia do Lobo Temporal/fisiopatologia , Sistema Límbico/patologia , Sistema Límbico/fisiopatologia , Odorantes , Condutos Olfatórios/patologia , Condutos Olfatórios/fisiopatologia , Olfato/fisiologia , Adulto , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Eletroencefalografia , Feminino , Lateralidade Funcional/fisiologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Psicofísica , Mecânica Respiratória/fisiologiaRESUMO
The progesterone derivative 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are candidate compounds for human pheromones. In previous positron emission tomography studies, we found that smelling AND and EST activated regions primarily incorporating the sexually dimorphic nuclei of the anterior hypothalamus, that this activation was differentiated with respect to sex and compound, and that homosexual men processed AND congruently with heterosexual women rather than heterosexual men. These observations indicate involvement of the anterior hypothalamus in physiological processes related to sexual orientation in humans. We expand the information on this issue in the present study by performing identical positron emission tomography experiments on 12 lesbian women. In contrast to heterosexual women, lesbian women processed AND stimuli by the olfactory networks and not the anterior hypothalamus. Furthermore, when smelling EST, they partly shared activation of the anterior hypothalamus with heterosexual men. These data support our previous results about differentiated processing of pheromone-like stimuli in humans and further strengthen the notion of a coupling between hypothalamic neuronal circuits and sexual preferences.
Assuntos
Androstadienos/metabolismo , Encéfalo/anatomia & histologia , Estrenos/metabolismo , Homossexualidade Feminina , Feromônios/metabolismo , Adulto , Encéfalo/patologia , Feminino , Humanos , Masculino , Modelos Neurológicos , Tomografia por Emissão de Pósitrons , Fatores Sexuais , OlfatoRESUMO
The testosterone derivative 4,16-androstadien-3-one (AND) and the estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) are candidate compounds for human pheromones. AND is detected primarily in male sweat, whereas EST has been found in female urine. In a previous positron emission tomography study, we found that smelling AND and EST activated regions covering sexually dimorphic nuclei of the anterior hypothalamus, and that this activation was differentiated with respect to sex and compound. In the present study, the pattern of activation induced by AND and EST was compared among homosexual men, heterosexual men, and heterosexual women. In contrast to heterosexual men, and in congruence with heterosexual women, homosexual men displayed hypothalamic activation in response to AND. Maximal activation was observed in the medial preoptic area/anterior hypothalamus, which, according to animal studies, is highly involved in sexual behavior. As opposed to putative pheromones, common odors were processed similarly in all three groups of subjects and engaged only the olfactory brain (amygdala, piriform, orbitofrontal, and insular cortex). These findings show that our brain reacts differently to the two putative pheromones compared with common odors, and suggest a link between sexual orientation and hypothalamic neuronal processes.