Separating the contribution of glucocorticoids and wakefulness to the molecular and electrophysiological correlates of sleep homeostasis.

Study Objectives: The sleep-deprivation-induced changes in delta power, an electroencephalographical correlate of sleep need, and brain transcriptome profiles have importantly contributed to current hypotheses on sleep function. Because sleep deprivation also induces stress, we here determined the contribution of the corticosterone component of the stress response to the electrophysiological and molecular markers of sleep need in mice. Design: N/A Settings: Mouse sleep facility. Participants: C57BL/6J, AKR/J, DBA/2J mice. Interventions: Sleep deprivation, adrenalectomy (ADX). Measurements and Results: Sleep deprivation elevated corticosterone levels in 3 inbred strains, but this increase was larger in DBA/2J mice; i.e., the strain for which the rebound in delta power after sleep deprivation failed to reach significance. Elimination of the sleep-deprivation-associated corticosterone surge through ADX in DBA/2J mice did not, however, rescue the delta power rebound but did greatly reduce the number of transcripts affected by sleep deprivation. Genes no longer affected by sleep deprivation cover pathways previously implicated in sleep homeostasis, such as lipid, cholesterol (e.g., Ldlr, Hmgcs1, Dhcr7, -24, Fkbp5), energy and carbohydrate metabolism (e.g., Eno3, G6pc3, Mpdu1, Ugdh, Man1b1), protein biosynthesis (e.g., Sgk1, Alad, Fads3, Eif2c2, -3, Mat2a), and some circadian genes (Per1, -3), whereas others, such as Homer1a, remained unchanged. Moreover, several microRNAs were affected both by sleep deprivation and ADX. Conclusions: Our findings indicate that corticosterone contributes to the sleep-deprivation-induced changes in brain transcriptome that have been attributed to wakefulness per se. The study identified 78 transcripts that respond to sleep loss independent of corticosterone and time of day, among which genes involved in neuroprotection prominently feature, pointing to a molecular pathway directly relevant for sleep function.

Beta-adrenoceptor stimulation increases neuropeptide Y release from sympathetic nerves in intact rats.

This study was undertaken to assess in conscious normotensive rats the effects of beta-adrenoceptor stimulation on plasma neuropeptide Y (NPY) levels. Wistar rats were subjected to adrenal demedullation on the right side and were either adrenalectomized or sham-operated on the left side. Eleven days later, the conscious rats were infused i.v. for 30 min with either isoproterenol (10 ng/min) or its vehicle. Plasma NPY levels were significantly lower (23.8 +/- 2.6 pM, means +/- S.E.M., n = 12, P < 0.01) in vehicle-treated medullectomized rats than in corresponding sham-operated controls (36.7 +/- 4.1 pM, n = 12). The medullectomized rats infused with isoproterenol showed plasma NPY levels (36.7 +/- 3.3 pM, n = 11) comparable to those of sham-operated rats having received the vehicle. These data therefore demonstrate that plasma NPY levels are lower in rats without adrenal medulla and that in these animals isoproterenol increases NPY release, most likely by activating pre-synaptic beta-adrenoceptors.

Hyperaldostéronisme primaire sur adénome ou hyperplasie de la surrénale: opérer ou non [Primary hyperaldosteronism with adrenal adenoma or hyperplasia: surgical case or not?].

Primary hyperaldosteronism is one of the most frequent causes of secondary hypertension. Cardiovascular morbimortality is higher than in essential hypertonic and justifies diagnostic and specific treatment of this pathology. Therapeutic choice depends of health and desire of the patient. It is either medical with mineralocorticoid receptor antagonists, or surgical through adrenalectomy. In this case, a pre-surgery exam including a radiologic examination and a venous adrenal catheterism has to be done. Surgery allows a normalisation of kaliema and a blood pressure decrease in 50 to 88% of the patients. Beyond them, 30% are able to stop entirely their medication. Both therapeutic choices decrease cardiovascular risks equally if blood pressure is controlled.

Primärer Hyperaldosteronismus bei Katzen [Primary hyperaldosteronism in cats].

Primary hyperaldosteronism is a clinical syndrome characterized by an elevated aldosterone secretion by the adrenals. The present case series describes 7 cats with primary hyperaldosteronism, which were presented between 2002 and 2011. Common clinical symptoms were weakness, anorexia, cervical ventroflexion and blindness. All cats showed hypokalemia. In 6 cats, blood pressure was determined: 5 cats showed hypertension, of which 4 animals exhibited retinal detachment and blindness. In the ultrasonographic examination, unilateral adrenomegaly was present in 6 cats whereas one animal showed normal adrenals. In 4 cats, the serum aldosterone concentration was above the reference range. Five cats underwent unilateral adrenalectomy, which was accomplished uneventfully and returned the electrolytes back to normal. Histopathological examination of the adrenals revealed 2 carcinomas and 4 adenomas; one cat with ultrasonographic normal adrenals exhibited bilateral nodular hyperplasia.

Cystic lymphangioma of the adrenal gland: report of a case and review of the literature.

BACKGROUND: Cystic lymphangioma is a rare tumor of the lymphatic vessels that occurs more frequently in women. Location of this pathology can be diverse but most commonly occurs in the neck or axilla. Cystic lymphangioma originating from the adrenal tissue represents a very rare entity. CASE PRESENTATION: We report here the case of a 38-year-old woman who was diagnosed with a cystic retroperitoneal mass. After further investigations, the patient was suspected to have a left adrenal cystic lymphangioma. She underwent successful open left adrenalectomy as curative treatment, and the diagnosis of cystic lymphangioma of the left adrenal gland was confirmed at histology. The postoperative course was uneventful. CONCLUSION: This case report and review of the literature bring new insights into the diagnostic difficulty and management of cystic lymphangioma of the adrenal gland.

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule.

Aldosterone and corticosterone bind to mineralocorticoid (MR) and glucocorticoid receptors (GR), which, upon ligand binding, are thought to translocate to the cell nucleus to act as transcription factors. Mineralocorticoid selectivity is achieved by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that inactivates 11β-hydroxy glucocorticoids. High expression levels of 11β-HSD2 characterize the aldosterone-sensitive distal nephron (ASDN), which comprises the segment-specific cells of late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). We used MR- and GR-specific antibodies to study localization and regulation of MR and GR in kidneys of rats with altered plasma aldosterone and corticosterone levels. In control rats, MR and GR were found in cell nuclei of thick ascending limb (TAL), DCT, CNT, CD cells, and intercalated cells (IC). GR was also abundant in cell nuclei and the subapical compartment of proximal tubule (PT) cells. Dietary NaCl loading, which lowers plasma aldosterone, caused a selective removal of GR from cell nuclei of 11β-HSD2-positive ASDN. The nuclear localization of MR was unaffected. Adrenalectomy (ADX) resulted in removal of MR and GR from the cell nuclei of all epithelial cells. Aldosterone replacement rapidly relocated the receptors in the cell nuclei. In ASDN cells, low-dose corticosterone replacement caused nuclear localization of MR, but not of GR. The GR was redistributed to the nucleus only in PT, TAL, early DCT, and IC that express no or very little 11β-HSD2. In ASDN cells, nuclear GR localization was only achieved when corticosterone was replaced at high doses. Thus ligand-induced nuclear translocation of MR and GR are part of MR and GR regulation in the kidney and show remarkable segment- and cell type-specific characteristics. Differential regulation of MR and GR may alter the level of heterodimerization of the receptors and hence may contribute to the complexity of corticosteroid effects on ASDN function.

Síndrome de conn causada por adenoma de adrenal-tratamento por videolaparoscopia

The authors present a case-report a 43 years old, female patient presenting with an eight-year history of hypertension caused by an adrenal adenoma. Hypokalemia and supressed plasma renina confirmed the diagnosis of primary hyperaldosteronism. An abdominal computed tomography revealed a right adrenal mass. The patient was successfully treated laparoscopically. The histopathological diagnosis was adenoma. The patient had normal blood pressure within three months.

Hiperplasia endotelial papilífera de supra-renal: relato de caso

Intravascular papillary endothelial hyperplasia is a benign and rare intravascular process thought to arise from an organizing thrombus. Involvement of the adrenal gland is extremely rare, with only one case reported in the literature. We report a case of this vascular lesion in the adrenal gland, treated with laparoscopic adrenalectomy.

Hiperaldosteronismo primário: relato de dois casos

The authors present two cases of Primary Hiperaldosteronism, caused by functioning adenoma of the adrenal's cortex. The two females patients presented classic symptoms of the Conn's disease, especially hypocalemia and hypertension. Both were operated and unilateral adrenalectomy was done, with excelent outcome in one and satisfactory in the other one. It is discussed many aspects related to the incidence, the problems with the diagnosis, indication and surgery treatment.

Adrenal incidentaloma

Incidentally discovered adrenal masses, or adrenal incidentalomas, have become a common clinical problem owing to wide application of radiologic imaging techniques. This definition encompasses a heterogeneous spectrum of pathologic entities, including primary adrenocortical and medullary tumors, benign or malignant lesions, hormonally active or inactive lesions, metastases, and infections. Once an adrenal mass is detected, the clinician needs to address two crucial questions: is the mass malignant, and is it hormonally active? This article provides an overview of the diagnostic clinical approach and management of the adrenal incidentaloma. Mass size is the most reliable variable to distinguish benign and malignant adrenal masses. Adrenalectomy should be recommended for masses greater than 4.0 cm because of the increased risk of malignancy. Adrenal scintigraphy has proved useful in discriminating between benign and malignant lesions. Finally, fine-needle aspiration biopsy is an important tool in the evaluation of oncological patients and it may be useful in establishing the presence of metastatic disease. The majority of adrenal incidentalomas are non-hypersecretory cortical adenomas but an endocrine evaluation can lead to the identification of a significant number of cases with subclinical Cushing's syndrome (5-15%), pheochromocytoma (1.5-13%) and aldosteronoma (0-7%). The first step of hormonal screening should include an overnight low dose dexamethasone suppression test, the measure of urinary catecholamines or metanephrines, serum potassium and, in hypertensive patients, upright plasma aldosterone/plasma renin activity ratio. Dehydroepiandrosterone sulfate measurement may show evidence of adrenal androgen excess.

Role of endogenous glucocorticoids in hyperalgesia and edema in old arthritic rats

We compared the intensity and frequency of arthritis in old (8-12 months, N = 12) and juvenile (2 months, N = 10) rats and determined the role played by adrenal glands in this disorder. Arthritis was induced by subcutaneous injection of Mycobacterium butyricum at the base of the tail of female Holtzman rats at day zero. Paw edema and hyperalgesia were monitored from day zero to day 21 after induction as signs of arthritis development. Some (N = 11) old animals were adrenalectomized bilaterally and treated with dexamethasone or celecoxib immediately following surgery. All bilaterally adrenalectomized old animals became susceptible to arthritis and the onset of disease was shortened from the 10th to the 5th day. Hyperalgesia and paw edema responses were less frequent in older animals (50 and 25% compared to control juvenile rats, respectively), although old responder animals showed responses of similar intensity to those of their juvenile counterparts: by the 14th day the data for hyperalgesia were juvenile = 0.8 ± 0.07/old = 0.8 ± 0.09, and for paw edema juvenile = 56.6 ± 6.04/old = 32.24 ± 12.7, reported as delta% increase in paw edema. Chronic treatment of adrenalectomized old animals with dexamethasone (0.01 or 0.1 mg/kg) but not celecoxib (3 mg/kg), once daily for 21 days by gavage, abolished the effects of adrenalectomy, in particular those related to the hyperalgesia response (old = 0.95 ± 0.03/dexamethasone = 0 ± 0; 14th day), thus suggesting a specific participation of circulating corticosteroids in the modulation of pain in old arthritic rats.

Pre-B-cell transcription factor 1 and steroidogenic factor 1 synergistically regulate adrenocortical growth and steroidogenesis

variety of transcription factors including Wilms tumor gene (Wt-1), steroidogenic factor 1 (Sf-1), dosage-sensitive sex reversal, adrenal hypoplasia congenita on the X-chromosome, Gene 1 (Dax-1), and pre-B-cell transcription factor 1 (Pbx1) have been defined as necessary for regular adrenocortical development. However, the role of Pbx1 for adrenal growth and function in the adult organism together with the molecular relationship between Pbx1 and these other transcription factors have not been characterized. We demonstrate that Pbx haploinsufficiency (Pbx1(+/-)) in mice is accompanied by a significant lower adrenal weight in adult animals compared with wild-type controls. Accordingly, baseline proliferating cell nuclear antigen levels are lower in Pbx1(+/-) mice, and unilateral adrenalectomy results in impaired contralateral compensatory adrenal growth, indicating a lower proliferative potential in the context of Pbx1 haploinsufficiency. In accordance with the key role of IGFs in adrenocortical proliferation and development, real-time RT-PCR demonstrates significant lower expression levels of the IGF-I receptor, and up-regulation of IGF binding protein-2. Functionally, Pbx1(+/-) mice display a blunted corticosterone response after ACTH stimulation coincident with lower adrenal expression of the ACTH receptor (melanocortin 2 receptor, Mc2-r). Mechanistically, in vitro studies reveal that Pbx1 and Sf-1 synergistically stimulates Mc2-r promoter activity. Moreover, Sf-1 directly activates the Pbx1 promoter activity in vitro and in vivo. Taken together, these studies provide evidence for a role of Pbx1 in the maintenance of a functional adrenal cortex mediated by synergistic actions of Pbx1 and Sf-1 in the transcriptional regulation of the critical effector of adrenocortical differentiation, the ACTH receptor.

Effect of heat stress or lipopolysaccharide (E-coli) injection on HSP70 levels in the liver and brain of adrenalectomized rats

Hsp70 content (ng Hsp70 mu g total protein(-1)) in the liver and brain of control and adrenalectomized male rats was investigated by Western Blotting after heat stress (40 degrees C) or endotoxin-induced fever (E. coli lipopolysaccharide injection). The increase in rectal temperature was higher after heat stress than after LPS injection, Heat stress affected Hsp70 content of the liver, but not of the brain; however adrenalectomy did not influence any parameter. These results suggest that, under these circumstances, there is no relationship between the hypothalamic-pituitary-adrenal axis and Hsp70 synthesis in liver and brain. (C) 2000 Elsevier B.V. Ltd. All rights reserved.

The sympathetic adrenomedullary system, but not the hypothalamic-pituitary-adrenal axis, participates in aorta adaptive response to stress: nitric oxide involvement

Stress induced a decrease in the reactivity of the aorta to noradrenaline (NA), as a consequence of an endothelial nitric oxide (NO) system hyperactivity. The main characteristic of the stress response is activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SA) system. The participation of the HPA axis and SA system in the decreased reactivity to NA in the aorta of rats exposed to 4-h immobilization was investigated. Concentration-response relationships for NA were obtained in the aorta, with and without endothelium, isolated from normal and stressed rats, following these procedures: (1) in the absence and presence of L-NAME; (2) after adrenalectomy (ADX) or not, in the absence or presence of L-NAME; (3) ADX rats treated or not with corticosterone; (4) ADX associated with stress; and (5) treated or not with reserpine. The reactivity of aorta without endothelium was unaffected by the procedures. The reactivity of aorta with endothelium was decreased by either stress or ADX. This effect was reversed by both L-NAME and corticosterone. ADX did not potentiate the decrease in the aorta reactivity induced by stress. Reserpine did not change the reactivity of aorta with endothelium from normal rats, but prevented the decrease in reactivity induced by stress. It is concluded that the HPA axis participates in endothelium-dependent modulation of aorta reactivity in normal conditions and that thr SA system participates in hyperactivity of the endothelial NO-system induced by stress, which is responsible for the decreased aorta reactivity to NA. (C) 2000 Elsevier B.V. B.V. All rights reserved.

Molecular analysis of the Von Hippel-Lindau (VHL) gene in a family with non-syndromic pheochromocytoma: the importance of genetic testing

Dois pacientes índices da família analisada neste estudo foram submetidos a adrenalectomia bilateral devido a feocromocitoma. Foi, então, realizado o estudo genético dos pacientes e de sete parentes de primeiro grau. Os dois pacientes com feocromocitoma e dois outros membros assintomáticos da família apresentaram a mutação c496G>T no exon 3 do gene VHL. A família perdeu seguimento médico. Três anos após a realização da avaliação genética, a irmã dos pacientes, portadora da mutação, foi encaminhada para o nosso serviço após uma gestação complicada por pré-eclampsia. Ela referia paroxismos sugestivos de feocromocitoma, mas as metanefrinas urinárias eram negativas. Entretanto, a tomografia computadorizada de abdômen evidenciou uma massa adrenal que também se contrastou na cintilografia com metaiodobenzilguanidina (MIBG). Esse estudo mostra que a análise molecular do paciente índice pode levar à identificação de parentes assintomáticos portadores da mutação. Além disso, mesmo com as metanefrinas urinárias negativas, a identificação de uma mutação específica levou a um aumento da suspeita e detecção de feocromocitoma na irmã dos afetados pela doença.