Graves’ disease: Introduction, epidemiology, endogenous and environmental pathogenic factors

Graves’ disease is the most frequent cause of hyperthyroidism. Many questions remain about the choice of diagnostic evaluations and treatment strategy according to clinical context (age, gender, pregnancy, etc.) and about the best management of the main extrathyroidal complication that is Graves orbitopathy. The exact pathogenic mechanisms are not fully clear. They associate genetic factors, interactions between endogenous and environmental factors, and immune system dysregulation. Graves’ orbitopathy is one of the consequences of this partial understanding. Iatrogenic Graves’ disease induced by the new targeted therapies are described and could help to better understand the molecular pathways involved in the disease and to develop new therapeutic approaches

Trim17, novel E3 ubiquitin-ligase, initiates neuronal apoptosis

Accumulating data indicate that the ubiquitin-proteasome system controls apoptosis by regulating the level and the function of key regulatory proteins. In this study, we identified Trim17, a member of the TRIM/RBCC protein family, as one of the critical E3 ubiquitin ligases involved in the control of neuronal apoptosis upstream of mitochondria. We show that expression of Trim17 is increased both at the mRNA and protein level in several in vitro models of transcription-dependent neuronal apoptosis. Expression of Trim17 is controlled by the PI3K/Akt/GSK3 pathway in cerebellar granule neurons (CGN). Moreover, the Trim17 protein is expressed in vivo, in apoptotic neurons that naturally die during post-natal cerebellar development. Overexpression of active Trim17 in primary CGN was sufficient to induce the intrinsic pathway of apoptosis in survival conditions. This pro-apoptotic effect was abolished in Bax(-/-) neurons and depended on the E3 activity of Trim17 conferred by its RING domain. Furthermore, knock-down of endogenous Trim17 and overexpression of dominant-negative mutants of Trim17 blocked trophic factor withdrawal-induced apoptosis both in CGN and in sympathetic neurons. Collectively, our data are the first to assign a cellular function to Trim17 by showing that its E3 activity is both necessary and sufficient for the initiation of neuronal apoptosis. Cell Death and Differentiation (2010) 17, 1928-1941; doi: 10.1038/cdd.2010.73; published online 18 June 201

Algoritmos de Detecçao de Taquicardias Incorporado a Desfibriladores Automáticos Implantáveis. 1) Desfibriladores Monocamerais

Diversos algoritmos foram incorporados aos cardioversores-desfibriladores automáticos implantáveis (CDIs) para identificar os distúrbios do ritmo ventricular e, sobretudo, para os diferenciar de taquicardias supraventriculares que nao necessitam terapia. Esses benefícios também sao encontrados nos CDIs bicamerais que têm como benefício a detecçao atrial acoplada à detecçao do ventrículo. O objetivo dos algoritmos é de identificar todas as arritmias ventriculares (sensibilidade de 100%), para que sejam tratadas corretamente. Devem ainda evitar erros de identificaçao de arritmias supraventriculares (especificidade máxima). Infelizmente, nao é possível alcançar 100% de sensibilidade e especificidade. Além disso, todo aumento da especificidade será acompanhado por uma diminuiçao da sensibilidade. Essa diminuiçao de especificidade pode conduzir a falha na detecçao dos distúrbios do ritmo ventricular, e como conseqüência, isto é pior que o tratamento inadequado de uma taquicardia sinusal ou supraventricular

Algoritmos de Detecçao de Taquicardias Incorporado a Desfibriladores Automáticos Implantáveis. 1) Desfibriladores Monocamerais

Diversos algoritmos foram incorporados aos cardioversores-desfibriladores automáticos implantáveis (CDIs) para identificar os distúrbios do ritmo ventricular e, sobretudo, para os diferenciar de taquicardias supraventriculares que nao necessitam terapia. Esses benefícios também sao encontrados nos CDIs bicamerais que têm como benefício a detecçao atrial acoplada à detecçao do ventrículo. O objetivo dos algoritmos é de identificar todas as arritmias ventriculares (sensibilidade de 100%), para que sejam tratadas corretamente. Devem ainda evitar erros de identificaçao de arritmias supraventriculares (especificidade máxima). Infelizmente, nao é possível alcançar 100% de sensibilidade e especificidade. Além disso, todo aumento da especificidade será acompanhado por uma diminuiçao da sensibilidade. Essa diminuiçao de especificidade pode conduzir a falha na detecçao dos distúrbios do ritmo ventricular, e como conseqüência, isto é pior que o tratamento inadequado de uma taquicardia sinusal ou supraventricular

Fractionated Stereotactic Radiation Therapy for Pituitary Adenomas: An alternative escalating protocol of hypofractionated stereotactic radiotherapy delivering 35Gy in 5 fractions

PURPOSE: Evaluate efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) for patients treated for pituitary adenoma (PA) with an alternative HSRT escalating protocol delivering 35Gy in 5 fractions. MATERIAL AND METHODS: From June 2007 to March 2017, 29 patients with pituitary adenoma were treated in Antoine Lacassagne Cancer Centre with an alternative HSRT protocol. Prescribed dose was 35Gy in 5 fractions of 7Gy. Radiographic responses were assessed by annual MRI. Hormone blood samples were evaluated each year after HSRT. RESULTS: A total of 29 patients aged between 23 and 86 years (median 54 years) were included. Twelve patients received HSRT for recurrent cases and 12 received postoperative adjuvant HSRT, 5 patients did not have surgery. After a median follow-up period of 47 months local control rate was 96%. One patient presented an out-field tumor regrowth 73 months after HSRT. The majority of PA were endocrine-active (18 patients, 62%). After HSRT, 8 patients (44%) presented complete response on initial secretion, 4 patients (23%) presented partial response on initial secretion. Four patients (14%) presented grade 2 or more acute radiation toxicities. One grade 4 visual disorder was observed for one patient. CONCLUSIONS: HSRT delivering 35Gy in 5 fractions represents a feasible treatment and shows promising results to reduce hormonal overproduction and to improve local control in PA

Implantable cardioverter defibrillator therapy for primary prevention of sudden cardiac death in the real world: Main findings from the French multicentre DAI-PP programme (pilot phase)

This review summarizes the main findings of the French multicentre DAI-PP pilot programme, and discusses the related clinical and research perspectives. This project included retrospectively (2002–2012 period) more than 5000 subjects with structural heart disease who received an implantable cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death, and were followed for a mean period of 3 years. The pilot phase of the DAI-PP programme has provided valuable information on several practical and clinically relevant aspects of primary prevention ICD implantation in the real-world population, which are summarized in this review. This pilot has led to a prospective evaluation that started in May 2018, assessing ICD therapy in primary and secondary prevention in patients with structural and electrical heart diseases, with remote monitoring follow-up using a dedicated platform. This should further enhance our understanding of sudden cardiac death, to eventually optimize the field of preventative actions

Botulinum toxin in gastric submucosa reduces stimulated HCl production in rats

BACKGROUND: Botulinum toxin blocks acetylcholine release from nerve endings and acts as a long term, reversible inhibitor of muscle contraction as well as of salivary, sweat gland, adrenal and prostatic secretions. The aim of the present study is to investigate whether gastric submucosal injection of botulinum toxin type A reduces stimulated gastric production of HCl. METHODS: Sixty-four rats were randomized in two groups and laparotomized. One group was treated with botulinum toxin-A 10 U by multiple submucosal gastric injections, while the second group was injected with saline. Two weeks later, acid secretion was stimulated by pyloric ligation and acid output was measured. Body weight, food and water intake were also recorded daily. RESULTS: HCl production after pyloric ligation was found to be significantly lower in botulinum toxin-treated rats (657 ± 90.25 micromol HCl vs. 1247 ± 152. P = 0.0017). Botulinum toxin-treated rats also showed significantly lower food intake and weight gain. CONCLUSIONS: Botulinum toxin type A reduces stimulated gastric acidity. This is likely due either to inhibition of the cholinergic stimulation of gastric parietal cells, or to an action on the myenteric nervous plexuses. Reduction of growth and food intake may reflect both impaired digestion and decreased gastric motility

Regulation of Postsynaptic Function by the Dementia-Related ESCRT-III Subunit CHMP2B

The charged multivesicular body proteins (Chmp1–7) are an evolutionarily conserved family of cytosolic proteins that transiently assembles into helical polymers that change the curvature of cellular membrane domains. Mutations in human CHMP2B cause frontotemporal dementia, suggesting that this protein may normally control some neuron-specific process. Here, we examined the function, localization, and interactions of neuronal Chmp2b. The protein was highly expressed in mouse brain and could be readily detected in neuronal dendrites and spines. Depletion of endogenous Chmp2b reduced dendritic branching of cultured hippocampal neurons, decreased excitatory synapse density in vitro and in vivo, and abolished activity-induced spine enlargement and synaptic potentiation. To understand the synaptic effects of Chmp2b, we determined its ultrastructural distribution by quantitative immuno-electron microscopy and its biochemical interactions by coimmunoprecipitation and mass spectrometry. In the hippocampus in situ, a subset of neuronal Chmp2b was shown to concentrate beneath the perisynaptic membrane of dendritic spines. In synaptoneurosome lysates, Chmp2b was stably bound to a large complex containing other members of the Chmp family, as well as postsynaptic scaffolds. The supramolecular Chmp assembly detected here corresponds to a stable form of the endosomal sorting complex required for transport-III (ESCRT-III), a ubiquitous cytoplasmic protein complex known to play a central role in remodeling of lipid membranes. We conclude that Chmp2b-containing ESCRT-III complexes are also present at dendritic spines, where they regulate synaptic plasticity. We propose that synaptic ESCRT-III filaments may function as a novel element of the submembrane cytoskeleton of spines