Introdução: O acesso pterional é uma das craniotomias mais utilizadas. Entretanto, apresenta algumas desvantagens, como a dissecação ampla do músculo temporal, que pode causar atrofia e deformidade do contorno facial. A craniotomia minipterional descrita em 2007 propiciou exposição anatômica semelhante a da craniotomia pterional clássica. Objetivos: Comparar os resultados clínicos, funcionais e estéticos dos dois acessos cirúrgicos destinados ao tratamento de aneurismas da circulação anterior. Métodos: Cinquenta e oito doentes, com aneurismas rotos (40) e não rotos (18) foram admitidos no estudo. No grupo A, 28 indivíduos foram submetidos à craniotomia minipterional. No grupo B, 30 doentes foram operados com a craniotomia pterional clássica. Doentes com hematomas intracranianos, aneurismas do segmento oftálmico e aneurismas gigantes foram excluídos. Os resultados estéticos foram analisados por meio de dois métodos. No primeiro, uma autoavaliação utilizava uma régua escalonada de 0 a 100, na qual o zero representou o melhor resultado e 100 o pior resultado na percepção do próprio doente. Fotografias dos doentes foram mostradas a dois observadores independentes. Os resultados foram classificados como ótimo, bom, regular e mau (de acordo com uma escala pré-determinada). A gradação da atrofia foi mensurada por meio de três métodos, utilizando a tomografia computadorizada de crânio. No primeiro, observou-se a percentagem de redução do complexo músculo temporal, tecido subcutâneo e pele. No segundo método, a percentagem de redução da espessura do músculo temporal foi analisada isoladamente. O terceiro método foi a mensuração da volumetria do músculo temporal, tecido subcutâneo e pele calculados a partir da margem superior do arco zigomático até a linha temporal superior utilizando-se o software OsiriX (Pixmeo Sarl Geneva/ Suíça OsiriX). Para os resultados clínicos e funcionais, foi utilizada a Escala de Rankin modificada. Outras variáveis, como paralisia do ramo frontal do nervo facial, hemorragia pós-operatória, fistula liquórica, hidrocefalia e mortalidade, também foram analisadas. Resultados: Em ambos os grupos, os dados demográficos e as características pré-operatórias foram similares. A satisfação com o resultado estético foi observada em 79% (19) no grupo A e 52% (13) no grupo B (p=0,07). O valor médio da régua foi 27 no grupo A e 45,8 no grupo B (p=0,03). Quando somente doentes classificados como Rankin modificado 0 ou 1 foram analisados, o valor médio da régua foi de 25,2 no grupo A e 39,4 no grupo B (p=0,11). Dois avaliadores independentes analisaram as fotografias dos doentes e o coeficiente de correlação kappa para os resultados estéticos foi de 0,73. De acordo com os mesmos ótimo e bom, foram observados em 87% (21) no grupo minipterional e 48% (12) no grupo pterional. A percentagem de redução do músculo temporal, subcutâneo e pele (método 1) foi de 14,9% no grupo A e 24,3% no grupo B (p=0,01). Quando somente o músculo temporal foi analisado (método 2), a percentagem de redução foi de 12,7% no grupo A e 22% no grupo B (p=0,005). A redução volumétrica das estruturas (método 3) foi de 14,8% no grupo A e 24,5% no grupo B (p=0,012). Na avaliação clínica no 6? mês, os valores da Escala de Rankin modificada foram similares (p=0,99). O óbito ocorreu em 4 doentes no grupo A e 5 doentes no grupo B (p=1,0). Conclusão: Os resultados clínicos demonstraram que a craniotomia minipterional é um procedimento seguro, com prognóstico similar ao da técnica convencional. Os resultados cosméticos foram melhores com menor deformidade no contorno facial, uma vez que a percentagem de redução da espessura, do volume do músculo temporal, do tecido subcutâneo e da pele foi menor com a técnica proposta. A craniotomia minipterional foi a melhor alternativa em relação à craniotomia pterional clássica para tratar aneurismas rotos e não rotos da circulação anterior / Introduction: The pterional approach is one of the most commonly used craniotomy. However it has disadvantages, such as complete dissection of the temporalis muscle. This may lead to muscular atrophy and facial deformity. The minipterional craniotomy was described in 2007 and the anatomic exposure provided by the pterional and minipterional approaches were similar in the total area of exposure and angular view. Objectives: This prospective randomized study was designed to compare the clinical, functional and aesthetic results of two surgical techniques for microsurgical clipping of anterior circulation aneurysms. Methods: Overall, 58 eligible patients admitted with ruptured and unruptured anterior circulation aneurysms were enrolled in the study. In group A, 28 patients were operated with the minipterional technique. In Group B 30 patients were operated according to the classical pterional craniotomy. Patients with intracranial haematomas, ophthalmic aneurysms and giant aneurysms were excluded. The aesthetic results were analyzed with 2 methods. In the first, the patients were showed to a rule, with a scale from 0 to 100, in which 0 mean the best result and 100 the worst result. Photos were taken and showed to two independent observers, the results were classified as excellent, good, regular or poor, according to a pre-determined scale. The degree of atrophy was measured with three methods. In the first one, the authors observed the percentage of thick reduction in the temporal muscle, subcutaneous tissue and skin. In the second method the percentage of thick reduction of the isolated temporal muscle was observed and the third the volumetric analysis of the temporal muscle, subcutaneous tissue and skin was calculated from the superior edge of zygomatic arch to superior temporal line using the OsiriX software (OsiriX - Pixmeo Sarl Geneva/Suíça). The functional results were compared using the Modified Rankin Score. Others variables such frontal facial palsy, post-operative hemorrhage, cerebrospinal fistulas, hydrocephalus and mortality were also analyzed. Results: In both groups the demographic and pre-operative characteristics were similar. The satisfaction with aesthetic results were observed in 79% (19) in group A and 52% (13) in group B (p=0,07). The mean value observed in the rule was 27 in group A and 45,8 in group B (p=0,03). When patients classified as Rankin Modified Score of 0 or 1 only were included the mean value observed in the rule was 25,2 in group A and 39,4 in group B (p=0,11). Two independent observers analyzed the patients photos and the kappa coefficient correlation for the aesthetic results was 0,73. According to them excellent and good results were observed in 87% (21) in minipterional group and 48% (12) in the pterional group. The degree of atrophy of temporal muscle, subcutaneous tissue and skin (method 1) was14,9% in group A and 24,3% in group B (p=0,01). The measurement of temporal muscle (method 2) revealed that the degree of atrophy was 12,7% in group A and 22% in group B (p=0,005). The volumetric reduction of the structures (method 3) was 14,8% in group A and 24,5% in group B (p=0,012). Rankin Modified Score was similar in both groups in the 6-month evaluation (p=0,99). Mortality occurred in 4 patients in group A and 5 patients in group B (p=1,0). Conclusion: These clinical results indicate that the minipterional is a safe procedure. We can estimate the better cosmetic results with less facial contour deformity since the percentage of thick and volumetric reduction in temporal muscle, subcutaneous tissue and skin were demonstrated. It can be an excellent and better alternative to the classical pterional approach

Neste trabalho, avaliamos os efeitos da suplementação crônica de leucina e do treinamento de força sobre a miopatia diabética. 40 ratos machos da linhagem Wistar Hannover foram distribuídos em 5 grupos: controle, não diabético (C), diabético não tratado (D), diabético treinado (DT), diabético suplementado com leucina e treinado (DLT). O início das intervenções ocorreu na 4ª semana de vida dos animais, e perdurou por 8 semanas. Foram avaliados: massa corporal, consumo de ração e água, concentrações sanguíneas de glicose, insulina e perfil lipídico; capacidade funcional muscular voluntária através de testes de força de preensão e de ambulação; conteúdo intracelular de proteínas relacionadas à via anabólica mTOR e p70S6K, totais e fosforiladas, no músculo extensor longo dos dedos. Os ratos diabéticos não tratados (grupo D) apresentaram hiperglicemia e hipoinsulinemia moderada, menor massa corporal, maior consumo de ração e água, menor peso absoluto dos músculos extensor longo dos dedos e gastrocnêmio, menor força de preensão, menor capacidade de ambulação e menor atividade das proteínas mTOR e p70S6K comparado ao grupo C, o que caracteriza o quadro de miopatia diabética. O peso relativo do músculo gastrocnêmico (peso absoluto/100g de peso do animal) foi maior nos grupos DT e DLT comparado com o grupo D, e maior no grupo DLT comparado com o grupo DL (p < 0,05). Não houve diferença estatística entre os grupos DL e D sobre os pesos relativos dos músculos, ou seja, a suplementação crônica de leucina não afetou este parâmetro nos ratos diabéticos. Interessantemente, houve diferença estatística entre os grupos DL e D sobre a força muscular (p < 0,05), sem haver diferença entre grupos DL e C quanto à glicemia; ou seja, a dieta suplementada com leucina foi capaz de controlar a glicemia e atenuar a perda de força muscular. O treinamento de força também controlou a glicemia, recuperou a força muscular e melhorou a capacidade de ambulação, bem como a regulação da via mTOR-p70S6K. A fosforilação da via mTOR-p70S6K foi maior nos grupos DT e DLT comparado com o grupo D (p < 0,05), e sem diferença entre estes grupos treinados e o grupo C, sugerindo que o treinamento de força combinado com a suplementação de leucina recuperou a atividade da via do mTOR-p70S6K nos animais diabéticos, que pode refletir em maior síntese proteica muscular. O colesterol total do grupo D foi maior comparado com o do grupo C; e nos grupos diabéticos treinados (DT e DLT), este parâmetro foi menor do que no grupo D (p < 0,05). Adicionalmente, o HDL-c aumentou nos grupos treinados (DT e DLT) quando comparado com o grupo D, mas não alterou no grupo que recebeu apenas a suplementação de leucina (grupo DL). Portanto, neste estudo, a suplementação crônica de leucina por si só normalizou a glicemia e melhorou a força muscular dos animais diabéticos. Além disso, o treinamento de força foi responsável pelo maior aumento de força e da massa muscular, bem como pela normalização da glicemia, pela elevação da concentração de HDL-c e pela redução do colesterol total dos animais diabéticos e ambas foram capaz de recuperar a via mTOR-p70S6K. / In this study, we evaluated the effects of chronic supplementation with leucine and resistance training on diabetic myopathy. 40 Wistar Hannover rats were divided into 5 groups: control, non-diabetic (C), untreated diabetic (D), trained diabetic (DT), diabetic supplemented with leucine and trained (DLT). The beginning of the interventions occurred in the 4th week of life of the animals, and lasted for 8 weeks. Were evaluated: body weight, food and water intake, blood concentrations of glucose, insulin and lipid profile; voluntary muscle functional capacity through grip strength and ambulation test; intracellular content of proteins related to the anabolic mTOR and p70S6K pathway, total and phosphorylated in the extensor digitorum longus muscle. Diabetics untreated mice (group D) had hyperglycemia and moderate hypoinsulinemia, lower body mass, food and water intake, reduced absolute weights of the muscles of the long extensor digitorum, and gastrocnemius, the lower grip strength, lower ambulation capacity and lower activity of mTOR and p70S6K protein compared the C group, featuring diabetic myopathy. The relative weight of the gastrocnemius muscle (absolute weight / 100g of body weight) was greater in DT and DLT groups compared with group D, and higher in the DLT group compared to the DL group (P < 0.05). No statistical difference between the DL and D groups on the relative weights of the muscles, that is, chronic supplementation of leucine did not affect this parameter in diabetic rats. Interestingly, there was statistical difference between the DL and D groups on muscle strength (P < 0.05), with no difference between groups DL and C on the blood glucose; that is, the diet supplemented with leucine was able to control glycemia and avoid loss of muscle strength of diabetic animals. Resistance training also controlled glycemia, recovered muscle strength and improved the capacity of ambulation of diabetic animals and the regulation of the mTOR-p70S6K pathway. The phosphorylation of mTOR-p70S6K pathway was higher only in the DT and DLT groups compared with the D group (P < 0.05), and no difference between the DT and C groups, suggesting that the training recovered muscle mass in diabetic animals. Total cholesterol was greater in Group D compared to the group C; and trained diabetic groups (DLT and DT), this parameter was lower than that of the D group (P < 0.05). In addition, HDL-C increased in trained groups (DT and DLT) as compared to group D, but had no effect the group that received only leucine supplementation (DL group). Therefore, in this study, chronic supplementation of leucine alone normalized glucose and improved muscle strength of diabetic animals. In addition, resistance training was responsible for the largest increase in strength and muscle mass, as well as the normalization of glucose, elevated concentrations of HDL-C and reduction in total cholesterol of animals diabetics and both were able to recover mTOR- p70S6K pathway.

Memory structure, memory assessment, Grober-Buschke paradigm, Alzheimer disease, and vascular dementia were discussed in the first part of the present thesis. Present study aims to examine the relationship between white matter changes, hippocampal atrophy and the performance in Enhanced Cued Recall test in nondemented geriatric population (n = 104). Partial neparametric correlations were used while controlling for age and Fazekas score. Medium correlations were found between left/right hippocampal volumes and free and total recall. No correlations were found between Fazekas score and ECR scores while controlling for age and left and right hippocampal volumes. Keywords: hippocampal atrophy, white matter changes, cued recall, ECR

Background: The patient's prerequisites form the basis for the pre-and postoperative care period. One of the aspects that affect health care is the patient's physical activity where immobilizing surgery involves atrophy of muscle mass. A low preoperative activity level, perioperative immobilization and postoperative immobilization increase the risk of postoperative complications. Aim: The purpose was to investigate how much skeletal muscle mass patients lose related to immobilizing surgery and how immobilization affects the patient's care time postoperatively. Method: A literature study that reviewed 12 original articles. The articles were reviewed according to Forsberg and Wengström (2016) where article’s contents and results were compared with the aim of this literature study. Results: After examination, no general loss of muscle mass after immobilized surgery could be identified. The muscle mass's ability to atrophy varies depending on the area of surgery and individual-based conditions. However, muscle mass and its quality were identified as a potential prognostic marker for how post-operative care time will play out where lower levels of muscular quality imply increased risk of complications and mortality. Care time for patients with a low muscle grade has been identified as prolonged related to immobilizing surgery. A care period that can be shortened by muscular activation in the form such as electrical stimulus or resistance exercises. Conclusion: The conclusion of this literature study is that the muscle mass lost in immobilized surgery and how postoperative care is affected is individual-based and influenced by preoperative muscle size and type of surgical procedure. Further research is needed on preoperative and postoperative skeletal muscle mass measurement and a routine for measuring muscle mass, since muscle atrophy has been identified as an important marker for postoperative care and survival. / Bakgrund: Patientens förutsättningar ligger till grund för hur den pre- och postoperativa vårdtiden kommer att fortlöpa. En av aspekterna som påverkar vården är patientens fysiska aktivitet där immobiliserande kirurgi innebär atrofi av muskelmassa. En låg preoperativ aktivitetsnivå, perioperativ immobilisering och postoperativ immobilisering ökar risken för postoperativa komplikationer relaterade till muskelatrofi. Syfte: Syftet var att undersöka hur mycket skelettmuskulatur patienter förlorar i samband med immobiliserande operation samt hur immobiliseringen påverkar patientens vårdtid postoperativt. Metod: En litteraturstudie som granskade 12 originalartiklar. Artiklarna granskades enligt Forsberg och Wengström (2016) där innehåll och resultat jämfördes med denna litteraturstudies syfte. Resultat: Efter granskning har ingen generell förlust av muskelmassa efter kirurgi kunnat identifieras. Muskelmassans förmåga att atrofiera varierar beroende på operationsområde och individbaserade förutsättningar. Muskelmassan och dess kvalitet kunde dock identifieras som en prognostisk markör för hur den postoperativa vårdtiden kommer att fortlöpa där lägre grad av muskulär kvalitet innebär ökad risk för komplikationer och mortalitet. Vårdtiden för patienter med muskelgrad av låg kvalitet har kunnat identifieras som förlängd i samband med immobiliserande kirurgi. En vårdtid som kan förkortas genom muskulär aktivering i form av t.ex. elektrisk stimulans eller motståndsövningar. Slutsats: Konklusionen av denna litteraturstudie är att den muskelmassa som förloras vid immobiliserande kirurgi samt hur den postoperativa vårdtiden påverkas är individbaserat och påverkas av preoperativ muskelgrad och typ av kirurgiskt ingrepp. Efter genomförd granskning eftersöks vidare forskning gällande preoperativ och postoperativ mätning av skelettmuskelmassa och en standardiserad rutin för att mäta muskelmassa, detta då muskelatrofi har identifierats som en viktig markör för postoperativ vård och överlevnad.

Le diagnostic de la maladie d’Alzheimer (MA) s’appuie sur des critères clinico-biologiques combinant un déficit de la mémoire épisodique et un marqueur biologique (dosage dans le liquide céphalorachidien, imagerie nucléaire) indicateur des changements qui signent le début de la maladie. Un phénomène biologique précoce de la maladie est la production de dépôts du peptide amyloïde dont le principal site de production à partir de son précurseur, l’APP, est le compartiment endosomal. L’apparition dans le cerveau d’endosomes élargis précède celle des dépôts amyloïdes.Nous avons analysé deux marqueurs biologiques. D’abord la charge amyloïde cérébrale par fixation du ligand [PiB] en tomographie d’émission de positrons (TEP) dans le cerveau des malades atteints d’une atrophie corticale postérieure (ACP). Puis nous avons étudié les endosomes dans les cellules périphériques (leucocytes mononucléaires et fibroblastes) de patients MA, et dans des lignées lymphoblastoïdes (LCL) d’individus porteurs d’une trisomie 21 dont 45% développent une MA à l’âge de 60 ans (contre 3 % dans la population générale), principalement en raison de la présence d’une troisième copie du gène codant l’APP, localisé sur le chromosome 21. Nos travaux montrent des profils de marquage [PiB] similaires entre la MA et l’atrophie corticale postérieure (ACP) aussi bien en intensité qu’en topographie. L’étude des endosomes montre que les modifications du compartiment endosomal sont détectables en périphérie du système nerveux central et sont corrélées au marquage des dépôts amyloïdes cérébraux. Ces altérations pourraient constituer un outil de diagnostic à partir de prélèvements sanguins. / Alzheimer’s disease (AD) diagnostic is based on clinical and biological criteria, and is dependent on impairment of the episodic memory together with a marker of the underlying pathophysiologic process. One of the earliest events in AD pathology in the brain is formation of Amyloid deposits in the extracellular space. One of the main subcellular sites of amyloid-β (Aβ) production from amyloid precursor protein (APP) processing is the endosomal compartment. Appearance of endosomal abnormalities precede the formation of amyloid deposits, in the brain areas affected by disease progression in AD. In the present work we first studied brain amyloid load in patients with posterior cortical atrophy using [11C]PiB ligand retention in positron emitting tomography (PET). In a second part we studied the endosomal compartment in peripheral cells (fibroblasts and mononuclear leucocytes, PBMC) from AD patients, and in lymphoblastoid cell lines (LCL) from Down’s syndrome (DS) individuals where a third copy of amyloid-precursor-protein-coding gene located on chromosome 21 is known to initiate early Alzheimer’s pathology in most DS individuals. Our work shows similar profiles in topography and intensity of [PiB] binding in AD and posterior cortical atrophy (PCA), confirming underlying AD pathology in atypical focal presentations of AD. Analysis of endosomes yielded a significant increase in the frequency of cells with large endosomes in all analyzed cell types, and mean endosome volume correlated to [PiB] binding in PBMC. This result indicates that modifications of the endosomal compartment are seen in the periphery of central nervous system and may represent diagnostic tool from blood.

Spinal muscular atrophy is an autosomal recessive genetic disease that results from the loss and/or degeneration of alpha motor neurons in the lower part of the spinal cord. With ~ 1 in 6000 live births per year being affected, this disease is the second leading cause of infant death and is caused by the loss or decrease of the Survival of Motor Neuron protein (SMN). While a lot is known about the role that SMN plays in the cytoplasmic assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs), it remains a crucial question in the field to gain a better understanding of what specific/distinct function(s) SMN might have in motor neurons. We have identified novel interactions between SMN and two RNA-binding proteins (RBPs) known to be components of axonal RNA granules. More specifically, we demonstrated that SMN interacts with HuD and SERBP1 in a direct fashion in foci-like structures along neurites of motor neuron-derived cells. We have also demonstrated that the SMN/HuD interaction is required for the localization of HuD into RNA granules in neurites of motor neuron-derived cells. Furthermore, I have shown that SERBP1 is down-regulated in the absence of normal levels of SMN and, most importantly, that over-expression of SERBP1 can rescue SMA-like neuronal defects using a cell culture model of the disease. These findings may help shed light on the non-canonical molecular pathway(s) involving SMN and RBPs in motor neurons and underscores the possible therapeutic benefits of targeting these RBPs in the treatment of SMA.

Skeletal muscle atrophy is a debilitating condition caused by pathological conditions including cancer cachexia, disuse and denervation. Disuse atrophy is characterized by reduction in fiber size, fiber-type change and induction of markers of atrophy such as MuRF1 and Fn14. Recent studies have focused on understanding the fundamental role of signalling pathways and the proteolytic system in response to muscle atrophy. Unfortunately the exact mechanisms behind atrophy remain poorly understood. I recently demonstrated that cIAP1 and/or cIAP2 proteins are critical regulators of NF-kB activation, which has been shown to be involved in skeletal muscle atrophy. Here, I used genetic and pharmacological means to investigate the role of cIAP1 in a denervation-induced skeletal muscle atrophy model. Interestingly, I found that upon denervation loss of cIAP1 rescues muscle fiber size, prevents fiber-type changing and inhibits the expression of MuRF1 and Fn14. Moreover, treatment of mice with Smac mimetic compounds (SMC), a novel class of small molecule IAP antagonists, showed successful knockdown of cIAP1 in muscle and protects against denervation-induced muscle atrophy. Taken together, these data reveal that cIAP1 is both a novel mediator of skeletal muscle atrophy and an important therapeutic target.

Trichostatin A (TSA) is a histone deacetylase inhibitor with beneficial effects in spinal muscular atrophy mouse models that carry the human SMN2 transgene. Whether TSA specifically targets the upregulation of the SMN2 gene or whether other genes respond to TSA and in turn provide neuroprotection in SMA mice is unclear. We have taken advantage of the Smn2B/- mouse model that does not harbor the human SMN2 transgene, to test the hypothesis that TSA has its beneficial effects through a non-Smn mediated pathway. Daily intraperitoneal injection of TSA from postnatal day 12 to 25 was performed in the Smn2B/- mice and littermate controls. Previous work from our laboratory demonstrated that treatment with TSA increased the median lifespan of Smn2B/- mice from twenty days to eight weeks. As well, there was a significant attenuation of weight loss and improved motor behavior. Pen test and righting reflex both showed significant improvement, and motor neurons in the spinal cord of Smn2B/-mice were protected from degeneration. Both the size and maturity of neuromuscular junctions were significantly improved in TSA treated Smn2B/- mice. Here, we have shown that TSA treatment does not increase the levels of Smn protein in mouse embryonic fibroblasts or myoblasts obtained from the Smn2B/- mice. Further, qPCR analysis revealed no changes in the level of Smn transcripts in the brain or spinal cord of TSA-treated SMA mice. Similarly, western blot analysis revealed no significant increase in Smn protein levels in the brain, spinal cord, hind limb muscle, heart muscle, or the liver of TSA treated Smn2B/- mice. However, TSA has beneficial effects in the muscles of Smn2B/- mice and improves motor behavior and myofiber size. TSA improves muscle development by enhancing the activity of myogenic regulatory factors independent of the Smn gene. The beneficial effect of TSA is therefore likely through an Smn-independent manner. Identification of these protective pathways will be of therapeutic value for the treatment of SMA.

HDAC6 est une histone déacétylase hautement conservée, principalement cytoplasmique. Contrairement à d'autres désacétylases, HDAC6 a une spécificité de substrat unique pour les protéines non - histones . Outre les domaines de désacétylation, HDAC6 contient également un domaine de liaison à l'ubiquitine , qui relie HDAC6 de la voie ubiquitine / protéasome .L’atrophie du muscle squelettique est une condition sévère de perte progressive de masse musculaire au cours de certaines maladies telles le cancer, le diabète, le SIDA ou également immobilizations prolongées. Le contrôle de la masse musculaire est sous la dépendance d’un équilibre entre les processus anaboliques et cataboliques. L’atrophie se caractérise par une augmentation substantielle de la dégradation des protéines par le système ubiquitine-protéasome, causée par l'expression d'une série de gènes spécifiques, les atrogenes . Un des atrogenes induits plus spectaculaire est le muscle spécifique de l'ubiquitine ligase E3 MAFbx/Atrogin-1, qui prend soin de la dégradation de MyoD et de eIF3 -f. La dégradation de ces deux protéines inhibe l'expression de gènes et la traduction myotrophiques empêchant le remplacement de protéines dégradées.Récemment, nous avons identifié l’Histone Deacetylase 6 (HDAC6) comme un nouvel atrogène. L’expression de HDAC6 augmente au cours de l’atrophie musculaire, à la fois chez la souris et l’homme, à travers un mécanisme FOXO3 -dépendante. La déplétion de cet enzyme in vivo (electroporation de l’shRNA contre HDAC6 dans des muscle squelettiques de souris ou analyse de souris invalidées pour ce gène) protège contre l’atrophie. De plus, l’inhibition de HDAC6 après déclenchement de l’atrophie peut aussi atténuer le phénotype. Lors de la caractérisation du mécanisme d’action de HDAC6, nous avons montré que HDAC6 intéragit avec MAFbx et que elle est nécessaire pour l’ubiquitination de MyoD par MAFbx. Nos résultats montrent que la surexpression d’un mutant MyoD resistant à la degradation par MAFbx protège contre l’atrophie provoqué par la denervation.. De plus, certaines données préliminaires indiquent une implication de HDAC6 dans la dégradation de eIF3-f et dans le processus de autophagy dans le tissu musculaire , révélant une double rôle de HDAC6 dans le muscle squelettique .Ces preuves suggèrent que HDAC6 représente potentiellement une cible utile pour des traitements curatifs. / HDAC6 is a highly conserved histone deacetylase, mostly cytoplasmic. Unlike other deacetylases, HDAC6 has unique substrate specificity for non-histone proteins. Besides the deacetylation domains, HDAC6 also contains an ubiquitin-binding domain, which links HDAC6 to the ubiquitin/proteasome pathway. Skeletal muscle atrophy is a severe condition of muscle mass loss occurring during aging or in many clinical disorders as cancer, diabetes and AIDS. The maintenance of muscle mass is subtly controlled by an equilibrium between catabolic and anabolic processes. Muscle atrophy results as a partial suppression of protein synthesis and a substantial increase of protein breakdown by the ubiquitin-proteasome system, caused by the expression of a series of specific genes, the atrogenes. One of the atrogenes induced more dramatically is the muscle specific E3 ubiquitin ligase MAFbx/Atrogin-1, which takes care of the degradation of MyoD and of eIF3-f. Degradation of those two proteins inhibits expression of myotrophic genes and translation preventing the replacement of degraded proteins.We identified HDAC6 as a new atrogene. HDAC6 expression is up regulated during muscle atrophy in mouse and human through a mechanism FoxO3-dependent. In vivo depletion of this enzyme by shRNA electroporation or homologous recombination gives protection against atrophy and its inhibition during atrophy can partially reverse the muscle wasting phenotype. HDAC6 can interact with MAFbx and is required for MAFbx-mediated degradation of MyoD. According to our results, forced expression of a MyoD mutant resistant to HDAC6 and MAFbx dependent degradation prevents muscle wasting induced by denervation. Furthermore, some preliminary data show an involvement of HDAC6 in the degradation of eIF3-f and in the autophagy process in muscle tissue, revealing a double role of HDAC6 in skeletal muscle.These evidences suggest that HDAC6 potentially represents a valuable target for curative treatments.

Rotavírus (RV) é um importante patógeno viral que causa diarreia em leitões e indivíduos jovens de várias outras espécies animais. RV dos grupos A, B, C e E foram descritos como causa de diarreia em suínos. Este estudo reúne achados histopatológicos, imunohistoquímicos e de reação em cadeia da polimerase com transcriptase reversa (RT-PCR) presentes em quatro surtos de diarreia causados por RV de um e de múltiplos grupos na região sul do Brasil. Vacinação para RV não era aplicada em nenhuma das granjas estudadas. Necropsia, exames histológicos e imuni-histoquímicos foram realizados em 34 suínos de maternidade que apresentavam diarreia severa, além disso, realizou-se cultivo bacteriano e RT-PCR para RV dos grupos A, B e C, vírus da gastroenterite transmissível (TGEV), vírus da diarreia epidêmica dos suínos (PEDV), sapovírus (SaV), norovírus (NoV) e kobuvírus (Aichi vírus C) em 30 dessas amostras. Desidratação e conteúdo pastoso a líquido no cólon foram observados em todos os suínos. Exame histológico revelou atrofia de vilosidades em 29 casos, vacuolização de enterócitos em 27 casos e debris celulares na lâmina própria em 20 casos. Houve marcação imunohistoquímica positiva em 21 casos. RT-PCR foi positiva para RV em 20 casos e RV do grupo C foi o mais frequentemente detectado, presente em 17 amostras. Cultivo e isolamento de Escherichia coli ocorreu em todos os casos e quatro destes foram de E. coli α-hemolítica. Em 15 amostras houve isolamento de Clostridium sp. Sapovirus foi detectado em oito amostras, duas amostras foram positivas para norovírus e detectou-se kobuvírus em 11 animais. Os achados histológicos foram consistentes com infecção por RV e a imuno-histoquímica revelou dois padrões de marcação para o agente no intestino delgado. Os resultados de RT-PCR mostraram que o RV do grupo C foi o principal agente detectado neste estudo. O isolamento de E. coli e a detecção de SaV os destacou como agentes associados à infecção por RV. A detecção de kobuvírus o enfatiza como um novo candidato em associação com RV. / Rotavirus is an important viral pathogen causing diarrhea in piglets and other animal species worldwide. Groups A, B, C and E have been described causing diarrhea in swine. This study reunites histopathological, immunohistochemical and reverse transcriptase polymerase chain reaction (RT-PCR) findings present in four outbreaks of diarrhea caused by single and multiple groups of rotavirus in the south of Brazil. None of the herds studied applied vaccination against rotavirus. Necropsy, histological examination and immunohistochemistry were performed in 34 nursing piglets that presented severe diarrhea, bacterial culture and reverse transcriptase polymerase chain reaction (RT-PCR) for rotavirus from groups A, B and C, transmissible gastroenteritis virus (TGEV), porcine epidemic diarrhea virus (PEDV), sapovirus (SaV), norovirus (NoV) and kobuvirus (Aichi virus C) were carried out in 30 of the animals necropsied. Additionally, RT-PCR was performed in fecal pools from two outbreaks. Dehydration and fluid to pasty contents were observed in the colon of all 34 swine examined. Histological examination revealed villus atrophy in 29 cases, vacuolation of enterocytes in 27 cases and necrotic debris in the lamina propria of 20 cases. IHC was positive in 21 samples. RT-PCR was positive for rotavirus in 20 samples and group C rotavirus was the most frequently detected, present in 17 samples. Escherichia coli was isolated from all cases, and in four cases, it was α-hemolytic. Clostridium sp. was isolated from 15 samples. Sapovirus was detected in eight samples, samples from two animals were positive for norovirus and kobuvirus was detected from 11 samples. Histological findings were consistent with rotavirus infection and immunohistochemistry revealed two patterns of staining for rotavirus in the small intestine. RT-PCR results have shown group C rotavirus as the main agent detected in this study. The isolation of Escherichia coli and the detection of sapovirus highlighted them as possible agents associated to rotavirus infection. Kobuvirus detection has emphasized it as a new candidate in the association with rotavirus.