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.

Orientadores: Liana Maria Cardoso Verinaud, Wilson Savino / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-26T20:13:37Z (GMT). No. of bitstreams: 1 Francelin_Carolina_D.pdf: 110859425 bytes, checksum: e99991048374fbaee764c7b0f509643f (MD5) Previous issue date: 2014 / Resumo: O timo é o órgão linfoide primário responsável pela geração de linfócitos T maduros. Para que isso ocorra, células precursoras de linfócitos T, provenientes da medula óssea, entram no timo e migram constantemente através do microambiente tímico ¿ o qual é composto por componentes linfoides e não linfoides. Esta migração intratímica é fundamental para que os precursores das células T encontrem os sinais necessários para sobrevivência, proliferação, diferenciação e geração de diversidade de repertório. Assim como os outros órgãos linfoides, o timo está sujeito a um rígido controle neuroendócrino, o qual impõe consequências diretas sobre o funcionamento do sistema imunológico através de neurotransmissores, hormônios e citocinas. Entretanto, ainda é pouco o que se sabe sobre as interações entre os componentes do timo e hormônios do eixo HPA. Neste trabalho, foram avaliados os compartimentos linfoide e estromal na atrofia tímica observada no modelo experimental da diabetes tipo I. Nesse estudo foi observado que camundongos diabéticos apresentaram redução nos níveis séricos e intratímicos de leptina e elevados níveis séricos e intratímicos de corticosteroide, acompanhando a queda dos níveis séricos de insulina. Diante das alterações hormonais, nós observamos: modificações nos componentes linfoides e estromais do timo, caracterizadas por redução no número de timócitos, aumento na secreção de elementos de matriz extracelular, contração da porção cortical do timo acompanhada por acúmulo de linfócitos no estágio pré - seleção positiva, aumento da apoptose de células epiteliais tímicas e timócitos e aumento na exportação de células T imaturas para os órgãos linfoides secundários. Sucintamente, após o estabelecimento da hiperglicemia e ausência de insulina circulante, o timo de animais diabéticos apresentou alterações morfológicas e em todos os tipos celulares e fatores solúveis que compõe o estroma tímico, culminando em alterações nas células presentes na periferia do sistema imune. Acreditamos que os dados gerados nesse estudo contribuem, s.m.j., para um melhor entendimento da deficiência na resposta imune em indivíduos diabéticos e do desenvolvimento do linfócito T na ausência de insulina / Abstract: Thymus is the primary lymphoid organ responsible for the generation of T lymphocytes. For this to occur, precursor cells of T lymphocytes from bone marrow enter the thymus and migrate continuously through the thymic microenvironment - which consists of lymphoid and non-lymphoid components. This intrathymic migration is essential for T cell precursors get contact with signs that promote survival, proliferation, differentiation and generation of diversity of repertoire. Like other lymphoid organs, the thymus is subject to a rigid neuro-endocrine control, which requires direct consequences on the functioning of the immune system through neurotransmitters, hormones and cytokines. However, it is still little known about the interactions between the components of thymus hormones and the HPA axis. In this study, we evaluated the alterations in lymphoid and stromal thymic compartiments in thymic atrophy during experimental model of diabetes type I. Here in, we found that diabetic mice exhibit a reduction in serum aand intrathymic levels of leptin yet, intrathymic and serum corticosteroid levels were high, followed by a drop in serum insulin levels. Given the hormonal changes, we observed: changes in lymphoid and non-lymphoid component of the thymus, characterized by reduction in the number of thymocytes, increased secretion of extracellular matrix elements, contraction of the cortical portion of the thymus accompanied by accumulation of lymphocytes in the pre stage - positive selection, increased apoptosis of thymic epithelial cells and thymocytes and increase in export of immature T cells to secondary lymphoid organs. Briefly, after the onset of hyperglycemia and lack of circulating insulin, thymus in diabetic animals showed alterations in all cell types that comprise the thymic microenvironment, resulting in abnormal cells present in the periphery of the immune system. We believe that the data generated in this study will contribute to a better understanding of the immune deficiency in diabetic individuals and the development of T lymphocytes in the absence of insulin response / Doutorado / Imunologia / Doutora em Genética e Biologia Molecular