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Pastaraisiais metais medicinos literatūroje vis dažniau minima sąvoka :“gyvenimo kokybė“. Nors dar nėra visuotinai priimto jos apibrėžimo, gyvenimo kokybė tapo mokslinių tyrinėjimų objektu. Gyvenimo kokybė yra įvairiapusis kiekvieno žmogaus esamų gyvenimo aplinkybių įvertinimas, tai pirmiausia subjektyvus gerovės, suvokimas, apimantis fizinį, psichologinį ir dvasinį lygmenis. Progresuojančios nervų raumenų ligos yra nepagydomos, todėl gydytojai pataria sergantiems nervų - raumenų ligomis kuo daugiau judėti. Fizinio aktyvumo pratimai yra vienas iš būdų padedančių pagerinti neįgalaus paauglio gyvenimo kokybę. Tyrimo hipotezė, fiziškai aktyvių neįgalių paauglių gyvenimo kokybė geresnė pagal daugelį jos komponentų negu fiziškai neaktyvių neįgalių paauglių. Tyrimo tikslas – išanalizuoti fiziškai aktyvių ir neaktyvių paauglių, sergančių nervų-raumenų ligomis, gyvenimo kokybę pagal atskirus jos komponentus. Uždaviniai: 1. Išanalizuoti ir palyginti fiziškai aktyvių ir neaktyvių paauglių, sergančių nervų-raumenų ligomis, išorinę gyvenimo kokybės sferą. 2. Išanalizuoti ir palyginti fiziškai aktyvių ir neaktyvių paauglių, sergančių nervų-raumenų ligomis, asmeninę gyvenimo kokybės sferą. 3. Išanalizuoti fiziškai aktyvių ir neaktyvių paauglių, sergančių nervų-raumenų ligomis, tarpasmeninę gyvenimo kokybės sferą. Tiriamasis kontingentas Tyrime dalyvavo 39 neįgalūs paaugliai, sergantys nervų – raumenų ligomis, iš įvairių Lietuvos vietovių. Iš jų 16 kultivavo fizinį aktyvumą ir 23... [toliau žr. visą tekstą] / In recent years the coception “the quality of life” is mention more and more often in the medicine literature. Even though this definition is not accepted, but the quality of life became the main research object of science. The quality of life is the estimate of everybody’s life circumstances. At first it is the subjective apprehension of welfare, which include physical, psychological and spiritual levels. Nervous - muscle illnesses, which grow progressively worse are incurable diseases. Therefore doctors advise to move as much as possible to people who have nervous – muscle disease. Physical activity excercises are one of the better ways, which can improve the quality of life of disabled teenagres. The hypothesis of this research – the quality of life of physical active disabled teenagres is better then physical non active disabled teenagres’ in many different components. The purpose of the research – to analyse physical active and non active teenagres, who have nervous – muscle disease according seperate components. Tasks: 1. To analyse and to compare the outward quality of life of physical active and non active teenagres, who have nervous – muscle disease. 2. To analyse and to compare the individual sphere of quality of life of physical active and non active teenagres, who have nervous – muscle disease. 3. To analyse intercommunication quality of life of physical active and non active teenagres, who have nervous – muscle disease. Contingent. 39 disabled teenagres who have... [to full text]

Caveolae are small plasma membrane invaginations present in many different cell types, which have been linked to diverse cellular functions, including cell signalling, membrane rearrangements and lipid regulation. The caveolae markers, members of the caveolin family of proteins, are essential for caveola formation and function. Recently, however, a protein named PTRF (Polymerase I and Transcript Release Factor) or cavin, originally identified as a nuclear factor that regulates transcription in vitro, was shown to be associated with caveolae in adipocytes. In the first chapter of this thesis, I have used the zebrafish Danio rerio to investigate the relation of PTRF/cavin to caveolae as well as caveola function in vivo. During zebrafish development, PTRF/cavin was highly expressed in the notochord in 18 h, 24 h and 35 h post-fertilization embryos, as detected by in situ hybrydization. Analysis of later development stages showed that PTRF/cavin is also present in the otic vesicle, brachial arches, and periderm. Disruption of PTRF/cavin expression, via morpholino-mediated inhibition, caused severely defective development of the notochord as well as heart edema, in a dose-dependent manner. PTRF/cavin knockdown embryos had curved notochords and were shorter than the controls. Examination of the notochord by electron microscopy showed that the number of caveolae was greatly reduced in PTRF/cavin-morpholino-injected embryos. Similar effects were observed when caveolin-1, the major protein of caveolae in non-muscle cells, was down-regulated. Altogether, these results indicated a role for PTRF/cavin during formation and/or stabilization of caveolae as well as an essential role for caveolae during zebrafish embryo development. Combined with results obtained in mammalian cells, these findings identify PTRF/cavin as the first component of a caveolar coat, required for caveola formation and function (Hill et al., 2008). We subsequently identified a family of PTRF/cavin-related proteins, the cavins, that all associate with caveolae. Using biochemistry, light microscopy, and FRET-based approaches we characterised PTRF/cavin and the new members of this family of proteins SDR/cavin-2, SRBC/cavin-3 and MURC/cavin-4. We have shown that the four members of the cavin family form a multi-protein complex that associates with caveolae. This complex can constitutively assemble in the cytosol and then associate with caveolin at the plasma membrane caveolae; interestingly, caveolin is essential for the plasma membrane translocation of the cavin complex, and in caveolin-1 knockout cells the four cavin proteins are restricted to the cytosol. PTRF/cavin-1, but not other cavins, can induce caveola formation in a heterologous system and is required for the recruitment of the cavin complex to caveolae. The four cavin proteins present distinct patterns of tissue expression, which suggests that caveolae may perform tissue-specific functions regulated by the composition of the cavin complex. MURC/cavin-4 is expressed predominantly in muscle and its distribution is perturbed in human muscle disease associated with caveolin-3 dysfunction, identifying MURC/cavin-4 as a novel muscle disease candidate caveolar protein. To functionally investigate the relation of cavins and caveolae, we explored a caveolar function in mechanosensation. Through the use of hypo-osmotic media, we induced membrane-stretch and showed that the increased membrane tension leads to dissociation of the caveolin-cavin module and caveola disassembly as observed by immunofluorescence and FLIM/FRET techniques. Once released from caveolae, caveolin was seen internalized in late endosomes and lysosomes. Cavin-1, on the other hand, was found to be diffused in the cytosol and from there it was translocated to the nuclear compartment. The nuclear translocation was observed in several different cell types, which suggests a universal role for nuclear cavin-1, and was independent of caveolin expression. Analysis of live cells using real-time FLIM/FRET showed that cells quickly respond to variations in membrane tension by dissociation/re-association of caveolin and cavin-1. Altogether, in the course of this project, I was able to show that cavin-1 is an essential regulator of caveola biogenesis in cultured cells and in vivo. Cavin-1 and the other members of the PTRF/Cavin family form a multiprotein complex that is recruited to caveolae by caveolin and coats plasma membrane caveolae. The association between cavin-1 and caveolin is crucial for caveolae assembly and this interaction has a role in the cellular sensation of plasma membrane tension. Under high membrane tensions, caveolin and cavin-1 dissociate with the consequent flattening of caveolae. Under these circumstances, caveolin is internalized into enlarged endosomes and lysosomes while cavin-1 is translocated to the nucleus, identifying for the first time a caveola- to nucleus signalling pathway. The exact role of nuclear cavin-1 under plasma membrane stretch is now amenable to analysis.

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Seconde espèce de mollusque bivalve la plus exploitée au monde, la palourde japonaise Venerupis philippinarum représente un intérêt économique majeur. A l’échelle du bassin d’Arcachon, la maladie du muscle marron ou BMD (pour Brown Muscle Disease), pathologie émergente découverte en 2005 inquiète tout particulièrement le secteur de la pêche. Cette pathologie affecte le muscle adducteur postérieur de la palourde et perturbe l’ouverture-fermeture des valves. Cette perturbation entraine la remontée des individus à la surface du sédiment et la mort.Ces travaux de thèse ont porté d’une part sur l’épizootiologie de la maladie et son impact sur l'hôte et d’autre part sur l’identification de l’agent responsable de la maladie.Une étude sur la distribution des palourdes dans le bassin d’Arcachon (littoral Atlantique français) montre que la prévalence de la BMD a diminué entre 2010 et 2012. Toutefois cette baisse ne concerne pas les individus ayant atteint la taille légale de pêche (> 35mm). De plus, la maladie semble apparaitre chez des individus de plus en plus petit et risque donc d’accroitre la mortalité aux plus jeunes stades. L’analyse des facteurs environnementaux impliqués dans la distribution de la maladie souligne la corrélation entre la prévalence de la BMD et un hydrodynamisme relativement « calme ».La BMD affecte tout particulièrement le métabolisme énergétique de l’hôte, les mécanismes de réponse au stress oxydant et également le système immunitaire. De nombreuses fonctions sont surexprimées chez les hôtes malades mais d’autres voies comme celle de l’apoptose sont régulées négativement par l’agent infectieux.Si l’origine virale est maintenant une hypothèse solide (microscopie électronique, transcriptomique), la nature exacte de l’agent étiologique (famille virale) ne peut à ce jour être déterminée avec certitude. Des particules virales ont bien été observées dans les tissus malades mais pas dans les tissus sains, et ont pu être purifiées sur gradient de sucrose. Toutefois, les essais pour provoquer la maladie chez des individus sains ont échoué. / The Manila clam Venerupis philippinarum is the second most exploited mollusk bivalve in the world and represents a major economic interest. At the scale of Arcachon bay, the Brown Muscle Disease or BMD, an emergent pathology discovered in 2005, concerns fishing activity. This pathology affects the posterior adductor muscle of the clam and disrupts the valve opening and closing process. It induces the migration of clams to the surface and their death.This thesis concerns on the one hand the epizootiology of the disease and its impact on host and on the other hand the identification of the causal agent of the disease. A study of the clam distribution in Arcachon bay (French Atlantic coast) shows that prevalence of BMD decreased between 2010 and 2012. However this decrease doesn't affect clams of the legal harvesting size (> 35mm). Furthermore, the disease seems to appear in individuals with increasingly smaller size and thus risks to increase mortality in the youngest stages. The analysis of the environmental factors that are involved in the disease distribution highlights the correlation between prevalence of the BMD and relatively "quiet" hydrodynamism.BMD particularly affects the energy metabolism of the host, the oxidative stress response mechanisms and the immune system.Many functions are up-regulated in the BMD-affected hosts but other ways, as the apoptosis, are down-regulated by the infectious agent.Although viral origin of BMD is now a convincing hypothesis (electronic microscopy, transcriptomic), the nature of the etiological agent (viral family) cannot so far be determined with certainty. Viral particles were observed in tissues of BMD-diseased hosts but not in tissues of healthy host. They have been purified on sucrose gradient. However, the attempt to provoke the disease in healthy individuals failed.

La dystrophie myotonique de type 1 (DM1) ou maladie de Steinert est la maladie génétique neuromusculaire la plus commune avec une incidence de 1/8000 à travers le monde. Cette maladie multisystémique touche particulièrement les muscles squelettiques (myotonie, faiblesse et perte musculaires) et le coeur qui présente des symptômes variés comme des troubles de la conduction et des arythmies. La DM1 est causée par une expansion instable de répétitions CTG dans la région 3’ non traduite du gène DMPK. Les individus sains possèdent entre 5 et 37 répétitions CTG tandis que les patients DM1 portent entre 50 et plusieurs milliers de répétitions. Il est bien établi que les expansions de répétitions non codantes forment des foci dans les noyaux musculaires où elles séquestrent le facteur d'épissage MBNL1. Toutefois, l'implication de la stabilisation et l'accumulation de CUGBP1 hyperphosphorylé par la PKC dans la maladie est un sujet controversé dans la communauté DM1. Dernièrement, en plus de la rupture de l'équilibre entre MBNL1/CUGBP1, plusieurs mécanismes ont été mis en cause dans la pathogenèse de la DM1. Parmi eux, l'expression perturbée de facteurs de transcription, la maturation altérée de miARNs, l'activation de kinases... chacune de ces altérations menant au final à une perturbation du transcriptome. Afin d'étudier l'effet de la toxicité des répétitions sur les phénotypes et lestranscriptomes, nous avons généré trois lignées de Drosophile inductibles et site-spécifiques exprimant 240, 600 et 960 répétitions de triplets. Nous avons travaillé en parallèle sur une lignée atténuée pour mbl (orthologue de MBNL1) et deux lignées gain de fonction bru -3 (orthologue de CUGBP1). Exprimées dans les muscles somatiques, les répétitions CTG conduisent à une mobilité réduite, le fractionnement des fibres musculaires, une réduction de leur taille et une altération du processus de fusion des myoblastes de manière dépendante de Mbl et Bru-3. En outre, l'expression des répétitions cause une hypercontraction musculaire dépendante de Mbl et due à un mauvais épissage de dSERCA. L'analyse transcriptionnelle comparative réalisée sur les muscles larvaires des différentes conditions pathologiques montre que l'atténuation de mbl reproduit 70-82% des dérégulations transcriptomiques des larves DM1 alors que le gain de fonction bru-3 représente 32-53% des altérations transcriptomiques des lignées DM1. Ainsi Mbl est un facteur clé des dérégulations observées dans les muscles somatiques des lignées DM1. Au contraire, les analyses physiologiques effectuées sur les coeurs adultes suggèrent que Bru-3 est un facteur clé dans la mise en place des phénotypes cardiaques. En effet, d'une part, l'atténuation de mbl dans le coeur cause une cardiomyopathie dilatée, un symptôme rarement diagnostiqué chez les patients. D'autre part, les lignées gain de fonction bru-3 et DM1 présentent de la fibrillation qui évolue avec l'âge ou la taille des répétitions vers un phénotype qui rappelle l'insuffisance cardiaque chez les patients. / Myotonic Dystrophy Type 1 (DM1) or Steinert's disease is the most common genetic neuromuscular disorder affecting 1 out of 8000 people worldwide. This multisystemic disease affects particularly the skeletal muscles (myotonia, muscle weakness and wasting) and the heart, which can exhibit various symptoms like conduction disturbances and arrhythmia (auricular fibrillation and flutter). DM1 is caused by an unstable CTG repeat expansion in the 3' non-translated region of the DMPK gene. In healthy individuals, the number of CTG repeats ranges from 5 to 37 whereas DM1 patients carry from 50 to thousands repeats. It is well established that when expanded non-coding repeats aggregate into foci within muscle nuclei and sequester the MBNL1 splicing factor. However, the involvement of the stabilization and accumulation of CUGBP1 following PKC hyper-phosphorylation in the disease is a controversial matter in the DM1 community. Lately, in addition to the disruption of the balance between MBNL1/CUGBP1, several mechanisms were identified as part of the DM1 pathogenesis. Among them, transcription factors perturbations, altered maturation of miRNA, kinases activation… each of them leading eventually to transcriptomic alterations. In order to investigate the effect of toxic repeat expression on phenotypic and transcriptomic alterations, we generated three inducible site-specific Drosophila lines expressing 240, 600 and 960 triplet repeats. We worked in parallel on a mbl (MBNL1 orthologue) knocked-down line and two bru-3 (CUGBP1 orthologue) gain of function lines. When expressed in somatic muscles, CTG repeats lead to altered motility, fiber splitting, reduced fiber size and affected myoblast fusion process in a Mbl and Bru-3 dependent manner. In addition, toxic repeats cause fiber hyper-contraction in a Mbldependentmanner due to dSERCA mis-splicing. Comparative transcriptional profiling performed on larval muscles of different conditions show that mbl attenuation reproduces 70-82% of DM1 transcriptomic deregulations whereas bru-3 gain of function represents 32-53% of transcritomic alterations. Thus Mbl appears as a key factor of transcripts deregulations observed in DM1 muscles. On the contrary, physiologic analyses performed on adult hearts suggest that Bru-3 is a key factor for cardiac phenotypes. Indeed, on one hand, mbl attenuated flies display dilated cardiomyopathy, a symptom barely diagnosed in patients. On the other hand, bru-3 gain of function line and DM1 lines display fibrillation, which evolves withage or repeat size into a phenotype reminiscent of heart insufficiency in patients.