Critically ill patients admitted to the intensive care unit (ICU) commonly develop severe muscle wasting and weakness and consequently impaired muscle function. This not only delays respirator weaning and ICU discharge, but has deleterious effects on morbidity, mortality, financial costs, and quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders underlying ICU muscle wasting and paralysis, and is a consequence of modern intensive care interventions, although the exact causes remain unclear. Muscle gene/protein expression, intracellular signalling, post-translational modifications, muscle membrane excitability, and contractile properties at the single muscle fibre level were explored in order to unravel the mechanisms underlying the muscle wasting and weakness associated with AQM and how this can be counteracted by specific intervention strategies. A unique experimental rat ICU model was used to address the mechanistic and therapeutic aspects of this condition, allowing time-resolved studies for a period of two weeks. Subsequently, the findings obtained from this model were translated into a clinical study. The obtained results showed that the mechanical silencing of skeletal muscle, i.e., absence of external strain (weight bearing) and internal strain (myosin-actin activation) due to the pharmacological paralysis or sedation associated with the ICU intervention, is likely to be the primary mechanism triggering the preferential myosin loss and muscle wasting, features specifically characteristic of AQM. Moreover, mechanical silencing induces a specific gene expression pattern as well as post-translational modifications in the motor domain of myosin that may be critical for both function and for triggering proteolysis. The higher nNOS expression found in the ICU patients and its cytoplasmic dislocation are indicated as a probable mechanism underlying these highly specific modifications. This work also demonstrated that passive mechanical loading is able to attenuate the oxidative stress associated with the mechanical silencing and induces positive effects on muscle function, i.e., alleviates the loss of force-generating capacity that underlie the ICU intervention, supporting the importance of early physical therapy in immobilized, sedated, and mechanically ventilated ICU patients.

<p>The purpose of this study was to gain more knowledge about the deleterious effects of decreased muscle protein concentration on skeletal muscle function, by measuring the concentrations of myosin and actin in single pig muscle fibres. The pigs were earlier used in an experimental animal model to study the early stages of acute quadriplegic myopathy (AQM), a disease that is found in mechanically ventilated intensive care unit patients. Percutaneous biopsies were taken from these pigs and where now used in this study.</p><p>Even though the method used was accurately tested and theoretically working, certain problems arose. These problems were unexpected and caused problems to the study. The method used to measure the concentration of myosin and actin, an ELISA, gave no logical results. The reason could not be found and because of the time limit of this project no results from the AQM-pigs were gained. The efforts to make the method work is described and discussed.</p>

The purpose of this study was to gain more knowledge about the deleterious effects of decreased muscle protein concentration on skeletal muscle function, by measuring the concentrations of myosin and actin in single pig muscle fibres. The pigs were earlier used in an experimental animal model to study the early stages of acute quadriplegic myopathy (AQM), a disease that is found in mechanically ventilated intensive care unit patients. Percutaneous biopsies were taken from these pigs and where now used in this study. Even though the method used was accurately tested and theoretically working, certain problems arose. These problems were unexpected and caused problems to the study. The method used to measure the concentration of myosin and actin, an ELISA, gave no logical results. The reason could not be found and because of the time limit of this project no results from the AQM-pigs were gained. The efforts to make the method work is described and discussed.

This study explored the meaning people with spinal cord injuries give to physical activity and recreation participation as they make the transition from the protected environment of hospital rehabilitation to the reality of returning to their homes and communities. The experiences of 4 individuals between 15 and 24 years of age who had sustained spinal cord injuries within the previous five years were captured using the phenomenological methods of semi-structured individual interviews, focus group interviews, photographs, and field notes. Rimmers (1999) model of health promotion for people with disabilities combined with Peters (1996) model of disablement provided the conceptual framework for the study and facilitated the interpretation of the findings. The participants indicated that physical activity was a very important component to living a psychologically, socially and physically healthy lifestyle following a spinal cord injury. A thematic analysis revealed three themes: (a) as my body heals, (b) learning to be me, and (3) getting back to life. The importance of physical activity in maintaining a healthy lifestyle following a spinal cord injury was reflected in stories of physical activity as a component of hospital rehabilitation, the importance of physical activity during the transition from the hospital to the challenges of returning home, and finally, engagement in community based physical activity. A gap in the continuity of physical activity opportunities during the transition from in-hospital rehabilitation to the return to the community was identified.

This study explored the meaning people with spinal cord injuries give to physical activity and recreation participation as they make the transition from the protected environment of hospital rehabilitation to the reality of returning to their homes and communities. The experiences of 4 individuals between 15 and 24 years of age who had sustained spinal cord injuries within the previous five years were captured using the phenomenological methods of semi-structured individual interviews, focus group interviews, photographs, and field notes. Rimmers (1999) model of health promotion for people with disabilities combined with Peters (1996) model of disablement provided the conceptual framework for the study and facilitated the interpretation of the findings. The participants indicated that physical activity was a very important component to living a psychologically, socially and physically healthy lifestyle following a spinal cord injury. A thematic analysis revealed three themes: (a) as my body heals, (b) learning to be me, and (3) getting back to life. The importance of physical activity in maintaining a healthy lifestyle following a spinal cord injury was reflected in stories of physical activity as a component of hospital rehabilitation, the importance of physical activity during the transition from the hospital to the challenges of returning home, and finally, engagement in community based physical activity. A gap in the continuity of physical activity opportunities during the transition from in-hospital rehabilitation to the return to the community was identified.

Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors. The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.

<p>The combination of a severe systemic illness, corticosteroids, and neuromuscular blocking agents in patients on the mechanical ventilator often results in a condition known as Acute Quadriplegic Myopathy (AQM). While severe weakness of all spinal nerve innervated muscles is known to be a significant clinical characteristic of the disease, this symptom is typically not recognized until the disease has progressed to an advanced stage. End result effects have been classified, which include the loss of the thick filament, or myosin heavy chain, an in-excitable muscle membrane, and an up-regulation of protein degradation; however, there is little known about the acute stage of AQM. This project has focused on understanding the underlying mechanisms of AQM, specifically in regard to protein synthesis, both at the mRNA and nuclear transcription levels. To study the early stages of the disease two animal models have been developed: rat and pig. Further, we have examined AQM muscle tissue, to investigate the similarities of our animal models to patients, as well as to study the recovery process. Particular interest was directed on the myofibrillar proteins myosin (MyHC) and actin, as they are the primary proteins involved in muscle contraction, as well as the myosin associated proteins, myosin binding protein C and H. </p><p>At the mRNA level, MyHC and actin are both down-regulated in response to AQM. The myosin binding proteins are affected differently, with H protein increasing during severe atrophy and C protein either being slightly down-regulated or unchanged. Nuclear transcription factors were also affected, with such factors as MuRF1 and MAFbx up-regulated. </p><p>Thus far results have shown that protein synthesis is altered in AQM and largely contributes to both the development and recovery of the disease. The pathways of protein synthesis may prove to be an ideal target for the prevention of AQM and/or symptom alleviation.</p>

The combination of a severe systemic illness, corticosteroids, and neuromuscular blocking agents in patients on the mechanical ventilator often results in a condition known as Acute Quadriplegic Myopathy (AQM). While severe weakness of all spinal nerve innervated muscles is known to be a significant clinical characteristic of the disease, this symptom is typically not recognized until the disease has progressed to an advanced stage. End result effects have been classified, which include the loss of the thick filament, or myosin heavy chain, an in-excitable muscle membrane, and an up-regulation of protein degradation; however, there is little known about the acute stage of AQM. This project has focused on understanding the underlying mechanisms of AQM, specifically in regard to protein synthesis, both at the mRNA and nuclear transcription levels. To study the early stages of the disease two animal models have been developed: rat and pig. Further, we have examined AQM muscle tissue, to investigate the similarities of our animal models to patients, as well as to study the recovery process. Particular interest was directed on the myofibrillar proteins myosin (MyHC) and actin, as they are the primary proteins involved in muscle contraction, as well as the myosin associated proteins, myosin binding protein C and H. At the mRNA level, MyHC and actin are both down-regulated in response to AQM. The myosin binding proteins are affected differently, with H protein increasing during severe atrophy and C protein either being slightly down-regulated or unchanged. Nuclear transcription factors were also affected, with such factors as MuRF1 and MAFbx up-regulated. Thus far results have shown that protein synthesis is altered in AQM and largely contributes to both the development and recovery of the disease. The pathways of protein synthesis may prove to be an ideal target for the prevention of AQM and/or symptom alleviation.

La thèse porte sur l’accompagnement de patients atteints de déficiences motrices handicapantes soumis à l’épreuve intime de soi à la suite d’une atteinte radicale du corps. Elle repose sur une enquête ethnographique, associant observations et entretiens, menée dans deux structures hospitalières du CHU de Saint-Etienne : le service de Soins de Rééducation Post Réanimation, dit SRPR et, pour une plus grande part, le service de Médecine Physique et Réadaptation, dit MPR. En présentant le travail de « recapacitation » de la personne à l’épreuve d’un nouveau corps devenu « non autonome », la thèse explore le travail relationnel entre les professionnels de santé et le patient au cours des soins et des activités de rééducation fonctionnelle, mais aussi la manière dont sont inclus les proches, afin d’infléchir la perception de la situation de handicap et de construire collectivement un projet acceptable de vie après le séjour en milieu hospitalier. Cette perspective donne à voir la manière dont, face aux fortes contraintes de l’épreuve intime de soi, la parole partagée devient ressource pour faire advenir les interactions et engager ainsi le patient dans la réappropriation intrasubjective de son corps et intersubjective de la continuité de son être. Une place importante est donnée au parcours des patients tétraplégiques, un cas extrême et à part dans la prise en charge des patients en MPR. La thèse présente une chronique du vécu de ces patients particuliers, et montre ainsi la spécificité des « étapes » passées, qui structurent l’expérience du corps « non autonome » et de la personne qui, devenue « dépendante », est incluse dans un collectif d’actants humains – les professionnels de santé, les proches  mais aussi d’objets techniques, au sein duquel son agir est distribué. Le récit rend compte des temps et des moments vécus par ces patients dans ce collectif, au cours d’une prise en charge pouvant se compter en mois, voire en années, en déclinant les activités ordinaires des chambres, celles du plateau technique, celles des réunions de professionnels et enfin celles, exceptionnelles, d’un dispositif de rencontre ad hoc qui réunit un collectif d’anciens patients venus avec leurs conjointes et un patient tétraplégique et sa compagne afin de finaliser le projet de retour de ce dernier dans l’espace social ordinaire. / The doctoral thesis focuses on the assistance of functional impaired patients passing throug a personal self experience following a severe physical injury. It is based on an ethnographic inquiry, combining observations and interviews that have been conducted in two hospital services of Saint-Etienne’s UH. The first service is the functional rehabilitation recovery service and, for the major part, the other is the physical medecine and rehabilitation service. In presenting the « recapacitation » work of a person experimenting a new « non autonomous » body, the thesis explores relations between the medical professionals and patients, during the care and functional rehabilitation activities, but also the way in which relatives are included, in order to impact the perception of the handicap situation and to build collectively an acceptable life project after the hospital stay. This perspective reveals how to confront strong constraints of personal self experience by sharing words, this last become as a ressource to bring into the interactions and thus to engage the patient in an intrasubjective reappropriation of his body and an intersubjective continuity of his being. An important place is given to the hospitalization of quadriplegic patients, which is an extreme case and apart in the patient’s care in the physical medecine and rehabilitation service. The thesis presents a chronicle of a lived experience of these particular patients and thus shows the specificity of the process taken place in order to structure the experience of non autonomous body and to the one who has become dependent, and included in a collective composed of human actors  medical professionals, relatives  but also technical objects in which his act is distribued. The narrative takes into consideration the time and the moments experienced by these patients in this collective, during the care which can be counted by months and sometimes by years, by describing the ordinary activities in the rooms, those of the technical installations, those of professional’s meetings, finally and exceptionally a meeting’s structure where a group of former patients come with their spouses and a quadriplegic patient accompanied by his partner, to finalize the project of his return to an ordinary social environment.