Avaliação dos ajustes posturais em indivíduos com instabilidade funcional do tornozelo

Introdução:O Controlo Postural é um processo neural complexo envolvido na organização da estabilidade e orientação da posição do corpo no espaço. A Instabilidade Funcional (IF) do tornozelo é descrita como uma perceção subjetiva de instabilidade articular, que afeta o controlo postural. Apesar de vários estudos terem investigado os fatores inerentes à IF ainda existe inconsistência nos resultados da literatura sobre os mecanismos envolvidos nesta. Objetivo (s):avaliar os ajustes posturais envolvidos na resposta a uma perturbação externa realizada de forma previsível e imprevisível em indivíduos com IF. Métodos:Estudo observacional analítico transversal, teve uma amostra de 20 indivíduos, que foram divididos em grupo com IF e grupo de controlo. Foi recolhida atividade eletromiográfica bilateral dos músculos longo e curto peroneal (PL e PC), tibial anterior (TA) e solear (SOL) associado a uma perturbação externa aplicada de forma previsível e imprevisível. Os ajustes posturais foram avaliados através da análise do início da atividade muscular, da magnitude global dos ajustes posturais compensatórios e antecipatórios e magnitude das respostas de curta e média latência Resultados: Na perturbação imprevisível não se verificaram diferenças significativas no início da atividade muscular (p>0,05). Enquanto na magnitude das respostas de curta e média latência verificou-se diferenças nos músculos TA (Ia,p=0,000; II, p=0,011), CP (Ia,p=0,029; II, p=0,001) e LP (Ia, p=0,030) entre o membro com IF e o controlo e no LP (II, p=0,011) entre o membro sem IF do grupo com IF e o controlo. Na perturbação previsível observaram-se diferenças nos ajustes posturais antecipatórios (APA) dos músculos TA (p=0,006) e LP (p=0,020) entre o membro sem IF do grupo com IF e o controlo. Conclusão: Os indivíduos com IF apresentam défices na magnitude das respostas de média e curta latência numa perturbação imprevisível e nos APA na perturbação previsível.

Influência do alinhamento do pé nos Ajustes Posturais Antecipatórios em crianças com Paralisia Cerebral

Introdução: A dificuldade na organização dos ajustes posturais antecipatórios (APAs) é frequentemente associada ao défice de controlo postural (CP) em crianças/jovens com um quadro motor de hemiplegia espástica, resultante de paralisia cerebral. As alterações biomecânicas da tibiotársica e do pé são características comummente observadas nestas crianças/jovens e influenciam o CP na sua globalidade. Objectivo(s): descrever o comportamento dos APAs associados ao início da marcha, face à modificação do alinhamento do pé em crianças/jovens com hemiplegia espástica, após 12 semanas de intervenção, segundo o Conceito Bobath-TND e aplicação de uma Ligadura Funcional (LF). Métodos: Foram avaliadas quatro crianças/jovens num momento inicial (M0) e após 12 semanas de intervenção e de aplicação de uma LF (M1). Recorrendo à eletromiografia de superfície, registaram-se os timings de activação dos músculos tibial anterior, solear, recto abdominal e erector da espinha (bilateralmente). O início do movimento foi calculado a partir da alteração do sinal obtido através da plataforma de pressões. Recorreu-se à aplicação da TMFM-88 para avaliar a função motora global e à aplicação da CIF-CJ para classificar a funcionalidade mediante as actividades e a participação. Procedeu-se ao registo de imagem para facilitar a observação/avaliação das componentes de movimento das crianças/jovens em estudo. Resultados: Após o período de intervenção, verificou-se uma modificação nos valores dos timings de ativação dos músculos em análise, que se aproximaram da janela temporal definida como APAs, bem como na distribuição de carga na base de suporte, nos scores da TMFM-88 e nos qualificadores das “Actividades e Participação”, sugestivos de uma melhor organização dos mecanismos de controlo postural. Conclusão: As crianças/jovens em estudo evidenciaram, após uma intervenção de fisioterapia baseada no Conceito Bobath- TND e aplicação de uma LF, uma evolução favorável tanto ao nível do CP da tibiotársica e do pé, apresentando timings de ativação muscular temporalmente mais ajustados à tarefa, com repercussões positivas nas actividades e participação.

Protocolo de Treino dos Músculos do Pavimento Pélvico em Mulheres com Incontinência Urinária de Esforço: Revisão Sistemática

Introdução: Os exercícios de fortalecimento dos músculos do pavimento pélvico (EFMPP) são considerados a primeira intervenção no tratamento da incontinência urinária de esforço (IUE), porém os EFMPP são distintos, não existindo evidência sobre os parâmetros de treino. Objetivo: Identificar o protocolo e/ ou os parâmetros de treino dos músculos do pavimento pélvico (MPP) mais eficaz no tratamento da IUE feminina. Método: A pesquisa bibliográfica foi realizada entre janeiro de 1992 a março de 2014 nas bases de dados PubMed, Cochrane Library, PEDro, web of Science e LILACS. Os artigos incluídos eram de língua inglesa, estudos experimentais, no qual comparavam EFMPP com o tratamento placebo, usual ou sem tratamento, com idade compreendida entre os 18 e os 65 anos e diagnóstico de IUE. Os critérios de exclusão abrangeram o diagnóstico de IUE desencadeada por fatores externos ao trato urinário inferior, grávidas, puérperas, prolapso ≥ 2 e outros tipos de IU. A avaliação da qualidade metodológica for realizada através da escala PEDro. Resultados: Sete artigos de elevada qualidade metodológica foram incluídos na presente revisão. A amostra foi constituída por 331 mulheres, com idade média de 44,4 anos, duração média das perdas urinárias de 64 meses e a gravidade da IUE variou entre ligeira a severa. Os programas de EFMPP eram distintos em relação aos parâmetros de treino dos MPP, sendo que alguns estudos incluíram o treino abdominal, supervisão e técnicas adjuvantes. A taxa de curada da quantidade de perda urinária variou entre 28,6 a 80%, enquanto a força dos MPP variou de 15,6% a 161,7%. Conclusão: Na presente revisão sistemática, os EFMPP combinados com palpação digital, biofeedback e cones vaginais parecem ser mais eficazes na redução da quantidade de perda urinária, comparado com os EFMPP isolados ou sem tratamento. Esta revisão permitiu igualmente identificar as 12 semanas de duração da intervenção, 10 repetições por série e diferentes posições, sendo os parâmetros de treino mais consistentes na redução dos sintomas.

Efeito da compressão isquémica no ponto gatilho latente do trapézio superior, na magnitude de atividade muscular do complexo articular do ombro

Introdução: A síndrome dolorosa miofascial é um dos principais problemas encontrados na prática clínica, tendo como principais características os pontos gatilho (PG), ativos ou latentes. Os PG latentes têm uma elevada prevalência na musculatura da cintura escapular, nomeadamente ao nível do trapézio superior (TS), influenciando o controlo motor do ombro. A compressão isquémica aplicada no PG do TS poderá influenciar o comportamento muscular dos sinergistas durante o movimento de abdução no plano da omoplata. Objetivos: Este estudo visa estudar a influência da compressão isquémica aplicada no PG do TS na magnitude de ativação dos músculos TS, trapézio inferior (TI), grande dentado (GD), infra-espinhoso (IE) e deltóide médio (DM), assim como a relação muscular através da razão entre o TS e os restantes músculos em análise, durante o movimento de abdução no plano da omoplata. Métodos: O presente estudo é experimental, aleatório e controlado. Foram criados dois grupos, grupo controlo (GC) (n=14) e grupo experimental (GE) (n=15), a partir de uma amostra de 67 indivíduos. No GC foi aplicado um procedimento placebo e no GE foi aplicada no PG latente do TS a técnica de compressão isquémica. Antes e após a intervenção foi recolhida a atividade eletromiográfica dos músculos em análise, assim como os dados cinemáticos, durante o movimento de elevação do ombro no plano da omoplata. Para a análise registou-se a amplitude máxima de abdução e foi analisada a atividade muscular individual dos músculos em estudo assim como a razão entre o TS e os restantes músculos. Esta análise foi realizada em intervalos de 30° até ao final do movimento. Resultados: Não se verificaram diferenças na amplitude máxima de abdução, nem entre grupos (1º momento p=0,608, t=0,816; 2º momento p=0,119; t=1,252) nem entre os dois momentos em cada grupo (GC, t=-1,119; p=0,256; GE, t=-1,604, p=0,135). Na magnitude de ativação individual de cada músculo também não se verificaram diferenças significativas com a aplicação da técnica, tendo-se verificado no DM uma tendência para o aumento da ativação aquando da intervenção, ao longo de todo o arco de movimento, em comparação com a pré-intervenção, já no GC de controlo não se verificaram alterações entre momentos. Também na análise da razão entre músculos não se verificaram diferenças entre grupos. Conclusão: A intervenção realizada não influenciou nenhum dos parâmetros em análise do complexo articular do ombro nem a amplitude de movimento de abdução.

Spatiotemporal mechanisms for actomyosin ring assembly and contraction in budding yeast cell division

Dissertation presented to obtain the Ph.D degree in Molecular Medicine

Regulatory RNA binding molecules : implication for diabetes pathogenesis

Le glucose est notre principale source d'énergie. Après un repas, le taux de glucose dans le sang (glycémie) augmente, ce qui entraine la sécrétion d'insuline. L'insuline est une hormone synthétisée au niveau du pancréas par des cellules dites bêta. Elle agit sur différents organes tels que les muscles, le foie ou le tissu adipeux, induisant ainsi le stockage du glucose en vue d'une utilisation future.¦Le diabète est une maladie caractérisée par un taux élevé de glucose dans le sang (hyperglycémie), résultant d'une incapacité de notre corps à utiliser ou à produire suffisamment d'insuline. A long terme, cette hyperglycémie entraîne une détérioration du système cardio-vasculaire ainsi que de nombreuses complications. On distingue principalement deux type de diabète : le diabète de type 1 et le diabète de type 2, le plus fréquent (environ 90% des cas). Bien que ces deux maladies diffèrent sur beaucoup de points, elles partagent quelques similitudes. D'une part, on décèle une diminution de la quantité de cellules bêta. Cette diminution est cependant partielle dans le cas d'un diabète de type 2, et totale dans celui d'un diabète de type 1. D'autre part, la présence dans la circulation de médiateurs de l'inflammation nommés cytokines est décelée aussi bien chez les patients de type 1 que de type 2. Les cytokines sont sécrétées lors d'une inflammation. Elles servent de moyen de communication entre les différents acteurs de l'inflammation et ont pour certaines un effet néfaste sur la survie des cellules bêta.¦L'objectif principal de ma thèse a été d'étudier en détail l'effet de petites molécules régulatrices de l'expression génique, appelées microARNs. Basé sur le fait que de nombreuses publications ont démontré que les microARNs étaient impliqués dans différentes maladies telles que le cancer, j'ai émis l'hypothèse qu'ils pouvaient également jouer un rôle important dans le développement du diabète.¦Nous avons commencé par mettre des cellules bêta en culture en présence de cytokines, imitant ainsi un environnement inflammatoire. Nous avons pu de ce fait identifier les microARNs dont les niveaux d'expression étaient modifiés. A l'aide de méthodes biochimiques, nous avons ensuite observé que la modulation de certains microARNs par les cytokines avaient des effets néfastes sur la cellule bêta : sur sa production et sa sécrétion d'insuline, ainsi que sur sa mort (apoptose). Nous avons en conséquence pu démontrer que ces petites molécules avaient un rôle important à jouer dans le dysfonctionnement des cellules bêta induit par les cytokines, aboutissant au développement du diabète.¦-¦La cellule bêta pancréatique est une cellule endocrine présente dans les îlots de Langerhans, dans le pancréas. L'insuline, une hormone sécrétée par ces cellules, joue un rôle essentiel dans la régulation de la glycémie. Le diabète se développe si le taux d'insuline relâché par les cellules bêta n'est pas suffisant pour couvrir les besoins métaboliques corporels. Le diabète de type 1, qui représente environ 5 à 10% des cas, est une maladie auto-immune qui se caractérise par une réaction inflammatoire déclenchée par notre système immunitaire envers les cellules bêta. La conséquence de cette attaque est une disparition progressive des cellules bêta. Le diabète de type 2 est, quant à lui, largement plus répandu puisqu'il représente environ 90% des cas. Des facteurs à la fois génétiques et environnementaux sont responsables d'une diminution de la sensibilité des tissus métabolisant l'insuline, ainsi que d'une réduction de la sécrétion de l'insuline par les cellules bêta, ce qui a pour conséquence le développement de la maladie. Malgré les différences entre ces deux types de diabète, ils ont pour points communs la présence d'infiltrat immunitaire et la diminution de l'état fonctionnel des cellules bêta.¦Une meilleure compréhension des mécanismes aboutissant à l'altération de la cellule bêta est primordiale, avant de pouvoir développer de nouvelles stratégies thérapeutiques capables de guérir cette maladie. Durant ma thèse, j'ai donc étudié l'implication de petites molécules d'ARN, régulatrices de l'expression génique, appelées microARNs, dans les conditions physiopathologiques qui aboutissent au développement du diabète. J'ai débuté mon étude par l'identification de microARNs dont le niveau d'expression était modifié lorsque les cellules bêta étaient exposées à des conditions favorisant à la fois le développement du diabète de type 1 (cytokines) et celui du diabète de type 2 (palmitate). Nous avons découvert qu'une modification de l'expression des miR-21, -34a et -146a était commune aux deux traitements. Ces changements d'expressions ont également été confirmés dans deux modèles animaux : les souris NOD qui développent un diabète s'apparentant au diabète de type 1 et les souris db/db qui développent plutôt un diabète de type 2. Puis, à l'aide de puces à ADN, nous avons comparé l'expression de microARNs chez des souris NOD pré-diabétiques. Nous avons alors retrouvé des changements au niveau de l'expression des mêmes microARNs mais également au niveau d'une famille de microARNs : les miR-29a, -29b et -29c. De manière artificielle, nous avons ensuite surexprimé ou inhibé en conditions physiopathologiques l'expression de tous ces microARNs et nous nous sommes intéressés à l'impact d'un tel changement sur différentes fonctions de la cellule bêta comme la synthèse et la sécrétion d'insulinè ainsi que leur survie. Nous avons ainsi pu démontrer que les miR-21, -34a, -29a, -29b, -29c avaient un effet délétère sur la sécrétion d'insuline et que la surexpression de tous ces microARNs (excepté le miR-21) favorisait la mort. Finalement, nous avons démontré que la plupart de ces microARNs étaient impliqués dans la régulation d'importantes voies de signalisation responsables de l'apoptose des cellules bêta telles que les voies de NFKB, BCL2 ou encore JNK.¦Par conséquent, nos résultats démontrent que les microARNs ont un rôle important à jouer dans le dysfonctionnement des cellules bêta lors de la mise en place du diabète.

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy.

Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.

Static and dynamic shoulder stabilizer adaptations in javelin throwers: A preliminary study

BACKGROUND: Adaptations to Internal (IR) and external (ER) rotator shoulder muscles improving overhead throwing kinematics could lead to muscular strength imbalances and be considered an intrinsic risk factor for shoulder injury, as well as modified shoulder range of motion (RoM). OBJECTIVE: To establish profiles of internal and external rotation RoM and isokinetic IR and ER strength in adolescent- and national-level javelin throwers. METHODS: Fourteen healthy subjects were included in this preliminary cross-sectional study, 7 javelin throwers (JTG) and 7 nonathletes (CG). Passive internal and external rotation RoM were measured at 90 degrees of shoulder abduction. Isokinetic strength of dominant and non-dominant IR and ER was evaluated during concentric (60, 120 and 240 degrees/s) and eccentric (60 degrees/s) contractions by Con-Trex (R) dynamometer with the subject in a seated position with 45 degrees of shoulder abduction in the scapular plane. RESULTS: We reported significantly lower internal rotation and significantly higher external rotation RoM in JTG than in CG. Concentric and eccentric IR and ER strength were significantly higher for the dominant shoulder side in JTG (P < 0.05), without significant differences in ER/IR ratios. CONCLUSIONS: The main finding of this preliminary study confirmed static and dynamic shoulder stabilizer adaptations due to javelin throw practice in a population of adolescent- and national-level javelin throwers.

A musculoskeletal shoulder model based on pseudo-inverse and null-space optimization.

The goal of the present work was assess the feasibility of using a pseudo-inverse and null-space optimization approach in the modeling of the shoulder biomechanics. The method was applied to a simplified musculoskeletal shoulder model. The mechanical system consisted in the arm, and the external forces were the arm weight, 6 scapulo-humeral muscles and the reaction at the glenohumeral joint, which was considered as a spherical joint. The muscle wrapping was considered around the humeral head assumed spherical. The dynamical equations were solved in a Lagrangian approach. The mathematical redundancy of the mechanical system was solved in two steps: a pseudo-inverse optimization to minimize the square of the muscle stress and a null-space optimization to restrict the muscle force to physiological limits. Several movements were simulated. The mathematical and numerical aspects of the constrained redundancy problem were efficiently solved by the proposed method. The prediction of muscle moment arms was consistent with cadaveric measurements and the joint reaction force was consistent with in vivo measurements. This preliminary work demonstrated that the developed algorithm has a great potential for more complex musculoskeletal modeling of the shoulder joint. In particular it could be further applied to a non-spherical joint model, allowing for the natural translation of the humeral head in the glenoid fossa.

Mitochondrial uncoupling prevents cold-induced oxidative stress: a case study using UCP1 knockout mice.

The relationship between metabolism and reactive oxygen species (ROS) production by the mitochondria has often been (wrongly) viewed as straightforward, with increased metabolism leading to higher generation of pro-oxidants. Insights into mitochondrial functioning show that oxygen consumption is principally coupled with either energy conversion as ATP or as heat, depending on whether the ATP-synthase or the mitochondrial uncoupling protein 1 (UCP1) is driving respiration. However, these two processes might greatly differ in terms of oxidative costs. We used a cold challenge to investigate the oxidative stress consequences of an increased metabolism achieved either by the activation of an uncoupled mechanism (i.e. UCP1 activity) in the brown adipose tissue (BAT) of wild-type mice or by ATP-dependent muscular shivering thermogenesis in mice deficient for UCP1. Although both mouse strains increased their metabolism by more than twofold when acclimatised for 4 weeks to moderate cold (12°C), only mice deficient for UCP1 suffered from elevated levels of oxidative stress. When exposed to cold, mice deficient for UCP1 showed an increase of 20.2% in plasmatic reactive oxygen metabolites, 81.8% in muscular oxidized glutathione and 47.1% in muscular protein carbonyls. In contrast, there was no evidence of elevated levels of oxidative stress in the plasma, muscles or BAT of wild-type mice exposed to cold despite a drastic increase in BAT activity. Our study demonstrates differing oxidative costs linked to the functioning of two highly metabolically active organs during thermogenesis, and advises careful consideration of mitochondrial functioning when investigating the links between metabolism and oxidative stress.

Patient satisfaction after biofeedback for constipation and pelvic floor dyssynergia.

Patients referred for chronic constipation frequently report symptoms of straining, feeling of incomplete evacuation, or the need to facilitate defecation digitally (dyschezia). When such patients show manometric evidence of inappropriate contraction or failure to relax the pelvic floor muscles during attempts to defecate, they are diagnosed as having pelvic floor dyssynergia (Rome I). To evaluate long-term satisfaction of patients with pelvic floor dyssynergia after biofeedback. Forty-one consecutive patients referred for chronic constipation at an outpatient gastrointestinal unit and diagnosed as having pelvic floor dyssynergia who completed a full course of biofeedback. Data have been collected using a standardised questionnaire. A questionnaire survey of patients' satisfaction rate and requirement of aperients was undertaken. Mean age and symptom duration were respectively 41 and 20 years. Half of patients reported fewer than 3 bowel motions per week. Patients were treated with a mean of 5 biofeedback sessions. At the end of the therapy pelvic floor dyssynergia was alleviated in 85% of patients and 49% were able to stop all aperients. Satisfaction was maintained at follow-up telephone interviews undertaken after a mean period of 2 years, as biofeedback was helpful for 79% of patients and 47% still abstained from intake of aperients. Satisfaction after biofeedback is high for patients referred for chronic constipation and diagnosed with pelvic floor dyssynergia. Biofeedback improves symptoms related to dyschezia and reduces use of aperients.

Transfer factor for carbon monoxide: a glance behind the scene.

The transfer factor for carbon monoxide (TLCO) is widely used in pulmonary function laboratories because it represents a unique non-invasive window on pulmonary microcirculation. The TLCO is the product of two primary measurements, the alveolar volume (VA) and the CO transfer coefficient (KCO). This test is most informative when VA and KCO are examined, together with their product TLCO. In a normal lung, a low VA due to incomplete expansion is associated with an elevated KCO, resulting in a mildly reduced TLCO. Thus, in case of low VA, a seemingly "normal KCO" must be interpreted as an abnormal gas transfer. The most common clinical conditions associated with an abnormal TLCO are characterised by a limited number of patterns for VA and KCO: incomplete lung expansion, discrete loss of alveolar units, diffuse loss of alveolar units, emphysema, pulmonary vascular disorders, high pulmonary blood volume, alveolar haemorrhage.

Mitochondrial uncoupling as a regulator of life-history trajectories in birds: an experimental study in the zebra finch.

Mitochondria have a fundamental role in the transduction of energy from food into ATP. The coupling between food oxidation and ATP production is never perfect, but may nevertheless be of evolutionary significance. The 'uncoupling to survive' hypothesis suggests that 'mild' mitochondrial uncoupling evolved as a protective mechanism against the excessive production of damaging reactive oxygen species (ROS). Because resource allocation and ROS production are thought to shape animal life histories, alternative life-history trajectories might be driven by individual variation in the degree of mitochondrial uncoupling. We tested this hypothesis in a small bird species, the zebra finch (Taeniopygia guttata), by treating adults with the artificial mitochondrial uncoupler 2,4-dinitrophenol (DNP) over a 32-month period. In agreement with our expectations, the uncoupling treatment increased metabolic rate. However, we found no evidence that treated birds enjoyed lower oxidative stress levels or greater survival rates, in contrast to previous results in other taxa. In vitro experiments revealed lower sensitivity of ROS production to DNP in mitochondria isolated from skeletal muscles of zebra finch than mouse. In addition, we found significant reductions in the number of eggs laid and in the inflammatory immune response in treated birds. Altogether, our data suggest that the 'uncoupling to survive' hypothesis may not be applicable for zebra finches, presumably because of lower effects of mitochondrial uncoupling on mitochondrial ROS production in birds than in mammals. Nevertheless, mitochondrial uncoupling appeared to be a potential life-history regulator of traits such as fecundity and immunity at adulthood, even with food supplied ad libitum.

Artificial muscle: the human chimera is the future.

Severe heart failure and cerebral stroke are broadly associated with the impairment of muscular function that conventional treatments struggle to restore. New technologies enable the construction of "smart" materials that could be of great help in treating diseases where the main problem is muscle weakness. These materials "behave" similarly to biological systems, because the material directly converts energy, for example electrical energy into movement. The extension and contraction occur silently like in natural muscles. The real challenge is to transfer this amazing technology into devices that restore or replace the mechanical function of failing muscle. Cardiac assist devices based on artificial muscle technology could envelope a weak heart and temporarily improve its systolic function, or, if placed on top of the atrium, restore the atrial kick in chronic atrial fibrillation. Artificial sphincters could be used to treat urinary incontinence after prostatectomy or faecal incontinence associated with stomas. Artificial muscles can restore the ability of patients with facial paralysis due to stroke or nerve injury to blink. Smart materials could be used to construct an artificial oesophagus including peristaltic movement and lower oesophageal sphincter function to replace the diseased oesophagus thereby avoiding the need for laparotomy to mobilise stomach or intestine. In conclusion, in the near future, smart devices will integrate with the human body to fill functional gaps due to organ failure, and so create a human chimera.

Calpain 3, the "gatekeeper" of proper sarcomere assembly, turnover and maintenance.

Calpain 3 is a member of the calpain family of calcium-dependent intracellular proteases. Thirteen years ago it was discovered that mutations in calpain 3 (CAPN3) result in an autosomal recessive and progressive form of limb girdle muscular dystrophy called limb girdle muscular dystrophy type 2A. While calpain 3 mRNA is expressed at high levels in muscle and appears to have some role in developmental processes, muscles of patients and mice lacking calpain 3 still form apparently normal muscle during prenatal development; thus, a functional calpain 3 protease is not mandatory for muscle to form in vivo but it is a pre-requisite for muscle to remain healthy. Despite intensive research in this field, the physiological substrates of the calpain 3 protein (hereafter referred to as CAPN3) and its alternatively spliced isoforms remain elusive. The existence of these multiple isoforms complicates the search for the physiological functions of CAPN3 and its pathophysiological role. In this review, we summarize the genetic and biochemical evidence that point to loss of function of the full-length isoform of CAPN3, also known as p94, as the pathogenic isoform. We also argue that its natural substrates must reside in its proximity within the sarcomere where it is stored in an inactive state anchored to titin. We further propose that CAPN3 has many attributes that make it ideally suited as a sensor of sarcomeric integrity and function, involved in its repair and maintenance. Loss of these CAPN3-mediated activities can explain the "progressive" development of muscular dystrophy.