No description available.

Duchenne muscular dystrophy (DMD) is an X-linked lethal condition associated with high morbidity and mortality. There is currently no cure for this disease. Several gene-based therapeutic approaches for treating DMD are currently under development but all are dependent on the knowledge of the causative dystrophin gene mutation. A combined mutation detection approach consisting of a quantitative PCR based analysis and DNA sequencing of the dystrophin gene resulted in a mutation etection rate of 96% in the New South Wales (NSW) DMD cohort. The proportion of exon duplication mutations was twice that generally reported for similar patient opulations. The clinical utility of the combined mutation protocol for DMD carrier testing clarified the carrier status of an additional one-third (33%) of female relatives compared to a conventional approach of biochemical, pedigree and linkage studies. The generally accepted view that two-thirds of mothers of isolated cases of DMD are themselves mutation carriers is challenged. Although this assumption is valid for duplication and DNA sequence mutations, it is not valid for deletion mutations in the NSW cohort. The incidence of new cases of DMD in the New South Wales population was educed from approximately 1 in 3594 live male births to 1 in 6022 live male births over a 25 year period, indicative of a significant effect of the combination of genetic counselling and improved methods of carrier detection over that period. In a study of a cohort of boys with DMD, who had both psychological and mutational analysis, it was shown that mutations affecting the shorter, C-terminal isoforms of dystrophin are associated with decreased mean intellectual function. A hypothesis is presented that mutations within the long 5' untranslated region of the Dp140 isoform are unlikely to significantly affect expression of this brain-expressed isoform. During the course of studying the NSW DMD cohort a family was identified which exhibited X-linkage and a unique clinical presentation involving episodes of severe and prolonged muscle weakness. A novel variant in the pyruvate dehydrogenase E1 alpha subunit (PDHA 1) was identified. The phenotypic effect of this variant is not proven but a body of evidence implicates this as likely to be causative of the observed phenotype.

No description available.

<b>Introduction</b>: Kinesiology-style manual muscle testing (kMMT) is a non-invasive assessment method used by various types of practitioners to detect a wide range of target conditions. It is distinctly different from the muscle testing performed in orthopaedic/neurological settings and from Applied kinesiology. Despite being estimated to be used by over 1 million people worldwide, the usefulness of kMMT has not yet been established. The aim of this thesis was to assess the validity of kMMT by examining its accuracy and precision. <b>Methods</b>: A series of 5 diagnostic test accuracy studies were undertaken. In the first study, the index test was kMMT, and the target condition was deceit in verbal statements spoken by Test Patients (TPs). The comparator reference standard was a true gold standard: the actual verity of the spoken statement. The outcomes of the muscle tests were interpreted consistently: a weak result indicated a Lie and a strong result indicated a Truth. A secondary index test was included as a comparator: Intuition, where Practitioners used intuition (without using kMMT) to ascertain if a Lie or Truth was spoken. Forty-eight Practitioners were recruited and paired with 48 unique kMMT-naïve TPs. Each Pair performed 60 kMMTs broken up into 6 blocks of 10, which alternated with blocks of 10 Intuitions. For each Pair, an overall percent correct was calculated for both kMMT and Intuition, and their means were compared. Also calculated for both tests were sensitivity, specificity, positive predictive value and negative predictive value. The second study was a replication of the first, using a sample size of 20 Pairs and a less complex procedure. In the third study, grip strength dynamometry replaced kMMT as the primary index test. In the fourth study, the reproducibility and repeatability of kMMT were examined. In the final study, TPs were presented with emotionally-arousing stimuli in addition to the affect-neutral stimuli used in previous studies, to assess if stimuli valence impacted kMMT accuracy. <b>Results</b>: Throughout this series of studies, mean kMMT accuracies (95% Confidence Intervals; CIs) ranged from 0.594 (0.541 – 0.647) to 0.659 (0.623 - 0.695) and mean Intuition accuracies, from 0.481 (0.456 - 0.506) to 0.526 (0.488 - 0.564). In all studies, mean kMMT accuracies were found to be significantly different from mean Intuition accuracies (p ≤ 0.01), and from Chance (p < 0.01). On the other hand, no difference was found between grip strength following False statements compared to grip strength following True statements (p = 0.61). In addition, the Practitioner-TP complex accounted for 57% of the variation in kMMT accuracy, with 43% unaccounted for. Also, there was no difference in the mean kMMT accuracy when using emotionally-arousing stimuli compared to when using affect-neutral stimuli (p = 0.35). Mean sensitivities (95% CI) ranged from 0.503 (0.421 - 0.584) to 0.659 (0.612 - 0.706) while mean specificities (95% CI) ranged from 0.638 (0.430 - 0.486) to 0.685 (0.616 - 0.754). Finally, while a number of participant characteristic seemed to influence kMMT accuracy during one study or another, no one specific characteristic was found to influence kMMT accuracy consistently (i.e. across the series of studies). <b>Discussion</b>: This series of studies has shown that kMMT can be investigated using rigorous evidence-based health care methods. Furthermore, for distinguishing lies from truths, kMMT has repeatedly been found to be significantly more accurate than both Intuition and Chance. Practitioners appear to be an integral part of the kMMT dynamic because when replaced by a mechanical device (i.e. a grip strength dynamometer), distinguishing Lies from Truth was not possible. In addition, since specificities seemed to be greater than sensitivities, Truths may have been easier to detect than Lies. A limitation of this series of studies is that I have a potential conflict of interest, in that I am a practitioner of kMMT who gets paid to perform kMMT. Another limitation is these results are not generalisable to other applications of kMMT, such as its use in other paradigms or using muscles other than the deltoid. Also, these results suggest that kMMT may be about 60&percnt; accurate, which is statistically different from Intuition and Chance; however it has not been established if 60&percnt; correct is "good enough" in a clinical context. As such, further research is needed to assess its clinical utility, such as randomised controlled trials investigating the effectiveness of whole kMMT technique systems. Also, future investigators may want to explore what factors, such as specific Practitioner and TP characteristics, influence kMMT accuracy, and to investigate the validity of using kMMT to detect other target conditions, using other reference standards and muscles other than the deltoid. <b>Summary</b>: This series of diagnostic test accuracy studies has found that kMMT can be investigated using rigorous methods, and that kMMT used to distinguish Lies from Truths is significantly more accurate that both Intuition and Chance. Further research is needed to assess kMMT’s clinical utility.

Introdução. Pacientes portadores de diabetes mellitus tipo 2 (DM2) podem apresentar fraqueza da musculatura inspiratória. O efeito do treinamento muscular inspiratório (TMI) nesses pacientes ainda é desconhecido. Objetivos. Avaliar os efeitos do TMI sobre a força muscular inspiratória, a função pulmonar, a capacidade funcional e a modulação autonômica em pacientes com DM2 com fraqueza da musculatura inspiratória. Métodos. A pressão inspiratória máxima (PImáx) foi avaliada em uma amostra de 148 pacientes com DM2 da qual 25 pacientes com PImáx < 70% do previsto foram randomizados para um programa de 8 semanas de TMI diário (n=12) ou TMI-placebo (n=13). A PImáx, a função pulmonar, o consumo máximo de oxigênio e a variabilidade da freqüência cardíaca foram avaliados antes e após o TMI. Resultados. Do total de pacientes avaliados, 29,05% (43 pacientes) apresentaram fraqueza muscular inspiratória. O TMI aumentou significativamente a PImáx (118%) e a resistência muscular inspiratória (320%), sem alterar a função pulmonar, a capacidade funcional e a modulação autonômica. Conclusões. O TMI, em pacientes com DM2 e fraqueza dos músculos inspiratórios, aumentou significativamente a PImáx sem modificar a função pulmonar, a capacidade funcional e a modulação autonômica. / Introduction. Subject with type 2 diabetes mellitus (DM2) can present weakness of the inspiratory muscle. The effect of the inspiratory muscle training (IMT) in these patients still is unknown. Objectives. To evaluate the effect of the IMT on the inspiratory muscle force, the pulmonary function, the functional capacity and the autonômica modulation in patients DM2 with weakness of the inspiratory muscle. Methods. The maximum inspiratory pressure (PImáx) was evaluated in a sample of 148 patients with DM2 of which 25 patients with PImáx < 70% of the foreseen one had been randomizeds for a program of 8 weeks of daily IMT (n=12) or IMT-placebo (n=13). The PImáx, the function pulmonary, the VO2 and the variability of the cardiac frequency had been evaluated before and after the IMT. Results. Of the total of evaluated patients, 29.05% (43 patients) had presented inspiratory muscle weakness. The IMT significantly increased the PImáx (118%) and the inspiratory muscle resistance (320%), without modifying the function pulmonary, the exercise capacity and the modulation autonomic. Conclusions. The IMT in patients with DM2 and weakness of the inspiratory muscles increased the PImáx without modifying the function pulmonary, the exercise capacity and the modulation autonomic significantly.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / OBJECTIVE: To assess the relationship between physical performance (PP) and muscle strength (MS) in elderly subjects with and without diabetes in a public hospital of Lima, Peru. SUBJECTS AND METHOD: A cross-sectional analysis of subjects aged 60 years or older with and without diabetes. MS was measured with a handheld dynamometer, and PP with the «timed get-up-and-go» test. Nutritional status was determined using body mass index, body fat percentage measured with a handheld fat loss monitor and protein intake based on the 24-hour recall. Age, sex, and history of hospitalization and supplementation were also recorded. The association was assessed using adjusted prevalence ratios. RESULTS: Overall, 139 patients with diabetes (26.6% with low PP and 13.7% with decreased MS) and 382 subjects without diabetes (36.6% with low PP and 23.0% with decreased MS) were evaluated. No association was found between T2DM and MS (aPR: 0.99; 95% CI: 0.67-1.57) or PP (aPR: 1.13; 95% CI: 0.84-1.52). Protein and supplement consumption was also unrelated (P>.05); however, history of hospitalization, age, sex, nutritional status, and body fat percentage were related (P>.05). CONCLUSIONS: No association was found between T2DM, MS, and PP. However, low PP was associated to female sex and overweight/obesity, and decreased MS was associated to high body fat percentage and underweight. Moreover, MS and PP were related to older age and history of hospitalization. / Revisión por pares

Sepsis is a severe life-threatening critical illness that damages multiple physiological systems. After hospital discharge, more than 70% of severe sepsis survivors report profound weakness which significantly impacts quality of life. Such weakness gives rise to new limitations of daily living, which ultimately leads to loss of independence in many patients. Despite wide recognition of this serious issue by clinicians and researchers alike, the mechanisms contributing to chronic skeletal muscle dysfunction after sepsis are not well understood. Lack of progress in this field is largely due to the absence of an appropriate animal model; current models are either too mild to induce muscle weakness or too severe and cause death within a few days. As such, this dissertation work first focused on establishing a clinically-relevant animal model of sepsis which yields surviving mice with chronic skeletal muscle weakness (Aim 1). This aim involved refining the cecal slurry injection model of polymicrobial sepsis in young adult animals, as well as optimizing the timing, duration, and dose of multiple therapeutic agents. The resulting resuscitation protocol was adapted for use in late-middle-aged animals, and muscle strength was evaluated using an ex vivo system which confirmed significant muscle weakness in sepsis survivors, long after sepsis was resolved. Next, using this novel model, we sought to characterize sepsis-induced long-term muscle dysfunction at the molecular level (Aim 2). The first set of experiments under this aim was designed to identify the primary global mechanism(s) (i.e. atrophy, polyneuropathy, and/or myopathy) responsible for muscle weakness in sepsis survivors. Analysis of the force-frequency curves and specific force measurements led to the conclusion that myopathy is the primary cause. Electron micrograph observation, functional assays, and protein analysis then showed that sepsis survivors’ skeletal muscles are characterized by profound mitochondrial abnormalities and oxidative damage. Collectively, these studies demonstrate that long-term muscle weakness is apparent in sepsis-surviving animals, and the functional decline is associated with unresolved mitochondrial damage and dysfunction. This work suggests that medical treatments beyond targeting muscle wasting alone could allow sepsis survivors to regain function and return to productive lives.

Thesis (M.S.)--University of Missouri-Columbia, 2009. / Thesis advisor: Dr. Catherine Peterson. The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. "May 2009" Includes bibliographical references.

Introdução. Pacientes portadores de diabetes mellitus tipo 2 (DM2) podem apresentar fraqueza da musculatura inspiratória. O efeito do treinamento muscular inspiratório (TMI) nesses pacientes ainda é desconhecido. Objetivos. Avaliar os efeitos do TMI sobre a força muscular inspiratória, a função pulmonar, a capacidade funcional e a modulação autonômica em pacientes com DM2 com fraqueza da musculatura inspiratória. Métodos. A pressão inspiratória máxima (PImáx) foi avaliada em uma amostra de 148 pacientes com DM2 da qual 25 pacientes com PImáx < 70% do previsto foram randomizados para um programa de 8 semanas de TMI diário (n=12) ou TMI-placebo (n=13). A PImáx, a função pulmonar, o consumo máximo de oxigênio e a variabilidade da freqüência cardíaca foram avaliados antes e após o TMI. Resultados. Do total de pacientes avaliados, 29,05% (43 pacientes) apresentaram fraqueza muscular inspiratória. O TMI aumentou significativamente a PImáx (118%) e a resistência muscular inspiratória (320%), sem alterar a função pulmonar, a capacidade funcional e a modulação autonômica. Conclusões. O TMI, em pacientes com DM2 e fraqueza dos músculos inspiratórios, aumentou significativamente a PImáx sem modificar a função pulmonar, a capacidade funcional e a modulação autonômica. / Introduction. Subject with type 2 diabetes mellitus (DM2) can present weakness of the inspiratory muscle. The effect of the inspiratory muscle training (IMT) in these patients still is unknown. Objectives. To evaluate the effect of the IMT on the inspiratory muscle force, the pulmonary function, the functional capacity and the autonômica modulation in patients DM2 with weakness of the inspiratory muscle. Methods. The maximum inspiratory pressure (PImáx) was evaluated in a sample of 148 patients with DM2 of which 25 patients with PImáx < 70% of the foreseen one had been randomizeds for a program of 8 weeks of daily IMT (n=12) or IMT-placebo (n=13). The PImáx, the function pulmonary, the VO2 and the variability of the cardiac frequency had been evaluated before and after the IMT. Results. Of the total of evaluated patients, 29.05% (43 patients) had presented inspiratory muscle weakness. The IMT significantly increased the PImáx (118%) and the inspiratory muscle resistance (320%), without modifying the function pulmonary, the exercise capacity and the modulation autonomic. Conclusions. The IMT in patients with DM2 and weakness of the inspiratory muscles increased the PImáx without modifying the function pulmonary, the exercise capacity and the modulation autonomic significantly.

A fraqueza muscular inspiratória pode estar presente em 30 a 50 % dos pacientes ambulatoriais com insuficiência cardíaca crônica, com implicações na qualidade de vida e prognóstico. Entretanto, não está claro quais características clínicas e comportamentais que estariam associadas a essa disfunção. Além disso, como não estão claros os mecanismos moleculares que conduzem a disfunção do diafragma. Parâmetros contráteis incluindo força de contração máxima, força passiva e cinética de pontes cruzadas podem estar alterados em pacientes com IC, e podem estar associados a FMI. Esta tese investigou, primeiramente, determinantes da FMI em comparação com a fraqueza muscular periférica (preensão manual), em pacientes com ICC. Neste estudo foram avaliadas variáveis clínicas, antropométricas e comportamentais destes pacientes. Os resultados demonstraram que apenas aproximadamente 50 % da FMI pode ser explicada pelas variáveis analisadas. Além disso, as variáveis associadas à fraqueza de preensão manual não são diferentes das encontradas em sujeitos saudáveis (gênero e idade). Entretanto, a força inspiratória máxima pode estar associada com marcadores de capacidade funcional do paciente. Em seguida, foram investigadas propriedades contráteis, ativas e passivas de miofibrilas de músculo cardíaco e diafragma, em um novo modelo animal de camundongos com insuficiência cardíaca desenvolvida por knockout para arginilação cardíaco-específica. Resultados do músculo cardíaco demonstram compatibilidade com a disfunção contrátil encontrada em humanos com insuficiência cardíaca congestiva, tais como redução da contração máxima, redução da força passiva e redução da cinética de relaxamento. Entretanto, nos resultados do músculo diafragma, encontramos aumento da força de contração máxima, o que pode sugerir uma mudança adaptativa compensatória associada ao aumento do trabalho inspiratório associado à insuficiência cardíaca crônica. Em conclusão, menos de 50 % da variância da força muscular inspiratória pode ser explicada por variáveis clínicas e comportamentais de pacientes com insuficiência cardíaca crônica. Em um modelo animal de insuficiência cardíaca que resulta em diminuição da contratilidade de cardiomiofibrilas, observa-se aumento da contratilidade das miofibrilas do diafragma, sugerindo que a fraqueza muscular inspiratória associada à insuficiência cardíaca crônica não seja secundária à disfunção contrátil da musculatura inspiratória. / The inspiratory muscle weakness may be present in 30-50% of outpatients with chronic heart failure, with implications for the quality of life and prognosis. However, it is unclear what clinical and behavioral characteristics that would be associated with this dysfunction. Moreover, as are unclear the molecular mechanisms leading to dysfunction of the diaphragm. Contractile parameters including contraction force maximum passive force and kinetics of cross-bridges can be altered in patients with HF, and may be associated with the IMF. This thesis investigated, firstly, the determinants of IMF in comparison to peripheral muscle weakness (handgrip) in patients with CHF. We evaluated clinical, anthropometric and behavioral disorders in these patients. The results showed that only about 50% of IMW can be explained by the variables. Furthermore, the variables associated with weakness of grip are not different from those found in healthy subjects (gender and age). However, maximum inspiratory force may be associated with markers of patient's functional capacity. Next, we investigated the contractile properties, assets and liabilities of myofibrils of cardiac muscle and diaphragm in an animal model of mice with heart failure developed by knockout arginilação cardiac-specific. Results show compatibility with the cardiac muscle contractile dysfunction found in human with congestive heart failure, such as reduction of maximum contraction, reduction and reduction of the passive force relaxation kinetics. However, the results of the diaphragm, we found increased maximum force of contraction, which may suggest a compensatory adaptive changes associated with increased inspiratory work associated with chronic heart failure. In conclusion, less than 50% of the variance in inspiratory muscle strength can be explained by behavioral and clinical variables of patients with chronic heart failure. In an animal model of heart failure that results in decreased contractility cardiomyofibrils, there was an increase in contractility of the diaphragm myofibrils, suggesting that inspiratory muscle weakness associated with chronic heart failure is not secondary to contractile dysfunction of the respiratory muscles.