The words of Gowers are as true today as they were nearly a century ago. My interest in muscular dystrophy started in 1957 when, as Senior House Officer at Queen Mary's Hospital for Children, Carshalton, Surrey, I first observed a large number of children suffering from this tragic disease. The frustration of helplessly, watching its inevitable course stimulated the present study.After obtaining an initial impression or' the collection from my clinical observations and a review of the hospital records between 1920 and 1950, I started a more systematic enquiry. The present investigation compromises my personal observations on 65 cases ranging in age from 3 to 16 years. Of these, 57 were seen and followed up at Queen Mary's Hospital for Children, and 8 at the Southern Hospital, Dartford, Kent.

Duchenne Muscular Dystrophy (DMD) is a severe X-linked progressive muscle wasting disease resulting from the absence of the membrane-associated protein dystrophin and the secondary components of the dystrophin-glycoprotein complex. Although the genetic basis of the disease has been known for over 15 years, the onset mechanism of the disease is not yet known and no treatment is yet available to significantly increase the lifespan of DMD patients. Increased levels of intracellular calcium have been noted in dystrophic muscle (Turner et al., 1991) and increased intracellular levels of calcium in skeletal muscle lead to increased levels of calcium-dependent proteolysis (Zeman et al., 1985). Increased levels of calpain, a calcium-dependent protease have been reported as early as age 4 weeks in mdx (dystrophin-deficient) mice (Spencer et al., 1995). Increased calpain activity has been demonstrated in mdx myotubes (Alderton et al., 2000a). There is also evidence of a role for calpain in DMD, but the contribution of calpain activity to the onset of DMD has not yet been determined. The purpose of this study was to test the hypothesis that increased calpain activity contributes to the onset of DMD in maturing (birth to weaning) dystrophic skeletal muscles and to determine if increased calpain activity was due to the relative distribution of calpain and calpastatin, calpain's endogenous inhibitor. Calpain activity was assessed in quadriceps and diaphragm muscle homogenate supernatant and pellet fractions from C57BL/6 control and mdx mice at ages 7, 14, and 21 days. Total calpain and calpastatin content were determined by Western analysis. In both the quadriceps and diaphragm samples, calpain activity in the supernatant increased with age. There was a significant increase (47.7%; p<0.05) in calciumdependent calpain activity in mdx quadriceps pellet compared to control at age 7 days. In the quadriceps at age 7 days, calpain activity in the pellet in the presence of calcium was significantly greater than at age 14 (61.2%) and 21 days (52.6%; p<0.05). In the diaphragm, there were no significant differences in pellet activity in either the presence or absence of calcium at any age between control and mdx samples. In both control and mdx diaphragms, pellet calpain activity in the absence compared with the presence of calcium was significantly greater at both age 7 (control, 46.4%; mdx, 45.4%) and 14 days (control, 42.4%; mdx, 43.6%; p<0.05). At age 21 days, both control and mdx calpain activities in the diaphragm supernatants in the presence of calcium were significantly greater than those at ages 7 (control, 66.7%; mdx, 72.1%) and 14 days (control, 39.9%; mdx 49.5%; p<0.05). In general, there were no differences in total calpain and calpastatin content that would account for the differences in calpain activity. There were similar patterns of calpain activity and total calpain and calpastatin content in both control and mdx samples, suggesting a similar pattern of development in control and mdx muscle from ages 7-21 days. The increase in calcium-dependent calpain activity in mdx quadriceps pellet compared to control at age 7 days may be due to differences in regulation and/or distribution of the calpain system early in mdx maturation compared to control. From the present study, the role of calpain in the onset of DMD appears to be minor if global calcium-dependent activity is evaluated. / Master of Science

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Increased calcium-activated calpain proteolysis in the sarcolemma membrane is thought to be a primary mechanism in the pathophysiology of Duchenne Muscular Dystrophy (DMD). However, few studies have tested this possibility prior to the overt signs of the dystrophy. The purpose of this study was to test the hypothesis that there is greater calpain content and total relative calpain activity in membranes obtained from dystrophic (mdx; mdx:utrophin-deficient (mdx:utrn-/-)) compared to wildtype (wt) mouse skeletal muscles during maturation at ages 7- and 21-d,and at a post-maturation age of 35-d. Calpain activity was determined as the calcium-dependent cleavage of the flurogenic substrate SLY-AMC, and content was determined by Western analysis with an anti-calpain antibody. There were several intriguing findings: 1. There was an inverse relationship between calpain content and relative activity in the whole muscle in both wt and mdx mice from age 7- to 35-d: calpain content decreased, and relative calpain activity increased as the mice aged. This suggests a similar role for calpain in both genotypes, which might relate to specific maturation processes, possibly up to age 21-d. Although the inverse relation was evident at 35-d, the targets for calpain in mdx compared to wt likely differed. 2. The increased relative calpain activity in the membrane fraction of mdx mice at age 35-d (26.73 Arbitrary Units, (AU)) compared to that of age 7- (4.9AU; p<0.05) and 21-d (8.74AU; p<0.05) is temporally related to degeneration and regeneration processes, and may also indicate activation of apoptosis, in mdx muscles at this age. 3. At age 7-d, there were no significant differences in either calpain content or relative calpain activity in all subcellular fractions for wt and mdx mice. This result might suggest similar calpain distribution and activities that are related to the regulation of muscle maturation and differentiation in both genotypes. (Note:data were not obtained for the mdx:utrn-/- mice at age 7-d because of insufficient animals). 4. At age 21-d, there was greater relative calpain activity in the myofibrillar supernatant fraction in mdx (15.13AU) than wt mice (1.18AU; p<0.05). This could indicate calpain's role in the initiation of myofibrillar protein turnover and the proteolysis of submembranous networks in the mdx muscles. 5. At age 21-d, greater calpain content in the mdx (1.40ìg) compared to wt (0.23 ìg; p<0.05) membrane fraction might suggest a broader distribution of calpain along membranes that contributes to the onset of dystrophy in the mdx muscles. 6. At age 35-d, there was greater calpain content in the mdx:utrn-/- compared to the wt membrane (0.48ìg vs 0.13 ìg), cytosolic (0.88ìg vs 0.30ìg), and myofibrillar supernatant (0.49ìg vs 0.17ìg; p<0.05 ) fractions This increased content and broad distribution across several subcellular fractions may reflect degeneration and regeneration processes, and potentially activation of apoptosis, in the mdx:utrn-/- muscles. These data suggest that calpain activity contributes to dystrophic pathophysiology mainly in the membrane fraction of mdx skeletal muscles at age ~21-d, but appears to contribute later at 35-d and in more subcellular fractions in mdx:utrn-/- skeletal muscles. / Master of Science

Pre-workout(PWO) är idag ett välkänt fenomen som med ökat användande varje år. I denna studie testas preworkout-preparatet Rampage™ som är ett av Sveriges mest använda preparat. Det finns för få studier som testar preworkout-preparat i samband med muskulär uthållighet och vår hypotes är att det är där pre-workout har som störst effekt. Syftet med den här studien är att undersöka hur Rampage™ påverkar muskulär uthållighet hos män i åldern 18 och uppåt. För att undersöka detta har ett experiment med dubbelblind crossover-design skapats, där 13 deltagare efter behandling av antingen placebo eller Rampage™, blivit utsatta för tre set knäböj, tre set armhävningar och tre set sit-ups var. Antalet repetitioner som utfördes användes sedan till statistisk analys och resultatet visade ingen signifikant skillnad mellan grupperna(p=0,858). Det finns några orsaker till varför det kan vara såhär och det finns anledning att fortsätta forska om det här specifikt. Vår hypotes att pre-workout påverkar muskulär uthållighet är fortfarande under prövning. / Pre-workout supplementation is today a well-known phenomenon ever increasing in popularity every year. In this study, we investigate Rampage™; a popular product in Sweden. There’s too few studies that investigate the link between pre-workout and strength training to failure and we believe that is where pre-workout is most effective. The aim of this study is to research Rampage’s™ effects on muscular endurance in male participants above the age group of 18. To do this a double-blind cross-over design has been applied to 13 participants who, unknowingly, either ingest a placebo or the actual pre-workout in order to do three sets of squats, three sets of push-ups and three sets of sit-ups. When they couldn’t perform one more repetition the set was concluded. The number of repetitions was later used for statistical analysis and we found no significance between the groups (p=0,858). There are some reasons this might be the case, and we believe this could be investigated further, although our hypothesis remains unproven.

Introdução: A Distrofia Muscular de Duchenne (DMD) é uma doença genética que causa limitações físicas e motoras progressivas, além de alterações da função pulmonar em fase mais tardia. A escala da medida da função motora (MFM) e do teste de caminhada de 6 minutos (TC6) são ferramentas confiáveis e precisas para avaliar pacientes com DMD. A capacidade de realização desses testes pode ser influenciada pela condição cardiorrespiratória, resistência e força muscular, mas ainda não está bem definido qual, ou quais, destas variáveis podem interferir de forma mais significativa na função motora e na capacidade funcional de exercício. Objetivo: Avaliar a função motora por meio da MFM e correlacionar com a função pulmonar e capacidade funcional de exercício em pacientes com DMD. Métodos: Trata-se de um estudo transversal que envolveu 61 voluntários com DMD submetidos a um protocolo de avaliação composto por informações pessoais, antropometria, escala MFM, espirometria (CVF,VEF1,VEF1/CVF, FEF25-75, PFE, CVL, VVM), ventilometria (VC, VM e CVL), pico de fluxo expiratório (PFE) e pico de fluxo de tosse (PFT) no medidor portátil, pressão inspiratória máxima (PImax) e pressão expiratória máxima (PEmax), pressão inspiratória nasal (SNIP), oscilometria de impulso (R5, R20, R5-R20, X5) e TC6. Foi realizada a análise de correlação entre as variáveis e posteriormente a comparação entre os grupos de voluntários deambuladores e não deambuladores. Resultados: A média de idade dos voluntários foi de 13,70±3,93. Na espirometria, houve correlação positiva do escore total, domínios 1(D1) e 2 (D2) da MFM com a porcentagem do previsto da CVF% (r=0,58, r=0,51, r=0,57, respectivamente), correlação negativa do escore total, domínios 1, 2 e 3 com VEF1/CVF (r=-0,61, r=-0,57, r=-0,49 e r=-0,49, respectivamente), correlação negativa do escore total, domínio 1 e domínio 3 com o FEF25-75% (r=-0,48, -0,47, -0,42, respectivamente). Na manobra de PFE realizada no medidor portátil, houve correlação do PFE% com o escore total e todos os domínios da MFM. O escore total, domínio 1, 2 e 3 se correlacionaram positivamente com os valores percentuais da PEmax (r=0,67, r=0,60, r=0,63 e 0,42, respectivamente) e SNIP (r=0,56, r=0,42, r=0,64 e r=0,45, respectivamente). Na oscilometria de impulso (IOS), houve correlação da resistência total (R5) com o escore total, domínio 1 e 2 (r=0,55; r=0,52 e r=0,50, respectivamente) e resistência central (R20) com o escore total, domínios 1 e 2 (r=0,52; r=0,51 e r=0,45, respectivamente); correlação da resistência periférica (R5-R20) com o escore total (r = 0,46) e domínio 2 (r=0,49), e da reatância (X5) com o escore total, D1 e D2(r=-0,43; r=- 0,40 e r=-0,36, respectivamente). No TC6, a distância em metros foi de 294,75±96,97 e se correlacionou fortemente com a MFM, e a percepção da dispneia relatada no TC6 se correlacionou negativamente com o domínio 3 daMFM (r=-0,75). Na análise comparativa entre os grupos de deambuladores (D) e não deambuladores (ND), o IOS demonstrou valores obtidos significativamente menores no grupo ND de R5, R20, R5-R20, X5 e da porcentagem do previsto de R5-20. No mesmo grupo (ND), a espirometria demonstrou valores obtidos significativamente maiores de VVM, da VEF1/CVF, FEF25-75 e porcentagem do previsto de VEF1/CVF, além da diminuição da porcentagem do previsto da CVF, PFE no medidor portátil, PEmax, SNIP e MFM (escore total e domínios 1,2 e 3). Conclusão: A diminuição da MFM se correlacionou com a diminuição da resistência e reatância das vias aéreas, com a diminuição da PEmax, SNIP e da CVF. Além desses parâmetros, houve correlação da diminuição da MFM com o aumento dos valores de PFE, FEF25-75 e VEF1/CVF. Na comparação entre os grupos, os resultados confirmam o que foi encontrado nas correlações no grupo de pacientes que não deambulavam, com diminuição das resistências e reatância das vias aéreas, da força muscular respiratória e valores maiores de volume (VEF1/CVF) e fluxo pulmonar (FEF25-75). Apesar da forte correlação entre a distância percorrida no teste de caminhada com a função motora, não houve alteração dos dados vitais, o que pode indicar que os pacientes não atingiram o esforço submáximo estimado / Introduction: Duchenne Muscular Dystrophy (DMD) is a genetic disease which causes progressive physical and motor limitations, including alterations to the pulmonary function in later stages. The scale of the motor function measure (MFM) and of the six minute walking test (TC6) are reliable and precise tools to assess DMD patients. The possibility of performing these tests may be influenced both by the patient\'s cardiopulmonary condition, resistance and muscular strength. However, it has not been yet demonstrated which of these variables can have the most significant impact on the patient\'s motor function and functional capacity of exercise. Objective: To assess the motor function though the application of the MFM scale and correlate it with the pulmonary function and functional capacity of exercise on DMD patients. Methodology: The approach adopted in this study consisted of a transversal analysis involving sixty one DMD patients who have volunteered to submit themselves to an evaluation protocol which includes the following parameters: personal information, anthropometry, MFM scale, spirometry (CVF,VEF1,VEF1/CVF, FEF25-75, PFE, CVL, VVM), ventilometry (VC, VM e CVL), peak expiratory flow (PFE) and peak cough flow (PFT) according to the portable meter measurements, maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax), nasal inspiratory pressure (SNIP), impulse oscillometry (R5, R20, R5-R20, X5) and TC6. The study focused on the analysis of the correlation between variables, followed by a comparison between two groups of patients: wanderers and non-wanderers. Results: The average age of patients was 13,70±3,93. On spirometry, there was a positive correlation between the total score, domains 1(D1) and 2 (D2) of the MFM and the expected CVF percentage (r=0,58, r=0,51, r=0,57, respectively); there was a negative correlation between the total score, domains 1, 2 and 3 and VEF1/CVF (r=-0,61, r=-0,57, r=-0,49 and r=-0,49, respectively), as well as a negative correlation between domain 1, domain 3 and FEF25-75% (r=-0,48, -0,47, -0,42, respectively). On the PFE maneuver performed using the portable meter, there was a correlation between the expected PFE percentage, the total score and all MFM domains. The total score and domains 1, 2 and 3 had a positive correlation with the percentage values of PEmax (r=0,67, r=0,60, r=0,63 and 0,42, respectively) and SNIP (r=0,56, r=0,42, r=0,64 and r=0,45, respectively). Regarding the impulse oscillometry system (IOS), there was a correlation between the total resistance (R5), the total score and domains 1 and 2 (r=0,55; r=0,52 and r=0,50, respectively); and between the central resistance (R20) and total score, domains 1 and 2 (r=0,52; r=0,51 and r=0,45, respectively); in addition, there were correlations between the peripheral resistance (R5-R20), the total score (r = 0,46) and domain 2 (r=0,49), as well as between the reactance (X5) and total score, D1 and D2(r=-0,43; r=-0,40 and r=-0,36, respectively). Thedistance in meters reached in the TC6 was of 294,75±96,97 and had a strong correlation with the MFM. The perception of dyspnoea reported through the TC6 had a negative correlation with domain 3 of the MFM (r=-0,75). On the comparative analysis between groups of wanderers (D) and non-wanderers (ND), the IOS has shown significantly lower values in the group of ND (R5, R20, R5- R20, X5), as well as on the expected percentage of R5-20. In the same group (ND), the spirometry has shown significantly higher values of VVM, VEF1/CVF, FEF25-75 and the expected percentage of VEF1/CVF; in addition to a reduction of the expected percentage of CVF and PFE on the portable meter, PEmax, SNIP e MFM (total score and domains 1, 2 and 3). Conclusion: The reduction of the MFM correlates with the reduction of airways resistance and reactance, and with the reduction of PEmax, SNIP and CVF. In addition to these parameters, there was a correlation between the MFM reduction and the increase of the PFE, FEF25- 75 e VEF1/CVF values. In the comparison between groups, the results confirm the findings in the correlations of the non-wanderers group, with reduction of the airways resistance and reactance, of the respiratory muscular strength and higher volume values (VEF1/CVF) and pulmonary flow (FEF25-75). Despite the strong correlation between the distance covered during the walking test and the motor function, there was no alteration on vital indicators, which may point out to the fact that the patients did not achieve the expected sub-maximum effort level

MSc (Med), Genetic Counselling, Faculty of Health Sciences, University of the Witwatersrand, 2009 / Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are severe X-linked recessive, degenerative neuromuscular diseases. DMD/BMD are caused by deletions, duplications and point mutations in the DMD gene situated on the X-chromosome. Studies have shown that the risk of being a carrier for DMD/BMD has a psychosocial impact on individuals and affects their requests for DNA testing and their choices regarding reproduction. Very few articles have been published to date and this study is the first South African study to investigate the behaviours of individuals in DMD/BMD families. The study aimed to investigate why individuals attended genetic counselling and who referred them. It also aimed to identify factors that influence at-risk individuals‟ decisions regarding genetic counselling, carrier testing and reproduction. The study was retrospective and data were obtained by reviewing genetic counselling files at the Division of Human Genetics, National Health Laboratory Service and the University of the Witwatersrand. The sample consisted of 79 files of families seen for genetic counselling regarding DMD/BMD from 1995 to 2008. Subjects included the maternal female relatives of affected individuals, who were all of reproductive age (15-49 years); the total number of at-risk individuals identified was 237. Subjects were divided into three groups according to their assigned reproductive risks: low (0-9%), intermediate (10-24%) and high (>25%). The influence of reproductive risk and other identified variables on decisions to attend genetic counselling, have carrier testing and having children were analysed using chi-squared and logistic regression analysis. iii Reproductive risk and relationship to the affected individuals were shown to be significant predictors of individuals‟ decisions. Other factors that contributed significantly to the behaviour of at-risk individuals were ethnicity, age, whether a mutation was de novo and whether an individual had affected children.