•This study contributes to the natural history of DMD, linking the ambulant and non-ambulant phases.•Respiratory measurements, upper limb function, pinch and grip force are reported.•A composite ...score combining respiratory outcomes, upper limb function and strength is explored.
The field of translational research in Duchenne muscular dystrophy (DMD) has been transformed in the last decade by a number of therapeutic targets, mostly studied in ambulant patients. A paucity of studies focus on measures that capture the non-ambulant stage of the disease, and the transition between the ambulant and non-ambulant phase. In this prospective natural history study, we report the results of a comprehensive assessment of respiratory, upper limb function and upper limb muscle strength in a group of 89 DMD boys followed in 3 European countries, 81 receiving corticosteroids, spanning a wide age range (5–18 years) and functional abilities, from ambulant (n = 60) to non-ambulant (n = 29). Respiratory decline could be detected in the early ambulatory phase using Peak Expiratory Flow percentage predicted (PEF%), despite glucocorticoid use (mean annual decline: 4.08, 95% CI −7.44,−0.72, p = 0.02 in ambulant; 4.81, 95% CI −6.79,−2.82, p < 0.001 in non-ambulant). FVC% captured disease progression in non-ambulant DMD subjects, with an annual loss of 5.47% (95% CI −6.48,−4.45, p < 0.001). Upper limb function measured with the Performance of Upper Limb (PUL 1.2) showed an annual loss of 4.13 points (95% CI −4.79,3.47, p < 0.001) in the non-ambulant cohort. Measures of upper limb strength (MyoGrip and MyoPinch) showed a continuous decline independent of the ambulatory status, when reported as percentage predicted (grip force −5.51%, 95% CI −6.54,−4.48, p < 0.001 in ambulant and a slower decline −2.86%; 95% CI −3.29,−2.43, p < 0.001, in non-ambulant; pinch force: −2.66%, 95% CI −3.82,−1.51, p < 0.001 in ambulant and −2.23%, 95% CI −2.92,−1.53, p < 0.001 in non-ambulant). Furthermore, we also explored the novel concept of a composite endpoint by combining respiratory, upper limb function and force domains: we were able to identify clear clinical progression in patients in whom an isolated measurement of only one of these domains failed to appreciate the yearly change. Our study contributes to the field of natural history of DMD, linking the ambulant and non-ambulant phases of the disease, and suggests that composite scores should be explored further.
Muscle contraction is due to myosin motors that transiently attach with their globular head to an actin filament and generate force. After a sudden reduction of the load below the maximum isometric ...force (T0), the attached myosin heads execute an axial movement (the working stroke) that drives the sliding of the actin filament toward the center of the sarcomere by an amount that is larger at lower load and is 11 nm near zero load. Here, we show that an increase in temperature from 2 to 17°C, which increases the average isometric force per attached myosin head by 60%, does not affect the amount of filament sliding promoted by a reduction in force from T0to 0.7T0, whereas it reduces the sliding under low load by 2.5 nm. These results exclude the possibility that the myosin working stroke is due to the release of the mechanical energy stored in the initial endothermic force-generating process and show that, at higher temperatures, the working stroke energy is greater because of higher force, although the stroke length is smaller at low load. We conclude the following: (i) the working stroke is made by a series of state transitions in the attached myosin head; (ii) the temperature increases the probability for the first transition, competent for isometric force generation; and (iii) the temperature-dependent rise in work at high load can be accounted for by the larger free energy drop that explains the rise in isometric force.
Aim
To develop a patient‐reported outcome measure (PROM) assessing upper limb function related to activities of daily living (ADL) that cannot be observed in a clinical setting, specifically for ...patients with Duchenne muscular dystrophy (DMD) across a wide age range, applicable in the different stages of the disease.
Method
The developmental process was based on US Food and Drug Administration guidelines. This included item generation from a systematic review of existing tools and expert opinion on task difficulty and relevance, involving individuals with DMD. Cultural aspects affecting ADL were taken into consideration to make this tool applicable to the broad DMD community. Items were selected in relation to a conceptual framework reflecting disease progression covering the full range of upper limb function across different ADL domains.
Results
After pilot testing and iterative Rasch analyses, redundant or clinically irrelevant items were removed. The final questionnaire consists of 32 items covering four domains of ADL (food, self‐care, household and environment, leisure and communication). Test–retest reliability was excellent.
Interpretation
A DMD‐specific upper limb PROM was developed on the basis of clinical relevance and psychometric robustness. Its main purpose is to document the patient self‐reported natural history of DMD and assess the efficacy of interventions.
What this paper adds
A new patient‐reported outcome measure (PROM) for Duchenne muscular dystrophy (DMD) has been developed.
The DMD Upper Limb PROM targets upper limb function in daily life.
Psychometric techniques confirmed its unidimensionality, internal consistency, and test–retest reliability.
Involvement of different stakeholders guaranteed the clinical relevance of the tool.
This article is commented on by Pangalila on pages 123–124 of this issue.
Part One: https://youtu.be/Xllfkotw7Dg
Part Two: https://youtu.be/BuEwCLG_l1E
Generation of force and shortening in striated muscle is due to the cyclic interactions of the globular portion (the head)
of the myosin molecule, extending from the thick filament, with the actin ...filament. The work produced in each interaction
is due to a conformational change (the working stroke) driven by the hydrolysis of ATP on the catalytic site of the myosin
head. However, the precise mechanism and the size of the force and length step generated in one interaction are still under
question. Here we reinvestigate the endothermic nature of the force-generating process by precisely determining, in tetanised
intact frog muscle fibres under sarcomere length control, the effect of temperature on both isometric force and force response
to length changes. We show that raising the temperature: (1) increases the force and the strain of the myosin heads attached
in the isometric contraction by the same amount (â¼70 %, from 2 to 17 °C); (2) increases the rate of quick force recovery following
small length steps (range between â3 and 2 nm (half-sarcomere) â1 ) with a Q 10 (between 2 and 12 °C) of 1.9 (releases) and 2.3 (stretches); (3) does not affect the maximum extent of filament sliding accounted
for by the working stroke in the attached heads (10 nm (half-sarcomere) â1 ). These results indicate that in isometric conditions the structural change leading to force generation in the attached myosin
heads can be modulated by temperature at the expense of the structural change responsible for the working stroke that drives
filament sliding. The energy stored in the elasticity of the attached myosin heads at the plateau of the isometric tetanus
increases with temperature, but even at high temperature this energy is only a fraction of the mechanical energy released
by attached heads during filament sliding.
Glycogen storage disease type 3 (GSD3) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme, which releases glucose from glycogen. Current ...therapy is primarily based on dietary modifications but pharmacological approaches are emerging. The pattern of muscle clinical involvement is poorly described in the literature. However, the need for outcome measures is becoming crucial to assess the efficacy of new treatments in future clinical trials. Here we present a cross-sectional study of 17 GSD3 patients aged between 12 and 56 years old. We found that above 20 years of age the Motor Function Measure (MFM) scale total score decreased with increasing age. A negative correlation was found between age and MFM total score (rho = −0.841, p < 0.001), D1-standing and transfers score (rho=-0.815, p < 0.001), D2-axial and proximal score (rho = −0.719, p < 0.01) and D3-distal score (rho = −0.651, p < 0.01). Focussing on upper limb performance, Manual Muscle Testing (MMT) detected no or slight bilateral weakness in shoulder abduction, elbow flexion/extension, wrist flexion/extension and thumb abduction with scores between 4 and 5 in all patients below 35 years old. Between 35 and 60 years of age, patients’ wrist flexion strength was the same as in younger patients but strength decreased, for elbow flexion/extension, wrist extension and shoulder and thumb abduction. Handgrip and key pinch strengths (measured by dynamometry) and the Purdue assembly subtask performance were also reduced in patients above 30 years of age. In conclusion, standing and transfers (D1) MFM score is the outcome the most sensitive to age in adult GSD3 patients. With regards to the upper limb, strength and motor performance of shoulder and hand appears most affected with age in GSD3 patients older than 30–35 years old.
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