The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop ...a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.
One of the issues highlighted in amyotrophic lateral sclerosis (ALS) clinical trials is the lack of appropriate outcome measures. The aim of this multicentric study was to evaluate the 6-min walk ...test (6MWT) as tool to monitor the natural history of a cohort of ALS patients followed up over a 6-month interval. Forty-four ambulant patients were assessed at baseline and after 1, 3 and 6 months. Eight out of forty-four lost the ability to walk before the end of the study. The 6MWT and the objective measures linked to motor function, such as 10 m walking test (10MWT) and Time-up and go (TUG), the ALSFRS-R and the ALSFRS-R items 7-9 showed a good responsiveness to change over the 6-month interval. There was a strong correlation between 6 and 10MWT, TUG, ALSFRS-R, ALSFRS-R items 7-9 and FVC% at baseline. There was no correlation with Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and Modified Borg Scale (MBS). The Δ of 6MWT from T0 to T6 significantly correlated with the Δs of 10MWT and TUG. There was no correlation with the Δs of ALSFRS-R, ALSFRS-R items 7 9, ECAS, MBS and FVC%. The discordance between changes of the 6MWT and ALSFRS-R at 6 month highlights the different content validity among these instruments. The concordance among 6MWT, 10MWT and TUG indicates that the 6MWT is an objective, sensitive and robust tool to measure motor performances in a longitudinal setting. The main limitations of our study were the small sample size and the high percentage of patients (18%) lost at follow-up. Therefore, further studies on larger cohorts, and exploring the relation between 6MWT and need of ventilator support or survival could strengthen our results.
We investigated whether the
repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS ...patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the
repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients (
= 84) were younger at disease onset, at the first clinical observation and at diagnosis (
< 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS (
< 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the
repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07-2.33,
= 0.021), but not in women (
> 0.05) as well as in the whole sample (
> 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of
-related disease.
Genistein has a preventive role against bone mass loss during menopause. However, experimental data in animal models of osteoporosis suggest an anti-osteoporotic potential for this isoflavone. We ...performed a post-hoc analysis of a previously published trial investigating the effects of genistein in postmenopausal women with low bone mineral density. The parent study was a randomized, double-blind, placebo-controlled trial involving postmenopausal women with a femoral neck (FN) density <0.795 g/cm². A cohort of the enrolled women was, in fact, identified at the baseline as osteoporotic (
= 121) on the basis of their T-score and analyzed thereafter for the 24 months' treatment with either 1000 mg of calcium and 800 IU vitamin D3 (placebo;
= 59); or calcium, vitamin D3, and Genistein aglycone (54 mg/day; genistein;
= 62). According to the femoral neck T-scores, 31.3% of the genistein and 30.9% of the placebo recipients were osteoporotic at baseline. In the placebo and genistein groups, the 10-year hip fracture probability risk assessed by Fracture Risk Assessment tool (FRAX) was 4.1 ± 1.9 (SD) and 4.2 ± 2.1 (SD), respectively. Mean bone mineral density (BMD) at the femoral neck increased from 0.62 g/cm² at baseline to 0.68 g/cm² at 1 year and 0.70 g/cm² at 2 years in genistein recipients, and decreased from 0.61 g/cm² at baseline to 0.60 g/cm² at 1 year and 0.57 g/cm² at 2 years in placebo recipients. At the end of the study only 18 postmenopausal women had osteoporosis in the genistein group with a prevalence of 12%, whereas in the placebo group the number of postmenopausal women with osteoporosis was unchanged, after 24 months. This post-hoc analysis is a proof-of concept study suggesting that genistein may be useful not only in postmenopausal osteopenia but also in osteoporosis. However, this proof-of concept study needs to be confirmed by a large, well designed, and appropriately focused randomized clinical trial in a population at high risk of fractures.
In Duchenne muscular dystrophy (DMD), telomere shortening has been postulated to contribute to the failure of regenerative activity promoting the premature senescence of satellite cells. The aim of ...the present study was to investigate the telomere length and the expression of telomeric repeat-binding factor-1 (TRF1), poly (ADP-ribose) polymerase-1 (PARP1) and mouse telomerase reverse transcriptase (MTERT) in gastrocnemius, tibialis anterior and diaphragm muscles of the murine model of DMD, the
mdx
mouse and whether a chronic protocol of forced exercise impacts on them. Our results confirmed a telomere shortening in
mdx
muscles, more evident in the diaphragm, in which exercise induced a greater shortening than in wild-type mice. Moreover, we showed for the first time in
mdx
an increased TRF1 and PARP1 expression and an augmented activity of MTERT, further enhanced by exercise. These results reinforce the hypothesis that a deregulation of mechanisms involved in telomere length occurs and may pave the way for the test of compounds targeting proteins modulating telomere maintenance as a novel strategy to treat dystrophinopathies.
Highlights • The mean age at diagnosis of Duchenne Muscular Dystrophy is around 4.2 -5 years all over the world. • A delayed diagnosis of DMD has several clinical and therapeutic implication • The ...mean age at diagnosis of DMD in Italy in the last decade was around 3.5 years. • All male children should be screened in early infancy for DMD to avoid a delay in diagnosis
Objective
The aim of this paper was to report the 2‐year follow‐up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, ...or SMN2 copy number.
Methods
Sixty‐eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE‐2) at the time they started treatment and 12 and 24 months after that.
Results
For both CHOP and HINE‐2 repeated measures analysis of variance showed a significant difference (P < 0.001) between baseline and 12 months, 12 months and 24 months, and baseline and 24‐month scores for the whole group. When age subgroups (<210 days, <2 years, 2–4 years, 5–11 years, 12–18 years) were considered, on the CHOP INTEND the difference was significant between baseline and 24 months in all age subgroups. On the HINE‐2, the difference between baseline and 24 months was significant in all the subgroups before the age of 4 years. Age was predictive of changes on both scales (P < 0.05), whereas SMN2 copy number and decimal classification were not.
Interpretation
Our results suggest that some improvement of motor function can be observed even after the first year of treatment. This is more obvious in the infants treated in the first 2 years but some improvement can also be found in older children.
Objective
We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort.
Methods
Patients were assessed using Hammersmith ...Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment.
Results
Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33).
When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT.
Interpretation
Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.
The study reports real world data in type 2 and 3 SMA patients treated for at least 2 years with nusinersen. Increase in motor function was observed after 12 months and during the second year. The ...magnitude of change was variable across age and functional subgroup, with the largest changes observed in young patients with higher function at baseline. When compared to natural history data, the difference between study cohort and untreated patients swas significant on both Hammersmith Functional Motor Scale and Revised Upper Limb Module both at 12 months and at 24 months.
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