Duchenne muscular dystrophy (DMD) is a progressive muscle disease. No curative therapy is currently available, but in recent decades standards of care have improved. These improvements include the use of corticosteroids and mechanical ventilation.To present a detailed population based report of the DMD disease course in The Netherlands (1980-2006) and evaluate the effect of changes in care by comparing it with an historical Dutch DMD cohort (1961-1974).Information about DMD patients was gathered through the Dutch Dystrophinopathy Database using a standardized questionnaire and information from treating physicians.The study population involved 336 DMD patients (70% of the estimated prevalence), of whom 285 were still alive. Mean age at disease milestones was: diagnosis 4.3 years, wheelchair dependence 9.7 years, scoliosis surgery 14 years, cardiomyopathy (fractional shortening <27%) 15 years, mechanical ventilation 17 years and death 19 years. Within our cohort, corticosteroid use was associated with an increased age of wheelchair dependence from 9.8 to 11.6 years (p < 0.001). When comparing the recent cohort to the historical cohort, mean survival improved from 17 to 27 years (p < 0.001).The current study gives detailed information about the disease course of DMD patients, provides evidence for the positive effect of steroid treatment and mechanical ventilation and supports the use of patient registries as a valuable resource for evaluating improvements in care.
The effector programs of CD8+ memory T cells are influenced by the transcription factors RUNX3, EOMES and T-bet. How these factors define brain-homing CD8+ memory T cells in multiple sclerosis (MS) remains unknown. To address this, we analyzed blood, CSF and brain tissues from MS patients for the impact of differential RUNX3, EOMES and T-bet expression on CD8+ T cell effector phenotypes. The frequencies of RUNX3- and EOMES-, but not T-bet-expressing CD8+ memory T cells were reduced in the blood of treatment-naïve MS patients as compared to healthy controls. Such reductions were not seen in MS patients treated with natalizumab (anti-VLA-4 Ab). We found an additional loss of T-bet in RUNX3-expressing cells, which was associated with the presence of MS risk SNP rs6672420 (RUNX3). RUNX3+EOMES+T-bet− CD8+ memory T cells were enriched for the brain residency-associated markers CCR5, granzyme K, CD20 and CD69 and selectively dominated the MS CSF. In MS brain tissues, T-bet coexpression was recovered in CD20dim and CD69+ CD8+ T cells, and was accompanied by increased coproduction of granzyme K and B. These results indicate that coexpression of RUNX3 and EOMES, but not T-bet, defines CD8+ memory T cells with a pre-existing brain residency-associated phenotype such that they are prone to enter the CNS in MS.
Exon-skipping drugs in Duchenne muscular dystrophy (DMD) aim to restore truncated dystrophin expression, which is present in the milder Becker muscular dystrophy (BMD). MRI skeletal muscle T2 relaxation times as a representation of edema/inflammation could be quantitative outcome parameters for such trials.We studied T2 relaxation times, adjusted for muscle fat fraction using Dixon MRI, in lower leg muscles of DMD and BMD patients and healthy controls.T2 relaxation times correlated significantly with fat fractions in patients only (P < 0.001). After adjusting for muscle fat, T2 relaxation times were significantly increased in 6 muscles of DMD patients (P < 0.01), except for the extensor digitorum longus. In BMD, T2 relaxation times were unchanged.T2 relaxation times could be a useful outcome parameter in exon-skipping trials in DMD but are influenced by fat despite fat suppression. This should be accounted for when using quantitative T2 mapping to investigate edema/inflammation.
Abstract Background Vascular endothelial growth factor (VEGF) has neurotrophic activity which is mediated by its main agonist receptor, VEGFR2. Dysregulation of VEGF causes motor neurone degeneration in a mouse model of amyotrophic lateral sclerosis (ALS), and expression of VEGFR2 is reduced in motor neurones and spinal cord of patients with ALS. Methods We have screened the promoter region and 4 exonic regions of functional significance of the VEGFR2 gene in a UK population of patients with ALS, for mutations and polymorphisms that may affect expression or function of this VEGF receptor. Results No mutations were identified in the VEGFR2 gene. We found no association between polymorphisms in the regulatory regions of the VEGFR2 gene and ALS. Conclusion Mechanisms other than genetic variation may downregulate expression or function of the VEGFR2 receptor in patients with ALS.
To uncover how naive B-cell development is functionally related to auto-IgG serostatus, steroid treatment and relapse occurrence in neuromyelitis optica spectrum disorder (NMOSD).
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