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This paper summarizes and discusses some critical aspects of flying hypersonically. The first is the L/D (lift over drag) ratio determining thrust and that in turn depends on the slenderness Küchemann’s τ parameter. This second parameter is found to depend on the relative importance of wave versus friction drag. Ultimately, all engineering drag is argued to depend on vorticity formed at the expense of the vehicle kinetic energy, thus requiring work by thrust. Different mixing strategies are discussed and shown to depend also on mechanisms forming vorticity when the regime is compressible. Supersonic combustion is briefly analyzed and found, at sufficiently high combustor Mach, to take place locally at constant volume, unlike conventional Brayton cycles.

The advent of new therapies has increased the need to achieve early diagnosis in Spinal Muscular Atrophy (SMA). The aim of the present study was to define the age of diagnosis in the three main types of SMA with pediatric-onset and the timing between the recognition of clinical signs and confirmed genetic diagnosis. All patients with a confirmed diagnosis of type I, II, III SMA followed in 5 Italian centers were included in this study, assessing age at symptoms onset, presenting sign or symptom, age at diagnosis, interval between clinical onset and diagnosis and type of medical investigations conducted in order to obtain the diagnosis. The cohort included 480 patients, 191 affected by SMA type I, 210 by type II and 79 by type III. The mean age at diagnosis was 4.70 months (SD ±2.82) in type I, 15.6 months (SD±5.88) in type II, and 4.34 years (SD±4.01) in type III. The mean time between symptom onset and diagnosis was 1.94 months (SD±1.84) in type I, 5.28 months (SD±4.68) in type II and 16.8 months (SD±18.72) in type III. Our results suggest that despite improved care recommendations there is still a marked diagnostic delay, especially in type III. At the time new therapies are becoming available more attention should be devoted to reducing such delay as there is consistent evidence of the benefit of early treatment.

Monoamine oxidase type B (MAO-B) inhibitors, such as selegiline and rasagiline, can be used as monotherapy or adjuvant therapy to levodopa in Parkinson’s disease (PD). Data on long-term efficacy of MAO-B inhibitors are limited with no head-to-head comparison available to date. The aim of this case–control retrospective study was to analyze data from patients with PD attending the Parkinson Institute (Milan, Italy) over a 6-year period (2009–2015) and compare the effects of selegiline and rasagiline on levodopa treatment outcomes. Patients with PD treated with either selegiline ( n  = 85) or rasagiline ( n  = 85) for 3 years as well as a control group of patients ( N  = 170) who have never received MAO-B inhibitors, were matched for gender, disease duration (±1 year) and age (±1 year) at baseline assessment (ratio 1:1:2). The Unified PD Rating Scale and the Hoehn–Yahr staging system were used for clinical comparisons. At baseline, mean PD duration was 6.5 years and clinical features were comparable across all three groups. After a mean follow-up of approximately 37 months, no differences in clinical progression of motor and non-motor symptoms were observed between the three groups. However, MAO-B inhibitor use was associated with ~2-fold lower change in daily dose of levodopa ( p  < 0.001) and lower dyskinesia scores ( p  = 0.028) than non-users. No intra-class differences were observed between selegiline and rasagiline. Long-term use of MAO-B inhibitors resulted in a significant reduction in levodopa requirements and a lower frequency of dyskinesias in patients with PD. Selegiline and rasagiline had equal efficacy in controlling motor symptoms in PD patients on optimized therapy.

Congenital agenesis of the tensor fascia lata (TFL) muscle is an extremely rare anomaly, with very few reports in the literature and unclear clinical significance. We report the incidental finding of unilateral TFL agenesis in a 25-year-old male physician who had been enrolled as a healthy control in a muscle MRI study on genetic myopathies. Imaging demonstrated a complete absence of the right TFL with mild compensatory hypertrophy of the ipsilateral rectus femoris, while the contralateral side and all other muscles appeared normal. The subject had no history of neuromuscular disease, exhibited only a subtle waddling gait, and had previously completed the New York Marathon in 4 h and 16 min without symptoms. Laboratory tests, including creatine kinase, were within normal limits. Thirteen years later, he remains in good health, continues regular sports activities, and has not developed pain or functional impairment. This case emphasizes that TFL agenesis may remain clinically silent and compatible with high levels of physical activity. Nevertheless, awareness of such anomalies is important, as compensatory mechanisms might predispose to long-term biomechanical imbalance, and recognition on imaging can prevent misinterpretation or unnecessary investigations

In muscle tissue the protein caveolin-3 forms caveolae – flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with caveolin-3 mutations.

Risdiplam (EVRYSDI®) is an oral survival of motor neuron 2 (SMN2) pre-mRNA splicing modifier approved by the EMA and MHRA for the treatment of patients aged ≥2 months with Types 1–3 spinal muscular atrophy (SMA) or 1–4 SMN2 copies.JEWELFISH (NCT03032172) is an open-label study of risdiplam in 174 patients with SMA who previously received RG7800 (RO6885247), nusinersen (SPINRAZA®), olesoxime or onasemnogene abeparvovec (ZOLGENSMA®). JEWELFISH assesses the safety, tolerability and pharmacokinetics/pharmacodynamics of risdiplam in a broad range of ages (1–60 years), SMA types (1–3), SMN2 copy numbers (1–4) and motor functions (non-sitters/sitters/walkers).Thirteen patients previously received RG7800, 76 received nusinersen, 70 received olesoxime and 14 received onasemnogene abeparvovec; one patient withdrew at baseline. Risdiplam led to a >2-fold increase in SMN protein within 4 weeks versus baseline, irrespective of previous treatment. No drug-re- lated safety findings led to withdrawal in any patients. The safety profile of risdiplam was consistent with observations in the FIREFISH (NCT02913482) and SUNFISH (NCT02908685) studies.Exploratory analyses demonstrated overall stabilisation of motor function following 24-month risdiplam treatment in patients aged 2–60 years as assessed by the 32-item Motor Function Measure and Revised Upper Limb Module (data-cut: 31 January 2022).

Duchenne muscular dystrophy (DMD) is a devastating X-linked muscular disease, caused by mutations in the DMD gene encoding Dystrophin and affecting 1:5000 boys worldwide. Lack of Dystrophin leads to progressive muscle wasting and degeneration resulting in cardiorespiratory failure. Despite the absence of a definitive cure, innovative therapeutic avenues are emerging. Myopathologic studies are important to further understand the biological mechanisms of the disease and to identify histopathologic benchmarks for clinical evaluations. We conducted a myopathologic analysis on twenty-four muscle biopsies from DMD patients, with particular emphasis on regeneration, fibro-adipogenic progenitors and muscle stem cells behavior. We describe an increase in content of fibro-adipogenic progenitors, central orchestrators of fibrotic progression and lipid deposition, concurrently with a decline in muscle regenerative capacity. This regenerative impairment strongly correlates with compromised activation and expansion of muscle stem cells. Furthermore, our study uncovers an early acquisition of a senescence phenotype by DMD-afflicted muscle stem cells. Here we describe the myopathologic trajectory intrinsic to DMD and establish muscle stem cell senescence as a pivotal readout for future therapeutic interventions.

Background Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards. Results Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4–1.6) and 4.1 (2.1–6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages. Conclusions These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth.

Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease associated to a widespread cerebral leukodystrophy. MRI shows a typical centripetal pattern where U-fibers are mainly affected with a relative spare of periventricular white matter. Recently, different patterns of spinal cord involvement have been described in KSS. Here we report 4 new cases with typical cerebral leukodystrophy associated with spinal cord lesions. A pattern characterized by abnormal signal intensity in the H gray matter and posterior columns was found in 2 patients, while the remaining 2 presented a peculiar involvement of the spinal trigeminal nuclei at the junction of low medulla and cervical cord. MRI spinal cord involvement in KSS is probably an underestimated finding and should be evaluated in the diagnostic work up of these patients.

Background Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database. Results Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date. Conclusion We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.