DMTs and Covid-19 severity in MS: a pooled analysis from Italy and France

We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39–3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18–0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon

A strictly noninvasive MR setup dedicated to longitudinal studies of mechanical performance, bioenergetics, anatomy, and muscle recruitment in contracting mouse skeletal muscle

1522-2594 (Electronic) 0740-3194 (Linking) Journal Article Research Support, Non-U.S. Gov'tMR techniques have proven their ability to investigate skeletal muscle function in situ. Their benefit in terms of noninvasiveness is, however, lost in animal research, given that muscle stimulation and force output measurements are usually achieved using invasive surgical procedures, thereby excluding repeated investigations in the same animal. This study describes a new setup allowing strictly noninvasive investigations of mouse gastrocnemius muscle function using (1)H-MRI and (31)P-MR spectroscopy. Its originality is to integrate noninvasive systems for inducing muscle contraction through transcutaneous stimulation and for measuring mechanical performance with a dedicated ergometer. In order to test the setup, muscle function was investigated using a fatiguing stimulation protocol (6 min of repeated isometric contractions at 1.7 Hz). T(2)-weighted imaging demonstrated that transcutaneous stimulation mainly activated the gastrocnemius. Moreover, investigations repeated twice with a 7-day interval between bouts did show a high reproducibility in measurements with regard to changes in isometric force and energy metabolism. In conclusion, this setup enables us for the first time to access mechanical performance, energy metabolism, anatomy, and physiology strictly noninvasively in contracting mouse skeletal muscle. The possibility for implementing longitudinal studies opens up new perspectives in many research areas, including ageing, pharmaceutical research, and gene and cell therapy

Effects of stimulation frequency and pulse duration on fatigue and metabolic cost during a single bout of neuromuscular electrical stimulation

1097-4598 (Electronic) 0148-639X (Linking) Journal Article Research Support, Non-U.S. Gov'tWe have investigated the effects of stimulation frequency and pulse duration on fatigue and energy metabolism in rat gastrocnemius muscle during a single bout of neuromuscular electrical stimulation (NMES). Electrical pulses were delivered at 100 Hz (1-ms pulse duration) and 20 Hz (5-ms pulse duration) for the high (HF) and low (LF) frequency protocols, respectively. As a standardization procedure, the averaged stimulation intensity, the averaged total charge, the initial peak torque, the duty cycle, the contraction duration and the torque-time integral were similar in both protocols. Fatigue was assessed using two testing trains delivered at a frequency of 100 Hz and 20 Hz before and after each protocol. Metabolic changes were investigated in vivo using 31P-magnetic resonance spectroscopy (31P-MRS) and in vitro in freeze-clamped muscles. Both LF and HF NMES protocols induced the same decrease in testing trains and metabolic changes. We conclude that, under carefully controlled and comparable conditions, the use of low stimulation frequency and long pulse duration do not minimize the occurrence of muscle fatigue or affect the corresponding stimulation-induced metabolic changes so that this combination of stimulation parameters would not be adequate in the context of rehabilitation

Downregulation of uncoupling protein-3 in vivo is linked to changes in muscle mitochondrial energy metabolism as a result of capsiate administration.

Although it has been suggested that the skeletal muscle mitochondrial uncoupling protein-3 (UCP3) is involved in regulating energy expenditure, its role is still poorly understood. In the present study, we aimed at investigating noninvasively, using magnetic resonance techniques, metabolic changes occurring in exercising muscle as a result of capsiate treatment, which has been previously linked to UCP3 upregulation. We showed that capsiate ingestion strongly reduced UCP3 gene expression in rat gastrocnemius muscle. This large underexpression was accompanied by a significant increase in the rate of mitochondrial ATP production and phosphocreatine level both at rest and during muscle stimulation. Similarly, the stimulation-induced ATP fall and ADP accumulation were significantly less after capsiate administration than in untreated rats. The larger oxidative ATP production rate could not be explained by a proportional decrease in the anaerobic component, i.e., glycolysis and phosphocreatine breakdown. In addition, the mechanical performance was not affected by capsiate administration. Finally, the plasma free fatty acid (FFA) level increased in capsiate-treated rats, whereas no significant change was observed after muscle stimulation in the control group. Considering the corresponding enhanced UCP3 mRNA expression occurring in the control group after muscle stimulation, one can suggest that changes in FFA level and UCP3 mRNA expression are not mechanistically correlated. Overall, we have shown that capsiate administration induced a UCP3 downregulation coupled with an increased mitochondrial ATP synthesis, whereas the muscle force-generating capacity was unchanged. This suggests that a decrease in muscle efficiency and/or additional noncontractile ATP-consuming mechanisms result from UCP3 downregulation

Endotoxemia does not limit energy supply in exercising rat skeletal muscle

International audienc

In vivo reduction in ATP cost of contraction is not related to fatigue level in stimulated rat gastrocnemius muscle

We tested whether the reduction in ATP cost of contraction during in vivo stimulation of rat gastrocnemius muscle was related to fatigue level.Muscles (n = 44) were electrically stimulated to perform 6 min repeated isometric contractions at different frequencies; one non-fatiguing protocol (stimulation at 0.8 Hz) and five fatiguing protocols (2, 3.2, 4, 5.2 and 7.6 Hz) were used. Anaerobic and oxidative ATP turnover rates were measured non-invasively using 31P-magnetic resonance spectroscopy.At the onset of the stimulation period, no signs of fatigue were measured in the six protocols and ATP cost of contraction did not differ significantly (P = 0.45) among protocols (mean value of 1.76 ± 0.11 mm (N s)−1).For the six protocols, ATP cost of contraction was significantly reduced (P < 0.05) at the end of the stimulation period when compared with the initial value. This reduction did not differ significantly (P = 0.61) among the five fatiguing protocols (averaging 35 ± 3 % of initial value), whereas isometric force decreased significantly as stimulation frequency increased. No significant correlation (P = 0.87, r2= 0.01) was observed between isometric force and ATP cost of contraction at the end of the stimulation period. In addition, this reduction was significantly lower (P < 0.05) for the non-fatiguing protocol (67 ± 9 % of initial value) when compared with the fatiguing protocols.These results demonstrate that (i) the reduction in ATP cost of contraction during in vivo stimulation of rat gastrocnemius muscle is not related to the fatigue level; (ii) surprisingly, this reduction was significantly larger during the fatiguing protocols compared with the non-fatiguing protocol

Immunological Hallmarks of JC Virus Replication in Multiple Sclerosis Patients on Long-Term Natalizumab Therapy

Review of Pedro Calderón de la Barca, Céfalo y Pocris, introd. Enrica Cancelliere, ed. Ignacio Arellano, New York, IDEA, 2013, 190 pp. ISBN 978-1-938795-93-