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Type 1 and type 2 diabetes are growing public health problems. Despite having different pathophysiologies, both diseases are associated with defects in immune regulation. Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipids presented by CD1d. These cells not only play a key role in the defense against pathogens, but also exert potent immunoregulatory functions. The regulatory role of iNKT cells in the prevention of type 1 diabetes has been demonstrated in murine models and analyzed in diabetic patients. The decreased frequency of iNKT cells in non-obese diabetic mice initially suggested the regulatory role of this cell subset. Increasing the frequency or the activation of iNKT cells with agonists protects non-obese diabetic mice from the development of diabetes. Several mechanisms mediate iNKT regulatory functions. They can rapidly produce immunoregulatory cytokines, interleukin (IL)-4 and IL-10. They induce tolerogenic dendritic cells, thereby inducing the anergy of autoreactive anti-islet T cells and increasing the frequency of T regulatory cells (Treg cells). Synthetic agonists are able to activate iNKT cells and represent potential therapeutic treatment in order to prevent type 1 diabetes. Growing evidence points to a role of immune system in glucose intolerance and type 2 diabetes. iNKT cells are resident cells of adipose tissue and their local and systemic frequencies are reduced in obese patients, suggesting their involvement in local and systemic inflammation during obesity. With the discovery of potential continuity between type 1 and type 2 diabetes in some patients, the role of iNKT cells in these diseases deserves further investigation.

Abstract Background In 2017, a new treatment by nusinersen, an antisense oligonucleotide delivered by repeated intrathecal injections, became available for patients with spinal muscular atrophy (SMA), whereas clinical trials had mainly involved children. Since 2020, the oral, selective SMN2-splicing modifier risdiplam has been available with restrictions evolving with time. In this peculiar context of lack of data regarding adult patients, many questions were raised to define the indications of treatment and the appropriate follow-up in this population. To homogenize access to treatment in France, a national multidisciplinary team meeting dedicated to adult SMA patients, named SMA multidisciplinary team meeting, (SMDTs) was created in 2018. Our objective was to analyze the value of SMDTs in the decision-making process in SMA adult patients and to provide guidelines about treatment. Methods From October 2020 to September 2021, data extracted from the SMDT reports were collected. The primary outcome was the percentage of cases in which recommendations on validating treatment plans were given. The secondary outcomes were type of treatment requested, description of expectations regarding treatment and description of recommendations or follow-up and discontinuation. Data were analyzed using descriptive statistics. Comparisons between the type of treatment requested were performed using Mann–Whitney test or the Student t test for quantitative data and the Fisher’s exact test or the χ2 test for qualitative data. Results Cases of 107 patients were discussed at the SMDTs with a mean age of 35.3 (16–62). Forty-seven were SMA type 2, and 57 SMA type 3. Twelve cases were presented twice. Out of 122 presentations to the SMDTs, most of requests related to the initiation of a treatment (nusinersen (n = 46), risdiplam (n = 54), treatment without mentioning preferred choice (n = 5)) or a switch of treatment (n = 12). Risdiplam requests concerned significantly older patients (p = 0.002), mostly SMA type 2 (p

Abstract The exploitation of sharks and the degradation of their habitats elevate the urgency to understand the factors that influence offspring survival and ultimately shark reproductive success. We monitored and sampled blacktip reef sharks (Carcharhinus melanopterus) in nursery habitats of Moorea Island (French Polynesia), to improve knowledge on shark reproductive behavior and biology. We sampled fin clips and morphometrics from 230 young-of-the-year sharks and used microsatellite DNA markers to process parentage analysis to study the reproductive philopatric behavior in female sharks and the matrotrophy within litters. These traits are driving the success of the local replenishment influencing selection through birth site and maternal reserves transmitted to pups. Parentage analysis revealed that some female sharks changed their parturition areas (inter-seasonally) while other female sharks came back to the same site for parturition, providing evidence for a plastic philopatric behavior. Morphometrics showed that there was no significant relationship between body condition indices and nursery locations. However, similarities and differences in body condition were observed between individuals sharing the same mother, indicating that resource allocation within some shark litters might be unbalanced. Our findings further our understanding of the reproductive biology and behavior that shape shark populations with the aim to introduce these parameters into future conservation strategies.

Background: The incidence of neurological complications associated with nitrous oxide (N2O) abuse, including N2O-induced myelopathy and neuropathy, has risen in the past decade. N2O-induced neuropathy often presents as a subacute axonal pathology; however, demyelinating patterns mimicking Guillain–Barré syndrome have also been observed. This study explores the metabolic pathophysiology of N2O-induced neuropathy, focusing on the alteration in metabolism to provide a deeper understanding of the biochemical pathways influencing the diverse electrophysiological patterns observed. Methods: We conducted a combined metabolic and electrophysiological exploration of 35 patients who underwent electromyographic exams at our referral center over a three-year period for sensorimotor symptoms linked to recreational N2O use. We collected demographic, clinical, radiological, electrophysiological, and biological data. Patients were categorized into axonal or demyelinating groups based on their electrophysiological patterns, and metabolic parameters were compared. Results: Our cohort predominantly exhibited a length-dependent sensorimotor axonal symmetrical neuropathy affecting the lower limbs. Among the patients, 40% met the demyelinating criteria, with four patients exhibiting conduction blocks. The demyelinating group had a significantly higher peripheral neuropathy disability (PND) score at diagnosis. Elevated homocysteine and methylmalonic acid (MMA) levels were noted in all patients, but these were lower in the demyelinating group. Conclusions: This study highlights the diverse electrophysiological manifestations of N2O-induced neuropathy and underscores the potential role of metabolic parameters as biomarkers to understand its pathophysiology. Lower hyperhomocysteinemia and MMA levels were observed in demyelinating patterns. In this study, we did not observe further improvement, but it is well-known that demyelinating features have a better prognosis related to the further remyelination. These findings contribute to a better understanding of N2O-related neuropathic damage and could guide future therapeutic interventions based on biochemical–neurophysiological stratifications.

Abstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.

Abstract Background Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. Results Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. Conclusion During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.

In the last few years, there has been an increase in the recreational use of nitrous oxide (N2O), which can lead to neurological symptoms such as sensory or motor disorders. The literature links these symptoms to a functional inactivation of vitamin B12 by oxidation of its cobalt ion, which prevents the vitamin B12 from acting as a cofactor for methionine synthase. Thus, demyelination related to methionine deficiency could be responsible for the neurological disorders associated with N2O consumption, including the combined sclerosis of the spinal cord. We aimed to study the correlation between the plasma methionine levels and clinical severity observed in N2O users. We retrospectively collected clinical and biological data from 93 patients who chronically consumed N2O. The patients were divided into four groups based of the severity of their clinical symptoms (based on their Peripheral Neuropathy Disability (PND) score). The plasma amino acids measurement, including methionine, were performed systematically by liquid chromatography coupled with mass spectrometry. Plasma methionine is significantly correlated with the clinical severity (Spearman coefficient: −0.42; p-value < 10−5), however, the average methionine level in the four groups is within the physiological values (N: 16–23 µmol/L). There is a significant inverse correlation between plasma methionine and homocysteine (Spearman coefficient: −0.57; p-value < 10−9), which confirms the action of nitrous oxide on the methionine synthase. A decrease in plasma methionine cannot be imputed as the only mechanism involved in the pathophysiology of the neurological disorders in nitrous oxide consumption. In addition, there are few therapeutic indications for the use of methionine. Thus, we should be careful concerning the potential use of methionine in nitrous oxide consumption. As a consequence, other pathophysiological mechanisms probably need to be identified in order to find potential therapeutic targets.

Parkinson's disease patients with freezing of gait also experience sudden motor blocks (freezing) during other repetitive motor tasks. We assessed the proportion of patients with advanced PD and freezing of gait who also displayed segmental "freezing" in tapping tasks.Fifteen Parkinson's disease patients with freezing of gait were assessed. Freezing of gait was evaluated using a standardized gait trajectory with the usual triggers. Patients performed repetitive tapping movements (as described in the MDS-UPDRS task) with the hands or the feet in the presence or absence of a metronome set to 4 Hz. Movements were recorded with a video motion system. The primary endpoint was the occurrence of segmental freezing in these tapping tasks. The secondary endpoints were (i) the relationship between segmental episodic phenomena and FoG severity, and (ii) the reliability of the measurements.For the upper limbs, freezing was observed more frequently with a metronome (21% of trials) than without a metronome (5%). For the lower limbs, the incidence of freezing was higher than for the upper limbs, and was again observed more frequently in the presence of an auditory cue (47%) than in its absence (14%).Although freezing of the lower limbs was easily assessed during an MDS-UPDRS task with a metronome, it was not correlated with the severity of freezing of gait (as evaluated during a standardized gait trajectory). Only this latter was a reliable measurement in patients with advanced Parkinson's disease.

BACKGROUND:Axial disorders are considered to appear late in the course of Parkinson's disease (PD). The associated impact on quality of life (QoL) and survival and the lack of an effective treatment mean that understanding and treating axial disorders is a key challenge. However, upper-body axial disorders (namely dysarthria, swallowing and breathing disorders) have never been prospectively assessed in early-stage PD patients. OBJECTIVES:To characterize upper-body axial symptoms and QoL in consecutive patients with early-stage PD. METHODS:We prospectively enrolled 66 consecutive patients with early-stage PD (less than 3 years of disease progression) and assessed dysarthria, dysphagia and respiratory function (relative to 36 controls) using both objective and patient-reported outcomes. RESULTS:The mean disease duration was 1.26 years and the mean UPDRS motor score was 19.4 out of 108. 74% of the patients presented slight dysarthria (primarily dysprosodia). Men appeared to be more severely affected (i.e. dysphonia). This dysfunction was strongly correlated with low swallowing speed (despite the absence of complaints about dysphagia), respiratory insufficiency and poor QoL. Videofluorography showed that oral-phase swallowing disorders affected 60% of the 31 tested patients and that pharyngeal-phase disorders affected 21%. 24% of the patients reported occasional dyspnea, which was correlated with anxiety in women but not in men. Marked diaphragmatic dysfunction was suspected in 42% of the patients (predominantly in men). CONCLUSION:Upper body axial symptoms were frequent in men with early-stage PD, whereas women presented worst non-motor impairments. New assessment methods are required because currently available tools do not reliably detect these upper-body axial disorders.