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Here we present a cohort study of the serum inflammatory profile in adult patients with genetically defined MDs, to better elucidate the role of peripheral immune response in these neurogenetic disorders. This is an observational case–control study performed at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS, including subjects with a molecular diagnosis of primary mitochondrial myopathy. Full demographic and clinical data of the MD patients and healthy controls (HCs) are reported in Data S1. Thirty adult patients with a genetically defined MD with predominant involvement of skeletal muscle and 26 age-and sex-matched HCs were included in the study. Summing up, our results suggest that inflammation plays a role in primary MDs and may represent an interesting field for future therapeutic perspective

Acute hospitalisation may be required to support patients with Neuromuscular disorders (NMDs) mainly experiencing respiratory complications, swallowing difficulties, heart failure, urgent surgical procedures. As NMDs may need specific treatments, they should be ideally managed in specialized hospitals. Nevertheless, if urgent treatment is required, patients with NMD should be managed at the closest hospital site, which may not be a specialized centre where local emergency physicians have the adequate experience to manage these patients. Although NMDs are a group of conditions that can differ in terms of disease onset, progression, severity and involvement of other systems, many recommendations are transversal and apply to the most frequent NMDs. Emergency Cards (EC), which report the most common recommendations on respiratory and cardiac issues and provide indications for drugs/treatments to be used with caution, are actively used in some countries by patients with NMDs. In Italy, there is no consensus on the use of any EC, and a minority of patients adopt it regularly in case of emergency. In April 2022, 50 participants from different centres in Italy met in Milan, Italy, to agree on a minimum set of recommendations for urgent care management which can be extended to the vast majority of NMDs. The aim of the workshop was to agree on the most relevant information and recommendations regarding the main topics related to emergency care of patients with NMD in order to produce specific ECs for the 13 most frequent NMDs.

Objective:Neurological sequelae of SARS-CoV-2 infection have already been reported, but there is insufficient data about the impact of the pandemic on the management of the patients with chronic neurological diseases. We aim to analyze the effect of COVID-19 pandemic and social restriction rules on these fragile patients. Methods:Patients with chronic neurologic diseases routinely followed at the outpatient clinic of Gemelli University Hospital, Rome, were assessed for symptoms suggestive of SARS-CoV-2 infection in the pandemic period, consequences of social restrictions, and neurological disease features, concomitant medical conditions, current medical and disease-specific treatments. Data source: a dedicated telephone survey designed to encompass questions on COVID-19 symptoms and on pandemic effects in chronic neurologic conditions. Results:Overall, 2,167 individuals were analyzed: 63 patients reported contact with COVID-19 positive cases, 41 performed the swab, and 2 symptomatic patients tested positive for COVID-19 (0.09%). One hundred fifty-eight individuals (7%) needed urgent neurological care, deferred due to the pandemic; 641 patients (30%) suspended hospital treatments, physiotherapy or other support interventions; 405 individuals (19%) reported a subjective worsening of neurological symptoms. Conclusions:In our population, the presence of neurological chronic diseases did not increase the prevalence of COVID-19 infection. Nevertheless, the burden of neurological disorders has been worsened by the lockdown.

The diagnosis of LGMD2A (calpainopathy) can be challenging due to genetic heterogeneity and to high similarity with other LGMDs or neuromuscular disorders. In this setting, NGS panels are highly recommended to perform differential diagnosis, identify new causative mutations and enable genotype-phenotype correlations. In this manuscript, the case of a patient affected by LGMD2A is reported, for which the application of a defined custom designed NGS panel allowed to confirm the diagnosis of calpainopathy linked with two heterozygous variants in CAPN3, namely c.550delA and c.1813G>C. The first variant has been extensively described in relation to calpainopathy. The second variant c.1813G>C, instead, is novel and has been predicted to be probably damaging. In addition, NGS analysis on the proband revealed a heterozygous variant (c.550C>T) in the LMNA gene, which is associated with dilated cardiomyopathy. The variant is novel and has been predicted to be deleterious by subsequent bioinformatic analysis. Successively, segregation analysis was performed on family members. Interestingly, none of them showed neuromuscular symptoms but the mother was diagnosed with bradycardia and syncopal episodes and showed a positive family history for cardiomyopathy. The segregation analysis reported that the proband inherited the c.1813G>C (CAPN3) from the father who was a healthy carrier. The mother was positive for c.550delA (CAPN3) and c.550C>T (LMNA), suggesting thereby a possible genetic explanation for her cardiovascular problems. Segregation analysis, therefore, confirmed the inheritance pattern of the variants carried by the proband and highlighted a familiarity for cardiomyopathy which should not be neglected. The NGS analysis was further performed on the partner of the proband, to estimate the reproductive risk of the couple. The partner was negative to NGS screening, suggesting thereby a low risk to have an affected child with calpainopathy and 50% probability t

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Introduction: We evaluated whether near infrared spectroscopy (NIRS) can determine the metabolic patterns of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). Methods: We enrolled 10 consecutive patients affected by DM, 11 by PM, 9 by IBM, and 3 groups of healthy controls. We measured changes in oxygenated and deoxygenated hemoglobin/myoglobin in the extensor digitorum communis during venous and arterial occlusion testing (VOT) and post-occlusion hyperemia. Results: DM showed lower oxygen consumption (P=0.04) during VOT and reduced oxygen supply after VOT (P=0.04) versus controls. IBM showed higher oxygen consumption (P=0.04) during VOT and higher oxygen supply after VOT (P=0.03) than controls. DM showed reduced oxidative metabolism compared with IBM (P=0.001) and impaired ability to supply oxygen compared with PM (P= 0.03) and IBM (P= 0.001). Discussion: NIRS differentiates samples of DM and IBM patients from controls, but it cannot distinguish PM patients from a sample of healthy subjects. © 2014 Wiley Periodicals, Inc.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most frequent inherited myopathy. We previously demonstrated that mesoangioblasts can be efficiently isolated from FSHD muscles, although their differentiation ability into skeletal muscle was variably impaired. This correlates with overall disease severity and degree of histopathologic abnormalities, since mesoangioblasts from morphologically normal muscles did not show any myogenic differentiation block. The aim of our present study was to verify whether mesoangioblasts from differentially affected FSHD muscles reproduce in vivo the same differentiation ability shown in vitro by studying their capability to form new muscle fibers during muscle regeneration of experimentally damaged muscles. We show that a diverse ability of FSHD mesoangioblasts to engraft and differentiate into skeletal muscle of SCID mice is strictly related to the characteristics of the muscle of origin, closely replicating in vivo what was previously observed in vitro. Moreover, we demonstrate that mesoangioblasts obtained from severely affected muscles scarcely integrate into muscle fibers, remaining mainly localized in the connective tissue. This suggests a defective migration in response to chemoattractants released by damaged fibers, as indicated by cell migration assays in response to HMGB1 and very low levels of RAGE expression, along with a decreased ability to fuse or to appropriately trigger the myogenic program. Our study indicates that FSHD mesoangioblasts from unaffected muscles can be used as selective treatment to halt muscle degeneration in severely affected muscles, and suggests that pharmacological and molecular interventions aimed to ameliorate homing and engraftment of transplanted autologous mesoangioblasts may open the way to cell therapy for FSHD patients, without requiring immunosuppression or genetic correction in vitro.

The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy.

Mesoangioblasts are a class of adult stem cells of mesoderm origin, potentially useful for the treatment of primitive myopathies of different etiology. Extensive in vitro and in vivo studies in animal models of muscular dystrophy have demonstrated the ability of mesoangioblast to repair skeletal muscle when injected intra-arterially. In a previous work we demonstrated that mesoangioblasts obtained from diagnostic muscle biopsies of IBM patients display a defective differentiation down skeletal muscle and this block can be corrected in vitro by transient MyoD transfection. We are currently investigating different pathways involved in mesoangioblasts skeletal muscle differentiation and exploring alternative stimulatory approaches not requiring extensive cell manipulation. This will allow to obtain safe, easy and efficient molecular or pharmacological modulation of pro-myogenic pathways in IBM mesoangioblasts. It is of crucial importance to identify factors (ie. cytokines, growth factors) produced by muscle or inflammatory cells and released in the surrounding milieu that are able to regulate the differentiation ability of IBM mesoangioblasts. To promote myogenic differentiation of endogenous mesoangioblasts in IBM muscle, the modulation of such target molecules selectively dysregulated would be a more handy approach to enhance muscle regeneration compared to transplantation techniques. Studies on the biological characteristics of IBM mesoangioblasts with their aberrant differentiation behavior, the signaling pathways possibly involved in their differentiation block and the possible strategies to overcome it in vivo, might provide new insights to better understand the etiopathogenesis of this crippling disorder and to identify molecular targets susceptible of therapeutic modulation.

Over the last years, the existence of different stem cells with myogenic potential has been widely investigated. Besides the classical skeletal muscle progenitors represented by satellite cells, numerous multipotent and embryologically unrelated progenitors with a potential role in muscle differentiation and repair have been identified. In order to conceive a therapeutic approach for degenerative muscle disorders, it is of primary importance to identify an ideal stem cell endowed with all the features for a possible use in vivo. Among all emerging populations, vessel-associated stem cells are a novel and promising class of multipotent progenitors of mesodermal origin and with high myogenic potential which seem to best fit all the requirements for a possible cell therapy. In vitro and in vivostudies have already tested the effectiveness and safety of vessel-associated stem cells in animal models. This leads to the concrete possibility in the future to start pilot human clinical trials, hopefully opening the way to a turning point in the treatment of genetic and acquired muscle disorders.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and a defect in the regulatory T-cell subset seems to be involved in the pathogenesis of the disease. Foxp3 is a transcription factor that is selectively expressed in CD4+ CD25+ regulatory T cells and is required for their development and function. T-bet is a key transcription factor for the development of T helper 1 (Th1) cells. We found that both the percentage of circulating CD4+ CD25+ Foxp3+ cells and Foxp3 expression were lower in relapsing-remitting (RR) MS patients during relapses than during remission. Otherwise, the percentage of CD4+ T-bet+ T cells and T-bet expression in CD4+ T cells were higher in relapsing than in remitting RRMS patients. CD4+ CD25+ T cells both from relapsing and from remitting RRMS patients showed significantly less capacity than corresponding cells from healthy subjects to suppress autologous CD4+ CD25(-) T-cell proliferation, despite a similar Foxp3 expression level. CD4+ CD25+ T cells from healthy subjects and patients in remission clearly reduced T-bet mean fluorescence intensity (MFI) in CD4+ CD25(-) T cells up to a ratio of 1:10, whereas CD4+ CD25+ T cells from patients in relapse were able to reduce T-bet expression only at a high ratio. Our data indicate that the increased number of regulatory T (T-reg) cells and the increased Foxp3 expression in circulating CD4+ CD25+ T cells may contribute to the maintenance of tolerance in the remission phase of MS. Moreover, the inhibitory capacity of CD4+ CD25+ T cells seems to be impaired in relapsing patients under inflammatory conditions, as shown by the high levels of T-bet expression in CD4+ T cells.

High dose glucocorticoid (GC) treatment has been demonstrated to have a short-term beneficial effect on functional recovery in relapsing multiple sclerosis (MS) patients but the exact mechanism of action of GCs in MS is unclear. We found that high dose intravenous GCs strongly reduced T-bet and pSTAT1 expression in CD4+, CD8+, CD14+ circulating cells in RRMS patients in relapse. pSTAT1and T-bet reduction was associated with the decline of IFNgamma production by PBMCs. A significant increase of AV-positive CD4+ and CD8+ T cells was detectable after GC treatment without any variation in the percentage of annexin V-positive monocytes. By in vitro analysis, patients during relapse, either before or after GC treatment, exhibited a lower proportion of apoptotic lymphocytes than remitting patients and controls. Our study suggests that GCs can modulate T-bet and STAT1 expression and that IFNgamma signalling inhibition contributes to anti-inflammatory action of GCs in the treatment of relapses of MS patients

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system, and it is considered to be a T helper 1 (Th1) cell-mediated autoimmune disease. T-bet has been identified as a key transcription factor for the development of Th1 cells and the induction of interferon (IFN)-gamma production. T-bet is induced during T-cell activation by the IFN-gamma signal transducer and activator of transcription (STAT)-1 signalling pathway. In this study we found an up-regulation of T-bet and pSTAT1 in peripheral blood CD4+ and CD8+ T cells and monocytes from relapsing-remitting MS patients in relapse compared with patients in remission and with healthy subjects. The increased expression of pSTAT1 strongly correlated with T-bet expression in CD4+ and CD8+ cells and monocytes from patients in relapse and was associated with an increased production of IFN-gamma by peripheral blood mononuclear cells (PBMCs). pSTAT3 was also up-regulated in CD4+ and CD8+ cells and monocytes from patients in relapse and was associated with an increased production of interleukin (IL)-10 but not of IL-6. pSTAT1, pSTAT3, and T-bet expression strongly correlated with Gd-DTPA-enhanced lesions on brain and spinal cord magnetic resonance imaging. Our data show for the first time that there is an up-regulation of type 1 immunity-correlated transcription factors such as STAT1 and T-bet in peripheral blood subpopulations of MS patients in the active phase of disease. The evaluation of T-bet and pSTAT1 expression in peripheral blood CD4+, CD8+ T cells and monocytes could be used as a marker of disease activity in relapsing-remitting MS.

OBJECTIVE: Mitoxantrone is an antineoplastic agent also used for the treatment of multiple sclerosis (MS). However, despite its efficacy, few data are available on its mechanism of action. The current study was designed to evaluate the short-term (1 month) and long-term (12 months) in vivo effects of mitoxantrone on pro- and anti-inflammatory cytokine production by the peripheral blood mononuclear cells (PBMC) of secondary progressive MS patients. METHODS: Eighteen patients with secondary progressive MS underwent mitoxantrone therapy (at a dose of 12 mg/m(2) once every 3 months) over a 1-year period. Blood samples were obtained at baseline, after 1 month and after 12 months of treatment. The production of cytokines in the PBMC was measured by enzyme-linked immunosorbent assay. RESULTS: There were no significant effects of mitoxantrone on proinflammatory cytokines [interleukin (IL) 6 and IL-12p40] and anti-inflammatory cytokines (IL-10 and transforming growth factor-beta) in our patients. Patients who showed no signs of therapeutic response were characterized by a higher basal PBMC production of IL-6 compared with that of the responding patients (p < 0.05) and mitoxantrone reduced this production after 12 months of treatment (p < 0.05). In the responding patients, IL-10 was significantly increased by mitoxantrone after 12 months of treatment (p < 0.05). CONCLUSION: These findings provide additional information useful in the selection of the patient population suitable for mitoxantrone treatment and suggest that most probably the therapeutic action of mitoxantrone in MS is not entirely mediated by its immunosuppressant effects.

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Retrospective examination.Objective:To define the clinical characteristics and response to therapy of spinal multiple sclerosis (MS).