Generation of the first human in vitro model for McArdle disease based on iPSC Technology

McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C>T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity.This work has been funded by grants from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (ISCIII): PI15/00484, CP16/00046 and PI18/00151 to MEG and PI17/02052 to JA (co-funded by European Regional Development Fund “A way to make Europe”); PI21/00162 and CPII21/00011 co-funded by the European Union to MEG. MdCOC receives grant support from the ‘Ministerio de Educación, Cultura y Deporte’ (FPU16/03895), ‘Fundación para la Investigación Biomédica Hospital 12 de Octubre’ (2022/0065, i+12-AY20220114-1) and EMBO Grant 8917. CL and MD were recipient of a fellowship from the French Ministry of Education. The work in FM’s laboratory was funded by “Association Française contre les Myopathies” (AFM; TRIM-RD and MoThARD) and from the Excellence Initiative of Aix-Marseille University-A*Midex, a French “investissement d’avenir programme” AMX-19-IET-007 through the Marseille Maladies Rares (MarMaRa) Institute (phD fellowship to CL)

The stigma of mental health professionals towards users with a mental disorder

INTRODUCTION Individuals with mental disorders are labeled in such a way that it leads to stigmatization. This generates a disadvantage as regards to the rest of the members of the society, limiting their participation as active members within it and at the same time being deleterious to their way of life. Mental health professionals are not safe from internalizing these stereotypes and prejudices assumed from their environment, thereby showing stigmatizing attitudes and behaviors towards the users in the different mental health resources. METHODOLOGY The design used in this study to determine the stigma of mental health professionals is a quantitative study, which was used to analyze the level of stigma presented by professionals using the Attribution Questionnaire-27 (AQ- 27). The sample consisted of 59 professionals. RESULTS The results obtained showed the existence of stigmatizing attitudes and behaviors by the professionals analyzed. Within the sociodemographic data of the sample, it should be noted that the higher level of education of the professionals decreased the attitudes and behaviors associated to stigma. CONCLUSIONS It was possible to confirm the existence of different stigma factors such as helping, coercion, pity and avoidance that affect mental health professionals

Occupational Therapy in Severe Mental Disorder—A Self-Controlled Quasi-Experimental Study

Severe mental disorder (SMD) produces a significant functional limitation that affects the performance of daily activities. The occupational therapist intervenes on this limitation by seeking greater autonomy of these patients through specific activities. This study aims to identify the main limitations of people with SMD and to examine whether an occupational intervention has any effect in helping to overcome or ameliorate these limitations. A quasi-experimental study including 103 participants was carried out. An evaluation using the World Health Organization Disability Assessment Schedule (WHODAS 2.0) questionnaire was performed before and after the intervention. Within the activity program, those with a higher attendance rating during cognitive stimulation, cooking workshop, therapeutic walks, relaxation, and creative activities were mainly men. Both patients and professionals indicated that Understanding and Communicating, Participation in Society, and Activities of Daily Living were the main perceived limitations. Upon discharge, patients and professionals reported positive outcomes. The intervention programs carried out by occupational therapy, along with the other aspects of the treatment that SMD patients received, played an important part in improving the performance and occupational interests of these patients

Daptomycin plus Fosfomycin versus Daptomycin Alone for Methicillin-Resistant Staphylococcus 2 aureus Bacteremia and Endocarditis. A Randomized Clinical Trial

Background We aimed to determine whether daptomycin plus fosfomycin provides higher treatment success than daptomycin alone for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia and endocarditis. Methods A randomized (1:1) phase 3 superiority, open-label, and parallel group clinical trial of adult inpatients with MRSA bacteremia was conducted at 18 Spanish hospitals. Patients were randomly assigned to receive either 10 mg/kg of daptomycin intravenously daily plus 2 g of fosfomycin intravenously every 6 hours, or 10 mg/kg of daptomycin intravenously daily. Primary endpoint was treatment success 6 weeks after the end of therapy. Results Of 167 patients randomized, 155 completed the trial and were assessed for the primary endpoint. Treatment success at 6 weeks after the end of therapy was achieved in 40 of 74 patients who received daptomycin plus fosfomycin and in 34 of 81 patients who were given daptomycin alone (54.1% vs 42.0%; relative risk, 1.29 [95% confidence interval, .93-1.8]; P = .135). At 6 weeks, daptomycin plus fosfomycin was associated with lower microbiologic failure (0 vs 9 patients; P = .003) and lower complicated bacteremia (16.2% vs 32.1%; P = .022). Adverse events leading to treatment discontinuation occurred in 13 of 74 patients (17.6%) receiving daptomycin plus fosfomycin, and in 4 of 81 patients (4.9%) receiving daptomycin alone (P = .018). Conclusions Daptomycin plus fosfomycin provided 12% higher rate of treatment success than daptomycin alone, but this difference did not reach statistical significance. This antibiotic combination prevented microbiological failure and complicated bacteremia, but it was more often associated with adverse events

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Nutritional Status Measurement Instruments for Diabetes: A Systematic Psychometric Review.

Diabetes is a serious chronic disease associated with a large number of complications and an increased risk of premature death. A dietary evaluation is of utmost importance for health promotion, disease prevention and individual treatment plans in patients with diabetes. An exhaustive search was carried out in various databases-Medline, Web of Science, Open Gray Cochrane Library and Consensus-based Standards for the selection of health status Measurement Instruments (COSMIN)-for systematic review of the measurement properties of instruments that evaluate the dietary intake of people with diabetes mellitus type 1 and/or 2 according to COSMIN standards. Seven instruments were identified. There was no instrument measuring nutritional status for which all the psychometric properties were evaluated. The methodological quality for each of the psychometric properties evaluated was 'inadequate' or 'doubtful' for all instruments. The Food Frequency Questionnaire (FFQ) evaluated the most psychometric characteristics and with a better score in terms of quality of the evidence. Several instruments have been developed for the evaluation of dietary intake in people with diabetes. Evaluation of this construct is very useful, both in clinical practice and in research, requiring new knowledge in this area. The FFQ is the best instrument available to assess dietary intake in people with diabetes

Oxidative stress in skin fibroblasts cultures from patients with Parkinson's disease

Abstract Background In the substantia nigra of Parkinson's disease (PD) patients, increased lipid peroxidation, decreased activities of the mitochondrial complex I of the respiratory chain, catalase and glutathione-peroxidase, and decreased levels of reduced glutathione have been reported. These observations suggest that oxidative stress and mitochondrial dysfunction play a role in the neurodegeneration in PD. We assessed enzymatic activities of respiratory chain and other enzymes involved in oxidative processes in skin fibroblasts cultures of patients with PD. Methods We studied respiratory chain enzyme activities, activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, and coenzyme Q10 levels in skin fibroblasts cultures from 20 Parkinson's disease (PD) patients and 19 age- and sex- matched healthy controls. Results When compared with controls, PD patients showed significantly lower specific activities for complex V (both corrected by citrate synthase activity and protein concentrations). Oxidized, reduced and total coenzyme Q10 levels (both corrected by citrate synthase and protein concentrations), and activities of total, Cu/Zn- and Mn-superoxide-dismutase, gluthatione-peroxidase and catalase, did not differ significantly between PD-patients and control groups. Values for enzyme activities in the PD group did not correlate with age at onset, duration, scores of the Unified Parkinson's Disease Rating scales and Hoehn-Yahr staging. Conclusions The main result of this study was the decreased activity of complex V in PD patients. This complex synthesizes ATP from ADP using an electrochemical gradient generated by complexes I-IV. These results suggest decreased energetic metabolism in fibroblasts of patients with PD.</p

Generation of the First Human In Vitro Model for McArdle Disease Based on iPSC Technology

McArdle disease is a rare autosomal recessive disorder caused by mutations in the PYGM gene. This gene encodes for the skeletal muscle isoform of glycogen phosphorylase (myophosphorylase), the first enzyme in glycogenolysis. Patients with this disorder are unable to obtain energy from their glycogen stored in skeletal muscle, prompting an exercise intolerance. Currently, there is no treatment for this disease, and the lack of suitable in vitro human models has prevented the search for therapies against it. In this article, we have established the first human iPSC-based model for McArdle disease. For the generation of this model, induced pluripotent stem cells (iPSCs) from a patient with McArdle disease (harbouring the homozygous mutation c.148C&gt;T; p.R50* in the PYGM gene) were differentiated into myogenic cells able to contract spontaneously in the presence of motor neurons and generate calcium transients, a proof of their maturity and functionality. Additionally, an isogenic skeletal muscle model of McArdle disease was created. As a proof-of-concept, we have tested in this model the rescue of PYGM expression by two different read-through compounds (PTC124 and RTC13). The developed model will be very useful as a platform for testing drugs or compounds with potential pharmacological activity

Physical exercise and epicardial adipose tissue: A systematic review and meta‐analysis of randomized controlled trials

We performed a meta-analysis of the effects of exercise on epicardial adipose tissue (EAT). A systematic search was conducted in PubMed and Scopus (since inception to 1 February 2020) of randomized controlled trials assessing the effects of exercise interventions alone (with no concomitant weight loss intervention) on EAT. The standardized mean difference (Hedges' g) and 95% confidence interval between interventions were computed using a random effects model. Ten studies (including 521 participants who had, on average, overweight/obesity) met all inclusion criteria. Interventions were supervised and lasted 2 to 16 weeks (≥3 sessions·per week). Exercise significantly reduced EAT (g = 0.82 [0.57-1.07]) irrespective of the duration of the intervention or the EAT imaging assessment method. Exercise benefits were separately confirmed for endurance (six studies, n = 287; g = 0.83 [0.52-1.15]) but not for resistance exercise training (due to insufficient data for quantitative synthesis). It was not possible to compare the effect of high-intensity interval training (HIIT) versus moderate-intensity continuous training (two studies, one reporting higher benefits with HIIT and the other no differences). Physical exercise interventions-particularly endurance training, with further evidence needed for other exercise modalities-appear as an effective strategy for reducing EAT in individuals with overweight/obesity, which supports their implementation for cardiovascular risk reduction.Instituto de Salud Carlos IIIUnión EuropeaMinisterio de Ciencia, Innovación yUniversidadesUniversidad de AlcaláDepto. de MedicinaFac. de MedicinaTRUEpu