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We examined in a rat model of Gulf War illness (GWI), the potential of (−)-epicatechin (Epi) to reverse skeletal muscle (SkM) atrophy and dysfunction, decrease mediators of inflammation and normalize metabolic perturbations. Male Wistar rats (n = 15) were provided orally with pyridostigmine bromide (PB) 1.3 mg/kg/day, permethrin (PM) 0.13 mg/kg/day (skin), DEET 40 mg/kg/day (skin) and were physically restrained for 5 min/day for 3 weeks. A one-week period ensued to fully develop the GWI-like profile followed by 2 weeks of either Epi treatment at 1 mg/kg/day by gavage (n = 8) or water (n = 7) for controls. A normal, control group (n = 15) was given vehicle and not restrained. At 6 weeks, animals were subjected to treadmill and limb strength testing followed by euthanasia. SkM and blood sampling was used for histological, biochemical and plasma pro-inflammatory cytokine and metabolomics assessments. GWI animals developed an intoxication profile characterized SkM atrophy and loss of function accompanied by increases in modulators of muscle atrophy, degradation markers and plasma pro-inflammatory cytokine levels. Treatment of GWI animals with Epi yielded either a significant partial or full normalization of the above stated indicators relative to normal controls. Plasma metabolomics revealed that metabolites linked to inflammation and SkM waste pathways were dysregulated in the GWI group whereas Epi, attenuated such changes. In conclusion, in a rat model of GWI, Epi partially reverses detrimental changes in SkM structure including modulators of atrophy, inflammation and select plasma metabolites yielding improved function.

Muscular dystrophies are a group of well-defined genetic disorders characterized by the variable distribution of muscle wasting and progressive weakness. The diagnosis and treatment of these diseases remain challenging due to genetic heterogeneity and clinical overlapping. Herein, we describe our 10 years' experience with the diagnosis and management of muscular dystrophy patients. In total, 169 patients were screened for pathogenic variants in eleven genes linked to frequent muscular dystrophies using MLPA and NGS sequencing panels. Most frequent muscular dystrophies found in the Mexican population were dystrophinopathies, dysferlinopathies and calpainopathies. Novel variants were found in genes: DMD, CAPN3, DYSF, and FKRP. For Duchenne muscular dystrophy, improvements in early diagnosis and prolonged ambulation were achieved, on the contrary, for limb-girdle muscular dystrophies and congenital muscular dystrophies, uncomplimentary follow-up and lack of detection strategies were observed. For most common muscular dystrophies, improvements in diagnosis and management have been achieved in the last 10 years, due to a collaborative effort done nationwide.

DMD is a rare disorder characterized by progressive muscle degeneration and premature death. Therapy development is delayed by difficulties to monitor efficacy non‐invasively in clinical trials. In this study, we used RNA‐sequencing to describe the pathophysiological changes in skeletal muscle of 3 dystrophic mouse models. We show how dystrophic changes in muscle are reflected in blood by analyzing paired muscle and blood samples. Analysis of repeated blood measurements followed the dystrophic signature at five equally spaced time points over a period of seven months. Treatment with two antisense drugs harboring different levels of dystrophin recovery identified genes associated with safety and efficacy. Evaluation of the blood gene expression in a cohort of DMD patients enabled the comparison between preclinical models and patients, and the identification of genes associated with physical performance, treatment with corticosteroids and body measures. The presented results provide evidence that blood RNA‐sequencing can serve as a tool to evaluate disease progression in dystrophic mice and patients, as well as to monitor response to (dystrophin‐restoring) therapies in preclinical drug development and in clinical trials., This study explored the potential of RNA‐sequencing of peripheral blood to track non‐invasively disease progression and response to treatment in dystrophic mice and in patients affected by Duchenne Muscular Dystrophy (DMD).

Background: The development of skills, behaviors and attitudes regarding patient safety is of utmost importance for promoting safety culture for the next generation of health professionals. This study describes our experience of implementing a course on patient safety and quality improvement for fourth year medical students in Mexico during the COVID-19 outbreak. The course comprised essential knowledge based on the patient safety curriculum provided by the WHO. We also explored perceptions and attitudes of students regarding patient safety. Methods: Fourth year medical students completed a questionnaire regarding knowledge, skills, and attitudes on patient safety and quality improvement in medical care. The questionnaire was voluntarily answered online prior to and after the course. Results: In total, 213 students completed the questionnaires. Most students were able to understand medical error, recognize failure and the nature of causation, perform root-cause analysis, and appreciate the role of patient safety interventions. Conversely, a disapproving perspective prevailed among students concerning the preventability of medical errors, utility of reporting systems, just culture and infrastructure (p &lt, 0.05). Conclusion: We found students had a positive perspective concerning learning quality in healthcare and patient safety during our course, nevertheless, their perception of the usefulness of reporting systems to prevent future adverse events and prevent medical errors is uncomplimentary. Medical education should promote error reporting and just culture to change the current perception of medical students.

Duchenne muscular dystrophy (DMD) is a progressing disorder characterized by muscle wasting and weakness due to the absence or alteration of the function of dystrophin that protects muscle cells from mechanical stress induced by a movement during contraction. The function of dystrophin isoforms expressed in the brain is not fully understood, but the presence of non-progressing cognitive impairment (including disorders of learning and memory) is a common feature in patients with DMD. To establish correlation between the cognitive event-related potential P300 and psychological evaluation with an intelligence test based on the Stanford Binet Intelligence Quotient (IQ) in patients with DMD and a control group, the respective tests were performed in 31 patients with DMD and 30 controls. The mean age of the group with DMD was 9.35 ± 2.88 years, while that in control children was 9.43 ± 2.69 years (P = 0.89). The IQ was 90.77 ± 12.62 in the DMD group and 106.77 ± 9.62 in the controls (P < 0.0001). The amplitude of the cognitive potential P300 in leads Fz, Cz, and Pz showed no statistically significant differences between the groups. Thus, parameters of the P300 potential and cognitive assessment showed nearly no relationship in patients with DMD vs. controls.

Novel therapeutic approaches are emerging to restore dystrophin function in Duchenne Muscular Dystrophy (DMD), a severe neuromuscular disease characterized by progressive muscle wasting and weakness. Some of the molecular therapies, such as exon skipping, stop codon read-through and internal ribosome entry site-mediated translation rely on the type and location of mutations. Hence, their potential applicability worldwide depends on mutation frequencies within populations. In view of this, we compared the mutation profiles of the populations represented in the DMD Leiden Open-source Variation Database with original data from Mexican patients (n = 162) with clinical diagnosis of the disease. Our data confirm that applicability of exon 51 is high in most populations, but also show that differences in theoretical applicability of exon skipping may exist among populations, Mexico has the highest frequency of potential candidates for the skipping of exons 44 and 46, which is different from other populations (p &lt, 0.001). To our knowledge, this is the first comprehensive comparison of theoretical applicability of exon skipping targets among specific populations.

The Asn118Asn (rs11615) variant in the ERCC1 gene, and the Lys751Gln (rs13181) and Asp312Asn (rs1799793) variants in the ERCC2 gene have been associated with the development of varied types of cancer. The aim of the present study was to test for any association between the ERCC1 and ERCC2 gene variants and three different types of cancer in Mexican-mestizo patients. Patients and their respective controls were formed into three groups: The osteosarcoma group, with 28 patients and 97 controls; the colorectal group, with 108 patients and 119 controls; and the breast cancer group, with 71 patients and 74 controls. Genotyping was performed using TaqMan probes and quantitative polymerase chain reaction. Allele and genotype frequencies were compared using a χ2 test. Only one SNP (rs1799793) was found to be associated with breast cancer. This is the first study analyzing the SNPs in ERCC1 and ERCC2 genes and the susceptibility to cancer in Mexican-mestizo patients with osteosarcoma, and colorectal and breast cancer.

Among susceptibility genes for Sporadic Parkinson´s Disease (SPD), the MTHFR gene has been suggested as candidate. The A allele of the functional variant rs13306560 in its promoter region has been liked to decreased transactivation capacity. Therefore, we sought to determine a possible association of the rs13306560 and SPD.In total, 237 individuals were genotyped, 113 patients with SPD diagnosed according to the Queen Square Brain Bank criteria and 124 neurologically healthy controls. Genotyping was performed using TaqMan probes for the rs13306560 and real-time PCR.The A allelle was associated to protection in SPD, under the dominant model, (OR=0.22, C.I.=[0.048-1.080], p=0.04), nevertheless, after logistic regression analysis with adjustment for gender, resulted only in a trend (Exp (β)=0.211, [I.C. 95.0%, 0.042-1.057], p=0.058).Although further studies are needed, our data suggest an important role of the MTHFR gene variants in the fine-tuning regulation of one-carbon metabolism in the brain.

Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a “liquid biopsy” for carrier detection and genetic counseling in DMD.

Chinchilla laniger has been reported as an experimental definitive host for Taenia solium; however no information about its suitability and yield of gravid tapeworm proglottids containing viable and infective eggs has been published. In total 55 outbred female chinchillas were infected with 4 cysticerci each; hosts were immunodeppressed with 6 or 8 mg of methyl-prednisolone acetate every 14 days starting the day of infection and their discomfort was followed. Kinetics of coproantigen ELISA or expelled proglottids was used to define the infection status. Efficiency of tapeworm establishment was 21% and of parasite gravidity was 8%; chinchillas showed some degree of suffering along the infection. Viability of eggs obtained from gravid proglottids was tested comparing methods previously published, our results showed 62% viability with propidium iodide, 54% with trypan blue, 34% with neutral red, 30% by oncosphere activation and 7% with bromide 3-(4,5-dimetil-tiazol-2-il)-2,5-difenil-tetrazolio (MTT) reduction; no statistical differences were obtained between most techniques, except activation. Four piglets were infected with 50,000 eggs each, necropsy was performed 3 months later and, after counting the number of cysticerci recovered, the percentage of infection was similar to data obtained with T. solium eggs recovered from humans. Our results demonstrate that the experimental model of T. solium taeniasis in C. laniger is a good alternative for providing eggs and adult tapeworms to be used in different types of experiments; optimization of the model probably depends on the use of inbred hosts and on the reduction of infected animals' suffering.

Non-invasive biological indicators of the absence/presence or progress of the disease that could be used to support diagnosis and to evaluate the effectiveness of treatment are of utmost importance in Duchenne Muscular Dystrophy (DMD). This neuromuscular disorder affects male children, causing weakness and disability, whereas female relatives are at risk of being carriers of the disease. A biomarker with both high sensitivity and specificity for accurate prediction is preferred. Until now creatine kinase (CK) levels have been used for DMD diagnosis but these fail to assess disease progression. Herein we examined the potential applicability of serum levels of matrix metalloproteinase 9 (MMP-9) and matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), myostatin (GDF-8) and follistatin (FSTN) as non-invasive biomarkers to distinguish between DMD steroid naïve patients and healthy controls of similar age and also for carrier detection. Our data suggest that serum levels of MMP-9, GDF-8 and FSTN are useful to discriminate DMD from controls (p &lt, 0.05), to correlate with some neuromuscular assessments for DMD, and also to differentiate between Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy (LGMD) patients. In DMD individuals under steroid treatment, GDF-8 levels increased as FSTN levels decreased, resembling the proportions of these proteins in healthy controls and also the baseline ratio of patients without steroids. GDF-8 and FSTN serum levels were also useful for carrier detection (p &lt, 0.05). Longitudinal studies with larger cohorts are necessary to confirm that these molecules correlate with disease progression. The biomarkers presented herein could potentially outperform CK levels for carrier detection and also harbor potential for monitoring disease progression.

gene disrupting the read-ing frame result in Duchenne muscular dystrophy (DMD)(OMIM: 310200), whereas in-frame mutations producingsmall but functional dystrophin result in a milder form,Becker muscular dystrophy (BMD) (OMIM: 300376). This‘reading frame rule’ holds true for more than 90% ofcases (Tuffery-Giraud

Duchenne muscular dystrophy is a severe, debilitating and progressive disease that affects 1 in 3,500 live male births in the world. The diagnosis should be confirmed by genetic testing to identify the mutation in the DMD gene or muscle biopsy and immunostaining to demonstrate the absence of dystrophin. Although up to now continues to be an incurable disease, this does not mean it has no treatment. Treatment should be multidisciplinary, looking for the functionality of the patient and avoiding or correcting complications, mainly cardio-respiratory and skeletal. Many proposals have been evaluated and implemented with the aim of improving the quality of life for these patients. The long-term steroids have shown significant benefits, such as prolonging ambulation, reduce the need for spinal surgery, improve cardiorespiratory function and increase survival and the quality of life. This document presents the recommendations based on the experience of the working group and experts worldwide on the diagnosis and treatment with steroids for patients with Duchenne muscular dystrophy.Diagnostico y tratamiento con esteroides de pacientes con distrofia muscular de Duchenne: experiencia y recomendaciones para Mexico.La distrofia muscular de Duchenne es una enfermedad grave, incapacitante y progresiva que afecta a 1 de cada 3.500 recien nacidos varones alrededor del mundo. El diagnostico debera confirmarse mediante pruebas geneticas para identificar la mutacion en el gen DMD, o bien por biopsia muscular e inmunotincion para demostrar la ausencia de distrofina. Aunque actualmente continua siendo una enfermedad incurable, no significa que no tenga tratamiento. Este debe ser multidisciplinario, buscando la funcionalidad del paciente y evitando o corrigiendo las complicaciones, principalmente cardiorrespiratorias y esqueleticas. Se han evaluado e implementado multiples propuestas con la finalidad de mejorar la calidad de vida en estos pacientes. Los esteroides a largo plazo han demostrado importantes beneficios para los pacientes, prolongan la deambulacion, reducen la necesidad de cirugia de columna, mejoran la funcion cardiorrespiratoria, y aumentan la supervivencia y la calidad de vida. En este documento se presentan las recomendaciones con base en la experiencia del grupo de trabajo y de los expertos de ambito mundial sobre el diagnostico y el tratamiento con esteroides para los pacientes con distrofia muscular de Duchenne.

Introduction: The muscular dystrophies (MDs) result from perturbations in the myofibers. These alterations are induced in part by mechanical stress due to membrane cell fra- gility, disturbances in mechanotransduction pathways, muscle cell physiology, and metabolism. Methods: We analyzed 290 biopsies of patients with a clinical diagnosis of muscular dystro- phy. Using immunofluorescence staining, we searched for pri- mary and secondary deficiencies of 12 different proteins, including membrane, costamere, cytoskeletal, and nuclear pro- teins. In addition, we analyzed calpain-3 by immunoblot. Results: We identified 212 patients with varying degrees of pro- tein deficiencies, including dystrophin, sarcoglycans, dysferlin, caveolin-3, calpain-3, emerin, and merosin. Moreover, 78 biop- sies showed normal expression of all investigated muscle pro- teins. The frequency rates of protein deficiencies were as follows: 52.36% dystrophinopathies; 18.40% dysferlinopathies; 14.15% sarcoglycanopathies; 11.32% calpainopathies; 1.89% merosinopathies; 1.42% caveolinopathies; and 0.47% emerino- pathies. Deficiencies in lamin A/C and telethonin were not detected. Conclusion: We have described the frequency of common muscular dystrophies in Mexico. Muscle Nerve 45: 338-345, 2012

Duchenne muscular dystrophy (DMD) is a genomic disorder characterized by progressive muscle wasting and weakness due to the absence or abnormal function of dystrophin; a protein that protects muscle cells from mechanical induced stress during contraction. Mutations in the DMD gene, may lead to different clinical phenotypes, collectively known as dystrophinopathies, of which DMD has the earliest onset and most severe progression.We report a novel deletion of exons 24-41, predicted to maintain the reading frame and expected to result in a mild phenotype. Conversely, the patient has a severe DMD phenotype.Our report supports the hypothesis that disruption of the gamma-actin-binding site located in the central rod domain plays a crucial role in the shock absorber function of dystrophin in muscle cells. Description of pathogenic variants in the DMD gene and the resulting phenotypes has important implications on the designing of molecular therapeutic approaches for DMD.

INTRODUCTION. Dystrophinopathies are X-linked genetic disorders caused by mutations in the DMD gene. Genetic tests are of utmost importance for management and genetic counseling of these diseases. However, the complexity of the DMD gene is a challenge for diagnosis. AIM. To describe recent advances in the diagnosis of dystrophinopathies, after 20 years since the firsts molecular assays for genetic screening for these diseases. DEVELOPMENT. Currently, a variety of strategies such as automated mutation detection, cell-based methods and high throughput haplotyping have been developed to facilitate diagnosis of dystrophinopathies, carrier detection, prenatal and preimplantation diagnosis. CONCLUSION. New technologies have improved early detection and optimal management of dystrophinopathies and have established the basis for future molecular medicine. The most significant advances in dystrophinopathy diagnosis are reviewed herein.

This study analysed the inhibition produced by the agonists moxonidine (imidazoline I-1 receptors > alpha(2)-adrenoceptors) and agmatine (endogenous ligand of imidazoline I-1/I-2 receptors), using B-HT 933 (6-ethyl-5,6,7,8-tetrahydro-4H-oxazolo[4,5-d]azepin-2-amine dihydrochloride; alpha(2)-adrenoceptors) for comparison, on the rat cardioaccelerator sympathetic outflow. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. Sympathetic stimulation or noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. l.v. continuous infusions of moxonidine (3 and 10 mu g/kg min). agmatine (1000 and 3000 mu g/kg min) and B-HT 933 (30 and 100 mu g/kg min) inhibited the tachycardic responses to sympathetic stimulation, but not those to noradrenaline. The cardiac sympatho-inhibition by either moxonidine (3 mu g/kg min) or B-HT 933 (30 mu g/kg min) was not modified by i.v. injections of saline or the antagonists AGN192403 [(+/-)-2-endo-Amino-3-exo-isopropylbicyclo[2.2.1]heptane hydrochloride; 3000 mu g/kg; imidazoline I-1 receptors] or BU224 (2-(4,5-dihydroimidazol-2-yl)quinoline hydrochloride; 300 mu g/kg; imidazoline I-2 receptors) and abolished by rauwolscine (300 mu g/kg; alpha(2)-adrenoceptors). At the same doses of these compounds, the sympatho-inhibition to moxonidine (10 mu g/kg min) and agmatine (1000 mu g/kg min) was: (1) not modified by saline, AGN192403 or BU224; (2) partially blocked by rauwolscine or the combination of rauwolscine plus BU224: and (3) abolished by the combination of rauwolscine plus AGN192403. These results demonstrate that the cardiac sympatho-inhibition to: (1) 3 mu g/kg min moxonidine or 30 mu g/kg min B-HT 933 involves alpha(2)-adrenoceptors; and (2) 10 mu g/kg min moxonidine or 1000 mu g/kg min agmatine involves alpha(2)-adrenoceptors and imidazoline I-1 receptors. (C) 2009 Elsevier B.V. All rights reserved.

Introduccion. La distrofia muscular de Duchenne (DMD) es un trastorno caracterizado por atrofia muscular progresiva y debilidad, debido a la ausencia o alteracion de la funcion de la distrofina, una proteina que protege a las celulas del muscu­lo de la tension mecanica inducida durante la contraccion. Las mutaciones en el gen DMD pueden dar lugar a diferentes fenotipos clinicos, conocidos colectivamente como distrofinopatias, de los cuales la DMD es el mas grave. Caso clinico. Se presenta una delecion nueva de los exones 24-41, que no interrumpe el marco de lectura y se espera que origine un fenotipo leve. Por el contrario, el paciente tiene un fenotipo DMD grave. Conclusiones. Nuestra comunicacion apoya la hipotesis de que la interrupcion del sitio de union a gamma-actina situado en el dominio cilindrico central desempena un papel crucial en la funcion de amortiguador de distrofina en las celulas musculares. La descripcion de las variantes patogenicas en el gen DMD y los fenotipos resultantes tienen importantes implicaciones en el diseno de estrategias terapeuticas moleculares para la DMD.

Introduccion. Las distrofinopatias son trastornos geneticos ligados al cromosoma X causados por mutaciones en el gen DMD. Las pruebas geneticas son de suma importancia para la gestion y el asesoramiento genetico de estas enfermedades. Sin embargo, la complejidad del gen DMD es un desafio para el diagnostico. Objetivo. Describir los avances recientes en el diagnostico de distrofinopatias, despues de 20 anos de los primeros ensayos moleculares para la deteccion genetica de estas enfermedades. Desarrollo. En la actualidad, se han desarrollado una variedad de estrategias, como la deteccion de mutaciones automatizada, los metodos basados en celulas y la haplotipificacion de alto rendimiento, para facilitar el diagnostico de distrofinopatias, la deteccion de portadoras, el diagnostico prenatal y preimplantacional. Conclusion. Las nuevas tecnologias han mejorado la deteccion temprana y el manejo optimo de distrofinopatias, y han establecido la base para la medicina molecular en el futuro. Los avances mas importantes en el diagnostico de distrofinopatias se revisan en este documento.