Transcription-terminating mutation in telethonin causing autosomal recessive muscular dystrophy type 2G in a European patient

A 27-year-old woman of Moldavian origin presented at the age of 15 with progressive proximal limb weakness and painful cramps in her calf muscles. Clinical examination revealed prominent Muscle weakness in proximal muscles of the lower extremities and distal anterior compartment of legs, and mild weakness in shoulder girdle muscles. In addition, she had marked calf hypertrophy, Muscle atrophy involving the anterior and posterior compartments of the thighs, and the distal anterior compartment of legs, as well as mild scapular winging and hyperlordosis. A muscle biopsy taken from the biceps brachii showed mild dystrophic changes, absent vacuoles, and abundant lobulated fibers. Immunofluorescence and Western blot assays demonstrated complete telethonin deficiency. Molecular analysis revealed a homozygous Trp25X mutation in the telethonin (TCAP) gene resulting in termination of transcription at an early point. Four families from Brazil with telethonin deficiency have previously been reported and classified as LMD2G, but the actual frequency of this disease is unknown. With this current identification of a case outside the Brazilian Population, telethonin mutation-associated LGMD should be considered worldwide. (C) 2008 Elsevier B.V. All rights reserved

Nemaline myopathy type 6: clinical and myopathological features

Nemaline myopathy (NEM) is one of the most common congenital myopathies. A unique subtype, NEM6, maps to chromosome 15q21-q23 in two pedigrees, but the causative gene has not been determined. We conducted clinical examination and myopathological studies in a new NEM family. Genotyping and gene screening were accomplished by searching known and 18 new candidate genes. The disease started in childhood by affecting proximal and distal muscles and causing slowness of movements. Muscle biopsies showed numerous nemaline rods and core-like formations. Suggestive linkage to chromosome 15q22-q23 was established. Genes known to be mutated in NEM or core-rod myopathy were screened and excluded. No pathogenic mutations were identified in other candidate genes. The disease in this Spanish family was classified as NEM6. It is phenotypically similar and probably allelic to the two previously reported NEM6 pedigrees. Further studies of these families will lead to the identification of the NEM6 gene

Therapeutic Potential of EWSR1-FLI1 Inactivation by CRISPR/Cas9 in Ewing Sarcoma.

Ewing sarcoma is an aggressive bone cancer affecting children and young adults. The main molecular hallmark of Ewing sarcoma are chromosomal translocations that produce chimeric oncogenic transcription factors, the most frequent of which is the aberrant transcription factor EWSR1-FLI1. Because this is the principal oncogenic driver of Ewing sarcoma, its inactivation should be the best therapeutic strategy to block tumor growth. In this study, we genetically inactivated EWSR1-FLI1 using CRISPR-Cas9 technology in order to cause permanent gene inactivation. We found that gene editing at the exon 9 of FLI1 was able to block cell proliferation drastically and induce senescence massively in the well-studied Ewing sarcoma cell line A673. In comparison with an extensively used cellular model of EWSR1-FLI1 knockdown (A673/TR/shEF), genetic inactivation was more effective, particularly in its capability to block cell proliferation. In summary, genetic inactivation of EWSR1-FLI1 in A673 Ewing sarcoma cells blocks cell proliferation and induces a senescence phenotype that could be exploited therapeutically. Although efficient and specific in vivo CRISPR-Cas9 editing still presents many challenges today, our data suggest that complete inactivation of EWSR1-FLI1 at the cell level should be considered a therapeutic approach to develop in the future.This research was funded by the Instituto de Salud Carlos III, grant numbers PI20CIII/00020, DTS18CIII/00005, PI16CIII/00026; Asociación Pablo Ugarte, grant numbers TRPV205/18, TPI-M 1149/13; Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant numbers TVP333-19, TVP-1324/15; ASION, grant number TVP141/17, and by the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER, ER19P5AC728/2021, grant to M.M.), and by the Regional Government of Madrid (CAM, B2017/BMD3721, grant to M.A.M.-P.). R.M.M-F.d.M. was supported by a grant from the Spanish Center for Biomedical Network Research on Rare Diseases (CIBERER).S

Factores climáticos y su relación con la presencia de fasciola hepatica en caprinos de las distintas regiones productivas de la provincia de Mendoza, Argentina

La producción caprina suele asociarse con áreas de-gradadas, escaso alimento, manejo y desarrollo tecnológico. En Mendoza hay tres regiones productivas: Noreste, Valle de Uco, y Sur. Fasciola hepatica causa pérdidas económicas en el ganado y es una zoonosis en expansión. La temperatura y precipitaciones determinan persistencia en el ambiente del parasito y su vec-tor, caracoles acuáticos de la familia Lymneidae. Variaciones de temperatura y precipitaciones pueden alterar el desarrollo del ciclo

Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene

Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations

CD44 modulates cell migration and invasion in Ewing sarcoma cells

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1low cells present a migratory and invasive phenotype, while EWSR1::FLI1high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.: This project was funded by Instituto de Salud Carlos III, grant numbers PI20CIII/00020, DTS18CIII/00005, Asociación Pablo Ugarte, grant numbers TRPV205/18; Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, grant numbers TVP333-19, TVP-1324/15; ASION, grant number TVP141/17. Enrique Fernández-Tabanera is supported by Asociación Candela Riera, Asociación Todos Somos Iván & Fundación Sonrisa de Alex, Saint T. Cervera is supported by Asociación Pablo Ugarte and Raquel M. Melero is supported by a CIBERER contract

Percepción de los usuarios de la farmacia comunitaria sobre la COVID-19 al final de la alarma y comparación con la situación al inicio

Objetivos: evaluar la percepción de los usuarios de las farmacias sobre la repercusión de la COVID-19 en su salud al final del confinamiento y comparar los resultados con los obtenidos al inicio. Material y métodos: estudio observacional transversal aleatorizado, en farmacias de Pontevedra y Ourense, del 10 al 25 de junio de 2020. Sujetos: ≥18 años que acuden en demanda de medicamentos y/o material de protección. Procedimiento: el usuario cumplimentaba un cuestionario anónimo, depositándolo en una bandeja desinfectada diariamente. Resultados: 839 encuestas. 492 (58,6 %) mujeres, edad media 54,6 (DE=17,4) años. 144 (17,2 %) viven solos. 771 (91,9 %) creen que la COVID-19 es más peligrosa que la gripe, 233 (27,7 %) desconocen estar en algún grupo de riesgo. 137 (16,4 %) dicen sentirse mal/muy mal con el aislamiento. Aspectos más afectados: familiar 429 (51,1 %) y emocional 377 (44,9 %). La afectación de los aspectos físico 210 (25,0 %) y laboral 183 (21,8 %) mejoraron significativamente en fase final. En 2020/21 piensan vacunarse de la gripe 376 (44,4 %), en 2019/20 lo hicieron 243 (34,4 %). 541 (64,5 %) se vacunarán frente a la COVID-19 cuando exista vacuna. Aumentan los que se vacunarán, aunque no esté financiada: 511 (60,9 %) / 280 (39,7 %). Conclusiones: no ha variado significativamente la percepción sobre la peligrosidad de la COVID-19 y la repercusión en su salud. Los aspectos del bienestar más afectados siguen siendo el familiar y el emocional. Aumenta el número de los que se sintieron mal/muy mal con el confinamiento y el de mayores afectados por la soledad. Aumenta la intención de vacunarse del SARS-CoV-2, aunque no sea financiada

Differences In Adipose Tissue And Lean Mass Distribution In Patients With Collagen Vi Related Myopathies Are Associated With Disease Severity And Physical Ability

Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients

Differences in Adipose Tissue and Lean Mass Distribution in Patients with Collagen VI Related Myopathies Are Associated with Disease Severity and Physical Ability

Mutations in human collagen VI genes cause a spectrum of musculoskeletal conditions in children and adults collectively termed collagen VI-related myopathies (COL6-RM) characterized by a varying degree of muscle weakness and joint contractures and which include Ullrich Congenital Muscular Dystrophy (UCMD) and Bethlem Myopathy (BM). Given that collagen VI is one of the most abundant extracellular matrix proteins in adipose tissue and its emerging role in energy metabolism we hypothesized that collagen VI deficiency might be associated with alterations in adipose tissue distribution and adipokines serum profile. We analyzed body composition by means of dual-energy X-ray absorptiometry in 30 pediatric and adult COL6-RM myopathy patients representing a range of severities (UCMD, intermediate-COL6-RM, and BM). We found a distinctive pattern of regional adipose tissue accumulation which was more evident in children at the most severe end of the spectrum. In particular, the accumulation of fat in the android region was a distinguishing feature of UCMD patients. In parallel, there was a decrease in lean mass compatible with a state of sarcopenia, particularly in ambulant children with an intermediate phenotype. All children and adult patients that were sarcopenic were also obese. These changes were significantly more pronounced in children with collagen VI deficiency than in children with Duchenne Muscular Dystrophy of the same ambulatory status. High molecular weight adiponectin and leptin were significantly increased in sera from children in the intermediate and BM group. Correlation analysis showed that the parameters of fat mass were negatively associated with motor function according to several validated outcome measures. In contrast, lean mass parameters correlated positively with physical performance and quality of life. Leptin and adiponectin circulating levels correlated positively with fat mass parameters and negatively with lean mass and thus may be relevant to the disease pathogenesis and as circulating markers. Taken together our results indicate that COL6-RM are characterized by specific changes in total fat mass and distribution which associate with disease severity, motor function, and quality of life and which are clinically meaningful and thus should be taken into consideration in the management of these patients

Demanda de medicamentos sin receta: evaluación de la intervención farmacéutica

Introducción La modificación de los usos y actitudes de los demandantes de dispensación de medicamentos que precisan receta médica sin presentarla es un campo donde el farmacéutico comunitario, desde su responsabilidad profesional, puede contribuir a obtener importantes resultados en la consecución de su uso correcto. Objetivo Evaluar el resultado de la intervención del farmacéutico en la demanda de medicamentos (ibuprofeno y paracetamol) sin presentar receta médica en presentaciones que la requieren. Métodos Diseño: estudio experimental transversal aleatorizado con intervención farmacéutica mediante educación sanitaria en Emplazamiento: nueve farmacias de Pontevedra y Ourense. Octubre-noviembre de 2019. Participantes: usuarios de la farmacia que solicitaban sin receta presentaciones de paracetamol o ibuprofeno que la requerían. Mediciones principales: número de solicitudes, problemas de salud y motivos, aceptación o no de una alternativa de medicamento sin receta (MSR). Resultados 424 peticiones, 303 (71,5%) aceptaron la dispensación del MSR. Ibuprofeno 600 mg fue el principio activo más solicitado (73,3%) y la automedicación el principal motivo de petición sin receta (89,9%). Entre los problemas de salud referidos destacó el dolor de cabeza (22,9%). No se encontraron diferencias significativas entre el resultado de la intervención y el medicamento solicitado, el sexo, el motivo, ni el problema de salud que originó la solicitud. Sí entre edad de los pacientes, medicamento solicitado y resultado de la intervención. 30 (14,2%) pacientes fueron derivados al médico. Conclusiones La actuación del farmacéutico en el cambio a un medicamento sin receta logró una alta aceptación por los pacientes, lo que contribuye a su uso adecuado