Role of miRNA-mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death and fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-ß have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy of autopsied human hearts. Our results showed 697 differentially expressed genes and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathways and inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of the miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis, highlighting their value as potential key targets for therapeutic approaches.

Deletion of the Wilms' Tumor Suppressor Gene in the Cardiac Troponin-T Lineage Reveals Novel Functions of WT1 in Heart Development.

Expression of Wilms' tumor suppressor transcription factor (WT1) in the embryonic epicardium is essential for cardiac development, but its myocardial expression is little known. We have found that WT1 is expressed at low levels in 20-25% of the embryonic cardiomyocytes. Conditional ablation of WT1 using a cardiac troponin T driver (Tnnt2 Cre ) caused abnormal sinus venosus and atrium development, lack of pectinate muscles, thin ventricular myocardium and, in some cases, interventricular septum and cardiac wall defects, ventricular diverticula and aneurisms. Coronary development was normal and there was not embryonic lethality, although survival of adult mutant mice was reduced probably due to perinatal mortality. Adult mutant mice showed electrocardiographic anomalies, including increased RR and QRS intervals, and decreased PR intervals. RNASeq analysis identified differential expression of 137 genes in the E13.5 mutant heart as compared to controls. GO functional enrichment analysis suggested that both calcium ion regulation and modulation of potassium channels are deeply altered in the mutant myocardium. In summary, together with its essential function in the embryonic epicardium, myocardial WT1 expression is also required for normal cardiac development.

Isolation and Culture of Quiescent Skeletal Muscle Satellite Cells.

It has been shown that freshly isolated satellite cells from adult muscle constitute a stem cell-like population that exhibits more efficient engraftment and self-renewal activity in regenerating muscle than myoblast. Thus, purification of pure populations of quiescent satellite cells from adult skeletal muscle is highly necessary, not only for understanding the biology of satellite cells and myoblasts but also for improving cell-based therapies for muscle regeneration. This chapter describes a basic protocol used in our laboratory to isolate quiescent muscle satellite cells from adult skeletal muscle by enzymatic dissociation followed by a sequential magnetic-activated cell sorting (MACS). This method is cheap and fast providing and alternative procedure to other purification methods that require fluorescence-activated cell sorting (FACS) machines. Freshly isolated quiescent satellite cells purified by this method can be used in a broad range of experiments including cell transplantation for satellite cell self-renewal experiments or cell therapies.

Glutathione Is the Resolving Thiol for Thioredoxin Peroxidase Activity of 1-Cys Peroxiredoxin Without Being Consumed During the Catalytic Cycle.

AIMS: A three-step catalytic cycle is common to all peroxiredoxins (Prxs), despite structural and kinetic differences. The second step in 1-Cys type Prxs is a matter of debate since they lack an additional cysteine to play the resolving role, as happens with the 2-Cys Prxs. The aim of this study was to elucidate the role of glutathione (GSH) in the thioredoxin-dependent peroxidase activity of Saccharomyces cerevisiae mitochondrial Prx1p, a 1-Cys type Prx. RESULTS: The peroxidatic Cys91 residue of two Prx1p peptides can be linked by a disulfide, which can be reduced by thioredoxin and by GSH (Km=6.1 µM). GSH forms a mixed disulfide with the peroxidatic cysteine spontaneously in vitro and in vivo. Mitochondrial Trx3p deglutathionylates Prx1p without formation of GSSG so that GSH is not consumed in the process. The structural unit of native Prx1p is a dimer whose subunits are not covalently linked, but a hexameric assembly of three disulfide-bound dimers can also be formed. INNOVATION: GSH is presented as a protective cofactor of Prx1p, which is not consumed during the peroxidase reaction, but provides a robust mechanism as the resolving cysteine and efficiently prevents Prx1p overoxidation. GSH exerts these roles at concentrations well below those commonly considered necessary for its antioxidant and redox buffering functions. CONCLUSION: A 1-Cys peroxide scavenging mechanism operates in yeast mitochondria involving an autonomous glutathione molecule and the thioredoxin system, which could have universal validity. Prx1p is fairly well protected from overoxidation, questioning its role in a floodgate mechanism for H2O2 signaling.

Quality of medical care and patient surgical safety: medical error, malpractice and professional liability.

BACKGROUND: over time, a significant number of definitions and concepts on quality of care have been identified. This study focuses on quality of care from the perspective of medical patients. DISCUSSION: quality of medical care includes different areas: opportunity, professional qualifications, safety, respect for ethical principles of medical practice and satisfaction with care outcomes. In this regard, at the Conamed (National Commission for Medical Arbitration), 8062 complaints have been followed, analyzed and completed between June 1996 and December 2008: in 16.8% of the complaints there were insufficient data to determine whether or not there was evidence of malpractice; 20.8% of the complaints had evidence of malpractice and in 62.4% of complaints the existence of good practice was determined according to the lex artis. Among the surgical specialties with the highest malpractice cases were the following: general surgery, gynecology, orthopedics, ophthalmology, emergency surgery, urology and traumatology. CONCLUSIONS: acknowledgment of the concept of quality of health care provides a starting point to determine the source of errors, malpractice and professional responsibility in order to resolve and prevent them. Conamed offers alternative means for conflict resolution related to physician-patient relationship by means of conciliation and arbitration, favoring patient and family, as well as the medical profession.

Perfil epidemiológico de la mortalidad por influenza humana A (H1N1) en México / Epidemiological profile of mortality due to human influenza A (H1N1) in Mexico

OBJETIVO: Efectuar el análisis epidemiológico de 122 defunciones por influenza A (H1N1) confirmadas por laboratorio y contribuir a mejorar el diagnóstico y atención oportuna de casos. MATERIAL Y MÉTODOS: Se Analizaron 122 expedientes de pacientes fallecidos por influenza A (H1N1). RESULTADOS: Una proporción de 51 por ciento correspondió a mujeres y 49 por ciento a varones. Hasta 45.1 por ciento ocurrió entre los 20 y 39 años. La letalidad general fue de 2.2 por ciento y varió entre 0.3 por ciento en el grupo de 10 a 19 años y 6.3 por ciento en el de 50 a 59. Una cifra de 43 por ciento de las defunciones se concentró en dos de las 32 entidades federativas y 5l por ciento se atendió en instituciones de seguridad social. Sólo 17 por ciento recibió atención hospitalaria en las primeras 72 horas y 42 por ciento falleció en las primeras 72 horas de hospitalización. En 58.2 por ciento de los fallecidos había algún padecimiento asociado. DISCUSIÓN: El Nuevo virus A (H1N1) produce mayor mortalidad en personas jóvenes, al contrario de lo que sucede con la influenza estacional que muestra un mayor impacto en niños pequeños y personas de edad avanzada. El retraso de la atención médica y la morbilidad asociada fueron factores relevantes del fallecimiento.

OBJECTIVE: To carry out the epidemiological analysis of 122 influenza A (H1N1) deaths confirmed by laboratory and help to improve the diagnosis and timely managing of cases. MATERIAL AND METHODS: A total of 122 clinical records were analyzed of patients with confirmed influenza A (H1N1) virus infection who died. RESULTS: Fifty-one percent of patients were female and 49 percent were male. A total of 45.l percent who died were between 20 and 39 years old. Overall fatality was 2.2 percent and ranged between 0.3 percent for the l0 to l9 year-old group to 6.3 percent for the 50 to 59 year-old group. Forty-three percent of deaths were concentrated in only two of the thirty-two states and 5l percent received medical attention in social security institutions. Only l7 percent received hospital attention within 72 hours and 42 percent died within 72 hours of hospital attention. DISCUSSION: Novel Influenza A (H1N1) virus produces higher mortality in young people whereas seasonal influenza has a greater impact on young children and older people. Delay in medical care and the associated morbidity were relevant factors for death.

Perfil epidemiológico general de las quejas médicas atendidas en la Comisión Nacional de Arbitraje Médico: 1996-2007 / Epidemiological general profile of complaints treated at the National Medical Arbitration Commission: 1996-2007

OBJECTIVE: To analyze medical complaints over a period of 11 years, for making recommendations for prevention and improving planning for responding. MATERIAL AND METHODS: We studied the medical complaints at the National Medical Arbitration Commission (Conamed, per its acronym in Spanish) between 1996 and 2007 using descriptive statistics to identify their general profile in relation to the variables of time, place and person. We also studied the frequency of evident medical malpractice as well as the severity of the damage it produces. RESULTS: The request for responses to medical complaints increased between 1996 and 2007 and there was less demand between July and December. Two states in the country account for 69.7 percent of the complaints and 74.0 percent are from public institutions. Fifty-eight percent come from women and the 25-34 and 65+ age groups have the highest percentage. We found in 27.0 percent of the complaints there is evidence of medical malpractice and obstetrics and gynecology have the highest percentage of complaints, physical harm and severity of injury. Complaints about treatment are nearly four times more than diagnosis. CONCLUSIONS: It is necessary to improve the quality of diagnosis and treatment and identify cost-effective measures to reduce medical malpractice and the severity of physical damage in patients.

OBJETIVO: Analizar las quejas médicas atendidas en un periodo de 11 años con el fin de formular recomendaciones para prevenirlas y mejorar la planeación para su atención. MATERIAL Y MÉTODOS: Se estudiaron las quejas de la Comisión Nacional de Arbitraje Médico (Conamed) recibidas entre 1996 y 2007 y se utilizaron medidas de estadística descriptiva para conocer su perfil general en relación con las variables de tiempo, lugar y persona. También se determinó la frecuencia de mala práctica médica evidente, así como la gravedad del daño que producen. RESULTADOS: La solicitud de atención de quejas se incrementó entre 1996 y 2007, y existió menor demanda de atención en julio y diciembre. Dos estados del país concentran 69.7 por ciento de las quejas y 74 por ciento proviene de instituciones públicas. El 58 por ciento son de mujeres y los grupos de 25 a 34, y de 65 y más años tienen el mayor porcentaje. En 27 por ciento de las quejas atendidas hay evidencia de mala práctica médica y ginecología y obstetricia presenta el mayor porcentaje de quejas, daño físico y gravedad del daño. Las quejas por tratamiento son casi cuatro veces más que las de diagnóstico. CONCLUSIONES: Es necesario mejorar la calidad del diagnóstico y el tratamiento e identificar medidas efectivas para el costo que reduzcan la mala práctica médica y la gravedad del daño físico en los pacientes.

Pitx2c overexpression promotes cell proliferation and arrests differentiation in myoblasts.

Pitx2 is a paired-related homeobox gene that has been shown to play a central role during development. In the mouse, there are three isoforms, Pitx2a, b, and c, which differ only in their amino terminal regions. Pitx2 is expressed in myotomes, myoblasts, and myofibers and may be involved in muscle patterning. However, the mechanism by which Pitx2 acts in muscle cell lineages as well as the distinct functions of the individual isoforms have not been investigated. In this study, we used Sol8 myoblasts to investigate the function of Pitx2 in skeletal myogenesis. We found that Pitx2c is the main Pitx2 isoform present in Sol8 myoblasts. Overexpression of Pitx2c in Sol8 myoblasts inhibited myocyte differentiation and myotube formation. Furthermore, Sol8 cells overexpressing Pitx2c maintained high proliferative capacity and a significant up-regulation of the cell cycle genes cyclin D1, cyclin D2, and c-myc. Gene expression analysis for Pax3 and the s MyoD and myogenin showed that Pitx2c-overexpression caused Sol8 cells to remain as myoblasts, in an undifferentiated myogenic state. Furthermore, down-regulation of the muscle-specific genes sTnI and MyHC3 demonstrated that Sol8-overexpressing Pitx2c myoblasts failed to reach terminal differentiation. This study sheds light on previously unknown functions of the Pitx2c isoform in balancing proliferation vs. differentiation in a myogenic cell line.

"El milagro invisible" / \"The invisible miracle\"

Lectura dirigida a los trabajadores de salud local y a la población en general, sobre conocimientos en salud pública, así como los principios que la sustentan y los métodos y disciplinas que se utilizan en su uso diario. Contenido: Capítulo I. Salud pública: principios básicos y campo de acción. Capítulo II. Problemas y pogramas de salud pública. Capítulo III. Niveles de organización operativa del Sector Salud. Capítulo IV. La epidemiología. Capítulo V. La bioestadística. Capítulo VI. La unidad sociedad y salud. Capítulo VII. De la administración a la gerencia en salud. Capítulo VIII. Del control a la regulación sanitaria. Capítulo IX. Integración de conocimientos: el diagnóstico de la salud pública Capítulo X. Respuesta programática: diseño de intervenciones Capítulo XI. Utilización tangible: la municipalización de la salud. Capítulo XII. Glosario de términos