Activation of the Innate Immune Response against DENV in Normal Non-Transformed Human Fibroblasts

In this work, we demonstrate that that both human whole skin and freshly isolated skin fibroblasts are productively infected with Dengue virus (DENV). In addition, primary skin fibroblast cultures were established and subsequently infected with DENV-2; we showed in these cells the presence of the viral antigen NS3, and we found productive viral infection by a conventional plaque assay. Of note, the infectivity rate was almost the same in all the primary cultures analyzed from different donors. The skin fibroblasts infected with DENV-2 underwent signaling through both TLR3 and RIG-1, but not Mda5, triggering up-regulation of IFNβ, TNFα, defensin 5 (HB5) and β defensin 2 (HβD2). In addition, DENV infected fibroblasts showed increased nuclear translocation of interferon (IFN) regulatory factor 3 (IRF3), but not interferon regulatory factor 7 IRF7, when compared with mock-infected fibroblasts. Our data suggest that fibroblasts might even participate producing mediators involved in innate immunity that activate and contribute to the orchestration of the local innate responses. This work is the first evaluating primary skin fibroblast cultures obtained from different humans, assessing both their susceptibility to DENV infection as well as their ability to produce molecules crucial for innate immunity

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses

Consenso Mexicano para el Tratamiento de la Hepatitis C

El objetivo del Consenso Mexicano para el Tratamiento de la Hepatitis C fue el de desarrollar un documento como guía en la práctica clínica con aplicabilidad en México. Se tomó en cuenta la opinión de expertos en el tema con especialidad en: gastroenterología, infectología y hepatología. Se realizó una revisión de la bibliografía en MEDLINE, EMBASE y CENTRAL mediante palabras claves referentes al tratamiento de la hepatitis C. Posteriormente se evaluó la calidad de la evidencia mediante el sistema GRADE y se redactaron enunciados, los cuales fueron sometidos a voto mediante un sistema modificado Delphi, y posteriormente se realizó revisión y corrección de los enunciados por un panel de 34 votantes. Finalmente se clasificó el nivel de acuerdo para cada oración. Esta guía busca dar recomendaciones con énfasis en los nuevos antivirales de acción directa y de esta manera facilitar su uso en la práctica clínica. Cada caso debe ser individualizado según sus comorbilidades y el manejo de estos pacientes siempre debe ser multidisciplinario. Abstract The aim of the Mexican Consensus on the Treatment of Hepatitis C was to develop clinical practice guidelines applicable to Mexico. The expert opinion of specialists in the following areas was taken into account: gastroenterology, infectious diseases, and hepatology. A search of the medical literature was carried out on the MEDLINE, EMBASE, and CENTRAL databases through keywords related to hepatitis C treatment. The quality of evidence was subsequently evaluated using the GRADE system and the consensus statements were formulated. The statements were then voted upon, using the modified Delphi system, and reviewed and corrected by a panel of 34 voting participants. Finally, the level of agreement was classified for each statement. The present guidelines provide recommendations with an emphasis on the new direct-acting antivirals, to facilitate their use in clinical practice. Each case must be individualized according to the comorbidities involved and patient management must always be multidisciplinary

Programa de herramientas de negocio I

Reporte final del PAP en el que se participó en las acciones de capacitación y asesoría que el Laboratorio Empresarial de Zapopan Emprende desarrolla en alianza con el Centro Productivo Empresarial Comunitario (CPEC) del DIF Zapopan, en su programa de atención para emprendedores. El equipo de este proyecto colaboró en el desarrollo del laboratorio empresarial otoño 2014 atendiendo a 21 personas con 21 iniciativas. Se participó en un circuito interdisciplinario para lograr los resultados esperados; se llevaron a cabo sesiones del programa NAFIN (Nacional Financiera), talleres y asesorías sobre el modelo de negocio y prospectación de fondos. Lo que se obtuvo a través del laboratorio empresarial impartido, fue la propuesta en cada caso del lienzo de negocio (CANVAS) como herramienta para proyectar su iniciativa de negocio a corto y mediano plazo. En este trabajo participaron alumnos de la Licenciatura en Mercadotecnia, de la Licenciatura en Administración de Empresas, de la Licenciatura en Administración Financiera y de Ingeniería Industrial

HLA concordance between hematopoietic stem cell transplantation patients and umbilical cord blood units: Implications for cord blood banking in admixed populations

Umbilical cord blood stem cell transplantation is an important choice for treating a variety of hematopoietic, neoplastic, and genetic disorders. The optimal size for a cord blood bank to provide matching units for 80 of patients requiring a stem cell transplantation procedure depends on the particular characteristics of each population. In this study, we analyzed the immunogenetic diversity of a sample set of Mexican patients suffering from blood, hematopoietic, and immunological diseases, to assess the best strategy for cord blood banking. For achieving that, we analyzed HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1 genotype and allele frequencies of both units from the bioarchive of the Umbilical Cord Blood Bank from La Raza and patients requiring a stem cell transplant and compared these variables with data from the same geographic and genetic context. We were able to detect significant differences for at least half of the alleles were observed for HLA class I and class II genes between units and patients. Five Native American haplotypes had lower frequencies in patients sample than in the cord blood units. Genetic admixture estimations for both groups showed a higher contribution of Native American component in the cord blood units. Differences in ancestral components in the Umbilical Cord Blood Bank from La Raza and six virtual banks modeled from a pool of Mexican mixed ancestry individuals show that genetic background is important in cord blood collection. In conclusion, increasing diversity over quantity of new cord blood units will improve the cost effectiveness of cord blood banking and health policies regarding hematopoietic stem cell transplantation in admixed populations such as those present in Latin American countries

Genetic diversity of HLA system in six populations from Mexico City Metropolitan Area, Mexico: Mexico City North, Mexico City South, Mexico City East, Mexico City West, Mexico City Center and rural Mexico City

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 1217 Mexicans from the Mexico City Metropolitan Area living in the northern (N = 751), southern (N = 52), eastern (N = 79), western (N = 33), and central (N = 152) Mexico City, and rural communities (N = 150), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes include 11 Native American haplotypes. Admixture estimates revealed that the main genetic components are Native American (63.85 ± 1.55 by ML; 57.19 of Native American haplotypes) and European (28.53 ± 3.13 by ML; 28.40 of European haplotypes), and a less apparent African genetic component (7.61 ± 1.96 by ML; 7.17 of African haplotypes)

Genetic diversity of HLA system in two populations from Querétaro, Mexico: Querétaro city and rural Querétaro

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 88 Mexicans from the state of Querétaro living in the city of Querétaro (N = 45) and rural communities (N = 43), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Querétaro include seven Native American, two European and one Asian haplotype. Admixture estimates revealed that the main genetic components in the state of Querétaro are Native American (51.82 ± 4.42 by ML; 42.61 of Native American haplotypes) and European (48.18 ± 3.55 by ML; 46.02 of European haplotypes), with a virtually absent African genetic component (0.00 ± 4.25 by ML; 4.55 of African haplotypes)