Effectiveness, tolerability and safety of Direct Acting Antivirals in Mexican individuals with Hepatitis C virus genotype-1 and previous pegylated interferon and ribavirin therapy.

BACKGROUND: Direct Acting Antivirals (DAAs) represent a large improvement in the treatment of chronic hepatitis C, resulting in <90% sustained virological response (SVR). There are no reports on the real-world DAA response for Mexico and few reports exist for Latin America. The aim of the study was to report SVR, and immediate benefits with the DAA treatments sofosbuvir, ledispavir, with/without ribavirin (SOF/LDV ± RBV) and ombitasvir, paritaprevir, ritonavir, dasabuvir with/without RBV (OBV/PTV/r/DSV ± RBV) in patients with viral genotype 1a or 1b, and who did not respond to previous peginterferon/ribavirin (PegIFNα2a+RBV) therapy. METHODS: A descriptive, ambispective, longitudinal study was conducted. A cohort of 261 adult patients received PegIFNα2a+RBV therapy before 2014; 167 (64%) did not respond, 83 of these were subsequently treated with SOF/LDV ± RBV or OBV/PTV/r/DSV ± RBV. Child-Pugh-Score (CPS), Fibrosis-4 (FIB-4), and AST to Platelet Ratio Index (APRI) were evaluated before and after treatment. RESULTS: SVR with PegIFNα2a+RBV was 36%, and 97.5% with DAAs. CPS, FIB-4 and APRI improved significantly after DAA treatment, mainly because of liver transaminase reduction. CONCLUSIONS: DAA treatment showed excellent SVR rates in Mexican patients who had not responded to PegIFNα2a+RBV therapy. Improvement in CPS, FIB-4 and APRI without improvement in fibrosis was observed in cirrhotic and non-cirrhotic patients, as well as considerable reduction in liver transaminases, which suggests a reduction in hepatic necroinflammation.

A comprehensive update of the status of hepatitis C virus (HCV) infection in Mexico-A systematic review and meta-analysis (2008-2019).

INTRODUCTION AND OBJECTIVES: HCV infection is targeted by the WHO's Global Health Sector Strategy on Viral Hepatitis to be reduced notably by 2030. However, renovated epidemiological data is needed to line up with such goals. Herein, we provide an updated review of incidence, prevalence, genotypes (GTs), and risk factors (RFs) of HCV infection in Mexico to build elimination strategies. MATERIAL AND METHODS: HCV incidence was charted using the cumulative new cases/year at week 52. Prevalence, GTs, and RFs data from low-risk (LR-G) and high-risk (HR-Gs) groups were searched in PubMed/MEDLINE/Medigraphic/Scielo databases from January 2008 to December 2019 as per PRISMA guidelines. Weighted mean prevalence (WMP) was estimated; GTs and RFs were registered. RESULTS: In this study, 25,247 new cases were reported. Ten states accumulated 76.32% of HCV incidence that peaked in men at 50-59 years and women at 60-64 years. Thirty-four studies revealed a WMP between 0.774%-2.5% in LR-Gs and 11.8%-39.6% in HR-Gs that included mainly prison inmates, drug users, and dialyzed patients. GT1 and GT2 were predominant; GT3a emerged. Subtypes 1a and 1b circulate differentially, whereas novel GT2 subtypes appeared. Unsafe blood transfusion was infrequent in younger groups, but parenteral/intravenous transmission through drug-related risk behaviors has arisen. CONCLUSIONS: HCV transmission increased notably among LR-Gs and HR-Gs in Mexico. Novel genotypes/subtypes emerged as well as risky behavioral routes of transmission. A national elimination strategy will require pro-active screening in designated risk groups, research in molecular epidemiology, medical training, robust epidemiological databases, and antiviral treatment available to all eligible HCV-infected patients.

Complications in pregnancies achieved by assisted reproduction.

INTRODUCTION: Pregnancies resulting from assisted reproductive technologies (ART) have been documented to have a higher risk of adverse effects. OBJECTIVE: To provide evidence on obstetric and perinatal complications associated with conceptions by ART versus spontaneous pregnancies. METHOD: Comprehensive review of original articles published between 2010 and 2018 addressing the more common obstetric and perinatal complications in pregnancies resulting from in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), in comparison with spontaneous conceptions. RESULTS: Thirty-seven original articles, which reported on 26 cohort studies and 11 case-control trials, were included. IVF and ICSI conceptions were associated with a larger number of obstetric and perinatal complications such as low birth weight, prematurity, low weight for gestational age, admission to the neonatal intensive care unit, congenital malformations, C-sectionand premature rupture of membranes, among others. CONCLUSIONS: Pregnancies by ART are associated with an increased risk of obstetric and perinatal complications in comparison with spontaneous conceptions. Further research is needed to determine which aspects result in higher risk.

INTRODUCCIÓN: Se ha documentado que los embarazos por técnicas de reproducción asistida (TRA) presentan mayor riesgo de efectos adversos. OBJETIVO: Proporcionar evidencia actualizada de las complicaciones obstétricas y perinatales asociadas con concepciones mediante TRA versus embarazos espontáneos. MÉTODO: Revisión de artículos originales publicados entre 2010 y 2018, que abordan complicaciones obstétricas y perinatales de mayor frecuencia en embarazos por fertilización in vitro (FIV) e inyección intracitoplasmática de espermatozoides (ICSI) comparados con concepciones espontáneas. RESULTADOS: Se incluyeron 37 artículos originales, 26 de cohorte y 11 de casos y controles. Las concepciones por FIV e ICSI se asociaron con más complicaciones obstétricas y perinatales como bajo peso al nacimiento, prematuridad, menor peso para la edad gestacional, ingreso a la unidad de cuidados intensivos neonatales, malformaciones congénitas, cesárea, ruptura prematura de membranas, entre otras. ­. CONCLUSIONES: Las concepciones por TRA se asocian con mayor riesgo de complicaciones obstétricas y perinatales en comparación con las espontáneas. Es necesario realizar estudios adicionales que determinen qué aspectos derivan en mayor riesgo.

Complicaciones en embarazos logrados por reproducción asistida / Complications in pregnancies achieved by assisted reproduction

Resumen Introducción: Se ha documentado que los embarazos por técnicas de reproducción asistida (TRA) presentan mayor riesgo de efectos adversos. Objetivo: Proporcionar evidencia de las complicaciones obstétricas y perinatales asociadas a concepciones mediante TRA versus embarazos espontáneos. Método: Revisión de artículos originales publicados entre 2010 y 2018, que abordan complicaciones obstétricas y perinatales de mayor frecuencia en embarazos por fertilización in vitro (FIV) e inyección intracitoplasmática de espermatozoides (ICSI) comparados con concepciones espontáneas. Resultados: Se incluyeron 37 artículos originales, 26 de cohortes y 11 de casos y controles. Las concepciones por FIV e ICSI se asociaron con más complicaciones obstétricas y perinatales como bajo peso al nacimiento, prematuridad, menor peso para la edad gestacional, ingreso a la unidad de cuidados intensivos neonatales, malformaciones congénitas, cesárea, ruptura prematura de membranas, entre otras. Conclusiones: Las concepciones por TRA se asocian con mayor riesgo de complicaciones obstétricas y perinatales en comparación con las espontáneas. Es necesario realizar estudios adicionales que determinen qué aspectos derivan en mayor riesgo.

Abstract Introduction: Pregnancies resulting from assisted reproductive technologies (ART) have been documented to have a higher risk of adverse effects. Objective: To provide evidence on obstetric and perinatal complications associated with conceptions by ART versus spontaneous pregnancies. Method: Comprehensive review of original articles published between 2010 and 2018 addressing the most common obstetric and perinatal complications in pregnancies resulting from in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) in comparison with spontaneous conceptions. Results: Thirty-seven original articles, which reported on 26 cohort studies and 11 case-control trials, were included. IVF and ICSI conceptions were associated with a larger number of obstetric and perinatal complications such as low birth weight, prematurity, low weight for gestational age, admission to the neonatal intensive care unit, congenital malformations, C-section and premature rupture of membranes, among others. Conclusions: Pregnancies by ART are associated with an increased risk of obstetric and perinatal complications in comparison with spontaneous conceptions. Further research is needed to determine which aspects result in higher risk.

Nutrientes y alimentos en la esclerosis múltiple / Nutrients and foods in multiple sclerosis. Abstract

La alimentación influye en la mejora de la sintomatología de cualquier enfermedad, incluida la esclerosis múltiple (EM),la cual, se caracteriza por un proceso inflamatorio crónico, autoinmune del sistema nervioso central generando situaciones como inflamación, alteraciones; digestivas y mentales, discapacidad, y fatiga. El propósito de la presente revisión fue identificar la evidencia científica sobre los aspectos nutricionales que mejoran la progresión de EM. La metodología consistió en la búsqueda de literatura, en bases de datos electrónicas, referente a nutrición y esclerosis múltiple, principalmente entre los años 2015-2020. Entre los resultados de los aspectos nutricionales que mostraron eficacia en mejorar la progresión de EM, se encuentran el zinc, vitamina D, fibra, probióticos, aceite de pescado y de oliva, cacao, cúrcuma, y salmón. Existen evidencias del papel inmunomodulador del Zn y de la vitamina D en la inhibición de la producción de citocinas proinflamatorias. Niveles bajos de ambos componentes se asocian con mayor riesgo de padecer EM. Otros componentes de interés nutricional son la fibra y probióticos; producen ácidos grasos de cadena corta, con propiedades antiinflamatorias. La primera se conoce por su papel en la motilidad gastrointestinal y los segundos por su acción celular y molecular en procesos inflamatorios, y modulación del microbioma, por mencionar algunos. Los aspectos nutricionales antes mencionados pueden contribuir a modular la inflamación y mejorar la fatiga. Finalmente, este documento genera un panorama importante para continuar con la investigación referente a la influencia de la alimentación en pacientes con EM(AU)

Diet influences the improvement of the symptoms of any disease, including multiple sclerosis (MS), which is characterized by a chronic, autoimmune inflammatory process of the central nervous system generating situations such as inflammation, mental and digestive alterations, disability and fatigue. The aim of this review was to identify the scientific evidence on the nutritional aspects that improve the progression of MS. The methodology consisted of searching literature, in electronic databases, referring to nutrition and multiple sclerosis, mainly between the years 2015-2020. The results of the nutritional aspects that showed effectiveness in improving the progression of MS, are zinc, vitamin D, fiber, probiotics, fish oil and olive oil, cocoa, turmeric and salmon. There is evidence of the immunomodulatory role of Zn and vitamin D in inhibiting the production of proinflammatory citokines. Low levels of both components are associated with an increased risk of MS. Other components of nutritional interest are fiber and probiotics; they produce short chain fatty acids, with anti-inflammatory properties. The first is known for its role in gastrointestinal motility and the second one for its cellular and molecular actions in inflammatory processes and the microbiome modulation, to name a few. The nutrition aspects mentioned above, can contribute to modulate inflammation and improve fatigue. Finally, this paper creates an important perspective to continue the investigation concerning the influence of diet in MS patients(AU)

Differential Transcription of SOCS5 and SOCS7 in Multiple Sclerosis Patients Treated with Interferon Beta or Glatiramer Acetate.

The participation of proinflammatory cytokines in the progression of Multiple Sclerosis (MS) has been well documented. Cytokines activate the JAK-STAT pathway, in which the suppressors of cytokine signaling (SOCS) exert a negative feedback. This paper analyzes the levels of SOCS5 and SOCS7 transcripts, quantified by RT-qPCR, in MS patients, and the concentrations of proinflammatory cytokines, IFN-γ, IL17, and IL6, determined by ELISA. Samples of peripheral blood were obtained from MS patients in the relapsing-remitting phase, treated with IFN-ß or glatiramer acetate (GA), and from healthy individuals. SOCS7 mRNA was significantly higher in patients treated with GA (1.36 ± 0.23) than in those treated with IFN-ß (0.65 ± 0.1). Regarding gender, the level of SOCS5 and SOCS7 transcripts were similar between MS and healthy females; in MS males, the level of SOCS7 transcripts were significantly lower (0.59 ± 0.03) than in healthy males (1.008 ± 0.05). Plasmatic levels of IFN-γ were significantly higher in MS patients (60 pg/mL, range 0-160) than in healthy subjects (0 range, 0-106). The same pattern was observed in MS patients treated with IFN-ß (68 pg/mL, range 0-160) compared to patients treated with GA (51 pg/mL, range 0-114), and in MS females (64 pg/mL, range 0-161) compared to healthy females (0, range 0-99). We hypothesize that the increase in SOCS7 transcription in patients treated with GA could partially explain the action mechanism of this drug, while the increase in the concentration of IFN-γ in MS patients could help elucidate the immunopathology of the disease.

IL-10 and socs3 Are Predictive Biomarkers of Dengue Hemorrhagic Fever.

BACKGROUND: Cytokines play important roles in the physiopathology of dengue infection; therefore, the suppressors of cytokine signaling (socs) that control the type and timing of cytokine functions could be involved in the origin of immune alterations in dengue. OBJECTIVE: To explore the association of cytokine and socs levels with disease severity in dengue patients. METHODS: Blood samples of 48 patients with confirmed dengue infection were analyzed. Amounts of interleukins IL-2, IL-4, IL-6, and IL-10, interferon- (IFN-) γ, and tumor necrosis factor- (TNF-) α were quantified by flow cytometry, and the relative expression of socs1 and socs3 mRNA was quantified by real-time RT-PCR. RESULTS: Increased levels of IL-10 and socs3 and lower expression of socs1 were found in patients with dengue hemorrhagic fever (DHF) with respect to those with dengue fever (DF) (p < 0.05). Negative correlations were found between socs1 and both IL-10 and socs3 (p < 0.01). The cutoff values of socs3 (>199.8-fold), socs1 (<1.94-fold), and IL-10 (>134 pg/ml) have the highest sensitivity and specificity to discriminate between DF and DHF. CONCLUSION: Simultaneous changes in IL-10 and socs1/socs3 could be used as prognostic biomarkers of dengue severity.

Polymorphisms in the hepatitis C virus core and its association with development of hepatocellular carcinoma.

Little is known about the mechanisms underlying hepatocellular carcinoma (HCC). Some studies have focused on the role of HCV viral proteins in hepatocyte transformation. In this work we have compiled and analysed current articles regarding the impact of polymorphisms in the HCV core gene and protein on the development of HCC. An exhaustive search for fulltext articles until November 2016 in PubMed database was performed using the MeSH keywords: 'hepatitis C', 'polymorphisms', 'core', 'hepatocellular cancer' and 'hepatocarcinogenesis'. Nineteen full-text articles published between 2000 and 2016 were considered. Different articles associate not only the HCC development with polymorphisms at residues 70 and 91 in the core protein, but more with mortality and treatment response. Also, different polymorphisms were found in core and other viral proteins related to HCC development. Eleven articles reported that HCC development is significantly associated with Gln/His70, four associated it with Leu91 and two more associated it with both markers together. Additional studies are necessary, including those in different types of populations worldwide, to validate the possibility of the usability and influence in chronically HCV-infected patients as well as to observe their interaction with other risk factors or prognosis and genetic markers of the host.

Upregulation of the Suppressors of Cytokine Signaling 1 and 3 Is Associated with Arrest of Phosphorylated-STAT1 Nuclear Importation and Reduced Innate Response in Denguevirus-Infected Macrophages.

To clarify whether the suppressors of cytokine signaling (SOCS) are associated with denguevirus (DENV) evasion of the antiviral response, we analyzed the expression kinetics of SOCS1 and SOCS3 and of the antiviral genes MxA and OAS during DENV infection of U937 macrophages that were or not treated with interferon (IFN)-α. DENV infection produced a viral titer three times higher in untreated than in IFN-α-treated cells (p < 0.001 at 72 h postinfection [p.i.]). Partial inhibition of DENV replication was associated with reduced expression of MxA and OAS antiviral genes as well as higher SOCS1 and SOCS3 expression in DENV-infected cells than in cells treated only with IFN-α. Complete loss of phosphorylated-signal transducer and activator of transcription (p-STAT)2 and reduced nuclear importation of p-STAT1 were observed in DENV-infected cells compared to IFN-α treatment that induced p-STAT1 and p-STAT2. Our data thus suggest that overexpression of SOCS1 and SOCS3 induced by DENV infection leads to impairment of antiviral response through the inhibition of STAT functionality.

Hepatitis C virus infection in patients and family members attending two primary care clinics in Puebla, Mexico.

BACKGROUND: Approximately 180 million persons (~2.8%) globally are estimated to be infected by hepatitis C virus (HCV). HCV prevalence in Mexico has been estimated to be between 1.2 and 1.4%. The aim of present work was to determine the prevalence of HCV infection in patients and family members attending two primary care clinics in Puebla, Mexico. MATERIAL AND METHODS: Patients and their accompanying family members in two clinics were invited to participate in this study between May and September 2010. RESULTS: A total of 10,214 persons were included in the study; 120 (1.17%) persons were anti-HCV reactive. Of the reactive subjects, detection of viral RNA was determined in 114 subjects and 36 were positive (31%). The more frequent risk factors were having a family history of cirrhosis (33.1%) and having a blood transfusion prior to 1995 (29%). After a multiple logistic regression analysis only transfusion prior to 1995 resulted significant to HCV transmission (p = 0.004). The overall detected HCV genotypes were as follows: 1a (29%), 1b (48.5%), 2/2b (12.8%), and 3a (6.5%). CONCLUSION: The HCV prevalence in this population is in agreement with previous studies in other regions of Mexico.

Quantitative analysis of the suppressors of cytokine signaling 1 and 3 in peripheral blood leukocytes of patients with multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease characterized by a triad of inflammation, demyelination and gliosis. Because the suppressors of cytokine signaling (Socs) regulate the immune response, we quantified SOCS1 and SOCS3 transcription in peripheral blood leukocytes of patients with MS. SOCS1 transcription decreased significantly in MS patients compared with neurologically healthy persons (0.08±0.02 vs. 1.02±0.23; p=0.0001); while SOCS3 transcription increased in MS patients compared with controls (2.76±0.66 vs. 1.03±0.27; p=0.0008). Our results showed an imbalance of SOCS1 and SOCS3 transcription in MS patients, and a moderated negative correlation between them (Spearman's r=-0.57; p=0.0003).

Quantitative analysis of interferon alpha receptor subunit 1 and suppressor of cytokine signaling 1 gene transcription in blood cells of patients with chronic hepatitis C.

BACKGROUND: Interferon (IFN)-α receptor 1 (ifnar1) and suppressor of cytokine signaling 1 (socs1) transcription levels were quantified in peripheral blood mononuclear cells (PBMC) of 59 patients infected with hepatitis C virus (HCV) and 17 non-infected individuals. Samples were obtained from patients infected with HCV that were either untreated or treated with IFN-α2 plus ribavirin for 1 year and divided into responders and non-responders based on viral load reduction 6 months after treatment. Ifnar1 and socs1 transcription was quantified by real-time RT-PCR, and the fold difference (2(⁻ΔΔCT)) with respect to hprt housekeeping gene was calculated. RESULTS: Ifnar1 transcription increased significantly in HCV-infected patients either untreated (3.26 ± 0.31), responders (3.1 ± 0.23) and non-responders (2.18 ± 0.23) with respect to non-infected individuals (1 ± 0.34; P = 0.005). Ifnar1 transcription increased significantly (P = 0.003) in patients infected with HCV genotypes 1a (4.74 ± 0.25) and 1b (2.81 ± 0.25) but not in 1a1b (1.58 ± 0.21). No association was found of Ifnar1 transcription with disease progress, initial viral load or other clinical factors. With respect to socs1 transcription, values were similar for non-infected individuals (1 ± 0.28) and untreated patients (0.99 ± 0.41) but increased in responders (2.81 ± 0.17) and non-responder patients (1.67 ± 0.41). Difference between responder and non-responder patients was not statistically significant. Socs1 transcription increased in patients infected with HCV genotypes 1a and 1b (2.87 ± 0.45 and 2.22 ± 0.17, respectively) but not in 1a1b (1.28 ± 0.40). Socs1 transcript was absent in three patients infected with HCV genotype 1b. A weak correlation between ifnar1 and socs1 transcription was found, when Spearman's correlation coefficient was calculated. CONCLUSION: Our results suggest that HCV infection may up-regulate ifnar1 transcription. HCV genotypes differ in their capacity to affect ifnar1 and socs1 transcription, as well as in the ability to evade the antiviral response.