Demographic, hemodynamic characteristics, and therapeutic trends of pulmonary hypertension patients: The Pulmonary Hypertension Mexican registry (REMEHIP).

Data on demographic characteristics and therapeutic approaches in Latin American pulmonary arterial hypertension (PAH) patients are scarce. Pulmonary Hypertension Mexican registry (REMEHIP) is a multicenter Mexican registry of adult and pediatric patients, including prevalent and incident cases. Objective: assess clinical characteristics, treatment trends, and in-hospital outcomes. Inclusion: age >2 years, diagnosis of pulmonary hypertension (PH) (groups 1 and 4), right heart catheterization with mPAP ≥25 mmHg, PWP ≤ 15 mmHg, and PVR > 3 Wood unit (WU). We included 875 PH patients, 619 adults, 133 pediatric idiopathic PAH (IPAH), and 123 chronic thromboembolic pulmonary hypertension (CTEPH) patients. We enrolled 48.4% of the incident and 51.6% of the prevalent adult and pediatric patients. PAH adults: age 43 ± 15, females 81.9%, functional class (FC) (I/II) 66.5%, 6-min walk distance (6MWD) 378 ± 112 m, mPAP 57.3 ± 19.0 mmHg, confidence interval (CI) 3.3 ± 1.5 L/min/m2, PVR 12.0 ± 8.1 WU. PAH pediatrics: age 9 ± 5, females 51.1%, FC (I/II) 85.5%, 6MWD 376 ± 103 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 16.4 ± 13.5 WU. CTEPH: age 44 ± 17, females 56.1%, FC (I/II) 65.5%, 6MWD 369 ± 126 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 10.5 + 6.5 WU. When we analyzed the IPAH group separately, it sustained a high functional class I/II incidence. REMEHIP shows better functional class in young females with severe PAH than in American and European patients. Also, PAH pediatric patients had a better functional class than other registries. However, our registry also shows that our population's access to specific pharmacologic treatments is still far from optimal.

The impact of comorbidity status in COVID-19 vaccines effectiveness before and after SARS-CoV-2 omicron variant in northeastern Mexico: a retrospective multi-hospital study.

Introduction: The end of the coronavirus disease 2019 (COVID-19) pandemic has been declared by the World Health Organization on May 5, 2023. Several vaccines were developed, and new data is being published about their effectiveness. However, the clinical trials for the vaccines were performed before the Omicron variant appeared and there are population groups where vaccine effectiveness still needs to be tested. The overarching goal of the present study was to analyze the effects of COVID-19 vaccination before and after the Omicron variant in patients considering comorbidities in a population from Nuevo Leon, Mexico. Methods: Epidemiological COVID-19 data from the Mexican Social Security Institute were collected from 67 hospitals located in northeastern Mexico, from July 2020 to May 2023, and a total of 669,393 cases were compiled, 255,819 reported a SARS-CoV-2 positive reverse transcription quantitative polymerase chain reaction (RT-qPCR) test or a positive COVID-19 antigen rapid test. Results: Before Omicron (BO, 2020-2021), after 14 days of two doses of COVID-19 vaccine, BNT162b2 and ChAdOx1 vaccines were effective against infection in non-comorbid and all comorbid subgroups, whereas after Omicron (AO, 2022- 2023) there was no significant effectiveness against infection with none of the vaccines. Regarding hospitalization BO, BNT162b2, ChAdOx1, CoronaVac and mRNA-1273 significantly protected non-comorbid patients whereas BNT162b2, ChAdOx1, and mRNA-1273, protected all comorbid subgroups against hospitalization. AO, BNT162b2, ChAdOx1, CoronaVac and mRNA-1273 were effective against hospitalization in non-comorbid patients whereas for most comorbid subgroups BNT162b2, ChAdOx1 and CoronaVac were effective against hospitalization. Non-comorbid patients were protected against death as an outcome of COVID-19 during the BO period with most vaccines whereas a reduction in effectiveness was observed AO with mRNA-1273 vaccines in patients with hypertension, and diabetes mellitus. Discussion: BO, COVID-19 vaccines were effective against infection, hospitalization, and death whereas AO, COVID-19 vaccines failed to protect the population from COVID-19 infection. A varying effectiveness against hospitalization and death is observed AO.

Paxlovid™ reduces the incidence of pneumonia, hospitalization, and death in a cohort of COVID-19 patients from northeast Mexico.

BACKGROUND: Information on Paxlovid™ effectiveness must be monitored and updated in real world scenarios. Our research question was what is the effectiveness of Paxlovid™ in adult patients with COVID-19? Therefore, we investigated the effectiveness of Paxlovid™ on reducing the incidence of pneumonia, hospitalization, and mortality in a cohort of COVID-19 positive adult patients from northeast Mexico. METHODS: A retrospective cohort study of COVID-19 positive adult patients from Nuevo Leon, Mexico from December 2020 to May 2023 (after Omicron BA-5 circulation) was performed. Paxlovid™ use was authorized in September 2022. Therefore, we analyzed effectiveness in patients with confirmed diagnosis who met selection criteria between September 2022 and May 2023 (n = 20,799; 5,673 with and 15,126 without Paxlovid™). RESULTS: The pneumonia (0.1% vs. 0.4%, p < 0.0001), hospitalization (0.1% vs. 1.2%, p < 0.0001), and death rates (0.04% vs. 0.2%, p < 0.0001) were lower in patients with Paxlovid™ treatment independently of age, sex, comorbidity, and COVID-19 and pneumococcal vaccination history. Effectiveness was 88.2%, 95.9% y 91.9% for pneumonia, hospitalization, and death, respectively. CONCLUSIONS: Paxlovid™ reduces the presentation of pneumonia, hospitalization, and death secondary to COVID-19. It is recommended to continue monitoring Paxlovid™ effectiveness, as other SARS-CoV-2 variants continue to emerge.

Mechanistic Insights about Sorafenib-, Valproic Acid- and Metformin-Induced Cell Death in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is among the main causes of death by cancer worldwide, representing about 80-90% of all liver cancers. Treatments available for advanced HCC include atezolizumab, bevacizumab, sorafenib, among others. Atezolizumab and bevacizumab are immunological options recently incorporated into first-line treatments, along with sorafenib, for which great treatment achievements have been reached. However, sorafenib resistance is developed in most patients, and therapeutical combinations targeting cancer hallmark mechanisms and intracellular signaling have been proposed. In this review, we compiled evidence of the mechanisms of cell death caused by sorafenib administered alone or in combination with valproic acid and metformin and discussed them from a molecular perspective.

ESX-3 secretion system in Mycobacterium: An overview.

Mycobacteria are microorganisms distributed in the environment worldwide, and some of them, such as Mycobacterium tuberculosis or M. leprae, are pathogenic. The hydrophobic mycobacterial cell envelope has low permeation and bacteria need to export products across their structure. Mycobacteria possess specialized protein secretion systems, such as the Early Secretory Antigenic Target 6 secretion (ESX) system. Five ESX loci have been described in M. tuberculosis, called ESX-1 to ESX-5. The ESX-3 secretion system has been associated with mycobacterial metabolism and growth. The locus of this system is highly conserved across mycobacterial species. Metallo-proteins regulate negative ESX-3 transcription in high conditions of iron and zinc. Moreover, this secretion system is part of an antioxidant regulatory pathway linked to Zinc. EccA3, EccB3, EccC3, EccD3, and EccE3 are components of the ESX-3 secretion machinery, whereas EsxG-EsxH, PE5-PPE4, and PE15-PPE20 are proteins secreted by this system. In addition, EspG3 and MycP3 are complementary proteins involved in transport and proteolysis respectively. This system is associated to mycobacterial virulence by releasing the bacteria from the phagosome and inhibiting endomembrane damage response. Furthermore, components of this system inhibit the host immune response by reducing the recognition of M. tuberculosis-infected cells. The components of the ESX-3 secretion system play a role in drug resistance and cell wall integrity. Moreover, the expression data of this system indicated that external and internal factors affect ESX-3 locus expression. This review provides an overview of new findings on the ESX-3 secretion system, its regulation, expression, and functions.

Side Effects of COVID-19 Vaccines in Pregnant and Lactating Mexican Women and Breastfed Infants: A Survey-Based Study.

COVID-19 vaccines' safety has been extensively studied; however, further analysis is required in pregnant women, nursing mothers, and breastfed infants. Our aim was to compare the extension and severity of self-reported COVID-19 vaccine side effects in pregnant and breastfeeding women, and breastfed infants. In this cross-sectional study, COVID-19-vaccinated subjects were enrolled using an online survey in Mexico. Women were classified by pregnancy and breastfeeding status at the time of vaccination (n = 3167). After the first or only dose, there was a trend toward fewer systemic effects in pregnant women (p = 0.06). BNT162b2 (Pfizer-BioNTech) had a higher frequency of local symptoms in pregnancy. Lactating women experienced fewer local symptoms after the first or single dose (p = 0.04) and the opposite occurred after the second dose (p = 0.001). ChAdOx1 (AstraZeneca) increased the chances of developing both local and systemic symptoms after the first dose but decreased them after the second dose. The severity was similar across groups, although the result of lack of association in pregnancy requires studies with a larger sample size. Irritability was the most reported symptom in breastfed infants. This study contributes to the knowledge about the side effects in pregnant and lactating women, and breastfed babies.

Suspension culture improves iPSC expansion and pluripotency phenotype.

BACKGROUND: Induced pluripotent stem cells (iPSCs) offer potential to revolutionize regenerative medicine as a renewable source for islets, dopaminergic neurons, retinal cells, and cardiomyocytes. However, translation of these regenerative cell therapies requires cost-efficient mass manufacturing of high-quality human iPSCs. This study presents an improved three-dimensional Vertical-Wheel® bioreactor (3D suspension) cell expansion protocol with comparison to a two-dimensional (2D planar) protocol. METHODS: Sendai virus transfection of human peripheral blood mononuclear cells was used to establish mycoplasma and virus free iPSC lines without common genetic duplications or deletions. iPSCs were then expanded under 2D planar and 3D suspension culture conditions. We comparatively evaluated cell expansion capacity, genetic integrity, pluripotency phenotype, and in vitro and in vivo pluripotency potential of iPSCs. RESULTS: Expansion of iPSCs using Vertical-Wheel® bioreactors achieved 93.8-fold (IQR 30.2) growth compared to 19.1 (IQR 4.0) in 2D (p < 0.0022), the largest expansion potential reported to date over 5 days. 0.5 L Vertical-Wheel® bioreactors achieved similar expansion and further reduced iPSC production cost. 3D suspension expanded cells had increased proliferation, measured as Ki67+ expression using flow cytometry (3D: 69.4% [IQR 5.5%] vs. 2D: 57.4% [IQR 10.9%], p = 0.0022), and had a higher frequency of pluripotency marker (Oct4+Nanog+Sox2+) expression (3D: 94.3 [IQR 1.4] vs. 2D: 52.5% [IQR 5.6], p = 0.0079). q-PCR genetic analysis demonstrated a lack of duplications or deletions at the 8 most commonly mutated regions within iPSC lines after long-term passaging (> 25). 2D-cultured cells displayed a primed pluripotency phenotype, which transitioned to naïve after 3D-culture. Both 2D and 3D cells were capable of trilineage differentiation and following teratoma, 2D-expanded cells generated predominantly solid teratomas, while 3D-expanded cells produced more mature and predominantly cystic teratomas with lower Ki67+ expression within teratomas (3D: 16.7% [IQR 3.2%] vs.. 2D: 45.3% [IQR 3.0%], p = 0.002) in keeping with a naïve phenotype. CONCLUSION: This study demonstrates nearly 100-fold iPSC expansion over 5-days using our 3D suspension culture protocol in Vertical-Wheel® bioreactors, the largest cell growth reported to date. 3D expanded cells showed enhanced in vitro and in vivo pluripotency phenotype that may support more efficient scale-up strategies and safer clinical implementation.

Sex, Age, and Comorbidities Are Associated with SARS-CoV-2 Infection, COVID-19 Severity, and Fatal Outcome in a Mexican Population: A Retrospective Multi-Hospital Study.

People with comorbidities and the male sex are at a higher risk of developing severe COVID-19. In the present study, we aim to investigate the associated factors for infection, severity, and death due to COVID-19 in a population from Nuevo León, México. Epidemiological COVID-19 data were collected from 65 hospitals from December 2020 to May 2022. A total of 75,232 cases were compiled from which 25,722 cases were positive for SARS-CoV-2. Male sex, older age, diabetes, obesity, and hypertension were associated with infection. In addition to the above-mentioned factors, renal disease, cardiovascular disease, and immunosuppression were found to be associated with increased COVID-19 severity. These factors, as well as neurological diseases, are also associated with death due to COVID-19. When comparing the different variants of SARs-CoV-2, the variant B1.1.519 increased the probability of death by 2.23 times compared to the AY.20 variant. Male sex, older age, diabetes, obesity, and hypertension are associated with SARS-CoV-2 infection, severity, and death. Along with the aforementioned comorbidities, renal disease, cardiovascular disease, and immunosuppression are also associated with severity and death. Another factor associated with death is the presence of neurological disease. The SARS-CoV-2 B1.1.519 variant increases the odds of death compared to the SARS-CoV-2 AY.20 variant.

ABC-GOALScl score predicts admission to the intensive care unit and mortality of COVID-19 patients over 60 years of age.

BACKGROUND: One of the risk factors for getting seriously ill from COVID-19 and reaching high mortality rates is older age. Older age is also associated with comorbidities, which are risk factors for severe COVID-19 infection. Among the tools that have been evaluated to predict intensive care unit (ICU) admission and mortality is ABC-GOALScl. AIM: In the present study we validated the utility of ABC-GOALScl to predict in-hospital mortality in subjects over 60 years of age who were positive for SARS-CoV-2 virus at the moment of admission with the purpose of optimizing sanitary resources and offering personalized treatment for these patients. METHODS: This was an observational, descriptive, transversal, non-interventional and retrospective study of subjects (≥ 60 years of age), hospitalized due to COVID-19 infection at a general hospital in northeastern Mexico. A logistical regression model was used for data analysis. RESULTS: Two hundred forty-three subjects were included in the study, whom 145 (59.7%) passed away, while 98 (40.3%) were discharged. Average age was 71, and 57.6% were male. The prediction model ABC-GOALScl included sex, body mass index, Charlson comorbidity index, dyspnea, arterial pressure, respiratory frequency, SpFi coefficient (Saturation of oxygen/Fraction of inspired oxygen ratio), serum levels of glucose, albumin, and lactate dehydrogenase; all were measured at the moment of admission. The area under the curve for the scale with respect to the variable of discharge due to death was 0.73 (IC 95% = 0.662-0.792). CONCLUSION: The ABC-GOALScl scale to predict ICU admission in COVID-19 patients is also useful to predict in-hospital death in COVID-19 patients ≥ 60 years old.

Cell-type dependent regulation of pluripotency and chromatin remodeling genes by hydralazine.

BACKGROUND: The generation of induced pluripotent stem cells has opened the field of study for stem cell research, disease modeling and drug development. However, the epigenetic signatures present in somatic cells make cell reprogramming still an inefficient process. This epigenetic memory constitutes an obstacle in cellular reprogramming. Here, we report the effect of hydralazine (HYD) and valproic acid (VPA), two small molecules with proven epigenetic activity, on the expression of pluripotency genes in adult (aHF) and neonatal (nbHF) human fibroblasts. METHODS: aHF and nbHF were treated with HYD and/or VPA, and viability and gene expression assays for OCT4, NANOG, c-MYC, KLF4, DNMT1, TET3, ARID1A and ARID2 by quantitative PCR were performed. aHF and nbHF were transfected with episomal plasmid bearing Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) and exposed to HYD and VPA to determine the reprogramming efficiency. Methylation sensitive restriction enzyme (MSRE) qPCR assays were performed on OCT4 and NANOG promoter regions. Immunofluorescence assays were carried out for pluripotency genes on iPSC derived from aHF and nbHF. RESULTS: HYD upregulated the expression of OCT4 (2.5-fold) and NANOG (fourfold) genes but not c-Myc or KLF4 in aHF and had no significant effect on the expression of all these genes in nbHF. VPA upregulated the expression of NANOG (twofold) in aHF and c-MYC in nbHF, while it downregulated the expression of NANOG in nbHF. The combination of HYD and VPA canceled the OCT4 and NANOG overexpression induced by HYD in aHF, while it reinforced the effects of VPA on c-Myc expression in nbHF. The HYD-induced overexpression of OCT4 and NANOG in aHDF was not dependent on demethylation of gene promoters, and no changes in the reprogramming efficiency were observed in both cell populations despite the downregulation of epigenetic genes DNMT1, ARID1A, and ARID2 in nbHF. CONCLUSIONS: Our data provide evidence that HYD regulates the expression of OCT4 and NANOG pluripotency genes as well as ARID1A and ARID2 genes, two members of the SWI/SNF chromatin remodeling complex family, in normal human dermal fibroblasts.

Effect of Ethanol Consumption on the Placenta and Liver of Partially IGF-1-Deficient Mice: The Role of Metabolism via CYP2E1 and the Antioxidant Enzyme System.

Ethanol use during pregnancy is a risk factor for developing adverse outcomes. Its metabolism by cytochrome P450 2E1 (CYP2E1) produces radical oxygen species (ROS), promoting cellular injury and apoptosis. To date, no studies have been conducted to elucidate the teratogenic effects due to both IGF-1 deficiency and ethanol consumption in mice placentas. The aim of this study is to determine the effect of ethanol consumption on the placenta and liver of partially IGF-1-deficient mice, the role of metabolism via CYP2E1, and the antioxidant enzyme system. Heterozygous (HZ, Igf1+/-) pregnant female mice were given water or 10% ethanol. Wild-type (WT, Igf1+/+) female mice were used as controls. At gestational day 19, pregnant dams were euthanized, and maternal liver and placentas were collected. Pregnant HZ dams were smaller than controls, and this effect was higher due to ethanol consumption. Cyp2e1 gene was overexpressed in the liver of HZ pregnant dams exposed to ethanol; at the protein level, CYP2E1 is reduced in placentas from all genotypes. The antioxidant enzymatic system was altered by ethanol consumption in both the maternal liver and placenta. The results in this work hint that IGF-1 is involved in intrauterine development because its deficiency exacerbates ethanol's effects on both metabolism and the placenta.

Extension and Severity of Self-Reported Side Effects of Seven COVID-19 Vaccines in Mexican Population.

A few studies examined the comparative side effects of Coronavirus Disease-19 (COVID-19) vaccines. We compared the extension and severity of self-reported side effects of seven COVID-19 vaccines [BNT162b2 (Pfizer-BioNTech), ChAdOx1 (AstraZeneca), mRNA-1273 (Moderna), CoronaVac (Sinovac Life Sciences), Gam-COVID-Vac (Gamaleya's Sputnik V), Ad5-nCoV (CanSinoBIO), and Ad26.CoV2.S (Johnson & Johnson/Janssen)] in the Mexican population. We also evaluated the association of type of vaccine, sex, age, comorbidity, and history of allergies to the extent and severity of side effects. This was a cross-sectional study carried out online between August 12 and September 3, 2021 in Mexico. The first inclusion criterion was to receive a COVID-19 vaccine and the second, being at least 18 years old. The survey link was distributed via multiple social media platforms. We questioned about the type of vaccine and symptoms based on short-term side effects reported in the literature. Side effect extension was classified as local, systemic, or both. We asked about the need to take medicine, stop activities/miss work, or seek medical attention. Then, a severity index was constructed based on responses. Descriptive and stepwise multivariate logistic ordinal regression analyses were used to calculate odds ratio (OR) and 95% CI for each outcome adjusted by potential confounders. The mean age was 38.9 ± 11.0 years (n = 4,024). Prevalence of at least one side effect varied between vaccines and by a number of doses. At dose 1, ChAdOx1 was the vaccine with the highest rate of at least one side effect (85%) followed by Gam-COVID-Vac (80%). Both were associated to greater extension (adjusted OR 2.53, 95% CI 2.16, 2.96 and adjusted OR 2.41, 95% CI 1.76, 3.29, respectively) and severity of side effects (adjusted OR 4.32, 95% CI 3.73, 5.00 and adjusted OR 3.00, 95% CI 2.28, 3.94, respectively). Young age (<50 years), female sex, comorbidity, and history of allergies were associated with greater extension and severity, independent of the type of vaccine and potential confounders. At dose 2, mRNA-1273 was the vaccine with the highest rate of side effects (88%) and the only vaccine associated to greater extension (adjusted OR 2.88, 95% CI 1.59, 5.21) and severity of symptoms (adjusted OR 3.14, 95% CI 1.82, 5.43). Continuous studies are necessary to acknowledge more post-vaccine symptoms in different populations.

Two New Dihydrosphingosine Analogs Against Mycobacterium tuberculosis Affect gltA1, lprQ, and rpsO Expression.

The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis strains threaten the control of tuberculosis. New antitubercular dihydrosphingosine analogs, named UCIs, have been evaluated in preclinical studies but their cellular and molecular mechanisms of action against M. tuberculosis are still unknown. The aim of this study was to evaluate the effect of UCI exposure on gene expression of drug-sensitive H37Rv and MDR CIBIN:UMF:15:99 clones of M. tuberculosis which were isolated, phenotypically, and genetically characterized, cultured to log phase and treated with UCI compounds; followed by total RNA isolation, reverse transcription and hybridization assays on Affymetrix genomic microarrays. Data were validated with RT-qPCR assays. As results, UCI-05 and UCI-14 exposure increased gltA1 expression in drug-sensitive H37Rv clones. Furthermore, UCI-05 increased lprQ expression in MDR CIBIN:UMF:15:99 M. tuberculosis clones while UCI-14 reduced the expression of this gene in drug-sensitive H37Rv clones. In addition, UCI-05 reduced rpsO expression in drug-sensitive H37Rv clones. We found gene expression alterations that suggest these molecules may alter carbon and lipid metabolism as well as interfere in the protein-producing machinery in M. tuberculosis.

Isotretinoin and Thalidomide Down-Regulate c-MYC Gene Expression and Modify Proteins Associated with Cancer in Hepatic Cells.

Hepatocellular carcinoma (HCC) is the most common form of liver cancer. The number of cases is increasing and the trend for the next few years is not encouraging. HCC is usually detected in the advanced stages of the disease, and pharmacological therapies are not entirely effective. For this reason, it is necessary to search for new therapeutic options. The objective of this work was to evaluate the effect of the drugs isotretinoin and thalidomide on c-MYC expression and cancer-related proteins in an HCC cellular model. The expression of c-MYC was measured using RT-qPCR and western blot assays. In addition, luciferase activity assays were performed for the c-MYC promoters P1 and P2 using recombinant plasmids. Dose-response-time analyses were performed for isotretinoin or thalidomide in cells transfected with the c-MYC promoters. Finally, a proteome profile analysis of cells exposed to these two drugs was performed and the results were validated by western blot. We demonstrated that in HepG2 cells, isotretinoin and thalidomide reduced c-MYC mRNA expression levels, but this decrease in expression was linked to the regulation of P1 and P1-P2 c-MYC promoter activity in isotretinoin only. Thalidomide did not exert any effect on c-MYC promoters. Also, isotretinoin and thalidomide were capable of inducing and repressing proteins associated with cancer. In conclusion, isotretinoin and thalidomide down-regulate c-MYC mRNA expression and this is partially due to P1 or P2 promoter activity, suggesting that these drugs could be promising options for modulating the expression of oncogenes and tumor suppressor genes in HCC.

Selenite Downregulates STAT3 Expression and Provokes Lymphocytosis in the Liver of Chronically Exposed Syrian Golden Hamsters.

Arsenic is considered a worldwide pollutant that can be present in drinking water. Arsenic exposure is associated with various diseases, including cancer. Antioxidants as selenite and α-tocopherol-succinate have been shown to modulate arsenic toxic effects. Since changes in STAT3 and PSMD10 gene expression have been associated with carcinogenesis, the aim of this study was to evaluate the effect of arsenic exposure and co-treatments with selenite or α-tocopherol-succinate on the expression of these genes, in the livers of chronically exposed Syrian golden hamsters. Animals were divided into six groups: (i) control, (ii) chronically treated with 100 ppm arsenic, (iii) treated with 6 ppm α-tocopherol-succinate (α-TOS), (iv) treated with 8.5 ppm selenite, (v) treated with arsenic + α-TOS, and (vi) treated with arsenic + selenite. Urine samples and livers were collected after 20 weeks of continuous exposure. The urine samples were analyzed for arsenic species by atomic absorption spectrophotometry, and real-time RT-qPCR analysis was performed for gene expression evaluation. A reduction in STAT3 expression was observed in the selenite-treated group. No differences in PSMD10 expression were found among groups. Histopathological analysis revealed hepatic lymphocytosis in selenite-treated animals. As a conclusion, long-term exposure to arsenic does not significantly alter the expression of STAT3 and PSMD10 oncogenes in the livers of hamsters; however, selenite down-regulates STAT3 expression and provokes lymphocytosis.

NAT2 polymorphisms associated with the development of hepatotoxicity after first-line tuberculosis treatment in Mexican patients: From genotype to molecular structure characterization.

BACKGROUND AND AIMS: To assess the relevance of the slow acetylator phenotype based on NAT2 genotypes, among patients with pulmonary tuberculosis (PTB) that developed hepatotoxicity after first-line tuberculosis treatment in a Northeastern Mexican population. METHODS: Ninety one PTB patients were included, 7 of them developed hepatotoxicity. NAT2 SNPs (rs1801279, rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931) were genotyped by TaqMan allelic discrimination assay. Statistical analyses were performed using Epi Info statistical software 7.0 and SHEsisPlus for haplotype reconstruction. The NAT2 slow non-synonymous SNP were studied by molecular dynamic analysis (MDA). RESULTS: The frequency of the haplotype associated with slow acetylation status for PTB was 58%, and for with hepatotoxicity (PTB-H) represented 42.6%. Three haplotypes, NAT2*5Q, NAT2*5U, NAT2*5Va were exclusively present in seven PTB-H patients, (P = 0.01, P = 0.0006, P = 0.01, respectively). These haplotypes include the combination of two SNPs (I114T + R197Q or I114T + G286E). The effect of the SNPs on protein structure is to disrupt the CoA binding site affecting acetylation activity. CONCLUSION: Our study provides insight into slow acetylation NAT2 haplotypes associated with hepatotoxicity after first-line tuberculosis treatment, for first time, in a Mexican population. The molecular mechanism acts at the CoA binding site.

5-Aza-2'-Deoxycytidine and Valproic Acid in Combination with CHIR99021 and A83-01 Induce Pluripotency Genes Expression in Human Adult Somatic Cells.

A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2'-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects.

Progress in Translational Regulatory T Cell Therapies for Type 1 Diabetes and Islet Transplantation.

Regulatory T cells (Tregs) have become highly relevant in the pathophysiology and treatment of autoimmune diseases, such as type 1 diabetes (T1D). As these cells are known to be defective in T1D, recent efforts have explored ex vivo and in vivo Treg expansion and enhancement as a means for restoring self-tolerance in this disease. Given their capacity to also modulate alloimmune responses, studies using Treg-based therapies have recently been undertaken in transplantation. Islet transplantation provides a unique opportunity to study the critical immunological crossroads between auto- and alloimmunity. This procedure has advanced greatly in recent years, and reports of complete abrogation of severe hypoglycemia and long-term insulin independence have become increasingly reported. It is clear that cellular transplantation has the potential to be a true cure in T1D, provided the remaining barriers of cell supply and abrogated need for immune suppression can be overcome. However, the role that Tregs play in islet transplantation remains to be defined. Herein, we synthesize the progress and current state of Treg-based therapies in T1D and islet transplantation. We provide an extensive, but concise, background to understand the physiology and function of these cells and discuss the clinical evidence supporting potency and potential Treg-based therapies in the context of T1D and islet transplantation. Finally, we discuss some areas of opportunity and potential research avenues to guide effective future clinical application. This review provides a basic framework of knowledge for clinicians and researchers involved in the care of patients with T1D and islet transplantation.

High Prevalence of Avian Influenza Virus Among Wild Waterbirds and Land Birds of Mexico.

Aquatic wild birds, especially waterfowl, have been long considered the main reservoirs of the avian influenza A virus; however, recent surveys have found an important prevalence of these viruses among land birds as well. Migration has been suggested as an important factor in the avian influenza virus dissemination. We aimed to estimate the prevalence of influenza A viruses in wild birds (waterbirds and land birds; resident and migratory) in eastern Mexico, where the three main North American migration flyways converge and where there was no previous information on this subject. We detected influenza with reverse transcription coupled with a PCR approach. Of the 534 birds sampled between 2010 and 2012, we detected the influenza A virus in a high proportion of birds (39%). Prevalence was particularly high in land birds (49%) when compared to aquatic birds (26%); there was no difference in overall prevalence between resident (39%) and migratory birds (39%). The high prevalence of the avian influenza virus in land birds was noteworthy in the innermost sampling areas in northern Mexico (Coahuila [82%] and Nuevo Leon [43%]).

Alta prevalencia del virus de la influenza aviar entre aves acuáticas silvestres y aves terrestres de México. Las aves silvestres acuáticas, especialmente las aves anseriformes, han sido consideradas durante mucho tiempo los principales reservorios del virus de la influenza aviar A; sin embargo, muestreos recientes también han encontrado una importante prevalencia de estos virus entre las aves terrestres. Se ha sugerido que la migración es un factor importante en la diseminación del virus de la influenza aviar. El objetivo de este estudio fue estimar la prevalencia de los virus de la influenza A en aves silvestres (aves acuáticas y terrestres; residentes y migratorias) en el este de México, donde convergen las tres rutas migratorias principales de América del Norte y donde no había información previa sobre este tema. Se detectó al virus de influenza mediante transcripción reversa acoplada a PCR. De las 534 aves muestreadas entre los años 2010 y 2012, se detectó al virus de la influenza A en una alta proporción de aves (39%). La prevalencia fue particularmente alta en las aves terrestres (49%) en comparación con las aves acuáticas (26%); no se observó diferencia en la prevalencia general entre las aves residentes (39%) y las migratorias (39%). La alta prevalencia del virus de la influenza aviar en las aves terrestres fue notable en las áreas de muestreo hacia el interior del norte de México (Coahuila [82%] y Nuevo León [43%]).

Role of esxG and esxH Genes in Drug-Resistant Mycobacterium.

Tuberculosis drug resistance (DR) is a global problem that is not fully elucidated. Previously, overexpression of esxG and esxH genes was reported in a multidrug-resistant (MDR) Mycobacterium tuberculosis isolate compared with a reference H37Rv strain. To evaluate the roles of esxG and esxH in DR, analysis of their regulatory and coding sequences in sensitive and resistant strains was performed, and the expression levels of their transcriptional regulators IdeR, Zur, and MntR were evaluated. esxG and esxH were expressed heterologously using mycobacterial constructs, and the orthologs Msmeg_0620 and Msmeg_0621 were attenuated in Mycobacterium smegmatis by antisense knockdown. We found no differences in the regulatory and coding sequences of esxG and esxH between the sensitive strain and the MDR isolate. Expression analysis of transcriptional regulators showed that ideR was upregulated in isoniazid (INH)-resistant isolates; in addition, growth inhibition of the M. smegmatis strain was observed in the presence of rifampicin (RIF) and INH when esxG and esxH were expressed heterologously, while faster growth in the presence of RIF was observed when the orthologs were attenuated. In conclusion, the expression of esxG and esxH altered the growth of Mycobacterium in the presence of INH and RIF, suggesting a potential association with DR.