Publications by authors named "Manuel Castillejos-López"

28 Publications

  • Page 1 of 1

The rs776746 variant of CYP3A5 is associated with intravenous midazolam plasma levels and higher clearance in critically ill Mexican paediatric patients.

J Clin Pharm Ther 2021 Feb 26. Epub 2021 Feb 26.

Laboratory of Pharmacology, National Institute of Pediatrics (INP, Mexico City, Mexico.

What Is Known And Objective: Midazolam is a drug that is metabolized by cytochrome P450 (CYP450) enzymes, particularly CYP3A4 and CYP3A5. The presence of single-nucleotide polymorphisms (SNPs) in the genes encoding these enzymes, such as CYP3A4*1B which is associated with low enzyme expression and activity and CYP3A5*3, has been associated with decrease in enzymatic activity and reduced drug clearance, with potential effects on drug levels and/or toxicity. The present study was conducted to determine the frequencies of the allelic variants of the CYP3A4 (rs2740574) and CYP3A5 (rs776746) genes and their effects on the plasma levels and clearance of intravenous midazolam in critically ill Mexican paediatric patients.

Methods: Seventy-two DNA samples were genotyped by real-time PCR with TaqMan probes. Plasma midazolam levels were determined at 3 and 24 h post infusion by high-performance liquid chromatography.

Results And Discussion: The allelic variant rs776746 (CYP3A5*3) was associated with high midazolam plasma levels; the median concentration in patients with the normal genotype (CC) <0.01 ng/ml (Q 0.01-Q 196.09), whereas patients with the allelic variant (TT+TC) had a median midazolam concentration of 320.3 ng/ml (Q 37.51-Q 529.51), p = 0.001. The median pharmacokinetic clearance rates were 0.10 L/kg/h (Q 0.01-Q 0.34) in patients with the allelic variant (TT+TC) and 0.03 L/kg/h (Q 0.002-Q 0.13) in patients with the normal genotype (CC), p = 0.042.

What Is New And Conclusion: This is the first study that reports the frequency of the rs776746 polymorphism in critically ill paediatric patients, which is relevant, since carriers of the *1 allele synthesizing a functional enzyme may need higher doses to achieve adequate sedation. Our results show that compared with carriers of the normal allele, patients with the CYP3A5*3 allelic variant (rs776746) had increased plasma midazolam levels at 3 h after infusion discontinuation (320.3 ng/ml) and greater clearance (0.10 L/kg/h) of the drug.
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http://dx.doi.org/10.1111/jcpt.13388DOI Listing
February 2021

Expression profiles of the Wnt/β-catenin signaling-related extracellular antagonists during proliferation and differentiation in human osteoblast-like cells.

Exp Ther Med 2020 Dec 23;20(6):254. Epub 2020 Oct 23.

Genomics of Bone Metabolism Laboratory, National Institute of Genomic Medicine (INMEGEN), Mexico City 14610, Mexico.

Bone formation is a dynamic process directed by osteoblast activity. The transition from the proliferation to differentiation stage during osteoblast maturation involves the downregulation of the Wnt/β-catenin signaling pathway, and extracellular antagonists are important for the regulation of Wnt signaling. However, the expression levels of Wnt antagonists in these stages of human osteoblast maturation have not been fully elucidated. Therefore, the aim of the present study was to investigate the expression levels of extracellular Wnt antagonists during proliferation and differentiation in osteoblast-like cell lines. The results demonstrated an overlap between the differential expression of secreted Frizzled-related protein ()2, , and Dickkopf ) 2 genes during the differentiation stage in the MG-63 and Saos-2 cells. Furthermore, high expression levels of in MG-63 cells, Wnt inhibitory factor 1 () in Saos-2 cells and in hFOB 1.19 cells during the same stage (differentiation), were observed. The upregulated expression levels of Wnt antagonists were also correlated with the high expression of during the differentiation stage. These findings suggested that Wnt-related antagonists could modulate the Wnt/β-catenin signaling pathway. By contrast, was the only gene that was found to be upregulated during the proliferation stage in hFOB 1.19 and Saos-2 cells. To the best of our knowledge, the present study provides, for the first time, the expression profile of Wnt antagonists during the proliferation stage and the initial phases of differentiation in osteoblast-like cell lines. The current results offer a basis to investigate potential targets for bone-related Wnt-signaling modulation in bone metabolism research.
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http://dx.doi.org/10.3892/etm.2020.9384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654218PMC
December 2020

Antitumor Therapy under Hypoxic Microenvironment by the Combination of 2-Methoxyestradiol and Sodium Dichloroacetate on Human Non-Small-Cell Lung Cancer.

Oxid Med Cell Longev 2020 12;2020:3176375. Epub 2020 Oct 12.

Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas", CDMX, Mexico.

A hypoxic microenvironment is a hallmark in different types of tumors; this phenomenon participates in a metabolic alteration that confers resistance to treatments. Because of this, it was proposed that a combination of 2-methoxyestradiol (2-ME) and sodium dichloroacetate (DCA) could reduce this alteration, preventing proliferation through the reactivation of aerobic metabolism in lung adenocarcinoma cell line (A549). A549 cells were cultured in a hypoxic chamber at 1% O for 72 hours to determine the effect of this combination on growth, migration, and expression of hypoxia-inducible factors (HIFs) by immunofluorescence. The effect in the metabolism was evaluated by the determination of glucose/glutamine consumption and the lactate/glutamate production. The treatment of 2-ME (10 M) in combination with DCA (40 mM) under hypoxic conditions showed an inhibitory effect on growth and migration. Notably, this reduction could be attributed to 2-ME, while DCA had a predominant effect on metabolic activity. Moreover, this combination decreases the signaling of HIF-3 and partially HIF-1 but not HIF-2. The results of this study highlight the antitumor activity of the combination of 2-ME 10 l/DCA 40 mM, even in hypoxic conditions.
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http://dx.doi.org/10.1155/2020/3176375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603622PMC
May 2021

Heterozygous Genotype rs17580 AT (PiS) in is Associated with COPD Secondary to Biomass-Burning and Tobacco Smoking: A Case-Control and Populational Study.

Int J Chron Obstruct Pulmon Dis 2020 27;15:1181-1190. Epub 2020 May 27.

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.

Purpose: The protease inhibitor S (PiS) and Z (PiZ) variants have been stated as the only genetic cause of chronic obstructive pulmonary disease (COPD) in Caucasians. However, its frequency in admixed populations is low. We aimed to identify genetic susceptibility between PiS (rs17580) and PiZ (rs28929474) polymorphisms with COPD related to tobacco smoking and biomass-burning smoke as well as to determine its frequencies in Mestizo and Amerindian populations from Mexico.

Patients And Methods: One thousand and eight hundred seventy-eight subjects were included in two comparisons of cases and controls, (1) smokers with and without COPD (COPD-S, n=399; SWOC, n=1106); (2) Biomass-burning smoke-exposed subjects with and without COPD (COPD-BS, n=98; BBES, n=275). In addition, 2354 Mexican subjects identified as Mestizos (n=1952) and Amerindian (n=402) were included. The population structure was evaluated using 59 informative ancestry markers.

Results: The AT genotype of rs17580 is associated with COPD in both comparisons (COPD-S vs SWOC p<0.001, OR=2.16; COPD-BS vs BBES p<0.0001, OR=11.50). The population of the Mexico-North has a greater Caucasian contribution (54.7%) compared to the center (46.9%) and southeast (42.7%).

Conclusion: The rs17580, AT genotype, is associated with COPD in Mexican-Mestizo smokers and exposed to biomass-burning smoke. The rs17580 AT is more frequent in the Mexican-Mestizo population of the North of the country, which has a high Caucasian component.
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http://dx.doi.org/10.2147/COPD.S247446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261677PMC
May 2020

Single Nucleotide and Copy-Number Variants in IL4 and IL13 Are Not Associated with Asthma Susceptibility or Inflammatory Markers: A Case-Control Study in a Mexican-Mestizo Population.

Diagnostics (Basel) 2020 Apr 30;10(5). Epub 2020 Apr 30.

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Calzada de Tlalpan 4502, Sección XVI, Mexico City 14080, Mexico.

Background: Asthma is a complex and chronic inflammatory airway disease. Asthma's etiology is unknown; however, genetic and environmental factors could affect disease susceptibility. We designed a case-control study aimed to evaluate the role of single-nucleotide polymorphisms (SNP), and copy-number variants (CNV) in the and genes in asthma susceptibility and their participation in plasma cytokine levels depending on genotypes Methods: We include 486 subjects, divided into asthma patients (AP, = 141) and clinically healthy subjects (CHS, = 345). We genotyped three SNP, two in the and two in the gene; also, two CNVs in . The IL-4, IL-13 and IgE plasma levels were quantified.

Results: Biomass-burning smoke exposure was higher in the AP group compared to CHS (47.5% vs. 20.9%; < 0.01, OR = 3.4). No statistical differences were found in the genetic association analysis. In both CNV, we only found the common allele. For the analysis of IL-4, IL-13, and IgE measures stratified by genotypes, no significant association or correlation was found.

Conclusion: In the Mexican-mestizo population, SNPs neither CNVs in nor are associated with asthma susceptibility or involved serum cytokine levels. Biomass-burning smoke is a risk factor in asthma susceptibility.
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http://dx.doi.org/10.3390/diagnostics10050273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277638PMC
April 2020

Analysis of gene allelic variants can predict ifosfamide toxicity in Mexican paediatric patients.

Biomarkers 2020 Jun 30;25(4):331-340. Epub 2020 Apr 30.

Department of Biomedical Oncology Laboratory, National Institute of Respiratory Diseases, Mexico City, Mexico.

Ifosfamide (IFA) is an effective antineoplastic for solid tumours in children, although it is associated with high levels of systemic toxicity and causes death in some cases. The aim of this study was to determine whether the presence of certain allelic variants of genes , , and increases the risk of toxicity in children with solid tumours treated with ifosfamide. A total of 131 DNA samples were genotyped by real-time polymerase chain reaction (RT-PCR) using TaqMan probes. Toxicity was assessed using WHO criteria, and survival analysis was performed using Kaplan-Meier curves. The rs3745274 allelic variant in was associated with haematological toxicity, affecting neutrophils; variant rs2740574 was also associated with toxicity, affecting both leukocytes and neutrophils. Additionally, the gene variant rs776746 was found to affect haemoglobin. Our results show that allelic variants rs3745274 (, rs2740574 ( and rs776746 ( increase the risk for high haematological toxicity. 068/2013.
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http://dx.doi.org/10.1080/1354750X.2020.1754913DOI Listing
June 2020

An association between glycine and insulin levels is observed in patients with pulmonary tuberculosis and type 2 diabetes.

Clin Nutr 2020 10 14;39(10):3019-3023. Epub 2020 Feb 14.

Department of Biochemistry, National Institute of Respiratory Diseases "Ismael Cosío Villegas", Mexico City, 14080, Mexico. Electronic address:

Background & Aims: Adequate nutrition from which amino acids are part gives us protection against infectious or metabolic diseases. In particular, glycine has immunomodulatory properties and is a secretagogue of insulin. However, its absorption rate or plasma levels are impaired in bacterial infection or high glucose levels. The aim of this study was to evaluate the association between glycine and insulin plasma levels in patients with pulmonary tuberculosis (PTB) and type 2 diabetes mellitus (DM2).

Methods: Plasma levels of insulin and glycine were determined in four groups: 1) patients with PTB; 2) patients with PTB-DM2; 3) household contacts with DM2 (C-DM2), and 4) healthy household contacts (H-C). Likewise, we analyzed the plasma levels of glucose, serine, arginine, lysine, taurine, and glutamic acid.

Results: We observed significant differences in the glycine levels between PTB and PTB-DM2 vs C-DM2 and H-C groups (P < 0.05). We observed also important differences in insulin and glucose levels after comparisons between PTB, PTB-DM2, and C-DM2 vs. H-C groups (P < 0.05). A correlation between glycine and insulin levels in the PTB (r = 0.326) and PTB-DM2 (r = 0.318) groups was found.

Conclusion: Our results showed a significant association between glycine and insulin plasma levels in patients with PTB and PTB-DM2, which suggests that the determination of glycine levels could be used as a reference test to evaluate both pathologic conditions. An additional support to the above is that significant changes in the glucose levels in these groups were observed, too.
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http://dx.doi.org/10.1016/j.clnu.2020.02.007DOI Listing
October 2020

Amino acid changes in HA and determinants of pathogenicity associated with influenza virus A H1N1pdm09 during the winter seasons 2015-2016 and 2016-2017 in Mexico.

Virus Res 2019 10 21;272:197731. Epub 2019 Aug 21.

Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, Mexico.

Biennial H1N1pdm09 influenza A virus (IAV) epidemics have been associated with major severity of respiratory disease in Mexico. Atypically and in contrast with what happened in USA, Canada and Europe during 2017, an increase of infections due to the H1N1pdm09 pandemic virus instead of H3N2 was observed. In order to determine the viral contribution to severe acute respiratory disease, we characterized the pathogenicity determinants of IAV in Mexico during the 2015-2016 and 2016-2017 seasons. The RNA segments of 20 IAV samples were sequenced by NGS platform and phylogenetic analysis was conducted. The analysis of the hemagglutinin (HA) sequences established that all virus samples, except one, belong to clade (6B.1). The IAVs presented the substitution S162 N, which introduces a new glycosylation site in the hemagglutinin. We also found the D222 G substitution, which has been associated with a higher tropism towards the lower respiratory tract, and a non-reported insertion of one Ile in NS1 (Ile113). The IAVs from 2016 to 2017 in Mexico belong to the new clade 6B.1. The new glycosylation site in HA (S162 N) is a major change that may affect the efficacy of the current vaccine. We detected in several patients pathogenicity determinants associated with the severity of the respiratory disease.
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http://dx.doi.org/10.1016/j.virusres.2019.197731DOI Listing
October 2019

Dysregulated expression of hypoxia-inducible factors augments myofibroblasts differentiation in idiopathic pulmonary fibrosis.

Respir Res 2019 Jun 24;20(1):130. Epub 2019 Jun 24.

Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Tlalpan 4502, 14080, Mexico City, CP, Mexico.

Background: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described.

Methods: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients.

Results: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation.

Conclusions: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.
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http://dx.doi.org/10.1186/s12931-019-1100-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591870PMC
June 2019

Comorbidity Index as a Predictor of Mortality in Pediatric Patients With Solid Tumors.

Front Pediatr 2019 1;7:48. Epub 2019 Mar 1.

Epidemiological Surveillance Unit, National Institute of Respiratory Diseases, Mexico City, Mexico.

The objective of this study was to determine whether a comorbidity index could be used to predict mortality in pediatric patients with chemotherapy-treated solid tumors. Pediatric patients who underwent chemotherapy treatment for solid tumors were included, and demographic, clinical, and comorbidity data were obtained from patient electronic records. A total of 196 pediatric patients with embryonic solid tumors were included. Metastatic tumors were the most frequently observed ( = 103, 52.6%). The most common comorbidities encountered for the Charlson comorbidity index (CCI) were cellulitis ( = 24, 12.2%) and acute renal failure ( = 15, 7.7%). For the Pediatric Comorbidity Index (PCI), the most frequent comorbidities were pneumonia and sepsis, with = 64 (32.7%) for each. We evaluated established the prognostic values for both indexes using Kaplan-Meier curves, finding that the CCI and PCI could predict mortality with < 0.0001. Using the PCI, we observed 100% survival in patients without comorbidities, 70% survival in patients with a low degree of comorbidity, and 20% survival in patients with a high degree of comorbidity. Greater discrimination of probability of survival could be achieved using degrees of comorbidity on the PCI than using degrees of comorbidity on the CCI. The application of the PCI for assessing the hospitalized pediatric population may be of importance for improving clinical evaluation.
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http://dx.doi.org/10.3389/fped.2019.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405632PMC
March 2019

Association between IL-15 and insulin plasmatic concentrations in patients with pulmonary tuberculosis and type 2 diabetes.

Tuberculosis (Edinb) 2018 07 8;111:114-120. Epub 2018 Jun 8.

Department of Biochemistry, National Institute of Respiratory Diseases "Ismael Cosío Villegas", Mexico City, 14080, Mexico. Electronic address:

IL-15 is part of the immune response in pulmonary tuberculosis (PTB) but amazingly, it may also induce physiological effects similar to those of insulin. We evaluated the IL-15 and insulin plasmatic levels in adults with PTB and with or without type 2 diabetes mellitus (DM2), who received previous antituberculosis therapy for at least 2 months. We analyzed the concentrations of glucose, glycated hemoglobin, insulin, as well as levels of IL-15, IL-2, IFN-γ, and TNF-α in patients with PTB, patients with PTB-DM2, household contacts with DM2 (C-DM2), and healthy household contacts (H-C). Our results showed unexpected high levels of glucose, insulin, and IL-15 in the PTB and C-DM2 groups. In comparison, low levels of these same indicators were observed in the PTB-DM2 and H-C groups. Interestingly, our analysis showed a positive correlation of IL-15 with insulin in the PTB group (r = 0.73) and in the C-DM2 group (r = 0.66). In comparison, a weak correlation between IL-15 and insulin was observed in the PTB-DM group (r = 0.10) and in the H-C group (ρ = 0.26). Our results suggest an association between IL-15 and insulin levels in the patient with PTB. Intriguingly, this association was weaker in the patient with PTB-DM2.
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http://dx.doi.org/10.1016/j.tube.2018.06.009DOI Listing
July 2018

An Increased Frequency in HLA Class I Alleles and Haplotypes Suggests Genetic Susceptibility to Influenza A (H1N1) 2009 Pandemic: A Case-Control Study.

J Immunol Res 2018 25;2018:3174868. Epub 2018 Feb 25.

Hospital Epidemiological Surveillance Unit, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080 Ciudad de México, Mexico.

Background: The influenza A H1N1/09 pandemic infected a small number of exposed individuals, which suggests the involvement of genetic factors. There are scarce data available on classical HLA class I association with the influenza A H1N1/09 pandemic.

Methods: We analyzed the frequency of classical HLA class I alleles and haplotypes in A H1N1/09 influenza in a case-control study including 138 influenza patients (INF-P) and 225 asymptomatic healthy contacts (INF-C) simultaneously recruited. HLA class I typing was performed by high-resolution sequence-based typing method.

Results: Our analysis revealed higher frequency of C∗07:02:01, B∗39:06:02, C∗03:02:01, B∗44:03:01, B∗51:01:05, and B∗73:01 ( < 0.05; OR = 1.84-9.98) and of two haplotypes-A∗68:01:02-C∗07:02:01 ( = 1.05 - 05; OR = 23.99) and B∗35:01:01-C∗07:02.01 ( = 4.15 - 04, OR = 2.15)-in A H1N1/09 influenza subjects. A∗68:01:01 was exclusively present only in the INF-P group (5/138). A decrease in the frequency of C∗03:03:01, A∗11:01:01, B∗39:01:01, A∗24:02:01, C∗03:04:01, B∗51:01:01, and C∗07:01:01 ( < 0.05; OR = 0.12-0.52) and of haplotypes A∗02:01:01-B∗35:01:01-C∗04:01:01, A∗24:02:01-B∗35:01:01, B∗39:01:01-C∗07:02:01, and B∗40:02:01-C∗03:04:01 ( < 0.05; OR = 0.08-0.22) were observed in INF-P group.

Conclusion: Selective classical HLA class I allele and haplotype combinations predispose individuals towards susceptibility or protection against the influenza A H1N1/09 pandemic. This work has significant implications for accessing population transmission risk for A H1N1/09 or a similar strain breakout in the future.
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http://dx.doi.org/10.1155/2018/3174868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845504PMC
August 2018

Virome and bacteriome characterization of children with pneumonia and asthma in Mexico City during winter seasons 2014 and 2015.

PLoS One 2018 15;13(2):e0192878. Epub 2018 Feb 15.

Departamento de Investigación en Virología, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, Mexico.

Background: Acute asthma exacerbations and pneumonia are important causes of morbidity and mortality in children and may coexist in the same children, although symptom overlap may lead to difficulties in diagnosis. Microbial and viral diversity and differential abundance of either may play an important role in infection susceptibility and the development of acute and chronic respiratory diseases.

Objectives: To describe the virome and bacteriome present in the upper respiratory tract of hospitalized children with a clinical diagnosis of asthma and pneumonia during an acute exacerbation and an acute respiratory illness ARI episode respectively.

Methods: During the winter seasons of 2013-2014 and 2014-2015, 134 nasopharyngeal swabs samples of children <15 years of age with ARI hospitalized at a referral hospital for respiratory diseases were selected based on clinical diagnosis of asthma or pneumonia. The virome and bacteriome were characterized using Whole Genome Sequencing (WGS) and in-house bioinformatics analysis pipeline.

Results: The Asthma group was represented mainly by RV-C, BoV-1 and RSV-B and the pneumonia group by Bacteriophage EJ-1 and TTMV. TTV was found in both groups with a similar amount of reads. About bacterial composition Moraxella catarrhalis, Propionibacterium acnes and Acinetobacter were present in asthma and Veillonella parvula and Mycoplasma pneumoniae in pneumonia. Streptococcus pneumoniae and Haemophilus influenzae were mostly found with both asthma and pneumonia.

Conclusions: Our results show a complex viral and bacterial composition in asthma and pneumonia groups with a strong association of RV-C presence in asthmatic children. We observed Streptococcus pneumoniae and Haemophilus influenzae concurrently in both groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192878PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813968PMC
April 2018

Aggressive fluid accumulation is associated with acute kidney injury and mortality in a cohort of patients with severe pneumonia caused by influenza A H1N1 virus.

PLoS One 2018 15;13(2):e0192592. Epub 2018 Feb 15.

Centro de Investigación en Enfermedades Infecciosas, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Ciudad de México, México.

Introduction: Fluid accumulation is associated with adverse outcomes such as acute kidney injury (AKI) in critically ill patients. This study aimed to describe the factors associated with AKI in individuals with influenza A H1N1 severe pneumonia, and explore the relation of fluid accumulation with AKI and mortality.

Material And Methods: We reviewed medical records of individuals with influenza A H1N1 severe pneumonia and no history of chronic kidney disease, attending a national referral center for respiratory diseases between November 2014 and May 2015. Demographic information, risk factors for AKI, physiologic and laboratory data, outcomes and information on fluid intake and output were recorded. Categorical variables were compared using the chi-square test. Quantitative variables were compared using the Mann-Whitney test. Factors associated with AKI and mortality were identified by binary logistic regression. Linear models of fluid accumulation rates for individuals and groups were estimated using segmented linear regression.

Results: Of 60 patients studied, 43 developed AKI (71.6%). Male gender was protective for AKI (p = 0.019). AKI was associated with nephrotoxic drugs (p = 0.016); PEEP>10 cm H2O on admission (p = 0.031); mortality (p = 0.037); and fluid accumulation ≥10% (fluid overload) at day 7 of hospitalization (p = 0.00026). Mortality was associated with older age (p = 0.009); nephrotoxic drugs (p = 0.034); and higher Pneumonia Severity Index score (112 vs. 76, p = 0.008) on admission. The Deceased-AKI group had a higher rate of fluid accumulation (expressed as ml/kg/body weight) than the Survivors-No AKI group during the study period of 7 days (Survivors-No AKI = 13.31 vs. Deceased-AKI = 22.76, p = 0.019). During the highest phase of fluid accumulation, the Survivors-No AKI group had a slower rate of fluid accumulation than the Survivors-AKI group (14.91 vs. 28.49, p = 0.001).

Conclusions: A high rate of fluid accumulation was associated with AKI and mortality. We support the approach of resuscitation in acute illness, with an early transition to neutral and then negative fluid balances.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192592PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813941PMC
April 2018

A Pilot Genome-Wide Association Study in Postmenopausal Mexican-Mestizo Women Implicates the RMND1/CCDC170 Locus Is Associated with Bone Mineral Density.

Int J Genomics 2017 3;2017:5831020. Epub 2017 Aug 3.

Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.

To identify genetic variants influencing bone mineral density (BMD) in the Mexican-Mestizo population, we performed a GWAS for femoral neck (FN) and lumbar spine (LS) in Mexican-Mestizo postmenopausal women. In the discovery sample, 300,000 SNPs were genotyped in a cohort of 411 postmenopausal women and seven SNPs were analyzed in the replication cohort ( = 420). The combined results of a meta-analysis from the discovery and replication samples identified two loci, (rs6904364, = 2.77 × 10) and (rs17081341, = 1.62 × 10), associated with FN BMD. We also compared our results with those of the Genetic Factors for Osteoporosis (GEFOS) Consortium meta-analysis. The comparison revealed two loci previously reported in the GEFOS meta-analysis: (rs7128738) and (rs11887431) associated with FN and LS BMD, respectively, in our study population. Interestingly, rs17081341 rare in Caucasians (minor allele frequency < 0.03) was found in high frequency in our population, which suggests that this association could be specific to non-Caucasian populations. In conclusion, the first pilot Mexican GWA study of BMD confirmed previously identified loci and also demonstrated the importance of studying variability in diverse populations and/or specific populations.
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http://dx.doi.org/10.1155/2017/5831020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559934PMC
August 2017

EV-D68 infection in children with asthma exacerbation and pneumonia in Mexico City during 2014 autumn.

Influenza Other Respir Viruses 2016 May;10(3):154-60

Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas, Mexico City, Mexico.

Background: Human enterovirus D68 (EV-D68) recently caused an increase in mild-to-severe pediatric respiratory cases in North America and some European countries. Even though few of these children presented with acute paralytic disease, direct causal relationship cannot yet be assumed.

Objectives: The purposes of this report were to describe the clinical findings of an outbreak of EV-D68 infection in Mexico City and identify the genetic relationship with previously reported strains.

Patients/methods: Between September and December 2014, 126 nasopharyngeal samples (NPS) of hospitalized children <15 years of age with ARI were tested for the presence of respiratory viruses using a multiplex RT-qPCR and EV-D68-specific RT-qPCR. Clinical, epidemiological, and demographic data were collected and associated with symptomatology and viral infections. Phylogenetic analyses were performed using VP1 region.

Results: Enterovirus/rhinovirus infection was detected in 40 patients (31·7%), of which 24 patients were EV-D68-positive. EV-D68 infection prevailed over September and October 2014 and was associated with neutrophilia and lymphopenia, and patients were more likely to develop hypoxemia. Phylogenetic analyses showed that Mexican EV-D68 belongs to the new B1 clade.

Conclusions: This is the first EV-D68 outbreak described in Mexico and occurred few weeks after the United States reported similar infections. Although EV-D68 belongs to new B1 clade, no neurological affection was observed.
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http://dx.doi.org/10.1111/irv.12384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814865PMC
May 2016

Effects of 2-methoxyestradiol on apoptosis and HIF-1α and HIF-2α expression in lung cancer cells under normoxia and hypoxia.

Oncol Rep 2016 Jan 4;35(1):577-83. Epub 2015 Nov 4.

Instituto Nacional de Enfermedades Respiratorias 'Ismael Cosío Villegas', Mexico City, DF, Mexico.

Hypoxic tumor cells are known to be more resistant to conventional chemotherapy and radiation than normoxic cells. However, the effects of 2-methoxyestradiol (2-ME), an anti-angiogenic, antiproliferative and pro-apoptotic drug, on hypoxic lung cancer cells are unknown. The aim of the present study was to compare the effects of 2-ME on cell growth, apoptosis, hypoxia-inducible factor 1α (HIF-1α) and HIF-2α gene and protein expression in A549 cells under normoxic and hypoxic conditions. To establish the optimal 2-ME concentration with which to carry out the apoptosis assay and to examine mRNA and protein expression of HIFs, cell growth analysis was carried out through N-hexa-methylpararosaniline staining assays in A549 cell cultures treated with one of five different 2-ME concentrations at different times under normoxic or hypoxic growth conditions. The 2-ME concentration of 10 mM at 72 h was selected to perform all further experiments. Apoptotic cells were analyzed by flow cytometry. Western blotting was used to determine HIF-1α and HIF-2α protein expression in total cell extracts. Cellular localization of HIF-1α and HIF-2α was assessed by immunocytochemistry. HIF-1α and HIF-2α gene expression was determined by real-time PCR. A significant increase in the percentage of apoptosis was observed when cells were treated with 2-ME under a normoxic but not under hypoxic conditions (p=0.006). HIF-1α and HIF-2α protein expression levels were significantly decreased in cells cultured under hypoxic conditions and treated with 2-ME (p<0.001). Furthermore, 2-ME decreased the HIF-1α and HIF-2α nuclear staining in cells cultured under hypoxia. The HIF-1α and HIF-2α mRNA levels were significantly lower when cells were exposed to 2-ME under normoxia and hypoxia. Our results suggest that 2-ME could have beneficial results when used with conventional chemotherapy in an attempt to lower the invasive and metastatic processes during cancer development due to its effects on the gene expression and protein synthesis of HIFs.
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http://dx.doi.org/10.3892/or.2015.4399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699616PMC
January 2016

Analysis of heat shock protein 70 gene polymorphisms Mexican patients with idiopathic pulmonary fibrosis.

BMC Pulm Med 2015 Oct 24;15:129. Epub 2015 Oct 24.

Instituto Nacional de Enfermedades Respiratorias "Ismael Cosío Villegas" Tlalpan 4502, Col. Sección XVI, 14080, Mexico, México.

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown etiology. Genetic variation within different major histocompatibility complex (MHC) loci contributes to the susceptibility to IPF. The effect of 70 kDa heat shock proteins (HSP70) gene polymorphisms in the susceptibility to IPF is unknown. The aim of this study was to explore the association between HSP70 polymorphisms and IPF susceptibility in the Mexican population.

Methods: Four HSP70 single nucleotide polymorphisms (SNPs) were evaluated using real time PCR assays in 168 IPF patients and 205 controls: +2763 C>T of HSPA1L (rs2075800), +2437 of HSP HSPA1L A>G (rs2227956), +190 of HSPA1A G>C (rs1043618) and +1267 of HSPA1B G>A (rs1061581).

Results: The analysis of the recessive model revealed a significant decrease in the frequency of the genotype HSPA1B AA (rs1061581) in IPF patients (OR = 0.27, 95 % CI = 0.13-0.57, Pc = 0.0003) when compared to controls. Using a multivariate logistic regression analysis in a codominant model the HSPA1B (rs1061581) GA and AA genotypes were associated with a lower risk of IPF compared with GG (OR = 0.22, 95 % CI = 0.07-0.65; p = 0.006 and OR = 0.17, 95 % CI = 0.07-0.41; p = <0.001). Similarly, HSPA1L (rs2227956) AG genotype (OR = 0.34, 95 % CI = 0.12-0.99; p = 0.04) and the dominant model AG + GG genotypes were also associated with a lower risk of IPF (OR = 0.24, 95 % CI = 0.08-0.67; p = 0.007). In contrast, the HSPA1L (rs2075800) TT genotype was associated with susceptibility to IPF (OR = 2.52, 95 % CI = 1.32-4.81; p = 0.005).

Conclusion: Our findings indicate that HSPA1B (rs1061581), HSPA1L (rs2227956) and HSPA1 (rs1043618) polymorphisms are associated with a decreased risk of IPF.
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http://dx.doi.org/10.1186/s12890-015-0127-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4619986PMC
October 2015

Detection and characterization of respiratory viruses causing acute respiratory illness and asthma exacerbation in children during three different seasons (2011-2014) in Mexico City.

Influenza Other Respir Viruses 2015 Nov;9(6):287-292

Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.

Background: Viral infections play a significant role in causing acute respiratory infections (ARIs) and exacerbations of chronic diseases. Acute respiratory infections are now the leading cause of mortality in children worldwide, especially in developing countries. Recently, human rhinovirus (HRV) infection has been emerged as an important cause of pneumonia and asthma exacerbation.

Objectives: To determine the role of several viral agents principally, respiratory syncytial virus, and HRV in children with ARIs and their relationship with asthma exacerbation and pneumonia.

Methods: Between October 2011 and March 2014, 432 nasopharyngeal samples of children <15 years of age with ARI hospitalized at a referral hospital for respiratory diseases were tested for the presence of respiratory viruses using a multiplex RT-qPCR. Clinical, epidemiological, and demographic data were collected and associated with symptomatology and viral infections.

Results: Viral infections were detected in at least 59·7% of the enrolled patients, with HRV (26·6%) being the most frequently detected. HRV infections were associated with clinical features of asthma and difficulty in breathing such as wheezing (P = 0·0003), supraesternal (P = 0·046), and xiphoid retraction (P = 0·030). HRV subtype C (HRV-C) infections were associated with asthma (P = 0·02).

Conclusions: Human rhinovirus was the virus most commonly detected in pediatric patients with ARI. There is also an association of HRV-C infection with asthma exacerbation, emphasizing the relevance of this virus in severe pediatric respiratory disease.
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http://dx.doi.org/10.1111/irv.12346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4605408PMC
November 2015

Analysis of association of MEF2C, SOST and JAG1 genes with bone mineral density in Mexican-Mestizo postmenopausal women.

BMC Musculoskelet Disord 2014 Nov 28;15:400. Epub 2014 Nov 28.

Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica, Mexico City, Mexico.

Background: Osteoporosis, a disease characterized by low bone mineral density (BMD), is an important health problem in Mexico. BMD is a highly heritable trait, with heritability estimates of 50-85%. Several candidate genes have been evaluated to identify those involved in BMD variation and the etiology of osteoporosis. This study investigated the possible association of single-nucleotide polymorphisms (SNPs) in the MEF2C, SOST and JAG1genes with bone mineral density (BMD) variation in postmenopausal Mexican-Mestizo women.

Methods: Four hundred unrelated postmenopausal women were included in the study. Risk factors were recorded and BMD was measured in total hip, femoral neck and lumbar spine using dual-energy X-ray absorptiometry. In an initial stage, a total of twenty-five SNPs within or near SOST gene and seven SNPs in the JAG1 gene were genotyped using a GoldenGate assay. In a second stage, three MEF2C gene SNPs were also genotyped and SOST and JAG1 gene variants were validated. Real time PCR and TaqMan probes were used for genotyping.

Results: Linear regression analyses adjusted by age, body mass index and ancestry estimates, showed that five SNPs in the SOST gene were significantly associated with BMD in total hip and femoral neck but not lumbar spine. The lowest p value was 0.0012, well below the multiple-test significance threshold (p=0.009), with mean effect size of -0.027 SD per risk allele. We did not find significant associations between BMD and MEF2C/JAG1 gene variants [rs1366594 "A" allele: β=0.001 (95% CI -0.016; 0.017), P=0.938; rs2273061 "G" allele: β=0.007 (95% CI -0.007; 0.023), p=0.409].

Conclusions: SOST polymorphisms may contribute to total hip and femoral neck BMD variation in Mexican postmenopausal women. Together, these and prior findings suggest that this gene may contribute to BMD variation across populations of diverse ancestry.
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http://dx.doi.org/10.1186/1471-2474-15-400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258010PMC
November 2014

WNT3A gene polymorphisms are associated with bone mineral density variation in postmenopausal mestizo women of an urban Mexican population: findings of a pathway-based high-density single nucleotide screening.

Age (Dordr) 2014 Jun 3;36(3):9635. Epub 2014 Mar 3.

Laboratorio de Genómica del Metabolismo Óseo, Instituto Nacional de Medicina Genómica, México, D.F., C.P. 14610, México,

Osteoporosis (OP) is a common skeletal disorder characterized by low bone mineral density (BMD) and is a common health problem in Mexico. To date, few genes affecting BMD variation in the Mexican population have been identified. The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) located in genes of the Wnt pathway with BMD variation at various skeletal sites in a cohort of postmenopausal Mexican women. A total of 121 SNPs in or near 15 Wnt signaling pathway genes and 96 ancestry informative markers were genotyped in 425 postmenopausal women using the Illumina GoldenGate microarray SNP genotyping method. BMD was measured by dual-energy X-ray absorptiometry in total hip, femoral neck, Ward's triangle, and lumbar spine. Associations were tested by linear regression for quantitative traits adjusting for possible confounding factors. SNP rs752107 in WNT3A was strongly associated with decreased total hip BMD showing the highest significance under the recessive model (P = 0.00012). This SNP is predicted to disrupt a binding site for microRNA-149. In addition, a polymorphism of the Wnt antagonist DKK2 was associated with BMD in femoral neck under a recessive model (P = 0.009). Several LRP4, LRP5, and LRP6 gene variants showed site-specific associations with BMD. In conclusion, this is the first report associating Wnt pathway gene variants with BMD in the Mexican population.
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http://dx.doi.org/10.1007/s11357-014-9635-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082595PMC
June 2014

[Factors involved in host-pathogen interaction for the risk of Hodgkin lymphoma induced by Epstein Barr virus].

Invest Clin 2013 Sep;54(3):311-24

Unidad de Vigilancia Epidemiológica Hospitalaria, Instituto Nacional de Enfermedades Respiratorias, Delegación Tlalpan, Mexico, D.F.

Hodgkin lymphoma (HL) is a neoplasm characterized by malignant cells called Reed Sternberg and Hodgkin's cells in the lymphatic system. Such cells comprise 1% of the tumor while the remainder is made up of lymphocytes, histiocytes, eosinophils and plasma non-neoplastic cells. The annual global incidence of HL is 3-10/100,000 inhabitants and is most commonly found in young adults. The mechanism by which cell transformation is accomplished is not entirely clear; however, some evidences suggest that oncogenic viruses like the Epstein Barr virus (EBV) may have a high impact on the pathogenesis of lymphoproliferation. Genetic and environmental factors could be involved, since it has been found a high incidence of HL among members of the same family. In Mexico, there have been studies to determine the prevalence of EBV in patients with HL and found the presence of this virus in up to 64.2% of the cases. EBV has been detected in the Reed Sternberg cells and Hodgkin cells in 50% of cases of classical HL. There is not a satisfactory explanation for this, but it has been proposed that geographic and immunological variabilities play a role in the positivity of EBV in HL. However, despite recent advances in the field, there is insufficient evidence to show a clear association between host factors, environment and pathogens, and the risk of lymphoproliferation leading to the development of HL. This review aims to give an overview about the risk factors that influence the interaction of host, pathogens and environment in the etiology of HL.
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September 2013

Pandemic influenza A/H1N1 virus infection and TNF, LTA, IL1B, IL6, IL8, and CCL polymorphisms in Mexican population: a case-control study.

BMC Infect Dis 2012 Nov 13;12:299. Epub 2012 Nov 13.

Coordinación de Investigación en Salud, Instituto Mexicano del Seguro Social (IMSS), Torre Academia Nacional de Medicina 4to piso, Av, Cuauhtémoc 330, 06720 México, DF, México.

Background: Some patients have a greater response to viral infection than do others having a similar level of viral replication. Hypercytokinemia is the principal immunopathological mechanism that contributes to a severer clinical course in cases of influenza A/H1N1. The benefit produced, or damage caused, by these cytokines in severe disease is not known. The genes that code for these molecules are polymorphic and certain alleles have been associated with susceptibility to various diseases. The objective of the present study was to determine whether there was an association between polymorphisms of TNF, LTA, IL1B, IL6, IL8, and CCL1 and the infection and severity of the illness caused by the pandemic A/H1N1 in Mexico in 2009.

Methods: Case-control study. The cases were patients confirmed with real time PCR with infection by the A/H1N1 pandemic virus. The controls were patients with infection like to influenza and non-familial healthy contacts of the patients with influenza. Medical history and outcome of the disease was registered. The DNA samples were genotyped for polymorphisms TNF rs361525, rs1800629, and rs1800750; LTA rs909253; IL1B rs16944; IL6 rs1818879; IL8 rs4073; and CCL1 rs2282691. Odds ratio (OR) and the 95% confidence interval (95% CI) were calculated. The logistic regression model was adjusted by age and severity of the illness in cases.

Results: Infection with the pandemic A/H1N1 virus was associated with the following genotypes: TNF rs361525 AA, OR = 27.00; 95% CI = 3.07-1248.77); LTA rs909253 AG (OR = 4.33, 95% CI = 1.82-10.32); TNF rs1800750 AA (OR = 4.33, 95% CI = 1.48-12.64); additionally, LTA rs909253 AG showed a limited statistically significant association with mortality (p = 0.06, OR = 3.13). Carriers of the TNF rs1800629 GA genotype were associated with high levels of blood urea nitrogen (p = 0.05); those of the TNF rs1800750 AA genotype, with high levels of creatine phosphokinase (p=0.05). The IL1B rs16944 AA genotype was associated with an elevated number of leukocytes (p <0.001) and the IL8 rs4073 AA genotype, with a higher value for PaO2 mm Hg.

Conclusion: The polymorphisms of genes involved in the inflammatory process contributed to the severity of the clinical behavior of infection by the pandemic influenza A/H1N1 virus.
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http://dx.doi.org/10.1186/1471-2334-12-299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3534505PMC
November 2012

High mortality associated with hyperglycemia, neutrophilia, and lymphopenia in critically ill patients.

Tohoku J Exp Med 2012 03;226(3):213-20

Graduate and Research Section, Higher School of Medicine of the National Polytechnical Institute, México City, México.

A common finding in patients admitted to an Intensive Care Unit (ICU) is hyperglycemia without prior history of diabetes. This increase in blood glucose is considered a negative prognostic factor for patients in the ICU. Hence, we performed a retrospective cohort study in patients admitted at the ICU of the National Institute of Respiratory Diseases (INER) in a 7-month period; we collected data about their blood glucose concentration during their stay at the ICU. We gathered the available medical records of 30 patients out of 58 admitted to the ICU. Among the 30 patients, 21 patients survived (70%) and 9 patients with community-acquired pneumonia (CAP) died (30%). The 21 surviving patients included 17 patients with acute respiratory distress secondary to CAP and 4 patients with asthmatic crisis upon admission to the ICU. After admission, all patients progressed to sepsis and showed an increase in blood glucose. We detected higher glucose concentrations in deceased patients (147 mg/dl ± 4.23), as compared to surviving patients (129 mg/dl ± 2.17) (P < 0.001). In addition, the percentage of lymphocytes was lower in deceased patients than that in surviving patients (5.7 vs. 11.8%, P < 0.001), whereas percentage of neutrophils was elevated in the deceased patients (90.7 vs. 80.9%, P < 0.001). It is therefore important to measure continuously glucose concentrations, as well as the numbers of neutrophils and lymphocytes in critically ill patients with hyperglycemia. Such a simple monitoring plan may prevent fatal complications in patients admitted to ICU.
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http://dx.doi.org/10.1620/tjem.226.213DOI Listing
March 2012

[Association between penoscopy data and urethral cytology among men with partners who had cervical lesions associated with human papilloma virus].

Gac Med Mex 2010 Jul-Aug;146(4):274-80

Servicio de Ginecoobstetricia, Secretaría de Salud del Estado de Guerrero, México.

Objective: The aim of this study was to identify human papillomavirus lesions in a group of men whose sexual partners had cervical intraepithelial lesions associated with low-grade HPV confirmed by PCR-DNA. We carried out a correlation between urethral cytology penoscopy data and PCR-DNA results.

Methods: We studied 100 male volunteers with an age range of 21-45 (median 30 years) and divided them into two groups according to the identified virus; two groups were conformed, a high risk and a low risk virus.

Results: For the penoscopy data we included the following: type of hirsutoide papillomatosis in 40 (40%) cases, common warts in 24 (24%) cases, papillomatosis in plaque in 6 (6%) and 47% displayed an urethra with a foamy appearance. In urethral cytology we did not find evidence of koilocytes in 58% and 42% showed no koilocytes. Inflammation was observed in 44 cases; an added infection was noted among 60 cases. Depending on the type of infection we found non-specific bacteria in 8%, bacillary in 10%, mixed infection in 12%, changes suggestive of Gardnerella vs 24%, and Chlamydia treatment in 6%. Dyskeratosis was noted in 47% of study participants. 67 patients were treated with imiquimod cream 5% and 33% received non-specific treatment. Regarding improvement we noted that 67 (67%) cases showed 46/67 hypochromic stains after treatment with imiquimod. Disappearance of the lesions in the penis were observed among 65 cases and only 35 remained with lesions. Regarding high-risk HPV we found a significant difference in odor (p = .004, phi = .004), urethral discharge (p = .007), pearly papules in raphe (p = .023), with inflammation, dyskeratosis and added infection (p = .000 respectively). We also noted hypochromic spots or skin discoloration after treatment with imiquimod among 5% of subjects (p = .046).

Conclusions: In our study we observed that high-risk HPV is associated with increased penile lesions and frank evidence of koilocytes in urethral cytology. We recommend that sexual partners of women with cervical lesions associated with HPV complete a control study with penoscopy data and urethral cytology, since most have concurrent infections and lesions that can treated in early stages.
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December 2010

[Clinical pathological study of craniopharyngioma. Fifteen years at the National Institute of Neurology and Neurosurgery "Manuel Velasco Suárez"].

Gac Med Mex 2009 Sep-Oct;145(5):361-8

Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México DF, México.

Background: Craniopharyngioma is a sellar region benign cyst It's frequency ranges from 1.2% to 4.6% of all brain tumors.

Objective: To carry out a clinical pathological correlation of craniopharyngioma among adults and describe the tumor's biological characteristics.

Methods: We included 115 craniopharyngiomas; 100 were adamantimomatous and 15 were papillary type. Patient's age range was 15-90 years (mean 52.5 yrs); 54 (47%) were males and 61 (53%) females. The most frequent location was the supraselar region in 49 (42.6%) of cases. Total exeresis was performed in 72 patients (62.6%) and partial exeresis in 43 (37.4%).

Results: We noted a recurrence among 50 patients (43%), of which 5/15 were papillary and 45/100 adamantinomatous. The mean patient age for recurrent tumors was 50.46+/-14.13yrs and 48.65+/-11.95 for non recurrent tumors. Thirteen patients died (11.3%). We observed a statistical correlation between recurrence, exeresis (p=0.014), and death (p=0.047). Follow-up was longer among females than males and in suprasellar tumor location, papillary type, external epithelium cysts and laxo stellate reticulum.

Conclusions: However a good prognostic factor in craniopharyngiomas was observed in older female patients with complete exeresis, small tumors, external epithelium cysts, edematous stroma, inflammation, and absence of atypical cell and mitosis.
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March 2010

[Cytochrome P450 and NAT2 polymorphisms and drug metabolism in DOTS].

Rev Invest Clin 2008 Jan-Feb;60(1):47-57

Instituto Nacional de Enfermedades Respiratorias, México, DF.

It has been described an increase of the frequency of Directly Observed Therapy Short-course (DOTS) failure in countries with high rates of mycobacterial drug resistance. This increase could be due to the standardized doses of DOTS results in low or insufficient dosage of drugs in plasma. Several members of cytochrome P450 enzymes superfamily could explain the variations on acetylation velocity and in drug disposition. A population with slow acetylation has a higher risk of toxicity, as that potent inhibition of cytochrome P450 (CYP450) isoforms by isoniazid (CYP2C19 y CYP3A) are dependent of INH plasmatic concentration. This inhibitory effect has been described also for CYP12, CYP2C9 and CYP2E1. INH is metabolized by N-acetyltransferase 2 (NAT2). The wide variability interethnic and intraethnic in acetylation velocity is associated with the polymorphisms of NAT2. Patients with rapid acetylation have plasmatic concentration of INH low or insufficient which induces treatment failure. The study of genotypes of P450 and NAT2 allow us to predict therapeutic and individualized dosages.
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October 2008