The Relationship Between CYP46A1 Polymorphism and Suicide Risk: A Preliminary Investigation.

Suicide is a global public health issue, with a particularly high incidence in individuals suffering from Major Depressive Disorder (MDD). The role of cholesterol in suicide risk remains controversial, prompting investigations into genetic markers that may be implicated. This study examines the association between CYP46A1 polymorphisms, specifically SNPs rs754203 and rs4900442, and suicide risk in a Mexican MDD patient cohort. Our study involved 188 unrelated suicide death victims, 126 MDD patients, and 144 non-suicidal controls. Genotypic and allelic frequencies were assessed using the Real Time-polymerase chain reaction method, and associations with suicide risk were evaluated using chi-square tests. The study revealed significant differences in allelic and genotypic frequencies in rs754203 SNP between suicide death and controls. The CYP46A1 rs754203 genotype G/G was significantly linked with suicide, and the G allele was associated with a higher risk of suicide (OR = 1.370, 95% CI = 1.002-1.873). However, we did not observe any significant differences in genotype distribution or allele frequencies of CYP46A1 rs4900442. Our study suggests that carriers of the CYP46A1 rs754203 G allele (A/G + G/G) may play a role in suicidal behavior, especially in males. Our findings support that the CYP46A1 gene may be involved in susceptibility to suicide, which has not been investigated previously. These results underscore the importance of further research in different populations to elucidate the genetic underpinnings of the role of CYP46A1 in suicide risk and to develop targeted interventions for at-risk populations.

Evaluation of DNA damage in obese children using the chromatin dispersion test.

Childhood obesity predicts adult obesity and may increase the lifetime risk of adverse health outcomes. Obesity is characterized by oxidative stress that can induce DNA damage; however, studies of childhood and adolescent obesity are scarce. We investigated DNA damage due to obesity in Mexican children using the chromatin dispersion test (CDT). We evaluated DNA damage to peripheral lymphocytes of 32 children grouped according to body mass index as normal weight (controls), overweight and obese groups using guidelines from the Centers for Disease Control (CDC). We found that the greatest DNA damage occurred in cells of obese children compared to normal weight and overweight children. Our findings support preventive action to obviate adverse health outcomes due to obesity.

Mitochondrial dysfunction: The pathological link between psoriasis and insulin resistance?

BACKGROUND: Psoriasis is strongly associated with insulin resistance (IR). Lipid profile disturbances and upregulation of enzymes crucial for fatty acid oxidation have been reported in patients with psoriasis. Mitochondrial ß-oxidation is altered in patients with IR. Common mitochondrial dysfunction may be involved in the origin of both diseases. OBJECTIVE: This study aimed to evaluate mitochondrial ß-oxidation, intermediary metabolism, and mitochondrial content in psoriatic patients with or without IR and compare them to healthy controls. METHODS: The participants were divided into three groups: (1) psoriasis and IR (n = 26); (2) psoriasis without IR (n = 17); and (3) healthy controls (n = 17). Quantification of amino acids and acylcarnitines (AC) by tandem mass spectrometry, determination of urinary organic acids by gas chromatography/mass spectrometry (GC/MS), and mitochondrial DNA quantification were performed in all groups. RESULTS: When comparisons were made between the two psoriatic groups, no differences were found between: C5DC + C6OH, C16:1, Met/Leu, Met/Phe, C16:1/C16, and C5DC + C6OH/C4DC + C5OH ratios. Nine analytes were different: phenylalanine, Cit/Phe, and Cit/Tyr ratios, C0, C3, C5, C6DC, C16, and C18:1OH. There were no correlations between psoriasis area and severity index (PASI), body mass index (BMI) and duration of disease with ACs. A higher proportion of patients with psoriasis showed increased urine levels of uric acid and hippuric acid (p = 0.01). The mtDNA content was significantly higher in cases than in controls, with no differences between IR and non-IR psoriatic patients. CONCLUSIONS: Psoriasis patients with and without IR have a different acylcarnitine profile reflecting impaired ß-oxidation. A distinctive profile of acylcarnitines suggests an involvement of mitochondrial function associated with an increase in stearoyl CoA desaturase (SCD) activity in psoriatic patients with and without IR.

Genomic analysis of virulence factors and antimicrobial resistance of group B Streptococcus isolated from pregnant women in northeastern Mexico.

INTRODUCTION: Group B Streptococcus (GBS) causes infections in women during pregnancy and puerperium and invasive infections in newborns. The genes lmb, cylE, scpB, and hvgA are involved with increased virulence of GBS, and hypervirulent clones have been identified in different regions. In addition, increasing resistance of GBS to macrolides and lincosamides has been reported, so knowing the patterns of antibiotic resistance may be necessary to prevent and treat GBS infections. This study aimed to identify virulence genes and antibiotic resistance associated with GBS colonization in pregnant women from northeastern Mexico. METHODS: Pregnant women with 35-37 weeks of gestation underwent recto-vaginal swabbing. One swab was inoculated into Todd-Hewitt broth supplemented with gentamicin and nalidixic acid, a second swab was inoculated into LIM enrichment broth, and a third swab was submerged into a transport medium. All samples were subcultured onto blood agar. After overnight incubation, suggestive colonies with or without hemolysis were analyzed to confirm GBS identification by Gram staining, catalase test, hippurate hydrolysis, CAMP test, and incubation in a chromogenic medium. We used latex agglutination to confirm and serotype GBS isolates. Antibiotic resistance patterns were assessed by Vitek 2 and disk diffusion. Periumbilical, rectal and nasopharyngeal swabs were collected from some newborns of colonized mothers. All colonized women and their newborns were followed up for three months to assess the development of disease attributable to GBS. Draft genomes of all GBS isolates were obtained by whole-genome sequencing. In addition, bioinformatic analysis to identify genes encoding capsular polysaccharides and virulence factors was performed using BRIG, while antibiotic resistance genes were identified using the CARD database. RESULTS: We found 17 GBS colonized women out of 1154 pregnant women (1.47%). None of the six newborns sampled were colonized, and no complications due to GBS were detected in pregnant women or newborns. Three isolates were serotype I, 5 serotype II, 3 serotype III, 4 serotype IV, and 2 serotype V. Ten distinct virulence gene profiles were identified, being scpB, lmb, fbsA, acp, PI-1, PI-2a, cylE the most common (3/14, 21%). The virulence genes identified were scpB, lmb, cylE, PI-1, fbsA, PI-2a, acp, fbsB, PI-2b, and hvgA. We identified resistance to tetracycline in 65% (11/17) of the isolates, intermediate susceptibility to clindamycin in 41% (7/17), and reduced susceptibility to ampicillin in 23.5% (4/17). The tetM gene associated to tetracyclines resistance was found in 79% (11/14) and the mel and mefA genes associated to macrolides resistance in 7% (1/14). CONCLUSIONS: The low prevalence of colonization and the non-occurrence of mother-to-child transmission suggest that the intentional search for GBS colonization in this population is not justified. Our results also suggest that risk factors should guide the use of intrapartum antibiotic prophylaxis. The detection of strains with genes coding virulence factors means that clones with pathogenic potential circulates in this region. On the other hand, the identification of decreased susceptibility to antibiotics from different antimicrobial categories shows the importance of adequately knowing the resistance patterns to prevent and to treat GBS perinatal infection.

Risk Association of TOX3 and MMP7 Gene Polymorphisms with Sporadic Breast Cancer in Mexican Women.

Breast cancer (BC) has one of the highest incidences and mortality worldwide. Single nucleotide polymorphisms (SNPs) in TOX3 rs3803662 and MMP7 rs1943779 have been associated with susceptibility to BC. In this case-control study, we evaluated the association of rs3803662 (TOX3)/rs1943779 (MMP7) SNPs with clinical features, immunohistochemical reactivity, and risk association with BC in women from northeastern Mexico. We compared 212 BC cases and 212 controls. DNA was isolated from peripheral blood to perform the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. We calculated genotype frequencies, odds ratios, and 95% confidence intervals. We found that CT (Cytocine-Thymine) and TT (Thymine -Thymine) genotypes, and T alleles of TOX3 rs3803662, were associated with BC risk (p = 0.034, p = 0.011, respectively). SNP TOX3 rs3803662 was associated with positive progesterone receptors (PR) and triple-negative BC (TNBC) but not with estrogen receptor (ER) or HER2 reactivity. CT and TT genotypes (p = 0.006) and T alleles (p = 0.002) of SNP MMP7 rs1943779 were associated with risk of BC. We found that T alleles of TOX3 rs3803662 and MMP7 rs1943779 SNPs are associated with BC risk. These findings contribute to personalized medicine in Mexican women.

The Mitochondrial DNA Landscape of Modern Mexico.

Mexico is a rich source for anthropological and population genetic studies with high diversity in ethnic and linguistic groups. The country witnessed the rise and fall of major civilizations, including the Maya and Aztec, but resulting from European colonization, the population landscape has dramatically changed. Today, the majority of Mexicans do not identify themselves as Indigenous but as admixed, and appear to have very little in common with their pre-Columbian predecessors. However, when the maternally inherited mitochondrial (mt)DNA is investigated in the modern Mexican population, this is not the case. Control region sequences of 2021 samples deriving from all over the country revealed an overwhelming Indigenous American legacy, with almost 90% of mtDNAs belonging to the four major pan-American haplogroups A2, B2, C1, and D1. This finding supports a very low European contribution to the Mexican gene pool by female colonizers and confirms the effectiveness of employing uniparental markers as a tool to reconstruct a country's history. In addition, the distinct frequency and dispersal patterns of Indigenous American and West Eurasian clades highlight the benefit such large and country-wide databases provide for studying the impact of colonialism from a female perspective and population stratification. The importance of geographical database subsets not only for forensic application is clearly demonstrated.

The Convoluted Tubules of the Nephron Must Be Considered Elliptical, and Not Circular, in Stereological Studies of the Kidney.

INTRODUCTION: The diameter and area of the proximal convoluted tubule (PCT) and the distal convoluted tubule (DCT) are of the main parameters analyzed in stereological studies of the kidney. However, there is no consensus about if the PCT and DCT should be considered circular or elliptical in shape. OBJECTIVE: To analyze if there are significant differences in the diameter and area of the PCT and DCT, depending on whether they are considered circular or elliptical. METHODS: Paraffin-embedded sections of kidneys from CD1 mice were stained with hematoxylin and eosin and examined using a light microscope. Images were captured using a camera linked to image analysis software. A short diameter (d) and a long diameter (D) were measured in both PCT and DCT. A small circular area (SCA), a large circular area (LCA), and an elliptical area (EA) were calculated with mathematical formulas that incorporate d and D values, while a program area (PA) was provided by the software. RESULTS: There was a significant difference between d and D in both PCT (F = 1.354, Sig = 0.000) and DCT (F = 4.989, Sig = 0.000). Also, there were significant differences in the tubular areas in both PCT (F = 34.843, Sig = 0.000) and DCT (F = 22.390, Sig = 0.000); circular areas were different from elliptical areas (SCA and LCA vs. EA and PA). CONCLUSION: The convoluted tubules of the nephron must not be considered circular, but rather elliptical; care should be taken every time the tubules are analyzed in stereological studies of the kidney, especially when evaluating their diameters and areas.

Quick assessment of DNA damage in cervical epithelial cells using a chromatin dispersion test.

PURPOSE: This study was aimed to quantify genomic DNA breakages in the cervical epithelium cells of patients diagnosed with different grades of cervical lesions using a quick test based on chromatin dispersion after controlled protein depletion. The association between the progressive stages of cervical dysplasia and the levels of DNA damage, taking into account the presence of papillomavirus human (HPV) infection, was investigated. METHODS: A hospital-based unmatched case-control study was conducted during 2018 with a sample of 78 women grouped according to histological diagnosis as follows: 23 women with low grade-squamous intraepithelial lesion (LG-SIL), 34 women with high grade- squamous intraepithelial lesion (HG-SIL), and three women with cervical carcinoma (CC). In parallel, 15 women without cervical lesions were included as a Control cohort. DNA damage levels in cervical epithelial cells were assessed using the chromatin dispersion test (CDT) and controlled in parallel with DNA breakage detection coupled with florescent in situ hybridization (DBD‒FISH) using whole genomic DNA probes. RESULTS: CDT produces different morphotypes in the cervical epithelium that can be associated with the level of DNA breakage revealed with DBD‒FISH. A significant increase of DNA damage was correlated with the histological progression of the patients and human papillomavirus (HPV) infection. CONCLUSION: The CDT is a simple, accurate and inexpensive morphological bioassay to identify different levels DNA damage that can be associated with the level of abnormal cells present in the cervical epithelium in patients who commonly present HPV infection.

DBD-FISH, an effective marker for detecting genotoxicity in buccal mucosa exfoliated cells of patients with oral cancer.

Oral squamous cell carcinoma (OSCC) is characterized by increased genetic instability as an essential variable of event of neoplastic transformation. The aim of this study was to evaluate genomic instability in exfoliated cells from the buccal mucosa of patients with OSCC vs. the control group, using DNA Breakage Detection/Fluorescence In Situ hybridization (DBD-FISH). Exfoliated cells from the buccal mucosa were obtained from 38 patients with oral cancer (case group) and from 10 individuals without oral lesions (control group). DNA damage was evaluated by DBD-FISH using the whole-genome DNA probe and digital imaging analysis. Collaterally, HPV infection was determined utilizing the INNO-LiPA HPV kit. Patients with OSCC showed an increase in the hybridization signal five times more intense than that of the baseline level of DNA damage detected in control individuals. The best cutoff value for predicting oral squamous cell carcinoma was 67.46, and an Odds Ratio (OR) value of 87. HPV detection analysis revealed than one patient with OSCC (2.6%) was positive for HPV. All controls were negative HPV. In conclusion, DBD-FISH permitted the clear visualization of level high of DNA damage in the buccal epithelial cells of patients with OSSC respect to control group. Chromosome instability in oral mucosa may be an individual marker of malignant transformation in OSCC.

ADIPOQ single nucleotide polymorphisms and breast cancer in northeastern Mexican women.

BACKGROUND: Adiponectin gene (ADIPOQ) polymorphisms have been shown to affect adiponectin serum concentration and some have been associated with breast cancer (BC) risk. The aims of this study were to describe the frequency of single nucleotide polymorphisms (SNPs) of ADIPOQ in Mexican women with BC and to determine if they show an association with it. METHODS: DNA samples from 397 patients and 355 controls were tested for the ADIPOQ gene SNPs: rs2241766 (GT) and rs1501299 (GT) by TaqMan allelic discrimination assay. Hardy-Weinberg equilibrium (HWE) was tested. Multiple SNP inheritance models adjusted by age and body mass index (BMI) were examined for the SNP rs1501299. RESULTS: We found that in the frequency analysis of rs1501299 without adjusting the BMI and age, the genotype distribution had a statistically significant difference (P = 0.003). The T allele was associated with a BC risk (OR, 1.99; 95% CI 1.13-3.51, TT vs. GG; OR, 1.53; 95% CI 1.12-2.09, GT vs. GG). The SNP rs2241766 was in HW disequilibrium in controls. In conclusion, the rs1501299 polymorphism is associated with a BC risk. CONCLUSIONS: Identification of the genotype of these polymorphisms in patients with BC can contribute to integrate the risk profile in both patients and their relatives as part of a comprehensive approach and increasingly more personalized medicine.

Asociación de horas de sueño y adiposidad en niños y adolescentes del noreste de México / Association of sleep duration and adiposity in children and adolescents in northeastern Mexico

FUNDAMENTOS: Se ha identificado que el sueño es un factor de riesgo de adiposidad en la población pediátrica que procede de países de altos ingresos económicos. El objetivo de este estudio fue determinar la asociación entre horas de sueño nocturno y adiposidad mediante índice de masa corporal (IMC) y perímetro de cuello (PC) en niños y adolescentes del noreste de México, país de ingresos medios. MÉTODOS: Se realizó un análisis de regresión logística a partir de 746 escolares de 4 a 18 años de edad y se estimaron las tasas de posibilidad de riesgo de obesidad según IMC y PC frente a horas de sueño entre semana y fines de semana. RESULTADOS: El promedio de horas de sueño nocturno en preescolares fueron 9,1 (±1,2), en escolares 8,3 (±1,2) y adolescentes 6,21 (±1,0). Los factores asociados a adiposidad mediante PC fueron horas de sueño entre semana, edad, sexo masculino y roncar; para adiposidad por IMC fueron sexo masculino y roncar (p < 0,05). CONCLUSIONES: Existe asociación entre adiposidad del cuello con horas de sueño en días entre semana, no así con adiposidad mediante IMC. La medición del PC puede ser un enfoque innovador para determinar adiposidad y para intervenciones de prevención que ayuden a garantizar la duración adecuada del sueño en la población pediátrica

BACKGROUND: It has been identified that sleep is risk factor adiposity in the pediatric population who come from high income countries. The objective of this study was to determine the association between hours of nighttime sleep and adiposity using body mass index (BMI) and neck circumference (NC) in children and adolescents in northeastern Mexico, middle-income country. METHODS: A logistic regression analysis was carried out from 746 schoolchildren aged from 4 to 18 years and the obesity risk possibility rates by BMI and PC were estimated against sleep hours during the week and weekends. RESULTS: The average hours of nighttime sleep in preschoolers were 9.1 (±1.2), in schoolchildren 8.3 (±1.2) and adolescents 6.21 (±1.0). The factors associated with adiposity by NC were hours of sleep during the week, age, male sex and snoring; the factors for adiposity by BMI were male sex and snoring (p <0.05). CONCLUSIONS: There is an association between adiposity of the neck with hours of sleep on weekdays, but not with adiposity by to BMI. NC measurement can be an innovative approach to determine adiposity andfor prevention interventions that help ensure adequate sleep duration in the pediatric population

Association study in Mexican patients with thyrotoxic hypokalemic periodic paralysis.

Hypokalemic periodic paralysis type 1 (OMIM; HOKPP1) and type 2 (OMIM; HOKPP2) are diseases of the muscle characterized by episodes of painless muscle weakness, and is associated with low potassium blood levels. Hyperthyroidism has been associated with thyrotoxic periodic paralysis (TTPP) (OMIM; TTPP1 and TTPP2), and genetic susceptibility has been implicated. In the present study, the clinical and epidemiological characteristics of patients with TTPP are described, together with their association with genetic variants reported previously in other populations. A prospective and a retrospective search of the medical records of patients who attended the emergency department at the Hospital Universitario 'Dr. Jose E. Gonzalez' in Monterrey, Nuevo León, Mexico, and were diagnosed with TTPP was performed. A total of 16 gene variants in the genes MUC1, CACNA1S, KCNE3 and SCN4A, and nine ancestry informative markers (AIMs), were analysed by Multiplex TaqMan™ Open Array assay, and a genetic association study was performed. A total of 11 patients were recruited, comprising nine males and two females (age range, 19-52 years) and 64 control subjects. Only two cases (18%) had a previous diagnosis of hyperthyroidism; the rest were diagnosed subsequently with Graves' disease. Based on the analysis, two DNA variants were found to potentially confer an increased risk for TTPP: S1PR1 rs3737576 [odds ratio (OR), 4.38; 95% confidence interval (CI), 1.08-17.76] and AIM rs2330442 (OR, 4.50; 95% CI, 1.21-16.69), and one variant was suggested to be possibly associated with TTPP, namely MUC1 rs4072037 (OR, 3.08; 95% CI, 0.841-1.38). However, there were no statistically significant associations between any of the 24 DNA variants and TTPP in a population from northeast Mexico.

Multiple HPV Infections and Viral Load Association in Persistent Cervical Lesions in Mexican Women.

Persistent high-risk human papillomavirus (HR-HPV) infections play a major role in the development of invasive cervical cancer (CC), and screening for such infections is in many countries the primary method of detecting and preventing CC. HPV typing can be used for triage and risk stratification of women with atypical squamous cells of undetermined significance (ASC-US)/low-grade cervical lesions (LSIL), though the current clinical practice in Mexico is to diagnose CC or its preceding conditions mainly via histology and HR-HPV detection. Additional information regarding these HPV infections, such as viral load and co-infecting agents, might also be useful for diagnosing, predicting, and evaluating the possible consequences of the infection and of its prevention by vaccination. The goal of this follow-up hospital case study was to determine if HPV types, multiple HPV infections, and viral loads were associated with infection persistence and the cervical lesion grade. A total of 294 cervical cytology samples drawn from patients with gynecological alterations were used in this study. HPV types were identified by real-time PCR DNA analysis. A subset of HPV-positive patients was reevaluated to identify persistent infections. We identified HPV types 16, 18, and 39 as the most prevalent. One hundred five of the patients (59%) were infected with more than one type of HPV. The types of HPV associated with multiple HPV infections were 16, 18, and 39. In the follow-up samples, 38% of patients had not cleared the initially detected HPV infection, and these were considered persistent. We found here an association between multiple HPV infections and high viral loads with and infection persistence. Our findings suggest there are benefits in ascertaining viral load and multiple HPV infections status of HR-HPV infections for predicting the risk of persistence, a requirement for developing CC. These findings contribute to our understanding of HPV epidemiology and may allow screening programs to better assess the cancer-developing risks associated with individual HR-HPV infections.

Whole exome sequencing identifies multiple novel candidate genes in familial gastroschisis.

BACKGROUND: Genetic association studies for gastroschisis have highlighted several candidate variants. However, genetic basis in gastroschisis from noninvestigated heritable factors could provide new insights into the human biology for this birth defect. We aim to identify novel gastroschisis susceptibility variants by employing whole exome sequencing (WES) in a Mexican family with recurrence of gastroschisis. METHODS: We employed WES in two affected half-sisters with gastroschisis, mother, and father of the proband. Additionally, functional bioinformatics analysis was based on SVS-PhoRank and Ensembl-Variant Effect Predictor. The latter assessed the potentially deleterious effects (high, moderate, low, or modifier impact) from exome variants based on SIFT, PolyPhen, dbNSFP, Condel, LoFtool, MaxEntScan, and BLOSUM62 algorithms. The analysis was based on the Human Genome annotation, GRCh37/hg19. Candidate genes were prioritized and manually curated based on significant phenotypic relevance (SVS-PhoRank) and functional properties (Ensembl-Variant Effect Predictor). Functional enrichment analysis was performed using ToppGene Suite, including a manual curation of significant Gene Ontology (GO) biological processes from functional similarity analysis of candidate genes. RESULTS: No single gene-disrupting variant was identified. Instead, 428 heterozygous variations were identified for which SPATA17, PDE4DIP, CFAP65, ALPP, ZNF717, OR4C3, MAP2K3, TLR8, and UBE2NL were predicted as high impact in both cases, mother, and father of the proband. PLOD1, COL6A3, FGFRL1, HHIP, SGCD, RAPGEF1, PKD1, ZFHX3, BCAS3, EVPL, CEACAM5, and KLK14 were segregated among both cases and mother. Multiple interacting background modifiers may regulate gastroschisis susceptibility. These candidate genes highlight a role for development of blood vessel, circulatory system, muscle structure, epithelium, and epidermis, regulation of cell junction assembly, biological/cell adhesion, detection/response to endogenous stimulus, regulation of cytokine biosynthetic process, response to growth factor, postreplication repair/protein K63-linked ubiquitination, protein-containing complex assembly, and regulation of transcription DNA-templated. CONCLUSION: Considering the likely gene-disrupting prediction results and similar biological pattern of mechanisms, we propose a joint "multifactorial model" in gastroschisis pathogenesis.

Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico.

Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

Objetivo: Los antiplaquetarios orales son clave en la farmacoterapia moderna de las enfermedades aterotrombóticas cardiovasculares. Clopidogrel (CLO) constituye el principal tratamiento preventivo de aterotrombosis (AT). Sin embargo, se ha documentado una considerable variación interindividual en la respuesta a CLO, lo que da como resultado una terapia subóptima y mayor riesgo de efectos adversos en algunos pacientes. La enzima CYP2C19 es la isoforma CYP que activa CLO a su metabolito activo. Se han identificado varios polimorfismos de un solo nucleótido en el gen CYP2C19 como fuertes predictores de respuesta farmacológica alterada a CLO. Al menos 16 variantes se han asociado con cambios en la actividad de CYP2C19. Método: Se reclutaron un total de 102 sujetos con alto riesgo cardiovascular del noreste de México, con dosis de mantenimiento de 75 mg de CLO/día. La reactividad plaquetaria se midió con el ensayo Verify Now P2Y12, la presencia de CYP2C19*2 se identificó mediante polymerase chain reaction en tiempo real. Resultado: Los pacientes fueron clasificados por el estado metabolizador CYP2C19*2 utilizando nomenclatura consenso, como metabolizador normal (G/G), metabolizador intermedio (G/A) y metabolizador pobre (A/A), respectivamente. La frecuencia del fenotipo para CYP2C19*2 fue 74.5% (G/G), 21.6% (G/A) y 3.9% (A/A). Los sujetos con alelo A presentaron ≥235 niveles P2Y12 reaction unit, clasificándolos como metabolizadores deficientes. La prevalencia de eficacia reducida a CLO se asoció con la presencia del polimorfismo CYP2C19*2 en pacientes mexicanos. Conclusiones: La presencia del alelo CYP2C19*2 se relaciona con resistencia al efecto antiagregante plaquetario del CLO (p = 0.003).

Association of CYP2C19*2 polymorphism with clopidogrel resistance among patients with high cardiovascular risk in Northeastern Mexico / Asociación del polimorfismo CYP2C19*2 con resistencia a clopidogrel en pacientes con alto riesgo cardiovascular en el noreste de México

abstract Objective: Oral antiplatelet drugs are a key to modern pharmacotherapy in cardiovascular atherothrombotic diseases. Clopidogrel (CLO) constitutes the main preventive treatment of atherothrombosis. However, a considerable inter-individual variation in CLO response has been documented, resulting in suboptimal therapy and an increased risk of recurrent adverse effects in some patients. The enzyme CYP2C19 has been reported to be the CYP isoform that activates CLO to its active metabolite. Several single nucleotide polymorphisms in the CYP2C19 gene have been identified as strong predictors of CLO-impaired pharmacological response. At least 16 variants have been associated with changes in CYP2C19 activity. Materials and Methods: The following research was composed of a total of 102 subjects with high cardiovascular risk in the northeast of Mexico, with a maintenance dose of 75 mg of CLO per day. The platelet reactivity was measured with VerifyNow P2Y12 assay, while the presence of CYP2C19*2 was identified by real-time polymerase chain reaction. Results: Patients were categorized by CYP2C19 metabolizer status based on *2 genotypes using the common consensus star allele nomenclature as normal metabolizer (G/G), intermediate metabolizer (G/A), and poor metabolizer (A/A), respectively. The phenotype frequency for CYP2C19*2 was 74.5% (G/G), 21.6% (G/A), and 3.9% (A/A). The subjects with the A allele presented ≥235 P2Y12 reaction unit levels, classifying them how poor metabolizer. The prevalence of reduced CLO effectiveness was associated with the presence of CYP2C19*2 polymorphism among Mexican patients. Conclusion: The presence of the CYP2C19*2 allele is related to resistance to the antiplatelet effect of CLO (p = 0.003).

Resumen Objetivo: Los antiplaquetarios orales son clave en la farmacoterapia moderna de las enfermedades aterotrombóticas cardiovasculares. Clopidogrel (CLO) constituye el principal tratamiento preventivo de aterotrombosis (AT). Sin embargo, se ha documentado una considerable variación interindividual en la respuesta a CLO, lo que da como resultado una terapia subóptima y mayor riesgo de efectos adversos en algunos pacientes. La enzima CYP2C19 es la isoforma CYP que activa CLO a su metabolito activo. Se han identificado varios polimorfismos de un solo nucleótido en el gen CYP2C19 como fuertes predictores de respuesta farmacológica alterada a CLO. Al menos 16 variantes se han asociado con cambios en la actividad de CYP2C19. Método: Se reclutaron un total de 102 sujetos con alto riesgo cardiovascular del noreste de México, con dosis de mantenimiento de 75 mg de CLO/día. La reactividad plaquetaria se midió con el ensayo Verify Now P2Y12, la presencia de CYP2C19*2 se identificó mediante polymerase chain reaction en tiempo real. Resultado: Los pacientes fueron clasificados por el estado metabolizador CYP2C19*2 utilizando nomenclatura consenso, como metabolizador normal (G/G), metabolizador intermedio (G/A) y metabolizador pobre (A/A), respectivamente. La frecuencia del fenotipo para CYP2C19*2 fue 74.5% (G/G), 21.6% (G/A) y 3.9% (A/A). Los sujetos con alelo A presentaron ≥235 niveles P2Y12 reaction unit, clasificándolos como metabolizadores deficientes. La prevalencia de eficacia reducida a CLO se asoció con la presencia del polimorfismo CYP2C19*2 en pacientes mexicanos. Conclusiones: La presencia del alelo CYP2C19*2 se relaciona con resistencia al efecto antiagregante plaquetario del CLO (p = 0.003).

Genetic Variants at the rs4720169 Locus of TBX20 and the rs12921862 Locus of AXIN1 May Increase the Risk of Congenital Heart Defects in the Mexican Population: A Pilot Study.

Background: Congenital heart defects (CHDs) are the most common type of birth defects and a major cause of infant mortality. Although knowledge of genetic risk variants for CHDs is scarce, most cases of CHDs are considered to be due to multifactorial inheritance. Objective: To analyze the association of 14 single nucleotide polymorphic variants previously associated with a risk of CHDs in a Mexican population with isolated CHDs. Materials and Methods: DNA samples obtained from healthy subjects and from subjects with isolated atrial, ventricular, or atrioventricular septal defects living in Northeastern Mexico were analyzed by real time-polymerase chain reaction for allelic discrimination of genetic variants of the genes TBX1, TBX20, ASTX-18-AS1, AXIN1, MTHFR, NKX2.5, BMP4, and NFATc1. The odds ratios (ORs) for allele and genotype frequencies and inheritance models were obtained. Results: Forty-two patients and 138 controls were included. Two variants were found to confer a risk of CHDs: variant rs4720169 of TBX20 in which the OR for the heterozygous state was 1.88 (95% confidence interval [CI]: 1.12-3.14, p = 0.010), whereas the OR for the homozygous state was 3.82 (95% CI: 1.18-12.3, p = 0.010); and variant rs12921862 of AXIN1 in which the OR for the heterozygous state was 4.15 (95% CI: 2.42-7.10; p ≤ 0.001), whereas the OR for the homozygous state was 9.2 (95% CI: 1.31-64.7, p = 0.008) for allele A. Conclusion: Genetic variants of the TBX20 and AXIN1 genes confer a significantly increased risk of congenital septal heart defects in a population from Northeastern Mexico.

Morphometric analysis of the non-epithelial areas of mouse bronchioles through the normal aging process.

Aging is associated with changes in the structure and function of the lung that may increase susceptibility to chronic lung diseases. The aim of this study was the morphometric assessment of the non-epithelial areas of the bronchioles of mouse through the normal aging process. Lungs from CD1 mice at the age of 2, 6, 12, 18, or 24 months were fixed in neutral-buffered formalin and paraffin-embedded. Sections were cut, stained with Masson trichrome, and examined using a light microscope. High-resolution color images were captured using a camera linked to image analysis software to measure areas and lengths. We observed in the bronchioles through the aging process an increase of the total area, an increase of the lumen area, and a decrease of the wall area. In conclusion, our results revealed structural changes in the bronchioles of mouse through the normal aging process. These alterations are likely to contribute to development of chronic lung diseases.

Bioinformatic Analysis of Gene Variants from Gastroschisis Recurrence Identifies Multiple Novel Pathogenetic Pathways: Implication for the Closure of the Ventral Body Wall.

We investigated whether likely pathogenic variants co-segregating with gastroschisis through a family-based approach using bioinformatic analyses were implicated in body wall closure. Gene Ontology (GO)/Panther functional enrichment and protein-protein interaction analysis by String identified several biological networks of highly connected genes in UGT1A3, UGT1A4, UGT1A5, UGT1A6, UGT1A7, UGT1A8, UGT1A9, UGT1A10, AOX1, NOTCH1, HIST1H2BB, RPS3, THBS1, ADCY9, and FGFR4. SVS-PhoRank identified a dominant model in OR10G4 (also as heterozygous de novo), ITIH3, PLEKHG4B, SLC9A3, ITGA2, AOX1, and ALPP, including a recessive model in UGT1A7, UGT1A6, PER2, PTPRD, and UGT1A3. A heterozygous compound model was observed in CDYL, KDM5A, RASGRP1, MYBPC2, PDE4DIP, F5, OBSCN, and UGT1A. These genes were implicated in pathogenetic pathways involving the following GO related categories: xenobiotic, regulation of metabolic process, regulation of cell adhesion, regulation of gene expression, inflammatory response, regulation of vascular development, keratinization, left-right symmetry, epigenetic, ubiquitination, and regulation of protein synthesis. Multiple background modifiers interacting with disease-relevant pathways may regulate gastroschisis susceptibility. Based in our findings and considering the plausibility of the biological pattern of mechanisms and gene network modeling, we suggest that the gastroschisis developmental process may be the consequence of several well-orchestrated biological and molecular mechanisms which could be interacting with gastroschisis predispositions within the first ten weeks of development.

Pediatric pituitary adenomas in Northeast Mexico. A follow-up study.

PURPOSE: To review incidence, treatment and outcome of pediatric pituitary adenomas (PAs). METHODS: A follow-up study patients with the age of ≤19 years old who were treated from 1995 to 2015 in Mexico. RESULTS: Out of 1244 diagnosed PA, 43 patients were children (35 females, 8 males) with a mean age of 17.2 years. The majority were macroadenomas (70%) with prolactinomas (PRL) dominating (63%) followed by non-functioning adenomas (21%). In total, 40% were diagnosed as invasive. Growth hormone (GH) secreting adenomas, adrenocorticotropic hormone secreting and mixed GH-PRL secreting were rare. The treatment modalities were dopamine agonists and surgery. The average treatment time was 44 months with an average follow-up period of 104 months. Sixty-eight percent (27/40) of the patients had complete response after long time follow-up. Thirty-one percent did not respond to treatment whereof three patients died due to advanced disease and late intervention. The principal causes for treatment failure were treatment resistance, late intervention and poor patient compliance. CONCLUSIONS: Sixty eight percent had complete treatment response without any sign of disease, while ~31% did not respond to treatment or did not comply to follow up/treatment. Optimized early diagnose, treatment methods with early intervention, long time follow-up and with better measures for patient compliance should improve outcomes.