Down Regulation of Catsper1 Expression by Calmodulin Inhibitor (Calmidazolium): Possible Implications for Fertility.

The CatSper channel localizes exclusively in the flagella of sperm cells. The Catsper1 protein, together with three pore units, is essential for the CatSper Channel formation, which produces flagellum hyperactivation and confers sperm fertility. Catsper1 expression is dependent on Sox transcription factors, which can recognize in vitro at least three Sox binding sites on the promoter. Sox transcription factors have calmodulin-binding domains for nuclear importation. Calmodulin (CaM) is affected by the specific inhibitor calmidazolium (CMZ), which prevents the nuclear transport of Sox factors. In this work, we assess the regulation of the Catsper1 promoter in vivo by Sox factors in the murine testis and evaluate the effects of the inhibitor calmidazolium on the expression of the Casper genes, and the motility and fertility of the sperm. Catsper1 promoter has significant transcriptional activity in vivo; on the contrary, three Sox site mutants in the Catsper1 promoter reduced transcriptional activity in the testis. CaM inhibition affects Sox factor nuclear transport and has notable implications in the expression and production of Catsper1, as well as in the motility and fertility capability of sperm. The molecular mechanism described here might conform to the basis of a male contraceptive strategy acting at the transcriptional level by affecting the production of the CatSper channel, a fundamental piece of male fertility.

HLA Risk Haplotype: Insulin Deficiency in Pediatric Type 1 Diabetes.

BACKGROUND: Certain HLA class II haplotypes have long been related with the risk of developing type 1 diabetes. The presence of the HLA haplotype DRB1*04/DQA1*03/DQB1*03:02, together with specific ß-cell autoantibodies, contributes to the development and/or severity of insulin deficiency in type 1 diabetes. OBJECTIVE: To evaluate the association of HLA risk haplotype HLA-DRB1/-DQA1/-DQB1 with ß-cell function and antibody markers in recent-onset type 1 diabetes patients, their siblings, and controls. METHODS: We studied recently diagnosed type 1 diabetes pediatric patients, their siblings, and healthy controls, analyzing autoantibodies (anti-glutamic acid decarboxylase, anti-IA-2, and anti-insulin), HLA risk and protector haplotypes, and ß-cell function (plasma proinsulin, insulin and C-peptide). X2, ANOVA or Kruskal-Wallis and multiple logistic regression were used to analyze data. RESULTS: We included 46 patients, 72 siblings, and 160 controls. Prevalence of anti-tyrosine phosphatase-related islet antigen 2 and anti-glutamic acid decarboxylase antibodies was higher in patients than siblings and controls. We found risk haplotype DRB1*04/DQA1*03/DQB1*03:02 in 95.7% of patients vs. 51.87% of controls; DRB1*03:01/DQA1*05/DQB1*02 in 47.8% of patients vs. 8.12% of controls; and DRB1*14/DQA1*05/DQB1*03:01 in 2.2% of patients vs. 20.0% of controls. With DRB1*04/DQA1*03/DQB1*03:02, the prevalence of antibodies was significantly higher in patients, although not within any single group. In regression model based on insulin secretion, only anti-tyrosine phosphatase-related islet antigen 2 antibodies and age were associated with the risk haplotype. CONCLUSIONS: The DRB1*04/DQA1*03/DQB1*03:02 haplotype increased the risk for lower insulin, proinsulin, and C-peptide concentrations, suggesting an association with the severity of insulin deficiency in type 1 diabetes patients. This haplotype, added to antibody positivity, is a predictor of deficient insulin secretion in a Mexican pediatric population.

[Level of expression of gene CTSL and its correlation with natural killer T-Cells in mexican pediatric patients with recent-onset type 1 diabetes]. / Asociación de células NKT con la expresión del gen CTSL en población pediátrica mexicana con diabetes tipo 1 de reciente diagnóstico.

OBJECTIVE: To compare the level of expression of the gene CTSL and its correlation with NKT cells in patients with recent-onset type 1 diabetes (T1D), their siblings, and healthy controls. METHODS: Analytical cross-sectional design. Patients with T1D < 3 months evolution, their siblings, and healthy controls were included. Percentages and absolute numbers of NKT cells were measured with expression of the CTSL gene. RESULTS: 124 subjects: with T1D (n = 48), siblings (n = 44) and controls (n = 32) were included. HbA1c was greater and C-peptide lower in T1D than the other groups and sibling age was higher (p < 0.001). There were no differences in NKT cells between T1D (0.176 ± 0.202) and controls (0.118 ± 0.133), but the percentage was higher in siblings (0.246 ± 0.188; p = 0.002). Lower level of expression of the CTSL gene associated with both absolute number (r: 0.4607; 95% CI: -0.08425 to -0.7935; p = 0.043) and percentage of NKT cells (r: 0.4540; 95% CI: -0.0927 to -0.7903; p = 0.045) in the T1D group. CONCLUSIONS: Patients with T1D have lower percentage and absolute number of NKT cells compared to their siblings. NKT cells absolute numbers are correlated with the expression of CTSL in T1D patients.

Susceptibility to advanced age-related macular degeneration and alleles of complement factor H, complement factor B, complement component 2, complement component 3, and age-related maculopathy susceptibility 2 genes in a Mexican population.

PURPOSE: To investigate the association of age-related macular degeneration (AMD)-high risk alleles of the complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), complement component 3 (C3), and age-related maculopathy susceptibility 2 (ARMS2) genes in a Mexican population for the first time. METHODS: Genotyping was performed for the Y402H variant of CFH, for the L9H, R32Q, and K565E variants of CFB, the E318D variant of C2, the A69S variant of ARMS2, and the R102G variant of C3 in 159 Mexican mestizo patients at advanced stages of AMD, i.e., CARMS (Clinical Age-Related Maculopathy Staging System) grade 4 or 5. The frequency of these variants was also investigated in a group of 152 control subjects without AMD. Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. Allele-specific restriction enzyme digestion was used to detect the R102G polymorphism in C3. RESULTS: There were significant differences in the allelic distribution between the two groups for CFH Y402H (p=1×10(-5)), ARMS A69S (p=4×10(-7)), and CFB R32Q (p=0.01). The odds ratios (95% confidence interval) obtained for the risk alleles of these three variants were 3.8 (2.4-5.9), 3.04 (2.2-4.3), and 2.5 (1.1-5.7), respectively. Haplotype analysis including the two most significantly associated alleles (CFH Y402H and ARMS A69S) indicated that the C-T combination conferred an odds ratio (95% confidence interval) of 6.9 (3.2-14.8). The exposed attributable risk for this particular haplotype was 85.5%. CONCLUSIONS: This is the first case-control investigation of AMD-high risk alleles in a Latino population. Our results support that CFH, ARMS2, and CFB AMD-risk alleles are consistently associated with the disease, even in ethnic groups with a complex admixture of ancestral populations such as Mexican mestizos.

Favipiravir and/or nitazoxanide: a randomized, double-blind, 2×2 design, placebo-controlled trial of early therapy in COVID-19 in health workers, their household members, and patients treated at IMSS (FANTAZE).

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.

Seroprevalence of Trypanosoma cruzi in Eight Blood Banks in Mexico.

BACKGROUND: The true prevalence of Chagas disease in Mexico is unknown. However, it has been estimated that 1.1-4 million people are infected with Trypanosoma cruzi, which represents a potential risk for transmission of the disease via contaminated blood. AIM OF THE STUDY: To determine the Chagas disease seroprevalence in donors from eight blood banks in the north of Mexico City, and the northeast of the State of Mexico. STUDY DESIGN AND METHODS: Serum samples from blood donors (n = 515,038) were tested to detect the presence of anti-Trypanosoma cruzi antibodies in eight blood banks. The serologic screening test was performed in each of the blood banks. To confirm the seropositive blood donors, only two out of the eight blood banks used a test with a different principle with the aim of identifying anti-Trypanosoma cruzi antibodies. All tests were validated by the Mexican Institute for Epidemiological Diagnosis and Reference. RESULTS: One thousand two hundred and ten blood donors were seropositive for Trypanosoma cruzi, which represents a 0.23% seroprevalence (95% CI 0.22-0.25%). Of the seropositive blood donors, 97.03 % resided in the northeast area of the State of Mexico, Mexico City, and southern part of the State of Hidalgo. CONCLUSIONS: Active transmission of Chagas disease may be occurring in non-endemic regions in the northeast of the State of Mexico.

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

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 2827 Mexicans from the state of Puebla living in the city of Puebla (N = 1994) and rural communities (N = 833), to obtain information regarding allelic and haplotypic frequencies. We found that the 16 most frequent haplotypes in Puebla are all of them Native American. Admixture estimates revealed that the main genetic components in the state of Puebla are Native American (72.21 ±â€¯1.25% by ML; 63.30% of Native American haplotypes) and European (21.05 ±â€¯1.92% by ML; 23.86% of European haplotypes), and a less prominent African genetic component (6.74 ±â€¯2.20% by ML; 6.20% of African haplotypes).

Genetic diversity of HLA system in two populations from Yucatán, Mexico: Mérida and rural Yucatán.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 324 Mexicans from the state of Yucatán living in the city of Mérida (N = 192) and rural communities (N = 132), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Yucatán include 16 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Yucatán are Native American (81.54 ±â€¯4.99% by ML; 62.92% of Native American haplotypes) and European (11.50 ±â€¯15.43% by ML; 23.26% of European haplotypes), and a less prominent African genetic component (6.96 ±â€¯10.47% by ML; 5.93% of African haplotypes).

Genetic diversity of HLA system in two populations from Quintana Roo, Mexico: Cancún and rural Quintana Roo.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 98 Mexicans from the state of Quintana Roo living in the city of Cancún (N = 48) and rural communities (N = 50), to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We found that the most frequent haplotypes in Quintana Roo include ten Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in Quintana Roo are Native American (80.85 ±â€¯3.70% by ML; 60.20% of Native American haplotypes) and European (15.19 ±â€¯14.25% by ML; 26.02% of European haplotypes), and a less prominent African genetic component (3.96 ±â€¯10.75% by ML; 6.63% of African haplotypes).

Genetic diversity of HLA system in three populations from Sonora, Mexico: Ciudad Obregón, Hermosillo and rural Sonora.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 439 Mexicans from the state of Sonora living in Ciudad Obregón (N = 143), Hermosillo (N = 99), and rural communities (N = 197) to obtain information regarding allelic and haplotypic frequencies. We find that the 13 most frequent haplotypes for the state of Sonora include nine Native American, three European and one Asian haplotypes. Admixture estimates revealed that the main genetic components in the state of Sonora are European (51.25 ±â€¯2.90% by ML; 37.70% of European haplotypes) and Native American (43.35 ±â€¯2.57% by ML; 39.64% of Native American haplotypes), while the African genetic component was less apparent (5.39 ±â€¯2.54% by ML; 11.04% of African haplotypes).

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

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 81 Mexicans from the state of Campeche living in the city of Campeche (N = 34) and rural communities (N = 47), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Campeche include ten Native American, three European, one African and one Asian haplotype. Admixture estimates revealed that the main genetic components in the state of Campeche are Native American (65.56 ±â€¯0.96% by ML; 51.24% of Native American haplotypes), European (34.44 ±â€¯10.94% by ML; 30.25% of European haplotypes), and a virtually absent African genetic component (0.00 ±â€¯10.31% by ML; 9.26% of African haplotypes).

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

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 636 Mexicans from the state of Oaxaca living in the city of Oaxaca (N = 151) and rural communities (N = 485), to obtain information regarding allelic and haplotypic frequencies. We found that the 13 most frequent haplotypes in Oaxaca are all of putative Native American origin. Admixture estimates revealed that the main genetic components in the state of Oaxaca are Native American (73.12 ±â€¯2.77% by ML; 61.52% of Native American haplotypes) and European (17.36 ±â€¯2.07% by ML; 20.69% of European haplotypes), and a relatively high African genetic component (9.52 ±â€¯0.88% by ML; 8.94% of African haplotypes).

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

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 1011 Mexicans from the state of Tlaxcala residing in the city of Tlaxcala (N = 181) and rural communities (N = 830), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes in Tlaxcala are all of Native American origin. Admixture estimates revealed that the main genetic components are Native American (75.13 ±â€¯1.56% by ML; 69.24% based on of Native American haplotypes) and European (16.10 ±â€¯4.98% by ML; 19.74% of European haplotypes), with a less prominent African genetic component (8.78 ±â€¯4.09% by ML; 4.35% of African haplotypes).

Genetic diversity of HLA system in two populations from Tabasco, Mexico: Villahermosa and rural Tabasco.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 224 Mexicans from the state of Tabasco living in the city of Villahermosa (N = 82) and rural communities (N = 142), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in Tabasco include 13 Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in Tabasco are Native American (67.79 ±â€¯1.59% by ML; 56.25% of Native American haplotypes) and European (27.21 ±â€¯3.97% by ML; 29.91% of European haplotypes), and a less prominent African genetic component (5.01 ±â€¯4.42% by ML; 8.93% of African haplotypes).

Genetic diversity of HLA system in three populations from Zacatecas, Mexico: Zacatecas city, Fresnillo and rural Zacatecas.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 453 Mexicans from the state of Zacatecas living in Zacatecas city (N = 84), Fresnillo (N = 103) and rural communities (N = 266) to obtain information regarding allelic and haplotypic frequencies and their linkage disequilibrium. We find that the most frequent haplotypes for the state of Zacatecas include seven Native American most probable ancestry (A*02 ∼ B*39 ∼ DRB1*04 ∼ DQB1*03:02; A*02 ∼ B*35 ∼ DRB1*08 ∼ DQB1*04; A*24 ∼ B*39 ∼ DRB1*14 ∼ DQB1*03:01; A*02 ∼ B*35 ∼ DRB1*04 ∼ DQB1*03:02; A*24 ∼ B*35 ∼ DRB1*04 ∼ DQB1*03:02; A*68 ∼ B*35 ∼ DRB1*04 ∼ DQB1*03:02 and A*24 ∼ B*35 ∼ DRB1*08 ∼ DQB1*04) and two European MPA haplotypes (HLA ∼ A*01 ∼ B*08 ∼ DRB1*03:01 ∼ DQB1*02 and A*29 ∼ B*44 ∼ DRB1*07 ∼ DQB1*02). Admixture estimates revealed that the main genetic components in the state of Zacatecas are European (47.61 ±â€¯1.85%) and Native American (44.74 ±â€¯1.12%), while the African genetic component was less apparent (7.65 ±â€¯1.12%). Our findings provide a starting point for the study of population immunogenetics of urban and rural populations from the state of Zacatecas and add to the growing knowledge on the population genetics of Northern Mexico.

Genetic diversity of HLA system in two populations from Nayarit, Mexico: Tepic and rural Nayarit.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 161 Mexicans from the state of Nayarit living in Tepic (N = 97) and rural communities (N = 64), to obtain information regarding allelic and haplotypic frequencies. We find that the ten most frequent haplotypes found in the state of Nayarit include eight Native American and two European haplotypes. Admixture estimates revealed that the main genetic components in the state of Nayarit are Native American (50.79 ±â€¯5.03% by ML; 42.24% of Native American haplotypes) and European (37.04 ±â€¯6.21% by ML; 35.72% of European haplotypes), while African genetic component is less apparent but relatively high (12.17 ±â€¯2.50% by ML; 13.36% of African haplotypes).

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

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 104 Mexicans from the state of Colima living in the city of Colima (N = 61) and rural communities (N = 43), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes in the state of Colima include eight Native American, two European and one African haplotype. Admixture estimates revealed that the main genetic components in the state are Native American (52.74 ±â€¯3.88% by ML; 48.10% of Native American haplotypes) and European (37.52 ±â€¯8.94% by ML; 26.66% of European haplotypes), and a relatively high African genetic component (9.74 ±â€¯8.40% by ML; 11.91% of African haplotypes).

Genetic diversity of HLA system in six populations from Jalisco, Mexico: Guadalajara city, Tlajomulco, Tlaquepaque, Tonalá, Zapopan and rural Jalisco.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 2046 Mexicans from the state of Jalisco living in the city of Guadalajara (N = 1189), Tlajomulco (N = 30), Tlaquepaque (N = 39), Tonalá (N = 35), Zapopan (N = 168) and rural communities (N = 585), to obtain information regarding allelic and haplotypic frequencies. We find that the most frequent haplotypes found in the state of Jalisco include nine Native American most probable ancestry and three European haplotypes. Admixture estimates revealed that the main genetic components in the state of Jalisco are European (48.45 ±â€¯1.18% by ML; 41.66% of European haplotypes) and Native American (44.02 ±â€¯1.24% by ML; 39.86% of Native American haplotypes), while African genetic component is less apparent (7.53 ±â€¯0.30% by ML; 9.62% of African haplotypes).

Genetic diversity of HLA system in two populations from Chiapas, Mexico: Tuxtla Gutiérrez and rural Chiapas.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 173 Mexicans from the state of Chiapas living in the city of Tuxtla Gutiérrez (N = 52) and rural communities (N = 121), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in Chiapas include 12 Native American and one European haplotype. Admixture estimates revealed that the main genetic components in Chiapas are Native American (71.61 ±â€¯0.58% by ML; 53.16% of Native American haplotypes) and European (26.39 ±â€¯5.05% by ML; 25.86% of European haplotypes), and a less prominent African genetic component (2.00 ±â€¯5.20% by ML; 9.77% of African haplotypes).

Genetic diversity of HLA system in two populations from Tamaulipas, Mexico: Ciudad Victoria and rural Tamaulipas.

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) alleles by PCR-SSP based typing in 148 Mexicans from the state of Tamaulipas living in Ciudad Victoria (N = 23) and rural communities (N = 125), to obtain information regarding allelic and haplotypic frequencies. We found that the most frequent haplotypes in the state of Tamaulipas include ten Native American, three European and one African haplotypes. Admixture estimates revealed that the main genetic components in the state of Tamaulipas are Native American (54.69 ±â€¯0.93% by ML; 47.65% of Native American haplotypes) and European (34.66 ±â€¯5.62% by ML; 33.56% of European haplotypes), and a relatively high African genetic component (10.65 ±â€¯5.05% by ML; 12.42% of African haplotypes).