Environmental and Genetic Risk Factors in Developmental Dysplasia of the Hip for Early Detection of the Affected Population.

Diagnosis of developmental dysplasia of the hip (DDH) mostly relies on physical examination and ultrasound, and both methods are operator-dependent. Late detection can lead to complications in young adults. Current evidence supports the involvement of environmental and genetic factors, such as single nucleotide variants (SNVs). Incorporating genetic factors into diagnostic methods would be useful for implementing early detection and management of affected individuals. Our aim was to analyze environmental factors and SNVs in DDH patients. We included 287 DDH cases and 284 controls. Logistic regression demonstrated an association for sex (OR 9.85, 95% CI 5.55-17.46, p = 0.0001), family history (OR 2.4, 95% CI 1.2-4.5, p = 0.006), fetal presentation (OR 3.19, 95% CI 1.55-6.54, p = 0.002), and oligohydramnios (OR 2.74, 95%CI 1.12-6.70, p = 0.026). A model predicting the risk of DDH including these variables showed sensitivity, specificity, PPV, and NPV of 0.91, 0.53, 0.74, and 0.80 respectively. The SNV rs1800470 in TGFB1 showed an association when adjusted for covariables, OR 0.49 (95% CI 0.27-0.90), p = 0.02. When rs1800470 was included in the equation, sensitivity, specificity, PPV and NPV were 0.90, 0.61, 0.84, and 0.73, respectively. Incorporating no-operator dependent variables and SNVs in detection methods could be useful for establishing uniform clinical guidelines and optimizing health resources.

Obesity Is Associated with Oxidative Stress Markers and Antioxidant Enzyme Activity in Mexican Children.

The relationship between metabolic disorders and oxidative stress is still controversial in the child population. The present cross-sectional study aimed to analyze the associations between obesity, cardiometabolic traits, serum level of carbonylated proteins (CPs), malondialdehyde (MDA), and the enzyme activity of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) in children from Mexico City (normal weight: 120; obesity: 81). Obesity resulted in being positively associated with CAT (ß = 0.05 ± 0.01, p = 5.0 × 10-3) and GPx (ß = 0.13 ± 0.01, p = 3.7 × 10-19) enzyme activity. A significant interaction between obesity and sex was observed in MDA and SOD enzymatic activity (PMDA = 0.03; PSOD = 0.04). The associations between obesity, MDA level, and SOD enzyme activity were only significant in boys (boys: PMDA = 3.0 × 10-3; PSOD = 7.0 × 10-3; girls: p ≥ 0.79). In both children with normal weight and those with obesity, CP levels were positively associated with SOD enzyme activity (PNormal-weight = 2.2 × 10-3; PObesity = 0.03). In conclusion, in Mexican children, obesity is positively associated with CAT and GPx enzyme activity, and its associations with MDA levels and SOD enzyme activity are sex-specific. Therefore, CP level is positively related to SOD enzyme activity independently of body weight.

Electroacupuncture efficacy in diabetic polyneuropathy: Study protocol for a double-blinded randomized controlled multicenter clinical trial.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is the most common complication of type 2 diabetes mellitus (T2DM); its diagnosis and treatment are based on symptomatic improvement. However, as pharmacological therapy causes multiple adverse effects, the implementation of acupunctural techniques, such as electroacupuncture (EA) has been suggested as an alternative treatment. Nonetheless, there is a lack of scientific evidence, and its mechanisms are still unclear. We present the design and methodology of a new clinical randomized trial, that investigates the effectiveness of EA for the treatment of DPN. METHODS: This study is a four-armed, randomized, controlled, multicenter clinical trial (20-week intervention period, plus 12 weeks of follow-up after concluding intervention). A total of 48 T2DM patients with clinical signs and symptoms of DPN; and electrophysiological signs in the Nerve Conduction Study (NCS); will be treated by acupuncture specialists in outpatient units in Mexico City. Patients will be randomized in a 1:1 ratio to one of the following four groups: (a) short fibre DPN with EA, (b) short fibre DPN with sham EA, (c) axonal DPN with EA and (d) axonal DPN with sham EA treatment. The intervention will consist of 32 sessions, 20 min each, per patient over two cycles of intervention of 8 weeks each and a mid-term rest period of 4 weeks. The primary outcome will be NCS parameters, and secondary outcomes will include DPN-related symptoms and pain by Michigan Neuropathy Screening Instrument (MNSI), Michigan Diabetic Neuropathy Score (MDNS), Dolour Neuropatique Score (DN-4), Semmes-Westein monofilament, Numerical Rating Scale (NRS) for pain assessment, and the 36-item Short Form Health Survey (SF-36). To measure quality of life and improve oxidative stress, the inflammatory response; and genetic expression; will be analysed at the beginning and at the end of treatment. DISCUSSION: This study will be conducted to compare the efficacy of EA versus sham EA combined with conventional diabetic and neuropathic treatments if needed. EA may improve NCS, neuropathic pain and symptoms, oxidative stress, inflammatory response, and genetic expression, and it could be considered a potential coadjutant treatment for the management of DPN with a possible remyelinating effect. TRIAL REGISTRATION: ClinicalTrials.gov. NCT05521737 Registered on 30 August 2022. International Clinical Trials Registry Platform (ICTRP) ISRCTN97391213 Registered on 26 September 2022 [2b].

Association of the rs5186 polymorphism of the AGTR1 gene with decreased eGFR in patients with type 2 diabetes from Mexico City.

BACKGROUND: Early biomarkers search for Diabetic Kidney Disease (DKD) in patients with Type 2 Diabetes Mellitus (T2DM), as genetic markers to identify vulnerable carriers of the disease even before Glomerular Filtration Rate (GFR) decline or microalbuminuria development, has been relevant during the last few years. The rs5186 (A116C) polymorphism of the Angiotensin II Receptor Type I gene (AGTR1), has been associated to multiple effects of renal injury risk, commonly detected in patients with Diabetes Mellitus (DM). It has been described that rs5186 could have an effect in stability proteins that assemble Angiotensin II Receptor Type I (AT1), modifying its action, which is why it should be considered as a risk factor for Chronic Kidney Disease (CKD), characterized by a GFR progressive reduction. Even though, the association between rs5186 AGTR1 gene polymorphism and DKD in patients with T2DM has been controversial, inconclusive, and even absent. This disputable issue might be as a result of association studies in which many and varied clinical phenotypes included are contemplated as CKD inductors and enhancers. Although, the sample sizes studied in patients with T2DM are undersized and did not have a strict inclusion criteria, lacking of biochemical markers or KDOQI classification, which have hindered its examination. OBJECTIVE: The aim of our study was to establish an association between rs5186 AGTR1 gene polymorphism and GFR depletion, assessed as a risk factor to DKD development in patients with T2DM. METHODS: We analyzed 297 not related patients with T2DM, divided into 221 controls (KDOQI 1) and 76 cases (KDOQI 2). Arterial pressure, anthropometric and biochemical parameters were measured. rs5186 of AGTR1 genotyping was performed by TaqMan assay real-time PCR method. Allele and genotype frequencies, and Hardy-Weinberg equilibrium were measured. Normality test for data distribution was analyzed by Shapiro-Wilk test, variable comparison by Student's t-test for continuous variables, and Chi-squared test for categorical variables; ANOVA test was used for mean comparison of more than two groups. Effect of rs5186 to DKD was estimated by multiple heritability adjustment models for risk variables of DKD. Statistical significance was indicated by p<0.05. Data was analyzed using Statistical Package STATA v11 software. RESULTS: Dominant and Over-dominant models showed a likelihood ratio to GFR depletion of 1.89 (1.05-3.39, p=0.031) and 2.01 (1.08-3.73, p=0.023) in patients with T2DM. Risk factor increased to 2.54 (1.10-5.89) in women in Over-dominant model. CONCLUSION: In clinical practice, most of nephropathies progress at a slow pace into a total breakdown of renal function, even asymptomatic. This is the first study, reporting that rs5186 polymorphism of AGTR1 gene contribution to GFR depletion, and this could be evaluated as a predisposing factor for DKD in patients with T2DM.

Administration of Tamoxifen Can Regulate Changes in Gene Expression during the Acute Phase of Traumatic Spinal Cord Injury.

Traumatic spinal cord injury (SCI) causes irreversible damage leading to incapacity. Molecular mechanisms underlying SCI damage are not fully understood, preventing the development of novel therapies. Tamoxifen (TMX) has emerged as a promising therapy. Our aim was to identify transcriptome changes in the acute phase of SCI and the effect of Tamoxifen on those changes in a rat model of SCI. Four groups were considered: (1) Non-injured without TMX (Sham/TMX-), (2) Non-injured with TMX (Sham/TMX+), (3) injured without TMX (SCI/TMX-), and (4) injured with TMX (SCI/TMX+). Tamoxifen was administered intraperitoneally 30 min after injury, and spinal cord tissues were collected 24 h after injury. Clariom S Assays Array was used for transcriptome analysis. After comparing Sham/TMX- versus SCI/TMX-, 708 genes showed differential expression. The enriched pathways were the SCI pathway and pathways related to the inflammatory response. When comparing SCI/TMX- versus SCI/TMX+, only 30 genes showed differential expression, with no pathways enriched. Our results showed differential expression of genes related to the inflammatory response after SCI, and Tamoxifen seems to regulate gene expression changes in Ccr2 and Mmp12. Our study contributes data regarding the potential value of tamoxifen as a therapeutic resource for traumatic SCI during the acute phase.

Pancreatic ß-Cell Apoptosis in Normoglycemic Rats is Due to Mitochondrial Translocation of p53-Induced by the Consumption of Sugar-Sweetened Beverages.

Overstimulation of pancreatic ß-cells can lead to dysfunction and death, prior to the clinical manifestations of type 2 diabetes (T2D). The excessive consumption of carbohydrates induces metabolic alterations that can affect the functions of the ß-cells and cause their death. We analyzed the role of p53 in pancreatic ß cell death in carbohydrate-supplemented Sprague Dawley rats. For four months, the animals received drinking water containing either 40% sucrose or 40% fructose. The glucose tolerance test was performed at week 15. Apoptosis was assessed with the TUNEL assay (TdT-mediated dUTP-nick end-labeling). Bax, p53, and insulin were assessed by Western blotting, immunofluorescence, and real-time quantitative PCR. Insulin, triacylglycerol, and serum glucose and fatty acids in pancreatic tissue were measured. Carbohydrate consumption promotes apoptosis and mobilization of p53 from the cytosol to rat pancreatic ß-cell mitochondria before blood glucose rises. An increase in p53, miR-34a, and Bax mRNA was also detected (P < 0.001) in the sucrose group. As well as hypertriglyceridemia, hyperinsulinemia, glucose intolerance, insulin resistance, visceral fat accumulation, and increased pancreatic fatty acids in the sucrose group. Carbohydrate consumption increases p53 and its mobilization into ß-cell mitochondria and coincides with the increased rate of apoptosis, which occurs before serum glucose levels rise.

Unraveling the role of relative telomere length and CAG expansion on initial symptoms of juvenile Huntington disease.

BACKGROUND AND PURPOSE: Juvenile-onset Huntington disease (JHD) is defined when symptoms initiate before 20 years of age. Mechanisms explaining differences between juvenile and adult onset are not fully understood. Our aim was to analyze the distribution of initial symptoms in a cohort of JHD patients and to explore its relationship with CAG expansion and relative telomere length (RTL). METHODS: A total of 84 JHD patients and 54 neurologically healthy age and sex matched individuals were recruited. CAG length was measured by southern blot or triplet repeat primed polymerase chain reaction. RTL was measured using the Cawthon method. RESULTS: Psychiatric symptoms were most frequent when considering the entire cohort. When divided into onset before or after 10 years, cognitive symptoms were more frequent in the youngest, whilst in the older group psychiatric symptoms prevailed. Motor symptoms were rare in the youngest and epilepsy was observed only in this group as well as a larger CAG expansion. RTL analysis revealed shorter telomeres in JHD patients compared to controls. This difference is not influenced by age, initial symptoms, time of disease or CAG expansion. CONCLUSIONS: To the best of our knowledge this is the largest cohort of JHD patients reported. Psychiatric manifestations deserve special attention when JHD is suspected and epilepsy is especially important in the youngest patients. Initial symptoms seem to be influenced by CAG expansion and therefore age of onset. RTL is significantly reduced in JHD patients which can influence the characteristic neurodegeneration of JHD and contribute to the clinical discrepancy between adult and juvenile forms of Huntington disease.

miR-145, miR-92a and miR-375 Show Differential Expression in Serum from Patients with Diabetic Retinopathies.

Diabetic retinopathies are important disabling conditions. Micro-RNAs (miRNAs) are regulators of gene expression and diseases can change their expression. Our aim was to analyze the expression of miRNAs in serum and vitreous samples from patients with diabetic retinopathies. The following groups and number of individuals were included: proliferative diabetic retinopathy (PDR) (n = 16), diabetic macular edema (DME) (n = 17), and idiopathic epiretinal membrane (IEM) as non-diabetic controls (n = 23). The initial miRNA expression was explored using TaqMan low-density arrays (TLDAs) with subsequent validation through a quantitative polymerase chain reaction (qPCR). Target genes were identified through bioinformatic tools for enrichment analysis. The TLDAs revealed the following miRNAs with differential expression in terms of PDR vs. IEM: miR-320a-3p, miR-92a-3p, and miR-375-3p in the serum, with miR-541-5p and miR-223-5p in the vitreous samples. DME vs IEM: miR-486-5p, miR-145-5p, miR-197-3p, and miR-125b-5p in the serum, and miR-212-3p in vitreous samples. PDR vs. DME: miR-486-5p, miR-100-5p, miR-328-3p, miR-660-5p, and miR-145 in the serum and none in the vitreous samples. Validation was confirmed only for miR-145, miR-92a, and miR-375 in the serum. The relevant enriched pathways for these three validated miRNAs, miR-145, miR-92a, and miR-375 were the vascular endothelial growth factor and its receptor, hepatocyte growth factor receptor, epidermal growth factor, focal adhesion, and phosphoinositide 3-kinase. Our results support the involvement of miRNAs in the pathophysiology of diabetic retinopathies and reinforce their potential as biomarkers or therapeutic resources.

[Activation of endoplasmic reticulum stress sensors by metabolic disease-associated diets and COVID-19]. / Activación de sensores del estrés del retículo endoplásmico por dietas asociadas a enfermedades metabólicas y COVID-19.

The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identification of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted.

El retículo endoplásmico es un organelo abundante, dinámico y sensor de energía. Sus abundantes membranas, rugosa y lisa, se encuentran distribuidas en diferentes proporciones dependiendo del linaje y requerimiento celular. Su función es llevar a cabo la síntesis de proteínas y lípidos, y es el almacén principal de Ca2+ intracelular. La sobrecarga calórica y la glucolipotoxicidad generada por dietas hipercalóricas provoca la alteración del retículo endoplásmico, activando la respuesta a proteínas mal plegadas (UPR, Unfolded Protein Response, por sus siglas en inglés) como reacción al estrés celular relacionado con el retículo endoplásmico y cuyo objetivo es restablecer la homeostasis del organelo al disminuir el estrés oxidante, la síntesis de proteínas y la fuga de Ca2+. Sin embargo, durante un estrés crónico, la UPR induce formación de especies reactivas de oxígeno, inflamación y apoptosis, exacerbando el estado del retículo endoplásmico y propagando un efecto nocivo para los demás organelos. Es por ello que el estrés del retículo endoplásmico se ha considerado un inductor del inicio y desarrollo de enfermedades metabólicas, incluido el agravamiento de COVID-19. Hasta el momento, existen pocas estrategias para reestablecer la homeostasis del retículo endoplásmico, las cuales son dirigidas a los sensores que desencadenan la UPR. Por tanto, se justifica con urgencia la identificación de nuevos mecanismos y terapias novedosas relacionadas con mitigar el impacto del estrés del retículo endoplásmico y las complicaciones asociadas.

Activación de sensores del estrés del retículo endoplásmico por dietas asociadas a enfermedades metabólicas y COVID-19 / Activation of endoplasmic reticulum stress sensors by metabolic disease-associated diets and COVID-19

El retículo endoplásmico es un organelo abundante, dinámico y sensor de energía. Sus abundantes membranas, rugosa y lisa, se encuentran distribuidas en diferentes proporciones dependiendo del linaje y requerimiento celular. Su función es llevar a cabo la síntesis de proteínas y lípidos, y es el almacén principal de Ca2+ intracelular. La sobrecarga calórica y la glucolipotoxicidad generada por dietas hipercalóricas provoca la alteración del retículo endoplásmico, activando la respuesta a proteínas mal plegadas (UPR, Unfolded Protein Response, por sus siglas en inglés) como reacción al estrés celular relacionado con el retículo endoplásmico y cuyo objetivo es restablecer la homeostasis del organelo al disminuir el estrés oxidante, la síntesis de proteínas y la fuga de Ca2+. Sin embargo, durante un estrés crónico, la UPR induce formación de especies reactivas de oxígeno, inflamación y apoptosis, exacerbando el estado del retículo endoplásmico y propagando un efecto nocivo para los demás organelos. Es por ello que el estrés del retículo endoplásmico se ha considerado un inductor del inicio y desarrollo de enfermedades metabólicas, incluido el agravamiento de COVID-19. Hasta el momento, existen pocas estrategias para reestablecer la homeostasis del retículo endoplásmico, las cuales son dirigidas a los sensores que desencadenan la UPR. Por tanto, se justifica con urgencia la identificación de nuevos mecanismos y terapias novedosas relacionadas con mitigar el impacto del estrés del retículo endoplásmico y las complicaciones asociadas.

The endoplasmic reticulum is an abundant, dynamic and energy-sensing organelle. Its abundant membranes, rough and smooth, are distributed in different proportions depending on the cell lineage and requirement. Its function is to carry out protein and lipid synthesis, and it is the main intracellular Ca2+ store. Caloric overload and glycolipotoxicity generated by hypercaloric diets cause alteration of the endoplasmic reticulum, activating the Unfolded Protein Response (UPR) as a reaction to cellular stress related to the endoplasmic reticulum and whose objective is to restore the homeostasis of the organelle by decreasing oxidative stress, protein synthesis and Ca2+ leakage. However, during chronic stress, the UPR induces reactive oxygen species formation, inflammation and apoptosis, exacerbating the state of the endoplasmic reticulum and propagating a deleterious effect on the other organelles. This is why endoplasmic reticulum stress has been considered an inducer of the onset and development of metabolic diseases, including the aggravation of COVID-19. So far, few strategies exist to reestablish endoplasmic reticulum homeostasis, which are targeted to sensors that trigger UPR. Therefore, the identif ication of new mechanisms and novel therapies related to mitigating the impact of endoplasmic reticulum stress and associated complications is urgently warranted.

Association of MTHFR rs1801133 and homocysteine with Legg-Calvé-Perthes disease in Mexican patients.

BACKGROUND: Legg-Calvé-Perthes disease (LCPD) is the avascular osteonecrosis of the proximal femoral epiphysis. It is a rare disease of unclear etiology in children, although alterations in coagulation or the collagen gene have been described and could be associated with its etiology. Our objective was to evaluate the following alterations: COL1A1 (rs1107946, rs2412298), COL2A1 (rs121912891 and rs387106558), MTHFR rs1801133, CBS rs115742905, and PT rs1799963 and their relationship with LCPD. METHODS: DNA was obtained and genotyped by real-time PCR with TaqMan probes. Prothrombin (FII) and homocysteine (Hcy) were determined by a coagulometric method. The variables were described as mean and standard deviation or percentages, and genotypic and allelic distributions were analyzed using the Student's t-test. The Hardy-Weinberg equilibrium and OR were also used. RESULTS: We studied 23 patients with LCPD and 46 controls. We did not find any association of the MTHFR, CBS, PT, COL1A1, and COL2A1 genetic variants with LCPD. However, when adjusting the data with the Hcy values for the MTHFR C677T polymorphism, the C/C genotypes showed an association with the recessive model (p = 0.038), with susceptibility to LCPD. CONCLUSION: No association was found with the CBS, PT, COL1A1, and COL2A1 genes. Nevertheless, our results suggest a significant link between moderately elevated Hcy levels and the MTHFR C677T polymorphism in a cohort of Mexican children with LCPD.

Micronutrients of the one-carbon metabolism cycle are altered in mothers and neonates by gestational diabetes and are associated with weight, height and head circumference at birth.

While several studies have previously described the levels of one-carbon metabolism-related micronutrients in women with gestational diabetes mellitus (GDM) and their neonates, the results in these literature reports have been contradictory. We hypothesized that the concentrations of micronutrients involved in the one-carbon cycle are altered in pregnant women and their neonates by GDM, and that these changes could further modify the neonatal anthropometry. Micronutrient levels were measured in 123 pregnant women with normal glucose levels (M-ND) and their neonates (N-ND), as well as in 54 pregnant women with gestational diabetes (M-GDM) and their neonates (M-GDM). Folate and vitamin B12 levels were measured via competitive ELISA, and betaine, choline, and glycine levels were measured via ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS). Vitamin B12 and Glycine were found to be higher in M-GDM compared to M-ND. N-GDM had higher levels of folic acid and vitamin B12 and lower levels of betaine and choline compared to N-ND. In general, neonates presented with high concentrations of micronutrients compared to their mothers, and the fetus/maternal ratio of micronutrients was higher among the N-ND as compared to the N-GDM. Micronutrients were also variably associated with anthropometric measurements. The association of betaine with neonatal anthropometry in N-GDM is highlighted. In summary, our results implicate a potential role of GDM in altering the levels of one-carbon metabolism-related micronutrients among pregnant women and their neonates. Likewise, our results also elucidate a potential association between the concentrations of micronutrients and the weight, height, and head circumference of neonates.

Association of Polymorphisms in Estrogen Receptor Genes (ESR1 and ESR2) with Osteoporosis and Fracture-Involvement of Comorbidities and Epistasis.

Single-nucleotide polymorphisms (SNPs) in the ESR1/ESR2 genes play a role in osteoporosis (OP). Our objective was to determine associations of polymorphisms in ESR genes with OP and fracture, SNP-SNP interactions, and involvement of comorbidities. We analyzed 170 Mexican osteoporotic women (FNOP), 173 with hip fracture (HFx), and 210 controls. The SNPs, ESR1 rs2234693CC, rs851982CC and rs1999805AA, were associated with reduced OP risk (odds ratios [ORs] = 0.35, 0.40 and 0.32, respectively; p < 0.05); rs2234693CC was associated with reduced fracture risk (OR = 0.24; p < 0.05). The obese/overweight carriers of rs9340799GG had a lower OP (OR = 0.15, p = 0.016) and fracture (OR = 0.12, p = 0.0057) risk. The rs9479055AA and rs3020404AA hypertensive carriers had a higher OP risk (OR = 5.96, p = 0.032; and OR = 5.29, p = 0.02, respectively). In addition, rs3020404AA had a higher risk of fracture (OR = 4.90, p = 0.045). The rs2228480GG hypertensive carriers had a higher risk of fracture (OR = 6.22, p = 0.0038). We found a synergic relation between the ESR1 rs3020331 and rs1999805 in femoral neck OP and HFx. The rs2234693 (PvuII) and rs9340799 (XbaI) polymorphisms are associated with a high risk forming a haplotype. The epistasis analysis suggests the contribution of both genes (ESR1/ESR2) to the risk of OP and fracture. Epistasis and involvement of obesity and hypertension lead to a significant modification of the risk.

A proposed HLA-B*27 screening method for ankylosing spondylitis detection based on tag-single nucleotide polymorphisms: a preliminary study.

BACKGROUND: Ankylosing spondylitis (AS) is a type of inflammatory arthritis that affects primarily the spine. There is a strong association of the HLA-B*27 allele with AS pathogenesis, but recent studies have demonstrated the participation of ERAP1 gene in the genetic susceptibility. The aim of this study was to determine whether HLA-B tag-single nucleotide polymorphisms (SNPs) and ERAP1-related genetic variations associated with AS have equal or similarly performance in patients´ screening compared to HLA-B*27 standard genotyping in Mexican population. METHODS AND RESULTS: Genomic DNA from patients with AS and population-based controls from Mexico City was analyzed for five single nucleotide polymorphisms (SNPs): rs4349859, rs13202464, rs116488202, tagging HLA-B*27; and rs30187 and rs27044 in ERAP1 gene. TaqMan genotype assay method was used for SNPs genotyping. We found a significant association between AS and the heterozygote genotypes and minor alleles of the HLA-B*27 tag-SNPs, as well as for their haplotypes. With respect to ERAP1 polymorphisms, no significant associations were observed (p > 0.05). The sensitivity and specificity analysis showed values of 0.96 and 1.00 for the rs4349859 SNP, and 0.96 and 0.94 for the rs116488202 SNP, respectively, in detecting HLA-B*27 compared to the B27 test as the gold standard. CONCLUSIONS: HLA-B*27 tag-SNPs are associated with AS susceptibility; furthermore, the rs4349859 SNP by its own have an outstanding performance in detecting HLA-B*27 and therefore can be proposed as screening marker in the identification of HLA-B*27 in our population.

circRNA Regulates Dopaminergic Synapse, MAPK, and Long-term Depression Pathways in Huntington Disease.

Huntington disease (HD) is the most common neurogenetic disorder caused by expansion of the CAG repeat in the HTT gene; nevertheless, the molecular bases of the disease are not fully understood. Non-coding RNAs have demonstrated to be involved in the physiopathology of HD. However, the role of circRNAs has not been investigated. The aim of this study was to identify the circRNAs with differential expression in a murine cell line model of HD and to identify the biological pathways regulated by the differentially expressed circRNAs. CircRNA expression was analyzed through a microarray, which specifically detects circular species of RNA. The expression patterns between a murine cell line expressing mutant Huntingtin and cells expressing wild-type Huntingtin were compared. We predicted the miRNAs with binding sites for the differentially expressed circRNAs and the corresponding target genes for those miRNAs. Using the target genes, we performed a function enrichment analysis. We identified 23 circRNAs differentially expressed, 19 downregulated and four upregulated. Most of the downregulated circRNAs derive from the Rere gene. The dopaminergic synapse, MAPK, and long-term depression pathways were significantly enriched. The three identified pathways have been previously associated with the physiopathology of HD. The understanding of the circRNA-miRNA-mRNA network involved in the molecular mechanisms driving HD can lead us to identify novel biomarkers and potential therapeutic targets. To the best of our knowledge, this is the first study analyzing circRNAs in a model of Huntington disease.

A novel model to culture cells from giant cell tumor of bone using three-dimensional (3D) polycaprolactone scaffold.

Two-dimensional (2D) culture of cells from giant cell tumor of bone (GCTB) is affected by loss of the multinucleated giant cells in subsequent passages. Therefore, there is limited time to study GCTB with all its histological components in 2D culture. Here, we explored the possibility of culturing GCTB cells on a polycaprolactone (PCL)-printed scaffold. We also evaluated the viability of the cultured cells and their adherence to the PCL scaffold at day 14 days using immunofluorescence analysis with calcein, vinculin, and phalloidin. Using the histological technique with hematoxylin and eosin staining, we observed all the histological components of GCTB in this 3D model. Immunohistochemical assays with cathepsin K, p63, and receptor activator of nuclear factor (NF)-κB ligand (RANKL) yielded positive results in this construct, which allowed us to confirm that the seeded cells maintained the expression of GCTB markers. Based on these findings, we concluded that the PCL scaffold is an efficient model to culture GCTB cells, and the cell viability and adherence to the scaffold can be preserved for up to 14 days. Moreover, this model can also be used in subsequent studies to assess in vitro cell-cell interactions and antineoplastic efficacy of certain agents to establish a treatment against GCTB.

Perfect Match Genomic Landscape strategy: Refinement and customization of reference genomes.

When addressing a genomic question, having a reliable and adequate reference genome is of utmost importance. This drives the necessity to refine and customize reference genomes (RGs). Our laboratory has recently developed a strategy, the Perfect Match Genomic Landscape (PMGL), to detect variation between genomes [K. Palacios-Flores et al.Genetics 208, 1631-1641 (2018)]. The PMGL is precise and sensitive and, in contrast to most currently used algorithms, is nonstatistical in nature. Here we demonstrate the power of PMGL to refine and customize RGs. As a proof-of-concept, we refined different versions of the Saccharomyces cerevisiae RG. We applied the automatic PMGL pipeline to refine the genomes of microorganisms belonging to the three domains of life: the archaea Methanococcus maripaludis and Pyrococcus furiosus; the bacteria Escherichia coli, Staphylococcus aureus, and Bacillus subtilis; and the eukarya Schizosaccharomyces pombe, Aspergillus oryzae, and several strains of Saccharomyces paradoxus. We analyzed the reference genome of the virus SARS-CoV-2 and previously published viral genomes from patients' samples with COVID-19. We performed a mutation-accumulation experiment in E. coli and show that the PMGL strategy can detect specific mutations generated at any desired step of the whole procedure. We propose that PMGL can be used as a final step for the refinement and customization of any haploid genome, independently of the strategies and algorithms used in its assembly.

Effect of Argemone mexicana on Local Edema and LPS-Induced Neuroinflammation.

Argemone mexicana L. is a widely used plant in Mexican traditional medicine to treat inflammatory and nervous medical conditions. It has been subjected to several pharmacological and chemical studies in which acute anti-inflammatory activity is indicated. This work aimed at finding an extract and fraction with anti-inflammatory activity by means of 2-O-tetradecanoylphorbol-13-acetate (TPA)-induced auricular edema. Afterward, the extract and the fraction were tested on neuroinflammation caused by lipopolysaccharides (LPS). Treatments obtained from A. mexicana included the methanolic extract (AmMeOH), a fraction extracted with ethyl acetate (AmAcOEt), and four sub-fractions (AmF-1 to AmF-4), which were evaluated in auricular edema with the TPA assay. Both treatments with the most significant inhibitory effect were employed to test these in the LPS neuroinflammation model. AmAcOEt and AmF-3 induced a higher inhibition of edema (%), and both diminished ear inflammation when viewed under a microscope. These treatments also raised an increase in spleen, but not in brain of mice with neuroinflammation. They were able to decrease the concentration of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) in both organs. Furthermore, the accumulation of amyloid-ß (Aß) in hippocampus was not visible. AmF-3 contains the flavonoids isoquercetin, luteolin, and rutin, the former being the most concentrated.

Health of refugees and migrants from former Soviet Union countries in the Russian Federation: a narrative review.

This narrative review was conducted to synthesize and summarize available up-to-date evidence on current health status, including both non-communicable diseases and infectious diseases, of migrants and refugees from the former Soviet Union countries in the Russian Federation. Epidemiological and sociological studies with one or more determinants of the health, as well as relevant qualitative studies characterizing risk factors, well-being indicators, and lifestyles of migrants and refugees from the former Soviet Union countries in Russia published from 2004 to 2019 in Russian and English languages were included in the review. Despite significant limitations of the available research literature in the field, some patterns in migrants' health in Russia and issues that need to be addressed were identified. In particular, the syndemic epidemics of communicable and non-communicable diseases, additively increasing negative health consequences, including cardiovascular diseases and chronic digestive system diseases, high rates of sexually transmitted infections and HIV, respiratory diseases and a growing percentage of new tuberculosis cases among migrants from the former Soviet Union countries are all of great concern. Possibly, the burden of these co-occurring morbidities is linked to commonly reported issues among this population group, such as poor nutrition and living conditions, high prevalence of unskilled manual labour, non-compliance with sanitary norms, lack of basic vaccinations, lack of basic knowledge about safe sexual practices and risky sexual behaviour, low healthcare seeking behaviour and limited access to health care. Importantly, these findings may urge the government to increase efforts and promote international collaboration in combating the threat of infectious diseases. Additionally, it was found that migrants had higher levels of anxiety and post-traumatic stress disorder, and those who stayed in the receiving country 5 years or more had a higher level of somatic pathology than those whose stay was less than 5 years. In order to ensure an adequate health system response and fulfil the main Universal Health Coverage principle of "leaving no one behind", a robust monitoring system of the health status of refugees and migrants and an integrated legal framework for the standardized and more inclusive routine care for this population in Russia is urgently needed.

Single-nucleotide polymorphism rs10036727 in the SLIT3 gene is associated with osteoporosis at the femoral neck in older Mexican postmenopausal women.

AIMS: Osteoporosis (OP) remains a major public health problem worldwide. The most serious complications of this disease are fragility fractures, which increase morbidity and mortality. Management of OP represents an economic burden for health systems. Therefore, it is necessary to develop new screening strategies to identify the population at risk and implement preventive measures. We previously identified the SNPs rs3801387 in WNT16, rs7108738 in SOX6, rs10036727 in SLIT3 and rs7584262 in PKDCC as associated with bone mineral density in postmenopausal women through a genome-wide association study. The aim of this study was to validate those SNPs in two independent cohorts of non-related postmenopausal women. MATERIALS AND METHODS: We included 1160 women classifying them as normal, osteopenic or osteoporotic and a group with hip fragility fracture. Genotyping was performed using predesigned TaqMan assays. RESULTS: The variants rs10036727 and rs7108738 showed a significant association with BMD at the femoral neck. SLIT3 has been previously proposed as a potential biomarker and therapeutic resource. CONCLUSIONS: Our results provide new evidence regarding a possible involvement of SLIT3 in bone metabolisms and encourage the development of more studies in different populations to support these observations.