Detection of rotavirus and norovirus among children with acute gastroenteritis in Merida and Chihuahua cities, Mexico.

INTRODUCTION: Infantile acute gastroenteritis (AGE) is a leading cause of morbidity and mortality, particularly in developing countries. The most frequent etiological agents of viral gastroenteritis in children are adenovirus, astrovirus, rotavirus, and norovirus, the last two, leading causes. Thus, the aim of this study was to identify the presence of these two viruses in children with AGE, from two cities located in the Southeast and the Northwest regions of México. METHODOLOGY: HuNoVs were detected and characterized by RT-PCR and sequencing, while RVs were detected by RNA electrophoresis. RESULTS: The presence of RV and HuNoV was evaluated in 81 stool samples; 37 were collected between April and July 2013 from patients with acute diarrhea in Merida, and 44 were collected between January and June 2017 in Chihuahua, who attended health services. Despite vaccination, RV resulted in the predominant viruses detected, with 30.8% (25/81) positivity, while HuNoV infection was present in 8.6% (7/81) of the stool samples; GII strains were identified circulating in the Southeast, while GI strains were identified in the Northwest. Moreover, co-infections with both viruses were detected at a prevalence rate of 2.4% (2/81). CONCLUSIONS: The circulation of RV and HuNoV in the country is continuous and should be constantly monitored due to their impact on public health.

Current knowledge in the use of bacteriophages to combat infections caused by Pseudomonas aeruginosa in cystic fibrosis.

Pseudomonas aeruginosa (PA) is considered the first causal agent of morbidity and mortality in people with cystic fibrosis (CF) disease. Multi-resistant strains have emerged due to prolonged treatment with specific antibiotics, so new alternatives have been sought for their control. In this context, there is a renewed interest in therapies based on bacteriophages (phages) supported by several studies suggesting that therapy based on lytic phages and biofilm degraders may be promising for the treatment of lung infections in CF patients. However, there is little clinical data about phage studies in CF and the effectiveness and safety in patients with this disease has not been clear. Therefore, studies regarding on phage characterization, selection, and evaluation in vitro and in vivo models will provide reliable information for designing effective cocktails, either using mixed phages or in combination with antibiotics, making a great progress in clinical research. Hence, this review focuses on the most relevant and recent findings on the activity of lytic phages against PA strains isolated from CF patients and hospital environments, and discusses perspectives on the use of phage therapy on the treatment of PA in CF patients.

The metabolic phenotype of the patient influences the reduction in carotid intima-media thickness achieved following metabolic surgery.

OBJECTIVES: To determine whether metabolic phenotype is associated with the change in carotid intima-media thickness (CIMT) in patients undergoing bariatric /metabolic surgery (BMS). METHODS: We performed a case-control study of BMS candidates who had metabolically unhealthy obesity (MUO) or metabolically healthy obesity (MHO). We measured the change in CIMT during the 9 months following BMS. The plasma tumor necrosis factor-α, interleukin-1ß, adiponectin, leptin, nitric oxide (NO), vascular endothelial growth factor A (VEGF-A), and malondialdehyde concentrations were determined, adipocyte area was measured histologically, and adipose tissue area was estimated using computed tomography. RESULTS: Fifty-six patients (mean age 44.5 years, mean body mass index 44.9 kg/m2, 53% women, and 53% had MUO) were studied. Nine months following BMS, the MUO phenotype was not associated with a significant reduction in CIMT, and that of the MHO group was larger. In addition, fewer participants achieved a 10% reduction in CIMT in the MUO group. A CIMT reduction was associated with lower VEGF-A and NO in the MUO group, while that in the MHO group was associated with a higher NO concentration. CONCLUSION: The metabolic phenotype of patients may influence their change in CIMT following BMS, probably through circulating vasodilatory and pro-inflammatory molecules.

Neurological Involvement in Pediatric Patients with Acute Leukemia: A Retrospective Cohort.

Acute leukemia (AL) is an important cause of morbidity and mortality in children, and neurological manifestations (NM) are frequent. The objective of this study was to analyze neurological manifestations in children with acute leukemia from cases attended in the last five years at the Centro Médico Nacional "20 de Noviembre". METHODS: Conducting a retrospective and analytical study from 1 January 2015 to 31 December 2020 in children with AL classified according to sex, age range and AL type. Participants were grouped according the presence of NM. RESULTS: We analyzed 607 patients: 54.85% boys and 44.14% girls, with a mean age of 7.27 ± 4.54 years. When comparing groups, the NM group was significantly older (p = 0.01), and the highest prevalence was between 6 and 12 years old. ALL was predominant over the other lineages (p ≤ 0.01). The most frequent NM was CNS infiltration, seizures, headache and neuropathy. Death outcomes occurred in 18.7% of children with AML, 11.8% with ALL and 50% with MPAL (p ≤ 0.002). The NM group was associated with higher mortality during a follow-up time of 77.9 ± 49 months (44.4% vs. 8.9% deaths, NM vs. non-NM, respectively; OR = 3.3; 95% CI 2.4 to 4.6; p ≤ 0.0001). CONCLUSIONS: ALL was the most prevalent leukemia type. CNS infiltration, seizures, headache, neuropathy and PRES were the most frequent symptoms in the NM group. NM was associated with a higher mortality rate.

Neurological Manifestations in Pediatric Patients Hospitalized for COVID-19: Experiences of the National Medical Center "20 de Noviembre" in Mexico City.

COVID-19 has affected millions of children and, while it was previously considered as a respiratory disease, neurologic involvement has also been documented. The objective of this study was to identify the neurological manifestations (NMs) and the outcomes of children with COVID-19 who attended the National Medical Center "20 de Noviembre". METHODS: A retrospective cohort study of children hospitalized for COVID-19 from April 2020 to March 2021 was conducted. Clinical-demographic data were registered. Neurologic manifestations were defined as any clinical neurological expression of the central and/or peripheral nervous system that occurred during admission or hospitalization. RESULTS: In total, 46 children with a confirmed COVID-19 result, 26 (56.5%) boys and 20 (43.5%) girls with a median age of 8.9 ± 4.6 years, constituted the study population. Half of the children showed some NMs, and this group of patients concomitantly showed acute lymphoblastic leukemia (ALL, 56%), obesity (17.3%), or acute myeloblastic leukemia (AML, 4.3%). The most frequently described NMs were headache (13, 56%), encephalopathy (10, 43.47%), and epilepsy (4, 17.39%). The mortality rate in children with NMs was 21.7% and they had a higher mortality rate when compared to those without NM p ≤ 0.025. CONCLUSIONS: NMs occurred predominantly in male children aged 6 to 12 years; ALL was the most frequent comorbidity. Headache prevailed and hypoxemia, hypocalcemia, elevated ferritin, and C-reactive protein were associated with NM. Finally, NMs were a risk factor for mortality.

The high methylation level of a novel 151-bp CpG island in the ESR1 gene promoter is associated with a poor breast cancer prognosis.

BACKGROUND: The ESR1 gene suffers methylation changes in many types of cancers, including breast cancer (BC), the most frequently diagnosed cancer in women that is also present in men. Methylation at promoter A of ESR1 is the worse prognosis in terms of overall survival; thus, the early detection, prognostic, and prediction of therapy involve some methylation biomarkers. METHODS: Therefore, our study aimed to examine the methylation levels at the ESR1 gene in samples from Mexican BC patients and its possible association with menopausal status. RESULTS: We identified a novel 151-bp CpG island in the promoter A of the ESR1 gene. Interestingly, methylation levels at this CpG island in positive ERα tumors were approximately 50% less than negative ERα or control samples. Furthermore, methylation levels at ESR1 were associated with menopausal status. In postmenopausal patients, the methylation levels were 1.5-fold higher than in premenopausal patients. Finally, according to tumor malignancy, triple-negative cancer subtypes had higher ESR1 methylation levels than luminal/HER2+ or luminal A subtypes. CONCLUSIONS: Our findings suggest that methylation at this novel CpG island might be a promising prognosis marker.

Identification of adipose tissue-related predictors of the reduction in cardiovascular risk induced by metabolic surgery.

OBJECTIVES: We aimed to determine whether parameters associated with adipose tissue (adipocyte density and the circulating concentrations of markers of adipose tissue pathology) predict cardiovascular risk (CVR) modification after metabolic surgery (MS). METHODS: We performed a case-control study of patients with morbid obesity who were candidates for MS. CVR was defined using flow-mediated dilation (FMD) and carotid intima media thickness (CIMT), which were measured during the 9 months following MS. Subgroups of CVR reduction were defined using the following cut-offs: CIMT 10% and/or a two-fold increase in FMD. RESULTS: We studied 40 patients with morbid obesity (mean age 44.5 years, 75% women, mean body mass index 46.4 kg/m2) and high prevalences of the metabolically unhealthy obesity phenotype, hypertension, and diabetes mellitus. A significant reduction in CVR was associated with lower vascular endothelial growth factor-A concentration (6.20 vs. 1.59 pg/mL, respectively), low adipocyte density in visceral adipose tissue (100 vs. 80 cells/field), low infiltration with CD68+ cells (18 vs. 8 cells/field) and higher concentrations of lipid peroxidation markers and malondialdehyde (313.7 vs. 405.7 ng/mL). CONCLUSION: The characteristics of adipose tissue and the circulating concentrations of markers of adipose pathology might represent useful predictors of the reduction in CVR following MS.Clinical trial registration number: NCT0356198 (https://clinicaltrials.gov).

Enlarged adipocytes from subcutaneous vs. visceral adipose tissue differentially contribute to metabolic dysfunction and atherogenic risk of patients with obesity.

Morphological characteristics and source of adipose tissue as well as adipokines may increase cardiometabolic risk. This study aimed to explore whether adipose tissue characteristics may impact metabolic and atherogenic risks. Subcutaneous Adipose Tissue (SAT), Visceral Adipose Tissue (VAT) and peripheral blood were obtained from obese patients submitted to bariatric surgery. Adipose tissue (morphometry), plasma adiponectin, TNF-α, resistin (multiplexing) and biochemical chemistry were analyzed; as well as endothelial dysfunction (Flow Mediated Dilation, FMD) and atherogenesis (Carotid Intima Media Thickness, CIMT). Subgroups divided by adipocyte size and source were compared; as well as correlation and multivariate analysis. Sixty patients 36.6% males, aged 44 years-old, BMI 46.7 kg/m2 were included. SAT's adipocytes showed a lower range of size expandability than VAT's adipocytes. Independent from their source, larger adipocytes were associated with higher glucose, lower adiponectin and higher CIMT. Particularly, larger adipocytes from SAT were associated with higher blood pressure, lower insulin and HDL-cholesterol; and showed positive correlation with glucose, HbA1c, systolic/diastolic values, and negatively correlated with insulin and adiponectin. VAT's larger adipocytes particularly associated with lower resistin and lower FMD values. Gender and Diabetes Mellitus significantly impacted the relation of adipocyte size/source with the metabolic and atherogenic risk. Multivariable analysis suggested hypertension-resistin-HbA1c interactions associated with SAT's larger adipocytes; whereas potential insulin-adiponectin associations were observed for VAT's larger adipocytes. Adipocyte morphology and source are differentially related with cardiometabolic and atherogenic risk in population with obesity, which are potentially affected by gender and Diabetes Mellitus.

EsxA mainly contributes to the miR-155 overexpression in human monocyte-derived macrophages and potentially affect the immune mechanism of macrophages through miRNA dysregulation.

BACKGROUND/PURPOSE: Mycobacterium tuberculosis is a successful intracellular pathogen that uses multiple proteins to survive within macrophages, one of the most remarkable is the virulence factor EsxA. In this study, we evaluate the participation of EsxA in the miRNAs expression profile of human monocyte-derived macrophages (hMDM), to mapping out the contribution of this virulence factor in the miRNA profile and how these changes can influence and alter immune-related processes and pathways. METHODS: The cytotoxic effect of rEsxA on hMDM was evaluated by the neutral red assay. The evaluation of miRNA expression profile in infected and rEsxA-stimulated hMDM was done using TaqMan Low Density Assays, and in silico analyses was carried on to construct Protein-Protein Interaction network of miRNAs targets. RESULTS: miR-155 was the only miRNA upregulated consistently in hMDM infected with M. tuberculosis H37Rv or stimulated with rEsxA. In hMDM stimulated with rEsxA, we found 25 miRNA's dysregulated (8 up-regulated and 17 down-regulated). The most significant were the miR-155 and miR-622 that has been observed in the analysis carried out with two different endogenous controls (U6 snRNA and RNU44) for the normalization of expression analysis. This result suggests that rEsxA induces the deregulation of miRNAs that potentially target genes in key pathways for the infection control, like the MAPK signaling pathway, cytokines, and chemokine signaling pathways, and several connected pathways involved in mycobacterial uptake, vesicular traffic, and endosome maturation. CONCLUSION: Higher expression levels of miR-155 suggest potential roles of these miRNA in EsxA-dependent immune subversion.

Breast cancer-related single-nucleotide polymorphism and their risk contribution in Mexican women.

CONTEXT: Four single-nucleotide polymorphisms (SNPs) in Mexican patients and their association with the development of breast cancer (BC). AIMS: This work is focused on determining the association of fibroblast growth factor receptor (rs12196489), TOX3 (rs3803662), human telomerase reverse transcriptase (h TERT, rs10069690), and FTO (rs17817449) polymorphisms and BC in a cohort of Mexican women. SETTINGS AND DESIGN: The study included 56 patients with a confirmed diagnosis of BC and 83 controls. Clinical characteristics were obtained from medical records. SUBJECTS AND METHODS: Genomic DNA from the samples was obtained from lymphocytes, and the genotyping of rs12196489, rs3803662, rs10069690, and rs17817449 polymorphisms was performed by real-time polymerase chain reaction using specific TaqMan probes. Statistical analysis was assessed to evaluate the distribution of genotype frequencies between cases and controls. STATISTICAL ANALYSIS: We used the STATA Statistical Package (version 10.1; STATA Corp., College Station, TX, USA). Student's t-test, χ2 test, or Fisher's exact test was used to evaluate the distribution of genotype frequencies. RESULTS: No statistical differences in allelic and genotypic frequencies were found between patients with BC and controls for SNPs: rs1219648, rs3803662, and rs17817449. Interestingly, according to the χ2 test, a significant difference was exhibited for rs10069690 (odds ratio = 0.095; 95% confidence interval = 0.038-0.214; P < 0.001). CONCLUSIONS: The h TERT (rs10069690) polymorphism might be associated with BC in Mexican women. Nevertheless, additional studies in a larger cohort are required to confirm this association and to possibly use this polymorphism as a potential biomarker in the early diagnosis of BC.

Synthesis of Pyrrolo[3,4-b]pyridin-5-ones via Multicomponent Reactions and In Vitro-In Silico Studies Against SiHa, HeLa, and CaSki Human Cervical Carcinoma Cell Lines.

A series of 12 polysubstituted pyrrolo[3,4-b]pyridin-5-ones were synthesized via a one-pot cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/decarboxylation/dehydration) and studied in vitro using human epithelial cervical carcinoma SiHa, HeLa, and CaSki cell line cultures. Three compounds of the series exhibited significative cytotoxicity against the three cell lines, with HeLa being the most sensitive one. Then, based on these results, in silico studies by docking techniques were performed using Paclitaxel as a reference and αß-tubulin as the selected biological target. Worth highlighting is that strong hydrophobic interactions were observed between the three active molecules and the reference drug Paclitaxel, to the αß-tubulin. In consequence, it was determined that hydrophobic-aromatic moieties of bioactive compounds and Paclitaxel play a key role in making stronger interactions to the ligand-target complex. A quantitative structure activity relationship (QSAR) study revealed that the six membered rings are the most significant molecular frameworks, being present in all proposed models for the in vitro-studied cell lines. Finally, also from the docking interpretation, a ligand-based pharmacophore model is proposed in order to find further potential polyheterocyclic candidates to bind stronger to the αß-tubulin.

Papel de la adiponectina en obesidad y diabetes tipo 2 / Role of adiponectine on obesity and diabetes type 2

Resumen: La adiponectina es una hormona sensibilizadora a la insulina y antiinflamatoria secretada por el tejido adiposo que tiene un inmenso potencial como objetivo terapéutico de una multitud de enfermedades relacionadas con la obesidad, incluida la diabetes tipo 2, la aterosclerosis y las enfermedades cardiovasculares. El gen de la adiponectina se encuentra en el cromosoma 3q27, un locus de susceptibilidad para la diabetes tipo 2 y los trastornos metabólicos. El aumento de las concentraciones circulantes de adiponectina se asocia con reducción del síndrome metabólico y las reducciones son muy predictivas del riesgo de diabetes. Se han hecho grandes esfuerzos para comprender cómo pueden elevarse las concentraciones de adiponectina. El complejo procesamiento postraduccional y la secreción de adiponectina proporciona un área rica en la que puede desarrollarse la manipulación farmacológica para aumentar las concentraciones de adiponectina en humanos. Las concentraciones circulantes de adiponectina se incrementan con muchos fármacos de administración común, como las estatinas, los inhibidores de la enzima convertidora de angiotensina y las tiazolidinedionas, lo que da una oportunidad importante para conocer los mecanismos que subyacen a sus efectos. Esta revisión describe la relación que existe entre la obesidad, la diabetes tipo 2 y la adiponectina, se discuten las funciones específicas en los tejidos y las células de la adiponectina, con insistencia en la regulación de las vías de señalización de adiponectina, así como las posibles vías de señalización implicadas en la regulación metabólica.

Abstract: Adiponectin is an insulin-sensitizing and anti-inflammatory fat cell hormone that has immense potential as a therapeutic target for a multitude of obesity-associated diseases including type 2 diabetes, atherosclerosis and cardiovascular diseases. The adiponectin gene is located in chromosome 3q27, a susceptibility locus for type 2 diabetes and metabolic disorders. Increased circulating levels of adiponectin are associated with improvement in the metabolic syndrome and reductions are strongly predictive of diabetes risk. Extensive efforts have been made to understand how adiponectin levels can be elevated. The complex posttranslational processing and secretion of adiponectin provides a rich area where pharmacologic manipulation may be developed to increase adiponectin levels in humans. Circulating adiponectin levels are increased by many commonly used drugs, such as statins, angiotensin converting enzyme inhibitors, and thiazolidinediones providing an important opportunity to gain insight into the mechanisms underlying their effects. This review describes the relationship among obesity, type 2 diabetes and adiponectin, we discuss the specific functions in tissues and cells of adiponectin, with emphasis on the regulation of adiponectin signaling pathways, as well as possible pathways of signaling involved in metabolic regulation.

Neutrophil-to-lymphocyte ratio and its relation with pro-inflammatory mediators, visceral adiposity and carotid intima-media thickness in population with obesity.

BACKGROUND: Atherosclerosis represents a cardiovascular risk. Chronic inflammation is a key factor for atherogenic progression. Neutrophil-to-lymphocyte ratio (NLR) has been proposed as a novel biomarker for cardiovascular risks. We aimed to explore whether NLR was related to surrogate pro-atherogenic promoters driving atherogenic progression, as measured by carotid intima-media thickness (CIMT). STUDY DESIGN: Thirty-one patients with obesity candidates for bariatric surgery were recruited from Centro Médico Nacional "20 de Noviembre", ISSSTE, Mexico City. The results are part of the "CROP" study (NCT03561987). NLR was calculated from routine complete blood count, and its relation with plasma pro-inflammatory mediators (hsCRP, TNF-α and IL-1ß), adipokines (adiponectin and leptin), adiposity markers (visceral adipose tissue [VAT] determined from CT scan image and VAT individual adipocyte area at histological sample) and CIMT were determined. RESULTS: Neutrophil-to-lymphocyte ratio correlated with hsCRP (Spearman's r = 0.70 [95% CI 0.46 to 0.85], P < 0.01), TNF-α (r = 0.69 [0.44 to 0.84], P < 0.0001) and adiponectin (r = -0.69 [-0.84 to -0.45], P < 0.03), as well as with VAT individual adipocyte area (r = 0.64 [0.37 to 0.81], P < 0.0001) and with VAT area (r = 0.43; [0.07 to 0.68], P < 0.01). Leptin and adiponectin showed further independent association with higher NLR (multivariate regression analysis OR 7.9 [95% CI 1.1 to 56.2] P = 0.03 and 0.1 [0.01 to 1.0] P = 0.05, respectively). Moreover, NLR distribution significantly varied between subgroups divided according to progressive CIMT (P = 0.05); whereas adiponectin and VAT adipocyte area associated with CIMT > 0.9 mm (univariate analysis OR 0.1 [0.01 to 1.0] P = 0.05 and 13.1 [1.4 to 126.3] P = 0.03, respectively). CONCLUSION: Neutrophil-to-lymphocyte ratio was related to pro-inflammatory, adiposity biomarkers and progressive subclinical atherogenesis.

A recurrent de novo mutation in ATP1A3 gene in a Mexican patient with alternating hemiplegia of childhood detected by massively parallel sequencing / Mutación de novo recurrente en el gen ATP1A3 en una paciente mexicana con hemiplejia alternante de la infancia detectada por secuenciación masiva en paralelo

Abstract Background: Pediatric movement disorders represent a diagnostic challenge for pediatricians and pediatric neurologists due to their high clinical heterogeneity and shared common features. Therefore, specific diagnoses require different approaches including metabolic work-up and specific tests for frequent genetic conditions. Alternating hemiplegia of childhood (AHC) is an ultra-rare pediatric movement disorder, characterized by paroxysmal alternating hemiplegia, dystonia, and seizure-like episodes that can be misleading during the evaluation of a child with a movement disorder. Case report: We present a Mexican patient with abnormal movements referred to the Genetics clinic because of hyperammonemia and a possible organic acidemia. Our assessment did not find clinical features compatible with an inborn error of metabolism. A massively parallel sequencing approach with targeted panel sequencing was used to get a final diagnosis. A missense variant c.2839G>A (p.Gly947Arg) located at exon 21 of ATP1A3 gene was demonstrated. This variant (rs398122887) has been previously reported as de novo producing alternating hemiplegia of childhood (AHC). Conclusions: AHC is an ultra-rare syndrome presented as a movement disorder with seizure-like episodes and a unique facial phenotype. Clinicians should be aware of this combination in order to diagnose this condition in a timely manner. Massive parallel sequencing panels are emerging as the best approach to diagnose rare movement disorders and simultaneously rule out metabolic disorders and common epileptic syndromes.

Resumen Introducción: Los trastornos pediátricos del movimiento representan un reto diagnóstico para pediatras y neurólogos pediatras debido a su gran heterogeneidad clínica y características comunes compartidas. Por lo tanto, los diagnósticos específicos requieren de diferentes abordajes que incluyen la búsqueda de desórdenes metabólicos y pruebas específicas para condiciones genéticas frecuentes. La hemiplejia alternante de la infancia (AHC) es un trastorno pediátrico del movimiento poco común, caracterizado por cuadros paroxísticos de hemiplejia alternante, distonía y episodios semejantes a crisis epilépticas, que pueden resultar desorientadores durante el abordaje diagnóstico de un infante con un desorden del movimiento. Caso clínico: Presentamos una paciente mexicana con movimientos anormales referida a la Clínica de Genética por hiperamonemia y una posible acidemia orgánica. Nuestro abordaje no identificó características clínicas compatibles con un error innato del metabolismo. Se utilizó un abordaje basado en secuenciación masiva en paralelo para obtener un diagnóstico final. Se demostró una variante de sentido equivocado c.2839G>A (p.Gly947Arg) localizada en el exón 21 del gen ATP1A3. Esta variante (rs398122887) ha sido previamente reportada como de novo, ocasionando AHC. Conclusiones: La AHC es un síndrome excepcionalmente raro que se presenta con un trastorno del movimiento con cuadros semejantes a crisis epilépticas y un fenotipo facial particular. Los médicos deben ser conscientes de esta combinación con el fin de diagnosticar oportunamente esta condición. Los paneles de secuenciación masiva están emergiendo como el mejor abordaje para diagnosticar trastornos del movimiento raros y, simultáneamente, descartar trastornos metabólicos y síndromes epilépticos comunes.

A recurrent de novo mutation in ATP1A3 gene in a Mexican patient with alternating hemiplegia of childhood detected by massively parallel sequencing.

Background: Pediatric movement disorders represent a diagnostic challenge for pediatricians and pediatric neurologists due to their high clinical heterogeneity and shared common features. Therefore, specific diagnoses require different approaches including metabolic work-up and specific tests for frequent genetic conditions. Alternating hemiplegia of childhood (AHC) is an ultra-rare pediatric movement disorder, characterized by paroxysmal alternating hemiplegia, dystonia, and seizure-like episodes that can be misleading during the evaluation of a child with a movement disorder. Case report: We present a Mexican patient with abnormal movements referred to the Genetics clinic because of hyperammonemia and a possible organic acidemia. Our assessment did not find clinical features compatible with an inborn error of metabolism. A massively parallel sequencing approach with targeted panel sequencing was used to get a final diagnosis. A missense variant c.2839G>A (p.Gly947Arg) located at exon 21 of ATP1A3 gene was demonstrated. This variant (rs398122887) has been previously reported as de novo producing alternating hemiplegia of childhood (AHC). Conclusions: AHC is an ultra-rare syndrome presented as a movement disorder with seizure-like episodes and a unique facial phenotype. Clinicians should be aware of this combination in order to diagnose this condition in a timely manner. Massive parallel sequencing panels are emerging as the best approach to diagnose rare movement disorders and simultaneously rule out metabolic disorders and common epileptic syndromes.

Introducción: Los trastornos pediátricos del movimiento representan un reto diagnóstico para pediatras y neurólogos pediatras debido a su gran heterogeneidad clínica y características comunes compartidas. Por lo tanto, los diagnósticos específicos requieren de diferentes abordajes que incluyen la búsqueda de desórdenes metabólicos y pruebas específicas para condiciones genéticas frecuentes. La hemiplejia alternante de la infancia (AHC) es un trastorno pediátrico del movimiento poco común, caracterizado por cuadros paroxísticos de hemiplejia alternante, distonía y episodios semejantes a crisis epilépticas, que pueden resultar desorientadores durante el abordaje diagnóstico de un infante con un desorden del movimiento. Caso clínico: Presentamos una paciente mexicana con movimientos anormales referida a la Clínica de Genética por hiperamonemia y una posible acidemia orgánica. Nuestro abordaje no identificó características clínicas compatibles con un error innato del metabolismo. Se utilizó un abordaje basado en secuenciación masiva en paralelo para obtener un diagnóstico final. Se demostró una variante de sentido equivocado c.2839G>A (p.Gly947Arg) localizada en el exón 21 del gen ATP1A3. Esta variante (rs398122887) ha sido previamente reportada como de novo, ocasionando AHC. Conclusiones: La AHC es un síndrome excepcionalmente raro que se presenta con un trastorno del movimiento con cuadros semejantes a crisis epilépticas y un fenotipo facial particular. Los médicos deben ser conscientes de esta combinación con el fin de diagnosticar oportunamente esta condición. Los paneles de secuenciación masiva están emergiendo como el mejor abordaje para diagnosticar trastornos del movimiento raros y, simultáneamente, descartar trastornos metabólicos y síndromes epilépticos comunes.

Progressive Multifocal Leukoencephalopathy associated to treatment with natalizumab in Mexican patient Multiple Sclerosis. Case report, analysis and update.

One of the most dreaded complications in Multiple Sclerosis (MS) patients treated with natalizumab is the appearance of the Progressive Multifocal Leukoencephalopathy (PML). A 54-year-old Mexican woman diagnosed eight years before with MS, received natalizumab for the last three years. The patient developed PLM that was confirmed by clinical, radiological, blood and CSF tests. Her treatment included methylprednisolone, plasmapheresis, immunoglobulin and mirtazapine. Risks, causes, treatments, preventive measures and opportune diagnosis for these patients are analyzed in this report.

Epigenetic mechanisms in odontogenic tumors: A literature review.

OBJECTIVE: Epigenetic mechanisms, such as DNA methylation, regulate important biological processes as gene expression and it was suggested that these phenomena play important roles in the carcinogenesis and tumor biology. The aim of this review is to provide the current state of knowledge about epigenetic alterations, focusing mainly on DNA methylation, reported in odontogenic tumors. DESIGN: Literatures were searched based in the combination of the following keywords: odontogenic tumors, epigenetics, DNA methylation, histone modifications, non-coding RNA, microRNA, DNA methyltransferases. Electronic databases (Medline/PubMed, Scopus and Web of Science) were screened. RESULTS: The analysis of epigenetic alterations in different tumors has rapidly increased; however, limited information is available about epigenetic mechanisms involved in the formation of odontogenic tumors. DNA methylation is the most studied epigenetic modification in these tumors and the participation of non-coding RNA's in odontogenic tumors has been recently addressed. Differential expression of DNA methyltransferases, altered DNA methylation patterns and aberrant expression of non-coding RNA's were reported in odontogenic tumors. CONCLUSIONS: Current studies suggest epigenetics as an emerging mechanism, possibly implicated in etiopathogenesis of odontogenic tumors. Deeper understanding of the epigenetic abnormalities in these tumors could show potential applications as biomarkers or therapeutic possibilities in the future.

Pro-atherogenic mediators and subclinical atherogenesis are related to epicardial adipose tissue thickness in patients with cardiovascular risk.

Objective To evaluate the relationship between pro-atherogenic biomarkers and epicardial adipose tissue (EAT) thickness in patients with cardiovascular risk factors. Methods Plasma nitric oxide (NO), soluble intercellular adhesion molecule-1 and malondialdehyde (MDA) levels, EAT thickness, flow-mediated dilation (FMD) and carotid intima media thickness (CIMT) were determined in patients aged >18 years who were referred for echocardiography for heart ischemia or non-ischemic diseases. Cardiovascular risk factors (Framingham score [FS] ≥ 20) were weighted. Results Hypertension, dyslipidaemia and type 2 diabetes mellitus were prevalent (≥55% of 40 patients). Patients with FS ≥ 20 ( n = 21) showed significantly higher EAT and CIMT values. Globally, MDA, CIMT, age, waist circumference, high-density lipoprotein cholesterol (HDL-C) and FS were associated with EAT thickness. EAT was significantly associated with NO in patients with FS ≥ 20. Significant differences in EAT thickness were found between patients stratified by NO value, FMD, age, smoking status, dyslipidaemia, type 2 diabetes mellitus and FS. An EAT-associated atherogenic risk (CIMT ≥ 1 mm) model was statistically significant when MDA and type 2 diabetes mellitus were included. Conclusion EAT thickness was associated with MDA, CIMT, age, waist circumference, HDL-C and FS globally, but with NO only in patients with FS≥20. EAT may be used to identify vascular damage stage, possibly influenced by MDA and type 2 diabetes mellitus.

Low Proteolytic Clipping of Histone H3 in Cervical Cancer.

Chromatin in cervical cancer (CC) undergoes chemical and structural changes that alter the expression pattern of genes. Recently, a potential mechanism, which regulates gene expression at transcriptional levels is the proteolytic clipping of histone H3. However, until now this process in CC has not been reported. Using HeLa cells as a model of CC and human samples from patients with CC, we identify that the H3 cleavage was lower in CC compared with control tissue. Additionally, the histone H3 clipping was performed by serine and aspartyl proteases in HeLa cells. These results suggest that histone H3 clipping operates as part of post-translational modification system in CC.

Construction of self-replicating subgenomic dengue virus 4 (DENV4) replicon.

Dengue virus serotypes 1-4 are members of mosquito-borne flavivirus genus of Flaviviridae family that encode one long open reading frame (ORF) that is translated to a polyprotein. Both host and virally encoded proteases function in the processing of the polyprotein by co-translational and posttranslational mechanisms to yield 10 mature proteins prior to viral RNA replication. To study cis- and trans-acting factors involved in viral RNA replication, many groups [1-8] have constructed cDNAs encoding West Nile virus (WNV), DENV, or yellow fever virus reporter replicon RNAs. The replicon plasmids constructed in our laboratory for WNV [9] and the DENV4 replicon described here are arranged in the order of 5'-untranslated region (UTR), the N-terminal coding sequence of capsid (C), Renilla luciferase (Rluc) reporter gene with a translation termination codon, and an internal ribosome entry site (IRES) element from encephalomyocarditis virus (EMCV) for cap-independent translation of the downstream ORF that codes for a polyprotein precursor, CterE-NS1-NS2A-NS2B-NS3-NS4A-NS4B-NS5, followed by the 3'-UTR. In the second DENV4 replicon, the Rluc gene is fused sequentially downstream to the 20 amino acid (aa) FMDV 2A protease coding sequence, neomycin resistance gene (Neo(r)), a termination codon, and the EMCV leader followed by the same polyprotein coding sequence and 3'-UTR as in the first replicon. The first replicon is useful to study by transient transfection experiments the cis-acting elements and trans-acting factors involved in viral RNA replication. The second DENV4 replicon is used to establish a stable monkey kidney (Vero) cell line by transfection of replicon RNA and selection in the presence of the G418, an analog of neomycin. This replicon is useful for screening and identifying antiviral compounds that are potential inhibitors of viral replication.