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The alteration of epigenetic modifications often causes cancer onset and development. In a similar way, aberrant alternative splicing may result in oncogenic products. These issues have often been individually reviewed, but there is a growing body of evidence for the interconnection of both causes of cancer. Actually, aberrant splicing may result from abnormal epigenetic signalization and epigenetic factors may be altered by alternative splicing. In this way, the interrelation between epigenetic marks and alternative splicing form the base of a triangle, while cancer may be placed at the vertex. The present review centers on the interconnections at the triangle base, i.e., between alternative splicing and epigenetic modifications, which may result in neoplastic transformations. The effects of different epigenetic factors, including DNA and histone modifications, the binding of non-coding RNAs and the alterations of chromatin organization on alternative splicing resulting in cancer are first considered. Other less-frequently considered questions, such as the epigenetic regulation of the splicing machinery, the aberrant splicing of epigenetic writers, readers and erasers, etc., are next reviewed in their connection with cancer. The knowledge of the above-mentioned relationships has allowed increasing the collection of biomarkers potentially useful as cancer diagnostic and/or prognostic tools. Finally, taking into account on one hand that epigenetic changes are reversible, and some epigenetic drugs already exist and, on the other hand, that drugs intended for reversing aberrations in alternative splicing, therapeutic possibilities for breaking the mentioned cancer-related triangle are discussed.

The objective of this study was to analyze the eco-epidemiological aspects of Leptospira seroprevalence and seroincidence, and its associated factors in two municipalities of northwest Colombia. A prospective study was performed in rural areas of Urabá, Antioquia, Colombia. The study enrolled 597 people between November-2015 and January-2016, of which 274 people were followed up one year later. Serologic testing was performed by a microscopic agglutination. The outcomes were seroprevalent and seroincident cases, and the main exposure was an outdoor occupation. A binary and mixed-effect multinomial logistic regression model was used to estimate factors associated with seroprevalent or seroincident cases of Leptospira infection. The overall Leptospira seroprevalence was 27.81% (95%CI:23.62-32.49) and the overall cumulative seroincidence for Leptospira was 14.60% (95%CI:10.33–20.23). Multivariable analysis showed that factors associated with L. interrogans serogroups seropositivity were outdoor occupation, male gender, older age, the presence of dirt soil in the household, and the presence of piglets and opossums. It also showed that factors associated with other Leptospira species serogroups were the presence of pit latrines and of turkeys. In addition, the multivariable model of seroincident cases of L. interrogans serogroups evidenced outdoor occupations, the presence of rats, and corn cultivation as risk factors. Likewise, the multivariable model for seroincident cases of other Leptospira species showed that the presence of hunting canines and cassava cultivation were risk factors. We found specific factors associated with the transmission of Leptospira serogroups contribute to the understanding of the epidemiology of Leptospira infection in rural areas of Urabá, Colombia.AUTHOR SUMMARYMore than one million cases of leptospirosis occur each year, and about 60,000 people die of the disease worldwide. Leptospirosis is a zoonotic bacterial disease imparting its heaviest burden on resource-poor populations. It is also a major cause of economic loss in farm animals causing fetal infections, abortion, stillbirths, infertility, and increased culling rate. Leptospires also contaminate surface waters and survive in mud and moist soils, facilitating transmission among hosts. This complex cycle of transmission makes the disease a suitable model for a one-health approach. This is a prospective study conducted in rural areas of Colombia aimed at identifying the factors associated with seroprevalent and seroincident Leptospira cases. In addition, the results showed that the presence of synanthropic and domestic animals, the characteristics of household materials, and individual variables were factors associated with Leptospira seropositivity. This study clarifies the epidemiology of Leptospira infection and could improve the surveillance program in Colombia, especially in rural areas.

Simple Summary The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in metastasis, but neither the mechanisms involved in this process nor the role of the different isoforms of the gene are known. Here we show that the ratio of these isoforms is related to the relapsing of the disease, and that the protein ZNF518B interacts with enzymes able to introduce epigenetic changes, which may affect the activity of many genes. We also report a list of genes affected in common by ZNF518B and by two of those related enzymes, namely, G9A and EZH2. An in-depth analysis of five of those genes revealed that ZNF518B is involved in the recruitment of the enzymes and in the deposition of the corresponding epigenetic marks. The results highlight the relevance of epigenetic changes in cancer development, and open the possibility of developing therapeutic approaches, as the introduction of epigenetic modifications is reversible. The ZNF518B gene, which is up-regulated in colorectal cancer, plays a role in cell dissemination and metastasis. It encodes a zinc-finger protein, which interacts with histone methyltransferases G9A and EZH2. The expression of the two major mRNA isoforms 1 (coding for the full protein) and 2 was quantified by RT-qPCR in a cohort of 66 patients. The effects of silencing ZNF518B on the transcriptome of DLD1 and HCT116 cells were analysed by Clariom-S assays and validated by RT-qPCR. The recruitment of methyltransferases and the presence of H3K27me3 were studied by chromatin immunoprecipitation (ChIP). The ratio (isoform 2)/(isoform 1) negatively correlated with the relapsing of disease. The study of the transcriptome of DLD1 and HCT116 cells revealed that many genes affected by silencing ZNF518B are related to cancer. After crossing these results with the list of genes affected by silencing the histone methyltransferases (retrieved in silico), five genes were selected. ChIP analysis revealed that the recruitment of EZH2 is ZNF518B-dependent in KAT2B, RGS4 and EFNA5; the level of H3K27me3 changes in accordance. G9A also binds RGS4 and PADI3 in a ZNF518B-dependent manner. The results highlight the importance of epigenetics in cancer and open a novel therapeutic possibility, as inhibition of histone methyltransferases may reverse the disease-linked histone marks.

OBJECTIVE: To validate and implement an optimized screening method for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA combining use of self-collected raw saliva samples, single-step heat-treated virus inactivation and RNA extraction, and direct RT-qPCR. METHODS: This was a three-phase study conducted in Barcelona (Spain) during June to October, 2020. The three phases were (1) analytical validation against standard RT-qPCR in saliva samples; (2) diagnostic validation against standard RT-qPCR using paired saliva-nasopharyngeal samples obtained from asymptomatic teenagers and adults in a sports academy; and (3) pilot screening of asymptomatic health workers in a tertiary hospital. RESULTS: In phase 1, the detection yield of the new method was comparable to that of standard RT-qPCR. In phase 2, the diagnostic sensitivity and specificity values in 303 self-collected saliva samples were 95.7% (95% confidence interval 79.0-99.2%) and 100.0% (95% confidence interval 98.6-100.0%), respectively. In phase 3, only 17 (0.6%) of the saliva samples self-collected by 2709 participants without supervision were invalid. The rapid analytical workflow with the new method (up to 384 batched samples could be processed in less than 2 hours) yielded 24 (0.9%) positive results in the remaining 2692 saliva samples. Paired nasopharyngeal specimens were all positive by standard RT-qPCR. CONCLUSIONS: Direct RT-qPCR on self-collected raw saliva is a simple, rapid, and accurate method with potential to be scaled up for enhanced SARS-CoV-2 community-wide screening.

Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice.

El objetivo del artículo es investigar sobre el uso de la telemedicina en Honduras. Para ello, se aplicó un instrumento de consulta y una entrevista, identificando los siguientes hallazgos: inexistencia de marco jurídico y de plataforma de registro único en salud interoperable, existencia de una marcada brecha digital; además, la participación del Gobierno y el Colegio Médico de Honduras como actores claves. Concluyendo en la necesidad de un marco jurídico, sistema único de salud y la reducción de brecha digital.

Acute pancreatitis is an inflammatory process of the pancreatic gland that may lead to dysregulation of the trans-sulfuration pathway. The aims of this work were firstly to study the methionine cycle as well as the trans-sulfuration pathway using metabolomic and proteomic approaches identifying the causes of this dysregulation in an experimental model of acute pancreatitis; and secondly to reveal the effects of S-adenosylmethionine administration on these pathways. Acute pancreatitis was induced by cerulein in mice, and a group of animals received S-adenosylmethionine treatment. Cerulein-induced acute pancreatitis rapidly caused marked depletion of methionine, S-adenosylmethionine, 5'-methylthioadenosine, cystathionine, cysteine, and glutathione levels in pancreas, but S-adenosylhomocysteine and homocysteine remained unchanged. Protein steady-state levels of S-adenosylhomocysteine-hydrolase and cystathionine gamma-lyase diminished but methylthioadenosine phosphorylase levels increased in pancreas with acute pancreatitis. Although cystathionine beta-synthase protein levels did not change with acute pancreatitis, Nos2 mRNA and protein levels were markedly up-regulated and caused tyrosine nitration of cystathionine beta-synthase in pancreas. S-adenosylmethionine administration enhanced Nos2 mRNA expression and cystathionine beta-synthase nitration and triggered homocysteine accumulation in acute pancreatitis. Furthermore, S-adenosylmethionine administration promoted enrichment of the euchromatin marker H3K4me3 in the promoters of Tnf-alpha, Il-6, and Nos2 and enhanced the mRNA up-regulation of these genes. Accordingly, S-adenosylmethionine administration increased inflammatory infiltrate and edema in pancreas with acute pancreatitis. In conclusion, tyrosine-nitration of cystathionine beta-synthase blockades the trans-sulfuration pathway in acute pancreatitis promoting homocysteine accumulation upon S-adenosylmethionine treatment. Copyright © 2019. Published by Elsevier B.V.

Artículo digital, Equine granulocytic anaplasmosis (EGA) and equine piroplasmosis (EP) are sidesases tramsitted by ticks, and affects equines in several places worldwide (1,2). EGA is caused by Anaplasma phagocytophilum, a bacteria of the Anaplasmataceae family, comprised by 4 genuses: Ehrlichia, Anaplasma, Wolbachia and Neorickettsia.all of them are obligate intracellular bacteria that replicate in small vacuoles derived from the host cell membrane. Each species may replicate inside vertebrate hosts, with the exception of Wolbachia, which has not been reported infecting mammals. Vectors for each species have been well studied, generally ticks or trematodes; however, the study of Wolbachia has not been clear due to the wide variety of invertebrate hosts where it has been found (3)., La anaplasmosis granulocítica equina (AGE) y la piroplasmosis equina (PE) son enfermedades transmitidas por garrapatas que afectan los equinos en diversos lugares del mundo (1,2). La AGE es causada por la bacteria Anaplasma phagocytophilum de la familia Anaplasmataceae, que está compuesta por 4 géneros Ehrlichia, Anaplasma, Wolbachia y Neorickettsia. La totalidad de sus miembros son bacterias intracelulares obligadas que se replican en pequeñas vacuolas derivadas de la membrana de la célula hospedera. Cada especie puede replicarse dentro hospederos vertebrados, excepto Wolbachia, de la cual no se tienen reportes de la infección en mamíferos. Los vectores para cada especie han sido bien estudiados, siendo generalmente garrapatas o tremátodos; sin embargo, el estudio de Wolbachia no ha sido claro debido a la gran variedad de hospederos invertebrados en los que se ha encontrado (3).

El estudio analiza la forma en la que el Estado implementa pol?ticas para el acceso a la educaci?n en la poblaci?n ind?gena del municipio de Nahuizalco y c?mo las instituciones educativas locales utilizan mecanismos para promover la diversidad cultural y la inclusi?n en el ?mbito educativo de los ni?os y las ni?as pertenecientes a los pueblos ind?genas de la zona; se analiza la influencia de estos aspectos en el ?mbito socioecon?mico y en la situaci?n en la que se encuentran dichos pobladores. La falta de acceso a la educaci?n de la poblaci?n ind?gena de Nahuizalco es una problem?tica que con el paso del tiempo ha impedido que estos grupos puedan desarrollarse en diversos campos dentro de la sociedad. Nahuizalco es uno de los municipios en los que se concentran parte de los pueblos ind?genas que hoy en d?a habitan en el occidente de El Salvador. La educaci?n es un ?mbito especial que no solo refleja y condensa los abusos, la discriminaci?n y marginaci?n que tradicionalmente han sufrido las poblaciones ind?genas, sino tambi?n su continua lucha por la igualdad y el respeto que siempre se les ha negado. Este estudio observa que en el actual sistema educativo de El Salvador a?n no se han dise?ado programas de ense?anza dirigidos a pueblos ind?genas. Universidad Tecnol?gica de El Salvador

Ehrlichia canis is the causative bacterium of canine monocytic ehrlichiosis (CME), a disease of global importance in veterinary and human medicine. Several studies have addressed the therapeutic efficacy of tetracycline hydrochloride and doxycycline hyclate (HD) for the treatment of CME, however the results are still controversial. Doxycycline is the treatment of choice for canine monocytic ehrlichiosis (CME), a well characterized disease that can serve as a model for research in diseases of the Rickettsial order and tick-borne zoonoses. Although the pharmacokinetics and efficacy of the treatment in the acute and subclinical CME phases have been known for decades, some results also indicate that Ehrlichia canis may persist in clinically normal dogs, even after an extensive treatment regimen. The purpose of this review is to (delve into / further investigate) the pharmacokinetics and adverse effects of doxycycline in the treatment of canine ehrlichiosis., Ehrlichia canis es la bacteria causante de la Ehrlichiosis monocítica canina (EMC), una enfermedad de importancia global en la medicina veterinaria y humana. Varios estudios han abordado la eficacia terapéutica de hidrocloruro de tetraciclina e hiclato de doxiciclina (HD) para el tratamiento de la EMC, sin embargo los resultados obtenidos siguen siendo controvertidos. La doxiciclina es el tratamiento de elección para la EMC, enfermedad bien caracterizada que puede servir como modelo para las investigaciones en el estudio de las enfermedades del orden de los Rickettsiales y las zoonosis transmitidas por garrapatas. Aunque desde décadas atrás se conoce su farmacocinética y la eficacia en el tratamiento de la EMC en fase aguda y subclínica, algunos resultados también indican que Ehrlichia canis puede persistir en perros clínicamente normales, incluso después de un amplio régimen de tratamiento. El propósito de esta revisión es hacer un acercamiento referente a la farmacocinética y los efectos adversos de la doxiciclina en el tratamiento de la EMC.

Objetive. To detect and identify Anaplasmataceae agents and piroplasms in equines from the slaughterhouse “La Rinconada” at Rionegro municipality in Antioquia. Materials and Methods. A descriptive cross-sectional study was carried out on equines selected by convenience during a period of 2015. Information about species, sex, age and origin of the animals. Whole blood was collected for DNA extraction procedure, and a PCR targeting a 360bp of Anaplasmataceae 16S ribosomal gene and 450bp of 18S ribosomal gene of Piroplasm were used for detection. PCR amplicons selected were submitted to direct sequencing for identification of hemoparasites through genetic analysis. Results. 135 equine samples from Antioquia, Cordoba y Sucre were analyzed. 78% were horses, 16% were donkeys and 6% were mules. Anaplasmataceae agents were not detected in any sample, meanwhile 13% were positive to piroplasm PCR. Sequence analysis reveals the circulation of Theileria equi in northwestern Colombia. Conclusion. This work presents the first molecular evidence of at least three genotypes of T. equi in equines of northwestern Colombia., Objetivo. Detectar e identificar agentes de la familia Anaplasmataceae y piroplasmas en equinos colombianos que llegan a la planta de beneficio La Rinconada ubicada en el municipio de Rionegro, Antioquia. Materiales y métodos. Se realizó un estudio descriptivo de corte transversal durante parte del 2015 a equinos seleccionados por conveniencia. Se recopiló información tal como especie, sexo, edad y localidad de procedencia. Se obtuvieron muestras de sangre para extracción de ADN, y se amplificó un fragmento de 360pb del gen 16S ribosomal de Anaplasmataceae y un fragmento de 450 pb del gen 18S ribosomal de piroplasmas para detección de hemoparásitos. Amplicones de PCR fueron sometidos a secuenciación para identificación de los hemoparásitos a través de análisis genético. Resultados. Se analizaron 135 equinos provenientes de los departamentos de Antioquia, Córdoba y Sucre. Un 78% eran caballos, un 16% eran asnos y un 6% eran mulas. El 100% de los animales fueron negativos para agentes de la familia Anaplasmataceae y un 13% fueron positivos para piroplasmas. Se identificó por secuenciación la circulación de Theileria equi en la zona norte de Colombia. Conclusión. Se presenta la primera evidencia molecular de al menos tres genotipos de T. equi infectando equinos del norte del país.

Chromatin remodeling seems to regulate the patterns of proinflammatory genes. Our aim was to provide new insights into the epigenetic mechanisms that control transcriptional activation of early-and late-response genes in initiation and development of severe acute pancreatitis as a model of acute inflammation. Chromatin changes were studied by chromatin immunoprecipitation analysis, nucleosome positioning, and determination of histone modifications in promoters of proinflammatory genes in vivo in the course of taurocholate-induced necrotizing pancreatitis in rats and in vitro in rat pancreatic AR42J acinar cells stimulated with taurocholate or TNF-alpha. Here we show that the upregulation of early and late inflammatory genes rely on histone acetylation associated with recruitment of histone acetyltransferase CBP. Chromatin remodeling of early genes during the inflammatory response in vivo is characterized by a rapid and transient increase in H3K14ac, H3K27ac, and H4K5ac as well as by recruitment of chromatin-remodeling complex containing BRG-1. Chromatin remodeling in late genes is characterized by a late and marked increase in histone methylation, particularly in H3K4. JNK and p38 MAPK drive the recruitment of transcription factors and the subsequent upregulation of early and late inflammatory genes, which is associated with nuclear translocation of the early gene Egr-1. In conclusion, specific and strictly ordered epigenetic markers such as histone acetylation and methylation, as well as recruitment of BRG-1-containing remodeling complex are associated with the upregulation of both early and late proinflammatory genes in acute pancreatitis. Our findings highlight the importance of epigenetic regulatory mechanisms in the control of the inflammatory cascade.

Background. The goals of the treatment of muscle injuries are to shorten the time of healing and to avoid relapses. The aim of this study was to assess the efficacy of autologous platelet-rich plasma (PRP) in the healing of muscle injuries. Materials and methods. A multicentre, randomised, double-blind, parallel, controlled clinical trial was conducted in 71 patients (81.8% males) aged 45.6 (SD=10.0) years with muscle tears in the legs and haematoma. The haematoma was evacuated in all patients. Thirty-three patients were randomised to a single dose of autologous PRP and 38 patients to simulation of PRP administration. The primary end-point was time to complete recovery of muscle injury. Secondary end-points were pain, relapses, ultrasound parameters, and adverse events. The total follow-up per patient was 12 months. Results. Time to complete recovery after the treatment was 31.63 days (SD=15.38) in the PRP group, and 38.43 days (SD=18.58) in the control group (p=0.261). Pain decreased over time in both groups without statistical differences between them. Eight patients relapsed (seven in the control group, and one in the PRP group). There were no adverse effects related to the interventions. Discussion. Autologous PRP did not significantly improve the time to healing compared to that in the control group.

Several drugs used for the treatment of colorectal cancer (CRC) are targeted at the epidermal growth factor receptor, but mutations in genes of the RAS family cause resistance to these drugs. Thus, extensive research is being carried out to counterbalance this resistance. The G13D mutation of KRAS is common in humans, and we previously reported that this mutation results in the epigenetic modification of hnRNP proteins, involved in RNA splicing. As aberrant splicing often results in oncogenicity, the present study aimed to identify the genes which show altered splicing patterns in connection with the G13D KRAS mutation. To accomplish this, we first carried out an in silico analysis of RNA-seq databases and found that the distribution of alternative splicing isoforms of genes RPL13, HSP90B1, ENO1, EPDR1 and ZNF518B was altered in human CRC cell lines carrying the G13D KRAS mutation when compared to cell lines carrying wild-type KRAS. The in silico results were experimentally validated by quantitative real-time PCR. Expression of the genes EPDR1 and ZNF518B was negligible in the Caco2, RKO and SW48 cell lines, which possess wild-type KRAS, while the HCT116, DLD1 and D-Mut1 cell lines, harbouring the G13D mutation, expressed these genes. Moreover, in both genes, the ratio of isoforms was significantly different between the parental DLD1 (+/G13D) and D-Mut1 cells, in which the wild-type allele had been knocked out. DWT7m cells also expressed both genes. These cells, derived from DLD1, have spontaneously acquired a G12D mutation in their single KRAS allele in 20% of the population. The present data suggest a relationship between KRAS mutations, particularly G13D, and the expression of the EPDR1 and ZNF518B genes and expression of their isoforms and provide enhanced understanding of the molecular mechanisms involved in the resistance of CRC cells to anti-EGF receptor therapies.