Uncovering a novel mechanism: Butyrate induces estrogen receptor alpha activation independent of estrogen stimulation in MCF-7 breast cancer cells.

Butyrate is a promising candidate for an antitumoral drug, as it promotes cancer cell apoptosis and reduces hormone receptor activity, while promoting differentiation and proliferation in normal cells. However, the effects of low-dose butyrate on breast cancer cell cultures are unclear. We explored the impact of sub-therapeutic doses of butyrate on estrogen receptor alpha (ERα) transcriptional activity in MCF-7 cells, using RT-qPCR, Western blot, wound-healing assays, and chromatin immunoprecipitation. Our results showed that sub-therapeutic doses of sodium butyrate (0.1 - 0.2 mM) increased the transcription of ESR1, TFF1, and CSTD genes, but did not affect ERα protein levels. Moreover, we observed an increase in cell migration in wound-healing assays. ChIP assays revealed that treatment with 0.1 mM of sodium butyrate resulted in estrogen-independent recruitment of ERα at the pS2 promoter and loss of NCoR. Appropriate therapeutic dosage of butyrate is essential to avoid potential adverse effects on patients' health, especially in the case of estrogen receptor-positive breast tumors. Sub-therapeutic doses of butyrate may induce undesirable cell processes, such as migration due to low-dose butyrate-mediated ERα activation. These findings shed light on the complex effects of butyrate in breast cancer and provide insights for research in the development of antitumoral drugs.

Efecto del confinamiento por COVID-19 en la prevalencia de la enfermedad hepática esteatósica asociada a disfunción metabólica / Effect of COVID-19 lockdown on the prevalence of metabolic dysfunction-associated steatotic liver disease

Introducción. La enfermedad hepática esteatósica asociada a disfunción metabólica (MASLD) es una condición clínica frecuente, relacionada con el sobrepeso, la dislipidemia y la diabetes. Como estos factores de riesgo están a su vez asociados al sedentarismo y la ganancia de peso, se esperaría un impacto como resultado del confinamiento por COVID-19 en la prevalencia de dicha condición. Metodología. Estudio longitudinal retrospectivo en un panel de datos de 132 pacientes de 2017 a 2022, en donde fueron incluidos pacientes con una ecografía hepática y una valoración médica y paraclínica 1,5 años antes y después del periodo de confinamiento (25 de marzo de 2020 a 28 de febrero de 2021). El desenlace primario fue un cambio significativo en la prevalencia de la MASLD, y se utilizó un modelo exploratorio de regresión logística de efectos fijos con panel de datos para hallar los predictores de cambio. Resultados. En un total de 132 pacientes analizados, la prevalencia global de la MASLD antes (31 %; IC95%: 23-39) y después (35,6 %; IC95%: 27,4-43,8) del confinamiento por COVID-19 no cambió significativamente, sin embargo, en las mujeres sí hubo un aumento significativo (RR: 4; IC95%: 1,0004-16). Se encontró una marcada diferencia de prevalencia entre sexos (17 % en mujeres y 46 % en hombres; p=0,001). El confinamiento se asoció a incrementos en la masa corporal (diferencia: +1 kg; IC95%: 0,1-1,9), el colesterol LDL (diferencia: +9,7 mg/dL; IC95%: 4,9-14,4) y al diagnóstico de prediabetes (RR: 2,1; IC95%: 1,4-3,1). La MASLD se asoció positivamente a la preferencia nutricional por la comida rápida (p=0,047). Solo el índice de masa corporal resultó predictor independiente de MASLD (RR: 1,49; IC95%: 1,07-1,93). Conclusión. La prevalencia global de la MASLD no varió después del confinamiento por COVID-19, pero sí se incrementó en mujeres, y algunos de sus factores de riesgo también aumentaron significativamente. Se encontró equivalencia numérica entre la MASLD y la definición previa de la enfermedad. Se requiere un estudio local más grande para desarrollar y validar un mejor modelo predictor del cambio de la MASLD a través del tiempo.

Introduction. Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common clinical condition, related to overweight, dyslipidemia and diabetes. As these risk factors are in turn associated with sedentary lifestyle and weight gain, an impact as a result of the COVID-19 confinement on the prevalence of MASLD would be expected. Methodology. Retrospective longitudinal study in a data panel of 132 patients from 2017 to 2022. Patients with a liver ultrasound and a medical and paraclinical assessment 1.5 years before and after the confinement period (March 25, 2020 to February 28, 2021) were included. The primary outcome was a significant change in the prevalence of MASLD, and an exploratory fixed-effects logistic regression model with panel data was used to find predictors of change. Results. In a total of 132 patients analyzed, the overall prevalence of MASLD before (31%, 95%CI: 23-39) and after (35.6%, 95%CI: 27.4-43.8) confinement by COVID-19 did not change significantly, however, in women there was a significant increase (RR: 4, 95%CI: 1.0004-16). A marked difference in prevalence was found between sexes (17% in women and 46% in men; p=0.001). Confinement was associated with increases in body mass (difference: +1 kg, 95%CI: 0.1-1.9), LDL cholesterol (difference: +9.7 mg/dL, 95%CI: 4.9-14.4) and the diagnosis of prediabetes (RR: 2.1, 95%CI: 1.4-3.1). MASLD was positively associated with nutritional preference for fast food (p=0.047). Only body mass index was an independent predictor of MASLD (RR: 1.49, 95%CI: 1.07-1.93). Conclusion. The overall prevalence of MASLD did not change after the COVID-19 lockdown, but it did increase in women, and some of its risk factors also increased significantly. Numerical equivalence was found between MASLD and the previous definition of the disease. A larger local study is required to develop and validate a better predictor model of MASLD change over time.

Iatrogenic Endometriosis of the Breast Mimicking Fat Necrosis: A Case Report.

A female patient with a history of ductal carcinoma in situ in the left breast, status-post bilateral mastectomy with deep inferior epigastric perforator artery flap reconstructive surgery, presented with a right breast asymmetry concerning for fat necrosis. Histological analysis revealed the presence of benign glands and associated stroma within fibroadipose tissue, confirmed as endometriosis by immunohistochemical analysis. Further investigation revealed that the patient had a previous diagnosis of endometriosis associated with a cesarean section scar that likely seeded the ectopic endometrial glands into a tertiary site by utilizing abdominal tissue that may have harbored endometriosis.

Occurrence Prediction of Riffle Beetles (Coleoptera: Elmidae) in a Tropical Andean Basin of Ecuador Using Species Distribution Models.

Genera and species of Elmidae (riffle beetles) are sensitive to water pollution; however, in tropical freshwater ecosystems, their requirements regarding environmental factors need to be investigated. Species distribution models (SDMs) were established for five elmid genera in the Paute river basin (southern Ecuador) using the Random Forest (RF) algorithm considering environmental variables, i.e., meteorology, land use, hydrology, and topography. Each RF-based model was trained and optimised using cross-validation. Environmental variables that explained most of the Elmidae spatial variability were land use (i.e., riparian vegetation alteration and presence/absence of canopy), precipitation, and topography, mainly elevation and slope. The highest probability of occurrence for elmids genera was predicted in streams located within well-preserved zones. Moreover, specific ecological niches were spatially predicted for each genus. Macrelmis was predicted in the lower and forested areas, with high precipitation levels, towards the Amazon basin. Austrelmis was predicted to be in the upper parts of the basin, i.e., páramo ecosystems, with an excellent level of conservation of their riparian ecosystems. Austrolimnius and Heterelmis were also predicted in the upper parts of the basin but in more widespread elevation ranges, in the Heterelmis case, and even in some areas with a medium level of anthropisation. Neoelmis was predicted to be in the mid-region of the study basin in high altitudinal streams with a high degree of meandering. The main findings of this research are likely to contribute significantly to local conservation and restoration efforts being implemented in the study basin and could be extrapolated to similar eco-hydrological systems.

Regional moderate hyperthermia for mild-to-moderate COVID-19 (TherMoCoV study): a randomized controlled trial.

Background: To prevent COVID-19 progression, low-cost alternatives that are available to all patients are needed. Diverse forms of thermotherapy have been proposed to prevent progression to severe/critical COVID-19. Objective: The aim of this study is to evaluate the efficacy and safety of local thermotherapy to prevent disease progression in hospitalized adult patients with mild-to-moderate COVID-19. Methods: A multicenter, open-label, parallel-group, randomized, adaptive trial is used to evaluate the efficacy and safety of local thermotherapy to prevent disease progression in hospitalized adult patients with mild-to-moderate COVID-19. Eligible hospitalized adult patients with symptoms of COVID-19 with ≤5 days from symptom onset, meeting criteria for mild or moderate COVID-19, were randomly assigned to the intervention consisting of local thermotherapy via an electric heat pad in the thorax (target temperature range 39.5­42°C) continuously for 90 min, twice daily, for 5 days, or standard care. The main outcome was the proportion of patients who progressed to severe-to-critical COVID-19 or death. Patients were randomized in a 1:1 ratio through a centralized computer-generated sequence of minimization with a random component of 20%. Participants and medical staff were not blinded to the intervention. Results: One-hundred and five participants (thermotherapy n = 54, control n = 51) with a median age of 53 (IQR: 41­64) years were included for analysis after the early cessation of recruitment due to the closure of all temporal COVID-19 units (target sample size = 274). The primary outcome of disease progression occurred in 31.4% (16/51) of patients in the control group vs. 25.9% (14/54) of those receiving thermotherapy (risk difference = 5.5%; 95%CI: −11.8­22.7, p = 0.54). Thermotherapy was well tolerated with a median total duration of thermotherapy of 900 (IQR: 877.5­900) min. Seven (13.7%) patients in the control group and seven (12.9%) in the thermotherapy group had at least one AE (p = 0.9), none of which were causally attributed to the intervention. No statistically significant differences in serum cytokines (IL-1ß, IL-6, IL-8, IL-10, IL-17, and IFN-γ) were observed between day 5 and baseline among groups. Conclusion: Local thermotherapy was safe and well-tolerated. A non-statistically significant lower proportion of patients who experienced disease progression was found in the thermotherapy group compared to standard care. Local thermotherapy could be further studied as a strategy to prevent disease progression in ambulatory settings.Clinical Trial registration: www.clinicaltrials.gov, identifier: NCT04363541.

A Simplified Correlation Index for Fast Real-Time Pulse Shape Recognition.

A simplified correlation index is proposed to be used in real-time pulse shape recognition systems. This index is similar to the classic Pearson's correlation coefficient, but it can be efficiently implemented in FPGA devices with far fewer logic resources and excellent performance. Numerical simulations with synthetic data and comparisons with the Pearson's correlation show the suitability of the proposed index in applications such as the discrimination and counting of pulses with a predefined shape. Superior performance is evident in signal-to-noise ratio scenarios close to unity. FPGA implementation of Person's method and the proposed correlation index have been successfully tested and the main results are summarized.

Nutritional status of pediatric patients living with human immunodeficiency virus in Bogotá, Colombia / Nutritional status in children with HIV

Abstract Background: Undernutrition is frequent among children living with HIV in developing countries. An interaction between malnutrition and HIV pediatric infection remains incompletely characterized in Colombia. Methodology: Retrospective longitudinal study, descriptive in nature, in 28 patients with a diagnosis of HIV infection, less than 18 years of age and receiving anti retroviral therapy. Variables were retrieved from clinical records at start of antiretroviral therapy and after 12 months. Statistical analysis was exploratory. Results: 4 out of 28 patients were stunted (14,3%; 95%CI: 1,3 - 27,2), 2 out of 7 patients were wasted (28,6%; 95%CI: 0 - 62), 5 out of 17 patients were underweight (27,8%; 95%CI: 7,1 - 48,5) and 4 out of 28 patients had thinness (29,6%; 95%CI: 12,4 - 46,8). No clinically relevant anthropometric change was detected during follow-up. Anemia prevalence was 52% and 82% of patients had some degree of dyslipidemia. Both viral load (p=0,001) and CD4 count (p=0,01), significantly increased and the proportion of patients with therapeutic failure remained invariable during follow-up. Conclusion: Malnutrition is frequent and its prevalence might have decreased. HIV program improved medical control of the disease, with stable therapeutic failure rates that were comparable with previous reports. Nonetheless, anemia and dyslipidemia remain to be a paramount therapeutic challenge.

Resumen Introducción: La desnutrición es frecuente en niños con VIH en países en desarrollo. En Colombia, la interacción entre la desnutrición y la infección pediátrica por VIH se encuentra insuficientemente caracterizada. Metodología: Estudio longitudinal retrospectivo de carácter descriptivo, en 28 pacientes con diagnóstico de infección por VIH, edad menor a 18 años y con terapia antirretroviral en curso. Se extrajeron variables mediante revisión de historias clínicas en el momento de inicio de la terapia antirretroviral y 12 meses después. El análisis estadístico fue exploratorio. Resultados: 4 de 28 pacientes sufrían retraso del crecimiento (14,3%; IC95%: 1,3 - 27,2), 2 de 7 pacientes sufrían emaciación (28,6%; IC95%: 0 - 62), 5 de 17 pacientes sufrían insuficiencia ponderal (27,8%; IC95%: 7,1 - 48,5) y 4 de 28 pacientes se encontraban en delgadez (29,6%; IC95%: 12,4 - 46,8). No hubo cambios antropométricos clínicamente relevantes con el seguimiento. La prevalencia de anemia fue del 52% y 82% de los pacientes tenían algún grado de dislipidemia. Tanto la carga viral (p=0,001) como el conteo de CD4 (p=0,01), mejoraron significativamente y la proporción de pacientes con fallo terapéutico no cambió durante el seguimiento. Conclusión: La desnutrición es frecuente y su prevalencia podría haber disminuido. El programa de VIH mejoró el control médico de la enfermedad, con tasas de fallo terapéutico estables y comparables con reportes previos. No obstante, la anemia y la dislipidemia continúan siendo un gran reto terapéutico.

Síndrome de cauda equina posterior a la administración por vía subaracnoidea de bupivacaina hiperbárica al 0, 75 % / Cauda equina syndrome following subarachnoid administration of hyperbaric bupivacaine 0. 75 %

El síndrome de cauda equina es una patología poco frecuente en el área de anestesiología. Esta se caracteriza por presentar un conjunto de signos y síntomas que involucran: dolor, disminución o abolición de la fuerza muscular, disfunción de esfínteres e hipoestesia de silla de montar. El objetivo del presente trabajo es presentar y discutir el caso clínico de una paciente con diagnóstico de síndrome de cauda equina posterior a la administración por vía subaracnoidea de bupivacaina al 0,75 % hiperbárica. Se trata de paciente femenina de 42 años a quien se le realizó cesárea segmentaria y salpingectomia bilateral con bloqueo anestésico subaracnoideo; y quien posteriormente a las dieciséis horas del posoperatorio presentó: disminución de la fuerza muscular de miembros inferiores e hipoestesia de región de silla de montar, reflejo rotuliano: 0/4 bilateral y retención urinaria. Se le inicia tratamiento farmacológico y fisiátrico inmediatamente establecido el diagnóstico de síndrome de cauda equina. La paciente fue dada de alta el día diez del posoperatorio, con disminución significativa de la clínica antes descrita, evidenciándose posteriormente retención urinaria por lo que requirió sondaje vesical intermitente. Una vez establecido el diagnostico se instaló inmediatamente tratamiento farmacológico y fisiátrico para dar una oportuna resolución de la patología(AU)

Cauda equina syndrome is a rare pathology in the area of anesthesiology. This is characterized by presenting a set of signs and symptoms that involve: pain, decrease or abolition of muscle strength, sphincter dysfunction and saddle hypoesthesia. The objective of this work is to present and discuss the clinical case of a patient with a diagnosis of cauda equina syndrome after the administration of hyperbaric 0.75% bupivacaine via the subarachnoid route. This is a 42-year-old female patient who underwent segmental cesarean section and bilateral salpingectomy with subarachnoid anesthetic block; and who subsequently at sixteen hours postoperatively presented: decreased muscle strength, lower limbs and hypoesthesia of the saddle region, knee jerk reflex: bilateral 0/4 and urinary retention. Pharmacological and physical treatment was started immediately, the diagnosis of cauda equina syndrome was established. The patient was discharged on postoperative day 10, with a significant decrease in the symptoms described above, later evidence of urinary retention, requiring intermittent bladder catheterization. Once the diagnosis was established, pharmacological and physiatric treatment was immediately installed to give a timely resolution of the pathology(AU)

Diseño de un dispositivo de asistencia ventilatoria temporal de lazo cerrado basado en bolsa válvula-mascarilla / Design of a closed-loop temporary ventilation assistance device based on bag valve mask

Desde inicios del 2020, el mundo se ha visto afectado por la COVID-19 causada por el SARS-CoV-2, que en agosto lo padecen más de 31 millones de pacientes, algunos de los cuales presentan el síndrome de distrés respiratorio, que requiere de ventilación mecánica. Por el alto número de contagios, la disponibilidad de ventiladores para el tratamiento es escasa. Se presenta la descripción de un prototipo de un dispositivo de asistencia ventilatoria temporal de lazo cerrado de bajo costo; el AR_CODEX, basado en una bolsa válvula-mascarilla (BVM), que contribuye al mantenimiento ventilatorio mínimo del paciente durante un tiempo corto en casos donde no hay disponibilidad de ventiladores mecánicos. Para esto, se diseñó y construyó un sistema mecánico ajustable que compresiona la bolsa de ventilación, el cual cuenta con sensores de flujo y presión. Además, se elaboró una interfaz gráfica para un adecuado monitoreo del paciente y un sistema de control para variables como volumen, presión máxima, frecuencia respiratoria y relación inspiración: espiración. Por otro lado, existe un problema de sensibilidad en el sensor de flujo debido a varios factores, como la variación del voltaje en los motores. Adicionalmente, la implementación de un lazo cerrado es importante para compensar variaciones aleatorias en el funcionamiento del dispositivo. Es necesario realizar pruebas en animales para evaluar el correcto funcionamiento de AR_CODEX en seres vivos.

In early 2020, the world has been affected from Covid-19 caused by SARS-CoV-2. By August there were more than 31 million patients, some of them suffering from respiratory distress that requires mechanical ventilation. Due to the rise of infection rates there is no ventilator availability for the treatment. In this work we describe a reduced cost closed loop temporal assisted ventilation device prototype, AR_CODEX. It is based on mask valve bag (BVM from its Spanish initials), contributing to the minimum ventilation maintenance for the patient du-ring a short period of time when there is no mechanical ventilation availability. For this purpose an adjustable mechanical system was designed and built to pressurize the ventilation bag that is equipped with flux and pres-sure sensors. Additionally a graphical interface was developed to include adequate monitoring and controlling system for volume, maximum pressure, respiratory frequency and inhalation/exhalation rate. In addition there is a sensibility issue on the flux sensor due to engine voltage variation. A closed loop implementation is important to overcome aleatory variations during the device operation. It is needed to run AR_CODEX device performance test on animals to evaluate prior to use it directly on human patients.

A Quest for New Cancer Diagnosis, Prognosis and Prediction Biomarkers and Their Use in Biosensors Development.

Traditional techniques for cancer diagnosis, such as nuclear magnetic resonance, ultrasound and tissue analysis, require sophisticated devices and highly trained personnel, which are characterized by elevated operation costs. The use of biomarkers has emerged as an alternative for cancer diagnosis, prognosis and prediction because their measurement in tissues or fluids, such as blood, urine or saliva, is characterized by shorter processing times. However, the biomarkers used currently, and the techniques used for their measurement, including ELISA, western-blot, polymerase chain reaction (PCR) or immunohistochemistry, possess low sensitivity and specificity. Therefore, the search for new proteomic, genomic or immunological biomarkers and the development of new noninvasive, easier and cheaper techniques that meet the sensitivity and specificity criteria for the diagnosis, prognosis and prediction of this disease has become a relevant topic. The purpose of this review is to provide an overview about the search for new cancer biomarkers, including the strategies that must be followed to identify them, as well as presenting the latest advances in the development of biosensors that possess a high potential for cancer diagnosis, prognosis and prediction, mainly focusing on their relevance in lung, prostate and breast cancers.

A Case of Hemophagocytic Lymphohistiocytosis Secondary to Disseminated Histoplasmosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by a pathologic immune dysregulation resulting in extreme inflammation. Clinical manifestations are varied but can include severe multiorgan failure and death. HLH has been associated with malignancies, autoimmune diseases, and infections, such as histoplasmosis. Histoplasmosis commonly has subclinical manifestations but can also present in its disseminated form. We present the case of an immunocompromised patient with worsening liver function caused by hepatic histoplasmosis that later triggered HLH with severe multiorgan dysfunction.

Impacto de la elevación de la cabecera de la cama en los síntomas de pacientes con enfermedad por reflujo gastroesofágico: estudio aleatorizado simple-ciego (IBELGA) / Impact of head of bed elevation in symptoms of patients with gastroesophageal reflux disease: a randomized single-blind study (IBELGA)

INTRODUCCIÓN: El impacto clínico de la elevación de la cabecera de la cama en pacientes con enfermedad por reflujo gastroesofágico es incierto, por inconsistencia y limitaciones metodológicas en estudios previos. PACIENTES Y MÉTODOS: Ensayo clínico controlado aleatorizado unicéntrico simple-ciego cruzado 2x2, en 39 pacientes con enfermedad por reflujo gastroesofágico tratados farmacológicamente. La intervención fue elevar la cabecera de la cama a 20 cm de altura durante 6 semanas y luego a dormir sin inclinación otras 6 semanas, con un lavado de 2 semanas entre períodos. El desenlace primario fue el cambio ≥ 10% de la puntuación RDQ y los desenlaces secundarios fueron el cambio ≥ 10% de la puntuación SF-36, preferencia del paciente y frecuencia de eventos adversos. RESULTADOS: 27 (69,2%) pacientes que utilizaron la intervención cumplieron el desenlace primario, vs. 13 (33,3%) pacientes en el grupo control (RR: 2,08; IC95%: 1,19 - 3,61). No se encontró efecto en la puntuación SF-36 (RR: 1,11; IC95%: 0,47 - 2,60). La preferencia por la intervención fue del 77,1% y la proporción de eventos adversos fue del 54,0%. CONCLUSIÓN: La elevación de la cabecera de la cama redujo los síntomas de reflujo, pero no tuvo efecto en la calidad de vida. Por un balance riesgo-beneficio no óptimo, se requieren estudios adicionales antes de recomendar esta intervención (IBELGA, identificador ClinicalTrials.gov NCT02706938)

BACKGROUND: The clinical impact of head-of-bed elevation in patients with gastro-oesophageal reflux disease is unclear, because of inconsistency and methodological limitations of previous studies. PATIENTS AND METHODS: A randomised single-blind single-centre controlled clinical trial with a 2x2 cross-over design, in 39 pharmacologically treated patients with gastro-oesophageal reflux disease. Active intervention was to use a head-of-bed-elevation of 20cm for 6 weeks and then to sleep without inclination for 6 additional weeks, with a wash-out of 2 weeks between periods. The primary outcome was a change ≥ 10% in RDQ score and secondary outcomes were a change ≥ 10% in SF-36 score, patient preference and frequency of adverse events. RESULTS: 27 (69.2%) patients who used the intervention reached the primary outcome vs 13 (33.3%) patients in the control group (RR: 2.08; 95 CI%: 1.19 - 3.61). No effect was found in SF-36 score (RR: 1.11; 95% CI: 0.47 - 2.60). Preference favouring the intervention was 77.1% and adverse event proportion was 54.0%. CONCLUSION: Head-of-bed elevation improved reflux symptoms but there was no effect on quality of life. The finding of a non-optimal risk-benefit ratio warrants additional studies before this intervention can be recommended (IBELGA, ClinicalTrials.gov identifier NCT02706938)

Assistance for Folding of Disease-Causing Plasma Membrane Proteins.

An extensive catalog of plasma membrane (PM) protein mutations related to phenotypic diseases is associated with incorrect protein folding and/or localization. These impairments, in addition to dysfunction, frequently promote protein aggregation, which can be detrimental to cells. Here, we review PM protein processing, from protein synthesis in the endoplasmic reticulum to delivery to the PM, stressing the main repercussions of processing failures and their physiological consequences in pathologies, and we summarize the recent proposed therapeutic strategies to rescue misassembled proteins through different types of chaperones and/or small molecule drugs that safeguard protein quality control and regulate proteostasis.

Impact of head of bed elevation in symptoms of patients with gastroesophageal reflux disease: a randomized single-blind study (IBELGA). / Impacto de la elevación de la cabecera de la cama en los síntomas de pacientes con enfermedad por reflujo gastroesofágico: estudio aleatorizado simple-ciego (IBELGA).

BACKGROUND: The clinical impact of head-of-bed elevation in patients with gastro-oesophageal reflux disease is unclear, because of inconsistency and methodological limitations of previous studies. PATIENTS AND METHODS: A randomised single-blind single-centre controlled clinical trial with a 2x2 cross-over design, in 39 pharmacologically treated patients with gastro-oesophageal reflux disease. Active intervention was to use a head-of-bed-elevation of 20cm for 6 weeks and then to sleep without inclination for 6 additional weeks, with a wash-out of 2 weeks between periods. The primary outcome was a change ≥10% in RDQ score and secondary outcomes were a change ≥10% in SF-36 score, patient preference and frequency of adverse events. RESULTS: 27 (69.2%) patients who used the intervention reached the primary outcome vs 13 (33.3%) patients in the control group (RR: 2.08; 95 CI%: 1.19 - 3.61). No effect was found in SF-36 score (RR: 1.11; 95% CI: 0.47 - 2.60). Preference favouring the intervention was 77.1% and adverse event proportion was 54.0%. CONCLUSION: Head-of-bed elevation improved reflux symptoms but there was no effect on quality of life. The finding of a non-optimal risk-benefit ratio warrants additional studies before this intervention can be recommended (IBELGA, ClinicalTrials.gov identifier NCT02706938).

Resveratrol up-regulates ATP2A3 gene expression in breast cancer cell lines through epigenetic mechanisms.

Resveratrol (RSV) is a phytoestrogen which has been related to chemoprevention of several types of cancer. In this work, we show up to a 6-fold increased expression of ATP2A3 gene induced by RSV that triggers apoptosis and changes of intracellular Ca2+ management in MCF-7 and MDA-MB-231 breast cancer cell lines. We explored epigenetic mechanisms for that RSV-induced ATP2A3 up-regulation. The results indicate that RSV-induced ATP2A3 up-regulation correlates with about 50% of reduced HDAC activity and reduced nuclear HDAC2 expression and occupancy on ATP2A3 promoter, increasing the global acetylation of histone H3 and the enrichment of histone mark H3K27Ac on the proximal promoter of the ATP2A3 gene in MDA-MB-231 cells. We also quantified HAT activity, finding that it can be boosted with RSV treatment; however, pharmacological inhibition of p300, one of the main HATs, did not have significant effects in RSV-mediated ATP2A3 gene expression. Additionally, DNMT activity was also reduced in cells treated with RSV, as well as the expression of Methyl-DNA binding proteins MeCP2 and MBD2. However, analysis of the methylation pattern of ATP2A3 gene promoter showed un-methylated promoter in both cell lines. Taken together, the results of this work help to explain, at the molecular level, how ATP2A3 gene is regulated in breast cancer cells, and the benefits of RSV intake observed in epidemiological data, studies with animals, and in vitro models.

Histone deacetylase inhibitors promote ATP2A3 gene expression in hepatocellular carcinoma cells: p300 as a transcriptional regulator.

Sarco(endo)plasmic reticulum Ca2+-ATPases (SERCA) expression is reduced or absent in several types of cancer and cancer cell lines; however, their expression and regulation in hepatocellular carcinoma (HCC) are unknown. Histone deacetylase inhibitors (HDACi) increase SERCA3 mRNA expression in gastric and breast cancer cell lines by increasing H3K9ac and binding of Sp1 and Sp3 transcription factors to the promoter; however, the molecular mechanism is not fully understood. Our results show that ATP2A3 (SERCA3) gene expression is decreased in human HCC samples and rat HCC AS-30D cells compared to normal liver, and HCC patients with high expression of ATP2A3 had longer overall survival than those with low expression. Sodium butyrate (NaB) and trichostatin A (TSA) increase SERCA3 mRNA expression in AS-30D cells, whereas SERCA2b mRNA expression did not change. NaB and TSA increase H3K9ac and H3K27ac in two ATP2A3 promoter regions. Besides, NaB treated cells increased Sp1 and Sp3 occupancy at ATP2A3 promoter; whereas TSA treated cells showed increased p300 levels at ATP2A3 promoter. Inhibition of p300 by C646, a specific inhibitor, mitigates SERCA3 mRNA induction by TSA, and reduces more than 70% of basal SERCA3 mRNA expression, suggesting that p300 is important for ATP2A3 gene transcription in AS-30D cells. Moreover, inhibition of p300 decreases H3K9ac in TSA treated cells. Our results provide evidence of decreased SERCA3 expression in human HCC samples and rat AS-30D cells and a correlation of SERCA3 expression with overall survival in HCC patients. Also, reveal new insights in SERCA3 transcriptional regulation mediated by HDACi.

Epigenetic regulation of the human ATP2A3 gene promoter in gastric and colon cancer cell lines.

The knowledge about the role of calcium-regulated pathways in cancer cell growth and differentiation could be useful for the development of new therapeutic approaches to diminish its mortality. The ATP2A genes encode for SERCA pumps, which modulate cytosolic Ca2+ concentration, regulating various cellular processes including cell growth. ATP2A3 gene transcriptional down-regulation has been reported in gastric and colon cancer, but there is still a lack of understanding about the epigenetic processes regulating its transcription. In this work, we report that butyrate, trichostatin A, and 5-azacytidine treatments increase SERCA3 expression, increased apoptosis, and decreased cell viability of the KATO-III gastric carcinoma cell line. We analyzed the methylation profile of the ATP2A3 gene promoter CpG island, finding clones with methylated status through -280 to -135 promoter region, harboring Sp1 and AP-2 binding sites, which could have a role in transcriptional repression. Post-translational modifications of histones show a major role in the ATP2A3 transcriptional regulation, and our results show histones marks linked to transcriptional repression associated with the -262 to -135 region, this repressive context changed to transcriptional permissive through SERCA3 re-expressing conditions. These results suggest that the nucleotide sequence from -280 to -135 position is an ATP2A3 epigenetic regulatory CpG region in KATO-III cells. Analyses of online-databases show a decreased SERCA3 expression in gastric and colon tumors, as well as overall survival results, showed that high SERCA3 expression could serve as a favorable prognostic marker for colon and gastric cancer patients.

Automatic classification of water samples using an optimized SVM model applied to cyclic voltammetry signals / Clasificación automática de muestras de agua usando un modelo SVM optimizado aplicado a señales de voltametría cíclica

Background: concern about the quality of the water for human consumption has become widespread among the population. The taste and some problems associated with drinking water have been the cause of increased demand for bottled water. Due to this, day to day, a large number of companies has manifested their interest in the production of bottled water. Objective: to evaluate a novel automatic classification model that differentiates bottled water from tap water. Methods: the voltammetric technique consisted of three electrode setup. The output current has been considered for data analysis. From the results of grid search, six pairs of values were pre-selected for the parameters of σ and C whose results were similar. High values of accuracy, specificity and sensitivity were achieved in test dataset. The final decision was made after performing an ANOVA test of 100 repetitions of 5-fold cross-validation, 3000 models were evaluated with the parameter combinations described above for the SVM. Results: the oxidation and reduction peaks of the water samples have been observed to be prominent. Absolute values of current (I) increased in the case of public water samples, possibly due to the largest concentration of chloride ions which have higher contributions to the conductivity. 5-fold cross-validation test mean specificity resulted in C parameters values greater than 0 and between 0 and 30; a σ value greater than 10 and between 0 and 15 were found for tap water and bottled water, respectively. The combination (σ = 10, C = 30) presented best results in accuracy 0.988 ± 0.037, specificity 0.973 ± 0.085 and sensitivity 1 ± 0.09. Conclusions: results of this research work have shown that voltammograms for values of current increased for tap water samples, 9.94e-6µA, compared to 7.99e-6µA due to higher chloride ions concentration in the former. The parameters combination (σ = 10, C = 20) was selected as optimal parameters since there were no significant difference between this and the former.

Antecedentes: en la población hay una preocupación generalizada por la calidad del agua de consumo humano. El sabor y algunos problemas asociados con el agua potable han sido la causa del incremento en la demanda del agua embotellada. Debido a esto, un gran número de empresas han manifestado su interés en la producción de agua en botella. Objetivo: evaluar un nuevo modelo de clasificación automática que diferencie el agua embotellada del agua del grifo. Metodología: la técnica de voltametría consistió en la configuración de tres electrodos. Para el análisis de datos se consideró la corriente de salida y de los resultados de la búsqueda de cuadrícula y se seleccionaron seis pares de valores para los parámetros de σ y C, cuyos resultados fueron similares. Se lograron altos valores de precisión, especificidad y sensibilidad en el conjunto de datos de prueba. La decisión final se tomó después de realizar una prueba ANOVA de 100 repeticiones de validación cruzada de 5 veces y se evaluaron 3000 modelos con las combinaciones de parámetros descritas anteriormente para el SVM. Resultados: se observó que los picos de oxidación y reducción de las muestras de agua son prominentes. Los valores absolutos de corriente (I) aumentaron en el caso de muestras de agua pública, posiblemente debido a la mayor concentración de iones de cloruro que tienen una mayor contribución a la conductividad. La especificidad media de la prueba de validación cruzada 5 veces dio como resultado valores de parámetros C mayores que 0 y entre 0 y 30; se encontró un valor σ mayor que 10 y entre 0 y 15 para el agua de red pública y el agua embotellada, respectivamente. La combinación (σ = 10, C = 30) presentó los mejores resultados en precisión 0,988 ± 0,037, especificidad 0,973 ± 0,085 y sensibilidad 1 ± 0,09. Conclusiones: los resultados de este trabajo demostraron que los voltamogramas para valores de corriente, aumentaron para muestras de agua corriente, 9,94e-6 µA, en comparación con 7,99e-6 µA debido a una mayor concentración de iones de cloruro en el primer caso. La combinación de parámetros (σ = 10, C = 20) se seleccionó como parámetros óptimos, ya que no mostró diferencias significativas entre éste y el primer caso.

Correction to: Hyper-response to Novelty Increases c-Fos Expression in the Hippocampus and Prefrontal Cortex in a Rat Model of Schizophrenia.

The original version of this article unfortunately contained a mistake. The spelling of the author Tommaso Ianniti was incorrect and has been corrected as Tommaso Iannitti. The original article has been corrected.

Effect of History of Mild Traumatic Brain Injury on Optic Nerve Sheath Diameter Changes after Valsalva Maneuver.

Optic nerve sheath diameter (ONSD) measured by transocular ultrasound is a marker of real-time intracranial pressure (ICP). The objective of this study was to evaluate the association between optic nerve sheath (ONS) dilation after a Valsalva maneuver and a prior history of mild to moderate traumatic brain injury (mTBI) in a heterogeneous sample of participants. Participants were excluded if they had had a recent brain injury, were symptomatic from a prior brain injury, had a history consistent with severe TBI and/or had undergone intracranial surgery. Ninety-five participants with and without a history of mTBI were included in the study. Transocular ultrasound of the ONS was performed before and after a Valsalva maneuver. Differences in the ONSD before and after a Valsalva maneuver were analyzed and correlated to the participants' history of mTBI. Baseline ONSD measurements between groups were not statistically significant. Following Valsalva, participants with a history of mTBI had a statistically significant increase in the ONSD compared with participants with no history of mTBI. This significant difference persisted after controlling for age, race, and sex. This study demonstrated an association between a prior history of mTBI and dilation of the ONS after Valsalva maneuver in a sample of asymptomatic participants, which was not seen in participants without a history of mTBI.