Experience with the use of intravitreal bevacizumab in cases with type I retinopathy of prematurity in a Latin American country.

In retinopathy of prematurity (ROP) type I, the use of intravitreal bevacizumab (IVB), which is an inhibitor of endothelial growth factor (VEGF), has become popular despite not being a therapy approved by regulatory agencies. However, IVB has shown positive effects in halting disease progression at lower costs compared to other anti-VEGF therapies (ranibizumab or aflibercept). In this report, we present the experience during the treatment with IVB of 102 Colombian children with ROP type I, with a success rate of 98% (100). Complications occurred in 3.9% (4). Finally, we conclude that a single dose of IVB is an effective therapy for the management of ROP type I, with a lower risk of complications and retreatment.

The non-vesicle cell-free DNA (cfDNA) induces cell transformation associated with horizontal DNA transfer.

BACKGROUND: Cell-free DNA (cfDNA) is a source for liquid biopsy used for cancer diagnosis, therapy selection, and disease monitoring due to its non-invasive nature and ease of extraction. However, cfDNA also participates in cancer development and progression by horizontal transfer. In humans, cfDNA circulates complexed with extracellular vesicles (EV) and macromolecular complexes such as nucleosomes, lipids, and serum proteins. The present study aimed to demonstrate whether cfDNA not associated with EV induces cell transformation and tumorigenesis. METHODS: Supernatant of the SW480 human colon cancer cell line was processed by ultracentrifugation to obtain a soluble fraction (SF) and a fraction associated with EV (EVF). Primary murine embryonic fibroblast cells (NIH3T3) underwent passive transfection with these fractions, and cell proliferation, cell cycle, apoptosis, cell transformation, and tumorigenic assays were performed. Next, cfDNA was analyzed by electronic microscopy, and horizontal transfer was assessed by human mutant KRAS in recipient cells via PCR and recipient cell internalization via fluorescence microscopy. RESULTS: The results showed that the SF but not the EVF of cfDNA induced proliferative and antiapoptotic effects, cell transformation, and tumorigenesis in nude mice, which were reduced by digestion with DNAse I and proteinase K. These effects were associated with horizontal DNA transfer and cfDNA internalization into recipient cells. CONCLUSIONS: The results suggest pro-tumorigenic effects of cfDNA in the SF that can be offset by enzyme treatment. Further exploration of the horizontal tumor progression phenomenon mediated by cfDNA is needed to determine whether its manipulation may play a role in cancer therapy.

Etiopathogenesis of drug dependence: an explanatory synthesis from an epigenetic perspective / Etiopatogenia de las drogodependencias: una síntesis explicativa desde una perspectiva epigenética / Etiopatogenia das toxicodependências: uma síntese explicativa a partir de uma perspectiva epigenética

The use of substances with addictive potential is a relevant health problem. Scientific evidence suggests that the underlying mechanisms that regulate behavioral processes in addictions involve a complex interplay between genetic and environmental factors. Therefore, this narrative review aims to provide a framework to synthesize the evidence on gene-environment-agent interactions from the perspective of the natural history of the disease and the stages of the addictive process for alcohol, nicotine, cannabis, psychostimulants, and opioids. In this review, we conducted an exhaustive literature search without time limits in PubMed, Ebsco, Lilacs, and SciELO, reviewing the title and abstract we selected original articles in humans or animals that addressed the etiology of addictions according to the methodological approach of gene-environment (G-E) interaction, including articles in Spanish, English, and Portuguese. Genetic studies have revealed the critical role of epigenetic modifiers (histone acetylation) in maintaining brain homeostasis in pathological conditions and focusing on G-E interactions will also allow characterizing subgroups (based on environmental factors) at high risk for addictive behaviors that can be targeted for specific interventions, Thus, treatment strategies should encompass a combination of psychosocial interventions with gene therapy involving pharmacological manipulations of histones that may contribute to design better therapies and perhaps lead to more successful management of drug dependencies.

El consumo de sustancias con potencial adictivo es un problema relevante de salud. La evidencia científica sugiere que los mecanismos subyacentes que regulan los procesos comportamentales en las adicciones involucran un complejo interjuego entre factores genéticos y ambientales. Por lo tanto, esta revisión narrativa tiene como objetivo aportar un marco de referencia que permita sintetizar la evidencia sobre interacciones genes- ambiente-agente desde la perspectiva de la historia natural de la enfermedad y los estadios del proceso adictivo para: alcohol, nicotina, cannabis, psicoestimulantes y opioides. En esta revisión realizamos una búsqueda exhaustiva de la literatura sin límites de tiempo en PubMed, Ebsco, Lilacs y SciELO, revisando el título y el resumen se seleccionaron artículos originales en humanos o animales que abordaran la etiología de las adiciones según el enfoque metodológico de interacción entre genes y ambiente (G-A), incluyendo artículos en español, inglés y portugués. Los estudios genéticos han revelado el papel crítico de los modificadores epigenéticos (acetilación de las histonas) en mantener la homeóstasis cerebral en condiciones patológicas y enfocarse en las interacciones G-A también permitirá caracterizar subgrupos (basados en los factoresambientales) de alto riesgo para conductas adictivas que pueden ser objeto de intervenciones específicas, por lo que, las estrategias de tratamiento deben englobar una combinación de intervenciones psicosociales con terapia génica que involucren las manipulaciones farmacológicas de las histonas que pueden contribuir a diseñar mejores terapias y tal vez conducir a un manejo más exitoso de las drogodependencias.

O consumo de substâncias com potencial viciante é um relevante problema de saúde. Evidências científicas sugerem que os mecanismos subjacentes que regulam os processos comportamentais em vícios envolvem uma interação complexa entre fatores genéticos e ambientais. Portanto, esta revisão narrativa visa fornecer um quadro de referência que permita sintetizar as evidências sobre interações gene-ambiente-agente sob a perspectiva da história natural da doença e as etapas do processo de dependência para: álcool, nicotina, cannabis, psicoestimulantes e opióides. Nesta revisão, realizamos uma busca exaustiva da literatura sem limites de tempo no PubMed, Ebsco , Lilacs e SciELO, revisando o título e o resumo, foram selecionados artigos originais em humanos ou animais que abordassem a etiologia dos acréscimos de acordo com a abordagem metodológica de interação entre genes e ambiente (GA), incluindo artigos em espanhol, inglês e português. Estudos genéticos revelaram o papel crítico dos modificadores epigenéticos (acetilação de histonas) na manutenção da homeostase cerebral em condições patológicas, e o direcionamento das interações GA também permitirá caracterizar subgrupos (com base em fatores ambientais) de alto risco para comportamentos aditivos que podem ser alvo de ataques específicos. intervenções, portanto, as estratégias de tratamento devem abranger uma combinação de intervenções psicossociais com terapia gênica envolvendo manipulações farmacológicas de histonas que podem contribuir para projetar melhores terapias e talvez levar a um manejo mais bem-sucedido das dependências de drogas.

"White-puncture": A simple technique to prevent tearing of the anterior capsule during capsulorhexis in intumescent white cataracts. / Blancopunción: una técnica simple para prevenir el desgarro de la cápsula anterior durante la capsulorrexis en cataratas blancas intumescentes.

In order to avoid radial tearing of the anterior capsule while performing continuous circular capsulorhexis (CCC) in a white intumescent cataract, called the "Argentinian flag sign" when CCC is associated with a previous capsular stain with trypan blue, an initial puncture of the anterior capsule is performed with a 30G needle as the first step of the surgical procedure, that means, prior to any previous aperture of the anterior chamber. This act seems to allow the pressure of the intracrystalline space and the pressure of the anterior chamber to be equalized, as the liquefied content of the intumescent white cataract is released into a presumably hermetic anterior chamber, avoiding the dreaded anterior capsular radial tear. This technique, called "white-puncture", has been used in 174 cases without any associated complications.

Efficacy and safety of immune checkpoint inhibitor immunotherapy in elderly cancer patients.

PURPOSE: There is limited evidence on the efficacy and safety of anti-programmed cell death protein 1 (PD-1)-/anti-programmed death-ligand 1 (PD-L1)-based immunotherapy in the elderly, particularly those aged over 75 years. METHODS/PATIENTS: The clinical response and toxicity profile of anti-PD-1-/anti-PD-L1-based immunotherapy in patients aged over 75 years were assessed in this retrospective observational study conducted in the Medical Oncology Service of a tertiary level hospital. The associations among clinical responses, adverse events, and geriatric syndromes were evaluated. RESULTS: In total, 20 patients aged between 75 and 94 years were evaluated. Pembrolizumab and nivolumab were the most commonly used drugs. A clinical benefit (stable disease, partial response or complete response) was documented in 13 patients (65%). This proportion was 80% in patients aged between 75 and 79 years, and 50% in those aged over 79 years (p = 0.236). The adverse events were similar to those reported in younger patients. At least one clinical adverse event (cAE) and one laboratory adverse event (lAE) was reported in 75% and 55% of patients, respectively. Polypharmacy was observed for all patients and multi-morbidity in 95%. Patients without gait disorders showed more responses to immunotherapy. The number of lAEs was significantly associated with the number of commonly prescribed drugs (slope = 0.218, p = 0.010), the Eastern Cooperative Oncology Group score, and the number of cAEs. CONCLUSIONS: The elderly can obtain benefits from anti-PD-1-/anti-PD-L1-based immunotherapy. The toxicity profile was similar to that reported in younger counterparts.

Flow cytometry diagnosis in myelodysplastic syndrome: Current practice in Latin America and comparison with other regions of the world.

BACKGROUND: Flow cytometry (FC) is a valuable tool for the diagnosis of myelodysplastic syndromes (MDS). We present results of a survey carried out to evaluate FC current practice for MDS diagnosis in Latin America (LA), focusing on markers used and characteristics of the clinical diagnostic report. Compliance to IMDSflow recommendations was also evaluated. These practices were then compared with those used in other countries. METHODS: An online survey was sent through the Grupo Latino-Americano de Mielodisplasia to LA cytometrists and other international scientific societies. RESULTS: 91 responses from 15 LA countries were received. The median of the number of markers used was 20 ± 4.5, but only 8.1% of participants adopted the complete panel proposed by the International/European LeukemiaNet Working Group (IMDSflow). We received 140 eligible answers from regions other than LA (66 Europe, 59 USA-Canada, 8 Oceania, 6 Asia and 1 Africa). LA utilized more markers for MDS diagnosis than USA/Canada (p = 0.006), but similar to Europe. The use of MDS scoring systems differed among regions: 10.3% in LA, 0% USA/Canada and 25.7% Europe reported the "Ogata score". Finally, 52.0% of all participants included a general interpretation statement in the final report about the consistency of the FC results with MDS diagnosis, with no statistical differences between regions. CONCLUSIONS: This survey shows a low compliance with the IMDSflow recommendations and a scarce use of the scoring systems proposed in the literature. However, the number of surface markers used is high. We will work to develop a FC consensus for MDS diagnosis adapted to the clinical practice requirements in LA.

CASO CLÍNICO: INTOLERANCIA A ANTIINFLAMATORIOS NO ESTEROIDES (AINES): INCLUIDO PARACETAMOL

Se presentan dos pacientes con urticaria y angioedema inducidos por reacción cruzada a AINES, incluido el Paracetamol. Los autores realizan una descripción diagnóstica y propuesta terapéutica.

Computational Study of the Binding Modes of Diverse DPN Analogues on Estrogen Receptors (ER) and the Biological Evaluation of a New Potential Antiestrogenic Ligand.

Estrogen (17ß-estradiol) is essential for normal growth and differentiation in the mammary gland. In the last three decades, previous investigations have revealed that Estrogen Receptor Alpha (ERα) plays a critical role in breast cancer. More recently, observations regarding the widespread expression of ERß-like proteins in normal and neoplastic mammary tissues have suggested that ERß is also involved in the mentioned pathology. Design of new drugs both steroidal and nonsteroidal that target any of these receptors represents a promise to treat breast cancer although it remains a challenge due to the sequence similarity between their catalytic domains. In this work, we propose a new set of compounds that could effectively target the estrogen receptors ERα and ERß. These ligands were designed based on the chemical structure of the ERß-selective agonist Diarylpropionitrile (DPN). The designed ligands were submitted to in silico ADMET studies, yielding in a filtered list of ligands that showed better drug-like properties. Molecular dynamics simulations of both estrogen receptors and docking analysis were carried-out employing the designed compounds, from which two were chosen due to their promising characteristics retrieved from theoretical results (docking analysis or targeting receptor predictions). They were chemically synthetized and during the process, two precursor ligands were also obtained. These four ligands were subjected to biological studies from which it could be detected that compound mol60b dislplayed inhibitory activity and its ability to activate the transcription via an estrogenic mechanism of action was also determined. Interestinly, this observation can be related to theoretical binding free energy calculations, where the complex: ERß-mol60b showed the highest energy ΔGbind value in comparison to others.

Epidemiología de las meningitis bacterianas en niños en un hospital pediátrico: 2011-2016 / Epidemiology of bacterial meningitis in children at a pediatric hospital: 2011-2016

Introducción: Las meningitis bacterianas en niños son causa de importante morbimortalidad. Los principales agentes etiológicos son Neisseria meningitidis, Streptococcus pneumoniae y Haemophilus influenzae. En los últimos años, luego de la introducción sucesiva de vacunas conjugadas al calendario nacional de inmunizaciones, se ha visto un cambio en la epidemiología de estas infecciones. Objetivo: Describir las características clínicas, epidemiológicas y evolutivas de los niños hospitalizados con meningitis bacteriana confirmada microbiológicamente entre 2011 y 2016 en un hospital de tercer nivel de complejidad. Materiales y métodos: Cohorte retrospectiva. Se incluyeron niños entre 1 mes de vida y 17 años con cuadro clínico compatible con meningitis bacteriana y cultivo positivo y/o PCR en líquido cefalorraquídeo y/o hemocultivos positivos para Neisseria meningitidis, Streptococcus pneumoniae y Haemophilus influenzae b. Se registraron las características demográficas, clínicas y evolutivas hasta los 30 días del egreso. Se utilizó mediana y rango intercuartilo (RIC) para variables continuas y porcentaje para variables categóricas. Se utilizó Stata 10. Resultados: n=65. Edad: mediana de 9 meses (RIC 4-35). Varones: 58% (n=38). Se identificó Neisseria meningitidis en un 48% (n=31), Haemophilus influenzae b en un 26% (n=17) y Streptococcus pneumoniae en un 26% (n=17). El 26% (n=17) de los pacientes presentaba alguna comorbilidad. Tuvieron hemocultivos positivos el 62% (n = 40) de los pacientes y 86% (n=55) de los líquidos cefalorraquídeos. Todos los pacientes recibieron tratamiento antimicrobiano con ceftriaxona tanto como tratamiento empírico como definitivo y 92% (n=60) recibieron corticoides empíricos. La mediana de días de internación fue de 11 (RIC 8-17). El 28% (n=18) requirió cuidados intensivos, y el 8% (n=5) falleció. Durante el período de estudio se observó que la frecuencia de meningitis por Streptococcus pneumoniae disminuyó en el final del estudio (9% en 2016 vs 60% en 2011), mientras que la frecuencia de meningitis por Neisseria meningitidis en 2016 fue mayor que al inicio del período (64% en 2016 vs. 40% en 2011). La frecuencia de identificación de Haemophilus influenzae b se mantuvo estable. Conclusiones: Las meningitis bacterianas confirmadas por Neisseria meningitidis, Streptococcus pneumoniae y Haemophilus influenzae b prevalecieron en niños menores de 12 meses. En esta cohorte se observó un predominio de las infecciones por Neisseria meningitidis en los últimos años, y una disminución en la frecuencia de meningitis por Streptococcus pneumoniae en el período post introducción de la vacuna conjugada 13 valente al calendario nacional de inmunizaciones. (AU)

Introduction: In children, bacterial meningitis is an important cause of morbidity and mortality. The main etiological agents are Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae. Over the last years, the successive introduction of conjugated vaccines in the national immunization calendar has led to a change in the epidemiology of these infections. Objective: To describe the clinical and epidemiological features and outcome of children admitted because of microbiologically confirmed meningitis seen between 2011 and 2016 at a tertiary care hospital. Material and methods: A retrospective cohort study was conducted. Children between 1 month of life and 17 years of age with clinical features compatible with bacterial meningitis and positive cultures and/or PCR in cerebrospinal fluid (CSF) and/or positive blood cultures for Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae b were included. Demographic, clinical, and outcome features were recorded until 30 days after discharge. Median and interquartile range (IQR) were calculated for continuous variables and percentages for categorical variables. The Stata 10 program was used. Results: n=65. Age: median was 9 months (IQR 4-35). Boys: 58% (n=38). Neisseria meningitidis was identified in 48% (n=31), Haemophilus influenzae b in 26% (n=17), and Streptococcus pneumoniae in 26% (n=17). Overall, 26% (n=17) of the patients presented with comorbidities. Positive blood cultures were found in 62% (n = 40) and positive CSF cultures in 86% (n=55) of the patients. All patients received antimicrobial treatment with ceftriaxone both empirically and as final treatment and corticosteroids were empirically started in 92% (n=60). Median hospital stay was 11 days (IQR 8-17). Overall, 28% (n=18) required intensive care and 8% (n=5) of the patients died. The incidence of meningitis due to Streptococcus pneumoniae was observed to diminish at the end of the study period (9% in 2016 vs 60% in 2011), while the incidence of meningitis due to Neisseria meningitidis in 2016 was higher than at the end of the study period (64% in 2016 vs. 40% in 2011). The frequency of identification of Haemophilus influenzae b remained stable. Conclusions: Confirmed bacterial infections due to Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae b were prevalent in infants younger than 12 months of age in this cohort of patients. Infections due to Neisseria meningitidis predominated over the last years and the incidence of meningitis due to Streptococcus pneumoniae diminished after the introduction of the 13 valent conjugated vaccine was introduced in the national immunization calendar.(AU)

Desarrollo de una Interfaz Visual del Metabolismo de Glucosa Basada en Modelos Matemáticos Compartimentales / Development of a Visual Interface of Glucose Metabolism Based on Compartment Mathematical Models

RESUMEN La diabetes es una pandemia mundial cuya incidencia ha aumentado en las últimas décadas. Por tal motivo, es prioritario proponer estrategias para su diagnóstico, tratamiento y seguimiento. Uno de los enfoques recientes en el tratamiento de la diabetes es el monitoreo continuo, el cual permite tener suficiente información sobre el estado metabólico del paciente a lo largo del día. Esta información puede servir para simular pacientes virtuales que sean herramientas para proponer estrategias de tratamiento. Por tanto, el objetivo de esta investigación es proponer una interfaz visual que simule pacientes virtuales, a partir de un conjunto de modelos matemáticos compartimentales que permiten ingresar parámetros del metabolismo y modificaciones en el tratamiento. El desarrollo de la interfaz se realizó en MATLAB® y simula tres tipos de pacientes (sano, diabético tipo I y diabético tipo II). Los resultados muestran una interfaz que presenta de manera ilustrativa el funcionamiento de los modelos matemáticos y permite una visualización del estado metabólico del paciente; así como el manejo de medicamentos e ingesta. Una limitante de esta investigación es la validación de la interfaz con datos experimentales de los tres tipos de pacientes. Una vez validada, esta herramienta aportaría en el desarrollo de tecnología in silico para la generación de pacientes virtuales.

ABSTRACT Diabetes is a pandemic disease whose incident rate has been rising in the last decades. Therefore, it is important to propose strategies for its diagnosis, treatment and monitoring. One of the recent approaches on diabetes treatment is the continuous monitoring, which provides enough information about the metabolic state of the patient throughout the day. This information can be used to simulate virtual patients which are useful tools in treatment strategies. Thus, the objective of this research is to propose a visual interface to simulate virtual patients, this is based on compartmental mathematical models considering changes in metabolic parameters and treatment modifications. The interface was made in MATLAB® and simulates three kinds of patients (healthy, type I diabetic, type II diabetic). The results show an interface that presents the functionality of the mathematical models in an illustrative way and it allows the visualization of the metabolic state of the patient; as well as the medication usage and meal intake. A limitation of this approach is the validation of the interface with experimental data of the three kinds of patients. Once it was validated, this tool could contribute to the development of in silico technology to generate virtual patients.

Seguridad y eficiencia de sedación balanceada con propofol y remifentanil en endoscopia digestiva alta diagnóstica. Una experiencia exitosa / A Successful Experience: Safety and Efficiency of Balanced Sedation with Propofol and Remifentanil in Diagnostic Endoscopy

Resumen La sedación es una técnica anestésica de amplio uso en los procedimientos endoscópicos digestivos actuales dado su claro beneficio en la tolerancia y comodidad para el paciente y el endoscopista. El medicamento de mayor uso en la actualidad para utilizarse como monosedación es el propofol, pero los esquemas balanceados utilizando más de un medicamento ahora son ampliamente usados en endoscopia diagnóstica o terapéutica. La sedación balanceada utilizando propofol y remifentanilo permite la potenciación sinérgica de un sedante con un opioide de ultracorta acción, lo que a su vez favorece la disminución respectiva de cada dosis. Se presenta una serie de 1148 pacientes llevados a endoscopia digestiva alta diagnóstica con dosis promedio de remifentanilo de 0,9 µg/kg de peso y de propofol de 0,47 mg/kg de peso, sin eventos adversos graves, con excelente satisfacción para el endoscopista y con muy bajo costo de la dosis por medicamento, con lo que se infiere que es un esquema seguro y eficiente.

Abstract Sedation is an anesthetic technique that is widely used in current digestive endoscopic procedures because of its clear benefits for patients' tolerance and comfort and for the endoscopist. Propofol is the most commonly used drug in monosedation, but balanced regimens using more than one drug are now widely used in diagnostic and therapeutic endoscopy. Balanced sedation using Propofol and Remifentanil allows synergistic potentiation of a sedative with an ultra-short acting opioid which in turn favors decreases of each dose. This is a series of 1,148 patients who underwent diagnostic endoscopy under balanced sedation with average Remifentanil doses of 0.9 mcg/kg of body weight and average Propofol doses of 0.47 mg/kg of body weight. There were no serious adverse events, endoscopists were highly satisfied with the procedures, and costs per drug dose were very low. This is clearly a safe and efficient scheme.

Tuning the target composition of amine-grafted CPO-27-Mg for capture of CO2 under post-combustion and air filtering conditions: a combined experimental and computational study.

A computational and experimental screening of hypothetical and real compounds exhibiting different degrees of ethylenediamine grafted to the CPO-27-Mg or Mg-DOBDC skeleton is performed in order to determine the target composition that optimizes the CO2 adsorption properties under flue gas and air filtering conditions. On the basis of the [Mg2(dobdc)] formula, eighteen hypothetical models involving 15-100% of functionalization of the coordinatively unsaturated sites (CUS) were considered by means of Grand Canonical Monte Carlo simulations to evaluate the CO2 adsorption at 298 K. In addition, post-synthesis modification was applied to CPO-27-Mg leading to three kinds of samples exhibiting 15, 50, and 60% of CUS functionalization with ethylenediamine, named CPO-27-Mg-a, CPO-27-Mg-b and CPO-27-Mg-c. Compounds were characterized using elemental analysis, TGA, FTIR spectroscopy, PXRD and DSC. Finally, bare and functionalized CPO-27-Mg materials were evaluated using gas adsorption and microcalorimetry in the 0.001-1 bar range, which is pertinent for the mentioned applications. Valuable information related to design criteria for synthesis of tuned CO2 adsorbents is derived through this computational and experimental investigation.

Mucosa gástrica heterotópica en esófago cervical: presentación de un caso de compromiso circunferencial con estenosis franqueable / A Case Report of Circumferential Presentation with Stricture of Heterotopic Gastric Mucosa in the Cervical Esophagus

La mucosa gástrica heterotópica en esófago cervical (MGHEC) es una condición probablemente subdiagnosticada. La gran mayoría de los pacientes son asintomáticos y su detección es un hallazgo incidental. En los pacientes sintomáticos, las manifestaciones se asocian con cambios no neoplásicos o neoplásicos, que permiten categorizarlos en cinco tipos. A la categoría tipo III corresponde el caso presentado del paciente, con disfagia y globus faríngeo por MGHEC de compromiso circunferencial con estenosis franqueable. Al momento de esta publicación, solo se encontraron siete casos similares en la literatura mundial. La detección de MGHEC (apoyada en nuevas tecnologías de imagen como la cromoendoscopia) puede ser un indicador de calidad en el desempeño endoscópico, similar a la detección de adenomas en colonoscopia.

Heterotopic gastric mucosa in the cervical esophagus is a condition that is probably underdiagnosed. The vast majority of patients are asymptomatic, and detection is an incidental finding. In symptomatic patients, manifestations are associated with non-neoplastic or neoplastic changes that allow categorization into five types. The case presented here is a patient who had Type III with dysphagia and pharyngeal globus due to heterotopic gastric mucosa in the cervical esophagus with circumferential presentation with stenosis. At the time of publication, only seven similar cases could be found in the literature. Detection, supported by new imaging technologies such as chromoendoscopy, may be an indicator of the quality of endoscopic performance in a manner that is similar to detection of adenomas in colonoscopy.

Nicotinamide sensitizes human breast cancer cells to the cytotoxic effects of radiation and cisplatin.

Poly(ADP-ribose) polymerase (PARP) inhibitors enhance the effect of DNA alkylating agents on BRCA1­ and BRCA2-deficient cell lines. The aim of this study was to analyze the effect of the PARP inhibitor nicotinamide (NAM) on breast cancer cells with different BRCA1 expression or function, such as BRCA1­deficient MDA-MB-436 cells, low expression BRCA1 MCF-7 cells, and the BRCA1 wild­type MDA-MB-231 cells, to demonstrate its effects as a chemo­ or radiosensitizing agent. PARP activity was analyzed in MDA-MB-436, MCF-7 and MDA-MB-231 breast cancer cells subjected or not to NAM. Inhibition of PARP by NAM in the presence of DNA damage was examined by Alexa Fluor 488 immunofluorescence. Crystal violet assays were used to test growth inhibition and the chemo­ and radiosensitization effects of NAM were investigated using clonogenic assays. Significant differences among data sets were determined using two-tailed ANOVA and Bonferroni tests. We demonstrated that NAM reduces PARP activity in vitro, and in cells subjected or not to DNA damage, it also reduces the viability of breast cancer cell lines and synergyzes the cytotoxicity of cisplatin in MDA-MB-436 and MCF-7 cells. Downregulation of PARP1 with siRNA led to modest growth inhibition, which was further increased by cisplatin. Nicotinamide also induced radiosensitization in MDA-MB-436 and MDA-MB-231 cells. In conclusion, NAM may be used as a chemo­ or radiosensitizing agent regardless of the BRCA1 status in breast cancer.

DNA synthesis in periportal and perivenous hepatocytes of intact and hepatectomized young mice.

DNA synthesis of hepatocytes in two areas of Intact and Hepatectomized young mice liver along a circadian period was studied. DNA synthesis was significantly different at all analyzed time points in Intact and Hepatectomized animals. Differences between periportal and perivenous hepatocytes were found in hepatectomized animals at 04/42 and 08/46 hr of day/hour post-hepatectomy. DNAs peak in periportal hepatocytes regenerating liver occurs 4 hr earlier than in perivenous hepatocytes, probably reflecting their shorter G1 phase. Besides, daily mean values of regenerating livers were higher than those observed in Intact animals, as a consequence of surgical removal.

Incidence of venous thromboembolism (VTE) in ambulatory pancreatic cancer patients receiving chemotherapy and analysis of Khorana's predictive model.

PURPOSE: To evaluate the incidence of venous thromboembolism (VTE) in ambulatory pancreas cancer patients receiving chemotherapy and analyze Khorana's predictive model of chemotherapy-associated thrombosis. METHODS/PATIENTS: We performed a retrospective review to determine the incidence of VTE in the gastrointestinal cancer unit of our center. Between 2008 and 2011, 84 consecutives patients diagnosed with pancreas adenocarcinoma were identified and included in the analysis. Pancreatic neuroendocrine tumors were excluded. RESULTS: Thirty patients experienced VTE (35.7 %) and 66 % of the events were diagnosed during the first 6 months after diagnosis. Khorana's score: 33.3 % of the intermediate category patients developed a venous thromboembolic event and 37.5 % in the high-risk category. CONCLUSIONS: The high incidence of VTE observed in this study is consistent with prior reports. Specific predictive model for chemotherapy-associated thrombosis in pancreatic cancer must be investigated.

Pre-operative training induces changes in the histomorphometry and muscle function of the pelvic floor in patients with indication of radical prostatectomy.

OBJECTIVE: To evaluate the efficacy of preoperative pelvic floor muscle training (PFMT) on histomorphometry, muscle function, urinary continence and quality of life of patients undergoing radical prostatectomy (RP). MATERIAL AND METHODS: A prospective intervention clinical study was designed in 16 patients with indication of RP who were randomized into two groups. The Control Group received routine pre-surgical education (hygienic-dietary measures). The intervention group received a training session with supervised PFMT, three times a day, for four weeks, 30 days before the PR. Muscle function of the external urethral sphincter, contraction pressure of the levator ani, urinary continence and quality of life related to health (HRQoL) were evaluated before and after the intervention. At the end of the intervention and day of the surgery, samples of residual muscle tissue were obtained from the external sphincter muscle of the urethra for histomorphometric analysis. RESULTS: After the intervention, those participants who carried out PFMT showed an increase in the cross-sectional area of the muscle fibers of the external urethral sphincter (1,313 ± 1,075 µm(2)vs. 1,056 ± 844 µm(2), P=.03) and higher pressure contraction of the levator ani (F=9.188; P=.010). After catheter removal, 62% of patients in the experimental group and 37% in the control group showed no incontinence. After removal of the catheter, 75% of the experimental group did not require any pad compared to 25% in the control group (p=NS). There were no significant differences between the two groups in any of the HRQoL domains studied. CONCLUSIONS: Pre-surgical PFMT in patients with RP indication induces changes in the histology and function of the pelvic floor muscles, without changes in urogenital function and HRQoL. These results provide new evidence regarding the benefit of PFMT in preventing RP associated complications.

Optimization of a Therapeutic Vaccine Candidate by Studying Routes, Immunization Schedules and Antigen Doses in HBsAg-positive Transgenic Mice.

Hepatitis B core antigens (HBcAg) and hepatitis B surface antigens (HBsAg) are the main structural antigens of hepatitis B virus (HBV). Both antigens are potent immunogens for experimental animals as well as in acutely infected patients. A novel formulation based on the combination of HBsAg and HBcAg has been developed as a therapeutic vaccine candidate, aimed at inducing an immune response capable of controlling the infection. An immunization schedule was conducted to evaluate the immunogenicity of this formulation after simultaneous immunization by the intranasal and parenteral routes using different schedules and doses. Humoral and cellular immune responses generated in blood and spleen were evaluated by engyme-linked immunosorbent assay (ELISA) and enzyme-liked immunospot (ELISPOT) assays respectively. A first experiment evaluated two groups of mice simultaneously immunized by intranasal (IN) and subcutaneous (SC) routes, one including alum by SC route and, in the other, the formulation was injected without adjuvant. As a result, alum adjuvant did not increase the immunogenicity under the studied conditions. In fact, the group without alum induced the most potent immune response. The immune response was enhanced by combining IN and SC immunization compared to the SC route alone. In a second experiment, mice were immunized by different mucosal routes at the same time, and compared to the simultaneously (IN/SC) immunized groups. It was demonstrated that there is no improvement on the resulting immune response by using multiple routes of immunizations simultaneously; however, the increase of the antigen dose induced a superior immune response. Interestingly, the increase of antigen dose only by SC route did not favor the resulting immunogenicity. In conclusion, the use of HBsAg transgenic mice has proven useful to optimize the formulation, avoiding the unnecessary use of alum as adjuvant as well as provided information of the role of different mucosal immunization routes and antigen dose on the resulting immune response. How to cite this article: Trujillo H, Blanco A, García D, Freyre F, Aguiar J, Lobaina Y, Aguilar JC. Optimization of a Therapeutic Vaccine Candidate by Studying Routes, Immunization Schedules and Antigen Doses in HBsAg-positive Transgenic Mice. Euroasian J Hepato-Gastroenterol 2014;4(2):70-78.

Animal models for endoscopic training: do we really need them?

Gastrointestinal endoscopy currently includes many therapeutic methods that are technically challenging and frequently associated with a significant risk of complications. Several issues such as the limited number of clinical cases and practice in emergency situations, and technical difficulty may limit the opportunity for training, and increased exposure in more relaxed situations would be desirable. Moreover, providing the patient with the best possible standard of care is a must. Animal models are the most easily available simulators. Training in these models has been recommended for several complex techniques, among which hemostasis, endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, and endoscopic submucosal dissection are reviewed here. Ex vivo models are much easier to set up and, from an ethical standpoint, they should be used for the initial step in training whenever possible before moving on to in vivo models. Although simulation with animal models has been the subject of a good number of studies, very few of them have evaluated the impact on clinical outcomes, and clearly more studies are needed. Nevertheless, available evidence does suggest that practicing on animal models has an influence on the learning curve and facilitates the acquisition of skills in the complex endoscopic techniques reviewed.