CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.

Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.

Impact of chronic alcohol exposure on conventional and regulatory murine T cell subsets.

Introduction: Chronic alcohol use poses significant negative consequences to public health and, among its many biologic effects, is associated with significant T cell dysregulation within the adaptive immune system that has yet to be fully characterized. Novel, automated strategies for high dimensional flow cytometric analysis of the immune system are rapidly improving researchers' ability to detect and characterize rare cell types. Methods: Using a murine model of chronic alcohol ingestion in conjunction with viSNE and CITRUS analysis tools, we performed a machine-driven, exploratory analysis comparing rare splenic subpopulations within the conventional CD4+, regulatory CD4+ and CD8+ T cell compartments between alcohol- and water-fed animals. Results: While there were no differences in the absolute numbers of bulk CD3+ T cells, bulk CD4+ T cells, bulk CD8+ T cells, Foxp3- CD4+ conventional T cells (Tconv) or Foxp3+ CD4+ regulatory T cells (Treg), we identified populations of naïve Helios+ CD4+Tconv and naïve CD103+ CD8+ splenic T cells that were decreased in chronically alcohol exposed mice versus water-fed controls. In addition, we identified increased CD69+ Treg and decreased CD103+ effector regulatory T cell (eTreg) subsets in conjunction with increased frequency of a population that may represent a transitional phenotype between central regulatory T cell (cTreg) and eTreg. Discussion: These data provide further resolution into the character of decreased naïve T cell populations known to be present in alcohol exposed mice, as well as describe alterations in effector regulatory T cell phenotypes associated with the pathogenesis of chronic alcohol-induced immune dysfunction.

Violent victimization among immigrants: Using the National Violent Death Reporting System to examine foreign-born homicide victimization in the United States.

Limited research attention has focused on homicides involving foreign-born victims. Using data from the National Violent Death Reporting System, we examined 9428 homicides that occurred in 2017 in the United States across 32 states and D.C. Approximately 8% of homicide victims were foreign-born. Homicide victimization rates were substantially lower for foreign-born persons, compared to U.S.-born persons. However, foreign-born persons from Honduras, El Salvador, and Jamaica had a substantially higher risk of homicide victimization. Notably, few homicides involving foreign-born victims were gang- or drug-trade-related. With the growing number of immigrants in the United States, policy and prevention efforts should be guided by research.

5-(Indol-2-yl)pyrazolo[3,4-b]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.

TASK channels belong to the two-pore-domain potassium (K2P) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. TASK-3 is expressed in different cancer cell types and neurons. Thus, the discovery of novel TASK-3 inhibitors makes these bioactive compounds very appealing to explore new cancer and neurological therapies. TASK-3 channel blockers are very limited to date, and only a few heterofused compounds have been reported in the literature. In this article, we combined a pharmacophore hypothesis with molecular docking to address for the first time the rational design, synthesis, and evaluation of 5-(indol-2-yl)pyrazolo[3,4-b]pyridines as a novel family of human TASK-3 channel blockers. Representative compounds of the synthesized library were assessed against TASK-3 using Fluorometric imaging plate reader-Membrane Potential assay (FMP). Inhibitory properties were validated using two-electrode voltage-clamp (TEVC) methods. We identified one active hit compound (MM-3b) with our systematic pipeline, exhibiting an IC50 ≈ 30 µM. Molecular docking models suggest that compound MM-3b binds to TASK-3 at the bottom of the selectivity filter in the central cavity, similar to other described TASK-3 blockers such as A1899 and PK-THPP. Our in silico and experimental studies provide a new tool to predict and design novel TASK-3 channel blockers.

In Silico Repositioning of Dopamine Modulators with Possible Application to Schizophrenia: Pharmacophore Mapping, Molecular Docking and Molecular Dynamics Analysis.

We have performed theoretical calculations with 70 drugs that have been considered in 231 clinical trials as possible candidates to repurpose drugs for schizophrenia based on their interactions with the dopaminergic system. A hypothesis of shared pharmacophore features was formulated to support our calculations. To do so, we have used the crystal structure of the D2-like dopamine receptor in complex with risperidone, eticlopride, and nemonapride. Linagliptin, citalopram, flunarizine, sildenafil, minocycline, and duloxetine were the drugs that best fit with our model. Molecular docking calculations, molecular dynamics outcomes, blood-brain barrier penetration, and human intestinal absorption were studied and compared with the results. From the six drugs selected in the shared pharmacophore features input, flunarizine showed the best docking score with D2, D3, and D4 dopamine receptors and had high stability during molecular dynamics simulations. Flunarizine is a frequently used medication to treat migraines and vertigo. However, its antipsychotic properties have been previously hypothesized, particularly because of its possible ability to block the D2 dopamine receptors.

Comparative Thermal Effects of J-Plasma®, Monopolar, Argon, and Laser Electrosurgery in a Porcine Tissue Model.

INTRODUCTION: The objective of this study was to understand how J-Plasma® (Bovie Medical Corporation, Clearwater, Florida) surgical energy compares to monopolar, argon beam, and CO2 laser devices in terms of depth of penetration and lateral thermal spread in a porcine tissue model. MATERIALS AND METHODS: Using a porcine animal model, we applied the thermal energy of the J-Plasma® laser, Bovie Monopolar Pencil™ (Bovie Medical Corporation, Clearwater, Florida), argon beam coagulator, and CO2 laser to porcine small bowel, bladder, and peritoneal tissues at equivalent settings. Tissue was excised and sent to pathology for histologic evaluation. Primary outcome was depth of penetration and lateral thermal spread. RESULTS: When applied to peritoneum tissue, CO2 laser had the greatest lateral thermal spread at 2.99mm, while the argon beam had the lowest at just under 1.5mm. With regard to depth of penetration, the monopolar pencil had the highest while J-Plasma® had the lowest. When applied to bladder tissue, the argon beam was associated with the greatest lateral thermal spread (3.1mm) as compared to the other three devices (all less than 1mm). In terms of depth of penetration of bladder tissue, J-Plasma® again had the lowest value, while the monopolar pencil had the highest. When applied to small intestine tissue, the argon beam had the greatest lateral spread (3.51mm), while J-Plasma® had the lowest (less than 1mm). Regarding depth of penetration of small intestine tissue, argon beam had the highest value at 1.8mm compared to the other three devices (all below 0.6mm). CONCLUSION: Consistent with our previous study, J-Plasma® had minimal lateral and depth spread when applied to various tissue types. J-Plasma® performed better or similar when compared to monopolar, argon beam, and laser electrosurgical devices. Further studies in-vivo are needed to evaluate safety and surgical application of the J-Plasma® device.

Tendencias temáticas en psicología publicadas por Psicogente en el período 2014-2017 / Subjects in psychology published by Psicogente between 2014 and 2017

Resumen Objetivo: Identificar las temáticas con mayor tendencia de publicaciones científicas de la Revista Psicogente en los años 2014 a 2017 lo que permitirá a los investigadores y científicos tener una ruta orientativa de los campos psicológicos que se encuentra en mayor auge investigativo según el análisis bibliográfico de la revista. Método: Artículo de revisión con diseño de tipo exploratorio de corte bibliográfico, se analizaron 111 artículos publicados por la Revista Psicogente con un sistema Open Access. Las variables analizadas fueron: temática de estudio, población y país de procedencia de cada uno de los artículos. A través de una matriz se agruparon las variables para identificar las tendencias con mayor frecuencia. Resultados: Psicología social y clínica con un 38.7 % y 19.4 % respectivamente tienen mayor relevancia en publicación en la Revista Psicogente, los países de Colombia y México mostraron una mayor frecuencia en publicación con un 54.8 % y 19.4 % respectivamente y la población de estudiantes de secundarias con un 49.5 % fue de mayor interés de los investigadores para sus publicaciones. Conclusión: Las revisiones bibliográficas de las revistas científicas son una ruta orientativa para los investigadores y científicos que requieran un mapa claro de la investigación, en el caso de la Revista Psicogente, este artículo permite cumplir con el objetivo planteado, mostrando resultados claros y que permiten al lector científico una herramienta esencial a la hora de iniciar un proceso de investigación. Con la muestra y análisis de 111 artículos se evidencio que la psicología social en Colombia es una de las mayores tendencias en investigación científica.

Abstract Objective: To identify the topics with the highest tendency of scientific publications of the Psicogente in the years 2014 to 2017. This will allow researchers and scientists to have an indicative route of the psychological fields that is in the highest research boom according to the bibliographic analysis of journal. Method: Review paper with bibliographic exploratory design. 111 articles published by the Psicogente with an Open Access system were analyzed. The variables analyzed were subject, population and country for each paper. The variables were organized on a matrix to identify the frequency of the trends. Results: Social and clinical psychology with 38.7 % and 19.4 % respectively have greater relevance in publication in the psychogenic journal, the countries of Colombia and Mexico showed a greater frequency in publication with 54.8 % and 19.4 % respectively and the population of high school students with 49.5 % was of greater interest to researchers for their publications. Conclusion: Bibliographic reviews of scientific journals are an indicative route for researchers and scientists who require a clear map of the research, in the case of psychogenic journal, this article allows to meet the stated objective, showing clear results and allowing the scientific reader an essential tool when starting a research process. With the sample and analysis of 111 articles it was evidenced that social psychology in Colombia is one of the biggest trends in scientific research.

Thermal Effect of J-Plasma® Energy in a Porcine Tissue Model: Implications for Minimally Invasive Surgery.

OBJECTIVE: To evaluate tissue effect of J-Plasma® (Bovie Medical Corporation, Clearwater, Florida) in porcine liver, kidney, muscle, ovarian, and uterine tissue blocks. DESIGN: Prospective study utilizing porcine tissue blocks to evaluate the thermal spread of J-Plasma® device on liver, kidney, muscle, ovarian, and uterine tissue at various power settings, gas flow, and exposure times. MATERIALS AND METHODS: J-Plasma® helium was used in porcine liver, kidney, and muscle tissue at 20%, 50%, and 100% power, and 1 L/min, 3 L/min, and 5 L/min gas flow at one, five, and 10-second intervals. J-Plasma® was then used in ovarian and uterine tissue at maximum power and gas flow settings in intervals of one, five, 10, and 30 seconds. Histologic evaluation of each tissue was then performed to measure thermal spread. RESULTS: Regardless of tissue type, increased power setting, gas flow rate, and exposure time correlated with greater depth of thermal spread in liver, kidney, and muscle tissue. J-Plasma® did not exceed 2 mm thermal spread on liver, kidney, muscle, ovarian, and uterine tissue, even at a maximum setting of 100% power and 5 L/min gas flow after five seconds. Prolonged exposure to J-Plasma® of up to 30 seconds resulted in increased length and width of thermal spread of up to 12 mm, but did not result in significantly increased depth at 2.84 mm. CONCLUSIONS: The J-Plasma® helium device has minimal lateral and depth of thermal spread in a variety of tissue types and can likely be used for a multitude of gynecologic surgical procedures. However, further studies are needed to demonstrate device safety in a clinical setting.

The McCarus-Volker ForniSee®: A Novel Trans-illuminating Colpotomy Device and Uterine Manipulator for Use in Conventional and Robotic-Assisted Laparoscopic Hysterectomy.

PURPOSE: The purpose of this paper is to introduce a novel trans-illuminating culdotomy and uterine manipulator device. MATERIALS AND METHODS: The study was a prospective, non-randomized, non-blinded observational clinical study involving 50 female patients undergoing total laparoscopic hysterectomy (TLH) or laparoscopic supracervical hysterectomy (LSH) for benign indications. The surgeries were performed from March through May 2012 at two institutions. The primary study objectives were to demonstrate the safety and adequate clinical performance of the uterine manipulator device and to illustrate its potential widespread future use in minimally invasive gynecologic procedures. RESULTS: Average patient age was 45.1 years and, of the 50 patients, 33 had undergone previous intra-abdominal surgery. There were no reports of adverse events, difficulty with placement of the instrument, multiple attempts at placement, or difficulty with uterine manipulation. There was only one device-related uterine perforation, and pneumoperitoneum was maintained in all cases during culdotomy. Vaginal tissue left on subjects was less than 5mm. Overall, there were no ureteral injuries, there were two reported incidental cystotomies, and average blood loss was 99.0cc. Postoperative courses were normal for all patients, with only two reported postoperative complications: a possible vaginal cuff abscess and a 2cm vaginal mucosal cuff separation. CONCLUSIONS: The McCarus-Volker ForniSee® (LSI Solutions, Inc., Victor, New York) is a novel trans-illuminating culdotomy device and uterine manipulator that is safe, efficient, functional, and easy to use. Trans-illumination additionally delineates and enhances identification of critical anatomic planes, such as the vesicovaginal junction and cervicovaginal junction.

Evolution of a sexually dimorphic trait in a broadly distributed topminnow (Fundulus olivaceus).

Understanding the interaction between sexual and natural selection within variable environments is crucial to our understanding of evolutionary processes. The handicap principle predicts females will prefer males with exaggerated traits provided those traits are indicators of male quality to ensure direct or indirect female benefits. Spatial variability in ecological factors is expected to alter the balance between sexual and natural selection that defines the evolution of such traits. Male and female blackspotted topminnows (Fundulidae: Fundulus olivaceus) display prominent black dorsolateral spots that are variable in number across its broad range. We investigated variability in spot phenotypes at 117 sites across 13 river systems and asked if the trait was sexually dimorphic and positively correlated with measures of fitness (condition and gonadosomatic index [GSI]). Laboratory and mesocosm experiments assessed female mate choice and predation pressure on spot phenotypes. Environmental and community data collected at sampling locations were used to assess predictive models of spot density at the individual, site, and river system level. Greater number of spots was positively correlated with measures of fitness in males. Males with more spots were preferred by females and suffered greater mortality due to predation. Water clarity (turbidity) was the best predictor of spot density on the drainage scale, indicating that sexual and natural selection for the trait may be mediated by local light environments.

Improving asthma management among African-American children via a community health worker model: findings from a Chicago-based pilot intervention.

OBJECTIVES: Asthma affects 25-30% of children living in certain disadvantaged Chicago neighborhoods, a rate twice the national prevalence (13%). Children living in poor, minority communities tend to rely heavily on the emergency department (ED) for asthma care and are unlikely to be properly medicated or educated on asthma self-management. A pilot project implemented and evaluated a community health worker (CHW) model for its effectiveness in reducing asthma morbidity and improving the quality of life among African-American children living in disadvantaged Chicago neighborhoods. METHODS: Trained CHWs from targeted communities provided individualized asthma education during three to four home visits over 6 months. The CHWs also served as liaisons between families and the medical system. Seventy children were enrolled into the pilot phase between 15 November 2004 and 15 July 2005, of which 96% were insured by Medicaid and 54% lived with a smoker. Prior to starting, the study was approved by an institutional review board. Data on 50 children (71.4%) who completed the entire 12-month evaluation phase were analyzed using a before and after study design. RESULTS: Findings indicate improved asthma control. Specifically, symptom frequency was reduced by 35% and urgent health resource utilization by 75% between the pre- and post-intervention periods. Parental quality of life also improved by a level that was both clinically and statistically significant. Other important outcomes included improved asthma-related knowledge, decreased exposure to asthma triggers, and improved medical management. The intervention was also shown to be cost-effective, resulting in an estimated $5.58 saved per dollar spent on the intervention. CONCLUSIONS: Findings suggest that individualized asthma education provided by a trained, culturally competent CHW is effective in improving asthma management among poorly controlled, inner-city children. Further studies are needed to affirm the findings and assess the model's generalizability.