Sex difference in the effect of environmental enrichment on food restriction-induced persistence of cocaine conditioned place preference and mechanistic underpinnings.

Psychosocial and environmental factors, including loss of natural reward, contribute to the risk of drug abuse. Reward loss has been modeled in animals by removal from social or sexual contact, transfer from enriched to impoverished housing, or restriction of food. We previously showed that food restriction increases the unconditioned rewarding effects of abused drugs and the conditioned incentive effects of drug-paired environments. Mechanistic studies provided evidence of decreased basal dopamine (DA) transmission, adaptive upregulation of signaling downstream of D1 DA receptor stimulation, synaptic upscaling and incorporation of calcium-permeable AMPA receptors (CP-AMPARs) in medium spiny neurons (MSNs) of nucleus accumbens (NAc). These findings align with the still evolving 'reward deficiency' hypothesis of drug abuse. The present study tested whether a compound natural reward that is known to increase DA utilization, environmental enrichment, would prevent the persistent expression of cocaine conditioned place preference (CPP) otherwise observed in food restricted rats, along with the mechanistic underpinnings. Because nearly all prior investigations of both food restriction and environmental enrichment effects on cocaine CPP were conducted in male rodents, both sexes were included in the present study. Results indicate that environmental enrichment curtailed the persistence of CPP expression, decreased signaling downstream of the D1R, and decreased the amplitude and frequency of spontaneous excitatory postsynaptic currents (EPSCs) in NAc MSNs of food restricted male, but not female, rats. The failure of environmental enrichment to significantly decrease food restriction-induced synaptic insertion of CP-AMPARs, and how this may accord with previous pharmacological findings that blockade of CP-AMPARs reverses behavioral effects of food restriction is discussed. In addition, it is speculated that estrous cycle-dependent fluctuations in DA release, receptor density and MSN excitability may obscure the effect of increased DA signaling during environmental enrichment, thereby interfering with development of the cellular and behavioral effects that enrichment produced in males.

Involvement of the Receptor for Advanced Glycation End Products (RAGE) in high fat-high sugar diet-induced anhedonia in rats.

Clinical and basic science investigation indicates a link between insulin resistance and anhedonia. Previous results of this laboratory point to impaired nucleus accumbens (NAc) insulin signaling as an underpinning of diet-induced anhedonia, based on use of a glucose lick microstructure assay. The present study evaluated whether advanced glycation end products (AGEs) and their receptor (RAGE), known to mediate obesogenic diet-induced inflammation and pathological metabolic conditions, are involved in this behavioral change. Six weeks maintenance of male and female rats on a high fat-high sugar liquid diet (chocolate Ensure) increased body weight gain, and markedly increased circulating insulin and leptin, but induced anhedonia (decreased first minute lick rate and lick burst size) in males only. In these subjects, anhedonia correlated with plasma concentrations of insulin. Although the diet did not alter plasma or NAc AGEs, or the expression of RAGE in the NAc, marginally significant correlations were seen between anhedonia and plasma content of several AGEs and NAc RAGE. Importantly, a small molecule RAGE antagonist, RAGE229, administered twice daily by oral gavage, prevented diet-induced anhedonia. This beneficial effect was associated with improved adipose function, reflected in the adiponectin/leptin ratio, and increased pCREB/total CREB in the NAc, and a shift in the pCREB correlation with pThr34-DARPP-32 from near-zero to strongly positive, such that both phospho-proteins correlated with the rescued hedonic response. This set of findings suggests that the receptor/signaling pathway and cell type underlying the RAGE229-mediated increase in pCREB may mediate anhedonia and its prevention. The possible role of adipose tissue as a locus of diet-induced RAGE signaling, and source of circulating factors that target NAc to modify hedonic reactivity are discussed.

Frecuencia de perforaciones radiculares en tratamientos endodónticos realizados por estudiantes de postgrados chilenos

Introducción: Este estudio evaluó la frecuencia de perforaciones radiculares provocadas por estudiantes de primer y segundo año de la especialidad de Endodoncia de la Facultad de Odontología de la Universidad Andrés Bello (UNAB), Santiago (Chile), entre 2019 y marzo de 2021. Materiales y Métodos: Se realizó un estudio observacional descriptivo a través de datos recopilados retrospectivamente en fichas clínicas de pacientes atendidos en el área de postgrado en Endodoncia de la universidad, durante 2019, 2020 y hasta marzo de 2021. Resultados: Un total de 569 pacientes fueron atendidos en el período, 118 fueron atendidos por estudiantes de primer año y 451 por los de segundo año. La frecuencia de perforaciones del primer año fue de un 0% y la del segundo año del 2 % (n = 9). Considerando el total general de pacientes, la frecuencia relativa de perforaciones fue de apenas 1,6 %. Con respecto a ubicación, 3 perforaciones fueron en el tercio cervical de la raíz, 3 en el tercio medio, 2 en el tercio apical y 1 en el piso cameral. Ninguna perforación resultó en la indicación inmediata de extracción y todas fueron selladas con materiales a base de silicato de calcio. Conclusiones: La frecuencia de perforaciones radiculares por los estudiantes de postgrado fue muy baja, lo que podría evidenciar la seguridad de los protocolos institucionales de tratamiento y enseñanza. La mayor ocurrencia de perforaciones fue con los estudiantes de segundo año, lo cual puede ser atribuido a que tratan casos de mayor complejidad.

Introduction: The present study evaluated the frequency of root perforations caused by first- and second-year students of the Endodontics specialty of the Faculty of Dentistry of the UNAB University in Santiago (Chile), between January 2019 and March 2021. Materials and Methods: A descriptive observational study was carried out through data collected retrospectively in clinical records of patients treated in the Postgraduate Endodontics Clinic of the Andrés Bello University (UNAB) during 2019, 2020 and until March 2021. Results: A total of 569 patients were treated during the period, 118 patients were seen by first-year students and 451 by second-year students. The frequency of perforations in the first year was 0% and in the second year it was 2% (n=9). Considering the overall total number of patients, the relative frequency of perforations was only 1.6%. Regarding location, 3 perforations were in the cervical third of the root, 3 in the middle third, 2 in the apical third and 1 in the pulp chamber floor. No perforation resulted in the immediate indication of extraction and all were sealed with calcium silicate-based materials. Conclusions: Te frequency of root perforations by postgraduate students was very low, which could evidence the safety of institutional treatment and teaching protocols. The greatest occurrence of perforations was with second-year students, which can be attributed to the fact that they treat cases of greater complexity.

Síndrome de plaquetas grises y embarazo: reporte de un caso y revisión de la bibliografía / Grey platelet syndrome and pregnancy: case report and literature review

Resumen ANTECEDENTES: Las repercusiones del embarazo en el síndrome de plaquetas grises no están definidas, la bibliografía reporta pocos casos; por tanto, los desenlaces no son muy conocidos. OBJETIVO: Describir el caso de una paciente con síndrome de plaquetas grises y embarazo para proponer pautas de atención y recomendaciones para el seguimiento antenatal, peri y posparto en este grupo de pacientes. Además, revisar la bibliografía más reciente. CASO CLÍNICO: Paciente primigesta de 29 años, con diagnóstico de trombocitopenia a partir de los 6 años. Durante el embarazo se consideró de origen genético por lo que se solicitó el exoma clínico que reportó una variante en el gen NBEAL2 c 7244G>T p G1y2415Val homocigoto, con diagnóstico de síndrome de plaquetas grises. Permaneció en seguimiento en los servicios de Hematología y Obstetricia, sin complicaciones mayores; cerca del parto requirió transfusión de plaquetas. A las 39 semanas de embarazo ingresó para atención del parto, se dio prueba de trabajo de parto; sin embargo, por indicación obstétrica (detención de la dilatación) se decidió la finalización mediante cesárea. METODOLOGÍA: Se revisaron las bases de datos de PubMed, LILACS, Medline, Clinical trials de los últimos 20 años. Los MeSH de búsqueda fueron "grey platelet" "syndrome" "pregnancy". Se encontraron 11 artículos de los que se descartaron 2 por estar fuera del rango de tiempo, un artículo duplicado y otros excluían embarazadas. En total se revisaron 9 artículos. CONCLUSIÓN: Este caso muestra que las mujeres con síndrome de plaquetas grises, si son debidamente acompañadas por un equipo interdisciplinario con experiencia pueden tener un embarazo y parto seguros.

Abstract BACKGROUND: The repercussions of pregnancy in grey platelet syndrome are undefined, with few cases reported in the literature; therefore, outcomes are not well known. OBJECTIVE: To describe the case of a patient with grey platelet syndrome and pregnancy in order to propose care guidelines and recommendations for antenatal, peri- and postpartum follow-up in this group of patients. In addition, to review the most recent literature. CLINICAL CASE: A 29-year-old primigravida patient diagnosed with thrombocytopenia since the age of 6. During pregnancy it was considered to be of genetic origin, so the clinical exome was requested, which reported a variant in the NBEAL2 c 7244G>T p G1y2415Val homozygous gene, with a diagnosis of grey platelet syndrome. She remained under follow-up in the haematology and obstetrics departments, without major complications; close to delivery she required platelet transfusion. At 39 weeks of pregnancy, she was admitted for delivery care, proof of labour was given; however, due to obstetric indications (arrest of dilatation) it was decided to terminate the pregnancy by caesarean section. METHODOLOGY: The databases of PubMed, LILACS, Medline, Clinical trials of the last 20 years were reviewed. The MeSH search terms were "grey platelet" "syndrome" "pregnancy". Eleven articles were found of which two were discarded for being out of time range, one article duplicated and others excluded pregnant women. In total 9 articles were reviewed. CONCLUSION: This case shows that women with grey platelet syndrome, if properly supported by an experienced interdisciplinary team, can have a safe pregnancy and delivery.

Neuronal-glial communication perturbations in murine SOD1G93A spinal cord.

Amyotrophic lateral sclerosis (ALS) is an incurable disease characterized by proteinaceous aggregate accumulation and neuroinflammation culminating in rapidly progressive lower and upper motor neuron death. To interrogate cell-intrinsic and inter-cell type perturbations in ALS, single-nucleus RNA sequencing was performed on the lumbar spinal cord in the murine ALS model SOD1G93A transgenic and littermate control mice at peri-symptomatic onset stage of disease, age 90 days. This work uncovered perturbed tripartite synapse functions, complement activation and metabolic stress in the affected spinal cord; processes evidenced by cell death and proteolytic stress-associated gene sets. Concomitantly, these pro-damage events in the spinal cord co-existed with dysregulated reparative mechanisms. This work provides a resource of cell-specific niches in the ALS spinal cord and asserts that interwoven dysfunctional neuronal-glial communications mediating neurodegeneration are underway prior to overt disease manifestation and are recapitulated, in part, in the human post-mortem ALS spinal cord.

Inflammation Meets Metabolism: Roles for the Receptor for Advanced Glycation End Products Axis in Cardiovascular Disease.

Fundamental modulation of energy metabolism in immune cells is increasingly being recognized for the ability to impart important changes in cellular properties. In homeostasis, cells of the innate immune system, such as monocytes, macrophages and dendritic cells (DCs), are enabled to respond rapidly to various forms of acute cellular and environmental stress, such as pathogens. In chronic stress milieus, these cells may undergo a re-programming, thereby triggering processes that may instigate tissue damage and failure of resolution. In settings of metabolic dysfunction, moieties such as excess sugars (glucose, fructose and sucrose) accumulate in the tissues and may form advanced glycation end products (AGEs), which are signaling ligands for the receptor for advanced glycation end products (RAGE). In addition, cellular accumulation of cholesterol species such as that occurring upon macrophage engulfment of dead/dying cells, presents these cells with a major challenge to metabolize/efflux excess cholesterol. RAGE contributes to reduced expression and activities of molecules mediating cholesterol efflux. This Review chronicles examples of the roles that sugars and cholesterol, via RAGE, play in immune cells in instigation of maladaptive cellular signaling and the mediation of chronic cellular stress. At this time, emerging roles for the ligand-RAGE axis in metabolism-mediated modulation of inflammatory signaling in immune cells are being unearthed and add to the growing body of factors underlying pathological immunometabolism.

Author Correction: Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Network Engagement in Action: Stakeholder Engagement Activities to Enhance Patient-centeredness of Research.

BACKGROUND: Stakeholders (ie, patients, policymakers, clinicians, advocacy groups, health system leaders, payers, and others) offer critical input at various stages in the research continuum, and their contributions are increasingly recognized as an important component of effective translational research. Natural experiments, in particular, may benefit from stakeholder feedback in addressing real-world issues and providing insight into future policy decisions, though best practices for the engagement of stakeholders in observational studies are limited in the literature. METHODS: The Natural Experiments for Translation in Diabetes 2.0 (NEXT-D2) network utilizes rigorous methods to evaluate natural experiments in health policy and program delivery with a focus on diabetes-related outcomes. Each of the 8 partnering institutions incorporates stakeholder engagement throughout multiple study phases to enhance the patient-centeredness of results. NEXT-D2 dedicates a committee to Engagement for resource sharing, enhancing engagement approaches, and advancing network-wide engagement activities. Key stakeholder engagement activities include Study Meetings, Proposal Development, Trainings & Educational Opportunities, Data Analysis, and Results Dissemination. Network-wide patient-centered resources and multimedia have also been developed through the broad expertise of each site's stakeholder group. CONCLUSIONS: This collaboration has created a continuous feedback loop wherein site-level engagement approaches are informed via the network and network-level engagement efforts are shaped by individual sites. Emerging best practices include: incorporating stakeholders in multiple ways throughout the research, building on previous relationships with stakeholders, enhancing capacity through stakeholder and investigator training, involving stakeholders in refining outcome choices and understanding the meaning of variables, and recognizing the power of stakeholders in maximizing dissemination.

Connexin43 expression in bone marrow derived cells contributes to the electrophysiological properties of cardiac scar tissue.

Cardiac pathologies associated with arrhythmic activity are often accompanied by inflammation. The contribution of inflammatory cells to the electrophysiological properties of injured myocardium is unknown. Myocardial scar cell types and intercellular contacts were analyzed using a three-dimensional reconstruction from serial blockface scanning electron microscopy data. Three distinct cell populations were identified: inflammatory, fibroblastic and endocardial cells. While individual fibroblastic cells interface with a greater number of cells, inflammatory cells have the largest contact area suggesting a role in establishing intercellular electrical connections in scar tissue. Optical mapping was used to study the electrophysiological properties of scars in fetal liver chimeric mice generated using connexin43 knockout donors (bmpKO). Voltage changes were elicited in response to applied current pulses. Isopotential maps showed a steeper pattern of decay with distance from the electrode in scars compared with uninjured regions, suggesting reduced electrical coupling. The tissue decay constant, defined as the distance voltage reaches 37% of the amplitude at the edge of the scar, was 0.48 ± 0.04 mm (n = 11) in the scar of the bmpCTL group and decreased 37.5% in the bmpKO group (n = 10). Together these data demonstrate inflammatory cells significantly contribute to scar electrophysiology through coupling mediated at least partially by connexin43 expression.

Disruption of Ca2+i Homeostasis and Connexin 43 Hemichannel Function in the Right Ventricle Precedes Overt Arrhythmogenic Cardiomyopathy in Plakophilin-2-Deficient Mice.

BACKGROUND: Plakophilin-2 (PKP2) is classically defined as a desmosomal protein. Mutations in PKP2 associate with most cases of gene-positive arrhythmogenic right ventricular cardiomyopathy. A better understanding of PKP2 cardiac biology can help elucidate the mechanisms underlying arrhythmic and cardiomyopathic events consequent to PKP2 deficiency. Here, we sought to capture early molecular/cellular events that can act as nascent arrhythmic/cardiomyopathic substrates. METHODS: We used multiple imaging, biochemical and high-resolution mass spectrometry methods to study functional/structural properties of cells/tissues derived from cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mice (PKP2cKO) 14 days post-tamoxifen injection, a time point preceding overt electrical or structural phenotypes. Myocytes from right or left ventricular free wall were studied separately. RESULTS: Most properties of PKP2cKO left ventricular myocytes were not different from control; in contrast, PKP2cKO right ventricular (RV) myocytes showed increased amplitude and duration of Ca2+ transients, increased Ca2+ in the cytoplasm and sarcoplasmic reticulum, increased frequency of spontaneous Ca2+ release events (sparks) even at comparable sarcoplasmic reticulum load, and dynamic Ca2+ accumulation in mitochondria. We also observed early- and delayed-after transients in RV myocytes and heightened susceptibility to arrhythmias in Langendorff-perfused hearts. In addition, ryanodine receptor 2 in PKP2cKO-RV cells presented enhanced Ca2+ sensitivity and preferential phosphorylation in a domain known to modulate Ca2+ gating. RNAseq at 14 days post-tamoxifen showed no relevant difference in transcript abundance between RV and left ventricle, neither in control nor in PKP2cKO cells. Instead, we found an RV-predominant increase in membrane permeability that can permit Ca2+ entry into the cell. Connexin 43 ablation mitigated the membrane permeability increase, accumulation of cytoplasmic Ca2+, increased frequency of sparks and early stages of RV dysfunction. Connexin 43 hemichannel block with GAP19 normalized [Ca2+]i homeostasis. Similarly, protein kinase C inhibition normalized spark frequency at comparable sarcoplasmic reticulum load levels. CONCLUSIONS: Loss of PKP2 creates an RV-predominant arrhythmogenic substrate (Ca2+ dysregulation) that precedes the cardiomyopathy; this is, at least in part, mediated by a Connexin 43-dependent membrane conduit and repressed by protein kinase C inhibitors. Given that asymmetric Ca2+ dysregulation precedes the cardiomyopathic stage, we speculate that abnormal Ca2+ handling in RV myocytes can be a trigger for gross structural changes observed at a later stage.

Permanent and Transient Electrophysiological Effects During Cardiac Cryoablation Documented by Optical Activation Mapping and Thermal Imaging.

OBJECTIVE: Cardiac catheter cryoablation is a safer alternative to radiofrequency ablation for arrhythmia treatment, but electrophysiological (EP) effects during and after freezing are not adequately characterized. The goal of this study was to determine transient and permanent temperature induced EP effects, during and after localized tissue freezing. METHODS: Conduction in right (RV) and left ventricles (LV) was studied by optical activation mapping during and after cryoablation in paced, isolated Langendorff-perfused porcine hearts. Cryoablation was performed endocardially (n=4) or epicardially (n=4) by a cryoprobe cooled to -120 °C for 8 minutes. Epicardial surface temperature was imaged with an infrared camera. Viability staining was performed after ablation. Motion compensation and co-registration was performed between optical mapping data, temperature image data, and lesion images. RESULTS: Cryoablation produced lesions 14.9 +/- 3.1 mm in diameter and 5.8 +/- 1.7 mm deep. A permanent lesion was formed in tissue cooled below -5 +/- 4 °C. Transient EP changes observed at temperatures between 17 and 37 °C during cryoablation surrounding the frozen tissue region directly correlated with local temperature, and include action potential (AP) duration prolongation, decrease in AP magnitude, and slowing in conduction velocity (Q10=2.0). Transient conduction block was observed when epicardial temperature reached <17 °C, but completely resolved upon tissue rewarming, within 5 minutes. CONCLUSION: Transient EP changes were observed surrounding the permanent cryo lesion (<-5 °C), including conduction block (-5 to 17 °C), and reduced conduction velocity (>17 °C). SIGNIFICANCE: The observed changes explain effects observed during clinical cryoablation, including transient increases in effective refractory period, transient conduction block, and transient slowing of conduction. The presented quantitative data on temperature dependence of EP effects may enable the prediction of the effects of clinical cryoablation devices.

Low Frequency of Asymptomatic and Submicroscopic Plasmodial Infections in Urabá Region in Colombia.

BACKGROUND: A screening for malaria parasites was conducted with asymptomatic residents in Colombia. METHODS: A descriptive study was carried out in December 2012 in four municipalities of Urabá region in Colombia. A convenience sample of 400 subjects was selected. Participants responded to a survey regarding epidemiological data and blood samples were taken from capillary blood obtained by finger prick for thick smear, rapid diagnostic test (RDT), and polymerase chain reaction (PCR). RESULTS: 399 subjects aged 0.2-98 years were studied (median 22; 221 female (55%)). Episodes of malaria in the last year confirmed by thick film were reported by 47 participants (12%). In 399 samples tested by RDT 4 (1%) were positive (1 with P. falciparum, 3 with P. vivax), and 3 were confirmed by PCR. In 399 thick blood smears examined 5 (1.3%) were positive (2 with P. falciparum, 3 with P. vivax), and 3 were confirmed by PCR. In 227 samples, PCR showed 6 (2.6%) positive samples. The parasitaemia was below 1,440 parasites/µL. The best agreement between diagnoses was found between the RDT and thick blood smears (Kappa = 0.75). CONCLUSION: Plasmodial afebrile infection was found in 2% of the studied population, by three diagnostic methods, in residents from a low endemic malaria region in Colombia.

Physician experiences with clinical pharmacists in primary care teams.

BACKGROUND: Improving medication management is an important component of comprehensive care coordination for health systems. The Managing Your Medication for Education and Daily Support (MyMeds) medication management program at the University of California Los Angeles addresses medication management issues by embedding trained clinical pharmacists in primary care practice teams. OBJECTIVES: The aim of this work was to examine and explore physician opinions about the clinical pharmacist program and identify common themes among physician experiences as well as barriers to integration of clinical pharmacists into primary care practice teams. METHODS: We conducted a mixed quantitative-qualitative methods study consisting of a cross-sectional physician survey (n = 69) as well as semistructured one-on-one physician interviews (n = 13). Descriptive statistics were used to summarize survey responses, and standard qualitative content-analysis methods were used to identify major themes from the interviews. RESULTS: The survey response rate was 61%; 13 interviews were conducted. Ninety percent of survey respondents agreed or strongly agreed that having the pharmacist in the office makes management of the patient's medication more efficient, 93% agreed or strongly agreed that pharmacist recommendations are clinically helpful, 71% agreed or strongly agreed that having access to a pharmacist has increased their knowledge about medications they prescribe, and 75% agreed or strongly agreed that having a pharmacist as part of the primary care team has made their job easier. Qualitative interviews corroborated survey findings, and physicians highlighted the value of the clinical pharmacist's communication, team care and expanded roles, and medication management. CONCLUSION: Primary care physicians valued the integrated pharmacy program highly, particularly its features of strong communication, expanded roles, and medication management. Pharmacists were viewed as integral members of the health care team.

Plakophilin-2 is required for transcription of genes that control calcium cycling and cardiac rhythm.

Plakophilin-2 (PKP2) is a component of the desmosome and known for its role in cell-cell adhesion. Mutations in human PKP2 associate with a life-threatening arrhythmogenic cardiomyopathy, often of right ventricular predominance. Here, we use a range of state-of-the-art methods and a cardiomyocyte-specific, tamoxifen-activated, PKP2 knockout mouse to demonstrate that in addition to its role in cell adhesion, PKP2 is necessary to maintain transcription of genes that control intracellular calcium cycling. Lack of PKP2 reduces expression of Ryr2 (coding for Ryanodine Receptor 2), Ank2 (coding for Ankyrin-B), Cacna1c (coding for CaV1.2) and Trdn (coding for triadin), and protein levels of calsequestrin-2 (Casq2). These factors combined lead to disruption of intracellular calcium homeostasis and isoproterenol-induced arrhythmias that are prevented by flecainide treatment. We propose a previously unrecognized arrhythmogenic mechanism related to PKP2 expression and suggest that mutations in PKP2 in humans may cause life-threatening arrhythmias even in the absence of structural disease.It is believed that mutations in desmosomal adhesion complex protein plakophilin 2 (PKP2) cause arrhythmia due to loss of cell-cell communication. Here the authors show that PKP2 controls the expression of proteins involved in calcium cycling in adult mouse hearts, and that lack of PKP2 can cause arrhythmia in a structurally normal heart.

Implementation and Evaluation of a Large-Scale Teleretinal Diabetic Retinopathy Screening Program in the Los Angeles County Department of Health Services.

Importance: Diabetic retinopathy (DR) is the leading cause of blindness in adults of working age in the United States. In the Los Angeles County safety net, a nonvertically integrated system serving underinsured and uninsured patients, the prevalence of DR is approximately 50%, and owing to limited specialty care resources, the average wait times for screening for DR have been 8 months or more. Objective: To determine whether a primary care-based teleretinal DR screening (TDRS) program reduces wait times for screening and improves timeliness of needed care in the Los Angeles County safety net. Design, Setting, and Participants: Quasi-experimental, pretest-posttest evaluation of exposure to primary care-based TDRS at 5 of 15 Los Angeles County Department of Health Services safety net clinics from September 1, 2013, to December 31, 2015, with a subgroup analysis of random samples of 600 patients before and after the intervention (1200 total). Exposure: Primary care clinic-based teleretinal screening for DR. Main Outcomes and Measures: Annual rates of screening for DR before and after implementation of the TDRS program across the 5 clinics, time to screening for DR in a random sample of patients from these clinics, and a description of the larger framework of program implementation. Results: Among the 21 222 patients who underwent the screening (12 790 female, 8084 male, and 348 other gender or not specified; mean [SD] age, 57.4 [9.6] years), the median time to screening for DR decreased from 158 days (interquartile range, 68-324 days) before the intervention to 17 days (interquartile range, 8-50 days) after initiation of the program (P < .001). Overall annual screening rates for DR increased from 5942 of 14 633 patients (40.6%) before implementation to 7470 of 13 133 patients (56.9%) after initiation of the program at all 15 targeted clinics (odds ratio, 1.9; 95% CI, 1.3-2.9; P = .002). Of the 21 222 patients who were screened, 14 595 (68.8%) did not require referral to an eye care professional, 4160 (19.6%) were referred for treatment or monitoring of DR, and 2461 (11.6%) were referred for other ophthalmologic conditions. Conclusions and Relevance: A digital TDRS program was successfully implemented for the largest publicly operated county safety net population in the United States, resulting in the elimination of the need for more than 14 000 visits to specialty care professionals, a 16.3% increase in annual rates of screening for DR, and an 89.2% reduction in wait times for screening. Teleretinal DR screening programs have the potential to maximize access and efficiency in the safety net, where the need for such programs is most critical.

Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure.

Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 °C causes coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 °C but are unexcitable at 40 °C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure.

Connexin43 contributes to electrotonic conduction across scar tissue in the intact heart.

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes, and coupling depends on Cx43 expression.

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias.

SCN5A encodes the α subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.

Riesgo suicida y factores asociados en inStituciones de rehabilitación para adictos a las drogas en la ciudad de Manizales(colombia), 2012 / Suicide risk factor and associated factors in rehabilitation institutions for drug addicts in the city of Manizales (Colombia), 2012

Objetivo: El objetivo de este estudio fue identificar el factor de riesgo suicida según la escala de Plutchik y factores asociados en una población de pacientes internados para rehabilitación por consumo de sustancias en la ciudad de Manizales (Colombia). Materiales y métodos: Estudio de corte transversal con una población de 93 pacientesen proceso de rehabilitación de instituciones para drogadicción de Manizales. Se aplicó el cuestionario de Plutchik para medir riesgo suicida, se aplicaron otros cuestionarios para factores asociados. Resultados: El 57% presentó riesgo suicida según escala de Plutchik, el 94,6% fueron hombres, el 47,3% incurrieron en intento de suicidio, el 51,6% tuvo buena funcionalidad familiar, presentaron una dependencia alcohólica del 44,1%, una proporción de 30,1% de casos de ansiedad y 20,4% de depresión, la baja autoestima fue de 45,2%. Los siguientes factores asociados presentaron relación significativa: consumo de éxtasis (p=0,01), trauma infantil (p=0,000), maltrato físico (p=0,000), maltrato psicológico (p=0,001), maltrato infantil (p=0,01), enfermedad mental(p=0,039), ansiedad (p=0,000). Según prueba t también la depresión (p=0.000), la autoestima (p=0,014), los reingresos al centro de rehabilitación (p=0,015).Conclusiones: El estudio confirma los datos de la literatura con respecto al factor de riesgo suicida y la presencia de otros factores en esta población. Se destaca el papel preponderante del maltrato infantil en todas sus formas en la alta proporción de factor de riesgo suicida en esta población...

Fibroblast KATP currents modulate myocyte electrophysiology in infarcted hearts.

Cardiac metabolism remains altered for an extended period of time after myocardial infarction. Studies have shown fibroblasts from normal hearts express KATP channels in culture. It is unknown whether fibroblasts from infarcted hearts express KATP channels and whether these channels contribute to scar and border zone electrophysiology. KATP channel subunit expression levels were determined in fibroblasts isolated from normal hearts (Fb), and scar (sMI-Fb) and remote (rMI-Fb) regions of left anterior descending coronary artery (LAD) ligated rat hearts. Whole cell KATP current density was determined with patch clamp. Action potential duration (APD) was measured with optical mapping in myocyte-only cultures and heterocellular cultures with fibroblasts with and without 100 µmol/l pinacidil. Whole heart optical mapping was used to assess KATP channel activity following LAD ligation. Pinacidil activated a potassium current (35.4 ± 7.5 pA/pF at 50 mV) in sMI-Fb that was inhibited with 10 µmol/l glibenclamide. Kir6.2 and SUR2 transcript levels were elevated in sMI-Fb. Treatment with Kir6.2 short interfering RNA decreased KATP currents (87%) in sMI-Fb. Treatment with pinacidil decreased APD (26%) in co-cultures with sMI-Fb. APD values were prolonged in LAD ligated hearts after perfusion with glibenclamide. KATP channels are present in fibroblasts from the scar and border zones of infarcted hearts. Activation of fibroblast KATP channels could modulate the electrophysiological substrate beyond the acute ischemic event. Targeting fibroblast KATP channels could represent a novel therapeutic approach to modify border zone electrophysiology after cardiac injury.