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Contexto: La acromegalia es causada en la gran mayoría de los casos por tumores hipofisiarios productores de hormona de crecimiento. Estos tumores suelen ocurrir de manera esporádica y raramente de forma hereditaria. En los últimos años se ha explorado el panorama de las mutaciones y síndromes familiares asociados a la acromegalia y al gigantismo. Objetivo: Esta revisión se concentra en el conocimiento actual de las bases genéticas causantes de la acromegalia familiar. Metodología: Se revisaron las bases de datos electrónicas y textos guías de endocrinología y se resumen las enfermedades genéticas asociadas a acromegalia. Resultados: Las causas genéticas de acromegalia son el complejo de Carney, la neoplasia endocrina múltiple tipo 1, los adenomas pituitarios aislados familiares (FIPA), el acrogigantismo ligado al X (XLAG), la asociación de feocromocitoma/paraganglioma/adenoma pituitario familiar (3P), el síndrome de McCune-Albright (SMA) y la neurofibromatosis tipo 1. Conclusiones: Se debe buscar activamente neoplasia endocrina múltiple en los pacientes con acromegalia mediante la medición de calcio y hormona paratiroidea. Además, siempre debe preguntarse por antecedentes familiares buscando FIPA y en casos muy jóvenes o con manifestaciones asociadas sospechar una causa genética.

If narratives that uphold secular humanism have led to an “unparalleled catastrophe” as Sylvia Wynter notes in an interview with Katherine McKittrick, then it is time to unwrite them. In this essay, I examine the dead as a category that exceeds metaphysical classifications of subject and object and provides alternate possibilities of communication and hybridity. To do so, I call on work by Claire Colebrook, Jacques Derrida, John Durham Peters, Eve Tuck, and Unica Zürn, among others, with the cultural work and words of Sylvia Wynter as a guide and galvanising force. Here, I repopulate the life/death seam with gorgons, witches, fates, and revenge stories. If ghosts are seen simply as other beings, albeit taboo ones like bacteria, or require alternate cultural narratives like villains, or exist both in the symbolic sphere of the mystical and the so-called natural world like roses, what kinds of methodologies can be opened? What do the dead have to say and how do we listen?

Historically, brainstem gliomas have been one of the most difficult types of neoplasms to treat. They comprise 10%–20% of pediatric tumors of the central nervous system. The average age of diagnosis is 7–9 years, without a predilection for gender. The advent of magnetic resonance imaging and radiotherapy has significantly aided in the diagnosis and treatment of brainstem gliomas.

The risk and outcome of deep vein thrombosis (DVT) in patients who sustained spinal cord injury (SCI) remain a challenge. We aimed to assess the incidence, risk, burden, and prophylaxis of DVT after SCI. Thirty-nine studies were identified from among 250 relevant articles based on firstly, broad criterion of DVT among SCI cases. secondly, “risk factors” impacting DVT, thirdly, published reports from apex bodies of global importance such as World Health Organization, Centre for disease control, Atlanta USA, and others were given due weightage for their authenticity. SCI is characterized by loss of motor, sensory, and autonomic function with partial or total damage of the anatomical structure leading to increased risk of thrombogenesis. SCIs present a higher risk of venous DVT constituting 9.7% of deaths in the 1st year of follow-up. Currently, prophylaxis with mechanical methods, vena cava filters and antithrombotic chemoprophylaxis in SCI are interventions for the management of DVT. DVT in SCI patients is not uncommon and needs a high index of suspicion and implementation of institutional prophylaxis protocol.

We report the case of a five-year old boy with autism who demonstrated unanticipated increases in self-injurious behavior that had decreased following intervention. On these occasions, elevated self-injury was linked to physician diagnosed otitis media. The findings support an emerging clinical literature documenting possible negative effects from medical influences on challenging behaviors. [ABSTRACT FROM AUTHOR]

Objetivo: Establecer la frecuencia y las características demográficas de pacientes con diagnóstico de trombosis de stent coronario atendidos en el Hospital Universitario Clínica San Rafael, de Bogotá, durante un periodo de 24 meses. Métodos: Estudio descriptivo retrospectivo en el que se revisaron las historias clínicas de pacientes mayores de 18 años con diagnóstico de trombosis de stent coronario confirmado mediante arteriografías realizadas en dicha institución en un lapso de 24 meses, atendidos de forma ambulatoria, en los departamentos de urgencias y/o hospitalización. Resultados: Se realizaron 890 arteriografías con angioplastia e implante de stent, en las que se encontró un 2,7% de frecuencia de trombosis del stent; en el 70% los hombres presentaron un promedio de edad menor respecto a las mujeres (63,0 vs. 70,3 años). Las comorbilidades más frecuentes fueron: hipertensión arterial en el 65%, diabetes mellitus en el 25% y enfermedad renal crónica en el 10% de los casos. El promedio de fracción de eyección del ventrículo izquierdo fue del 38,7%. Incidentalmente, durante el análisis de datos se encontró fenómeno de reestenosis del stent en el 14,5% (n = 36) entre quienes se les hizo angioplastia más implante de stent. Conclusiones: La frecuencia de trombosis del stent coronario en la población analizada es similar a la reportada en la literatura mundial. Es más común en el sexo masculino, a una edad de aparición más temprana asociada con un deterioro marcado de la función ventricular izquierda. La alta frecuencia de evento de reestenosis del stent requiere más estudios en el futuro.

Introduction: Neurocysticercosis (NCC) is a common parasitic infection of the central nervous system caused by the larvae of the Taenia solium. Spinal cord involvement is very uncommon. Clinical case: A female patient with a history of NCC presented with chronic and recurrent headache associated with motor and sensory deficit, which develops tonic-clonic convulsion, with spatial disorientation. She also had intracranial hypertension syndrome, meningitis syndrome, and pyramidal sygns suggestive of spinal NCC. Conclusions: Neurocysticercosis usually occurs in developing countries and should be considered as a differential diagnosis of neurological diseases. Early diagnosis and treatment are mandatory, as well as education to the community to primary prevention.

Abstract Background Coxsackievirus B3 (CVB3) induces myocarditis, an inflammatory heart disease, which affects men more than women. Toll-like receptor (TLR) signaling has been shown to determine the severity of CVB3-induced myocarditis. No direct role for signaling through TLR2 had been shown in myocarditis although published studies show that cardiac myosin is an endogenous TLR2 ligand and stimulates pro-inflammatory cytokine expression by dendritic cells in vitro. The goal of this study is to determine which TLRs show differential expression in CVB3 infected mice corresponding to male susceptibility and female resistance in this disease. Methods Male and female C57Bl/6 mice were infected with 102 PFU CVB3 and killed on day 3 or 6 post infection. Hearts were evaluated for virus titer, myocardial inflammation, and TLR mRNA expression by PCR array and microarray analysis. Splenic lymphocytes only were evaluated by flow cytometry for the number of TLR+/CD3+, TLR+/CD4+, TLR+F4/80+ and TLR+/CD11c+ subpopulations and the mean fluorescence intensity to assess upregulation of TLR expression on these cells. Mice were additionally treated with PAM3CSK4 (TLR2 agonist) or ultrapure LPS (TLR4 agonist) on the same day as CVB3 infection or 3 days post infection to confirm their role in myocarditis susceptibility. Results Despite equivalent viral titers, male C57Bl/6 mice develop more severe myocarditis than females by day 6 after infection. Microarray analysis shows a differential expression of TLR2 at day 3 with female mice having higher levels of TLR2 gene expression compared to males. Disease severity correlates to greater TLR4 protein expression on splenic lymphocytes in male mice 3 days after infection while resistance in females correlates to preferential TLR2 expression, especially in spleen lymphocytes. Treating male mice with PAM reduced mortality from 55% in control CVB3 infected animals to 10%. Treating female mice with LPS increased mortality from 0% in control infected animals to 60%. Conclusion CVB3 infection causes an up-regulation of TLR2 in female and of TLR4 in male mice and this differential expression between the sexes contributes to disease resistance of females and susceptibility of males. While previous reports demonstrated a pathogenic role for TLR4 this is the first report that TLR2 is preferentially up-regulated in CVB3 infected female mice or that signaling through this TLR directly causes myocarditis resistance.

Abstract Background Viral myocarditis is a major cause of sudden unexpected death in children and young adults. Until recently, coxsackievirus B3 (CVB3) has been the most commonly implicated virus in myocarditis. At present, no standard diagnosis is generally accepted due to the insensitivity of traditional diagnostic tests. This has prompted health professionals to seek new diagnostic approaches, which resulted in the emergence of new molecular pathological tests and a more detailed immunohistochemical and histopathological analysis. When supplemented with immunohistochemistry and molecular pathology, conventional histopathology may provide important clues regarding myocarditis underlying etiology. Methods This study is based on post-mortem samples from sudden unexpected death victims and controls who were investigated prospectively. Immunohistochemical investigations for the detection of the enteroviral capsid protein VP1 and the characterization and quantification of myocardial inflammatory reactions as well as molecular pathological methods for enteroviral genome detection were performed. Results Overall, 48 sudden unexpected death victims were enrolled. As for controls, 37 cases of unnatural traffic accident victims were studied. Enterovirus was detected in 6 sudden unexpected death cases (12.5 %). The control samples were completely enterovirus negative. Furthermore, the enteroviral capsid protein VP1 in the myocardium was detected in enterovirus-positive cases revealed by means of reverse transcriptase-polymerase chain reaction (RT-PCR). Unlike control samples, immunohistochemical investigations showed a significant presence of T and B lymphocytes in sudden unexpected death victims. Conclusions Our findings demonstrate clearly a higher prevalence of viral myocarditis in cases of sudden unexpected death compared to control subjects, suggesting that coxsackie B enterovirus may contribute to myocarditis pathogenesis significantly.

Abstract Background Both coxsackievirus B3 (CVB3) and influenza A virus (IAV; H1N1) produce sexually dimorphic infections in C57BL/6 mice. Gonadal steroids can modulate sex differences in response to both viruses. Here, the effect of sex chromosomal complement in response to viral infection was evaluated using four core genotypes (FCG) mice, where the Sry gene is deleted from the Y chromosome, and in some mice is inserted into an autosomal chromosome. This results in four genotypes: XX or XY gonadal females (XXF and XYF), and XX or XY gonadal males (XXM and XYM). The FCG model permits evaluation of the impact of the sex chromosome complement independent of the gonadal phenotype. Methods Wild-type (WT) male and female C57BL/6 mice were assigned to remain intact or be gonadectomized (Gdx) and all FCG mice on a C57BL/6 background were Gdx. Mice were infected with either CVB3 or mouse-adapted IAV, A/Puerto Rico/8/1934 (PR8), and monitored for changes in immunity, virus titers, morbidity, or mortality. Results In CVB3 infection, mortality was increased in WT males compared to females and males developed more severe cardiac inflammation. Gonadectomy suppressed male, but increased female, susceptibility to CVB3. Infection with IAV resulted in greater morbidity and mortality in WT females compared with males and this sex difference was significantly reduced by gonadectomy of male and female mice. In Gdx FCG mice infected with CVB3, XY mice were less susceptible than XX mice. Protection correlated with increased CD4+ forkhead box P3 (FoxP3)+ T regulatory (Treg) cell activation in these animals. Neither CD4+ interferon (IFN)γ (T helper 1 (Th1)) nor CD4+ interleukin (IL)-4+ (Th2) responses differed among the FCG mice during CVB3 infection. Infection of Gdx FCG mice revealed no effect of sex chromosome complement on morbidity or mortality following IAV infection. Conclusions These studies indicate that sex chromosome complement can influence pathogenicity of some, but not all, viruses.

Abstract CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT) cells and a subpopulation of γδ T cells expressing the Vγ4 T cell receptor (TCR) recognize CD1d. NKT and Vγ4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vγ4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFβ, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vγ4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vγ4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3) myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection.

Abstract Background Conserved proteins preferentially expressed in synaptic terminals of the nervous system are likely to play a significant role in brain function. We have previously identified and molecularly characterized the Sap47 gene which codes for a novel synapse associated protein of 47 kDa in Drosophila. Sequence comparison identifies homologous proteins in numerous species including C. elegans, fish, mouse and human. First hints as to the function of this novel protein family can be obtained by generating mutants for the Sap47 gene in Drosophila. Results Attempts to eliminate the Sap47 gene through targeted mutagenesis by homologous recombination were unsuccessful. However, several mutants were generated by transposon remobilization after an appropriate insertion line had become available from the Drosophila P-element screen of the Bellen/Hoskins/Rubin/Spradling labs. Characterization of various deletions in the Sap47 gene due to imprecise excision of the P-element identified three null mutants and three hypomorphic mutants. Null mutants are viable and fertile and show no gross structural or obvious behavioural deficits. For cell-specific over-expression and "rescue" of the knock-out flies a transgenic line was generated which expresses the most abundant transcript under the control of the yeast enhancer UAS. In addition, knock-down of the Sap47 gene was achieved by generating 31 transgenic lines expressing Sap47 RNAi constructs, again under UAS control. When driven by a ubiquitously expressed yeast transcription factor (GAL4), Sap47 gene suppression in several of these lines is highly efficient resulting in residual SAP47 protein concentrations in heads as low as 6% of wild type levels. Conclusion The conserved synaptic protein SAP47 of Drosophila is not essential for basic synaptic function. The Sap47 gene region may be refractory to targeted mutagenesis by homologous recombination. RNAi using a construct linking genomic DNA to anti-sense cDNA in our hands is not more effective than using a cDNA-anti-sense cDNA construct. The tools developed in this study will now allow a detailed analysis of the molecular, cellular and systemic function of the SAP47 protein in Drosophila.

Background: Arterial stiffness measured by total pulse wave velocity (T-PWV) is associated with increased risk of multiple age-related diseases. T-PWV can be described by structural (S-PWV) and load-dependent (LD-PWV) arterial stiffening. T-cells have been associated with arterial remodeling, blood pressure, and arterial stiffness in humans and animals; however, it is unknown whether T-cells are related to S-PWV or LD-PWV. Therefore, we evaluated the cross-sectional associations of peripheral T-cell subpopulations with T-PWV, S-PWV, and LD-PWV stiffness., Methods: Peripheral blood T-cells were characterized using flow cytometry and the carotid artery was measured using B-mode ultrasound to calculate T-PWV at the baseline examination in a subset of the Multi-Ethnic Study of Atherosclerosis (MESA, n=1,984). A participant-specific exponential model was used to calculate S-PWV and LD-PWV based on elastic modulus and blood pressure gradients. The associations between five primary (p-significance<0.01) and twenty-five exploratory (p-significance<0.05) immune cell subpopulations, per 1-SD increment, and arterial stiffness measures were assessed using adjusted, linear regressions., Results: For the primary analysis, higher CD4 + CD28 - CD57 + T-cells were associated with higher LD-PWV (β=0.04 m/s, p<0.01) after adjusting for co-variates. For the exploratory analysis, T-cell subpopulations that commonly shift with aging towards memory and differentiated/immunosenescent phenotypes were associated with greater T-PWV, S-PWV, and LD-PWV after adjusting for co-variates., Conclusions: In this cross-sectional study, several T-cell subpopulations commonly associated with aging were related with measures of arterial stiffness. Longitudinal studies that examine changes in T-cell subpopulations and measures of arterial stiffness are warranted.

Myocarditis is an inflammation of the heart muscle often associated with viral infections and can lead to dilated cardiomyopathy. Interferon-induced transmembrane protein 3 (IFITM3) is a small endosomal membrane protein with anti-viral activity against multiple viruses and is also implicated in non-infectious diseases such as cancer and Alzheimer's Disease. Since the IFITM3 proteins are expressed both in T cells and in cardiomyocytes, it is reasonable to hypothesize that these molecules could affect myocarditis either through their effect on the autoimmune response or through direct modulation of cardiomyocyte damage. The aim of this study was to investigate the role of IFITM3 in experimental autoimmune myocarditis (EAM)-mediated myocardial injury. Immunization of rats with cardiac myosin results in substantial cardiac inflammation and is associated with increased expression of IFITM3 after 21 days. In vivo IFITM3 shRNA knockdown using the lentivirus transfection method reduced cardiac injury while restoring IFITM3 expression reversed the protective effect of IFITM3 RNA interference. To determine the direct impact of IFITM3, the rat ventricular cell line, H9c2, was treated with palmitic acid which causes apoptosis in these cells. Suppressing IFITM3 expression protects H9c2 cells while overexpressing IFITM3 enhances cell injury. JAK inhibitors reduced IFITM3-mediated myocardial cell injury. In conclusion, IFITM3 may mediate myocardial injury in EAM rats and palmitic acid-induced damage to H9c2 cells through the JAK2/STAT3 pathway., Competing Interests: Declaration of Competing Interest The authors have no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In this study, we aimed to evaluate the association of innate and adaptive immune cell subsets in peripheral blood mononuclear cells (PBMCs) with hip fracture. To conduct this study, we used data from the Cardiovascular Health Study (CHS), a U.S. multicenter observational cohort of community-dwelling men and women aged ≥ 65 years. Twenty-five immune cell phenotypes were measured by flow cytometry from cryopreserved PBMCs of CHS participants collected in 1998-1999. The natural killer (NK), γδ T, T helper 17 (Th17), and differentiated/senescent CD4 + CD28 - T cell subsets were pre-specified as primary subsets of interest. Hip fracture incidence was assessed prospectively by review of hospitalization records. Multivariable Cox hazard models evaluated associations of immune cell phenotypes with incident hip fracture in sex-stratified and combined analyses. Among 1928 persons, 259 hip fractures occurred over a median 9.7 years of follow-up. In women, NK cells were inversely associated with hip fracture [hazard ratio (HR) 0.77, 95% confidence interval (CI) 0.60-0.99 per one standard deviation higher value] and Th17 cells were positively associated with hip fracture [HR 1.18, 95% CI 1.01-1.39]. In men, γδ T cells were inversely associated with hip fracture [HR 0.60, 95% CI 0.37-0.98]. None of the measured immune cell phenotypes were significantly associated with hip fracture incidence in combined analyses. In this large prospective cohort of older adults, potentially important sex differences in the associations of immune cell phenotypes and hip fracture were identified. However, immune cell phenotypes had no association with hip fracture in analyses combining men and women., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In recent years, many studies have addressed cardiac aging and related diseases. This study aims to understand the research trend of cardiac aging and find new hot issues., Methods: We searched the web of science core collection database for articles published between 2003 and 2022 on the topic of "cardiac aging." Complete information including keywords, publication year, journal title, country, organization, and author were extracted for analysis. The VOS viewer software was used to generate network maps of keywords, countries, institutions, and author relationships for visual network analysis., Results: A total of 1002 papers were analyzed in the study. Overall, the number of annual publications on cardiac aging has increased since 2009, and new hot topics are emerging. The top 3 countries with the most publications were the United States (471 articles), China (209 articles) and Italy (101 articles). The University of Washington published the most papers (35 articles). The cluster analysis with author as the keyword found that the connections among different scholars are scattered and clustered in a small range. Network analysis based on keyword co-occurrence and year of publication identified relevant features and trends in cardiac aging research. According to the results of cluster analysis, all the articles are divided into 4 topics: "mechanisms of cardiac aging", "prevention and treatment of cardiac aging", "characteristics of cardiac aging", and "others." In recent years, the mechanism and treatment of cardiac aging have attracted the most attention. In both studies, animal models are used more often than in human populations. Mitochondrial dysfunction, autophagy and mitochondrial autophagy are hotspots in current research., Conclusion: In this study, bibliometric analysis was used to analyze the research trend of cardiac aging in the past 20 years. The mechanism and treatment of cardiac aging are the most concerned contents. Mitochondrial dysfunction, autophagy and mitophagy are the focus of future research on cardiac aging., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The team timeout (TTO) is a safety checklist to be performed by the surgical team prior to incision. Exchange of critical information is, however, important not only before but also during an operation and members of surgical teams frequently feel insufficiently informed by the operating surgeon about the ongoing procedure. To improve the exchange of critical information during surgery, the StOP?-protocol was developed: At appropriate moments during the procedure, the leading surgeon briefly interrupts the operation and informs the team about the current Status (St) and next steps/objectives (O) of the operation, as well as possible Problems (P), and encourages questions of other team members (?). The StOP?-protocol draws attention to the team. Anticipating the occurrence of StOP?-protocols may support awareness of team processes and quality issues from the beginning and thus support other interventions such as the TTO; however, it also may signal an additional demand and contribute to a phenomenon akin to "checklist fatigue." We investigated if, and how, the introduction of the StOP?-protocol influenced TTO quality., Methods: This was a prospective intervention study employing a pre-post design. In the visceral surgical departments of two university hospitals and one urban hospital the quality of 356 timeouts (out of 371 included operation) was assessed by external observers before (154) and after (202) the introduction of the StOP?-briefing. Timeout quality was rated in terms of timeout completeness (number of checklist items mentioned) and timeout quality (engagement, pace, social atmosphere, noise)., Results: As compared to the baseline, after the implementation of the StOP?-protocol, observed timeouts had higher completeness ratings ( F  = 8.69, p  = 0.003) and were rated by observers as higher in engagement ( F  = 13.48, p  < 0.001), less rushed ( F  = 14.85, p  < 0.001), in a better social atmosphere ( F  = 5.83, p  < 0.016) and less noisy ( F  = 5.35, p  < 0.022)., Conclusion: Aspects of TTO are affected by the anticipation of StOP?-protocols. However, rather than harming the timeout goals by inducing "checklist fatigue," it increases completeness and quality of the team timeout., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Timm-Holzer, Tschan, Keller, Semmer, Zimmermann, Huber, Hübner, Candinas, Demartines, Weber and Beldi.)

Introduction: Cellular senescence is a feature of aging implicated in the pathophysiology of diabetes mellitus (DM). Whether senescent lymphocytes are associated with the future occurrence of DM is uncertain., Methods: We used cryopreserved peripheral blood mononuclear cells collected from 1860 Cardiovascular Health Study participants (average age 80.2 years) and flow cytometry immunophenotyping to evaluate the longitudinal relationships of naive (CD45RA + ), memory (CD45RO + ), senescent (CD28 - ), and T effector memory RA + (TEMRA) (CD28 - CD57 + CD45RA + ) CD4 + and CD8 + T cells, and memory B cells (CD19 + CD27 + ), with the risk of incident DM. In exploratory analyses we evaluated the relationships of 13 additional innate lymphocyte and CD4 + and CD8 + subsets with incident DM risk., Results: Over a median follow-up time of 8.9 years, 155 cases of incident DM occurred. In Cox models adjusted for demographic variables (age, sex, race, study site and flow cytometry analytical batch) or diabetes risk factors (demographic variables plus education, body mass index, smoking status, alcohol use, systolic blood pressure, hypertension medication use and physical activity), no significant associations were observed for any CD4 + , CD8 + or CD19 + cell phenotypes with incident DM., Conclusions: These results suggest the frequencies of naive, memory and senescent T cells and memory B cells are not strongly associated with incident DM risk in older adults., (© 2022 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.)

Aims: Circulating inflammatory markers are associated with incident heart failure (HF), but prospective data on associations of immune cell subsets with incident HF are lacking. We determined the associations of immune cell subsets with incident HF as well as HF subtypes [with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF)]., Methods and Results: Peripheral blood immune cell subsets were measured in adults from the Multi-Ethnic Study of Atherosclerosis (MESA) and Cardiovascular Health Study (CHS). Cox proportional hazard models adjusted for demographics, HF risk factors, and cytomegalovirus serostatus were used to evaluate the association of the immune cell subsets with incident HF. The average age of the MESA cohort at the time of immune cell measurements was 63.0 ± 10.4 years with 51% women, and in the CHS cohort, it was 79.6 ± 4.4 years with 62% women. In the meta-analysis of CHS and MESA, a higher proportion of CD4+ T helper (Th) 1 cells (per one standard deviation) was associated with a lower risk of incident HF [hazard ratio (HR) 0.91, (95% CI 0.83-0.99), P = 0.03]. Specifically, higher proportion of CD4+ Th1 cells was significantly associated with a lower risk of HFrEF [HR 0.73, (95% CI 0.62-0.85), <0.001] after correction for multiple testing. No association was observed with HFpEF. No other cell subsets were associated with incident HF., Conclusions: We observed that higher proportions of CD4+ Th1 cells were associated with a lower risk of incident HFrEF in two distinct population-based cohorts, with similar effect sizes in both cohorts demonstrating replicability. Although unexpected, the consistency of this finding across cohorts merits further investigation., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Aims: Despite mechanistic data implicating unresolving inflammation in stroke pathogenesis, data regarding circulating immune cell phenotypes - key determinants of inflammation propagation versus resolution - and incident stroke are lacking. Therefore, we aimed to comprehensively define associations of circulating immune phenotypes and activation profiles with incident stroke., Methods: We investigated circulating leukocyte phenotypes and activation profiles with incident adjudicated stroke in 2104 diverse adults from the Multi-Ethnic Study of Atherosclerosis (MESA) followed over a median of 16.6 years. Cryopreserved cells from the MESA baseline examination were thawed and myeloid and lymphoid lineage cell subsets were measured using polychromatic flow cytometry and intracellular cytokine activation staining. We analyzed multivariable-adjusted associations of cell phenotypes, as a proportion of parent cell subsets, with incident stroke (overall) and ischemic stroke using Cox regression models., Results: We observed associations of intermediate monocytes, early-activated CD4 + T cells, and both CD4 + and CD8 + T cells producing interleukin-4 after cytokine stimulation (T h2 and T c2 , respectively) with higher risk for incident stroke; effect sizes ranged from 35% to 62% relative increases in risk for stroke. Meanwhile, differentiated and memory T cell phenotypes were associated with lower risk for incident stroke. In sex-stratified analyses, positive and negative associations were especially strong among men but null among women., Conclusions: Circulating IL-4 producing T cells and intermediate monocytes were significantly associated with incident stroke over nearly two decades of follow-up. These associations were stronger among men and not among women. Further translational studies are warranted to define more precise targets for prognosis and intervention., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Assessing students on-the-fly is an important but challenging task for teachers. In initial teacher education, a call has been made to better prepare pre-service teachers for this complex task. Advances in technology allow this training to be done through authentic learning environments, such as video-based simulations. To understand the learning process in such simulations, it is necessary to determine how cognitive and motivational learner characteristics influence situative learning experiences, such as the perception of authenticity, cognitive load, and situational motivation, during the simulation and how they affect aspects of performance. In the present study, N  = 150 pre-service teachers from German universities voluntarily participated in a validated online video-based simulation targeting on-the-fly student assessments. We identified three profiles of learner characteristics: one with above average knowledge, one with above average motivational-affective traits, and one with below average knowledge and motivational-affective traits. These profiles do not differ in the perception of the authenticity of the simulation. Furthermore, the results indicate that the profiled learners navigate differently through the simulation. The knowledgeable learners tended to outperform learners of the other two profiles by using more learning time for the assessment process, also resulting in higher judgment accuracy. The study highlights how learner characteristics and processes interact, which helps to better understand individual learning processes in simulations. Thus, the findings may be used as a basis for future simulation research with a focus on adaptive and individual support., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2022.)

Background: Operations require collaboration between surgeons, anaesthetia professionals, and nurses. The aim of this study was to determine whether intraoperative briefings influence patient outcomes., Methods: In a before-and-after controlled trial (9 months baseline; 9 months intervention), intraoperative briefings were introduced in four general surgery centres between 2015 and 2018. During the operation, the responsible surgeon (most senior surgeon present) briefed the surgical team using the StOP? protocol about: progress of the operation (Status), next steps (Objectives), possible problems (Problems), and encouraged asking questions (?). Differences between baseline and intervention were analysed regarding surgical-site infections (primary outcome), mortality, unplanned reoperations, and duration of hospital stay (secondary outcomes), using inverse probability of treatment (IPT) weighting based on propensity scores., Results: In total, 8256 patients underwent surgery in the study. Endpoint data were available for 7745 patients (93.8 per cent). IPT-weighted and adjusted intention-to-treat analyses showed no differences in surgical-site infections between baseline and intervention (9.8 versus 9.6 per cent respectively; adjusted difference (AD) -0.15 (95 per cent c.i. -1.45 to 1.14) per cent; odds ratio (OR) 0.92, 95 per cent c.i. 0.83 to 1.15; P = 0.797), but there were reductions in mortality (1.6 versus 1.1 per cent; AD -0.54 (-1.04 to -0.03) per cent; OR 0.60, 0.39 to 0.92; P = 0.018), unplanned reoperations (6.4 versus 4.8 per cent; AD -1.66 (-2.69 to -0.62) per cent; OR 0.72, 0.59 to 0.89; P = 0.002), and fewer prolonged hospital stays (21.6 versus 19.8 per cent; AD -1.82 (-3.48 to -0.15) per cent; OR 0.87, 0.77 to 0.98; P = 0.024)., Conclusion: Short intraoperative briefings improve patient outcomes and should be performed routinely., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd.)

BackgroundImmunomodulatory therapy may help prevent heart failure (HF). Data on immune cells and myocardial remodeling in older adults with cardiovascular risk factors are limited.MethodsIn the Multi-Ethnic Study of Atherosclerosis cohort, 869 adults had 19 peripheral immune cell subsets measured and underwent cardiac MRI during the baseline exam, of which 321 had assessment of left ventricular global circumferential strain (LV-GCS). We used linear regression with adjustment for demographics, cardiovascular risk factors, and cytomegalovirus serostatus to evaluate the cross-sectional association of immune cell subsets with left ventricular mass index (LVMI) and LV-GCS.ResultsThe average age of the cohort was 61.6 ± 10.0 years and 53% were women. Higher proportions of γ/δ T cells were associated with lower absolute (worse) LV-GCS (-0.105% [95% CI -0.164%, -0.046%] per 1 SD higher proportion of γ/δ T cells, P = 0.0006). This association remained significant after Bonferroni's correction. Higher proportions of classical monocytes were associated with worse absolute LV-GCS (-0.04% [95% CI -0.07%, 0.00%] per 1 SD higher proportion of classical monocytes, P = 0.04). This did not meet significance after Bonferroni's correction. There were no other significant associations with LV-GCS or LVMI.ConclusionPathways associated with γ/δ T cells may be potential targets for immunomodulatory therapy targeted at HF prevention in populations at risk.FundingContracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and grant R01 HL98077 from the National Heart, Lung, and Blood Institute/NIH and grants KL2TR001424, UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences/NIH.

[Figure: see text].

Background: Hypertension is a major source of cardiovascular morbidity and mortality. Recent evidence from mouse models, genetic, and cross-sectional human studies suggest increased proportions of selected immune cell subsets may be associated with levels of systolic blood pressure (SBP)., Methods: We assayed immune cells from cryopreserved samples collected at the baseline examination (2000-2002) from 1195 participants from the multi-ethnic study of atherosclerosis (MESA). We used linear mixed models, with adjustment for age, sex, race/ethnicity, smoking, exercise, body mass index, education, diabetes, and cytomegalovirus titers, to estimate the associations between 30 immune cell subsets (4 of which were a priori hypotheses) and repeated measures of SBP (baseline and up to four follow-up measures) over 10 years. The analysis provides estimates of the association with blood pressure level., Results: The mean age of the MESA participants at baseline was 64 ± 10 years and 53% were male. A one standard deviation (1-SD) increment in the proportion of γδ T cells was associated with 2.40 mmHg [95% confidence interval (CI) 1.34-3.42] higher average systolic blood pressure; and for natural killer cells, a 1-SD increment was associated with 1.88 mmHg (95% CI 0.82-2.94) higher average level of systolic blood pressure. A 1-SD increment in classical monocytes (CD14 ++ CD16 - ) was associated with 2.01 mmHG (95% CI 0.79-3.24) lower average systolic blood pressure. There were no associations of CD4 + T helper cell subsets with average systolic blood pressure., Conclusion: These findings suggest that the innate immune system plays a role in levels of SBP whereas there were no associations with adaptive immune cells.

Background and Aims: Cell-mediated immunity is implicated in atherosclerosis. We evaluated whether innate and adaptive immune cell subsets in peripheral blood are risk factors for coronary heart disease., Methods: A nested case-cohort study (n = 2155) was performed within the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS). Cases of incident myocardial infarction (MI) and incident angina (n = 880 total cases) were compared with a cohort random sample (n = 1275). Immune cell phenotypes (n = 34, including CD14 + monocytes, natural killer cells, γδ T cells, CD4 + , CD8 + and CD19 + lymphocyte subsets) were measured from cryopreserved cells by flow cytometry. Cox proportional hazards models with adjustment for cardiovascular disease risk factors were used to evaluate associations of cell phenotypes with incident MI and a composite phenotype of incident MI or incident angina (MI-angina) over a median 9.3 years of follow-up. Th1, Th2, Th17, T regulatory (CD4 + CD25 + CD127 - ), naive (CD4 + CD45RA + ), memory (CD4 + CD45RO + ), and CD4 + CD28 - cells were specified as primary hypotheses. In secondary analyses, 27 additional cell phenotypes were investigated., Results: After correction for multiple testing, there were no statistically significant associations of CD4 + naive, memory, CD28 - , or T helper cell subsets with MI or MI-angina in MESA, CHS, or combined-cohort meta analyses. Null associations were also observed for monocyte subsets, natural killer cells, γδ T cells, CD19 + B cell and differentiated CD4 + and CD8 + cell subsets., Conclusions: The proportions of peripheral blood monocyte and lymphocyte subsets are not strongly related to the future occurrence of MI or angina in adults free of autoimmune disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Cox proportional hazards regression models are used to evaluate associations between exposures of interest and time-to-event outcomes in observational data. When exposures are measured on only a sample of participants, as they are in a case-cohort design, the sampling weights must be incorporated into the regression model to obtain unbiased estimating equations., Methods: Robust Cox methods have been developed to better estimate associations when there are influential outliers in the exposure of interest, but these robust methods do not incorporate sampling weights. In this paper, we extend these robust methods, which already incorporate influence weights, so that they also accommodate sampling weights., Results: Simulations illustrate that in the presence of influential outliers, the association estimate from the weighted robust method is closer to the true value than the estimate from traditional weighted Cox regression. As expected, in the absence of outliers, the use of robust methods yields a small loss of efficiency. Using data from a case-cohort study that is nested within the Multi-Ethnic Study of Atherosclerosis (MESA) longitudinal cohort study, we illustrate differences between traditional and robust weighted Cox association estimates for the relationships between immune cell traits and risk of stroke., Conclusions: Robust weighted Cox regression methods are a new tool to analyze time-to-event data with sampling, e.g. case-cohort data, when exposures of interest contain outliers.

Background: Teams that regularly step back from action and deliberately reflect on their performance and strategies show higher performance. Ad hoc emergency teams with changing team composition cannot develop such habits but may engage in short postaction reflection to discuss shortcomings of past performance and potential adaptations of their strategies for future similar tasks. This study aimed to test the effect of a short postaction self-led reflective team briefing on resuscitation performance in a simulator setting in terms of three performance parameters: hands-on time, coordination between chest compression and ventilation, and defibrillation., Methods: We performed a randomised controlled trial including 56 ad hoc formed teams of three fourth-year medical students each. All groups performed a resuscitation task, followed by a self-guided reflective briefing, based on a general instruction (n=28 teams), or an unrelated discussion session (control condition; n=29), followed by a second resuscitation task in the same team composition., Results: Adjusted for performance in the first task, teams in the reflection condition showed higher performance gain in the second resuscitation than teams in the control condition (6.21 percentage points (95% CI 1.31 to 11.10, p<0.001)) for basic hands-on performance; 15.0 percentage points (95% CI 2 to 28, p<0.001) for coordinative performance but non-significantly lower performance for defibrillation (-9%, 95% CI -27% to -9%, p=0.312)., Conclusion: Even very short self-led postaction reflective briefings enhance basic resuscitation performance in ad hoc groups but may not influence more complex aspects of the task. We recommend including short self-led team debriefings as part of simulator training., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Cell-mediated immunity is implicated in glucose homeostasis and insulin resistance. Whether the levels of innate and adaptive immune cells in peripheral blood are risk factors for incident type 2 diabetes (T2D) remains unknown. We hypothesized that the proportions of naive, memory, CD28-, Th17, and T regulatory CD4+ cells would be associated with incident T2D. In secondary analyses, we evaluated the relationships of 28 additional immune cell phenotypes with T2D., Design: Immune cell phenotypes (n = 33) were measured by flow cytometry using cryopreserved cells collected from 1113 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) at the baseline examination (2000-2002). Cox proportional hazards models were used to evaluate associations of immune cell phenotypes with incident T2D over a median follow-up of 9.1 years, adjusted for age, sex, race/ethnicity, educational status, and body mass index., Results: Incident T2D was observed for 120 participants. None of the cell phenotypes included in the primary hypotheses were significantly associated with T2D (all P > 0.05). Among the secondary immune cells studied, a higher proportion of CD19+CD27+ B cells was associated with a reduced risk of T2D (hazard ratio: 0.72 (95% confidence interval: 0.56, 0.93), per 1-standard deviation (16%) increase). This association was no longer significant after correction for the multiple cell phenotypes tested (P > 0.0015)., Conclusions: Our results suggest that the frequencies of several subsets of monocytes, innate lymphocytes, and CD4+ and CD8+ T cells in circulating blood are not related to the future onset of T2D. Higher levels of CD19+CD27+ B cells may be associated with decreased T2D risk., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: The influence of online physician ratings is growing, yet their interpretation remains difficult. Our aim was to analyze the online content of urogynecologists on 1 website to transform these ratings into practical tools for care improvement., Methods: This cross-sectional analysis studied the ratings and reviews of every board-certified urogynecologist listed on Healthgrades.com. The ratio of 5:1 ratings was compared between various physician characteristics and practice qualities. Four investigators classified narrative reviews into one or more of the following themes: about the (1) physician, (2) clinical outcomes, (3) and/or staff. The content of the narrative reviews was analyzed, and word clouds were created to understand the primary motivators behind ratings., Results: In February 2018, the Healthgrades pages for 689 urogynecologists were evaluated, and 523 physicians were included in the study. Higher 5:1 ratios were found among men versus women (4.0 vs 3.0; P < 0.01), and OB-GYN-trained versus urology-trained (4.0 vs 2.2; P < 0.01) physicians. A benchmarking rubric was developed to illustrate the 5:1 ratio distribution for all physicians stratified by number of ratings. A total of 3300 narrative reviews were assigned themes with strong inter- and intrarater reliability (Table 3). Physician qualities most influenced extreme scores (1 or 5 stars), whereas average reviews were more influenced by staff. Commonly discussed physician qualities included professionalism, time with patient, and counseling., Conclusions: Using the 5:1 rating ratio and simplified review themes as tools, physicians can understand what their ratings signify both as an indicator of their online reputation compared with their peers and as a means for improving the patient experience.

The Maji ya Chai River in Northern Tanzania, a fluoride-rich tropical area, shows a seasonal variation of natural organic matter (NOM) and fluoride concentration. Water samples collected monthly during one year from two locations of the River were characterized. High levels of precipitation in the rainy seasons increased the total organic carbon (TOC) concentration to as high as 36 mgC L -1 and diluted the fluoride concentration from a dry season high of 24 mg L -1 to <4 mg L -1 . A black water swamp in the Maji ya Chai River catchment was confirmed as the main source of NOM, fluoride, salinity, and inorganic carbon entering the River in the rainy season. The water samples were filtered by a number of nanofiltration/reverse osmosis (NF/RO) membranes to identify the retention mechanisms and the impact of varying water quality on treatability. While the denser membranes removed fluoride due to size exclusion, for the membranes with bigger pore radius charge repulsion was the dominant mechanism of fluoride retention. Regardless of the seasonal conditions a TOC concentration <2 mgC L -1 was achieved by all membranes at 50% recovery, as NF/RO membranes remove TOC mainly by size exclusion. Two swamp water samples, containing high TOC (79 and 183 mgC L -1 ), were filtered to determine the characteristics of NOM which permeate the NF/RO membranes. Liquid chromatography organic carbon detection (LC-OCD) was used to characterize the fractions in the permeates, consisting of about 1% of the original NOM. The average molecular weight of the permeate humic substances (HS) was more than four times larger than the membrane molecular weight cut-off. This suggests that large HS can permeate the NF/RO membranes through diffusion. Moreover, the relatively high aromaticity of the permeate HS (1.7-5.2 L mg -1  m -1 ) indicated the high content of hydrophobic-aromatic fractions., (Copyright © 2018 Elsevier B.V. All rights reserved.)

For students, cognitive and motivational-affective characteristics are the most powerful prerequisites for successful learning. For teachers, judgments on their students' characteristics shape how they plan and implement instructional activities in order to offer individual learning support. On the student side, research is starting to find out more about the interplay of different characteristics within individual students. On the teacher side, studies still regard teacher judgment accuracy of only single characteristics. By taking a person-centered approach, regarding NS = 503 students and their NT = 41 mathematics and languages arts teachers, our manuscript joined teacher and student perspectives on student characteristics interplay and suggests methodology to compare them. We found that student assessments suggested ample diversity regarding this interplay-and teachers did not perceive this. In their views, "homogeneous" sets of average characteristics were dominant. Findings suggest addressing students' views and the diagnosis of their characteristics in teacher education to enable individual support., Competing Interests: The authors have declared that no competing interests exist.

Sexual bias is a hallmark in various diseases. This review evaluates sexual dimorphism in clinical and experimental coxsackievirus B3 (CVB3) myocarditis, and how sex bias in the experimental disease changes with increased age. Coxsackieviruses are major causes of viral myocarditis, an inflammation of the heart muscle, which is more frequent and severe in men than women. Young male mice infected with CVB3 develop heart-specific autoimmunity and severe myocarditis. Females infected during estrus (high estradiol) develop T-regulatory cells and when infected during diestrus (low estradiol) develop autoimmunity similar to males. During estrus, protection depends on estrogen receptor alpha (ERα), which promotes type I interferon, activation of natural killer/natural killer T cells and suppressor cell responses. Estrogen receptor beta has opposing effects to ERα and supports pro-inflammatory immunity. However, the sexual dimorphism of the disease is significantly ameliorated in aged animals when old females become as susceptible as males. This correlates to a selective loss of the ERα that is required for immunosuppression. Therefore, sex-associated hormones control susceptibility in the virus-mediated disease, but their impact can alter with the age and physiological stage of the individual.

The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)-like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress-induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome., (Copyright © 2016, American Association for the Advancement of Science.)

Introduction: Although the surgical restoration of apical support has been shown to decrease reoperation rates, it is unclear whether this has been incorporated into current practice. The aims of this study were to determine the rate of concomitant apical suspensory procedures in women with anterior vaginal wall prolapse undergoing surgical repair in 2011 and to identify associated factors., Methods: This cross-sectional study queried the Nationwide Inpatient Sample for women with a primary diagnosis of cystocele who underwent prolapse repair in 2011. The study cohort was analyzed for demographics, concomitant procedures, and hospital characteristics. The rate of apical suspensory procedures was determined. Factors potentially associated with receiving concomitant apical suspensory procedure were evaluated using univariate analysis and multivariate logistic regression., Results: A total of 2,900 women in the database had a primary diagnosis of cystocele and underwent surgical prolapse repair in 2011. 925 (31.9 %) subjects underwent a concomitant apical suspensory procedure. The mean age in the study cohort was 61.9 ± 12.8 years. Hysterectomies were performed in 11.1 % of subjects. 61.1 % were performed vaginally, 26.5 % laparoscopically, and 12.5 % abdominally. On multivariate analysis, age greater than 50 years, Caucasian race, concomitant hysterectomy, and an urban teaching hospital setting were independently associated with receiving concomitant apical suspensory procedure in 2011., Conclusions: Despite evidence that the restoration of apical support is important for optimal anterior support, the overall rate of concomitant apical suspensory procedures is low. Several factors may play a role in whether or not women receive an apical suspensory procedure. This study highlights opportunities to improve the quality of surgical care provided to women with anterior vaginal prolapse.

Although midurethral mesh tape slings are considered the standard of care in the treatment of female stress urinary incontinence (SUI), complications such as pain, dyspareunia, or erosion are known to occur in addition to persistent incontinence. The management of these types of mesh sling complications can be very complex, especially when the pain is not just isolated to the vagina but extends into other areas, such as the abdomen which requires a much more extensive dissection. Additionally, if a mesh sling needs to be removed, the patient will most likely have a return of her SUI that often necessitates subsequent treatment. Vaginal and/or laparoscopic removal or revision of mesh tape slings should be considered in patients presenting with complications such as vaginal pain, abdominal pain, dyspareunia, or urinary obstructive symptoms. In those patients who demonstrate persistent SUI, concomitant laparoscopic Burch urethropexy can be considered and can safely be performed at the time mesh removal. In this case report we present a patient who required a dual-approach removal of two painful midurethral slings in addition to concomitant treatment of persistent SUI with a laparoscopic Burch urethropexy procedure.

Myocarditis is an inflammation of the myocardium which often follows microbial infections and is a significant cause of sudden unexpected death in the young (<40 years of age) and an underlying cause of dilated cardiomyopathy. Although histologically, the disease is usually associated with infiltration of the myocardium with either eosinophils or leukocytes, use of immunosuppression is controversial outside of giant cell myocarditis and has been found to be of limited value in lymphocytic myocarditis. The relatively limited response might reflect the need for host immunity to control persistent virus infection in the heart which may be the predominant cause of the chronic myocarditis and dilated cardiomyopathy. Treating the persistent virus infection with interferon-beta improved cardiac function in a clinical trial. However, classic immunosuppressive drugs, such as cyclosporine A and cyclophosphamide, are not effective against all types of immunity and experimental myocarditis models have shown that certain immunopathogenic forms of the disease are resistant to these immunosuppressive agents. Understanding the molecular mechanisms underlying the pathogenesis of this disease and the various infectious agents which can cause it will be essential for developing effective therapeutic agents.

Objective: Distinct lymphocyte subpopulations have been implicated in the regulation of glucose homeostasis and obesity-associated inflammation in mouse models of insulin resistance. Information on the relationships of lymphocyte subpopulations with type 2 diabetes remain limited in human population-based cohort studies., Methods: Circulating levels of innate (γδ T, natural killer (NK)) and adaptive immune (CD4+ naive, CD4+ memory, Th1, and Th2) lymphocyte subpopulations were measured by flow cytometry in the peripheral blood of 929 free-living participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Cross-sectional relationships of lymphocyte subpopulations with type 2 diabetes (n = 154) and fasting glucose and insulin concentrations were evaluated by generalized linear models., Results: Each standard deviation (SD) higher CD4+ memory cells was associated with a 21% higher odds of type 2 diabetes (95% CI: 1-47%) and each SD higher naive cells was associated with a 22% lower odds (95% CI: 4-36%) (adjusted for age, gender, race/ethnicity, and BMI). Among participants not using diabetes medication, higher memory and lower naive CD4+ cells were associated with higher fasting glucose concentrations (p<0.05, adjusted for age, sex, and race/ethnicity). There were no associations of γδ T, NK, Th1, or Th2 cells with type 2 diabetes, glucose, or insulin., Conclusions: A higher degree of chronic adaptive immune activation, reflected by higher memory and lower naive CD4+ cells, was positively associated with type 2 diabetes. These results are consistent with a role of chronic immune activation and exhaustion augmenting chronic inflammatory diseases, and support the importance of prospective studies evaluating adaptive immune activation and type 2 diabetes.

Introduction and Hypothesis: The presacral space contains a dense and complex network of nerves that have significant effects on the innervation of the pelvic viscera and support structures. The proximity of this space to the bony promontory of the sacrum has lead to its involvement in an array of corrective surgical procedures for pelvic floor disorders including sacrocolpopexy and rectopexy. Other procedures involving the same space include presacral neurectomy which involves intentional transection of the contained neural plexus to relieve refractory pelvic pain and resection of retrorectal or presacral tumors. Potential complications of these procedures are postoperative constipation and voiding dysfunction., Methods: Our aim was to review the current published literature on outcomes following a variety of procedures involving the presacral space and review postoperative bowel and urinary function. We also include an overview of the functional and structural anatomy of the presacral space and its corresponding neural plexi., Results/conclusions: We conclude that quality data are lacking on the short-term and long-term rates for bowel and bladder dysfunction following surgical procedures involving the presacral space.

Cellular FLIP (c-FLIP) is an enzymatically inactive paralogue of caspase-8 and as such can block death receptor-induced apoptosis. However, independent of death receptors, c-FLIP-Long (c-FLIPL) can heterodimerize with and activate caspase-8. This is critical for promoting the growth and survival of T lymphocytes as well as the regulation of the RIG-I helicase pathway for type I interferon production in response to viral infections. Truncated forms of FLIP also exist in mammalian cells (c-FLIPS) and certain viruses (v-FLIP), which lack the C-terminal domain that activates caspase-8. Thus, the ratio of c-FLIPL to these short forms of FLIP may greatly influence the outcome of an immune response. We examined this model in mice transgenically expressing c-FLIPS in T cells during infection with Coxsackievirus B3 (CVB3). In contrast to our earlier findings of reduced myocarditis and mortality with CVB3 infection of c-FLIPL-transgenic mice, c-FLIPS-transgenic mice were highly sensitive to CVB3 infection as manifested by increased cardiac virus titers, myocarditis score, and mortality compared to wild-type C57BL/6 mice. This observation was paralleled by a reduction in serum levels of IL-10 and IFN-α in CVB3-infected c-FLIPS mice. In vitro infection of c-FLIPS T cells with CVB3 confirmed these results. Furthermore, molecular studies revealed that following infection of cells with CVB3, c-FLIPL associates with mitochondrial antiviral signaling protein (MAVS), increases caspase-8 activity and type I IFN production, and reduces viral replication, whereas c-FLIPS promotes the opposite phenotype.

Under normal conditions, autophagy maintains cardiomyocyte health and integrity through turnover of organelles. During stress, oxygen and nutrient deprivation, or microbial infection, autophagy prolongs cardiomyocyte survival. Sex differences in induction of cell death may to some extent explain the disparity between the sexes in many human diseases. However, sex differences in gene expression, which regulate cell death and autophagy, were so far not taken in consideration to explain the sex bias of viral myocarditis. Coxsackievirus B3 (CVB3)-induced myocarditis is a sex-biased disease, with females being substantially less susceptible than males and sex hormones largely determine this bias. CVB3 was shown to induce and subvert the autophagosome for its optimal viral RNA replication. Gene expression analysis on mouse and human, healthy and CVB3-infected, cardiac samples of both sexes, suggests sex differences in autophagy-related gene expression. This review discusses the aspects of sex bias in autophagy induction in cardiomyocytes.

Heart disease, the leading cause of death in humans, is estimated to affect one in four American adults in some form. One predominant cause of heart failure in young adults is myocarditis, which can lead to the development of dilated cardiomyopathy, a major indication for heart transplantation. Environmental microbes, including viruses, bacteria, and fungi that are otherwise innocuous, have the potential to induce inflammatory heart disease. As the list is growing, it is critical to determine the mechanisms by which microbes can trigger heart autoimmunity and, importantly, to identify their target antigens. This is especially true as microbes showing structural similarities with the cardiac antigens can predispose to heart autoimmunity by generating cross-reactive immune responses. In this review, we discuss the relevance of molecular mimicry in the mediation of infectious myocarditis.

Atherosclerosis is a chronic inflammatory disease characterized by T lymphocyte infiltration into the atherosclerotic plaque. Assessments of T cell subtypes have demonstrated a predominance of CD4(+) T helper (Th) cells, implicated Th1 and Th17 immunity in both human and mouse atherogenesis, and provided some evidence suggesting protective roles of Th2 and T regulatory cells. Observations that certain inbred mouse strains have an inherent T helper bias suggest a genetic predisposition toward developing a particular T helper phenotype. This review summarizes our current understanding of mechanisms of antigen processing for major histocompatibility complex molecules, describes the different T helper cell subsets and their roles in atherosclerosis, and discusses mechanisms of genetic predisposition toward Th1/Th2 bias in mice. We also present data from our laboratory demonstrating inherent Th1/Th2 phenotypes in apparently healthy human volunteers that are stable over time and discuss the potential implications for cardiovascular disease.