DNA demethylation fine-tunes IL-2 production during thymic regulatory T cell differentiation.

Regulatory T (T reg) cells developing in the thymus are essential to maintain tolerance and prevent fatal autoimmunity in mice and humans. Expression of the T reg lineage-defining transcription factor FoxP3 is critically dependent upon T cell receptor (TCR) and interleukin-2 (IL-2) signaling. Here, we report that ten-eleven translocation (Tet) enzymes, which are DNA demethylases, are required early during double-positive (DP) thymic T cell differentiation and prior to the upregulation of FoxP3 in CD4 single-positive (SP) thymocytes, to promote Treg differentiation. We show that Tet3 selectively controls the development of CD25- FoxP3lo CD4SP Treg cell precursors in the thymus and is critical for TCR-dependent IL-2 production, which drive chromatin remodeling at the FoxP3 locus as well as other Treg-effector gene loci in an autocrine/paracrine manner. Together, our results demonstrate a novel role for DNA demethylation in regulating the TCR response and promoting Treg cell differentiation. These findings highlight a novel epigenetic pathway to promote the generation of endogenous Treg cells for mitigation of autoimmune responses.

A systematic review and meta-analysis comparing second-generation cryoballoon and contact force radiofrequency ablation for initial ablation of paroxysmal and persistent atrial fibrillation.

INTRODUCTION: Cryoballoon ablation (CBA) and radiofrequency ablation (RFA) are the preferred modalities for catheter ablation of atrial fibrillation (AF). Technological advances have improved procedural outcomes, warranting an updated comparison. We sought to evaluate the efficacy and safety of CBA-2nd generation (CBA-2G) in comparison to RFA-contact force (RFA-CF) in patients with AF. METHODS: MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched until 03/01/2020 for relevant studies comparing CBA-2G versus RFA-CF in patients undergoing initial catheter ablation for AF. RESULTS: A total of 17 studies, involving 11 793 patients were included. There was no difference between the two groups in the outcomes of freedom from atrial arrhythmia (p = .67) and total procedural complications (p = .65). There was a higher incidence of phrenic nerve palsy in CBA-2G (odds ratio: 10.7; 95% confidence interval [CI]: 5.85 to 19.55; p < .001). Procedure duration was shorter (mean difference: -31.32 min; 95% CI: -40.73 to -21.92; p < .001) and fluoroscopy duration was longer (+3.21 min; 95% CI: 1.09 to 5.33; p = .003) in CBA-2G compared to RFA-CF. In the subgroup analyses of patients with persistent AF and >1 freeze lesion delivered per vein, there was no difference in freedom from atrial arrhythmia. CONCLUSIONS: In AF patients undergoing initial ablation, CBA-2G and RFA-CF were equally efficacious. The procedure duration was shorter, but with a higher incidence of phrenic nerve palsy in CBA-2G. In patients with persistent AF, there was no difference in the efficacy between CBA-2G or RFA-CF techniques.

Severe Anti-HMG-CoAR Necrotizing Autoimmune Myopathy Secondary to Statin Use.

Immune-mediated necrotizing myopathy is an uncommon but debilitating disease that can be triggered by drugs, toxins, or cancer. It is similar to polymyositis in presentation but is differentiated by findings on muscle biopsy. We present a case of a 79-year-old male on statin therapy who presented with proximal muscle weakness and elevated creatinine kinase (CK) levels. He had a confirmatory muscle biopsy for immune-mediated necrotizing myopathy. Unfortunately, the patient's condition eventually escalated, involving respiratory and esophageal muscles in spite of prompt diagnosis and treatment.

CD4 expression in effector T cells depends on DNA demethylation over a developmentally established stimulus-responsive element.

The epigenetic patterns that are established during early thymic development might determine mature T cell physiology and function, but the molecular basis and topography of the genetic elements involved are not fully known. Here we show, using the Cd4 locus as a paradigm for early developmental programming, that DNA demethylation during thymic development licenses a novel stimulus-responsive element that is critical for the maintenance of Cd4 gene expression in effector T cells. We document the importance of maintaining high CD4 expression during parasitic infection and show that by driving transcription, this stimulus-responsive element allows for the maintenance of histone H3K4me3 levels during T cell replication, which is critical for preventing de novo DNA methylation at the Cd4 promoter. A failure to undergo epigenetic programming during development leads to gene silencing during effector T cell replication. Our study thus provides evidence of early developmental events shaping the functional fitness of mature effector T cells.

Antiphospholipid antibodies and vitamin D deficiency in COVID-19 infection with and without venous or arterial thrombosis: A pilot case-control study.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is associated with thromboembolism. Antiphospholipid antibody (APLa) formation is one of the mechanisms. Vitamin D deficiency has been associated with thrombosis in antiphospholipid antibody syndrome. OBJECTIVE: Measure APLa and vitamin D in hospitalized COVID-19 patients with and without thrombosis to evaluate if thromboembolism is associated with concomitant APLa and vitamin D deficiency. METHODS: Case-control study. Hospitalized COVID-19 patients with a thromboembolic event (ischemic stroke, myocardial infarction, deep venous thrombosis/pulmonary embolism, Cases n = 20). Controls (n = 20): Age, sex-matched without thromboembolic events. Patients with autoimmune disorders, antiphospholipid antibody syndrome, thrombophilia, anticoagulation therapy, prior thromboembolism, chronic kidney disease 3b, 4, end-stage renal disease, and malignancy were excluded. Given the limited current literature on the role of concomitant antiphospholipid antibodies and vitamin D deficiency in causing venous and/or arterial thrombosis in hospitalized COVID-19 patients, we enrolled 20 patients in each arm. Anti-cardiolipin IgG/IgM, beta-2 glycoprotein-1 IgG/IgM, lupus anticoagulant and vitamin D levels were measured in both groups. RESULTS: Cases were 5.7 times more likely to be vitamin D deficient (OR:5.7, 95% CI:1.3-25.6) and 7.4 times more likely to have any one APLa (OR:7.4, 95% CI: 1.6-49.5) while accounting for the effects of sex. Patients with both APLa and vitamin D deficiency had significantly more thrombosis compared to patients who were antibody positive without vitamin D deficiency (100% vs 47.4%; p = 0.01). CONCLUSIONS: Thrombosis in COVID-19 was associated with concomitant APLa and vitamin D deficiency. Future studies in COVID-19 should assess the role of vitamin D in reducing thrombosis.

Occurrence of Post-Transplant Lymphoproliferative Disease in a Renal Transplant Patient.

Post-transplant lymphoproliferative diseases (PTLD) are a group of lymphoid disorders that occur in the setting of solid organ or hematopoietic transplantation. Risk factors for the development of PTLD include type of organ transplanted, degree/duration of T-cell immunosuppression, and Epstein-Barr virus (EBV) status. After initial infection, EBV lies dormant in memory B-cells and persists at low levels throughout the lifetime. In an environment of chronic T-cell immunosuppression, the underlying EBV infection remains uncontrolled, resulting in malignant B-cell lymphoproliferations that causes PTLD.  While PTLD is the most common malignancy associated with solid organ transplants, they are a serious complication and require a low threshold of suspicion for diagnosis. Oftentimes symptoms are nonspecific, such as weight loss and malaise, and many patients present without associated lymphadenopathy. We present the case of a 30-year-old Asian American female who developed PTLD, specifically large B-cell non-Hodgkin's lymphoma, five years after receiving a deceased-donor renal transplant.

Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP1RAs) are relatively newer anti-hyperglycemic agents, which have demonstrated cardiovascular benefits in patients with type 2 diabetes mellitus. DESIGN: We performed a meta-analysis of randomized controlled trials to evaluate the cardiovascular outcomes of GLP1RAs compared to placebo in type 2 diabetes mellitus patients. We performed an additional subgroup analysis to evaluate the role of GLP1RAs in patients with chronic kidney disease. METHODS: MEDLINE, Cochrane and ClinicalTrials.gov databases were searched from inception to 15 July 2019. The authors extracted relevant information from articles and independently assessed the study quality. RESULTS: Compared to placebo, GLP1RAs demonstrated a significant reduction in all-cause mortality (odds ratio (OR) 0.88, 95% confidence interval (CI) 0.82-0.95; P < 0.001), cardiovascular mortality (OR 0.88, 95% CI 0.81-0.96; P = 0.004), primary composite endpoint (OR 0.86, 95% CI 0.80-0.91; P < 0.001) and non-fatal stroke (OR 0.86, 95% 0.77-0.95; P = 0.004). There was no statistical difference in non-fatal myocardial infarction (OR 0.92, 95% CI 0.83-1.01; P = 0.09). In subgroup analyses of patients with estimated glomerular filtration rate less than 60 ml/min/1.73 m2 and less than 30 ml/min/1.73 m2, there was no significant difference in the primary composite endpoint. CONCLUSIONS: GLP1RAs demonstrated a significant reduction in all-cause mortality, cardiovascular mortality, primary composite endpoint and non-fatal stroke in patients with type 2 diabetes mellitus. There was no significant difference in the primary composite endpoint in patients with type 2 diabetes mellitus and chronic kidney disease.

Meta-Analysis Comparing Double Versus Triple Antithrombotic Therapy in Patients With Atrial Fibrillation and Coronary Artery Disease.

Atrial fibrillation (AF) and concomitant coronary artery disease (CAD) create a therapeutic dilemma as the risk of bleeding with triple antithrombotic therapy (TATT) must be balanced against the risk of ischemic events with double antithrombotic therapy (DATT). The aim of this meta-analysis is to compare the efficacy and safety of DATT versus TATT in AF and CAD. MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched for relevant articles published from inception to May 1, 2019. Studies comparing the safety and efficacy of DATT versus TATT in patients with AF and CAD were included. Among 9 studies, where 6,104 patients received DATT and 7,333 patients received TATT, there was no statistically significant difference in the outcomes of mortality, nonfatal myocardial infarction, stent thrombosis, and stroke. There was a lower rate of major bleeding in DATT (risk ratio [RR] 0.64 [95% confidence interval [CI] 0.54 to 0.75]; p <0.001). There was no significant difference in stent thrombosis (RR 1.52 [95% CI 0.97 to 2.38]; p = 0.07). However, subgroup analysis of trials with direct oral anticoagulant use demonstrated a borderline higher rate of stent thrombosis in DATT (RR 1.66 [95% CI 1.01 to 2.73]; p = 0.05). In conclusion, DATT showed no difference in the outcomes of mortality, stroke, nonfatal myocardial infarction, and stent thrombosis compared with TATT. DATT demonstrated a lower rate of major bleeding. DATT demonstrated a borderline higher rate of stent thrombosis in the subgroup analysis of trials with direct oral anticoagulant which needs to be evaluated in further studies.

Lithium-Induced Brugada Pattern: A Case Report and Review of Literature.

Lithium-induced type 1 Brugada pattern in asymptomatic patients is an uncommon occurrence that is challenging to manage and to estimate the risk of sudden cardiac death (SCD). We describe a case of a 74-year-old woman who presented with type 1 Brugada pattern while on lithium therapy. Her lithium level was within the therapeutic range at the time of presentation. There was no evidence of ventricular ectopy or malignant arrhythmias. Review of electrocardiogram (ECG) prior to initiation of lithium therapy demonstrated type 3 Brugada pattern. Lithium was promptly discontinued, and the patient was closely monitored in the hospital for 48 hours with serial ECGs and telemetry, as her lithium levels decreased. The Brugada pattern resolved on day 10 of discontinuation of lithium therapy and no further intervention was performed. Early diagnosis and prompt discontinuation of lithium leads to the resolution of type 1 Brugada pattern and may reduce the risk of SCD. The case highlights the importance of obtaining baseline ECG when initiating lithium especially in patients with type 2 or 3 Brugada pattern and provides an overview of the serial changes in ECG pattern until resolution following discontinuation of lithium. Electrophysiology study for risk stratification in asymptomatic patients does not appear to provide any additional benefit.

The Indian gut microbiota-Is it unique?

Colonization of the gut by microbes depends on a number of factors including age, diet, genetic makeup, gender, geographic location, and health status of an individual. India is a megadiverse country and includes 4 biodiversity hot spots. These features, along with the transitioning Indian sociodemographic profile, make the gut microbiota of Indian subjects an interesting area to study. In this review, we critically discuss the present status of the gut microbiome in the Indian population and its difference from other populations. We also discuss the aberrations in the available study designs that could introduce heterogeneity. An ideal study to evaluate the core gut microbiota of healthy Indians should involve a large homogeneous population across the country and use the same technology and data analytics tools. The "Landscape of Gut Microbiome-Pan India Exploration" (LogMPIE) is such a study that confirmed the most predominant organisms in Indians to be Prevotella copri and Faecalibacterium prausnitzii.

Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation.

BACKGROUND: Low-grade inflammation and metabolic dysregulation are common comorbidities of obesity, both of which are associated with alterations in iRhom2-regulated pro-inflammatory cytokine and epidermal growth factor receptor (EGFR) ligand signaling. OBJECTIVE: Our objective was to determine the role of iRhom2 in the regulation of low-grade inflammation and metabolic dysregulation in a murine model of diet-induced obesity. METHODS: Wild type (WT) and iRhom2-deficient mice were fed normal chow (NC) or a high-fat diet (HFD) starting at 5 weeks of age for up to 33 weeks. Body composition, glucose and insulin tolerance, feeding behavior, and indirect calorimetry were measured at defined time points. Adipose tissue cytokine expression and inflammatory lesions known as crown-like structures (CLS) were analyzed at the end-point of the study. RESULTS: iRhom2-deficient mice show accelerated fat gain on a HFD, accompanied by insulin resistance. Indirect calorimetry did not demonstrate changes in energy expenditure or food intake, but locomotor activity was significantly reduced in HFD iRhom2-deficient mice. Interestingly, CLS, macrophage infiltration, and tumor necrosis factor (TNF) production were decreased in adipose tissue from HFD iRhom2-deficient mice, but circulating cytokines were unchanged. In inguinal and perigonadal fat, the EGFR ligand amphiregulin was markedly induced in HFD controls but completely prevented in iRhom2-deficient mice, suggesting a potentially dominant role of EGFR-dependent mechanisms over TNF in the modulation of insulin sensitivity. CONCLUSIONS: This study elucidates a novel role for iRhom2 as an immuno-metabolic regulator that affects adipose tissue inflammation independent of insulin resistance.

Prosthetic Mitral Valve Obstruction with Left Atrial Appendage Thrombus: A Therapeutic Dilemma.

Valvular obstruction is a rare but life-threatening complication of mechanical prosthetic valves that raises significant challenges in management. We describe a unique case of mechanical mitral valve obstruction with co-existing left atrial appendage (LAA) thrombus. A 48-year-old man with a past medical history of atrial fibrillation and mechanical mitral valve replacement 18 months prior, presented with symptoms of new onset heart failure for 10 days. INR on presentation was sub-therapeutic. Trans-thoracic and trans-esophageal echocardiography revealed prosthetic mitral valve obstruction with mobile, echogenic masses seen on the mechanical valve as well as LAA, suggestive of thrombus. His clinical course rapidly deteriorated and he developed cardiogenic shock. He was deemed to have prohibitive risk for emergent surgical intervention. He received trial of thrombolytic therapy, with partial improvement of hemodynamic parameters and a mild decrease in thrombus burden. He then underwent surgical intervention with a favorable outcome. Intra-operative visualization of the prosthetic valve revealed a combination of pannus and thrombus. Prosthetic valve function should be promptly assessed in patients presenting with heart failure symptoms, as clinical deterioration can be rapid. Acute presentation, history of inadequate anticoagulation and appearance of soft mass on an echocardiogram, are suggestive of thrombus as the etiology of valve obstruction. However, thrombus and pannus are known to frequently co-exist. Emergent surgery is the recommended management strategy in patients with left-sided prosthetic valve thrombosis with the New York Heart Association (NYHA) III or IV symptoms, due to a lower rate of thrombo-embolism, major bleeding, and recurrent prosthetic valve thrombosis when compared with thrombolytic therapy. Slow-infusion, low-dose thrombolytics were recently shown to have favorable outcomes and can be considered when surgery is not available or the patient is deemed to have prohibitive surgical risk.