Late-Onset Sex Offending and the Assessment of Behavioral Variant Frontotemporal Dementia (bvFTD).

Behavioral variant frontotemporal dementia (bvFTD) is a common neuropsychiatric disorder, which is often missed or misdiagnosed by both neurologists and psychiatrists as a cause of emotional and behavioral problems. Inappropriate emotional responses and maladaptive behavior, including criminal behaviors, may be the first obvious expression of bvFTD caused by altered moral feelings, loss of empathy, disinhibition, and compulsive behavior. New onset sex offenses, including indecent exposure, sexually inappropriate comments, and unwanted sexual advances have been documented in early bvFTD. These behaviors may escalate with progressive disease and lead to harsh penalties. The presence of inappropriate sexual behaviors in older individuals with no prior history should raise concern about the presence of bvFTD in forensic examinations. In addition to the forensic examination, diagnostic evaluation requires psychological testing (including tests of social and affective cognition) and imaging studies. In sex offenders, a diagnosis of bvFTD has significant implications for risk assessments, requirements regarding supervision and management, and as evidence for mitigation. In this article, we review the neuropsychiatry of bvFTD, how the pathophysiology may contribute to sex offenses, and important psycholegal considerations for the forensic psychiatrist when evaluating bvFTD.

Polysomnography in AF patients without prior diagnosis of obstructive sleep apnea reveals significant sleep abnormality: A strong case for screening in all patients with atrial fibrillation?

BACKGROUND: Obstructive sleep apnea (OSA) and atrial fibrillation (AF) are known to often coexist together. However, whether all patients with AF should be screened for sleep abnormalities is not clear. No previous study has examined the association of asymptomatic OSA with AF. OBJECTIVE: This study sought to determine the prevalence of asymptomatic OSA in patients with persistent AF and whether asymptomatic OSA is an independent risk factor for atrial fibrillation. METHOD: Patients with persistent AF without a prior diagnosis of OSA and asymptomatic for sleep abnormalities were prospectively enrolled over 12 months. All patients underwent polysomnography after informed consent. Patients without AF or OSA who underwent polysomnography during the same period served as controls. RESULTS: A total of 97 patients were studied; 50 were in the case group (patients with persistent AF) and 47 were in the control group (patients in sinus rhythm). Asymptomatic OSA was diagnosed on polysomnography in 72% of patients in the AF group and 17% of the control population. Multivariable analysis of factors including diabetes, hypertension, coronary artery disease, hypothyroidism, prior MI, and asymptomatic OSA, suggested asymptomatic OSA as an independent factor associated with AF. CONCLUSION: A significant proportion (72%) of patients with persistent AF have underlying asymptomatic OSA. Sleep abnormality thus has a strong association with AF even in patients who are asymptomatic for OSA. Screening for OSA may be advised for all patients with AF, as this may have significant implications for management.

Establishing a diagnostic reference level of radiation dose in coronary angiography and intervention: A prospective evaluation.

INTRODUCTION: Invasive Coronary Angiography (CAG) leads to significant radiation exposure to the patients. Guidelines suggest that a local landmark or Diagnostic Reference Level (DRL) for these procedures should be established for every region and country. This study attempts to create a DRL for a tertiary care hospital, acting as an interim DRL for the country/region. METHODS: Radiation exposure data for all coronary procedures done at a tertiary care hospital between October 2016 to September 2018 were collected. Data was segregated into diagnostic Coronary Angiography (CAG) and single-vessel Percutaneous Intervention (PCI). The parameters collected include dose surface product (PKA), skin surface entry dose (KAR), and fluoroscopy time (FT). The 75th percentile of the PKA was used to define the DRL. RESULTS: 500 Patients were included in the CAG group, in which the Median KAR was 412.05 mGy, Median PKA was 2635.7 µGysqm, and median FT was 2.25 min. The DRL for coronary angiography was calculated as 3695.1 µGysqm. Two hundred fifty patients were in the PCI group, the Median KAR was 1649 mGy, Median PKA was 8822.1 µGysqm, the median FT being 8.2 min. The DRL for single-vessel coronary intervention was calculated as 11038 µGysqm. CONCLUSION: This study establishes a benchmark for radiation dose for diagnostic coronary angiography and single-vessel coronary intervention at a tertiary care hospital in NCR. It establishes an interim DRL that can be used for future studies in other institutions in the region and country and to compare with other countries.

Implications for preeclampsia: hypoxia-induced Notch promotes trophoblast migration.

In the first trimester of human pregnancy, low oxygen tension or hypoxia is essential for proper placentation and placenta function. Low oxygen levels and activation of signaling pathways have been implicated as critical mediators in the promotion of trophoblast differentiation, migration, and invasion with inappropriate changes in oxygen tension and aberrant Notch signaling both individually reported as causative to abnormal placentation. Despite crosstalk between hypoxia and Notch signaling in multiple cell types, the relationship between hypoxia and Notch in first trimester trophoblast function is not understood. To determine how a low oxygen environment impacts Notch signaling and cellular motility, we utilized the human first trimester trophoblast cell line, HTR-8/SVneo. Gene set enrichment and ontology analyses identified pathways involved in angiogenesis, Notch and cellular migration as upregulated in HTR-8/SVneo cells exposed to hypoxic conditions. DAPT, a γ-secretase inhibitor that inhibits Notch activation, was used to interrogate the crosstalk between Notch and hypoxia pathways in HTR-8/SVneo cells. We found that hypoxia requires Notch activation to mediate HTR-8/SVneo cell migration, but not invasion. To determine if our in vitro findings were associated with preeclampsia, we analyzed the second trimester chorionic villous sampling (CVS) samples and third trimester placentas. We found a significant decrease in expression of migration and invasion genes in CVS from preeclamptic pregnancies and significantly lower levels of JAG1 in placentas from pregnancies with early-onset preeclampsia with severe features. Our data support a role for Notch in mediating hypoxia-induced trophoblast migration, which may contribute to preeclampsia development.

First in man: percutaneous coronary angioplasty using non-fluoroscopic electro-anatomic mapping.

Reduction of radiography exposure and contrast use continue to be challenging goals for interventional cardiology. We present a case where percutaneous coronary intervention was done successfully using an electroanatomic mapping system (NavX™; Abbot Inc. USA); with near zero use of fluoroscopy or contrast agent.

Life-threatening ventricular arrhythmia as first presentation of Tuberculosis-Early diagnosis and successful treatment: A case series.

BACKGROUND: Tuberculosis of the myocardium is an extremely rare entity with few published case reports. Diagnosis is often delayed, and outcomes are unfavorable: particularly when cardiac involvement has been the presenting entity. METHODS: Four patients, aged 24-51 years, presented with life-threatening ventricular arrhythmia (VA). None had a previous history of tuberculosis or any structural heart disease. Electrocardiogram during sinus rhythm and Echocardiography did not show any gross abnormality. All patients underwent contrast-enhanced computer tomography of thorax and cardiac magnetic resonance imaging. Attempts to obtain tissue (cardiac or associated mediastinal lymph nodes) were associated with increased risk to the patients thus indirect evidence of Mantoux skin test and interferon gamma release assay results were used to aid diagnosis. RESULTS: Based on clinicoradiological findings, patients were put on antitubercular therapy (ATT). Supportive therapy included antiarrhythmic drugs (all patients), catheter ablation (two patients), and implantable cardioverter defibrillator (one patient). Arrhythmia suppression was achieved in all patients predischarge. On a follow-up of 2-24 months, none of the patients has had any recurrence of arrhythmia. ATT and antiarrhythmic drug therapy have been stopped in two patients who have completed the 6 months of ATT. Their radiological lesions showed resolution. CONCLUSIONS: Myocardial tuberculosis presenting as life-threatening VA in a rare but definite clinical entity. A high index of suspicion and cardiac imaging can lead to early diagnosis and appropriate treatment that ensures survival in all patients.

TLR4 counteracts BVRA signaling in human leukocytes via differential regulation of AMPK, mTORC1 and mTORC2.

TLR4 is implicated in diseases associated with chronic low-grade inflammation, yet homeostatic signaling mechanisms that prevent and/or are affected by chronic TLR4 activation are largely uncharacterized. We recently reported that LPS/TLR4 activates in human leukocytes signaling intermediates (SI), abbreviated TLR4-SI, which include mTORC1-specific effectors and targets, and that leukocytes of patients with T2D or after cardiopulmonary bypass (CPB) expressed similar SI. Extending these previous findings, here we show that TLR4-SI expression post-CPB was associated with low serum bilirubin and reduced preoperative expression of biliverdin reductase A (BVRA), the enzyme that converts biliverdin to bilirubin, in patient's leukocytes. Biliverdin inhibited TLR4 signaling in leukocytes and triggered phosphorylation of mTORC2-specific targets, including Akt, PKCζ, AMPKα-LKB1-TSC1/2, and their association with BVRA. Torin, PP242, and a PKCζ inhibitory peptide, but not rapamycin, prevented these biliverdin-induced responses and TLR4 inhibition. In contrast, LPS/TLR4 triggered decreases in BVRA, AMPKα and PKCζ expression, and an increase in haptoglobin, a heme binding protein, in leukocytes in vivo and in vitro, indicating that activated TLR4 may suppress biliverdin/BVRA signaling. Significantly, compared to non-diabetics, BVRA and PKCζ expression was low and haptoglobin was high in T2D patients leukocytes. Sustained TLR4 activation may deregulate homeostatic anti-inflammatory BVRA/mTORC2 signaling and thereby contribute to chronic inflammatory diseases.

Traumatic Common Carotid-Internal Jugular Arteriovenous Fistula Manifesting as Life-Threatening Epistaxis.

Post-traumatic common carotid artery-internal jugular vein fistula is extremely rare (4% to 7% of all traumatic arteriovenous fistulas). Clinical manifestations depend on the size, duration, and proximity to the heart. This report describes a case where the condition remained undiagnosed for years, and the patient was recently treated with transsternal ligation of the left common carotid artery. (Level of Difficulty: Advanced.).

Consensus statement for implantation and follow-up of cardiac implantable electronic devices in India.

Cardiac implantable electronic device (CIED) procedures are being done by many operators/centers and it is projected that this therapy will remarkably increase in India in the coming years. This document by IHRS, aims at guiding the Indian medical community in the appropriate use and method of implantation with emphasis on implanter training and center preparedness to deliver a safe and effective therapy to patients with cardiac rhythm disorders and heart failure.

Dexamethasone-Mediated Upregulation of Calreticulin Inhibits Primary Human Glioblastoma Dispersal Ex Vivo.

Dispersal of Glioblastoma (GBM) renders localized therapy ineffective and is a major cause of recurrence. Previous studies have demonstrated that Dexamethasone (Dex), a drug currently used to treat brain tumor-related edema, can also significantly reduce dispersal of human primary GBM cells from neurospheres. It does so by triggering α5 integrin activity, leading to restoration of fibronectin matrix assembly (FNMA), increased neurosphere cohesion, and reduction of neurosphere dispersal velocity (DV). How Dex specifically activates α5 integrin in these GBM lines is unknown. Several chaperone proteins are known to activate integrins, including calreticulin (CALR). We explore the role of CALR as a potential mediator of Dex-dependent induction of α5 integrin activity in primary human GBM cells. We use CALR knock-down and knock-in strategies to explore the effects on FNMA, aggregate compaction, and dispersal velocity in vitro, as well as dispersal ex vivo on extirpated mouse retina and brain slices. We show that Dex increases CALR expression and that siRNA knockdown suppresses Dex-mediated FNMA. Overexpression of CALR in GBM cells activates FNMA, increases compaction, and decreases DV in vitro and on explants of mouse retina and brain slices. Our results define a novel interaction between Dex, CALR, and FNMA as inhibitors of GBM dispersal.

Cardiovascular risk profile and management of atrial fibrillation in India: Real world data from RealiseAF survey.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia with high risk for many cardiovascular (CV) complications. Adherence to recommended management guidelines is important to avoid complications. In India, there is little knowledge on how AF is managed in real world. METHODS: This is a cross-sectional study of patients in India enrolled in RealiseAF survey between February 2010 and March 2010 with a diagnosis of AF within the last 12 months. RESULTS: From 15 centers, 301 patients {mean age 59.9 years (14.4); 52.5% males} were recruited. AF was controlled in 50% of patients with 77 (26.7%) in sinus rhythm and 67 (23.3%) with heart rate <80beats/min. Hypertension (50.8%), valvular heart disease (40.7%), heart failure (25.9%), and diabetes (20.4%) were the most common underlying CV diseases. Increased risk for stroke (CHADS2 score≥2) was present in 36.6%. Most of the patients (85%) were symptomatic. AF was paroxysmal, persistent, and permanent in 28.7%, 22.7%, and 34.3% respectively. In 14%, AF was diagnosed as first episode. Forty-six percent of patients had rate control, 35.2% rhythm control, 0.3% both strategies, and 18.4% received no therapy for AF before the visit. At the end of the visit, adoption to rate control strategy increased to 52.3% and patients with no therapy decreased to 7%. CONCLUSION: AF in India is not adequately controlled. Concomitant CV risk factors and risk of stroke are high. The study underscores the need for improved adoption of guideline-directed management for optimal control of AF and reducing the risk of stroke.

Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes.

BACKGROUND: Long QT syndromes (LQTS) are characterized by prolonged QTc interval on electrocardiogram (ECG) and manifest with syncope, seizures or sudden cardiac death. Long QT 1-3 constitute about 75% of all inherited LQTS. We classified a cohort of Indian patients for the common LQTS based on T wave morphology and triggering factors to prioritize the gene to be tested. We sought to identify the causative mutations and mutation spectrum, perform genotype-phenotype correlation and screen family members. METHODS: Thirty patients who fulfilled the criteria were enrolled. The most probable candidate gene among KCNQ1, KCNH2 and SCN5A were sequenced. RESULTS: Of the 30 patients, 22 were classified at LQT1, two as LQT2 and six as LQT3. Mutations in KCNQ1 were identified in 17 (77%) of 22 LQT1 patients, KCNH2 mutation in one of two LQT2 and SCN5A mutations in two of six LQT3 patients. We correlated the presence of the specific ECG morphology in all mutation positive cases. Eight mutations in KCNQ1 and one in SCN5A were novel and predicted to be pathogenic by in-silico analysis. Of all parents with heterozygous mutations, 24 (92%) of 26 were asymptomatic. Ten available siblings of nine probands were screened and three were homozygous and symptomatic, five heterozygous and asymptomatic. CONCLUSIONS: This study in a cohort of Asian Indian patients highlights the mutation spectrum of common Long QT syndromes. The clinical utility for prevention of unexplained sudden cardiac deaths is an important sequel to identification of the mutation in at-risk family members.

KCNQ1 mutations associated with Jervell and Lange-Nielsen syndrome and autosomal recessive Romano-Ward syndrome in India-expanding the spectrum of long QT syndrome type 1.

Long QT syndrome type 1 (LQT1) is the most common type of all Long QT syndromes (LQTS) and occurs due to mutations in KCNQ1. Biallelic mutations with deafness is called Jervell and Lange-Nielsen syndrome (JLNS) and without deafness is autosomal recessive Romano-Ward syndrome (AR RWS). In this prospective study, we report biallelic mutations in KCNQ1 in Indian patients with LQT1 syndrome. Forty patients with a clinical diagnosis of LQT1 syndrome were referred for molecular testing. Of these, 18 were excluded from the analysis as they did not fulfill the inclusion criteria of broad T wave ECG pattern of the study. Direct sequencing of KCNQ1 was performed in 22 unrelated probands, parents and at-risk family members. Mutations were identified in 17 patients, of which seven had heterozygous mutations and were excluded in this analysis. Biallelic mutations were identified in 10 patients. Five of 10 patients did not have deafness and were categorized as AR RWS, the rest being JLNS. Eight mutations identified in this study have not been reported in the literature and predicted to be pathogenic by in silico analysis. We hypothesize that the homozygous biallelic mutations identified in 67% of families was due to endogamous marriages in the absence of consanguinity. This study presents biallelic gene mutations in KCNQ1 in Asian Indian patients with AR JLNS and RWS. It adds to the scant worldwide literature of mutation studies in AR RWS. © 2016 Wiley Periodicals, Inc.

Dexamethasone-Mediated Activation of Fibronectin Matrix Assembly Reduces Dispersal of Primary Human Glioblastoma Cells.

Despite resection and adjuvant therapy, the 5-year survival for patients with Glioblastoma multiforme (GBM) is less than 10%. This poor outcome is largely attributed to rapid tumor growth and early dispersal of cells, factors that contribute to a high recurrence rate and poor prognosis. An understanding of the cellular and molecular machinery that drive growth and dispersal is essential if we are to impact long-term survival. Our previous studies utilizing a series of immortalized GBM cell lines established a functional causation between activation of fibronectin matrix assembly (FNMA), increased tumor cohesion, and decreased dispersal. Activation of FNMA was accomplished by treatment with Dexamethasone (Dex), a drug routinely used to treat brain tumor related edema. Here, we utilize a broad range of qualitative and quantitative assays and the use of a human GBM tissue microarray and freshly-isolated primary human GBM cells grown both as conventional 2D cultures and as 3D spheroids to explore the role of Dex and FNMA in modulating various parameters that can significantly influence tumor cell dispersal. We show that the expression and processing of fibronectin in a human GBM tissue-microarray is variable, with 90% of tumors displaying some abnormality or lack in capacity to secrete fibronectin or assemble it into a matrix. We also show that low-passage primary GBM cells vary in their capacity for FNMA and that Dex treatment reactivates this process. Activation of FNMA effectively "glues" cells together and prevents cells from detaching from the primary mass. Dex treatment also significantly increases the strength of cell-ECM adhesion and decreases motility. The combination of increased cohesion and decreased motility discourages in vitro and ex vivo dispersal. By increasing cell-cell cohesion, Dex also decreases growth rate of 3D spheroids. These effects could all be reversed by an inhibitor of FNMA and by the glucocorticoid receptor antagonist, RU-486. Our results describe a new role for Dex as a suppressor of GBM dispersal and growth.

The fate of internalized α5 integrin is regulated by matrix-capable fibronectin.

BACKGROUND: Assembly of fibronectin matrices is associated with integrin receptor turnover and is an important determinant of tissue remodeling. Although it is well established that fibronectin is the primary ligand for α5ß1 receptor, the relationship between fibronectin matrix assembly and the fate of internalized α5 integrin remains poorly characterized. MATERIALS AND METHODS: To evaluate the effect of fibronectin matrix on the fate of internalized α5 integrin, fibronectin-null Chinese hamster ovary and mouse embryo fibroblast cells were used to track the fate of α5 after exposure to exogenous fibronectin. RESULTS: In the absence of matrix-capable fibronectin dimer, levels of internalized α5 decreased rapidly over time. This correlated with a decline in total cellular α5 and was associated with the ubiquitination of α5 integrin. In contrast, internalized and total cellular α5 protein levels were maintained when matrix-capable fibronectin was present in the extracellular space. Further, we show that ubiquitination and degradation of internalized α5 integrin in the absence of fibronectin require the presence of two specific lysine residues in the α5 cytoplasmic tail. CONCLUSIONS: Our data demonstrate that α5 integrin turnover is dependent on fibronectin matrix assembly, where the absence of matrix-capable fibronectin in the extracellular space targets the internalized receptor for rapid degradation. These findings have important implications for understanding tissue-remodeling processes found in wound repair and tumor invasion.

Why are clinical trials necessary in India?

Clinical trials are emerging as an important activity in India as it is an essential component of the drug discovery and development program to which India is committed. The only robust way to evaluate a new medicine is by doing properly designed clinical trials. In addition to advancing science, clinical trials offer myriad benefits to the participants. The recent hue that created in India about clinical trials is probably an exaggeration of facts. However, these points to the need for ensuring proper compliance with the regulatory norms and proper training of concerned personnel in good clinical practice (GCP). This will ensure that India continues to reap the benefits of clinical trials and also become a world leader in this field.

Demonstration of posterior fascicle to myocardial conduction block during ablation of idiopathic left ventricular tachycardia: an electrophysiological predictor of long-term success.

BACKGROUND: Idiopathic left ventricular tachycardia (ILVT) is a common form of ventricular tachycardia (VT) in structurally normal heart. Different methods have been proposed for radiofrequency ablation (RFA) of ILVT that have good short-term results but recurrence is higher. Termination of tachycardia during RFA and/or noninduciblity has been the procedural end point. OBJECTIVE: To describe electrophysiological markers that add to long-term freedom from recurrences. METHODS: Fifteen patients with ILVT underwent RFA guided by 3-dimensional electroanatomical mapping. After creating a 3-dimensional geometry of the left ventricle (LV), the conduction system of the LV was mapped by tracing from His recording from the left ventricular outflow tract and distally till the fascicles and perifascicular myocardium. VT was induced by using programmed electrical stimulation. Ablation was done targeting the distal posterior fascicle and extended linearly to the surrounding myocardium till conduction block was achieved between the fascicle-Purkinje network and the left ventricular myocardium. RESULTS: All patients (13 men; mean age 32 ± 9 years) had inducible VTs. The mean tachycardia cycle length was 320 ± 28 ms. Radiofrequency energy was given to the distal posterior fascicle and the myocardium, with an aim to achieve a myocardial-fascicular conduction block in addition to the termination of VT and noninducibility. Ablation was successful in all. No recurrence of tachycardia was seen in any patient on follow-up (20.8 ± 8.5 months). CONCLUSIONS: Distal posterior fascicle and Purkinje-myocardial junction is an effective target site for ILVT ablation. The demonstration of myocardial to fascicle conduction block serves as an important electrophysiological marker of successful ablation and improved long-term success.