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Background T-cell Acute Lymphoblastic Leukemia (T-ALL) / Lymphoblastic Lymphoma (LBL) represent a class of devastating hematologic cancers with high rates of relapse and mortality in both children and adults. Development of CAR-T cell therapies for T-cell cancers has been complicated by induction of fratricide and the high risk of malignant cell contamination of the drug product in the autologous setting. Previously, Cooper et. al., demonstrated that CRISPR/Cas9 gene-editing to delete CD7 prevented self-killing, and deletion of the T-cell receptor alpha constant (TRAC) enabled the use of healthy donor-derived T-cells to manufacture CD7-targeted CAR-T cells without risk of malignancy and mitigating the risk of GvHD. Here we present preclinical data supporting the safety and efficacy of WU-CART-007, an IND ready, off-the-shelf, and fratricide resistant CD7-targeted CAR-T cell for the treatment of CD7+ T-cell malignancies. Methods WU-CART-007 was manufactured using T cells isolated from healthy donors by deletion of CD7 and TRAC, followed by CAR transduction, cell expansion, depletion of residual TCRa/b+ cells and cryopreservation. Donors were confirmed negative for a panel of adventitious viruses. CD7/TRAC deletion and CAR transduction were confirmed by flow cytometry. Off-target editing profile was assessed by GUIDE-Seq. The binding kinetics to human CD7 were conducted by bio-layer interferometry and CD7 selectivity was confirmed by cell microarray with a library of HEK-293 cells expressing approximately 6000 human proteins. The in vitro activity of WU-CART-007 was interrogated by co-culture with human CD7+ CCRF-CEM T-ALL cells and the potential on-target, off-tumor activity was assessed by co-culture with a panel of immune and non-immune primary human cells. In vivo anti-tumor functionality was confirmed in immunocompromised NSG mice after the establishment of low or high tumor burden CCRF-CEM xenografts engineered to express green fluorescent protein (GFP) and click beetle red (CBR) luciferase. The impact of WU-CART-007 on normal hematopoiesis was assessed using CD34+ humanized NCG mice. Results Several successful full-scale manufacturing runs were completed with consistently high dual CD7/TRAC deletion, transduction efficiency, and cell viability. Drug product was primarily composed of a T cell memory phenotype. Off- target nuclease analysis by GUIDE-seq and targeted NGS confirmed no evidence of off-target editing events. The WU-CART-007 scFv exhibited high affinity and exquisite specificity for human CD7. In vitro co-incubation experiments confirmed strong cytotoxicity against CD7-expressing cells including CCRF-CEM T-ALL cells, primary T and NK cells, but not CD7- cells such as myeloid cells, B cells, hepatocytes, astrocytes, cardiomyocytes, epithelial cells, and endothelial cells. Importantly, no cytotoxicity was observed against hematopoietic progenitor cells in human bone marrow or cord blood following co-incubation with WU-CART-007. Similarly, WU-CART-007 treatment of a non-tumor bearing humanized mouse model resulted in transient reductions in CD7+ cells (T-cells and NK cells) but not CD7- cells (myeloid and B cells), and the impacted cells recovered after circulating WU-CART-007 cells were no longer detectable. Assessment of in vivo anti-tumor efficacy revealed that WU-CART-007 effectively inhibited tumor progression (>99% TGI) in both low and high burden CCRF-CEM tumor models and improved survival in a dose-dependent manner, while CAR- cells were inactive, confirming CD7-dependent activity. Conclusions These preclinical studies support the use of WU-CART-007 in clinical trials and highlight the potential of WU-CART-007 to be a well-tolerated and active therapy for patients with CD7+ T-cell malignancies. A first in human Phase 1/2 trial in patients with R/R T-ALL/LBL is currently open for enrollment (NCT# 04984356). Disclosures No relevant conflicts of interest to declare.

Data from high-income countries suggest that women receive less intensive diagnostic and therapeutic management than men for acute coronary syndrome (ACS). There is a paucity of such data in the Indian population, which is 69% rural and prior studies focused mostly on urban populations. The objective of the present study was to identify the gender based differences in ACS management, if any, in a predominantly rural population.Data from 35 hospitals across Himachal Pradesh covering90% of state population were collected for one year (July 2015-June 2016). A total of 2118 ACS subjects met inclusion criteria and baseline characteristics, in-hospital treatments and mortality rates were analyzed.Women constituted less than one-third of ACS population. Women were older compared to men and were more likely to present with NSTEMI/UA. Misinterpretation of initial symptoms and late presentation were also common in women. Fewer women received optimal guideline based treatment and PCI (0.9% vs 4.2%, p0.01). Compare to men, women more often had Killip class1 (27.3% vs 20.4%, p0.01) and higher in-hospital mortality (8.5% vs 5.6%, p=0.009). On multivariate analysis the association between female gender and mortality was attenuated (adjusted odds ratio [OR]=1.36 [0.77-2.38]).The present study from India, is the first of its kind to evaluate the gender based differences among ACS patients, in a predominantly rural population. Our analysis demonstrates a significant gender based difference between symptom awareness and delay in presentation, management and in-hospital outcome. Further studies are warranted across other parts of country to investigate this gender disparity.

Existing metrics for grading mitral regurgitation (MR) are limited and fraught with high interobserver variability. We developed and evaluated a Doppler-based, semiquantitative novel index (Mitral Regurgitation Severity Index [MRSI]) of MR severity. In a total of 125 patients (70 in the derivation cohort and 55 in the validation cohort), MRSI was calculated as a ratio of time velocity integral of mitral inflow (continuous-wave Doppler-TVI MV) to the time velocity integral of the left ventricle outflow (pulse-wave Doppler-TVI LVOT). Inter-rater agreement for MRSI and predictive ability of the MRSI were then assessed. In the derivation cohort, MRSI differed significantly between patients with severe MR (2.6 ± 0.51) and mild-moderate (nonsevere) MR (1.4 ± 0.18) and a cutoff of ≥1.8 was associated with optimal diagnostic accuracy. In the validation cohort, MRSI exhibited excellent agreement between a level II and a level III reader with a mean difference of -0.14 (95% confidence limit of agreement: -0.80 to 0.53), correlation coefficient of 0.88 (p

Hypertrophic cardiomyopathy (HCM) affects the right ventricle (RV) because of the anatomically hypertrophied septum and plausibly by extension of the myopathic process to the RV. We sought to investigate RV strain in patients with left ventricular hypertrophy secondary to either HCM or hypertension (H-LVH). Our cross-sectional study included 32 patients with HCM, 21 patients with H-LVH, and 11 healthy subjects, who were evaluated with transthoracic echocardiography. Using a dedicated software package, bi-dimensional acquisitions were analyzed to measure segmental longitudinal strain in apical views. Right ventricular global longitudinal strain (GLS) was calculated by averaging septal and right free wall strains. The HCM and H-LVH groups were comparable for age and demographic characteristics. Right ventricular tricuspid annular plane systolic excursion was not significantly different between HCM and H-LVH subjects. Moreover, RV GLS, septal and lateral RV myocardial strain were significantly impaired in patients with HCM (all p0.001). Regional and global RV strain parameters were not significantly impaired in H-LVH compared to healthy controls An RV GLS cut-off value of14.9% differentiated HCM and H-LVH with a 90% sensitivity and a 95% specificity (p0.001). RV strain parameters are impaired in patients with HCM. Assessment of two-dimensional RV strain parameters could help differentiate between HCM and H-LVH.

The current definition of peripartum cardiomyopathy (PC) is restricted to patients with left ventricular systolic dysfunction (ejection fraction [EF]45%). Data on peripartum heart failure (HF) with normal EF are sparse. We describe clinical characteristics of patients with normal (≥55%) and patients with low (45%) left ventricular ejection fractions (LVEFs). Electronic medical records (2006 to 2013) of our tertiary care center were retrospectively screened to identify peripartum HF with normal EF, defined as an entity meeting Framingham criteria for HF with symptom onset during the last month of pregnancy or up to 5 months after delivery and with an EF of ≥55%. Clinical characteristics, echocardiographic parameters, and outcomes of these patients were compared with age-matched control patients with traditionally defined PC (EF45%). A total of 25 patients with PC and EF≥55% were identified. Exclusion of hypertension (n=9), preeclampsia (n=1), and diabetes mellitus (n=2) yielded 13 patients with PC and EF≥55%. Age-matched patients with traditional PC (EF45%) constituted controls (n=16). Compared with patients with PC and low LVEF, patients with PC and normal LVEF had lower B-type natriuretic peptide levels, systolic and diastolic left ventricular dimensions, left atrial size, and incidence of decompensated HF during delivery (p0.05). Compared with historical age-matched controls, patients with normal LVEF exhibited attenuated E' mitral annular velocities. On follow-up, these patients were associated with a lower New York Heart Association functional class. In conclusion, peripartum HF with normal LVEF appears to be a distinct entity.

Background Peripartum cardiomyopathy (PPCM) is a rare life-threatening condition of unclear etiology. Data on the use of cardiac magnetic resonance (CMR) imaging to characterize PPCM are limited. This study was done to assess the role of CMR imaging for the diagnosis and prognostication of patients with PPCM. Methods Medical records of a tertiary medical center were screened for PPCM patients with CMR imaging done within the past 5 years (2006-2011). Images were reviewed by 2 expert radiologists (blinded to clinical data) using cine sequences for chamber function and size, T2-weighted images for the determination of edema (T2-ratio), and late gadolinium enhancement (LGE) sequences for myocardial tissue characterization. Results Ten PPCM patients (aged 28 ± 6 years, 90% African American) had a total of 15 CMR examinations: 4 in the acute phase (within 7 days of diagnosis) and 11 during follow-up (median, 12 months; range, 1-72 months). Left ventricular ejection fraction was decreased in all 4 initial scans. Elevated T2 ratio (> 2) seen in 1 patient decreased on follow-up imaging. LGE was seen in 1 of the 4 acute-phase scans and in 4 of the 11 follow-up phase scans. These 4 patients had multiple readmissions because of heart failure exacerbations and persistently low left ventricular ejection fraction on subsequent echo- cardiograms. Conclusions LGE seems to be associated with a poor prognosis in the setting of PPCM. CMR imaging seems to have promising practical implications in the diagnosis and prognostication of PPCM patients.

Henoch-Schönlein purpura (HSP) is an acute systemic vasculitis with unknown etiology, although several studies have found HSP to be related to cytokines such as tumor necrosis factor α, interleukin (IL)-1, and adhesion molecules. In the present study we determined the levels of cytokines such as IL-18 and endothelin-1 (ET-1) in children with HSP. Subjects were divided into three groups (group 1, 20 subjects with HSP; group 2, 10 subjects belonging to group 1 during their follow-up 4 to 6 months later; and group 3, 16 controls who were healthy siblings of the subjects). IL-18 and ET-1 levels were determined using enzyme immunoassay and expressed as mean ± standard deviation. We observed higher IL-18 levels in children with HSP (767.6 ± 145.1 pg/mL) than in controls (614.6 ± 66.54 pg/mL, p 0.05), but IL-18 levels were found to be significantly lower in subjects with HSP in remission (502.7 ± 60.81 pg/mL) than in those who were in an active phase (1,050 ± 244.5 pg/mL, p 0.05, n = 10). ET-1 levels were found to be significantly higher in subjects with HSP (1.93 ± 0.19 pg/mL) than in controls (1.10 ± 0.13 pg/mL, p 0.05), although no significant difference was observed in ET-1 levels between subjects in group 1 (1.88 ± 0.30 pg/mL) and group 2 (1.91 ± 0.120, p 0.05, n = 10). A positive correlation was observed between IL-18 and ET-1 levels in subjects with HSP (correlation coefficient [r] = 0.5254, p 0.01). These results suggest that levels of IL-18 and ET-1 are worth monitoring during the clinical course of the disease, but caution must be exercised in extrapolating data based on small study samples.

Aim: The aim is to review the English literature for post-traumatic superolateral dislocation of mandibular condyle (SDMC),discuss their dynamics and clinical management and to propose to modify the existing classification of SDMC. Patients and Methods: A literature search was carried at Pubmed, Sciencedirect, Google and references from reported articles were crosschecked to look for the cases of SDMC from 1969 to 2015 in English language. Also, we have reviewed 11 of our patients with total of 18 superolateral dislocated intact or sagittal split condyles ,who visited our unit in the previous two years. Results: In our retrospective analysis 58 cases of SDMC were found in the literature, of which 38 had intact mandibular condyles and 20 had sagittal split. Early and intact SDMC were successfully managed conservatively with closed reduction, whereas old cases and largely fractured condyles necessitated open reduction. Additionally, we observed an unusual dislocation associated with fracture of contralateral posterior mandible(angle) in our series which did not gratify the existing classification. Conclusion: Alteration of the existing classification was required to accommodate the unusual type of dislocation.

Objectives The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). Background LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. Methods We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. Results All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I 2 = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10 −19 ). Conclusions Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.

Takayasu's arteritis (TA) is an inflammatory fibrosing arteritis affecting predominately the aorta and its main branches. Pathogenesis of this disease remains enigmatic. Despite the numerous studies, the role of adventitia in vascular lesion formation in the setting of TA has been ignored. Virtually nothing is known about the mechanism regulating inflammation in the adventitia in the setting of TA. The present study included subjects with Takayasu's arteritis and normal healthy control subjects. Isolated T cells from peripheral blood mononuclear cells (PBMCs) using nylon wool and HUT-78 (human cutaneous T lymphoma cell line) were stimulated with PHA for 24 h. Stimulated cell were fixed with paraformaldehyde and fractionated into membrane, cytosolic and nuclear fractions. These cellular fractions were co-cultured with human fibrosarcoma cell line (HT-1080) and transcriptional expression of matrix metalloproteinases (MMP-1, 3, 9 and TIMP-1) was determined using semiquantitative RT-PCR. Stimulation of MMPs-TIMP synthesis by HT-1080 cells was mimicked by a membranous fraction derived from activated T-cell isolated from TA subjects and activated HUT-78 cells, whereas cytosolic and nuclear fractions were ineffective. In conclusion, for the first time we provide evidence for the presence of a cell surface-specific antigenic moiety on T-cells of TA subjects, which is responsible for activation of fibroblasts (cells predominantly present in adventitia) to enhance MMP production and, therefore, may lead to extracellular matrix degradation.

BACKGROUND Despite the high prevalence of rheumatic heart disease (RHD) in developing countries such as India, data on characteristics, complications, and treatment practices are lacking. The HP-RHD (Himachal Pradesh Rheumatic Heart Disease) registry aimed at reporting these parameters in patients with RHD from a northern state of India. METHODS A total of 2,005 consecutive patients of RHD were enrolled over a period of 6 years (2011 to 2016) in the present study. The clinical characteristics, complications, and treatment practices were systematically recorded. RESULTS The mean age for patients with RHD was 40.3 ± 14.3 (range 5 to 83 years). RHD predominantly affected females (72.3%) and population from rural background (92%). Multivalvular involvement was frequent (43.2%), mitral valve was the commonest affected valve (83.3%). The majority of the patients had moderate-to-severe valvular dysfunction (69.3%). Mitral and tricuspid valve involvement was more frequent in female subjects compared with more frequent aortic valve involvement in male subjects (p

Background Receptor for advanced glycation end products (RAGE) may play an important role in inflammatory processes and endothelial activation. Extracellular newly identified RAGE binding protein (EN-RAGE), natural pro-inflammatory ligand for RAGE. The role of C-reactive protein (CRP) as a mediator in inflammation and atherosclerosis is the subject of recent investigations worldwide. In the present study, we investigated the effect of CRP on RAGE and EN-RAGE gene expression in THP-1 monocytic cell line. MAP kinases (ERK, p38 and JNK) were exploited as possible signaling pathways involved in the signal transduction by CRP. Further, atorvastatin was used as a therapeutic modality for modulation of these genes in the presence of CRP. Materials and methods Time and dose-dependent experiments were carried out in the presence of CRP. Specific MAPK pathways inhibitors were used to elucidate the signaling pathways involved. Effect of atorvastatin was also determined in the presence of CRP on the expression of these genes. Results Time and dose-dependent experiments revealed that, treatment of THP-1 cells with 100 μg of CRP/ml/10 6 cells for 24 h, augmented the expression of RAGE and EN-RAGE genes by 2.5–3.5 folds and 3.5–4.5 folds respectively. CRP acted via FcγRII and utilized ERK, p38 and JNK pathways to transduce signals. Atorvastatin in a dose of 20 μM, was able to attenuate up-regulation of CRP-induced genes ( p Conclusion Our data strongly suggests that blockade of RAGE–EN-RAGE by statins at an early stage may prevent inflammation in atherosclerosis and counteract the harmful effects mediated by CRP.

Aim: Accelerated extracellular matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) has been implicated in several rheumatological disorders and systemic vasculitides, especially Takayasu’s arteritis and Kawasaki disease. Therefore, the aim of the present study was to investigate the potential role of MMPs in Henoch–Schonlein purpura (HSP), an acute type of systemic vasculitis in children. Methods: We studied the activity of MMP-2 and MMP-9 in the sera using gelatin zymography and the transcriptional expression in peripheral blood mononuclear cells using semi-quantitative RT-PCR in 20 patients with HSP in acute and convalescent phase and in 20 healthy children, who were siblings of the subjects with same age group. Results: All 20 children with HSP showed increased levels of serum activity of MMP-2 and MMP9 in acute phase as compared with their convalescent phase [MMP-2 (p > 0.05); MMP-9 (p > 0.05)] and their control counterparts [MMP-2 (p < 0.001); MMP-9 (p < 0.001)]. Similarly, transcriptional expression of MMPs was found to be higher in the acute phase of HSP than in convalescent phase [MMP-2 (p < 0.05); MMP-9 (p < 0.001)] and in their healthy controls [MMP-2 (p < 0.001); MMP-9 (p < 0.01)]. Conclusion: The presence of excessive transcriptional expression and gelatinolytic activity of MMPs may be downstream to the actual aetiopathogenetic factors.

Inflammation participates in atherosclerosis from its inception onwards. RAGE (receptor for advanced glycation end products) and its natural pro-inflammatory ligand, EN-RAGE (extracellular newly identified RAGE-binding protein) have been implicated in various inflammatory diseases. In present study, we determined the expression of RAGE and EN-RAGE in peripheral blood mononuclear cells (PBMCs) of subjects with pre-mature coronary artery disease (CAD) for the first time.The study patients were angiographically proven non-diabetic patients with pre-mature CAD (Group I; N=100) and control group comprised of subjects with coronary risk factors and without coronary artery lesions (Group II; N=40). Semi-quantitative RT-PCR was performed to determine transcriptional expression of RAGE and EN-RAGE in PBMCs. Soluble RAGE (sRAGE) and C-reactive protein (hsCRP) levels were determined in serum of all study subjects using immunoassays. A significantly increased transcriptional expression of RAGE and EN-RAGE in PBMCs (p0.01) of Group I patients was observed. Increased circulating hsCRP (p0.01) levels and decreased sRAGE (p0.01) levels were observed in Group I as compared with the Group II subjects. Severity of disease determined by Gensini score was found to be positively correlated with transcriptional expression of RAGE (r=0.530) and EN-RAGE (r=0.323). EN-RAGE expression revealed a strong association with RAGE (r=0.326), hsCRP (r=0.251) and a negative association with sRAGE (r=-0.222).Increased expression of RAGE and EN-RAGE in non-diabetic pre-mature CAD and various associations discussed may amplify several cellular perturbations and thus significantly contribute to the pathophysiology of CAD.

Background Left main disease (LMD), defined as ≥ 50% lesion stenosis, occurs in 3% to 5% of patients undergoing catheterization. Limited data on the value of single-photon emission computed tomography (SPECT) imaging for diagnosis of LMD exists. Hypothesis This study sought to evaluate the diagnostic accuracy of SPECT imaging in the diagnosis of LMD. Methods A total of 74 consecutive patients with LMD, identified from our catheterization lab database (January 2003–December 2007) with gated exercise (15 patients) or adenosine (59 patients), thallium 201, or Tc-99m SPECT imaging within 6 months of index angiography were included. Group 1 (Gp 1) included 33 patients with isolated LMD. Group 2 (Gp 2) consisted of 41 patients with LMD and 1-vessel disease (6); LMD and 2-vessel disease (24); and LMD and 3-vessel disease (11). Results Reversible perfusion defects (PD) were absent in 6 (18%) of Gp 1 and 8 (20%) of Gp 2 patients. Among Gp 1 patients, PD in 1-vessel, 2-vessel, 3-vessel distribution were seen in 20 (61%), 5 (15%), and 2 (6%) patients respectively. In comparison, PD in 1-vessel, 2-vessel, 3-vessel distribution were observed in 20 (49%), 12 (29%), and 1 (2%) of Gp 2 patients respectively. Left main (LM) pattern was noted in 6 patients (Gp 1: 2, Gp 2: 4). Transient ischemic dilatation (TID) was encountered in 34 patients (Gp 1: 17, Gp 2: 17) and in 4 patients with normal perfusion scans. Conclusions These data represent the largest analysis of patients with “isolated” LMD. Approximately 19% of patients with LMD have no reversible PD on SPECT. While LM pattern is rare, 1-vessel distribution PD and TID represent the most frequent SPECT abnormalities. Copyright © 2009 Wiley Periodicals, Inc.

Aortic valve calcification is common in the elderly and in patients with congenital bicuspid aortic valve but unlike calcific mitral valve disease it is not a well recognized risk factor for stroke. Although autopsy studies have revealed evidence of systemic embolism in one-third of cases with calcific aortic valves, there is conflicting data from larger clinical studies examining the association between calcific aortic valve and stroke. There are only 8 reported cases of symptomatic stroke from spontaneous cerebral thromboembolism associated with calcific aortic valve in the literature. Computerized tomography (CT) angiography and CT without contrast are modalities of choice to diagnose calcific embolism, while MRI may be useful in delineating the extent of ischemia. Ideal management strategy, the role of antiplatelet therapy, anticoagulation or recommendations for valve replacements are poorly defined. We present a focused literature review on this topic.

Background: Acute coronary syndrome (ACS) resulting from culprit lesion in left main coronary artery (LMCA) can cause rapid hemodynamic deterioration. It is important to identify these patients early to facilitate timely revascularization. ST segment elevation in aVR greater than or equal to V 1 (aVR-V 1 ≥ 0) has been suggested as a sensitive predictor of LMCA disease. As a result of balanced forces, we hypothesized that ST deviation in V 6 greater than or equal to ST deviation in V 1 (V 6 -V 1 ≥ 0) might be a good determinant of LMCA disease. Methods: We compared admission 12-lead ECGs of ACS resulting from culprit LMCA lesion (n = 75, group I) with ACS resulting from culprit left anterior descending lesion (n = 81, group II). Group I was selected over a period of 10 years. We compared V 6 -V 1 ≥ 0 to aVR-V 1 ≥ 0 in both groups. We also looked at ratios of ST deviations in V 6 ,V 1 (V 6 /V 1 ≥ 1) and aVR,V 1 (aVR/V 1 ≥ 1) in patients where ST segment in V 1 was not isoelectric (group I = 54 and group II = 55). Results: ST deviation in V 6 was significantly greater in group I as compared to group II (P < 0.001). The reliabilities of V 6 -V 1 ≥ 0, V 6 /V 1 ≥ 1, aVR-V 1 ≥ 0, and aVR/V 1 ≥ 1 in predicting LMCA disease were determined. Conclusion: This is the largest series of ECG analysis on ACS resulting from culprit LMCA lesion. V 6 -V 1 ≥ 0 and V 6 /V 1 ≥ 1 were more sensitive in predicting LMCA as culprit vessel in comparison to previously reported greater ST segment elevation in aVR than V 1 .

Purpose Normal tissue toxicity remains a dose limitation for cancer radiotherapy and chemoradiotherapy. Growth factors offer a novel means of mitigating normal tissue radiotoxicity. In particular, keratinocyte growth factor (rHuKGF), whose proliferative activity is restricted to epithelial cells, holds promise on the basis of the findings of preclinical models of epithelial cytoprotection and the clinical developments to date. We report the radioprotection of murine lung by an increase in tissue cellularity after rHuKGF-induced proliferation. Methods and materials Flow cytometric and image analysis techniques after bromodeoxyuridine labeling were used to estimate proliferative parameters. Our specialized analytical methods measure not only labeling indexes, but also the durations of S and G 2 +M phases, potential doubling times, and the net cell production rate. Image analysis techniques were used to identify the specific cell types that were proliferating (type II pneumocytes). Results Lung labeling index control values (0.5%) rose to a maximum (5.5%) at 3 days after intratracheal rHuKGF, returning to normal by Day 7. The potential doubling time fell from 66 days to 4.4 days. The net cell production rate rose from a control value of 1%/d to >15%/d by Day 3. This resulted in a nearly twofold increase in alveolar epithelial cellularity, which remained significantly elevated on Day 7. Saline-treated control animals exhibited no significant changes in the proliferative parameter values or cellularity. On the basis of these data, mice were irradiated, solely to the thorax, with ranges of single doses of 250 kVp X-rays 7 days after either intratracheal administration of 5 mg/kg rHuKGF or phospate-buffered saline. This interval was chosen because the proliferative response of the type II cells was finished but the cellularity of the lung remained increased. Pretreatment with rHuKGF extended the latent period before onset of pneumonitis after all radiation doses. rHuKGF treatment 7 days before thoracic irradiation significantly protected against pneumonitis (median effective dose 13.7 Gy, 95% confidence limit 13.4–14.0) compared with the control pretreatment with phosphate-buffered saline (median effective dose 12.8 Gy, 95% confidence limit 12.6–13.1). Conclusion The data showed that an increase in tissue cellularity, caused by rHuKGF treatment before irradiation, protected the lung from damage due to pneumonitis.

Takayasu’s arteritis (TA) was reported as an eye disease in the year 1905 and later was confirmed as a vasculitis. Since then, the etiology of the disease remains unknown; however, characteristic clinical features suggest multiple causative factors. Recent progress in vascular biology and other disciplines enlightens the pathophysiology of TA and demonstrated induction of various nonspecific inflammatory symptoms and destruction of the arterial wall, which leads to aneurysms and rupture of the affected arteries. Matrix metalloproteinases (MMPs) as an enzyme family have well-established roles in several vascular pathologies including intima formation, atherosclerosiss and aneurysms. MMPs have been proposed to be one of the molecules with a potential of having dual role in the course of TA, first as an active participant in pathophysiology and secondly as a diagnostic biomarker for TA disease. The desire to improve our understanding of the importance of MMPs and their endogenous inhibitors (TIMPs) in TA disease and for the development of therapeutic agents has inspired basic and clinical scientists for over a decade. In the present paper, we summarized the scientific rationale which highlights the signatures of matrix metalloproteinases and their endogenous inhibitors in pathophysiology as well as their being a potential candidate as biomarker for Takayasu’s arteritis.

Systolic blood pressure (SBP) rises approximately linearly with age in most societies. The cause of this rise is unclear. We tested the hypothesis that SBP is causally associated with the rate of rise in SBP with age by evaluating the effect of 12 polymorphisms associated with lower SBP on the age-related rate of rise in SBP in a series of meta-regression analyses involving ≤199 477 participants in 63 studies. We then evaluated the effect of these polymorphisms on the odds of coronary heart disease in 22 223 case and 64 762 control subjects and compared it with the effect of lower SBP observed in both prospective cohort studies and blood pressure–lowering randomized trials. All 12 polymorphisms were associated with both lower SBP and a slower age-related rise in SBP. The weighted mean effect of these 12 polymorphisms was associated with a 0.32-mm Hg lower SBP ( P =1.79×10 −7 ) and a 0.093-mm Hg/decade slower age-related rise in SBP ( P =3.05×10 −5 ). The effect of long-term exposure to lower SBP on coronary heart disease mediated by these polymorphisms was 2-fold greater than that observed in prospective cohort studies ( P =0.006) and 3-fold greater than that observed in short-term blood pressure treatment trials ( P =0.001). We conclude therefore that SBP seems to be causally associated with the rate of rise in SBP with age and has a cumulative effect on the risk of coronary heart disease.

Background Oxidative stress and activation of matrix metalloproteinases (MMPs) together have been widely implicated in various inflammatory vascular disorders. As Takayasu's arteritis (TA) is an inflammatory disorder characterized by destruction of elastic fibers, we hypothesized that oxidative stress and MMPs might play an important role in pathophysiology of the disease. Methods 40 patients with clinically defined TA and equal number of normal, healthy, controls were enrolled in the study. Subjects with TA were further divided into clinically active disease or in remission phase of the disease. Results Augmented levels of 8-isoPGF 2α (238.9±125.7 vs 79.5±29.1ng/ml), nitrite (NO 2 − ) (14.9±15.6 vs 3.3±1.7μM) were observed in TA patients as compared to the controls ( p 2α (272.2±117.3 vs 105.9±43.5ng/ml) and NO 2 − (17.9±16.1 vs 3.1±2.5μM) levels were higher in subjects with active disease vs those in remission ( p p p >0.05). Further, gelatinolytic activity showed a positive correlation with 8-iso-PGF 2α and NO levels in patients with TA. Conclusions Increased oxidative stress and MMP activity may play an active role in the progression of Takayasu's arteritis disease.

Background Congestive heart failure in sinus rhythm ranks second after atrial fibrillation (AF) among cardiogenic risk-factors for stroke. Clinical and echocardiographic predictors of stroke in this high-risk population remain poorly defined. Methods Retrospective screening of 1886 consecutive patients with severe systolic dysfunction (LVEF ≤35%) at a tertiary medical center echocardiography database (Nov 2005–Sep 2008) identified 83 patients in sinus rhythm with cardioembolic stroke. Patients with AF on follow-up, prosthetic valve, ventricular arrhythmia and lack of consensus between reviewing neurologists were excluded ( n =10). Consecutive age and gender-matched controls in sinus rhythm formed GpII ( n =73). Results The incidence of stroke was 3.9% (73/1886) over 35 months in this study. There were no significant differences in prevalence of established clinical risk-factors for stroke. There was a significantly higher prevalence of LV non-compaction ( p =0.02), aneurysm ( p p p Conclusions LV non-compaction, aneurysm, spontaneous echo-contrast and pulmonary hypertension are associated with an increased risk of stroke. While anticoagulation of these high-risk subgroups appears reasonable, further study in a prospective randomized clinical trial merits consideration.

Hypertension is a disorder controlled by multiple genes and inflammation and vascular remodelling of arteries have been implicated in pathogenesis of this disease. Green tea polyphenols (GrTPs) are rich in antioxidants and are known to inhibit inflammatory responses. A significant time-dependent increase in mRNA expression of both IL-6 and MMP-9 were observed in THP-1 macrophages when cultured in normocholesterolaemic hypertensive sera (P

Objectives: Essential hypertension (EH) is a multifactorial disease and oxidative stress has been demonstrated to play an important role in its pathophysiology. Among several genes implicated in the pathophysiology of hypertension, endothelin-2 (ET-2), a potent vasoconstrictor, has been incriminated as a candidate gene for essential hypertension. To find out correlation of in vivo biomarkers of oxidative stress [oxidized low density lipoprotein (Ox-LDL), 8-iso- Prostaglandin F2α (8-iso-PGF2α)] and Nitrite (NO2-) are related to endothelin-2 levels and to determine their value as diagnostic markers in essential hypertension. Methods: 100 subjects with essential hypertension and 150 age and sex-matched normotensive controls were enrolled to determine levels of ET-2, Ox-LDL, 8-iso-PGF2α and NO2-. Results: We observed significantly augmented levels of ET-2 (P

Historically, the receptor for advanced glycation end products (RAGE) was thought to exclusively play an important role under hyperglycemic conditions. However, more and more evidence suggests that RAGE in fact is an inflammation perpetuating multi-ligand receptor and participates actively in various vascular and inflammatory diseases even in normoglycaemic conditions. Various ligands include advanced glycation end products (AGEs), S100 proteins and amphoterins etc. Besides full-length RAGE, numerous truncated forms of the receptor have also been described including the well-characterized soluble RAGE (sRAGE). sRAGE has an ability to act as a decoy to avoid interaction of RAGE with its pro-inflammatory ligands. Ligand engagement of RAGE activates multiple signaling pathways and also forms a positive feedback loop for its own enhanced expression. This review will discuss the role of multi-ligand receptor i.e. RAGE in context to various vascular diseases, which have a pathophysiologically important inflammatory component in normoglycaemic conditions.

Coronary atherosclerosis is a chronic progressive disease that begins early in life and progresses slowly over several decades before becoming clinically manifest. The causal relationship between low-density lipoprotein cholesterol (LDL-C) and the risk of coronary atherosclerosis is well established. Multiple randomized trials have demonstrated that lowering LDL-C levels during treatment with a statin reduces the risk of major atherosclerotic coronary events. However, individuals being treated with a statin continue to experience a high residual risk of events. Here we review the evidence that lowering LDL-C levels beginning earlier in life, and therefore earlier in the atherosclerotic disease process, can prevent or substantially delay the development of atherosclerosis and thereby substantially improve the clinical benefit of therapies that lower LDL-C levels. We focus on providing a critical appraisal of the naturally randomized evidence that is emerging from recently conducted genetic association studies.

Takayasu's arteritis (TA) is a rare primary and granulomatous large vessel vasculitis of unknown origin that predominantly affects the aorta and itsmajor branches. It has been shown toaffect individuals of anyage, gender and a wide variety of ethnic and racial population worldwide. The pathophysiology of TA is complex and multi-factorial and the exact pathogenesis remains to be elucidated; however, participation of autoimmunity, inflammation and oxidative stress has potentially been implicated [1–3]. Receptor for advanced glycation endproducts (RAGE) is amemberof the immunoglobulin superfamily and is expressed on the surface of various cells e.g. endothelium, mononuclear phagocytes, lymphocytes and smooth muscle cells. Extracellular newly identified RAGE-binding protein (EN-RAGE or S100A12), an inflammatory ligand of RAGE, is a member of the S100 protein family. Since its discovery twodecades back [4], the inflammatory role of RAGE and EN-RAGE interaction is nowwell established in various chronic inflammatory disorders. RAGE has a circulating truncated variant isoform and soluble RAGE (sRAGE), corresponds to its extracellular domain only. By competing with cell-surface RAGE for ligand binding, sRAGE contributes to the removal/neutralization of circulating ligands, thus, functioning as a decoy [5–7]. Previously, we demonstrated low sRAGE levels showing inverse correlation with MMPs in a group of forty TA subjects as compared to controls [8]. Keeping in mind the importance of RAGE biology in various diseases, we thought it worth to determine the expression of RAGE and its inflammatory ligand EN-RAGE at transcriptional level in peripheral blood mononuclear cells (PBMCs) fromTA subjects. For this, 24 subjectswith TA and 24 normal healthy controls were recruited as described previously [3,8,9]. The Institutional Ethics Committee approved the present study. Venous blood was collected from overnight fasted individuals in the morning from antecubital vein and processed as described previously [5,8]. Semi-quantitative RT-PCR was performed for determining the transcriptional expression of RAGE andEN-RAGE in PBMCs [5]. Circulating levels of sRAGE were determined in all the study subjects using commercially available enzyme-linked immunoassay as per manufacturer's instructions (DRG00, RD p=0.003, Fig. 1E). However, no significant correlation of sRAGE levels was observed with either RAGE or EN-RAGE mRNA in TA subjects. This is the first report in literature which demonstrates that mRNA levels of RAGE and its ligand EN-RAGE are up-regulated in subjects with TA. This study also demonstrates a positive correlation of RAGE and ENRAGE, in subjectswith TA for thefirst time. Our data is supported by other reports, which demonstrate that RAGE expression increases stably in certain pathological processes, and is associated with ligand-rich microenvironments [6,7]. In a previous study, we demonstrated that RAGE and EN-RAGE genes are augmented in non-diabetic CAD subjects and showed their positive correlation with the severity of disease [5]. Ligation of this receptor with its ligands activates the downstream signaling pathways such as NF-κB [10]. In addition, RAGE and EN-RAGE interactions could further induce the expression of adhesion molecules, migration and proliferation of leukocytes and augment cytokine release from the lymphocytes. Excessive expression of these genes at sites of inflammation may feasibly form a positive feedback loop that may further aggravate underlying inflammation. In corroboration to this, other reports in literature and our work have clearly demonstrated a potential participation of various cytokines, chemokines and MMPs in the pathophysiology of TA [3,8,9,11]. Significantly increased RAGE–EN-RAGE expression in TA further confirms a prevalent oxidative stress and inflammatory milieu in such a situation. Presence of various functional splice variants of RAGE is another important characteristic of this particular receptor. The production of endogenous secretory RAGE by alternative splicing may influence the actions of ligands on the full form of RAGE, located on the plasma membrane [12]. Finding increased RAGE mRNA levels in TA subjects, one

Background Left main disease (LMD) and three-vessel disease (3VD) have important prognostic value in patients with coronary artery disease. However, uncertainties still exist about their prevalence and predictors in patients with acute coronary syndrome (ACS) and also in patients with stable coronary disease. Thus the aim of this study was to perform an international collaborative systematic review and meta-analysis to appraise the prevalence and predictors of LMD and 3VD. Methods Medline/PubMed were systematically searched for eligible studies published up to 2010, reporting multivariate predictors of LMD or 3VD. Study features, patient characteristics, and prevalence and predictors of LMD and 3VD were abstracted and pooled with random-effect methods (95% CIs). Results 17 studies (22 740 patients) were included, 11 focusing on ACS (17 896 patients) and six on stable coronary disease (4844 patients). In the ACS subgroup, LMD or 3VD occurred in 20% (95% CI 7.2% to 33.4%), LMD in 12% (95% CI 10.5% to 13.5%), and 3VD in 25% (95% CI 23.1% to 27.0%). Heart failure at admission and extent of ST-segment elevation in lead aVR on 12-lead ECG were the most powerful predictors of LMD or 3VD. In the stable disease subgroup, LMD or 3VD was found in 36% (95% CI 18.5% to 48.8%), with the most powerful predictors being transient ischaemic dilation during the imaging stress test, extent of ST-segment elevation in aVR and V1 during the stress test, and hyperlipidaemia. Conclusions This meta-analysis demonstrated that severe coronary disease—that is, LMD or 3VD—is more common in patients with ACS or stable coronary disease than generally perceived, and that simple and low-cost tools may help in the selection of the most appropriate therapeutic approach.

Although there appears to be a role for statins in reducing cerebrovascular events, the exact role of different lipid fractions in the etiopathogenesis of cerebrovascular disease (CVD) is not well understood. A secondary analysis of data collected for the placebo arm (n = 2,078) of the Cholesterol and Recurrent Events (CARE) trial was performed. The CARE trial was a placebo-controlled trial aimed at testing the effect of pravastatin on patients after myocardial infarction. Patients with histories of CVD were excluded from the study. A Cox proportional-hazards model was used to evaluate the association between plausible risk factors (including lipid fractions) and risk for first incident CVD in patients after myocardial infarction. At the end of 5 years, 123 patients (6%) had incident CVD after myocardial infarction (76 with stroke and 47 with transient ischemic attack). Baseline non–high-density lipoprotein (HDL) cholesterol level emerged as the only significant lipid risk factor that predicted CVD; low-density lipoprotein cholesterol and HDL cholesterol were not significant. The adjusted hazard ratios (adjusted for age, gender, hypertension, diabetes mellitus, and smoking) for CVD were 1.28 (95% confidence interval [CI] 1.06 to 1.53) for non-HDL cholesterol, 1.14 (95% CI 0.96 to 1.37) for low-density lipoprotein cholesterol, and 0.90 (95% CI 0.75 to 1.09) for HDL cholesterol (per unit SD change of lipid fractions). This relation held true regardless of the level of triglycerides. After adjustment for age and gender, the hazard ratio for the highest natural quartile of non-HDL was 1.76 (95% CI 1.05 to 2.54), compared to 1.36 (95% CI 0.89 to 1.90) for low-density lipoprotein cholesterol. In conclusion, non-HDL cholesterol is the strongest predictor among the lipid risk factors of incident CVD in patients with established coronary heart disease.

stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435–41. [4] Takebayashi H, Mintz GS, Carlier SG, et al. Nonuniform strut distribution correlates with more neointimal hyperplasia after sirolimus-eluting stent implantation. Circulation 2004;110:3430–4. [5] Turco MA, Ormiston JA, Popma JJ, et al. Polymer-based, paclitaxel-eluting TAXUS Liberte stent in de novo lesions: the pivotal TAXUS ATLAS trials. J Am Coll Cardiol 2007;49:1676–83. [6] TakanoM, Ohba T, Inami S, et al. Angioscopic differences in neointimal coverage and in persistence of thrombus between sirolimus-eluting stents and bare metal stents after a 6-months implantation. Eur Heart J 2006;27:2189–95. [7] YamamotoM, Okamatsu K, Inami S, et al. Relationship between neointimal coverage of sirolimus-eluting stents and lesion characteristics: a study with serial coronary angioscopy. Am Heart J 2009;158:99–104. [8] Takano M, Yamamoto M, Murakami D, et al. Lack of association large angiographic late loss and low risk of in-stent thrombus: angioscopic comparison between paclitaxeland sirolimus-eluting stent. Circ Cardiovasc Intervent 2008;1:20–7. [9] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.

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Studies are lacking in literature, which demonstrate the cumulative impact of certain soluble markers in predicting the severity of CAD. Serum hsCRP, MMP-9, TIMP-1 and sRAGE levels were measured in non-diabetic 100 angiographically proven CAD patients (Group I) and 40 non-diabetic subjects with coronary risk factors and without any lesions (Group II). Increased levels of serum hsCRP, MMP-9, TIMP-1 and decreased levels of sRAGE were observed in Group I as compared to Group II. Gensini score, a measure for severity of CAD was found to be positively correlated with serum hsCRP, MMP-9, TIMP-1 and negatively with sRAGE. Multivariate analysis revealed serum MMP-9, hsCRP, sRAGE and family history as predictors of severity of CAD with a cumulative sensitivity and specificity of 92% and 82%, respectively. Cumulative impact of these soluble markers, in addition to the established markers will contribute to improve the predictive value for the assessment of disease severity.

Left main coronary artery disease carries a poor prognosis. The etiology of isolated and significant left main coronary artery (ILMCA) disease is not well understood. Studies so far were limited by small numbers. The authors identified 46 patients with ILMCA disease from their database over 10 years (group I) and compared them with 83 consecutive patients undergoing catheterization (group II). They also compared patients with ostial vs distal ILMCA disease. Group I represented 0.1% of catheterization patients. The demographic profile and atherosclerotic risk factor profile of the 2 groups as well as ostial and distal ILMCA disease were compared. This is the largest study of ILMCA disease. Risk factors for atherosclerosis were commonly seen. Nonatherosclerotic causes of ILMCA disease were not seen. This study suggests coronary atherosclerosis as the predominant cause of ILMCA disease. ILMCA disease is more common in women. Diabetes is more commonly associated with distal ILMCA lesion. There is a trend suggesting that ostial ILMCA lesion is more common in smokers and women.

Background Takayasu's arteritis (TA) is a chronic obliterative inflammatory disease. Inflammatory cell infiltration and destruction of the vessel wall in TA strongly suggest that cell mediated immunological mechanisms play an important role in the pathogenesis of this disease. Therefore, in the present study our aim was to focus on the role of chemokines and adhesion molecules in patients with Takayasu's disease. Methods Twenty-one patients with clinically defined TA and 21 healthy control volunteers were recruited by using the standard criteria. Patients with TA were divided into those with clear-cut clinically active or inactive disease based on vasculitis activity score. Results MCP-1 and hRANTES were significantly increased in patients with TA as compared to controls. MCP-1 and hRANTES values were reliably able to distinguish between patients with active disease vs. subjects in remission. sVCAM-1 levels remained unaltered between patients and controls. Conclusions C–C chemokines can be used as reliable markers/diagnostic tools in determining the activity of Takayasu's arteritis.

Background Elevated troponin I in the absence of angiographically visible coronary lesions is seen in up to 10–15% of those undergoing angiography for suspected coronary artery disease. This study aims to elucidate the etiology of elevated cardiac troponin I in patients with normal coronary arteries on angiography. Methods We identified 1551 (8.6%) patients with normal coronary arteries from our catheterization database of 17,950 patients from Jan 2000 to Jun 2004. Elevated troponin I levels were found in 217 (14%) of 1551 patients with normal coronary arteries. Of these 217 patients, 73 surgical patients were excluded, and the remaining 144 patients formed the study population. The study population was compared with age and gender matched patients with myocardial infarction and coronary artery disease (Group II). Results The patients with elevated cardiac troponin I (cTnI) with normal coronary arteries had significantly lower prevalence of atherosclerotic risk factors and significantly higher left ventricular ejection fractions. The cTnI in patients with normal coronary arteries was elevated due to a number of causes including tachycardia, myocarditis, pericarditis, severe aortic stenosis, gastrointestinal bleeding, sepsis, left ventricular hypertrophy, severe congestive heart failure, cerebrovascular accident, electrical trauma, myocardial contusion, hypertensive emergency, myocardial bridging, pulmonary embolism, diabetic ketoacidosis, chronic obstructive pulmonary disease exacerbation and coronary spasm. Conclusions Cardiac troponin I could be elevated in a number of conditions, apart from acute myocardial infarction, and could reflect myonecrosis. Acute myocardial infarction is a clinical diagnosis as the laboratory is an aide to, not a replacement for, informed decision making.

with advanced heart failure. J Am Coll Cardiol 2006;48:2485–9. [9] Okonko DO, Grzeslo A, Witkowski T, et al. Effect of intravenous iron sucrose on exercise tolerance in anemic and nonanemic patients with symptomatic chronic heart failure and iron deficiency: FERRIC-HF: a randomized, controlled, observerblinded trial. JACC 2008;51:103. [10] Beck da Silva L, Rohde LE, Clausell N. Etiology and management of anemia in patients with heart failure: how much iron is missing? Congest Heart Fail Jan-Feb 2008;14(1):25–30. [11] Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis 2001;38(5):988–91. [12] Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmen J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant 2006;21(2):378–82.

A55-year-old man presented to the emergency room (ER) with complaints of anorexia, feelings of being unwell and anuria from the previous day. He denied any chest pain, palpitations, dyspnoea on exertion or fever. He was recovering from a recent throat infection and had a past medical history of diabetes mellitus, hypertension and hypercholesterolaemia. He was pale-looking and his physical examination revealed hypotension (90/60 mmHg) and tachycardia. He appeared in mild respiratory distress. Examination of neck veins showed raised jugular venous pressure of 6 cm above the sternal angle. His chest was clear on auscultation and the intensity of heart sounds were diminished with no added sounds. He had a measured pulsus-paradoxus of 20 mmHg. His electrocardiogram showed diffuse low-voltage complexes with no evidence of electrical alternans. There were ST segment elevations in lateral leads with tall T-waves in anterior precordial leads suggestive of posterolateral myocardial infarction (Figure 1). Posterior changes were confirmed on a posterior electrocardiogram (Figure 2). Right-sided electrocardiogram failed to reveal any ST-T abnormalities suggestive of right ventricular infarction. The initial set of laboratory tests done in ER revealed high blood urea nitrogen (9.64 mmol/litre) and serum creatinine (150.28 μmol/litre). The first set of cardiac enzymes revealed high troponin I (23.05 μg/litre) with normal myoglobin and creatine kinase. An arterial line was placed that revealed pulsus-paradoxus of 20 mmHg. A Swan–Ganz catheter was placed and showed: right ventricle of 53/33 mmHg; right atrium of 28 mmHg; pulmonary artery of 50/32 mmHg; pulmonary capillary wedge pressure of 30 mmHg. The central venous pressure tracing showed complete obliteration of ‘y’ descent. Dopplerechocardiography was done. It showed mild-to-moderate pericardial effusion with possible thrombus overlying the right ventricular wall. Posterior and lateral walls were found to be hypokinetic. The patient underwent coronary angiography before emergency pericardiocentesis. Angiography revealed complete occlusion of the first obtuse marginal. Aortic-pulse tracing is shown in Figure 3. These pressure tracings were consistent with cardiac tamponade with a demonstrable pulsus-paradoxus of about 20 mmHg. Ventriculography was not performed because of a suspected subacute rupture of the myocardial wall. A cautious pericardiocentesis was performed. Examination of the pericardial cavity revealed 300 cm3 of blood clots. In the absence of an ongoing leak, a pericardial window was created and a drain was left in situ. The patient was dialysed once after the procedure. His haemodynamics improved significantly after surgery. He remained stable through the course of his stay in the hospital and was discharged 3 days after pericardiocentesis.

Sun et al. recently reported matrix metalloproteinase-9 (MMP-9) and interleukin-6 (IL-6) as potential biomarkers for disease activity in Takayasu's arteritis (TA) in Chinese population [1]. Authors determined serum levels ofMMPs (MMP-3 and 9), tissue inhibitor ofMMPs (TIMP-1) and IL-6 in subjectswith TA and correlatedwith the disease activity of the disease. In a subgroup offifteenTA subjects they demonstrated that levels ofMMP-9 and IL-6 are able to predict the imagingoutcomeof thepatients with TA, but at the same time failed to notice any significant correlation between the pathological findings and the serum levels of MMP-9 and MMP-3 and IL-6. While reading this article, we found that the authors missed a few important studies to discuss in context to this particular field, where importance of IL-6 andMMPs-TIMP-1 has been established as potential biomarkers for this disease. Noris et al [2] in Italian population demonstrated a close relation of serum IL-6 with disease activity and suggested that it could contribute to vasculitic lesion in TA and could be relevant in the setting of therapeutic management of TA. In another study from Japan, Matsuyama et al [3] suggested that monitoring of circulating levels of MMP-2 as a helpful marker in diagnosing TA and those of MMP-3 and MMP-9 as disease activity markers might help provide adequate evaluation of treatment and guide therapeutic decision making for individual patients with TA. Our research group in India has also demonstrated importance of different MMPs (MMP-1, MMP-2, MMP-3, MMP-9 and TIMP-1) and their significant correlation with oxidative stress biomarkers (8-isoPGF2α and nitrite levels) in Takayasu's arteritis [4,5]. The etiopathogenesis of Takayasu's arteritis disease remains enigmatic, and various mechanisms such as post-infective, autoimmune, ethnic susceptibility and a genetic predisposition have been postulated [4,6]. As concluding remarks, we want to emphasize the fact that TA has been reported all over theworld with awide variation in its prevalence in different geographical regions. Moreover, it has been reported to cause different aortic lesion at different places in different countries [7]. Comparing and thoroughly analyzing the results from various studies reported worldwide will be of great help to provide a correct direction for future research on TA, as each and every researcher in this particular area is teaming to address the questionwhether any of thesemolecules can beused as amarker tomonitor the clinical course of the disease or to predict the disease exacerbations. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [8].

Numerous randomized trials have demonstrated that treatment with a statin reduces the risk of major cardiovascular events (MCE). We sought to quantitatively estimate the potential pleiotropic effect of statins by estimating the magnitude of this clinical benefit not related to the low-density