The inflammation paradigm and coronary artery disease: What Celsus, Virchow and gene knock outs have taught us

Atherosclerotic vascular disease is a major cause of morbidity and mortality throughout the world. The clinical manifestations include coronary artery disease and myocardial infarction, cerebrovascular disease, renovascular disease and peripheral vascular disease. Initially considered a bland occlusive disease mediated to a great extent by lipids, atherosclerosis can now be considered an inflammatory disease, in its own right. This has led to a paradigm shift in disease management. We have come a long way since the time of Celsus, Galen, Virchow, Rokitansky and others when the components of the inflammatory cascade were first described. The development of mouse knock out models, improved molecular approaches to studying atheromatous blood vessels and development of sophisticated imaging and biomarker studies have enhanced our understanding of the molecular pathways in atherosclerosis. This brief review will attempt to weave together the historical, biochemical, immunological and molecular developments that have led to our current understanding of a deadly but treatable and potentially preventable disease.     

South Indian men with reduced CAG repeat length in the androgen receptor gene have an increased risk of prostate cancer

The androgen receptor (AR) gene possesses polymorphic CAG tandem repeats and the repeat length has been inversely related to the risk of prostate cancer (PCa). The distinct ethnic variation in the CAG repeat length may be correlated to differences in PCa risk in different populations. To evaluate the CAG repeat length in the AR gene and the implications for PCa, we screened 87 PCa patients and 120 control subjects from South India. The mean CAG repeat length in PCa patients was significantly smaller than that of controls (17.0 vs 20.7; P<0.001). Men with 19 CAG repeats had a significantly increased risk of cancer compared to those with >19 CAG repeats (age-adjusted OR=7.01; 95% CI=3.52–13.94; P<0.001). However, no significant association was observed between CAG repeats and age of onset or prostate-specific antigen levels. Although there was a trend towards shorter CAG repeat length in high grades of cancer, it was not significant (P=0.085). Thus, our results suggest an association between short CAG repeats in the AR gene and PCa risk in South Indian men. Further, we propose that CAG repeats could be used as a prognostic marker for PCa diagnosis.     

Tricuspid Regurgitation in Patients With Pacemakers and Implantable Cardiac Defibrillators: A Comprehensive Review

Implantable cardiac devices, including defibrillators and pacemakers, may be the cause of tricuspid regurgitation (TR) or may worsen existing TR. This review of the literature suggests that TR usually occurs over time after lead implantation. Diagnosis by clinical exam and 2‐dimensional echocardiography may be augmented by 3‐dimensional echocardiography and/or computed tomography. The mechanism may be mechanical perforation or laceration of leaflets, scarring and restriction of leaflets, or asynchronized activation of the right ventricle. Pacemaker‐related TR might cause severe right‐sided heart failure, but data regarding associated mortality are lacking. This comprehensive review summarizes the data regarding incidence, mechanism, and treatment of lead‐related TR.     

Catalase activity and innate immune response of Caenorhabditis elegans against the heavy metal toxin lead

The heavy metal lead‐induced oxidative stress on Caenorhabditis elegans was examined at the level of catalase activity and on innate immunity. Stress‐induced C. elegans was exposed to Pseudomonas aeruginosaPA14::GFP for monitoring the impact at the physiological level. Role of catalase on the innate‐immune responses of C. elegans was examined. PA14::GFP did not colonize lead pretreated C. elegans intestinal cells significantly compared to untreated controls, indicating stress‐mediated upregulation of host‐immunity. Semiquantitative PCR analyses of lead‐exposed and PA14‐infected C. elegans mRNA showed significant upregulation of candidate antimicrobial enzyme gene lys‐7 after 24 h of exposures. Upregulation of metallothionein(mtl‐1) when compared to mtl‐2 in response to the lead suggesting active detoxification of metal by mtl‐1. Exogenously provided Catalase (0.4–3.2 U) induced significant upregulation of lys‐7 compared to controls. lys‐7 upregulation during lead exposure was reconfirmed by real‐time PCR. Confocal microscopy and fluorescence spectrophotometer analyses indicated that the lead pretreated C. elegans was significantly less colonized by PA14::GFP when compared to controls. Relative expression of ctl‐1 and ctl‐2 mRNA was measured using real time PCR and found to be regulated during lead exposures. Over all, the upregulation of antimicrobial gene expression appears to be correlated with the level of catalase during stress emphasizing their key roles in defensive mechanism(s). These results provide a link between the stress and related immune responses which can be explored in higher systems. © 2011 Wiley Periodicals, Inc. Environ Toxicol, 2013.