Coronary heart disease:Significance of liver X receptor α genomics

Crosstalk between lipid peroxidation and inflammation is known to be a pathognomonic feature for the development of coronary heart disease(CHD).In this regard ligand activated liver X receptor(LXR)-α has emerged as a key molecular switch by its inherent ability to modulate an array of genes involved in these two fundamental cellular processes.In addition,LXR-α has also been found to play a role in hepatic lipogenesis and innate immunity.Although several lines of evidence in experimental model systems have established the atheroprotective nature of LXR-α,human subjects have been reported to possess a paradoxical situation in which increased blood cellular LXR-α gene expression is always accompanied by increased coronary occlusion.This apparent paradox was resolved recently by the finding that CHD patients possess a deregulated LXR-α transcriptome due to impaired ligand-receptor interaction.This blood cellular mutated LXR-α gene ex- pression correlated specifically with the extent of coro- nary occlusion and hence need is felt to devise new synthetic ligands that could restore the function of this mutated LXR-αprotein in order to modulate genes involved in reverse cholesterol transport and suppression of the inflammatory response leading to the effective treatment of CHD.

Coronary atherosclerosis:Significance of autophagic armour

Autophagy is a lysosomal degradation pathway of cellular components such as organelles and long-lived proteins.Though a protective role for autophagy has been established in various patho-physiologic conditions such as cancer,neurodegeneration,aging and heart failure,a growing body of evidence now reveals a protective role for autophagy in atherosclerosis,mainly by removing oxidatively damaged organelles and proteins and also by promoting cholesterol egress from the lipid-laden cells.Recent studies by Razani et al and Liao et al unravel novel pathways that might be involved in autophagic protection and in this commentary we highlight the importance of autophagy in atherosclerosis in the light of these two recent papers.

Aberrant promoter methylation of p16 in colorectal adenocarcinoma in North Indian patients

AIM:To investigate p16 gene methylation and its expression in 30 patients with sporadic colorectal adenocarcinoma in a North Indian population. METHODS:Methylation specific polymerase chain reaction was used to detect p16 gene methylation and immunohistochemistry was used to study the p16 expression in 30 sporadic colorectal tumors as well as adjoining and normal tissue specimens.RESULTS:Aberrant promoter methylation of p16 gene was detected in 12(40%)tumor specimens,whereas no promoter methylation was observed in adjoining and normal tissue.Immunohistochemistry showed expression of p16 protein in 26(86.6%)colorectal tumors whereas complete loss of expression was seen in 4(13.3%)and reduced expression was observed in 12(40%)tumors. In the adjoining mucosa,expression of p16 was in 11 (36.6%)whereas no clear positivity for p16 protein was seen in normal tissue.There was a significant difference in the expression of p16 protein in tumor tissue and adjoining mucosa(P<0.001).The methylation of the p16 gene had a significant effect on the expression of p16 protein(P=0.021).There was a significant association of methylation of p16 gene with the tumor size (P=0.015)and of the loss/reduced expression of p16 protein with the proximal site of the tumor(P=0.047). Promoter methylation and expression of p16 had no relation with the survival of the patients(P>0.05). CONCLUSION:Our study demonstrated that promoter hypermethylation of the p16 gene results in loss/reduced expression of p16 protein and this loss/reduced expression may contribute to tumor enlargement.

Correlation between soluble receptor for advanced glycation end products levels and coronary artery disease in postmenopausal nondiabetic women

BACKGROUND The established cardiovascular risk factors cannot explain the overall risk of coronary artery disease(CAD),especially in women.Therefore,there is a growing need for the assessment of novel biomarkers to identify women at risk.The receptor for advanced glycation end products(RAGE)and its interaction with the advanced glycation end product(AGE)ligand have been associated with atherogenesis.The soluble fraction of RAGE(sRAGE)antagonizes RAGE signaling and exerts an antiatherogenic effect.AIM The study aim was to explore the association between plasma levels of sRAGE and CAD in nondiabetic postmenopausal women.METHODS This case-control study included 110 nondiabetic postmenopausal women who were enrolled in two groups.Group I included 55 angiographically proven CAD subjects with>50%stenosis in at least one of the major coronary arteries and Group II included 55 healthy control women who did not have CAD or had<50%stenosis of the coronary arteries.Stenosis was confirmed by invasive angiography.Plasma sRAGE was determined by an enzyme-linked immunosorbent assay.RESULTS We observed significantly lower plasma sRAGE concentrations in subjects with CAD vs healthy controls(P<0.05).Univariate and multivariate logistic regression analysis also revealed a significant correlation between plasma sRAGE levels and CAD(P=0.01).Multivariate odds ratios for CAD revealed that subjects with sRAGE concentrations below 225 pg/mL(lowest quartile)had a 6-fold increase in CAD prevalence independent of other risk factors.CONCLUSION Our findings indicated that low sRAGE levels were independently associated with CAD in nondiabetic postmenopausal women.Risk assessment of CAD in postmenopausal women can be improved by including sRAGE along with other risk factors.

The incidence of sporadic viral hepatitis in North India:a preliminary study

BACKGROUND: Viral hepatitis is one of the major causes of mortality and morbidity in developing countries. Hepatitis E virus (HEV) among the major etiological agents is responsible for both sporadic and epidemic outbreaks. The epidemic outbreak is water-borne whereas the sporadic outbreak is possibly through contact. Various diagnostic tools at times fail to pinpoint the cause of viral hepatitis. This study was carried out to evaluate the utility of ELISA and nRT-PCR (nested reverse transcriptase polymerase chain reaction) for the diagnosis of sporadic and acute viral hepatitis (AVH) caused by HEV in an endemic situation in North India. METHODS: Serum samples were collected from all the affected and suspected persons and subjected to serological detection of HAV IgM, HBsAg, HCV antibody and HEV IgM. The samples that were positive for HEV IgM were further processed for the detection of HEV RNA by nRT-PCR. RESULTS: A total of 843 samples were collected from 685 patients with AVH, 70 patients with fulminant hepatic failure (FHF), 53 patients with chronic liver disease (CLD), 11 patients with antituberculosis therapy (ATT)-induced jaundice, and 24 pregnant women. The percentage of positivity for anti-HEV IgM was 58.3% in the pregnant women, 41.4% in the paients with FHF, 38.6% in the patients with AVH, 9.4% in the patients with CLD and 18.2% in the patients with ATT induced jaundice. 9.4% of HBsAg carriers were positive for anti-HEV IgM. Males outnumbered females (62.8% vs. 37.1%). Furthermore, the rates of fulminant and acute outbreaks of hepatitis with HEV RNA positivity were 41.4% and 9.4%, respectively. CONCLUSION: Serological and molecular analysis should be combined for the diagnosis of viral infections, especially in endemic areas.

Heart and Brain:A neutro-genomic link

The philosophy of heart and brain are very ancient in our literature where the things good for the heart are not suggested good for the brain and vice-versa.Modern medicine is characterized by a high degree of specialization and the heart-brain connection that could be targeted to treat these complex cardiovascular/brain disorders.The idea that adverse diet/genome interactions can cause disease is not new.In the recent era the science of nutritional genomics have increased our understanding of diet-health-gene interactions and have provided a number of benefits for individuals,groups and societies.Since dietary chemicals are regularly ingested and participate indirectly and directly in regulating gene expression,it follows that a subset of genes regulated by diet must be involved in disease initiation,progression,and severity.In this regards Liver X Receptor(LXR)-a,a key transcription factors,associated with the several chronic pathological situation including coronary heart disease and neurodegenerative diseases have recently been found to be regulated by the dietary components.The crucial findings at molecular biology unit,Post Graduate Institute of Medical Education and Research(PGIMER),Chandigarh,INDIA have not only forced us to explore nutritional genomics as a holistic systems approach to understand the relationship between diet and health,but also to look into the disease preventing and health promoting foods that match our lifestyles,cultures and genetics.After all,we are what we eat.

Antioxidants: Friend or foe for tuberculosis patients

Respiratory burst induced bacteria killing by oxidants are important mechanism of host defence. However, it is impaired in tuberculosis due to inhibition of respiratory burst by Mycobacterial factors. Antioxidants are compounds that cause chelation of reactive oxygen species. So, antioxidants are expected to play a negative role in the management of active tuberculosis. But, oxidative stress is a proved fact that invariably happens in tuberculosis patients which is known to cause immunosuppression. Immunosuppression in turn is expected to augment tuberculosis. Hence, antioxidant supplementation is expected to benefit tuberculosis patients by minimising oxidative stress induced immunosuppression. Therefore, the role of antioxidants in tuberculosis appears to be paradoxical and urgent. Understanding of the role of antioxidant supplementation in tuberculosis is warranted. It is in this context that we have reviewed the recent literature and addressed the problem for its solution.

Surveillance for Antibiotic Resistance in <i>Clostridium difficile</i>Strains Isolated from Patients in a Tertiary Care Center

Clostridium difficile is the major etiological agent of nosocomial diarrhea primarily precipitated by antimicrobial therapy. We prospectively investigated the antibiogram profile of C. difficile strains isolated from patients reporting to a tertiary care hospital in North India. Fecal samples obtained from 1110 suspected cases of C. difficile infection were cultured for isolation of C. difficile. Colonies suspected as those of C. difficile were identified by phenotypic and molecular methods. Antimicrobial susceptibility of C. difficile isolates for different classes of antibiotics was determined using the Epsilon test for vancomycin, metronidazole, clindamycin and ciprofloxacin. The fecal samples cultured for C. difficile belonged to 709 (63.9%) males and 401 (36.1%) females. The mean age of the patients was 38.7 years. C. difficile was cultured from 174 (15.7%) of the total samples. Antibiotic resistance was largely observed towards clindamycin (57.5%) and ciprofloxacin (38.5%) but was significantly low towards metronidazole (1.72%) and nil (0%) towards vancomycin. C. difficile isolates had a high degree of resistance towards clindamycin and ciprofloxacin with low level of resistance to metronidazole and none towards vancomycin. Antibiogram surveillance of C. difficile will help for clinical practice and add to the epidemiological data of the organisms.

Anti-endothelial cell antibody rich sera from rheumatic heart disease patients induces proinflammatory phenotype and methylation alteration in endothelial cells

Rheumatic heart disease(RHD)is a major cause of cardiovascular morbidity and mortality in developing nations like India.RHD commonly affects the mitral valve which is lined by a single layer of endothelial cells(ECs).The role of ECs in mitral valve damage during RHD is not well elucidated.In here,anti-endothelial cell antibody from RHD patients has been used to stimulate the ECs(HUVECs and HMVECs).ECs proinflammatory phenotype with increased expression of TNFa,IL-6,IL-8,IFNg,IL-1b,ICAM1,VCAM1,E-selectin,laminin B,and vimentin was documented in both ECs.The promoter hypomethylation of various key inflammatory cytokines(TNFa,IL-6,and IL-8),integrin(ICAM1)associated with leukocyte transendothelial migration,and extracellular matrix genes(vimentin,and laminin)were also observed.Further,the in-vitro data was in accordance with ex-vivo observations which correlated significantly with the etiological factors such as smoking,socioeconomic status,and housing.Thus,the study sheds light on the role of ECs in RHD which is a step forward in the elucidation of disease pathogenesis.