Medha Rajappa

Atherosclerosis Pathophysiology and the Role of Novel Risk Factors: A Clinicobiochemical Perspective:

Atherosclerosis is the root cause of the biggest killer of the 21st century. Mechanisms contributing to atherogenesis are multiple and complex. A number of theories—including the role of dyslipidemia, hypercoagulability, oxidative stress, endothelial dysfunction, and inflammation and infection by certain pathogens—have been propounded from time to time explain this complex phenomenon. Recently it has been suggested that atherosclerosis is a multifactorial, multistep disease that involves chronic inflammation at every step, from initiation to progression, and that all the risk factors contribute to pathogenesis by aggravating the underlying inflammatory process. A better understanding of the pathogenesis of atherosclerosis will aid in devising pharmaceutical and lifestyle modifications for reducing mortality resulting from coronary artery disease (CAD). A comprehensive literature search was conducted using the Web sites of the National Library of Medicine (http:// www.ncbl.nlm.nih.gov/) and PubMed Central, the US National Library of Medicines digital archive of life sciences literature (http:// www.pubmedcentral.nih.gov/). The data were accessed from books and journals in which relevant articles in this field were published. The whole spectrum of coronary artery disease evolves through various events that lead to the formation and progression of atherosclerotic plaque and finally its complications. Atherosclerosis is the culprit behind coronary artery disease, cerebral vascular disease, and peripheral vascular disease. The pathogenic mechanisms are varied and complex. Of late, the role of lipoprotein (a), homocysteine, and inflammation and infection as prime culprits in pathogenesis of CAD is the subject of intense research and debate. The appreciation of the role of inflammation in atherosclerosis provides a mechanistic framework to understand the clinical benefits of newer therapeutic strategies, and a better understanding of pathogenesis aids in formulating preventive and therapeutic strategies in reducing mortality resulting from CAD. An in-depth knowledge of the various pathogenic mechanisms involved in atherosclerosis can help in substantiating the current existing knowledge about the CAD epidemic. This knowledge will help clinicians to better manage the disease, which affects Indians in its most severe form.

Biomarkers of Cardiac Injury: An Update:

Conventional and promising new markers of myocardial injury have become an important diagnostic tool and their prognostic significance is also recognized. In addition, they help identify patients who will derive the most benefit from therapeutic interventions. The literature was searched from the websites of the National Library of Medicine (http://www.ncbi.nlm.nih.gov/) and PubMed Central, the U.S. National Library of Medicine’s digital archive of life sciences journal literature (http://www.pubmedcentral.nih.gov/). The data were accessed from books and journals that published relevant articles in this field. The diagnosis of acute myocardial infarction (AMI) has traditionally relied on the combination of chest pain, ECG features, and elevation in serum markers. However, chest symptoms are frequently atypical or absent and ECG changes may be nonspecific or absent. Hence, the diagnosis of acute coronary syndromes has become increasingly dependent on serum markers of cardiac injury. Among them, creatine kinase (CK) is an effective and widely used test, with the recent CKMB assay offering greater specificity and sensitivity. Cardiac troponins facilitate early and rapid diagnosis, enable effective risk stratification in patients with AMI (with or without traditional criteria for MI), and identify those who will benefit from aggressive medical or surgical intervention. Recent data suggest the potential of myoglobin and CKMB isoforms as sensitive markers in the early hours after symptom onset. Cardiac-specific troponins help in rapid diagnosis, prognostication, and treatment of AMI. Troponins also facilitate early detection of recent infarction owing to their prolonged diagnostic window and also aid in the detection of “microinfarction.” CKMB is used to detect reinfarction or infarct extension, if levels rise again after declining. Finally, novel biochemical markers are receiving attention in ongoing trials. They may prove to be more effective in diagnosis and prognosis than their existing counterparts.

Uveitis: Mechanisms and recent advances in therapy.

Uveitis is a sight threatening inflammatory disorder that affects all ages and remains a significant cause of visual loss. Animal models of autoimmune and inflammatory disease in the eye allow the scientist and clinician to study the basic mechanism of the disease, and serve as templates for the development of therapeutic approaches. The accumulating knowledge of the various steps that are involved in the pathogenesis make it possible to devise specific strategies that disrupt discrete stages in the process. Some of the strategies are in the process of being translated to the clinic. New technologies emerge, promising more specific and more easily applied therapies. In this review, we will concentrate specifically on mechanisms and recent advances in the therapy of uveitis.

Antioxidant status in advanced cervical cancer patients undergoing neoadjuvant chemoradiation.

Abstract Cervical cancer is the most common cancer in Indian women. The aim of this study is to assess the alterations in the circulating lipid peroxide, antioxidant components and activities of defence enzymes in advanced cervical cancer patients, and to monitor the variations in their levels before and after neoadjuvant chemoradiation. Sixty patients with advanced cancer of the cervix (FIGO IIIa–IVb) are included in the study, along with 60 healthy controls. Blood samples are collected before the start of therapy (S1), two weeks after the second course of chemotherapy (S2) and two weeks after completion of tele/brachyradiation (S3). Single blood samples are taken from controls. Lipid peroxides, conjugated dienes, reduced glutathione (GSH), catalase (CAT) and glutathione-S-transferase (GST) are estimated using standard methods. Glutathione peroxidase (GPx) and superoxide dismutase (SOD) are assayed using commercially available kits. The pretreatment levels of plasma lipid peroxide were significantly elevated in cancer patients, while significantly lowered levels of GSH, GPx, GST, SOD and CAT were observed when compared to controls. After chemotherapy, the levels of lipid peroxidation showed a significant decline (P<0.05), which became highly significant after chemoradiation (P<0.01). Levels of GSH, GPx, SOD, GST and CAT showed a mild increase after chemotherapy. After chemoradiation, levels reverted to normal or near normal (P<0.01). Low levels of antioxidants in the circulation of patients with cervical cancer may be due to their increased utilisation to scavenge lipid peroxidation as well as their sequestration by tumour cells. The observed increase in antioxidant concentration after therapy might be due to the death of tumour cells or the arrest of tumour growth by chemotherapeutic agents. The normalisation of these parameters may provide information about the efficacy of neoadjuvant chemoradiation. A larger patient cohort with a longer follow-up period for therapeutic response studies may yield more significant data.

TNF-α/IL-10 ratio and C-reactive protein as markers of the inflammatory response in CAD-prone North Indian patients with acute myocardial infarction

BACKGROUND Cytokines are responsible for the modulation of immunological and inflammatory processes and play a significant role in the pathogenesis of coronary artery disease (CAD). Tumor necrosis factor (TNF)-alpha is the major pro-inflammatory cytokine while interleukin-10 (IL-10) is the major anti-inflammatory cytokine in patients with CAD. We determined the significance of the TNF/IL-10 ratio and C-reactive protein (CRP) in patients of acute myocardial infarction as a marker for CAD in the atherosclerosis-prone North Indian population. METHODS The study group comprised of 100 patients of acute myocardial infarction (AMI) and 100 age and sex matched healthy controls. Lipid profile, apolipoprotein-A (Apo-A), apolipoprotein-B (Apo-B) and CRP concentrations were estimated using commercially available kits in all patients and control subjects. TNF-alpha, lipoprotein (a) (Lp(a)) and IL-10 concentrations were assayed by using commercially available ELISA kits. RESULTS The TNF-alpha concentrations were significantly higher in patients with acute myocardial infarction (86.9+/-4.7 pg/ml), as compared to control subjects (7.1+/-0.67 g/ml). AMI patients also exhibited higher serum concentrations of IL-10 (5.74+/-0.82 pg/ml), in comparison to the controls (1.22+/-0.06 pg/ml). The ratio of TNF-alpha to IL-10 was significantly increased in cases (15.2+/-1.13), in comparison to healthy subjects (5.8+/-0.64). CONCLUSIONS These cytokines underline the role of the immune processes during unstable atherosclerosis and in the pathogenesis of coronary artery disease in the Indian context.

Apo-B/apo-AI ratio: a better discriminator of coronary artery disease risk than other conventional lipid ratios in Indian patients with acute myocardial infarction.

Background — Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the developed world and is rapidly assuming epidemic proportions in developing countries including India.This has led to extensive research to determine the risk factors unique to this group which may predispose to the elevated risk of this disease. Important amongst them are lipoproteins, homocysteine, lipoprotein (a), pro-inflammatory cytokines etc. The following study was undertaken to evaluate the role of the apolipoprotein-B100 (apo-B)/apolipoprotein-AI (apo-AI) ratio as a predictor of CAD risk in the atherosclerosis-prone Indian population, as compared to other conventional lipid ratios. Material and methods — The study group comprised 100 clinically assessed patients with acute myocardial infarction (AMI) diagnosed on electrocardiographic and biochemical criteria and 100 agematched healthy control subjects. Apo-B and apo-AI levels were estimated by the immunoturbidimetric method, using kits from Randox, UK. Lipid profile was determined using standard enzymatic methods. The exponential regression coefficient β was calculated for total cholesterol/high-density lipoprotein cholesterol (TC/HDL), TC-HDL/HDL, low-density lipoprotein (LDL) cholesterol/HDL and apo-B/apo-AI ratios. Results — The TC/HDL ratio was 5.15 ± 1.7 and 3.45 ± 0.87 in patients with AMI and control subjects, respectively (P < 0.001).The TC-HDL/HDL ratio was 4.61 ± 2.6 and 2.22 ± 1.14 in the patients with AMI and the control subjects (P< 0.001).The LDL/HDL ratio was 3.32 ± 1.5 in the AMI patients and 1.84 ± 0.78 in the control subjects (P< 0.001); whilst the apo-B/apo-AI ratio in the patients with AMI was 0.96 ± 0.30 and 0.71 ± 0.20 in the control subjects (P< 0.001).The exponential value of the regression coefficient β (Exp [β]) for apo-B/apo-AI ratio was 111.9, as compared to 4.4 for the LDL/HDL ratio, 3.5 for the TC/HDL ratio and 2.2 for the TC-HDL/HDL ratio, though all the lipid ratios were significantly higher in cases than in control subjects. Conclusion — Our findings suggest that the apo-B/apo-AI ratio is a better discriminator of CAD risk in the atherosclerosis-prone Indian population, than any of the conventional lipid ratios.The reduction of value of the apo-B/apo-AI ratio may drastically decrease the risk for CAD. Hence, the apo-B/apo-AI ratio may be suggested as an alternative to other lipid ratios for risk assessment in patients with CAD.

Effect of treatment with methotrexate and coal tar on adipokine levels and indices of insulin resistance and sensitivity in patients with psoriasis vulgaris.

Recent studies have implicated adipokines in the pathogenesis of the immune‐mediated inflammatory disease, psoriasis and its associated comorbidities. Hence, we undertook to study adipokine levels and indices of insulin resistance and sensitivity in patients with psoriasis vulgaris, in comparison with controls and their association with disease severity and response to therapy.

Role of Pro-/Anti-Inflammatory Cytokines and Their Correlation With Established Risk Factors in South Indians With Coronary Artery Disease

Cytokines are responsible for the modulation of immunological and inflammatory processes and play a significant role in the pathogenesis of coronary artery disease. We estimated the levels of pro-/anti-inflammatory cytokines in South Indian patients with coronary artery disease. The study population comprised of groups 1-3: 100 patients each with acute myocardial infarction, unstable angina, and stable angina, respectively, and group 4 (100 healthy controls). Cytokine levels (interleukin-6, interleukin-8, interleukin-10, and tumor necrosis factor-α) were estimated by enzyme-linked immunosorbent assay (ELISA). Interleukin-6, interleukin-8, and tumor necrosis factor-α levels were significantly higher in patients from groups 1 and 2, than in group 3 and controls. Acute myocardial infarction patients exhibited higher serum levels of interleukin-10 compared with other groups and control subjects. Patients with unstable angina had significantly lower interleukin-10 concentrations than those with stable angina. The ratios of pro-/anti-inflammatory cytokines in all the study groups increased significantly when patients with unstable angina were compared to other groups. In patients with acute myocardial infarction, interleukin-10 and tumor necrosis factor-α levels showed significant correlation with established risk factors such as body mass index, blood pressure, and lipid levels. Acute myocardial infarction patients show elevation in proinflammatory and anti-inflammatory cytokines, while unstable angina is associated with low levels of serum interleukin-10. Higher levels of anti-inflammatory cytokine interleukin-10 may be needed to provide protection in unstable angina. These cytokines are markers of coronary artery disease and may be used for the identification of high-risk patients with unstable angina/acute myocardial infarction.

Early versus late enteral prophylactic iron supplementation in preterm very low birth weight infants: a randomised controlled trial

Objectives To evaluate whether preterm very low birth weight (VLBW) infants receiving early iron (EI) supplementation (2 mg/kg/day elemental iron) at 2 weeks postnatal age have improved serum ferritin levels compared with late iron (LI) supplementation at 6 weeks postnatal age. Design Single-blinded parallel-group interventional randomised controlled trial. Setting Tertiary care centre in southern India. Interventions Randomised at 2 weeks postnatal age to EI and LI groups and evaluated at 2, 6 and 12 weeks postnatal age. Outcome The primary outcome was serum ferritin level at 12 weeks, and the secondary outcomes were the incidence of neonatal morbidities, haemoglobin level, anthropometric parameters and blood transfusion requirements. Results Of the 104 babies randomised, outcomes were analysed in 46 and 47 babies in EI and LI groups, respectively. Serum ferritin level was significantly higher (p<0.001) at 12 weeks (82±5 vs 63±3 ng/mL) in the EI group. Haemoglobin (10.1±0.4 vs 9.2±0.4 g/dL) and mean corpuscular haemoglobin concentration (31±0.5 vs 29.4±0.5 g/dL) were also significantly (p<0.001) higher at 12 weeks in the EI group. There was a significant decrease of ferritin in the LI group and significant increase in ferritin in the EI group at 6 weeks compared with 2 weeks. There were no significant differences in the incidences of neonatal morbidities (necrotising enterocolitis, periventricular leukomalacia, retinopathy of prematurity), anthropometric parameters and blood transfusion requirements between the two groups. Conclusions EI supplementation in preterm VLBW infants improves serum ferritin and haemoglobin levels. Trial registration: CTRI/2013/01/003277.

Cytokines (TH1 and TH2) in patients with advanced cervical cancer undergoing neoadjuvant chemoradiation: correlation with treatment response.

Background and Objectives: Host factors are critical in regulating tumor growth, and cytokines that modulate immunological control may be of importance in cervical cancer. To study this, the cytokines were measured in peripheral blood mononuclear cells in women with cervical cancer, before and after neoadjuvant chemoradiation, and assessed their correlation with therapeutic response. Methods: Ninety patients with advanced cervical cancer and 90 healthy controls were enrolled, and human papillomavirus status was determined. Cytokines were estimated by enzyme-linked immunosorbent assay in pretreatment samples after chemotherapy, brachyradiation, and after follow-up. Response to therapy was assessed during and after therapy and after 1 and 3 years of follow-up. Results: Pretreatment levels of type 1 cytokines (IL-2 and IFN-&ggr;) showed significant decrease, whereas type 2 cytokines (IL-4 and IL-10) showed significant increase in patients versus controls. After chemotherapy, a mild increase in type 1 cytokine levels was observed in complete responders versus partial/nonresponders, which became highly significant after completion of therapy and remained significant during follow-up. A slight decrease in type 2 cytokine levels was seen in complete responders versus partial/nonresponders, which remained insignificant for IL-10 even after chemoradiation. Conclusions: This important finding suggests that pretreatment type 1 cytokine levels and the extent of their change during treatment can predict the therapeutic response to neoadjuvant chemoradiation in advanced cervical cancer.