Association of inflammatory markers with the disease & mutation status in pancreatic cancer

Background & objectives: Inflammation has been studied to be an important contributory factor to carcinogenesis through pro-inflammatory markers such as interleukin (IL)-6 and C-reactive protein (CRP). Furthermore, K-ras mutation is an important genetic alteration in the pathogenesis of pancreatic cancer. This study aimed to compare these inflammatory markers in pancreatic ductal adenocarcinoma (PDAC) with the diseased and healthy controls (HCs) and to check for any association between IL-6 and CRP serum levels with the disease status, survival and K-ras mutation status of PDAC patients. Methods: The study included 135 PDAC, 25 chronic pancreatitis (CP) patients and 25 HCs. The serum levels of IL-6 and CRP were detected by enzyme-linked immunosorbent assay and K-ras mutations were detected by polymerase chain reaction-restriction fragment length polymorphism technique. Results: The serum levels of both these markers were elevated in PDAC cases than that in HCs. High IL-6 levels and higher CRP levels were found to be associated with locally advanced disease, lymphatic invasion, metastasis and advanced stage of the PDAC. In patients with unresectable PDAC, higher IL-6 levels were found to be associated with the presence of K-ras mutations. Interpretation & conclusions: Higher IL-6 and CRP levels in patients with advanced PDAC suggest an important role of these inflammatory markers in tumour progression. Furthermore, the association of mutations in the K-ras gene with serum IL-6 indicates cross-talks that may contribute to the progression of the PDAC.

Potential diagnostic implications of miR-144 overexpression in human oesophageal cancer.

Background & objectives: Insidious symptomatology, late clinical presentation and poor prognosis of oesophageal cancer (EC) highlight the pressing need for novel non-invasive biomarkers for early tumour diagnosis and better prognosis. The present study was carried out to evaluate the clinical significance of circulating and tissue miR-144 expression in oesophageal cancer. Methods: Clinical significance of miR-144 expression was evaluated in preneoplastic (12) and neoplastic (35) oesophageal cancer tissues as well as matched distant non-malignant tissues using real-time PCR (qPCR). Circulating levels of miR-144 were also analyzed in serum samples of EC patients as well as normal individuals to determine the diagnostic potential of miR-144. Further, targets of miR-144 were predicted using bioinformatic tools and their gene ontology (GO) terms were assigned. Results: Real-time PCR analysis revealed significant upregulation of miR-144 in 29 of 35 (83%) EC tissues as compared to matched distant non-malignant tissues (P=0.010). All the dysplastic tissues showed upregulation of miR-144 as compared to their matched distant non-malignant tissues. Relative levels of circulating miR-144 in serum significantly distinguished EC patients from normal controls (P=0.015; AUC = 0.731) with high sensitivity of 94.7 per cent. Bioinformatically predicted target, PUR-aplha (PURA) was found to be significantly (P=0.018) downregulated in 81 per cent (26/32) EC patients and its expression was found to be significantly and negatively correlated with miR-144 expression at mRNA level. Interpretation & conclusions: Our findings showed significant upregulation of miR-144 in serum samples of EC patients indicating its potential as minimally invasive marker. Further studies need to be done to understand the role of miR-144 in the pathogenesis of EC.

Prognostic significance of D-dimer, natural anticoagulants and routine coagulation parameters in acute pancreatitis.

Aim: This study was conducted to assess the predictive value of coagulation abnormalities in determining disease severity and prognosis of acute pancreatitis (AP). Methods: Patients of AP and 25 healthy volunteers were included in this prospective observational study. The final outcomes were disease severity assessed by Computed Tomography Severity Index, Acute Physiological Assessment and Chronic Health Evaluation – II, presence of organ failure and mortality. Prothrombin time (PT), partial thromboplastin time (PTT), thrombin time (TT), fibrinogen, antithrombin-III (AT-III), protein-C, and protein-S levels were assessed on day 0, 3 and 7 of admission. Results: Of the 38 patients included, 13 died. Mean PT and TT were similar between patients and controls on any given day. PTT showed elevation on day 3 and 7 (p=0.001) compared to controls, although fibrinogen and D-dimer were significantly higher in patients on all days. Protein C and AT-III were significantly lower in patients and more so in non survivors ( (p=0.001)) than controls. Multiple logistic regression analysis revealed D-dimer levels >400 - 800 ng/ml and AT- III level of <71% at admission were associated with high mortality (OR 11.2, AUROC 0.70 and OR 16.6, AUROC 0.82 respectively) as well as predicted organ failure. Conclusion: Serum D-dimer and antithrombin-III levels can be used to assess disease severity and predict outcome of patients with acute pancreatitis.

Understanding the syndrome of techno-centrism through the epidemiology of vaccines as preventive tools.

Conquering disease and ill health has been an age old pursuit of man. The scientific and technological revolution of the last century ushered in major and important advances in preventive and curative medical technology which fired a new hope in the fight against communicable diseases. However, the experience over centuries shows that major decline in communicable diseases began much before the advent of modern technology due to advances in the socio-economic and environmental conditions of the people. There has been an attempt by the multilateral and unilateral agencies to supplant the expedient of technological interventions like vaccination campaigns as a substitute to socio-economic advancement in the third world countries. The dividends of this approach have been equivocal and have had an effect of distorting public health priorities in the third world. There seems to be an obsession with technology among the policy planners - a phenomenon that we call as techno-centrism; the latest example of which is the pulse polio campaign. This paper draws upon an epidemiological approach to vaccination programs as a tool to unravel this phenomenon.

Alterations in intestinal permeability and endotoxemia in severe acute pancreatitis.

Background: Intestinal permeability increases early in the course of acute pancreatitis and is associated with sepsis and organ failure. Aim: To evaluate the intestinal permeability (IP) and anti-endotoxin antibodies immunoglobulin G and A (AEA IgG and A) in severe acute pancreatitis (SAP) as compared to healthy controls and determine their significance in relation to various complications of SAP. Methods: IP was measured by urinary lactulose/mannitol (LM) excretion ratio and antiendotoxin antibodies by Endocab ELISA kit at days one and seven of admission (D1 and D7). Results: Thirty one patients of SAP [mean age (42.0±15.8) years, APACHE II scores (8.8±5.4) and CT severity index (6.4±2.0)] were included in this study. Infected pancreatic necrosis was detected in 13 (42%) patients of whom three died. Six died of persistent organ failure. Median values of LM ratio at D1 and D7 were similar to those in healthy controls. Patients experiencing complications [organ failure (4/9, 44%), infected pancreatic necrosis (5/10, 50%) and death (1/ 2, 50%)] manifested a substantial increase in their intestinal permeability at D7. Anti-endotoxin antibodies IgG were lower (p=0.003) in patients than the controls at admission. AEA IgG were lower (p=0.03) in non-survivors as compared to survivors at D7. Conclusion: Patients experiencing complications of severe acute pancreatitis showed an increase in intestinal permeability. Higher endotoxemia predicted poor outcome in severe acute pancreatitis.

Population based study to assess prevalence and risk factors of gastroesophageal reflux disease in a high altitude area.

Aim We did a population-based cross-sectional study to investigate the prevalence and risk factors of gastroesophageal reflux disease (GERD) in a high altitude area. Methods An observational study using a validated questionnaire consisting of demographic, lifestyle and dietary characteristics was administered in an interview based format by two clinicians on a sample of adult population residing in urban area and rural high altitude areas of Ladakh. Presence of GERD was defined as a score of ≥4 using a previously validated symptom score based on the severity and frequency of heartburn and regurgitation. Other factors studied were body mass index (BMI), oxygen saturation levels by pulse oximetry and serum lipid profile. A multivariate analysis was done to find out risk factors for symptomatic GERD. Results Of the 905 subjects analyzed, there were 399 (44.1%) men; 469 (51.8%) were from rural background and 722 (79.8%) lived in areas 3,000 m above sea level. Symptomatic GERD was present in 169 (18.7%) subjects. Regurgitation occurred once a week in 34.8% and heartburn occurred in 42.9% of subjects. Sixteen (9.5%) had moderate-severe disease activity while 153 (90.5%) had mild disease. Three hundred and eighty-eight (42.7%) and 315 (34.8%) subjects had symptom of heartburn and regurgitation (at least once a week), respectively. On multivariate analysis, risk factors for GERD were age ≤50 years (OR: 1.508, 95% CI: 1.028–2.213), sedentary lifestyle (OR: 2.78, 95% CI: 1.016–7.638), lower intake of salt tea (OR: 1.663, 95% CI: 1.014–2.726); whereas the protective factors were no intake of meat (OR: 0.841, 95% CI: 0.715–0.990), intake of fresh fruits ≥1/week (OR: 0.631, 95% CI: 0.409–0.973), and serum LDL ≤150 mg/dL (OR: 0.435, 95% CI: 0.218–0.868). Conclusion This population-based study in a high altitude area in India suggests a high prevalence (18.7%) of GERD. A younger age group, sedentary lifestyle, serum LDL >150 mg/dL, high consumption of meat, low consumption of salted tea and low consumption of fresh fruits were significant risk factors for development of GERD.

Healthcare financing: Approaches and trends in India.

Despite the importance of healthcare for the well-being of society, there is little public debate in India on issues relating to it. The ‘human capital approach’ to finance healthcare largely relies on private investment in health, while the ‘human development approach’ envisages the State as the guarantor of preventive as well as curative care to achieve universalization of healthcare. The prevailing health indices of India and challenges in the field of public health require a human development approach to healthcare. On the eve of Independence, India adopted the human development approach, with the report of the Bhore Committee emphasizing the role of the State in the development and provision of healthcare. However, more recently, successive governments have moved towards the human capital approach. Instead of increasing state spending on health and expanding the public health infrastructure, the government has been relying more and more on the private sector. The public–private partnership has been touted as the new-age panacea for the ills of the Indian healthcare system. This approach has led to a stagnation of public health indices and a decrease in the access of the poor to healthcare.

Effect of antioxidant therapy on hospital stayand complications in patients with early acutepancreatitis: A randomised controlled trial.

Background: Oxidative stress (OS) in acute pancreatitis (AP) has been pathologically linked with the systemic inflammatory response and antioxidant supplementation may have a clinical benefit. Methods : In this prospective, randomised open label, controlled pilot study, patients admitted within 72 hours of onset of pain were randomised to receive either placebo (only standard medical treatment; SMT) or antioxidants (vitamin C 500 mg, N-acetyl cysteine 200 mg 8 hourly and antoxyl forte 1 capsule hourly with standard medical treatment; SMT+AO) daily, following informed consent. Patients with co-morbid illness and pregnancy were excluded. Primary efficacy measures were length of hospital stay and complications whilst secondary measures were biochemical markers of oxidative stress (thiobarbituric acid reactive substances [TBARS] and superoxide dismutase [SOD] and total antioxidant capacity [TAC] and vitamin C) at Days 1, 3 and 7. Results: Of 53 patients, 30 patients were randomised to SMT and 23 patients to SMT+AO. The mean duration of hospital stay in the SMT group (10.3±7 days) was more compared to SMT+AOT (7.2±5 days), but was not statistically significant (p=0.07), complications were similar in the 2 groups. At Day 7, OS was significantly lower in the SMT+AO group when compared with the SMT group (TBARS, p=0.05; SOD, p=0.03) with a significant increase in FRAP and vitamin C (p=0.01). Conclusions: Antioxidant supplementation may decrease the length of hospital stay and complication rate in patients with AP, but a larger clinical trial is needed to support this hypothesis. Further, it decreased the OS and improved the antioxidant status in patients with AP.

Boom in clinical research industry: A dangerous trend.

Over the last decade or so India has witnessed a phenomenal growth in the clinical trial industry. The projections forecast a continuing growth of this trend. It has been predicted that by 2011 India will be in charge of 15% of global clinical trials.1 The enthusiasm for the growth of this industry in India is shared not just by the major pharmaceutical companies and CROs but also equally so by government agencies.2 The raison d’être for medical research is that it should lead to maximum possible benefit to the largest number of people. Hence, an examination of the extent to which public good is served can act as a measure for objective analysis of this exponential increase in the clinical trial industry. After all it is the health and lives of the people that are at stake. On the face of it, it would seem that all trials testing the safety and efficacy of various molecules, by their very nature work towards public welfare as they are indispensible to the development of any drug including the life-saving ones. An increasing number of clinical trials at all stages in a product’s life cycle are funded by the pharmaceutical industry.3,4 It would then seem that the industry-sponsored medical research is necessarily furthering the larger objective of human wellbeing. However, the operations of the pharmaceutical industry, the nature of the processes involved and the operative motives are a bit too complex to facilitate this larger objective so simply, just as yet. This warrants a closer look at the various aspects of industry-sponsored clinical research.

Variations in the levels of oxidative stress and antioxidants during early acute pancreatitis.

Aim: Acute pancreatitis (AP) is fatal when severe and oxidative stress (OS) is postulated to play an important role in its pathophysiology and the development of complications. OS and antioxidant status therefore need to be profiled during early AP. Methods: Patients presenting to the Gastroenterology wards with early AP i.e. within 72 hours of onset of pain were included in the study. Also samples from 50 healthy controls were obtained for comparison. OS was estimated by levels of blood superoxide dismutase (SOD) and lipid peroxidation (thiobarbituric acid reactive substances; TBARS) and antioxidant status (AOS) by the ferric reducing ability of plasma (FRAP) and vitamin C at days 1, 3, and 7 of admission. Results: OS was significantly higher in cases as compared with controls (p<0.001) on all days and showed a gradual decrease from day 1 to 7 (p<0.05). TBARS showed a higher fall in mild AP and better clinical outcome (p<0.003). Regarding the AOS, FRAP was significantly lower in cases (p<0.001) and decreased significantly from day 1 to 3 (p=0.017). Conclusions: High OS was observed during early phase of AP and a gradually improving AOS was associated with a better clinical outcome in patients with AP.

Micronutrient antioxidant intake in patients with chronic pancreatitis.

Increased oxidative stress has been postulated to be an important mechanism in the pathophysiology of chronic pancreatitis (CP). Micronutrient deficiency may increase the oxidative stress as they assist in free radical clearance. The present study was undertaken to assess the intake of micronutrients, i.e. vitamins E and C, carotene, selenium, copper, zinc, manganese, magnesium, sulphur, riboflavin, methionine and choline in patients with CP. All consecutive patients with CP attending the Pancreas Clinic at the All India Institute of Medical Sciences were enrolled in the study. The usual dietary intake was estimated by the 24-hour dietary recall method and food frequency questionnaire. Dietary restrictions, if any, were also noted. The micronutrient intake of patients not on any nutritional supplements (n=75, 65 males and 10 females, mean age 31.06 +/- 10.64 years) was compared with age- and sex- matched healthy controls (n=75). The micronutrients were calculated as per the Nutritive value of Indian Foods given by the National Institute of Nutrition, Indian Council of Medical Research, India and the US dietary intake guidelines as applicable. It was found that the Body Mass Index (BMI) of patients was significantly lower than that of healthy controls. The total intake in terms of calorie was lower in patients when compared to controls. The dietary intake of vitamin E, riboflavin, choline, magnesium, copper manganese and sulfur was significantly lower than that of controls as well as the Recommended Dietary Allowance (RDA). Dietary intake of selenium and vitamin C was within the limits of the RDA but was lower than that of controls, while the intake of carotene was similar in both the groups and met the RDA. We conclude that patients with CP had significantly decreased micronutrient intake owing to diet modification due to pain. Micronutrient deficiency might contribute to increased oxidative stress in these patients.

Vaccination for hepatitis A virus is not required for patients with chronic liver disease in India.

BACKGROUND: Hepatitis A virus (HAV) vaccination is recommended worldwide for patients with chronic liver disease to prevent decompensation due to superinfection with HAV. India being endemic for HAV, the prevalence of pre-existing antibodies against HAV due to subclinical exposure to the virus in childhood among patients with chronic liver disease may be high and, therefore, vaccination may not be needed. However, data are lacking on the prevalence of HAV antibody among patients with chronic liver disease in India. METHODS: Two hundred fifty-four patients attending the Liver Clinic at the All India Institute of Medical Sciences, New Delhi during the past 5 years and diagnosed to have either chronic hepatitis due to the hepatitis B virus (n = 76), hepatitis C virus (n = 84) or cirrhosis of the liver due to the hepatitis B (n = 47) or C (n = 47) virus were tested for the presence of IgG anti-HAV antibody in their sera (using a commercial ELISA kit). RESULTS: Two hundred forty-eight (97.6%) patients tested positive for IgG anti-HAV. The prevalence of anti-HAV positivity was similar among patients with chronic hepatitis B (74, 97.4%), chronic hepatitis C (82, 97.6%), cirrhosis of the liver due to the hepatitis B (46, 97.8%) and hepatitis C (46, 97.8%) virus. CONCLUSION: Vaccination against HAV is not required among patients with chronic liver disease in India as there is a very high prevalence of pre-existing antibodies in these patients.