Aminoguanidine pretreatment prevents methotrexate-induced small intestinal injury in the rat by attenuating nitrosative stress and restoring the activities of vital mitochondrial enzymes.

BACKGROUND: One of the major toxic side effects of methotrexate (MTX) is enterocolitis, for which there is no efficient standard treatment. Nitric oxide overproduction has been reported to play an important role in MTX-induced mucositis. This study was designed to investigate whether pretreatment with aminoguanidine (AG) - a selective iNOS inhibitor - prevents MTX-induced mucositis in rats. METHODS: Rats were pretreated with AG (30 and 50 mg/kg body weight) i.p. daily 1 h before MTX (7 mg/kg body weight) administration for 3 consecutive days. After the final dose of MTX, the rats were killed, and the small intestines were used for analysis. RESULTS: The small intestines of MTX-treated rats showed moderate to severe injury. Pretreatment with AG had a dose-dependent protective effect on MTX-induced mucositis. AG pretreatment reduced iNOS protein levels, mucosal nitric oxide levels, and protein tyrosine nitration. AG pretreatment also restored the activities of electron transport chain (ETC) complexes, vital tricarboxylic acid (TCA cycle) enzymes, and mitochondrial antioxidant enzymes. CONCLUSIONS: These findings suggest that AG is beneficial in ameliorating MTX-induced enteritis in rats.

Role for NF-κB inflammatory signalling pathway in tenofovir disoproxil fumarate (TDF) induced renal damage in rats.

Nephrotoxicity due to tenofovir treatment of HIV patients has been reported. However, the mechanism of tenofovir nephrotoxicity is not clear. NFκB is an important proinflammatory transcription factor that plays a pivotal role in oxidative stress-induced inflammation. We hypothesized that NFκB proinflammatory signalling pathway may play a role in tenofovir induced renal damage. Renal damage was induced in adult male Wistar rats by the oral administration of 600 mg/kg body wt. daily for 5 consecutive weeks. Kidneys were removed and used for histological and biochemical analysis. The protein and mRNA expressions of NFκB and its target genes namely iNOS, COX-2 and TNFα, and its inhibitor IκB-alpha were analysed by immunohistochemical methods, western blot and quantitative RT PCR. NFκBp65 activity was determined by ELISA. The protein and mRNA expressions of NFκB p65, iNOS, COX-2 and TNFα were increased in the kidneys of TDF treated rats. The activity of NFκBp65 was increased by 28 fold in the nuclear fractions of the TDF treated rat kidneys. Pretreatment with melatonin, a NFκB inhibitor attenuated TDF induced renal damage. It is concluded that the activation of NFκB and its downstream proinflammatory target genes iNOS, COX-2, and TNF-α may contribute to the pathophysiology of TDF induced renal damage.

Curriculum development for a module on noncommunicable diseases for the master of public health program.

BACKGROUND: As the burden of noncommunicable diseases (NCDs) has been rising globally, various educational programs have introduced chronic disease epidemiology teaching, which is now a component of most of the Master of Public Health (MPH) programs. However, the process of curriculum development for these courses has not been adequately documented for use by educators planning such courses. METHODS: A detailed process of curriculum development based on David Kern's six-step approach was undertaken for a 2-week course on NCDs, as part of the MPH program of a tertiary institution in South India. The processes were documented so that the method of curriculum development for such a course could be made available for educators across this field. RESULTS: The course on NCDs was carried out over 73 learning hours (2 weeks) for a group of MPH students including medical, dental, allied health, and nursing graduates. Evaluation of the revised curriculum at the end of the 2 weeks revealed that mean scores for knowledge and confidence in skills increased by 50% (11.1-16.6, t-test, P < 0.001) and 79% (3.3-5.9, t-test, P = 0.002), respectively, from baseline scores. DISCUSSION: The revised curriculum was effective in improving knowledge and confidence in epidemiological skills. The documented process of curricular development using standard methods if made publicly available can be of use to those involved in planning similar educational programs for students of public health.

Project-based faculty development for e-learning.

BACKGROUND: The Christian Medical College, Vellore, in collaboration with Tufts University, Boston, conducted an advanced workshop in e-learning for medical faculty members in India. CONTEXT: E-learning can enhance educational reforms for today's computer-literate generation, and keep faculty members up to speed in a rapidly changing world. The purpose of this paper is to report on the design and evaluation of a project-based faculty member development programme focused on developing faculty members as educators and as peer trainers who can use e-learning for educational reforms. INNOVATION: During a 2-day workshop, 29 participants in groups of two or three developed 13 e-learning projects for implementation in their institutions. Evaluation of the workshop was through written feedback from the participants at the end of the workshop and by telephone interview with one participant from each project group at the end of one year. Content analysis of qualitative data was perfomed. The participants reported that they were motivated to implement e-learning projects and recognised the need for and usefulness of e-learning. The majority of projects (10 out of 13) that were implemented 'to some extent' or 'to a great extent' faced challenges with a lack of resources and administrative support, but faculty members were able to overcome them. E-learning can enhance educational reforms for today's computer-literate generation IMPLICATIONS: Designing feasible e-learning projects in small groups and obtaining hands-on experience with e-learning tools enhance the effectiveness of subsequent implementation. To successfully incorporate e-learning when designing educational reforms, faculty member training, continuing support and infrastructure facilities are essential.

Neutrophil infiltration and oxidative stress may play a critical role in methotrexate-induced renal damage.

BACKGROUND: Nephrotoxicity is one of the adverse side effects of methotrexate (MTX) chemotherapy. The mechanism of renotoxicity of MTX is not fully understood. It is essential to understand the mechanism of nephrotoxicity of MTX in order to diminish the side effects and hence maximize the benefits of chemotherapy. OBJECTIVES: The aim of the study was to verify whether oxidative stress and neutrophil infiltration play a role in MTX-induced renal damage using a rat model. METHODS: Adult male rats were administered MTX at the dose of 7 mg/kg body weight intraperitoneally for 3 consecutive days and sacrificed 12 or 24 h after the last dose. Vehicle-treated rats served as controls. The kidneys were removed and used for light microscopic and biochemical studies. Myeloperoxidase activity, a marker of neutrophil infiltration was measured in kidney homogenates along with the markers of oxidative damage including protein carbonyl content, protein thiol and malondialdehyde. The activities of the antioxidant enzymes, namely glutathione peroxidase, glutathione S-transferase, superoxide dismutase and catalase, were also assayed. RESULTS: MTX treatment induced damage to the glomeruli and tubules. Plasma creatinine levels in the MTX-treated rats were significantly elevated compared with controls. A significant increase in myeloperoxidase activity (p<0.05) was observed in the kidneys of MTX-treated rats. Protein carbonyl content and malondialdehyde, sensitive and reliable markers of oxidative damage to proteins and lipids, respectively, were significantly elevated (p<0.01) in the kidneys of MTX-treated rats compared with controls. The activities of the antioxidant enzymes, namely, superoxide dismutase and glutathione peroxidase, were significantly elevated (p<0.01 and p<0.05, respectively) in kidneys of rats following MTX treatment. CONCLUSION: The results of the present study provide evidence for the role of neutrophil infiltration and oxidative stress in MTX-induced renal damage. Administration of inhibitors of myeloperoxidase or scavenging hypochlorous acid, the product of myeloperoxidase, by supplementation with antioxidants as an adjuvant therapy may be promising in alleviating the renal side effect of MTX.

Protective effect of aminoguanidine against oxidative stress and bladder injury in cyclophosphamide-induced hemorrhagic cystitis in rat.

Cyclophosphamide (CP) is an antineoplastic agent that is used for the treatment of many neoplastic diseases. Hemorrhagic cystitis (HC) is a major dose limiting side effect of CP. Recent studies show that aminoguanidine, an inhibitor of inducible nitric oxide synthase is a potent antioxidant and prevents changes caused by oxidative stress such as depletion of antioxidant activity and tissue injury. The purpose of the study is to investigate the effect of aminoguanidine on parameters of oxidative stress, antioxidant enzymes and bladder injury caused by CP. Adult male rats were randomly divided into four groups. Control rats were administered saline; the AG control group received 200 mg/kg body wt of aminoguanidine; The CP group received a single injection of CP at the dose of 150 mg/kg body wt intraperitoneally. The CP + AG group received aminoguanidine (200 mg/kg body wt) intraperitoneally 1 h before the administration of CP. The rats were sacrificed 16 h after CP/saline administration. The bladder was used for light microscopic studies and biochemical studies. The markers of oxidative damage including protein carbonyl content, protein thiol, malondialdehyde and conjugated dienes were assayed in the homogenates along with the activities of the antioxidant enzymes, superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase and glutathione S transferase. In the bladders of CP treated rats edema of lamina propria with epithelial and sub-epithelial hemorrhage was seen. All the parameters of oxidative stress that were studied were significantly elevated in the bladders of CP treated rats. The activities of the antioxidant enzymes were significantly lowered in the bladders of CP treated rats. Aminoguanidine pretreatment prevented CP-induced oxidative stress, decrease in the activities of anti-oxidant enzymes and reduced bladder damage. The results of the present study suggest the antioxidant role for aminoguanidine in CP-induced bladder damage.

Serum leptin levels in acute myocardial infarction.

BACKGROUND: Several studies have shown an association of serum leptin levels with cardiovascular diseases. The present study was undertaken to assess levels of serum leptin in patients presenting with acute ST segment elevation myocardial infarction. METHODS AND RESULTS: Ninety-four consecutive patients presenting with acute ST segment elevation myocardial infarction were studied and 46 controls were taken from patients who presented with chest pain but had no history of myocardial infarction in the past. There were 59 patients with anterior wall infarction and 31 had inferior wall infarction and in 4 it was a combination of anterior and inferior wall infarction. The serum leptin levels in patients with myocardial infarction was 6.51 +/- 6.76 ng/ml versus 2.86 +/- 2.22 ng/ml in controls. In the multivariate analysis the odds ratio for serum leptin with myocardial infarction was 1.45 with a 95% confidence interval of 1.2 to 1.8. CONCLUSIONS: Our results suggest that serum leptin level is elevated in patients with acute ST segment elevation myocardial infarction.

Utility of N-terminal pro-brain natriuretic peptide for the diagnosis of heart failure.

BACKGROUND: The goal of this study was to evaluate the utility of plasma N-terminal pro-brain natriuretic peptide for the diagnosis of heart failure in patients presenting with shortness of breath. METHODS AND RESULTS: We measured plasma levels of N-terminal pro-brain natriuretic peptide in 119 patients presenting with shortness of breath. The patients were divided into two groups based on the Framingham criteria and echocardiographic results--those with heart failure and those not in heart failure. Plasma levels of N-terminal pro-brain natriuretic peptide were compared in the two groups. The mean N-terminal pro-brain natriuretic peptide concentration in patients with heart failure (n=73) was higher than that in those not in heart failure (389+/-148 fmol/ml v. 142+/-54 fmol/ml, p<0.001). N-terminal pro-brain natriuretic peptide values increased significantly as the functional severity of heart failure increased (p<0.001). The mean N-terminal pro-brain natriuretic peptide levels were 261+/-34 fmol/ml for patients in New York Heart Association functional class I, 300+/-161 fmol/ml for patients in New York Heart Association functional class II, 427+/-103 fmol/ml for patients in New York Heart Association functional class III and 528+/-170 fmol/ml for patients in New York Heart Association functional class IV. Using a cut-off value of 200 fmol/ml, the sensitivity of N-terminal pro-brain natriuretic peptide was 97%, specificity was 89% and accuracy for differentiating heart failure from other causes of shortness of breath was 93%. CONCLUSIONS: Our results suggest that N-terminal pro-brain natriuretic peptide can be reliably used for the diagnosis of heart failure in an outpatient setting, and this will improve the ability of clinicians to differentiate patients with shortness of breath due to heart failure from those with other causes of shortness of breath.