The dose and duration limiting toxic effects of cisplatin are ototoxicity and nephrotoxicity. While several studies have attempted to shed some light on the causes of nephrotoxicity, the reasons for ototoxicity induced by cisplatin are poorly understood. Therefore, this investigation was undertaken to delineate the potential mechanisms underlying cisplatin ototoxicity. The role of glutathione (GSH), oxidized glutathione (GSSG) and malondialdehyde levels, and antioxidant enzyme activities [superoxide dismutase, catalase, GSH peroxidase, and GSH reductase] were examined in cochlear toxicity following an acute dose of cisplatin. Male Wistar rats were treated with various doses of cisplatin. Pretreatment auditory brain stem evoked responses (ABR) were performed and then post-treatment ABRs and endocochlear potentials were also performed after three days. Acute cochlear toxicity (ototoxicity) was evidenced as elevated hearing thresholds and prolonged wave I latencies in response to various stimuli (clicks and tone bursts at 2, 8, 16 and 32 kHz) on ABRs. The endocochlear potentials were reduced (50% control) in cisplatin-treated rats as compared to control animals. The rats were sacrificed and cochleae isolated. The GSH, GSSG and malondialdehyde levels, and antioxidant enzyme activities were determined. Cisplatin ototoxicity correlated with a decrease in cochlear GSH [0.45 +/- 0.012 nmol/mg] after cisplatin administration compared to 0.95-012 nmol/mg in control cochleae (P < 0.05). Superoxide dismutase, catalase activities and malondialdehyde levels were significantly increased in the cochleae of cisplatin injected rats. Cochlear GSH-peroxidase and GSH reductase activity significantly decreased after cisplatin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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Background:There has been a constant emphasis on developing management strategies to improve the outcome of high-risk cardiac patients undergoing surgical revascularization. The performance of coronary artery bypass surgery on an off-pump coronary artery bypass (OPCAB) avoids the risks associated with extra-corporeal circulation. The preliminary results of goal-directed therapy (GDT) for hemodynamic management of high-risk cardiac surgical patients are encouraging. The present study was conducted to study the outcome benefits with the combined use of GDT with OPCAB as compared to the conventional hemodynamic management.Material and Method:Patients with the European System for Cardiac Operative Risk Evaluation ≥3 scheduled for OPCAB were randomly divided into two groups; the control and GDT groups. The GDT group included the monitoring and optimization of advanced parameters, including cardiac index (CI), systemic vascular resistance index, oxygen delivery index, stroke volume variation; continuous central venous oxygen saturation (ScVO2), global end-diastolic volume, and extravascular lung water (EVLW), using FloTrac™, PreSep™, and EV-1000® monitoring panels, in addition to the conventional hemodynamic management in the control group. The hemodynamic parameters were continuously monitored for 48 h in Intensive Care Unit (ICU) and corrected according to GDT protocol. A total of 163 patients consented for the study.Result:Seventy-five patients were assigned to the GDT group and 88 patients were in the control group. In view of 9 exclusions from the GDT group and 12 exclusions from control group, 66 patients in the GDT group and 76 patients in control group completed the study.Conclusion:The length of stay in hospital (LOS-H) (7.42 ± 1.48 vs. 5.61 ± 1.11 days, P < 0.001) and ICU stay (4.2 ± 0.82 vs. 2.53 ± 0.56 days, P < 0.001) were significantly lower in the GDT group as compared to control group. The duration of inotropes (3.24 ± 0.73 vs. 2.89 ± 0.68 h, P = 0.005) was also significantly lower in the GDT group. The two groups did not differ in duration of ventilated hours, mortality, and other complications. The parameters such as ScVO2, CI, and EVLW had a strong negative and positive correlation with the LOS-H with r values of − 0.331, −0.319, and 0.798, respectively. The study elucidates the role of a goal-directed hemodynamic optimization for improved outcome in high-risk cardiac patients undergoing OPCAB.

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This investigation elucidates the role of antioxidant system in cisplatin induced nephrotoxicity and the nephroprotection with diethyldithiocarbamate (DDTC). Male Wistar rats were injected with 1) cisplatin; 2) cisplatin+DDTC and 3) vehicle control. Rats were sacrificed three days post-treatment and the corticomedullary junction of the kidney was isolated adn were analyzed for GSH, GSSG, SOD, CAT, and GSH.Px. Serum creatinine increased (500% of control) following cisplatin administration which decreased to 200% of control with DDTC. Cisplatin treated rats showed depletion of GSH levels, while cisplatin+DDTC injected rats had GSH values similar to controls. SOD and GSH.Px activities were found to be 63 and 40% of control following cisplatin administration which increased to 109 and 75% of control with DDTC respectively. Our findings suggest that cisplatin nephrotoxicity is mediated by impaired activities of SOD and GSH-Px enzymes and by GSH depletion. The protective mechanism of DDTC against cisplatin nephrotoxicity is related to the prevention of GSH depletion and restoring SOD and GSH-Px activities in the kidney of rats.

Innate immune molecules, SP-A1 (6A2, 6A4) and SP-A2 (1A0, 1A3), differentially affect young mouse survival after infection. Here, we investigated the impact of SP-A variants on the survival of aged mice. hTG mice carried a different SP-A1 or SP-A2 variant and SP-A-KO were either infected with Klebsiella pneumoniae or exposed to filtered air (FA) or ozone (O3) prior to infection, and their survival monitored over 14 days. In response to infection alone, no gene- or sex-specific (except for 6A2) differences were observed; variant-specific survival was observed (1A0 > 6A4). In response to O3, gene-, sex-, and variant-specific survival was observed with SP-A2 variants showing better survival in males than females, and 1A0 females > 1A3 females. A serendipitous, and perhaps clinically important observation was made; mice exposed to FA prior to infection exhibited significantly better survival than infected alone mice. 1A0 provided an overall better survival in males and/or females indicating a differential role for SP-A genetics. Improved ventilation, as provided by FA, resulted in a survival of significant magnitude in aged mice and perhaps to a lesser extent in young mice. This may have clinical application especially within the context of the current pandemic.

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