The occurrence of oxidative stress during reperfusion in experimental animals and men

Reperfusion is the prerequisite for the ischemic myocardium to recover its metabolic and mechanical function. However, reperfusion after a prolonged period of ischemia in the experimental animal may exacerbate, or at least accelerate, the occurrence of ischemic injury, whilst in humans at the least it is not beneficial. This entity has been called reperfusion damage, since much of the damage is believed to be caused by events occurring at the moment of reperfusion rather than by changes occurring during ischemia. The existence of reperfusion damage, however, has been questioned, and evidence in favour of the concept is sparse. At the moment the molecular events occurring at the time of reperfusion are not completely understood, and the relative importance of several proposed deleterious mechanisms is not yet established. One of the most fashionable ideas for the cause of reperfusion damage is that the function of cell membrane is modified by oxygen radicals generated at the moment of reperfusion. Evidence in favour of and against this hypothesis is described in detail in the present article.     

A retrospective study on 73 elderly patients (≥ 75 years) with aggressive B-cell non Hodgkin lymphoma: Clinical significance of treatment intensity and comprehensive geriatric assessment

ObjectiveThe clinical outcome of elderly (≥ 75 years) patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL) is not firmly established because few studies have specifically addressed this issue. In addition, the usefulness of a comprehensive geriatric assessment (CGA) in B-NHL still needs to be deeply explored.Materials and MethodsWe evaluated the prognostic factors of 73 patients aged ≥ 75 years (median age: 78) with B-NHL treated by clinical judgment with curative anthracycline-based approaches (n = 36) or with conservative treatments without anthracyclines (n = 37). Analysis of clinical outcomes also included baseline CGA stratification.ResultsThe curative approaches resulted in a better clinical outcome than conservative approaches [overall response rate: 91.2% vs. 69.7%, P = 0.003; 2-year progression-free survival: 47.2% vs. 21.6%, P = 0.006; and 2-year overall survival (OS): 58.3% vs 24.3%, P = 0.003] with similar safety profiles. Independent of treatment type, patients classified as “fit” and “intermediate” by CGA presented with better OS compared to patients classified as “frail” (P < 0.001). Patients classified as “fit” and “intermediate” who were receiving curative treatments presented with a significantly better OS when compared with those treated conservatively on the basis of clinical judgment. A curative anthracycline-based therapy (P = 0.048), the response to treatment (P = 0.017) and a “frail” condition (P = 0.031) were the only factors affecting OS in multivariate analysis.ConclusionsPresent data indicates that even in elderly patients with B-NHL curative anthracycline-based therapies are more effective than conservative approaches. However, choice of treatment should rely more on objective than on subjective parameters. Therefore, further prospective trials are warranted to better define the CGA role in hematopoietic malignancies.     

Prolonged protective effect of the calcium antagonist anipamil on the ischemic reperfused rabbit myocardium: Comparison with verapamil

Summary To assess whether pretreatment with the calcium antagonist anipamil protects the heart against ischemic and reperfusion damage and to establish how long the protection persists after cessation of the therapy, rabbits were injected subcutaneously twice daily for 5 days with 2 mg/kg body weight of this drug. The heart was then isolated 2, 6, or 12 hours after the last injection and was perfused by the Langendorff technique during a control period and 90 minutes of total ischemia (37°C), followed by 30 minutes ofreperfusion. Diastolic and developed pressure was monitored; coronary effluent was collected and assayed for creatine phosphokinase (CPK); mitochondria were harvested and assayed for respiratory activity, ATP production, and calcium content; and tissue concentration of adenosine triphosphate (ATP) and creatine phosphate were determined. The data obtained with anipamil were compared with those obtained with verapamil administered to the rabbit at the same dose and following the same procedure.Pretreatment with anipamil induced a negative inotropic effect under normoxic conditions; reduced the rate and extent of depletion of ATP and creatine phosphate during ischemia, with an incomplete restoration of the nucleotides after reperfusion; maintained mitochondrial function and calcium homeostasis during ischemia and reperfusion; reduced the rate of CPK release; and improved the recovery of ventricular function on reperfusion. The protective effects of anipamil persisted for as long as 12 hours after the last administration. In contrast, the protective and negative inotropic effects of verapamil were no longer apparent in heart isolated 6 or 12 hours after the last dose of the drug.It is concluded that anipamil pretreatment provides a protection against some of the deleterious effects of myocardial ischemia and reperfusion and that this effect is substantially longer than that of verapamil. The protective effect of anipamil (like that of verapamil) is probably secondary to a reduction of the rate of ATP hydrolysis during ischemia, although alternative mechanisms of action cannot be excluded.     

Diagnostic accuracy of rest-exercise first pass ventriculography with a fast single crystal gamma camera in detecting coronary artery disease

Rest and exercise radionuclide ventriculograms were performed in 61 non infarcted, male, patients who underwent cardiac catheterization for chest pain and in 16 normal control subjects. Studies were performed using the first pass method with a fast single crystal gamma camera, which allowed a count rate of 140±19 Kcounts/sec to be reached during left ventricular filling; the count integral on left ventricular area was 10.8±1.6 Kcounts and the maximum count/pixel 155±16. We analyzed sensitivity, specificity, positive and negative predictive value of global ejection fraction (EF) and of the regional wall motion in identifying ventricular function abnormalities due to obstructive coronary artery disease. The regional wall motion was evaluated with four functional images: regional ejection fraction (REF), amplitude (A) and phase (PH) from Fourier analysis and systolic transit times (TT). Sensitivity was near 90% for EF, REF, A and TT, while PH was less sensitive (80%); all functional images were more specific (nearly 90%) than EF (80%). Both sensitivity and specificity were lower for the exercise EKG (59% and 63%, respectively) in this patient group. Significant differences between single vessel and multiple vessel disease were also observed either for the EF increase/decrease (-1.34±7.4 and-7.82±9.96; P<0.05) or for the number of segments which developed wall motion abnormalities during exericise (1.22±0.73 and 2.15±1.04; P<0.02). In conclusion, with our method, a fast single crystal gamma camera is suitable for obtaining optimal first pass radionuclide ventriculograms with a count density sufficient either for global or regional left ventricular function evaluation. First pass radionuclide ventriculography seems to provide very high diagnostic accuracy in the detection of cornorary artery disease in non infarcted, male, subjects.     

Prevention of cyclophosphamide-induced urotoxicity by reduced glutathione and its effect on acute toxicity and antitumor activity of the alkylating agent

Summary The effect of reduced glutathione on acute lethal toxicity and urotoxicity induced by cyclophosphamide was studied on both mice and rats. The results of this investigation indicate that reduced glutathione is an effective protective agent against bladder damage from treatment with the alkylating agent. The timing of glutathione administration (IV) with respect to cyclophosphamide treatment influenced the uroprotective efficacy of the thiol compound. A schedule-dependent protective effect of glutathione against acute lethal toxicity of the antitumor drug was also observed. This partial protection was accompanied by a reduction in body weight loss following cyclophosphamide treatment. The therapeutic activity of cyclophosphamide on two experimental tumor systems (L1210 and Gross leukemia) was not impaired by combined treatment with glutathione, even at a relatively high dose of glutathione compared with cyclophosphamide.