Patterns of drug resistance among patients with tuberculous pleural effusion in Greece.

SETTING: Data on the relationship between pleural tuberculosis (TB) and anti-tuberculosis drug resistance are scarce. OBJECTIVE: To determine the patterns of drug resistance among pleural Mycobacterium tuberculosis isolates in Greece and the incidence of tuberculous pleural effusion (TPE) among patients with multidrug-resistant (MDR) or extensively drug-resistant (XDR) pulmonary TB. DESIGN: Drug susceptibility testing (DST) results recorded in the database of the National Reference Centre for Tuberculosis in Athens, Greece, over a 9-year period (2003-2011) were reviewed. Chest X-rays from hospitalised patients with pulmonary MDR/XDR-TB during the same period were also reviewed for the presence of TPE. RESULTS: Resistance to at least one first-line drug was observed in 11% of the cases (MDR-TB 3%, XDR-TB 1%), while 29% of the patients with pulmonary MDR/XDR-TB presented with TPE during the course of their disease, the majority ipsilateral to the lung lesions, which responded to guided anti-tuberculosis treatment. CONCLUSION: The prevalence of drug resistance among pleural M. tuberculosis isolates in Greece highlights the importance of DST prior to treatment selection in TPE patients. In our study population, TPE that developed in one third of the patients with pulmonary MDR/XDR-TB usually resolved with DST-guided anti-tuberculosis treatment.

Secreted phosphoprotein-1 directly provokes vascular leakage to foster malignant pleural effusion.

Secreted phosphoprotein-1 (SPP1) promotes cancer cell survival and regulates tumor-associated angiogenesis and inflammation, both central to the pathogenesis of malignant pleural effusion (MPE). Here, we examined the impact of tumor- and host-derived SPP1 in MPE formation and explored the mechanisms by which the cytokine exerts its effects. We used a syngeneic murine model of lung adenocarcinoma-induced MPE. To dissect the effects of tumor- versus host-derived SPP1, we intrapleurally injected wild-type and SPP1-knockout C57/BL/6 mice with either wild-type or SPP1-deficient syngeneic lung cancer cells. We demonstrated that both tumor- and host-derived SPP1 promoted pleural fluid accumulation and tumor dissemination in a synergistic manner (P<0.001). SPP1 of host origin elicited macrophage recruitment into the cancer-affected pleural cavity and boosted tumor angiogenesis, whereas tumor-derived SPP1 curtailed cancer cell apoptosis in vivo. Moreover, the cytokine directly promoted vascular hyper-permeability independently of vascular endothelial growth factor. In addition, SPP1 of tumor and host origin differentially affected the expression of proinflammatory and angiogenic mediators in the tumor microenvironment. These results suggest that SPP1 of tumor and host origin impact distinct aspects of MPE pathobiology to synergistically promote pleural fluid formation and pleural tumor progression. SPP1 may present an attractive target of therapeutic interventions for patients with MPE.

Carcinoembryonic antigen, neuron-specific enolase and cytokeratin fragment 19 (CYFRA 21-1) levels in induced sputum of lung cancer patients.

OBJECTIVES: The diagnosis of lung cancer is usually based on the histological and cytological examination of material obtained by bronchoscopy. Tumour markers in serum are of little use as a diagnostic tool for lung cancer. We hypothesized that induced sputum could be a suitable material for measuring tumour markers and, accordingly, attempted to evaluate the diagnostic value of such measurements in lung cancer. Induced sputum is minimally invasive and readily obtainable. MATERIAL AND METHODS: Fifty patients with lung cancer and 24 subjects with chronic obstructive pulmonary disease (COPD) were included in the study. CEA, NSE and CYFRA 21-1 levels in serum and induced sputum were measured by immunoradiometric assays. RESULTS: Serum and sputum CEA, serum and sputum NSE and serum CYFRA 21-1 did not differ significantly between lung cancer and COPD patients. Sputum CYFRA 21-1 was 7 times greater in the lung cancer group than in the COPD group. This finding was true in both small cell (SCLC) and non-small cell (NSCLC) lung cancer. The sensitivity, specificity, positive and negative predictive values were 86, 75, 88 and 72%, respectively. CONCLUSION: Of tumour markers in induced sputum, sputum CYFRA 21-1 offered the best predictive values, although not sufficiently satisfactory to suggest its routine use in lung cancer diagnosis.

Nonplatelet effects of aspirin during acute coronary occlusion: electrophysiologic and cation alterations in ischemic myocardium.

BACKGROUND: Mortality after acute myocardial ischemia has been reduced by aspirin (ASA) but mechanisms other than the antiplatelet effect have not been established. This article evaluates an antiarrhythmic action during sympathetic stimulation in the intact anesthetized dog with and without ischemia. METHODS AND RESULTS: The ventricular fibrillation threshold (VFT) was examined before and after epinephrine (E) in normals (group I). A VFT reduction during E was normalized after 1 week of ASA (P<.01). Regional myocardial ischemia for 1 hour resulted in similar hypoperfusion in controls of group II and after ASA. Action potential responses in isolated superfused ischemic tissue showed prolonged repolarization (APD90) in response to E, which was normalized after ASA (P<.01). To assess the antiarrhythmic role of the anion in group III, Na salicylate was given. During 1 hour of ischemia, the VF incidence was reduced and cation abnormalities diminished in ischemic myocardium compared with untreated ischemia. CONCLUSIONS: ASA antagonizes the reduction of the VFT induced by catecholamine in normals as well as the repolarization abnormality elicited by E during acute ischemia. The salicylate anion appears to be the active component in view of the efficacy in preventing VF during the early ischemic period.

Diabetic cardiomyopathy: experimental and clinical observations.

Heart failure, arrhythmia, or chest pain can be a consequence of diabetes independent of coronary disease or hypertension. Diastolic myocardial dysfunction is common, contributing to the high mortality during acute infarction. The authors discuss diabetic cardiomyopathy and its management.

Trimetazidine for prevention of hepatic injury induced by ischaemia and reperfusion in rats.

OBJECTIVE: To assess the effect of trimetazidine (an anti-anginal drug that acts as a scavenger of oxygen free radicals) in the protection of hepatocytes after a 90 minute period of warm ischaemia followed by reperfusion in rats. DESIGN: Prospective study. MATERIAL: 80 Wistar rats. INTERVENTIONS: 20 Rats were given a single dose of trimetazidine 2.5 mg/kg intravenously 30 minutes before the induction of ischaemia; 20 received the same dose intraperitoneally twice a day for five days before the experiment and one dose intravenously 30 minutes before; 20 were given a single dose of 2.5 mg/kg intravenously after reperfusion had been started; and 20 acted as controls. All rats underwent liver biopsy through a laparotomy incision on postoperative days 2, 7, and 21, and the activities of liver enzymes in their blood were measured before induction of ischaemia and two, seven, 14, and 21 days afterwards. OUTCOME MEASURES: Histological changes and serum enzyme activities. RESULTS: The amount of centrilobular necrosis of hepatocytes, and the activity of hepatic enzymes were greatest on day 2, as was the reduction in superoxide dismutase activity in the erythrocytes. A single dose of trimetazidine, whether given before or after the ischaemic episode, gave significant protection to hepatocytes, but pretreatment for five days was even more effective. CONCLUSION: Trimetazidine protected rats' livers from injury after a period of warm ischaemia and reperfusion.

Effect of sulfinpyrazone on ventricular fibrillation during acute myocardial ischemia.

In patients treated with sulfinpyrazone, an apparent reduction in the incidence of sudden death and presumed ventricular fibrillation has been reported. Using an intact animal model without microcirculatory thrombosis, we studied the effects of sulfinpyrazone on ischemic myocardium in 58 anesthetized dogs divided into three groups: control untreated (n =24), group 1 (n = 16), treated daily with 300 mg of sulfinpyrazone for 7 days, and group 2 (n = 18), treated daily with 300 mg of sulfinpyrazone for 7 days but omitting treatment on day 8. Although consistent hemodynamic differences were not apparent, the degree of injury determined by ECG mapping was significantly lower in group 1. The incidence of fibrillation was 54% for control and 0% in group 1. Group 2 had a 44% incidence, suggesting a limited duration of action. The apparent absence of microcirculatory thrombosis in this model suggests other mechanisms of action. A significantly smaller increase in tissue water and Na+ and smaller loss of K+ in group 1 may have contributed to the lower incidence of fibrillation, perhaps through selective prostaglandin inhibition.

Evaluation of thallium-201 imaging in nontransmural ischemia and infarction.

To assess the validity of thallium-201 myocardial imaging in the diagnosis of nontransmural ischemia and infarction, the proximal left anterior descending coronary artery was partially occluded for 60 minutes with a balloon-tip catheter in intact anesthetized dogs in a basal state or during atrial pacing. In vivo scintigrams of myocardium were compared with those obtained in the isolated heart and in the incised ventricle spread flat. None of the animals with partial occlusion with or without pacing demonstrated abnormal scintiscans in vivo. Removal of background by isolating the heart increased positive images to 30%; positive images were associated with an isotope count ratio between ischemic and normal muscle of less than 0.67. Removal of superimposed nonischemic muscle in the heart enface increased image detection after pacing to 11 of 15. Since animals with subendocardial scar failed to demonstrate a "cold area" in vivo, unfavorable geometry as well as extent and degree of ischemia appear to be important. Thus, thallium radioactivity in superimposed and adjacent myocardium, as well as background, may limit the detection of nontransmural ischemia and scar.

Relation of platelets to catecholamine induced myocardial injury.

To test the thesis that myocardial injury, induced by catecholamines, is ischaemic in origin due to platelet accumulation in the coronary microvasculature, sustained left intracoronary and systemic infusion of catecholamines in toxic dosage was given to dogs previously infused with autologous 51Cr-labelled platelets. Subsequent determination of tissue radioactivity and electrolytes, as well as electronmicrography, indicated that the induced myocardial injury was not related to microvascular occlusion by platelets.

Antiarrhythmic effects of aspirin during nonthrombotic coronary occlusion.

To study the action of aspirin upon the myocardium per se, independent of thrombosis, coronary occlusion with a balloon catheter was induced in 53 anesthetized dogs divided into two groups. One group (N = 20) was treated daily with aspirin (600 mg/dog) for seven days and another (N = 33) was untreated. Left ventricular hemodynamics and precordial ECG mapping were used to assess the influence of myocardial ischemia over a four hour period. There were no significant differences in left ventricular function or extent of injury as judged by ECG mapping between the two groups. However, there was a significant decrease in the incidence of ventricular fibrillation in the treated dogs (5% vs 39%). Serial plasma samples for free fatty acid determination showed a significant rise in the untreated group. Aspirin blocked the FFA increment in the treated animals. Tissue samples from the ischemic area of left ventricle exhibited a significant reduction of the sodium and water increments, as well as a lesser potassium loss in the treated animals compared to the controls and may have been the basis for the lower incidence of arrhythmias. Since infusion of 51Cr labelled platelets showed no myocardial accumulation of platelets in either group, microthrombi did not appear to contribute to the observed differences.

Myocardial function and coronary blood flow response to acute ischemia in chronic canine diabetes.

To examine the influence of preexistent diabetes mellitus on left ventricular performance and coronary blood flow responses to acute ischemia, mild normoglycemic diabetes was induced in nine mongrel dogs after three doses of alloxan, (20 mg/kg, iv), at monthly intervals. Hemodynamic measurements and coronary blood flow (85Kr clearance) were obtained before and after the onset of ischemia. This was produced by occlusion of the proximal left anterior descending coronary artery via a balloon-type catheter in nine intact anesthetized diabetic dogs and 10 nondiabetic dogs. During the 1st hour of ischemia in the diabetic group, the end-diastolic pressure rose from 7 +/- 1.1 (mean +/- SE) mm Hg to 23.8 +/- 2.3 without a significant increase of end-diastolic volume. In controls end-diastolic pressure rose from 8.6 +/- 1.1 mm Hg to 15.3 +/- 1.4, and end-diastolic volume was significantly increased, so that the ratio of end-diastolic pressure and volume was significantly higher in the diabetic group (P less than 0.005). Although indices of contractility did not differ, stroke volume and work reductions were significantly greater in diabetics, despite the fact that coronary blood flow was reduced to a similar extent. Size of the ischemic areas appeared comparable as judged by distribution of dye injected distal to the occlusion. Since potassium loss and sodium gain in the inner and outer layers of ischemic tissue did not differ between the two groups, the intensity of ischemia seemed similar. Glycogenolysis was unimpaired in the diabetic ischemic muscle but triglyceride levels remained elevated. Morphologically the diabetic myocardium was characterized by a diffuse accumulation of periodic acid-Schiff-positive glycoprotein in the interstitium, which was thought to limit diastolic filling of the ischemic ventricle and to contribute to the substantial reduction of ventricular performance.

Effect of coronary thrombus age on fibrinogen uptake.

A study was carried out to define the time limits during which an experimental coronary thrombus remains capable of incorporating fibrinogen. 131I-fibrinogen was given to intact anesthetized dogs at different time intervals, up to 67 hours, following the formation of a coronary thrombus by catheter-electrode. Radioactivity of the recovered thrombi as a whole and segmentally divided, was determined following variable time intervals of exposure to circulating fibrinogen and was expressed as thrombus/blood ratio. The results indicate that coronary thrombi formed in a normal coronary vessel remain capable of incorporating fibrinogen for at least eighteen hours, with no significant differences in the segmental distribution of radioactivity. These findings do not support the view that the recovery of isotopic fibrinogen, which was given after the onset of coronary symptoms, in thrombi from patients with myocardial infarction establishes that the thrombus was initiated after the ischemic process.

Chronic smoking in an animal model. Effects on clotting and fibrinolysis.

The effects of chronic smoking upon fibrinogen turnover and other clotting parameters, were studied prospectively in an animal model maintained on a chronic program for a period of 18 months. The animal received the equivalent on a weight basis of 11/2 packs of cigarettes daily, smoked by a human subject with the weight of 70 kg. The obtained results suggested significant enhancement of the coagulation mechanism in the smoking animals developing over the period of observation particularly when combined with high lipid diet.