O. Juhani Rämö

Oxidative stress has a role in malignant transformation in Barrett's oesophagus

Mechanisms underlying the development of oesophageal adenocarcinoma are poorly understood. To discover the role of oxidative stress and radical scavenger capacity in the malignant transformation of Barretts oesophagus, we measured myeloperoxidase activity, superoxide dismutase activity, glutathione content and total aromatic DNA adducts. Mucosal specimens came from 52 patients in 6 groups: symptomatic gastro‐oesophageal reflux disease (GORD) without and with endoscopic oesophagitis, Barretts epithelium without and with dysplasia, adenocarcinoma in the oesophagus and controls. In the GORD‐oesophagitis‐metaplasia‐dysplasia‐adenocarcinoma sequence, glutathione content was progressively lower and myeloperoxidase activity higher than in controls, plateauing at Barretts epithelium without dysplasia. Only in Barretts epithelium with dysplasia was SOD activity significantly increased. In all patient groups, DNA adduct levels were significantly higher than the control level. Though these levels between patient groups did not differ significantly, the level was highest in Barretts epithelium without dysplasia and progressively lower in Barretts with dysplasia and adenocarcinoma. Pooled data showed a negative correlation between glutathione content and DNA adducts (−0.28, p = 0.05). Simultaneous formation of DNA adducts, increased myeloperoxidase‐related oxidative stress, decreased antioxidant capacity (glutathione content) and the negative correlation between glutathione content and DNA adducts in the GORD–oesophagitis–metaplasia–dysplasia–adenocarcinoma sequence of Barretts oesophagus indicate a role in the pathogenesis and malignant transformation related to oxidative stress.

N‐Acetylcysteine as an additive to crystalloid cardioplegia increased oxidative stress capacity in CABG patients

Objective—This prospective, randomized study was designed to assess the effects of N‐acetylcysteine (NAC) in coronary artery bypass graft (CABG) patients. Design—Thirty‐five consenting CABG patients with normal myocardial function were randomly divided into control (C) patients (N = 20) who received crystalloid (Plegisol®) cardioplegia, and NAC patients receiving NAC in a 0.04 mol/l solution (N = 15) in Plegisol®. Simultaneous coronary sinus and aortic blood samples, and myocardial biopsies were taken 1, 5 and 10 min after declamping. Hemodynamics was measured invasively for 24 h. Results—There were no adverse effects observed. The myocardial glutathione content was significantly better preserved (p = 0.0001) and myeloperoxidase activity was over two times lower in the NAC group than in the C group (p = 0.03). The trap capacity gradient between the aorta and the coronary sinus increased significantly during the first minute of reperfusion in the treatment group (p = 0.001) when compared with the C group. In the first minute after reperfusion there were more leukocytes sequestered in the coronary circulation (p = 0.04) in the C group. The invasive hemodynamic data did not differ significantly between the groups. The incidence of arrhythmias was equal. Conclusion—NAC increased tissue capacity against oxidative stress and decreased inflammatory response in CABG patients with normal ejection fraction.

Cardiopulmonary bypass and activation of antithrombotic plasma protein C.

OBJECTIVE We hypothesized that antithrombotic plasma-activated protein C plays a defensive antithrombotic role during coronary ischemia and postischemic reperfusion. METHODS AND RESULTS We evaluated protein C activation during cardiopulmonary bypass and coronary reperfusion in 20 patients undergoing coronary bypass surgery. During cardiopulmonary bypass and during the 10 minutes after aortic unclamping, the plasma levels of protein C (mean +/- standard error of the mean) decreased from 123% +/- 7% to 74% +/- 5% of normal mean. In contrast, the levels of activated protein C in plasma increased from 122% +/- 8% to 159% +/- 21%, and the activated protein C/protein C ratio increased from 1.04 +/- 0.08 to 2.29 +/- 0. 31 (P =.006, 2-tailed Wilcoxon signed rank test). Patients were stratified on the basis of the increase in activated protein C in the coronary sinus plasma at 10 minutes after reperfusion by means of the arbitrary value of 1.5 for the activated protein C/protein C ratio. Within 24 hours, the patients with low increases in activated protein C (ratio < 1.5, n = 8) had a significantly (P <.05) lower cardiac output and mean pulmonary artery pressure, as well as a higher systemic vascular resistance, than patients (n = 11) with high increases in activated protein C (ratio > 1.5). The rapid increase in activated protein C during the first 10 minutes after aortic unclamping indicated protein C activation in the reperfused vascular beds. CONCLUSIONS The antithrombotic protein C pathway was significantly activated during cardiopulmonary bypass mainly during the minutes after aortic unclamping in the ischemic vascular beds. Suboptimal protein C activation during ischemia may impair the postischemic recovery of human heart and circulation.

Tuberculous fistula of the esophagus

BACKGROUND Tuberculous involvement of the esophagus has been extremely rare during the past 40 years. It will be, however, more frequently encountered in the future, as the number of immunocompromised patients is growing. This condition is usually secondary to infection in other thoracic sites, such as lungs, larynx, or mediastinum. The diagnosis is difficult if the suspicion of tuberculosis is not raised. Dysphagia and cough after ingestion of fluids and food are common symptoms without any other specific signs in these patients. Diagnosis is based on combination of esophagography, esophagoscopy, bronchoscopy, and computed tomographic scan. METHODS We present 3 patients with tuberculous fistulas of the esophagus. Two of our 3 patients were treated successfully with the combination of operation and antituberculous chemotherapy. Fistulas were resected and closed directly. Suture lines were secured with pedicled pleural flaps. RESULTS Both patients who underwent operation recovered without complications. One patient died without definitive diagnosis and treatment. CONCLUSIONS Treatment of tuberculous fistulas consists of operation and antituberculous chemotherapy, although antituberculous medication alone has been suggested to be effective if the diagnosis is early. However, operation is usually necessary to establish the correct diagnosis. Therefore, we believe that if the cause of the esophageal fistula cannot be verified, thoracotomy should be performed. If the fistula is left untreated the consequences are usually fatal.

pH-metric analysis after successful antireflux surgery: comparison of 24-hour pH profiles in patients undergoing floppy fundoplication or Roux-en-Y duodenal diversion

Fundoplication is the most widely used antireflux method, whereas Roux-en-Y duodenal diversion (partial gastrectomy, vagotomy, and Roux-en-Y reconstruction) has been used in fewer patients with more complicated gastroesophageal reflux disease. Abnormal esophageal pH values are normalized after successful fundoplication. However, very little is known about possible changes in the pH profile after successful Roux-en-Y duodenal diversion. A total of 37 patients with severe gastroesophageal reflux disease were treated by fundoplication (n=22) or Roux-en-Y duodenal diversion (n=15). Postoperatively all patients in both groups were symptom free and healing of esophagitis was verified endoscopically. After fundoplication, the 24-hour esophageal acid exposure decreased significantly (P=0.03) and the pH profile normalized (pH<4 in 5.8%±2.4% of the recorded time). However, the decrease in esophageal acid exposure was not significant (P=0.77) after successful Roux-en-Y reconstruction and the pH profile remained abnormal (pH<4 in 15.1%±4.3%). It was concluded that 24-hour esophageal pH monitoring is a reliable means of assessing the results of fundoplication, but the current test criteria should be reexamined in evaluating the results of Roux-en-Y duodenal diversion. Healing of esophagitis after Roux-en-Y duodenal diversion despite abnormal acid reflux, as shown by 24-hour pH measurements, suggests that duodenal contents also have a role in the pathogenesis of esophagitis in an acid milieu.

Long-term ethanol ingestion causes an increase of phospholipase A2 activity in acute experimental pancreatitis in rats

Alcohol is recognized as one etiological factor in pancreatitis and according to recent studies, phospholipase A2 (PLA2) may be an important factor in the pathogenesis of this disease. However, the effect of chronic ethanol ingestion on PLA2 activity has not been studied in pancreatitis. To clarify the possible relation of these two factors 48 male Wistar rats received 15% (v/v) ethanol in drinking water for 12 weeks and 48 rats served as controls drinking tap water. Blood samples were collected from the control animals by puncturing the abdominal aorta. Experimental pancreatitis was induced by intraductal retrograde infusion of normal rat bile and blood samples collected 24 hr after the infusion. PLA2 activities in the plasma were measured by using the substrate with a 3H-labeled fatty acid in position 2. PLA2 activities in the control group were 11.2 +/- 1.3 (mean +/- SE) nmole/ml/min and 21.7 +/- 3.5 twenty-four hours later (P less than 0.05). In alcoholic rats the activities were 11.1 +/- 1.4 and 54.0 +/- 10.3, respectively (P less than 0.003). The increase of the activities was greater in alcoholic rats and the difference between the groups statistically significant (P less than 0.025). The mortality rate was 4.2% among the control animals and 29.2% in the alcoholic groups (P less than 0.026). The results of this study suggest that chronic alcohol ingestion makes the pancreas vulnerable to severe pancreatitis with high mortality. This is associated with significantly increased activities of PLA2.

Increased DNA adducts in Barrett's esophagus and reflux-related esophageal malignancies.

BACKGROUND. DNA adduct formation can initiate carcinogenic processes. AIM. To examine the pre-malignant condition of Barretts esophagus by measuring the DNA adducts. METHODS. DNA adducts were measured in the proximal and distal esophagus of patients with Barretts esophagus (n = 9), patients with adenocarcinoma in the distal esophagus/esophagogastric junction (n = 28), and in control group of patients (n = 8) using the 32-P-postlabeling method. The average levels of DNA adducts are expressed as mean adducts/10 9 nucleotides - standard error of the mean. RESULTS. The average DNA adduct levels in the distal esophagus were significantly higher in both the Barretts esophagus (24.5 - 7.9) and the adenocarcinoma (12.0 - 3.0) than in the control patients (0.1 - 0.08), P < 0.001. In the proximal esophagus, the DNA adduct levels were approximately equal in the Barretts esophagus (7.0 - 1.0) and in the adenocarcinoma group (6.4 - 0.65). However, the levels in the proximal esophagus in both groups were significantly higher than in the control group (2.1 - 0.67), P < 0.05. CONCLUSIONS. Patients with Barretts esophagus and patients with esophageal/esophagogastric junction adenocarcinoma had significantly more DNA adducts than the control group. These results support the current concept of the carcinogenic potential of chronic gastroesophageal reflux, and the pre-malignant condition of Barretts esophagus.

The effect of nitecapone, a new antioxidant, on myocardial function after aortic cross-clamping in experimental heart ischemia

During aortic cross-clamping, the myocardium suffers from global ischemia, which is followed by reperfusion after declamping. The generation of free oxygen radicals increases during reperfusion, resulting in arrhythmias and impaired cardiac function. This study was conducted to evaluate the effect of a novel antioxidant nitecapone (NC) on cardiac reperfusion injuryin vivo. Twelve pigs were anesthetized and after sternotomy the aorta and the right atrium were cannulated for cardiopulmonary bypass. The heart was arrested with either +4°C crystalloid cardioplegia alone in the control group (n=6) or cardioplegia with NC (50 µM) added in the NC group (n=6). Cardioplegia was added every 20 minutes. After 1 hour of aortic crossclamping, blood samples for oxidative stress analysis were taken, and hemodynamic profile surveillance continued for 90 minutes. Heart rate (p=0.04) and left ventricular end diastolic pressure (LVEDP) (p=0.04) were significantly lower in the NC group than in the C group after aortic declamping. Cardiac output and myocardial contractility (dP/dtmax) were also enhanced in the group receiving NC, but the difference was not statistically significant. At 30 minutes after reperfusion, the coronary production (coronary sinus-aorta) of thiobarbituric acid reactive substances correlated inversely with cardiac output (r=−0.90,p=0.001) and stroke volume (r=−0.82,p=0.007). The effect of NC on lipid peroxidation seems to be modest and therefore the target of NC is unclear. NC would appear, however, to be a beneficial additive in the crystalloid cardioplegia in terms of functional recovery.

Effects of Lovastatin in Prevention of Restenosis after Percutaneous Transluminal Angioplasty in Lower Limbs

Percutaneous transluminal angioplasty (PTA) is frequently complicated by restenosis of the dilated arterial segment within a few months after the angioplasty. Cholesterol-lowering drugs have been shown to reduce the rate of restenosis after PTA, but the role of lipid fractions in susceptibility to restenosis after balloon angioplasty is not clear. The present prospective and randomized study was executed to find out the effects of lovastatin on restenosis after PTA in the arteries below the inguinal ligament. PTA was performed in 37 patients (age 68±12 years) because of severe claudication or critical ischemia of lower limbs. Regardless of their preoperative blood cholesterol level, all patients were given diet information and thereafter randomized into two groups, one receiving 250 mg asetosalisylic acid (ASA group, n=19) and one receiving 250 mg ASA and 20 mg of lovastatin (lovastatin group, n=18) daily. Clinical status was followed up for 1, 4, and 12 months after PTA. Control angiography was performed in every patient 12 months after PTA. However, if the clinical status suggested critical ischemia, angiography and necessary procedures were performed before 12 months. Two radiologists evaluated all angiographs independently and without knowledge of the medication patients were receiving. In the ASA group, forty-two percent (8/19) of the patients had total restenosis of the dilated segment 4.5±1.2 months after the first PTA, whereas only 22.2% (4/18) of the patients in the lovastatin group had total restenosis 2.8±1.5 months after the initial treatment. There were 2/18 amputations (11.1%) in the lovastatin group and 4/19 (21.1%) in the ASA group during the first year of surveillance. Total plasma cholesterol decreased from 6.0±1.1 mmol/L to 5.0±1.4 mmol/L, and cholesterol index (total cholesterol/ HDL-cholesterol) decreased from 5.4±2.3 to 4.9±2.5 in the lovastatin group during the follow-up period. In the ASA group, both plasma total cholesterol and cholesterol index stayed virtually at the same level. The number of restenosis and amputations in the ASA group was twice as high as in the lovastatin group 1 year after PTA. These preliminary results suggest that lovastatin has a beneficial effect on restenosis after balloon angioplasty.

Nitecapone as an additive to crystalloid cardioplegia in patients who had coronary artery bypass grafting

BACKGROUND Nitecapone has been shown to have a protective effect against ischemia-reperfusion injury in experimental heart transplantation and in Langendorff preparations. This prospective, randomized study assessed the effects of nitecapone in patients who had coronary artery bypass grafting. METHODS Thirty patients with normal myocardial function were randomly divided into control patients (n = 15), who received crystalloid (Plegisol) cardioplegia, and nitecapone patients, who received nitecapone in a 50 microM solution (n = 15) in Plegisol. Cardioplegia was administered as an initial dose of 15 mL/kg of body mass after cross-clamping and 2 mL/kg every 15 minutes. Simultaneous coronary sinus and aortic blood samples, and myocardial biopsies were taken at 1, 5, and 10 minutes after unclamping. Hemodynamics were measured invasively for 24 hours and with transesophageal echocardiography for 3 hours after cardiopulmonary bypass. RESULTS There were no adverse effects. The incidence of ventricular arrhythmias was significantly lower in the treatment group during the recovery period (p = 0.02). Cardiac output and stroke volume did not differ significantly between the groups. The conjugated dienes gradient between the aorta and the coronary sinus increased significantly during the first minute of reperfusion in the control group (p = 0.02) compared with the nitecapone group. Myeloperoxidase activity in myocardial biopsies was higher in the control group (2.3 times higher at 5 minutes and 3.2 times higher at 10 minutes) than in the nitecapone group (p = 0.13). CONCLUSIONS Nitecapone did not exert any significant hemodynamic effects in patients with normal ejection fraction.