E. Vänttinen

Human vascular adhesion protein-1 in smooth muscle cells

Human vascular adhesion protein-1 (VAP-1) is a dual-function molecule with adhesive and enzymatic properties. In addition to synthesis in endothelial cells, where it mediates lymphocyte binding, VAP-1 is expressed in smooth muscle cells. Here we studied the expression, biochemical structure, and function of VAP-1 in muscle cells and compared it to those in endothelial cells. VAP-1 is expressed on the plasma membrane of all types of smooth muscle cells, but it is completely absent from cardiac and skeletal muscle cells. In tumors, VAP-1 is retained on all leiomyoma cells, whereas it is lost in half of leiomyosarcoma samples. In smooth muscle VAP-1 predominantly exists as a approximately 165-kd homodimeric glycoprotein, but a trimeric (approximately 250 kd) form of VAP-1 is also found. It contains N-linked oligosaccharide side chains and abundant sialic acid decorations. In comparison, in endothelial cells dimeric VAP-1 is larger, no trimeric forms are found, and VAP-1 does not have N-glycanase-sensitive oligosaccharides. Unlike endothelial VAP-1, VAP-1 localized on smooth muscle cells does not support binding of lymphocytes. Instead, it deaminates exogenous and endogenous primary amines. In conclusion, VAP-1 in smooth muscle cells is structurally and functionally distinct from VAP-1 present on endothelial cells.

Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-Selectin mediate leukocyte binding to ischemic heart in humans

OBJECTIVES The expression of endothelial adhesion molecules and their functional significance in leukocyte adhesion to human myocardial blood vessels in acute myocardial infarction (AMI) were studied. BACKGROUND Leukocyte extravasation, mediated by specific adhesion molecules, exacerbates tissue injury after restoration of blood supply to an ischemic tissue. Experimental myocardial reperfusion injury can be alleviated with antibodies that block the function of adhesion molecules involved in leukocyte emigration, but the relevant molecules remain poorly characterized in human AMI. METHODS Semiquantitative immunohistochemistry and in vitro adhesion assays were used to study the expression and granulocyte binding abilities of different endothelial adhesion molecules in human AMI. Changes in the molecular nature of vascular adhesion protein-1 (VAP-1) were evaluated using immunoblotting. RESULTS Certain endothelial adhesion molecules (intercellular adhesion molecule [ICAM-2], CD31 and CD73) were expressed in myocardial blood vessels homogeneously in normal and ischemic hearts, whereas others (E-selectin and peripheral lymph node addressin) were completely absent from all specimens. The synthesis of ICAM-1 was locally, and that of P-selectin regionally, upregulated in the infarcted hearts when compared with nonischemic controls. Vascular adhesion protein-1 showed ventricular preponderance in expression and alterations in posttranslational modifications during ischemia-reperfusion. Importantly, P-selectin, ICAM-1 and VAP-1 mediated granulocyte binding to blood vessels in the ischemic human heart. CONCLUSIONS Human P-selectin, ICAM-1 and VAP-1 appear to be the most promising targets when antiadhesive interventions preventing leukocyte-mediated tissue destruction after myocardial ischemia are planned.

Composite graft in annulo-aortic ectasia : Nineteen years' experience without graft inclusion

OBJECTIVE The original Bentall procedure for the surgery of annulo-aortic ectasia (AAE) includes the risk of leakage and pseudo-aneurysm formation in the coronary anastomosis. To avoid the complications mentioned above we have used the open technique without the graft inclusion. In this study we evaluate our early and late results. MATERIAL AND METHODS One hundred consecutive patients with annuloaortic ectasia underwent surgical repair with composite graft between December 1975 and February 1994. In all cases the aneurysmal tissue was radically resected and the origins of the coronary arteries were directly reimplanted to the tube prosthesis. No wrapping was used. Twenty-two patients met the clinical criteria of Marfan syndrome. Thirteen of the patients underwent an emergency operation, because of a rupture of aneurysm in 2 cases and an acute dissection in 11 cases. Additional procedures were performed in 16 patients: mitral valve replacement in 2, coronary artery bypass grafting in 12 patients and in 2 cases the tube prosthesis included aortic arch, too. RESULTS The overall hospital mortality was 3.0% (3/100). In the elective group there was one hospital death (1/87; 1.1%). In the emergency group two patients died in the operation room (2/13; 16.7%). There have been 13 late deaths among the 97 hospital survivors (13.4%). Four of the late deaths were surgery related. Routine control angiography was performed in all patients 6 months after surgery. Sixty patients who had lived at least 3 years after surgery were called to reangiography and 53 of them came. No pseudo-aneurysm or leakage at distal anastomosis or coronary anastomosis could be seen. A slight dilatation of one or both coronary origins was observed on 15 patients; 9 of whom had Marfan syndrome. CONCLUSIONS The open technique is simple and can be used in all anatomical variations of the annulo-aortic ectasia. The early and late results are at least comparable with those achieved by other techniques.

Surgical treatment of aneurysms of the ascending aorta. With special reference to cystic medial necrosis of the aorta.

The clinical series comprised 14 patients with aneurysms of the ascending aorta. In the autopsy series, there were additionally 19 patients, who had died suddenly as a results of free perforation or dissection of the ascending aorta. In the clinical series, the cause of the aneurysmal formation was cystic medial necrosis in 10 patients, 8 of whom had severe aortic valve insufficiency. Twelve patients were operated on using extracorporeal circulation, Both the ascending aorta and aortic valve were replaced with prosthesis in 6 cases. Three patients underwent emergency surgery due to pericardial tamponade. All three died, despite a technically successful operation. One patient out of 9 electively operated upon died. A follow-up examination was carried out on the 5 surviving cystic medial necrosis patients. Aneurysms of the sinuses of Valsalva developed after supracoronary resection in 2 patients. The results showed that elective operations in the event of aneurysms of the ascending aorta can be carried out with an acceptably low mortality rate. However, after supracoronary resection, in cases of cystic medial necrosis, the risk of developing aneurysms of the proximal aortic remnant seems obvious. Therefore, in patients in whom the whole aortic root is involved, total removal of the ascending aorta and re-implantation of the coronary ostia into the prosthetic tube is preferable.

Prosthetic Valve Endocarditis

Prosthetic valve endocarditis is an infrequent but serious complication of valve surgery. It occurred in 25 (3.2%) of 772 patients who received aortic, mitral or double valve replacement in 1971-1987. The total follow-up time was 3,976 patient years, giving an incidence of 0.63/100 patient years. Staphylococci were the most common of the cultured organisms in early and late infections-60% and 64%, respectively. The endocarditis was disclosed at autopsy in two cases. Treatment was antibiotics alone in 11 cases, and surgery was required in 12, the indication always being congestive heart failure. C-reactive protein level fell more rapidly than erythrocyte sedimentation rate in response to antibiotic or surgical management. The mortality rate was 73% in the antibiotic group and 33% in the surgical group. The findings demonstrated that an infected valve prosthesis should be replaced without delay if complications develop.

THE ROLE OF MEDIASTINOSCOPY IN THE TREATMENT OF LUNG CARCINOMA

At the University Central Hospital, Turku, 398 mediastinoscopies were performed during the years 1959—1970 on patients in whom lung carcinoma was verified before, at or after mediastinoscopy. The latter revealed mediastinal lymph node metastases in 40.7% of the cases. It was positive in 13.4% of those with negative bronchoscopies.A positive mediastinoscopy finding was the principal reason for not operating in 17.1% of the non-operated cases. The proportion of exploratory thoracotomies declined from 24.3% in 1952–1958 to 17.0% in 1959–1970 and to 9.8% in 1965–1970. In the cases in which mediastinoscopy was negative and resection was undertaken, the operative finding regarding lymph nodes was also negative in 77.6%. Of the resected negative mediastinoseopy cases 36.5%, and of the patients whose operative finding was negative for lymph nodes 43.8% survived for over 5 years. Only one of the 14 patients, on whom resection was performed after a positive mediastinoscopy finding, lived over 2 years, and the resul...

Surgical Treatment of Active Native Valve Endocarditis

A report is presented of 24 patients (23 male), mean age 38 years, who underwent surgery for active native valve endocarditis of the left heart in 1975-1988. The aortic valve was affected in all patients, and also the mitral valve in five. Pre-existing aortic valve disorder was present in 17 cases (13 congenitally bicuspid 4 rheumatic affection). There were five hospital deaths (20.8%). Staphylococci as causal organism and extensive infection predicted the highest mortality and morbidity. The mean follow-up time was 39.7 (range 2-114) months. Two reoperations because of prosthetic valve dehiscence revealed endocarditis of the implanted valve. Strong correlation was found between favourable postoperative course and rapid normalization of C-reactive protein levels, which did not fall in patients with persistent infection. Early surgery is recommended if the course of bacterial endocarditis is severely complicated.

Effects of Extreme Haemodilution on the Immediate Post-Operative Course of Coronary Artery Bypass Patients

The immediate post-operative course was investigated in 70 patients who had undergone coronary artery bypass grafting under normovolaemic moderate and subsequent extreme haemodilution, and in 70 control patients who underwent a similar operation with a haemic prime in the heart-lung machine. Altogether 8 patients (5.7%), 4 from the haemodilution group and 4 from the controls required re-exploration for excessive post-operative bleeding and were examined as their own group. There were no marked differences in bleeding through chest tubes or in blood haemoglobin concentration between patients who had undergone intra-operative haemodilution and controls. Post-operatively both patient groups required approximately analogous amounts of infused blood, colloids and crystalloids. Central venous pressure was consistently lower in haemodiluted patients. Opening of peripheral circulation as indicated by a rise in skin temperature occurred significantly faster in haemodiluted patients than in controls. Before and after weaning from the respirator, arterial blood oxygen tension was slightly lower in patients who had undergone intra-operative haemodilution. Serum creatinine levels were lower and blood platelet counts significantly higher in haemodiluted patients than in controls. Rates of peri-operative myocardial infarctions showed no essential difference between the groups.

Reduced Lactate Washout from the Myocardium after Combining St. Thomas I Type Cardioplegia with Topical Cooling of the Heart: Myocardial Oxygenation and Performance after Cardioplegia in Coronary Artery Bypass Grafting Patients

The myocardial oxygen extraction was diminished with a resulting coronary sinus blood oxygen saturation of 48 +/- 5 (SEM) %, as compared to the pre-bypass control level of 30 +/- 1%, two minutes after the ischaemic period in St. Thomas I type cardioplegia (CPL) with topical cooling of the heart during a coronary bypass operation. The myocardial oxygen extraction returned to prebypass levels after ten minutes of reperfusion following ischaemia and remained so after the bypass. The postischaemic myocardial lactate washout of the CPL-patients was compared to that of another group of coronary surgical patients, in whom intermittent ischaemia and topical cooling (IITC) were used for myocardial protection. It was found that the lactate washout two minutes after the single ischaemic period in the CPL-patients was far less than the lactate washout two minutes after each ischaemic period in the IITC-group. The greatest arterial-coronary sinus lactate difference in the IITC-group was -1.7 +/- 0.2 mmol/l and in the CPL-group -0.7 +/- 0.2 mmol/l. Cardiac performance (assessed by the CI-PCWP relationship) which was moderately depressed by the anaesthesia and surgery before bypass, returned gradually to the control level within 20 hours after operation. The present study shows that no apparent postischaemic abnormality in myocardial oxygen utilization develops when single dose cardioplegia, together with topical cooling of the heart, is used for myocardial protection, and that the accumulation of myocardial lactate during ischaemia is less during cardioplegia with topical cooling of the heart than during intermittent ischaemic with topical cooling for coronary artery bypass grafting operations.

Toremifene concentration and multidrug resistance in lung tumors

Abstract In this pharmacokinetics study, concentrations of toremifene (TOR), a new antiestrogen, were measured after a 7-day oral treatment in serum, lung, and tumor tissue to determine the optimal dose of TOR for the modulation of clinical multidrug resistance in patients with lung cancer. Target levels of the antiestrogen were based on previous in vitro studies. Altogether, 18 patients with operable lung tumors were studied. TOR was given in an open, nonrandomized, phase I study at three different dose levels. The medication consisted of oral TOR given for 7 days at either 240, 480, or 600 mg/day before surgical removal of the tumor. At least five patients were scheduled to be included at each dose level, with all five receiving the full course of therapy before escalation of the dose. Blood samples for serum TOR concentration measurements were taken on days 0 and 7. Specimens of tumor and normal lung tissue of approximately 0.5 g were taken on day 7. The concentrations of TOR and its metabolites were determined in serum, lung, and tumor tissue at different dose levels. Altogether, 12 evaluable patients completed the scheduled treatment. The concentrations measured in serum, lung, and tumor tissue increased along with the dose used, such that the highest TOR values were achieved at 600 mg/day, with mean values being 4.9 μmol/l, 175.0 μmol/g, and 122.7 μmol/g, respectively. The concentrations of TOR and its metabolite N-demethyltoremifene were highest in lung tissue, but the values measured in tumor specimens were also well above the respective concentrations detected in serum samples. The TOR doses of 240 and 480 mg/day were well tolerated. One patient in the group treated at 600 mg/day had to discontinue the treatment because of headache and nausea. TOR given at doses ranging from 480 to 600 mg/day for 7 days will produce serum, lung, and tumor concentrations of the parent drug and its metabolites that have been shown to reverse multidrug resistance of cancer cells in vitro. As the 480-mg/day dose of TOR produced tumor concentrations high enough to reverse multidrug resistance without producing adverse drug reactions, the dose recommended for the foreseen clinical trials in the reversal of multidrug resistance would be 480 mg/day for 7 days.