Adhesion protein studies provide new clue to metastasis.
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Biomedical subjects
Publications and source records attributed to P Kahn.
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Fibronectin (FN; also called large external transformation-sensitive [LETS] protein or cell-surface protein [CSP]) is a large cell-surface glycoprotein that is frequently observed to be either absent or greatly reduced on the surfaces of malignant cells grown in vitro. Because FN may be a useful molecular marker of cellular malignancy, we have carried out an extensive screening to test the specific association among the degree of expression of FN, anchorage-independent growth, and tumorigenicity in the athymic nude mouse. A variety of diploid cell strains and established cell lines were tested for the expression of surface FN by indirect immunofluorescence using rabbit antisera against human cold insoluble globulin, rodent plasma FN, or chicken cell-surface FN. Concomitantly, the cells were assayed for tumor formation in nude mice and for the ability to form colonies in methylcellulose. Tumorigenic cells often showed very low surface fluorescence, confirming earlier reports. However, many highly tumorigenic fibroblast lines from several species stained strongly with all three antisera. In contrast, the anchorage-independent phenotype was nearly always associated with tumorigenicity in approximately 35 cell lines examined in this study. In another series of experiments, FN-positive but anchorage-independent cells were grown as tumors in nude mice and then reintroduced into culture. In five of the six tumor-derived cell lines, cell-surface FN was not significantly reduced; one such cell line showed very little surface FN. Our data thus indicate that the loss of cell-surface FN is not a necessary step in the process of malignant transformation and that the growth of FN-positive cells as tumors does not require a prior selection in vivo for FN-negative subpopulations.
Follow-up scintigraphies with 99m Tc pyrophosphate 3--4 weeks and 6--12 months after a myocardial infarction revealed the possibility of persisting a myocardial tracer activity in cases in which reinfarction can be excluded. There was a relation between the persistence of the tracer activity and the pressure in the pulmonary artery under stress conditions. The diastolic pulmonary pressure was regular in those patients whose scintiphotos showed no tracer activity in the myocardial area in the follow-up scintigraphy. Patients who showed a persisting tracer activity in the infarcted areal had elevated pressures in the pulmonary artery under stress conditions or even at rest. The elevation of the diastolic pulmonary pressure is a sign of an elevated enddiastolic pressure in the left ventricle caused by a limited left ventricular function. This could be proved by left ventriculography. The results in follow-up scintigraphy 3--4 weeks and 6--12 months after the infarction were quite similar. Therefore we believe that the results of a follow-up scintigraphy 3--4 weeks after an infarction allows to draw prognostic inferences about the further course of the disease.
In Austria primary carcinoma of the liver (plc) is no rare malignancy. From 1973 and 1979, in our department, 188 patients with plc had been registered. By separate evaluation of the results of alpha-1-fetoprotein (AFP)-determination and 67-gallium-liverscintigraphy, a diagnostic accuracy of 81.6%, resp. 78. % could be demonstrated. By combination of both methods, a correct diagnosis of plc was obtained in 95%. Based on the promising results of lobectomies performed in patients with plc, therapeutic nihilism is not longer justifiable.
A distinction can be made between invasive and non-invasive methods in myocardial scintigraphy. Myocardial perfusion scintigraphy as an invasive procedure always requires catherization of the coronary arteries and can be performed only in conjunction with coronary arteririography. The technique of this type of myocardial scintigraphy is described in detail and an explanation given of the normal scintigram and the results obtainable by this method in cases of coronary heart disease. In particular, the possibilities of "doulbe-radionuclide" scintigraphy are discussed. The non-invasive methods serve either to image the still-viable myocardium (cold-spot technique) or for direct visualization of recently-infarcted myocardial tissue (hot-spot technique). The diagnostic importance of these procedures is stressed, especially dual radionuclide investigation of recent myocardial infarct with technetium and thallium.
The results of 201-Thallium myocardial scintigraphy at rest and after stress conditions in 30 patients are discussed. Among those there were 4 patients without cardiac disease, 7 patients with anterior wall scars after transmural infarction, and 19 patients with coronary heart disease and at least one coronary stenosis greater than 75%. The obtained results were compared to findings in coronary angiography and perfusion scintigraphy. The noninvasive method of 201-Thalliumscintigraphy shows a good correlation to the results of invasive investigations when performed at rest and under stress conditions. It enables greater sensivity and specifity in selection of patients with coronary heart disease compared to stress electrocardiography alone.
The results of 201 thalliumszintigraphy under stress condition in patients with coronary heart disease with or without myocardial scars have not been uniform. We could show that pathologic stress szintigrams were only found in patients with a singular stenosis in one branch of the left coronary artery. In all those cases who had similar stenosis in both branches of the left coronary artery the stress szintigram appeared to be unchanged or normal. Therefore an unchanged stress szintigram allows no conclusion on the condition of the coronary arteries. A normal stress szintigram can be found as well in patients with normal coronary arteries as in patients with severe coronary heart disease. The examination of 201 thallium szintigrams under stress conditions therefore needs some critical evaluation.
Using 99m Tc-pyrophosphate there is a positive visualization of a transmural myocardial infarction by a localized tracer activity outside of the skeletal system. The uptake of the tracer in the infarcted area is expressed as percentage of the accumulation over the sternum. It reaches a maximum 48-60 hours after infarct onset and then recedes gradually but not strictly linearly. On the occasion of a control scintigraphy 3-4 weeks after the myocardial infarction and after full mobilization 56 per cent of the investigated patients showed a variable decrease of the tracer activity. On 44 per cent the tracer activity in the infarcted area remained unchanged or even increased slightly, though the infarction could be excluded. At the same time performed haemodynamic investigations with measuring the pulmonary artery pressure at rest and under stress conditions showed a good correlation between the persistence of the tracer activity in the infarcted area and the amount of the pulmonary pressure at rest and during stress, manifesting left ventricular function. So the result of a control scintigraphy 3-4 weeks after myocardial infarction allows to draw prognostic inferences about the further course of the disease.
To test the sensitivity and specificity of 99m-Technetium-Diphosphat myocardial scintigraphy in the diagnosis of acute myocardial infarction we examined the scintigrams of 53 patients admitted to our CCU. In all 38 patients with transmural myocardial infarction positive scintigrams with localized uptake of the tracer found. Myocardial imaging was performed 70--90 minutes after the intravenous injection of 15 mCi 99m-Technetium-Diphosphat in anterior and LAO position. The clinical value of the method for proving the presence or absence of a myocardial infarction is demonstrated on infarctions combined with bundle-branch block, pacemaker Ecg and on reinfarction. All normal cases in this group showed no tracer activity outside the bones. In unstable angina pectoris a faint but not localized tracer activity was found.
The effectiveness of scintigraphy, sonography and angiography is compared in a material of 140 cases of circumscribed disease of the liver. Typical clinical starting points are defined as points of reference of the diagnostic techniques. Clinical diagnosis is very safe in cases of secondary blastoma and hepatocellular carcinoma of the liver. Since the great majority of these conditions cause space-occupying lesions of the liver, problems of radiologic diagnosis are confined to the smaller number of clinically ill-defined lesions. For the diagnosis of secondary blastomas and cystic process of all kinds, scintigraphy and sonography are not improved by angiography. Solid space-occupying lesions of unknown origin, however, can only be recognized with angiography. Histology of both benign and malignant processes will be correct in more than 90% of cases.
In 41 patients myocardial scintigrams were performed using 2 mCi 201T1 and 15 mCi 99mTc-diphosphate. 9 healthy persons showed no myocardial imaging with 99mTc-diphosphate and normal 201T1 scintigrams. Transmural infarctions could be documented by both isotopes, excepted lateral and apical infarctions which could only be shown by means of 99mTc-diphosphate. Non-transmural infarctions could not be identified, myocardial scars however--as was to be expected--showed only activity defects within the 201T1 scintigrams without corresponding images in the 99mTc-diphosphate scans. One patient with severe coronary heart disease showed diffuse diphosphate uptake all over the myocardium with normal 201T1 scintigram. The combined myocardial scintigraphy provides a better diagnosis, enabling an improved localisation of infarction and avoiding misinterpretations.
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The injection of with different, energetic separable radioactive isotope labelled particles in the same coronary artery before and short after the injection of a contrast medium reveals in many cases variable scintigraphic pictures. The temporary vasodilatation caused by the contrast medium produces in presence of a coronary stenosis a disturbance of the regional blood flow. Thereby we find in the poststenotic myocardial area a transient ischemia, bringing about a decrease of the activity at the scintigram. As this transient ischemia is only demonstrable with a hemodynamic effective stenosis, in such cases a good effect of coronary surgery can be expected. On the other hand, in the presence of effective stenoses in all three coronary branches, in the double-scintigram alterations of the perfusion can be missed, showing the same scintigraphic picture as with normal coronary arteries.
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A hemodynamically effective coronary stenosis causes in the myocardial scintigram a maldistribution of the albumin particles within the corresponding myocardial regions. During exercise or after medicamental vasodilatation the differences in regional myocardial perfusion are amplified. Various scintigraphic pictures can be shown in a double-scintigram investigation using particles labelled by different radionuclides before and after vasodilatation. According to the method of double-scintigraphy the influence of coronary active media (dipyridamol, nitroglycerin, nifedipine) on regional myocardial perfusion is investigated. Because of its long-acting vasodilatation dipyridamol leads to a malperfusion in poststenotic myocardial areas. A similar vasodilatation effect combined with reduced activity in the second perfusion scintigram can be noticed after injection of contrast medium. In contrast to the drugs described above comparable scintigraphic changes after nitroglycerin and nifedipine are due to a different myocardial perfusion pattern, which is only showing a relative malperfusion in the poststenotic regions. At rest neither nitroglycerin nor nifedipine is able to normalize the regional myocardial perfusion.
In the course of coronary angiographies the blood flow of the right and left coronary artery was determined by the 133Xe lavage method in 89 patients with coronary heart disease. There was a statistically significant difference between the flow values of the LCA and RCA, while there was none between the blood flow values of blue- and white-collar workers suffering from coronary artery disease. Also a significantly better blood circulation of the right as well as of the left coronary artery was found in female employees in comparison to male employees.
Liver scintigraphy with 67-Ga citrate and alphafetoprotein (afp) determinations in the serum were carried out in 84 patients with liver mass lesions in the preceding sulphur colloid scans. Among these patients 51 cases were histologically verfied and 33 patients were regarded as clinically-proven cases. Scanning was carried out 72 hours after the intravenous injection of 3 mC 67-Ga-citrate. Corresponding to the intensity of 67-Ga uptake within the former liver lesions 3 groups of 67-Ga scans were differentiated: Ga 0 (the lesion showed no Ga uptake), Ga plus (the Ga uptake within the lesion was equal to that of the surrounding liver tissue) and Ga plus plus (the Ga uptake within the former lesion exceeded the physiological Ga uptake in the normal liver tissue). The number of cases, results of Ga scintigraphy and afp examinations as well as histological, clinical and nuclear medical diagnosis were correlated. It was shown that Ga plus plus cases were strongly suspect of hepatoma, whereas in Ga 0 cases a diagnosis of hepatoma could be excluded. In patients with Ga plus further investigations have to be performed (repeated afp examinations, angiography of the coeliac artery), because cirrhotic regeneration nodules, metastases and necrotic hepatomata were all found within this group. According to our experience liver scanning with 67Ga represents a useful auxiliary examination in liver diagnosis. Ga citrate scintigraphy of the liver is indicated in all cases with mass lesions detected by the routine sulphur colloid scan and in all patients in whom there is clinical suspicion of hepatoma, inorder to differentiate the origin of the lesions. In 2 cases of hepatoma marked Ga uptake was observed at a time when the afp was still negative.
Computerized molecular model building has been used to deduce the arrangement of sickle cell hemoglobin molecules (Hb-S) in the tubular fibers which form within sickling cells and in concentrated cell-free solutions of deoxygenated Hb-S. A "best" solution has been found which satisfies all of the reported properties of these fibers. In the proposed arrangement the contact between adjacent Hb-S molecules in the direction parallel to the fiber axis is primarily hydrophobic and in addition contains two salt bridges between the molecules. This contact would be disrupted with the Glu of Hb-A at the beta6 position instead of the Val of Hb-S, and it would not make a long fiber with oxygenated Hb-S. Residues in the A helix and the GH corner of the beta2 chain of one molecule are in contact with residues of the A, B, and E helices and the GH corner of the alpha1 chain of its neighbor. The intermolecular contact in the direction perpendicular to the fiber axis is mainly between the end of the E helix and the EF corner of the beta1 chain on the first molecule and the F helix and FG corner of the alpha2 chain of its neighbor. Some of the implications of these contacts are reported here, and others will be presented in subsequent papers.