Model approach of the breakthrough of a translation machine and the origin of the genetic code.
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Biomedical subjects
Publications and source records attributed to H Kuhn.
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An over-all organizational framework for the origin of life is outlined and attempts for realization are given. Evolution can be described as a process resulting in an increase of "knowledge" where knowledge is the number of carriers of genetic information discarded, on the average, until the evolutionary state under consideration is reached. A model for the evolution of a translation device, a crucial event in the origin of life, is described in detail. Aggregates of short polynucleotide strands in a hairpin conformation play a major role in this model. Experimental evidence for the selectivity of aggregation supports the idea of aggregates as error filters. Chromatographic separation as selection process during chemical evolution supports the model of the early translation device leading to the origin of the genetic code.
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In a comparative study on the pathomechanism of myocardial hypoxia we determined a parameter each of platelet activity and thrombin activity in 46 patients with angina pectoris, i.e., 15 patients with dilatative cardiomyopathy (DCM), 15 patients with latent cardiomyopathy (LCM) and 16 patients with coronary heart disease (CHD) compared to 15 normal subjects (N). beta-thromboglobulin (beta TG) and fibrinopeptide A (FPA) were measured both at rest (I) and after symptom-limited maximal exercise (II) in plasma. In N, beta TG was not increased in any case, neither at rest nor on exertion (I: 20.5 +/- 6.1 ng/ml, II: 22.4 +/- 6.7 ng/ml). Patients with LCM did not differ significantly from N (I: 20.9 +/- 6.1 ng/ml, II: 22.7 +/- 7.9 ng/ml). beta TG values of some patients with DCM and CHD were increased at rest and especially under exercise (DCM I: 27.9 +/- 9.6 ng/ml, vs. N p less than 0.025; II: 49.9 +/- 45.5 ng/ml, vs. N p less than 0.01; CHD I: 25.2 +/- 7.7 ng/ml, vs. N p less than 0.05; II: 38.6 +/- 34.3 ng/ml, vs. N p less than 0.01). Patients with DCM developing significant angina under exercise showed a higher beta TG under these exercise conditions than those with mild or no angina (p less than 0.01). In patients with coronary heart disease, this correlation was not to be found. With regard to FPA the four investigated groups differed in an analogous way, as they did with regard to beta TG; but only a weak correlation within both values was shown.(ABSTRACT TRUNCATED AT 250 WORDS)
Follow-up studies of left ventricular dimensions and function in latent cardiomyopathy (LCM) (as defined by abnormal left ventricular function during exercise in otherwise "normal" heart) have not yet been published. 36 patients with normal left ventricular data at rest (echocardiography, left ventricular angiography, coronary angiography, pulmonary artery pressure), but at least one pathologic function parameter during exercise, were studied prospectively by clinical means and by one- and two-dimensional echocardiography (mean follow-up 3.3 +/- 1.3 years). No patients died. The mean clinical class remained unchanged. The echocardiogram did not reveal an increase of left ventricular end-diastolic dimensions in any case. On average the end-systolic diameter of the left ventricle and shortening fraction in the M-mode echocardiogram did not change either. However, in 5 out of 9 patients with left bundle branch block the 2D-echocardiogram showed the development of a slight reduction of left ventricular contractions (without an increase in the end-diastolic dimensions). This was not to be observed in any patient without LBBB. Another finding was that the dimensions of the left atrium of LCM patients exceeded those of a group of normal subjects (p less than 0.02) with a further increase in the course of the disease (p less than 0.001). Thus, regarding the follow-up of patients with LCM without LBBB, there is no indication of any increase in the size of the left ventricle or reduction of its contractions at rest (mean follow-up 3.3 years). However, our results seem to underline the suspicion of a deterioration in left ventricular function of patients with LBBB.
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In a total of 339 patients with hypertrophic cardiomyopathies (typical HOCM, n = 224; atypical HOCM, n = 30; HNCM, n = 80) the clinical course, the Sokolow-Lyon index in the ECG and the prognosis as demonstrated by cumulative survival rates were analysed to get more differentiated information for the characterization of these myocardial disorders. No change in the type of hypertrophic cardiomyopathy was found, indicating different clinical entities. No increase of the Sokolow-Lyon index was observed during follow-up. Only a small proportion of patients seemed to benefit from treatment with propranolol. Surgical treatment appears to be the therapy of choice, at least in the advanced stage of the disease refractory to medical treatment. In addition, strong evidence was obtained that surgical treatment improved the prognosis in patients with typical HOCM.
Based on bicycle ergometer tests in 50 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 19 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) if clinical (NYHA) class I to IV, the profile of several haemodynamic parameters (heart rate, stroke volume index, cardiac index, pulmonary artery pressure) during exercise was evaluated. The following pattern was found: (1) with increasing degree of clinical symptoms, the mean values of stroke volume decrease and the mean values of pulmonary artery pressure increase; (2) stroke volume does not show the normal increase during exercise in a considerable number of patients (48% of HOCM, 26% of HNCM patients); (3) failing increase in stroke volume is in part compensated by increase in heart rate; (4) pathological increase in mean pulmonary artery pressure correlates with severity of clinical symptoms, but even a considerable number of clinically asymptomatic patients exhibit extremely pathological pressure increase; (5) there is no fundamental difference of the behaviour of the measured haemodynamic parameters between HOCM and HNCM; (6) there is marked overlapping of exercise-induced haemodynamic changes between patients of different NYHA classes of clinical impairment. Therefore, measurements of exercise haemodynamics are necessary to define clearly the degree of functional impairment in the individual patient. Based on identically performed exercise tests in 53 patients with HOCM, the clinical and haemodynamic effects of medical therapy with propranolol (n = 12) or verapamil (n = 25) and of surgical treatment (n = 21) were compared. Maximal exercise capacity was on an average not changed after propranolol but increased after verapamil and, most significantly, after surgery. This could be attributed to corresponding haemodynamic changes, especially concerning cardiac output and pulmonary artery pressure. As a whole, verapamil was clinically and haemodynamically superior to propranolol, but not as effective as surgical treatment.
The surgical therapy of hypertrophic cardiomyopathy (HOCM) has been shown to improve symptoms and the haemodynamic status. The prognosis after transaortic subvalvular myectomy seems to be relatively better compared to those patients with HOCM who undergo medical therapy. Complex ventricular arrhythmias have been shown to influence prognosis. Therefore, a study was undertaken to analyse the influence of surgery on ventricular arrhythmias in patients with HOCM. Thirty-one patients (23 male, eight female), mean age 44 +/- 13.6 years (range 13 to 72 years) underwent 48 h ambulatory monitoring pre- and postoperatively. Additionally 15 patients with hypertrophic non-obstructive cardiomyopathy (HNCM) were studied. Mean age was 49 +/- 11.5 years (range 28 to 69 years). Complex ventricular arrhythmias were defined as pairs (two consecutive QRS complexes) or non-sustained ventricular tachycardia (VT) (much greater than 3 QRS). Results in the operative group (HOCM) were as follows: The overall frequency of ventricular extrasystoles was low. There was no difference in the mean hourly ventricular extrasystole counts pre-operatively as compared to postoperatively. Thirteen patients had no pairs or VT pre- and postoperatively. Six patients had VT or pairs pre- and postoperatively. In five patients complex arrhythmias were detected only before surgery, whereas in another seven patients VT was first documented after operation. Overall, 11 patients had complex ventricular arrhythmias pre-operatively (pairs n = 3; VT n = 8, 3 to 8 QRS, rate 142 +/- 15 beats/min). Thirteen patients had complex ventricular arrhythmias after operation (pairs n = 4; VT n = 9, 4 to 10 QRS, rate 150 +/- 40 beats/min). Results in patients with HNCM were as follows: The overall frequency of ventricular extrasystoles was low, only three patients had a mean extrasystole count of more than 20 beats/h. Five patients had pairs and three patients ventricular tachycardia (5 QRS, rate 110 to 160 beats/min).(ABSTRACT TRUNCATED AT 250 WORDS)
Previous clinical studies in patients with hypertrophic cardiomyopathies predominantly comprised patients with typical subaortic HOCM and in many other studies patients with 'hypertrophic' cardiomyopathies were investigated; i.e. no distinction was made between patients with the typical obstructive, the atypical obstructive and the non-obstructive forms of hypertrophic cardiomyopathy. In addition, in the more differentiated studies, the differential diagnosis between HOCM and HNCM was based mainly on the presence and absence of the subaortic pressure gradient. This is also true for the clinical characterization of both types of hypertrophic cardiomyopathy. Finally, diagnostic descriptions of atypical (mid-ventricular) HOCM exist only in the form of case reports, i.e. they are not based on observations in a large number of patients. Therefore a comparative study in 353 patients with hypertrophic cardiomyopathies was designed to characterize the clinical picture of patients with HNCM and with atypical HOCM in relation to typical HOCM with special reference to the differential diagnosis. The study revealed a profoundly different diagnostic profile of the three subsets of hypertrophic cardiomyopathies. The distinction between the three subsets may serve as a more differentiated basis for clinical studies related to diagnosis, therapeutic approaches, long-term follow-up observations and prognostic evaluation of patients with hypertrophic cardiomyopathies.
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To characterize the different types of hypertrophic cardiomyopathy [typical (subaortic) hypertrophic obstructive cardiomyopathy (HOCM) (n = 235), atypical (midventricular or apical) HOCM (n = 33), and hypertrophic nonobstructive cardiomyopathy (HNCM) (n = 85)], studies of the clinical picture, course, and prognosis were performed in 353 patients. Clinical picture. There were found to be distinct differences between the diseases in terms of incidence, symptoms, findings at auscultation, carotid pulse tracings, ECG (incidence of abnormal negative T-waves), and echocardiography. Echochardiography proved to be diagnostically less specific than invasive methods, however, and in particular often failed to distinguish between atypical HOCM and HNCM. Clinical course. There was no evidence of a change from one form of hypertrophic cardiomyopathy to the other. The Sokolow-Lyon index in the ECG did not increase in any group. The rate of complications (endocarditis, systemic emboli) varied between 0.61 and 1.28 events per 100 patient years. Only 7.4%-23.5% of patients with HOCM improved as a result of conservative treatment, compared to 83%-87.5% of surgical patients. In addition, the rate of postoperative syncope was reduced by 90%. Prognosis. 90 patients were operated on. Operative mortality in typical HOCM was 4.5% over the last 5 years. If this is disregarded, the cumulative survival rates are significantly higher in surgical patients with typical HOCM than in those treated conservatively. The data confirm surgical treatment to be the therapy of choice in patients with HOCM refractory to conservative treatment. The prognosis seems to be improved by operation.
In left bundle branch block (LBBB) abnormal motions of the interventricular septum (IVS) are well known in echocardiography. We asked: (1) Is it possible to distinguish several kinds of IVS motion in the M-mode echocardiogram and (2) Is there any correlation with clinical data? We analyzed the M-mode echocardiograms of 100 patients in whom LBBB had been diagnosed, either alone or in connection with latent or dilatative cardiomyopathy. All showed a posterior motion of the IVS in early systole. Three kinds of motion could subsequently be identified: anterior (= paradox) (18%, type A), posterior (= normal) (58%, type B), and intermediate (24%, type AB). Group A had a more severe clinical stage of disease than group B (p less than 0.0005); ECG showed a longer QRS complex (p less than 0.0005), X-ray a bigger cardiac-thoracic ratio (p less than 0.0005), and M-mode-echocardiogram larger left ventricular end-diastolic diameters (p less than 0.025). Mean values of group AB fell between those of group A and those of group B. Moreover, ejection fraction at left ventricular angiography was lower in group A (52.0%) than in groups AB (58.0%) and B (62.9%) (A vs B p less than 0.005), and mean pulmonary artery pressure on exertion was higher in group A (43.3 mm Hg) than in groups AB (38.1 mm Hg) and B (28.7 mm Hg) (A vs. B p less than 0.0005). For types A and AB taken together, the likelihood of abnormal pulmonary artery pressure on exertion was 88%.(ABSTRACT TRUNCATED AT 250 WORDS)
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In devising models of the origin of life it is necessary to tackle the problems that the processes of genetic information transfer that are central to life depend on molecules that are themselves the products of such processes--enzymes. A proposed model must eventually yield a detailed chain of processes that can be checked experimentally. We have developed a model in which interactions between the helices of hairpin-loop 'adaptor' RNA molecules (amino acid carrying), lined up side-by-side by sequence complementarity to another 'messenger' RNA, promotes polypeptide synthesis.
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