Biomedical subjects

G Schuler

Publications and source records attributed to G Schuler.

At least 199 records · Page 11Linked to original sources

PubMed1996

Action profiles of predictors of death and survival time in stage I malignant melanoma.

BACKGROUND: Many studies have been performed to identify prognostic factors of malignant melanoma using multivariate regression models. In these models, it is generally assumed that quantitative predictors such as age or tumor thickness enter linearly into the model, or they are categorized. OBJECTIVE: The purpose of the present study is to investigate possible curvature (nonlinearity) of predictors of 'death from MM within 5 years after diagnosis' and 'survival time after diagnosis' avoiding the known shortcomings of categorizing predictors. METHODS: Our analyses are based on data of 677 patients with stage I melanoma of the skin collected at the Cancer Registry of the Canton of Zurich. In order to study non-linearity of predictors, we use 'generalized additive models' (GAM): in a GAM the usual prognostic index is replaced in an optimal way by a more flexible form where the individual linear terms are replaced by possibly curved functions of the predictors. Plotting the corresponding curves (the 'action profiles') allows one to visualize easily the shape by which predictors 'act' over the whole range of values. RESULTS: Essentially the same results emerged when studying 'death from melanoma' and 'survival time in melanoma': age and tumor thickness have a pronounced nonlinear association with both endpoints taking simultaneously into account effects of sex and tumor site. The action profile for age is J or U shaped. The action profile for thickness has a 'two-phase' pattern. It increases linearly for low thickness values and flattens for higher values. The shape of the action profiles was checked by performing a Monte Carlo simulation ('boot-strapping'). CONCLUSIONS: The best prognosis of melanoma was found within a middle age range while younger and older patients showed a poorer prognosis. In our data, the increase in thickness in the range above 2 mm is of much less clinical relevance than in the range below 2 mm. GAMs may be of great value for clinicians in providing a visualization of the shape by which predictors act and to obtain a better understanding of the complex relationships between predictors and survival. Not considering curvature of action profiles may result in excluding relevant predictors.

Adult↗

PubMed1996

Regression and non-progression of coronary artery disease with exercise.

Metabolic interventions using low-fat diets and lipid level-lowering drugs were successful in controlling the progression rate of coronary artery disease and reduced the number of clinical events. Only a few studies have examined the role of regular physical exercise as a therapeutic instrument to enhance these beneficial effects. The design of the available studies did not permit differentiation among the effects of physical exercise, lowering of serum cholesterol level and stress management. The decrease in total serum cholesterol level ranged from 10 to 24%, the change in high-density lipoprotein cholesterol level from -3 to +12%. There was predominant regression of coronary artery lesions in one study (the Lifestyle trial); in the other two trials, progression was either halted (in the Heidelberg trial) or reduced (in the Stanford trial). In contrast, significant progression was noted in all of the control groups. In addition to the beneficial effects on progression of coronary artery disease, patients taking regular physical exercise experienced significant improvements in their physical work capacity (+25%) and in myocardial perfusion, and reduction in anginal pain. There were fewer clinical events in the intervention group in the Stanford study only, whereas clinical events tended to be more frequent in the other studies because of exercise-induced arrhythmias.

Coronary Disease↗

PubMed1996

[Physical training of patients with high grade compromise of heart pumping function].

Regular exercise is regarded as a mainstay of physical fitness and endurance; it remains to be determined, however, whether patients with severe impairment of left ventricular performance derive profit from this treatment to the same extent as patients with normal myocardial contractility. Irrespective of the underlying cause profound changes are initiated by heart failure with respect to neurohumoral factors, ultrastructure of skeletal muscle, and peripheral vascular resistance. Initially these changes are set in motion by the inability of the heart to provide sufficient flow to the peripheral organs; eventually, however, they attain a role of their own and contribute to the disease independently. Intolerance of physical exercise, in particular, is not so much the result of pulmonary congestion and low cardiac output. Reduction of oxidative capacity of skeletal muscle, excessive peripheral vascular resistance, and impairment of vasodilatation in response to metabolic needs seem to contribute more to this incapacitating symptom. Until recently, physical exercise was regarded as harmful in patients with severe impairment of left ventricular performance; in order to prevent further deterioration patients were frequently treated by bedrest. Controlled trials, however, have shown that regular physical exercise in these patients may favourably influence the course of this disease, or even reverse some harmful changes. The following results were obtained in a group of 12 patients with depressed left ventricular ejection fraction (LV-EF 25 +/- 10%) participating in an ambulatory training program: 1) Left ventricular end-diastolic dimension was significantly reduced from 70 +/- 5 mm to 66 +/- 3 mm (p < 0.05). 2) There was significant improvement of skeletal muscle perfusion and oxygen uptake during submaximal and maximal exercise resulting in delayed onset of anaerobic metabolism and increased exercise capacity. 3) Intrinsic change of skeletal muscle ultrastructure were in part corrected; mitochondrial volume density increased significantly. There was a close correlation between changes in maximal oxygen uptake and changes of cytochrome-C-oxidase positive mitochondrial volume density. 4) Cardiac output and left ventricular ejection fraction in response to exercise, however, remained unchanged, indicating that no significant central effects were achieved by regular exercise.

Cardiac Output↗

PubMed1996

[Polymer microparticles for right and left heart echocardiography and imaging myocardial perfusion after peripheral vein injection].

It is conceivable that a stable ultrasound contrast agent could be used for reproducible right and left heart echocardiography and myocardial visualization after intravenous injection. Microparticles from different polymers and preparation procedures were screened in six dogs leading to one superior agent with reproducible high quality echo contrast in doses of 1 mg/kg. This special agent is based on condensates of aspartic acid, ethanolamine and decanoic acid. Out of this material particles were formed with an average diameter of 2 micrometers. The easily suspendable particles were used for the following studies in a dose of 1 mg/kg intravenously in eight pigs. Maximal video intensity averaged 116 +/- 42 relative intensity units (IU) in the right, 137 +/- 42 IU in the left ventricle, 42 +/- 7 in the normally perfused and 11 +/- 2 in the hypoperfused myocardium after circumflex ligature. The area under the intensity curve was 1942 +/- 100 IUxs in the right, 2452 +/- 1291 IUxs in the left ventricle, 518 +/- 124 in the normally perfused and 202 +/- 94 in the hypoperfused myocardium after circumflex ligature. There was no change of heart rate, central arterial or pulmonary artery pressure during and after the injections. There was also no loss of echo intensity during the passage of contrast material through the heart due to systolic pressure. The described agent can be used for the opacification and ultrasonic visualization of the right and left heart as well as normally and hypoperfused myocardium without visible side-effects in animal studies.

Animals↗

PubMed1995

IL-12 as mediator and adjuvant for the induction of contact sensitivity in vivo.

To determine whether IL-12 serves as a regulator of contact sensitivity reactions, mice were painted with either 1.0% trinitrochlorobenzene or 0.5% dinitrofluorobenzene on abdominal skin. At various time points thereafter, regional lymph nodes or spleens were prepared for RNA extraction, and the signals for IL-12 p35 and p40 chain were sought by quantitative reverse transcriptase-PCR. Time course analysis showed a constitutive expression of p35 chain mRNA signals throughout the experiment (0 to 72 h), whereas the signal for the p40 chain was transiently induced in lymph node and spleen cells after 12 to 14 h. Cellular depletion experiments and double label in situ hybridization studies showed that dendritic cells were sources for a major part of the p40 chain message. The presence of functional IL-12 in culture supernatants was indirectly assessed by addition of anti-IL-12 antiserum and analysis of IFN-gamma production. Significant amounts of IFN-gamma could only be detected in supernatants of allergen-treated animals. Addition of anti-IL-12 antiserum inhibited IFN-gamma production by about 55%. In a further attempt to assess the role of IL-12 in contact sensitivity, anti-IL-12 antiserum was injected i.p. into mice, and ear swelling responses were assessed following challenge. Injection of anti-IL-12 antiserum significantly reduced ear swelling responses by 85%. Thus anti-IL-12 treatment almost completely prevented sensitization. To assess whether IL-12 would be able to overcome in vivo tolerance, UV-tolerized animals were treated with i.p. IL-12 in a contact allergy system. Treatment of mice with IL-12 not only prevented tolerance induction, but was able to reverse UV-induced tolerance. In aggregate, our data point to an important role for IL-12 as a mediator and adjuvant for the induction of contact sensitivity in vivo.

Adjuvants, Immunologic↗

PubMed1995

Purification of crotonyl-CoA reductase from Streptomyces collinus and cloning, sequencing and expression of the corresponding gene in Escherichia coli.

A crotonyl-CoA reductase (EC 1.3.1.38, acyl-CoA:NADP+ trans-2-oxidoreductase) catalyzing the conversion of crotonyl-CoA to butyryl-CoA has been purified and characterized from Streptomyces collinus. This enzyme, a dimer with subunits of identical mass (48 kDa), exhibits a Km = 18 microM for crotonyl-CoA and 15 microM for NADPH. The enzyme was unable to catalyze the reduction of any other enoyl-CoA thioesters or to utilize NADH as an electron donor. A highly effective inhibition by straight-chain fatty acids (Ki = 9.5 microM for palmitoyl-CoA) compared with branched-chain fatty acids (Ki > 400 microM for isopalmitoyl-CoA) was observed. All of these properties are consistent with a proposed role of the enzyme in providing butyryl-CoA as a starter unit for straight-chain fatty acid biosynthesis. The crotonyl-CoA reductase gene was cloned in Escherichia coli. This gene, with a proposed designation of ccr, is encoded in a 1344-bp open reading frame which predicts a primary translation product of 448 amino acids with a calculated molecular mass of 49.4 kDa. Several dispersed regions of highly significant sequence similarity were noted between the deduced amino acid sequence and various alcohol dehydrogenases and fatty acid synthases, including one region that contains a putative NADPH binding site. The ccr gene product was expressed in E. coli and the induced crotonyl-CoA reductase was purified tenfold and shown to have similar steady-state kinetics and electrophoretic mobility on sodium dodecyl sulfate/polyacrylamide to the native protein.

Acyl-CoA Dehydrogenases↗

PubMed1995

Impact of intensive physical exercise and low-fat diet on collateral vessel formation in stable angina pectoris and angiographically confirmed coronary artery disease.

This randomized study was performed to assess the effects of > 3 hours of physical exercise per week and low-fat diet on collateral formation in nonselected patients with coronary artery disease (intervention group, n = 56). Results were compared with those of patients in a control group (n = 57), who received usual care by their private physicians. Coronary lesions were assessed by quantitative coronary angiography at the beginning and after 1 year of study (n = 92). As previously reported, after 1 year there was a significant retardation of progression of coronary artery disease in the intervention group as compared with the control group. In this study, evaluation of collateral formation revealed no significant difference between both groups, and changes in hemodynamic and metabolic variables or leisure time physical activity were not related to changes in collateral formation. Although progression of the disease was significantly related to an increase in collateral formation, regression was significantly related to a decrease in collateral formation (p < 0.00001). Because patients in the intervention group exercised for > 3 hours/week, and patients with regression of coronary artery disease even dedicated 5 to 6 hours to leisure time physical activity per week, these findings question whether an exercise program within the safety tolerance of patients will be able to induce coronary collateralization in the presence of regression of coronary artery disease.

Activities of Daily Living↗

PubMed1995

Antigen processing in populations of mature murine dendritic cells is caused by subsets of incompletely matured cells.

Immature dendritic cells (DC), such as freshly isolated Langerhans cells (LC), are excellent at processing native protein Ag. During short term culture they shut off MHC class II synthesis and down-regulate their processing capacity. They retain, however, the MHC/peptide complexes, up-regulate adhesion and costimulatory molecules, and acquire the ability to sensitize T cells. Two reports describing substantial processing activity in populations of mature DC prompted us to undertake an extensive comparative study of the Ag-processing capacities of immature vs mature DC. We used a panel of 17 peptide-specific T cell hybridomas restricted by six different MHC class II molecules: I-Ab, I-A(d), I-E(d), hybrid I-A beta dE alpha, I-Ak, and I-Ek. Side by side comparisons revealed in all cases that freshly isolated LC were superior to cultured mature LC in their ability to process native proteins. With some hybridomas, however, we found a considerable degree of processing by populations of cultured LC at high doses of Ag or Ag-presenting cells. This activity, however, did not correlate with the MHC haplotype. Direct comparison over wide ranges of DC doses or Ag doses showed that it was always less than that of corresponding fresh immature LC. Immunoperoxidase staining of cytospins and flow cytometry with mAb In1 disclosed a small (20% maximum) subset of cultured LC expressing the MHC class II-associated invariant chain, indicating ongoing biosynthesis of this molecule and, thus, incomplete maturation of these LC. Therefore, the residual processing activity observed in populations of mature DC may be explained by small subpopulations of incompletely matured DC.

Animals↗

PubMed1995