Biomedical subjects

S Schuster

Publications and source records attributed to S Schuster.

At least 37 records · Page 2Linked to original sources

PubMed2000

Cellular information transfer regarded from a stoichiometry and control analysis perspective.

Metabolic control analysis (MCA) allows one to formalize important aspects of information processing in living cells. For example, information processing via multi-level enzyme cascades can be quantified in terms of the response coefficient of a cellular target to a signal. In many situations, control and response coefficients cannot be determined exactly for all enzymes involved, owing to difficulties in 'observing' all enzymes experimentally. Here, we review a number of qualitative approaches that were developed to cope with such situations. The usefulness of the concept of null-space of the stoichiometry matrix for analysing the structure of intracellular signaling networks is discussed. It is shown that signal transduction operates very efficiently when the network structure is such that the null-space matrix can be block-diagonalized (which may or may not imply that the network consists of several disconnected parts) and some enzymes have low elasticities to their substrates.

Kinetics↗

PubMed2000

A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks.

A set of linear pathways often does not capture the full range of behaviors of a metabolic network. The concept of 'elementary flux modes' provides a mathematical tool to define and comprehensively describe all metabolic routes that are both stoichiometrically and thermodynamically feasible for a group of enzymes. We have used this concept to analyze the interplay between the pentose phosphate pathway (PPP) and glycolysis. The set of elementary modes for this system involves conventional glycolysis, a futile cycle, all the modes of PPP function described in biochemistry textbooks, and additional modes that are a priori equally entitled to pathway status. Applications include maximizing product yield in amino acid and antibiotic synthesis, reconstruction and consistency checks of metabolism from genome data, analysis of enzyme deficiencies, and drug target identification in metabolic networks.

Algorithms↗

PubMed2000

Soluble interleukin-2 receptor concentration as a biochemical indicator for acute graft-versus-host disease after allogeneic bone marrow transplantation.

When interleukin-2 (IL-2) binds to the IL-2 receptor (IL2-R) on activated T cells, a soluble portion of the receptor (sIL2-R) is released. After allogeneic bone marrow transplantation (BMT), the serum concentration of sIL2-R may, therefore, be a useful surrogate marker for T cell activation that results in acute graft-versus-host disease (aGVHD). To determine if the sIL2-R concentration is a useful marker to help establish a diagnosis of aGVHD, serial sIL2-R concentrations were measured weekly for 4 weeks in 43 patients after allogeneic BMT. Grafts were from HLA-matched siblings (n = 33), 5/6 HLA-matched siblings (n = 3) or matched unrelated donors (n = 7). GVHD prophylaxis included cyclosporine A (CSA)/methotrexate (MTX) (n = 25), solumedrol/CSA (n = 15), or T cell depletion (n = 3). Twenty-three patients developed aGVHD (Grade I, 7; Grade II, 12; Grade III, 4) a median of 28 days after transplant. There was a significant association between a clinical diagnosis of aGVHD and an increase in the sIL2-R concentration (p < 0.001). The mean percent increase (+/-SE) over baseline for patients with a clinical diagnosis of aGVHD was 294% (+/-57%) by week 2 (n = 12), 431% (+/-116%) by week 3 (n = 14), and 650% (+/-315%) by week 4 (n = 9) after BMT. For each 100% increase over baseline, the likelihood of having aGVHD increased by 18%. Six of 20 patients without aGVHD became critically ill and exhibited marked increases in sIL2-R concentrations, similar to patients with a clinical diagnosis of aGVHD who never became critically ill. Fourteen patients without aGVHD who did not become critically ill exhibited negligible increases of sIL2-R in 2- to 4-week period after BMT. These data suggest that serial measurements sIL2-R concentration are helpful in establishing the diagnosis of aGVHD, but are not useful in the most acutely ill patients.

Acute Disease↗

PubMed2000

Changes in electric organ discharge after pausing the electromotor system of Gymnotus carapo.

During their entire lives, weakly electric fish produce an uninterrupted train of discharges to electrolocate objects and to communicate. In an attempt to learn about activity-dependent processes that might be involved in this ability, the continuous train of discharges of intact Gymnotus carapo was experimentally interrupted to investigate how this pausing affects post-pause electric organ discharges. In particular, an analysis was conducted of how the amplitude and relative timing of the three major deflections of the complex discharge change over the course of the first 1000 post-pause discharges. The dependence of these variables on the duration of the preceding pause and on water temperature is analysed. In addition, pause-induced small reverberations at the end of the discharge are described. Common to all amplitude changes is a fast initial decrease in amplitude with a slow recovery phase; amplitude changes scale with the duration of the preceding pause and are independent of the interdischarge interval. The absence of changes in the postsynaptic-potential-derived first phase of the discharge together with changes in the amplitude ratio of the third and fourth deflections suggest that the amplitude changes are mainly due to pause-induced changes in the inner resistance of the electric organ. A model is formulated that approximates the pattern of amplitude changes. The post-pause changes described here may provide a new way to test current models of complex discharge generation in Gymnotus carapo and illustrate the speed at which changes of an electric organ discharge can take place.

Animals↗

PubMed1999

Pathway alignment: application to the comparative analysis of glycolytic enzymes.

Comparative analysis of metabolic pathways in different genomes yields important information on their evolution, on pharmacological targets and on biotechnological applications. In this study on glycolysis, three alternative ways of comparing biochemical pathways are combined: (1) analysis and comparison of biochemical data, (2) pathway analysis based on the concept of elementary modes, and (3) a comparative genome analysis of 17 completely sequenced genomes. The analysis reveals a surprising plasticity of the glycolytic pathway. Isoenzymes in different species are identified and compared; deviations from the textbook standard are detailed. Several potential pharmacological targets and by-passes (such as the Entner-Doudoroff pathway) to glycolysis are examined and compared in the different species. Archaean, bacterial and parasite specific adaptations are identified and described.

Enzymes↗

PubMed1999

Comparison of primary angioplasty with conservative therapy in patients with acute myocardial infarction and contraindications for thrombolytic therapy. Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Study Group.

The benefit of primary angioplasty in patients with acute myocardial infarction (AMI) and contraindications for thrombolysis compared to a conservative regimen is still unclear. Out of 5,869 patients with AMI registered by the MITRA trial, 337 (5.7%) patients had at least one strong contraindication for thrombolytic therapy. Out of these 337 patients 46 (13.6%) were treated with primary angioplasty and 276 (86.4%) were treated conservatively. Patients treated conservatively were older (70 years vs. 60 years; P=0.001), had a higher rate of a history with chronic heart failure (14.8% vs. 4.4%; P=0.053), a higher heart rate at admission (86 beats/min vs. 74 beats/min; P=0.001), and a higher prevalence of diabetes mellitus (27.1% vs. 12.8%; P=0.056). Patients treated with primary angioplasty received more often aspirin (91.3% vs. 74.6%; P=0.012), beta-blockers (60.9% vs. 46.1%; P = 0.062), angiotensin converting enzyme (ACE) inhibitors (71.7% vs. 44%; P=0.001), and the so-called optimal adjunctive medication (54.4% vs. 32.3%; P=0.004). Hospital mortality was significantly lower in patients who received primary angioplasty (univariate: 2.2% vs. 24.7%; P=0.001; multivariate: OR=0.46; P=0.0230). In patients with AMI and contraindications for thrombolytic therapy, primary angioplasty was associated with a significantly lower mortality compared to conservative treatment. Therefore, hospitals without the facilities to perform primary angioplasty should try to refer such patients to centers with the facilities for such a service, if this is possible in an acceptable time.

Aged↗

PubMed1999

Differences in patients with acute myocardial infarction treated with primary angioplasty or thrombolytic therapy. Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Study Group.

BACKGROUND: Little is known about the differences in patients with acute myocardial infarction (AMI) treated with primary angioplasty or intravenous thrombolysis in clinical practice. METHODS: In all, 5,906 patients with AMI were registered by the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) study. Of these, 491 (8.3%) patients were treated with primary angioplasty and 2,817 (47.7%) with intravenous thrombolysis. RESULTS: There were only minor differences in baseline characteristics between the two groups. Prehospital delay time (median) was longer in the angioplasty group than in the thrombolysis group (161 vs. 120, p = 0.001), as was door-to-treatment time (88 vs. 30 min; p = 0.001). Patients treated with primary angioplasty more often had contraindications for thrombolytic therapy (12.9 vs. 6%, p = 0.001) and received beta blockers (65 vs. 58.1%, p = 0.004), heparin (98.2 vs. 91.6%, p = 0.001), angiotensin-converting enzyme (ACE) inhibitors (64.8 vs. 50%, p = 0.001) and "optimal" concomitant medication (56.4 vs. 42.9%, p = 0.001) more often. Univariate analysis showed a significant lower incidence of heart failure (5.3 vs. 16.5%, p = 0.001), postinfarct angina (7.3 vs. 16.4%, p = 0.001), in-hospital death (7.9 vs. 11.7%, p = 0.015) and the combined end point (21.6 vs. 40.3%, p = 0.001) in these patients. Stepwise logistic regression analysis revealed optimal concomitant medication [odds ratio (OR) = 0.94, 95% confidence interval (CI): 0.89-0.98) and the type of revascularization (OR = 0.65, 95% CI: 0.58-0.73) to be associated with a significant reduction in the incidence of the combined end point. Similar results were obtained in all predefined subgroups. CONCLUSIONS: In clinical practice, patients treated with primary angioplasty are more often treated with beta blockers and ACE inhibitors than patients treated with intravenous thrombolysis. Thus, the selection of patients and the type of revascularization contributes to the reduction in mortality, overt heart failure, and postinfarct angina in these patients.

Angioplasty, Balloon, Coronary↗

PubMed1999

Use and limitations of modular metabolic control analysis in medicine and biotechnology.

By Metabolic Control Analysis (MCA), it has been shown that control on flux is in most cases shared by several enzymes rather than concentrated on one "rate-limiting step." This analysis also allows the quantification of the control exerted by groups (modules) of enzymes. The modules may correspond to spatial compartments or to functional units. A brief outline of the modular approach to MCA is given. The criteria by which the system can be modularized and the concept of monofunctional unit are explained. Various studies in which control analysis was applied to biotechnological and medical issues are reviewed. In particular, MCA has turned out to be helpful in the assessment of the severity of enzyme deficiencies. Another application is the search for target enzymes or enzyme groups where pharmaceuticals can suppress the metabolism of pathogenic microorganisms most. In biotechnology, modular and "traditional" control analyses are valuable tools for choosing the most promising targets for genetic manipulation so as to increase a biosynthetic flux. As control coefficients are linear approximations, the effect of enhancing the activities of enzymes to a larger extent is often overestimated. Further limitations such as the restriction to stationary states, uncertainties due to spatial heterogeneities and the impact of experimental error are discussed.

Animals↗

PubMed1999

[Use of coronary angiography after acute myocardial infarction in Germany: a comparison of daily clinical practice with international guidelines. MITRA Study].

OBJECTIVES: Two third of patients with acute myocardial infarction are admitted to hospitals without cardiac catheterization facilities. Whether a postinfarction patient will undergo cardiac catheterization or not is more often decided by general physicians than by cardiologists. The purpose of this presentation is to investigate the determinants for decision making to use cardiac catheterization in patients after myocardial infarction. METHODS: MITRA is a prospective, multicenter registry, which enrolls all consecutive patients with acute Q wave infarction admitted to 54 hospitals in Southwestern Germany. During the pilot phase 949 consecutive survivors of acute myocardial infarction were included, and inhospital outcome as well as therapeutic strategies were registered. RESULTS: Only half of the patients underwent cardiac catheterization regardless of whether a catheterization facility was available or not. In 63% of the patients under 65 years of age coronary angiography was performed; however, every fourth patient with age above 70 years was transferred to an invasive therapeutic strategy. The percentage of male patients was twice a high in the invasive group, whereas patients with prior infarction, clinical signs of congestive heart failure, patients with moderately or severely impaired left ventricular function, and finally patients with a prehospital delay of more than 4 hours were more frequent in the conservative group. The following three parameters were calculated to be independent determinants of an invasive strategy: pathological stress ECG (OR: 2.8; CI: 1.80-4.60), patients < 70 years without stress ECG (OR: 2.18; CI: 1.5-3.18), and male gender (OR: 1.45: CI: 1.10-2.00). Independent factors of a conservative strategy were primary PTCA (OR: 0.2; CI: 0.09-0.46), prehospital delay > 4 hours (OR: 0.71; CI: 0.51-0.97), and the combination of age > 70 years and the absence of a stress ECG (OR: 0.78; CI: 0.55-1.11). CONCLUSIONS: In Germany, patients with acute myocardial infarction are less likely to undergo cardiac catheterization compared to patients in other Western countries (e.g. , the United States). Despite recommended guidelines, invasive strategies are more frequent in low risk groups (younger patients, male gender) than in postinfarction patients at high risk (severely impaired left ventricular function, clinical signs of congestive heart failure, the elderly).

Adult↗

PubMed1999

Daytime and nighttime differences in patterns of performance of primary angioplasty in the treatment of patients with acute myocardial infarction. Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) Study Group.

BACKGROUND: Concern exists regarding the results of primary angioplasty for acute myocardial infarction when the procedure is performed during night hours. METHODS AND RESULTS: Between June 1994 and January 1997, 491 patients with acute myocardial infarction who underwent primary angioplasty procedures were consecutive registered in the Maximal Individual Therapy in Acute Myocardial Infarction (MITRA) study. Three hundred seventy-eight patients (77%) were treated during the day and 113 (23%) at night. Baseline characteristics showed no major differences between the 2 groups. Prehospital delay time was 60 minutes shorter during the night (median value 180 minutes for day, 120 minutes for night, P =.005), and in-hospital time to treatment was 9 minutes longer (median value 85 minutes day, 94 minutes night, P =.037). Patients treated during the night more often received angiotensin-converting enzyme blockers (61.4% day, 76.1% night, P =.004) and the so-called optimal adjunctive therapy (54% day, 64.6% night, P =.045). There were no differences concerning clinical events between the 2 groups. Hospital mortality was 8.7% during the day and 5.3% during the night (univariate analysis P =.238; logistic regression P =.653). CONCLUSIONS: In a clinical setting, primary angioplasty for acute myocardial infarction can be performed safely during the night with a clinically insignificant prolongation of in-hospital time to reperfusion compared with practice during the day.

Aged↗

PubMed1999

Detection of elementary flux modes in biochemical networks: a promising tool for pathway analysis and metabolic engineering.

Rational metabolic engineering requires powerful theoretical methods such as pathway analysis, in which the topology of metabolic networks is considered. All metabolic capabilities in steady states are composed of elementary flux modes, which are minimal sets of enzymes that can each generate valid steady states. The modes of the fructose-2,6-bisphosphate cycle, the combined tricarboxylic-acid-glyoxylate-shunt system and tryptophan synthesis are used here for illustration. This approach can be used for many biotechnological applications such as increasing the yield of a product, channelling a product into desired pathways and in functional reconstruction from genomic data.

Biochemistry↗

PubMed1999

Modular control analysis of slipping enzymes.

A theory is developed that deals with the metabolic control exerted by enzymes that catalyze two or more, incompletely coupled reactions. The starting point is modular (top-down) metabolic control theory. Slipping enzymes are considered as modules with more than one independent flux. Control by the coupled reaction is distinguished quantitatively from control by the extent of slippage. This is achieved by appropriate linear transformation of fluxes or logarithms thereof. Different transformations are proposed and discussed. Our examples include free-energy transducing proton pumps and the Na+, K+-ATPase. It is shown that control coefficients can be calculated on the basis of a description of slipping enzymes in terms of linear non-equilibrium thermodynamics.

Catalysis↗

PubMed1999

Autologous stem-cell transplant after conventional dose adjuvant chemotherapy for high-risk breast cancer: impact on the delivery of local-regional radiation therapy.

BACKGROUND: High-dose chemotherapy with autologous stem-cell transplantation is used increasingly in the treatment of poor-prognosis primary breast cancer. Because these patients may be cured with standard multimodality therapy, it is important to address both the efficacy of transplantation, and its effect on the delivery of standard treatments including local radiation therapy. PATIENTS AND METHODS: Patients with high risk primary breast cancer were treated with high-dose cyclophosphamide and thiotepa and stem-cell transplant following surgery and conventional-dose adjuvant chemotherapy. Outcome, including sites of failure and delivery of local radiation therapy, was assessed for 103 patients. RESULTS: Overall and disease-free survival rates at 18 months were 83% (+/- 4%) and 77% (+/- 4%) respectively. Twenty patients (19.4%) received radiation therapy prior to transplant. Of the remaining 83, 77 received radiation therapy after transplant. Overall, 5 (19.2%) of 26 first sites of recurrence were local alone. For patients receiving radiation prior to transplant, 3 of 7 (43%, 95% CI: 6%-80%) sites of first recurrence were local, while 2 of 19 (10.5%, 95% CI: 0%-24.5%) sites of first recurrence were local alone in patients receiving post-transplant radiation or no radiation. CONCLUSION: Transplantation does not appear to significantly compromise the delivery or outcome of local radiation therapy for primary breast cancer.

Adult↗

PubMed1999

Rituximab (anti-CD20 monoclonal antibody) therapy for progressive intermediate-grade non-Hodgkin's lymphoma after high-dose therapy and autologous peripheral stem cell transplantation.

We evaluated the response and toxicity of rituximab in the setting of progressive intermediate grade non-Hodgkin's lymphoma (NHL) after autologous peripheral stem cell transplantation (PSCT). Seven patients with a median age of 59 years (45-62), ECOG performance status 0-1, and CD20-positive diffuse large cell lymphoma with progression after PSCT were treated. All patients initially received 4-weekly infusions of rituximab (375 mg/m2). The maximum response was three CR and four PR. Median progression-free survival was 197 days (range 60-282). With a median follow-up of 204 (115-299) days, the patients' disease status is classified as two CR, one PR, and four PD. Four of five patients with ECOG performance status of 1 prior to treatment showed improvement to status 0 after treatment with rituximab. While follow-up is short, these results suggest that rituximab has significant activity in intermediate-grade non-Hodgkin's lymphoma that has relapsed after PSCT.

Antibodies, Monoclonal↗

PubMed1999

METATOOL: for studying metabolic networks.

MOTIVATION: To reconstruct metabolic pathways from biochemical and/or genome sequence data, the stoichiometric and thermodynamic feasibility of the pathways has to be tested. This is achieved by characterizing the admissible region of flux distributions in steady state. This region is spanned by what can be called a convex basis. The concept of 'elementary flux modes' provides a mathematical tool to define all metabolic routes that are feasible in a given metabolic network. In addition, we define 'enzyme subsets' to be groups of enzymes that operate together in fixed flux proportions in all steady states of the system. RESULTS: Algorithms for computing the convex basis and elementary modes developed earlier are briefly reviewed. A newly developed algorithm for detecting all enzyme subsets in a given network is presented. All of these algorithms have been implemented in a novel computer program named METATOOL, whose features are outlined here. The algorithms are illustrated by an example taken from sugar metabolism. AVAILABILITY: METATOOL is available from ftp://bmsdarwin.brookes.ac. uk/pub/software/ibmpc/metatool. SUPPLEMENTARY INFORMATION: http://www. biologie.hu-berlin.de/biophysics/Theory/tpfeiffer/metatoo l.html

Algorithms↗

PubMed1999

[Lifestyle, living conditions and health status--a cross-sectional study of the Saxon population in the period 1993 to 1994].

The aim of this cross-sectional study was to record the living conditions, lifestyle variables and health status in a part of the population of Saxony and to examine statistical relationships between the three categories. The interview by post took place from March 1993 to August 1994. The sample consisted of 602 participants, i.e. a return of 52.3%. The survey proved conditionally representative for the population of Saxony. Statistical methods used were Chi2 test, H test, Spearman correlation and multiple regression procedures. Males and females showed clear differences in their lifestyles and in the state of health. It was found that the lifestyle was associated with age. The following variables were significantly associated with the subjective health status: sex, daily routine, number of negative life events, utilisation of preventive measures, contentment, age, and domicile. Significant connections were found between the objective health status (number of chronic diseases) and the variables: utilisation of preventive measures, number of negative life events, employment, daily routine, smoking, alcohol consumption, contentment, and age. In the statistical relationship the primary health status had the most distinct influence on the lifestyle and this covered the influence of lifestyle on health status.

Adolescent↗

PubMed1999

Primary angioplasty in acute myocardial infarction: differences between referred patients and those treated in hospitals with on-site facilities?

BACKGROUND: Primary angioplasty for acute myocardial infarction (AMI) can only be performed in a limited number of centers. Therefore, some patients will be referred for this procedure. DESIGN: We analyzed the data of the prospective observational MITRA trial, which took place at 54 hospitals in southwest Germany, to describe current practices and outcomes in referred patients compared to patients treated on-site. RESULTS: Out of 491 patients treated with primary angioplasty, 63 (12.8%) were referred. Out of 46 hospitals without facilities to perform primary angioplasty, 29 (63%) never referred patients. Referred patients were less often male (60.3% versus 75.9%; p = 0.013), suffered more often from anterior wall infarction (62.9% versus 45.8%; p = 0.014), and more often had absolute contraindications against thrombolysis (11.1% versus 2.8%; p = 0.006). In-hospital time to treatment was 80 minutes in patients treated on-site compared to 190 minutes in referred patients (p = 0.001). There was a non-significant difference of in-hospital mortality between the two groups (11.1% for referred versus 7.5% on-site; p = 0.319). Referred patients had a higher hospital morbidity as expressed by a higher proportion of post-infarction angina (28.6% versus 4.2%; p = 0.001), a more frequent need for urgent revascularization (43.8% versus 16.4%; p = 0.001) and a higher proportion of advanced heart failure (11.1% versus 4.4%; p = 0.062). CONCLUSIONS: Referral of patients with AMI for primary angioplasty is used only in a minority of hospitals. The referred patients represent a selected, more ill subgroup, resulting in a higher hospital morbidity compared to patients treated on-site. Continuous efforts should be undertaken to decrease the time delay from admission at the initial hospital to the beginning of revascularization.

Acute Disease↗

PubMed1998

Mitochondria as an important factor in the maintenance of constant amplitudes of cytosolic calcium oscillations.

Theoretical models of intracellular calcium oscillations have hitherto focused on the endoplasmic reticulum (ER) as an internal calcium store. These models reproduced the large variability in oscillation frequency observed experimentally. In the present contribution, we extend our earlier model [Marhl et al., Biophys. Chem., 63 (1997) 221] by including, in addition to the ER, mitochondria as calcium stores. Simple plausible rate laws are used for the calcium uptake into, and release from, the mitochondria. It is demonstrated with the help of this extended model that mitochondria are likely to act in favour of frequency encoding by enabling the maintenance of fairly constant amplitudes over wide ranges of frequency.

Journal Article↗