Showing papers by "University of Freiburg published in 1992"

Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo.

Abstract: Clinical and experimental studies suggest that angiogenesis is a prerequisite for solid tumour growth. Several growth factors with mitogenic or chemotactic activity for endothelial cells in vitro have been described, but it is not known whether these mediate tumour vascularization in vivo. Glioblastoma, the most common and most malignant brain tumour in humans, is distinguished from astrocytoma by the presence of necroses and vascular proliferations. Here we show that expression of an endothelial cell-specific mitogen, vascular endothelial growth factor (VEGF), is induced in astrocytoma cells but is dramatically upregulated in two apparently different subsets of glioblastoma cells. The high-affinity tyrosine kinase receptor for VEGF, flt, although not expressed in normal brain endothelium, is upregulated in tumour endothelial cells in vivo. These observations strongly support the concept that tumour angiogenesis is regulated by paracrine mechanisms and identify VEGF as a potential tumour angiogenesis factor in vivo.

Alterations of skeletal muscle in chronic heart failure.

Abstract: BACKGROUNDThe present study was designed to define the prevalence and characteristics of skeletal muscle alterations in patients with chronic heart failure (CHF) and their relation to exercise capacity.METHODS AND RESULTSThe ultrastructure of skeletal muscle was analyzed by ultrastructural morphometry in 57 patients with CHF and 18 healthy controls. The volume density of mitochondria (Vvm) and the surface density (Svmc) of mitochondrial cristae were evaluated as a structural correlate of oxidative capacity of skeletal muscle. Vvm and Svmc were reduced by approximately 20% in patients with severe CHF irrespective of age and etiology. The cytochrome oxidase activity in mitochondria as determined by cytochemistry and subsequent morphometry in a subset of patients (n = 10) was significantly decreased in heart failure (p less than 0.01). The capillary length density of skeletal muscle was reduced in CHF (n = 12, p less than 0.05), and the fiber type distribution was shifted to type II fibers (n = 15, p less th...

Endothelial function in chronic congestive heart failure

Abstract: There is evidence that the endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. The hypothesis that an impairment of this mechanism is involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF) was tested. Acetylcholine and N-monomethyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine, were infused in the brachial artery of healthy volunteer subjects (controls) and patients with severe CHF. The radial artery diameter was determined by a high-precision A-mode ultrasound device, using a 10 MHz probe. Forearm blood flow was calculated from vessel diameter and blood flow velocity measured simultaneously by Doppler. The blood flow response to acetylcholine was blunted in patients with CHF compared with that in control subjects. In contrast, the decrease in blood flow induced by L-NMMA was exaggerated in CHF, and the blood flow response to nitroglycerin was preserved. The changes in radial artery diameter induced by acetylcholine and L-NMMA were not significant in control subjects and CHF patients, but dilation of the radial artery by nitroglycerin was significantly reduced in CHF. The results demonstrate an impaired endothelium-dependent dilation of forearm resistance vessels in CHF, suggesting a reduced release of nitric oxide on stimulation. In contrast, the basal release of nitric oxide from endothelium of forearm resistance vessels is preserved or may even be enhanced, and may play an important compensatory role in chronic CHF by antagonizing neurohumoral vasoconstrictor forces in CHF.

A bootstrap resampling procedure for model building: Application to the cox regression model

Abstract: A common problem in the statistical analysis of clinical studies is the selection of those variables in the framework of a regression model which might influence the outcome variable. Stepwise methods have been available for a long time, but as with many other possible strategies, there is a lot of criticism of their use. Investigations of the stability of a selected model are often called for, but usually are not carried out in a systematic way. Since analytical approaches are extremely difficult, data-dependent methods might be an useful alternative. Based on a bootstrap resampling procedure, Chen and George investigated the stability of a stepwise selection procedure in the framework of the Cox proportional hazard regression model. We extend their proposal and develop a bootstrap-model selection procedure, combining the bootstrap method with existing selection techniques such as stepwise methods. We illustrate the proposed strategy in the process of model building by using data from two cancer clinical trials featuring two different situations commonly arising in clinical research. In a brain tumour study the adjustment for covariates in an overall treatment comparison is of primary interest calling for the selection of even 'mild' effects. In a prostate cancer study we concentrate on the analysis of treatment-covariate interactions demanding that only 'strong' effects should be selected. Both variants of the strategy will be demonstrated analysing the clinical trials with a Cox model, but they can be applied in other types of regression with obvious and straightforward modifications.

Tumor necrosis factor alpha

Abstract: TNF-alpha (Cachectin) is a cytokine (tissue hormone) synthesized and secreted as a trimeric polypeptide; major producers are the cells of the RES after stimulation, e.g. by endotoxin. Its synthesis is strictly regulated. TNF elicits a great number of cell-specific responses. IL-1 and probably additional mediators cooperate in these effects. TNF is instrumental not only in the pathogenesis of inflammation, infections and some cell injuries, but also in the unspecific immune response, tumor toxicity and tissue homeostasis. TNF binding to specific receptors on cell surfaces initiates of secondary intracellular signals that, in turn, mediate the metabolic responses of the target cells. Pharmacological intervention may be envisaged at the level of synthesis (glucocorticoids, anti-oxidants) or interaction of the cytokine with its receptors.

The detector simulation program for the OPAL experiment at LEP

Abstract: The Monte Carlo program for the OPAL experiment at the LEP ee collider is described. This program is based on the GEANT simulation package. The general organization of the program is outlined, and a description is given of the techniques used for simulating the various subdetectors of OPAL. The performance of the program is illustrated by comparisons with recent data recorded by OPAL at LEP. (Submitted to Nucl. Instr. and Meth.) School of Physics and Space Research, University of Birmingham, Birmingham, B15 2TT, UK Dipartimento di Fisica dell' Universit a di Bologna and INFN, Bologna, 40126, Italy CNAF-INFN, Bologna, Italy Physikalisches Institut, Universitat Bonn, D-5300 Bonn 1, FRG Department of Physics, University of California, Riverside, CA 92521 USA Cavendish Laboratory, Cambridge, CB3 0HE, UK Carleton University, Dept of Physics, Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada Centre for Research in Particle Physics, Carleton University, Ottawa, Ontario K1S 5B6, Canada CERN, European Organisation for Particle Physics, 1211 Geneva 23, Switzerland Enrico Fermi Institute and Department of Physics, University of Chicago, Chicago Illinois 60637, USA Fakult at f ur Physik, Albert Ludwigs Universitat, D-7800 Freiburg, FRG Universitat Hamburg/DESY, II Inst. f ur Experimental Physik, 2000 Hamburg 52, FRG Physikalisches Institut, Universitat Heidelberg, Heidelberg, FRG Queen Mary and West eld College, University of London, London, E1 4NS, UK University College London, London, WC1E 6BT, UK Department of Physics, Schuster Laboratory, The University, Manchester, M13 9PL, UK Department of Physics and Astronomy, University of Maryland, College Park, Maryland 20742, USA Laboratoire de Physique Nucl eaire, Universit e de Montr eal, Montr eal, Quebec, H3C 3J7, Canada Rutherford Appleton Laboratory, Chilton, Didcot, Oxfordshire, OX11 0QX, UK DPhPE, CEN Saclay, F-91191 Gif-sur-Yvette, France International Centre for Elementary Particle Physics, University of Tokyo, Tokyo 113, Japan Brunel University, Uxbridge, Middlesex, UB8 3PH UK Nuclear Physics Department, Weizmann Institute of Science, Rehovot, 76100, Israel Present address: EPFL, Lausanne, Switzerland Present address: Applied Silicon Inc, Ottawa, Canada Present address: Rutherford Appleton Laboratory, Chilton, Didcot, Oxfordshire, OX11 0QX, UK On leave from Birmingham University, Birmingham B15 2TT, UK Present address: Culham Laboratory, Culham, Oxfordshire, UK Present address: Meiji Gakuin University, Yokohama 244, Japan

Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed.

Abstract: We investigated the mechanisms that are responsible for the basal release of endothelium-derived relaxing factor (EDRF), which is likely to be identical with nitric oxide, in the intact coronary circulation. The increase in cGMP content of platelets passing through the coronary bed of the isolated rabbit heart was used as an index of EDRF release. Platelet cGMP content after passage through the heart under control conditions (flow rate of 20 ml/min) amounted to 0.50 +/- 0.10 pmol/mg protein. Inhibition of endothelial nitric oxide synthesis by 30 microM NG-nitro-L-arginine (L-NNA) reduced this amount by more than 60%. Increasing flow rate from 20 ml/min to 40 and 60 ml/min led to flow-dependent dilation as reflected by the subsequent drop in perfusion pressure after an initial rise. The flow-dependent dilation was associated with a significant increase in the normalized platelet cGMP content. L-NNA abolished completely both the flow-dependent dilation and the increase in platelet cGMP content. Increasing shear stress by a strong vasoconstriction (1 nM endothelin-1) at constant flow was also accompanied by a 2.5-fold increase in platelet cGMP content. To investigate whether mechanical forces applied to the vascular wall by the myocardial contraction cycle were also a stimulus for EDRF release, cardiac arrest was induced by a continuous infusion of mepivacaine (final concentration, 0.02%). Under these conditions, a decrease in platelet cGMP content comparable to that after nitric oxide synthesis inhibition was observed in the arrested heart.(ABSTRACT TRUNCATED AT 250 WORDS)

High-dose UVA1 therapy in the treatment of patients with atopic dermatitis.

Abstract: Background: Besides glucocorticosteroids, there is currently no known effective therapy for patients with acute atopic dermatitis. Objective: The therapeutic effectiveness of high-dose UVA1 irradiation in the management of patients with acute exacerbation of atopic dermatitis was examined. Methods: Patients in the high-dose UVA1 group ( n =15) were irradiated with 130 joules/ cm 2 UVA1; the control group ( n =10) was treated with UVA-UVB therapy in a minimal erythema dose-dependent manner (total number of treatments 15). Results: High-dose UVA1 irradiation was found to induce a significant clinical improvement of atopic dermatitis (p Conclusion: These studies indicate that high-dose UVA1 irradiation may represent a novel phototherapeutic modality for the treatment of patients with an acute exacerbation of atopic dermatitis.

Growth control of cultured microglia

Abstract: Microglia, the resident macrophages of the brain, typically react to injuries or chronic diseases with proliferation and expression of differentiated features, such as production of cytokines associated with inflammatory events. Regulation and control of microglial cytokine expression, therefore, is a major focus of scientific interest. It has been shown that GMCSF and Il-3 are potent mitogens for microglia. Moreover, Il-3 and other cytokines are products of microglia. It is shown here that interleukin-1 (Il-1) as well as tumor necrosis factor (TNF alpha) increased microglial proliferation in mixed astrocyte-microglial cultures but had no mitogenic effects on isolated microglia. Lipopolysaccharide (LPS), the bacterial endotoxin, irreversibly inhibited microglial cell division in both mixed astrocyte-microglial cultures and in isolated microglial cultures. By contrast, the corticosteroids hydrocortisone and aldosterone and the synthetic glucocorticoid dexamethasone reversibly inhibited microglial proliferation. They also antagonized the stimulatory effects of Il-3 and granulocyte macrophage colony-stimulating factor (GMCSF). Estradiol and progesterone had no significant effects on mixed cultures but inhibited microglial proliferation in isolated cultures. Conditioned media from mixed cultures, isolated cultures, from the WEHI-2B cell line, or from fresh (serum-supplemented) media stimulated microglial proliferation to various extents. In summary, cytokine-mediated microglial proliferation can be down-regulated by a variety of steroid hormones. Along with their unimpaired access to brain cells in general, corticosteroids likely maintain an inhibitory tonus on microglial proliferation. It is hypothesized that this inhibition is overcome locally and temporally in brain injury and repair.

Characteristics of "anti" saccades in man.

Abstract: Four subjects — all made large numbers of Express saccades in the normal gap task — were instructed to make saccades in the direction opposite to the side where a visual stimulus appeared (“anti” task). Gap and overlap trials were used. Saccadic reaction time (SRT), velocity and amplitude of the corresponding eye movements were analysed and compared to those of saccades made in the normal task. The velocity of “anti saccades” was found to be slightly (up to 15%) but significantly slower in two subjects. The distributions of SRTs in normal gap tasks show a small group of anticipatory saccades (with SRT below 80 ms and slower velocities) followed by a group of saccades with fast reaction times between 80 ms and 120 ms (Express saccades) followed by another large group ranging up to 180 ms (regular saccades). In the gap anti task there are anticipatory saccades and saccades with SRTs above 100 ms; Express saccades are missing. The distribution of SRTs obtained in the overlap anti task was unimodal with a mean value of 231 ms as compared to 216 ms in the normal task. The introduction of the gap therefore clearly decreases the reaction times of the anti saccades. Control experiments show that the delay of anti saccades is not due to an interhemispheric transfer time but must be attributed to the saccade generating system taking more time to program a saccade to a position where no visual stimulus appears. These data are discussed as providing further evidence for the existence of a reflex-like pathway connecting the retina to the oculomotor nuclei mediating the Express saccade.

Regulation of bipedal stance: dependency on “load” receptors

Abstract: According to recent observations, influence of body load has to be taken into account for the neuronal control of upright stance in addition to the systems known to be involved in this regulation (e.g. afferent input from vestibular canals, visual and muscle stretch receptors). The modulation of compensatory leg muscle electromyographic (EMG) responses observed during horizontal body posture indicates the existence of a receptor system which responds to loading of the body against the supporting platform. This receptor should be located within the extensor muscles because a compensatory EMG response and a loading effect on this response was only present following translational, but not rotational impulses. As the EMG responses were identical to those obtained during upright stance, it is argued that these load receptors activate postural reflexes. According to recent observations in the spinal cat, this afferent input probably arises from Golgi tendon organs and represents a newly discovered function of these receptors in the regulation of stance and gait.

Hepatocyte heterogeneity in the metabolism of amino acids and ammonia.

Abstract: With respect to hepatocyte heterogeneity in ammonia and amino acid metabolism, two different patterns of sublobular gene expression are distinguished: 'gradient-type' and 'strict- or compartment-type' zonation. An example for strict-type zonation is the reciprocal distribution of carbamoylphosphate synthase and glutamine synthase in the liver lobule. The mechanisms underlying the different sublobular gene expressions are not yet settled but may involve the development of hepatic architecture, innervation, blood-borne hormonal and metabolic factors. The periportal zone is characterized by a high capacity for uptake and catabolism of amino acids (except glutamate and aspartate) as well as for urea synthesis and gluconeogenesis. On the other hand, glutamine synthesis, ornithine transamination and the uptake of vascular glutamate, aspartate, malate and alpha-ketoglutarate are restricted to a small perivenous hepatocyte population. Accordingly, in the intact liver lobule the major pathways for ammonia detoxication, urea and glutamine synthesis, are anatomically switched behind each other and represent in functional terms the sequence of the periportal low affinity system (urea synthesis) and a previous high affinity system (glutamine synthesis) for ammonia detoxication. Perivenous glutamine synthase-containing hepatocytes ('scavenger cells') act as a high affinity scavenger for the ammonia, which escapes the more upstream urea-synthesizing compartment. Periportal glutaminase acts as a pH- and hormone-modulated ammonia-amplifying system in the mitochondria of periportal hepatocytes. The activity of this amplifying system is one crucial determinant for flux through the urea cycle in view of the high Km (ammonia) of carbamoylphosphate synthase, the rate-controlling enzyme of the urea cycle. The structural and functional organization of glutamine and ammonia-metabolizing pathways in the liver lobule provides one basis for the understanding of a hepatic role in systemic acid base homeostasis. Urea synthesis is a major pathway for irreversible removal of metabolically generated bicarbonate. The lobular organization enables the adjustment of the urea cycle flux and accordingly the rate of irreversible hepatic bicarbonate elimination to the needs of the systemic acid base situation, without the threat of hyperammonemia.

Interleukin-8 and neutrophil activation in acute pancreatitis.

Abstract: It has been suggested that leucocytes play an important role in the pathogenesis of complicated pancreatitis. Indeed, increased plasma concentrations of neutrophil elastase as a marker of neutrophil activation could be detected in patients with a severe course of the disease. Recently, interleukin-8 (IL-8) has been described as a novel neutrophil activating peptide. To determine the role of IL-8 in acute pancreatitis we measured its serum concentrations by a specific enzyme-linked immunosorbent assay in 10 patients with acute pancreatitis daily during the first week of hospitalization. IL-8 levels were compared with plasma concentrations of neutrophil elastase and the clinical course of the disease. Three of the patients had uncomplicated pancreatitis, while seven showed various extrapancreatic complications. Patients with complicated pancreatitis had statistically significant (P less than 0.05) higher mean values of IL-8 (121 +/- 41 pg/ml-1 vs. 13 +/- 6 pg ml-1, mean +/- SEM) and neutrophil elastase (547 +/- 35 ng ml-1 vs. 250 +/- 20 ng ml-1) than patients with uncomplicated disease. There was a positive correlation (r = 0.52, P less than 0.0001) between IL-8 and neutrophil elastase in the lower concentration range of IL-8 (less than 100 pg ml-1). At IL-8 levels greater than 100 pg ml-1 neutrophil elastase was always greatly elevated; however, under these conditions the relationship between IL-8 and elastase was no longer linear. No measurable IL-8 concentrations were found when plasma elastase was less than 200 ng ml-1. During follow-up, initially elevated IL-8 concentrations decreased in correlation with clinical improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

From somites to vertebral column.

Abstract: We report on the development and differentiation of the somites with respect to vertebral column formation in avian and human embryos. The somites, which are made up of different compartments, establish a segmental pattern which becomes transferred to adjacent structures such as the peripheral nervous system and the vascular system. Each vertebra arises from three sclerotomic areas. The paired lateral ones give rise to the neural arches, the ribs and the pedicles of vertebrae, whereas the vertebral body and the intervening disc develop from the axially-located mesenchyme. The neural arches originate from the caudal half of one somite, whereas the vertebral body is made up of the adjacent parts of two somites. Interactions between notochord and axial mesenchyme are a prerequisite for the normal development of vertebral bodies and intervening discs. The neural arches form a frame for the neural tube and spinal ganglia. The boundary between head and vertebral column is located between the 5th and 6th somites. In the human embryo, proatlas, body of the atlas segment, and body of the axis fuse to form the axis.

Saccadic reaction times in patients with frontal and parietal lesions.

Abstract: The effect of unilateral circumscribed lesions in different areas of the frontal and parietal cortex on the distributions of saccadic reaction times (SRTs) was investigated in 32 patients under four stimulus conditions: (i) gap-random: a target light appeared 200 ms after extinction of a central fixation light randomly at 8 degrees either left or right; (ii) overlap-random: like (i), but the fixation light remained on ('overlap'); (iii) gap-simultaneous: two peripheral lights appeared simultaneously left and right 200 ms after the extinction of the fixation light, one predesignated by instruction as saccadic target; (iv) overlap-simultaneous: like (iii), but the fixation light remained on. Depending on SRT and condition and based on the data of control subjects, we evaluated the percentages of anticipatory (SRT: 0-90 ms), express (91-157 ms) and regular (158-400 ms) saccades, of time (> 400 ms) and direction errors as well as the mean latencies and the standard deviations. These data were compared across control subjects, frontal lobe patients with a lesion in the region of the frontal eye field (FEF), and frontal patients with a lesion outside the FEF, as well as across control subjects, parietal lobe patients with a lesion in the dorsolateral region, and parietal patients with a lesion outside the dorsolateral region. (i) Frontal patients with a lesion in the FEF region showed an increased percentage of express saccades (gap-random condition), especially with saccades directed towards the side of the lesion (ipsilateral). If fixation was not interrupted prior to target appearance (overlap-random), express saccades were largely suppressed, similar to normals. All patients with a frontal lesion, whether in the region of the FEF or not, showed a decreased percentage of contralateral anticipatory saccades (gap-simultaneous), whereas the percentages of direction and time errors were in the normal range, even if more than one stimulus was presented (e.g. overlap-simultaneous condition). (ii) Patients with dorsolateral parietal lesions showed decomposed SRT patterns (high SRT variability, increased percentages of time and direction errors, decreased percentages of express and anticipatory saccades). The decomposition had a contralateral preponderance and increased if more than one stimulus was visible beside the saccadic target. Our results suggest that FEF lesions impair mainly the volitional control over visually triggered express or reflex-like saccades if fixation is disrupted, whereas dorsolateral parietal lesions impair mainly the selection of the visual targets.

Photodissociation of water in the first absorption band: A prototype for dissociation on a repulsive potential energy surface

Abstract: The photodissociation of water in the first absorption band, H{sub 2}O(X) + {Dirac_h}{omega} {yields} H{sub 2}O(A{sup 1}B{sub 1}) {yields} H({sup 2}S) + OH({sup 2}II), is a prototype of fast and direct bond rupture in an excited electronic state. It has been investigated from several perspectives-absorption spectrum, final state distributions of the products, dissociation of vibrationally excited states, isotope effects, and emission spectroscopy. The availability of a calculated potential energy surface for the A state, including all three internal degrees of freedom, allows comparison of all experimental data with the results of rigorous quantum mechanical calculations without any fitting parameters or simplifying model assumptions. As the result of the confluence of ab initio electronic structure theory, dynamical theory, and experiment, water is probably the best studied and best understood polyatomic photodissociation system. In this article we review the joint experimental and theoretical advances which make water a unique system for studying molecular dynamics in excited electronic states. We focus our attention especially on the interrelation between the various perspectives and the correlation with the characteristic features of the upper-state potential energy surface. 80 refs., 14 figs.

Phase-dependent reversal of reflexly induced movements during human gait

Abstract: To investigate whether phase-dependent reversals in reflex responses on electromyography (EMG) are accompanied by movement reversals, a series of human volunteers were studied for their behavioural responses to sural nerve stimulation during running or walking on a treadmill. Low-intensity stimulation ( 2.5 x T) always gave rise to suppression of the ongoing activity. This resulted in a second type of movement reversal. During late stance and early swing the responses in TA were suppressive (i.e. below background activity) and related to ankle plantar flexion. In contrast, the responses during early and middle stance consisted of suppression in extensor activity (gastrocnemius medialis and soleus) and ankle dorsiflexion. The data are discussed in terms of a new hypothesis, which states that the responses to electrical stimulation of cutaneous nerves during locomotion do not correspond directly to corrections for stumbling following mechanical perturbations during the step cycle. Instead, the data invite a reinterpretation in terms of the opening and closing of reflex pathways, presumably by a central pattern generator for locomotion.

Spinodal decomposition in thin films of a polymer blend

Abstract: Spinodal decomposition in thin films of a blend of deuterated polystyrene and poly(styrene-co-4-bromostyrene) was studied with time-of-flight--elastic-recoil detection and light microscopy. We found different demixing behavior, depending on whether the films were prepared on the oxide layer of a silicon wafer or on a chromium-plated one. On the latter surface a bilayer of the two bulk phases is formed, whereas on the oxide layer a domain structure remains. The formation of the bilayer is ascribed to the complete wetting of each surface by the corresponding, preferentially adsorbed component.