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Showing papers by "University of Düsseldorf published in 1997"


Journal ArticleDOI
TL;DR: These low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases, which are termed ‘oxidative stress’.
Abstract: An imbalance between oxidants and antioxidants in favour of the oxidants, potentially leading to damage, is termed 'oxidative stress'. Oxidants are formed as a normal product of aerobic metabolism but can be produced at elevated rates under pathophysiological conditions. Antioxidant defense involves several strategies, both enzymatic and non-enzymatic. In the lipid phase, tocopherols and carotenes as well as oxy-carotenoids are of interest, as are vitamin A and ubiquinols. In the aqueous phase, there are ascorbate, glutathione and other compounds. In addition to the cytosol, the nuclear and mitochondrial matrices and extracellular fluids are protected. Overall, these low molecular mass antioxidant molecules add significantly to the defense provided by the enzymes superoxide dismutase, catalase and glutathione peroxidases.

4,485 citations


Journal ArticleDOI
TL;DR: In humans, the bioavailability of lycopene is greater from tomato paste than from fresh tomatoes, and only the AUC response for the cis-isomers was significantly higher after ingestion of tomato paste.

682 citations


Journal ArticleDOI
TL;DR: The results suggest that Efg1p has a dual role as a transcriptional activator and repressor, whose balanced activity is essential for yeast, pseudohyphal and hyphal morphogenesis of C.albicans.
Abstract: We identified a gene of the fungal pathogen Candida albicans, designated EFG1, whose high-level expression stimulates pseudohyphal morphogenesis in the yeast Saccharomyces cerevisiae. In a central region the deduced Efg1 protein is highly homologous to the StuA and Phd1/Sok2 proteins that regulate morphogenesis of Aspergillus nidulans and S. cerevisiae, respectively. The core of the conserved region is homologous to the basic helix-loop-helix (bHLH) motif of eukaryotic transcription factors, specifically to the human Myc and Max proteins. Fungal-specific residues in the bHLH domain include the substitution of an invariant glutamate, responsible for target (E-box) specificity, by a threonine residue. During hyphal induction EFG1 transcript levels decline to low levels; downregulation is effected at the level of transcriptional initiation as shown by a EFG1 promoter-LAC4 fusion. A strain carrying one disrupted EFG1 allele and one EFG1 allele under the control of the glucose-repressible PCK1 promoter forms rod-like, pseudohyphal cells, but is unable to form true hyphae on glucose-containing media. Overexpression of EFG1 in C. albicans leads to enhanced filamentous growth in the form of extended pseudohyphae in liquid and on solid media. The results suggest that Efg1p has a dual role as a transcriptional activator and repressor, whose balanced activity is essential for yeast, pseudohyphal and hyphal morphogenesis of C. albicans. Functional analogies between Efg1p and Myc are discussed.

605 citations


Journal ArticleDOI
TL;DR: Experiments with conditional uba2 mutants showed that Uba2p is required for Smt3p conjugation in vivo, and UBA2 and AOS1 are both essential genes, providing additional evidence that they act in a distinct pathway whose role in cell viability is to conjugate SmT3p to other proteins.
Abstract: SMT3 is an essential Saccharomyces cerevisiae gene encoding a 11.5 kDa protein similar to the mammalian ubiquitin-like protein SUMO-1. We have found that Smt3p, like SUMO-1 and ubiquitin, can be attached to other proteins post-translationally and have characterized the processes leading to the activation of the Smt3p C-terminus for conjugation. First, the SMT3 translation product is cleaved endoproteolytically to expose Gly98, the mature C-terminus. The presence of Gly98 is critical for Smt3p's abilities to be conjugated to protein substrates and to complement the lethality of a smt3Delta strain. Smt3p undergoes ATP-dependent activation by a novel heterodimeric enzyme consisting of Uba2p, a previously identified 71 kDa protein similar to the C-terminus of ubiquitin-activating enzymes (E1s), and Aos1p (activation of Smt3p), a 40 kDa protein similar to the N-terminus of E1s. Experiments with conditional uba2 mutants showed that Uba2p is required for Smt3p conjugation in vivo. Furthermore, UBA2 and AOS1 are both essential genes, providing additional evidence that they act in a distinct pathway whose role in cell viability is to conjugate Smt3p to other proteins.

541 citations


Journal ArticleDOI
TL;DR: The current understanding of cytotoxic versus cytoprotective effects of NO in mammalian cells is reviewed and the janus-faced properties of this important small molecule are highlighted.

512 citations


Journal ArticleDOI
TL;DR: The short-term application of tacrolimus ointment is effective in the treatment of atopic dermatitis, with the sensation of burning being the main side effect.
Abstract: Background Tacrolimus (FK 506) is an effective immunosuppressant drug for the prevention of rejection after organ transplantation, and preliminary studies suggest that topical application of tacrolimus is effective in the treatment of atopic dermatitis. Methods We conducted a randomized, double-blind, multicenter study that compared 0.03 percent, 0.1 percent, and 0.3 percent tacrolimus ointment with vehicle alone in patients with moderate-to-severe atopic dermatitis. The ointment was applied twice daily to a defined, symptomatic area of 200 to 1000 cm2 of skin for three weeks. The primary end point was the change in the summary score for erythema, edema, and pruritus between the first and last days of treatment. Results After three weeks of treatment, the median percentage decrease in the summary score for dermatitis on the trunk and extremities was 66.7 percent for the 54 patients receiving 0.03 percent tacrolimus, 83.3 percent for the 54 patients receiving 0.1 percent tacrolimus, 75.0 percent for the 51...

506 citations


Journal ArticleDOI
TL;DR: A novel function of GPx is demonstrated, and potentially of other selenoproteins containing selenocysteine or selenomethionine, in the GSH-dependent maintenance of a defense line against peroxynitrite-mediated oxidations, as a peroxlynitrite reductase.

477 citations


Journal ArticleDOI
TL;DR: The further characterization of this multigene family of hexose transporters should help to elucidate the role of transport in yeast sugar metabolism, and exhibit different affinities for their substrates.
Abstract: Transport across the plasma membrane is the first, obligatory step of hexose utilization. In yeast cells the uptake of hexoses is mediated by a large family of related transporter proteins. In baker's yeast Saccharomyces cerevisiae the genes of 20 different hexose transporter-related proteins have been identified. Six of these transmembrane proteins mediate the metabolically relevant uptake of glucose, fructose and mannose for growth, two others catalyze the transport of only small amounts of these sugars, one protein is a galactose transporter but also able to transport glucose, two transporters act as glucose sensors, two others are involved in the pleiotropic drug resistance process, and the functions of the remaining hexose transporter-related proteins are not yet known. The catabolic hexose transporters exhibit different affinities for their substrates, and expression of their corresponding genes is controlled by the glucose sensors according to the availability of carbon sources. In contrast, milk yeast Kluyveromyces lactis contains only a few different hexose transporters. Genes of other monosaccharide transporter-related proteins have been found in fission yeast Schizosaccharomyces pombe and in the xylose-fermenting yeast Pichia stipitis. However, the molecular genetics of hexose transport in many other yeasts remains to be established. The further characterization of this multigene family of hexose transporters should help to elucidate the role of transport in yeast sugar metabolism.

424 citations


Journal ArticleDOI
01 Sep 1997-Brain
TL;DR: It is concluded that the motor outputs in the unaffected hemisphere are significantly changed after stroke, including the unmasking of ipsilateral corticospinal projections, however, these pathways seem to be of little significance for recovery, as the existence of these responses was not correlated with clinical improvement.
Abstract: Motor evoked responses to focal transcranial magnetic stimulation were investigated over the unaffected hemisphere in 15 patients with hemiparesis after ischaemic stroke and compared with data from normal control subjects. Whereas responses to muscles ipsilateral to the stimulated hemisphere could only be elicited at maximal intensities in two out of 12 normal control subjects, such ipsilateral responses were recorded after stimulation of the unaffected hemisphere in patients with poor recovery after stroke at significantly lower thresholds, but not in patients with good recovery. These responses occurred with a somewhat longer (on average 6 ms) latency than the typical contralateral response. The duration of the silent period ipsilateral to stimulation of the unaffected hemisphere was longer than in control subjects. Also the contralateral threshold for the unaffected hemisphere was elevated in comparison with the control group. In one patient, who developed mirror movements after stroke, the ipsilateral threshold was exceptionally low and the latency of the ipsilateral response identical to that seen contralaterally. It is concluded that the motor outputs in the unaffected hemisphere are significantly changed after stroke, including the unmasking of ipsilateral corticospinal projections. However, these pathways seem to be of little significance for recovery, as the existence of these responses was not correlated with clinical improvement. The unaffected hemisphere after stroke shows plastic changes in motor output organization after a contralateral lesion.

416 citations


Journal ArticleDOI
TL;DR: The strength of the glucose repression signal correlated with the glucose consumption rates in the different strains, indicating that glucose transport limits the provision of a triggering signal rather then being directly involved in the triggering mechanism.
Abstract: In Saccharomyces cerevisiae, there are a large number of genes (HXT1-HXT17/SNF3/RGT2) encoding putative hexose transporters which, together with a galactose permease gene (GAL2), belong to a superfamily of monosaccharide facilitator genes. We have performed a systematic analysis of the HXT1-7 and GAL2 genes and their function in hexose transport. Glucose uptake was below the detection level in the hxt1-7 null strain growing on maltose. Determination of the kinetic parameters of individual hexose transporter-related proteins (Hxtp) expressed in the hxt null background revealed Hxt1p and Hxt3p as low-affinity transporters (Km(glucose) = 50-100 mM), Hxt2p and Hxt4p as moderately low in affinity (Km(glucose) about 10 mM), and Hxt6p, Hxt7p as well as Gal2p as high-affinity transporters (Km(glucosse) = 1-2 mM). However, Hxt2p kinetics in cells grown on low glucose concentrations showed a high-affinity (Km = 1.5 mM) and a low-affinity component (Km = 60 mM). Furthermore, we investigated the involvement of glucose transport in glucose signalling. Glucose repression of MAL2, SUC2 and GAL1 was not dependent on a specific transporter but, instead, the strength of the repression signal was dependent on the level of expression, the properties of the individual transporters and the kind of sugar transported. The strength of the glucose repression signal correlated with the glucose consumption rates in the different strains, indicating that glucose transport limits the provision of a triggering signal rather then being directly involved in the triggering mechanism.

401 citations


Journal ArticleDOI
TL;DR: The size of the ILPG was negatively correlated with age of commencement of musical training in keyboard players, supporting the hypothesis that the human motor cortex can exhibit functionally induced and long‐lasting structural adaptations.
Abstract: Recent studies in humans and nonhuman primates have shown that the functional organization of the human sensorimotor cortex changes following sensory stimulation or following the acquisition of motor skills. It is unknown whether functional plasticity in response to the acquisition of new motor skills and the continued performance of complicated bimanual movements for years is associated with structural changes in the organization of the motor cortex. Professional musicians, especially keyboard and string players, are a prototypical group for investigating these changes in the human brain. Using magnetic resonance images, we measured the length of the posterior wall of the precentral gyrus bordering the central sulcus (intrasulcal length of the precentral gyrus, ILPG) in horizontal sections through both hemispheres of right-handed keyboard players and of an age- and handedness-matched control group. Lacking a direct in vivo measurement of the primary motor cortex in humans, we assumed that the ILPG is a measure of the size of the primary motor cortex. Left-right asymmetry in the ILPG was analyzed and compared between both groups. Whereas controls exhibited a pronounced left-larger-than-right asymmetry, keyboard players had more symmetrical ILPG. The most pronounced differences in ILPG between keyboard players and controls were seen in the most dorsal part of the presumed cortical hand representation of both hemispheres. This was especially true in the nondominant right hemispheres. The size of the ILPG was negatively correlated with age of commencement of musical training in keyboard players, supporting our hypothesis that the human motor cortex can exhibit functionally induced and long-lasting structural adaptations.

Journal ArticleDOI
TL;DR: A model for the genomic alterations associated with meningioma progression is proposed on the basis of the most common aberrations identified in the various malignancy grades.
Abstract: Nineteen benign [World Health Organization (WHO) grade I; MI], 21 atypical (WHO grade II; MII), and 19 anaplastic (WHO grade III; MIII) sporadic meningiomas were screened for chromosomal imbalances by comparative genomic hybridization (CGH). These data were supplemented by molecular genetic analyses of selected chromosomal regions and genes. With increasing malignancy grade, a marked accumulation of genomic aberrations was observed; i.e., the numbers (mean +/- SEM) of total alterations detected per tumor were 2.9 +/- 0.7 for MI, 9.2 +/- 1.2 for MII, and 13.3 +/- 1.9 for MIII. The most frequent alteration detected in MI was loss on 22q (58%). In MII, aberrations most commonly identified were losses on 1p (76%), 22q (71%), 14q (43%), 18q (43%), 10 (38%), and 6q (33%), as well as gains on 20q (48%), 12q (43%), 15q (43%), 1q (33%), 9q (33%), and 17q (33%). In MIII, most of these alterations were found at similar frequencies. However, an increase in losses on 6q (53%), 10 (68%), and 14q (63%) was observed. In addition, 32% of MIII demonstrated loss on 9p. Homozygous deletions in the CDKN2A gene at 9p21 were found in 4 of 16 MIII (25%). Highly amplified DNA sequences were mapped to 12q13-q15 by CGH in 1 MII. Southern blot analysis of this tumor revealed amplification of CDK4 and MDM2. By CGH, DNA sequences from 17q were found to be amplified in 1 MII and 8 MIII, involving 17q23 in all cases. Despite the high frequency of chromosomal aberrations in the MII and MIII investigated, none of these tumors showed mutations in exons 5-8 of the TP53 gene. On the basis of the most common aberrations identified in the various malignancy grades, a model for the genomic alterations associated with meningioma progression is proposed.

Journal ArticleDOI
TL;DR: In this article, a geometrically based free-energy density functional unified the scaled-particle and Percus-Yevick theories for the hard-sphere fluid mixture.
Abstract: A geometrically based fundamental-measure free-energy density functional unified the scaled-particle and Percus-Yevick theories for the hard-sphere fluid mixture. It has been successfully applied to the description of simple ~‘‘atomic’’ ! three-dimensional ~3D! fluids in the bulk and in slitlike pores, and has been extended to molecular fluids. However, this functional was unsuitable for fluids in narrow cylindrical pores, and was inadequate for describing the solid. In this work we analyze the reason for these deficiencies, and show that, in fact, the fundamental-measure geometrically based theory provides a free-energy functional for 3D hard spheres with the correct properties of dimensional crossover and freezing. After a simple modification of the functional, as we propose, it retains all the favorable D53 properties of the original functional, yet gives reliable results even for situations of extreme confinements that reduce the effective dimensionality D drastically. The modified functional is accurate for hard spheres between narrow plates (D52), and inside narrow cylindrical pores ( D51), and it gives the exact excess free energy in the D50 limit ~a cavity that cannot hold more than one particle!. It predicts the ~vanishingly small! vacancy concentration of the solid, provides the fcc hard-sphere solid equation of state from closest packing to melting, and predicts the hard-sphere fluid-solid transition, all in excellent agreement with the simulations. @S1063-651X~97!07404-7#

Journal ArticleDOI
TL;DR: Investigating a possibly distinct cytokine and chemokine pattern that could explain the characteristic tissue eosinophilia in nasal polyps indicates that IL-5 plays a key role in the pathophysiology of eOSinophilic nasalpolyps and may be produced by eos inophils.
Abstract: Background: In most nasal polyps, tissue eosinophilia is a striking finding, the pathologic mechanism of which is not understood Objective: This study was performed to investigate a possibly distinct cytokine and chemokine pattern that could explain the characteristic tissue eosinophilia in nasal polyps Methods: Polyps from 23 patients and turbinate tissue from 18 control subjects were investigated The cytokine protein content (IL-1β, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, tumor necrosis factor-α, granulocyte-macrophage colony-stimulating factor, IL-1RA, RANTES, GRO-α) of tissue homogenates was measured by ELISA Immunohistochemistry was performed in selected samples to detect IL-5 + , major basic protein-positive, and EG2 + cells Results: IL-5 was detectable in only one sample of tissue from 18 control subjects but was found in 18 of 23 nasal polyps Immunohistochemistry revealed an abundant number of IL-5 + cells, of which 695% could be identified as eosinophils by morphology IL-6, IL-8, IL-10, tumor necrosis factor-α, GRO-α, and RANTES were detected in all specimens, without significant differences between groups ( p ≥005), whereas significantly higher concentrations of IL-1β and IL-1RA were found in turbinate mucosa ( p ≤005) IL-3 was not detectable; granulocyte-macrophage colony-stimulating factor could only occasionally be found Conclusion: This study indicates that IL-5 plays a key role in the pathophysiology of cosinophilic nasal polyps and may be produced by eosinophils

Journal ArticleDOI
TL;DR: In this article, the authors derived theoretical predictions for the learning theories and test these predictions by varying the information given to subjects, finding that some subjects imitate successful behavior if they have the necessary information; and if they imitate, markets are more competitive.
Abstract: This experiment was designed to test various learning theories in the context of a Cournot oligopoly. We derive theoretical predictions for the learning theories and test these predictions by varying the information given to subjects. The results show that some subjects imitate successful behavior if they have the necessary information; and if they imitate, markets are more competitive. Other subjects follow a best reply process. On the aggregate level we find that more information about demand and cost conditions yields less competitive behavior, while more information about the quantities and profits of other firms yields more competitive behavior.

Journal ArticleDOI
TL;DR: Findings from this laboratory confirm that NIDDM is associated with increased oxidative stress as assessed by plasma ROOHs and suggest that oxidative stress is an early stage in the disease pathology, which may contribute to the development of complications.
Abstract: Diabetes mellitus may be associated with increased lipid peroxidation which may contribute to long-term tissue damage. To test this hypothesis, we measured hydroperoxides (ROOHs) as well as α-tocopherol in plasma from healthy subjects and individuals with non-insulin-dependent diabetes mellitus (NIDDM) (n = 41 and 87, respectively). ROOHs were analysed using the ferrous oxidation with xylenol orange version II (FOX2) assay in conjunction with a specific ROOH reductant, triphenylphosphine. α-Tocopherol was analysed by HPLC with fluorimetric detection. NIDDM patients had lower cholesterol standardised α-tocopherol levels as compared to control subjects (3.3 ± 1.0 vs 5.1 ± 2.3 (μmol/l)/(mmol/l); p < 0.0005, Mann-Whitney test): range (1.5–6.5 vs 1.9–13.0, respectively). Plasma ROOHs were substantially higher in the diabetic subjects compared to those of the control subjects (9.4 ± 3.3 vs 4.1 ± 2.2 μmol/l; p < 0.0005 Mann-Whitney test: range 2.7–16.8 vs 0.4–10.3, respectively). ROOH/cholesterol standardised α-tocopherol ratio was significantly higher in the diabetic patients compared to control subjects (3.2 ± 1.6 vs 0.9 ± 0.6; p < 0.0005, Mann-Whitney test: range 0.7–8.3 and 0.1–2.7, respectively). Plasma levels of ROOHs and α-tocopherol were similar in diabetic patients with or without complications as well as in smokers and non-smokers. The present study confirms previous findings from this laboratory that NIDDM is associated with increased oxidative stress as assessed by plasma ROOHs. Increased oxidative stress in diabetic patients appears to be related to the underlying metabolic abnormalities in diabetes, rather than to the complications of this disease. We therefore suggest that oxidative stress is an early stage in the disease pathology, which may contribute to the development of complications. [Diabetologia (1997) 40: 647–653]

Journal Article
TL;DR: R reverse transcription-PCR analysis revealed increased PTCH expression levels compared to nonneoplastic brain tissue and normal skin in the majority of PNETs and BCCs investigated, suggesting that genetic alterations of PTCH are not only of significance in hereditary and sporadic BCCs but are also involved in the molecular pathogenesis of a subset of sporadic central nervous system P NETs.
Abstract: The human homologue of the Drosophila segment polarity gene patched (PTCH) has recently been identified as the tumor suppressor gene responsible for the nevoid basal cell carcinoma (BCC) syndrome (H. Hahn et al., Cell, 85: 841-851, 1996; R. L. Johnson et al., Science (Washington DC), 272: 1668-1671, 1996). In addition to multiple BCCs, patients with nevoid BCC syndrome have a predisposition for the development of primitive neuroectodermal tumors (PNETs) of the central nervous system. We have analyzed 9 sporadic BCCs and 37 PNETs for mutation and expression of the PTCH gene. PTCH mutations were found in 3 BCCs (33.3%) and in 5 PNETs (14%), including 1 of 5 cerebral PNETs, 2 of 15 medulloblastomas, and 2 of 17 desmoplastic medulloblastomas. The sequence changes in six of these tumors (four PNETs, two BCCs) were mutations predicted to result in truncated proteins. Missense mutations were detected in one PNET and one BCC each. In addition, novel sequence polymorphisms were found in exon 2, intron 5, intron 10, and intron 14 of PTCH. Reverse transcription-PCR analysis revealed increased PTCH expression levels compared to nonneoplastic brain tissue and normal skin in the majority of PNETs and BCCs investigated. Our data suggest that genetic alterations of PTCH are not only of significance in hereditary and sporadic BCCs but are also involved in the molecular pathogenesis of a subset of sporadic central nervous system PNETs.

Journal ArticleDOI
TL;DR: This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases.
Abstract: Breast cancer emerges by a multistep process which can be broadly equated to transformation of normal cells via the steps of hyperplasia, premalignant change and in situ carcinoma. The elucidation of molecular interdependencies, which lead to development of primary breast cancer, its progression, and its formation of metastases is the main focus for new strategies targetted at prevention and treatment. Cytogenetic and molecular genetic analysis of breast cancer samples demonstrates that tumour development involves the accumulation of various genetic alterations including amplification of oncogenes and mutation or loss of tumour suppressor genes. Amplification of certain oncogenes with concomitant overexpression of the oncoprotein seems to be specific for certain histological types. Loss of normal tumour suppressor protein function can occur through sequential gene mutation events (somatic alteration) or through a single mutational event of a remaining normal copy, when a germline mutation is present. The second event is usually chromosome loss, mitotic recombination, or partial chromosome deletion. Chromosome loci 16q and 17p harbour tumour suppressor genes, which seem to be pathognomonic for the development or progression of a specific histological subtype. There are an overwhelming number of abnormalities that have been identified at the molecular level which fit the model of multistep carcinogenesis of breast cancer. When the functions of all of these genes are known and how they participate in malignant progression, we will have the tools for a more rational approach to diagnosis, prevention and treatment. This review deals only with the factors that are involved in the conversion of a normal breast cell into a malignant cell rather than those required for invasion and metastases. A key critical long-term step in the molecular analysis of breast cancer will be to link the specific molecular damage with the effects of environmental carcinogens.

Journal ArticleDOI
TL;DR: An introduction to primary structure analysis of biomolecules by matrix-assisted laser desorption/ionization (MALDI) post-source decay (PSD) is given, sketching the principles and applications of the method for scientists in molecular biology, biochemistry and biomedicine.
Abstract: An introduction to primary structure analysis of biomolecules by matrix-assisted laser desorption/ionization (MALDI) post-source decay (PSD) is given, sketching the principles and applications of the method for scientists in molecular biology, biochemistry and biomedicine. The fundamentals of PSD are described in order to explain the potential and limitations of its applicability. Two examples of peptide sequencing of a completely unknown peptide and of a database-listed peptide are presented and the procedure of (non-automated) amino acid sequence elucidation is described. 1997 by John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine529, which results in an irreversible inhibition of Platelet-dependent thromboxane formation.
Abstract: The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine529. This prevents the access of the substrate (arachidonic aid) to the catalytic site of the enzyme at tyrosine385 and results in an irreversible inhibition of platelet-dependent thromboxane formation. Aspirin is an approximately 150- to 200-fold more potent inhibitor of the (constitutive) isoform of the platelet enzyme (COX-1) than the (inducible) isoform (COX-2) which is expressed by cytokines, inflammatory stimuli, and some growth factors. This explains the different dosage requirements of aspirin as an antithrombotic (COX-1) and an anti-inflammatory drug (COX-2), respectively. Aspirin is the "gold standard" antiplatelet agent for prevention of arterial thromboses. The optimum dose of aspirin as an antithrombotic drug can differ in different organ circulations. While 100 mg/day is sufficient for prevention of thrombus formation in the coronary circulation, higher doses may be required for the prevention of vascular events in the cerebral and peripheral circulation. However, any effective antiplatelet dose of aspirin is associated with an increased risk of bleeding. Therefore, the individual benefit/risk ratio determines the administration of the compound. There are no known prostaglandin-independent mechanisms for the antithrombotic action of aspirin in clinical use. Thus, platelet activation caused by other factors remains unchanged and might result in a resistance against inhibition of platelet function by aspirin. This involves platelet activation by shear stress and ADP. Additionally, there is no "sparing" of endothelial prostacyclin synthesis in clinical conditions of atherosclerotic endothelial injury. In this case, inhibition of COX-1 by aspirin will also reduce the amount of precursors for vascular prostacyclin synthesis, provided, for example, from adhering platelets.

Journal ArticleDOI
TL;DR: Some aspects of SOC that have not sufficiently been considered in the SOC literature are discussed and directions for further research are proposed.

Journal ArticleDOI
TL;DR: In this article, the behaviour of TiN, ZrN and CrN is compared, concentrating on the mechanism of their oxidation, and the sequence of the processes included in the electrochemical and thermal oxidation was followed by X-ray photoelectron spectroscopy.

Journal ArticleDOI
TL;DR: Empirical support is lent to the hypothesis that brain size may be an important factor influencing interhemispheric connectivity and lateralization by moderate linear and quadratic correlations and the previously described gender differences in CC anatomy may be better explained by an underlying effect of brain size.
Abstract: Using high-resolution in vivo magnetic resonance morphometry we measured forebrain volume (FBV), midsagittal size of the corpus callosum (CC) and four CC subareas in 120 young and healthy adults (49 women, 71 men). We found moderate linear and quadratic correlations, indicating that the CC and all CC subareas increase with FBV both in men and women (multiple r2 ranging from 0.10 to 0.28). Allometric equations revealed that these increases were less than proportional to FBV (r2 ranging from 0.02 to 0.30). Absolute CC measurements, as well as CC subareas relative to total CC or FBV (the latter measures termed the CC ratios), were further analyzed with regard to possible effects of handedness, gender, or handedness by gender interaction. Contrary to previous reports, left-handers did not show larger CC measurements compared to right-handers. The only apparent influence of gender was on the CC ratios, which were larger in women. However, smaller brains had larger CC ratios which were mainly independent of gender, a result of the less than proportional increase of callosal size with FBV. We suggest that the previously described gender differences in CC anatomy may be better explained by an underlying effect of brain size, with larger brains having relatively smaller callosa. This lends empirical support to the hypothesis that brain size may be an important factor influencing interhemispheric connectivity and lateralization

Journal ArticleDOI
01 Aug 1997-Gut
TL;DR: The pancreatic changes in patients with non-alcoholic Chronic pancreatitis clearly differ from those with alcoholic chronic pancreatitis, and the term chronic duct destructive pancreatitis is suggested for this type of pancreatic disease.
Abstract: Background —The pathology of non-alcoholic chronic pancreatitis has not yet been sufficiently studied. Aims —To identify the major changes of pancreatic tissue in patients surgically treated for non-alcoholic chronic pancreatitis. Patients —Pancreatectomy specimens from 12 patients with non-alcoholic chronic pancreatitis, including four patients with autoimmune or related diseases (Sjogren’s syndrome, primary sclerosing cholangitis, ulcerative colitis, and Crohn’s disease), were reviewed. Methods —Morphological changes were studied histologically and immunohistochemically (to type inflammatory cells) and compared with the pancreatic alterations found in 12 patients with alcoholic chronic pancreatitis. Results —In patients with non-alcoholic chronic pancreatitis, with or without associated autoimmune or related diseases, pancreatic inflammation particularly involved the ducts, commonly resulting in duct obstruction and occasionally duct destruction. None of these features was seen in alcoholic chronic pancreatitis which, however, showed pseudocysts and calcifications. Conclusion —The pancreatic changes in patients with non-alcoholic chronic pancreatitis clearly differ from those with alcoholic chronic pancreatitis. The term chronic duct destructive pancreatitis is suggested for this type of pancreatic disease.

Journal ArticleDOI
TL;DR: Because of the normal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induced inhibition of adenosine kinase causes the amplification of small changes in free AMP into a major rise inAdenosine, which plays an important role in the high sensitivity of the cardiac adenoine system to impaired oxygenation.
Abstract: To elucidate the physiological role of the AMP-adenosine metabolic cycle and to investigate the relation between AMP and adenosine formation, the O2 supply of isolated guinea pig hearts was varied (95% to 10% O2). The net adenosine formation rate (AMP-->adenosine) and coronary venous effluent adenosine release rate were measured; free cytosolic AMP was determined by 31P-nuclear magnetic resonance. Switching from 95% to 40% O2 increased free AMP and adenosine formation 4-fold, whereas free cytosolic adenosine and venous adenosine release rose 15- to 20-fold. In the AMP range from 200 to 3000 nmol/L, there was a linear correlation between free AMP and adenosine formation (R2 = .71); however, adenosine release increased several-fold more than formation. At 95% O2, only 6% of the adenosine formed was released; however, this fraction increased to 22% at 40% O2, demonstrating reduced adenosine salvage. Selective blockade of adenosine deaminase and adenosine kinase indicated that flux through adenosine kinase decreased from 85% to 35% of adenosine formation in hypoxia. Mathematical model analysis indicated that this apparent decrease in enzyme activity was not due to saturation but to the inhibition of adenosine kinase activity to 6% of the basal levels. The data show (1) that adenosine formation is proportional to the AMP substrate concentration and (2) that hypoxia decreases adenosine kinase activity, thereby shunting myocardial adenosine from the salvage pathway to venous release. In conclusion, because of the normal high turnover of the AMP-adenosine metabolic cycle, hypoxia-induced inhibition of adenosine kinase causes the amplification of small changes in free AMP into a major rise in adenosine. This mechanism plays an important role in the high sensitivity of the cardiac adenosine system to impaired oxygenation.

Journal ArticleDOI
TL;DR: It is demonstrated that singlet oxygen is a potent trigger for the induction of human T cell apoptosis andSinglet oxygen generation is identified as a fundamental mechanism of action operative in phototherapy.
Abstract: Ultraviolet A (UVA) irradiation is effectively used to treat patients with atopic dermatitis and other T cell mediated, inflammatory skin diseases. In the present study, successful phototherapy of atopic dermatitis was found to result from UVA radiation-induced apoptosis in skin-infiltrating T helper cells, leading to T cell depletion from eczematous skin. In vitro, UVA radiation-induced human T helper cell apoptosis was mediated through the FAS/FAS-ligand system, which was activated in irradiated T cells as a consequence of singlet oxygen generation. These studies demonstrate that singlet oxygen is a potent trigger for the induction of human T cell apoptosis. They also identify singlet oxygen generation as a fundamental mechanism of action operative in phototherapy.

Journal ArticleDOI
Dan Ziegler1, Schatz H, Conrad F, Gries Fa, Ulrich H, Reichel G 
TL;DR: Treatment with ALA using a well-tolerated oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM patients, suggesting a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum.
Abstract: OBJECTIVE To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV). RESEARCH DESIGN AND METHODS In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neuropathie [DEKAN] Study), NIDDM patients with reduced HRV were randomly assigned to treatment with daily oral dose of 800 mg ALA ( n = 39) or placebo ( n = 34) for 4 months. Parameters of HRV at rest included the coefficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.05–0.15 Hz) and high-frequency (HF; 0.15–0.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed. RESULTS Seventeen patients dropped out of the study (ALA n = 10; placebo n = 7). Mean blood pressure and HbA 1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA ( P P 2 (−0.09 to 0.62) in ALA, whereas it declined by −0.01 bpm 2 (−0.48 to 1.86) in placebo ( P P = 0.097 and P = 0.094 for ALA vs. placebo). The changes in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS These findings suggest that treatment with ALA using a well-tolerated oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM patients.

Journal Article
TL;DR: A non-technical introduction to logistic regression models for ordinal response variables, and issues such as the global concept and interpetation of logistic models, the model building procedure from a practical point of view, and the assessment of the model adequacy are addressed.
Abstract: Medical research workers are making increasing use of logistic regression analysis for binary and ordinal data. The purpose of this paper is to give a non-technical introduction to logistic regression models for ordinal response variables. We address issues such as the global concept and interpretation of logistic models, the model building procedure from a practical point of view, and the assessment of the model adequacy. For illustrative purposes we apply these methods to real data of a study investigating the association between glycosylated haemoglobin and retinopathy. We give some recommendations for the use and assessment of ordinal logistic regression models in medical research.

Journal ArticleDOI
TL;DR: Lithium seems to be superior to carbamazepine in maintenance treatment of bipolar disorder, in particular when applying broader outcome criteria including psychotropic comedication and severe side effects.

Journal ArticleDOI
TL;DR: The methylotrophic yeasts Hansenula polymorpha, Pichia pastoris and Candida boidinii have been developed as production systems for recombinant proteins and are rapidly becoming the systems of choice for heterologous gene expression in yeast.