Nitric oxide synthases catalyze a complex reaction converting L-arginine to citrulline and nitric oxide. In addition to heme, FAD, FMN and NADPH, nitric oxide synthases require tetrahydrobiopterin as cofactor. Tetrahydrobiopterin is known... more
Nitric oxide synthases catalyze a complex reaction converting L-arginine to citrulline and nitric oxide. In addition to heme, FAD, FMN and NADPH, nitric oxide synthases require tetrahydrobiopterin as cofactor. Tetrahydrobiopterin is known to stabilize the active, dimeric conformation of the enzyme (1), which has a high-spin heme iron (2) and an increased affinity for the substrate L-arginine (3). In addition to these allosteric roles, an electronic contribution of the tetrahydrobiopterin cofactor to the nitric oxide synthase reaction has been intensely searched for. The most convincing evidence for such an electronic contribution provided the detection of tetrahydrobiopterin-derived radicals being formed in dependence of the nitric oxide synthase reaction (4, 5, 6).
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Assisted reproductive technologies (ARTs) and reproductive genetic technologies (RGTs) are intertwined and coevolving. These technologies are increasingly used to fulfill socially and culturally framed requests, for example, "family... more
Assisted reproductive technologies (ARTs) and reproductive genetic technologies (RGTs) are intertwined and coevolving. These technologies are increasingly used to fulfill socially and culturally framed requests, for example, "family balancing," or to enable postmenopausal women or homosexual couples to have genetically linked children. The areas of ART and RGT are replete with ethical issues, because different social practices and legal regulations, as well as economic inequalities within and among countries, create vulnerable groups and, therefore, the potential for exploitation. This article provides an overview of the ART and RGT landscape in Pakistan and analyzes the available online content addressing Pakistani citizens and international clients. We explored the topic in view of socioeconomic challenges in Pakistan, particularly deeply rooted poverty, lack of education, gender discrimination, and absence of regulation. As online information given by ART and RGT provid...
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Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured... more
Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultati...
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Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special occurrence in the brain and in immune cell membranes. Plasmanylethanolamine desaturase (PEDS1) is the final enzyme of plasmalogen biosynthesis,... more
Plasmalogens are an abundant class of glycerophospholipids in the mammalian body, with special occurrence in the brain and in immune cell membranes. Plasmanylethanolamine desaturase (PEDS1) is the final enzyme of plasmalogen biosynthesis, which introduces the characteristic 1-O-alk-1′-enyl double bond. The recent sequence identification of PEDS1 as transmembrane protein 189 showed that its protein sequence is related to a special class of plant desaturases (FAD4), with whom it shares a motif of 8 conserved histidines, which are essential for the enzymatic activity. In the present work, we wanted to gain more insight into the sequence–function relationship of this enzyme and mutated to alanine additional 28 amino acid residues of murine plasmanylethanolamine desaturase including those 20 residues, which are also totally conserved—in addition to the eight-histidine-motif—among the animal PEDS1 and plant FAD4 plant desaturases. We measured the enzymatic activity by transient transfecti...
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Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured... more
Clinical ethics consultation is a relatively young field of expertise that supports ethically reflected decision-making. This process shakes up the existing hierarchy in two ways; first, by involving further perspectives in a structured and transparent way, and, second, by shifting the focus to a more comprehensive, interdisciplinary view. A major challenge for those providing clinical ethics consultation is building trust, which involves being considerate towards the needs of patients, relatives and healthcare professionals as well as towards customs and organizational culture. As this service emphasizes the relational aspect of medical care, it is difficult to realize within existing institutional frameworks. This paper explores how clinical ethics consultation developed and changed over the past few decades alongside an evolving understanding of respect for patient autonomy within an ethics of care approach. One of the most influential images related to clinical ethics consultati...
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Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und zeigen die Entwicklung des Gutachtens als einen Prozess auf, der zunehmend der Diskussion, Ausverhandlung und dem Einfluss von Wissen und... more
Die Beitrage des Bandes beschaftigen sich mit Begutachtungspraktiken verschiedener Epochen und zeigen die Entwicklung des Gutachtens als einen Prozess auf, der zunehmend der Diskussion, Ausverhandlung und dem Einfluss von Wissen und Gegenwissen um soziokulturelle Normen unterliegt. Ausgehend von der Annahme, dass der Medizin in der Klassifikation, Bewertung und Einschatzung bzw. in der Subjektivierung von Einzelnen und Gruppen eine besondere Bedeutung zukommt, ruckt insbesondere jenes Verhaltnis in den Fokus, das durch die Tatigkeit des Gutachtens zwischen und fur Menschen hergestellt wird.
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Research Interests: Engineering, Ethics, Human Genetics, Bioethics, Computational Biology, and 15 morePolitical Science, Critical Bioethics, Medicine, Genetic Engineering, Embryo, Public Engagement, Biological Sciences, Eugenics, Ethics of Human Genetic Engineeting, Designer Babies, Human Genome, Public Engagement with Science and Technology, Germline, Gene Editing, and Genome Editing
Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduction (MAR) has proliferated in multiple clinical innovations. Consequently, egg cells have become an object of demand for both infertility... more
Since the successful introduction of in vitro fertilization in 1978, medically assisted reproduction (MAR) has proliferated in multiple clinical innovations. Consequently, egg cells have become an object of demand for both infertility treatment and stem cell research, and this raises complex legal, ethical, social and economic issues.In this paper we compare how the procurement and use of human egg cells is regulated in two countries: Israel and Austria. Israel is known for its scientific leadership, generous public funding, high utilization and liberal regulation of assisted reproductive technology (ART). Austria lies at the other extreme of the regulatory spectrum in terms of restrictions on reproductive interventions.In both countries, however, there is a constant increase in the use of the technology, and recent legal developments make egg cells more accessible. Also, in both countries the scarcity of egg cells in concert with the rising demand for donations has led to the emerg...
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Biomedicine is a fast moving and often challenging research field. To this extent, it seems that preserving one's integrity is becoming more and more complex and occasionally stressful for individual researchers. Highly competitive... more
Biomedicine is a fast moving and often challenging research field. To this extent, it seems that preserving one's integrity is becoming more and more complex and occasionally stressful for individual researchers. Highly competitive funding and publication, the commercialization of biomedicine in general, the media hype about some scientific fields, the politicization of research and higher education, and, last but not least, the increasing specialization necessary to deal with increasingly sophisticated experimental systems and technologies are aspects of this complexity. While guidelines and overseeing control boards are important regulatory instruments, which also serve to enhance awareness of scientific integrity and to increase transparency, are not sufficient to maintain and further develop a positive academic climate that motivates the community to adhere to high and consistent professional ethics. Here, scientific misconduct and misbehaviour will be illustrated by referri...
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Research Interests: Immunology, Multivariate Statistics, Biology, Medicine, HIV, and 15 moreHomosexuality, Humans, Classification, Male, Hiv Infection, CD, Adult, DDC, Hiv seropositivity, Disease Progression, Cohort Studies, Acquired immunodeficiency syndrome, HIV infections, Linear discriminate analysis, and multivariate analyses
Research Interests: Biology, Biological Chemistry, Medicine, Biological Sciences, Lipopolysaccharide, and 15 moreHumans, Proteins, CHEMICAL SCIENCES, Lipopolysaccharides, Phenylalanine, Time Factors, Alanine, Recombinant Proteins, Protein Binding, Tetrahydrobiopterin, Phenylalanine hydroxylase, Interferon gamma, Tissue distribution, GTP, and Medical and Health Sciences
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Research Interests: Chemistry, Biology, Oxidative Stress, Apoptosis, Medicine, and 15 moreCell line, Reactive Oxygen Species, Animals, Programmed cell death, Superoxide Dismutase, Hydrogen Peroxide, Necrosis, Tumor necrosis factor-alpha, Neopterin, N-Acetylcysteine, Tumor Necrosis Factor–α (TNF), Biochemistry and cell biology, Tumor necrosis factor, Drug synergism, and acetylcysteine
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Chronic inflammatory disorders are associated with an increased risk of patients developing anaemia. There is some evidence that cytokines released during cell-mediated immune responses are capable of inhibiting bone marrow... more
Chronic inflammatory disorders are associated with an increased risk of patients developing anaemia. There is some evidence that cytokines released during cell-mediated immune responses are capable of inhibiting bone marrow haematopoiesis. In vitro, interferon gamma and tumour-necrosis factor alpha inhibit growth of erythroid precursor cells. The mode of action of these cytokines is probably associated with their antiproliferative capacity. Decrease of serum iron and increase of storage iron in patients appears to be a consequence of the defense strategy of macrophages during long-lasting inflammatory disorders. Decreased serum iron correlates to decreased haemoglobin concentrations. In view of this, the development of anaemia seems likely to result from the altered iron metabolism induced by stimulated macrophages. Low haemoglobin levels and associated hypoxia up-regulate the release of erythropoietin, which can explain why increased circulating erythropoietin is usually found in patients with anaemia.
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A T-cell attracting CXC chemokine phylogenetically related to MIG and SCYB10 was recently characterized and termed SCYB11 (alias βR1/H174/SCYB9B/I-TAC/IP-9/CXCL11). Here, we cloned the cDNA of the murine homologue of this protein, Scyb11,... more
A T-cell attracting CXC chemokine phylogenetically related to MIG and SCYB10 was recently characterized and termed SCYB11 (alias βR1/H174/SCYB9B/I-TAC/IP-9/CXCL11). Here, we cloned the cDNA of the murine homologue of this protein, Scyb11, from interferon-γ/lipopolysaccharide-stimulated RAW264.7 mouse macrophage-like cells. The nucleotide sequence of Scyb11 shares 63% identity with its human counterpart. It encodes a 100 amino acid immature protein of 11,265 Da which contains a putative signal peptide of 21 amino acids. The molecular mass of the mature protein was calculated to be 9,113 Da. Sequence identity of the murine and human SCYB11 proteins is 68%. Phylogenetic tree analysis of mouse CXC chemokines places SCYB11 together with the murine homologues of MIG and SCYB10 (Crg-2/muIP-10) on an individual branch. A genomic sequence was obtained by genome walking and subcloning DNA fragments from a BAC clone containing Scyb11. Like human SCYB11, Scyb11 contains 4 exons with intron/exon...
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Research Interests: Oncology, Immunohistochemistry, Medicine, Gene expression, Colorectal cancer, and 15 moreMultivariate Analysis, Humans, Internal Medicine, Female, Male, Enzyme, Clinical Sciences, Middle Aged, Adult, Disease Progression, Immune Tolerance, Interferon gamma, Extremities, Colorectal Neoplasms, and Cardiovascular medicine and haematology
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Research Interests: Medical Microbiology, Biology, Macrophages, Medicine, Cell Culture, and 12 moreBiological Sciences, Cell line, Humans, Physical sciences, Interferon, Tryptophan, High Pressure Liquid Chromatography, Kynurenine pathway, Extracellular, Biochemistry and cell biology, Interferon gamma, and Enzyme Induction
Research Interests: Pathology, Microcirculation, Medicine, Ischemia Reperfusion Injury, Transplantation, and 15 moreMice, Nitric oxide, Animals, Male, American, Peroxynitrite, Nitric Oxide Synthase, Reperfusion injury, Pancreas Transplantation, Intravital Microscopy, Inflammatory response, Normal Saline, Nitrotyrosine, hematoxylin and eosin, and Medical and Health Sciences
Urine concentrations of total porphyrins and of porphyrin precursors, delta-aminolaevulinic acid and porphobilinogen, were analysed in the first-morning urine samples of 36 people with established HIV-1 infection. For comparison, we also... more
Urine concentrations of total porphyrins and of porphyrin precursors, delta-aminolaevulinic acid and porphobilinogen, were analysed in the first-morning urine samples of 36 people with established HIV-1 infection. For comparison, we also analysed the urine samples of 26 healthy HIV-seronegative people. In patients with HIV-1 infection concentrations of total porphyrins were found to be significantly higher than in healthy controls. Furthermore, there was a close correlation between concentrations of total porphyrins and porphobilinogen and urine neopterin concentrations in patients. Our data indicate an association between chronic immune activation and altered porphyrin metabolism. The data may provide a rationale for the observation of acute porphyria in patients with HIV-1 infection.
Research Interests: Adolescent, Porphyrins, Medicine, Biological Sciences, Humans, and 15 moreFemale, Male, AIDS, Porphyria, Middle Aged, Adult, Porphyrin, Hiv seropositivity, Morning, Neopterin, Aminolevulinic Acid, Acquired immunodeficiency syndrome, Psychology and Cognitive Sciences, excretion, and Medical and Health Sciences
Significance We have recently identified the sequence of the ether lipid-cleaving enzyme alkylglycerol monooxygenase. Like nitric oxide synthases and aromatic amino acid hydroxylases, alkylglycerol monooxygenase needs tetrahydrobiopterin... more
Significance We have recently identified the sequence of the ether lipid-cleaving enzyme alkylglycerol monooxygenase. Like nitric oxide synthases and aromatic amino acid hydroxylases, alkylglycerol monooxygenase needs tetrahydrobiopterin as cofactor. Whereas the former enzymes have well-established roles in the cell, the physiology of alkylglycerol monooxygenase is still not clear. Here we show its regulation in murine macrophage differentiation and its dependence on the cofactor tetrahydrobiopterin in live murine macrophage-like RAW264.7 cells. Upon modulation of the activity of alkylglycerol monooxygenase and the key enzyme in tetrahydrobiopterin biosynthesis, we observe extensive changes in various lipid classes ranging from ether lipids to far more complex lipids. These findings point to an important role of tetrahydrobiopterin in cellular lipid homeostasis.
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A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer’s... more
A significant fraction of the glycerophospholipids in the human body is composed of plasmalogens, particularly in the brain, cardiac, and immune cell membranes. A decline in these lipids has been observed in such diseases as Alzheimer’s and chronic obstructive pulmonary disease. Plasmalogens contain a characteristic 1-O-alk-1′-enyl ether (vinyl ether) double bond that confers special biophysical, biochemical, and chemical properties to these lipids. However, the genetics of their biosynthesis is not fully understood, since no gene has been identified that encodes plasmanylethanolamine desaturase (E.C. 1.14.99.19), the enzyme introducing the crucial alk-1′-enyl ether double bond. The present work identifies this gene as transmembrane protein 189 (TMEM189). Inactivation of theTMEM189gene in human HAP1 cells led to a total loss of plasmanylethanolamine desaturase activity, strongly decreased plasmalogen levels, and accumulation of plasmanylethanolamine substrates and resulted in an ina...
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Reduced tryptophan and increased kynurenine concentrations have been reported in patients with human immunodeficiency virus type 1 (HIV-1) infection. From in vitro data it appears that activated indoleamine 2,3-dioxygenase (IDO) is... more
Reduced tryptophan and increased kynurenine concentrations have been reported in patients with human immunodeficiency virus type 1 (HIV-1) infection. From in vitro data it appears that activated indoleamine 2,3-dioxygenase (IDO) is involved in this metabolic change. IDO is inducible by interferon-(IFN)-gamma. We compared serum concentrations of IFN-gamma and neopterin (the biosynthesis of which is also inducible by IFN-gamma) with serum, tryptophan and kynurenine of 42 patients with HIV-1 infection. IFN-gamma, neopterin and kynurenine levels were significantly increased compared to HIV-1 seronegative controls whereas tryptophan was significantly decreased. Various significant correlations were found between tryptophan, kynurenine, IFN-gamma and neopterin concentrations. Highest degree of correlation was found between neopterin, IFN-gamma and the kynurenine per tryptophan quotient which is the ratio between the product and the substrate concentration of IDO. The data indicate that decreased tryptophan in HIV-1 seropositives may result from chronic immune activation and can be referred to increased activation of IDO.
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AIDS incidence rates were calculated for Austria based on cumulative data up to October 31st 1988. Geographical differences are obvious, provinces of the northwest showing higher incidence rates than south-east provinces. An association... more
AIDS incidence rates were calculated for Austria based on cumulative data up to October 31st 1988. Geographical differences are obvious, provinces of the northwest showing higher incidence rates than south-east provinces. An association of high AIDS incidence rates with intravenous drug abuse is suggested by the data.
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ABSTRACT
Albert (Clin Chem 1982;28:1113-9) has proposed estimation of likelihood ratios by logistic regression analysis. The usual likelihood-ratio approach for estimation of post-test probability of disease from sensitivity and specificity data... more
Albert (Clin Chem 1982;28:1113-9) has proposed estimation of likelihood ratios by logistic regression analysis. The usual likelihood-ratio approach for estimation of post-test probability of disease from sensitivity and specificity data of a diagnostic test has been extended by Birkett (J Clin Epidemiol 1988; 41:491-4) for situations with more than two diagnostic categories. We suggest here a combination of these ideas, demonstrating this by a re-evaluation of previously published data on the validity of neopterin as a tool for differential diagnosis between chronic non-A, non-B hepatitis and fatty liver. Analysis of neopterin data in combination with the ratio between serum concentrations of aspartate aminotransferase and of alanine aminotransferase yielded a good discrimination between three mutually exclusive diagnostic categories, namely, fatty liver and chronic persistent and chronic aggressive non-A, non-B hepatitis. The approach is flexibly applicable to situations with different pre-test probabilities. The sum of estimated post-test probabilities deviates slightly from the sum of pre-test probabilities. This deviation is a function of the coefficients obtained in logistic regression, and an analytical expression for the deviation is given. The generalized likelihood-ratio approach appears promising in complex diagnostic situations when multiple diagnostic tests are available.
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ABSTRACT
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ABSTRACT
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A review is presented on studies concerning neopterin determination in patients with malignant neoplastic diseases. Neopterin is produced chiefly by human macrophages through their activation by T-cell-derived interferon gamma. In vivo,... more
A review is presented on studies concerning neopterin determination in patients with malignant neoplastic diseases. Neopterin is produced chiefly by human macrophages through their activation by T-cell-derived interferon gamma. In vivo, determinationof neopterin in various body fluids provides a convenient way to monitor early events that are involved in cell-mediated immune responses. In malignant neoplasia, elevation of neopterin concentrations in body fluids depends on tumor type. Within a given type of tumor, more advanced stages are generally associated with higher levels than early disease. In a variety of different tumor types and sites, a significantly poorer prognosis was associated with high pretherapeutic neopterin concentrations. This predictive value is independent of several possible confounders such as stage or therapy. During follow-up malignant disease, neopterin elevations may predict deterioration of the clinical status of the patients and thereby provide a valuable additional marker for monitoring such patients. Possible immunobiological implications of the results are discussed.
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In a number of mammalian cell types, pteridine biosynthesis from guanosine 5'-triphosphate and formation of nitric oxide from L-arginine are induced by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS). We... more
In a number of mammalian cell types, pteridine biosynthesis from guanosine 5'-triphosphate and formation of nitric oxide from L-arginine are induced by gamma interferon (IFN-gamma) and bacterial lipopolysaccharide (LPS). We assessed the possibility of using such metabolic alterations for the in vitro detection of pyrogens. Products from gram-negative and gram-positive bacteria and related synthetic compounds were tested for their potential to induce either of these pathways. Stimulation of pteridine biosynthesis was monitored as the formation of neopterin in the human myelomonocytic cell line THP-1. The formation of nitric oxide was determined as nitrite in murine J774A.1 macrophage cultures. The substances tested included toxic and detoxified parts of LPS and lipid A from Escherichia coli, Salmonella typhimurium, Salmonella minnesota, and Klebsiella pneumoniae as well as lipoteichoic acid and toxic shock syndrome toxin 1 from Staphylococcus aureus. Furthermore, two cell wall compounds from Mycobacterium tuberculosis, trehalose 6,6'-dimycolate and N-acetylmuramyl-L-alanyl-D-isoglutamine, which are active components of Freund's adjuvant, were used. When applied as a single stimulus, only the whole LPS molecule potently stimulated neopterin or nitrite formation. Lipid A and products from gram-positive bacteria were weakly active. For neopterin formation, lipid A required the presence of fetal calf serum. Besides detoxified LPS and independently from the presence of serum, all bacterial compounds tested strongly increased the effects mediated by IFN-gamma. Our results show that bacterial pyrogens can be detected by monitoring the formation of neopterin or nitrite. This may provide a basis for the development of an in vitro assay for the detection of pyrogenic contamination with the aim of replacing the currently used animal test.
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Research Interests: Erythropoietin, Pregnancy, Humans, Female, Blood, and 3 moreAnemia, Clinical Sciences, and Erythropoiesis
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ABSTRACT