Biomedical subjects

S Schulz

Publications and source records attributed to S Schulz.

At least 109 records · Page 6Linked to original sources

PubMed1999

The guanylyl cyclase family of natriuretic peptide receptors.

Guanylyl cyclases are cytoplasmic and membrane-associated enzymes that catalyze the conversion of GTP to cyclic GMP, an intracellular signaling molecule. Molecular cloning has identified a multigene family encoding both soluble and particulate forms of the enzymes. Diffusible agents such as nitric oxide and carbon monoxide activate the soluble guanylyl cyclases. The particulate members of the family share a characteristic domain arrangement, with a single transmembrane span separating a variable extracellular ligand-binding domain from a conserved intracellular regulatory and cyclase catalytic domain. Seven members of the particulate guanylyl cyclase family have been identified, and they include the receptors for natriuretic peptides and Escherichia coli heat-stable enterotoxin. Recently, animal models have been developed to study the role of natriuretic peptides and their guanylyl cyclase-coupled receptors in renal and cardiovascular physiology.

Animals↗

PubMed1999

Selective targeting of somatostatin receptor 3 to neuronal cilia.

Recently, five members of the somatostatin receptor family have been cloned. However, little is known about their cellular and subcellular localization in the central nervous system. Using specific anti-peptide antisera, we observed somatostatin receptor 3-like immunoreactivity in many brain regions, including the cerebral cortex, hippocampus, hypothalamus, amygdala and cerebellum. In all of these regions (except for the cerebellar cortex), somatostatin receptor 3-like immunoreactivity was selectively targeted to 4-8-microm-long rod-shaped profiles which did not co-localize with axonal or dendritic markers. One immunoreactive profile was always associated with one neuronal cell body. This staining pattern was resistant to colchicine treatment and showed a closely overlapping distribution with somatostatin receptor 3 messenger RNA, suggesting that the receptor protein is not transported over long distances. Electron microscopic analysis revealed that somatostatin receptor 3-like immunoreactivity is localized to the plasma membrane of neuronal cilia which extended into an intercellular pocket and showed a 9+0 filament pattern in their basal body and proximal segments. Thus, somatostatin receptor 3 demonstrates a unique example of a G-protein-coupled receptor not localized to "classical" pre- or postsynaptic sites, but selectively targeted to neuronal cilia. The presence of the somatostatin receptor 3 receptor on neuronal cilia suggests that these presumably non-motile cilia may not merely represent developmental remnants, but rather function as chemical sensors of the immediate milieu.

Amino Acid Sequence↗

PubMed1999

How knowledge drives understanding--matching medical ontologies with the needs of medical language processing.

In this article, we introduce a knowledge-based approach to medical text understanding. From an in-depth consideration of deep sentence and text understanding we distill basic requirements for an adequate knowledge representation framework. These requirements are then matched with currently available medical ontologies (thesauri, terminologies, etc.). A fundamental trade-off is recognized between large-scale conceptual coverage on the one hand, and formal mechanisms for integrity preservation and conceptual expressiveness on the other hand. We discuss various shortcomings of the most wide-spread ontologies to capture medical knowledge in-the-large. As a result, we argue for the need of a formally sound and expressive model along the lines of KL-ONE-style terminological representation systems in the format of description logics. These provide an adequate methodology for designing more sophisticated, flexible medical ontologies serving the needs of 'deep' knowledge applications which are by no means restricted to medical language processing.

Artificial Intelligence↗

PubMed1999

Discourse structures in medical reports--watch out! The generation of referentially coherent and valid text knowledge bases in the MEDSYNDIKATE system.

The automatic analysis of medical narratives currently suffers from neglecting text structure phenomena such as referential relations between discourse units. This has unwarranted effects on the descriptional adequacy of medical knowledge bases automatically generated from texts. The resulting representation bias can be characterized in terms of incomplete, artificially fragmented and referentially invalid knowledge structures. We focus here on four basic types of textual reference relations, viz. pronominal and nominal anaphora, textual ellipsis and metonymy and show how to deal with them in an adequate text parsing device. Since the types of reference relations we discuss show an increasing dependence on conceptual background knowledge, we stress the need for formally grounded, expressive conceptual representation systems for medical knowledge. Our suggestions are based on experience with MEDSYNDIKATE, a medical text knowledge acquisition system designed to properly deal with various sorts of discourse structure phenomena.

Artificial Intelligence↗

PubMed1999

Interruption of transmembrane signaling as a novel antisecretory strategy to treat enterotoxigenic diarrhea.

Bacteria that produce heat-stable enterotoxins (STs), a leading cause of secretory diarrhea, are a major cause of morbidity and mortality worldwide. ST stimulates guanylyl cyclase C (GCC) and accumulation of intracellular cyclic GMP ([cGMP]i), which opens the cystic fibrosis transmembrane conductance regulator (CFTR)-related chloride channel, triggering intestinal secretion. Although the signaling cascade mediating ST-induced diarrhea is well characterized, antisecretory therapy targeting this pathway has not been developed. 2-ChloroATP (2ClATP) and its cell-permeant precursor, 2-chloroadenosine (2ClAdo), disrupt ST-dependent signaling in intestinal cells. However, whether the ability to disrupt guanylyl cyclase signaling translates into effective antisecretory therapy remains untested. In this study, the efficacy of 2ClAdo to prevent ST-induced water secretion by human intestinal cells was examined. In Caco-2 human intestinal cells, ST increased [cGMP]i, induced a chloride current, and stimulated net basolateral-to-apical water secretion. This effect on chloride current and water secretion was mimicked by the cell-permeant analog of cGMP, 8-bromo-cGMP. Treatment of Caco-2 cells with 2ClAdo prevented ST-induced increases in [cGMP]i, chloride current and water secretion. Inhibition of the downstream consequences of ST-GCC interaction reflects proximal disruption of cGMP production because 8-bromo-cGMP stimulated chloride current and water secretion in 2ClAdo-treated cells. Thus, this study demonstrates that disruption of guanylyl cyclase signaling is an effective strategy for antisecretory therapy and provides the basis for developing mechanism-based treatments for enterotoxigenic diarrhea.

2-Chloroadenosine↗

PubMed1999

Aortic input impedance and ventriculoarterial coupling following cardioversion/defibrillation.

Defibrillation shocks are commonly used after cardiac surgery or during defibrillator implantation. The hemodynamic consequences of countershocks on circulatory dynamics are not completely understood, and there is a lack of information concerning the effects on ventriculoarterial interaction. The study presented here was performed to assess the influence of defibrillation shocks on arterial hemodynamics and ventriculoarterial coupling. Eight mongrel dogs (weight 15-18 kg) were anesthetized and median thoracotomy was performed. Pressure in the ascending aorta and the left ventricle and flow in the ascending aorta were continuously monitored. After induction of atrial or ventricular fibrillation, termination was achieved by epicardial low energy shocks (atrium, 3J; ventricle, 51). In an additional attempt ventricular fibrillation was terminated by a high energy shock (34J). Aortic input impedance was calculated by fast-Fourier-transformation of aortic flow and pressure signals, while ventriculoarterial coupling was expressed by the ratio of aortic and ventricular end systolic elastance (Ea/Ees). Defibrillation by low energy shocks of atrial or ventricular fibrillation did not result in changes of the aortic impedance spectrum, and ventriculoarterial coupling remained unaltered compared to control conditions. High energy defibrillation, however, resulted in a marked rise in total peripheral resistance (P < 0.03). The ratio of Ea/Ees increased significantly (P < 0.005). These effects were reversible within 15 minutes. Low energy defibrillation does not alter arterial hemodynamics and ventriculoarterial coupling in this experimental setup. High energy defibrillation, however, results in a temporary increase of ventricular load. This finding may be of particular interest in patients with poor left ventricular function.

Animals↗

PubMed1999

Replacement of threonine 394 by alanine facilitates internalization and resensitization of the rat mu opioid receptor.

Signaling of G protein-coupled receptors is terminated by phosphorylation of intracellular serine and threonine residues. Resensitization of these receptors requires internalization and subsequent dephosphorylation. We have recently shown that the resensitization rate of the rat micro opioid receptor (MOR) isoforms MOR1 and MOR1B is mainly determined by the amino acid composition of their alternatively spliced C-terminal tails. Upon agonist stimulation, MOR1B passes through an accelerated cycle of receptor endocytosis and reactivation, which in turn promotes a greater resistance to agonist-induced desensitization, as compared with MOR1. Given the fact that MOR1B lacks only one putative phosphorylation site (T394 of MOR1), we replaced this threonine by an alanine and stably expressed the wild-type MOR1 and its T394A mutant in mouse neuroblastoma Neuro2a cells. We show that during prolonged [D-Ala2, MePhe4, Gly5-ol]enkephalin exposure (5 h), the T394A receptor mutant desensitized at a slower rate than MOR1. In contrast, T394A is more rapidly removed from the cell surface than MOR1, as determined by flow cytometry using epitope-tagged receptors. This fast internalization was followed by immediate resensitization of T394A during 20 min of agonist removal while the wild-type MOR1 remained inactive. Similar to MOR1B, rapid internalization and reactivation of T394A may explain its delayed desensitization. These findings suggest that T394 represents a negative regulatory signal for MOR1 internalization. Furthermore, phosphorylation of this threonine residue may influence the time course of micro opioid receptor resensitization.

Alanine↗

PubMed1999

Mathematical modelling of extracorporeal circulation: simulation of different perfusion regimens.

Computer- and sensor-aided control of the heart-lung machine is considered a major goal for perfusion sciences for the next few years. At present, control of perfusion is achieved by surgeons, anaesthesiologists and perfusionists making short-term decisions, which leads to variations of the perfusion regimens between different centres and even between different teams in the operating theatre. As the basis for an integrated control of extracorporeal circulation (ECC), we proposed a mathematical model for simulating haemodynamics during pulsatile perfusion. This model was then modified to allow it to simulate the effects of different perfusion regimens on arterial haemodynamics and whole body oxygen consumption. The model was constructed on a PC using MATLAB/SIMULINK. The human arterial tree was divided into a multibranch structure consisting of 128 segments characterized by their particular physical properties. Peripheral branches were terminated by a resistance term representing smaller vessels like arterioles and capillaries. Flow and pressure were expressed by the intensity of current and voltage in an electrotechnical analogon; inductivity, resistance and capacitance were implemented according to the physical properties of the arterial tree and the rheology of blood. The effects of different perfusion regimens (pulsatility, flow amount, acid-base regulation) were studied. After introducing an input signal to the model, flow and pressure waves established themselves throughout the simulated arterial tree. During the simulation experiments, marked differences among different perfusion regimens were displayed by the model. Variations in acid-base management mainly influenced the distribution of perfusion: during simulation of low-flow perfusion (1.2 l/min/m2), cerebral blood flow was 6.2 ml/s using an alpha-stat regimen, while it was increased to 9.4 ml/s during pH-stat, caused by an implementation of reduced cerebral resistance. Whole body oxygen consumption was predominantly regulated by the perfusion rate. While central venous oxygen saturation was calculated to be 84.7% during simulation of high-flow perfusion (2.4 l/min/m2), it dropped to 70% during simulation of low-flow perfusion regimens. The model proved to be useful for a realistic simulation of different perfusion regimens. Therefore it can be considered a continuing step for the derivation of a 'state' observer leading to the realization of an automatically controlled heart-lung machine.

Blood Transfusion↗

PubMed1999

Patterning of the R7 and R8 photoreceptor cells of Drosophila: evidence for induced and default cell-fate specification.

Opsin gene expression in the R7 and R8 photoreceptor cells of the Drosophila compound eye is highly coordinated. We have found that the R8 cell specific Rh5 and Rh6 opsins are expressed in non-overlapping sets of R8 cells, in a precise pairwise fashion with Rh3 and Rh4 in the R7 cells of individual ommatidia. Removal of the R7 cells in sevenless, boss or sina mutants, disrupts Rh5 expression and dramatically increases the number of Rh6-expressing R8 cells. This suggests that the expression of Rh5 may be induced by an Rh3-expressing R7 cell, whereas Rh6 expression is most likely a default state of the R8 cell. We found that the paired expression of opsin genes in the R7 and R8 cells occurs in a sevenless and boss independent manner. Furthermore, we found that the generation of both Rh3- and Rh4-expressing R7 cells can occur in the absence of an R8 cell. These results suggest that the specification of opsin expression in the R7 cells may occur autonomously, whereas the R7 photoreceptor cell may be responsible for regulating a binary developmental switch between induced and default cell-fates in the R8 cell.

Amino Acid Sequence↗

PubMed1999

Streamlining semantic interpretation for medical narratives.

We introduce two abstraction mechanisms by which the process of semantic interpretation of medical narratives can be simplified and further optimized. One relates to generalized triggering conditions, the other to inheritance-based specifications of semantic rules. The proposed methodology leads to a parsimonious inventory of abstract, simple and domain-independent semantic interpretation schemata whose effectiveness has been evaluated on a medical text corpus.

Evaluation Studies as Topic↗

PubMed1999

Towards a multilingual morpheme thesaurus for medical free-text retrieval.

We introduce a methodology for the segmentation of complex compounds into medically plausible morphemes. A tool for thesaurus compilation and management is presented, and design principles for a multilingual morpheme thesaurus are outlined. Our goal is to enhance the quality of medical free-text retrieval by replacing lexically based through morpheme-based search procedures.

Germany↗

PubMed1998

Differential distribution of alternatively spliced somatostatin receptor 2 isoforms (sst2A and sst2B) in rat spinal cord.

We have recently shown that the cytoplasmic tail of the somatostatin receptor sst2 undergoes alternative splicing giving rise to two isoforms, SSt2A and sst2B. In the present study, we have raised polyclonal antibodies that specifically detect either sst2A or sst2B and used these antisera for immunocytochemical localization of the receptor proteins in the rat spinal cord. sst2A-immunoreactivity formed a dense network consisting of neuronal perikarya and dendrites in the superficial layers of the dorsal horn. In contrast, prominent sst2B-immunoreactivity was found on neuronal perikarya and proximal dendrites throughout the gray matter of the spinal cord. Taken together, we show that alternative carboxy-terminal splicing is involved in cell-specific expression of somatostatin receptor sst2 isoforms in rat spinal cord, and that sst2A and sst2B mediate effects of somatostatin at different cellular sites.

Amino Acid Sequence↗

PubMed1998

Protective effects of cortistatin (CST-14) against kainate-induced neurotoxicity in rat brain.

Cortistatin (CST-14) is a recently discovered endogenous peptide which shares similarity to somatostatin and binds to somatostatin receptors. In this study, we show that CST-14 exhibits anticonvulsive and neuroprotective effects in rats. Injection of rats with kainic acid (KA; 10 mg/kg; i.p.) generated a strong seizure activity which was attenuated by the i.c.v. application of 1 and 10 nmol CST-14 when given 10 min before KA. Moreover, 3 days after KA injection, a marked loss of neurons in cortex and hippocampus of rats was observed which was inhibited by pretreatment with CST-14. An immunohistochemical analysis using specific antibodies revealed that KA reduced immunoactive sst2A and sst3 somatostatin receptors in the hippocampus-an effect which was largely prevented by pretreatment with CST-14. Superfusion of hippocampal slices with CST-14 also reduced the stimulated release of 3H-d-aspartate. We conclude that CST-14 exerts neuroprotective effects by binding to somatostatin receptors which in turn leads to a reduced release of excitotoxic neurotransmitters.

Animals↗

PubMed1998

Carboxyl-terminal splicing of the rat mu opioid receptor modulates agonist-mediated internalization and receptor resensitization.

The rat mu opioid receptor is alternatively spliced into two isoforms (MOR1 and MOR1B) which differ in length and amino acid composition at the carboxyl terminus. When stably expressed in HEK 293 cells, both splice variants bind the mu receptor agonist [D-Ala2,N-Me-Phe4,-Gly-ol5]enkephalin (DAMGO) with similar affinity and exhibit functional coupling to adenylyl cyclase with similar efficiency. However, the shorter isoform, MOR1B, desensitized at a slower rate during prolonged DAMGO exposure (4 h) but resensitized at a faster rate than MOR1 during agonist withdrawal (20 min). Immunocytochemical analysis revealed that DAMGO-induced internalization of MOR1B proceeded much faster than that of MOR1 followed by rapid recycling of the receptor to the cell surface. In addition, the greater resistance of MOR1B to homologous desensitization compared with MOR1 as well as MOR1B resensitization was abolished when receptor reactivation/recycling was blocked with monensin, an inhibitor of endosomal acidification. It is concluded that the sequence at the cytoplasmic tail of MOR1B facilitates clathrin-coated vesicle-mediated endocytosis which, in turn, promotes accelerated receptor reactivation. Taken together, our findings suggest that carboxyl-terminal splicing of the rat mu opioid receptor modulates agonist-induced internalization and receptor resensitization.

Alternative Splicing↗

PubMed1998

Immunofluorescent identification of endomorphin-2-containing nerve fibers and terminals in the rat brain and spinal cord.

Endomorphin-1 and -2 are potent and selective agonists for the mu-opioid receptor which have recently been isolated from bovine brain extracts. In the present study we used polyclonal antibodies specific for endomorphin-2 to determine its immunocytochemical distribution in the rat brain and spinal cord Endomorphin-2-like immunoreactivity was confined to varicose fibers with an overall discrete distribution within the central nervous system. The immunostaining was completely abolished by preincubation of the antiserum with endomorphin-2 but not with endomorphin-1. Endomorphin-2-like immunoreactivity was enriched in many but not all brain regions known to contain dense mu-opioid receptors, including nucleus accumbens, septum, midline thalamic nuclei, hypothalamic and amygdala nuclei, locus coeruleus, periaqueductal gray and spinal cord dorsal horn. In contrast, endomorphin-2 was absent from the cortex, striatum, hippocampus, nucleus of the solitary tract and dorsal root ganglia. Dual-labeling experiments revealed that endomorphin-2-immunoreactive nerve fibers did not co-contain any other opioid peptide. Thus, the present findings strongly suggest that endomorphin-2 may be a natural ligand for the mu-opioid receptor likely to be involved in the modulation of nociceptive transmission and reward-seeking behavior.

Animals↗

PubMed1998

The cloning and expression of a new guanylyl cyclase orphan receptor.

A novel membrane form of guanylyl cyclase (GC-G) has been identified through the isolation of a full-length cDNA clone; it is predicted to contain an extracellular ligand binding domain, a single transmembrane segment, and intracellular protein kinase-like and cyclase catalytic domains. That GC-G represents a guanylyl cyclase was confirmed by both transient expression in COS-7 cells and stable expression in H293 cells. Endogenous cyclic GMP concentrations of transfected or stable cells, however, were much higher than control cells, suggesting an inability of the cells to effectively regulate GC-G cyclase activity. Of six Cys residues found within the extracellular domain of guanylyl cyclase-A (GC-A), the receptor for atrial natriuretic peptide, five are conserved within GC-G. Ligands for the other cyclase receptors, nevertheless, failed to stimulate GC-G expressed in transient or stable cells, suggesting that the unknown ligands possess a structure different from the natriuretic peptides or heat-stable enterotoxins. 125I-ANP also failed to bind to H293 cells overexpressing GC-G. Based on Northern hybridization, mRNA for GC-G was predominantly expressed in lung, intestine, and skeletal muscle. Using the candidate gene approach to potentially define function, the gene for GC-G was mapped to the distal region of mouse chromosome 19 (syntenic with human chromosome 10q), but no human genetic defect has been ascribed to the GC-G locus. The finding of a new membrane form of guanylyl cyclase in peripheral tissues suggests the existence of another family or subfamily of ligands that signal through elevations of cGMP.

Amino Acid Sequence↗

PubMed1998

Low-density lipoprotein receptor-related protein in atherosclerosis development: up-regulation of gene expression in patients with coronary obstruction.

The low-density lipoprotein receptor-related protein (LRP) is a multifunctional cell-surface receptor that binds and mediates the endocytosis of several structurally and functionally distinct ligands. Involved in a variety of biological processes, including the regulation of the coagulation-fibrinolysis balance, the lipoprotein metabolism, cellular migration, proliferative processes and degenerative diseases, it has very recently become an interesting candidate for functional studies of the development of atherosclerosis. We investigated the individual cellular LRP gene expressions in 100 patients with angiographically confirmed severe coronary obstructions (myocardial infarction, patients with coronary angioplasty and patients with coronary bypass). Using a competitive reverse transcriptase polymerase chain reaction analysis we measured the specific LRP mRNA levels in monocytes from venous blood. In comparison with 110 unselected controls (122.1 ag/cell) the patient group demonstrated significantly higher LRP message levels (171.92 ag/cell). We found the most evident increase in the coronary angioplasty group (+43.5%). Investigating the intraindividual range of expression in healthy controls over a period of 4 weeks, we found nearly constant individual levels. Our results demonstrate a significant correlation of increased LRP mRNA levels with atherosclerotic processes (P<0.001), suggest an important implication of the LRP in atherosclerotic vascular processes, and emphasize the inclusion of LRP investigations in risk constellation studies.

Adult↗

PubMed1998

Immunolocalization of two mu-opioid receptor isoforms (MOR1 and MOR1B) in the rat central nervous system.

We have recently shown that the cytoplasmic tail of the rat mu-opioid receptor undergoes alternative splicing giving rise to two isoforms, rMOR1 and rMOR1B. These isoforms exhibit similar pharmacological profiles, however, differ in agonist-induced desensitization of coupling to adenylate cyclase. In the present study, we have raised polyclonal antibodies that specifically detect either rMOR1 or rMOR1B and used these antisera for immunocytochemical localization of the receptor proteins in the rat central nervous system. Prominent MOR1B-like immunoreactivity was found in the external plexiform layer of the main olfactory bulb localized to a dense plexus of dendrites mostly originating from mitral cells and extending into the glomerular layer. MOR1-like immunoreactivity was restricted to the perikarya of mitral cells and to distinct juxtaglomerular cells as well as their processes. While MOR1-, DOR1- and KOR1-like immunoreactivity was absent from the external plexiform layer, high densities of opioid peptides were found in this layer suggesting that MOR1B may be a targeted receptor of these peptides. MOR1-like immunoreactivity was observed in many pain-controlling brain areas including the spinal cord dorsal horn, sensory trigeminal complex, raphe nuclei and periaqueductal gray while MOR1B-like immunoreactivity was not detectable in these regions. Taken together, we provide evidence that the mu receptor isoforms, MOR1 and MOR1B, exhibit a strikingly different distribution in that MOR1 appears to be the major isoform widely distributed throughout the central nervous system and MOR1B being predominantly localized to the olfactory bulb.

Alternative Splicing↗