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Biomedical subjects

M Schwarz

Publications and source records attributed to M Schwarz.

At least 199 records · Page 11Linked to original sources
PubMed1997

Pax-2 in the chiasm.

Pax genes are expressed in specific patterns in the nervous system during development and in the adult. Recent findings suggest a link between the expression of Pax-2 and axonal guidance. Mice with a targeted deletion of Pax-2 are an excellent tool for studying axonal pathfinding at the molecular level, especially with respect to the optic chiasm. The date reviewed here suggest that Pax-2 regulates the expression of surface molecules involved in contact attraction and that the mutual regulation of the expression of Pax-2 and the Sonic hedgehog gene is of importance in the formation of the chiasm region.

Animals↗
PubMed1997

Correlation between hippocampal neuronal damage and spatial learning deficit due to global ischemia.

Global cerebral ischemia leads to selective neuronal damage in the CA1 sector of the hippocampus and in the striatum. This ischemia leads to a deficit in spatial learning and memory in the water maze. The results of earlier studies that have examined the relationship between neuronal damage and the deficit in the water maze were not clear-cut. It has been observed that neuroprotection reduces both the deficit in the water maze and the neuronal damage. The present study therefore approached the relationship between the neuronal damage and the deficit in the water maze by pharmacological means. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 min. Ischemic rats were then treated with the noncompetitive non-NMDA receptor antagonist GYKI 52466 (30 mg/kg), the radical scavenger LY 231617 (20 mg/kg), the inhibitor of protein kinase C staurosporine (0.1 mg/kg), or solvent. Treatment with GYKI 52466 or LY 231617 reduced the deficit in spatial learning by limiting the increase in swim distance due to ischemia. In addition, LY 231617 reduced the deficit in spatial memory as demonstrated by minimizing the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial. Staurosporine had no influence on the ischemia-induced behavioural changes. Histological examination revealed neuronal damage in the hippocampus and in the striatum in all of the ischemic rats. However, treatment with GYKI 52466 or LY 231617 reduced the hippocampal damage. Correlation analysis demonstrated a correlation between hippocampal damage and total swim distance (r = 0.88, P < 0.001). No correlation was found between hippocampal damage and quadrant time of the probe trial (r = -0.24, p > 0.1). No correlation was observed between striatal damage and either total swim distance of the escape trials (r = 0.28. p > 0.1) or quadrant time of the probe trial (r = -0.08, p > 0.6). It is concluded that a correlation exists between hippocampal damage and the deficit in spatial learning following global cerebral ischemia.

Animals↗
PubMed1997

Lymphocyte-derived cytokines induce sequential expression of monocyte- and T cell-specific chemokines in human mesangial cells.

Chemokines are a family of small related proteins that play an important role in the selective recruitment of different leukocyte populations to the sites of inflammation. Human glomerular mesangial cells are potent producers of a variety of chemokines. Here we examined the kinetics of mesangial cell chemokine expression with focus on the C-C or beta chemokines monocyte chemoattractant protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and the C-X-C or alpha chemokine interleukin-8 (IL-8) in response to lymphocyte- or monocyte-derived cytokines and mesangial cell growth factors. It was found that interferon-gamma (IFN-gamma), a cytokine produced by TH1 lymphocytes, synergized with tumor necrosis factor-alpha (TNF-alpha) in RANTES expression and with IL-1 beta in MCP-1 synthesis. Time course studies revealed an early peak of mRNA expression of monocyte-specific MCP-1 upon activation with TNF-alpha in contrast to T cell-specific RANTES, which reached the highest mRNA level after 18 hours. This sequence of TNF-alpha-induced MCP-1 and RANTES expression was confirmed on the protein level. As another T-lymphocyte specific chemokine, MIP-1 alpha mRNA and protein was expressed only in response to TNF-alpha plus IFN-gamma with kinetics similar to those of RANTES expression. Finally, unlike other mesangial growth factors basic fibroblast growth factor (bFGF) induced MCP-1, RANTES, and IL-8 mRNA expression, suggesting an involvement of autocrine regulation mechanisms in mesangial chemokine expression.

Autocrine Communication↗
PubMed1997

Differential abscisic acid regulation of guard cell slow anion channels in Arabidopsis wild-type and abi1 and abi2 mutants.

Abscisic acid (ABA) regulates vital physiological responses, and a number of events in the ABA signaling cascade remain to be identified. To allow quantitative analysis of genetic signaling mutants, patch-clamp experiments were developed and performed with the previously inaccessible Arabidopsis guard cells from the wild type and ABA-insensitive (abi) mutants. Slow anion channels have been proposed to play a rate-limiting role in ABA-induced stomatal closing. We now directly demonstrate that ABA strongly activates slow anion channels in wild-type guard cells. Furthermore, ABA-induced anion channel activation and stomatal closing were suppressed by protein phosphatase inhibitors. In abi1-1 and abi2-1 mutant guard cells, ABA activation of slow anion channels and ABA-induced stomatal closing were abolished. These impairments in ABA signaling were partially rescued by kinase inhibitors in abi1 but not in abi2 guard cells. These data provide cell biological evidence that the abi2 locus disrupts early ABA signaling, that abi1 and abi2 affect ABA signaling at different steps in the cascade, and that protein kinases act as negative regulators of ABA signaling in Arabidopsis. New models for ABA signaling pathways and roles for abi1, abi2, and protein kinases and phosphatases are discussed.

Abscisic Acid↗
PubMed1997

Overexpression of metallothionein decreases sensitivity of pulmonary endothelial cells to oxidant injury.

Metallothionein (MT) is a low-molecular-weight cysteine-rich protein with extensive metal binding capacity and potential nonenzymatic antioxidant activity. Despite the sensitivity of vascular endothelium to either heavy metal toxicity or oxidative stress, little is known regarding the role of MT in endothelial cells. Accordingly, we determined the sensitivity of cultured sheep pulmonary artery endothelial cells (SPAEC) that overexpressed MT to tert-butyl hydroperoxide (t-BOOH), hyperoxia, or 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN; peroxyl radical generator). Nontoxic doses of 10 microM Cd increased MT levels from 0.21 +/- 0.03 to 2.07 +/- 0.24 microg/mg and resulted in resistance to t-BOOH and hyperoxia as determined by reduction of Alamar blue or [3H]serotonin transport, respectively. SPAEC stably transfected with plasmids containing either mouse or human cDNA for MT were resistant to both t-BOOH and hyperoxia. In addition, we examined transition metal-independent, noncytotoxic AMVN-induced lipid peroxidation after metabolic incorporation of the oxidant-sensitive fluorescent fatty acid cis-parinaric acid into phospholipids and high-performance liquid chromatography separation. SPAEC that overexpressed MT after gene transfer completely inhibited peroxyl oxidation of phosphatidylserine, phosphatidylcholine, and sphingomyelin (but not phosphatidylethanolamine) noted in wild-type SPAEC. These data show for the first time that MT can 1) protect pulmonary artery endothelium against a diverse array of prooxidant stimuli and 2) directly intercept peroxyl radicals in a metal-independent fashion, thereby preventing lipid peroxidation in intact cells.

Animals↗
PubMed1997

Cerebral hemispheric low-flow infarcts in arterial occlusive disease. Lesion patterns and angiomorphological conditions.

BACKGROUND AND PURPOSE: Among the pathogenetic causes of subcortical hemispheric infarcts are small-vessel disease, thromboembolic occlusions of small arteries, and hemodynamic compromise in low-flow conditions. A topographic classification of these infarcts based on CT and MRI can be misleading. METHODS: We evaluated 30 consecutive patients with presumed supratentorial low-flow infarcts. CT was available in all cases, with additional MRI in 14 patients. In all cases the occlusion pattern of the extracranial and intracranial arterial system was studied in detail with angiography. RESULTS: The dominant lesion patterns seen on CT and MRI were multilocal chainlike lesions in 19 and confluent striated lesions in 8 cases located in the supraventricular and paraventricular deep white matter. In 8 patients subcortical lesions extended into the adjacent cortex. Angiography revealed that extracranial occlusive disease (n = 24) or stenosis of the middle cerebral artery (n = 6) was always accompanied by impairment of the circle of Willis, in either the anterior part (n = 25) and/or the posterior part (n = 16). Moreover, leptomeningeal pathways indicative of vascular hemispheric compromise were identified in 26 cases. In total, 29 of 30 patients displayed a noncompetent circle of Willis. CONCLUSIONS: Low-flow infarcts show typical but not pathognomonic lesion patterns on CT and MRI. Definite diagnosis requires knowledge of the complex vascular compromise of the extracranial and/or intracranial arterial system. A noncompetent circle of Willis should be regarded as the additional predisposing condition in hemispheric low-flow infarcts.

Arterial Occlusive Diseases↗
PubMed1997

Magnetic resonance imaging studies on the effect of the fibrinogen-lowering agent ancrod on cerebral lesions in two rat models of acute stroke.

In vivo magnetic resonance imaging was used to study the effect of ancrod (CAS 9046-56-4, Arwin), a plasma fibrinogen level lowering agent, on brain lesion in two rat models of acute focal cerebral ischaemia. Total lesion volume was determined by multislice T2-weighted magnetic resonance imaging 24 h after permanent middle cerebral artery occlusion. Intravenous infusion of ancrod starting 30 min after middle cerebral artery occlusion at dosages of 10, 30, 50 or 70 IU/kg (n = 9/group) significantly diminished cerebral lesion volume by 20 to 33% as compared to vehicle-infused controls (n = 12). None of the ancrod-treated rats showed evidence of intracerebral bleeding on T2-weighted magnetic resonance images taken after 24 h. In photochemically induced (rose bengal) unilateral thrombotic cortical infarction brain damage was displayed by multislice diffusion-weighted magnetic resonance imaging after 24 h. Again, post treatment with ancrod reduced total volume of cerebral lesion dose-dependently from 142 +/- 28 mm3 in the controls (n = 10) to 121 +/- 28 mm3 (n = 10) and 111 +/- 20 mm3 (n = 11, p < 0.05) in rats treated with 10 and 30 IU/kg ancrod, respectively (means +/- S.D.). These results suggest cerebroprotection in focal cerebral ischaemia by improvements in the cerebral microcirculation which may offer a potential and safe approach for therapy of acute stroke.

Acute Disease↗
PubMed1996

Dextromethorphan reduces functional deficits and neuronal damage after global ischemia in rats.

Glutamate antagonists have been shown to be neuroprotective in animal models of cerebral ischemia. Global cerebral ischemia in rats leads to selective neuronal damage in the hippocampus and striatum. Following ischemia a transient locomotor hyperactivity and a deficit in spatial learning and memory occurs. The aim of the present study was to investigate the potential neuroprotective effect of dextromethorphan, an antagonist at the N-methyl-D-aspartate receptor, with behavioural and histological measures of global ischemia in rats. Global ischemia was induced by four-vessel occlusion (4VO) for 20 min in rats. Dextromethorphan was administered 20 min before induction of ischemia at a dose of 10 or 50 mg/kg. Before and on day 1, 3 and 5 after operation the spontaneous locomotor activity was measured. One week after surgery spatial learning was tested in the Morris water maze. After behavioural testing the animals were sacrificed and the neuronal damage was assessed. Treatment with 50 mg/kg of dextromethorphan reduced the increase in locomotor activity observed on day 1 and 3 after ischemia. In the water maze dextromethorphan reduced the increase in escape latency and in swim distance induced by 4VO. Furthermore, the ischemia-induced reduction in time spent in the quadrant of the former platform position during the probe trial was increased by treatment with dextromethorphan. Neuronal damage in the CA1 sector of the hippocampus and in the dorsolateral striatum produced by 4VO was significantly attenuated by dextromethorphan. The present results demonstrate that protective effects on neuronal damage may be related to an attenuation of deficits in spatial leaning and memory following global ischemia.

Animals↗
PubMed1996

Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation.

Mice deficient in cholesterol 7alpha-hydroxylase, the rate-limiting enzyme of bile acid biosynthesis, were constructed by targeted disruption of the Cyp7 gene. The introduced mutation removed exons 3-5 of the gene and gave rise to a null allele that encoded no immunoreactive or enzymatically active protein. Heterozygous carriers of the disrupted gene (Cyp7+/-) were phenotypically normal. Homozygous animals (Cyp7-/-) appeared normal at birth, but died within the first 18 days of life. Approximately 40% of the animals died between postnatal days 1 and 4 and 45% between days 11 and 18. The addition of vitamins to the water of nursing mothers prevented deaths in the early period, whereas the addition of cholic acid to chow prevented deaths in the later period. Newborn Cyp7-/- mice whose mothers were maintained on unsupplemented chow failed to gain weight at a normal rate and developed oily coats, hyperkeratosis, and apparent vision defects. These symptoms waned at 3 weeks of life, and their disappearance was accompanied by a marked increase in survival. In the accompanying study, the induction of an alternate pathway of bile acid biosynthesis is shown to underlie this unusual time course (Schwarz, M., Lund, E. G., Setchell, K. D. R., Kayden, H. J., Zerwekh, J. E., Björkhem, I., Herz, J., and Russell, D. W. (1996) J. Biol. Chem. 271, 18024-18031). We conclude that cholesterol 7alpha-hydroxylase is an essential enzyme for normal postnatal development.

Amino Acid Sequence↗
PubMed1996

Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase.

Past experiments and current paradigms of cholesterol homeostasis suggest that cholesterol 7alpha-hydroxylase plays a crucial role in sterol metabolism by controlling the conversion of cholesterol into bile acids. Consistent with this conclusion, we show in the accompanying paper that mice deficient in cholesterol 7alpha-hydroxylase (Cyp7-/- mice) exhibit a complex phenotype consisting of abnormal lipid excretion, skin pathologies, and behavioral irregularities (Ishibashi, S., Schwarz, M., Frykman, P. K. , Herz, J., and Russell, D. W.(1996) J. Biol. Chem. 261, 18017-18023). Aspects of lipid metabolism in the Cyp7-/- mice are characterized here to deduce the physiological basis of this phenotype. Serum lipid, cholesterol, and lipoprotein contents are indistinguishable between wild-type and Cyp7-/- mice. Vitamin D3 and E levels are low to undetectable in knockout animals. Stool fat content is significantly elevated in newborn Cyp7-/- mice and gradually declines to wild-type levels at 28 days of age. Several species of 7alpha-hydroxylated bile acids are detected in the bile and stool of adult Cyp7-/- animals. A hepatic oxysterol 7alpha-hydroxylase enzyme activity that may account for the 7alpha-hydroxylated bile acids is induced between days 21 and 30 in both wild-type and deficient mice. An anomalous oily coat in the Cyp7-/- animals is due to the presence of excess monoglyceride esters in the fur. These data show that 7alpha-hydroxylase and the pathway of bile acid synthesis initiated by this enzyme are essential for proper absorption of dietary lipids and fat-soluble vitamins in newborn mice, but not for the maintenance of serum cholesterol and lipid levels. In older animals, an alternate pathway of bile acid synthesis involving an inducible oxysterol 7alpha-hydroxylase plays a crucial role in lipid and bile acid metabolism.

Age Factors↗
PubMed1996

Memantine reduces functional and morphological consequences induced by global ischemia in rats.

In this study the effect of memantine, an antagonist at the N-methyl-D-aspartate receptor, on spatial learning deficit and on neuronal damage following transient cerebral ischemia was evaluated. Global ischemia was induced by four-vessel-occlusion (4VO) for 20 min in rats. Memantine was administered 20 min before induction of ischemia at a dose of 10 or 20 mg/kg. One week after surgery spatial learning was tested in the Morris water maze. Treatment with the higher dose of memantine reduced the increase in escape latency and in swim distance induced by 4VO. Neuronal damage in the CA1 sector of the hippocampus and in the striatum produced by 4VO was significantly attenuated by 20 mg/kg memantine. Treatment with the lower dose of memantine had no influence on the deficit in spatial learning and the neuronal damage resulting from ischemia. The present data demonstrate that treatment with a neuroprotective agent like memantine can reduce functional as well as morphological sequelae induced by ischemia.

Animals↗
PubMed1996

Antiparkinsonian effect of flupirtine in monoamine-depleted rats.

Excitatory amino acid receptor antagonists lead to marked suppression of parkinsonian-like symptoms in rodent and primate models of Parkinson's disease and are able to potentiate the ability of L-DOPA to reverse akinesia and ameliorate muscular rigidity displayed in these animal models. Flupirtine, which is clinically used as a non-opioid analgesic agent, has some N-methyl-D-aspartate (NMDA) antagonistic properties in several in vivo and in vitro experiments. We now report that in monoamine depleted rats (pretreated with reserpine, 5 mg/kg, and alpha-methyl-para-tyrosine, 250 mg/ kg i.p.) flupirtine dose-dependently (1-20 mg/kg i.p.) suppressed rigidity, measured as tonic EMG activity in the gastrocnemius muscle, but had no effect on akinesia, measured as locomotor activity. In addition, it potentiated the antiparkinsonian effect of L-DOPA on akinesia and rigidity in this rodent model of Parkinson's disease. These effects of flupirtine are of particular clinical relevance, since flupirtine is devoid of the typical side effects of NMDA-receptor antagonists.

Aminopyridines↗
PubMed1996

Application of capillary zone electrophoresis for analyzing biotin in pharmaceutical formulations--a comparative study.

The detection limit and reproducibility of capillary zone electrophoresis (CZE) measurement of biotin were compared to those of a spectrophotometric method and those of the determination of the sulphur content by combustion of the biotin sample followed by coulometric titration of the formed SO2. Drug analysis showed that all three methods gave consistent results and were suitable for the determination of biotin. CZE was found to be the best method for the determination of pharmaceutical formulations containing biotin because of its high separation efficiency, short analysis time, ease of instrumentation and sample preconditioning, and good precision.

Biotin↗
PubMed1996

Stretch reflexes of the proximal arm in a patient with mirror movements: absence of bilateral long-latency components.

The stretch reflex responses evoked by unilateral limb displacement in distal (first dorsal interosseus (FDI)) and in proximal (biceps brachii (Bb)) arm muscles were studied during matched bilateral contractions in a patient with congenital mirror movements. In this patient unilateral transcortical magnetic stimulation (TMS) elicited not only the normal contralateral EMG response but also a clear ipsilateral component in the EMG of both proximal and distal arm muscles. As expected from previous studies, the ipsilateral FDI muscle responded to stretch of the index finger with short- (M1) and long-latency (M2) reflex components. In addition, the FDI contralateral to displacement exhibited an abnormal mirrored response corresponding to the M2 interval. In contrast, whereas the ipsilateral Bb responded to imposed elbow extension with a marked M1/M2 reflex response, no mirroring of either reflex component was apparent in the contralateral Bb EMG. If the mirroring of the M2 in the FDI is accepted as evidence for the transcortical nature of the M2 reflex response, then it follows that the absence of such mirroring in the Bb indicates that a transcortical mechanism cannot play a major role in the generation of long-latency stretch reflex responses in proximal arm muscles.

Adult↗
PubMed1996

Expression of hepatocyte-enriched nuclear transcription factors in mouse liver tumours.

Preneoplastic and neoplastic lesions in rodent liver show alterations in the expression of various enzymes which can be used for their identification. To address the question whether these enzymatic alterations result from specific changes in the levels of hepatocyte-enriched nuclear factors (HNF), we analysed the mRNA levels of six different HNFs (HNF-1alpha, beta, HNF-3alpha, beta, gamma, and HNF-4) by RNase protection assay in chemically induced liver tumours and corresponding normal liver tissue from mice of three different strains. When compared with the normal liver tissue, HNF-1beta, HNF-3alpha and HNF-3beta showed unchanged expression levels in the various liver tumours, which HNF-1alpha and HNF-4 mRNAs were lowered by 20-30%, and HNF-3gamma mRNA was increased by 50%. There were no significant differences in HNF-expression between tumours harbouring point mutations at codon 61 of the Ha-ras protooncogene and tumours without detectable Ha-ras mutations.

9,10-Dimethyl-1,2-benzanthracene↗