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Biomedical subjects

M Jung

Publications and source records attributed to M Jung.

At least 163 records · Page 9Linked to original sources
PubMed1997

pH-dependent changes of nitric oxide, peroxynitrite, and reactive oxygen species in hepatocellular damage.

Low arterial blood pH and sustained nitric oxide (NO) production are critical parameters in inflammatory events such as sepsis, and appropriate treatment is still under debate. Because the stability of nitrogen and oxygen intermediates is dependent on the surrounding pH, we investigated whether the relationship among NO, peroxynitrite (ONOO-), and reactive oxygen species production also depends on the pH value, particularly with respect to their effects on hepatocellular damage. Our studies demonstrate that the extracellular pH influences NO and hydroxyl radical (OH) production in hepatocytes. Acidification (pH 7.0) of the medium revealed a significant increase (P < 0.05) of OH-like radicals, enhanced hepatocellular damage, and a sharp drop in cellular glutathione (GSH) content compared with levels measured at physiological or alkaline pH conditions. Furthermore, inhibition of NO synthesis at all pH conditions resulted in decreased NO production and cellular GSH levels but a simultaneous increase of OH-like radicals and hepatocellular damage with a maximum seen at pH 7.0. Our results suggest that hepatocellular damage is in part regulated by the surrounding pH and that inhibition of NO synthesis at acidic conditions (e.g., in sepsis) leads to increased reactive oxygen-mediated cell injury.

Animals↗
PubMed1997

Attenuated central pressor response to nitric oxide synthesis inhibition in chronic renal failure rats.

OBJECTIVES: Central and peripheral roles of nitric oxide (NO) in blood pressure regulation have been suggested. The present study was aimed at examining if the role of NO in blood pressure regulation is altered in chronic renal failure. METHODS: Blood pressure responses to acute inhibition of NO were examined in 5/6 nephrectomized rats. Three weeks after the renal ablation, under thiopental (50 mg/kg, i.p.) anesthesia, an intracerebroventricular cannula was placed in the left lateral ventricle and the femoral vein was cannulated to serve as an infusion route. The arterial blood pressure was measured in the right femoral artery. NG-nito-L-arginine methyl ester (L-NAME) was infused (100 microgram/kg per min for 60 min either intracerebroventricularly or intravenously. RESULTS: Chronic renal failure rats showed a significantly higher arterial pressure than the control rats (147 +/- 14 mmHg vs. 122 +/- 13 mmHg). Intracerebroventricular L-NAME did not affect the arterial pressure in chronic renal failure rats (0.5 +/- 4 mmHg increase from the basal), while it significantly increased the arterial pressure in normal rats (22 +/- 3 mmHg increases from the basal). Intravenous L-NAME increased the arterial pressure, the magnitude of which did not differ between the normal and chronic renal failure rats (24 +/- 3 vs. 16 +/- 3 mmHg increases from the basal). CONCLUSION: These results indicate that the central role of NO in the regulation of blood pressure is altered in chronic renal failure.

Analysis of Variance↗
PubMed1997

The gene for the ataxia-telangiectasia variant, Nijmegen breakage syndrome, maps to a 1-cM interval on chromosome 8q21.

Nijmegen breakage syndrome (NBS; Seemanová II syndrome) and Berlin breakage syndrome (BBS), also known as ataxia-telangiectasia variants, are two clinically indistinguishable autosomal recessive familial cancer syndromes that share with ataxia-telangiectasia similar cellular, immunological, and chromosomal but not clinical findings. Classification in NBS and BBS was based on complementation of their hypersensitivity to ionizing radiation in cell-fusion experiments. Recent investigations have questioned the former classification into two different disease entities, suggesting that NBS/BBS is caused by mutations in a single radiosensitivity gene. We now have performed a whole-genome screen in 14 NBS/BBS families and have localized the gene for NBS/BBS to a 1-cM interval on chromosome 8q21, between markers D8S271 and D8S270, with a peak LOD score of 6.86 at D8S1811. This marker also shows strong allelic association to both Slavic NBS and German BBS patients, suggesting the existence of one major mutation of Slavic origin. Since the same allele is seen in both former complementation groups, genetic homogeneity of NBS/BBS can be considered as proved.

Alleles↗
PubMed1997

[Risk of gastrectomy for stomach carcinoma in relation to reconstruction methods].

Between 1982 and 1996 we performed 452 total gastrectomies due to gastric cancer. 108 patients underwent a pouch reconstruction called Ulm pouch with preservation of the duodenal passage. In 251 patients, the reconstruction was made according to Hunt-Lawrence-Rodino and in 93 patients, a Roux-en-Y reconstruction without pouch was performed. In the Ulm pouch group, the rate of anastomotic leakage as well as the 30-day mortality was 0.8% and its relative risk was 2.6 times lower than in the other reconstruction groups (n = 452) and therefore, this type of reconstruction can be recommended for all curatively resected patients also with regard to morbidity and mortality.

Adult↗
PubMed1996

Monoclonal antibody O10 defines a conformationally sensitive cell-surface epitope of proteolipid protein (PLP): evidence that PLP misfolding underlies dysmyelination in mutant mice.

Mutations in the gene for proteolipid protein (PLP) have been associated with CNS dysmyelination and abnormal oligodendrocyte death in spontaneous mouse mutants and in Pelizaeus-Merzbacher disease; however, the effect of mutations on PLP structure and function are little understood. We have identified a monoclonal antibody directed against a novel cell surface epitope of PLP, termed O10. By immunofluorescence analysis, COS-7 cells transiently transfected to express PLP (or its isoform DM20) can be stained with antibody O10 and another antibody (A431) directed against the C terminus of PLP/DM20. The subcellular distribution of immunofluorescence labels for the two antibodies is not identical, suggesting that the O10 epitope is acquired post-translationally. When PLP/DM20 from jimpy, jimpymsd, and rumpshaker mutant mice is expressed in COS-7 cells and compared with wild-type PLP/DM20, none of the mutant isoforms displays the O10 epitope, whereas the C-terminal epitope is detected. Because the O10 but not the A431 epitope is also sensitive to SDS and reducing agents, this strongly suggests abnormal protein folding in the PLP mutants. PLP from jimpymsd mice is obviously misfolded, because the amino acid substitution (Ala242 --> Val) is located within a transmembrane domain to which the O10 antibody does not bind. We propose that the O10 epitope emerges as the full length protein reaches a functional tertiary structure and that the absence of this epitope marks a structural defect of PLP that leads to dysmyelination.

Animals↗
PubMed1996

[Sphincter of Oddi disfunction in "idiopathic" recurrent pancreatitis].

OBJECTIVE: As the pathogenesis of acute recurrent pancreatitis remains unclear in 30% of patients, it was the aim of this study to find out whether and how often changes in sphincter of Oddi motility is present in these patients and whether endoscopic treatment promises success. PATIENTS AND METHODS: 18 patients (three men, 15 women; mean age 41.5 [30-56] years) with "idiopathic" acute recurrent pancreatitis seen consecutively between April 1991 and November 1995, were included in the study. In none had laboratory examinations, sonography, computed tomography and endosonography (n = 11) demonstrated any unusual findings. Neither exocrine (pancreaolauryl test in 8, secretin-pancreozymin test in 10 patients), nor endocrine (oral glucose tolerance test) pancreatic insufficiency had been found. Endoscopic retrograde cholangiopancreatography had excluded morphological changes in the biliary-pancreatic system. All patients underwent endoscopic manometry. When a basal sphincter of Oddi pressure > or = 40 mm Hg was demonstrated in the pancreatic sphincter segment, combined endoscopic sphincterotomy was done of both the biliary and the pancreatic component. RESULTS: Nine patients had a raised basal sphincter pressure in the pancreatic segment of the sphincter, but in only four in the biliary one as well. The phasic sphincter motility was normal in all patients. In four patients iatrogenic pancreatitis developed after the procedure (mild in three, moderately severe in one). Eight of the nine patients who had a sphincterotomy remained symptom-free during a mean follow-up period of 21 months, but only three of the nine with normal manometric findings. CONCLUSION: Half of the patients with acute recurrent pancreatitis of unknown cause have sphincter of Oddi dysfunction, usually limited to the pancreatic segment of the sphincter, Endoscopic sphincterotomy can prevent recurrent pancreatitis in most of the patients.

Acute Disease↗
PubMed1996

[Endoscopic manometry in suspected dysfunction of the sphincter of Oddi].

BASIC PROBLEM AND OBJECTIVE OF STUDY: Dysfunction of the sphincter of Oddi may be a cause of persistent problems after cholecystectomy. The aim was to find out whether various factors are of value in predicting abnormal manometric results and thus aid in deciding whether endoscopic manometry is indicated. PATIENTS AND METHODS: 97 patients were investigated prospectively (13 men, 84 women; mean age 50.2 [29-72] years) in which endoscopic cholangiopancreatography (ERCP) had not revealed any cause of the biliary complaints. The patients were divided into three types according to four criteria: (1) history (biliary colics); (2) biochemistry (cholestasis); (3) dilated biliary tract (at ERCP); (4) contrast retention in biliary tract (at ERCP). Type I: all four criteria present; type II: positive history and one or two other criteria; type III: biliary colic only. Endoscopic manometry (EM) was performed after classification of the patients. RESULTS: EM was successful in 83 of 97 patients (86%). All 15 patients of type I had sphincter of Oddi dysfunction (SOD) defined as basic sphincter pressure > 40 mm Hg. SOD was demonstrated in only 23 of 38 patients of type II (61%) and 15 of 30 patients of type III (50%) (P < 0.01). Increased rate of sphincter of Oddi contraction ("tachyoddi") was demonstrated in only four patients (4%), in two of them in combination with an increased basic sphincter pressure. Mild to moderate pancreatitis occurred within 24 hours of manometry in ten of 83 patients. CONCLUSIONS: Endoscopic manometry is not necessary in patients of type I for confirming the diagnosis. But it is obligatory for patients of type II and III, because the demonstration of SOD has therapeutic consequences, and should be performed in clinical studies, if possible.

Adult↗
PubMed1996

Analysis of the catalytic site of the actin ADP-ribosylating Clostridium perfringens iota toxin.

The enzyme component of actin ADP-ribosylating Clostridium perfringens iota toxin was affinity labelled by UV irradiation in the presence of [carbonyl-14C]NAD. A peptide containing the radiolabel was generated by CNBr cleavage and subsequent proteolysis with trypsin. Its amino acid sequence is Gly-Ser-Pro-Gly-Ala-Tyr-Leu-Ser-Ala-Ile-Pro-Gly-Tyr-Ala-Gly-X-Tyr-Glu-Va l-Leu-Leu-Asn-His-Gly-Ser-Lys corresponding with the region Gly-363 through Lys-388 in the C. perfringens iota toxin. Mass spectrometric data as well as results of the PTH-amino acid analysis are in line with a modification of a glutamic acid side chain located at position 378. Therefore, in addition to Glu-380, as could be concluded by analogy with other ADP-ribosyltransferases, Glu-378 may play a pivotal role in the active site of C. perfringens iota toxin.

ADP Ribose Transferases↗
PubMed1996

Active site mutation of the C3-like ADP-ribosyltransferase from Clostridium limosum--analysis of glutamic acid 174.

Clostridium limosum ADP-ribosyltransferase modifies low molecular mass GTP-binding proteins of the Rho subtype family. Here we cloned and sequenced the gene of the transferase and expressed it in Escherichia coli. The gene encodes a protein of 250 amino acids (M(r) = 27,840), with a putative signal peptide of 45 amino acids, that shows about 60-65% identity with C3 transferases from Clostridium botulinum. The mature C. limosum transferase was expressed as a maltose-binding fusion protein in E. coli and purified to apparent homogeneity. To study the functional role of Glu174 of C. limosum transferase, which was recently photoaffinity-labeled with [carbonyl-14C]NAD [Jung, M., et al. (1993) J. Biol. Chem. 268, 23215-23218], two mutants E174D and E174Q were constructed by a polymerase chain reaction-based system. The E174D and E174Q mutants showed a dramatic decrease in kcat, but no major changes in Km,NAD. Furthermore, replacement of Glu174 by aspartic acid and glutamine largely reduced and completely blocked UV-induced incorporation of [carbonyl-14C]NAD into the transferase. The data indicate that Glu174 is an active site residue of C. limosum transferase.

ADP Ribose Transferases↗
PubMed1996

Radiation-induced neoplastic transformation of human prostate epithelial cells.

We report the malignant transformation of human prostate epithelial cells (267B1) after multiple exposures to ionizing radiation. Carcinogenic progression of cells from immortal growth to anchorage-independent growth in soft agar to tumorigenicity in athymic mice resulted after a cumulative X-ray dose of 30 Gy. The tumors were characterized histologically as poorly differentiated adenocarcinomas, expressed prostate-specific antigen, and stained positive for keratin. No p53 or ras mutations were observed. Numerous chromosomal defects were noted on karyotypes after radiation exposure. However, chromosome 3 and 8 translocations were observed predominantly in the tumor outgrowths. These findings provide the first evidence of malignant transformation of human prostate epithelial cells exposed to ionizing radiation.

Animals↗
PubMed1996

Dextrin sulfopropyl ether: a novel anionic chiral buffer additive for enantiomer separation by electrokinetic chromatography.

Dextrin 10 sulfopropyl ether (DSPE) was prepared and characterized by matrix-assisted laser-desorption ionization-mass spectrometry (MALDI-MS) using a recently developed matrix. The anionic compound was used as a novel chiral buffer additive for enantiomer separation by capillary electrophoresis, thereby changing into the elektrokinetic chromatography (EKC) mode. DSPE was systematically evaluated as a chiral selector and was compared to the respective nonderivatized maltodextrin. DSPE showed an increased separation power for cationic racemic solutes. Although not quite as versatile and powerful as cyclodextrins, the inexpensive dextrin 10 and its derivative DSPE showed remarkable enantioselectivity in some cases.

Anions↗
PubMed1996

Electrophysiological, behavioural and biochemical evidence for activation of brain noradrenergic systems following neurokinin NK3 receptor stimulation.

The objective of the present in vitro and in vivo experiments was to examine the involvement of neurokinin NK3 receptors in the regulation of the noradrenergic function in gerbils and guinea-pigs. Application of senktide, a peptide NK3 receptor agonist, on guinea-pig locus coeruleus slices increased the firing rate of presumed noradrenergic neurons (EC50 = 26 nM) in a concentration-dependent manner. Given i.c.v., senktide (0.5-2 micrograms) and (MePhe7)neurokinin B (1-10 micrograms), another NK3 receptor agonist, reduced exploratory behaviour in gerbils in a dose-dependent manner (2 micrograms of senktide producing a 50% reduction of locomotor activity and rearing). In vivo microdialysis experiments in urethane-anaesthetized guinea-pigs showed that senktide (2-8 micrograms i.c.v.) induced a dose-dependent increase in norepinephrine release in the medial prefrontal cortex. The electrophysiological, behavioural and biochemical changes elicited by senktide were concentration- or dose-dependently reduce by SR 142801, the selective non-peptide NK3 receptor antagonist. In the locus coeruleus slice preparation, complete antagonism of senktide (30 nM) was observed with 50 nM of SR 142801, while injected i.p. (0.1-1 mg/kg) it abolished the senktide-induced norepinephrine release in guinea-pigs. In gerbils, SR 142801 (1-10 mg/kg i.p.) reversed the reduction of exploratory behaviour induced by senktide (1 microgram). By contrast, the 100-fold less active enantiomer, SR 142806, did not exert any antagonism in these models. Finally, the reduction of exploratory behaviour in gerbils was found to be reversed by prazosin (0.25-2.56 micrograms/kg i.p.) and to some extent by clonidine, drugs known to depress noradrenergic function. All these experiments strongly support the hypothesis that brain noradrenergic neurons can be activated by stimulation of neurokinin NK3 receptors.

Adrenergic Fibers↗
PubMed1996

Signal Transduction and Cellular Responses to Ionizing Radiation.

The current understanding of cellular responses to ionizing radiation fuses traditional radiobiological concepts with recent insight into underlying molecular mechanisms. Cell cycle arrest, induction of specific cascades of genes, and activation of DNA repair mechanisms have been reported after radiation exposure. Of particular importance is the mitogen-activated protein (MAP) kinase signaling pathway, in which the ras and raf oncogenes participate. Both of these genes have been implicated in the cellular resistance to killing by ionizing radiation. Furthermore, regulated NF-gammaB transcriptional activation may be important for the pleiotrophic responses of cells to ionizing radiation. Disruption of this signaling cascade may contribute to the radiation sensitivity syndrome seen in ataxia telangiectasia. In this review, these pathways are consolidated into ionizing radiation signal transduction pathways that lead from the cell membrane/cytosol to the nuclear DNA.

Journal Article↗
PubMed1996

Linkage of the gene for the triple A syndrome to chromosome 12q13 near the type II keratin gene cluster.

The triple A or Allgrove's syndrome (MIM*231550) is an autosomal recessive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima. Since its first description by Allgrove et al. (1978) more than 70 cases from all over the world have been reported. The syndrome manifests itself during the first decade of life with severe hypoglycaemic episodes which can cause sudden death. The frequent association with neurological disorders presenting as a mixed pattern of upper and lower motor neuropathy, sensory impairment, autonomic neuropathy and mental retardation may result in a severely disabling disease. As an additional feature some patients have hyperkeratosis of their palms and soles. We have performed a systematic genome linkage scan in eight triple A families of which three were consanguineous [including the large highly inbred kindred described by Moore et al. (1991)]. We obtained conclusive evidence for linkage of the triple A syndrome locus to markers on chromosome 12q13 (D12S368, theta max = 0, Zmax = 10.81) with no indication of genetic heterogeneity. Haplotype and multipoint analyses suggest that the gene is located on a chromosomal segment flanked by the markers D12S1629 and D12S312 which are 6 cM apart. This region harbors the type II keratin gene cluster, and potential candidate genes include SCN8A and HOXC genes.

Adrenal Insufficiency↗