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Biomedical subjects

K Schmidt

Publications and source records attributed to K Schmidt.

At least 325 records · Page 18Linked to original sources
PubMed1992

Neonatal hemochromatosis: genetic counseling based on retrospective pathologic diagnosis.

We report a case of neonatal hemochromatosis in which the genetic counseling was initiated by, and based on, retrospective pathologic diagnosis. Perinatal or neonatal hemochromatosis is beginning to be recognized as a distinct clinical entity and one of the most common causes of perinatal cirrhosis. The exact mechanism of liver damage and the relationship to adult type hemochromatosis have not been fully clarified. The pattern of fibrosis in the liver plus the abundant iron deposition in the liver and other organs separate this entity pathologically from other causes of neonatal liver failure. We report on a case of neonatal hemochromatosis that was diagnosed on retrospective autopsy review of an infant with supposed hereditary tyrosinemia, when the family presented for genetic counseling. This case emphasizes to the genetic counselor and pathologist the need to consider the diagnosis prenatally, after birth, or at death, as failure to do so would result in the inability to identify families at genetic risk for neonatal hemochromatosis or in mislabeling a family with another inborn error.

Female↗
PubMed1992

Hydrogenase mutants of Alcaligenes eutrophus H16 show alterations in the electron transport system.

Mutations in the genes coding for the soluble and the membrane-bound hydrogenase of Alcaligenes eutrophus strain H16 significantly affected the expression of respiratory chain components. In lithoautotrophically grown wild type cells electron flow mainly proceeded via the cytochrome c oxidases. Mutants defective in the membrane-bound hydrogenase contained a 2- to 3-fold higher cytochrome a content than the wild type and cytochrome c oxidase of the aa3-type was preferentially used by these cells for substrate oxidation. Mutants impaired in the soluble hydrogenase revealed slow growth on hydrogen, presumably due to inefficient reverse electron flow mechanisms which provide the cells with NADH for autotrophic CO2-fixation. In this class of mutants the two quinol oxidases of the o- and d-type in addition to the co-type oxidase were the predominant electron-transport branches.

Alcaligenes↗
PubMed1992

SK&F 96365 inhibits histamine-induced formation of endothelium-derived relaxing factor in human endothelial cells.

Formation of endothelium-derived relaxing factor (EDRF) strictly correlates with the intracellular free Ca2+ ([Ca2+]i) concentration. We now demonstrate that the histamine-induced rise in [Ca2+]i of human umbilical vein endothelial cells is mostly due to activation of a membrane current which allows Ca2+ entry. This membrane current is sensitive to the novel inhibitor of agonist-induced Ca2+ entry, SK&F 96365, which blocked the histamine-induced sustained rise in [Ca2+]i, as well as 45Ca2+ uptake and membrane currents. Inhibition of the above cellular responses to histamine was accompanied by a considerable reduction of EDRF formation and release. Thus biosynthesis and release of EDRF from human umbilical vein endothelial cells significantly depend on agonist-induced Ca2+ entry involving receptor-operated Ca(2+)-permeable channels which can be blocked by SK&F 96365.

Calcium↗
PubMed1992

High-density lipoprotein antagonizes the inhibitory effects of oxidized low-density lipoprotein and lysolecithin on soluble guanylyl cyclase.

Oxidatively modified LDL (LDLox) reduces the response of soluble guanylyl cyclase to nitrovasodilators. We now demonstrate that this desensitization can be antagonized by HDL. Similar to its protective effect against LDLox, HDL also inhibited the lysolecithin-induced desensitization of soluble guanylyl cyclase. Since the lysolecithin content of LDLox correlated with the amount of lysolecithin necessary to diminish stimulation of soluble guanylyl cyclase, our data support the hypothesis that lysolecithin may be responsible for the inhibitory effect of LDLox on smooth muscle relaxation and provide evidence that the antagonistic effect of HDL against desensitization of soluble guanylyl cyclase by atherogenic compounds could be responsible for the protective role of HDL in atherosclerosis.

Animals↗
PubMed1992

Tetrahydrobiopterin-dependent formation of endothelium-derived relaxing factor (nitric oxide) in aortic endothelial cells.

Inhibition of tetrahydrobiopterin (H4biopterin) biosynthesis in endothelial cells almost completely abolished the agonist-induced formation of endothelium-derived relaxing factor (EDRF) (NO). This inhibitory effect could be antagonized when H4biopterin biosynthesis was restored by activating a salvage pathway. These data indicate that the formation of EDRF strictly depends on the presence of intracellular H4biopterin, which, in addition to Ca2+, may represent a further physiological and/or pathophysiological regulatory of endothelial NO synthases.

Animals↗
PubMed1992

Is the bradykinin-induced Ca2+ influx and the formation of endothelium-derived relaxing factor mediated by a G protein?

In cultured porcine aortic endothelial cells bradykinin produced a long-lasting Ca2+ influx. In contrast to the G protein-independent Ca2+ entry evoked by ionomycin or digitonin, bradykinin-induced Ca2+ influx was antagonized by Ni2+ with an IC50 value of about 50 microM. Since identical IC50 values for Ni2+ were found when Ca2+ entry was induced by sodium fluoride or GTP gamma S, we suggest that stimulation of G protein(s) results in the activation of the same Ca2+ channels as stimulation by bradykinin. This conclusion is supported by our findings that inhibition of GTPase by mepacrine amplified bradykinin-stimulated Ca2+ influx, but did not interfere with the effect of the Ca2+ ionophore A23187. Similar to its effect on Ca2+ influx, mepacrine also potentiated endothelium-derived relaxing factor (EDRF) formation by bradykinin and sodium fluoride, but did not affect A23187-induced EDRF biosynthesis. We therefore suggest that in endothelial cells the bradykinin-induced Ca2+ influx and the resulting formation of EDRF are regulated by a G protein.

Animals↗
PubMed1992

Hypercalcemia in idiopathic myelofibrosis: modulation of calcium and collagen homeostasis by 1,25-dihydroxyvitamin D3.

A case of idiopathic myelofibrosis (IMF) presenting with hypercalcemia and hypercalcitriolemia is reported. It is proposed that ectopic production of the active vitamin D metabolite related to ongoing clonal expansion in the bone marrow accounts for the hypercalcemic state. Consistently low levels of circulating type I procollagen propeptide (PICP) and lack of progression of the bone marrow fibrosis during almost 6 months of follow-up point to an in vivo inhibition of type I collagen synthesis by 1,25-dihydroxyvitamin D3.

Adult↗
PubMed1992

Gallstones in acromegalic patients undergoing different treatment regimens.

The frequency of gallstones during long-term treatment with the somatostatin analogue octreotide reported in different studies varies from 0% to 50%, the reason for this variation being unknown. Therefore, we examined 58 acromegalic patients undergoing different treatment regimens for the frequency of gallstones. Thirteen were treated with octreotide, 20 with bromocriptine, and 25 had no medical treatment after successful neurosurgery. Also, 58 patients without known gallbladder disease served as controls. The postprandial gallbladder contraction was also investigated in 27 acromegalic patients (10 with octreotide, 10 with bromocriptine, and 7 with no medical therapy). Ten of the 58 acromegalic patients were found to have gallstones, 4 of 25 receiving no medical treatment, 4 of 20 treated with dopamine agonists, and 2 of 13 treated with octreotide. In 9 of the 58 control patients, gallstones were detected. Although in the octreotide group the gallstones were newly formed under therapy, there was no difference in gallstone prevalence between the different treatment regimens and the control group. However, the postprandial gallbladder contraction was significantly more often inhibited during octreotide therapy, and this effect was most pronounced during the first hours following injection. Differences in the timing of injections therefore may be an explanation of the variable incidence of cholelithiasis in the different studies.

Acromegaly↗
PubMed1992

Molecular diagnosis of the Prader-Willi and Angelman syndromes by detection of parent-of-origin specific DNA methylation in 15q11-13.

The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are distinct genetic disorders that are caused by a deletion of chromosome region 15q11-13 or by uniparental disomy for chromosome 15. Whereas PWS results from the absence of a paternal copy of 15q11-13, the absence of a maternal copy of 15q11-13 leads to AS. We have found that an MspI/HpaII restriction site at the D15S63 locus in 15q11-13 is methylated on the maternally derived chromosome, but unmethylated on the paternally derived chromosome. Based on this difference, we have devised a rapid diagnostic test for patients suspected of having PWS and AS.

Adult↗
PubMed1992

Effect of constituents of burned skin and in vivo skin burning on the respiratory activity of rat liver mitochondria.

The formation of toxic substances in the skin, due to the influence of thermal energy, is supposed to be one possible mechanism responsible for the high mortality rate after severe burns covering large areas of the body surface. The effects of low-molecular-weight volatile substances (dry distillates) generated after burning mouse skin were investigated. They led to reductions of the respiratory activity of rat liver mitochondria. Among other substances carbon disulphide, methylethylketone and pyrrole were isolated and characterized using gas chromatography. All of them had strong uncoupling effects on mitochondrial respiration. In a second study respiratory measurements were made on mitochondria from rats with 20-30 per cent TBSA full skin thickness burns. A decreased respiratory control ratio and thus uncoupling of mitochondrial respiration was found on days 1, 2 and 5 postburn. The basal mitochondrial respiration was significantly decreased on day 5, which could be important for the mortality mentioned above. Finally after cross-transplantations rats having burned skin grafted showed a reduction of the RCR when compared with rats with the unburned graft. Thus it can be concluded that toxic substances must have been present in burned skin.

Animals↗
PubMed1992

Errors introduced by tissue heterogeneity in estimation of local cerebral glucose utilization with current kinetic models of the [18F]fluorodeoxyglucose method.

The effects of tissue heterogeneity on the estimation of regional cerebral glucose utilization (rCMRglc) in normal humans with [18F]2-fluoro-2-deoxy-D-glucose ([18F]FDG) and positron emission tomography (PET) were compared with respect to the various kinetic models of the [18F]FDG method. The kinetic models were conventional homogeneous tissue models of the [18F]FDG method, with (4K Model) and without (3K Model) a rate constant to account for an apparent loss of [18F]2-fluoro-2-deoxy-D-glucose-6-phosphate ([18F]FDG-6-P), and a tissue heterogeneity model (TH Model). When either of the kinetic models designed for homogeneous tissues was applied to heterogeneous tissues, estimates of the rate constant for efflux of [18F]FDG from the tissue (k2*) and of the rate constant for phosphorylation of [18F]FDG (k3*) decreased as the duration of the experimental period was increased. When the 4K Model was used, estimates of the rate constant for the apparent dephosphorylation of [18F]FDG-6-P (k4*) were significantly greater than zero and fell with increasing duration of the experimental period. Although the TH Model included no term to describe an apparent dephosphorylation of [18F]FDG-6-P, the fit of the TH Model to the time course of total tissue radioactivity was at least as good as and often better than the fit of the 4K Model in the 120-min period following the pulse of [18F]FDG. Hence, the high estimates of k4* found in PET studies of less than or equal to 120 min can be explained as the consequence of measuring radioactivity in a heterogeneous tissue and applying a model designed for a homogeneous tissue; there remains no evidence of significant dephosphorylation of [18F]FDG-6-P in this time period. Furthermore, use of the 4K Model led to an overestimation of rCMRglc; whole-brain glucose utilization calculated with the 4K Model was greater than 20% higher than values usually obtained in normal humans by the model-independent Kety-Schmidt technique. rCMRglc was accurately estimated by the TH Model and, in experimental periods sufficiently long to minimize the effects of tissue heterogeneity, also by the original 3K Model of the deoxyglucose method.

Adult↗
PubMed1992

Nitric oxide synthase-catalyzed activation of oxygen and reduction of cytochromes: reaction mechanisms and possible physiological implications.

Purified cerebellar nitric oxide (NO) synthase was found to reduce molecular oxygen to hydrogen peroxide at low concentrations of its substrate L-arginine or its cofactor tetrahydrobiopterin. The characteristics of oxygen reduction appeared to be similar to NO synthesis, as both reactions required reduced nicotinamide adenine dinucleotide phosphate (NADPH), were dependent on Ca2+/calmodulin, and showed optimal reaction rates at slightly acidic conditions. The electron transport from NADPH to molecular oxygen is probably mediated by the reduced flavins, flavine adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are bound in stoichiometrical amounts to the enzyme. NO synthase shows similarities to cytochrome P450 (cytochrome c) reductase, another FAD- and FMN-containing enzyme, and we found that NO synthase reduced cytochromes and artificial, low molecular mass electron acceptors in a superoxide dismutase-insensitive manner. Thus, NO synthase apparently represents a Ca(2+)-regulated, soluble isoform of cytochrome P450 reductase.

Amino Acid Oxidoreductases↗
PubMed1992

The isolation and identification of Leptospira interrogans serovar bratislava from a pig in Germany.

During a study on the improvement of selective media for the isolation of leptospires from clinical material, leptospires were isolated from the kidneys of a pig. Test material was cultured in EMJH-medium containing 0.4% rabbit serum and 3 inhibitory substances (Rifampicin 10 micrograms/ml, Amphotericin B 2 micrograms/ml, 5-Fluorouracil 100 micrograms/ml). The cultured leptospira-strain (Berlin 406) was identified to serogroup level using the cross agglutination method and it was further typed to serovar level by MAB's, factor analysis and restriction endonuclease analysis (REA). MAB typing of Berlin 406 gave an agglutination pattern profile typical of serovar bratislava. Factor serum identification clearly identified this strain as serovar bratislava. On REA examination, Berlin 406 gave a profile identical to that of the serovar bratislava type strain Jez Bratislava i.e. genotype B1. This is the first report of a confirmed isolate of Leptospira interrogans serovar bratislava from domestic animals in Germany. There exist a number of possibly important implications as this agent is being incriminated in the cause of clinical disease not only in pigs, but also in horses and dogs in other countries.

Animals↗
PubMed1992

Regulation of neuronal nitric oxide and cyclic GMP formation by Ca2+.

Nitric oxide (NO) acts as a messenger molecule in the CNS by activating soluble guanylyl cyclase. Rat brain synaptosomal NO synthase was stimulated by Ca2+ in a concentration-dependent manner with half-maximal effects observed at 0.3 microM and 0.2 microM when its activity was assayed as formation of NO and L-citrulline, respectively. Cyclic GMP formation was apparently inhibited, however, at Ca2+ concentrations required for the activation of NO synthase, indicating a down-regulation of the signal in NO-producing cells. Purified synaptosomal guanylyl cyclase was not inhibited directly by Ca2+, and the effect was not mediated by a protein binding to guanylyl cyclase at low or high Ca2+ concentrations. In cytosolic fractions, the breakdown of cyclic GMP, but not that of cyclic AMP, was highly stimulated by Ca2+, and 3-isobutyl-1-methylxanthine did not block this reaction effectively. The effects of Ca2+ on cyclic GMP hydrolysis and on apparent guanylyl cyclase activities were abolished almost completely in the presence of the calmodulin antagonist calmidazolium, whose effect was attenuated by added calmodulin. Thus, a Ca2+/calmodulin-dependent cyclic GMP phosphodiesterase is highly active in synaptic areas of the brain and may prevent elevations of intracellular cyclic GMP levels in activated, NO-producing neurons.

1-Methyl-3-isobutylxanthine↗
PubMed1992

Filtration dynamics and natriuretic response to volume expansion in humans.

We used differential solute clearances and a theoretical analysis of glomerular ultrafiltration and dextran sieving to characterize the hemodynamic response of nine healthy humans to infusion of isoncotic, 5% albumin in saline or saline vehicle alone. During albumin infusion (10.2 +/- 0.2 ml.kg-1.30 min-1) plasma volume increased by 18%, but oncotic pressure rose by only 0.8 mmHg. Despite the hypervolemia, renal blood flow (RBF) declined by 140 ml/min and glomerular filtration rate (GFR) declined by 16 ml/min during the infusion. RBF increased progressively postinfusion, exceeding baseline by 135 ml/min after 4 h; GFR was restored to baseline. Although oncotic pressure declined by 2 mmHg, a similar transient decline in GFR (-13 ml/min) was associated also with infusion of saline vehicle alone (9.4 +/- 0.3 ml.kg-1.30 min-1), which increased plasma volume by 9%. Sieving coefficients of dextrans (radius 32-42 A) were lowered during and after either infusion, a phenomenon that we compute to reflect a reduction in glomerular pore size. Assuming that the transcapillary hydraulic pressure difference was not lowered, we calculate that there was a simultaneous depression of the ultrafiltration coefficient (Kf) during volume expansion with saline and possibly also to a lesser extent with albumin. The hypofiltration during either infusion delayed the onset of a natriuretic response until the filtered sodium load was restored to baseline in the postinfusion period. We propose that the net effect of changes in intracapillary pressures and Kf during volume expanding infusions is to transiently lower GFR, thereby preventing the human kidney from mounting an immediate natriuretic response to acute hypervolemia.

Adult↗