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Biomedical subjects

J Stadler

Publications and source records attributed to J Stadler.

At least 19 recordsLinked to original sources
PubMed1992

Inhibition of nitric oxide synthesis during endotoxemia promotes intrahepatic thrombosis and an oxygen radical-mediated hepatic injury.

Corynebacterium parvum-treated mice produce large amounts of circulating nitrogen oxides and develop a severe liver injury in response to lipopolysaccharide (LPS). Concurrent administration of NG-monomethyl-L-arginine not only suppresses nitric oxide synthesis in these animals but also profoundly increases the hepatic damage following LPS. In this report, we present evidence that the increased hepatic damage from inhibition of nitric oxide synthesis is mediated in part by superoxide and hydroxyl radicals. The hepatic damage induced by suppressing nitric oxide production during endotoxemia could be reduced by treating mice with superoxide dismutase and deferoxamine, scavengers of superoxide and hydroxyl radicals, respectively. This damage could also be prevented by treating mice with the anticoagulant heparin sodium. The results suggest that nitric oxide synthesis during endotoxemia is important in preventing hepatic damage by reducing oxygen radical-mediated hepatic injury and preventing intravascular thrombosis.

Animals↗
PubMed1992

The effect of lowering faecal pH on the rate of proliferation of the normal colonic mucosa.

Epidemiological and animal studies suggest that faecal pH may be a risk factor for colorectal cancer with low faecal pH associated with a lower incidence of the disease. The aim of this study was to determine whether faecal pH (or dietary fibre) affects the short-term risk factors for colon cancer. Sixty-nine normal volunteers were randomized into three equal groups (A-C). They provided food records, faecal specimens and submitted to rectal biopsy for thymidine labelling studies before and after a 2-week intervention. Group A received a placebo of fruit juice. Group B, approximately 3.0 g d-1 sodium sulphate in juice. Group C, 30 g d-1 supplementary dietary fibre as wheat bran in bread. Age, sex, weight, height and intake of macronutrients and minerals were similar in the groups prior to intervention. Faecal pH was similar for the three groups before and was reduced in Group B after intervention (P = 0.001) with a relative reduction of 0.5 pH units. The labelling index for the three groups was similar prior to intervention; after, it was lowest in Group B with a relative reduction of 0.5% points, although this difference was not statistically significant. The results thus do not support the hypothesis that an acidification of faecal pH leads to a reduction in risk markers for colon cancer.

Adult↗
PubMed1992

Tumor necrosis factor alpha inhibits hepatocyte mitochondrial respiration.

Although direct cytotoxicity is a well-established phenomenon of tumor necrosis factor alpha (TNF alpha)-induced tissue damage, the intracellular events leading to cell death are still poorly understood. To study the cytotoxic effects of TNF alpha on normal parenchymal cells, rat hepatocytes were purified and incubated with various concentrations of TNF alpha. Mitochondrial respiration, total protein synthesis, and enzyme release were measured to assess metabolic performance and cell integrity. Treatment with TNF alpha suppressed mitochondrial respiration in a concentration-dependent fashion, resulting in a reduction of the activity of complex I of the respiratory chain to 67.0 +/- 3.5% of that of untreated hepatocytes by 2000 U/mL TNF alpha. Under these conditions protein synthesis and the release of intracellular enzymes were significantly increased. Both hepatocellular enzyme release and inhibition of mitochondrial respiration appear to be associated with the generation of reactive oxygen intermediates by the hepatocyte itself, because oxygen radical scavengers prevented these adverse effects of TNF alpha. Inhibition of protein synthesis by cycloheximide as well as addition of cyclic adenosine monophosphate synergistically enhanced the suppression of mitochondrial respiration by TNF alpha, resulting in complex I activity of 6.9 +/- 1.6% and 24.9 +/- 2.9% of that of untreated cells. These data indicate that inhibition of mitochondrial respiration is one of the mechanisms by which TNF alpha induces tissue injury.

Alanine Transaminase↗
PubMed1992

Nitric oxide synthesis serves to reduce hepatic damage during acute murine endotoxemia.

BACKGROUND AND METHODS: Nitric oxide synthesis occurs both in vitro and in vivo in response to inflammatory stimuli and can have profound effects on the local cellular environment. Hepatocytes, Kupffer cells, and endothelial cells produce nitric oxide in vitro, but the in vivo role of this reactive mediator in the liver is unknown. We assessed the role of nitric oxide synthesis during endotoxemia in mice by inhibiting its synthesis with NG-monomethyl-L-arginine after lipopolysaccharide injection and by determining the effects of this inhibition on hepatic damage. RESULTS: Injection of lipopolysaccharide in mice increased plasma nitrite and nitrate concentrations, the stable end products of nitric oxide metabolism, and caused mild hepatic damage as measured by increased circulating hepatocellular enzyme levels. NG-monomethyl-L-arginine decreased plasma nitrite and nitrate values, but increased the lipopolysaccharide-induced hepatic injury. NG-monomethyl-L-arginine caused no hepatic damage when given without lipopolysaccharide. The extent of hepatic damage with NG-monomethyl-L-arginine was proportional to the dose of lipopolysaccharide used and could be reduced with concurrent administration of L-arginine but not D-arginine. CONCLUSIONS: Nitric oxide synthesis provides a protective function against lipopolysaccharide-induced liver injury that increases in importance as the degree of endotoxemia increases. The production of nitric oxide is, therefore, an important part of the liver's response to a systemic inflammatory stimulus.

Acute Disease↗
PubMed1992

Association between synthesis and release of cGMP and nitric oxide biosynthesis by hepatocytes.

Hepatocytes are known to synthesize nitric oxide (NO) from L-arginine via an inducible NO synthase. Studies were performed to determine the relationship between hepatocyte NO production and the stimulation of hepatocyte soluble guanylate cyclase. A combination of lipopolysaccharide (LPS), interferon-gamma, tumor necrosis factor, and interleukin-1 stimulates the biosynthesis of large quantities of nitrite and nitrate (NO2- + NO3-). Hepatocyte NO2- + NO3- production was associated with only small increases in intracellular guanosine 3',5'-cyclic monophosphate (cGMP) levels but much greater increases in extracellular cGMP release over an 18-h time period. This cGMP synthesis was dependent on the L-arginine concentration and was inhibited in a reversible manner by NG-monomethyl-L-arginine. The cytokines or LPS added alone induced small increases in nitrogen oxide production and concomitant minor elevations in cGMP release. Atrial natriuretic peptide also stimulated the release of cGMP by hepatocytes which appeared to be independent of the cytokine+LPS-induced cGMP release. The addition of probenecid reduced the cGMP release by 66%, while cell damage was excluded as a cause for the extracellular release. Addition of 3-isobutyl-1-methylxanthine, but not M&B 22948, increased hepatocyte intra- and extracellular cGMP levels after cytokine+LPS stimulation. Induction of nitrogen oxide synthesis by hepatocytes in vivo by injecting rats with killed Corynebacterium parvum resulted in increased cGMP levels in freshly isolated hepatocytes and increased cGMP release by the hepatocytes when placed in culture.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Articular chondrocytes synthesize nitric oxide in response to cytokines and lipopolysaccharide.

Although IL-1 is an important modulator of chondrocyte metabolism, the postreceptor events triggered by IL-1 remain obscure. The present study shows that IL-1 induces the biosynthesis of nitric oxide (.N = O) by articular chondrocytes. Synthesis of .N = O is also induced by LPS. Other inflammatory mediators such as IFN-gamma, fibroblast growth factor, and TNF-alpha fail to provoke the production of .N = O, but they increase the potency of IL-1. A combination of IL-1, LPS, and TNF-alpha was shown to induce maximal production of 355 +/- 51 nmol/10(6) cells/72 h of nitrite (NO2-), which was measured as a stable end-product of .N = O generation. The biosynthesis of .N = O requires an induction period of approximately 6 h and continues for at least 72 h. Inhibition of .N = O production with the competitive inhibitor NG-monomethyl-L-arginine (NMA) leads to a suppression of gelatinase and PGE2 synthesis by chondrocytes activated with IL-1 alone. In contrast, NMA enhances the synthesis of both gelatinase and PGE2 after activation with a combination of IL-1, LPS, and TNF-alpha. An increase of PGE2 synthesis from 42.0 +/- 21.0 to 174.0 +/- 33.5 ng/10(6) cells/72 h resulted from the addition of NMA when these stimulatory agents were combined. Exposure of IL-1 and fibroblast growth factor-stimulated chondrocytes to authentic, exogenous .N = O led to an increase of PGE2 synthesis from 5.6 +/- 1.7 of untreated cells to 15.8 +/- 6.8 ng/10(6) of .N = O treated cells within the 1st h. This was followed by a suppression of PGE2 synthesis within the next 2 h.

Animals↗
PubMed1991

Effect of endogenous nitric oxide on mitochondrial respiration of rat hepatocytes in vitro and in vivo.

Nitric oxide, a highly reactive radical, was recently identified as an intermediate of L-arginine metabolism in mammalian cells. We have shown that nitric oxide synthesis is induced in vitro in cultured hepatocytes by supernatants from activated Kupffer cells or in vivo by injecting rats with nonviable Corynebacterium parvum. In both cases, nitric oxide biosynthesis in hepatocytes was associated with suppression of total protein synthesis. This study attempts to determine the effect of nitric oxide biosynthesis on the activity of specific hepatocytic mitochondrial enzymes and to determine whether inhibition of protein synthesis is caused by suppression of energy metabolism. Exposure of hepatocytes to supernatants from activated Kupffer cells led to a 30% decrease of aconitase (Krebs cycle) and complex I (mitochondrial electron transport chain) activity. Using NG-monomethyl-L-arginine, an inhibitor of nitric oxide synthesis, we demonstrated that the inhibition of mitochondrial aconitase activity was due, in part, to the action of nitric oxide. In contrast, in vivo nitric oxide synthesis of hepatocytes from Corynebacterium parvum-treated animals had no effect on mitochondrial respiration. This suggests that inhibition of protein synthesis by nitric oxide is not likely to be mediated by inhibition of energy metabolism.

Aconitate Hydratase↗
PubMed1991

Intraoperative ultrasonographic detection of occult liver metastases in colorectal cancer.

The efficacy of intraoperative ultrasonographic detection of colorectal cancer liver metastases was evaluated in 85 patients undergoing operation for primary colorectal tumors or liver secondaries. The results of intraoperative ultrasonography were compared with those of preoperative ultrasonography and computed tomography, as well as the intraoperative appearances of the liver. Additional information about the number of metastases was obtained in 12 cases (14.1%); 17 (24.3%) out of 70 metastases could only be detected by intraoperative ultrasonography. In 4 cases (4.7%) these lesions were solitary. As a result, the operative procedure of choice was changed in 15.3% of the patients. We conclude that intraoperative ultrasonography has a significantly higher ability to detect colorectal cancer liver metastases than preoperative methods or intraoperative inspection and palpation. Intraoperative ultrasonography should be performed in patients without preoperative evidence of liver metastases and in all patients with planned resection of metastases.

Adenocarcinoma↗
PubMed1991

Oral colon lavage solutions containing polyethylene glycol may interfere with ELISA detection of tumor-associated antigens in colonic effluent.

Immunologic methods for detection of colorectal neoplasia based on examination of stool or colonic effluent are being developed. Most current oral lavage preparations contain polyethylene glycol (PEG), and if PEG adversely interferes with immunologic testing these tests may become less useful. We describe a decrease in sensitivity of ELISA for tumor-associated antigens (TAA) when effluent samples are diluted in PEG-electrolyte lavage solution, equivalent to a commonly used oral lavage solution based on PEG. Radioisotope-labeled antigen binding to plastic plates was decreased by dilution in the PEG lavage solution. Antigen binding, present in colonic effluent collected by the laxative purge method, was absent in effluent collected by PEG oral lavage from the same patient. We conclude that PEG and PEG-containing lavage solutions interfere with ELISA detection of TAA in colonic effluents. We speculate that the in vitro, and possibly the in vivo, effect occurs at the level of antigen binding to the plate either by a steric effect or alteration of charge by the nonpolar properties of PEG.

Absorption↗
PubMed1991

Interlaboratory evaluation of three culture media for postimplantation rodent embryos.

The first aim of the study was to compare the ability of rat serum, human serum, and a mixture of human and rat serum (4:1) to support in vitro development of rodent postimplantation embryos. The comparison was made in three laboratories using rat embryos and in one laboratory using mouse embryos. Batches of sera, initial developmental stage, duration of culture, and endpoints were identical in the laboratories. The second aim of the study was to evaluate if other variables that could not be standardized would significantly influence the results of the laboratories. No reproducible difference was observed among the culture media or among the laboratories except that growth and differentiation were slower in the laboratory using mouse embryos. Further experiments are needed to exclude small differences in performance of the media.

Animals↗
PubMed1991

Effect of high-fat and low-fiber meals on the cell proliferation activity of colorectal mucosa.

Normal healthy volunteers (n = 43) were divided into four groups that received diets providing low or high levels of dietary fat (33 or 96 g/day) and low or high levels of dietary fiber (6 and 41 g/day) for a period of five days. Proliferation was assessed with tritiated thymidine labeling of three rectal biopsies. After five days on the prescribed diets, the average thymidine labeling index (LI) of the group on the high fat-low fiber diet was only 25% higher than the average LI of the group on the low fat-high fiber diet, a difference that is not statistically significant. We conclude that a short-term increase in dietary fat and decrease in dietary fiber does not result in a large increase in cell proliferation rate.

Adult↗
PubMed1991

Nitric oxide and nitric oxide-generating compounds inhibit hepatocyte protein synthesis.

Hepatocytes are stimulated to produce nitric oxide (NO.) from L-arginine in response to conditioned Kupffer cell medium or a combination of cytokines. Associated with the production of NO.in hepatocytes, there is a profound decrease in total protein synthesis ([3H]leucine incorporation). This report demonstrates that authentic NO.and the NO.-generating compound S-nitroso-N-acetylpenicillamine inhibit hepatocyte total protein synthesis in a reversible and concentration-dependent fashion. In parallel with the suppression of hepatocyte total protein synthesis, authentic NO.inhibits the production of two specific hepatocyte proteins, albumin and fibrinogen, without influencing the quantity of albumin mRNA. Although authentic NO.induces a rapid increase in cGMP levels in hepatocytes, the addition of the cGMP analog 8-bromoguanosine 3':5' cyclic monophosphate to unstimulated HC cultures does not reproduce the inhibition of total protein synthesis. These data show that NO.is the hepatocyte L-arginine metabolite that inhibits protein synthesis. Furthermore, these findings indicate that NO.does not inhibit hepatocyte protein synthesis solely through the activation of soluble guanylate cyclase but appears to affect a translational or posttranslational process.

Albumins↗
PubMed1991

Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes.

Although nitric oxide (.N = O) biosynthesis is inducible in rat hepatocytes (HC), the physiological significance of .N = O production by these cells is unknown. Short exposure of HC to authentic .N = O led to a concentration-dependent inhibition of mitochondrial aconitase, NADH-ubiquinone oxidoreductase, and succinate-ubiquinone oxidoreductase (complexes I and II of the mitochondrial electron transport chain). Most susceptible to .N = O inhibition was mitochondrial aconitase, in which a reduction in enzyme activity to 20.2 +/- 1.6% of control was observed. In contrast to mitochondrial aconitase, cytosolic aconitase activity was not inhibited by .N = O. After exposure to a maximal inhibitory concentration of .N = O, mitochondrial aconitase activity recovered completely within 6 h. Complex I did not fully recover within this incubation period. Endogenous .N = O biosynthesis was induced in HC by a specific combination of cytokines and lipopolysaccharide. After 18 h of incubation with these stimuli, a significant inhibition of mitochondrial aconitase activity to 70.8 +/- 2.4% of controls was detected. However, this was due only in part to the action of .N = O. A non- .N = O-dependent inhibition of mitochondrial function appeared to be mediated by tumor necrosis factor.

Animals↗
PubMed1990

Inducible cytosolic enzyme activity for the production of nitrogen oxides from L-arginine in hepatocytes.

The in vivo conditions needed for the induction of nitrogen oxide synthesis by hepatocytes were determined. Hepatocytes obtained from rats injected with killed Corynebacterium parvum spontaneously produced NO2(-)+NO3- in culture and were found to contain cytosolic enzyme activity for nitrogen oxide synthesis. The enzyme activity required both L-arginine and NADPH, and was not found in hepatocytes obtained from normal rats or rats injected with lipopolysaccharide (LPS) alone. In contrast, nonparenchymal cells were stimulated to synthesize NO2(-)+NO3- by LPS. These results show the presence of inducible cytosolic enzyme activity for nitrogen oxide synthesis in hepatocytes, which is distinct from nonparenchymal cell NO. synthesis.

Animals↗
PubMed1990

A rapidly reversible effect of a single dose of phenoxybenzamine on the fertility of male rats.

Male Sprague-Dawley rats received a single subcutaneous injection of phenoxybenzamine and each was allowed to mate with an untreated receptive female at 5, 29 or 53 h post-injection. At 5 h the number of males ejaculating was reduced and fertility virtually abolished; at 29 h all males ejaculated, but fertility was still low; at 53 h the performance of the males was normal.

Animals↗
PubMed1990

Long-term effects of dietary calcium on risk markers for colon cancer in patients with familial polyposis.

There is conflicting evidence regarding the benefit of calcium in prevention of colon cancer. Patients who have undergone ileorectal operations for familial polyposis can be useful to study hypotheses on prevention of colon cancer. In this study we evaluated the effect of long-term calcium supplementation on risk markers of colon cancer. Thirty-one patients with familial polyposis, after subtotal colectomy, were randomized to group A, which received placebo, and group B, which received 1200 mg of calcium daily. Intervention lasted 9 months, in which they underwent four 3-monthly evaluations that included food records, fecal pH, calcium and bile acids, and rectal biopsy for thymidine labeling. Age, height, weight, macronutrients, and dietary fiber were comparable in both groups. More women were in the group that received placebo. Fecal pH, weight, and bile acid levels were similar before intervention and remained unchanged. Fecal calcium levels were similar before intervention and increased in the calcium group throughout the study (p less than 0.05). Labeling index of placebo and calcium groups was similar before intervention (4.8 and 6.1, respectively). After 3 months it was reduced in both groups (3.1 and 4.4, respectively; p less than 0.05). After 6 months it was reduced only in the calcium group (3.4; p less than 0.05). After 9 months it did not differ from the starting point (3.4 and 4.0, respectively). In a long-term intervention study with a homogenous group of patients with familial polyposis, supplemental dietary calcium did not affect mucosal risk factors for colon cancer.

Adenomatous Polyposis Coli↗
PubMed1989

The contact site A glycoprotein of Dictyostelium discoideum carries a phospholipid anchor of a novel type.

The contact site A glycoprotein, a cell adhesion protein of aggregating Dictyostelium cells, was labeled with fatty acid, myo-inositol, phosphate and ethanolamine in vivo, indicating that the protein is anchored in the membrane by a lipid. This lipid was not susceptible to phosphatidyl inositol specific phospholipase C. When cleaved with nitrous acid or when subjected to acetolysis, the anchor released lipids which were different from those released from Trypanosoma variant cell surface glycoprotein, a protein with a known phosphatidyl inositol-glycan anchor. Resistance to weak and sensitivity to strong alkali indicated that the fatty acid in the contact site A glycolipid anchor was in an amide bond. On incubation with sphingomyelinase, a lipid with the chromatographic behavior of ceramide was released. These results suggest that the contact site A glycoprotein is anchored by a ceramide based lipid glycan.

Antigens, Surface↗