Biomedical subjects

J E Fischer

Publications and source records attributed to J E Fischer.

At least 181 records · Page 10Linked to original sources

PubMed1992

Evidence that tumor necrosis factor participates in the regulation of muscle proteolysis during sepsis.

The role of tumor necrosis factor (TNF) in the regulation of muscle protein turnover was studied in rats. Protein synthesis and total and myofibrillar protein breakdown rates were measured in incubated extensor digitorum longus muscles. Intraperitoneal administration of recombinant TNF-alpha (300 micrograms/kg of body weight) increased total and myofibrillar protein breakdown rates by 28% and threefold, respectively, with no effect on protein synthesis. In subsequent experiments, sepsis was induced by cecal ligation and puncture or a sham-operation was performed. Rats received TNF antiserum (1 mL/100 g of body weight) or control serum 2 hours before cecal ligation and puncture or sham-operation. Treatment with TNF antiserum reduced the mortality rate from 25% to 5% following cecal ligation and puncture. The treatment had no effect on protein synthesis but reduced total and myofibrillar protein breakdown rates by 26% and 39%, respectively, in septic animals. Results suggest TNF is involved in the regulation of sepsis-induced muscle proteolysis.

Animals↗

PubMed1992

Effect of sepsis or cytokine administration on release of gut peptides.

The effect of sepsis on plasma levels of various gut peptides was studied in rats. Sepsis was induced by cecal ligation and puncture (CLP); control animals underwent sham operation. Sixteen hours after CLP or sham operation, portal and systemic blood was drawn, and plasma levels of gastrin, vasoactive intestinal peptide (VIP), secretin, peptide YY (PYY), gastrin-releasing peptide (GRP), and substance P were determined by radioimmunoassay. Plasma levels of gastrin, VIP, PYY, and secretin were elevated in septic rats compared with nonseptic animals, with the highest levels noted in portal blood. There was no effect of sepsis on GRP or substance P levels. In other experiments, human recombinant interleukin 1 alpha (IL-1 alpha) or recombinant tumor necrosis factor alpha (TNF alpha) was injected intraperitoneally (300 micrograms/kg body weight in 3 divided doses over 16 hours). There was no change in plasma levels of gut peptides after IL-1 alpha injection. TNF alpha induced elevation of PYY levels in portal plasma with no change in other gut peptide levels. The results suggest that sepsis stimulates release of certain gut peptides and that TNF, but not IL-1, may be partly responsible for this response. The mechanism of the release of gut peptides and its significance in the pathophysiologic changes induced by sepsis remain to be determined.

Animals↗

PubMed1992

Is the metabolic response to sepsis in skeletal muscle different in infants and adults? An experimental study in rats.

In this study we compared the effect of sepsis on muscle protein metabolism in infant (3 to 4 weeks) and adult (3 to 4 months) rats. Sepsis was induced by cecal ligation and puncture (CLP). Control animals underwent sham operation. Sixteen hours after CLP or sham operation, metabolic studies were performed in incubated intact extensor digitorum longus muscles from infant rats or in strips of the same muscle from adult rats. Protein synthesis rate was determined as incorporation of 3H-phenylalanine into protein; total and myofibrillar protein breakdown rates were determined as release of tyrosine and 3-methylhistidine, respectively. Mortality rate following CLP was similar in both age groups. Basal protein synthesis rate was 3 times higher, total protein breakdown rate was 50% higher, and myofibrillar protein breakdown rate was 3 times higher in infant than in adult animals. However, the relative changes in protein turnover rates induced by sepsis were similar in infant and adult rats: protein synthesis rate decreased by approximately 30%, total protein breakdown increased by 40% to 50%, and myofibrillar protein breakdown increased severalfold. The data suggest that despite prominent differences in basal protein turnover rates between infant and adult rats, the effect of sepsis on muscle protein metabolism is not age dependent.

Adenosine Triphosphate↗

PubMed1992

Roux-en-Y jejunal bypass abolishes postprandial neuropeptide Y release.

Numerous physiologic aberrations occur after Roux-en-Y bypass procedures. Neuropeptide Y (NPY), a 36 amino acid polypeptide, has been shown to have many effects on gastrointestinal physiology, including alterations in blood flow, motility, and secretion and absorption. Recent work demonstrating a postprandial increase in circulating NPY prompted this investigation into its potential roles after Roux-en-Y bypass. Three groups of rats underwent Roux-en-Y cholangiojejunostomy, jejunojejunostomy, or proximal jejunal transection with reanastomosis. After a 3-month recovery, the animals were tested with both mixed and fat meals. Control animals had rapid increases in circulating NPY after the mixed meal. This response was not seen in either of the Roux-en-Y groups (P less than 0.05). No animals had circulating changes in NPY after the fat meal. Additionally, small intestinal NPY receptor analysis revealed high NPY affinity to the epithelial cells of the proximal small intestine. Our results demonstrate a dependence of postprandial NPY release on proximal small intestinal continuity that is abolished by Roux-en-Y bypass of a jejunal segment. The absence of postprandial elevation in plasma NPY after proximal jejunal bypass and the abundance of NPY receptors in the proximal small intestine merits further investigation into the physiologic roles of NPY in the foregut.

Anastomosis, Roux-en-Y↗

PubMed1992

Individual regulation of different hepatocellular functions during sepsis.

The purpose of this study was to test the hypothesis that different hepatocellular functions are regulated individually during sepsis. This was done by simultaneously measuring bile production, release of liver transaminases, and synthesis of secreted proteins in perfused livers from control and septic rats. Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham-operated. After 16 hours, livers were perfused in situ, and bile flow, synthesis rates of albumin and alpha 1-acid glycoprotein (a major acute-phase protein in rats), and release of glutamic-oxaloacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) into perfusate were determined. Within the same livers, sepsis resulted in a 54% increase in the synthesis of alpha 1-acid glycoprotein and approximately 30% inhibition of albumin synthesis concomitant with 50% lower bile flow. The concentrations of GOT and GPT in the perfusate increased slightly during the experiments, both when control and septic livers were perfused. The maintained tissue levels of adenosine triphosphate (ATP) and the uptake of Evans blue dye by less than 1% of the hepatocytes, although a late test of viability, suggest that both control and septic livers remained viable during perfusion. The results are consistent with the concept that different hepatocellular functions are individually regulated during sepsis. Thus, impairment of certain hepatocellular functions does not necessarily imply generalized liver failure.

Adenosine Triphosphate↗

PubMed1992

Muscle protein breakdown during endotoxemia in rats and after treatment with interleukin-1 receptor antagonist (IL-1ra).

The purpose of this study was to examine the effect of endotoxemia on muscle protein degradation and to test the hypothesis that muscle proteolysis during endotoxemia is regulated by interleukin-1 (IL-1). Both total and myofibrillar protein breakdown rates in incubated extensor digitorum longus muscles were increased after the subcutaneous injection of 0.1 or 1.0 mg/kg endotoxin in rats. The endotoxin-induced increase in muscle protein breakdown was blunted by IL-1 receptor antagonist, administered intraperitoneally at a total dose of 45 or 105 mg/kg. Results suggest that endotoxemia in rats gives rise to sepsislike changes in muscle protein breakdown. Increased muscle protein breakdown during endotoxemia may be regulated, at least in part, by IL-1.

Animals↗

PubMed1992

Management of myasthenia gravis by extended thymectomy with anterior mediastinal dissection.

BACKGROUND: Thymectomy has continued to gain acceptance as definitive treatment for myasthenia gravis. Because of the nature of thymic embryology with scattered rests throughout the anterior mediastinum, we advocate a transsternal thymectomy with extended anterior mediastinal dissection. METHODS: A series of 48 patients with myasthenia gravis treated by thymectomy between 1979 and 1991 were reviewed. RESULTS: The mean length of duration of disease from onset to operation was 48.7 +/- 11.3 months, and the mean length of follow-up was 51.6 +/- 6.5 months. The operation was associated with a 21% morbidity rate (4% major morbidity) with no deaths. Forty-five patients (94%) have improved, requiring decreased medication. The overall drug-free remission rate was 42%. Of the 20 patients in remission, three had thymomas and four had hyperplastic glands. All of the patients who achieved drug-free remission were classified as Osserman's I or II. CONCLUSIONS: An aggressive surgical approach to myasthenia gravis can result in a high percentage of overall improvements and drug-free remissions. The best results are achieved in patients with lower-stage disease. Therefore transsternal extended thymectomy for myasthenia gravis appears to be the procedure of choice and should be advocated as soon as the diagnosis is made and the patient stabilized.

Adult↗

PubMed1992

Postprandial peptide YY release is mediated by cholecystokinin.

Peptide YY (PYY), a 36 amino acid peptide, is a member of the structurally and functionally related pancreatic polypeptide (PP) family of gastrointestinal and neurally active peptides. Peptide YY is released postprandially from the distal small intestine and colon and has been shown to inhibit many physiologic actions of cholecystokinin (CCK), an integral foregut hormonal stimulant of pancreatic and gastric secretion. The specific signals for the release of PYY have not been ascertained, although foregut signals, both neural and hormonal, are likely. In this study, we evaluated the possible role for CCK in postprandial PYY release in eight conscious dogs. Conscious dogs were given a fat meal or a one hour intravenous infusion of CCK-8. On separate days, the dogs were pretreated with the specific CCK receptor antagonist L-364,718. Peripheral blood samples were collected for radioimmunoassay for PYY, PP and neuropeptide Y. The fat meal and exogenous CCK stimulated PYY and PP release, effects that were abolished by pretreatment with the CCK receptor antagonist. The results provide support for a physiologic role of CCK in the mediation of postprandial PYY and PP release. Furthermore, an inhibitory feedback loop is suggested between the hindgut (PYY) and the foregut (CCK).

Animals↗

PubMed1991

Aphagic and adipsic effects of interleukin-1.

Intake of rat chow and water was reduced 4 and 8 h after the intrahypothalamic injection of 5 ng interleukin-1a (IL-1a). Although core body temperature was also elevated significantly for at least 4 h by the administration of this cytokine, resting energy expenditure was not altered. These results suggest that IL-1a may be involved in the reduction of feeding associated with trauma, infection or cancer, by inducing early satiety. Additionally, hyperthermia associated with the injection of IL-1a appears to be maintained by decreased heat dissipation rather than by increased thermogenesis.

Analysis of Variance↗

PubMed1991

Anorexia following the intrahypothalamic administration of amylin.

The intrahypothalamic injection of rat amylin reduced feeding in schedule-fed rats for eight hours. Specificity of this anorectic response was indicated by an appropriate dose-response relationship and the absence of effect of human amylin. Amylin-induced anorexia was accompanied by alterations in neurotransmitter metabolism similar to those observed in anorectic tumor-bearing rats. These results indicate that amylin may inhibit feeding by acting directly on hypothalamic neurons to alter metabolism of neurotransmitter systems known to affect feeding behavior.

Amyloid↗

PubMed1991

Lipid-free total parenteral nutrition and macrophage function in rats.

Certain lipids are immunosuppressive when used for nutritional support, while other lipids and nutritional additives may enhance immunologic function. We hypothesized that total parenteral nutrition (TPN) may be immunosuppressive irrespective of lipids. Twenty-four rats underwent central vein catheterization and received either intravenous saline solution and oral chow or TPN alone. At 7 or 14 days, the animals were killed. Splenic and bone marrow macrophages were isolated and cultured in either M199 medium alone or were stimulated with Escherichia coli lipopolysaccharide. The supernatants were tested for prostaglandin E2 and C3. The splenic prostaglandin E2 levels were significantly higher in the TPN group following lipopolysaccharide stimulation at 7 days but not at 14 days. Administration of TPN to rats, even without lipids, may be immunosuppressive through the release of prostaglandin E2 from splenic macrophages following a septic challenge. This effect appears to be abolished after 14 days of TPN infusion.

Animals↗

PubMed1991

Intraluminal ileal recovery of pancreatic polypeptide.

Pancreatic polypeptide (PP) is a normal constituent of pancreatic islet cells. Enterocytes containing PP have been identified but incompletely characterized. We previously demonstrated independent intravascular and intraluminal release of two related peptides, peptide YY and neuropeptide Y. In this study, using ileal segments in conscious dogs, we evaluated the intravascular and ileal intraluminal presence of PP to test meals. Fasted plasma and recoverable ileal PP concentrations averaged 139 +/- 2 and 65 +/- 4 pg/mL, respectively. A mixed protein meal resulted in a sustained rise of circulating PP levels associated with a brief evaluation of ileal luminal PP levels. Fat meals were followed by elevations in plasma PP levels without luminal changes. Glucose ingestion altered neither plasma nor luminal PP levels. Our data support the existence of ileal PP-containing cells that respond independently of circulatory PP-releasing cells to different ingested stimuli.

Animals↗

PubMed1991

A simple method for biliary-enteric anastomosis and chronic bile diversion in the rat.

A simple method of biliary-enteric anastomosis, without the use of surgical microscopy, is described. There were no signs of cholestasis after 3 mo of follow-up. A modified procedure using a silicone elastomer catheter as a stent for the biliary-enteric anastomosis resulted in biliary obstruction within 3 wk after surgery. Our experimental bile duct implantation technique is a simple and useful experimental method for the investigation of chronic biliary diversion and biliary physiology. Additionally, it can be performed safely and easily in a rodent model without sophisticated microscopic techniques.

Anastomosis, Surgical↗

PubMed1991

Effects of glucose on circulating and ileal intraluminal peptide YY and pancreatic polypeptide release.

Peptide YY (PYY) and pancreatic polypeptide (PP) are related hormones released systemically after a meal. The effects of glucose stimulation and vagal involvement on circulating and ileal luminal PYY and PP concentrations were evaluated in awake dogs. An oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGT), 2-deoxyglucose bolus (2-DG), or atropine pretreatment prior to OGTT were administered to awake dogs with 25-cm ileal Thiry-Vella fistulas. Circulating and ileal intraluminal PYY and PP levels were measured by radioimmunoassay. No changes were noted in circulating PYY, and circulating PP increased (p less than 0.05) only after administration of 2-DG. Ileal luminal PP recovery was minimal (less than 60 pg/mL) and was unchanged after all tests. Ileal luminal PYY recovery increased significantly after both OGTT and IVGT. Pretreatment with atropine abolished the luminal PYY response to OGTT, and 2-DG did not affect luminal PYY recovery. Blood glucose and insulin levels were similar in all groups. Peripheral cholinergic control of luminal PYY release is suggested by our findings, whereas a central mediation of circulatory PP release is supported by 2-DG stimulation.

Animals↗

PubMed1991

Clenbuterol plus acivicin decrease tumor growth and increase muscle mass in rats maintained on total parenteral nutrition.

Two problems associated with supplemental nutrition of tumor-bearing organisms are control of tumor growth and reduction of cachexia. To investigate these problems, rats bearing methylcholanthrene-induced sarcomas were maintained on total parenteral nutrition (TPN) for 10 to 12 days beginning 23 days after tumor inoculation. Combined treatment of one group of these rats with the glutamine antimetabolite, acivicin, and the beta 2-adrenergic agonist, clenbuterol, arrested tumor growth, increased skeletal muscle mass and protein content, increased gut mass, and decreased total plasma lipid levels. Resting energy expenditure and cardiac mass were increased by TPN and were increased further by acivicin plus clenbuterol. These results demonstrate that tumor growth and muscle wasting can be controlled during TPN of tumor-bearing organisms. Therefore, cachectic depletion of lean body tissue may not be obligatory in neoplastic disease.

Animals↗

PubMed1991

Cytokines and glucocorticoids in the regulation of the "hepato-skeletal muscle axis" in sepsis.

Sepsis results in muscle catabolism and peripheral release of amino acids with a concomitant uptake of amino acids in liver and acute-phase protein synthesis. In addition, there appears to be a cytokine-induced process that blocks muscle amino acid uptake in sepsis, further diverting amino acids from the periphery to the liver. In this article, evidence that cytokines and glucocorticoids play an important role in the regulation of hepatic and muscle protein metabolism during sepsis is presented.

Amino Acids↗

PubMed1991

Decreased myofibrillar protein breakdown following treatment with clenbuterol.

Daily treatment of Fischer-344 rats for 14 days with the beta 2-adrenergic agonist, clenbuterol, increased gastrocnemius muscle mass and protein content. Coadministration with the beta-adrenergic antagonist, nadolol, significantly reduced these anabolic effects of clenbuterol. Although clenbuterol treatment reduced food intake during the first 4 days, clenbuterol-treated rats were hyperphagic during the second week of drug administration. Nadolol treatment also blocked these effects of clenbuterol on feeding. In a second experiment, in vitro incubation of extensor digitorum longus muscles taken from post weaning food-deprived rats demonstrated decreased release of 3-methylhistidine by clenbuterol-treated rats, suggesting decreased breakdown of myofibrillar protein. Protein synthesis was not increased in vitro in the soleus muscles taken from these rats. These experiments demonstrate that the anabolic effect of clenbuterol is due in part to beta-adrenergic activity and may involve reduced myofibrillar protein degradation. These results appear to have direct application to nutrition and protein repletion in various catabolic diseases.

Adrenergic beta-Antagonists↗

PubMed1991

The effect of interleukin-1 alpha and the glucocorticoid receptor blocker RU 38486 on total and myofibrillar protein breakdown in skeletal muscle.

The purpose of the present study was to test the hypothesis that muscle proteolysis induced by interleukin-1 alpha (IL-1 alpha) is mediated by glucocorticoids. Male Sprague-Dawley rats, weighing 40-60 g, were treated with recombinant IL-1 alpha (rIL-1 alpha), 300 micrograms/kg in three divided intraperitoneal doses over 16 hr, or corresponding control injections. Groups of rats received the glucocorticoid receptor blocker RU 38486 by gavage (15 mg/kg in three divided doses over 16 hr) or were subjected to sham-gavage. In other experiments we tested the effectiveness of the same dose of RU 38486 to block muscle proteolysis in rats treated with corticosterone (200 mg/kg in two divided doses over 16 hr). Total and myofibrillar protein breakdown rates in incubated extensor digitorum longus muscles were determined by measuring release of tyrosine and 3-methylhistidine, respectively. Administration of rIL-1 alpha increased total and myofibrillar protein breakdown by 49 and 134%, respectively. This effect of the cytokine was not affected by RU 38486. The same dose of RU 38486, however, completely blocked the increase in total and myofibrillar protein breakdown induced by corticosterone. The results suggest that muscle proteolysis induced by the administration of rIL-1 alpha is not mediated by glucocorticoids.

Animals↗