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Biomedical subjects

J E Fischer

Publications and source records attributed to J E Fischer.

At least 217 records · Page 12Linked to original sources
PubMed1990

Is there a circulating proteolysis-inducing factor during sepsis?

Muscles from fed or 72-hour fasted rats were incubated in the presence of plasma from septic rats, recombinant interleukin 1 alpha (rIL-1 alpha), or recombinant tumor necrosis factor alpha (rTNF alpha), and breakdown of total and myofibrillar protein was assessed by determining release of tyrosine and 3-methylhistidine, respectively. Septic plasma stimulated total protein breakdown in muscles from 72-hour fasted rats by 10% to 20%, while myofibrillar protein breakdown was not affected. When septic plasma was added to muscles from fed rats, neither tyrosine nor 3-methylhistidine release was altered. Various concentrations of recombinant interleukin 1 alpha or recombinant tumor necrosis factor alpha did not affect total or myofibrillar protein breakdown. Since septic plasma did not stimulate myofibrillar protein breakdown, the role of a circulating factor for muscle proteolysis during sepsis remains unclear.

Animals↗
PubMed1990

Medium-chain acyl CoA dehydrogenase deficiency: electron microscopic differentiation from Reye syndrome.

Inborn errors involving the oxidative metabolism of fatty acids may present clinically with a Reye syndrome-like picture. This case report of a patient with medium-chain acyl CoA dehydrogenase (MCAD) deficiency illustrates that electron microscopy may help to differentiate this disorder from Reye syndrome even if a liver biopsy is performed in a patient who recovered from an acute metabolic decompensation. Together with this case, a review of the few reports in the literature of pathological findings in MCAD deficiency is given. Changes uncharacteristic for Reye syndrome are a large-droplet steatosis and the presence of distinctive mitochondrial abnormalities on electron microscopy. The detection of an electron dense mitochondrial matrix and a widened space of inner mitochondrial membranes rules out Reye syndrome and is suggestive of a disorder of mitochondrial fatty acid oxidation.

Acyl-CoA Dehydrogenase↗
PubMed1990

Addition of L-glutamine to total parenteral nutrition and its effects on portal insulin and glucagon and the development of hepatic steatosis in rats.

Infusion of total parenteral nutrition (TPN) with excess carbohydrate calories leads to hepatic steatosis in rats and is associated with an elevated portal insulin/glucagon molar ratio. Previously we have shown that adding glucagon to TPN prevents and reverses hepatic steatosis in rats, possibly by increasing hepatic lipid export. It has been reported that steatosis is eliminated in rats by the addition of L-glutamine to TPN. In this study, we examined the effect of glutamine on portal insulin and glucagon levels and the development of hepatic steatosis. Adult rats (n = 19) received internal jugular catheters: Group 1 (n = 6), saline (3 cc/hr) and chow ad libitum; Group 2 (n = 7), 25% dextrose base TPN; Group 3 (n = 6), 25% dextrose base TPN with 2% glutamine. The infusion rate of TPN was 1.2 cc/100 g body wt/hr. Daily nitrogen balance was determined and at 7 days, portal venous blood was drawn for insulin and glucagon radioimmunoassay, livers were removed for histology and lipid content determination, and the small intestines were removed for mucosal protein and DNA content determination. Panlobular vacuolization of the hepatocytes was noted on histology in Group 2 (TPN) while Group 1 (chow) and Group 3 (TPN + glutamine) showed normal liver morphology. Hepatic lipid content was significantly elevated in Group 2 (P less than 0.05). The portal insulin/glucagon molar ratio was increased because of excessive portal venous insulin in Group 2 (TPN). In contrast, portal glucagon was significantly elevated while the insulin/glucagon ratio and hepatic lipid content did not increase above control levels in the glutamine-supplemented Group 3 rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Hepatic protein synthesis in a modified septic rat model.

The aim of this study was to develop a reproducible and sustained sepsis model in rats, lasting 3-4 days and characterized by appropriate metabolic changes, including increased hepatic protein synthesis, consistent with an acute-phase response. The rat cecal ligation and puncture (CLP) model was modified by decreasing the size and number of cecal punctures and increasing fluid resuscitation, which resulted in a 60% survival rate at 96 hr compared to 20% for standard CLP. Cultures of blood and peritoneal fluid 96 hr following induction of sepsis were positive in all septic animals with a mixed aerobic and anaerobic flora but with predominant growth of Escherichia coli. Septic rats demonstrated increased serum lactate levels and leukocytosis, while serum glucose and resting energy expenditure were not different from controls. Hepatic protein synthesis, measured in vivo by flooding dose technique, was increased by 74% in septic animals. Synthesis of the acute-phase proteins alpha 1-acid glycoprotein, complement component C3, and transferrin, measured by incorporation of [14C]leucine into proteins during a 120-min isolated liver perfusion, was increased twofold in septic animals. The present modified CLP model in rats may be useful in studies on the regulation of acute-phase protein synthesis during prolonged sepsis and in experiments aimed at modulating the septic response in liver by different treatments.

Animals↗
PubMed1990

Endogenous peptide YY is dependent on jejunal exposure to gastrointestinal contents.

Peptide YY (PYY), a homolog of pancreatic polypeptide, has been shown to be released after stimulation of colonic mucosa with bile and fatty acids. In this study proximal jejunal and biliary involvement in the regulation of circulating PYY and the distribution of PYY-containing cells in rat intestine was evaluated. Six rats underwent proximal jejunal bypass, six rats had Roux-en-Y cholangiojejunostomies, and six sham-operated rats were used as controls. Three months after surgery feeding studies using either a mixed meal or a pure fat meal were performed in unanesthetized animals and venous blood was collected for plasma PYY radioimmunoassays. After the feeding studies, fresh specimens were taken from multiple areas of the intestine for immunohistochemical analysis. The surgical procedures did not significantly affect basal PYY plasma levels. Both mixed and fat meals significantly increased circulating PYY in control animals. Exclusion of the proximal jejunum resulted in inhibition of postprandial PYY release. The PYY response in rats with Roux-en-Y cholangiojejunostomies was blunted after a mixed meal and delayed after a fat meal. The incidence of PYY-containing cells increased along the functional gut in all rats. The bypassed jejunum in both experimental groups of animals contained fewer PYY-staining cells than sham-operated rats. Our results suggest that the exclusion of a segment of proximal jejunum from gastrointestinal continuity in rats leads to an inhibition of postprandial PYY release. PYY release may be controlled in part by stimulatory neural and/or endocrine signals originating from the proximal jejunum.

Animals↗
PubMed1990

Corticosterone alone does not explain increased muscle proteolysis in septic rats.

The mediators and mechanisms of muscle proteolysis in sepsis are not fully known. We investigated the role of corticosterone in increased muscle proteolysis during sepsis in rats. In one series of experiments, plasma corticosterone and total and myofibrillar protein breakdown rates, determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively, were measured 16 hr after sham operation (control) or cecal ligation and puncture (sepsis). In other experiments, corticosterone (10 mg/100 g body wt) was injected subcutaneously twice over 16 hr; thereafter, plasma hormone levels and muscle protein breakdown rates were determined. Plasma corticosterone was increased from 14 +/- 1 micrograms/dl in control rats to 38 +/- 8 micrograms/dl in septic rats and total and myofibrillar protein breakdown rates were increased by 99 and 326%, respectively, in muscles from septic rats. When administration of corticosterone resulted in plasma levels similar to those observed in septic rats, total or myofibrillar protein breakdown rates were not altered. The results suggest that corticosterone alone is not responsible for increased muscle proteolysis in septic rats. The data, however, do not rule out the possibility that glucocorticoids may be a cofactor to some other substance or substances in the induction of muscle proteolysis during sepsis.

Animals↗
PubMed1990

The postprandial circulatory and ileal intraluminal release of neuropeptide Y in conscious dogs.

Neuropeptide Y (NPY), a 36-amino-acid peptide, was measured in the peripheral circulation and ileal lumen of conscious dogs using a sensitive radioimmunoassay. Fasting NPY concentrations averaged 448 +/- 15 pg/ml in the peripheral blood and 364 +/- 23 pg/ml in the ileal effluent. Following a mixed meal, circulating NPY levels rose to 499 +/- 37 pg/ml (P less than 0.05), whereas recoverable quantities of ileal intraluminal NPY fell to 257 +/- 19 pg/ml (P less than 0.05). Neither fat nor glucose meals significantly changed circulating or ileal intraluminal NPY recovery. These results demonstrate release of NPY into the blood and ileal lumen for the first time and support NPY as a candidate gut hormone.

Animals↗
PubMed1990

Effect of sepsis on amino acid transport system A and its response to insulin in incubated rat skeletal muscle.

The effect of sepsis on neutral amino acid transport systems A, ASC, and L, was studied in incubated rat soleus (SOL) muscles. We also examined the effects of plasma from septic rats and of varying concentrations of insulin (10 to 10(5) microU/mL), added in vitro to incubated muscles, on system A amino acid transport. Sepsis was induced by cecal ligation and puncture (CLP) in rats weighing 40 to 60 g. Control rats were sham-operated. System A activity was assessed by determining uptake of 2-(methylamino)isobutyrate (MeAIB) 16 hours after CLP or sham-operation. System ASC was studied by measuring uptake of alpha-aminoisobutyric acid (AIB) in the presence of 25 mmol/L MeAIB and 25 mmol/L 2-amino-2-norbornane carboxylic acid (BCH) to inhibit uptake by systems A and L. System L activity was defined as sodium-independent uptake of cycloleucine. MeAIB uptake was reduced by 28% in muscles of septic rats, while amino acid transport by systems ASC and L was almost identical in muscles from control and septic rats. Addition of plasma from septic rats to incubated normal SOL muscles inhibited MeAIB uptake by 31%. Addition of insulin to the incubation medium resulted in increased uptake of MeAIB, both in nonseptic and septic muscle. The lowest hormone concentration tested that significantly enhanced MeAIB uptake in nonseptic muscle was 10(2) microU/mL and in septic muscle 10 microU/mL. The results suggest that sepsis in rats specifically inhibits amino acid transport system A and that reduced muscle amino acid uptake may be caused by a circulating factor in sepsis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1990

Tyrosine loading increases dopamine metabolite concentrations in the brain.

Administration of haloperidol (1.5 mg/kg) to rats increased concentrations of dopamine metabolites in the corpus striatum, nucleus accumbens, hypothalamus and amygdala. Treatment of similar rats with various doses (25, 100 or 400 mg/kg) of tyrosine methyl ester in combination with the haloperidol led to additional elevations of 3,4-dihydroxyphenylacetic acid (DOPAC) in the corpus striatum and hypothalamus at the lowest dose tested. Therefore, it is concluded that during periods of increased neuronal activity, as induced by haloperidol, tyrosine availability may become a rate-limiting factor in dopamine metabolism.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Interaction of 125I-neuropeptide Y with rat cardiac membranes.

125I-Neuropeptide Y (NPY) bound specifically with high affinity to rat atrial and ventricular membranes. Scatchard analysis revealed the presence of single class of binding sites in both atrial and ventricular membranes. The apparent Kd and Bmax for atrial membranes were 0.63 nM and 70 fmol/mg protein, respectively; ventricular membranes had an apparent kd of 0.39 nM and a Bmax of 283 fmol/mg protein. NPY structural homologues peptide YY (PYY) and pancreatic polypeptide (PP) bound to the ventricular membranes NPY receptor, but with several fold lower potency compared to NPY. Binding of 125I-NPY to ventricular membranes was sensitive to guanosine triphosphate (GTP) suggesting that the NPY receptor is linked to adenylate cyclase system. The receptor characterized in this system may play a crucial role in mediating the cardiac effects of NPY.

Animals↗
PubMed1990

Effect of catabolic hormone infusion on protein turnover and amino acid uptake in skeletal muscle.

Increased plasma levels of the catabolic hormones glucagon, epinephrine, and cortisol have been implicated in mediating various metabolic alterations in trauma and sepsis. Their role in altered protein turnover and amino acid transport in skeletal muscle during sepsis, however, is not known. In the current study, rats were infused with a mixture of the catabolic hormones for 16 hours. Control animals were infused with vehicle solution. Protein synthesis and degradation rates were measured in incubated, intact soleus muscles as incorporation of 14C-phenylalanine into protein and release of tyrosine into incubation medium, respectively. Muscle amino acid uptake was determined by measuring the intracellular to extracellular ratio of [3H]-alpha-aminoisobutyric acid after incubation for 2 hours. Infusion of catabolic hormones for 16 hours resulted in elevated plasma glucose and lactate levels, reduced plasma concentrations of most amino acids, and accelerated muscle protein breakdown, similar to previous findings in septic rats. Protein synthesis rates and amino acid uptake in incubated muscles were not significantly different in control and hormone-infused rats. The current study suggests that increased muscle proteolysis in sepsis and severe injury may be mediated in part by catabolic hormones. In contrast, reduced muscle protein synthesis and amino acid uptake are probably signaled by other substances or mechanisms.

Amino Acids↗
PubMed1990

Reduced amino acid transport in skeletal muscle caused by a circulating factor during endotoxemia.

The present study was designed to determine whether reduced amino acid uptake in skeletal muscle during endotoxemia is due to associated hypotension or is caused by a factor present in plasma. Three series of experiments were performed. In the first series of experiments, mean arterial pressure (MAP), heart rate, and amino acid uptake in incubated soleus muscles were measured after intravenous injection of endotoxin (1 mg/kg) in male Sprague-Dawley rats (40 to 60 g). Amino acid transport was measured by determining intracellular uptake of [3H]-alpha-amino-isobutyric acid (AIB) during 2 hours of incubation. In the second series of experiments, hypotension was induced by bleeding and muscle amino acid uptake was measured. In the third series of experiments, whole plasma or a low molecular weight fraction (less than 10,000 d) of plasma from endotoxin-injected rats was added in vitro to incubated muscles and amino acid uptake was determined. One hour after injection of endotoxin, MAP was reduced from 80 +/- 2 mmHg to 54 +/- 4 mmHg (p less than 0.05). AIB uptake was reduced by 20% (p less than 0.05) 2 hours after endotoxin injection. When MAP was maintained at 50 mmHg for 1 hour by bleeding, no changes in muscle AIB uptake were noted. When plasma obtained from rats 2 hours after endotoxin injection was added to incubated soleus muscles, AIB uptake was reduced by 22%. This effect was duplicated by a fraction of endotoxic plasma containing substances with a molecular weight less than 10,000 d. The present results suggest that reduced muscle amino acid uptake during endotoxemia is not due to associated hypotension, but may be caused by a circulating factor(s) with a molecular weight less than 10,000 d.

Amino Acids↗
PubMed1990

Effects of elevated temperature on protein breakdown in muscles from septic rats.

Elevated temperature has been proposed to contribute to accelerated muscle protein degradation during fever and sepsis. The present study examined the effect of increased temperature in vitro on protein turnover in skeletal muscles from septic and control rats. Sepsis was induced by cecal ligation and puncture (CLP); control rats were sham operated. After 16 h, the extensor digitorum longus (EDL) and soleus (SOL) muscles were incubated at 37 or 40 degrees C. Protein synthesis was determined by measuring incorporation of [14C]phenylalanine into protein. Total and myofibrillar protein breakdown was assessed from release of tyrosine and 3-methylhistidine (3-MH), respectively. Total protein breakdown was increased at 40 degrees C by 15% in EDL and by 29% in SOL from control rats, whereas 3-MH release was not affected. In muscles from septic rats, total and myofibrillar protein breakdown was increased by 22 and 30%, respectively, at 40 degrees C in EDL but was not altered in SOL. Protein synthesis was unaffected by high temperature both in septic and nonseptic muscles. The present results suggest that high temperature is not the primary mechanism of increased muscle protein breakdown in sepsis because the typical response to sepsis, i.e., a predominant increase in myofibrillar protein breakdown, was not induced by elevated temperature in normal muscle. It is possible, however, that increased temperature may potentiate protein breakdown that is already stimulated by sepsis because elevated temperature increased both total and myofibrillar protein breakdown in EDL from septic rats.

Animals↗
PubMed1990

Proximal jejunal and biliary effects on the enteroinsular axis.

The objective of this study was to investigate the roles of the proximal jejunum and endogenous bile within the proximal jejunum on the enteroinsular axis. Twelve Sprague-Dawley rats underwent proximal jejunal bypass, 11 rats underwent Roux-en-Y cholangiojejunostomies, and 12 rats underwent sham operations. After 3 months, oral glucose tolerance tests were performed in unanesthetized animals and venous blood was collected for plasma glucose and insulin measurements. The surgical procedures did not significantly affect the basal glucose and insulin levels compared with sham-operated animals. The insulin response in rats with excluded proximal jejunal segments was inhibited. The decreased insulinogenic index seen in these animals indicates a possible diabetogenic effect of this procedure. An oral glucose challenge resulted in significant hyperinsulinemia, with an increased insulinogenic index in animals that had undergone Roux-en-Y cholangiojejunostomies. These findings suggest that bile is a potential mediator in the proximal jejunal involvement in the enteroinsular axis.

Anastomosis, Roux-en-Y↗
PubMed1990

Interaction between corticosterone and tumor necrosis factor stimulated protein breakdown in rat skeletal muscle, similar to sepsis.

Protein synthesis and breakdown rates were determined in incubated extensor digitorum longus muscles of rats treated with tumor necrosis factor (TNF; 20 micrograms/100 gm body weight), corticosterone (20 mg/100 gm body weight), or a combination of the two substances. Protein synthesis was measured as incorporation of carbon 14-labeled phenylalanine into protein. Total and myofibrillar protein breakdown rates were assessed as release of tyrosine and 3-methylhistidine, respectively. Administration of TNF alone did not affect muscle protein turnover rates. Corticosterone inhibited muscle protein synthesis and stimulated total and myofibrillar protein breakdown. When TNF was administered together with corticosterone, total and myofibrillar protein breakdown rates were increased further compared with rats treated with corticosterone alone. Because plasma corticosterone levels in rats treated with both TNF and the glucocorticoid were higher than in animals treated with corticosterone alone, it is possible that muscle proteolysis noted after TNF, injected together with costicosterone, was caused by the high glucocorticoid levels. To test that hypothesis, corticosterone alone or in combination with TNF was injected in rats that had undergone adrenalectomy. In these experiments, TNF did not increase plasma corticosterone levels or muscle protein breakdown rates. The results suggest that muscle catabolism induced by administration of TNF is mediated by glucocorticoids.

Adrenalectomy↗
PubMed1989

Synthesis and biological properties of 4-norleucine-neuropeptide Y; secondary structure of neuropeptide Y.

Neuropeptide Y (NPY) is a 36 amino acid peptide amide isolated from porcine brain. The NPY analog, 4-norleucine-NPY was synthesized by a solid-phase method and purified to homogeneity in 20% yield by reverse-phase chromatography. Investigation of the biological properties indicated that the analog is an agonist of NPY. Secondary structural analyses revealed that NPY and the analog exhibited predominantly alpha-helical and beta-sheet structures, respectively; however, experiments in trifluoroethanol indicated that the analog has the potential of assuming an alpha-helical structure. Based on circular dichroism (CD), Raman spectroscopy and Chou-Fasman analyses, a model has been proposed for the secondary structure of NPY.

Amino Acid Sequence↗