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Biomedical subjects

J E Fischer

Publications and source records attributed to J E Fischer.

At least 235 records · Page 13Linked to original sources
PubMed1989

Possible role of ammonia in experimental cancer anorexia.

Plasma concentrations of ammonia were elevated significantly in tumor-bearing rats prior to the onset of anorexia and continued to increase as the tumor grew and anorexia developed. Associated with this hyperammonemia were elevated levels of brain glutamine and large neutral amino acids (phenylalanine, tyrosine, tryptophan, methionine, histidine). Concentrations of the dopamine metabolites, DOPAC or HVA were elevated in the corpus striatum, nucleus accumbens, hypothalamus and amygdala of anorectic tumor-bearing rats only, while levels of the serotonin metabolite, 5-HIAA, were increased in these brain regions in both anorectic and non-anorectic tumor-bearing rats. Infusing ammonium salts into non-tumor-bearing rats elicited anorexia and alterations in brain amino acid profile and neurotransmitter metabolism that were similar to those observed in anorectic tumor-bearing rats. Therefore, we conclude that ammonia released by tumor tissue may have a direct role in the etiology of experimental cancer anorexia.

Amino Acids↗
PubMed1989

Transduodenal sphincteroplasty and transampullary septotomy for primary sphincter of Oddi dysfunction.

We examined 29 patients without stone disease or pancreatic ductal ectasia who underwent transduodenal sphincteroplasty and transampullary septotomy for symptoms of biliary colic or pancreatitis. The combination of biliary symptoms and a fibrotic ampulla of Vater portends a favorable surgical outcome in virtually all such patients. Patients with pancreatitis did worse overall, perhaps due to the existence of unappreciated subclinical parenchymal disease not related to sphincter dysfunction. Although endoscopic retrograde cholangiography was sensitive in demonstrating abnormalities of the pancreaticobiliary system, its specificity as a predictor of good results was poor. It seems prudent to temper one's enthusiasm for sphincteroplasty in the patient with pancreatitis, whereas patients with biliary symptoms, the postcholecystectomy syndrome, or both will usually benefit significantly from this procedure.

Adult↗
PubMed1989

Reversal of hepatic steatosis in rats by addition of glucagon to total parenteral nutrition (TPN).

Infusion of total parenteral nutrition (TPN) with excess carbohydrate calories leads to hepatic steatosis in rats that is associated with an elevated portal insulin/glucagon molar ratio. Previously we have shown that adding glucagon to TPN prevents hepatic steatosis in rats. In this study we attempted to reverse the steatosis by adding glucagon to TPN after 1 week of TPN alone. Adult rats (n = 28) received internal jugular catheters: Group 1 (n = 7), saline (3 cc/h) and chow ad libitum; Group 2 (n = 7), 25% dextrose base TPN solution for 1 week; Group 3 (n = 7), 25% dextrose base TPN for 2 weeks; Group 4 (n = 7), 25% dextrose base TPN for 1 week and then glucagon (15 micrograms/100 g/day) added to TPN for the second week. The infusion rate of TPN was 1.2 ml/100 g/hr (40% kcal greater than control). At 7 days (Group 2) and 14 days (Groups 1, 3, and 4) portal and peripheral venous blood levels were drawn for insulin and glucagon radioimmunoassay, blood glucose determination, and liver function tests; livers were removed for histology and lipid content determination. Blood glucose was equivalent among all groups. Liver function tests were within normal limits. Panlobular vacuolization of the hepatocytes was noted on histology in Groups 2 and 3. Hepatic lipid content was significantly elevated in Group 3. The portal insulin/glucagon molar ratio was increased because of excessive portal venous insulin in Groups 2 and 3 (P less than 0.05 by ANOVA). In contrast, portal venous insulin and the insulin/glucagon molar ratio did not increase in Group 4 and hepatic lipid infiltration was absent when glucagon was added to the TPN solution after 1 week of TPN solution alone. The results suggest that the addition of glucagon to hypertonic dextrose TPN is not only protective in preventing hepatic steatosis, but may reverse steatosis, possibly by increasing hepatic lipid export.

Animals↗
PubMed1989

Independent release of peptide YY (PYY) into the circulation and ileal lumen of the awake dog.

Peptide YY (PYY) is a recently discovered polypeptide found in the endocrine cells of the distal small intestine, colon, and rectum. This study was designed to evaluate the postprandial release of PYY into the peripheral blood and the ileal lumen in response to different ingested nutrients. Six adult conditioned mongrel dogs had 25-cm distal ileal Thiry-Vella segments surgically constructed. After a 2-week postoperative recovery period the animals were fed meals consisting of protein (2 g/kg), fat (5 g/kg), or glucose (1.5 g/kg). Circulating and ileal intraluminal PYY concentrations were measured by a sensitive radioimmunoassay developed in our laboratory. Significant increases in circulating PYY levels were seen only after the fat meal in dogs. Ileal intraluminal PYY concentrations were significantly greater than those concentrations seen in the peripheral blood. A significant rise in ileal intraluminal PYY was seen only after the glucose meal without concomitant changes in circulating PYY. These findings document independent release mechanisms of PYY into the circulation and ileal lumen of the awake dog. We believe that the release of PYY into the canine circulation and into the ileal lumen after feeding may be dependent on the type of nutrient ingested and may serve to regulate the diverse physiologic roles of PYY in the gastrointestinal tract.

Animals↗
PubMed1989

Protein synthesis in liver following infusion of the catabolic hormones corticosterone, epinephrine, and glucagon in rats.

The mediator(s) and mechanism(s) of acute-phase protein synthesis in the liver following injury and sepsis are not fully known. Elevated plasma levels of the catabolic hormones cortisol, glucagon, and epinephrine have been reported in trauma and sepsis. In previous reports, when these hormones were infused simultaneously (triple hormone infusion), several, but not all, of the metabolic alterations characteristic of sepsis occurred. In the current investigation, the effect of triple hormone infusion on hepatic protein synthesis was studied. Rats were infused intravenously during 16 hours with a solution containing corticosterone (4.2 mg/kg/h), glucagon (2.5 micrograms/kg/h), and epinephrine (6 micrograms/kg/h). Control animals were infused with a corresponding volume of vehicle. Total hepatic protein synthesis in vivo was measured with a flooding dose technique using [14C]-leucine. The synthesis of total secretory proteins and of the individual proteins albumin, complement component C3, and alpha 1-acid glycoprotein was measured in isolated, perfused liver using [3H]-leucine and a recirculating technique. Urinary excretion of nitrogen and plasma concentration of glucose were higher and plasma total amino acid concentration was lower in hormone-infused than in control rats. Total hepatic protein synthesis in vivo, expressed as the proportion of the protein pool that was replaced each day, was increased from 39% +/- 2% per day to 48% +/- 3% per day (P less than .05) by hormone infusion, but synthesis of secretory proteins in perfused liver was not significantly altered. The results suggest that although total hepatic protein synthesis may be increased by catabolic hormones, other mediator(s) are probably responsible for the stimulation of acute-phase protein synthesis in sepsis.

Acute-Phase Proteins↗
PubMed1989

Total and myofibrillar protein breakdown in different types of rat skeletal muscle: effects of sepsis and regulation by insulin.

Proteolysis is increased in sepsis, but it is not known whether myofibrillar and non-myofibrillar proteins are broken down in the same fashion, or respond to the same regulatory forces as in non-septic muscle. In this study, therefore, the effect of sepsis on total and myofibrillar protein breakdown in incubated rat extensor digitorum longus (EDL) and soleus (SOL) muscles was determined, and the response in vitro to different concentrations of insulin (10 to 10(5) microU/mL) of protein degradation was studied in incubated EDL muscles from control and septic rats. Sepsis was induced in rats weighing 40 to 60 g by cecal ligation and puncture (CLP). Control animals were sham operated. Sixteen hours after CLP or sham operation, intact EDL and SOL muscles were incubated for two hours in oxygenated Krebs-Henseleit bicarbonate buffer containing glucose (10 mmol/L) and cycloheximide (0.5 mmol/L), and total and myofibrillar protein breakdown was assessed from release into incubation medium of tyrosine and 3-methylhistidine (3-MH), respectively. Tyrosine and 3-MH were determined fluorometrically by high performance liquid chromatography (HPLC). Tissue levels of tyrosine and 3-MH remained stable both in control and septic muscles during incubation for two hours. The rate of tyrosine release was increased during sepsis by 58% (P less than .001) and 15% (NS) in EDL and SOL muscle, respectively. The corresponding figures for 3-MH were 103% (P less than .001) and 21% (NS). Tyrosine release was reduced by insulin at a concentration of 10(3) microU/mL in control muscle and at a concentration of 10(4) microU/mL in septic muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Brain 3-methyoxytyramine varies inversely with blood glucose in decapitated rats.

Concentrations of the dopamine metabolite, 3-methyoxytyramine, were decreased significantly in the corpus striatum and nucleus accumbens of rats 30 min after the IP injection of D-glucose (2 g/kg). Conversely, 90 min after the administration of regular insulin (6 U/kg), significant increases in the concentrations of 3-methoxytyramine were observed in these two brain regions. Brain levels of the major metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid, did not correlate well with blood glucose concentration. The significant negative correlation of blood glucose with striatal and accumbens 3-methoxytyramine suggests an inverse relationship between dopamine metabolism and blood glucose concentration, that may be secondary to decapitation-induced anoxia.

Animals↗
PubMed1989

Radioimmunoassay to determine postprandial changes in plasma neuropeptide Y levels in awake dogs.

A specific, precise and sensitive double-antibody radioimmunoassay for Neuropeptide Y (NPY) has been developed. There was no appreciable cross-reactivity with the structurally related peptides, peptide YY (PYY) and pancreatic polypeptide (PP). The minimum detectable plasma NPY level was 3 nM. Application of radioimmunoassay to canine models revealed that portal and systemic NPY levels increased significantly following a standard meal.

Animals↗
PubMed1989

The relationship of burn-induced hypermetabolism to central and peripheral catecholamines.

The role of brain and circulating catecholamines as mediators of burn-induced hypermetabolism was investigated in two experiments. Following a 30% body surface area full-thickness open-flame burn, rats exhibited a short period (3 to 4 days) of anorexia followed by a more prolonged (several weeks) hyperphagic-hypermetabolic response. During this hypermetabolic period, norepinephrine concentrations were increased in the brain and circulating epinephrine levels were elevated. Depletion of brain norepinephrine using 6-hydroxydopamine led to increased body weight gain, but did not increase resting energy expenditure in burned rats. Similarly, the reduction of circulating catecholamines through removal of the adrenal medulla resulted in a decreased loss of body weight and only slight reductions in resting energy expenditure. Therefore, these results suggest that although brain norepinephrine and circulating epinephrine have a role in the full expression of hypermetabolism, these compounds do not appear to be major mediators of this response to burn trauma.

Adrenal Medulla↗
PubMed1989

Nitrosoureas. Modes of action and perspectives in the use of hormone receptor affinity carrier molecules.

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds are discussed. CNUs are alkylating agents that form DNA-DNA cross-links as well as 2-chloroethylated and 2-hydroxyethylated adducts, the N-7-position of guanine being the predominantly alkylated site. A close correlation exists between the potential of a given compound to induce DNA-DNA cross-links and its antineoplastic effectiveness. However, levels of DNA-DNA cross-linking in bone marrow and extent of myelosuppression as measured in rodents are also closely correlated. The design of new cross-linking analogues capable of directing the antineoplastically relevant activity predominantly to the target tumour appears therefore to be of great promise. Cross-linking agents have been attached to a variety of steroid hormone carrier molecules and the conjugates have been tested in structure-activity studies using hormone-receptor containing animal tumours. These studies have revealed that some hormone-linked antineoplastic agents are highly effective in receptor positive experimental tumours and are superior to mixtures of unlinked alkylating agents with hormones. Indications for a relative enrichment of DNA damaging effects in the tumour tissue and for reduced myelotoxicity have been obtained with specific hormone conjugates.

Animals↗
PubMed1989

Effect of sepsis on calcium uptake and content in skeletal muscle and regulation in vitro by calcium of total and myofibrillar protein breakdown in control and septic muscle: results from a preliminary study.

Because high calcium concentration in vitro stimulates muscle proteolysis, calcium has been implicated in the pathogenesis of increased muscle breakdown in different catabolic conditions. Protein breakdown in skeletal muscle is increased during sepsis, but the effect of sepsis on muscle calcium uptake and content is not known. In this study the influence of sepsis, induced in rats by cecal ligation and puncture, on muscle calcium uptake and content was studied. Sixteen hours after cecal ligation and puncture or sham operation, calcium content of the extensor digitorum longus (EDL) and soleus (SOL) muscles was determined with an atomic absorption spectrometer. Calcium uptake was measured in intact SOL muscles incubated in the presence of calcium 45 (45Ca) for between 1 and 120 minutes. Total and myofibrillar protein breakdown was determined in SOL muscles, incubated in the presence of different calcium concentrations (0; 2.5; 5.0 mmol/L), and measured as release into the incubation medium of tyrosine and 3-methylhistidine (3-MH), respectively. Calcium content was increased by 51% (p less than 0.001) during sepsis in SOL and by 10% (p less than 0.05) in EDL muscle. There was no difference in 45Ca uptake between control and septic muscles during the early phase (1 to 5 minutes) of incubation. During more extended incubation (30 to 120 minutes), muscles from septic rats took up significantly more 45Ca than control muscles (p less than 0.05). Tyrosine release by incubated SOL muscles from control and septic rats was increased when calcium was added to the incubation medium, and at a calcium concentration of 2.5 mmol/L, the increase in tyrosine release was greater in septic than in control muscle. Addition of calcium to the incubation medium did not affect 3-MH release in control or septic muscle. The results suggest that calcium uptake and content in skeletal muscle are increased during sepsis and that high calcium concentrations in vitro stimulate nonmyofibrillar protein breakdown. Muscles from septic animals may be more sensitive to the effect of calcium in vitro than muscles from nonseptic rats. Whether increased calcium uptake and content in skeletal muscle is partly responsible for accelerated muscle proteolysis during sepsis remains to be determined.

Animals↗
PubMed1989

Hemodynamic and metabolic alterations during experimental sepsis in young and adult rats.

Cecal ligation and puncture (CLP) has been extensively used as a model of sepsis in adult rats. It is not known if the response to sepsis is similar in young and adult rats. This investigation was done to compare hemodynamic and metabolic alterations in young (four to six weeks of age, 60 to 90 grams) and adult (12 to 14 weeks of age, 270 to 340 grams) rats after CLP. In one series of experiments, survival rate was determined for 96 hours, and in other experiments, mean arterial blood pressure (MAP), heart rate (HR), white blood cell count, hematocrit, platelets, plasma glucose, lactate, amino acids, blood urea nitrogen (BUN), blood and peritoneal cultures and resting energy expenditure (REE) were determined eight and 16 hours after CLP. Levels of glycogen in liver and muscle were determined 16 hours after CLP. Mortality rate was similar in young and adult rats. MAP was stable throughout the course of sepsis, with no significant differences between the two groups of rats. HR was higher in young rats at all times studied. The adult rats became hyperglycemic after CLP while the young were hypoglycemic eight hours after CLP but normalized at 16 hours. Plasma lactate and BUN were similar in the two groups of rats, and no alterations were seen during sepsis. Both young and adult rats became hypoaminoacidemic after CLP. The phenylalanine to tyrosine ratio increased in a similar manner during sepsis in both experimental groups. REE was higher in young than in adult rats, but no significant changes were observed during the course of sepsis in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1988

Evidence that cathepsin B contributes to skeletal muscle protein breakdown during sepsis.

The mechanisms of accelerated skeletal muscle protein degradation during sepsis have not been fully elucidated. Activity of the lysosomal protease cathepsin B is increased in skeletal muscle during various catabolic states other than sepsis. In the present study the protein degradation rate and cathepsin B activity were determined in extensor digitorum longus and soleus muscles from nonseptic and septic rats. The protein degradation rate during incubation in vitro with or without the cathepsin B inhibitor leupeptin was also determined. Both protein degradation and cathepsin B activity were increased in muscles from septic rats. Incubation with leupeptin reduced, but did not normalize, the protein degradation rate in both extensor digitorum longus and soleus muscles from septic animals. These studies suggest that increased cathepsin B activity contributes to the accelerated muscle proteolysis seen during sepsis and that proteases other than cathepsin B are also involved.

Animals↗
PubMed1988

Protein synthesis and degradation in skeletal muscle from septic rats. Response to leucine and alpha-ketoisocaproic acid.

It has been suggested that leucine and alpha-ketoisocaproic acid (KIA) stimulate protein synthesis and reduce protein breakdown and may be useful in the treatment of muscle catabolism during sepsis. However, whether leucine and KIA regulate protein turnover in septic skeletal muscle is not known. In this study, intact muscles from untreated normal rats or from rats subjected to cecal ligation and puncture were incubated in the presence of leucine or KIA. In normal muscle, leucine stimulated protein synthesis and reduced protein degradation, while KIA decreased protein breakdown. In septic muscle, protein synthesis was also stimulated by leucine, but only at a concentration higher than that needed to affect protein synthesis in normal muscle. Protein breakdown in septic muscle was unaffected by leucine and KIA even at an extracellular concentration as high as 5 mmol/L. Since other experiments showed that the intracellular concentration of leucine was not different in incubated normal and septic muscles, these results suggest that sepsis induces changes in skeletal muscle protein turnover that are resistant to the effects of leucine.

Animals↗
PubMed1988

Current concepts of protein turnover and amino acid transport in liver and skeletal muscle during sepsis.

The metabolic response to trauma and sepsis is characterized by a negative nitrogen balance, accelerated muscle proteolysis, increased ureagenesis, and stimulated acute-phase protein synthesis in liver. Inhibited uptake of amino acids and accelerated protein breakdown in muscle increase the flux of amino acids from the periphery to the liver. Concomitantly, hepatic uptake of amino acids is stimulated and protein synthesis and gluconeogenesis in the liver are enhanced. These events are important to the survival of patients with sepsis. Stimulated ureagenesis resulting in nitrogen loss from the body is another important aspect of hepatic nitrogen metabolism following trauma and sepsis. The mediator(s) initiating metabolic changes is not yet exactly defined, although regulatory protein(s) released from stimulated macrophages (particularly interleukin 1 and tumor necrosis factor) may play a major role in altered amino acid and protein metabolism in muscle and liver during sepsis. However, these factors alone are probably not responsible for the metabolic disturbances, since the catabolic hormones cortisol, glucagon, and the catecholamines can simulate the metabolic pattern observed in sepsis. Other possible mediators include prostaglandins and thyroid hormones. It is possible that the interaction between different types of mediators is necessary for the full manifestation of host responses to severe injury and sepsis.

Amino Acids↗
PubMed1988

Amino acid uptake in isolated, perfused liver: effect of trauma and sepsis.

To examine alterations in amino acid metabolism after trauma and sepsis, male Sprague-Dawley rats underwent no operation (control, CON), celiotomy (trauma, TRA), or cecal ligation and puncture (sepsis, CLP). After 16 hr, plasma amino acid concentrations were determined. A second group of similarly prepared animals underwent isolated liver perfusion, and net amino acid uptake or release was determined over 30 min. Sepsis significantly decreased total amino acid concentration in portal plasma (CON, 3486 +/- 156 nmole/ml; TRA, 3407 +/- 150 nmole/ml; CLP, 2738 +/- 148 nmole/ml). Glutamine concentrations were uniformly lower in portal plasma than in arterial plasma in all states. There were depressed concentrations of the branched chain amino acids (BCAA) in portal plasma after trauma but not sepsis. In the isolated liver perfusion model, a marked increase in amino acid uptake was induced by sepsis (CON, 39.9 +/- 7.9 mumol/g liver protein; TRA, 49.5 +/- 17.3 mumol/g liver protein; CLP, 124 +/- 11 mumol/g liver protein). In addition, there was significantly greater uptake of threonine, asparagine, proline, methionine, tyrosine, and arginine. Although the BCAA isoleucine and valine were taken up to a greater extent in sepsis, the overall BCAA uptake was not significantly greater in sepsis than in control (CON 6.92 +/- 2.15 mumol/g liver protein vs CLP 15.8 +/- 1.9 mumol/g liver protein). The greatest increase in uptake following sepsis was among the gluconeogenic precursor amino acids alanine, glycine, threonine, and serine (CON, 27.0 +/- 4.2 mumol/g liver protein, TRA, 38.8 +/- 8.9 mumol/g liver protein; CLP, 62.8 +/- 6.0 mumol/g liver protein).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1988

Effects of indomethacin and leupeptin on muscle cathepsin B activity and protein degradation during sepsis.

The roles of prostaglandins and lysosomal proteases in accelerated skeletal muscle proteolysis during sepsis are not yet fully understood. In this study rats received intraperitoneal injections of the prostaglandin synthesis inhibitor indomethacin (IND, 5.0 mg/kg), the lysosomal cathepsin B inhibitor leupeptin (LEU, 2.5 mg/kg), or normal saline 2 hr before cecal ligation and puncture (a model of intraabdominal sepsis) or sham-operation. The injections were repeated every 6 hr for a total of four doses. Sixteen hours after operation, intact extensor digitorum longus (EDL) muscles were harvested and cathepsin B activity was measured in one muscle. The contralateral muscle was incubated in oxygenated Krebs-Henseleit bicarbonate buffer containing glucose (10 mM) and cycloheximide (0.5 mM), and protein degradation rate was determined as the release of tyrosine into the incubation medium. Both muscle cathepsin B activity and protein degradation rate were higher in septic than in sham-operated rats. Treatment with IND or LEU significantly reduced the elevated cathepsin B activity in septic muscles, but failed to significantly alter muscle proteolysis. In nonseptic muscle, both cathepsin B activity and protein degradation rate were unaffected by the different types of treatment. The results suggest that although prostaglandins may influence muscle lysosomal protease activity, neither prostaglandins nor the lysosomal protease cathepsin B appear to be major regulators of accelerated muscle protein breakdown during sepsis.

Animals↗