ACS conference links investigators and NIH.
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Financing, Government↗
Biomedical subjects
J E Fischer
Publications and source records attributed to J E Fischer.
Detrimental effect of nitric oxide synthase inhibition during endotoxemia may be caused by high levels of tumor necrosis factor and interleukin-6.
BACKGROUND: Nitric oxide (NO) production increases during sepsis and endotoxemia. Inhibition of NO synthase has been suggested as a therapeutic modality in sepsis and endotoxemia, but in recent reports NO synthase inhibition increased mortality rate. The mechanism of this phenomenon is not known. Other studies have shown that high levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) contribute to death during sepsis and endotoxemia. We tested the effect of NO synthase inhibition on survival in endotoxemic rats and hypothesized that inhibition of NO synthase during endotoxemia increases circulating levels of TNF and IL-6. METHODS: Rats were treated with subcutaneous injection of saline solution or 100 mg/kg of the NO synthase inhibitor N-nitro-L-arginine 1 hour before intravenous injection of endotoxin (15 mg/kg) or saline solution. Survival was followed for 24 hours. Plasma nitrite-nitrate (NO2/NO3), TNF, and IL-6 levels were determined at intervals. RESULTS: Endotoxin caused a significant increase in levels of plasma NO2-/NO3-, TNF, and IL-6 and a 33% mortality rate. Pretreatment with N-nitro-L-arginine increased mortality rate to 74%, decreased NO2/NO3, and substantially increased TNF and IL-6 levels. CONCLUSIONS: Inhibition of NO synthase increases mortality rate during endotoxemia. The detrimental effect of NO synthase inhibition during endotoxemia may be caused by excessive production of TNF and IL-6.
Amino Acid Oxidoreductases↗
Liver, biliary tract, and pancreas.
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Adult↗
Anorexia following the systemic injection of amylin.
The intravenous injection of 100 micrograms/kg of rat amylin reduced food intake in schedule-fed rats for 1 h of an 8 h measurement period. Associated with this brief anorexia was a hyperglycemic response, observed 30 min after a subsequent amylin administration. Determination of neurochemical alterations revealed increased concentration of serotonin in the hypothalamus and decreased level of the dopamine metabolite, 3-methoxytyramine, in the corpus striatum. Since similar neurochemical alterations were observed following the systemic injection of glucose, both the neurochemical changes and anorexia following intravenous amylin treatment may be secondary to hyperglycemia.
Amyloid↗
Nitric oxide may upregulate in vivo hepatic protein synthesis during endotoxemia.
Nitric oxide (NO) has been implicated as a mediator of hemodynamic and metabolic changes associated with endotoxemia and inflammation. In vitro studies suggest that NO inhibits hepatocyte protein synthesis but the role of NO in the regulation of hepatic protein synthesis in vivo is not known. In this study, rats were given endotoxin or saline after pretreatment with the NO synthase inhibitor NG-nitro-L-arginine or solvent, and plasma levels of nitrite (NO2), nitrate (NO3), and aspartate aminotransferase and hepatic protein synthesis rate in vivo were measured after 4 and 10 hours. The NG-nitro-L-arginine effectively blocked the increase in serum NO2/NO3 seen in endotoxemia and also inhibited the increase in hepatic protein synthesis in endotoxemic rats. The aspartate aminotransferase levels were elevated in endotoxemic rats pretreated with NG-nitro-L-arginine. Results support previous reports of a protective effect of NO on the liver in endotoxemia and suggest that NO may upregulate hepatic protein synthesis in vivo. Further study is needed to clarify the reason for the apparent difference between the effect of NO on hepatic protein synthesis in vivo and in vitro.
Amino Acid Oxidoreductases↗
Intracellular glutamine concentration does not decrease in all muscles during sepsis.
The concentrations of glutamine and other amino acids were measured in plasma and intracellular fluid of soleus and extensor digitorum longus (EDL) muscles of rats 4, 8, and 16 hr after induction of sepsis by cecal ligation and puncture or after sham operation. Previous studies have shown that muscle protein breakdown is greatly increased in EDL, but not in soleus muscle, in this sepsis model. Corresponding to previous observations of protein breakdown in sepsis, muscle glutamine was markedly depleted (< 50%) in EDL by sepsis, while no significant fall in glutamine concentration in soleus was observed. Changes in muscle glutamine concentration in sepsis could not be attributed to changes in the precursor of glutamine, glutamic acid. Data were examined for changes consistent with hypothesized alterations in glutamine transport. Correlations among glutamine and other amino acids in muscle, histidine in particular, were consistent with a sepsis-induced alteration in activity of the sarcolemmal glutamine transporter, system Nm. These results thus strengthen the proposed connection between muscle glutamine content and muscle protein metabolism under catabolic conditions.
Amino Acids↗
In vivo administration of interleukin-1 alpha induces muscle proteolysis in normal and adrenalectomized rats.
The effect on muscle protein turnover of recombinant interleukin-1 alpha (rIL-1 alpha), 300 micrograms/kg body weight (BW) administered intraperitoneally (IP) in three divided doses over 18 hours, was studied in rats. Protein synthesis rate was determined by measuring incorporation of 14C-phenylalanine into protein, and total and myofibrillar protein breakdown rates were determined by measuring release of tyrosine and 3-methylhistidine, respectively, in incubated extensor digitorum longus muscles. To assess the role of glucocorticoids in rIL-1 alpha-related metabolic alterations, plasma levels of corticosterone following rIL-1 alpha injection and the effect of rIL-1 alpha on muscle protein breakdown in adrenalectomized and sham-adrenalectomized rats were determined. Total and myofibrillar protein breakdown rates were increased by 45% and 167%, respectively, following treatment of normal rats with rIL-1 alpha; muscle protein synthesis was not altered by the cytokine. Plasma corticosterone levels were markedly elevated following rIL-1 alpha injection, with a maximal level occurring at 30 minutes. However, administration of rIL-1 alpha resulted in increased total and myofibrillar protein breakdown rates in both adrenalectomized and sham-adrenalectomized rats. The results suggest that increased muscle proteolysis following administration of rIL-1 alpha is independent of glucocorticoids.
Adrenal Glands↗
Evidence that inhibition of muscle amino acid uptake during endotoxemia is not mediated by glucocorticoids.
Sepsis and endotoxemia are associated with increased muscle protein breakdown and inhibited amino acid uptake. Glucocorticoids are important for the regulation of muscle protein breakdown in catabolic conditions; in contrast, the role of glucocorticoids in the regulation of muscle amino acid transport during sepsis or endotoxemia is not known. The present study was designed to test the role of glucocorticoids in the regulation of muscle amino acid uptake during endotoxemia. Amino acid transport, determined as uptake of 3H-alpha-aminoisobutyric acid (AIB) by incubated soleus muscles in vitro, was reduced by approximately 40% 2 hours after intraperitoneal (IP) injection of 10 micrograms/kg endotoxin in rats. Administration of 5 mg/kg of the glucocorticoid receptor antagonist RU 38486 2 hours before endotoxin injection did not affect the inhibition of amino acid uptake. In vitro addition of plasma from endotoxemic rats to incubated rat soleus muscles inhibited amino acid uptake by approximately 30%. This effect of endotoxic plasma also was noted when muscles were from rats that had been treated with RU 38486 and when RU 38486 was present in the incubation medium. Results confirm previous reports of reduced muscle amino acid transport during endotoxemia and of the presence of a circulating factor that inhibits muscle amino acid uptake in this condition. Data suggest that inhibited muscle amino acid transport during endotoxemia is not regulated by glucocorticoids.
Aminoisobutyric Acids↗
Effects of increased beta 2-agonist dose in tumor-bearing animals.
Cachexia and malnutrition are major contributing causes of significant morbidity and mortality in the cancer patient. Although supplemental nutrition alone does not reverse the cachectic process, the use of anabolic beta 2-adrenergic agonists in conjunction with supplemental nutrition does significantly reverse cachectic processes in tumor-bearing (TB) animals. To determine the most efficacious dose of the beta 2-agonist cimaterol (CIM), male Fischer-344 rats with dorsal subcutaneous methylcholanthrene sarcomas were maintained on supplemental enteral nutrition via surgically placed gastrostomy tubes. TB rats were given daily subcutaneous injections of either saline (Sal) or one of three doses of CIM for seven days. TB-Sal animals demonstrated significant cachexia with decreased extensor digitorum longus and gastrocnemius muscle dry weight and protein content. There was a significant increase in both extensor digitorum longus and gastrocnemius muscle dry weight and protein content in all treatment groups compared with TB controls. The greatest increase was in the 0.30 mg/kg CIM treatment group. Increased cardiac mass was associated with increasing dosage, with the greatest effect being observed in the 0.60 mg/kg CIM treatment group. This dosage, however, was associated with a decreased effect on muscle weight and protein content compared with the 0.30 mg/kg CIM dose. Thus the peak anabolic effect in TB animals was reached with the 0.30 mg/kg dose of CIM. Therefore, use of the beta 2-agonist CIM may prove useful in the treatment of cancer-induced cachexia.
Adrenergic beta-Agonists↗
Serum transferrin as a prognostic indicator of spontaneous closure and mortality in gastrointestinal cutaneous fistulas.
OBJECTIVE: This study determined whether there are any laboratory or other features that will enable prediction of spontaneous closure in patients with gastrointestinal cutaneous fistulas. SUMMARY BACKGROUND DATA: Although the anatomic criteria for spontaneous closure of gastrointestinal cutaneous fistulas have been presented by several authors, less than 50% of such fistulas tend to close, even in the most recent series. METHODS: A group of patients with gastrointestinal cutaneous fistulas with anatomical features favorable to study were investigated with respect to a series of parameters including the usual demographic parameters, plus fistula output, number of blood transfusions, presence of sepsis, as well as metabolic parameters including serum transferrin, retinol-binding protein, thyroxin-binding prealbumin, and serum albumin. RESULTS: Of 79 patients with 116 fistulas, 16 (20.3%) died. Causes of death were uncontrolled sepsis in eight patients and cancer in five patients. Postoperative fistulas constituted 80% of the group. The presence of local sepsis, systemic sepsis, remote sepsis (such as pneumonia or line sepsis), the number of fistulas, fistula output, and the number of blood transfusions were not predictive of spontaneous closure, whereas serum transferrin was predictive of spontaneous closure. Serum transferrin, retinol-binding protein, and thyroxin-binding prealbumin were predictive of mortality. CONCLUSIONS: Serum transferrin does not appear to be an entirely independent variable, but seems to identify those patients with significant remote sepsis, systemic sepsis, and neoplasia in whom these processes are clinically significant. The results, if confirmed, and provided that nutritional needs are met, suggest that short-turnover proteins, particularly serum transferrin, might be useful in predicting which patients with gastrointestinal cutaneous fistulas should undergo surgery despite anatomic criteria favorable for spontaneous closure.
Adolescent↗
CAD/CAM subperiosteal implants in Australia. Case report.
This is the first known report of a subperiosteal implant inserted in Australia using computer assisted design (CAD) and computer assisted manufacture (CAM). A case report is presented describing a method of eliminating first stage surgery in treating fully edentulous patients with subperiosteal implants.
Computer-Aided Design↗
Comparison of distal and proximal splenorenal shunts: a ten-year experience.
BACKGROUND: This study evaluated the effectiveness of distal (DSRS) versus the central or proximal (PSRS) splenorenal shunts in the elective treatment of bleeding varices. METHODS: A series of 48 patients with portal hypertension and established variceal bleeding were randomized to undergo PSRS or DSRS. Preoperative evaluation included endoscopic examination, angiography, serum amino acid profile, liver chemistry studies, and neurologic evaluation. Any patient with significant ascites and hepatofugal flow underwent PSRS shunt procedures; the remainder were randomized prospectively. RESULTS: Between 1979 and 1989, 29 patients underwent PSRS and 19 underwent DSRS. The mean length of follow-up was 48 months. The groups were equivalent with regard to age, gender, child's class, number of preoperative bleeds, and cause of disease. No difference was found in any of the factors measured. In particular there were no differences in the operative mortality rate (17% PSRS; 11% DSRS), 5-year survival rate (52% PSRS; 52% DSRS), rebleeding (34% PSRS; 32% DSRS), shunt occlusion (7% PSRS; 11% DSRS), development of individual episodes of postoperative encephalopathy (28% PSRS; 26% DSRS), chronic postoperative encephalopathy (17% PSRS; 11% DSRS), or mean branched-chain/aromatic amino acid ratios (PSRS = 0.88 +/- 0.05; DSRS = 0.66 +/- 0.05). CONCLUSIONS: The results do not support the contention that DSRS is associated with either greater survival or less encephalopathy than PSRS.
Ascites↗
The pull-through procedure: technical factors in influencing outcome, with emphasis on pouchitis.
BACKGROUND: The purpose of the study was to review those features that we believed to be critical to the successful performance of the ileal pouch-anal anastomosis, or pull-through, procedure, and specifically the complication of pouchitis. METHODS: The charts of 205 patients who successfully underwent ileal pouch-anal anastomosis procedure were reviewed. No follow-up was available in five patients; therefore, the basis of this report and its analysis was based on 200 consecutive procedures in which at least two of the three surgeons participated. Particular emphasis was placed on continence, particularly nighttime continence. The incidence of pouchitis, either a single episode or intermittent episodes, was surveyed. Particular attention was paid to the level of rectal mucosectomy and anastomosis at the top of the columns of Morgagni, thus retaining the transitional zone. RESULTS: Only 5% of patients were incontinent in the absence of pouchitis. Twenty-five patients (13%) wore a pad at night, but only nine (5%) wore a pad during the day. Of those patients with pouchitis, 6% (12) have had a single episode and 12% (23) were intermittently on medication. Therapy of pouchitis was usually carried out with ciprofloxacin 500 mg by mouth everyday or twice a day. CONCLUSIONS: Ileal pouch-anal anastomosis is an excellent procedure, provided technical details are adhered to. Satisfactory outcome with respect to nighttime continence can be achieved with rectal mucosectomy with minimal manipulation and retaining the transitional epithelium, performing the pouch anastomosis at the top of the columns of Morgagni. The incidence of pouchitis is disappointing but need not be inhibiting of either patients or carrying out this life-saving procedure in patients with ulcerative colitis and familial polyposis.
Adolescent↗
Effect of tumor necrosis factor or interleukin-1 on muscle amino acid uptake and the role of glucocorticoids.
Muscle amino acid uptake is inhibited during sepsis and endotoxemia. Cytokines, in particular tumor necrosis factor (TNF) and interleukin-1 (IL-1), have been implicated as mediators of metabolic alterations in sepsis and other critical illness. In this study, we examined the effect of TNF and IL-1 on muscle amino acid uptake and tested the hypothesis that cytokine-induced changes in muscle amino acid uptake are mediated by glucocorticoids. Intraperitoneal injection in rats of 100 micrograms per kilogram body weight of human recombinant TNF alpha (rTNF alpha) or rIL-1 alpha resulted, two hours later, in 36 and 24 percent reduction, respectively, of amino acid transport in incubated soleus muscles, determined as intracellular uptake of alpha-aminoisobutyric acid. When rats were treated with the glucocorticoid receptor antagonist RU 38486 (5 milligrams per kilogram of body weight) two hours before cytokine injection, the inhibitory effect on muscle amino acid transport of TNF was blocked, whereas that of IL-1 was unaffected. The present results suggest that TNF and IL-1 may regulate amino acid transport in skeletal muscle and that the effect of TNF, but not that of IL-1, is at least partly mediated by glucocorticoids.
Amino Acids↗
Amylin increases transport of tyrosine and tryptophan into the brain.
Injection of amylin (diabetes-associated peptide) into the hypothalamus induces anorexia, increases brain metabolism of dopamine and serotonin and elevates brain level of tryptophan. When male Sprague-Dawley rats were treated with 50 mg/kg L-tryptophan and L-tyrosine ethyl ester 30 min prior to the intrahypothalamic injection of 2 micrograms amylin, brain tryptophan and tyrosine levels were selectively increased as compared to rats treated with amylin alone. Hypothalamic and striatal serotonin metabolism also appeared to be increased following the amino acid-amylin treatment combination. These results suggest that amylin may increase transport of tyrosine and tryptophan into the brain, and that the increased availability of tryptophan may contribute to increased serotonin turnover observed following intrahypothalamic amylin treatment.
3,4-Dihydroxyphenylacetic Acid↗
Alterations in the subcellular distribution of p21ras-GTPase activating protein in proliferating rat acinar cells.
Rat parotid acinar cells undergo transient proliferation in response to chronic administration of the beta-adrenergic agonist isoproterenol or epidermal growth factor (EGF). Treatment with these agents caused an increase in tyrosine phosphorylation of p21ras-GTPase activating protein (GAP). This phosphorylation event was accompanied by a redistribution of the protein from the plasma membrane to internal membrane compartments. Separation of subcellular membranes revealed increased GAP associated with a low density population of vesicles concomitant with growth stimulation as well as to the nuclear membrane, but not the nucleoplasm. Upon cessation of hyperplasia induced by isoproterenol, phosphorylated GAP present in the plasma membrane returned to control cell levels.
Animals↗
Increased intestinal protein synthesis during sepsis and following the administration of tumour necrosis factor alpha or interleukin-1 alpha.
The influence of sepsis on intestinal protein synthesis was studied in rats. Sepsis was induced by caecal ligation and puncture (CLP); control rats were sham-operated. Protein synthesis was measured in vivo in the jejunum and ileum following a flooding dose of [14C]leucine. At 8 h after CLP the protein synthesis rate was increased by approx. 15% in jejunal mucosa, and at 16 h after CLP, the protein synthesis rate was increased by 50-60% in the mucosa and seromuscular layer of both jejunum and ileum. In a second series of experiments, rats were treated with recombinant tumour necrosis factor alpha (rTNF alpha) or recombinant interleukin-1 alpha (rIL-1 alpha) administered at a total dose of 300 micrograms/kg body weight over 16 h. Control rats received corresponding volumes of solvent. Treatment with rTNF alpha resulted in an approx. 25% increase in mucosal protein synthesis in jejunum. Following treatment with rIL-1 alpha, protein synthesis increased by 25% in jejunal mucosa and almost doubled in ileal mucosa. The results suggest that sepsis stimulates intestinal protein synthesis and that this response may, at least in part, be mediated by TNF and/or IL-1.
Animals↗
Amylin inhibits insulin-stimulated glucose uptake in C2C12 muscle cell line through a cholera-toxin-sensitive mechanism.
Rat amylin inhibits insulin-stimulated glucose uptake with an IC50 of 12.1 +/- 4.1 pM in C2C12 myotubes. The maximal inhibition is 64 +/- 5.4% observed at a 100-pM dose of the peptide. Consistently, presence of 100 pM amylin shifted the dose-response curve of insulin to the right, increasing the ED50 from 0.71 to 16 nM. No effect of amylin is observed on basal glucose uptake in these cells. Cholera-toxin treatment of the cells did not affect the insulin-stimulated glucose uptake, while the inhibitory effect is completely lost in toxin-treated cells. These findings strongly suggest that rat amylin is active at a physiological concentration and the amylin inhibition of glucose uptake is mediated through a cholera-toxin-sensitive mechanism.
Amyloid↗