Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis is a major catabolic insult resulting in modifications in carbohydrate and fat energy metabolism, and leading to increased muscle breakdown and nitrogen loss. Insulin resistance, which develops in sepsis, decreases glucose utilization, but plasma insulin levels are sufficiently elevated to prevent lipolysis, resulting in a further energy deficit. The availability of fuels in sepsis is therefore limited, and the body resorts to muscle breakdown, gluconeogenesis, and amino acid oxidation for energy supply. Previous work has not defined, however, the exact alterations in amino acid metabolism. Therefore, the following studies were undertaken. Blood samples were drawn from fifteen patients in whom the diagnosis of sepsis was clinically established; the samples were analyzed for amino acid, beta-hydroxyphenylethanolamines, glucose, insulin and glucagon concentrations. The plasma amino acid pattern observed was characterized by an increase in total amino acid content, due mainly to high levels of the aromatic amino acids (phenylalanine and tyrosine) and the sulfur-containing amino acids (taurine, cystine and methionine). Alanine, aspartic acid, glutamic acid and proline were also elevated, but to a lesser degree. The branched chain amino acids (valine, leucine and isoleucine) were within normal limits, as were glycine, serine, threonine, lysine, histidine and tryptophan. Those patients who did not survive sepsis had higher levels of aromatic and sulfur-containing amino acids as compared to those patients surviving sepsis. On the other hand, those patients surviving sepsis had higher levels of alanine and the branched chain amino acids. In a second group of five patients with overwhelming sepsis accompanied by a state of metabolic encephalopathy, a parenteral nutrition solution consisting of 23% dextrose, and an amino acid formulation enriched with branched chain amino acids was administered. In these five patients, normalization of the plasma amino acid pattern and reversal of encephalopathy was observed. The following sequence of events may be postulated: The septic patient develops insulin resistance in the peripheral tissues, primarily muscle, while the adipose tissue is much less affected. The insulin resistance and the inability to utilize fat leads to increased muscle proteolysis. Muscle breakdown results in release into the blood of enormous amounts of various amino acids; the muscle itself is able to oxidize the branched chain amino acids, supplying the muscles' own energy requirements and alanine for gluconeogenesis. The extensive muscle proteolysis coupled with relative hepatic insufficiency occurring early in sepsis results in the appearance in the plasma of high levels of most of the amino acids present in muscle, particularly the aromatic and the sulfur-containing amino acids. The outcome of patients with sepsis might be positively affected by combined therapy with glucose, insulin and branched chain amino acids.
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PMID:Amino acid derangements in patients with sepsis: treatment with branched chain amino acid rich infusions. 9 98

Eleven acute rejections were found in 9 patients with liver transplantation due to end-stage liver cirrhosis. The rejections were diagnosed with fine-needle aspiration biopsy (FNAB) giving the cellular picture of immunoactivation in the liver graft when compared to a simultaneous sample of peripheral blood. s-Alkaline phosphatase and s-bilirubin increased within 1 week after onset of rejection in 7 and 10 cases, respectively. s-Alanine amino-transferase and b-ammonium were of no value in the diagnosis of acute rejection. A core biopsy was obtained only in a case of severe liver damage, mainly to estimate the need for retransplantation. One year after grafting, 6 out of 7 cirrhotic patients are well, all with normal liver function. Two have died of sepsis. One patient died from pulmonary metastases of occult liver carcinoma 6 months after the transplantation. FNAB seems helpful in detecting early acute rejection and also excluding such an event in the liver graft.
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PMID:Diagnosis of acute rejection in liver transplantation. 304 94

The liver plays an important role in the acute-phase response to sepsis and injury, and host survival often depends upon an adequate hepatic response. Many of the metabolic sequelae to sepsis and injury are mediated by interleukin-1. This study was undertaken to investigate the impact of interleukin-1 upon hepatic metabolism and whether this mediator acted directly upon the liver. Interleukin-1 (5 rabbit pyrogen dose units) was administered to male Fisher F344 rats (175 to 200 g), and hepatocytes were isolated at three time periods; 2 to 4, 6 to 10, and 12 to 14 hours following an intraperitoneal injection. Alanine transport, gluconeogenesis, nonsecretory protein synthesis, and oxygen consumption were measured simultaneously in freshly isolated hepatocytes. Interleukin-1 stimulated initial rates of alanine uptake over a four-minute period. Peak stimulation of gluconeogenesis occurred at six to ten hours (0.52 +/- .14 v 0.08 +/- .01 nmol alanine converted/10(6) cells/min, P less than 0.05); nonsecretory protein synthesis was significantly stimulated at 12 to 14 hours (2.1 +/- .7 v 0.7 +/- 0.1 nmol valine converted/10(6) cells/min, P less than 0.05). These enhanced metabolic processes were associated with an increased oxygen consumption, with peak oxygen utilization occurring at six to ten hours (69 +/- 2 v 25 +/- 7 nmol of oxygen consumed 10(6) cells/min, P less than 0.05). In order to examine if interleukin-1 exerted its effect directly upon the liver, hepatocytes from normal rats were incubated in vitro with this mediator for two hours. Under these experimental conditions, interleukin-1 did not reproduce the stimulatory effect obtained following in vivo administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulatory effect of interleukin-1 upon hepatic metabolism. 348 38

Nitrogen flux across the splanchnic bed is altered following operation, injury, and sepsis, but the individual contributions of gut and liver and their interrelationships remain undefined. Since more than 60% of whole blood amino acid nitrogen is transported as glutamine and alanine, we determined the flux of these amino acids across the gastrointestinal tract and liver in splenectomized, awake dogs during a control period and a 2 and 4 days following a standard laparotomy. Blood flow was measured in all studies and substrate flux calculated from flow and arteriovenous and portovenous concentration differences. Portal blood flow decreased by 25% following operation from a control value of 26 +/- 2 ml/kg body weight . min to 19 +/- 2 (P less than 0.05). Total hepatic blood flow did not change significantly after operation, but the individual contributions of the hepatic artery and portal vein were altered; hepatic artery flow increased from a control value of 10 +/- 1 ml/kg . min to 23 +/- 3 (P less than 0.001). Glutamine uptake by teh gastrointestinal tract nearly doubled from a control value of 0.75 +/- 0.16 microM/kg . min to 1.31 +/- 0.13 (P less than 0.05) on postoperative day 2. This increase in flux occurred despite a diminished arterial concentration and a reduced portal blood flow, indicating that extraction of glutamine by the gastrointestinal tract was not primarily dependent on increased arterial concentration. Alanine, on the other hand, was released by the gut at a rate of 1.97 +/- 0.37 microM/kg . min in controls and decreased to 0.81 +/- 0.13 microM/kg . min (P less than 0.05) in dogs that had operation. Glutamine was released by the liver in control dogs at a rate of 1.59 +/- 0.59 microM/kg . min but switched to an organ of slight glutamine uptake (0.31 +/- 0.31, P less than 0.01) on postoperative day 2. Alanine uptake by the liver doubled from 2.94 +/- 0.29 to 5.46 +/- 0.63 microM/kg . min (P less than 0.05) following surgical stress. The gastrointestinal tract plays an active metabolic role in the processing of amino acids following operation and may be a key regulatory of interorgan substrate flux following injury and infection.
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PMID:Postoperative alteration of arteriovenous exchange of amino acids across the gastrointestinal tract. 687 48

The blood concentrations and the disappearance of injected beta-hydroxybutyrate (beta-OHB) and alanine were measured in 12 health subjects who had fasted overnight and in 25 surgical patients. Ten of the patients had had uncomplicated abdominal surgery two of five days before, six patients had moderate sepsis e.g. wound sepsis and nine patients had severe intra-abdominal sepsis. Separated bolus injections of beta-OHB and alanine were given intravenously and the blood concentration of the corresponding metabolite was measured over the following 40 mins. The disappearance of the injected metabolite was logarithmic, and the half-life (t 1/2) and clearance rate of the injected metabolite were calculated. The basal ketone concentration (beta-hydroxybutyrate and acetoacetate) were higher in the post operative group than in healthy subjects whereas the severely septic group had the same ketone concentration as the healthy subjects. Alanine concentration was significantly lower in the post-operative group. The t 1/2 and clearance rate of the injected metabolites were similar in all the groups for both beta-hydroxybutyrate and alanine. It is suggested that if the bolus is handled like the endogenously produced metabolite then the differences in concentration of beta-OHB and alanine in post-surgical and septic patients are likely to be due to changes in production rate.
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PMID:Blood concentration and disappearance of injected alanine and beta-hydroxybutyrate in surgical patients. 727 92

Tissue factor, the obligate cofactor for coagulation factor VII, plays an essential role in hemostasis by initiating the extrinsic pathway of blood coagulation upon vascular damage, making it a promising target for new anticoagulant therapies in the treatment of thrombosis and sepsis. The three-dimensional structure of the extracellular domain of tissue factor, determined by X-ray crystallography at a resolution of 2.4 A, consists of two domains of approximately equal size, with a topology characteristic of fibronectin type III modules. Comparison of tissue factor with the extracellular domain of the growth hormone receptor, which belongs to the same receptor superfamily, shows that the relative orientation between these domains as well as the domain-domain interface is very different. These differences have dramatic consequences for the residues in tissue factor that are homologous to the binding determinants of the growth hormone receptor. Alanine-scanning mutagenesis has identified tissue factor residues important for factor VIIa binding. The structure shows that the binding site is located in the domain-domain interface region but on the opposite side of the molecule compared to the growth hormone receptor, with the binding determinants residing on beta-strands rather than on loops.
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PMID:Structure of the extracellular domain of human tissue factor: location of the factor VIIa binding site. 808 3

Glutamine is considered to be a 'conditionally' essential amino acid. During situations of severe stress like sepsis or after trauma there is a fall in plasma glutamine levels, enhanced glutamine turnover and intracellular muscle glutamine depletion. Under these conditions, decreased intramuscular glutamine concentration correlates with reduced rates of protein synthesis. It has therefore been hypothesized that intracellular muscle glutamine levels have a regulatory role in muscle protein turnover rates. Administration of the glutamine synthetase inhibitor methionine sulphoximine (MSO) was used to decrease glutamine levels in male Wistar rats. Immediately after the MSO treatment (t=0 h), and at t=6 h and t=12 h, rats received intraperitoneal injections (10 ml/100 g body weight) with glutamine (200 mM) to test whether this attenuated the fall in plasma and intracellular muscle glutamine. Control animals received alanine and saline after MSO treatment, while saline was also given to a group of normal rats. At t=18 h rats received a primed constant infusion of L-[2,6-3H]phenylalanine. A three-pool compartment tracer model was used to measure whole-body protein turnover and muscle protein kinetics. Administration of MSO resulted in a 40% decrease in plasma glutamine and a 60% decrease in intracellular muscle glutamine, both of which were successfully attenuated by glutamine infusions. The decreased intracellular muscle glutamine levels had no effect on whole-body protein turnover or muscle protein kinetics. Also, glutamine supplementation did not alter these parameters. Alanine supplementation increased both hindquarter protein synthesis and breakdown but the net balance of phenylalanine remained unchanged. In conclusion, our results show that decreased plasma and muscle glutamine levels have no effect on whole-body protein turnover or muscle protein kinetics. Therefore, it is unlikely that, in vivo, the intracellular muscle concentration of glutamine is a major regulating factor in muscle protein kinetics.
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PMID:Effects in vivo of decreased plasma and intracellular muscle glutamine concentration on whole-body and hindquarter protein kinetics in rats. 1033 70

F165(1) (foo) and CS31A (clp) are bacterial adhesins synthesized by Escherichia coli strains associated with diarrhea and septicemia in piglets and calves. They belong to the P-regulatory family and as such are subject to a phase variation control mediated by Lrp (leucine responsive regulatory protein) and regulators homologous to PapI. Analysis of expression of transcriptional fusions between the fooB or fooI promoters and lacZ showed that Lrp is an activator of foo and fooI transcription, whereas it represses clp transcription. Furthermore, foo phase variation leads to a large majority of phase-ON cells, whereas clp phase variation leads to a majority of phase-OFF cells. We compared the influence of several environmental cues on foo and clp expression, with special attention to the effects of leucine and alanine known to be mediated by Lrp. Inhibition or significant repression of foo and clp transcription was observed at low temperature, in LB medium, and in the presence of glucose, alanine, or leucine. Glucose repression of foo but not of clp was totally relieved by addition of cAMP. Osmolarity and pH had little effect. Alanine but not leucine, and LB medium inhibited foo and clp phase variation, locking cells in the OFF phase. Low temperature inhibited clp phase variation and altered the switch frequency of foo phase variation, leading to more phase-OFF cells. Glucose altered the phase variation of both operons, increasing the number of phase-OFF cells in the population. The regulation pattern of foo and clp is consistent with F165(1) and CS31A production in low nutrient environments, even at moderately acidic pH or high osmolarity.
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PMID:Influence of environmental cues on transcriptional regulation of foo and clp coding for F165(1) and CS31A adhesins in Escherichia coli. 1524 65

Liver and kidney damage associated with polytrauma, endotoxic shock/sepsis, and organ transplantation, are among the leading causes of the multiple organ failure. Development of novel sensitive biomarkers that detect early stages of liver and kidney injury is vital for the effective diagnostics and treatment of these life-threatening conditions. Previously, we identified several hepatic proteins, including Argininosuccinate Synthase (ASS) and sulfotransferases which were degraded in the liver and rapidly released into circulation during Ischemia/Reperfusion (I/R) injury. Here we compared sensitivity and specificity of the newly developed sandwich ELISA assays for ASS and the sulfotransferase isoform SULT2A1 with the standard clinical liver and kidney tests Alanine Aminotransferase (ALT) and Aspartate Transaminase (AST) in various pre-clinical models of acute injury. Our data suggest that ASS and SULT2A1 have superior characteristics for liver and kidney health assessment in endotoxemia, Ischemia/Reperfusion (I/R), chemical and drug-induced liver injury and may be of high potential value for clinical applications.
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PMID:ASS and SULT2A1 are Novel and Sensitive Biomarkers of Acute Hepatic Injury-A Comparative Study in Animal Models. 2372 64