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)

Orthotopic liver transplantation (OLT) is the definitive therapy for severe liver failure. However, many patients die before an organ becomes available, mostly from cerebral edema. To provide temporary liver support, we developed a bioartificial liver (BAL) based on porcine hepatocytes and a charcoal column. Fifty-four consecutive BAL treatments were carried out in three groups of patients: Group I (n = 15) patients presented with FHF were listed for emergent OLT, Group II (n = 3) patients with primary non-function (PNF) of their liver grafts required urgent re-transplantation and Group III (n = 10) patients with acute exacerbation of chronic liver disease were not candidates for OLT. Patients were managed in a critical care unit receiving maximal standard support. Each BAL treatment was conducted for 6 hours. In Group I, all patients showed significant neurologic improvement, intracranial pressure (ICP) decreased and cerebral perfusion pressure (CPP) increased; other significant improvements, included lowered plasma ammonia and liver enzymes and increased glucose. One patient recovered spontaneously without OLT, all other patients were "bridged" to OLT, and recovered. Group II: PNF patients showed similar benefits. Group III: Chronic liver patients demonstrated transient beneficial effects after BAL treatment(s), however, most (n = 8) eventually succumbed to sepsis and multiple organ failure as they were not candidates for OLT; two patients, recovered, later were successfully transplanted and survived. Our clinical experience demonstrates that the BAL can serve as a bridge to OLT in patients with acute liver failure.
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PMID:Treatment of severe liver failure with a bioartificial liver. 961 27

The most abundant amino acid in the bloodstream, L-glutamine fulfills a number of biochemical needs. It operates as a nitrogen shuttle, taking up excess ammonia and forming urea. It can contribute to the production of other amino acids, glucose, nucleotides, protein, and glutathione. Glutamine is primarily formed and stored in skeletal muscle and lungs, and is the principal metabolic fuel for small intestine enterocytes, lymphocytes, macrophages, and fibroblasts. Supplemental use of glutamine, either in oral, enteral, or parenteral form, increases intestinal villous height, stimulates gut mucosal cellular proliferation, and maintains mucosal integrity. It also prevents intestinal hyperpermeability and bacterial translocation, which may be involved in sepsis and the development of multiple organ failure. L-glutamine use has been found to be of great importance in the treatment of trauma and surgery patients, and has been shown to decrease the incidence of infection in these patients. Cancer patients often develop muscle glutamine depletion, due to uptake by tumors and chronic protein catabolism. Glutamine may be helpful in offsetting this depletion; however, it may also stimulate the growth of some tumors. The use of glutamine with cancer chemotherapy and radiotherapy seems to prevent gut and oral toxic side-effects, and may even increase the effectiveness of some chemotherapy drugs.
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PMID:Therapeutic considerations of L-glutamine: a review of the literature. 1046 48

The liver shows net glutamine uptake after a protein-containing meal, during uncontrolled diabetes, sepsis and short-term starvation, but changes to net release during long-term starvation and metabolic acidosis. Some studies report a small net release of glutamate by the liver. The differential expression of glutamine synthetase (perivenous) and glutaminase (periportal) within the liver indicates that glutamine is used for urea synthesis in periportal cells, whereas glutamine synthesis serves to detoxify any residual ammonia in perivenous cells. Experiments in vivo suggest that changes in net hepatic glutamine balance are due predominantly to regulation of glutaminase activity, with the flux through glutamine synthetase being relatively constant.
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PMID:Glutamine and glutamate metabolism across the liver sinusoid. 1073 66

Sepsis and septic shock constitute an important cause of morbidity and mortality in critically ill children. Thus, the systemic response to infection and its management remains a major challenge in clinical medicine. Apart from antibiotic administration, the majority of available therapies are limited to supportive strategies, although considerable efforts are being undertaken to devise innovative approaches that modulate host inflammatory responses. In suspected sepsis, 2 or 3 days' empiric antibiotic therapy should begin immediately after cultures have been obtained without awaiting results. Antibiotics should be re-evaluated when the results of the cultures and susceptibility tests are available. The initial antibiotic (combination) is determined by the likely causative agent, susceptibility patterns within a specific institution, CNS penetration, toxicity, and the patient's hepatic and renal function. The likely offending micro-organism in turn depends primarily on the patient's age, coexistence of any premorbid condition leading to impaired immune response, and the presenting signs and symptoms. Close attention to cardiovascular, respiratory, fluid and electrolyte, haematological, renal and metabolic/nutritional support is essential to optimise outcome. Fluid resuscitation is of utmost importance to overcome hypovolaemia on the basis of a diffuse capillary leak. Monitoring and normalisation of the heart rate is essential. In case of nonresponse to fluid resuscitation, inotropic and vasoactive agents are commonly used to increase cardiac output, maintain adequate blood pressure and enhance oxygen delivery to the tissue. Because respiratory distress syndrome is seen in about 40% of critically ill children with septic shock, increased inspired oxygen is essential. To provide optimal relief from respiratory muscle fatigue and facilitate the provision of positive airway pressure, early intubation and mechanical ventilation should be considered. Renal support is essential to avoid prolonged renal shutdown in hypoperfusion states. Haematological support comprises replacement therapy of clotting factors to overcome disseminated intravascular coagulation. Metabolic support may include glucose support, extraction of ammonia from the body and recognition of liver dysfunction. Nutritional support may modify the inflammatory host response, and early enteral feeding can improve outcome in critical illness. To date, glucocorticoid and non-glucocorticoid anti-inflammatory agents have not shown significant benefit in septic patients.
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PMID:Management of sepsis and septic shock in infants and children. 1122 Apr 6

The branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) are the major nitrogen source for glutamine and alanine synthesis in muscle. Synthesis of glutamine, alanine, and BCAA use is activated in critical illnesses such as in sepsis, cancer, and trauma. The use of glutamine often exceeds its synthesis, resulting in the lack of glutamine in plasma and tissues. In critical illness, resynthesis of BCAA from branched-chain keto acids is activated, particularly in hepatic tissue. The BCAA released to circulation may be used for protein synthesis or synthesis of alanine and glutamine. Glutamine and/or alanine infusion has an inhibitory effect on the breakdown of body proteins and decreases BCAA catabolism in postabsorptive control, endotoxemic, and irradiated rats. Decreased protein breakdown also was observed when glutamine synthesis was activated by ammonia infusion. In conclusion some favorable effects of BCAA supply can be explained by its role in the synthesis of glutamine and some positive effects of glutamine exogenous supply can be explained by its effect on metabolism of BCAA.
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PMID:Relation between glutamine, branched-chain amino acids, and protein metabolism. 1184 43

Standard total parenteral nutrition (TPN), with or without fat, in amounts approximating the ad libitum intake of normal rats is highly lethal for rats following 70% hepatectomy. Because of significant metabolic changes including alterations of branched chain amino acids (BCAA), arginine (ARG), and glutamine (GLN) associated with serious injury, sepsis, and liver dysfunction, we hypothesized that (1) increasing concentrations of BCAA and ARG in TPN and (2) including glutamine in the TPN may diminish the lethality. Male Sprague-Dawley rats with 70% hepatectomy and jugular vein catheterization were divided into groups. Two sets of experiments were conducted. In Experiment 1, the effects of varying concentrations of BCAA and ARG in the TPN infusate, singly and together, were assessed: Group 1, Standard TPN (19% BCAA, 4.8 g ARG/L); Group II, High BCAA TPN (35% BCAA, 4.8 g ARG/L); Group III, High ARG TPN (19% BCAA, 9.6 g ARG/L); Group IV, High ARG, High BCAA TPN (35% BCAA, 9.6 g ARG/L; Group V, chow and tap water ad libitum. In experiment 2, the effect of 2% GLN in TPN was evaluated: Group A, Standard TPN and Group B, 2% GLN TPN. All infusates were isocaloric (216 Kcal/Kg/d) and isonitrogenous (1.94 g N/Kg/d) delivered at half concentration on postoperative day 1, 3/4 concentration on postoperative day 2, and at full concentration thereafter. Experiment 1: Thirty-three to 36% of rats in Groups I (Standard TPN) (4/11), II (High BCAA TPN) (4/11) and III (High ARG TPN) (4/12) died within 6 days. In sharp contrast, none died in Groups IV (High BCAA, High ARG TPN) and V (rat chow and tap water) (P < 0.05 in each comparison). Among rats in the 4 TPN groups surviving 7 days, there were no significant differences in body weight change (minus 3-4%), spleen or lung weight, extent of liver regeneration (61-66%). Serum total protein and albumin were significantly higher in Group V (chow-fed) (similar to values in normal rats) than in Groups I-IV, P < 0.05 in each case. Serum total bilirubin was significantly higher in Group I than in normals and in Groups II, III, and V. Serum lactate dehydrogenase levels were similar in normals and all 5 groups. Serum aspartate amino transferase level was higher in Group I than in normals but not significantly different from those groups II-V; the latter were similar to normals. Experiment 2: Thirty percent of rats in Groups A (Standard TPN) (3/10) and B (GLN TPN) (3/10) died within 6 days. Among rats surviving for 7 days, body weight change (minus 3-5%), liver regeneration (67-70%), and liver tests were similar in both groups. TPN modified to contain high concentrations of both BCAA and ARG (but not of either alone) prevented the high frequency of lethality induced by standard TPN in rats with 70% hepatectomy. No such salutary effect was shown by modifying the TPN to contain 2% GLN. The striking benefit observed when TPN containing high BCAA and high ARG was infused may be due to the high BCAA leading toward normalization of serum amino acid levels, reducing proteolysis, increasing protein synthesis, and accelerating early liver regeneration, combined with the high ARG likely reducing serum ammonia and leading to increased host defense, and perhaps, thereby, preventing bacterial translocation and bacteremia.
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PMID:Lethality of standard total parenteral nutrition following major liver resection in rats is prevented by high arginine and high branched chain amino acids but not by glutamine. 1185 Nov 95

We previously reported that a cytostatic protein that is found in ASC-17D Sertoli cell-conditioned media was Mycoplasma arginine deiminase (ADI), which hydrolyzes L-arginine into L-citrulline and ammonia. Here, we report the over-expression of recombinant ADI (rADI) in E. coli and the down-regulation of lipopolysaccharide (LPS) induced-nitric oxide (NO) production by rADI treatment. We cloned the ADI gene from Mycoplasma arginini genomic DNA by a polymerase chain reaction, and changed five TGA tryptophan codons (stop codon in E. coli) to TGG codons in the coding region by site-directed mutagenesis in order to express in E. coli. The rADI was purified to apparent homogeneity by DEAE-Sepharose and arginine-affinity chromatography. The rADI expressed in E. coli was identified as 45 kDa on SDS-PAGE and 90 kDa on native PAGE, implying that it exists as a dimer like ADI of M. arginini. The Km for arginine of rADI was approximately 370+/-50 microM. Its optimal temperature and pH were 41 degrees C and pH 6.4, respectively, and enzyme activity remained > or = 50% for 5 d at physiological temperature and pH. Treatment of purified rADI suppressed NO production in macrophage-like RAW 264.7 and primary glial cells that were exposed to LPS. Furthermore, an intraperitoneal injection of rADI significantly suppressed the rise of blood nitrite/nitrate levels that were induced by the systemic administration of bacterial endotoxin LPS to mice, resulting in an improvement in their survival rate. These results suggest that the depletion of blood arginine with an arginine-metabolizing enzyme, such as ADI, could suppress excessive production of NO that is caused by inducible NOS (iNOS) during the endotoxemia. Also, rADI may be used as a new approach to control NO-related diseases, such as sepsis.
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PMID:Characterization of mycoplasma arginine deiminase expressed in E. coli and its inhibitory regulation of nitric oxide synthesis. 1191 65

Expression of high activities of both glutamine synthetase and glutaminase allows the liver to play a major role in the regulation of glutamine homeostasis. The liver shows net glutamine output in metabolic acidosis, in prolonged starvation and animals bearing tumors, net glutamine uptake in the postabsorptive state, on consuming high protein diets, and in uncontrolled diabetes or sepsis. Liver glutamine synthetase is expressed only in a small population of perivenous cells that allows it to salvage any ammonia not incorporated into urea in periportal cells. Hepatic glutaminase is a unique isozyme found only in periportal liver parenchymal cells where it provides glutamate and ammonia for the urea cycle. Control of hepatic glutamine metabolism occurs almost exclusively through changes in the activity of glutaminase, with no change in glutamine synthetase flux.
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PMID:Hepatic glutamine metabolism. 1193 40

A group of 100 adult zebrafish were housed in a new system at a stocking density of 20 fish per tank. Four weeks after arrival, 15 fish presented with petechial hemorrhages and ulceration on the surfaces of the skin. Samples of the fish were collected for histopathology, fungal culture, and bacterial culture and sensitivity. Water samples were analyzed for pH, ammonia, nitrite, and submitted for bacterial and fungal culture. Histologically, the epidermis had multiple areas of ulceration and mononuclear cell infiltrate. Gram-positive bacteria were observed beneath the surface of the skin and surrounding the outer aspect of the spinal cord. Both Aeromonas hydrophila and A. sobria were isolated from the affected fish, and a diagnosis of motile aeromonad septicemia (MAS) was made. Water from the tanks had a nitrite level of 1-5 ppm, a toxic concentration that indicated poor water quality. Because the housing system had been seeded with Nitrobacter spp. and Nitrosomonas spp. only 2 weeks prior to the arrival of the fish, a lack of colonizing nitrifying bacteria was deemed to be the cause of the high nitrite level, which, along with over-crowding, stressed the fish and increased their susceptibility to MAS. No further cases of septicemia were observed once the nitrite level and stocking density were reduced.
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PMID:High Mortality in Zebrafish (Danio rerio). 1208 31

As reported in the literature, the mortality rates for patients with Acute Hepatic Failure (AHF) approaches 80% in cases in which liver transplantation is not possible. Post-transplant mortality mostly depends on the severity of the neurological condition at the time of the operation (20% in I-II degree coma patients and 44% in III degree coma patients). The primary indications for liver transplantation in AHF are Fulminant Hepatitis (FH)(93%), Subfulminant Hepatitis (5%) and other indications (2%). Other causes of AHF are Primary Non-Function (PNF) and Delayed Function (DF), which occur in 7-10%. Therefore it becomes necessary to monitor the patients with a Liver Support Device to be able to improve the clinical condition of the patients before liver transplantation (LT). In our experience we used the Molecular Adsorbent Recirculating System (MARS) (MARS Monitor; Teraklin AG, Rostock Germany), which enables the selective removal of albumin-bound substances accumulating in liver failure by the use of albumin-enriched dialysate. The system is used as a bridging device to orthotopic liver transplantation (OLT) of patients with FHF. We studied 34 patients, including 16 males and 18 females: 9 were affected by Primary-Non-Function (PNF), nine by Fulminant Hepatitis (FH), six by Delayed-Non-Function (DNF), and ten by Acute on Chronic Hepatic Failure (AOCHF). The average age of the patients was 41.8 years and the average number of applications was 6.4; the median length of application was about eight hours. The parameters that we monitored, before and after each treatment, were neurological status (EEG, cerebral CT, Glasgow Coma Score), haemodynamic parameters, acid base equilibrium, and blood gas analysis. We also monitored hepatic and renal function. In addition, the clinical conditions of the patients were monitored using kidney and liver ultrasound/ultrasonography (US). Inclusion criteria were bilirubin > 15 mg/dL, ammonia > 160 micro g/dL and a Glasgow Coma Score between 6 and 11. The reduction of bilirubin and ammonia were very significant (P < 0.01), whereas the changes of International Normalized Ratio (INR) were not significant. Also the modifications of albumin, total protein, sodium, potassium and calcium were not significant. In conclusion, four out of nine patients with PNF are alive without a second transplantation and were discharged after about 48 days; four out of nine underwent OLT, while one out of nine died; five out of six patients with DF are alive without a second transplantation, and they were discharged after an average time of 55.5 days, one out of six died; six out of nine patients with fulminant hepatitis underwent OLT and four of these are alive, while two died due to sepsis; three patients are alive without OLT. Four patients with AOCHF underwent OLT and are alive, three patients are alive and on a waiting list, two died while on a waiting list and one patient who experienced reactivation of HBV infection during chemotherapy for non-Hodgkin's lymphoma is alive. In spite of the limited number of cases of our study, we believe that MARS can be applied with high tolerance for a very long period of time. In addition, its repeatability allows it to be used in patients with DNF and FH as a bridge to transplant. In patients with DNF, it is used while waiting for complete recovery of the transplanted organ.
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PMID:MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure. 1222 Mar 3


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