Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of plasminogen activation and likely plays important roles in coronary thrombosis and arteriosclerosis. Tumor necrosis factor-alpha (TNFalpha) is one of many recognized physiological regulators of PAI-1 expression and may contribute to elevated plasma PAI-1 levels in sepsis and obesity. Although TNFalpha is a potent inducer of PAI-1 expression in vitro and in vivo, the precise location of the TNFalpha response site in the PAI-1 promoter has yet to be determined. Transient transfection studies using luciferase reporter constructs containing PAI-1 promoter sequence up to 6.4 kb failed to detect a response to TNFalpha. Moreover, TNFalpha failed to induce expression of enhanced green fluorescent protein under the control of a 2.9-kb human PAI-1 promoter in transgenic mice, although endogenous murine PAI-1 was strongly induced. These data suggested that the TNFalpha response element in the PAI-1 gene is remote from the proximal promoter region. In this study, seven candidate regulatory regions were identified using cross-species sequence homology analysis as well as DNase I-hypersensitive site analysis. We identified a 5' distal TNFalpha-responsive enhancer of the PAI-1 gene located 15 kb upstream of the transcription start site containing a conserved NFkappaB-binding site that mediates the response to TNFalpha. This newly recognized site is fully capable of binding NFkappaB subunits p50 and p65, whereas overexpression of the NFkappaB inhibitor IkappaB prevents TNFalpha-induced activation of this enhancer element.
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PMID:Tumor necrosis factor alpha activates the human plasminogen activator inhibitor-1 gene through a distal nuclear factor kappaB site. 1496 43

It is known that, among human patients with sepsis, acute renal failure (ARF) dramatically increases mortality rates to 50 to 80%. However, the pathogenesis of septic ARF is not fully understood. An increase in endotoxin-induced mortality rates for leptin-deficient ob/ob mice was recently demonstrated. In comparison with ob/ob mice, db/db mice, which are deficient in the long isoforms of leptin receptors (Ob/Rb), demonstrate lower mortality rates after exposure to the endotoxin LPS. In db/db mice, mRNA for the short isoforms of leptin receptors is constitutively expressed in the kidney, lung, liver, and macrophages. It is known that plasma leptin levels increase in rodents after exposure to LPS, and this was demonstrated for db/db mice. Because ob/ob and db/db mice are both obese, factors other than obesity must be involved in the increased mortality rates for ob/ob mice. In this study, the hypothesis that the short forms of leptin receptors might offer protection against endotoxin-induced lethality at least in part by providing protection against ARF was examined. Serum leptin levels were significantly increased with LPS treatment in wild-type and db/db mice but not ob/ob mice. GFR decreased significantly 16 h after the homozygous ob/ob mice received intraperitoneal injections of 0.3 mg/kg LPS (0.37 +/- 0.04 ml/min per g kidney versus 0.83 +/- 0.06 ml/min per g kidney, n = 6, P < 0.01); the mean arterial pressure (MAP) remained unchanged. For ob/ob littermates (+/?ob), there was no significant change in either MAP or GFR when the mice were challenged with the same time interval (16 h) and dose of LPS. In contrast to ob/ob mice, there was no significant change in GFR or MAP when homozygous db/db mice or their littermates received injections of an even higher dose of LPS (0.4 mg/kg). Mouse recombinant leptin had no effect on GFR when ob/ob mice received 0.3 mg/kg LPS injections. However, renal function (serum creatinine levels, 0.4 +/- 0.1 mg/dl versus 0.9 +/- 0.1 mg/dl, P < 0.01) and MAP (68 +/- 4 mmHg versus 51 +/- 2 mmHg, n = 6, P < 0.01) were significantly improved with leptin replacement when the ob/ob mice developed hypotensive ARF with a higher dose of LPS (0.5 mg/kg). In summary, the previously reported increased susceptibility to LPS of ob/ob mice, compared with db/db mice, may be attributable at least in part to increased susceptibility to ARF.
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PMID:Role of leptin deficiency in early acute renal failure during endotoxemia in ob/ob mice. 1497 66

Marginal liver donor criteria included the following: obesity (weight >100 Kg or BMI >27), age >50 years; macrovesicular steatosis >50%; intensive care unit stay >4 days; prolonged hypotensive episodes of >1 hour, and <60 mm Hg with high inotropic drug use (dopamine, [DPM] > 14 microg/kg per minute); cold ischemia time >14 hours, peak serum sodium >155 mEq/L; sepsis, viral infections, and alcoholism; high levels of bilirubin, ALT, and AST, or extrahepatic neoplasia. Between August 1992 and May 2003, we performed 251 liver transplants in 241 patients of whom 155 are presently alive. We used 124 (49.4%) standard donors and 127 (50.6%) marginal donors. Among the group that received a standard donor, 81 (65.3%) are still alive. Among recipients of organs from marginal donors. 81 (63.8%) are still alive. We also assessed the quality of donors according to the severity of recipient disease. For standard donors these outcomes were 61.5% for UNOS 1, 37.5% for UNOS 2A, 73.2% for UNOS 2B, and 80% for UNOS 3 for marginal donors they were 46.1% for UNOS 1, 53.6% for UNOS 2A, 70.7% for UNOS 2B, and 63.6% for UNOS 3. Among the patients who received a liver from a donor >60 years old, there were no survivors in UNOS 1 and 2A, but there were good results in groups 2B and 3. These results suggest there is no difference between marginal and standard donors, even in sick patients, with the exception of donor age.
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PMID:Marginal donors in liver transplantation. 1511 May 80

Calciphylaxis is a confusing disease process that affects people with end-stage renal disease. The prognosis of this increasingly common condition is poor and mortality rates range from 60% to 80% related to wound infection, sepsis, and organ failure. Its presenting sign is skin necrosis related to calcification of the arteriole microvasculature. The disease is painful and debilitating, particularly due to the necrotic wounds. Aggressive wound care to prevent infection is vital when eschar does not protect the wound and drainage is present, but debridement is contraindicated for wounds covered with dry, noninfected eschars. The decision to debride is based on the patient's total clinical picture. Patients with calciphylaxis have poor healing potential due to ischemia and comorbidity factors such as diabetes mellitus, peripheral vascular disease, and obesity. The goal of care is prevention of infection and pain management. Some of the sensitizers and challengers responsible for the chemical imbalance leading to the arteriole calcification, as well as risk factors and clinical manifestations of calciphylaxis, are reviewed. A discussion of treatment focuses on wound care of stable necrotic ulcers and a case report illustrating the progression of calciphylaxis is presented.
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PMID:Mysterious calciphylaxis: wounds with eschar--to debride or not to debride? 1525 2

Mortality of obese patients with severe sepsis is higher than non-obese patients. Thus far, a pathophysiologic mechanism has not been identified that explains this higher mortality. The central nervous system is now becoming increasingly recognized as a target organ in sepsis and the systemic inflammatory response syndrome and may hold clues to the deleterious affects of obesity in patients with sepsis syndrome. In this study, obese and non-obese mice were given LPS IP and the brains were harvested 2 hours after injection. The brains were processed and mRNA isolated and hybridized to a microarray chip and processed. Analysis of gene expression demonstrated distinct expression difference between the lean and obese animals. Ontology data supports clear differences between the lean and obese groups in the coagulation system, neuro-endocrine system, lipid transport and insulin receptors. Approximately eighty genes were identified to show 10-fold differential expression between the obese and lean mice.
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PMID:Brain RNA expression in obese vs lean mice after LPS-induced systemic inflammation. 1535 6

Hyperglycemia, a frequent complication in critically ill patients, has been shown to have a negative influence on morbidity and mortality. Many factors contribute to hyperglycemia, including the stress response, diabetes, obesity, advanced age, corticosteroids, sepsis, pancreatitis, and the use of nutrition support. Application of intensive insulin therapy, when compared with conventional glycemic control measures, seems to improve outcomes in the critically ill patient. Therefore, effective insulin therapy along with appropriate nutrition support prescriptions provide a means for the critical care nurse and other health care team members to lower complications and enhance recovery in the ICU setting.
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PMID:Benefits and methods of achieving strict glycemic control in the ICU. 1557 42

Plasminogen activator inhibitor-1 (PAI-1), a 45-kDa serine proteinase inhibitor with reactive site peptide bond Arg345-Met346, is the main physiological plasminogen activator inhibitor. It occurs in human plasma at an antigen concentration of about 20 ng mL(-1). Besides the active inhibitory form of PAI-1 that spontaneously converts to a latent form, also a substrate form exists that is cleaved at the P1-P1' site by its target enzymes, but does not form stable complexes. Besides its role in regulating hemostasis, PAI-1 plays a role in several biological processes dependent on plasminogen activator or plasmin activity. Studies with transgenic mice have revealed a functional role for PAI-1 in wound healing, atherosclerosis, metabolic disturbances such as obesity and insulin resistance, tumor angiogenesis, chronic stress, bone remodeling, asthma, rheumatoid arthritis, fibrosis, glomerulonephritis and sepsis. It is not always clear if these functions depend on the antiproteolytic activity of PAI-1, on its binding to vitronectin or on its intereference with cellular migration or matrix binding.
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PMID:Pleiotropic functions of plasminogen activator inhibitor-1. 1563 64

TNF-alpha is a mediator of insulin resistance in sepsis, obesity, and type 2 diabetes and is known to impair insulin signaling in adipocytes. Akt (protein kinase B) is a crucial signaling mediator for insulin. In the present study we examined the posttranslational mechanisms by which short-term (<6-h) exposure of 3T3-L1 adipocytes to TNF-alpha decreases Akt levels. TNF-alpha treatment both increased the ubiquitination of Akt and decreased its protein level. The decrease in protein was associated with the presence of an (immunoreactive) Akt fragment after TNF-alpha treatment, indicative of Akt cleavage. The broad-spectrum caspase inhibitor t-butoxycarbonyl-Asp(O-Me)-fluoromethyl ketone markedly suppressed these effects of TNF-alpha. The caspase-6 inhibitor Z-Val-Glu(OMe)-Ile-Asp(OMe)-CH(2)F potently suppressed Akt ubiquitination, degradation, and fragment formation, whereas the proteasome inhibitor Z-Leu-Leu-Leu-CHO modestly attenuated the decline in Akt levels. Exposure to TNF-alpha also enhanced the association of Akt with an E3 ligase activity. Adipocytes preexposed to TNF-alpha for 5 h and then stimulated with insulin for 30 min exhibited decreased levels of Akt, phosphorylated Akt, as well as phosphorylated Mdm2, which is a known direct substrate of Akt, and glucose uptake. Caspase inhibition attenuated these inhibitory effects of TNF-alpha. Collectively, our results suggest that TNF-alpha induces the caspase-dependent degradation of Akt via the cleavage and ubiquitination of Akt, which results in its degradation through the 26S proteasome. Furthermore, the caspase- and proteasome-mediated degradation of Akt due to TNF-alpha exposure leads to impaired Akt-dependent insulin signaling in adipocytes. These findings expand the mechanism by which TNF-alpha impairs insulin signaling.
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PMID:Tumor necrosis factor-{alpha} decreases Akt protein levels in 3T3-L1 adipocytes via the caspase-dependent ubiquitination of Akt. 1574 49

Mortality of obese patients with sepsis has been reported to be significantly higher than lean patients. The underlying basis for this difference is not currently known. However, it has been suggested that obesity is associated with an altered immune response to a septic or inflammatory insult. Since obesity is based on exclusion in many sepsis trials, little is known about how obesity affects mortality or whether obese individuals respond differently to therapeutic interventions. In this study, obese and non-obese mice were given intra-peritoneal injection of saline or LPS and the livers were harvested 2 hours later. RNA from these livers were subjected to DNA microarray. Analysis showed distinct differences in gene expression between lean and obese animals. The expression of one hundred and seventeen genes was found to be different among the groups. In the obese animals treated with LPS, the expression of 20 genes showed a significant change. Ontology analysis revealed increased expression of 15 genes and significant decrease in expression of 5 genes. This study shows different gene expression of liver in response to LPS in lean versus obese animals. These genes might play a role in the outcome of sepsis.
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PMID:Differential RNA expression of hepatic tissue in lean and obese mice after LPS-induced systemic inflammation. 1576 70

THE PREGNANT PATIENT: Age; maternal disease; prophylactic antibiotics; gastroesophageal reflux; obesity; starvation; genotyping; coagulopathy; infection; substance abuse; altered drug responses in pregnancy; physiological changes of pregnancy. THE FETUS: Fetal monitoring; intrauterine surgery. THE NEWBORN: Breastfeeding; maternal infection, fever, and neonatal sepsis evaluation. OBSTETRIC COMPLICATIONS: Embolic phenomena; hemorrhage; preeclampsia; preterm delivery. OBSTETRIC MANAGEMENT: External cephalic version and cervical cerclage; elective cesarean delivery; fetal malpresentation; vaginal birth after cesarean delivery; termination of pregnancy. OBSTETRIC ANESTHESIA: Analgesia for labor and delivery; anesthesia for cesarean delivery; anesthesia for short obstetric operations; complications of anesthesia. MISCELLANEOUS: Consent; ethics; history; labor support; websites/books/leaflets/journal announcements.
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PMID:What's new and novel in obstetric anesthesia? Contributions from the 2003 scientific literature. 1579 48


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