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)

The maternal deaths occurring in the Kilimanjaro Christian Medical Center (KCMC), which serves as a supraregional reference hospital for the 5 regions of Northern and Central Tanzania, are reviewed for the 1971-1977 period and avoidable factors are discussed. All deaths occurring within the hospital during pregnancy or the first 6 weeks of the puerperium were included in this survey. Postmortem examination was performed in 35% of the cases. In the remaining cases the diagnosis was made on clinical grounds. During the period under review, there were 10 deaths among 83 cases, a mortality of 12%. The major cause of rupture was obstructed labor associated with a contracted pelvis or abnormal lie. 25% of the patients had had a previous cesarean section scar give way. 2 other deaths were attributed to anesthetic accidents and 1 was probably due to pulmonary embolism. The primary cause of death in the 7 remaining cases was hemorrhage (4) and sepsis (3). If deaths from ruptured uterus are to be avoided, early diagnosis is essential. 1044 cases of moderate and severe EPH gestosis (preeclampsia) were treated in KCMC during the period under review together with 54 cases of eclampsia. There were 5 deaths among the patients with eclampsia, a mortality of 9%. In addition to the 11 sepsis deaths there were 3 others included among the cases of ruptured uterus. There were 4 cases of septic abortion and 3 of those admitted to criminal interference. Preexisting anemia was a complicating factor in 5 cases, all of whom died within 15 minutes of arrival. There were 4 deaths among 251 cases of ruptured ectopic pregnancy. There were 10 deaths associated with cesarean section among 1271 sections peformed during the period under review. Deaths from associated diseases included the following: enterocolitis (12 deaths); renal and hypertensive disease (4 deaths); cardiac disease (2 deaths); anemia (2 deaths); malaria (2 deaths); tuberculous meningitis (2 deaths); and miscellaneous associated conditions (11 deaths).
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PMID:Maternal deaths in the Kilimanjaro region of Tanzania. 47 24

Serum amino acid (AA) levels were determined for 18 cholecystectomy patients who had preserved and immediately utilized G-I function for absorption of 3,000 kcal/day elemental diet. Ten were given 132 gm AA/day; eight were given only 66 gm AA/day. Historical controls were 27 comparable patients who had received conventional hypocaloric intravenous (IV) regimens. Unfed patients' branched chain AAs (BCAAs) + TYR were depressed initially, then rebounded by day 3 or 4. Their glucogenic AAs were still depressed after 72 hours. Complete restoration of the basal pattern required five to ten days. Fully nourished patients maintained basal levels of all AAs on day 1. Every AA rose above basal, some with statistical significance as early as day 2. Moderately fed patients had BCAA depression, but for only 24 hours. LEU, ILE, VAL, TYR, MET, ASP, LYS, and ARG had already returned to basal levels on day 2, while the remaining AAs were much less depressed than in the unfed controls. All fed patients were discharged uneventfully 24-48 hours postcholecystectomy. The positive protein balance and elevated AA levels correlate with enhanced wound healing, host sepsis resistance, and shortened hospitalization.
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PMID:Elevation of postoperative plasma amino acid concentrations by immediate full enteral nutrition. 643 8

Ninety minutes after i.v. injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) into rats, phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide anion (O2-) secretion was enhanced in suspensions of in vivo LPS-treated alveolar macrophages (AM phi) when compared with saline (SAL)-treated AM phi. The purpose of this investigation was to dissect the in vitro mechanism of PMA-stimulated O2- generation in both LPS and SAL-treated rat AM phi, with a panel of inhibitors of protein kinase C (PKC), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), phospholipase A2 (PLA2), cyclooxygenase (CO) and 5-lipoxygenase (5-LO). The following agents blocked PMA-stimulated O2- generation in both LPS- and SAL-treated AM phi (expressed as percentage of control): 1) PKC inhibitors: staurosporine: 100 nM, 7.0% (LPS) and 5.6% (SAL); sphingosine: 10 microM, 21% (LPS) and 10.5% (SAL); 2) PTK inhibitor: genistein: 100 microM, 44% (LPS) and 31% (SAL); 3) PTP inhibitors: phenylarsine oxide, 10 microM, 12.1% (LPS) and 18% (SAL); diamide, 1000 microM, 10.1% (LPS) and 10.5% (SAL); and 4) PLA2 inhibitors: manoalide: 1 microM, 29.3% (LPS) and 5.2% (SAL); scalaradial: 1 microM, 7.7% (LPS) and 7.1% (SAL); and WAY 125,984: 10 microM, 17.1% (LPS) and 14.5% (SAL). In addition, it was observed that exogenously added arachidonic acid (AA)-stimulated O2- generation in a time- and dose-dependent manner in both LPS and SAL-treated AM phi. The following inhibitors enhanced or did not affect PMA-stimulated O2- generation in LPS- and SAL-treated AM phi (expressed as percentage of of control): 1) PSP inhibitors: okadaic acid: 0.5 microM, 117% (LPS) and 153% (SAL); calyculin A: 1 microM, 112% (LPS) and 101% (SAL); 2) CO and 5-LO inhibitors: indomethacin: 10 microM, 107% (LPS) and 90% (SAL); WY 50, 295: 1 microM, 99% (LPS) and 103% (SAL); and 3) the PTP inhibitor orthovanadate upon prolonged preincubation. In both in vivo LPS- or SAL-primed AM phi, PMA-stimulated O2- generation appears to be modulated by PKC, PLA2, AA, PTK, PTP and PSP. No modulatory role was evident for either CO or 5-LO metabolites. These findings might bear on the design of therapeutic approaches for the modulation of O2- release by AM phi in the early stages of sepsis and adult respiratory distress syndrome.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed rat alveolar macrophages by arachidonic acid and inhibitors of protein kinase C, phospholipase A2, protein serine-threonine phosphatase(s), protein tyrosine kinase(s) and phosphatase(s). 761 27

Stimulation of human neutrophils by LPS is central to the pathogenesis of sepsis and the adult respiratory distress syndrome. The intracellular signaling pathway that results in cellular responses following LPS stimulation in neutrophils is unknown. We report that exposure of neutrophils to LPS results in the phosphorylation and activation of a p38 mitogen-activated protein (MAP) kinase, occurring in a concentration-dependent manner, with maximum response at 20 to 25 min. Partial purification of a p38 MAP kinase by ion exchange chromatography established it as distinct from the p42/p44 (extracellular signal-regulated kinases (ERK-1 and ERK-2) MAP kinases). Activation of the p38 MAP kinase by LPS in human neutrophils occurs via CD14, a proposed LPS receptor, and requires the presence of plasma containing the LPS-binding protein. This intracellular signaling pathway is independent of protein kinase C and does not involve Raf, MAP/ERK kinase kinase-1, MAP/ERK kinase-1, or MAP/ERK kinase-2 and does not result in the activation of the p42/p44 ERK MAP kinases or the c-jun N-terminal kinases.
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PMID:Activation of a p38 mitogen-activated protein kinase in human neutrophils by lipopolysaccharide. 864 36

Altered vascular responsiveness is the hallmark of septic shock. Recently, these changes have frequently been attributed to increased production of nitric oxide (NO). Continued exposure to high levels of NO may alter both endothelial and vascular smooth muscle cell function. Although ex vivo studies demonstrate hyporeactivity of large conduit arteries during established sepsis, it is unclear if the same phenomena exist during early sepsis. This is especially true in the small resistance arterioles of the viscera. We used in vivo microscopy of the rat small intestine to assess (1) endothelial-dependent relaxation and vasomotion (periodic contraction and relaxation of blood vessels) in response to acetylcholine (ACH; 10(-8) to 10(-5) M), (2) endothelial-independent relaxation to nitroprusside (NTP; 10(-5) M), and (3) vascular smooth muscle response to norepinephrine (NE; 10(-10) to 10(-7) M) in normal and bacteremic rats (Escherichia coli). There were no alterations in endothelial-dependent or -independent relaxation during bacteremia as measured by mean diameters. However, acute E. coli bacteremia severely impaired vasomotion in A1 (inflow) and A3 (premucosal) arterioles. Vasomotion was returned to baseline levels in A1 with low-dose ACH (10(-8) M) but only partially improved in A3 arterioles (P < 0.05). A1 response to NE was impaired, while A3 were minimally altered despite being more sensitive to E. coli-induced vasoconstriction. These data suggest that bacteremia causes a rapid, differential impairment of both endothelial-dependent (A3 vasomotion) and vascular smooth muscle cell (A1 constriction) functions. These microvascular impairments occur much earlier than previously described and may contribute to sepsis-induced mucosal ischemia of the intestines.
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PMID:Differential intestinal microvascular dysfunction occurs during bacteremia. 907 Jan 84

Altered endotoxin (LPS) signal transduction in macrophages (Mphi) may mediate development of organ dysfunction in sepsis. C3H/HeJ Mphi have a specific genetic defect that renders them "tolerant" to in vitro LPS activation. LPS tolerance can be induced in normal C3H/HeN Mphi following in vitro LPS pretreatment. In these experiments, in vitro LPS-stimulated activation of Mphi mitogen-activated protein (MAP) kinases were compared in C3H/HeJ and C3H/HeN mice. C3H/HeJ and C3H/HeN Mphi were cultured+/-10 ng/mL LPS pretreatment for 24 h, then stimulated with 0-1,000 ng/mL LPS for 6 h. Western blots were performed on lysates with monoclonal antibody to active ERK1,2 (p42/44), stress-activated protein kinase (SAPK, p54/46), and p38 kinase. Supernatant TNF or IL-1 was determined by bioassay. High dose LPS stimulation activated ERK, SAPK, and p38 kinases in both C3H/HeN and C3H/HeJ Mphi. ERK activation, p46 SAPK, and p38 activation were inhibited in C3H/HeN Mphi after LPS pretreatment, whereas they were unchanged or increased in HeJ Mphi. TNF secretion was significantly decreased in C3H/HeN Mphi following LPS pretreatment, but absent in C3H/HeJ Mphi at all times. Mphi from normal C3H/HeN mice rendered endotoxin tolerant by in vitro, low dose LPS pretreatment have specific signal transduction defects that are not present in genetically LPS hyporesponsive C3H/HeJ mice.
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PMID:In vitro macrophage endotoxin tolerance: defective in vitro macrophage map kinase signal transduction after LPS pretreatment is not present in macrophages from C3H/HeJ endotoxin resistant mice. 992 18

During gram-negative sepsis, human monocytes are triggered to produce large quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have identified signal transduction pathways that are activated by LPS, including activation of nuclear factor-kappaB (NF-kappaB) and activation of mitogen-activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS-induced TNF-alpha production by primary human monocytes has been addressed with PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1. TNF-alpha levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml, were reduced by PD-098059 (50 microM). In addition, PD-098059 also reduced TNF-alpha mRNA expression when cells were stimulated for 1 h with LPS. On the other hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK inhibitor, completely abrogated TNF-alpha levels at nanomolar concentrations. IL-10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09-2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2. Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2 in a time- and concentration (50% effective concentration between 1 and 10 ng of LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50 microM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was prevented by Ro 09-2210. These data further support the view that the ERK signal transduction pathway is causally involved in the synthesis of TNF-alpha by human monocytes stimulated with LPS.
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PMID:Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. 1041 44

The vascular endothelium has a central role in the control of microvascular tone, and it has been proposed that vascular endothelial damage occurs in septic shock, producing multiorgan failure. We have developed a method of detecting circulating endothelial cells (EC) that provides direct evidence of EC shedding in human sepsis. Human umbilical vein endothelial cells (HUVEC) were seeded in whole blood and recovered by isopycnic centrifugation to validate the technique. Blood samples were subsequently taken from 11 healthy volunteers, nine ventilated intensive care unit (ICU) control patients without sepsis, eight patients with sepsis but without shock, and 15 patients with septic shock. EC were identified by indirect immunofluorescence, using antibodies to von Willebrand factor (vWf) and the vascular endothelial growth factor receptor KDR. Mean HUVEC recovery was 86% for 20 to 100 seeded cells/ml of blood. vWf-positive EC counts per milliliter were significantly higher (analysis of variance [ANOVA], p < 0.0001) in patients with sepsis (16.1 +/- 2.7 [mean +/- SEM]) and septic shock (30.1 +/- 3.3) than in healthy (1.9 +/- 0.5) or ICU controls (2.6 +/- 0.6). KDR-positive EC counts per milliliter were also significantly higher (ANOVA, p < 0.0001) in patients with sepsis (4.2 +/- 1.1/ml) and septic shock (10.4 +/- 1.2/ml) than in healthy (0.7 +/- 0.3/ml) or ICU controls (0.5 +/- 0.2/ml). Cell counts made with anti-vWf antibody were consistently higher than those made with anti KDR antibody, but correlation between the two counts was high (r(2) = 0.93). The number of circulating KDR-positive EC was significantly higher in patients who died of septic shock than in survivors (12.0 +/- 1.6/ml versus 7.1 +/- 1.2/ml, p = 0.026). An increase in circulating EC can be identified during sepsis and septic shock. This supports the hypothesis that endothelial damage occurs in human sepsis.
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PMID:Circulating endothelial cells in patients with septic shock. 1120 46

Neutrophils exposed to low concentrations of gram-negative lipopolysaccharide (LPS) become primed and have an increased oxidative response to a second stimulus (e.g., formyl-methionyl-leucyl-phenylalanine [fMLP]). In studies aimed at understanding newborn sepsis, we have shown that neutrophils of newborns are not primed in response to LPS. To further understand the processes involved in LPS-mediated priming of neutrophils, we explored the role of extracellular signal-related protein kinases (ERK 1 and 2) of the mitogen-activated protein kinase family. We found that LPS activated ERK 1 and 2 in cells of both adults and newborns and that activation was plasma dependent (maximal at > or =5%) through LPS-binding protein. Although fibronectin in plasma is required for LPS-mediated priming of neutrophils of adults assessed by fMLP-triggered oxidative burst, it was not required for LPS-mediated activation of ERK 1 and 2. LPS-mediated activation was dose and time dependent; maximal activation occurred with approximately 5 ng of LPS per ml and at 10 to 40 min. We used the inhibitor PD 98059 to study the role of ERK 1 and 2 in the LPS-primed fMLP-triggered oxidative burst. While Western blotting showed that 100 microM PD 98059 completely inhibited LPS-mediated ERK activation, oxidative response to fMLP by a chemiluminescence assay revealed that the same concentration inhibited the LPS-primed oxidative burst by only 40%. We conclude that in neutrophils, LPS-mediated activation of ERK 1 and 2 requires plasma and that this activation is not dependent on fibronectin. In addition, we found that the ERK pathway is not responsible for the lack of LPS priming in neutrophils of newborns but may be required for 40% of the LPS-primed fMLP-triggered oxidative burst in cells of adults.
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PMID:Activation of extracellular signal-related protein kinases 1 and 2 of the mitogen-activated protein kinase family by lipopolysaccharide requires plasma in neutrophils from adults and newborns. 1129 34

Reduction of neutrophil apoptosis represents a major cause for granulocytosis and increases the destructive potential of theses cells during systemic inflammatory response syndrome (SIRS) and sepsis. In this light, the role of protein kinases for the regulation of altered neutrophil apoptosis under infectious conditions was investigated. Neutrophils, obtained from patients with severe sepsis (n = 18), were incubated ex vivowith either LPS (1 microg/mL) or interferon-gamma (IFN-gamma; 10 ng/mL) for 16 h. Apoptosis was determined by propidium iodine (PI) staining of DNA fragments and was compared with the rate of spontaneous apoptosis. Tyrosine kinases were inhibited by herbimycin (1 microM), the mitogen-activated protein (MAP) kinase ERK was inhibited with PD98059 (50 microM), and p38 MAP kinase was inhibited with SB203580 (5 microM). Herbimycin reconstituted LPS-reduced apoptosis in neutrophils from controls (39.9 +/- 3.8%) and patients (20.8 +/- 2.8%) to levels seen in spontaneous apoptosis (70.9 +/- 2.8% and 40.7 +/- 3.7%, respectively). Inhibition of the ERK kinase yielded similar results, whereas SB203580 had no effect on LPS-reduced apoptosis. However, inhibition of p38 partially reconstituted IFN-gamma-reduced apoptosis (51.3 +/- 7.7% and 25.6 +/- 5.8%) and increased spontaneous apoptosis (82.4 +/- 3.3% and 42.0 +/- 5.8%) in controls and patients, respectively. Western blot analysis revealed phosphorylation of both MAP kinases by LPS, but not by IFN-gamma. Inhibition of MAP kinases did not augment neutrophil apoptosis in patients to the level seen in controls, indicating that other mechanisms must be involved in the regulation of neutrophil apoptosis. Although the ERK kinase regulates LPS-induced reduction of apoptosis, the p38 MAP kinase might be involved in IFN-gamma signaling and the feedback regulation of neutrophil apoptosis.
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PMID:Activation of mitogen-activated protein kinases during granulocyte apoptosis in patients with severe sepsis. 1241 17


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