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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irreversible sepsis, in spite of advancements in topical therapy and antimicrobial agents, remains the leading cause of death in major thermal injury. A defect in intracellular bactericidal capacity in leukocytes from severely burned patients appears to correspond with increases in bacterial wound colonization and ultimate sepsis. This leukocyte defect has been demonstrated by abnormally low nitroblue tetrazolium reduction (NBT) and oxygen consumption of white cells in patients with major thermal injury. The subcellular mechanisms responsible for decreased bactericidal capacity were therefore investigated. Nicotinamide-adenine dinucleotide (NADH) and nicotinamide-adenine phosphodinucleotide (NADPH) oxidase activity was measured in patients with major burns, controls (normals), and in patients with nonburn stress or infection. NADH and NADPH oxidase levels in leukocytes from burn patients were not significantly different from those of normal nonchallenged controls but were significantly lower than the leukocyte values found in the patients with nonburn infections or stress. This NADH and NADPH defect in the subcellular leukocyte fraction suggests that it may be a significant factor in the reduced bactericidal function of the intact leukocyte in thermally injured patients.
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PMID:The role of NADH-NADPH oxidase activity in the leukocyte function of burned patients. 76 16

There is poor correlation between the MICs and zone sizes obtained for erythromycin against Haemophilus influenzae. The effect of two media, Mueller-Hinton medium supplemented with 3% lysed horse blood and 10 micrograms of NAD per ml (MHA + LYHB) and Mueller-Hinton agar supplemented with 1% bovine hemoglobin and 1% IsoVitaleX (MHA + HGB), on the MICs and zone sizes of erythromycin against H. influenzae was determined. The effect of three different methods for inoculum preparation on the susceptibility of H. influenzae was also determined. The MICs were independent of the method of inoculum preparation, but the zone sizes were smaller if the inoculum was carefully adjusted to contain approximately 10(8) CFU/ml. MICs were higher and zone sizes were smaller when MHA + HGB was used instead of MHA + LYHB. Good correlation was found when MHA + LYHB was used for determining the MIC and MHA + HGB was used for determining susceptibility by the disk method. When the inoculum was adjusted to match a McFarland 0.5 standard, the viable counts had to be approximately 10(8) CFU/ml for good correlation between MICs and zone sizes. A-56268, a new macrolide antibiotic, was tested against H. influenzae, and its MICs and tentative breakpoints against this organism were determined. The MICs obtained by various methods were correlated with in vivo efficacy by using a mouse septicemia model. MICs obtained on MHA + HGB or MHA + LYHB incubated without a 5% CO2 atmosphere showed the best correlation with in vivo efficacy.
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PMID:Susceptibility testing of macrolide antibiotics against Haemophilus influenzae and correlation of in vitro results with in vivo efficacy in a mouse septicemia model. 295 54

Both Neisseria meningitidis and Haemophilus influenzae are important isolates recovered in blood cultures from septicemic children. Sodium polyanetholsulfonate is present in most blood culture media and can inhibit the growth of certain bacteria, including N. meningitidis. The addition of gelatin to blood culture media neutralizes this inhibition. The growth of H. influenzae is enhanced by specific growth factors such as hemin and NAD. The addition of gelatin and V-factor-analog (a proprietary supplement for enhancing the growth of H. influenzae) might have a positive effect on the yield and on the speed of detection of septicemia in children. To evaluate this possibility, we did 4,565 paired comparisons of blood cultured in BACTEC 6B (aerobic) medium with and without the addition of both 1.2% gelatin and V-factor-analog. More aerobic and facultative bacteria grew in the 6B than in the 6B-gelatin-V-factor-analog medium (P less than 0.01). Only seven isolates of Neisseria spp. were recovered during this study period, with the 6B medium performing as well as the supplemented medium. When microorganisms grew in both bottles, they did so at the same time except for H. influenzae and Candida albicans. H. influenzae was recovered earlier from the 6B-gelatin-V-factor-analog bottle (P less than 0.01), with a mean time to detection of 8.5 h compared with 15.9 h for the 6B bottle. C. albicans was recovered earlier from the 6B bottle (P less than 0.02), with a mean time to detection of 34.9 h compared with 71.6 h for the 6B-gelatin-V-factor-analog bottle. We conclude that the 6B medium in its present formulation is superior to bB supplemented with gelatin and V-factor-analog.
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PMID:Controlled evaluation of blood culture medium containing gelatin and V-factor-analog for detection of septicemia in children. 336 69

The effects of intravenous bolus injection of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) on hepatic mitochondrial energy metabolism were investigated in rats. The rats were injected with 15 micrograms/kg body wt of human recombinant TNF-alpha and IL-1 beta. The hepatic energy charge decreased to 0.794 +/- 0.005 and 0.789 +/- 0.006 in comparison with the sham control value of 0.838 +/- 0.007 and 0.835 +/- 0.011 at 12 and 24 hr after the treatment. The mitochondrial redox state (NAD+/NADH) increased from 17.4 +/- 1.9, 16.6 +/- 1.4, and 19.2 +/- 2.1 to 33.5 +/- 3.5, 27.8 +/- 2.8, and 30.9 +/- 2.6 concomitant with an increase in arterial blood ketone body ratio (acetoacetate/beta-hydroxybutyrate) from 0.49 +/- 0.04, 0.34 +/- 0.04, and 0.44 +/- 0.09 to 1.00 +/- 0.16, 0.69 +/- 0.13, and 0.86 +/- 0.15 at 3, 12, and 24 hr after the treatment. Total ketone body concentration in liver tissue and arterial blood was significantly lower at 24 hr after the treatment. State 3 respiration rate of isolated mitochondria increased by 29.2, 30.3, and 19.2% concomitant with an increase in oxidative phosphorylation rate by 26, 33.7, and 24.3% at 3, 12, and 24 hr after the treatment. These results showed that the administration of TNF-alpha and IL-1 beta in rats induced a hypermetabolic state in hepatic mitochondrial energy metabolism, which is a pattern similar to sepsis and presumably a compensatory reaction to the increased energy consumption.
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PMID:The effect of a bolus injection of TNF-alpha and IL-1 beta on hepatic energy metabolism in rats. 774 63

Reactive oxygen species (ROS) can be generated in experimental shock states through several different mechanisms. We measured ROS production in metabolically active liver mitochondria from rats rendered septic by cecal ligation and puncture. By polarography, the State 4 and State 3 respiration rates of liver mitochondria isolated from septic animals were no different from control organelles. During oxidation of succinate, however, nonenzymatic hydroxylation of salicylic acid to 2,3-dihydroxybenzoic acid by mitochondria from septic rats was increased, indicating generation of hydroxyl radical (OH.). Inhibition of electron transport at Complex I with rotenone had no effect on this pattern of OH. production, but rotenone and cyanide abolished the differences in OH. formation between control and septic liver mitochondria. Measurements of H2O2 release suggested that septic mitochondria will increase rates of H2O2 production in the presence of succinate. Additional investigations revealed no difference in the release of iron between septic and control mitochondria. When referenced to respiration rate, both OH. and H2O2 production were greater in septic liver mitochondria. The reproducible effect of sepsis on generation of reactive oxygen species by liver mitochondria utilizing FAD-linked but not NAD-linked substrates suggests that enhanced mitochondrial oxidative stress in sepsis is related to alterations in the activity of Complex II of the electron transport chain.
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PMID:Reactive oxygen species produced by liver mitochondria of rats in sepsis. 784 Jun 80

1. The pulmonary vasculature is constantly exposed to oxygen and reactive oxygen species such as nitric oxide (NO) and superoxide anions which can combine at a near diffusion limited rate, to form the powerful, oxidant, peroxynitrite (ONOO-). When formed in large amounts, ONOO- is thought to contribute to tissue injury and vascular dysfunction seen in diseases such as the acute respiratory distress syndrome (ARDS) and septic shock. Recent studies have shown that ONOO- can cause vasodilatation and at higher concentrations can activate poly (adenosine 5'-diphosphoribose) synthase (PARS) leading to consumption of nicotinamide adenine dinucleotide (NAD+) and adenosine 5'-triphosphate (ATP). As the lung represents a prime site for ONOO- formation, we characterized its effects on pulmonary vascular tone and on endothelial function. In addition, we have assessed the role of PARS in producing the vasoactive properties of ONOO- on pulmonary artery rings. 2. Isolated pulmonary artery rings from rats were mounted in organ baths containing warmed and gassed (95% O2: 5% CO2) Krebs buffer. Force was measured with isometric force transducers. After equilibration, ONOO- (10 nM-100 microM) was added in a cumulative manner. In separate experiments designed to assess any vasodilator properties of ONOO-, tissues were pre-contracted with the thromboxane mimetic U46619 (1 microM). Once a stable base-line was achieved, ONOO- was added in a cumulative fashion. ONOO- had no significant effect on resting pulmonary artery tone but caused concentration-dependent relaxations of pre-contracted vessels in the range 1 microM to 100 microM. In some experiments the effects of freshly prepared ONOO- solutions were compared with those allowed to decay at 4 degrees C for 2 days. 3. In some experiments either vehicle or ONOO- (1, 10 or 100 microM) was added for 15 min before U46619 (1 microM). Concentration-response curves to the endothelium-dependent vasodilator, acetylcholine (10 nM-100 microM) were then constructed. In these experiments, ONOO- (1 microM or 10 microM) had no effect on the actions of acetylcholine. However, at the highest concentration tested (100 microM), ONOO- increased acetylcholine-induced relaxations. 4. The vasodilator actions of ONOO- were unaffected by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) or by removal of superoxide anions with superoxide dismutase (SOD) (30 units ml-1). However, the relaxations induced by ONOO- were significantly inhibited by the PARS inhibitor, 3-aminobenzamide (10 microM). In contrast to its effects on ONOO-, 3-aminobenzamide had no effect on the relaxation caused by acetylcholine or sodium nitrite, but actually increased that induced by sodium nitroprusside. 5. These data show that ONOO- causes vasodilatation of rat pulmonary arteries, probably via activation of PARS. Moreover, at concentrations where relaxation was achieved, ONOO- did not affect the ability of pulmonary artery rings to relax to acetylcholine. We propose that ONOO-, but not endothelially derived NO, activates PARS resulting in the rapid depletion of ATP and a consequent reduction in contraction as well as other active processes of vascular smooth muscle. The finding that 3-aminobenzamide inhibited the actions of ONOO- but not acetylcholine, suggests that NO and ONOO- cause relaxation by independent mechanisms. It has been suggested that ONOO- is responsible for the vascular hyporesponsiveness to constrictor agents seen in experimental sepsis. This observation together with our current finding, that 3-aminobenzamide inhibits the relaxation induced by ONOO- but not by acetylcholine, suggests that inhibitors of PARS may reduce the persistent hypotension seen in sepsis without affecting the actions of endothelium-derived NO. Thus, the use of PARS inhibitors may represent a novel therapeutic approach to the treatment of septic shock.
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PMID:Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine 5'-diphosphoribose) synthase. 917 90

We have previously demonstrated that treatment of hepatocytes with IFN gamma results a series of cellular injury processes, including DNA synthesis arrest, membrane breakage and apoptosis. In the present work, we show that IFN gamma suppresses cellular respiration and protein synthesis in hepatocytes, and that cellular respiration suppression is an early event in the IFN gamma-induced cellular injuries. Polyunsaturated fatty acids (PUFAs) increased cellular respiration of hepatocytes, but only linoleic acid showed some protective effect against IFN gamma-induced cellular respiration suppression. Linoleic acid also reduced other IFN gamma-mediated cellular injuries, including membrane breakage and protein synthesis inhibition. Like linoleic acid, fetal bovine serum also inhibited IFN gamma-induced cellular damage. Increased NAD levels were found in both IFN gamma-treated and non-treated hepatocytes following the addition of PUFAs, but clofibrate, a peroxisome proliferator, bromophenacyl bromide (BPB), an inhibitor of phospholipase, nordihydroguaiaretic acid (NDGA), an inhibitor of lipoxygenase, and arachidonic acid, a metabolite of linoleic acid, did not inhibit IFN gamma-induced cellular injury. In addition, the combination of linoleic acid and IFN gamma induced nitric oxide (NO) synthesis in hepatocytes. These results suggest that fatty acid may play an important role in liver homeostasis during chronic inflammatory states and sepsis.
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PMID:Protective effect of linoleic acid on IFN gamma-induced cellular injury in primary culture hepatocytes. 953 94

Severe muscle wasting is a characteristic feature of sepsis. We have previously established that the rate of protein synthesis in muscles composed of fast-twitch fibers is severely diminished in response to sepsis. The present studies investigate the biochemical reactions responsible for the decreased rate of protein synthesis using gastrocnemius from control and septic rats perfused in situ. Analysis of free ribosomal subunits indicated peptide-chain initiation was impaired by infection. To characterize biochemical reactions in the pathway of peptide-chain initiation affected, the effect of sepsis on the incorporation of initiator [35S]methionyl-tRNA (met-tRNA(imet)) into the 40S initiation complex was examined. Sepsis caused a 65% decrease in the binding of radiolabelled met-tRNA(imet) to the 40S initiation complex compared with controls. The binding of met-tRNA(met) to the 40S ribosome is regulated by eukaryotic initiation factor eIF-2B, whose activity can be modulated in part by the redox state of pyridine dinucleotides. The mean cytoplasmic NADH/NAD+ ratio was increased 2 fold in sepsis, while the NADPH/NADP+ ratio was unchanged. These findings identify the formation of the 40S initiation complex as a defect in the protein synthesis machinery during sepsis. The decreased formation of the 40S initiation complex in muscle could not be explained by changes in the cytoplasmic redox state.
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PMID:Reduced 40S initiation complex formation in skeletal muscle during sepsis. 954 85

1. Although hepatic function is well known to deteriorate following bacterial infection, the underlying mechanisms remain poorly understood. We have previously reported that nitric oxide (NO) radical leads to a decrease in the ketone body ratio (KBR) and in ATP content due to the inhibition of mitochondrial electron transport in primary cultured rat hepatocytes. 2. To evaluate the effects of NO radical on the liver in patients with postoperative sepsis, we analysed both the stable end-product of nitric oxide radical (NOx) as well as the arterial KBR (AKBR), which reflects liver tissue NAD+/NADH. 3. Twenty patients who had undergone general abdominal surgery and who developed postoperative sepsis were divided into two groups: (i) surviving; and (ii) non-surviving. Blood samples were collected before the development of postoperative sepsis and every 3 days until the patient either died or was discharged from hospital. 4. Plasma NOx levels in seven patients who subsequently died became progressively higher than those in the 13 surviving patients over the clinical course of postoperative sepsis. 5. In the non-surviving group, the AKBR was significantly lower than in surviving patients, indicating impaired hepatic function. In contrast, plasma NOx levels in non-surviving patients were significantly higher than in surviving patients. 6. Decreases in AKBR to levels below 0.7 in non-surviving patients followed high NOx levels. Moreover, plasma NOx levels were closely correlated with the AKBR, indicating that NO radical is associated with mitochondrial dysfunction in the liver. 7. It is likely that the overproduction of NO radical plays an important role in causing fatal metabolic disorders in patients with postoperative sepsis.
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PMID:Nitric oxide production and hepatic dysfunction in patients with postoperative sepsis. 1074 47

Poly (ADP-ribose) synthetase (PARS) is a DNA protective enzyme activated by single-strand breakage. It is suspected that exaggerated PARS activation related to biochemical stress by reactive oxygen and nitrogen species contributes to cellular injury in sepsis. The main hypothesis is that PARS activation leads to massive ATP and NAD consumption and consequent cellular energy depletion. The PARS inhibitor 3-amino-benzamide (3AB) is protective in rodents challenged with either endotoxin or intraperitoneal zymozan. The present experiment was designed to test the effect of 3AB in a more clinically relevant model of sepsis, namely polymicrobial sepsis induced by cecal ligature and puncture (CLP). Adult male Wistar rats were anesthetized, instrumented with catheters in the jugular vein and in the carotid artery, and then randomized into three groups: Sham (no laparotomy, n = 13), CLP (n = 15), and CLP/3AB (n = 18). All animals were allowed to recover and they received a continuous intravenous infusion of saline (20 mL/kg/h) and fentanyl (20 microg/kg/h). 3AB was administered to the CLP/3AB group as an intravenous bolus (10 mg/kg) followed by a continuous intravenous infusion (10 mg/kg/h). After 24 h, blood was drawn for the determination of biological indicators of organ injury. Rats were then anesthetized and biopsies of the liver were quickly frozen into liquid nitrogen for the subsequent determination of NAD and ATP levels. Further organ samples were collected for the assay of myeloperoxidase (MPO) to indicate tissue infiltration by leukocytes, and nitrotyrosine to indicate the level of biochemical stress by reactive nitrogen species. Twenty-four-hour mortality was 0/13 (Sham), 1/15 (CLP), and 5/18 (CLP/3AB; p = NS). In the surviving rats, CLP induced a clear elevation of liver enzymes, bilirubin, and pancreatic lipase, but not creatinine in the plasma, as well as a marked increase of MPO activity in liver, jejunum, and lung, but not kidney or heart. None of these variables was affected by treatment with 3AB. Furthermore, CLP did not cause depletion of NAD or ATP in the liver, nor any change in the nitrotyrosine content of any organ. These data argue against a general role of PARS activation in the pathogenesis of sepsis-induced tissue injury.
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PMID:Does the activation of poly (ADP-ribose) synthetase mediate tissue injury in the sepsis induced by cecal ligation and puncture? 1202 68


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