A synthetic dextran derivative inhibits complement activation and complement-mediated cytotoxicity in an in vitro model of hyperacute xenograft rejection.
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Animals↗
Biomedical subjects
E Fischer
Publications and source records attributed to E Fischer.
Changes in the biliary excretion of exogenous organic anions by streptozotocin-induced diabetes.
A transient depression of blood-glucose level was found after streptozotocin administration, which can be explained by insulin release due to the destroying effect of streptozotocin on beta-cells of pancreas, the biliary flow was elevated, when blood sugar level was low. After the transient decrease the blood glucose level was elevated and remained in a diabetic range (300-500 mg/100 ml). During the diabetic period a biphasic change was observed in the biliary flow: 23-48 hours after streptozotocin injection a depression, however, 5-10 days after streptozotocin administration an elevation was detected in the bile flow. Changes found in biliary excretion rate of exogenous organic anions were parallel with those of biliary flow.
Animals↗
Effect of hyperglycemia on the intestinal elimination of p-nitrophenol in the rat.
Effect of hyperglycemia on the intestinal elimination of p-nitrophenol has been investigated in rats. Hyperglycemia was produced by a continuous i.v. infusion of glucose, p-nitrophenol was used as a model compound for the investigation of intestinal metabolism and excretion of drugs. Intestinal conjugation of p-nitrophenol with glucuronic acid did not change significantly in hyperglycemic rats, however, formation of sulfoconjugate of p-nitrophenol was enhanced by hyperglycemia. Sum of metabolites (p-nitrophenol glucuronide and sulfate) appeared in the intestinal lumen in hyperglycemic rats was similar to the total luminal appearance of these metabolites of control rats.
Animals↗
Dose-dependent intestinal and hepatic glucuronidation and sulfatation of P-nitrophenol in the rat.
The jejunum was able to metabolize p-nitrophenol (PNP) rapidly and to transport the metabolites efficiently back into the luminal solution. About 21, 16, 6 and 3.5% of recirculated amount of PNP could be detected in 90 minutes as glucuronide in the lumen of jejunal loop, when 20, 100, 500 or 1,000 microM PNP was perfused, which shows that the luminal appearance of p-nitrophenol-glucuronide (PNP-G) tended to saturability. Biliary excretion rate of PNP-G was lower than the luminal appearance of this metabolite, when PNP was recirculated at 20 or 100 microM concentrations, however, at higher concentrations (500, 1,000 microM) the biliary excretion exceeded the luminal appearance of this conjugate and no saturability was observed in the biliary glucuronidation of PNP. Biliary excretion of sulfate conjugate of p-nitrophenol (PNP-S) exceeded the luminal appearance of this metabolite.
Animals↗
Contribution of interleukin-1 to activation of coagulation and fibrinolysis, neutrophil degranulation, and the release of secretory-type phospholipase A2 in sepsis: studies in nonhuman primates after interleukin-1 alpha administration and during lethal bacteremia.
Although studies with interleukin-1 receptor antagonist (IL-1ra) in animal models have shown that IL-1 contributes to mortality in sepsis, the mechanisms whereby IL-1 mediates lethal effects are not well established. A possible mechanism is that IL-1 enhances the activation and release of other inflammatory mediator systems such as coagulation, fibrinolysis, neutrophils, and secretory-type phospholipase A2 (sPLA2). We investigated this possibility by assessing the effect of intravenously injected recombinant human IL-1 alpha (rhIL-1 alpha) on these plasma parameters in baboons. In addition, we examined the course of these inflammatory parameters in baboons after a challenge with a lethal dose of Escherichia coli and while receiving a 24-hour constant infusion of IL-1ra or placebo. Intravenous administration of IL-1 alpha (10 micrograms/kg) induced the formation of thrombin, as evidenced by the appearance of thrombin-antithrombin III (TAT) complexes into the circulation (peak levels, 188 +/- 92 ng/mL at 2 hours), as well as the activation of fibrinolysis, assessed by circulating plasmin-alpha 2-antiplasmin complexes (PAP complexes; peak levels, 0.4% +/- 0.03% of fully activated plasma at 1 hour), the release of tissue-type plasminogen activator (t-PA; peak levels, 6 +/- 2 ng/mL at 2 hours), and its inhibitor, plasminogen activator inhibitor (PAI; peak levels, 724 +/- 246 ng/mL at 4 hours). Il-1 alpha administration also induced the release of sPLA2 (maximal levels, 336 +/- 185 ng/mL at 8 hours), but not degranulation of neutrophils. In the septic baboons, a significant reduction of the formation of thrombin (peak TAT levels decreased from 582 +/- 78 ng/mL to 219 +/- 106 ng/mL; P < .005), the release of t-PA (peak levels decreased from 37 +/- 11 ng/mL to 17 +/- 2 ng/mL; P < .001), and its inhibitor, PAI (peak levels decreased from 2,639 +/- 974 ng/mL to 1,110 +/- 153 ng/mL; P <.001), was observed in the group receiving IL-1ra compared to that receiving placebo. The release of neutrophilic elastase was also significantly attenuated in IL-1a-treated animals (peak levels, 1,024 +/- 393 and 655 +/- 104 ng/mL in control and treatment groups, respectively; P < .05). The difference between sPLA2 levels in both groups, although higher in the controls (maximal levels, 3,140 +/- 1,435 ng/mL in control v 2,217 +/- 1,375 ng/mL in IL-1ra-treated group), was not significant. Thus, IL-1 contributes to activation of various other mediator systems in severe sepsis in nonhuman primates. We propose that these effects may explain the lethal actions of IL-1 in this sepsis model and suggest a similar role for IL-1 in severe human sepsis.
Animals↗
Comparison of APACHE II and III scoring systems for mortality prediction in critical surgical illness.
OBJECTIVE: To determine whether the Acute Physiology and Chronic Health Evaluation III (APACHE III), an updated version of APACHE II that contains a larger number of postoperative patients in the normative database, offers better prediction in critical surgical illness. DESIGN: Prospective cohort study. SETTING: Surgical intensive care unit of an urban, tertiary-care university hospital. PARTICIPANTS: Eight hundred forty-four consecutive patients in the surgical intensive care unit. Overall scores were determined, as well as scores for survivor, nonsurvivor, trauma, nontrauma, postoperative, and nonoperative patient subgroups. MAIN OUTCOME MEASURES: Survival to hospital discharge, and survival compared with published normative APACHE II and III databases. RESULTS: Mean age was 65.1 +/- 0.5 years. Overall mortality was 7.0% in the surgical intensive care unit and 9.1% in the hospital. The relationship between APACHE II and APACHE III scores for individual patients was linear and correlated significantly (P < .0001) (range of correlation coefficients, .72 to .86) overall and in all subgroups. Both scoring systems overestimated our mortality, but estimations made by APACHE III were significantly (P < .01) higher overall and in all subgroups. CONCLUSIONS: In institutions or groups of patients where APACHE II underestimates mortality, APACHE III may be corrective. However, the differences are subtle and may be difficult to detect in smaller studies.
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PEG-BP-30 monotherapy attenuates the cytokine-mediated inflammatory cascade in baboon Escherichia coli septic shock.
Septic shock following gram-negative infection is a leading cause of mortality in critically ill patients, accounting for nearly 200,000 deaths a year. The exaggerated production of tumor necrosis factor-alpha (TNF alpha) is known to contribute to hemodynamic collapse and the hematological dyscrasia associated with gram-negative sepsis. Although previous studies have shown TNF alpha antibodies and TNF immunoadhesins to be effective in experimental gram-negative sepsis, we postulated that administration of a novel construct of two modified soluble p55 receptors linked to polyethylene glycol (PEG-BP-30) would also attenuate the hemodynamic and hematologic alterations to lethal Escherichia coli septic shock in non-human primates. Nine adult female and male baboons (Papio anubis), weighing 10-17 kg, were anesthetized and invasively monitored. The nine animals were randomized to receive either 0.2 mg/kg body wt PEG-BP-30 (n = 3), 5.0 mg/kg body wt PEG-BP-30 (n = 3), or placebo (n = 3). One hour after pretreatment, animals were infused with 5-10 x 10(10) CFU/kg of live E. coli iv and vital signs were recorded for the next 8 hr. Arterial blood was drawn for baseline parameters and throughout the study to obtain total and differential white blood cell and platelet counts and cytokine levels (TNF alpha, IL-1 beta, IL-6, IL-8). E. coli bacteremic baboons receiving only placebo demonstrated a significant fall in mean blood pressure and leukopenia. Two of the three animals expired. In contrast, five of the six baboons receiving the PEG-BP-30 survived and these animals exhibited markedly attenuated declines in blood pressure and leukocyte numbers.(ABSTRACT TRUNCATED AT 250 WORDS)
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Vergence eye movement control and multivalent perception of autostereograms.
We introduce a dynamical model for automatic vergence eye movement control. In connection with our dynamical system of binocular model neurons that solves the correspondence problem of stereo-vision, we present a complete model for stereo-vision. Our automatic vergence eye movement control adjusts an image segment, which is of momentary interest to the observer. The adjustment is done in such a way that we only need to define a disparity search range of minimal extension. Recently, a new method of encoding (3D) three-dimensional information in 2D pictures was designed in the form of computer-generated patterns of colored dots. At first glimpse, these so-called autostereograms appear as structured but meaningless patterns. After a certain period of observation, a 3D pattern emerges suddenly in an impressive way. Applying our algorithm to autostereograms, we find a fully satisfactory agreement with the multivalent perception experienced by humans. As in nature, in our model the phase transition between the initial state and the 3D perception state takes place in a very short time. Our algorithm is very robust against noise, and there is no need to interpolate a sparse depth map.
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Sialic acid-binding lectins: submolecular specificity and interaction with sialoglycoproteins and tumour cells.
We examined the specificity of limulin, Limax flavus agglutinin (LFA) and Sambucus nigra agglutinin I (SNA I) at the submolecular level of sialic acid, and characterized their interactions with a panel of structurally distinct sialoglycoproteins. In haemagglutination inhibition assays NeuAc-alpha-glycosides were stronger inhibitors for limulin and LFA than native N-acetylneuraminic acid (NeuAc). The N-acetyl of NeuAc was crucial for binding to both lectins. N-thioacetylated NeuAc lost affinity for LFA, but still bound to limulin. Thus, distinct intermolecular interactions are involved in binding of sialic acid to the lectins. The glyceryl side chain was required for interaction with LFA, but not with limulin. SNA I specifically bound NeuAc alpha 2 --> 6Gal beta 1 --> 4Glc, but not monomeric sialic acids. Limulin and LFA strongly interacted with O-chain glycoproteins, whereas SNA I preferred N-chain proteins that carry NeuAc alpha 2 --> 6 residues. The lectins were compared with those from Cepaea hortensis and Tachypleus tridentatus (TTA) and to wheat-germ agglutinin, and were then used to probe tumour cell lines for cell surface sialylation. With the exception of TTA, all lectins interacted with the tumour cells. Limulin distinguished between the low (Eb) and highly (ESb) metastatic mouse lymphoma lines by selectively agglutinating sialidase-treated ESb cells.
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Influence of hypercortisolemia on soluble tumor necrosis factor receptor II and interleukin-1 receptor antagonist responses to endotoxin in human beings.
BACKGROUND: We have previously reported that the antecedent administration of glucocorticoids altered both the hormonal and proinflammatory cytokine responses to lipopolysaccharide (LPS) when administered to human volunteers. In that study, subjects with vastly exaggerated levels of tumor necrosis factor (TNF) and interleukin (IL)-6 12 and 144 hours after cortisol infusion exhibited hemodynamic and hormonal responses no different from those of untreated subjects after endotoxin. The current study examined levels of the antiinflammatory cytokines interleukin-1 receptor antagonist (IL-1ra) and soluble receptors to tumor necrosis factor (sTNF-R) in the same setting of the previous report. METHODS: Hydrocortisone succinate was infused into healthy volunteers. LPS was then injected immediately or was delayed by 6, 12, or 144 hours (C, C-6, C-12, and C-144, respectively). Subjects receiving LPS alone served as controls. Plasma was analyzed to determine levels of TNF, sTNF-R and IL-1ra by enzyme-linked immunosorbent assay before administration of LPS and at 30-minute intervals after administration of LPS for 6 hours. RESULTS: Levels of sTNF-R increased after LPS administration in all groups (p < 0.05 versus baseline) with a significantly higher level recorded in the subjects having received hydrocortisone 144 hours before (C-144, p < 0.05 versus all other groups). TNF levels remained undetectable in association with immediate infusion of LPS (C) and the relatively short delay group (C6). This cytokine peaked 90 minutes after LPS in all other groups, with a significantly higher peak in the C-144 subjects when compared with controls. IL-1ra levels rose in all groups but to a lesser extent in the C group (p < 0.05). CONCLUSIONS: These data confirm that glucocorticoids influence the production of both sTNF-R and IL-1ra. The potential for an exaggerated response of sTNF-R exists for an extended period of time after exposure to glucocorticoids.
Adult↗
Hypothermia during elective abdominal aortic aneurysm repair: the high price of avoidable morbidity.
PURPOSE: Adverse outcomes apparently associated with hypothermia led us to examine patients undergoing elective abdominal aortic aneurysm (AAA) repairs to test the hypothesis that hypothermia (temperature less than 34.5 degrees C) is associated with increased morbidity and excess mortality rates. METHODS: Two hundred sixty-two elective AAA repairs were retrospectively reviewed for preoperative and intraoperative risk factors. Core temperature, age, Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III scores (raw and temperature-adjusted), fluid resuscitation, and perioperative organ dysfunction were recorded prospectively. Outcome measures included lengths of stay in the intensive care unit and in the hospital, and hospital mortality rates. RESULTS: Except for a higher risk of hypothermia in women (p < 0.05), by univariate analysis, preoperative risk factors were similar in patients in the hypothermic and normothermic groups. After operation, patients with hypothermia had significantly greater APACHE scores (p < 0.0001), and patients in the hypothermic nonsurvivor group took significantly longer to rewarm (p < 0.05), suggesting marked hypoperfusion. Patients with hypothermia had significantly greater fluid (p < 0.05), transfusion (p < 0.01), vasopressor (p < 0.05), and inotrope (p < 0.05) requirements, resulting in significantly higher incidences of organ dysfunction (53.0% vs 28.7%, p < 0.01) and death (12.1% vs 1.5%, p < 0.01) and markedly prolonged lengths of stay in the unit (9.2 +/- 2.0 vs 5.3 +/- 0.6, p < 0.05) and in the hospital (24.3 +/- 2.9 vs 15.0 +/- 0.08, p < 0.01). By multivariate analysis, female gender (p = 0.004) was the only predictor of intraoperative hypothermia, whereas initial hypothermia was significantly predictive of both prolonged hypothermia and development of organ failure (p < 0.05). Organ failure (p < 0.05) and acute myocardial infarction (p < 0.01) were independent predictors of death. CONCLUSIONS: After AAA repair, patients with hypothermia have multiple physiologic derangements associated with adverse outcomes. Although multiple etiologic factors are interacting, body temperature is one variable that should be controlled during aortic surgery.
APACHE↗
Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis.
Studies were done in baboons and humans to assess the role of interleukin (IL)-1 on the release of soluble tumor necrosis factor receptors (sTNFRs) during sepsis. In baboons, IL-1 alpha induced increased levels of sTNFR types I and II. Infusion of Escherichia coli into baboons also led to higher sTNFR levels. Treatment with IL-1 receptor antagonist (ra) attenuated the rise in sTNFR-I, which was positively correlated with a partial preservation of renal function by IL-1ra. In patients with sepsis, treatment with IL-1ra also was associated with lower levels of sTNFR-1 but did not influence plasma creatinine levels. IL-1ra did not affect sTNFR-II in baboons or humans. These data suggest that IL-1 produced during sepsis is involved in increases in sTNFR-I. Such increases during rapidly fatal septic shock may in part be explained by an effect on the renal clearance of sTNFR-I.
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High-risk intrahospital transport of critically ill patients: safety and outcome of the necessary "road trip".
OBJECTIVE: Intrahospital transport of critically ill patients is often necessary for optimal patient care. However, transport of intensive care unit (ICU) patients within the hospital has been associated with a high rate of potentially detrimental complications. This study was designed to determine the occurrence rate of transport-related complications and to determine if these complications have any effect on patient morbidity and mortality. DESIGN: Prospective, cohort-matched study. SETTING: A 780-bed urban, university teaching hospital. PATIENTS: Seven hundred fifty-nine surgical ICU patients. INTERVENTIONS: One hundred seventy-five patients were transported out of the surgical ICU for diagnostic testing or operative interventions deemed necessary by their surgical or critical care team. MEASUREMENTS AND MAIN RESULTS: Acute Physiology and Chronic Health Evaluation (APACHE) II and APACHE III scores were determined 24 hrs after admission. Transport patients were stratified into low-risk and high-risk transport groups. Patients were considered a high-risk transport if they required positive end-expiratory pressure of > 5 cm H2O, a continuous infusion of dobutamine, or a continuous infusion of norepinephrine. The high-risk group was further stratified into three groups based on the number of defined treatment regimens required to maintain the patient during transport. The patients were then followed during their transport for any potentially detrimental complications, such as a need for an increased dose of vasoactive medications, loss of intravenous access, a need for additional ventilatory support, or cardiopulmonary arrest. APACHE-matched control cohorts were identified as patients who did not leave the surgical ICU. The overall occurrence rate of complications was similar in the two groups (low-risk group, 6.3%; high-risk group, 5.5%). The mortality rate for all transport patients was 28.6%, which was statistically higher (p < .01) than the mortality rate for all control patients (11.4%). However, there was no mortality as a direct result of a transport. The overall mortality rate (10.9%) of the low-risk group was not significantly different from the APACHE-matched controls (6.0%). The overall mortality rate (51.4%) in the high-risk group was significantly higher (p < .01) than the APACHE-matched controls, but was not statistically higher than predicted mortality (p = .416). Both the low-risk and the high-risk groups stayed in the surgical ICU three times as long as the APACHE-matched control cohorts. CONCLUSIONS: Intrahospital transport of critically ill patients is safe and carries a low risk of detrimental complications. Although patients requiring "high-risk" interventions experienced a higher mortality rate than did APACHE-matched controls, the increase in mortality does not appear to be directly related to the intrahospital transport. Patients requiring transport out of the surgical ICU are a more critically ill group of patients. These patients require a greater length of stay in the surgical ICU and may experience an increased mortality rate by virtue of the severity of their illness.
APACHE↗
Thyrotoxicosis in pregnancy presenting as pancytopenia.
Delay in diagnosis of thyroid disease can result in morbidity and mortality. Thyroid disorders are not uncommon in the reproductive age group and therefore in pregnancy; recognition of both the common and the more unusual manifestations will optimize outcome.
Adult↗
Ontogeny of NO synthase and renin in juxtaglomerular apparatus of rat kidneys.
The presence of NO synthase (NOS) in cells of the macula densa (MD) suggests a role for arginine-derived NO in tubulovascular information transfer. To investigate the postnatal development of the neuronal isoform of NOS and of renin in the kidney, the cellular distribution of these enzymes was examined in perfusion-fixed kidneys of 2-, 6-, and 15-day-old rats at both the protein and mRNA level (n = 4 rats/group). NOS and renin and their mRNAs were localized by immunohistochemical and in situ hybridization methods. In addition, NOS levels were assessed by using NADPH diaphorase (NADPH-d) histochemistry. For quantification, the fraction of NOS- and renin-positive glomeruli as well as the number of NOS-positive MD cells was evaluated at all stages. Presence of NOS in single cells of the developing distal tubule was encountered already in the S-shaped body. Full expression of a NOS signal in MD cells was seen as soon as a glomerular urinary space was developed. Double labeling with NADPH-d and antibody to Tamm-Horsfall protein (THP) indicated mutual exclusiveness of NADPH-d-positive MD cells and neighboring THP-positive distal tubule cells at all levels of development. The relative intensity of renin status was 2 day > 6 day > 15 day, whereas NOS expression was maximal on postnatal day 6. Our data are consistent with an involvement of MD NO synthesis in the early organization of the juxtaglomerular apparatus during nephrogenesis and suggest an interdependent relation with renin-producing cells.
Aging↗
Acute acalculous cholecystitis.
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Acute Disease↗
Intestinal elimination of p-nitrophenol in the rat.
The intestinal metabolism and metabolite transport of p-nitrophenol (PNP), as a model compound have been investigated in an in vivo isolated intestinal loop preparation in the rat. Different PNP concentrations (20 microM, 100 microM and 500 microM) were recirculated to determine the formation and transport of PNP-metabolites (PNP-glucuronide: PNP-G and PNP-sulphate: PNP-S) in the jejunal loop. It was found that the jejunum of the rat was able to metabolize PNP rapidly and to transport the metabolites efficiently back into the luminal solution. About 21, 16 and 6% of recirculated amount of PNP could be detected in 90 minutes as PNP-G in the lumen of jejunal loop when 20, 100 or 500 microM PNP was perfused. These results show that the luminal appearance of PNP-G tended to saturability. Sulphate conjugate of PNP was undetectable in the intestinal lumen at 20 and 100 microM PNP concentrations and PNP-S amounted to 0.07% of recirculated amount of PNP when it was used in a concentrations of 500 microM. These results indicate that the intestinal metabolism and the excretion of metabolites may play a role in the elimination of xenobiotics containing phenolic hydroxyl groups and that the small intestine of the rat forms predominantly PNP-G after luminal administration of PNP.
Animals↗