Daily interruption of sedative infusions in critically ill patients.
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Analgesics↗
Biomedical subjects
J E Mazuski
Publications and source records attributed to J E Mazuski.
Clostridium difficile toxins influence hepatocyte protein synthesis through the interleukin 1 receptor.
HYPOTHESIS: Clostridium difficile toxins require interleukin 1 (IL-1) production or a functioning IL-1 receptor to elicit acute-phase protein production by murine hepatocytes. DESIGN: Experimental study. SETTING: Research laboratory at the DVA Medical Center, St Louis, Mo. CELLS STUDIED: Hepatocytes prepared from normal mice, from knockout mice deficient in IL-1 production due to loss of IL-1 converting enzyme, or from knockout mice deficient in the IL-1 p80 receptor. INTERVENTIONS: Cells were treated with lipopolysaccharide, a crude C difficile toxin extract, or purified C difficile toxins A or B for 24 hours in vitro, then radiolabeled with (35)S methionine. Newly synthesized acute-phase proteins were identified by electrophoresis and autoradiography. MAIN OUTCOME MEASURES: Synthesis of a 23-kd acute-phase protein in response to the various stimuli. RESULTS: Lipopolysaccharide, C difficile culture extract, and purified toxins A and B stimulated the synthesis of the 23-kd acute-phase protein by hepatocytes from normal mice and by hepatocytes from knockout mice deficient in the IL-1 converting enzyme. However, hepatocytes from knockout mice deficient in the IL-1 p80 receptor failed to produce this acute-phase protein when treated with the C difficile toxins, although they responded fully to lipopolysaccharide. CONCLUSIONS: Stimulation of acute-phase protein synthesis by C difficile toxins does not require IL-1 production, but does require a functioning IL-1 p80 receptor. This suggests that some of the actions of these toxins are mediated by this receptor.
Acute-Phase Proteins↗
Clostridium difficile toxin: cytoskeletal changes and lactate dehydrogenase release in hepatocytes.
BACKGROUND: We have found that Clostridium difficile toxins can evoke hepatocyte acute-phase protein synthesis, and that this effect is dependent on a functioning interleukin-1 (IL-1) receptor. The present study was undertaken to determine if C. difficile toxicity, as determined by actin rearrangement and lactate dehydrogenase (LDH) release, also requires a functioning IL-1 receptor. METHODS: Primary hepatocyte cultures were prepared from normal mice, knockout mice deficient in the IL-1-converting enzyme (ICE), and knockout mice deficient in the IL-1 p80 receptor. Hepatocytes were treated for 24 h with C. difficile culture extract, purified C. difficile toxin A, or purified C. difficile toxin B. The actin cytoskeleton was examined using confocal microscopy, and LDH release was measured by spectrophotometric analysis. RESULTS: C. difficile culture extract, toxin A, and toxin B induced collapse of the actin cytoskeleton in hepatocytes from normal mice. Hepatocytes from both the ICE-deficient mice and the IL-1 p80 receptor-deficient mice demonstrated similar responses to both toxins. These toxins also induced significant LDH release in a concentration-dependent fashion in the normal hepatocytes and the ICE-deficient hepatocytes. However, no significant increase in LDH release was observed in hepatocytes from IL-1 p80 receptor-deficient mice. CONCLUSIONS: C. difficile toxins induce actin cytoskeletal collapse independent of IL-1 or the IL-1 receptor. In contrast, toxin-stimulated LDH release was dependent on the presence of the IL-1 receptor. Thus, separate pathways appear to mediate toxic effects as manifested by actin rearrangement and LDH release.
Actins↗
The role of cyclooxygenase enzymes in the growth of human gall bladder cancer cells.
Information suggests that the cyclooxygenase (COX) metabolites, the prostanoids, play a role in gall bladder physiology and disease. Non-steroidal anti-inflammatory drugs which inhibit COX enzymes have been shown in vivo and in vitro to alter the growth patterns of intestinal epithelial cells, and specific COX-2 inhibitors have been shown to decrease mitogenesis in intestinal epithelial cells. The present study was intended to evaluate the effect of specific COX inhibitors on the growth patterns of gall bladder cancer cells. Employing a human gall bladder cancer cell line, mitogenesis, apoptosis and prostaglandin E(2) (PGE(2)) formation were evaluated in response to serum and hepatocyte growth factor and transforming growth factor alpha stimulation in the presence and absence of specific COX-1 and -2 inhibitors. The effect of the mitogens on COX enzyme expression was also evaluated. Serum and the growth factors increased COX enzyme expression and mitogenesis, and decreased apoptosis as evaluated by the percentage of cells that were floating in culture media rather than attached. There was more DNA degradation in floating than in attached cells. The specific COX-2 inhibitor, but not the COX-1 inhibitor, decreased mitogenesis and increased gall bladder cell apoptosis as evaluated by the number of floating versus attached cells and the number of floating cells in the terminal phase of apoptosis or dead. The inhibition of mitogenesis and the increased apoptosis produced by the COX-2 inhibitor was associated with decreased PGE(2) production. The inhibition of replication of gall bladder cancer cells and the increase in apoptosis produced by the selective COX-2 inhibitor suggests that the COX enzymes and the prostanoids may play a role in the development of gall bladder cancer and that the COX-2 inhibitors may have a therapeutic role in the prevention of gall bladder neoplasms.
Apoptosis↗
The effect of phospholipase A2 inhibitors on proliferation and apoptosis of murine intestinal cells.
BACKGROUND: Group II phospholipase A2 (PLA2) enzymes, the rate controlling enzymes in arachidonic acid metabolism, have been well characterized and subdivided into secretory 14-kDa PLA2 (sPLA2) and cytoplasmic 85-kDa PLA2 (cPLA2). Previous research has demonstrated increased PLA2 in colorectal tumors. The present study was performed to determine the effect of specific PLA2 inhibitors on the proliferation and induction of apoptosis of intestinal epithelial cells. METHODS: A continuously proliferating rat small intestinal cell line (IEC-18) and a mouse colon cancer cell line (WB-2054-M4) were utilized for these experiments. The cells were placed in microwells with serum-free or serum-supplemented media. The effects of serum on proliferation were then evaluated in the presence of the cPLA2 inhibitor, methylarachidonyl fluorophosphate (MAFP), or the sPLA2 inhibitor p-bromophenacyl bromide (BPB). The sPLA2 and cPLA2 protein was estimated by Western blotting. Proliferation of intestinal cells was quantitated by incorporation of [3H]thymidine into DNA and PLA2 activity was evaluated by quantitating arachidonic acid formation and prostaglandin E2 production. RESULTS: Western blotting of IEC-18 and WB-2054 cell protein demonstrated sPLA2 and cPLA2 enzyme in cells incubated in media containing 10% serum. Spontaneous DNA synthesis was present in both cell lines and serum consistently increased proliferation. In IEC-18 cells [3H]thymidine incorporation stimulated by serum was inhibited by MAFP and BPB, while in the malignant cell line, proliferation was inhibited only by BPB. BPB, but not MAFP, produced a dose-dependent increase in apoptotic ratios in both cell lines. Arachidonic acid and PGE2 formation, stimulated by serum, was inhibited by MAFP and BPB. CONCLUSIONS: A differential effect on intestinal cell mitogenesis was seen with different PLA2 inhibitors. The sPLA2 inhibitor, but not the cPLA2 inhibitor, significantly inhibited [3H]thymidine incorporation in the malignant cell line. This occurred with an induction of apoptosis. sPLA2 inhibitors may be specific inhibitors of growth of malignant cells. The inhibition of arachidonic acid and PGE2 production did not correlate with the inhibition of proliferation, suggesting that the two processes may be unrelated.
Acetophenones↗
The effect of selective cyclooxygenase inhibitors on intestinal epithelial cell mitogenesis.
INTRODUCTION: Previous research has demonstrated that nonsteroidal anti-inflammatory agents alter the incidence of colorectal cancer. It has been postulated that the response may be due to the effect of these agents on the activities of the cyclooxygenase (COX) enzymes. The COX enzymes catalyze the conversion of arachidonic acid to biologically active prostanoids. Two forms of COX have been identified. COX-1 is a constitutive enzyme, generally involved in cell functions, while COX-2 is commonly an enzyme which is inducible in response to various stimuli, including mitogens. Recently, specific inhibitors of COX-1 and COX-2 enzymes have been developed. PURPOSE: The present study was undertaken to determine the effects of specific COX-1 and COX-2 inhibitors on the proliferation and the induction of apoptosis of intestinal epithelial cells. METHODS: A continuously proliferating rat small intestinal cell line (IEC-18) and a mouse colon cancer cell line (WB-2054) were utilized for these experiments. The cells were placed in microwells with serum-free or serum-supplemented media. The effects of serum on proliferation were then evaluated in the presence of the COX-1 inhibitor, valerylsalicyclic acid (VSA), the COX-2 inhibitor, SC-58125, or indomethacin. The presence of COX-1 and COX-2 protein was evaluated by Western blotting. Proliferation of intestinal cells was quantitated by incorporation of [3H]thymidine into DNA and cell counting, and apoptosis was determined by evaluating cell attachment. COX activity was evaluated by prostaglandin E2 production measured by enzyme-linked immunoabsorbent assay (ELISA). RESULTS: Western blotting of IEC-18 and WB-2054 cell protein demonstrated COX-1 enzyme in cells incubated in serum-free media with increased COX-1 expression produced by incubation in media supplemented with 10% serum. COX-2 enzyme was not demonstrated in serum-free media; however, it was present in cells maintained in 10% serum-supplemented media. Spontaneous DNA synthesis was present in both cell lines and serum increased proliferation. In both cell lines [3H]thymidine incorporation stimulated by serum was inhibited by the COX-2 inhibitor SC-58125, but not by the COX-1 inhibitor VSA. Both indomethacin and SC-58125 produced a dose-dependent increase in apoptotic ratios in both cell lines. PGE2 formation, stimulated by serum, was inhibited by SC-58125, VSA, and indomethacin. CONCLUSION: A differential effect on intestinal cell mitogenesis was seen with different COX inhibitors. The COX-2 inhibitor, but not the COX-1 inhibitor, significantly inhibited [3H]thymidine incorporation in both cell types, suggesting COX-2 inhibitors may be specific inhibitors of normal epithelial cell proliferation and growth of malignant cells. SC-58125, a selective inhibitor of COX-2, has a potent apoptosis inducing effect. The inhibition of PGE2 production did not correlate with the inhibition of proliferation, suggesting the two processes are unrelated.
Animals↗
Endotoxin stimulates hepatocyte interleukin-6 production.
BACKGROUND: Interleukin-6 (IL-6) is a multifunctional cytokine which mediates many aspects of the acute phase response. Although known to be produced by macrophages and other proinflammatory cells, IL-6 is also released by many types of epithelial cells. The present studies were performed to determine if endotoxin and proinflammatory cytokines stimulate the release of IL-6 from native murine hepatocytes. METHODS: Cultured hepatocytes were treated with various concentrations of lipopolysaccharide (LPS), interleukin-1 (IL-1), or tumor necrosis factor (TNF), in the presence or absence of the IL-1 receptor antagonist (IL-1 RA), an anti-TNF antibody, or dexamethasone. Culture supernatants were assayed for murine IL-6 using an ELISA. The cellular source of IL-6 was investigated using immunohistochemical staining. RESULTS: Hepatocyte IL-6 production was significantly increased following treatment with LPS, IL-1, and TNF. Combinations of LPS and these cytokines were synergistic in stimulating IL-6 release. Dexamethasone, but not IL-1 RA or an anti-TNF antibody, inhibited hepatocyte production of IL-6 in response to LPS. Immunohistochemical staining revealed that the hepatocytes, and not contaminating nonparenchymal cells, were the principal source of the IL-6 produced in these cultures. CONCLUSIONS: Murine hepatocytes release significant amounts of IL-6 when exposed to endotoxin or proinflammatory cytokines. LPS appears to stimulate hepatocyte IL-6 production directly, and this effect does not appear to be mediated by IL-1 or TNF.
Animals↗
Synthetic pathways of gallbladder mucosal prostanoids: the role of cyclooxygenase-1 and 2.
Acute cholecystitis is associated with increased gallbladder prostanoid formation and the inflammatory changes and prostanoid increases can be inhibited by nonsteroidal anti-inflammatory agents. Recent information indicates that prostanoids are produced by two cyclooxygenase (COX) enzymes, COX-1 and COX-2. The purpose of this study was to determine the COX enzymatic pathway in gallbladder mucosal cells involved in the production of prostanoids stimulated by inflammatory agents. Human gallbladder mucosal cells were isolated from cholecystectomy specimens and maintained in cell culture and studied in comparison with cells from a well differentiated gallbladder mucosal carcinoma cell line. COX enzymes were evaluated by Western immunoblotting and prostanoids were measured by ELISA. Unstimulated and stimulated cells were exposed to specific COX-1 and COX-2 inhibitors. In both normal and transformed cells constitutive COX-1 was evident and in gallbladder cancer cells lysophosphatidyl choline (LPC) induced the formation of constitutive COX-1 enzyme. While not detected in unstimulated normal mucosal cells and cancer cells, COX-2 protein was induced by both lipopolysaccharide (LPS) and LPC. Unstimulated gallbladder mucosal cells and cancer cells produced prostaglandin E2 (PGE2) and prostacyclin (6-keto prostaglandin F1alpha, 6-keto PGF1alpha) continuously. In freshly isolated normal gallbladder mucosal cells, continuously produced 6 keto PGF1alpha was inhibited by both COX-1 and COX-2 inhibitors while PGE2 levels were not affected. Both LPS and LPC stimulated PGE2 and 6 keto PGF1alpha formation were blocked by COX-2 inhibitors in freshly isolated, normal human gallbladder mucosal cells and in the gallbladder cancer cells. The prostanoid response of gallbladder cells stimulated by proinflammatory agents is inhibited by COX-2 inhibitors suggesting that these agents may be effective in treating the pain and inflammation of gallbladder disease.
6-Ketoprostaglandin F1 alpha↗
Overuse of splenic scoring and computed tomographic scans.
BACKGROUND: As the most commonly injured abdominal organ in blunt trauma, the management of splenic injury has undergone evolution. The risk of blood transfusions administered in an attempt to save the spleen has lowered the threshold for operation and also expanded the limits for nonoperative management. An in-depth analysis was carried out of risk factors on patients requiring immediate surgery and those who fail non-operative management based on organ injury scaling grading by computed tomographic (CT) scan and operation. The application of nonoperative management in the elderly population and the use of follow-up CT scanning and sonography in the outpatient setting was also examined. METHODS: Between January of 1991 and June of 1996, 226 consecutive blunt splenic trauma, injured patients at a Level I trauma center were evaluated. All subsequent CT scans and sonograms in the inpatient and outpatient setting were analyzed. The Student's t test, Pearson chi2 analysis with Yates correction, and analysis of variance were used to compare between and among groups. RESULTS: There were 153 men (67.7%), an average age of 34.8 years, an average Injury Severity Score of 24.4, and 28 deaths (12%). There was a significant difference with respect to Injury Severity Score, Glasgow Coma Scale score, Revised Trauma Score, units of packed red blood cells transfused, length of stay, intensive care unit length of stay, mean splenic injury grade, and cost between patients observed initially and those operated on initially. There was no significant difference in age between the two groups. Of 170 patients, 37 patients (22%) who had an initial CT scan underwent immediate exploratory laparotomy. The remaining 133 patients (78%) had nonoperative management; however, 15 patients (11%) failed the period of observation. Five in this group had a laparotomy secondary to other causes and another six were operated on within 24 hours of their injury for their splenic injury. Thus, only four of the nonoperative management patients (3%) actually failed nonoperative splenic management after 24 hours of injury. There were 100 second CT scans obtained. Three of these patients, who had developed hemodynamic instability, required operation for a bleeding spleen. The subsequent CT scan was confirmatory in these three patients who resided in the intensive care unit. All other CT scans and sonograms for clinically unremarkable patients failed to yield any alteration in care based on the scans. CONCLUSION: Blunt splenic injured patients can be safely observed; however, there are certain risk factors in those requiring immediate surgery and those failing nonoperative management. The CT scan underestimates injury, possibly related to a progression of bleeding found at the time of operation. No outpatient studies altered the course of management. Age also did not influence outcome. Thus, in the dedicated trauma center, nonoperative management of blunt splenic injury patients does not lead to undue morbidity or mortality. Once discharged, follow-up radiographs in asymptomatic patients are not necessary.
Adolescent↗
In vitro effects of Clostridium difficile toxins on hepatocytes.
BACKGROUND: Clostridium difficile infections are associated with development of the systemic inflammatory response, including the production of hepatic acute phase proteins. Lipopolysaccharide (LPS) directly stimulates the production of at least one of these proteins, a 23-kDa acute phase protein (the LPS-induced protein, or LIP) by murine hepatocytes in vitro. The aim of the present study was to determine if C. difficile toxins also stimulated the synthesis of this protein in vitro. METHODS: Cultured murine hepatocytes were treated for 24 h with various concentrations of C. difficile culture extract or purified toxins A and B in the presence or absence of dexamethasone or interleukin-1 (IL-1) receptor antagonist (IL-1 RA). The cells were then metabolically radiolabeled with [35S]methionine. Secretory proteins were identified using electrophoresis and autoradiography, and their synthesis was quantitated by image analysis of the autoradiograms. RESULTS: The C. difficile culture extract, at dilutions as low as 1:200,000, significantly stimulated LIP synthesis in vitro. Toxins A and B, at concentrations as low as 1.6 and 0.02 pg/ml, respectively, also induced production of this protein. Dexamethasone further augmented C. difficile toxin-stimulated synthesis of LIP, but IL-1 RA inhibited the effects of these toxins on the synthesis of this protein. Only minimal quantities of IL-1 were found in culture supernatants following treatment with the toxins. CONCLUSIONS: C. difficile toxins A and B, at very low concentrations, stimulate hepatocyte acute phase protein synthesis. Even though IL-1 RA inhibits this process, it does not appear that local production of IL-1 mediates the action of these toxins.
Acute-Phase Proteins↗
The role of selective cyclooxygenase isoforms in human intestinal smooth muscle cell stimulated prostanoid formation and proliferation.
Intestinal smooth muscle plays a major role in the repair of injured intestine and contributes to the prostanoid pool during intestinal inflammatory states. Cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostanoids exists in two isoforms, COX-1 and COX-2. The purpose of this study was to determine the relative contributions of COX-1 and COX-2 in the production of prostanoids by human intestinal smooth muscle (HISM) cells when stimulated by interleukin-1beta (IL-1beta) and lipopolysaccharide (LPS). Furthermore the effects of specific COX-1 and COX-2 inhibitors on the proliferation of smooth muscle cells was also evaluated. Confluent monolayer cultures of HISM cells were incubated with IL-1beta or LPS for 0-24h while control cells received medium alone. PGE2 and PGI2 as 6-keto-PGF1alpha and LTB4 were measured by a specific radioimmunoassay. COX enzymes were evaluated by Western immunoblotting. Unstimulated and stimulated cells were exposed to the specific COX-1 inhibitor valerylsalicylic acid (VSA) and the COX-2 inhibitors NS-398 and SC-58125. The effects of serum on proliferation were then evaluated in the presence of each of the specific COX inhibitors by incorporation of 3H-thymidine into DNA. IL-1beta and LPS increased both PGE2 and 6-keto-PGF1alpha in a dose dependent fashion with enhanced production detected two hours following exposure. Neither stimulus stimulated LTB4 release. Immunoblot analysis using isoform-specific antibodies showed that both COX-1 and COX-2 were present constitutively. Furthermore, COX-1 was upregulated by each inflammatory stimulus. In a separate set of experiments cells were pretreated with either the selective COX-1 inhibitor VSA or the selective COX-2 inhibitors NS-398 or SC-58125 prior to treatment with IL-1beta or LPS. The COX-1 and COX-2 inhibitors decreased both basal and IL-1beta and LPS stimulated prostanoid release. Spontaneous DNA synthesis was present and serum consistently increased proliferation. 3H-thymidine incorporation, stimulated by serum, was inhibited by both COX-1 and COX-2 inhibitors. This study suggests that the prostanoid response stimulated by proinflammatory agents of gut-derived smooth muscle cells appears to be mediated by both COX-1 and COX-2 enzymes. Proliferation of smooth muscles cells also appears to be influenced by both COX-1 and COX-2.
Blotting, Western↗
The role of cyclooxygenase-1 and cyclooxygenase-2 in lipopolysaccharide and interleukin-1 stimulated enterocyte prostanoid formation.
Lipopolysaccharide is an inflammatory agent and interleukin-1 is a cytokine. Their pro-inflammatory effects may be mediated by prostanoids produced by inducible cyclooxygenase-2. The aim of this study was to determine the prostanoids produced by lipopolysaccharide and interleukin-1 stimulated enterocytes through the cyclooxygenase-1 and 2 pathways. Cultured enterocytes were stimulated with lipopolysaccharide or interleukin-1beta with and without cyclooxygenase inhibitors. Low concentrations of indomethacin and valerylsalicylic acid (VSA) were evaluated as cyclooxygenase-1 inhibitors and their effects compared with the effects of a specific cyclooxygenase-2 inhibitor, SC-58125. Prostaglandin E2, 6-keto prostaglandin F1alpha, prostaglandin D2 and leukotriene B4 levels were determined by radioimmunoassay. Immunoblot analysis using isoform-specific antibodies showed that the inducible cyclooxygenase enzyme (COX-2) was expressed by 4 h in LPS and IL-1beta treated cells while the constitutive COX-1 remained unaltered in its expression. Interleukin-1beta and lipopolysaccharide stimulated the formation of all prostanoids compared with untreated cells, but failed to stimulate leukotriene B4. Indomethacin at 20 microM concentration, and VSA inhibited lipopolysaccharide and interleukin 1beta stimulated prostaglandin E2, but not 6-keto prostaglandin F1alpha formation. SC-58125 inhibited lipopolysaccharide and interleukin-1beta stimulated 6-keto prostaglandin F1alpha but not prostaglandin E2 release. The specific cyclooxygenase-2 inhibitor also inhibited lipopolysaccharide produced prostaglandin D2 but not interleukin-1beta stimulated prostaglandin D2. While SC-58125 inhibited basal 6-keto prostaglandin-F1alpha formation it significantly increased basal prostaglandin E2 and prostaglandin D2 formation. As SC-58125 inhibited lipopolysaccharide and interleukin-1beta induced 6-keto prostaglandin F1alpha production but not prostaglandin E2 production, it suggests that these agents stimulate prostacyclin production through a cyclooxygenase-2 mediated mechanism and prostaglandin E2 production occurs through a cyclooxygenase-1 mediated mechanism. Prostaglandin D2 production appeared to be variably produced by cyclooxygenase-1 or cyclooxygenase-2, depending on the stimulus.
Animals↗
Effects of cytokine antagonists on the hepatic acute-phase response.
Endotoxin-induced hepatic acute-phase protein synthesis has been thought to be primarily regulated through cytokines such as interleukin-1 (IL-1) and interleukin-6 (IL-6). Previously, it was found that a 23-kDa murine acute-phase protein, the lipopolysaccharide (LPS)-induced protein (LIP), was synthesized following treatment of hepatocytes in vitro with LPS. Since this protein was also induced by IL-1 and IL-6, the present studies were undertaken to determine if the effect of endotoxin was mediated through these cytokines. Primary cultures of murine hepatocytes were treated with LPS, IL-1, IL-6, or an LPS-stimulated macrophage supernatant in the presence or absence of the IL-1 receptor antagonist (IL-1 RA) and/or an anti-IL-6 antibody. The cells were then radiolabeled with [35S]methionine. LIP was detected by electrophoresis and autoradiography of the secreted proteins. In vitro, IL-1 RA completely inhibited the stimulation of LIP synthesis elicited by IL-1 and the macrophage supernatant, but did not affect LPS-stimulated synthesis of this protein. The anti-IL-6 antibody inhibited IL-6-triggered synthesis of LIP, but had no effect on LPS-stimulated synthesis. Hepatocytes isolated from mice treated in vivo with both IL-1 RA and LPS synthesized LIP to the same degree as hepatocytes isolated from mice treated with LPS alone. LPS-stimulated synthesis of LIP in vitro does not require IL-1 or IL-6 as an obligatory intermediate. These results are consistent with the hypothesis that endotoxin can directly stimulate hepatocyte acute-phase protein synthesis in the absence of cytokines.
Acute-Phase Proteins↗
Role of cytokines and platelet-activating factor in inflammatory bowel disease. Implications for therapy.
BACKGROUND: Platelet-activating factor (PAF) and cytokines, such as interleukins, tumor necrosis factor, and others, are thought to play a role in the inflammatory process involving gastrointestinal disorders such as Crohn's disease, ulcerative colitis, ischemic colitis, or antibiotic-associated colitis. PURPOSE: This study was undertaken to review the latest literature on the role of PAF and cytokines in the genesis of inflammatory bowel disease and implications for therapy and management. RESULTS: PAF is an endogenous phospholipid involved in hypersensitivity and inflammatory reactions such as platelet and neutrophil aggregation, vasodilation, increased vascular permeability, and leukocyte adhesion, which have been associated with inflammatory processes. Cytokines are peptides that regulate and coordinate inflammatory and immunologic responses. Increased production of cytokines has been reported during Crohn's disease and ulcerative colitis and is correlated with disease activity. CONCLUSIONS: Because PAF and cytokines may have an important role in the pathogenesis of inflammatory bowel disease, their inhibition by specific antagonists, mediators, or other agents such as steroids may have a potential therapeutic benefit in treatment and management of these inflammatory diseases in the near future.
Animals↗
Clinical trials of new and novel therapeutic agents.
Throughout this issue of World Journal of Surgery are recommendations and descriptions of therapy to prevent the development of multiple organ failure (MOF). The subjects include advances in monitoring; circulatory, pulmonary, and gut support; blood treatment; immune modulation; and control of the inflammatory process. Additional methods of organ support include recommendations for resuscitation and initial care and for early definitive operations. New therapeutic agents such as growth factors, glucan, ketaconazole, and antithrombin III are described. Finally, methods to support organ function before it fails (circulation, lungs, and kidneys) are described.
Antithrombin III↗
Selective management of embolized intracardiac missiles.
Intracardiac projectiles are occasionally found in stable patients who have sustained penetrating trauma. These missiles may arise from embolization from a peripheral injury site. We describe 3 patients with embolized intracardiac projectiles. The diagnosis was suggested by the presence of a foreign body within the cardiac silhouette on chest roentgenograms and was confirmed using fluoroscopy, echocardiography, or computed tomography. The management of embolized intracardiac missiles should be individualized to each patient. All of our patients had fixed intracavitary right-sided missiles and were successfully managed expectantly.
Adult↗
Management of selected rectal injuries by primary repair.
BACKGROUND: Diversion of the fecal stream with or without primary repair has been the mainstay of therapy for rectal injuries. Because primary repair has replaced colostomy as the treatment of choice for most colon injuries, we reviewed our experience with primary repair of rectal injuries in order to determine if primary repair without diversion is a feasible option in selected patients. MATERIALS AND METHODS: All traumatic rectal injuries over the past 48 months were reviewed for mechanism of injury, diagnosis, treatment, and outcome. RESULTS: Thirty consecutive patients with extraperitoneal rectal injuries were identified. Six of the 30 patients underwent primary repair without diversion. Five were repaired transanally, and 1 was repaired at celiotomy. There was no morbidity related to the rectal repair in patients who underwent primary repair without diversion, and there were no deaths. CONCLUSIONS: Based on a small number of patients, these data suggest that primary repair of rectal injuries in selected patients may be feasible. Further prospective investigation is needed to determine which patients may be successfully treated in this fashion.
Adolescent↗
Outcome and utility of scoring systems in the management of the mangled extremity.
BACKGROUND: The role of scoring systems as predictors of amputation and functional outcome in severe blunt extremity trauma was examined. METHODS: All severe extremity injuries treated over a 10-year period were scored retrospectively using four scoring systems: Mangled Extremity Syndrome Index (MESI), Mangled Extremity Severity Score (MESS), Predictive Salvage Index (PSI), and Limb Salvage Index (LSI). RESULTS: Twenty-three upper (UE) and 51 lower extremity (LE) injuries were evaluated. Sensitivity and specificity, respectively, were MESI 100% and 50%, MESS 79% and 83%, PSI 96% and 50%, and LSI 83% and 83%. For each system, there were no differences between patients with good and poor functional outcomes. CONCLUSION: All of the scoring systems were able to identify the majority of patients who required amputation. However, prediction in individual patients was problematic. None of the scoring systems were able to predict functional outcome.
Adult↗