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Biomedical subjects

A C Windsor

Publications and source records attributed to A C Windsor.

At least 19 recordsLinked to original sources
PubMed2006

Inflammatory bowel disease: the view of the surgeon.

Despite advances in medical therapy, surgery is required in approximately 30-40% of patients with ulcerative colitis (UC) and 70-80% of patients with Crohn's disease (CD) at some point during their lifetime. For patients with UC, surgery may be curative, whereas recurrence of CD following surgery is common due to the potentially pan-enteric distribution of the disease. As a result, the indications and surgical management of the disease may be quite different. For UC, the surgeon is involved in the identification of new cases, management of severe disease, recognition of dysplasia and restorative proctocolectomy. Most of the advances in surgery for UC have been in novel techniques relating to the ileal pouch-anal anastomosis, which can now be performed safely for UC with a 10% pouch failure rate long term. For CD, the surgeon is involved in the management of small bowel and ileo-colonic disease, Crohn's colitis and perianal disease. Advances in the surgical management of CD include strictureplasty for extensive small bowel disease, laparoscopic ileo-caecal resection and a combined medical and surgical approach to perianal disease. For both CD and UC close liaison between the gastroenterologist and colorectal surgeon is essential.

Anastomosis, Surgical↗
PubMed2005

The potential interactions between polyunsaturated fatty acids and colonic inflammatory processes.

n-3 Polyunsaturated fatty acids (PUFAs) are recognized as having an anti-inflammatory effect, which is initiated and propagated via a number of mechanisms involving the cells of the immune system. These include: eicosanoid profiles, membrane fluidity and lipid rafts, signal transduction, gene expression and antigen presentation. The wide-range of mechanisms of action of n-3 PUFAs offer a number of potential therapeutic tools with which to treat inflammatory diseases. In this review we discuss the molecular, animal model and clinical evidence for manipulation of the immune profile by n-3 PUFAs with respect to inflammatory bowel disease. In addition to providing a potential therapy for inflammatory bowel disease there is also recent evidence that abnormalities in fatty acid profiles, both in the plasma phospholipid membrane and in perinodal adipose tissue, may be a key component in the multi-factorial aetiology of inflammatory bowel disease. Such abnormalities are likely to be the result of a genetic susceptibility to the changing ratios of n-3 : n-6 fatty acids in the western diet. Evidence that the fatty acid components of perinodal adipose are fuelling the pro- or anti-inflammatory bias of the immune response is also reviewed.

Dietary Fats, Unsaturated↗
PubMed2000

Prognostic value of magnetic resonance imaging in the management of fistula-in-ano.

PURPOSE: Magnetic resonance imaging of fistula-in-ano has been shown to predict surgical anatomy accurately and identify complex features. In addition, fistula complexity has been correlated with poor outcome after surgical intervention. We investigated whether preoperative magnetic resonance imaging could predict clinical outcome after surgery for fistulous disease better than clinical examination under anesthetic. METHODS: Seventy patients with clinically suspected fistula-in-ano underwent preoperative dynamic contrast-enhanced magnetic resonance imaging before surgical exploration. Outcome was assessed at a minimum of one year after surgical exploration and correlated in a blinded fashion with the surgical and magnetic resonance grading of the severity of the fistulous disease. RESULTS: Of 70 patients, 12 were not operated on and 6 were lost to follow-up, making 52 patients eligible for analysis. Assessment by dynamic contrast-enhanced magnetic resonance imaging more accurately predicted outcome than the findings at initial surgical exploration. Dynamic contrast-enhanced magnetic resonance imaging had a sensitivity of 81 percent, specificity of 73 percent, and positive predictive value of 75 percent; surgery had a sensitivity of 77 percent, specificity of 46 percent, and positive predictive value of 59 percent. Surgical assessment of apparent disease severity bore no relation to final outcome. Dynamic contrast-enhanced magnetic resonance imaging could accurately predict whether patients were likely to have a satisfactory or unsatisfactory outcome after surgery. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging better predicts clinical outcome of patients with fistula-in-ano than initial surgical exploration.

Adult↗
PubMed2000

Localization of cyclooxygenase-2 in human sporadic colorectal adenomas.

A putative target for the anti-colorectal cancer action of nonsteroidal anti-inflammatory drugs is the inducible isoform of cyclooxygenase (COX), COX-2. COX-2 is expressed within intestinal adenomas in murine polyposis models, but expression has been poorly characterized in human colorectal neoplasms. Therefore, we investigated the localization of the COX-2 protein in human sporadic colorectal adenomas. Immunohistochemistry for COX-2 and CD68 (a tissue macrophage marker) was performed on formalin-fixed, paraffin-embedded (n = 52) and frozen, acetone-fixed (n = 6) sections of human sporadic colorectal adenomas. Forty of 52 (77%) formalin-fixed adenomas expressed immunoreactive COX-2. COX-2 was localized to superficial interstitial macrophages in 39 cases (75%) and to deep interstitial macrophages in 9 cases (17%). COX-2 staining of dysplastic epithelial cells was observed in 15 cases (29%). A logistic regression analysis identified the adenoma site (P = 0.012) and histological type (P = 0.001) as independent predictors of superficial macrophage COX-2 expression. There was no relationship between the number of macrophages within an adenoma and macrophage COX-2 expression. These results indicate that COX-2 is expressed predominantly by interstitial macrophages within human sporadic colorectal adenomas. If COX-2 does indeed play a role in the early stages of colorectal carcinogenesis in man, these data suggest COX-2-mediated paracrine signaling between the macrophages and epithelial cells within adenomas.

Adenoma↗
PubMed2000

Lack of correlation between failure of gut barrier function and septic complications after major upper gastrointestinal surgery.

OBJECTIVE: To determine the influence of abnormal gut barrier function on the risk of septic complications in patients undergoing major resectional surgery for upper gastrointestinal cancer. SUMMARY BACKGROUND DATA: A failure of the gut mucosal barrier to exclude bacteria and endotoxin from the portal and systemic circulation is incriminated in the development of sepsis and multiple organ failure. Although the experimental data is compelling, corroborative evidence from studies in humans is sparse. This study attempted to correlate both preoperative gut barrier dysfunction and the pattern of change after surgery with septic outcome. METHODS: Sixty-eight patients undergoing curative resectional surgery for upper gastrointestinal cancer were monitored for 30-day septic morbidity (intraabdominal abscesses/empyema and pneumonia). Intestinal permeability, serum IgM and IgG anti-endotoxin antibodies (EndoCAb), and serum C-reactive protein were measured before surgery and on postoperative days 1 and 7. RESULTS: Increased intestinal permeability before surgery did not predict septic outcome. Major surgery was associated with increased intestinal permeability and evidence of endotoxin exposure. Comparing sepsis and nonsepsis groups, however, there was no significant difference in intestinal permeability, endotoxin exposure, and the acute phase response after surgery. CONCLUSIONS: This study demonstrates that gut barrier dysfunction occurs after surgery, but the magnitude of change does not differentiate patients in whom sepsis develops and those in whom it does not. Preoperative increased intestinal permeability had no predictive value for sepsis. This study failed to support the thesis that gut barrier dysfunction is directly linked to sepsis.

Acute-Phase Reaction↗
PubMed1999

Monocyte human leukocyte antigen-DR expression correlates with intrapulmonary shunting after major trauma.

BACKGROUND: Severe injury is often complicated by the development of sepsis and the adult respiratory distress syndrome. Since the outcome from severe injury also correlates with changes in monocyte human leukocyte antigen (HLA)-DR expression in such patients, the present study aimed to determine whether or not there was a relationship between monocyte HLA-DR expression and indicators of early pulmonary dysfunction. METHODS: Monocyte HLA-DR expression and serum interleukin (IL)-6 were measured on admission and then again on days 1, 3, 5, and 7 after major injury in 29 patients admitted for the management of trauma with an injury severity score of 9 or more. Noninvasive intrapulmonary shunt measurement was also performed in all these patients within 6 hours of emergency surgery in all patients. RESULTS: Monocyte HLA-DR followed the characteristic suppression followed by recovery in those who followed an uncomplicated course but progressively declined in those who suffered septic complications. The degree of intrapulmonary shunting observed 6 hours after injury in the patients who developed sepsis was significantly higher than that in the uncomplicated group. Peak monocyte HLA-DR expression during the recovery phase correlated inversely with the degree of intrapulmonary shunting. CONCLUSIONS: The degree of intrapulmonary shunting observed following severe trauma correlates with the failure of circulating monocytes to re-express HLA-DR antigen, and this may provide some insights into the early events that result in the adult respiratory distress syndrome after major injury.

Adult↗
PubMed1998

Stimulation of inflammatory markers after blunt trauma.

BACKGROUND: Inflammatory mediators are released after trauma and may be related to the pathogenesis of sepsis. A prospective combined study of the pattern of release of an inflammatory mediator, interleukin (IL) 6, leucocyte activation (polymorphonuclear leucocyte (PMN) CD11b receptor expression and plasma elastase-alpha1 proteinase inhibitor complex (E-alpha1PI)) and soluble endothelial adhesion molecule expression (soluble E-selectin (sE-selectin) and soluble intracellular adhesion molecule 1 (sICAM-1)) was performed in patients suffering blunt trauma without adult respiratory distress syndrome (ARDS) or multiple organ failure syndrome (MOFS). METHODS: Thirty-one patients with a mean Injury Severity Score (ISS) of 14 (range 9-57) were studied. Venous blood samples were collected within 6 h of injury and then at 1, 3, 5 and 7 days. Leucocyte CD11b expression was quantified by flow cytometry. Serum IL-6, plasma E-alpha1PI, sE-selectin and sICAM-1 were measured by enzyme-linked immunosorbent assay. RESULTS: Serum IL-6, CD11b expression and E-alpha1PI levels were significantly raised above control values (P < 0.0001) on admission, slowly returning towards control values over the study period (median IL-6, 140 pg/ml versus undetectable; CD11b, 14.8 versus 6.4 mean channel fluorescence units; E-alpha1 PI, 208 versus 52 microg/l). The sICAM-1 level rose to a median of 539 ng/ml at 5 days (control 243 ng/ml). The median sE-selectin level also progressively increased to a maximum level of 80 ng/ml at 5 days (control 49 ng/ml). Eleven patients developed postoperative sepsis. Significant differences in CD11b expression were seen at days 3, 5 and 7 and in E-alpha1 PI at 6 h, 24 h and 3 days in patients who subsequently developed sepsis (P < 0.05). Severe injury (ISS 16 or greater) was associated with significantly greater responses in these measurements. CONCLUSION: These data show that markers of inflammation are specifically stimulated by trauma even when ARDS and MOFS do not occur. The CD11b receptor on PMNs may be useful in screening patients destined to develop post-traumatic sepsis.

Adult↗
PubMed1998

Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis.

BACKGROUND: In patients with major trauma and burns, total enteral nutrition (TEN) significantly decreases the acute phase response and incidence of septic complications when compared with total parenteral nutrition (TPN). Poor outcome in acute pancreatitis is associated with a high incidence of systemic inflammatory response syndrome (SIRS) and sepsis. AIMS: To determine whether TEN can attenuate the acute phase response and improve clinical disease severity in patients with acute pancreatitis. METHODS: Glasgow score, Apache II, computed tomography (CT) scan score, C reactive protein (CRP), serum IgM antiendotoxin antibodies (EndoCAb), and total antioxidant capacity (TAC) were determined on admission in 34 patients with acute pancreatitis. Patients were stratified according to disease severity and randomised to receive either TPN or TEN for seven days and then re-evaluated. RESULTS: SIRS, sepsis, organ failure, and ITU stay, were globally improved in the enterally fed patients. The acute phase response and disease severity scores were significantly improved following enteral nutrition (CRP: 156 (117-222) to 84 (50-141), p < 0.005; APACHE II scores 8 (6-10) to 6 (4-8), p < 0.0001) without change in the CT scan scores. In parenterally fed patients these parameters did not change but there was an increase in EndoCAb antibody levels and a fall in TAC. Enterally fed patients showed no change in the level of EndoCAb antibodies and an increase in TAC. CONCLUSION: TEN moderates the acute phase response, and improves disease severity and clinical outcome despite unchanged pancreatic injury on CT scan. Reduced systemic exposure to endotoxin and reduced oxidant stress also occurred in the TEN group. Enteral feeding modulates the inflammatory and sepsis response in acute pancreatitis and is clinically beneficial.

APACHE↗
PubMed1998

Outcome after surgery for perianal fistula: predictive value of MR imaging.

OBJECTIVE: The purpose of this study was to determine if MR findings are predictive of long-term outcome in a cohort of patients whose initial surgery was performed without access to the findings of MR imaging. SUBJECTS AND METHODS: Forty patients with surgically proven perianal fistulas underwent preoperative dynamic contrast-enhanced MR imaging. The MR and surgical findings were independently recorded on an identical anatomic form. Three patients were subsequently lost to follow-up. The outcome for the remaining 37 patients was determined from surgical review, case notes, and questionnaires. Minimum follow-up period was 14 months (range, 14-39 months). Outcome was determined by one observer who was unaware of the initial MR grading and had not been present during surgery. Outcome was considered unsatisfactory if further surgery was required. RESULTS: MR imaging was better than surgical exploration in predicting outcome (for MR imaging: positive predictive value, 73%; negative predictive value, 87%; sensitivity, 89%; and specificity, 68%; for surgical exploration: positive predictive value, 57%; negative predictive value, 64%; sensitivity, 73%; and specificity, 47%). MR classification of fistulas was significantly associated with outcome (p = .0004), and surgical classification was not significantly associated with outcome (p = .22, chi-square test). Also MR grades differed significantly for patients with satisfactory and unsatisfactory outcomes (p < .001, Mann-Whitney U test). CONCLUSION: MR imaging is valuable in the management of patients with perianal fistulas. MR imaging accurately reveals surgical anatomy and can be used to make better predictions regarding patient outcome than surgical findings.

Adult↗
PubMed1997

Interleukin-10. A role in the development of postoperative immunosuppression.

BACKGROUND: The cause of diminished monocyte major histocompatibility complex class II antigen expression after surgery or trauma is unclear. Interleukin-10 (IL-10) regulates inflammatory cytokine production and major histocompatibility complex class II (HLA-DR) expression in vitro. OBJECTIVES: To quantify in vivo IL-10 messenger RNA (mRNA) and protein and monocyte HLA-DR expression after major surgery and to investigate the effects of IL-10 neutralizing blockade on monocyte HLA-DR expression in vitro. DESIGN: Inception cohort study of 48 surgical patients from preoperative status to postoperative day 7 and 9 healthy volunteers (controls). SETTING: Large teaching hospital, Northern England. PATIENTS: Monocyte HLA-DR and cytokine mRNA expression was determined in 32 of 48 consecutive patients undergoing elective major resectional surgery. Mononuclear cells for in vitro studies and serum samples for IL-10 measurement were obtained from the remaining 16 patients. MAIN OUTCOME MEASURES: Monocyte HLA-DR expression determined by flow cytometry, IL-10, and tumor necrosis factor mRNA in peripheral blood mononuclear cells assayed by multiplex reverse transcriptase polymerase chain reaction, and serum IL-10 determined by enzyme-linked immunosorbent assay. RESULTS: Monocyte HLA-DR expression (in mean channel fluorescence units [MCF]) was significantly reduced 24 hours after surgery (MCF [+/- SEM], 32.6 +/- 2.3 vs 16.3 +/- 1.2; P < .001) and remained low during the first postoperative week. A relative increase in IL-10 to G3PDH mRNA ratio (mean [+/- SEM], 0.95 +/- 0.08 vs 0.59 +/- 0.06; P < .01) and serum IL-10 (mean [+/- SEM], 18.1 +/- 4.1 vs 5.4 +/- 0.8 pg/mL; P < .01) was noted on the first postoperative day. A significant correlation existed between HLA-DR antigen expression and the presence of IL-10 mRNA transcript on the first postoperative day (P < .01). Lipopolysaccharide-induced up-regulation of monocyte HLA-DR expression was significantly impaired on the first postoperative day (mean [+/- SEM], 151% +/- 24.4% vs 60% +/- 10.1%; P < .01), but this was partially reversed by IL-10 neutralizing antibody (mean [+/- SEM], 60% +/- 10.1% vs 115% +/- 11.6%; P < .01). CONCLUSIONS: Interleukin-10 gene expression correlates with the fall in monocyte HLA-DR antigen expression in patients undergoing major abdominal surgery and may account for the immunosuppression associated with surgical injury.

Gene Expression↗
PubMed1997

Enhanced polymorphonuclear leucocyte adhesion after surgical injury.

OBJECTIVE: To evaluate the relationship between the expression of the neutrophil adhesion receptor CD11b, functional neutrophil adhesion, and clinical outcomes in patients undergoing major surgical resections. DESIGN: Laboratory study. SETTING: University hospital, United Kingdom. SUBJECTS: 25 patients undergoing surgical resections for malignant disease. INTERVENTIONS: Blood obtained preoperatively and on postoperative days 1, 3, and 6. Neutrophils were assayed for CD11b expression in whole blood and following isolation using flow cytometry, and adhesion was measured using a chromogenic, gelatin-dependent adhesion assay, with and without stimulation by FMLP. Postoperative outcomes were classified as uncomplicated (n = 20) or sepsis according to ACCP/SCCM definitions (n = 5). RESULTS: Whole blood neutrophil CD11b expression was significantly increased on the first postoperative day and in all patients was significantly higher in the sepsis group (p < 0.001, ANOVA). There was a significant increase in CD11b expression above preoperative concentrations after separation and stimulation with FMLP only in the sepsis group, 3 and 6 days postoperatively (p < 0.01, paired t-test). Functional neutrophil adhesion was significantly higher in the sepsis compared with the uncomplicated group at all time points postoperatively (p < 0.001, two way ANOVA). CONCLUSION: Major operations are accompanied by upregulation of baseline CD11b expression mirrored by changes in neutrophil adhesion. Those patients who develop sepsis have greater degrees of CD11b expression and adhesion. These data present a potential pathophysiological role for neutrophils throughout the postoperative period in the development of sepsis and its sequelae after major operations.

Adult↗
PubMed1996

Pulmonary artery endothelial cell function in swine pseudomonas sepsis.

A substantial increase in pulmonary vascular resistance is associated with sepsis and its sequelae (sepsis syndrome and septic shock). It is postulated that increased resistance may result from sepsis-induced endothelial cell injury or altered vasoreactivity secondary to pulmonary hypertension. We, therefore, tested the hypothesis that sepsis causes endothelial cell injury and that increased pulmonary pressure alters vascular reactivity. Young swine (15-25 kg) were anesthetized and ventilated. Septic animals received a 1-hr infusion of live Pseudomonas aeruginosa (n = 11), and the control cohort received 0.9% NaCl (n = 7). All animals were studied for 300 min following the infusion. Postmortem branches of peripheral pulmonary arteries were prepared and tested in a vessel myograph. Ring segments were set to 90% of the circumference the vessels would have at pressures of 20, 30, 40, or 50 mmHg (L90), corresponding to varying pulmonary pressures observed in sepsis. A high dose of potassium was used to obtain maximum possible contraction. Prostaglandin was used to precontract the vessels before testing endothelial cell responses to acetylcholine or bradykinin. Sodium nitroprusside was added at the end of each experiment to obtain maximum possible smooth muscle relaxation. No differences in contraction or relaxation were observed when vessels were set to different pressures (i.e., 20 vs 50 mmHg). Maximum possible contraction to KCl was significantly decreased after 300 min of sepsis compared to control. No differences between groups were found in contractility to prostaglandin. Bradykinin-induced EDRF/NO production, mediated by BK2 receptors, was not altered in Pseudomonas sepsis (97-98% of total relaxation control and 91-95% septic cohort). Response to acetylcholine was significantly decreased after sepsis (89-95% of total relaxation control and 51-61% of septic cohort relaxation). Decreased response to acetylcholine could not be attributed to decreased smooth muscle sensitivity to nitric oxide because the response to bradykinin plus sodium nitroprusside was not altered following sepsis. Vessel reactivity was not altered by increasing pressure settings reflective of changing pulmonary pressure in vivo. These results strongly suggest a sepsis-induced alteration in pulmonary artery endothelial cell receptor sensitivity to acetylcholine, independent of changing pulmonary arterial pressures. This is the first time this decrease has been shown in pseudomonas sepsis.

Animals↗
PubMed1995

Sepsis-induced acute lung injury is attenuated by selectin blockade following the onset of sepsis.

OBJECTIVE: To determine the effect of infusion with a dual-binding antibody to E- and L-selectin, EL-246, in a postonset model of sepsis. DESIGN: Nonrandomized controlled study. STUDY SUBJECTS: Young Yorkshire swine. INTERVENTIONS: Three groups were studied. Controls (n = 8) received saline solution only. Untreated animals with sepsis (n = 8) received a 1-hour intravenous infusion of live Pseudomonas aeruginosa. Animals treated with EL-246 (n = 6) received the same bacterial infusion and a 2-mg/kg bolus of EL-246 at 30 minutes. OUTCOME MEASURES: Systemic and pulmonary hemodynamics, arterial blood gas determination, bronchoalveolar lavage protein and neutrophil content, neutrophil integrin and selectin expression, neutrophil oxidant burst, and organ myeloperoxidase content. RESULTS: Treatment with EL-246 significantly reduced lung injury, as indicated by improved bronchoalveolar lavage protein and neutrophil content, resulting in a significant improvement in arterial oxygenation. This reduction in lung injury was produced by a reduction in lung myeloperoxidase content. Treatment with EL-246 failed to prevent the development of pulmonary hypertension and systemic hypotension. Neutrophils from animals with sepsis exhibited significant activation and upregulation of CD18, shedding of L-selectin, and production of increased levels of oxidants compared with controls. CONCLUSION: Treatment of animals with EL-246 soon the onset of sepsis produced significant protection against acute lung injury but failed to attenuate hemodynamic derangements associated with sepsis.

Animals↗
PubMed1995

Manipulation of local and systemic host defence in the prevention of perioperative sepsis.

This review addresses some of the immunological issues surrounding the complex problem of perioperative sepsis. It identifies an immunological paradox between the relative immunosuppression of the immediate postoperative period and the relative immune activation of established sepsis, in addition to discussing current knowledge of the mechanisms surrounding these phenomena. Much remains unknown about perioperative immunoregulation; there are a number of potential mechanisms, however, whereby local and systemic immune defences can be modified or enhanced. Provided patients at risk can be identified, such manipulations may find application in preventing infection and sepsis after surgery.

Humans↗
PubMed1995

Tumor necrosis factor-alpha and interleukin-6 selectively regulate neutrophil function in vitro.

The neutrophil is an important effector cell of the host response to sepsis. Tumor necrosis factor-alpha (TNF-alpha), a cytokine mediator of the septic response, is rapidly released following endotoxemia or gram-negative bacteremia. Interleukin-6 (IL-6) is another cytokine mediator of the host response to sepsis whose role is less well understood than that of TNF-alpha. It is known to be elevated in gram-negative sepsis, where peak levels have been correlated with mortality. This study examined the effect of IL-6 alone and in combination with TNF-alpha on three neutrophil functions--CD18 adhesion receptor expression, phagocytosis, and superoxide anion generation. Neutrophils from human volunteers were incubated with amounts of IL-6 ranging from 10 to 1000 ng/ml. At a concentration of 1000 ng/ml, IL-6 increased neutrophil phagocytosis of opsonized bacteria (826 +/- 255 x 10(3) MESF vs 552 +/- 103 MESF, P < 0.05) and also increased neutrophil superoxide anion generation (18.41 +/- 1.86 vs 12.6 nmol O2-/10(6) PMN/10 min, P < 0.05). Lesser amounts of IL-6 had no effect on phagocytosis or superoxide generation. IL-6 did not increase neutrophil CD18 adhesion receptor expression. Combining IL-6 with TNF-alpha at doses of 100 ng/ml and 100 U/ml, respectively, neutrophil phagocytosis (221 +/- 455 MESF vs 552 +/- 103 MESF) and superoxide generation (23.18 +/- 1.86 vs 12.6 nmol O2-/10(6) PMN/10 min) were significantly (P < 0.05) increased above control by an amount similar to that seen with 1000 U/ml TNF-alpha alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗