Recombinant bactericidal/permeability-increasing protein attenuates the systemic inflammatory response syndrome in lower limb ischemia-reperfusion injury.

OBJECTIVES: Hind limb ischemia-reperfusion (I/R) injury increases gut permeability, and resultant endotoxemia is associated with an amplified systemic inflammatory response syndrome leading to multiple organ dysfunction syndrome. We studied the potential role of recombinant bactericidal/permeability-increasing protein (rBPI(21) ), a novel antiendotoxin therapy, in modulating endotoxin-enhanced systemic inflammatory response syndrome in hind limb I/R injury. METHODS: In this prospective, randomized, controlled, experimental animal study, 48 male Wistar rats, weighing 300 to 350 g, were randomized to a control group (sham) and five groups undergoing 3 hours bilateral hind limb ischemia with 2 hours reperfusion (I/R) (n = 8 per group). The control and untreated I/R groups received thaumatin, a control-protein preparation, at 2 mg/kg. Treatment groups were administered rBPI(21) intravenously at 1, 2, or 4 mg/kg body weight at the beginning of reperfusion; an additional group was administered rBPI(21) intravenously at 2 mg/kg after 1 hour of reperfusion. Plasma interleukin-6 concentration was estimated by bioassay as a measure of systemic inflammation. Plasma endotoxin concentration was determined by use of an amebocyte lysate chromogenic assay. Crossreactive immunoglobulin G and M antibodies to the highly conserved inner core region of endotoxin were measured by use of an enzyme-linked immunosorbent assay. The lung tissue wet-to-dry weight ratio and myeloperoxidase concentration were used as markers of edema and neutrophil sequestration, respectively. RESULTS: I/R provoked highly significant elevation in plasma interleukin-6 concentrations (1351.20 pg/mL [860.16 - 1886.40 pg/mL]) compared with controls (125.32 pg/mL [87.76-157.52 pg/mL; P <.0001]), but treatment with rBPI(21) 2 mg/kg at onset of reperfusion (715.89 pg/mL [573.36-847.76 pg/mL]) significantly decreased interleukin-6 response compared with the nontreatment group ( P <.016). I/R increased plasma endotoxin concentrations significantly (21.52 pg/mL [6.20-48.23 pg/mL]), compared with control animals (0.90 pg/mL [0.00-2.30 pg/mL; P <.0001]), and treatment with rBPI(21) 4 mg/kg at reperfusion significantly decreased endotoxemia (1.30 pg/mL [1.20-2.20 pg/mL]), compared with the untreated group ( P <.001). The lung tissue myeloperoxidase level was significantly increased in the untreated I/R group (208.18% [128.79%-221.81%]), compared with in controls (62.00% [40.45%-80.92%; P <.0001]), and attenuated in those treated with rBPI(21) 2 mg/kg (129.54% [90.49%-145.78%; P <.05]). Data represent median and interquartile range, comparisons made with the nonparametric Mann-Whitney U test. CONCLUSIONS: These findings show that hind limb ischemia-reperfusion injury is associated with endotoxemia, elevations in plasma interleukin-6, and pulmonary leukosequestration. Treatment with rBPI(21) after ischemia reduces endotoxemia, the interleukin-6 response, and attenuates pulmonary leukosequestration in response to hind limb reperfusion injury.

Hartmann procedure revisited.

OBJECTIVE: To assess the complications and results of Hartmann's procedure and secondary restoration of continuity for left-sided colonic disease. DESIGN: Retrospective study. SETTING: University hospitals, Northern Ireland. SUBJECTS: 72 Patients who required a Hartmann's procedure over a 13 year period (1985-1998). INTERVENTION: Of these 45 (63%) were done as emergencies and 27 (38%) as elective procedures. The indications for an emergency procedure were obstruction and perforation. MAIN OUTCOME MEASURES: Mortality, morbidity, reversal of stoma rate. RESULTS: The overall postoperative mortality was 7/72 (10%), with no significant difference between the emergency (4/45, 9%) and the elective (3/27, 11%) groups. Postoperative complications occurred in 31 patients (43%), and 8 developed wound infections (11%). Of the 43 surviving patients who where deemed suitable for re-establishment of continuity, 30 (70%) have had it done. There were no postoperative deaths or anastomotic dehiscences after the restoration of continuity. CONCLUSION: Hartmann's procedure remains a safe and suitable option in patients with left sided colonic emergencies.

Reperfusion injury is greater with delayed restoration of venous outflow in concurrent arterial and venous limb injury.

BACKGROUND: Complex limb trauma often involves combined arterial and venous injury, and the resultant ischaemia-reperfusion injury (IRI) causes both local and remote organ injury. This study assessed the influence of the timing of restoration of venous drainage on IRI. METHODS: Male New Zealand white rabbits (n = 36) were randomized into six groups: sham operation (group 1) and unilateral hind limb arterial and venous occlusion for 1 h followed by no reflow for 2 h (group 2), arterial and venous reflow for 2 h (group 3), arterial reflow alone for 2 h (group 4), arterial reflow alone for 1 h followed by arterial and venous (delayed) reflow for a further 1 h (group 5), and pretreatment with an enteral combination antioxidant before occlusion of both artery and vein and delayed venous reflow (group 6). Plasma hydroperoxide (HPO) and glutathione peroxidase concentration, hind limb skeletal muscle and lung tissue wet : dry weight ratios and myeloperoxidase (MPO) concentration were measured. RESULTS: The plasma HPO level in the femoral vein effluent was significantly greater after delayed venous reflow (mean(s.e.m.) 2. 02(0.54) micromol/l) than in control animals (0.98(0.10) micromol/l) (P < 0.05). There was also a significantly greater tissue wet : dry weight ratio after delayed venous reflow than in controls, in skeletal muscle (mean(s.e.m.) 6.89(0.14) versus 5.34(0.54); P < 0. 05) and lung (9.20(1.14) versus 7.23(0.38); P < 0.05) tissue. Lung tissue MPO activity was significantly greater after delayed venous reflow compared with controls (3.20(0.28) versus 1.86(0.14) units/g; P < 0.005), and also in comparison to simultaneous arterial and venous reflow (2.40(0.24) units/g; P < 0.05). In the antioxidant pretreatment group there was no significant increase in plasma HPO concentration, tissue MPO level or tissue wet : dry weight ratio compared with the control group. CONCLUSION: In combined major arterial and venous injury of the limb, delayed restoration of venous drainage leads to significantly greater local skeletal muscle injury and remote neutrophil-mediated lung injury. These results support the clinical rationale for early restoration not only of arterial inflow but also venous drainage by means of intraluminal shunts.

Lower limb ischaemia-reperfusion injury causes endotoxaemia and endogenous antiendotoxin antibody consumption but not bacterial translocation.

BACKGROUND: It has been suggested that reperfusion of the acutely ischaemic lower limb alters gut permeability. The effect of lower limb ischaemia-reperfusion on systemic endotoxin and antiendotoxin antibody concentrations and the incidence of bacterial translocation was investigated. METHODS: Systemic endotoxin and antiendotoxin antibody concentrations were measured in five groups of male Wistar rats: control, after 3 h of bilateral hind limb ischaemia alone, and after 3 h of bilateral hind limb ischaemia followed by 1, 2 or 3 h of reperfusion. A second experiment examined translocation of indigenous bacteria following 2 h of reperfusion in a similar model. RESULTS: Ischaemia followed by reperfusion for 1, 2 or 3 h caused a significant increase in plasma endotoxin concentration to mean(s.e.m.) 10.0(3.0), 44.8(19.2) and 20.2(6.2) pg/ml compared with that in control animals (2.58(0.91) pg/ml) or animals in the ischaemia alone group (1.2(0.9) pg/ml) (P < 0.05). This was associated with a significant reduction in endogenous antiendotoxin antibody (immunoglobulin (Ig) G and IgM) concentration. No significant bacterial translocation was detected in any of the groups studied. CONCLUSION: These results demonstrate that a remote and isolated ischaemia-reperfusion injury to the lower limb, in the absence of infection or bacterial translocation, causes endotoxaemia. Further studies are needed to evaluate the role of endogenous antiendotoxin antibodies in this situation.

Lower limb ischaemia-reperfusion injury alters gastrointestinal structure and function.

BACKGROUND: It has been suggested that bowel permeability is altered following abdominal aortic aneurysm surgery. The effect of ischaemia-reperfusion injury to the lower limb on the morphological structure, neutrophil infiltration and permeability of the bowel was investigated. METHODS: Histological assessment of the bowel was undertaken in five groups of Wistar rats: control, 3 h of bilateral hind limb ischaemia and 3 h of bilateral hind limb ischaemia followed by 1, 2 or 3 h of reperfusion. Using an everted gut sac model and 14C-labelled polyethylene glycol, the effect of ischaemia-reperfusion on small bowel permeability was studied. RESULTS: The small bowel showed a significant decrease in mucosal thickness, villus height and crypt depth in animals subjected to ischaemia followed by 2-hr reperfusion (mean(s.e.m.) 420(15), 217(9) and 163(6) microns respectively) compared with controls (481(11), 245(6) and 195(6) microns) (P < 0.05). Neutrophil count within the lamina propria was similar in the different groups. A significant increase in mean(s.e.m.) 14C-labelled polyethylene glycol translocation was detected in animals subjected to ischaemia-reperfusion compared with controls (760(40) versus 560(27) c.p.m. per ml per h) (P < 0.05). CONCLUSION: These data suggest that reperfusion of acutely ischaemic extremities produces structural and functional changes in the small intestine, although these changes are not associated with increased neutrophil infiltration within the bowel wall.

Pathogenesis, clinical features and management of hidradenitis suppurativa.

Hidradenitis suppurativa is a chronic skin condition involving the apocrine glandular zones. Affected patients may present with acute abscesses, but the condition often progresses to a chronic state with persistent pain, sepsis, sinus tract and fistula formation, purulent discharge and dermal scarring. Treatment of patients with severe disease can be difficult and may require complex surgical intervention. This review encompasses the pathogenesis, clinical manifestations and management options for patients with hidradenitis suppurativa.

Malignant eccrine spiradenoma with carcinomatous and sarcomatous elements.

A case of a 60 year old man with malignant eccrine spiradenoma involving the perineum is described. Areas of typical eccrine spiradenoma were admixed with carcinomatous and sarcomatous elements. Immunohistochemical and ultrastructural analysis revealed no evidence of epithelial differentiation in the sarcomatous areas. The tumour qualified for the designation carcinosarcoma arising in eccrine spiradenoma. The clinical course was aggressive with rapid development of nodal and pulmonary metastases.

Caecal adenocarcinoma with multiple synchronous small intestinal adenocarcinoma.

We describe a patient who presented with iron deficiency anaemia in whom both upper and lower gastrointestinal investigation were initially negative. Management included successive blood transfusions. Repeat investigation six months later revealed caecal adenocarcinoma. At laparotomy, the patient was also found to have two separate primary synchronous adenocarcinomas of the proximal small bowel. Right hemicolectomy and excision of the small bowel lesions were carried out. The patient eventually succumbed to the disease six weeks after discharge from hospital.

Familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominant condition resulting in the development of more than 100 adenomatous polyps in the large bowel. In addition, a number of extracolonic manifestations of the condition may occur. Recently, increasing knowledge relating to the extracolonic abnormalities, and localization and sequencing of the gene for FAP, have had important implications for screening and long-term follow-up of those affected. In this review the natural history of the disease and the extracolonic manifestations associated with it are considered. Surgical management and advances in understanding at a molecular level are discussed, as well as the problems relating to screening for FAP and the implications of the new knowledge.

Jass' classification revisited.

BACKGROUND: In 1986, Jass and colleagues claimed to have improved on Dukes' classification of prognosis for carcinoma of the colon and rectum. To have clinical relevance, such results should be reproducible and confirmed by other institutions. STUDY DESIGN: Retrospective clinicopathologic study of 312 carcinomas of the colon and rectum to determine whether or not Jass' classification is superior to that of Dukes' as assessed by their relative reproducibility and prognostic significance. RESULTS: Dukes' classification had excellent intraobserver and interobserver reproducibility (kappa values of 0.86 and 0.93, respectively). In contrast, the reproducibility of variables assessed by Jass showed only slight to fair agreement (lymphocytic infiltration: intraobserver and interobserver kappa values of 0.08 and 0.05, respectively, growth pattern: intraobserver and interobserver kappa values of 0.37 and 0.41, respectively). Dukes' stage and patient age were the most important prognostic variables on multivariate regression analysis. Tumor differentiation, nuclear polarity, tubule configuration, and lymphocytic infiltration remained significantly related to survival in the presence of Dukes' stage and age. The model which best predicted prognosis was a combination of Dukes' stage, patient age and tumor differentiation. Further addition of the variables assessed by Jass to this model did not significantly improve the prediction of prognosis. CONCLUSIONS: Dukes' classification is of greater prognostic value and more reproducible than the components of Jass' classification. The continued use of Dukes' classification is, therefore, warranted for prognostic and therapeutic decisions in patients with carcinoma of the colon and rectum.

Colorectal carcinoma: importance of clinical and pathological factors in survival.

A series of clinicopathological variables was assessed on 312 patients undergoing surgical resection for primary colorectal cancer. Although the presence of venous invasion was related to mortality (P = 0.02), classifying invasion into involvement of thick-walled or thin-walled veins did not produce a variable of prognostic value. Intestinal obstruction (P = 0.04) and the macroscopic appearance of the tumour (P = 0.04) were related to mortality from colorectal cancer, but not from all causes of death. Duke's stage, increasing patient age and poorly differentiated tumours were the variables which were individually most significantly related to poor prognosis (P < 0.001 for each analysis). Cox's regression analysis identified these three variables as independent predictors of outcome in colorectal cancer. This study confirms that Duke's stage, patient age and tumour differentiation are still the most important clinicopathological variables in colorectal cancer.

The role of congenital hypertrophy of the retinal pigment epithelium in screening for familial adenomatous polyposis.

Retinal examination by indirect ophthalmoscopy was performed on seventy members from 20 kindreds demonstrating the clinical manifestations of familial adenomatous polyposis and forty controls. Thirty-four of 43 affected patients manifested CHRPE lesions compared with 2 of 27 at risk and 2 of 40 controls giving a sensitivity of 79% and specificity of 95% based on the control group. The difference between the affected and at risk groups was significant (Chi-squared = 34.098, 1 df, P = 0.001). The low sensitivity and variation in incidence of CHRPE in FAP patients and general population documented in the world literature prevent its use as a sole marker for the condition. With advances in knowledge of the disease at a molecular level it is now possible to alter risks for families by DNA analysis. There remain a number of patients in whom such techniques do not significantly alter risks. In these families by combining the results of DNA analysis, sigmoidoscopy and retinal examination it may be possible to alter risks by a significant degree. Retinal examination should be reserved for those families in whom risks cannot be altered sufficiently by DNA analysis alone.

DNA densitometry of colorectal cancer.

DNA analysis was assessed by densitometry for 281 cases of colorectal adenocarcinoma. Detection of aneuploidy in a single case rose from 65% if one, to 92.5% when three or more sections, were analysed. Although aneuploid tumours had significantly larger nuclear areas than near diploid tumours (p = 0.009), densitometric measurements showed no association with clinicopathological variables. DNA content determined by densitometry was compared with that from flow cytometry on 465 tissue sections from 241 cases. Aneuploidy assessed by flow cytometry was significantly associated with that determined by densitometry (p < 0.01 for all comparisons), ploidy state being similar in 381 sections (82%, kappa = 0.63, p < 0.001), and 187 cases (77.6%, kappa = 0.57, p < 0.001). Univariate survival analysis showed that DNA densitometric variables had no significant association with survival in (a) all cases, (b) cases without lymph node metastases, or (c) cases without distant metastases. Multivariate regression analysis of densitometric and clinicopathological variables identified Dukes's stage, patient age, and tumour differentiation as the combination of variables most closely related to survival. Densitometric measurement of DNA content could not significantly improve on the prognostic model containing these three variables. It is concluded that, although the assessment of DNA content by densitometry is comparable with that of flow cytometry, conventional histological variables remain the best predictors of prognosis in colorectal cancer.

The usefulness of tests in anorectal disease.

Specialized tests of anorectal function are designed to complement but not to replace good clinical examination and sound professional judgement. The different methods of recording pressure changes have advantages and disadvantages. Poor correlation exists when data recorded using miniature balloons are compared with data from microtransducers. Prolonged ambulatory monitoring of anal sphincter and rectal pressure reveal that spontaneous transient episodes of sphincter relaxation are demonstrable in normal subjects. In the investigation of patients with possible traction injury to the pudendal nerve, electromyography and pudendal nerve terminal motor latency data are more precise than manometry data. Good correlation between noninvasive surface electromyography using an intra-anal plug electrode and anal manometry can be attained. Mapping of sphincter defects using concentric needle technology is reasonably accurate but distinctly painful. Dynamic defecography readily demonstrates abnormalities of the rectal wall. The division between what is normal and what is clinically relevant is rather imprecise. Comparative studies of sonographic and electromyographic mapping of sphincter defects give good correlation. Recent application of fine hooked electrodes have demonstrated periodic episodes of smooth muscle and sphincter relaxation. The saline infusion test and balloon expulsion test help to accurately quantify the difficulty patients experience in retention or evacuation, respectively. Perineometry is a simple, rapid, noninvasive method of measuring the extent of perineal descent on straining. Although reproducible, it tends to underestimate the degree of descent when compared with the radiological method but it avoids the use of ionized radiation.

Prognostic factors in colorectal cancer.

The prognostic power of the extent of tumour invasion is indisputable; Dukes' classification has repeatedly been proven to be strongly correlated with patient survival. Modifications have led only to confusion, resulting in caution being required in the classification of patients with Dukes' A tumours. In the UK, the American tumour node metastasis and Australian clinicopathological systems are frequently considered too complex for routine clinical use. Meanwhile, Jass's classification may be complicated by observer variation between pathologists, and recent evidence suggests that it offers no advantage over that of Dukes. All the conventional staging systems also fail to take the skill of the surgeon into account when determining outcome. Attempts at quantifying tumour structure have not heralded the expected major advance. For instance, the expense and uncertain prognostic value of tumour DNA content assessed by flow cytometry are likely to restrict widespread use of this technique. It may soon be possible, however, to provide optimum treatment for patients based on individual tumour doubling times. Classification using knowledge of how a small number of cells in the tumour have the ability to invade locally, enter blood vessels and metastasize would also provide important prognostic information on which treatment could be based. Until then, the ease of use and high prognostic power of Dukes' classification ensure that, after 60 years, it is still the 'gold standard' against which all other prognostic classifications in colorectal cancer should be assessed.

The surgical management of familial adenomatous polyposis in Northern Ireland.

Sixty-eight patients from 18 families have been identified as having familial adenomatous polyposis during the past 30 years in Northern Ireland (population 1.5 million). Six of the 18 probands (33%) had developed colonic carcinoma when first seen at mean age 34 years. Ten of the 44 patients identified by surgical screening (21%) at a significantly lower mean age of 23 years had colonic carcinoma. Surgical management has generally been by subtotal colectomy with ileorectal anastomosis, or by panproctocolectomy and ileostomy.

Surgical training posts in Northern Ireland: assessment by surgeons in training.

Northern Ireland has one of the largest surgical training programmes in the United Kingdom. The surgical trainees' assessment of the quality of training provided has been collated prospectively since 1983, and provides a useful insight into the strengths and weaknesses of the programme, as well as the training value of individual posts. The overall quality of clinical training in surgery was considered to be well above average, but some registrars felt that supervision of operative surgery could be improved. Clinical research was considered to be of average quality in the teaching hospitals but below average in district general hospitals. In the current climate of restriction of the number of training posts in general surgery, the views of the trainees should not be neglected in assessing which posts are best suited for training.

Closure of persistent post-proctectomy perineal sinus using a rectus muscle flap.

A persistent perineal sinus following proctocolectomy or proctectomy is a not infrequent complication associated with considerable morbidity. Two cases are presented where the perineal sinus was closed using a rectus abdominis flap. This method of closure allows safe, complete excision of the sinus and insertion of a muscle flap which completely fills the defect, enabling complete, primary healing of the perineum.