6-trans-leukotriene B4 is a neutrophil chemotaxin in the guinea pig dermis.

The products of the 5- and 12-lipoxygenase (5-LO, 12-LO) pathways of arachidonic acid metabolism are implicated as proinflammatory mediators in a number of disease states. 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] is present in large quantities in human psoriatic lesional skin and can be further metabolized by 5-LO to 5(S), 12(R)-dihydroxy-(6E,8Z,10E,14Z)-eicosatetraenoic acid (6-trans-LTB4). Furthermore, leukotriene B4 (LTB4) and the sulfidopeptide leukotrienes (LTC4, LTD4) can be transformed to 6-trans-LTB4. When injected into the guinea pig dermis, 6-trans-LTB4 (1.0, 10.0, 20.0 micrograms/intradermal site) caused a significant (P less than 0.02) infiltration of polymorphonuclear leukocytes (PMN) at 4 hr as assessed by histology and the levels of the PMN marker enzyme myeloperoxidase. 6-trans-LTB4 is a more potent PMN chemoattractant than 12(R)-HETE in the guinea pig dermis but is far less potent than LTB4. Pharmacological interdiction of leukotriene production or receptor binding should take into account the proinflammatory activity of 6-trans-LTB4.     

The long duration, in vivo, inhibition of prostaglandin synthetase by 2-methyl-8-cis-12-trans-14-cis-eicosatrienoic acid

Competitive inhibition of prostaglandin synthetase by 8-cis-12-trans-14-cis-eicosatrienoic acid has been reported to occur in vitro. No in vivo effects were observed, possibly due to rapid metabolic degradation of this fatty acid by beta-oxidation. The present study involved the evaluation of this compound in vivo, and the preparation and evaluation in vivo of its alpha and beta methyl-substituted analogs which retain the carbon skeleton of the parent compound, and which might be expected to be resistant to beta-oxidation. Using a newly developed radioimmunoassay for the total urinary metabolites of prostaglandin E, data were obtained that indicates that both the parent compound and its 2-methyl analog are prostaglandin synthetase inhibitors in vivo. The 2-methyl analog exhibited an unusually long duration of activity as compared to both indomethacin and the parent compound. The lengthened duration of action of the 2-methyl analog may be explained both by its possible resistance to beta-oxidation, and to possible alteration in rates of either fatty acid transport, or incorporation/release from triglycerides (acylation/deacylation of triglycerides).     

The effect of leukotriene-B4 receptor antagonist,SC-41930, on acetic acid-induced colonic inflammation

SC-41930, 7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)-propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid, is a potentin vitro leukotriene-B₄ (LTB₄) receptor antagonist. LTB₄ levels are elevated in colonic tissue of inflammatory bowel disease (IBD) patients which may account for the high degree of neutrophil (PMN) infiltration. The guinea pig acetic acid-induced colonic inflammation model has characteristics of IBD including PMN infiltration, edema, ulceration and necrosis. The model was used to evaluate the effect of SC-41930. SC-41930 was given orally, 30 min before and after intrarectal administration of 3% acetic acid. The PMN marker enzyme, myeloperoxidase, was measured along with histological evaluation to assess inflammation. Both parameters showed significantly less inflammation in SC-41930 treated animals with an oral ED₅₀ of 20 mg/kg. These study results with an LTB₄ receptor antagonist indicate a role for LTB₄ in colonic inflammation and that an LTB₄ receptor antagonist may be beneficial for treatment of IBD.     

Oral administration of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) yields PhIP-DNA adducts but not tumors in male Syrian hamsters congenic at the N-acetyltransferase 2 (NAT2) locus.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a heterocyclic amine carcinogen present in well-done meat. PhIP must undergo host-mediated bioactivation to exert its mutagenic and carcinogenic effects. Following N-hydroxylation, N-acetyltransferases catalyze the O-acetylation (activation) of N-hydroxy-PhIP to an electrophile causing DNA damage. A well-defined genetic polymorphism in N-acetyltransferase 2 (NAT2) activity exists in humans and the Syrian hamster. Since some human epidemiological studies suggest an association between acetylator genotype and cancer susceptibility in individuals who consume well done meats, this study was designed to investigate the specific role of acetylator genotype in PhIP-induced tumors using a Syrian hamster model congenic at the NAT2 locus. Following oral administration of PhIP to male rapid and slow acetylator Syrian hamsters, DNA adducts were identified in each tissue examined with levels in the relative order: pancreas > heart and urinary bladder > prostate, small intestine and transverse colon > ascending colon, liver, cecum, descending colon, and rectum. However, no tumors were observed in male rapid and slow acetylator congenic hamsters administered 11 oral doses of PhIP (75 mg/kg) and maintained on a high fat diet for one year.     

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine induces a higher number of aberrant crypt foci in Fischer 344 (rapid) than in Wistar Kyoto (slow) acetylator inbred rats.

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine carcinogen in the human diet and is a colon carcinogen in the rat. N-Acetyltransferase-2 (NAT2) catalyzes the conversion of PhIP and other heterocyclic amines to a DNA-reactive form. NAT2 has a polymorphic distribution in humans and other mammals, including rats. The rapid NAT2 genotype has been shown to be associated with increased colorectal cancer risk in some, but not all, human epidemiological studies. This investigation was designed to study the role of acetylator genotype in PhIP-induced colon carcinogenesis using aberrant crypt foci (ACF) as an intermediate biomarker. Five-week-old male, rapid-acetylator Fischer 344 (F344) rats and slow-acetylator Wistar-Kyoto (WKY) rats were fed the semipurified AIN76A diet with 0.01% PhIP, 0.04% PhIP, or no PhIP (control) for 8 weeks. PhIP induced ACF in both rapid- and slow-acetylator rats; 0.04% PhIP induced more ACF than 0.01% PhIP. There was no difference in the number of ACF between rapid- and slow-acetylator rats that were fed 0.01% PhIP. However, 0.04% PhIP induced 2-fold higher ACF and a greater dose-dependent increase in PhIP-induced ACF in the rapid-acetylator F344 rats compared with the slow-acetylator WKY rats. The results support human epidemiological studies showing higher risk for colorectal cancer in rapid acetylators who frequently consume meat that is very well done.     

Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis.

Reactive oxygen species have been implicated as mediators of inflammation in ulcerative colitis. Chemiluminescence is a reliable means of estimating reactive oxygen species in biological media. Increased reactive oxygen species values in the inflamed colonic mucosa in rats were seen by chemiluminescence. The aims of the study were to find out if chemiluminescence is raised in the colonic mucosa of patients with ulcerative colitis and correlates with disease activity, and to elucidate the sources of the chemiluminescence. It was found that reactive oxygen species, as measured by the chemiluminescence technique, are raised in inflamed colonic mucosa and correlates with symptom score, sigmoidoscopic score, disease activity, and activity of the neutrophil enzyme myeloperoxidase. Chemiluminescence was inhibited by a myeloperoxidase inhibitor (azide) and an H2O2 scavenger (catalase) but not by allopurinol, an inhibitor of the enzyme xanthine oxidase. Chemiluminescence was also inhibited by indomethacin, but this did not seem to be related to inhibition of cyclo-oxygenase. These findings suggest that a likely cellular source of reactive oxygen species in the inflamed colon of patients with ulcerative colitis is the neutrophil and that myeloperoxidase conversion of H2O2 to hypochlorous acid, contributes to the chemiluminescence signal and possibly, to the tissue injury. Neither cyclo-oxygenase nor lipoxygenase seem to play a part as sources for the chemiluminescence.     

Margin status after laparoscopic resection of colorectal liver metastases: does a narrow resection margin have an influence on survival and local recurrence?

Objectives

Recent studies of margin-related recurrence have raised questions on the necessity of ensuring wide resection margins in the resection of colorectal liver metastases. The aim of the current study was to determine whether resection margins of 10 mm provide a survival benefit over narrower resection margins.

Methods

A total of 425 laparoscopic liver resections were carried out in 351 procedures performed in 317 patients between August 1998 and April 2012. Primary laparoscopic liver resections for colorectal metastases were included in the study. Two-stage resections, procedures accompanied by concomitant liver ablations and one case of perioperative mortality were excluded. A total of 155 eligible patients were classified into four groups according to resection margin width: Group 1, margins of < 1 mm [n = 33, including 17 patients with positive margins (Group 1a)]; Group 2, margins of 1 mm to < 3 mm (n = 31); Group 3, margins of ≥ 3 mm to < 10 mm (n = 55), and Group 4, margins of ≥ 10 mm (n = 36). Perioperative and survival data were compared across the groups. Median follow-up was 31 months (range: 2–136 months).

Results

Perioperative outcomes were similar in all groups. Unfavourable intraoperative incidents occurred in 9.7% of procedures (including 3.2% of conversions). Postoperative complications developed in 11.0% of patients. Recurrence in the resection bed developed in three (1.9%) patients, including two (6.1%) patients in Group 1. Rates of actuarial 5-year overall, disease-free and recurrence-free survival were 49%, 41% and 33%, respectively. Median survival was 65 months. Margin status had no significant impact on patient survival. The Basingstoke Predictive Index (BPI) generally underestimated survival. This underestimation was especially marked in Group 1 when postoperative BPI was applied.

Conclusions

Patients with margins of < 1 mm achieved survival comparable with that in patients with margins of ≥ 10 mm. When modern surgical equipment that generates an additional coagulation zone is applied, the association between resection margin and survival may not be apparent. Further studies in this field are required. Postoperative BPI, which includes margin status among the core factors predicting postoperative survival, seems to be less precise than preoperative BPI.     

Colonic inflammation in the rabbit induced by phorbol-12-myristate-13-acetate

Neutrophil (PMNL) infiltration of inflamed colonic tissue is a prominent feature of human inflammatory bowel disease (IBD). Colitis was established in New Zealand white rabbits by the intrarectal instillation of 1.5 mg/kg (in 10 ml 20% ethanol) phorbol-12-myristate-13-acetate (PMA) and assessed by visual grading of colonic inflammation, levels of the neutrophil marker enzyme myeloperoxidase (MPO), and histological examination. After 24 h there was a significant (P<0.001) increase in MPO levels in the PMA-treated colons compared to ethanol control. There was also increased inflammation based on visual scoring. Histologically, PMA-treated colons were necrotic with focal ulceration, heavy PMNL infiltration and edema at 24 h; by 96 h colitis was sustained with mild edema, crypt abscesses, and a staining pattern suggesting altered mucus quality. These results suggest that PMA-induced colitis in rabbits may be a new model of IBD in which to evaluate drugs known to mitigate the inflammatory process.     

High density lipoproteins (HDL) and physical activity: the influence of physical exercise, age and smoking on HDL-cholesterol and the HDL-/total cholesterol ratio.

220 trained men, examined the day before participation in a cross country ski-race, had significantly higher HDL-cholesterol and HDL-/total cholesterol ratio than untrained men, but did not differ signficantly from untrained women. HDL-cholesterol was significantly higher in skiers above 60 years than in skiers of younger age. Tobacco smokers ahd lower HDL-cholesterol and HDL-/total cholesterol ratio than non-smokers, but the differences were only significant in skiers, not in controls. HDL-cholesterol was positively correlated to total cholesterol in skiers. The HDL-cholesterol level may possibly contribute to the lower morbidity of CHD in men who are physically active during leisure time.