Chemoprevention of colon and small intestinal tumorigenesis in APC(Min/+) mice by licofelone, a novel dual 5-LOX/COX inhibitor: potential implications for human colon cancer prevention

Preclinical and clinical studies suggest that 5-lipoxygenase (5-LOX), such as COX-2, is a potential target for colon cancer inhibition and, in part, contributes to cardiovascular side effects associated with COX-2 inhibitors. Experiments were designed to assess the chemopreventive effects of a novel dual 5-LOX/COX inhibitor, licofelone {[6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-pyrrolizin-5-yl] acetic acid}, in APC(Min/+) mouse intestinal tumorigenesis. Six-week-old male and female APC(Min/+) mice (n = 10 per group) were fed with control American Institute of Nutrition-76A diet or diets containing 150 or 300 ppm licofelone for 14 weeks (～100 days), and intestinal tumors were evaluated for tumor multiplicity and size. Licofelone significantly inhibited total intestinal tumor multiplicity and size in a dose-dependent manner (P < 0.0001; mean tumors for 0, 150, and 300 ppm: 48.8, 17, and 8, respectively, in male mice; and 34.3, 8.8, and 5.5, respectively, in female mice). Licofelone at high dose showed more than 83% (P < 0.0001) tumor inhibition in both genders of mice. One hundred and fifty and 300 ppm licofelone resulted in 86% to 97% inhibition of polyps having size greater than 2 mm. One hundred and fifty and 300 ppm licofelone caused more than 72% and 100% inhibition of colonic tumors, respectively. Importantly, in mice fed with licofelone, tumors showed significantly reduced proliferating cell nuclear antigen expression (70%, P < 0.0001), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells (75%, P < 0.0001), and there was dose-dependent suppression of serum triglycerides (71%-83%, P < 0.0001), decreased inflammatory cytokines; and decreased COX and 5-LOX activities (57%-64%, P < 0.0001). Also, compared with 300 ppm celecoxib, 300 ppm licofelone provided better efficacy in suppressing tumor growth. These observations show that a novel dual 5-LOX/COX inhibitor dramatically suppresses small intestinal and colonic tumor formation in APC(Min/+) mice.     

SHORT BOWEL SYNDROME IN CHILDREN

Short bowel syndrome, a devastating outcome after major intestinal resection, manifests as malabsorption and diarrhoea. Improved outcome in recent years has come about with better understanding of the disease and its sequelae. Medical therapy using H₂ receptor antagonists, loperamide and growth hormone analogues has been found useful. Total parenteral nutrition has revolutionized the outcome of this crippling disorder. Diverse spectrums of surgical procedures aimed at deceleration of intestinal transit and intestinal lengthening have not found favour in clinical practice. Intestinal transplantation remains the only viable option when intestinal adaptation is inadequate and complications of total parenteral nutrition ensue.KEY WORDS: Adaptation, Intestinal transplantation, Small bowel syndrome, Small gut syndrome, Total parenteral nutrition     

Radiofrequency modified maze procedure for chronic atrial fibrillation

Background We studied the effectiveness of Radiofrequency (RF) modified maze in early and late restoration of sinus rhythm in patients with rheumatic heart disease (RHD). Methods We studied 84 patients with RHD over 23.6±12.5 months after the RF modified maze and another group of 64 patients over six months after valvular surgery alone (the Non-Maze group). Any thromboembolic episodes and NYHA class of the patient were recorded. The short term survivors in sinus rhythm, underwent stress test and echocardiography for atrial transport function at 3–6 months after surgery. Results In the Maze group, sinus rhythm was restored in 60/70 patients (85.71%) immediately and sustained in 55/70 patients (78.57%) over the follow-up as against an immediate conversion rate of 5.3% (5/53 patients, p<0.001) in the Non-maze group. The additional Cardiopulmonary (CP) bypass time (p=0.13) and cross clamp time (p=0.511) needed for maze is not statistically significant. Left atrial (LA) transport function was preserved in 41/51 patients (80.4%) and Right atrial (RA) transport function in 51/51 patients (100%). Stress test showed good chronotropic response in all the 41 patients in whom it was performed. In the Maze group one patient presented with acute valve thrombosis and subsequently, succumbed to it. In the non maze group 3/55 patients (5.66%) were hospitalized for stroke. No patient needed permanent pacemaker nor was sinus node dysfunction seen. The immediate postoperative morbidity and mortality was comparable in the two groups. Conclusions The RF modified maze is safe, effective and brief without any additional risk. It restores sinus rhythm in the majority, however there is an attrition in some.     

Chemoprevention of Colon Carcinogenesis by Oleanolic Acid and Its Analog in Male F344 Rats and Modulation of COX-2 and Apoptosis in Human Colon HT-29 Cancer Cells

PURPOSE: To assess the chemopreventive effect of oleanolic acid (ONA) and its synthetic analog 18alpha-olean-12-ene-3beta-23,28-triol (OT) on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in F344 rats and understand anti-inflammatory properties and apoptosis effects in HT29 colon cancer cells and Raw 264.7 macrophage cell lines. METHODS: Five week-old male F344 rats were fed a control diet or experimental diets containing two doses of ONA (750 and 1,500 ppm) and OT (250 and 500 ppm). After 1 week, all animals were s.c. injected with AOM (15 mg/kg body weight, once weekly for 2 weeks). At 14 weeks of age, all rats were killed and colons were evaluated for ACF. Cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expressions and apoptosis were assessed in cell lines exposed to OT using western blots and 4',6-diamidino-2-phenylindole staining. RESULTS: Administration of ONA and OT inhibited mean colonic ACF and multi-crypt AC/foci in a dose dependent manner (p < 0.001-0.0001). OT blocked the COX-2 expression induced by phorbol 12-myristate 13-acetate in a dose-dependent manner and induced apoptosis in HT-29 cancer cells, and suppressed iNOS activation in RAW264.7 macrophages. CONCLUSIONS: ONA and OT possess chemopreventive activity against colon carcinogenesis in rat and OT inhibits the COX-2 and iNOS and induces apoptosis in cell lines.     

Understanding the Hawthorne effect in wound research—A scoping review

The Hawthorne Effect (HE) is considered a methodological artefact in research, although its definition and influence on research outcomes lack consensus. This review explored how this term has been mentioned and discussed in the area of wound research. A scoping review was conducted on ProQuest Central, Scopus, EbscoHost, and online databases of indexed wound journals using the methodological framework by Arksey and Malley. A review protocol was applied to detail key terms, truncation and Boolean operators, and inclusion and exclusion criteria. Search findings were reported using PRISMA guidelines. A total of 38 articles reporting primary evidence were identified. Three themes emerged from the review: wound researchers'' awareness of HE, the acknowledgement of the existence or otherwise of HE, and the mentioning of HE in passing. These results reflect a lack of attention to and understanding and awareness of the HE in the area of wound research. It is suggested that the HE receives more attention as a methodological concern, and its potential influence is considered and mitigated when planning future studies. Recommendations are provided to minimise the impact of the HE on the rigour of the research and confidence afforded to research findings.