Gene deletion of P-Selectin and ICAM-1 does not inhibit neutrophil infiltration into peritoneal cavity following cecal ligation-puncture

BACKGROUND: Neutrophil infiltration is one of the critical cellular components of an inflammatory response during peritonitis. The adhesion molecules, P-selectin and intercellular adhesion molecule (ICAM)-1, mediate neutrophil-endothelial cell interactions and the subsequent neutrophil transendothelial migration during the inflammatory response. Despite very strong preclinical data, recent clinical trials failed to show a protective effect of anti-adhesion therapy, suggesting that the length of injury might be a critical factor in neutrophil infiltration. Therefore, the objective of this study was to determine the role of P-selectin and ICAM-1 in neutrophil infiltration into the peritoneal cavity during early and late phases of peritonitis. METHODS: Peritonitis was induced in both male wild-type and P-selectin/ICAM-1 double deficient (P/I null) mice by cecal ligation-puncture (CLP). Peripheral blood and peritoneal lavage were collected at 6 and 24 hours after CLP. The total leukocyte and neutrophil contents were determined, and neutrophils were identified with the aid of in situ immunohistochemical staining. Comparisons between groups were made by applying ANOVA and student t-test analysis. RESULTS: CLP induced a severe inflammatory response associated with a significant leukopenia in both wild-type and P/I null mice. Additionally, CLP caused a significant neutrophil infiltration into the peritoneal cavity that was detected in both groups of mice. However, neutrophil infiltration in the P/I null mice at 6 hours of CLP was significantly lower than the corresponding wild-type mice, which reached a similar magnitude at 24 hours of CLP. In contrast, in peritonitis induced by intraperitoneal inoculation of 2% glycogen, no significant difference in neutrophil infiltration was observed between the P/I null and wild-type mice at 6 hours of peritonitis. CONCLUSIONS: The data suggest that alternative adhesion pathway(s) independent of P-selectin and ICAM-1 can participate in neutrophil migration during peritonitis and that the mode of stimuli and duration of the injury modulate the neutrophil infiltration

The management of patients with primary chronic anal fissure: a position paper

Anal fissure is one of the most common and painful proctologic diseases. Its treatment has long been discussed and several different therapeutic options have been proposed. In the last decades, the understanding of its pathophysiology has led to a progressive reduction of invasive and potentially invalidating treatments in favor of conservative treatment based on anal sphincter muscle relaxation. Despite some systematic reviews and an American position statement, there is ongoing debate about the best treatment for anal fissure. This review is aimed at identifying the best treatment option drawing on evidence-based medicine and on the expert advice of 6 colorectal surgeons with extensive experience in this field in order to produce an Italian position statement for anal fissures. While there is little chance of a cure with conservative behavioral therapy, medical treatment with calcium channel blockers, diltiazem and nifepidine or glyceryl trinitrate, had a considerable success rate ranging from 50 to 90%. Use of 0.4% glyceryl trinitrate in standardized fashion seems to have the best results despite a higher percentage of headache, while the use of botulinum toxin had inconsistent results. Nonresponding patients should undergo lateral internal sphincterotomy. The risk of incontinence after this procedure seems to have been overemphasized in the past. Only a carefully selected group of patients, without anal hypertonia, could benefit from anoplasty

Laparoscopic management of adhesive small bowel obstruction.

The objective of this review is to present a current opinion on the management of small-bowel obstruction. The topic is limited to small-bowel obstruction secondary to postoperative adhesions. Other causes of small-bowel obstruction are not addressed. We attempt to give readers a concise insight into the evidence available in the English language literature. This paper does not offer a comprehensive review of the topic; rather it highlights some relevant issues and then outlines what role, if any, laparoscopic surgery should play in the management of adhesive small-bowel obstruction

Nitrogen isotopes provide clues to amino acid metabolism in human colorectal cancer cells

AbstractGlutamic acid and alanine make up more than 60 per cent of the total amino acids in the human body. Glutamine is a significant source of energy for cells and also a prime donor of nitrogen in the biosynthesis of many amino acids. Several studies have advocated the role of glutamic acid in cancer therapy. Identification of metabolic signatures in cancer cells will be crucial for advancement of cancer therapies based on the cell’s metabolic state. Stable nitrogen isotope ratios (15N/14N, δ15N) are of particular advantage to understand the metabolic state of cancer cells, since most biochemical reactions involve transfer of nitrogen. In our study, we used the natural abundances of nitrogen isotopes (δ15N values) of individual amino acids from human colorectal cancer cell lines to investigate isotope discrimination among amino acids. Significant effects were noticed in the case of glutamic acid, alanine, aspartic acid and proline between cancer and healthy cells. The data suggest that glutamic acid is a nitrogen acceptor while alanine, aspartic acid and proline are nitrogen donors in cancerous cells. One plausible explanation is the transamination of the three acids to produce glutamic acid in cancerous cells.</jats:p

Targeting Melanoma with Cancer-Killing Viruses

Melanoma is the deadliest skin cancer with ever-increasing incidence. Despite the development in diagnostics and therapies, metastatic melanoma is still associated with significant morbidity and mortality. Oncolytic viruses (OVs) represent a class of novel therapeutic agents for cancer by possessing two closely related properties for tumor reduction: virus-induced lysis of tumor cells and induction of host anti-tumor immune responses. A variety of viruses, either in “natural” or in genetically modified forms, have exhibited a remarkable therapeutic efficacy in regressing melanoma in experimental and/or clinical studies. This review provides a comprehensive summary of the molecular and cellular mechanisms of action of these viruses, which involve manipulating and targeting the abnormalities of melanoma, and can be categorized as enhancing viral tropism, targeting the tumor microenvironment and increasing the innate and adaptive antitumor responses. Additionally, this review describes the “biomarkers” and deregulated pathways of melanoma that are responsible for melanoma initiation, progression and metastasis. Advances in understanding these abnormalities of melanoma have resulted in effective targeted and immuno-therapies, and could potentially be applied for engineering OVs with enhanced oncolytic activity in future.</jats:p

The Influence of Diverting Loop Ileostomy vs. Colostomy on Postoperative Morbidity in Restorative Anterior Resection for Rectal Cancer: A Systematic Review and Meta-Analysis

BACKGROUND: The aim of this systematic review and meta-analysis was to evaluate the morbidity of loop ileostomy (LI) and loop colostomy (LC) creation in restorative anterior resection for rectal cancer as well as the morbidity of their reversal. METHODS: PubMed, EMBASE, MEDLINE via Ovid, and Cochrane Library were systematically searched for records published from 1980 to 2017 by three independent researchers. The primary endpoint was overall morbidity after stoma creation and reversal. Mantel-Haenszel odds ratio (OR) was used to compare categorical variables. Clinical significance was evaluated using numbers needed to treat (NNT). RESULTS: Six studies (two randomized controlled trials and four observational studies) totaling 1063 patients (666 LI and 397 LC) were included in the meta-analysis. Overall morbidity rate after both stoma creation and closure was 15.6% in LI vs. 20.4% in LC [OR(95%CI) = 0.67 (0.29, 1.58); p = 0.36] [NNT(95%CI) = 21 (\u3e 10.4 to benefit, \u3e 2430.2 to harm)]. Morbidity rate after stoma creation was both statistically and clinically significantly lower after LI [18.2% vs. 30.6%; OR(95%CI) = 0.42 (0.25, 0.70); p = 0.001; NNT(95%CI) = 9 (4.7, 29.3)]. Dehydration rate was 3.1% (8/259) in LI vs. 0% (0/168) in LC. The difference was not statistically or clinically significant [OR(95%CI) = 3.00 (0.74, 12.22); p = 0.13; NNT (95%CI) = 33 (19.2, 101.9)]. Ileus rates after stoma closure were significantly higher in LI as compared to LC [5.2% vs. 1.7%; OR(95%CI) = 2.65 (1.13, 6.18); p = 0.02]. CONCLUSIONS: This meta-analysis found no difference between LI and LC in overall morbidity after stoma creation and closure. Morbidity rates following the creation of LI were significantly decreased at the cost of a risk for dehydration