Roman Inglin

Characterisation of Acute Murine Dextran Sodium Sulphate Colitis: Cytokine Profile and Dose Dependency

Background/Aims: In our experience with the acute murine dextran sodium sulphate (DSS) model of experimental colitis, we noted both interstrain and interanimal variations in daily water consumption. One might critically question whether observed differences in injuries are just a dose dependency phenomenon reflecting variations in DSS intake. To clarify this important topic, we performed a dose and concentration dependency study of DSS in Balb/c mice. We also determined Th1 and Th2 cytokine levels to compare the cytokine profile to that from inflammatory bowel disease (IBD). Methods: In four groups (14 animals each group) different concentrations of DSS (0, 2.5, 5 and 7.5%) were given for 7 days ad libitum. Mucosal injury of the entire colon was histologically assessed and graded. Cytokine levels were determined by competitive quantitative RT-PCR. Results: A linear increase in the crypt damage score was noted with increasing concentrations (0, 4.9 ± 0.7, 11.9 ± 0.5 and 18.9 ± 1.3, respectively), but the total dose of DSS intake did not correlate with mucosal damage. Progressive upregulation in the transcripts for Th1 cytokines (IL-12, IFN-γ, IL-1, TNF-α) was observed with increasing dosage of DSS. Interestingly, an increase in IL-10, but not IL-4 mRNA transcripts was also noted. Discussion: Acute DSS-induced mucosal injury is dependent on the administered DSS water concentration but not on the consumed DSS dose. The cytokine profile is a classic Th1 response and is similar to that of various inflammatory conditions in the colon. Conclusions: Minor variations in fluid consumption do not affect the severity of DSS-induced injury in mice. The acute murine DSS colitis model is useful for studying the pathophysiological aspects of colonic inflammatory diseases as IBD and for evaluating new potential therapeutic agents

Randomized controlled trial on single dose steroid before thyroidectomy for benign disease to improve postoperative nausea, pain, and vocal function.

Objective:To evaluate the effects of a single preoperative dose of steroid on thyroidectomy outcomes. Background:Nausea, pain, and voice alteration frequently occur after thyroidectomy. Because steroids effectively reduce nausea and inflammation, a preoperative administration of steroids could improve these thyroidectomy outcomes. Methods:Seventy-two patients (men = 20, women = 52) undergoing thyroidectomy for benign disease were included in this randomized, controlled, 2 armed (group D: 8 mg dexamethasone, n = 37; group C: 0.9% NaCl, n = 35), double-blinded study (clinical trial number NCT00619086). Anesthesia, surgical procedures, antiemetics, and analgesic treatments were standardized. Nausea (0–3), pain (visual analog scale), antiemetic and analgesic requirements, and digital voice recording were documented before and 4, 8, 16, 24, 36, and 48 hours after surgery. Patients were followed-up 30 days after hospital discharge. Results:Baseline characteristics were similar among the 2 treatment groups. Nausea was pronounced in the first 16 hours postoperatively (scores were <0.3 and 0.8–1.0 for group D and C, respectively (P = 0.005)), and was significantly lower in group D compared with group C during the observation period (P = 0.001). Pain diminished within 48 hours after surgery (visual analog scale 20 and 35 in group D and C, respectively (P = 0.009)). Antiemetic and analgesic requirements were also significantly diminished. Changes in voice mean frequency were less prominent in the dexamethasone group compared with the placebo group (P = 0.015). No steroid-related complications occurred. Conclusion:A preoperative single dose of steroid significantly reduced nausea, vomiting, and pain, and improved postoperative voice function within the first 48 hours (most pronounced within 16 hours) after thyroid resection; this strategy should be routinely applied in thyroidectomies.

MYCOPHENOLATE MOFETIL IMPAIRS HEALING OF LEFT-SIDED COLON ANASTOMOSES 1

Introduction. Inadequate healing and consequent leakage from bowelanastomoses are a significant cause of postoperative morbidity and mortality.Immunosuppressive drugs are known to disturb healing processes and to impairthe mechanical stability of bowel anastomosis. Mycophenolate mofetil (MMF) isan immunosuppressive agent that selectively inhibits the proliferation of Tand B lymphocytes and has been shown to be effective in preventing allograftrejection after organ transplantation. Adverse effects are few; however,nothing is known in regard to possible adverse effects of MMF administrationon the healing of bowel anastomosis. The aim of the present study was toevaluate the effect of systemic MMF administration on the healing of colonanastomoses inrats. Methods. Rats underwent laparotomy, division of the left colon, andsigmoidostomy. MMF (25 mg/kg) or vehicle was administered intraperitoneally intwo groups (n=21 per group) 3 days before surgery and then once dailyuntil euthanization (7 animals per group; 2, 4, and 6 days after surgery).Bursting pressure measurements, histologic evaluation, morphometric analysis,mucin and collagen staining, and BrdU immunohistochemistry of the anastomoticsite were performed. Furthermore, matrix protein expression at the anastomoticsite was determined by collagen I and fibronectin Westernblots. Results. Administration of MMF significantly decreased anastomoticbursting pressure postoperatively. Accordingly, histology, mucin staining, andBrdU immunohistochemistry and measurements of the colonic crypt depth showedmore extended inflammation, a significantly lower proliferation rate, and asignificantly thinned mucosal layer in the MMF-treated groups when compared tocontrol animals, whereas matrix synthesis at the anastomotic site was notdifferent. Conclusions. The administration of the immunosuppressive agent MMFsignificantly impairs healing and mechanical stability of colon anastomosis inrats during the early postoperative period. MMF act to disturb host reparativeprocesses mainly by impairment of reparative colonic epithelium proliferationand less by a disturbance of matrixsynthesis.

Sirolimus and intraoperative hyperthermic peritoneal chemoperfusion with mitomycin-C do not impair healing of bowel anastomoses

Surgeons will increasingly have to address the development of gastrointestinal disease in transplant patients or deal with extended bowel resection and bowel anastomosis in advanced cancer patients. Immunosuppressants as well as intraoperative hyperthermic peritoneal chemoperfusion (IHPC) may alter intestinal anastomotic healing. We evaluated the effects of the immunosuppressant sirolimus and of IHPC on healing and stability of bowel anastomoses in pigs. Twenty‐four pigs were divided into four groups (SIR: sirolimus was administered orally; IHPC: animals received IHPC with mitomycin‐C; COMP: combination of sirolimus and IHPC was administered; CON: sham‐treated control group). Animals underwent hand‐sutured small bowel and left colon anastomoses and were killed on postoperative day 4. Anastomoses were evaluated by morphometric analysis and immunohistochemistry (IHC) and by measuring the bursting pressure (BP). In all experimental groups (SIR, IHPC, COMP), anastomotic BPs remained unaltered and were not statistically different compared with control (CON). In addition, ileum villous height and colonic crypt depth analysis revealed no significant difference in mucosal thickness, and IHC showed no difference among groups in proliferation, as assessed by the number of KI‐67‐ and bromodeoxyuridine‐labeled cells. Immunosuppression with sirolimus as well as IHPC with mitomycin‐C do not alter healing of intestinal anastomosis in pigs.

Current aspects and future prospects of total anorectal reconstruction—a critical and comprehensive review of the literature

PurposeMany rectal cancer patients undergo abdominoperineal excision worldwide every year. Various procedures to restore perineal (pseudo-) continence, referred to as total anorectal reconstruction, have been proposed. The best technique, however, has not yet been defined. In this study, the different reconstruction techniques with regard to morbidity, functional outcome and quality of life were analysed. Technical and timing issues (i.e. whether the definitive procedure should be performed synchronously or be delayed), oncological safety, economical aspects as well as possible future improvements are further discussed.MethodsA MEDLINE and EMBASE search was conducted to identify the pertinent multilingual literature between 1989 and 2013. All publications meeting the defined inclusion/exclusion criteria were eligible for analysis.ResultsDynamic graciloplasty, artificial bowel sphincter, circular smooth muscle cuff or gluteoplasty result in median resting and squeezing neo-anal pressures that equate to the measurements found in incontinent patients. However, quality of life was generally stated to be good by patients who had undergone the procedures, despite imperfect continence, faecal evacuation problems and a considerable associated morbidity. Many patients developed an alternative perception for the urge to defecate that decisively improved functional outcome. Theoretical calculations suggested cost-effectiveness of total anorectal reconstruction compared well to life with a permanent colostomy.ConclusionsMany patients would be highly motivated to have their abdominal replaced by a functional perineal colostomy. Given the considerable morbidity and questionable functional outcome of current reconstruction technique improvements are required. Tissue engineering might be an option to design an anatomically and physiologically matured, and customised continence organ.

Bioengineering of Colo-Rectal Tissue

About 30 years ago, first reports have appeared in the literature on successful substitution of gastrointestinal wall defects by synthetic materials. An either absorbable or non-absorbable polymer patch sutured into a full-thickness wall defect of stomach, small intestine, and even colon of different animal species generally showed to be initially integrated and overgrown by neomucosa, and eventually absorbed or intraor extraluminally extruded (Thompson et al., 1986; Harmon et al., 1979; Contieri et al., 1980; Smyrnis, 1982). Though this approach has been revived in several publications reporting good results (Oh et al., 2002; Uzun et al., 2010), treatment of damaged bowel by implantation of synthetic material has never gained general acceptance in the surgical community, and is, therefore, out of common clinical practice. This may be due to the general concern regarding the use of synthetic material in tissue which is naturally colonized with bacteria, as it is particularly the case in the colon. More recently, also natural materials like collagen sponge or acellular matrix have been tested for their ability either to support healing of an intestinal wall damage or to entirely substitute a full thickness defect. Implantation of patches of these natural biomaterials yielded good results with respect to histological and, to some extent, even functional reconstitution (Wang et al., 2005; Wang et al., 2003; Demirbilek et al., 2003; Badylak, S. et al., 2000; Isch et al., 2001; Kajitani et al., 2001; Mutter et al., 1996). As far as concerns the interposition of a synthetic or natural scaffold of tubular shape into esophagus or small intestine, results are less promising. Poor mucosal regeneration, stricture formation or high mortality rate of the experimental animals due to anastomotic leaks were reported, no matter whether the implanted biomaterial was synthetic absorbable (Thompson et al., 1986), non-absorbable (Fukushima et al., 1983; Watson et al., 1980), or of natural origin (Badylak, S. et al., 2000; Badylak, S.F., 2005; Chen & Badylak, 2001). There are no results reported in the current literature dealing with implantation of a tubular scaffold into the large intestine. In recent years there is a growing effort being done to apply tissue engineering methods for the complete, thus tubular, reconstruction of gastrointestinal organs. A driving force of the endeavours of gastrointestinal tissue engineering is the intention to circumvent transplantation and the associated lifetime need for immunosuppression as the sole alternative to the complete absence of the respective organ. Since loss of the entire colon is absolutely compatible with life, this is not a condition that would require transplantation, indeed. However, total colectomy leads to important changes in enterohepatic circulation,