Reduced Intestinal Tumorigenesis in APCmin Mice Lacking Melanin-Concentrating Hormone

Background: Melanin-concentrating hormone (MCH) is an evolutionary conserved hypothalamic neuropeptide that in mammals primarily regulates appetite and energy balance. We have recently identified a novel role for MCH in intestinal inflammation by demonstrating attenuated experimental colitis in MCH deficient mice or wild type mice treated with an anti-MCH antibody. Therefore, targeting MCH has been proposed for the treatment of inflammatory bowel disease. Given the link between chronic intestinal inflammation and colorectal cancer, in the present study we sought to investigate whether blocking MCH might have effects on intestinal tumorigenesis that are independent of inflammation. Methodology Tumor development was evaluated in MCH-deficient mice crossed to the APCmin mice which develop spontaneously intestinal adenomas. A different cohort of MCH−/− and MCH+/+ mice in the APCmin background was treated with dextran sodium sulphate (DSS) to induce inflammation-dependent colorectal tumors. In Caco2 human colorectal adenocarcinoma cells, the role of MCH on cell survival, proliferation and apoptosis was investigated. Results: APCmin mice lacking MCH developed fewer, smaller and less dysplastic tumors in the intestine and colon which at the molecular level are characterized by attenuated activation of the wnt/beta-catenin signaling pathway and increased apoptotic indices. Form a mechanistic point of view, MCH increased the survival of colonic adenocarcinoma Caco2 cells via inhibiting apoptosis, consistent with the mouse studies. Conclusion: In addition to modulating inflammation, MCH was found to promote intestinal tumorigenesis at least in part by inhibiting epithelial cell apoptosis. Thereby, blocking MCH as a therapeutic approach is expected to decrease the risk for colorectal cancer

Pathological Margin Clearance and Survival After Pancreaticoduodenectomy in a US and European Pancreatic Center

Background: The optimal definition of a margin-negative resection and its exact prognostic significance on survival in resected pancreatic adenocarcinoma remains unknown. This study was designed to assess the relationship between pathological margin clearance, margin type, and survival. Methods: Patients who underwent pancreaticoduodenectomy with curative intent at two academic institutions, in Amsterdam, the Netherlands, and Boston, Massachusetts, between 2000 and 2014 were retrospectively evaluated. Overall survival, recurrence rates, and progression-free survival (PFS) were assessed by Kaplan–Meier estimates and multivariate Cox proportional hazards analysis, according to pathological margin clearance and type of margin involved. Results: Of 531 patients identified, the median PFS was 12.9, 15.4, and 24.1 months, and the median overall survival was 17.4, 22.9, and 27.7 months for margin clearances of 0, < 1, and ≥1 mm, respectively (all log-rank p < 0.001). On multivariate analysis, patients with a margin clearance of ≥1 mm demonstrated a survival advantage relative to those with 0 mm clearance [hazard ratio (HR) 0.71, p < 0.01], whereas survival was comparable for patients with a margin clearance of < 1 mm versus 0 mm (HR: 0.93, p = 0.60). Patients with involvement (0 or < 1 mm margin clearance) of the SMV/PV margin demonstrated prolonged median overall survival (25.7 months) relative to those with SMA involvement (17.5 months). Conclusions: In patients undergoing pancreaticoduodenectomy for pancreatic adenocarcinoma, a margin clearance of ≥1 mm correlates with improved survival relative to < 1 mm clearance and may be a more accurate predictor of a complete margin-negative resection in pancreatic cancer. The type of margin involved also appears to impact survival. Electronic supplementary material The online version of this article (10.1245/s10434-018-6467-9) contains supplementary material, which is available to authorized users

Minimally invasive and computer-navigated total hip arthroplasty: a qualitative and systematic review of the literature

ABSTRACT: BACKGROUND: Both minimally invasive surgery (MIS) and computer-assisted surgery (CAS) for total hip arthroplasty (THA) have gained popularity in recent years. We conducted a qualitative and systematic review to assess the effectiveness of MIS, CAS and computer-assisted MIS for THA. METHODS: An extensive computerised literature search of PubMed, Medline, Embase and OVIDSP was conducted. Both randomised clinical trials and controlled clinical trials on the effectiveness of MIS, CAS and computer-assisted MIS for THA were included. Methodological quality was independently assessed by two reviewers. Effect estimates were calculated and a best-evidence synthesis was performed. RESULTS: Four high-quality and 14 medium-quality studies with MIS THA as study contrast, and three high-quality and four medium-quality studies with CAS THA as study contrast were included. No studies with computer-assisted MIS for THA as study contrast were identified. Strong evidence was found for a decrease in operative time and intraoperative blood loss for MIS THA, with no difference in complication rates and risk for acetabular outliers. Strong evidence exists that there is no difference in physical functioning, measured either by questionnaires or by gait analysis. Moderate evidence was found for a shorter length of hospital stay after MIS THA. Conflicting evidence was found for a positive effect of MIS THA on pain in the early postoperative period, but that effect diminished after three months postoperatively. Strong evidence was found for an increase in operative time for CAS THA, and limited evidence was found for a decrease in intraoperative blood loss. Furthermore, strong evidence was found for no difference in complication rates, as well as for a significantly lower risk for acetabular outliers. CONCLUSIONS: The results indicate that MIS THA is a safe surgical procedure, without increases in operative time, blood loss, operative complication rates and component malposition rates. However, the beneficial effect of MIS THA on functional recovery has to be proven. The results also indicate that CAS THA, though resulting in an increase in operative time, may have a positive effect on operative blood loss and operative complication rates. More importantly, the use of CAS results in better positioning of acetabular component of the prosthesis

Reduced angiotensinogen expression attenuates renal interstitial fibrosis in obstructive nephropathy in mice

A novel approach was employed to assess the contribution of the renin-angiotensin system (RAS) to obstructive nephropathy in neonatal mice having zero to four functional copies of the angiotensinogen gene (Agt). Two-day-old mice underwent unilateral ureteral obstruction (UUO) or sham operation; 28 days later, renal interstitial fibrosis and tubular atrophy were quantitated. In all Agt genotypes, UUO reduced ipsilateral renal mass and increased that of the opposite kidney. Renal interstitial collagen increased after UUO linearly with Agt expression, from a fractional area of 25% in zero-copy mice to 54% in two-copy mice. Renal expression of transforming growth factor-β1 was increased by ipsilateral UUO in mice expressing Agt, but not in zero-copy mice. However, the prevalence of atrophic tubules due to UUO did not vary with Agt expression. Blood pressure was not different in all groups, except for a reduction in sham zero-copy mice. We conclude that a functional RAS is not necessary for compensatory renal growth. This study demonstrates conclusively that angiotensin regulates at least 50% of the renal interstitial fibrotic response in obstructive nephropathy, an effect independent of systemic hemodynamic changes. Angiotensin-induced fibrosis likely is a mechanism common to the progression of many forms of renal disease

Olanzapine increases weight and serum triglyceride levels

Background: Previous studies have suggested that clozapine is associated with increases in both weight and serum triglyceride (but not cholesterol) levels. Because of the pharmacologic similarities between clozapine and olanzapine, we decided to evaluate if olanzapine use was associated with an increase in triglycerides. Method: Twenty-five inpatients (21 men, 4 women) were treated with olanzapine, and their outcomes were tracked prospectively in a medication utilization evaluation study. Results: After 12 weeks on a mean ± SD dose of 13.8 ± 4.4 mg/day, weight increased a mean of 12 lb (5.4 kg; from 190 ± 37 lb [85.5 ± 16.7 kg] to 202 ± 30 lb [90.9 ± 13.5 kg]), while fasting triglycerides increased a mean of 60 mg/dL (from 162 ± 121 mg/dL to 222 ± 135 mg/dL). Both increases were significant at p \u3c .05. Fasting total cholesterol did not increase. The triglyceride increase was even larger when we excluded 8 patients who received various interventions to lower lipid levels (e.g., pravastatin, low-fat diet) during the olanzapine trial. There was a strong association between weight change and triglyceride change (p \u3c .02); after controlling for weight, analysis of covariance showed no independent increase in triglycerides. Conclusion: These results suggest olanzapine has significant effects on weight and serum triglyceride levels. Clinical implications are discussed