Intestinal Upregulation of Melanin-Concentrating Hormone in TNBS-Induced Enterocolitis in Adult Zebrafish

Background: Melanin-concentrating hormone (MCH), an evolutionarily conserved appetite-regulating neuropeptide, has been recently implicated in the pathogenesis of inflammatory bowel disease (IBD). Expression of MCH is upregulated in inflamed intestinal mucosa in humans with colitis and MCH-deficient mice treated with trinitrobenzene-sulfonic acid (TNBS) develop an attenuated form of colitis compared to wild type animals. Zebrafish have emerged as a new animal model of IBD, although the majority of the reported studies concern zebrafish larvae. Regulation MCH expression in the adult zebrafish intestine remains unknown. Methods: In the present study we induced enterocolitis in adult zebrafish by intrarectal administration of TNBS. Follow-up included survival analysis, histological assessment of changes in intestinal architecture, and assessment of intestinal infiltration by myeloperoxidase positive cells and cytokine transcript levels. Results: Treatment with TNBS dose-dependently reduced fish survival. This response required the presence of an intact microbiome, since fish pre-treated with vancomycin developed less severe enterocolitis. At 6 hours post-challenge, we detected a significant influx of myeloperoxidase positive cells in the intestine and upregulation of both proinflammatory and anti-inflammatory cytokines. Most importantly, and in analogy to human IBD and TNBS-induced mouse experimental colitis, we found increased intestinal expression of MCH and its receptor in TNBS-treated zebrafish. Conclusions: Taken together these findings not only establish a model of chemically-induced experimental enterocolitis in adult zebrafish, but point to effects of MCH in intestinal inflammation that are conserved across species

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

Implementation of Guidelines for the Management of Arterial Hypertension. The Impulsion Study

This study assessed the effects of a pilot best practice implementation enhancement program on the control of hypertension. We enrolled 697 consecutive known hypertensive patients with other vascular risk factors but free from overt vascular disease. There was no “control” group because it was considered unethical to deprive high-risk patients from “best medical treatment”. Following a baseline visit, previously trained physicians aimed to improve adherence to lifestyle measures and drug treatment for hypertension and other vascular risk factors. Both at baseline and at study completion (after 6 months), a 1-page form was completed showing if patients achieved treatment targets. If not, the reasons why were recorded. This program enhanced compliance with lifestyle measures and increased the use of evidence-based medication. There was a substantial increase in the number of patients who achieved treatment targets for blood pressure (p<0.0001) and other vascular risk factors. In non-diabetic patients (n=585), estimated vascular risk (PROCAM risk engine) was significantly reduced by 41% (p<0.0001). There was also a 12% reduction in vascular risk according to the Framingham risk engine but this did not achieve significance (p=0.07). In conclusion, this is the first study to increase adherence to multiple interventions in hypertensive patients on an outpatient basis, both in primary care and teaching hospitals. Simple, relatively low cost measures (e.g. educating physicians and patients, distributing printed guidelines/brochures and completing a 1-page form) motivated both physicians and patients to achieve multiple treatment goals. Further work is needed to establish if the improvement observed is sustained. [ClinicalTrials.gov NCT00416611]

Compliance with Once-Daily versus Twice or Thrice-Daily Administration of Antibiotic Regimens: A Meta-Analysis of Randomized Controlled Trials

<div><p>Objective</p><p>To investigate whether compliance of patients to antibiotic treatment is better when antibiotics are administered once than multiple times daily.</p><p>Methods</p><p>We performed a systematic search in PubMed and Scopus databases. Only randomized controlled trials were considered eligible for inclusion. Compliance to antibiotic treatment was the outcome of the meta-analysis.</p><p>Results</p><p>Twenty-six studies including 8246 patients with upper respiratory tract infections in the vast majority met the inclusion criteria. In total, higher compliance was found among patients treated with once-daily treatment than those receiving treatment twice, thrice or four times daily [5011 patients, RR=1.22 (95% CI, 1.11, 1.34]. Adults receiving an antibiotic once-daily were more compliant than those receiving the same antibiotic multiple times daily [380 patients, RR=1.09 (95% CI, 1.02, 1.16)]. Likewise, children that received an antibiotic twice-daily were more compliant than those receiving the same antibiotic thrice-daily [2118 patients, RR=1.10 (95% CI, 1.02, 1.19)]. Higher compliance was also found among patients receiving an antibiotic once compared to those receiving an antibiotic of different class thrice or four times daily [395 patients, RR=1.20 (95% CI, 1.12, 1.28)]. The finding of better compliance with lower frequency daily was consistent regardless of the study design, and treatment duration.</p><p>Conclusion</p><p>This meta-analysis showed that compliance to antibiotic treatment might be associated with higher when an antibiotic is administered once than multiple times daily for the treatment of specific infections and for specific classes of antibiotics. </p></div

Forest plot depicting the risk ratios (RR) of compliance of patients receiving antibiotic treatment once-daily versus multiple times daily.

<p><i>(Vertical line = “no difference” point between the two regimens. Squares = risk ratios; Diamonds = pooled risk ratios for all studies. Horizontal lines = 95% CI)</i>.</p

Flow diagram of the systematic search and study selection process.

<p>Flow diagram of the systematic search and study selection process.</p

Forest plot depicting the risk ratios (RR) of compliance of patients receiving an antibiotic once-daily versus an antibiotic of the same broad class thrice-daily.

<p>Forest plot depicting the risk ratios (RR) of compliance of patients receiving an antibiotic once-daily versus an antibiotic of the same broad class thrice-daily.</p

Forest plot depicting the risk ratios (RR) of compliance of patients receiving an antibiotic once-daily versus an antibiotic of different class thrice or four times daily.

<p>Forest plot depicting the risk ratios (RR) of compliance of patients receiving an antibiotic once-daily versus an antibiotic of different class thrice or four times daily.</p

Forest plot depicting the risk ratios (RR) of compliance of patients receiving an antibiotic twice-daily versus the same antibiotic or antibiotic of the same class thrice-daily.

<p>Forest plot depicting the risk ratios (RR) of compliance of patients receiving an antibiotic twice-daily versus the same antibiotic or antibiotic of the same class thrice-daily.</p

Forest plot depicting the risk ratios (RR) of compliance of patients receiving antibiotic treatment twice-daily versus thrice or four times daily.

<p>Forest plot depicting the risk ratios (RR) of compliance of patients receiving antibiotic treatment twice-daily versus thrice or four times daily.</p