No abstract

Osteoarthritis (OA) is a major cause of suffering for millions of people. Investigating the disease directly on humans may be challenging. The aim of the present study is to investigate the advantages and limitations of the animal models currently used in OA research. The animal models are divided into induced and spontaneous. Induced models are further subdivided into surgical and chemical models, according to the procedure used to induce OA. Surgical induction of OA is the most commonly used procedure, which alters the exerted strain on the joint and/or alter load bearing leading to instability of the joint and induction of OA. Chemical models are generated by intra-articular injection of modifying factors or by systemically administering noxious agents, such as quinolones. Spontaneous models include naturally occurring and genetic models. Naturally occurring OA is described in certain species, while genetic models are developed by gene manipulation. Overall, there is no single animal model that is ideal for studying degenerative OA. However, in the present review, an attempt is made to clarify the most appropriate use of each model.

Aims/hypothesis Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue that has been demonstrated to successfully treat diabetes and promote weight loss. The mechanisms by which liraglutide confers weight loss remain to be fully clarified. Thus, we investigated whether GLP-1 receptors are expressed in human brains and whether liraglutide administration affects neural responses to food cues in diabetic individuals (primary outcome). Methods In 22 consecutively studied human brains, expression of GLP-1 receptors in the hypothalamus, medulla oblongata and parietal cortex was examined using immunohistochemistry. In a randomised (assigned by the pharmacy using a randomisation enrollment table), placebo-controlled, double-blind, crossover trial, 21 individuals with type 2 diabetes (18 included in analysis due to lack or poor quality of data) were treated with placebo and liraglutide for a total of 17 days each (0.6 mg for 7 days, 1.2 mg for 7 days and 1.8 mg for 3 days). Participants were eligible if they had type 2 diabetes and were currently being treated with lifestyle changes or metformin. Participants, caregivers, people doing measurements and/or examinations, and people assessing the outcomes were blinded to the medication assignment. We studied metabolic changes as well as neurocognitive and neuroimaging (fMRI) of responses to food cues at the clinical research centre of Beth Israel Deaconess Medical Center. Results Immunohistochemical analysis revealed the presence of GLP-1 receptors on neurons in the human hypothalamus, medulla and parietal cortex. Liraglutide decreased activation of the parietal cortex in response to highly desirable (vs less desirable) food images (p < 0.001; effect size: placebo 0.53 ± 0.24, liraglutide −0.47 ± 0.18). No significant adverse effects were noted. In a secondary analysis, we observed decreased activation in the insula and putamen, areas involved in the reward system. Furthermore, we showed that increased ratings of hunger and appetite correlated with increased brain activation in response to highly desirable food cues while on liraglutide, while ratings of nausea correlated with decreased brain activation. Conclusions/interpretation For the first time, we demonstrate the presence of GLP-1 receptors in human brains. We also observe that liraglutide alters brain activity related to highly desirable food cues. Our data point to a central mechanism contributing to, or underlying, the effects of liraglutide on metabolism and weight loss. Future studies will be needed to confirm and extend these findings in larger samples of diabetic individuals and/or with the higher doses of liraglutide (3 mg) recently approved for obesity.

No abstract

BACKGROUND.CXC chemokine receptor 4 (CXCR4) expression in acute myeloid leukemia (AML) is reported to correlate with FLT3 gene mutation and poorer prognosis. The prognostic significance of CXCR4 expression in patients with AML that have a normal karyotype and no evidence of FLT3 gene mutations was examined.METHODS.The prognostic significance of CXCR4 expression in 122 AML patients with normal karyotype and no evidence of FLT3 gene mutation treated at our institution between 1997 and 2003 was analyzed. All patients received intensive chemotherapy according to institutional protocols; 84% received cytarabine‐containing regimens. Bone marrow biopsy or clot specimens obtained before treatment were immunostained for CXCR4.RESULTS.There were 70 men and 52 women with a median age of 62 years (range, 22–82 years). Median follow‐up was 18 months (range, <1–97 months). Seventy‐six patients achieved complete remission (CR); 39 had recurrence. Sixty‐six patients died, including 9 with no evidence of disease. CXCR4 was positive in 70 and negative in 52 patients, with CR rates of 58% and 71%, respectively (P = .09). Multivariate analysis demonstrated that CXCR4 expression, presence of multilineage dysplasia, and high creatinine level predicted poorer overall (OS) and event‐free (EFS) survival.CONCLUSIONS.The results suggest that CXCR4 expression is associated with poor prognosis in AML patients with an unmutated FLT3 gene. Cancer 2007. © 2007 American Cancer Society.