Effects of melanocortin receptor activation and blockade on ethanol intake: a possible role for the melanocortin-4 receptor

BACKGROUND: The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor pro-opiomelanocortin. A growing body of literature suggests that the MC system modulates neurobiological responses to drugs of abuse. Because ethanol has direct effects on central pro-opiomelanocortin activity, it is possible that MC neuropeptides participate in the control of voluntary ethanol consumption. Here we assessed the possibility that MC receptor (MCR) agonists modulate ethanol intake via the MC3 receptor (MC3R) and/or the MC4 receptor (MC4R) and whether the MCR antagonist AgRP-(83-132) controls ethanol consumption. METHODS: Mc3r-deficient (Mc3r) and wild-type (Mc3r) littermate mice were given intraperitoneal (10 mg/kg) and intracerebroventricular (1.0 microg ICV) doses of melanotan II (MTII), a nonselective MCR agonist. To assess the role of MC4R, C57BL/6J mice were given an ICV infusion of the highly selective MC4R agonist cyclo(NH-CH2-CH2-CO-His-d-Phe-Arg-Trp-Glu)-NH2 (1.0 or 3.0 microg). Finally, na?ve C57BL/6J mice were given an ICV infusion of AgRP-(83-132) (0.05 and 1.0 microg). RESULTS: MTII was similarly effective at reducing ethanol drinking in Mc3r-deficient (Mc3r) and wild-type (Mc3r) littermate mice. Furthermore, ICV infusion of the MC4R agonist significantly reduced ethanol drinking, whereas ICV infusion of AgRP-(83-132) significantly increased ethanol drinking in C57BL/6J mice. Neither MTII nor AgRP-(83-132) altered blood ethanol levels at doses that modulated ethanol drinking. CONCLUSIONS: The present results suggest that MC4R, and not MC3R, modulates MCR agonist-induced reduction of ethanol consumption and that ethanol intake is increased by the antagonistic actions of AgRP-(83-132). These findings strengthen the argument that MCR signaling controls ethanol consumption and that compounds directed at MCR may represent promising targets for treating alcohol abuse disorders in addition to obesity.     

Association between smoking and outcomes in older adults with atrial fibrillation

Tobacco smoking is a risk factor for atrial fibrillation (AF), but little is known about the impact of smoking in patients with AF. Of the 4060 patients with recurrent AF in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, 496 (12%) reported having smoked during the past two years. Propensity scores for smoking were estimated for each of the 4060 patients using a multivariable logistic regression model and were used to assemble a matched cohort of 487 pairs of smokers and nonsmokers, who were balanced on 46 baseline characteristics. Cox and logistic regression models were used to estimate the associations of smoking with all-cause mortality and all-cause hospitalization, respectively, during over 5 years of follow-up. Matched participants had a mean age of 70 ± 9 years (± S.D.), 39% were women, and 11% were non-white. All-cause mortality occurred in 21% and 16% of matched smokers and nonsmokers, respectively (when smokers were compared with nonsmokers, hazard ratio=HR=1.35; 95% confidence interval=95%CI=1.01-1.81; p=0.046). Unadjusted, multivariable-adjusted and propensity-adjusted HR (95% CI) for all-cause mortality associated with smoking in the pre-match cohort were: 1.40 (1.13-1.72; p=0.002), 1.45 (1.16-1.81; p=0.001), and 1.39 (1.12-1.74; p=0.003), respectively. Smoking had no association with all-cause hospitalization (when smokers were compared with nonsmokers, odds ratio=OR=1.21; 95%CI=0.94-1.57, p=0.146). Among patients with AF, a recent history of smoking was associated with an increased risk of all-cause mortality, but had no association with all-cause hospitalization.     

CD44 Isoform Expression Follows Two Alternative Splicing Pathways in Breast Tissue

The repertoire of distinct CD44 protein isoforms is generated by means of alternative pre-mRNA splicing of 10 variable exons located in the central region of the CD44 gene. We have used human breast ductal carcinoma as a model to identify two alternative splicing pathways of the CD44 pre-mRNA variable region that account for the generation of all of the CD44 isoforms described in breast tissue. An alternative splicing pathway that reflects inclusion of variable exons in a gradual 3′-to-5′ fashion is evidenced in breast ductal carcinoma and its lymph node metastases. This pathway is compatible with a mechanism that generates the standard form of CD44 (devoid of variable exons) and is distinguishable from an alternative splicing pathway that involves exclusively variant exon 3 and is observable in both normal and carcinoma breast tissue. We show that both pathways are detectable in the same cell type in the breast and provide a speculative model by which these splicing routes could take place.     

Different pattern of pleiotrophin and midkine expression in neuropathic pain: Correlation between changes in pleiotrophin gene expression and rat strain differences in neuropathic pain

Pleiotrophin (PTN) and midkine (MK) are two growth factors highly redundant in function that exhibit neurotrophic actions and are upregulated at sites of nerve injury, both properties being compatible with a potential involvement in the pathophysiological events that follow nerve damage (i.e. neuropathic pain). We have tested this hypothesis by comparatively studying PTN and MK gene expression in the spinal cord and dorsal root ganglia (DRG) of three rat strains known to differ in their behavioural responses to chronic constriction injury (CCI) of the sciatic nerve: Lewis, Fischer 344 (F344) and Sprague–Dawley (SD). Real time RT-PCR revealed minimal changes in PTN/MK gene expression in the spinal cord after CCI despite the strain considered, but marked changes were detected in DRG. A significant upregulation of PTN gene expression occurred in injured DRG of the F344 strain, the only strain that recovers from CCI-induced mechanical allodynia 28 days after surgery. In contrast, PTN was found to be downregulated in injured DRG of SD rats, the most sensitive strain in behavioural studies. These changes in PTN were not paralleled by concomitant modifications of MK gene expression. The results demonstrate previously unidentified differences between PTN and MK patterns of expression. Furthermore, the data suggest that upregulation of PTN, but not MK, could play an important role in the recovery from CCI.     

Composition of lower urinary tract stones in canines in Mexico City

Effective long-term management of urolithiasis depends on identification and manipulation of factors contributing to initial stone formation; identification of these factors depends on accurate identification of the mineral composition of the urolith involved. The purpose of this study was to determine the chemical composition of uroliths obtained from the low urinary tract of dogs in Mexico City. One hundred and five cases of urolithiasis were studied in which stones were surgically obtained from the low urinary tracts of dogs treated in different hospitals. The chemical composition of the uroliths was quantitatively and qualitatively determined by stereoscopic microscopy, IR-spectroscopy, scanning electron microscopy and X-ray microanalysis. Age of animals ranged from 4 months to 14 years, with a median of 5 years. Composition and distribution of the uroliths were struvite 38.1%, calcium oxalate 26.7%, silica 13.3%, urate 7.6%, mixed 11.4%, compounds 1.9%, and cystine 1%. Most uroliths were found in pure breed dogs (75.2%); 23 different breeds were identified, and more than half of the submissions were from breeds of small size. In our study, the frequency of struvite, calcium oxalate, cystine, urates, mixed and compounds stones are in agreement with papers that report on dog populations in America and Europe, but a higher frequency of silica uroliths was observed in Mexico City dogs.