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.     

A retrospective comparison of outcomes using three different precut needle knife techniques for biliary cannulation

GOALS: To assess the outcome differences following different precut biliary sphincterotomy needle-knife techniques. BACKGROUND: Precut biliary needle-knife sphincterotomy (NKS) allows biliary access when standard cannulation techniques fail. Little comparative data exist on the outcome of precut NKS. STUDY: Retrospective comparison of outcome differences of three NKS techniques performed by three pancreaticobiliary endoscopists at a tertiary referral center. RESULTS: A total of 139 consecutive biliary NKS were performed. In 44 cases (technique A), NKS was performed using a precut fistulotomy technique avoiding the papillary orifice, with pure cutting current, and occasional pancreatic duct (PD) stenting (6 of 44). In 47 cases (technique B), NKS was performed starting from the papillary orifice cutting upward with blended current, and no PD stenting. In 48 cases (technique C), NKS was performed as B but using pure cutting current and frequent PD stenting (15 of 48). NKS was successful in 95.5%, 95.7%, and 89.6% at initial endoscopic retrograde cholangiopancreatography and 100%, 97.8%, and 95.6% after a second endoscopic retrograde cholangiopancreatography. Total complications were not significantly different between the three groups; however, a lower incidence of pancreatitis occurred using technique A compared with techniques B and C (not significant). CONCLUSIONS: NKS techniques result in a high success rate of biliary cannulation with a similar overall complication rate. Avoiding cutting at the papillary orifice may reduce the risk of pancreatitis. When cutting at the papillary orifice, pancreatic duct stenting, pure cutting current, or both may reduce the incidence of pancreatitis.     

Association between the CYP3A5 genotype and blood pressure

We tested the hypothesis that the presence of a CYP3A5*1 allele is associated with increases in blood pressure in 2 studies of subjects with a total of 683 participants. The first study involving 271 subjects was part of a longitudinal study conducted at Indiana University Medical Center that consisted of 2 phases. The first phase studied the relationship of salt sensitivity with blood pressure, whereas the second phase, conducted approximately 26 years later, studied the relationship between blood pressure, carbohydrate intolerance, and vascular compliance in the same subjects. The second study was a cross-sectional evaluation of 412 normotensive and hypertensive subjects conducted at the University of California San Diego. The second study (Mantel-Haenszel chi(2) test; P=0.05) showed that a greater proportion of black participants with poor blood pressure control had CYP3A5*1/*1 genotype. Evaluation of the untreated blood pressure from phase 1 of the first study showed that the blacks with CYP3A5*3/*3 (146+/-35 mm Hg) had a higher systolic blood pressure than those with the *1/*3 (119+/-14.1 mm Hg; P=0.0006) and *1/*1 (125+/-17.4 mm Hg; P=0.009) genotypes. For blacks in study 2, the CYP3A5*1 allele was more common in hypertensives (Fisher exact test; P=0.025) than normotensives. In whites there was no association between CYP3A5 genotype and blood pressure in either study. We conclude that although untreated blood pressure may be higher in blacks with the CYP3A5*3/*3 genotype, the CYP3A5*1 allele may be associated with hypertension that is more refractory to treatment in this ethnic group.     

Head and neck malignancy: is PET/CT more accurate than PET or CT alone?

PURPOSE: To prospectively determine whether combined positron emission tomography (PET) and computed tomography (CT) is more accurate than either PET or CT alone in depicting malignant lesions in the head and neck. MATERIALS AND METHODS: Study was approved by the institutional review board, and patient informed consent was waived. Sixty-five consecutive patients (42 men, 23 women; age range, 43-83 years) known to have or suspected of having head and neck cancer were examined with combined PET/CT. CT was performed with intravenous administration of a contrast agent, and the CT data were used for attenuation correction. Each examination was interpreted in three ways: PET images in the absence of CT data, CT images in the absence of PET data, and fused PET/CT images. Probability of malignancy of each lesion was assigned a score by using a five-point scale. Receiver operating characteristic (ROC) analyses were performed by using biopsy, imaging, or clinical follow-up as the reference standard. The minimum follow-up was 6 months (range, 6-12 months). The results were additionally analyzed to assess the degree of radiologist confidence. RESULTS: Follow-up was available for 64 (98%) of 65 patients. ROC analyses demonstrated that PET/CT is significantly superior to PET or CT alone for depiction of malignancy in the head and neck (P < .05). In this series, PET/CT had a sensitivity of 98%, a specificity of 92%, and an accuracy of 94%. Radiologist confidence was substantially higher with the combined modality. CONCLUSION: Combined PET/CT is more accurate than PET or CT alone for the depiction of malignancy in the head and neck. Radiologist confidence is improved with the combined modality.     

FDG-PET imaging in Pneumocystis carinii pneumonia

The authors present a case of a 26-year-old man, under investigation for Cushing syndrome, who presented acutely with a dry cough and fever. The blood tests were unremarkable apart from a moderate to severe leukopenia. Imaging tests were suggestive of an atypical pneumonia, which was proven to be Pneumocystis carinii pneumonia (PCP) on cytology examination of a bronchoalveolar lavage (BAL). The acute lung changes were demonstrated on a whole-body F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) study. After treatment, a follow-up study showed complete resolution of these changes. The authors suggest that FDG PET may have a role to play in the diagnosis and, in particular, the monitoring of PCP in immunocompromised patients.     

Interferon treatment for chronic hepatitis B: enhanced response in children 5 years old or younger

OBJECTIVE: To test the hypothesis that there is an improved response to interferon in children with chronic hepatitis B (HBV) who are < or =5 years of age. STUDY DESIGN: Retrospective chart review of 22 consecutive children with chronic HBV (ages 17 months to 17 years; median, 83.9 months; 14 male, 8 female) treated with interferon-alpha2b. RESULTS: Ten patients (48%) responded to treatment [HBeAg (-), Anti-HBe (+), HBV DNA (-), HBsAg (+) and normal alanine aminotransferase/aspartate aminotransferase (ALT/AST) at 6 months after treatment], and 5 seroconverted HBsAg [above plus HBsAg negative and anti-HBs (+)]. Seven of 9 patients (78%) < or =5 years of age responded (5 cleared HBsAg). Three of 13 patients (23%) >5 years of age responded. Patient age at treatment was significantly lower in responders (63 +/- 70 months) versus nonresponders (104 +/- 55 months, P =.005). AST, ALT, and HBV DNA at the start of treatment were not different between responders and nonresponders or between patients < or =5 and >5 years old. CONCLUSIONS: Interferon treatment may be more effective in younger children with chronic hepatitis B.     

The Minneapolis-Manchester Quality of Life instrument: Reliability and validity of the Youth Form

OBJECTIVE: Improvements in survival after childhood cancer have increased emphasis on health-related quality of life (HRQoL) of survivors. We developed the Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF) as a standardized patient self-report instrument designed to assess HRQoL in childhood cancer survivors between the ages of 8 and 12 years. STUDY DESIGN: To validate the instrument, the MMQL-YF was administered to 643 children (481 healthy, 162 with cancer). Factor analysis was conducted to refine the instrument, and Cronbach's alpha coefficient was used to measure its internal reliability. Known-groups validity was determined by comparing healthy children with those with cancer. Construct validity was studied by a comparison of similar domains in the MMQL-YF and the Child Health Questionnaire (CHQ). Stability was tested by re-administration of the MMQL-YF 2 weeks later. RESULTS: Internal consistency reliability was in the acceptable range for this instrument. The MMQL-YF was able to distinguish between known groups, and its scales correlated highly with similar CHQ domains. Test-retest reliability showed that the instrument was extremely stable in all scales tested. CONCLUSION: Data provide evidence for the validity and reliability of the MMQL-YF as a comprehensive, multidimensional, self-report instrument for measuring HRQoL among childhood cancer survivors.