Identification of 2-(4-benzyloxyphenyl)-N- [1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide, an orally efficacious melanin-concentrating hormone receptor 1 antagonist for the treatment of obesity

Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.     

Feasibility of Accessing Data in Hospitalized Patients to Support Diagnosis of Malnutrition by the Academy‐A.S.P.E.N. Malnutrition Consensus Recommended Clinical Characteristics

Background: The feasibility of accessing data in hospitalized patients to support a malnutrition diagnosis using the new Academy of Nutrition and Dietetics–American Society for Parenteral and Enteral Nutrition (AND‐A.S.P.E.N.) consensus recommended clinical characteristics of malnutrition is largely unknown. We sought to characterize baseline practice to guide the development of appropriate interventions for implementation of the recommended approach. Materials and Methods: A cross‐sectional survey was conducted of 262 consecutive adults who were referred for dietitian or nutrition support team assessments at 2 tertiary teaching hospitals in Pennsylvania. The availability of data to support the proposed AND‐A.S.P.E.N. approach and the resulting malnutrition diagnoses were examined. Results: Mean ± SD age was 58.2 ± 17.1 years, and half were female. Food intake history was available for 76%, weight history for 67%, and physical examination for loss of fat and muscle mass for 94% and for edema for 84%. Hand‐grip strength was not available. The prevalence of malnutrition among the patients referred for nutrition assessment was 6.7% moderate, 7.6% severe with acute illness; 12.2% moderate, 11% severe with chronic illness; and 0.8% moderate, 0.4% severe with social circumstances. Decline in typical food intake and weight loss were the most commonly used clinical characteristics. Conclusion: Data could generally be accessed to support the AND‐A.S.P.E.N. consensus clinical characteristics for malnutrition diagnosis, but further testing in multiple care settings is needed before these observations may be generalized. Training in assessment methods and dissemination of the necessary tools will be necessary for full implementation.     

Effect of proton pump inhibitors on the detection of Helicobacter pylori in gastric biopsies.

BACKGROUND: Proton pump inhibitors are known to decrease the activity of Helicobacter pylori organisms within the stomach and to shift their distribution proximally. This effect may reduce the sensitivity of histological examination and rapid urease testing for H. pylori on biopsies taken from recommended sites. It is of particular relevance if a proton pump inhibitor has been prescribed before the patient has undergone diagnostic endoscopy. METHODS: We studied patients referred to our open-access upper gastrointestinal endoscopy service who had either been on no medication (controls) or were already taking proton pump inhibitors. Biopsies taken from the gastric antrum and corpus were used for rapid urease testing and for histological examination. Sera, taken from patients who had no evidence of H. pylori in biopsies, were tested for IgG H. pylori antibodies as an alternative indicator of infection. RESULTS: H. pylori organisms were detected by histological examination in 27 of 40 controls (68%) and in 13 of 25 patients taking proton pump inhibitors (52%). Among patients with positive histology (organisms detected in either antral or corpus biopsies, or both), only the sensitivity of the antral urease test read at 1 h was significantly lower in patients taking proton pump inhibitors than in controls, with no significant difference in sensitivities of the antral urease test at 24 h, of the corpus urease test at 1 or 24 h, or of histology from the antrum or corpus. Of patients with negative histology, none of 13 controls compared with six of 12 patients taking proton pump inhibitors (50%) had positive serology (P = 0.005). Five (83%) of the six histology-negative, seropositive patients taking proton pump inhibitors had histological changes consistent with H. pylori gastritis even though no organisms were detected. CONCLUSIONS: Treatment with a proton pump inhibitor before endoscopy reduces the sensitivity of antral and corpus biopsies for H. pylori detection, both by urease testing and histological examination. If proton pump inhibitors already prescribed cannot be discontinued for an adequate period before endoscopy, patients should have biopsies taken from the corpus as well as from the antrum, and serum should be tested for H. pylori.     

Patient expectations of radiology in noninteractive encounters

Open-ended interviews with 107 patients documented specific patient expectations of radiologic procedures during which there was no direct radiologist-patient interaction. Patient expectations could be classified into those related to the facility and those related to interactions with radiology staff. Among facility-related expectations, waiting time far outweighed all other concerns. Interpersonal skills were the predominant expectation of radiology staff. The role of the radiologist in fulfilling patient expectations was less clear. Only 10% of unprompted patients cited the radiologist as a factor in their expectations. When patients were specifically prompted to discuss the radiologist's role, communication skills, accuracy of interpretation, and interpersonal skills were the predominant concerns.     

Myocardial tagging in polar coordinates with use of striped tags

Regional deformation abnormalities in the heart wall provide a good indicator of ischemia. Myocardial tagging with magnetic resonance imaging is a new method of assessing heart wall motion during contraction. Current methods of myocardial tagging either do not provide two-dimensional information or lack a coordinate system well adapted to the morphology of the heart. In this article, the authors describe a new tagging method that provides a true polar coordinate system, with both radial and angular dimensions. This is accomplished with use of a section-selective version of spatially modulated magnetization resulting in striped tags (STAGs). These STAG planes are placed in the myocardium in a star pattern so that they intersect on the long axis of the heart and stripes appear through the width of the heart wall. In the short-axis view during contraction, rotation around the long axis yields angular information such as shear and twist, while separation of the stripes within the myocardium permits measurement of radial thickening. Therefore, this method provides a coordinate system for calculating two-dimensional strain that is adapted to the morphology of the left ventricle.     

Multilocus Analyses Reveal Involvement of the ESR1, ESR2, and FSHR Genes in Migraine

Objective.— Female hormone genes have been investigated in migraine in recent years. Research in this field has been controversial, especially in regard to ESR1 gene findings. None of the reports have yet to approach the problem from a multigenic point of view. Methods.— We investigated 5 polymorphisms implicated in female hormone metabolism (FSHR, CYP19A1, ESR1, NRIP1, and ESR2) in a cohort of 730 subjects matched for age and sex. The effect of gene–gene interaction was assessed using the set association approach, and the corresponding haplotypes were studied with PM Plus software. To corroborate initial results, we analyzed the selected markers using a cohort of 134 families in which 168 trios were suitable for transmission‐disequilibrium test (TDT) analysis under the migraine with aura (MA) phenotype. Results.— A total of 356 consecutive migraine patients (198 with MA [76% females] and 158 migraine without aura [MO, 74% females], and 374 matched controls [71% females]) were genotyped. In the 2‐point analyses, the ESR1 and ESR2 polymorphisms showed nominal association under MA/MO phenotype, and this association was higher with the FSHR polymorphism in MA females (P = .004, uncorrected). Using the SUMSTAT program, we observed ESR2‐ESR1‐FSHR significant gene–gene interaction, suggesting association with the MA/MO phenotype (P = .005; P = .003 in females), and with MA alone (P = .021; P = .030 for females). We corroborated that ESR2‐ESR1‐FSHR haplotypes interacted for migraine under a model‐free hypothesis (empirical P = .010 for the whole sample; P = .001 for females), and the association was stronger for the MA phenotype alone (empirical P = 5.0e‐4, under the heterogeneity model; P = .001 for females). These results were corroborated using family‐based association approaches. We observed nominal association for ESR2 and ESR1 (P = .031 and .034, respectively) in the TDT study, and significant association for ESR1 using family‐based association test statistics. Haplotype‐TDT analyses showed further significant gene–gene interaction for ESR1‐ESR2 (global P = .009), ESR2‐FSHR (global P = .011), and nominally significant interaction for ESR2‐ESR1‐FSHR genes (global P = .037). Conclusion.— We found significant association of female hormone metabolism polymorphisms under the perspective of multigene approach.     

Biomechanical Characteristics of Biplane Multiplanar Tension-Side Fixation for Lapidus Fusion

Although plating on the plantar, tension-side of the metatarsocuneiform joint provides an inherent biomechanical advantage for Lapidus arthrodesis, it has not been widely adopted owing to the morbidity associated with plantar application. To overcome these limitations, a modification to 90-90 locked biplanar plating was developed to provide the biomechanical advantages of multiplanar fixation and tension-side fixation, allowing application through a conventional incision. We tested the hypothesis that biplanar plating with tension-side fixation (low-profile straight dorsal plate and anatomic medial-plantar plate) would demonstrate improved mechanical stability compared with a previously tested 90-90 biplanar construct (small straight plate dorsally and medially) under cyclic loading. Both constructs were tested in static load to failure (3 pairs) and cyclic loading (10 pairs) with plantar cantilever bending using surrogate anatomic bone models. With static ultimate failure, the biplanar plate construct with tension-side fixation failed at a significantly greater failure load than did the straight biplanar plate construct (247.3?±?18.4 N versus 210.9?±?10.4 N; p?=?.04). With cyclic failure testing, the biplanar plate construct with tension-side fixation endured a significantly greater number of cycles (206,738?±?49,103 versus 101,780?±?43,273; p?<?.001) and a significantly greater dynamic failure load (207.5?±?24.3 N versus 162.5?±?20.6 N; p?<?.001) compared with the straight biplanar plate construct. These results have demonstrated that under simulated static and cyclic Lapidus arthrodesis loading, biplanar plating with tension-side fixation provides superior strength compared with the straight biplanar construct. Thus, this construct shows promise for clinical application as a practical approach to tension-side fixation and an early return to weightbearing after Lapidus fusion.