Two functional serotonin polymorphisms moderate the effect of food reinforcement on BMI.

Food reinforcement, or the motivation to eat, has been associated with increased energy intake, greater body weight and prospective weight gain. Much of the previous research on the reinforcing value of food has focused on the role of dopamine, but it may be worthwhile to examine genetic polymorphisms in the serotonin and opioid systems as these neurotransmitters have been shown to be related to reinforcement processes and to influence energy intake. We examined the relationship among 44 candidate genetic polymorphisms in the dopamine, serotonin and opioid systems, and food reinforcement and body mass index (BMI) in a sample of 245 individuals. Polymorphisms in the Monoamine oxidase A (MAOA-LPR) and serotonin receptor 2A genes (rs6314) moderated the effect of food reinforcement on BMI, accounting for an additional 5-10% variance and revealed a potential role of the single nucleotide polymorphism, rs6314 in the serotonin 2A receptor as a differential susceptibility factor for obesity. Differential susceptibility describes a factor that can confer either risk or protection depending on a second variable, such that rs6314 is predictive of both high and low BMI based on the level of food reinforcement, while the diathesis stress or dual-gain model influences only one end of the outcome measure. The interaction with MAOA-LPR better fit the dual-risk or diathesis stress model, with the 3.5R/4R allele conferring protection for individuals low in food reinforcement. These results provide new insight into genes theoretically involved in obesity and support the hypothesis that genetics moderate the association between food reinforcement on BMI

Comparison of Intravenous Medetomidine and Medetomidine/Ketamine for Immobilization of Free-Ranging Variable Flying Foxes (Pteropus hypomelanus)

Medetomidine (0.03 mg/kg) and medetomidine/ketamine (0.05/5.0 and 0.025/2.5 mg/kg), administered by intravenous injection, were evaluated for short-term immobilization of wild-caught variable flying foxes (Pteropus hypomelanus). Medetomidine alone produced incomplete chemical restraint and a stressful, prolonged induction. Both ketamine/medetomidine doses produced a smooth induction and complete immobilization. The combined medetomidine/ketamine dose of 0.025/2.5 mg/kg produced a rapid induction (232±224 sec) with minimal struggling and vocalization, a complete and effective immobilization period, and tended to lead to a faster and better quality recovery than medetomidine alone or a higher dose of medetomidine and ketamine (0.05/5.0 mg/kg), thus reducing holding time and permitting an earlier release of the bat back into the wild

EPP in T: More Controversial Subjects

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72351/1/j.1467-9612.2005.00075.x.pd

Immunoprevention of Basal Cell Carcinomas with Recombinant Hedgehog-interacting Protein

Basal cell carcinomas (BCCs) are driven by abnormal hedgehog signaling and highly overexpress several hedgehog target genes. We report here our use of one of these target genes, hedgehog-interacting protein (Hip1), as a tumor-associated antigen for immunoprevention of BCCs in Ptch1+/− mice treated with ionizing radiation. Hip1 mRNA is expressed in adult mouse tissues at levels considerably lower than those in BCCs. Immunization with either of two large recombinant Hip1 polypeptides was well tolerated in Ptch1+/− mice, induced B and T cell responses detectable by enzyme-linked immunosorbent assay, Western blot, delayed type hypersensitivity, and enzyme-linked immunospot assay, and reduced the number of BCCs by 42% (P < 0.001) and 32% (P < 0.01), respectively. We conclude that immunization with proteins specifically up-regulated by hedgehog signaling may hold promise as a preventive option for patients such as those with the basal cell nevus syndrome who are destined to develop large numbers of BCCs

High Resolution Cine Displacement Encoding with Stimulated Echoes (DENSE) at 3T with Navigator Feedback for Quantification of Cardiac Mechanics

Background: Measures of cardiac mechanics such as myocardial wall strain are better predictors of outcomes in patients with heart disease compared to traditional clinical measures and ejection fraction. Cine displacement encoding with stimulated echoes (DENSE) is an ideal method for quantifying cardiac motion which encodes tissue displacement in the phase of the MR signal and provides pixel-level resolution for quantifying cardiac mechanics. To date, DENSE has been implemented with resolution limited to 2-3 pixels across the myocardium. While this resolution is higher than most other techniques for quantifying cardiac mechanics, it may limit the ability of DENSE to quantify finer details such as transmural strains (subendocardial, midmyocardial and subepicardial) and right ventricular mechanics. We hypothesized that it is possible to efficiently increase the resolution of DENSE by a factor of 4 utilizing a navigator feedback system. Methods: 10 subjects (age 27 ± 3) with normal ECG and no history of cardiovascular disease were consented. A 3.0T Siemens Tim Trio with a 6-element chest and 24-element spine coil was configured with a navigator feedback system. The feedback system projected the navigator image of the diaphragm to the subject in real time to optimize breathold position. Standard resolution 2D cine DENSE was acquired with: 6 spiral interleaves, FOV = 340 mm, matrix = 96 × 96, thickness = 8 mm, TE/TR = 1.08/17, flip angle = 20, averages = 1, navigator acceptance window = ± 3 mm. High resolution 2D cine DENSE images were acquired by quadrupling the number of spirals to 24, increasing the matrix to 256 × 256, and increasing the averages to 3. Three short- and two long-axis images were acquired with each technique. Left ventricular strains and torsion were compared between the techniques using Bland-Altman. Results: The high resolution images took 11 times longer to acquire but the navigator feedback system provided good efficiency (69 ± 9%) for a total acquisition time of roughly 5 minutes per slice. The high resolution images had excellent quality with a noticeable improvement over standard resolution. There was a systematic but negligible difference between standard and high resolution data for circumferential and longitudinal strains. Radial strains showed the largest differences consistent with a systematic under-estimation of radial strain from standard resolution DENSE. Torsion was not significantly different between the two methods. Conclusions: High resolution cine DENSE MRI with navigator feedback is feasible at 3T and produces high quality images with 4 times the resolution of standard DENSE. Left ventricular circumferential strains, longitudinal strains, and torsion showed negligible differences between high and low resolution DENSE. Radial strains were significantly different, potentially due to better accuracy with high resolution DENSE due to the increased number of pixels within the thickness of the myocardial wall

Characterizing the Temporal Evolution of Altered Cardiac Mechanics in Diet-Induced Obese Mice Using Cine DENSE CMR

Background Obesity and metabolic syndrome are associated with increased risk of cardiovascular disease. Research suggests that altered cardiac mechanics (i.e., reduced strains, torsion, and synchrony of contraction) are present in obesity; yet, the causes of this mechanical dysfunction and its relationship to other sequelae of obesity (e.g., hypertension and elevated blood glucose) are not well understood. We hypothesize that diet-induced obesity in mice leads to reductions in measures of left ventricular (LV) mechanics, which develop in acute response to the onset of hyperglycemia, hypertension, and ventricular remodeling. Methods Twenty 4-week-old C57BL/6J mice were randomized (n = 10 per group) to either a high-fat (60% kcal from fat) or sucrose-matched low-fat (10% kcal from fat) diet for 28 weeks. After 4 weeks and every 6 weeks thereafter, LV mechanics were quantified using cine displacement encoding with stimulated echoes (DENSE) on a 7T ClinScan MRI (Bruker, Ettlingen, Germany) with a 4-element phased array cardiac coil. Three short-axis and two long-axis slices were acquired with 13-20 frames per cardiac cycle. Semi-automated post-processing was performed using custom software in MATLAB (Mathworks, Natick, MA). Additionally, systolic blood pressure (via tail cuff measurement) and fasting blood glucose were assessed every 4 weeks on staggered schedules. Results Mice on the high-fat diet became obese relative to the low-fat controls (49.9 vs. 29.2 g, respectively, by week 28;). Fasting blood glucose was elevated in the high-fat group (202 vs. 112 mg/dL; p \u3c 0.05) starting from the earliest measurement (week 7 on diet), whereas significant differences in LV mass (88 vs. 79 mg) and systolic blood pressure (172 vs. 162 mmHg) developed much later (weeks 22 and 25 on diet, respectively). Significant reductions in peak LV radial (15%) and circumferential (8%) strains and reduced contractile synchrony were detected in the high-fat group for the first time in week 28. A 10% reduction in peak torsion was also observed at that time, but did not reach statistical significance (p = 0.075). There were no differences in LV cavity volumes or ejection fraction. Conclusions Diet-induced obesity in mice is associated with reduced left ventricular mechanics. This dysfunction develops long after the manifestation of hyperglycemia in this model, which suggests that chronic alterations in glucose/insulin levels and/or signaling may contribute more to cardiac contractile dysfunction than acute elevations. Late development of concentric ventricular hypertrophy and hypertension prior to suppressed cardiac mechanics also suggests an important role of these processes in the reduced ventricular function

Quantification of Right Ventricular Function from Short-Axis Displacement-Encoded Images

Background Right ventricular (RV) function is important in many disease states, but is difficult to quantify from routine MR imaging. Previous work has shown that long-axis deformation/strain is the most critical contributor to global RV function; however, short-axis datasets allow for better coverage of the RV. Thus it would be ideal to be able to quantify RV long-axis function using short-axis slice orientations. We hypothesized that a stack of three-dimensional (3D) displacement encoded (DENSE) images could reliably quantify longitudinal deformation of the RV to overcome the need for acquiring additional long-axis views of the RV. Methods A contiguous stack of cine short-axis DENSE images encompassing the entire RV was acquired with 3D encoding in eight healthy volunteers (Age: 27 ± 3 years) using a 3T Siemens Tim Trio scanner. Endo- and epicardial boundaries were manually drawn on each image to generate a 3D reconstruction of the RV myocardium. The measured displacement field was used to deform the mesh and longitudinal strains were computed at every point throughout the volume. For comparison to the short-axis stack with 3D encoding, a standard four-chamber DENSE image with two-dimensional in-plane displacement encoding was acquired. Similar to the 3D analysis, a mesh was deformed using the measured displacements and was subsequently used to determine longitudinal RV strain values. For comparison with the four-chamber data, only short-axis points lying within the four-chamber imaging slices were used to compute peak longitudinal strain. All strains were compared using a two-tailed paired t-test. Results Right ventricular longitudinal strains derived from short-axis 3D DENSE images (-20 ± 4%) were comparable to values obtained from four-chamber images (-16 ± 2%) (p = 0.14). In addition to obtaining information solely at the four-chamber/short-axis intersection, we computed a global RV longitudinal strain of -17 ± 2% from 3D DENSE data (p = 0.64 relative to four-chamber only). Bland Altman analysis yielded a non-significant bias of 3 ± 11% between four-chamber and short-axis longitudinal strain estimates. Conclusions We have demonstrated that short-axis 3D DENSE imaging allows for accurate characterization of right ventricular longitudinal strain compared to a standard long-axis four-chamber acquisition which is typically used to look at RV function. In addition, 3D DENSE acquired in a short-axis orientation allows for more complete coverage of the RV compared to acquisitions based on long-axis image planes. It is likely that the more complete assessment of RV function provided by 3D DENSE could potentially improve upon the accuracy, reproducibility and prognostic ability of common echocardiographic techniques such as the tricuspid annular plane systolic excursion (TAPSE), but future work will need to investigate this

Two-Dimensional Estimates of Left Ventricular Strains are Significantly Affected by Through-Plane Motion

Background Advanced measures of cardiac mechanics such as left ventricular (LV) strains can be used in conjunction with classical biomarkers to gauge cardiovascular health and improve prediction of patient outcomes. Several imaging techniques, including displacement-encoded magnetic resonance imaging (DENSE), are used to non-invasively assess cardiac mechanics. These data are predominantly acquired in two dimensions (2D) due to simplified post-processing and shorter acquisition times; however, this type of acquisition and subsequent analysis cannot account for through-plane motion caused by longitudinal contraction of the left ventricle. We hypothesized that through-plane motion has a significant effect on 2D strain estimates. Methods Cine DENSE data were acquired in eight healthy volunteers (Age: 27 ± 3 years) with a 3T Siemens Tim Trio scanner. Short-axis slices with 2.8 mm in-plane resolution and an 8 mm slice thickness were acquired to span the entire LV. Displacements were encoded in both through-plane and in-plane directions with an effective temporal resolution of 34 ms. Endocardial and epicardial boundaries were delineated on the magnitude image of all short axis DENSE images. Radial and circumferential strains were computed based upon the deformation of the myocardium relative to the end-diastolic frame. Through-plane displacements were ignored for 2D analysis. For three-dimensional (3D) analysis, a 3D representation of the myocardium derived from the same endocardial and epicardial boundaries was deformed using the measured displacement field. The resulting radial and circumferential strain values were compared directly between the 2D and 3D analyses using a two-tailed paired t-test. Results Two dimensional processing consistently overestimated radial strain and underestimated circumferential strain. Peak circumferential strain was significantly different at the basal and mid-ventricular segments (p = 0.001 and 0.009, respectively). Peak radial strain decreased from the base to the apex in both 2D and 3D analyses; however, 2D significantly overestimated radial strain at the mid-ventricular and apical slices compared to 3D (p = 0.002). Global peak radial and circumferential strains from 3D were 30 ± 5% and -20 ± 2%, respectively, compared to 36 ± 5% and -18 ± 2% for 2D (both p \u3c 0.001). Conclusions Two-dimensional imaging methods for assessing left ventricular mechanics consistently overestimate radial strain and underestimate circumferential strain when compared to three-dimensional imaging. This limitation of two-dimensional imaging is likely due to the through-plane motion of the heart, which is ignored in two-dimensional techniques but easily accounted for when using three-dimensional techniques. Future research needs to determine the clinical and prognostic significance of this difference. Funding This research was funded in part by an NIH Early Independence Award to BKF (DP5 OD012132); contributions made by local businesses and individuals through a partnership between Kentucky Children\u27s Hospital and Children\u27s Miracle network; and the University of Kentucky Cardiovascular Research Center, grant UL1RR033173 from the National Center for Research Resources (NCRR), funded by the Office of the Director, National Institutes of Health (NIH) and supported by the NIH Roadmap for Medical Research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources