ECG-triggered 18F-fluorodeoxyglucose positron emission tomography imaging of the rat heart is dramatically enhanced by acipimox.

PURPOSE: 18F-Fluorodeoxyglucose (FDG) imaging, provided by current positron emission tomography (PET) systems dedicated to small animals,might provide a precise functional assessment of the left ventricle (LV) in rats, although conventional metabolic conditioning by hyperinsulinaemic glucose clamping is not well adapted to this setting. This study was aimed at assessing cardiac FDG PET in rats premedicated with acipimox, a potent nicotinic acid derivative yielding comparable image quality to clamping in man. METHODS: Metabolic conditioning was compared in Wistar rats between a conventional oral glucose loading (1.5 mg/kg) and acipimox, which was given at high but well tolerated doses subcutaneously (25 mg/kg) or orally (50 mg/kg). Myocardial to blood (M/B) activity ratio and myocardial signal to noise (S/N) ratio were analysed on gated FDG PET images. RESULTS: The S/N ratio of the gated cardiac images evolved in parallel with the M/B activity ratio and these two ratios were independently enhanced by glucose loading and acipimox. However, these enhancements were: (1) dramatic for acipimox, especially for the high oral dose of 50 mg/kg (from 2.85 +/- 0.57 to 10.73 +/- 0.54 for the M/B ratio of rats with or without glucose loading; p<0.0001) and (2) much more limited for glucose loading (from 6.61 +/- 0.49 to 7.89 +/- 0.41 for the M/B ratio of rats with or without acipimox administration; p=0.049). With the high oral dose of acipimox, the gated cardiac FDG PET images had very high S/N ratios, at least equivalent to those currently documented in man. CONCLUSION: Metabolic conditioning by oral doses of acipimox is highly efficient for experimental studies planned with cardiac FDG PET in rats.

Voxel-based quantitative analysis of brain images from ¹8F-FDG PET with a block-matching algorithm for spatial normalization.

OBJECTIVE: Statistical Parametric Mapping (SPM) is widely used for the quantitative analysis of brain images from ¹8F fluorodeoxyglucose positron emission tomography (FDG PET). SPM requires an initial step of spatial normalization to align all images to a standard anatomic model (the template), but this may lead to image distortion and artifacts, especially in cases of marked brain abnormalities. This study aimed at assessing a block-matching (BM) normalization algorithm, where most transformations are not directly computed on the overall brain volume but through small blocks, a principle that is likely to minimize artifacts. METHODS: Large and/or small hypometabolic areas were artificially simulated in initially normal FDG PET images to compare the results provided by statistical tests computed after either SPM or BM normalization. RESULTS: Results were enhanced by BM, compared with SPM, with regard to (i) errors in the estimation of large defects volumes (about 2-fold lower) because of a lower image distortion, and (ii) rates of false-positive foci when numerous or extended abnormalities were simulated. These observations were strengthened by analyses of FDG PET examinations from epileptic patients. CONCLUSIONS: Results obtained with the BM normalization of brain FDG PET appear more precise and robust than with SPM normalization, especially in cases of numerous or extended abnormalities.

Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention.

The availability of both the mouse and human genome sequences allows for the systematic discovery of human gene function through the use of the mouse as a model system. To accelerate the genetic determination of gene function, we have developed a sequence-tagged gene-trap library of >270,000 mouse embryonic stem cell clones representing mutations in approximately 60% of mammalian genes. Through the generation and phenotypic analysis of knockout mice from this resource, we are undertaking a functional screen to identify genes regulating physiological parameters such as blood pressure. As part of this screen, mice deficient for the Wnk1 kinase gene were generated and analyzed. Genetic studies in humans have shown that large intronic deletions in WNK1 lead to its overexpression and are responsible for pseudohypoaldosteronism type II, an autosomal dominant disorder characterized by hypertension, increased renal salt reabsorption, and impaired K+ and H+ excretion. Consistent with the human genetic studies, Wnk1 heterozygous mice displayed a significant decrease in blood pressure. Mice homozygous for the Wnk1 mutation died during embryonic development before day 13 of gestation. These results demonstrate that Wnk1 is a regulator of blood pressure critical for development and illustrate the utility of a functional screen driven by a sequence-based mutagenesis approach.