A tracer kinetic model for 18F-FHBG for quantitating herpes simplex virus type 1 thymidine kinase reporter gene expression in living animals using PET.

Reporter probe 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (18F-FHBG) and reporter gene mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) have been used for imaging reporter gene expression with PET. Current methods for quantitating the images using the percentage injected dose per gram of tissue do not distinguish between the effects of probe transport and subsequent phosphorylation. We therefore investigated tracer kinetic models for 18F-FHBG dynamic microPET data and noninvasive methods for determining blood time-activity curves in an adenoviral gene delivery model in mice. METHODS: 18F-FHBG (approximately 7.4 MBq [approximately 200 microCi]) was injected into 4 mice; 18F-FHBG concentrations in plasma and whole blood were measured from mouse heart left ventricle (LV) direct sampling. Replication-incompetent adenovirus (0-2 x 10(9) plaque-forming units) with the E1 region deleted (n = 8) or replaced by HSV1-sr39tk (n = 18) was tail-vein injected into mice. Mice were dynamically scanned using microPET (approximately 7.4 MBq [approximately 200 microCi] 18F-FHBG) over 1 h; regions of interest were drawn on images of the heart and liver. Serial whole blood 18F-FHBG concentrations were measured in 6 of the mice by LV sampling, and 1 least-squares ratio of the heart image to the LV time-activity curve was calculated for all 6 mice. For 2 control mice and 9 mice expressing HSV1-sr39tk, heart image (input function) and liver image time-activity curves (tissue curves) were fit to 2- and 3-compartment models using Levenberg-Marquardt nonlinear regression. The models were compared using an F statistic. HSV1-sr39TK enzyme activity was determined from liver samples and compared with model parameter estimates. For another 3 control mice and 6 HSV1-sr39TK-positive mice, the model-predicted relative percentage of metabolites was compared with high-performance liquid chromatography analysis. RESULTS: The ratio of 18F-FHBG in plasma to whole blood was 0.84 +/- 0.05 (mean +/- SE) by 30 s after injection. The least-squares ratio of the heart image time-activity curve to the LV time-activity curve was 0.83 +/- 0.02, consistent with the recovery coefficient for the partial-volume effect (0.81) based on independent measures of heart geometry. A 3-compartment model best described 18F-FHBG kinetics in mice expressing HSV1-sr39tk in the liver; a 2-compartment model best described the kinetics in control mice. The 3-compartment model parameter, k3, correlated well with the HSV1-sr39TK enzyme activity (r2 = 0.88). CONCLUSION: 18F-FHBG equilibrates rapidly between plasma and whole blood in mice. Heart image time-activity curves corrected for partial-volume effects well approximate LV time-activity curves and can be used as input functions for 2- and 3-compartment models. The model parameter k3 from the 3-compartment model can be used as a noninvasive estimate for HSV1-sr39TK reporter protein activity and can predict the relative percentage of metabolites.     

Clinical and technical factors influencing recurrent carotid stenosis and occlusion after endarterectomy

Carotid endarterectomy was performed in 152 patients during a 27-month period. The first 82 patients had primary closure of the arteriotomy, whereas the subsequent 70 patients underwent closure with Dacron patch angioplasty. Duplex scanning was undertaken postoperatively in 102 of these patients with a mean follow-up period of 17 months. Perioperative thrombosis occurred in two patients (1.3%), late postoperative recurrent stenosis in 14 patients (13.7%), and late postoperative occlusion in three patients (2.9%). Of the various factors investigated for their correlation with late recurrent stenosis or occlusion, only three were significant: the female sex (recurrent stenosis in 29% vs. 8%, p less than 0.05), a small (less than 4 mm) internal carotid artery (37% vs. 12%, p less than 0.05), and failure to close the arteriotomy with a patch (29% vs. 6%, p less than 0.05). The development of recurrent carotid lesions appeared independent of smoking history, antiplatelet therapy, use of a shunt, or extent of carotid plaque. These data suggest that patients with small internal carotid arteries, specifically female patients, are at greater risk for recurrent carotid stenosis. Patch angioplasty may decrease this risk and should be considered in these patients.     

Tumor-associated retinal pigment epithelial proliferation simulating retinal pigment epithelial tear

A lesion with both the clinical and fluorescein angiographic appearance of the classical retinal pigment epithelial (RPE) tear was discovered over the dome of an actively growing metastatic choroidal tumor in a patient with a previous history of breast carcinoma. However, our patient exhibited no evidence of pigment epithelial detachment or age-related macular degeneration, the underlying cause of the RPE tear. Although we cannot be sure that a true RPE tear did not exist over our patient's tumor, more likely, we are observing a tumor induced zone of RPE dehiscence accompanied by RPE proliferation at its border, giving a very similar fundus appearance. Possible pathogenic mechanisms for the finding in our patient, and a comparison to those mechanisms responsible for the classical RPE tear, are discussed.     

Bipolar disorder in children and adolescents: obstacles to early diagnosis and future directions

Aim: This article reviews research centred around juvenile bipolar disorder with particular reference to diagnostic difficulties. Putative deficits are scrutinized with respect to trait likelihood and the roles of neuropsychology and neuroimaging in enhancing our understanding of juvenile bipolar disorder are discussed. Methods: Search terms including childhood, adolescent, youth and juvenile combined with the terms ‘bipolar disorder’, mania, depression and hypomania were used to identify relevant studies in MEDLINE and PsychLit. Results: Over recent years research into this relatively new disorder has increased phenomenally. Key issues within the field include diagnostic specificity, the heritability of the disorder, the impact of comorbidity and the implications of neuropsychological and neuroimaging findings. Conclusion: Despite concerning controversies in literature the diagnosis of bipolar disorder in children and adolescents as compared with adults, promising future research directions include better neurological characterization of the disorder through the application of findings from clinical populations, neuropsychological and neuroimaging research.