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.     

Gastroesophageal reflux disease (GERD), extraesophageal reflux (EER) and recurrent chronic rhinosinusitis

Chronic polypoid rhinosinusitis (CRS) is a common disease, affecting approximately 16% of the adult population in the US every year. In addition to many well known predisposing factors, an association with reflux disease is hypothesized. Such an association might explain the recurrence of polyposis in the face of improved surgical techniques and postsurgical treatment of CRS. At present it is unclear whether extraesophageal reflux directly injures the sinus mucosa, whether gastroesophageal reflux leads to vagus-mediated neuroinflammatory changes, or whether both mechanisms occur separately or simultaneously. In patients suffering from recurrent CRS (n=20) and healthy volunteers (n=20), ambulatory 24 h two channel pH testing was performed. The number of reflux events, the fraction of the total time during which pH was below 4, and the reflux area index (RAI) were determined in the esophagus as well as in the hypopharynx. Patients with recurrent CRS had significantly more reflux events in the esophagus and the fraction of pH<4 and the RAI were increased up to 10-fold compared to healthy volunteers. In contrast to the esophagus, these differences were not observed in the hypopharynx. Recurrent CRS is often associated with GERD but not with EER. Recurrent disease or prolonged recovery after surgery should raise the suspicion of reflux disease as a possible triggering factor. Because GERD itself cannot be diagnosed by laryngoscopy, and because of the subjectivity of symptoms such as heartburn, the otolaryngologist should consider double-probe pH testing as the diagnostic procedure of choice.     

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.     

The effect of immigrant generation and duration on self-rated health among US adults 2003–2007

Global self-rated health (SRH) is increasingly a key indicator in the assessment of immigrant health. However, evidence of the impact on SRH of generational status, duration of residence in the US, and socioeconomic status (SES) among immigrants and their offspring is limited and inconsistent. We overcome limitations in existing research on this topic by using a uniquely large and diverse data source, the March Annual Social and Economic Supplement of the Current Population Survey (CPS; 2003–2007) (n = 637,209). As a result, we are able to disaggregate results by race/ethnicity, account for country of origin, and consider the role of multiple dimensions of SES. We find that overall first-generation immigrants in the US have lower odds of poor/fair SRH compared to the third-generation. This association is particularly strong for blacks and Hispanics but not significant for Asians. Among first-generation Asians and Hispanics, longer duration of residence is positively associated with poor/fair SRH. Finally, socioeconomic gradients in SRH tend to be less pronounced among the first-generation (versus the third) and, within the first-generation, among recent arrivals (versus those with longer durations). Our results highlight the importance of explicitly accounting for multiple immigration-related variables and their interactions with race/ethnicity and SES. Otherwise, studies may misestimate SRH differences by race/ethnicity and socioeconomic status. The continued growth of the US immigrant population and the second-generation underscore the need to examine patterns in immigrant health systematically.     

Glutathione trapping to measure microsomal oxidation of furan to cis-2-butene-1,4-dial.

Furan is a liver carcinogen and toxicant. Furan is oxidized to the reactive dialdehyde, cis-2-butene-1,4-dial, by microsomal enzymes. This reactive metabolite readily reacts with glutathione nonenzymatically to form conjugates. A high-performance liquid chromatography-electrochemical method for the detection of cis-2-butene-1,4-dial-glutathione (GSH) conjugates in microsomal preparations was developed to measure the extent of furan metabolism to cis-2-butene-1,4-dial in vitro. Previously unobserved mono-GSH reaction products of cis-2-butene-1,4-dial were detected in addition to the already characterized bis-GSH conjugates. Chemical characterization of these compounds indicated that the alpha-amino group of glutathione had reacted with cis-2-butene-1,4-dial to form a thiol-substituted pyrrole adduct. The analytical method was used to estimate the extent of furan oxidation in rat liver microsomes from untreated or acetone-pretreated F344 rats as well as in human P450 2E1 Supersomes. Our results confirm that cytochrome P450 2E1 can catalyze the oxidation of furan to cis-2-butene-1,4-dial. However, the data are also consistent with the involvement of other P450 enzymes in the oxidation of furan in untreated animals. This assay will be a valuable tool to explore tissue and species differences in rates of furan oxidation.     

Is Coronary Graft Doppler More Sensitive for Indiviual Graft Flows Than TEE During CABG Surgery?

Abstract    In this case report we describe a situation where despite a normal TEE exam immediately postcardiopulmonary bypass, there was no flow in the left internal mammary artery graft to the left anterior descending artery. This was picked up by coronary Doppler and subsequently repaired.