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.     

Transmyocardial revascularization ameliorates ischemia by attenuating paradoxical catecholamine-induced vasoconstriction

Background  The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates ischemia by reversing paradoxical catecholamine-induced vasoconstriction. Methods and Results  Chronic ischemic cardiomyopathy was created in 11 dogs by placing ameroid constrictors on the proximal coronary arteries and their major branches. Six weeks later, 35 channels were created percutaneously in the left circumflex artery region, with the left anterior descending artery region serving as control. At rest, wall thickening and myocardial blood flow did not change in the treated region, whereas they deteriorated in the control bed. Contractile and myocardial blood flow reserve increased in the treated region but deteriorated in the control region. There was diminished iodine 123 metaiodobenzylguanidine uptake and a significant reduction in noradrenergic nerves in the treated region compared with the control region, with a corresponding reduction in tissue tyrosine hydroxylase activity. Conclusions  We conclude that the absence of a catecholamine-induced reduction in MBF reserve and contractile reserve in the TMR-treated region with associated evidence of neuronal injury indicates that the relief of exercise-induced ischemia after TMR most likely results from reversal of paradoxical catecholamine-induced vasoconstriction. These findings may have implications in selecting patients who would benefit from TMR. Supported in part by grants from the National Institutes of Health (R01-HL66034 and K-08-HL074290-01). Bethesda. Md. The radio-labeled microspheres were provided by DuPont Pharmaceuticals, North Billerica. Mass, and the ultrasound equipment was supplied by Philips. Andover, Mass. Dr Leong-Poi was the recipient of a Fellowship Training Grant from the Canadian Institute of Health Research and the Heart and Stroke Foundation of Canada.     

Reproducibility of 18F-FDG microPET studies in mouse tumor xenografts.

(18)F-FDG has been used to image mouse xenograft models with small-animal PET for therapy response. However, the reproducibility of serial scans has not been determined. The purpose of this study was to determine the reproducibility of (18)F-FDG small-animal PET studies. METHODS: Mouse tumor xenografts were formed with B16F10 murine melanoma cells. A 7-min small-animal PET scan was performed 1 h after a 3.7- to 7.4-MBq (18)F-FDG injection via the tail vein. A second small-animal PET scan was performed 6 h later after reinjection of (18)F-FDG. Twenty-five sets of studies were performed. Mean injected dose per gram (%ID/g) values were calculated from tumor regions of interest. The coefficient of variation (COV) from studies performed on the same day was calculated to determine the reproducibility. Activity from the second scans performed after 6 h were adjusted by subtracting the estimated residual activity from the first (18)F-FDG injection. For 7 datasets, an additional scan immediately before the second injection was performed, and residual activity from this additional delayed scan was subtracted from the activity of the second injection. COVs of both subtraction methods were compared. Blood glucose values were measured at the time of injection and used to correct the %ID/g values. RESULTS: The COV for the mean %ID/g between (18)F-FDG small-animal PET scans performed on the same day 6 h apart was 15.4% +/- 12.6%. The delayed scan subtraction method did not produce any significant change in the COV. Blood glucose correction increased the COV. The injected dose, tumor size, and body weight did not appear to contribute to the variability of the scans. CONCLUSION: (18)F-FDG small-animal PET mouse xenograft studies were reproducible with moderately low variability. Therefore, serial small-animal PET studies may be performed with reasonable accuracy to measure tumor response to therapy.     

Neuroimaging studies of children with serious emotional disturbances: a selective review.

OBJECTIVES: To critically review and integrate, from a developmental perspective, recent magnetic resonance imaging (MRI) studies of 4 childhood psychiatric disorders: schizophrenia, bipolar disorder (BD), attention-deficit hyperactivity disorder (ADHD), and major depressive disorder (MDD). METHOD: We reviewed published reports in refereed journals. We briefly describe the major findings with respect to the brain morphometry, chemistry, and function of children with psychiatric disorders and synthesize the reports in a summary to update clinicians. RESULTS: Some cortical grey matter abnormalities associated with schizophrenia appear to predate the onset of frank psychosis and continue to advance after the onset of psychosis, at least in more severe cases. Pediatric BD is associated with abnormalities in a circuit, thought to be involved in mood regulation, that encompasses the amygdala, striatum, and ventral PFC. Frontostriatal abnormalities are reported consistently in ADHD, potentially reflecting abnormalities in the development of cognitive control. Children with MDD show prefrontal cortical alterations that may differ in familial and nonfamilial subtypes of MDD. CONCLUSIONS: Results from neuroimaging studies of childhood psychopathology reveal abnormalities in the developmental trajectories observed in healthy children. Although MRI has increased our understanding of the pathophysiology of these disorders, routine neuroimaging for children with severe emotional disturbances is not indicated for diagnostic purposes.     

Biofeedback in colorectal practice

PURPOSE: Biofeedback treatment is often offered to patients in colorectal centers; however, standards of treatment are still lacking. A dedicated team approach is desirable but difficult to coordinate. We present our three-year experience of electromyographic-based biofeedback treatment offered within a multicenter, statewide organization. METHODS: Between October 1992 and October 1995, 188 patients completed a biofeedback treatment program in one of five coordinated centers within a 200-mile radius. A unified common database was established and continuously updated. A colorectal surgeon served as statewide director, and dedicated teams were established at each location. Each local team included the medical director and a certified biofeedback therapist and had access to a dietitian and a nurse data coordinator. Electromyographic-based biofeedback sessions were given weekly, and a home trainer program was established. RESULTS: A total of 116 patients with chronic constipation had a mean of eight (range, 2–14) weekly sessions. A total of 72 patients with fecal incontinence had a mean of seven (range, 2–11) weekly sessions. A total of 84 percent of the constipated and 85 percent of the incontinent patients had significant improvement with biofeedback treatment. Patient compliance and satisfaction were high. Constipated patients increased the mean number of weekly unassisted bowel movements from 0.8 to 6.5. Incontinent patients decreased the mean number of weekly gross incontinence episodes from 11.8 to 2. CONCLUSIONS: Biofeedback treatment can be extremely successful in both incontinent and constipated patients. A large geographic area can be covered with coordinated centers in which each dedicated team uses a unified treatment protocol, and a common database is established.Poster presentation at the meeting of The American Society of Colon and Rectal Surgeons, Seattle, Washington, June 9 to 14, 1996.     

Mitochondrial diseases: an overview of genetics, pathogenesis, clinical features and an approach to diagnosis and treatment

Defects in structures or functions of mitochondria, mainly involving the oxidative phosphorylation, mitochondrial biogenesis and other metabolic pathways have been shown to be associated with a wide spectrum of clinical phenotypes. The ubiquitous nature of mitochondria and their unique genetic features contribute to the clinical, biochemical and genetic heterogenecity of mitochondrial diseases. This article focuses on the recent advances in the field of mitochondrial disorders with respect to the consequences for an advanced clinical and genetic diagnostics. In addition, an overview on recently identified genetic defects and their pathogenic molecular mechanisms are given.     

Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling

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Melanoma

The incidence of melanoma in the US is rising at a rate second only to that of lung cancer in women. Early stage melanoma is curable, but once metastatic, it is almost uniformly fatal. The immunotherapy of melanoma is a new and exciting therapeutic modality that is being extensively investigated worldwide. Interferon-alpha has an approximately 16% response rate in metastatic melanoma. In the randomised trials to date, no combination of chemotherapeutic or hormonal agent with interferon-alpha has proven to be superior to dacarbazine, the reference agent for the treatment of metastatic melanoma. The role of interferon-alpha-2b in the adjuvant therapy of localised melanoma at high risk for relapse has recently been established, with the results of 2 large randomised trials conducted by the US Intergroup, one showing improvement in both relapse-free survival and overall survival, and the other in relapse-free survival only. Interferon-gamma has not been effective in the adjuvant setting or in metastatic disease, but is part of combination protocols used for regional therapy for extremity melanomas. Interleukin-2 has an overall response rate of 15 to 20% in metastatic melanoma and produces some complete and durable remissions. The US Food and Drug Administration has recently approved the use of high-dose bolus administration of recombinant interleukin-2 for the therapy of metastatic melanoma. Results of combination chemotherapy and immunotherapy regimens containing interleukin-2 (biochemotherapy) are promising, and ongoing research will determine whether a survival impact will be confirmed in randomised studies. Vaccine therapy is another exciting area of research, and clinical trials are ongoing in both metastatic melanoma and as adjuvant therapy. A bewildering array of vaccines (whole cell, carbohydrate and peptide) is available, and it remains to be seen which of these numerous preparations will be most effective. Adjuvant therapy trials with a ganglioside GM2 vaccine and others are ongoing. Numerous peptide vaccines are also being investigated for metastatic melanoma, singly and in combination with other immunotherapeutic agents.