Mechanism of uptake and retention of F-18 BMS-747 158-02 in cardiomyocytes: a novel PET myocardial imaging agent

Background BMS-747158-02 is a novel fluorine 18-labeled pyridazinone derivative designed for cardiac imaging. The uptake and retention mechanisms of F-18 BMS-747158-02 in cardiac myocytes were studied in vitro, and the biodistribution of F-18 BMS-747158-02 was studied in vivo in mice. Methods and Results Fluorine 19 BMS-747158-01 inhibited mitochondrial complex I (MC-I) in bovine heart submitochondrial particles with an IC₅₀ of 16.6±3 nmol/L that was comparable to the reference inhibitors of MC-1, rotenone, pyridaben, and deguelin (IC₅₀ of 18.2±6.7 nmol/L, 19.8±2.6 nmol/L, and 23.1±1.5 nmol/L, respectively). F-18 BMS-747158-02 had high uptake in monolayers of neonatal rat cardiomyocytes (10.3%±0.7% of incubated drug at 60 minutes) that was inhibited by 200 nmol/L of rotenone (91%±2%) and deguelin (89%±3%). In contrast, an inactive pyridaben analog, P-0 (IC₅₀ value>4 μmol/L in MC-1 assay), did not inhibit the binding of F-18 BMS-747158-02 in cardiomyocytes. Uptake and washout kinetics for F-18 BMS-747158-02 in rat cardiomyocytes indicated that the time to half-maximal (t_1/2) uptake was very rapid (approximately 35 seconds), and washout t_1/2 for efflux of F-18 BMS-747158-02 was greater than 120 minutes. In vivo biodistribution studies in mice showed that F-18 BMS-747158-02 had substatial myocardial uptake (9.5%±0.5% of injected dose per gram) at 60 minutes and heart-to-lung and heart-to-liver ratios of 14.1±2.5 and 8.3±0.5, respectively. Positron emission tomography imaging in the mouse allowed clear cardiac visualization and demonstrated sustained myocardial uptake through 55 minutes. Conclusions F-18 BMS-747158-02 is a novel positron emission tomography cardiac tracer targeting MC-I in cardiomyocytes with rapid uptake and slow washout. These characteristics allow fast and sustained accumulation in the heart.     

Age-linked prognostic categorization based on a new histologic grading system of neuroblastomas. A clinicopathologic study of 211 cases from the Pediatric Oncology Group.

Histologic sections (minimum of four sections per patient) from 211 patients with neuroblastoma were reviewed. The tumors were resected before therapy, which was standardized according to age and stage. Low mitotic rate (MR) (less than or equal to ten per ten high-power fields) and calcification emerged as the most significant prognostic features after statistical analysis by stepwise log-rank tests (P less than 0.0001 and P = 0.0065, respectively). Histologic Grades 1, 2, and 3 were defined on the basis of the presence of both, any one, or none of these two prognostic features, respectively (Grade 3 had absence of low MR, i.e., these tumors had high MR [greater than ten per ten high-power fields]). Statistically significant differences in survival were observed in the grades after adjusting for age and stage (P less than 0.001). The degree of differentiation, although significant by itself, was no longer significant after adjusting for the grades. Age groups (less than or equal to 1 versus greater than 1 year of age), which also emerged as an independent prognostic feature (P less than 0.001), were linked with the grades to define two risk groups as follows: (1) a low-risk (LR) group consisting of patients in both age groups with Grade 1 tumors and patients 1 year of age or younger with Grade 2 tumors and (2) a high-risk (HR) group consisting of patients older than 1 year of age with Grade 2 tumors and patients in both age groups with Grade 3 tumors. The difference in survival between LR (160 cases) and HR groups (51 cases) was statistically significant (P less than 0.001). Concordance between these LR and HR groups and the Shimada classification was observed in 84% of cases. The new histologic grading system has the following advantages: (1) use of familiar terminology and histologic features in the grading system and (2) relative ease of assessment because the degree of differentiation does not need to be determined. The grading system should be tested on a new data set with an appropriate histologic sample of similar size to confirm these results.     

Oral Health Status of Children and Adolescents by Rural Residence, United States

CONTEXT: The limited information available on the oral health status of rural children in the United States makes it difficult to devise policy strategies to address perceived problems. PURPOSE: To document the oral health status and dental care utilization of US children by place of residence, METHODS: Data from National Health Interview Surveys for 1995, 1997, and 1998, and from the third National Health and Nutrition Examination Survey (1988-1994) were analyzed. FINDINGS: Children residing in rural areas were more likely to be uninsured for dental care than were children from urban areas (41.1% versus 34.7%). A greater percentage of rural than urban children reported unmet dental needs (7.5% versus 5.6%); there was no difference in self-reported poor dental status. Urban children were more likely than rural children to have visited the dentist in the past year (73.6% versus 69.9%) and were also more likely to be regular users of dental care (61.7% versus 51.4%). Differences in percentage of rural and urban children with caries lesions and caries experience were not significant. CONCLUSIONS: Children residing in rural areas have less access to and utilization of dental care compared to children residing in urban areas. Moreover, poor rural children display less utilization of dental services than poor urban children. Differences in the sum of decayed and filled primary teeth and the sum of decayed, missing, and filled permanent teeth were not significant.     

The effect of awareness of measurement error on physical therapists' confidence in their decisions.

This study examined whether physical therapists understand the meaning of measurement error and whether information about measurement error affects their decisions. One of four versions of two physical therapy problems was mailed to 500 randomly selected physical therapists. Therapists were asked to define reliability and error of measurement, to estimate the error of measurement of two assessments, and to make decisions about an intervention based on specific measurements. They were also asked to rate their confidence in those decisions. Problems varied on the presence or absence of measurement information and on the difference between an observed measurement and a criterion measurement against which the observed measurement must be compared to make a decision. The response rate was 62%; respondents represented a typical profile of practicing physical therapists. The therapists understood reliability, but they did not correctly describe the relationship between reliability and error of measurement. Their estimates of the error of measurement of the two assessments were reasonable for only one procedure. The presence or absence of measurement information and difference between observed and criterion measurements affected their confidence, albeit inappropriately, in only one problem. Confidence was not affected by the therapists' level of experience, type of reading, formal study, or degree earned. Therapists responded to the two problems differently. The problems involved different measures, roles, utilities, and structures. The process of decision making does not generalize to all decision types. Measurement principles and strategies of use in decision making must be emphasized in physical therapy curricula so that physical therapists can consider the quality of their assessment data in making clinical decisions.