The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Comparison of 2-dimensional and 3-dimensional acquisition for 18F-FDG PET oncology studies performed on an LSO-based scanner.

Three-dimensional (3D) PET acquisition has the potential to reduce image noise but the advantage of 3D PET for studies outside the brain has not been well established. To compare the performance of 2-dimensional (2D) and 3D acquisition for whole-body (18)F-FDG applications, a series of patient studies were performed using a lutetium oxyorthosilicate (LSO)-based tomograph. METHODS: Comparative 2D and 3D images were acquired for 27 oncology patients using an LSO-based tomograph. Data acquisition (350-650 keV, 6 ns) started 99 +/- 12 min (mean +/- SD) after injection of 624 +/- 76 MBq (18)F-FDG. Bias caused by tracer redistribution and decay was eliminated by acquiring dynamic data over a single-bed position using a protocol that alternated between septa-in and septa-out modes (2D, 3D, 2D, 3D, 2D, 3D). Frames were combined to form 8 statistically independent sinograms: four 2D replicates (105 s) and four 3D replicates (90 s). The different frame durations in 2D and 3D compensated for the different number of overlapping bed positions required for an 85-cm whole-body study. Images were reconstructed with either 2D or fully 3D ordered-subsets expectation maximization (2 iterations and 8 subsets; 2D 6-mm gaussian, 3D 5- and 6-mm gaussian). Image target-to-background ratio was assessed by dividing the lesion maximum by the mean within a neighboring background region. Image noise was assessed by applying background regions of interest to the replicate images and calculating the within-patient coefficient of variation. RESULTS: The difference in target-to-background ratio between the 2D and 3D images, when they were filtered with 6-mm and 5-mm gaussian filters, respectively, was not highly statistically significant (P = 0.16). The mean ratio of 3D to 2D image values was 0.94 with 95% limits of agreement of 0.63-1.41. The within-patient coefficients of variation for the 2D and 3D images were 13% +/- 15% and 9% +/- 10%, respectively (P = 0.0005). CONCLUSION: Under conditions of matched target to-to-background ratios, the 3D mode was found to produce images with significantly less variability than the 2D mode. These data provide support for the use of 3D acquisition with LSO detectors to reduce scan times in whole-body (18)F-FDG applications.     

Instillation of bacillus Calmette-Guerin into the renal pelvis of a solitary kidney for the treatment of transitional cell carcinoma

Intravesical bacillus Calmette-Guerin is effective in the treatment and prophylaxis of superficial urothelial cancer of the bladder. There have been few reports of its efficacy and toxicity when instilled into the upper urinary tract. We elected to use intracavitary bacillus Calmette-Guerin in a patient with recurrent high grade transitional cell carcinoma in the renal pelvis of a solitary autotransplanted kidney. The patient required hospitalization and triple-drug therapy after 5 instillations. She was free of tumor 1 year after bacillus Calmette-Guerin instillations.     

Predictive validity of certification by the American Board of Internal Medicine

STUDY OBJECTIVE: To determine the predictive validity of the American Board of Internal Medicine (ABIM) certification process. DESIGN: Prospective measurement of the knowledge, skills, and attitudes of 185 ABIM-certified and 74 noncertified internists by a written examination; evaluation by professional associates; a patient questionnaire assessing satisfaction with care, physician's counseling role, and preventive care; and review of records of patients with common illnesses. SUBJECTS: Practicing internists who completed training or received ABIM certification 5 to 10 years previously. SETTING: Office-based practices in six western states. RESULTS OF DATA ANALYSIS: Physicians certified by the ABIM had significantly higher scores on the written examination than the noncertified physicians, and scores on our examination correlated highly with the ABIM certification examination (r = 0.73). Ratings of clinical skills by professional associates were significantly higher for certified internists and also correlated highly with ABIM examination scores (r = 0.53 to 0.59). Regression analysis showed that ABIM certification status was the major variable affecting performance on these measures of clinical competence. Results from other measures did not show many differences between certified and noncertified physicians in the care of patients with common illnesses, but modest differences in preventive care and a few differences in outcome favored the certified physicians. CONCLUSIONS: Comparison of findings from the written examination and the professional associate ratings with certification status and original ABIM certification examination scores shows predictive validity of ABIM certification. Further studies are needed to determine if certification status predicts important differences in the care of patients with complex illnesses.     

Extradural lymphoma presenting as an acute surgical emergency

Extradural lymphoma can present as an acute neurosurgical emergency. The clinical presentation and radiological appearance may suggest epidural hematoma or meningioma. Lymphoma should be considered as a rare but possible diagnosis before operation. High resolution computed tomography using direct coronal imaging with and without contrast enhancement may aid in suggesting the correct preoperative diagnosis.     

'What do you notice?' Using posters containing questions and general instructions to guide preschoolers' science and mathematics learning

To increase preschoolers' science and mathematics learning experiences both within and outside the classroom, we developed age-appropriate materials containing general questions and instructions that teachers and parents could use when interacting with their students and children. The questions and instructions were related to a specific science or mathematics skill (e.g., classifying), but were general enough so that they could be applied to a variety of situations. Observations of three classrooms and interviews with the classroom teachers and aides, and the parents of the children in the classrooms suggested that use of these materials was beneficial to the children, teachers, and parents, and resulted in increasing the amount of science and mathematics activities and discussions in two of the classrooms as well as outside the classrooms.