Several groups have reported that okadaic acid (OA) and some other tight-binding protein phosphatase inhibitors including microcystin-LR (MCLR), calyculin-A and tautomycin prevent each other from binding to protein phosphatase 2A (PP2A). In this paper, we have introduced an improved procedure for examining to what extent the affinity of an enzyme for a labelled tight-binding ligand is reduced by binding of an unlabelled tight-binding, ligand to the enzyme. Using this procedure, we have analysed the dose-dependent reduction of PP2A binding of [24-3H]OA by addition of OA, MCLR, calyculin-A and tautomycin. The results indicate that the binding of the unlabelled inhibitors to the PP2A molecule causes a dramatic (10(6)-10(8)-fold) increase in the dissociation constant associated with the interaction of [24-3H]OA and PP2A. This suggests that OA and the other inhibitors bind to PP2A in a mutually exclusive manner. The protein phosphatase inhibitors may share the same binding site on the PP2A molecule. We have also measured values of the dissociation constant (Ki) for the interaction of these toxins with protein phosphatase 1 (PP1). For MCLR and calyculin-A, the ratio of the Ki value obtained for PP1 to that for PP2A was in the range 4-9, whereas it was 0.01-0.02 for tautomycin. The value of tautomycin is considerably smaller than that (0.4) calculated from previously reported Ki values.

In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 microg/ml in a standard continuous infusion schedule over 2 h and 4 h.

Background and purpose — Deep-learning approaches based on convolutional neural networks (CNNs) are gaining interest in the medical imaging field. We evaluated the diagnostic performance of a CNN to discriminate femoral neck fractures, trochanteric fractures, and non-fracture using antero-posterior (AP) and lateral hip radiographs. Patients and methods — 1,703 plain hip AP radiographs and 1,220 plain hip lateral radiographs were included in the total dataset. 150 images each of the AP and lateral views were separated out and the remainder of the dataset was used for training. The CNN made the diagnosis based on: (1) AP radiographs alone, (2) lateral radiographs alone, or (3) both AP and lateral radiographs combined. The diagnostic performance of the CNN was measured by the accuracy, recall, precision, and F1 score. We further compared the CNN’s performance with that of orthopedic surgeons. Results — The average accuracy, recall, precision, and F1 score of the CNN based on both anteroposterior and lateral radiographs were 0.98, 0.98, 0.98, and 0.98, respectively. The accuracy of the CNN was comparable to, or statistically significantly better than, that of the orthopedic surgeons regardless of radiographic view used. In the CNN model, the accuracy of the diagnosis based on both views was significantly better than the lateral view alone and tended to be better than the AP view alone. Interpretation — The CNN exhibited comparable or superior performance to that of orthopedic surgeons to discriminate femoral neck fractures, trochanteric fractures, and non-fracture using both AP and lateral hip radiographs.

The population pharmacokinetics and pharmacodynamics of cisplatin (CDDP) were evaluated based on a mixed-effect model using the NONMEM program. Unchanged CDDP in plasma was measured as a biologically active platinum species during CDDP chemotherapy, using high-performance liquid chromatography. Plasma concentration measurements (157) of unchanged CDDP from 26 patients with cancer receiving 80 mg/m2 CDDP by infusion over 2 hours, 3.5 hours, or 4 hours were analyzed according to a one-compartment model. The influences of individual characteristics such as body weight, dose schedule, course, and clinical laboratory values (renal function markers, albumin) on total body clearance (Cl) and volume of distribution (Vd) were examined. In the final pharmacokinetic model, body surface area and dose schedule affected Cl of unchanged CDDP. The Cl of CDDP was increased by 27.3% after the 2-hour infusion schedule compared with Cl after the longer infusions. The Vd was estimated as 13.4 L/m2. The interindividual variability for Cl and Vd and residual variability were 22.9%, 30.9%, and 35.5%, respectively. The relationships between maximum concentration (Cmax) of unchanged CDDP and maximum blood urea nitrogen (BUNmax), or minimum creatinine clearance (ClCr,min) over a 1-month period after CDDP administration were evaluated according to linear, exponential, or maximum response (Emax) models. The linear or Emax model described pharmacodynamics most successfully, with relatively large interindividual variability for both slope and EC50 (more than 25%). Residual variability was 15.3% and 17.1% in BUNmax and Clcrmin, respectively. The population means and interindividual and residual variability of pharmacokinetics and pharmacodynamics of CDDP were evaluated using the NONMEM program. The results of this study show that the population pharmacokinetic and pharmacodynamic approach could be useful to manage CDDP nephrotoxicity using sparse data in a clinical setting.

Abstract:The polymerase chain reaction (PCR) assay is a powerful tool for quick diagnosis of various infectious diseases. We applied this technique as well as conventional histopathological examination to diagnose oral tuberculosis. Ziehl-Neelsen staining of oral mucosal specimens often fails to detect Mycobacterium (M.) tuberculosis due to the low number of bacteria in the tissue. Specific primers and probes were synthesized based upon the nucleotide sequence of the 65 kDa membrane protein of M. tuberculosis.DNA extracted from the paraffinembedded tissue was amplified using tali polymerase. PCR assay detected M. tuberculosis in 5 of 6 samples. Although the gene segments from these species were quite similar, the 732P labeled noligonucleotide probes distinguished between M. tuberculosis and M. fotuitum by southern blot hybridization. In all specimens that were Ziehl-Neelsen negative, M. tuberculosis DNA was detected by PCR. These results suggest that PCR is a useful means of diagnosing mycobacterium infection. (J. Oral Sci. 40, 31-36, 1998)