Inter-observer reliability of three different radiographic scores for adult haemophilia.

To evaluate the inter-observer reliability of radiological assessment systems for haemophilic arthropathy, three senior orthopaedic surgeons with expertise in haemophilia independently evaluated a total of 527 joint radiographs of adult haemophilia patients, without any knowledge of the clinical data. This study was the largest study to evaluate the reliability of radiological assessment systems. As for the results, the Arnold-Hilgartner staging system showed moderate reliability (kappa value: κ = 0.44, P = 0.000), and the De Palma grading system and the Pettersson scoring system showed fair reliability (κ = 0.40, P = 0.000) and slight reliability (κ = 0.12, P = 0.000) respectively. As for the reliability of the eight findings in the Pettersson scoring system, three findings, which were 'narrowing of joint space' (κ = 0.70 P = 0.000), 'irregular subchondral surface' (κ = 0.58, P = 0.000) and 'erosion of joint margins' (κ = 0.56, P = 0.000), showed substantial or moderate reliability. Other findings showed fair or less reliability. The traditional radiological assessment systems showed poor inter-observer reliability. Both progressive scales showed higher reliability than the additive scale, and the three findings in the Pettersson scoring system showed good reliability. These results suggested that the progressive scale, including the three reliable radiological findings, might be a more reliable radiological assessment system.

Survival and viral load in four groups of HIV-1 infected hemophiliacs compared by three-way data clustering.

We assigned a total of 131 hemophiliacs infected with HIV-1 into four clusters by applying a 3-way data analysis method. Sequentially acquired CD4+ and CD8+ cell counts obtained longitudinally over an observation period from 1986 to 1992 were analyzed. During the successive observation in this interval, a clustering of patients is not always coincident over all the times, because the cell counts vary with time. Therefore, the 3-way data clustering is to obtain the optimal result of the classification of patients through all the interval of observation. Examining patients' survival after that period, the cumulative mortality rate was highest among the 36 hemophiliacs in Cluster 1. Less mortality was found in Cluster 2, consisting of 49 hemophiliacs and none was reported in Clusters 3 and 4, which included 33 and 13 hemophiliacs, respectively. However, a significantly lower blood viral copy number was found in Cluster 3 than in Cluster 4. A total of six long-term non-progressors was found, five in Cluster 3 and one in Cluster 4, while none was found in Cluster 1 or 2. As demonstrated in this analysis, 3-way data clustering may represent a good data mining technique for handling various types of clinical data.

Determination of pharmacokinetic parameters of stavudine in Japanese patients infected with HIV-1, using a Gaussian-like input rate function.

We sought to examine variation in pharmacokinetic parameters of stavudine in Japanese patients infected with HIV-1. Stavudine concentrations were measured in two hemophiliacs (HIV-1 asymptomatic carriers (ACs)) and two non-hemophiliacs (both ACs). To simulate the plasma stavudine concentrations following a single oral dose, we used a Gaussian-like input rate function in a single compartment model. The theoretical equation successfully simulated changes in the time course of plasma stavudine concentrations in all four patients. The mean+/-SD of Tmax, Cmax, AUC0-infinity, and t 1/2 were 0.96+/-0.26 hr, 478+/-90 ng/mL, 1112+/-136 ng x hr/mL, and 1.26+/-0.23 hr, respectively. Pharmacokinetic characteristics were comparable to those reported in the literature, although the mean of Cmax was slightly lower and means of Tmax and t 1/2 slightly longer than those previously reported. Interpatient variability in plasma stavudine concentrations was not as dramatic as that seen with lamivudine. Thus, we confirmed the validity of the uniform therapeutic regimen of stavudine in Japanese people with HIV-1 infection.

Pharmacokinetic consideration on administration regimen of lamivudine in japanese patients infected with HIV-1.

OBJECTIVE: The typical regimen for lamivudine is 150 mg bis in die (bid). However, pharmacokinetic values of lamivudine will differ among individual patients. In addition, few studies regarding the pharmacokinetics of lamivudine in the Japanese people have so far been reported. Therefore, we have aimed to examine the variation in the pharmacokinetic values of lamiduvine present in six Japanese patients with HIV-1 infection. PATIENTS AND METHODS: Lamivudine concentrations were measured in three hemophiliacs (HIV-1-asymptomatic carrier, AC) and three non-hemophiliacs (2 of these patients were AC and one had AIDS-related complex, ARC). In order to simulate the lamivudine plasma concentrations found in chronic oral administration, we added an absorption compartment to the two-compartment model. RESULTS: The mean +/- SD of Tmax, Cmax, AUC(0 - infinity) and t1/2beta were 1.2 +/- 0.5 (hours), 1,280 +/- 267 (ng/ml), 6,778 +/- 2,763 (ng x h/ml), and 10.3 +/- 4.7 (hours), respectively. Although these values were comparable on average to those previously reported, there were noticeable differences with respect to the various time courses of drug plasma concentration among each patient. CONCLUSION: Computations speculated that the trough and peak plasma concentrations as well as the AUC at steady-state change significantly depending on each patient. It suggests that individual pharmacokinetic values of lamivudine should be determined before deciding the optimal administration dose for specific patients.

[Causes of death (1983-1997) in patients infected with human immunodeficiency virus by contaminated blood coagulation factor products: report of the clinical study group on prevention and treatments of HIV infection].

Our group conducted a national survey of patients who had died of acquired immunodeficiency syndrome (AIDS) after being infected with human immunodeficiency virus type 1 (HIV-1) by contaminated blood coagulation factor products. A total of 1446 hospitals, clinics, and other health-care institutions throughout Japan were enrolled in the study, which was supported by the Japanese government Ministry of Health and Welfare with a health sciences grant for research on HIV/AIDS. Of the 1434 registered patients who had been infected with HIV-1 by contaminated blood coagulation factor products, 493 (34%) had died as of Oct. 30, 1997. Most were hemophiliacs. The average CD4+ cell count was 25/microliter for the 398 who died of complications from AIDS, compared to an average of 158/microliter for those who died of other causes. Pneumocystis carinii pneumonia, cytomegalovirus infection, and atypical mycobacterial disease were the main causes of death in patients with AIDS. The annual death rate for AIDS patients in Japan dropped dramatically in 1997, 1 year later than a similar trend observed in the United States. The introduction and widespread adoption of new and effective drugs and treatment regimens for HIV-1 and opportunistic infections will be essential life-saving measures.

Using Gaussian-like input rate function in the two-compartment model. Formulation and application to analysis of didanosine plasma concentration in two Japanese hemophiliacs.

We used a time-dependent input rate function in the two-compartment model to simulate drug plasma concentrations after an oral administration. The input rate term has a Gaussian-like structure with two parameters, time to maximum absorption rate (tm) and measure of the duration of the absorption process (s). This structure corresponds to the scenario in which the absorption rate of the drug into the central compartment changes unimodally with respect to time after administration with a single peak at time tm. We demonstrate the applicability of this formulation in the simulation of plasma concentration of didanosine after oral administration in two Japanese hemophiliacs. We found that we were able to simulate the time courses of the didanosine plasma concentrations in both patients using the theoretical equation with the input term included, and that we were able to determine the six parameters in the equation by the least squares estimation. Pharmacokinetic values derived from the best-fit curve were almost comparable to those reported in other literature except that the Cmax and AUC0-infinity seemed to be slightly higher than those reported elsewhere. Although we are unable to verify the accuracy of this formulation because of the lack of sufficient Japanese data, we are able to demonstrate its efficacy and convenience in the application presented here.

Analysis of clinical AIDS-free interval after CD4+ cell counts fall below 200 x 10(6) L-1 in Japanese haemophiliacs infected with HIV-1.

We analysed the time from the date CD4+ cell counts fell below 200 x 10(6) L-1, defined as ti, to the onset of clinical AIDS, according to the 1987 Centers for Disease Control and Prevention case definition, in 129 Japanese haemophilia patients infected with HIV-1. The cumulative onset of clinical AIDS was analysed by the Kaplan-Meier method and proportional hazard model. Incorporated covariates were age of each patient at time ti, as well as CD4+ and CD8+ cell counts, serum levels of IgG, IgA, IgM, GOT and GPT at ti. The time of antiretroviral treatment initiation was also considered. The 50% AIDS-free interval after ti was 3.00 years (95% confidence interval (CI), range 0.49-5.51) and 1.71 years (95% CI, range 0.66-2.76) for the patients at CDC stage II and stage III, respectively (significantly different, P = 0.0013). Among the patients at CDC stage II at ti, higher levels of IgA were tightly associated with a shorter period from ti to onset of clinical AIDS (P < 0.0001), and relative hazard was 1.35 (95% CI, 1.11-1.64) with increase of IgA level by 1.0 g L-1. Thus there is a broad distribution in the time to onset of clinical AIDS in Japanese haemophiliacs even after CD4+ cell counts fall below 200 x 10(6) L-1. This should be taken into consideration in deciding upon the therapy and care of HIV-1 infected people.

Life time expectancy of hemophilia patients infected with HIV-1 with the risk of hepatocellular carcinoma after HCV infection.

1. INTRODUCTION. The latest statistics how that Japanese hemophilia patients infected with HIV-through clotting factor concentrates may survive more than 10 years after HIV-infection without showing an onset of AIDS [1]. Unfortunately, however, results of the recent surveillance have revealed that about half of hemophilia patients had also been infected with the hepatitis C virus (HCV) [2]. Therefore, some hemophilia patients might suffer from hepatocellular carcinoma triggered by HCV after some latent periods. In the present study, we computed the life time expectancy of hemophilia patients with two risks of HIV-and HCV infections. 2. METHOD. We used the Weibull hazard function h(t) for the hazard rate from AIDS after infection with HIV-1. In order to describe the hazard rate arising from hepatocellular carcinoma after HCV infection, we utilized the theoretical function c(t) with two parameters that were obtained previously by ourselves from a case-controlled study on hepatocellular carcinoma patients infected with HCV through blood transfusion [3]. Substituting necessary parameters estimated for Japanese hemophilia patients into h(t), the life time expectancy t was computed by the following integration; tau=integral of exp(-integral of h(t')+c(t¿) dt') dt, where t' means the time after HIV-infection, and t¿ is a variable composed of tU and times of HIV-and HCV infections. 3. RESULTS AND DISCUSSION. Without hepatocellular carcinoma, the life time expectancy tau of the patients infected with HIV-1 at the age of 20 was computed as 15.0 years. On the other hand, for the same patients with the risk of hepatocellular carcinoma through HCV infection at the age of 10, 15, 20 and 25 years old, values of tau were computed at 12.2, 13.3, 14.1 and 14.4 years, respectively. Especially noticeable was the reduction of tau in cases of HCV infection was prior to HIV-infection. In the present computation, the two risks from HIV-1 and HCV infections were assumed to be additive because no explicit interaction between them has been reported yet. Various long term effects have been found with the development of HIV/HCV therapies; that should also take into account the survival estimation and therapy planning for HIV-1 infected patients in the coming years.

Growth dynamics of the heart from perinatal period to childhood.

In order to obtain information useful for the diagnosis of fetus and newborn heart disease, we established a theoretical model of perinatal cardiac growth. We measured with the use of ultrasonic cross-section imaging system the mitral valve ring dimension, tricuspid valve ring dimension, and total cardiac dimension as morphological parameters of the heart in 45 cases composed of fetuses and children. The obtained data were entered into a computer. With the use of these data, simulation was made on the basis of the general theory of biological development. The present simulation showed that from the fetal stage to childhood the growth rates of the foregoing three morphological parameters mutually differ, but during the period of growth to the age of 12 years of the present study, they all demonstrated continuous growth up to 3 1/2 years after birth when they reached a growth saturation level.

Kinetics of suicide substrates. Steady-state treatments and computer-aided exact solutions.

A steady-state differential equation that describes the kinetics of suicide substrate was derived for a scheme presented by Walsh et al. (Walsh, C., Cromartie, T., Marcotte, P. and Spencer, r. (1978) Methods Enzymol. 53, 437-488). Using its analytical solutions, the progress curves of substrate disappearance, product formation and enzyme inactivation were calculated for a hypothetical model system, and were compared with the exact solutions which were obtained by the numerical computation on a set of rate equations. The results obtained with the present analytical solutions were much more consistent with the exact solutions than those obtained using Waley's solution (Waley, S.G. (1980) Biochem. J. 185, 771-773). The most important factor for a system of suicide substrates was found to be the term (1 + r)mu as proposed by Waley, where r is the ratio of the rate constant of product formation to that of enzyme inactivation and mu is the ratio of initial concentration of enzyme to that of suicide substrate. In cases where this term has a value greater than unity, all the molecules of suicide substrate are used up leaving some enzyme molecule still active. To the contrary, in cases where the term has a value smaller than unity, all the enzyme molecules are inactivated with some molecules of suicide substrate being left unreacted. When the term is equal to unity, then all the enzyme molecules are inactivated and all the molecules of the suicide ar converted. Practical methods for estimating kinetic parameters are described.

Characterization of porcine adrenocortical lysosomes.

Porcine adrenocortical lysosomes were characterized by differential centrifugation, acid hydrolase contents, latency of cathepsin D, release of bound acid hydrolases in soluble form, and isopycnic density gradient centrifugation. Cathepsins D and B, beta-N-acetylglucosaminidase, beta-galactosidase and arylsulphatase were found exclusively in the lysosomes, while alpha-mannosidase and beta-glucuronidase were in both the lysosomal and microsomal fractions. The activity of cathepsin D was remarkably high, amounting to more than 6 times that in porcine liver and to more than 10 times that in liver of Sprague-Dawley rats in terms of units per g wet tissue. Porcine adrenocortical lysosomes showed a modal isopycnic density value of 1.155, but mitochondria a value of 1.145. The validity of these values was studied by investigating the possibilities of agglutination of organelles, damage to lysosomal membranes, disruption of mitochondria due to the hydrostatic pressure and by applying the same procedures of isopycnic centrifugation to hog and rat livers. After these validity tests, porcine adrenocortical lysosomes were concluded to be unique in their strikingly high content of cathepsin D as well as in their low modal isopycnic density which is very close to that of porcine adrenocortical mitochondria.