Pharmacokinetics of 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil in woodchucks.

1-(2-Fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU) is a nucleoside analog with potent in vitro activity against hepatitis B virus (HBV) and Epstein-Barr virus. The purpose of this study was to characterize the disposition of L-FMAU following oral and intravenous administration in the woodchuck animal model. The numerous similarities between woodchuck hepatitis virus and HBV infection justify the use of the woodchuck as an animal model for preclinical studies of anti-HBV agents in vivo. Woodchucks were given 25 mg of L-FMAU per kg of body weight intravenously and orally. Concentrations of L-FMAU in urine and plasma were determined by high-performance liquid chromatography. Following intravenous administration of 25 mg of L-FMAU per kg to woodchucks, total clearance was moderate, averaging 0.23 +/- 0.07 liter/h/kg. Renal clearance and nonrenal clearance averaged 0.13 +/- 0.08 and 0.10 +/- 0.06 liter/h/kg, respectively. The steady-state volume of distribution averaged 0.99 +/- 0.17 liter/kg, indicative of intracellular distribution of the nucleoside. The terminal-phase half-life of L-FMAU following intravenous administration averaged 6.2 +/- 2.0 h, and mean residence time averaged 4.5 +/- 0.8 h. Absorption of L-FMAU after oral administration was incomplete, and bioavailability was approximately 20%. Concentrations of L-FMAU in plasma remained above the in vitro 50% effective concentration of 0.026 microg/ml for HBV (C. K. Chu, T. Ma, K. Shanmuganathan, C. Wang, Y. Xiang, S. B. Pai, G.-Q. Yao, J.-P. Sommadossi, and Y.-C. Cheng, Antimicrob. Agents Chemother. 39:979-981, 1995) for 24 h after both intravenous and oral administration of 25 mg of L-FMAU per kg.     

Cross-cultural validity of functional independence measure items in stroke: a study using Rasch analysis.

OBJECTIVE: To analyse cross-cultural validity of the Functional Independence Measure (FIM) in patients with stroke using the Rasch model. SETTINGS: Thirty-one rehabilitation facilities within 6 different countries in Europe. PARTICIPANTS: A total of 2546 in-patients at admission, median age 63 years. METHODS: Data from the FIM were evaluated with the Rasch model, using the Rasch analysis package RUMM2020. A detailed analysis of scoring functions of the 7 categories of the FIM items was undertaken prior to testing fit to the model. Categories were re-scored where necessary. Analysis of Differential Item Functioning was undertaken in pooled data for each of the FIM motor and social-cognitive scales, respectively. RESULTS: Disordered thresholds were found on most items when using 7 categories. Fit to the Rasch model varied between countries. Differential Item Functioning was found by country for most items. Adequate fit to the Rasch model was achieved when items were treated as unique for each country and after a few country-specific items were removed. CONCLUSION: Clinical collected data from FIM for patients with stroke cannot be pooled in its raw form, or compared across countries. Comparisons can be made after adjusting for country-specific Differential Item Functioning, though the adjustments for Differential Item Functioning and rating scales may not generalize to other samples.     

Demographic characteristics, unreported risk behaviors, and the prevalence and incidence of viral infections: a comparison of apheresis and whole-blood donors. The Retrovirus Epidemiology Donor Study

BACKGROUND: The demographics, deferrable risk behaviors, and the prevalence and incidence of viral infections of apheresis (PH) and whole-blood (WB) donors were compared, to characterize these two populations and to evaluate the relative safety of PH and WB donors in terms of transfusion-transmitted viral infections. STUDY DESIGN AND METHODS: A comparison was made of 36,119 PH donors (> or = 1 PH donation) and 1.38 million WB donors (> or = 1 WB donation) in terms of demographics and the prevalence (/100,000 donors) and incidence (/100,000 person-years) of viral infections, by using data collected at five United States blood collection centers between 1991 and 1994. Deferrable risk behaviors were defined as those risk behaviors that would have resulted in donor deferral, had they been reported. The prevalence of deferrable risk behaviors was estimated by using data collected through an anonymous mail survey. RESULTS: PH donors were older and more likely than repeat (2+ donations) WB donors to be female, white, and United States-born and to have a higher degree of education (p < or = 0.001). The prevalence of any viral infection was 50 percent higher in WB donors than in PH donors (p = 0.04), whereas the incidence of HIV, human T-lymphotropic virus, and hepatitis B surface antigen was nonsignificantly higher in WB donors. The prevalence of deferrable risk behaviors did not differ in the two groups. CONCLUSION: Further studies will be needed to evaluate whether the difference in the prevalence of viral infections observed in this study can be explained by demographic characteristics and patterns of donation frequency.     

Suppressive Effect of Immunization with Mouse Fetal Antigens on Growth of Cells Infected with Rauscher Leukemia Virus and on Plasma-Cell Tumors

The recovery of spleen cells infected with Rauscher leukemia virus (RLV) and grown in Millipore diffusion chambers, the development of RLV-induced splenomegaly, and the cumulative mortality from a transplanted ascites plasma-cell tumor were all suppressed in young adult BALB/c male mice previously primed at 3-weekly intervals with x-irradiated, syngeneic embryo cells. RLV-induced splenomegaly was also suppressed by adoptive transfer of postpartal spleen cells, as well as spleen cells for animals primed with syngeneic embryo cells. Similar suppressions were not observed in mice primed with neonatal or normal syngeneic cells. Further, injection of fetal cells was not effective in suppressing the immune function of normal spleen cells, as measured by ability to elaborate a primary immunoglobulin M response to heterologous erythrocyte antigen. The results of this study add to the broad spectrum of tumors of experimental animals and man known to contain neoantigens common to fetal cells.     

Metabolism of ara-C by blast cells from patients with ANLL

The dose-response relationship between extracellular concentration of cytosine arabinoside (ara-C) and intracellular formation of the putative active metabolites of ara-C [ara-C incorporation into DNA and intracellular pools of ara-C in triphosphate form (ara-CTP)] was investigated in blast cells obtained from patients with acute nonlymphocytic leukemia (ANLL) by exposing these cells in vitro to 10, 100, or 1,000 nmol/L of ara-C. We studied 23 untreated patients who subsequently achieved complete remission (CR) with a regimen using daunorubicin and conventional doses of ara-C (ara-C-sensitive group), and 30 patients judged to be ara-C-resistant either by failing initial induction therapy (16 patients) or by having relapsed on an ara-C- containing maintenance regimen (14 patients). In both patient groups, ara-C incorporation into DNA and intracellular ara-CTP both displayed statistically significant increases in response to increasing extracellular concentrations of ara-C (P = .0001 in both cases), with the rate of increase of ara-CTP greater than that of ara-C incorporation. Moreover, blast cells from all patients, even those who were most clinically resistant to ara-C, were able to form ara-CTP and to incorporate ara-C into DNA. Each tenfold increment in extracellular ara-C concentration caused an 8.5-fold increase in ara-CTP, but only a 3.6-fold increase in ara-C incorporation into DNA. Thus, the efficiency of incorporation of ara-C into DNA (defined as the ratio of ara-C incorporation to ara-CTP pools) decreased by 58% with each tenfold increment in the extracellular concentration of ara-C (P less than .0001), presumably as a result of the inhibitory effect of ara-CTP on DNA polymerase. Using an analysis of covariance, modest differences were found in the levels of the ara-C metabolite variables in the ara-C- sensitive group as compared with the resistant group. However, because there was considerable overlap in ara-C metabolite formation among the patient groups, it was not possible to predict clinical outcome by these in vitro assessments of ara-C metabolism.     

Phenotype‐driven molecular autopsy for sudden cardiac death

A phenotype‐driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1–40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty‐five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.