Pharmacokinetics of 2-oxothiazolidine-4-carboxylate, a cysteine prodrug, and cysteine

The pharmacokinetics of both 2-oxothiazolidine-4-carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2-hour intravenous infusion (56-66 mg/kg) or similarly infused (70-100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis-Menten kinetics with parallel first-order elimination. OTZ was efficiently removed from the plasma. The Michaelis-Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.     

Increasing incidence of carcinoma of the gastric cardia in Sweden from 1970 to 1985

Several American, Japanese and European centres have reported an increase in carcinoma of the gastric cardia, contrary to the general trend in the incidence of gastric cancer. The aim of this nationwide population-based study was to describe trends in the incidence of tumours of the gastric cardia in Sweden over the 16-year period from 1970 to 1985. The Swedish cancer register, which is more than 95 per cent complete, was used to identify cases. There were 1514 men and 481 women with cancer of the gastric cardia. The age-standardized rates increased in men from 1.9 per 10(5) population in 1970-1973 to 3.0 per 10(5) in 1982-1985, corresponding to a mean annual increase of 2.5 per cent (95 per cent confidence interval (c.i.) 1.6-3.4 per cent). In women, the age-standardized rates increased from 0.5 per 10(5) in 1970-1973 to 0.8 per 10(5) in 1982-1985, the mean annual increase being 0.9 per cent (95 per cent c.i. 0.0-1.8 per cent). The highest incidences were found in southern Sweden, contrary to the geographical distribution of gastric cancer in general, which shows a south-to-north gradient. The disparate epidemiological features of cancer of the cardia and gastric cancer at other sites suggest that the aetiologies may also be different. Since little is known about the aetiology of cancer of the cardia, and the incidence seems to be rising rapidly, analytical studies are urgently needed.     

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats

Three groups of amygdala-kindled rats received 10 bidaily treatment trials: On each trial, the drug-before group received a diazepam (2.5 mg/kg i.p.) injection 1 hr before a convulsive stimulation, the drug-after group received a diazepam injection 1 hr after a stimulation, and the vehicle control group received a vehicle injection either 1 hr before or 1 hr after a stimulation. After treatment, only the drug-before group displayed significantly longer forelimb clonus under the influence of diazepam (that is, they displayed contingent tolerance to diazepam's anticonvulsant effect) and significantly longer forelimb clonus while drug free. Following a 14-day retention period, the rats in the drug-before group retained significant levels of contingent tolerance but did not display significant increases when tested drug free. These data suggest that compensatory responses do not play a causal role in the expression of contingent tolerance.     

Surgical management of patients with persistent or recurrent medullary thyroid cancer

OBJECTIVE: To compare estimates based on vaccination cards, parental recall, and medical records of the percentages of children up-to-date on vaccinations for diphtheria, tetanus, and pertussis; polio; and measles, mumps, and rubella. METHOD: The authors analyzed parent interview and medical records data from the Baltimore Immunization Study for 525 2-year-olds born from August 1988 through March 1989 to mothers living in low-income Census tracts of the city of Baltimore. RESULTS: Only one-third of children had vaccination cards; based on medical records, these children had higher up-to-date coverage at 24 months of age than did children without cards. For individual vaccines, only two-thirds of parents could provide information to calculate coverage rates; however, almost all provided enough information to estimate coverage for the primary series. For each vaccine and the series, parental recall estimates were at least 17 percentage points higher than estimates from medical records. For children without vaccination cards whose parents could not provide coverage information, up-to-date rates based on medical records were consistently lower than for children with cards or with parents who provided coverage information. CONCLUSIONS: Population-based vaccine coverage surveys that rely on vaccination cards or parental recall or both may overestimate vaccination coverage.     

ZAP-70 association with T cell receptor zeta (TCRzeta): fluorescence imaging of dynamic changes upon cellular stimulation

The nonreceptor protein tyrosine kinase ZAP-70 is a critical enzyme required for successful T lymphocyte activation. After antigenic stimulation, ZAP-70 rapidly associates with T cell receptor (TCR) subunits. The kinetics of its translocation to the cell surface, the properties of its specific interaction with the TCRzeta chain expressed as a chimeric protein (TTzeta and Tzetazeta), and its mobility in different intracellular compartments were studied in individual live HeLa cells, using ZAP-70 and Tzetazeta fused to green fluorescent protein (ZAP-70 GFP and Tzetazeta-GFP, respectively). Time-lapse imaging using confocal microscopy indicated that the activation-induced redistribution of ZAP-70 to the plasma membrane, after a delayed onset, is of long duration. The presence of the TCRzeta chain is critical for the redistribution, which is enhanced when an active form of the protein tyrosine kinase Lck is coexpressed. Binding specificity to TTzeta was indicated using mutant ZAP-70 GFPs and a truncated zeta chimera. Photobleaching techniques revealed that ZAP-70 GFP has decreased mobility at the plasma membrane, in contrast to its rapid mobility in the cytosol and nucleus. Tzetazeta- GFP is relatively immobile, while peripherally located ZAP-70 in stimulated cells is less mobile than cytosolic ZAP-70 in unstimulated cells, a phenotype confirmed by determining the respective diffusion constants. Examination of the specific molecular association of signaling proteins using these approaches has provided new insights into the TCRzeta-ZAP-70 interaction and will be a powerful tool for continuing studies of lymphocyte activation.