Mechanisms contributing to barbiturate intolerance in rats

1. Female rats, 3 weeks after pretreatment with 200 or 400 (mg/kg)/day barbitone for 2 or 30 days, exhibited a prolonged sleeping time and a reduced awakening barbiturate brain level when challenged with either barbitone or pentobarbitone. After 3 additional weeks, the latter responses had returned, or were returning to, control values.2. Barbitone pretreatment schedules had no residual effect upon in vitro hepatic pentobarbitone-metabolizing activity measured 3 or 6 weeks later, except in one instance, when hepatic enzyme activity was significantly enhanced 3 weeks after 30 daily doses of 200 mg/kg barbitone. In this case, however, an enhanced barbiturate sleeping time, together with a reduced awakening barbiturate brain level, were observed.3. It is concluded that barbitone administered intraperitoneally in doses of 200 to 400 (mg/kg)/day for 2 or 30 days induces a non-hepatogenic intolerance to barbiturates, related to an increased sensitivity of the central nervous system to these drugs. This central intolerance is seen 3 weeks, but not 6 weeks, after pretreatment. Furthermore, this central intolerance has been observed to co-exist with an hepatic tolerance, a situation which could result in a reduced LD(50) coupled with an increase in ED(50).     

Transfection of wild-type deoxycytidine kinase (dck) cDNA into an AraC- and DAC-resistant rat leukemic cell line of clonal origin fully restores drug sensitivity

The AraC-resistant rat leukemic cell line RO/1-A has been shown to have a typical deoxycytidine kinase (DCK)-deficient phenotype and cannot metabolize the antileukemic drugs cytarabine (AraC) and decitabine (DAC). To investigate the relative contribution of mutations in the dck gene to the development of in vitro-induced AraC-resistance, a neomycin selectable plasmid construct harboring the wild-type dck coding region was transfected into RO/1-A. Polymerase chain reaction analysis confirmed the presence of vector DNA in the target cells (RO/1-ADCK) that were stably transfected and monitored over a period of 14 weeks. Northern and Western blot analysis showed restoration of dck mRNA and protein expression. Initial rate measurements of DCK activity showed that Km values for dck were only slightly altered as a result of transfection, whereas strongly increased Vmax values were observed, resulting in a 12-fold increased phosphorylation efficiency for both dC and AraC, compared with the AraC-sensitive parental cell line RO/1 from which the RO/1-A was originally derived. In vitro sensitivity to AraC- and DAC-mediated cytotoxicity was fully restored in RO/1-ADCK. The data pinpoint acquired DCK deficiency caused by mutations of the dck gene as the major cause of AraC resistance in this model.     

A comparison of capsule formation following breast augmentation by saline-filled or gel-filled implants

A retrospective analysis of data on 307 patients was made. The incidence of firmness in breasts augmented by saline-filled prostheses was compared to the incidence in breasts augmented by gel-filled prostheses. A statistically significant lower rate of constricting capsule formation was found in the saline-inflated group.     

Deep venous thrombophlebitis: detection with 4-hour versus 24-hour platelet scintigraphy

Thirty-one nonheparinized patients with suspected deep venous thrombophlebitis (DVT) underwent contrast venography and indium-111 platelet scintigraphy (In-111 PS). Venography permitted identification of acute DVT in 12 of 31 cases (39%). One additional patient was considered to have acute DVT despite nonconclusive venography results. In-111 PS results were positive at 4 hours in nine of 13 cases (69%) and at 24 hours in 12 of 13 cases (92%). Two of four patients with false-negative 4-hour In-111 PS studies had received warfarin. Thus, the sensitivity of 4-hour In-111 PS in patients not receiving anticoagulants was 82%. Venography results were negative for acute DVT in 18 cases, and 4-hour In-111 PS studies were negative or equivocal in each. In-111 PS is an alternative to contrast venography for detecting acute DVT. If 4-hour In-111 PS results are positive, anticoagulation can be initiated. Delayed images are necessary if the 4-hour images are negative or equivocal.     

Antibody-mediated enhancement of hormone activity

The enhancement of hormone activity by antibodies has been known for many years; however, investigation into the molecular basis of the phenomenon has only recently begun. A number of mechanisms for this enhancement, including "buffering" or slow release, bivalency and Fc region, and conformational and receptor "restriction" effects, have been documented or proposed. The availability of panels of monoclonal antibodies of distinct combining site specificity have aided in these studies and contributed substantially to our understanding of hormone-receptor interactions.