Time- and concentration-dependent induction of CYP1A1 and CYP1A2 in precision-cut rat liver slices incubated in dynamic organ culture in the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin

In a previous 24-h study, precision-cut rat liver slices were validated as a useful in vitro model for assessing the dose-related induction of CYP1A1 and CYP1A2 in rat liver following exposure to 2, 3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Further assessment of the utility of this model was accomplished by initially exposing rat liver slices to medium containing TCDD (0.01 nM) for 24 h and incubating the slices up to an additional 72 h in TCDD-free medium. The slices remained viable throughout the incubation period with an intracellular potassium content varying from 45.2 +/- 2.3 micromol/g at 48 h to 50.0 +/- 1.6 micromol/g at 72 h. In TCDD-exposed slices, CYP1A1 protein and its respective enzymatic activity, the O-deethylation of ethoxyresorufin (EROD), significantly increased with time over the 96-h incubation period, with EROD activity increasing from 63.6 +/- 14.2 at 24 h to 905 +/- 291 pmol/mg/min at 96 h. Under identical incubation conditions, but in the absence of TCDD, the EROD activity for the control liver slices ranged from 14. 3 +/- 4.3 to 44.9 +/- 11.9 pmol/min/mg. Conversely, the level of CYP1A2 protein and its respective activity (acetanilide hydroxylation) transiently decreased from 24 to 96 h with no significant differences observed between the control (0 nM TCDD) and treatment group (0.01 nM TCDD). The concentration-effect relationship at 96 h was characterized by incubating rat liver slices for the initial 24 h in medium containing TCDD at concentrations ranging from 0.1 pM to 10 nM. Induction of CYP1A1 protein and EROD activity was observed for all treatment groups with the 10 nM TCDD treatment group displaying greater than 100-fold induction compared to control (0 nM TCDD). Immunohistochemical localization of CYP1A1 protein within liver slices supported the time- and concentration-dependent induction of EROD activity by TCDD. The induction of CYP1A1 was initially observed to be centrilobular, with increased expression due to both elevated CYP1A1 within cells and the recruitment of additional cells expressing CYP1A1 throughout the entire liver slice. Additionally, the immunohistochemical analysis of the liver slices demonstrated the conservation of tissue architecture following up to 96 h of incubation in dynamic organ culture and provided further evidence for maintenance of tissue viability. In comparison to CYP1A1, the induction of CYP1A2 at 96 h was a less sensitive response, with significant induction of CYP1A2 protein and its respective activity occurring at a medium concentration of 0.1 nM TCDD (686 pg/g liver). In general, increasing the incubation period from 24 to 96 h markedly increased TCDD-induced expression of CYP1A1 and minimally enhanced CYP1A2 expression. Moreover, extending the incubation period to 96 h resulted in in vitro induction profiles for CYP1A1 and CYP1A2 that were qualitatively and quantitatively similar to that previously observed following in vivo exposure to TCDD (Drahushuk et al., Toxicol. Appl. Pharmacol. 140, 393-403, 1996).     

Erythromycin coadministration increases plasma atorvastatin concentrations

The effect of erythromycin on the pharmacokinetics of atorvastatin, an inhibitor of HMG-CoA reductase, was investigated in 12 healthy volunteers. Each subject received a single 10 mg dose of atorvastatin on two separate occasions, separated by 2 weeks. Erythromycin (500 mg qid) was given from 7 days before through 4 days after the second atorvastatin dose. Atorvastatin concentrations were determined by an enzyme inhibition assay, which measured both atorvastatin and active metabolites. When erythromycin was coadministered with atorvastatin, mean Cmax and AUC(0-infinity) increased by 37.7% and 32.5%, respectively. Mean terminal half-life was similar following each atorvastatin dose. Possible mechanisms for this interaction include erythromycin inhibition of first-pass conversion of atorvastatin to inactive metabolites and erythromycin inhibition of P-glycoprotein-mediated intestinal or biliary secretion.     

In vivo neutralization of vascular endothelial growth factor (VEGF) vascular permeability factor (VPF) inhibits ovarian carcinoma-associated ascites formation and tumor growth

Vascular endothelial growth factor (VEGF)/ vascular permeability factor (VPF) is emerging as an important growth factor in a variety of tumor types. As a potent endothelial cell mitogen and vascular permeabilizing agent, VEGF/VPF has the unique functional capacity to mediate the component events of solid tumor neovascularization and ascites tumor growth. In the present series of investigations, our experimental hypothesis was that VEGF/VPF is a critical mediator of ovarian carcinoma-associated ascites formation and solid tumor growth. Athymic nude mice xenotransplanted with human ovarian carcinoma cell lines received either a preimmune rabbit serum or VEGF/VPF antiserum. Compared with the control group receiving the preimmune serum, the antiserum-treated animals displayed a 10- and 12-fold reduction in ascites accumulation and solid tumor growth, respectively. The administration of a neutralizing antiserum to VEGF/VPF conferred a modest survival advantage to animals harboring intraperitoneal tumors. These data demonstrate the significance of VEGF/VPF in the pathogenesis of ovarian carcinoma and suggest that interventions targeting this growth factor and/or its receptor may be of therapeutic value in the management of ovarian cancer.     

Measures implemented to project personal privacy for an on-line national patient index: a case study

Increasing use of electronic data storage and exchange is inevitable. Although of considerable benefit to all concerned, they pose a potential threat to personal privacy. Measures to protect personal privacy in national information networks are essential. These and related security issues require the highest priority in strategic planning because experience shows that poor handling of security is the single factor most likely to lead to rejection of a system. It is increasingly important to be able to identify individuals uniquely for health-related purposes, and implementation of an on-line master index is the approach that has been adopted in New Zealand to address this need. Such an index, however, contains personal information, the privacy of which must be respected. Substituting the unique identifier for all personal details in electronic messages can provide a degree of security as long as access to the index is controlled and usage is monitored. The article outlines the measures, technical and otherwise, implemented to manage security concerns successfully in that context.     

RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.     

How in the world is WHO doing?

The World Health Organization has chalked up some impressive victories in its 43 years but is nowhere near reaching its ambitious goal of "Health for All by the Year 2000." Uphill battles against some intractable health conundrums and shrinking financial resources face the Geneva, Switzerland-based organization, threatening its stated goal of guaranteeing universal health care within the decade.     

The cardiovascular and metabolic effects of bench stepping exercise in females.

The purpose of this investigation was to measure cardiovascular and metabolic responses to 20 min continuous bouts of "choreographed" bench stepping exercise in healthy females. Four frequently used bench heights were employed in a cross-over design: 15.2 cm (6 inches, B-6), 20.3 cm (8 inches, B-8), 25.4 cm (10 inches, B-10), and 30.5 cm (12 inches, B-12). Oxygen uptake (VO2) responses were significantly more pronounced in direct relationship to the bench height: B-12 greater than B-10 greater than B-8 greater than B-6 (P less than 0.05). Mean responses for VO2 ranged from 28.4 ml.kg-1.min-1 for B-6 to 37.3 ml.kg-1.min-1 for B-12. Interestingly, no difference was revealed for heart rate and the respiratory exchange ratio between B-12 and B-10 despite a higher VO2 for B-12 (B-12, B-10 greater than B-8 greater than B-6, P less than 0.05). The incorporation of 0.91 kg (2 lb) hand weights with exercise on the 20.3 cm bench elicited a modest but statistically significant increase in VO2 compared with no hand weights. No significant increase in VO2 was revealed for conditions that employed 0.45 kg (1 lb) hand weights. The results demonstrate that aerobic bench stepping is an exercise modality that provides sufficient cardiorespiratory demand for enhancing aerobic fitness and promoting weight loss in females.     

A review of computerized tomography evaluation of acetabular fractures--part 1

Computerized tomography is an established modality for use in the evaluation of acetabular fractures. As open reduction and internal fixation of acetabular fractures becomes more common, the need for an accurate understanding of the fracture anatomy is critical. An anatomic study of the innominate bone is reported and the relevant standard radiographic landmarks as seen with computerized tomography are illustrated.