European integration and health policies: repercussions of the internal European Market on access to health services

This article explores the health policy repercussions of countries' regional integration into the European Union. The aim is to review the regulation of access in other countries, with the conclusion of the single European market and the free circulation of persons, services, goods, and capital. The article begins by reviewing the various forms of integration and describes the expansion and institutionalization of Community agencies. The repercussions of European integration on health policies and regulation of access are analyzed. Market impacts on health result from Treaty directives and internal policy adjustments to free circulation. Health services access is gradually regulated and granted by rulings. Projects along borders illustrate the dynamics where differences are used to achieve comprehensive care. In the oldest integration experience, the market regulation has generated intentional and non-intentional impacts on the health policies of member states, regardless of the organizational model. Knowledge and analysis of this experience signals challenges for the Southern Cone Common Market (Mercosur) and adds to future debates and decisions.     

Comparative disposition of the antineoplastic agent 9-nitrocamptothecin and the inactive isomer 12-nitro camptothecin in CASE-bearing nude mice: effect of route of administration on tissue distribution

Purpose: 9-Nitrocamptothecin (9-NC) and 12-nitrocamptothecin (12-NC) are synthetic structural analogues of camptothecin (CPT) which have been prepared to explore the structure/activity relationship of this group of compounds against a wide variety of experimental tumors. As part of our investigation of the pharmacology and the mechanism of tumor inhibition of these compounds, we examined the effect of route of administration on the distribution of tritium-labeled 9-NC and 12-NC, an active and a poor chemotherapeutic agent, respectively. Methods: Quantitative whole-body autoradiography was used and our results were compared with previous results obtained with the parent compound CPT. Results: These studies revealed that, independent of the route of administration, both CPT derivatives were rapidly distributed to gall bladder, gastrointestinal tract and kidney. The excretion from these organs was indicated by the high levels of radioactivity in urine (urinary bladder) and feces (large intestines). The studies also indicated that the distributions of 9-NC and 12-NC were qualitatively similar, but quantitatively higher uptake of radioactivity was observed in animals treated with 12-NC than in those treated with 9-NC at 30 min following treatment. With the exception of the late sampling time (12 h after administration), the accumulation of radioactivity in the lungs (bronchioles) of animals that received an intravenous (i.v.) dose of 9-NC or 12-NC was higher than those treated with an intramuscular (i.m.) dose. However, the retention of drug-derived radioactivity in the tumors of mice treated with an i.m. dose of 9-NC was higher than that in the tumors of i.v.-treated animals and was also higher than that in tumors of animals treated with 12-NC. Conclusions: These results suggest that higher accumulation of 9-NC in tumor tissues than of 12-NC may contribute to the more potent chemotherapeutic activity of the former agent. Our results also suggest that i.m. injection is a more effective route of administration than i.v. administration. Received: 22 November 1996 / Accepted: 4 April 1997     

Diagnostic criteria for detection of postinfarction ischemia by quantitative analysis of stepwise dobutamine radionuclide ventriculography

BACKGROUND: Application of the traditional diagnostic criteria validated for exercise testing may be inappropriate when dobutamine infusion is associated with radionuclide ventriculography (RNV). The objective of this study was to establish appropriate diagnostic criteria for evaluation of dobutamine stress testing with RNV for the detection of early postinfarction ischemia. METHODS: RNV was performed at baseline and during dobutamine infusion in 10 control subjects and in 30 patients who were studied within 1 week after uncomplicated myocardial infarction. Several quantitative parameters including left ventricular ejection fraction (EF), regional EF, and absolute change in global and regional EF were tested. In addition, regional wall-motion changes were scored by visual analysis. The limit of normal response for each quantitative parameter was defined as the 95th percentile of the distribution observed in control subjects. On the basis of predischarge clinical evaluation and exercise stress testing, patients were grouped as having evidence of residual ischemia (group 1, 15 patients) or no evidence of ischemia (group 2, 15 patients). Sensitivity, specificity, and accuracy in the detection of postinfarction ischemia were calculated for each parameter, and empiric receiver-operating characteristic curves were generated. RESULTS: The limits of the normal response to dobutamine infusion in the control subjects were found to be a 7.5% and a 12.5% increase in global EF at low and high dose, respectively. Median baseline EF was significantly lower in patients than in control subjects (Mann-Whitney U test: P < .001). There were no differences in resting EF between group 1 and group 2 patients. However, median high-dose EF and increase in EF were significantly lower in group 1 as compared with group 2 patients (56% vs 72% and 5% vs 17%, respectively; Mann-Whitney U test: P < .0001 for both). A biphasic (up-and-down) response with initial increase at low dose followed by decrease or no change in EF at high dose was observed in 66% of group 1 patients and only in 13% of group 2 subjects. The best criterion for detection of postinfarction ischemia was a change of <12.5% in global EF at high-dose dobutamine infusion, with 80% predictive accuracy. The traditional criterion, a change of <5 % or a decrease in EF, yielded an accuracy of only 63%. The association of a change of <12.5% with a biphasic response increased accuracy to 87%, with a sensitivity of 93% and a specificity of 80%. Quantitative regional wall motion analysis showed greater diagnostic accuracy than visual wall motion scoring (83% vs 70%). CONCLUSIONS: Application of appropriate criteria and stepwise quantitative analysis of RNV during dobutamine infusion may increase accuracy in the detection of early postinfarction ischemia.     

Partial characterization of human leukemia U-937 cell sublines resistant to 9-nitrocamptothecin P

Abstract: Human leukemia U-937 cell sublines exhibiting various levels of resistance to 9-nitrocamptothecin (9NC) were developed after exposure to progressively increased 9NC concentrations. Increases in 9NC resistance of the cells were accompanied by decreases in proliferation rate; appearance of morphological and functional features that correlate with granulocytic maturation; decreased synthesis of topoisomerase I; increased synthesis of topoisomerase II; and inability or decreased ability to induce tumors when xenografted in nude mice. 9NC-resistant cells, transferred and propagated in 9NC-free media for 6 months, continue to exhibit resistance and other features similar to cells propagated in continual presence of 9NC. Finally, 9NC-resistant U-937 cells respond to physiological and non-physiological agents of cell differentiation, indicating that alternative treatments can be successfully used to inhibit growth of 9NC-resistant U-937 cells and tumors.     

Diploid human lymphoblastoid and Burkitt lymphoma cell lines: susceptibility to murine NK cells and heterotransplantation to nude mice

Human lymphoid cell lines which had been classified on the basis of studies on clonality and morphological, on the basis of studies on clonality and morphological, chromosomal and functional parameters as lymphoblastoid cell line (LCL) of presumed non-neoplastic origin and Burkitt lymphoma (BL) lines of proven malignant origin, were tested for susceptibility to natural killer (NK) cells obtained from the spleens of athymic nude mice. The 20 lines included normal diploid LCL and aneuploid BL lines. All cells carried the Epstein-Barr virus (EBV) genome. In addition, two EBV-negative BL lines were tested. The pronase-induced release of 14C-DNA from 14C-thymidine-labelled target cells was used to assess the sensitivity of the cell lines to NK activity. When attempts were made to correlate the growth of the EBV-positive LCL and the EBV-positive BL cell lines in the subcutaneous space of adult nude mice with their susceptibility to NK cells, no significant correlation was observed. The EBV-negative BL cell line, Ramos, however, could be transplanted subcutaneously in nude mice and was more resistant to NK activity than was the EBV-negative BL cell line, BJAB, which cannot be transplanted subcutaneously. Growth of heterotransplanted EBV-converted cell lines in the subcutaneous space of adult nude mice may be influenced by immune effectors other than NK cells.     

Soft tissue sarcomas of the extremity: Multidisciplinary therapy employing hyperthermic perfusion

Cultured human sarcomatous cells that have been tested in our laboratory are more sensitive to the lethal effects of heat than are the normal cells from which they are derived. During an eight year period from March 1967 to March 1975, thirty-seven patients with soft tissue sarcomas of the extremities were treated with hyperthermic perfusion and, when possible, radiation therapy and radical local excision. Despite the fact that these tumors arise on the extremity, diagnosis was often delayed. With meticulous attention to all details, hyperthermic perfusion was performed with a minimum of morbidity and mortality. The combined use of hyperthermic perfusion, radiation therapy, and delayed excision has greatly reduced the necessity for amputation. Many useful limbs, heretofore not considered salvageable, can be saved with this method of treatment. Also, the possibility exists that destruction of tumor within the extremity followed by delayed excision enhances the immune response of the patient.     

An osteosarcoma cell line with hypodiploid chromosome number and complex structural anomalies.

Giemsa-banding analysis performed on a newly established metastatic osteosarcoma cell line (SP-388) that was passaged through the nude mouse revealed a hypodiploid stemline number of 39 chromosomes. This cell line showed both numerical and structural abnormalities, including the abnormally banded region in certain marker chromosomes. Chromosomes 3, 15, 17 and the X were the most frequently absent elements of this tumor. Segments of chromosomes 3, 15 and X could not be identified even in rearranged chromosomes (Ml to M15). We suggest that more cases of osteosarcoma should be studied so that specific primary and secondary chromosomal anomalies can be identified in human osteosarcoma.     

Activation in vitro by BUdR of a productive EB virus infection in the epithelial cells of nasopharyngeal carcinoma.

Material from a nasopharyngeal carcinoma (NCP) has been passaged in athymic (nude) mice to eliminate non-malignant infiltrating cells. The human origin and derivation from NPC malignant epithelial cells of the nude mouse tumours have been confirmed by chromosome examination, electron microscopy showing desmosomes and keratin fibrils, and postive EB virus nuclear antigen (EBNA) testing. Samples of the mouse-grown tumours were cultured and pure monolayers of epithelial cells were obtained which still expressed EBNA and contained desmosomes and keratin; these cultures grew well for about 3 weeks. Extensive electron microscope searches failed to reveal herpes virus particles. In contrast, cultures treated with BUdR showed typical immature and mature herpes virus particles in epithelial, keratin-containing cells, and immunofluorescence tests for virus capsid antigen with a battery of human sera identified this agent as EB virus. EB virus has thus, for the first time, been activated in NPC epithelial cells and shown to be capable of replication in a cell type other than a primate B-lymphocyte.