Single-center experience with primary orthotopic liver transplantation with FK 506 immunosuppression.

OBJECTIVE: The efficacy for primary orthotopic liver transplantation of a new immunosuppressive agent, FK 506 (tacrolimus, Prograf, Fujisawa USA, Deerfield, IL), was determined. SUMMARY BACKGROUND DATA: After 3 years of preclinical research, a clinical trial of FK 506 for orthotopic liver transplantation was begun in February 1989, first as a rescue therapy for patients with intractable rejection with conventional immunosuppression, then as a primary drug. METHODS: Between August 1989 and December 1993, 1391 recipients (1188 adult and 203 pediatric) of primary liver allografts were treated with FK 506 from the outset. Results from these patients were analyzed and compared with those of 1212 historical control patients (971 adult and 241 pediatric) given cyclosporine-based immunosuppression. RESULTS: Actuarial survival at 4 years was 86.2% with FK 506 versus 65.5% with cyclosporine in the pediatric patients (p < 0.0000) and 71.4% versus 65.5% in the adults (p < 0.0005). The need for retransplantation was reduced significantly for FK 506 patients. Four-year graft survival was 77.0% with FK 506 versus 48.4% with cyclosporine in the pediatric patients (p < 0.0000), and 61.9% with FK 506 versus 51.4% with cyclosporine in the adult recipients (p < 0.0000). Regression analysis revealed that reduction in mortality or graft loss from uncontrollable rejection, sepsis, technical failure, and recurrent original liver disease were responsible for the improved results with FK 506 therapy. CONCLUSIONS: FK 506 is a potent and superior immunosuppressive agent for orthotopic liver transplantation.     

Protein kinase C isoforms in multidrug resistant P388/ADR cells: a possible role in daunorubicin transport.

To identify the role of protein kinase C (PKC) isoforms in multidrug resistance in tumor cells, we examined the PKC isoform pattern in the multidrug resistant P388/ADR cell line and studied the effect of down regulation of PKC isoforms on intracellular daunorubicin accumulation and P-glycoprotein expression. Using monoclonal antibodies to PKC alpha, beta and gamma and flow cytometry technique we showed that P388/ADR cells overexpressed PKC alpha and beta as compared to drug sensitive P388 cells. Prolonged treatment of P388/ADR cells with phorbol myristate acetate (PMA), a procedure that is known to down regulate PKC, resulted in the down regulation of total PKC activity and the PKC beta isoform (at the protein level) that was accompanied by the correction of daunorubicin accumulation in P388/ADR cells. The level of expression of P-glycoprotein in PMA treated cells was similar to that of untreated cells. These results suggest that PKC beta regulates the drug efflux function of P-glycoprotein.     

Fertility reduction and the quality of family planning services

The purpose of this paper is to determine whether a focus on quality of family planning services is consistent with meeting demographic objectives. An analytical framework that links the six elements of quality with fertility is described. A review of existing literature and analysis suggest that improvements in quality of family planning services by enhancing the choice of contraceptive methods available in a country would increase the overall practice of contraception and thus would result in fertility reduction.     

Antiestrogenic effects of Z-1, 1-dichloro-2,3 diphenyl-2-(4-methoxyphenyl)cyclopropane(5a) on human breast cancer cells in culture.

Compound 5a ([Z]-1, 1-Dichloro-2,3 diphenyl-2-(4-methoxyphenyl)cyclopropane) is a novel cyclopropyl compound which was shown to be a pure antiestrogen. In the present study, the antiproliferative activity of 5a was examined on estrogen receptor (ER)-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells and A-549 human lung cancer cells using the hemocytometric trypan blue exclusion method. Compound 5a inhibited the growth of MCF-7 cells in a dose-related manner over a concentration range of 10(-9) to 10(-5) M, but did not alter the growth of MDA-MB-231 or A-549 cells. Co-administration of estradiol (10(-8) M) reversed the antiproliferative activity of 5a (10(-7) M) on MCF-7 cells. Further, an ER-dependent mechanism of action is supported by the specific ER binding of 5a in MCF-7 cells observed in this study. The influence of 5a on the cell surface morphology of MCF-7 and MDA-MB-231 cells was studied using scanning electron microscopy (SEM). Compound 5a at 10(-6) M reduced the length and density of microvilli (MV) on MCF-7 cells, which was reversed by co-administration of estradiol (10(-8) M). This compound did not alter the cell surface morphology of ER-negative MDA-MB-231 cells. In conclusion, 5a and tamoxifen inhibited the growth of ER-prositive MCF-7 cells in an estradiol-reversible manner, and had no effect on ER-negative MDA-MB-231 cells. The results of this study with human breast cancer cells suggest that 5a may be highly effective in the treatment of estrogen-dependent breast cancer and/or in the prophylactic treatment of women with a high risk of breast cancer development.     

CT demonstration of complex dorsal spinal dysraphism.

An unusual case of dorsal spinal dysraphism in a four year old child is presented. Various abnormalities including diastematomyelia, an extradural arachnoid cyst arising from one of the two dural tubes, and lipomeningomyelocele with a related rib-like bony structure were demonstrated with Iohexol CT and subsequently confirmed at surgery.     

Effect of titanium surface texture on the cell-biomaterial interface.

To improve the in vivo performance of engineered implants, this study examines the independent effects of surface chemistry and topography on fibroblast morphology and density in vitro. Titanium (Ti) was sputter-coated onto smooth and microtextured polyethylene terephthalate (PET). Test specimens were evaluated in 24-h, fibroblast cultures and assessed with scanning electron microscopy (SEM) for cellular morphology and density. Fibroblast density increased, as the Ti film thickness increased. The fibroblasts exhibited contact guidance on the textured test specimens. The greatest cellular density was found on the Ti-coated, textured test specimens. In conclusion, Ti and surface texture appeared to strongly influence fibroblast density and morphology as compared to PET and smooth surfaces.     

Geometric Resistance and Microvascular Network Architecture of Human Colorectal Carcinoma

Objective : To measure the geometric resistance to blood flow in human colorectal carcinoma. Although tumor blood flow is of central importance in both the detection and the treatment of cancer, the determinants of blood flow through the neoplastic circulation are poorly understood. Methods : Human colorectal carcinomas (tissue weight = 272 g ± 43 g (SD), n = 6) were perfused ex vivo with a buffered physiological salt solution of known viscosity at flow rates ranging from 2.5 to 40 ml/min and perfusion pressures from 8 to 100 mm Hg. The geometric resistance was determined from the slope of the pressure-flow curve. For examination of the principal determinant of geometric resistance, the vascular architecture, one of the tumors was perfused with Batson's No. 17 polymer and macerated in KOH to produce a positive vascular cast that was used for measurement of vascular branching patterns and dimensions. Results : The pressure-flow relationship was linear at perfusion pressures above 40 mm Hg, and the geometric resistance, z₀, was constant at approximately 6.5 ± 10⁹g/cm³. Below 40 mm Hg, z₀ increased rapidly. The architecture of the arteriolar and capillary networks of human colorectal carcinoma is similar to those of experimental rodent tumors. Capillaries in planar and nonplanar mesh-works had mean segment diameters of 11 ± 2 and 9.6 ± 2 μm, lengths of 46 ± 24 and 107 ± 40 μm, and intercapillary distances of 46 ± 13 and 74 ± 24 μm, respectively. Conclusions : The geometric flow resistance in neoplastic tissue is 1–2 orders of magnitude higher than that observed in normal tissues. A decrease in functional vascular cross-sectional area may explain the additional increase in resistance at small perfusion pressures. The observed flow resistance may be due to the specialized arteriolar and capillary network architecture, pressures exerted by proliferating cancer cells, and/or coupling between vascular and extravascular flow. These observations demonstrate that tumor vascularity alone may not be indicative of flow resistance or tumor susceptibility to blood-borne therapeutic agents.