Factors influencing the increase in glomerular filtration rate in the remaining kidney of transplant donors

Measurement of glomerular filtration rate (GFR) in 49 kidney donors on 259 occasions before and at varying periods after nephrectomy revealed that the predominant increase in GFR after nephrectomy occurs within three weeks. This initial percentage increment was not influenced by age, sex or GFR before nephrectomy. However, multiple-linear regression analysis of data derived from subsequent studies, performed up to four years after nephrectomy, indicates that there is a modest secondary increase which occurs subsequently and is inversely related to age, with time after nephrectomy and the GFR before nephrectomy also comprising significant variables. Analysis of concomitant creatinine and urea clearance data reveals that these parameters bear an inconstant relationship to true GFR, although they follow the same general trend.     

Proliferation of human malignant hematopoietic cells in immunodeficient mice: suppression by antibody to pluripotent K-562 leukemia cells involves direct cytolysis and effector cells

Six human hematopoetic cell lines were successfully heterotransplanted into athymic (nude) and asplenic-athymic (lasat) neonatal mice. The tumors arising from leukemia and lymphoma cells could then be serially transplanted into adult nude mice. Seven days after the fourth serial mouse passage, each mouse was treated with goat immune gamma globulin against K-562 cells. One control group was treated similarly, but with nonimmune (normal) gamma globulin, while another control group was not treated. The goat gamma globulin was not toxic for nude and lasat mice, and the immune, but not the normal, gamma globulin suppressed local subcutaneous growth of myelosarcomas, lymphosarcomas, and Burkitt lymphoma cells. On the other hand, the growth of lung, breast, and prostatic carcinomas and a melanoma of human origin were not altered by the immune gamma globulin. Since suppression of cell growth occurred equally well in decomplemented mice, a complement-mediated cytotoxicity apparently cannot be considered as responsible for the abrogation. The Fab fragment of the immunoglobulin did not suppress the growth of the myelosarcomas. We conclude that antibody suppression of the in vivo proliferation was specific for malignant hematopoietic cells and that the Fc portion of IgG is necessary for in vivo cytolysis of leukemia cells. The most probable mechanisms are direct antibody cytolysis and antibody-dependent macrophage-mediated cytotoxicity.     

Expression of bcl-xL can confer a multidrug resistance phenotype

It has been suggested that genes that regulate apoptotic cell death may play an important role in determining the sensitivity of tumor cells to chemotherapy. We have recently cloned a member of the bcl-2 family, bcl- x. To test whether bcl-XL expression affects the sensitivity of tumor cells to chemotherapy, we have created stable cell lines overexpressing bcl-XL and have tested these cells for resistance to cell death induced by metabolic inhibitors and chemotherapeutic agents. Bcl-XL expression dramatically reduces the cytotoxicity of bleomycin, cisplatin, etoposide, vincristine, hygromycin B, and mycophenolic acid for up to 4 days in culture. Bcl-XL does not prevent cells from undergoing cell cycle arrest in response to these drugs, but rather prevents treated cells from undergoing apoptosis. Cell-cycle analysis on cells treated with the chemotherapeutic agents bleomycin, cisplatin, etoposide, and vincristine, show that the drugs cause growth arrest in different positions within the cell cycle. Bcl-XL expressing cells treated with chemotherapeutic drugs retain their proliferative ability after the drugs are removed. Interestingly, vincristine-treated cells expressing bcl-XL become polyploid after drug removal. These data show that bcl-XL protects cells from a wide variety of apoptotic stimuli, acts in multiple positions within the cell cycle, and confers a multidrug resistance phenotype. The ability of bcl-XL to prevent apoptotic cell death in response to chemotherapy-induced DNA damage and cell-cycle arrest may contribute to the accumulation of chromosomal aberrations within tumors. The expression of bcl-XL in tumor cells is likely to be an important indicator of chemotherapeutic efficacy.     

The role of growth hormone and cortisone on glucose and gluconeogenic substrate regulation in fasted hypopituitary children.

Panhypopituitarism may be associated with spontaneous hypoglycemia and marked insulin sensitivity. Five children with both growth hormone (GH) and adrenocorticotrophin (ACTH) insufficiency were studied in three periods: a) on no therapy; b) during cortisone acetate; and c) during GH and cortisone acetate replacement. With total caloric restriction prior to therapy, all patients became hypoglycemic (109 +/- 18 leads to 37 +/- 3.5 mg/dl, mean +/- SEM) and ketonemic (beta-hydroxybutyrate 0.10 +/- 0.02 leads to 3.04 +/- 0.63 mM and acetoacetate 0.05 +/- .01 leads to 0.80 +/- 0.15 mM) within 30 hours. Glutamine and alanine concentrations fell with fasting (511 +/- 13 leads to 293 +/- 26 muM and 394 +/- 58 leads to 137 +/- 12 muM, respectively) but to levels lower than in normal children. However, only alanine was significantly lower (P less than 0.05). With cortisone plus GH therapy, fasting glycemia was improved (73 +/- 6 mg/dl) at 30 hours fasting and was associated with increased alanine and glutamine concentrations (206 +/- 28 muM and 448 +/- 40 muM, respectively) and less ketonemia (beta-hydroxybutyrate 1.13 +/- 0.39 mM). Cortisone therapy alone resulted in intermediate improvement of these values. Only combined therapy resulted in increased lactate and pyruvate concentrations, which fell to normal with fasting. Fasting urinary ammonia excretion was unchanged whereas urea nitrogen excretion decreased significantly with therapy. The responses to alanine infusions following each study period in one patient were normal. The glycemic response to iv glucose was similar during each study period; however, post-prandial and glucose-stimulated insulin responses were increased with cortisone and cortisone plus GH therapy. We suggest that the hypoglycemia observed in hypopituitary patients is a substrate-mediated phenomenon, and that cortisone and growth hormone replacement therapy improve fasting glucose homeostasis, increase circulating alanine and glutamine concentrations, and decrease hepatic gluconeogenesis. These effects may be mediated through an increase in fat catabolism.     

Bcl-x rather than Bcl-2 mediates CD40-dependent centrocyte survival in the germinal center

Both rapid B-cell proliferation and programmed cell death (PCD) occur during the differentiation and selection of B cells within the germinal center. To help elucidate the role of Bcl-x in B-cell antigen selection and PCD within the germinal center, we examined its expression in defined B-cell populations and by immunochemistry of tonsil tissue. Purified B-cell fractions enriched for centrocytes express high amounts of Bcl-x and relatively low amounts of Bcl-2, whereas fractions enriched for centroblasts lack significant levels of both proteins. Consistent with this observation, immunocytochemistry localized Bcl-x within cells scattered throughout the germinal center. Stimulation of tonsil B cells with either CD40 or Staphylococcus aureus Cowan increase bcl-x mRNA and protein levels. Treatment of a cell line with a germinal center phenotype (RAMOS) or the tonsillar B-cell centroblast fraction with CD40 rapidly increased Bcl-x levels and partially rescued B cells from PCD. These data suggest that Bcl-x rather than Bcl-2 may rescue centrocytes during selection in the germinal center.