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Biomedical subjects

L M Glode

Publications and source records attributed to L M Glode.

65 records · Page 4Linked to original sources
PubMed1979

A Phase 1 study of high doses of aminopterin with leucovorin rescue in patients with advanced metastatic tumors.

We have conducted a Phase 1 study of aminopterin (AMT) with leucovorin (LV) in 17 patients. AMT was administered by bolus injection every 7 to 14 days in dosages from 25 to 425 mg/sq m. LV rescue was instituted at 24 hr and continued for 48 to 72 hr. At dosages above 50 mg/sq m, we observed nephrotoxicity defined as greater than or equal to a 25% increase in serum creatinine 24 hr after AMT administration, but its incidence was not strictly dose related. Urinary alkalinization and volume expansion appeared to reduce the incidence of nephrotoxicity. Nephrotoxic drug courses were associated with 24-hr plasma AMT levels [3.6 +/- 2.0 (S.D.) X 10(-6) M] which were significantly higher than nonnephrotoxic courses (1.6 +/- 1.0 x 10(-6) M) (p less than 0.05). In nonnephrotoxic courses, serum elimination pharmacokinetics appeared to be biphasic with a t1/2 alpha of 1.08 +/- 0.01 hr and t1/2 beta of 12.31 +/- 0.06 hr. Systemic toxicity (myelosuppression and mucositis) could be prevented in patients with impaired AMT clearance by the administration of LV at an increased dose rate. In several courses, systemic toxicity occurred in spite of apparently normal plasma clearance, suggesting that 24-hr plasma levels may not accurately reflect intracellular drug effects. Cytokinetic studies on bone marrow aspirates allowed determination of the rescue effect of LV and may prove useful in predicting marrow protection.

Aminopterin↗
PubMed1977

Action of endotoxin on lymphoid cells.

Endotoxin (lipopolysaccharide, LPS) has been found to act on all three cell types of the immune system, thymus-derived (T-) cells, bone marrow-derived (B-) cells, and macrophages. LPS is mitogenic for B-lymphocytes and activates them to release a chemotactic lymphokine. Macrophage activation appears to be mediated by macrophage-activating factor, another lymphokine released from B-cells. In addition, LPS acts synergistically with phytohemagglutinin to initiate division of purified T-lymphocytes. All these phenomena are mediated by the lipid A moiety of LPS. The role of lymphoid cells in mediating the lethal effects of LPS have also been investigated. The adoptive transfer of spleen cells from LPS-responsive mice (C3H/HeN) to LPS-resistant but histocompatible mice (C3H/HeJ) rendered the LPS-resistant mice significantly more susceptible to LPS-induced lethality. These findings suggest that spleen cells play an essential role in mediating the lethal effects of LPS in vivo.

Animals↗
PubMed1976

Significant contribution of spleen cells in mediating the lethal effects of endotoxin in vivo.

Two closely related, histocompatible mouse strains that have marked differences in both in vitro and in vivo responses to endotoxin were used to evaluate the contribution of lymphoid cells to the lethal effect of endotoxin. C3H/HeJ mice are endotoxin resistant, whereas C3H/HeN mice are endotoxin sensitive. In vitro spleen cell mitogenic responses to endotoxin were similar in untreated mice and in mice that received sublethal irradiation (450 R) followed by reconstitution with autologous spleen cells. Reconstitution with spleen cells from the related strain produced chimeric animals with spleen cell mitogenic activity like that of the donor strain. When chimeric animals were subjected to a lethal challenge of endotoxin, their response was markedly altered by the transferred lymphoid cells. C3H/HeJ animals reconstituted with C3H/HeN cells became more endotoxin sensitive, whereas C3H/HeJ cells became more endotoxin resistant. These results indicate that spleen cells play a significant, detrimental role in endotoxin-induced lethality.

Animals↗
PubMed1976

Cellular mechanism of endotoxin unresponsiveness in C3H/HeJ mice.

B cells from C3H/HeJ mice fail to respond to an endotoxin (LPS K235) which is mitogenic for normal mice including the closely related C3H/HeN strain. The cellular basis for this unresponsive state has been investigated. The C3H/HeJ mice have normal numbers of B cells, which are capable of normal responses to other B cell mitogens, such as polyinosinic acid (Poly I). Addition of normal macrophages or spleen cells fails to reconstitute the normal response. Furthermore, neither macrophages nor spleen cells from the C3H/HeJ strain suppress the normal C3H/HeN spleen cells. Finally, spleen cells enriched for B cells by the removal of macrophages or T cells demonstrate the same differences in responsiveness to LPS. These results indicate that LPS unresponsiveness is a defect of the B cell itself and not due to suppressor cells or the absence of helper cells. When LPS is added to Poly I-stimulated cultures, there is additional enhancement of the response of normal C3H/HeN spleen cells. However, LPS causes a dose-dependent suppression of the Poly I response of C3H/HeJ spleen cells. This suppression is dependent on the time of addition of LPS to the Poly I-stimulated cultures. These data are interpreted as indicating that the binding of LPS to the membrane of C3H/HeJ B cells results in their inactivation or suppression, and that this is the basis of LPS unresponsiveness in this mouse strain.

Animals↗
PubMed1976

Genetic control of B cell activation by bacterial lipopolysaccharide is mediated by multiple distinct genes or alleles.

Eleven closely related C3H mouse strains were examined for differences in their DNA synthetic response to a highly discriminatory endotoxin, LPS Escherichia coli K-235. Strains of the C3H line were found to be either high, intermediate, or low responders to endotoxin. Three stains, C3H/St, C3H/Bi, and C3H/CR were high responders. Six strains, C3H/He, C3HfB/He, C3H/Hen, C3Heb/Fej, C3H/DiSn, and C3H/Avy were intermediate responders, suggesting that a mutation producing decreased LPS responsiveness occurred in the C3H/He(C3H/An) strain between 1931 and 1945. Two strains, C3H/HeJ and C3H/Bts were unresponsive due to a mutation that occurred between 1960 and 1968. Breeding experiments among high, intermediate, and low responding strains documented probable codominant genetic control by the genes or alleles in the C3H/HeN and C3H/HeJ strains. In the C3H/HeN x C3H/St cross, dominance of the C3H/St gene over the C3H/He gene was documented, whereas the C3H/HeJ x C3H/St cross indicated codominance of these two genes. These findings may represent either three alleles or three distinct genes in C3H mice. A second X-linked gene locus was documented in the CBA/N strain which also causes impaired B cell responsiveness to LPS E. coli K235 in serum-free conditions. The abnormal gene products in the CBA/N and C3H/HeJ strains exhibit complementarity since F1 female animals from the cross between these two unresponsive strains are responsive to LPS. We conclude that there is at least one distinct X-linked gene locus and either three additional autosomal genes or three possible alleles at one or more autosomal loci which determine the LPS sensitivity of murine B cells.

Animals↗
PubMed1975

Difference in B cell mitogen responsiveness between closely related strains of mice.

Spleen cells from C3H/HeJ mice respond very poorly to the mitogenic action of endotoxin (LPS) in vitro whereas cells from a very closely related strain, C3H/HeN respond very well. An analysis of the genetic similarity of these two strains was performed. There is no significant MLR measurable between cells of these strains under a variety of culture conditions. They do not manifest a significant graft-vs-host response nor do they reject reciprocal skin grafts. Because of this genetic similarity, it is possible to reconstitute the LPS response of nonresponder mice by an adoptive transfer of spleen cells from C3H/HeN mice. This strain pair should therefore prove useful in analyzing the genetic and cellular basis of endotoxin reactivity.

Animals↗
PubMedDate not supplied

Scrotal hypothermia and testicular blood flow in the dog. Absence of thermal regulation.

Two clinically tolerable methods of producing testicular hypothermia have been studied in dogs. Evaporative cooling produced a 3.7 degree fall and ice water a 9.7 degree fall in intratesticular temperatures. Scrotal skin blood flow (mls/100 gm/min) fell from 4.9 +/- 4.6 to 2.3 +/- 1.2 and 1.3 +/- .05 with the two techniques and was associated with increased vascular resistance. In contrast, no significant change was noted in testicular blood flow. These data show that testicular blood flow cannot be altered by clinically tolerable hypothermia.

Animals↗