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C Walker

Publications and source records attributed to C Walker.

At least 361 records · Page 20Linked to original sources
PubMed1985

Active suppression of host-vs-graft reaction in pregnant mice. VI. Soluble suppressor activity obtained from decidua of allopregnant mice blocks the response to IL 2.

The mammalian fetus expresses a variety of antigens against which the maternal immune system can react and which in an allogeneic mating bears paternal transplantation antigens. Although these antigens may be expressed on the fetal trophoblast cells that contact maternal uterine decidua, the "fetal allograft" is not usually rejected. Previous studies have demonstrated the presence of nonspecific non-thymus-derived suppressor cells in the lymph nodes draining the uterus and in decidua of laboratory mice undergoing first allogeneic pregnancy. These suppressor cells appeared to be small lymphocyte cells that inhibit the generation of cytotoxic T lymphocytes (CTL) in vitro and in vivo and elaborate a nonspecific non-MHC-restricted soluble suppressor activity when cultured for 48 hours at 37 degrees C in vitro. We now report that soluble suppressor activity obtained from the decidua (DS) of allopregnant C3H/HeJ mice inhibits both the primary and secondary (memory) CTL response in vitro but does not inhibit lysis of target cells by preformed CTL. DS did not suppress the proliferation of YAC lymphoma cells, P-815 cells, or a C3H placental trophoblastoma line. Suppressor activity was obtained from anti-thy-1.2 + complement-resistant cells in the decidua, could also be obtained from the decidua of allopregnant CD1 nu/nu mice, and was associated with a single peak of activity of approximately 100,000 daltons on Sephacryl 200 chromatography. Suppression could not be overcome by adding either crude or HPLC-purified IL 2 to the mixed lymphocyte cultures in vitro, and both crude and column-purified suppressor factor inhibited the IL 2-dependent proliferation of H-Y cells (a cloned T cell line with NK activity). Furthermore, DS inhibited the IL 2-dependent generation of cytotoxic effector cells in vitro in the absence of allogeneic stimulator cells. Thus, a soluble suppressor factor obtained from non-T cells present in the decidua of successfully allopregnant mice could block the response to IL 2 and inhibit the generation of both specific and nonspecific cytotoxic effector cells. The significance of this inhibition with respect to survival of the "fetal allograft" is discussed.

Animals↗
PubMed1985

Aortic endothelial cell during regeneration. Remodeling of cell junctions, stress fibers, and stress fiber-membrane attachment domains.

We have studied in regenerating endothelium of rat thoracic aortas (a) organization of tight and gap junctions by means of morphometry using freeze-fracture electron microscopy, (b) development of cytoplasmic actin microfilament bundles (stress fibers) by means of morphometry using thin section electron microscopy, and (c) distribution of filipin-sterol complexes in the endothelial plasma membrane using thin section and freeze-fracture electron microscopy. The index of complexity for tight junctions and the index expressing the average width of gap junctions were significantly higher in regenerating endothelium than in normal aortic endothelium. In regenerating endothelium, there was a significant increase of the stress fiber to endothelial volume density ratio as compared to normal. Stress fibers were connected to cytoplasmic microfilament condensations located at the abluminal plasma membrane; the surface density of these condensations was significantly increased in regenerating endothelium as compared to normal. Filipin-cholesterol complexes were few or absent at stress fiber-membrane attachment sites but numerous in the remaining endothelial plasma membrane. This morphologic remodeling of the aortic endothelial cell layer may help to explain changes of endothelial cell function occurring in situations associated with increased cell turnover and motion.

Animals↗
PubMed1984

Mechanisms of serotonin-induced lymphocyte proliferation inhibition.

When human peripheral blood lymphocytes were stimulated with phytohemagglutinin in the presence of serotonin, inhibition of [3H]thymidine incorporation occurred, the most marked inhibition occurring at high (10(-3)M) serotonin concentrations. This effect could not be reversed by the addition of Interleukin 2 (IL-2)-containing supernatants. Cytofluorometric analysis showed that virtually all of the cells remained in the G0 phase (unactivated) at 24 hr while some of the cells entered the G1a and G1b phases of the cell cycle by 42 hr. The cellular production of IL-2 was not affected by serotonin, as supernatants of treated cultures contained essentially the same IL-2 titers as did control cultures. Serotonin seemed to primarily affect cell activation and had little or no effect on proliferating cells. This was further confirmed by the lack of effects of serotonin on a variety of established proliferating lymphocyte, macrophage, and fibroblast cell lines. By contrast, dose-dependent inhibition of IL-2-dependent CTLL cells occurred. Serotonin was not toxic even at 10(-3) M concentrations. A marked decrease in IL-2 receptors and a change in their distribution on responder cells was seen when treated cultures were examined with the anti-Tac monoclonal antibody. At 24 hr this effect was contrastingly not seen for the OKT-8 marker, although a slight decrease in OKT-4-positive cells was seen. Serotonin thus produced an inhibition of lectin-stimulated lymphocyte proliferation via a mechanism independent of IL-2 production, and caused a decrease in the expression and distribution of IL-2 receptors on the surface of responder cells.

Adult↗
PubMed1984

Hemodynamic trial of sequential treatment with diuretic, vasodilator, and positive inotropic drugs in left ventricular failure following acute myocardial infarction.

The circulatory effects induced by two sequential intravenous treatment programs with a diuretic, arteriolar or venodilator , and a positive inotropic drug were studied in a randomized between-group trial in 20 male patients with radiographic and hemodynamic evidence of left ventricular (LV) failure following acute myocardial infarction (AMI). Furosemide induced a substantial diuresis in both groups of patients, in association with reductions in LV filling pressure (p less than 0.01) and cardiac output (p less than 0.05), without significant change in heart rate or systemic arterial pressure. The addition of isosorbide dinitrate was followed by reductions in the systemic arterial (p less than 0.01) and LV filling pressures (p less than 0.01) without significant change in the heart rate or cardiac output. Hydralazine after furosemide reduced systemic vascular resistance (p less than 0.01), but the fall in mean blood pressure (p less than 0.01) was limited by the increase in cardiac output (p less than 0.01); heart rate was also increased (p less than 0.01) and LV filling pressure fell (p less than 0.05). The final addition of the beta-1 adrenoceptor agonist, prenalterol, increased systemic arterial systolic pressure (p less than 0.05), cardiac output (p less than 0.05), and heart rate (p less than 0.01), and reduced systemic vascular resistance (p less than 0.01) in both groups; these changes were greatest in those pretreated with furosemide and isosorbide dinitrate. In both treatment pathways compared with control the reductions in systemic vascular resistance and left heart filling pressure were accompanied by increases in heart rate and cardiac output without substantial changes in systemic blood pressure. Which of these hemodynamic pathways offers the optimum prognosis awaits further study.

Adrenergic beta-Agonists↗
PubMed1984

Lymphokine regulation of human lymphocyte proliferation: formation of resting G0 cells by removal of interleukin 2 in cultures of proliferating T lymphocytes.

The question of whether lymphocytes which have once been activated and have completed one or several cell cycle(s) can return to the G0 phase and stay ready for a new activation (G0-G1 transition), rather than simply die, was investigated. To do so interleukin 2 (IL-2) was removed from cultures of continuously proliferating human T lymphocytes and the formation of resting (G0) cells was measured. Kinetic analyses in freshly prepared peripheral blood lymphocytes (PBL) revealed that the onset of detectable RNA synthesis and the appearance of structures binding the anti-Tac antibody occurred simultaneously. This allowed the expansion of the definition of G0 T lymphocytes as cells having a low RNA (and DNA) content, and no Tac antigen. When cultured human T cells proliferating continuously by means of IL-2 were characterized in terms of their distribution in the cell cycle, 7 days after the initial PHA stimulation, it could be demonstrated that very few cells were in the G0 phase, supporting the concept of direct S/G2/M-G1 transition. However, when IL-2 was removed from the cultures, the [3H]thymidine incorporation per 10(4) cells and correspondingly the number of cells in the S/G2/M and G1 phases were reduced drastically and during the following 72-hr period, the number of G0 cells increased markedly. Restimulation of such in vitro formed G0 cells, under conditions permitting observation of their shift from the G0 to G0 phase, demonstrated that most cells could respond normally. Based on these observations, it was concluded that IL-2 not only ensures T-lymphocyte survival and proliferation, but IL-2 starvation induces many continuously proliferating T lymphocytes to stop cycling and to return to the G0 phase of the cell cycle where they remain functional.

Antibodies, Monoclonal↗
PubMed1984

Transcription and translation dependent induction of interleukin 2 (IL-2) and IL-2 receptors.

Our previous findings on the expression of Interleukin 2 (IL-2) receptors have shown that under the influence of certain drugs, it was possible to dissociate IL-2 production from the appearance of IL-2 receptors on human peripheral blood lymphocytes (PBL). Therefore, we studied whether the induction of IL-2 receptors were transcription- or translation-dependent. Actinomycin D and puromycin inhibited the appearance of IL-2 receptors as well as the production of IL-2. Furthermore, both drugs also inhibited human PBL to enter the G1 phase of the cell cycle. Thus, these data suggested that both IL-2 production and the appearance of IL-2 receptors were dependent on transcription and translation in non-resting cells.

Adult↗
PubMed1984

Comparison of haemodynamic dose-response effects of beta- and alpha-beta-blockade in acute myocardial infarction.

The comparative haemodynamic dose-response effects of beta- (propranolol) or alpha- plus beta-blockade (labetalol) were evaluated in a randomised between-group study of 16 patients with an uncomplicated acute myocardial infarction. In equivalent beta-blocking doses both drugs equally reduced myocardial stroke work index and presumably myocardial oxygen requirements. However, although propranolol reduced heart rate and cardiac output, these haemodynamic changes were accompanied by an augmentation of systemic vascular resistance. In contrast, labetalol reduced heart rate, cardiac output without change in systemic vascular resistance. Moreover, concomitant alpha- and beta-blockade with labetalol resulted in lesser depression of cardiac output at equivalent beta-blocking doses to propranolol. These results suggest that the addition of alpha to beta-blockade may attenuate some of the adverse reflex circulatory consequences of pure beta-blockade; the usefulness of this pharmacological approach to the manipulation of the circulation in the early post-infarction period merits further study.

Aged↗
PubMed1984

Proliferative response of human venous endothelial cells to medium conditioned by human tumour cells.

Serum-free medium conditioned by the prior cultivation of cells of the IPT line (derived from a poorly differentiated carcinoma of the lung) contained material of a high MW which stimulated proliferation in cultures of endothelial cells from human umbilical vein. A response was shown by cells seeded on plastic, gelatin or collagen of type I or type IV, at densities of 25 to 200/mm2, and in media with serum concentrations ranging from 0.5 to 20% v/v. Cells plated on biological substrata showed a greater response than those on plastic.

Angiogenesis Inducing Agents↗
PubMed1984

Enhanced haemodynamic effects of propranolol in acute myocardial infarction.

To evaluate the possible influence of sympathetic activation on the haemodynamic response to intravenous beta-blockade, the dose-response characteristics of three boluses of propranolol were evaluated in 8 patients with uncomplicated infarction and compared in a similar number of patients with stable angina. Following a control period, when haemodynamic stability was confirmed, propranolol 2, 2 and 4 mg (cumulative dosage 2, 4 and 8 mg) was injected into the central circulation at 15 min intervals. Despite close matching in baseline control haemodynamic variables between the groups, in stable angina, propranolol resulted in dose-related depression of cardiac output without change in systemic blood pressure, whereas following myocardial infarction the drug induced significantly greater falls in cardiac output (P less than 0.05) and a dose-related decrease in systemic blood pressure. Despite the greater effects of propranolol on cardiac output following myocardial infarction, the left ventricular filling pressure was increased to a lesser extent compared with stable angina. The explanation for this observation may reside in a greater susceptibility of the left ventricular wall to increase its compliance, under conditions of high sympathetic stimulation, following beta-blockade. These data support experimental and biochemical evidence of sympathetic activation in myocardial infarction; the hyperadrenergic state conditions an augmented haemodynamic response to competitive antagonism of sympathetic stimulation at cardiac beta-adrenoceptors.

Aged↗
PubMed1984

5-Azacytidine induced myogenesis in a differentiation defective cell line.

A differentiation defective cell line variant, the T984-15, has lost the capacity to differentiate myogenically. Following treatment with the hypomethylating agent 5-azacytidine, T984-15 cells were induced to differentiate into myogenic colonies containing fused myotubes. Myogenic colonies when cloned, maintained their ability to differentiate after prolonged culture in the absence of further 5-azacytidine treatment. These results indicate that 5-azacytidine treatment resulted in a stable alteration in the capacity of T984-15 cells to differentiate and suggests that the loss of myogenic potential may have occurred as a result of an epigenetic phenomenon rather than a somatic mutational event.

Animals↗
PubMed1984

Clinical use of DNA markers linked to the gene for Duchenne muscular dystrophy.

Seventy families with Duchenne muscular dystrophy (DMD) known to the Institute of Child Health fall into three categories with respect to potential linkage analysis with the X chromosome DNA markers RC8 and L1.28 that bridge the DMD gene. Families in which there is at least one obligatory female heterozygote (n = 13). Here 'prediction' and 'exclusion' of DMD gene transmission may be possible, the accuracy being dependent on the closeness of the linkage of the DNA marker(s) to the DMD gene; an illustrative case is reported. Families in which there is a single affected boy, who also has one or more healthy brothers (n = 26). Given an informative restriction fragment length polymorphism (RFLP), the probability that the boy represents a new mutation can be reassessed; it is also possible to 'exclude' the DMD gene in a sister. Families with a single affected boy with no brother (n = 30). Here 'exclusion' of the DMD gene in a sister may be possible. Only in one family was there no possibility of useful linkage analysis. The linkage analysis required is described, and the need to check DMD families for informative RFLPs is stressed.

Base Sequence↗
PubMed1984

5-Azacytidine-induced uncoupling of differentiation and tumorigenicity in a murine cell line.

Highly tumorigenic, myogenically defective T984-15 murine cells were treated with the hypomethylating agent 5-azacytidine (5-azaC). In response to drug treatment, T984-15 cells formed colonies that were myosin-positive and contained fused myotubes. When cloned, these differentiated colonies gave rise to cells that maintained their myogenic potential even after prolonged growth in tissue culture. The myogenic differentiation observed in response to 5-azaC treatment was not the result of selection of a preexisting myogenic subpopulation, inasmuch as treatment of a subcloned population of nondifferentiating cells with 5-azaC also resulted in the induction of myogenesis. In addition to inducing myogenic potential, 5-azaC generally suppressed the tumorigenic potential of the treated cells. Whereas 19 of 19 untreated T984-15 clones when injected into BALB/c nude mice produced tumors, 8 of 9 of the 5-azaC-treated clones injected displayed suppressed tumorigenicity under identical conditions. Tumorigenic suppression, however, was independent of the induction of differentiation: 1 myogenic clone remained tumorigenic and 5 clones whose tumorigenic potential was suppressed were nonmyogenic. Thus treatment with the hypomethylating agent 5-azaC not only affected the expression of differentiated and tumorigenic phenotypes but also dissociated their usually coordinate regulation.

Animals↗
PubMed1984

Pharmacokinetics and pharmacodynamics of three different prednisolone prodrugs: effect on circulating lymphocyte subsets and function.

To be pharmacologically active, i.v. prednisolone disodium phosphate (prednisolone phosphate), prednisolone sodium tetrahydrophthalate (prednisolone phthalate), and oral prednisone have to be converted in vivo into prednisolone. The purpose of the present study was to establish whether these agents are functionally equivalent when given in equimolar doses. The peak concentrations of total and unbound prednisolone assessed by HPLC and equilibrium dialysis in five normal volunteers were five to 12 times higher after i.v. prednisolone phosphate than after i.v. prednisolone phthalate or oral prednisone (p less than 0.001). The area under the plasma concentration vs time curves (AUC) of total and unbound prednisolone was higher after i.v. prednisolone phosphate than after oral prednisone or i.v. prednisolone phthalate (p less than 0.001). The immunosuppressive activity of the plasma samples was determined as the percentage inhibition of the mixed lymphocyte reaction, and the area under the inhibition vs time curve of the MLR (AUIC), a measure of immunosuppressive capacity over time, was calculated. After i.v. prednisolone phthalate or oral prednisone, the mean AUC of unbound prednisolone were 45 and 61% of that obtained after i.v. prednisolone phosphate, and the corresponding AUIC were 76 and 68%, respectively, indicating lower systemic availability of prednisolone and less of an immunosuppressive effect in plasma after i.v. prednisolone phthalate or oral prednisone than after i.v. prednisolone phosphate. These differences in biologic activity of the plasma were corroborated by determining ex vivo the cell cycle progression within the G1 phase, and the interleukin 2 (IL 2) release after the activation of peripheral lymphocytes obtained at various time points after administration of the three steroids. After steroid doses corresponding to 1 mg/kg of prednisolone, a transient inhibition of 80% of IL 2 production was observed with all three glucocorticoids given, whereas the maximal inhibition of the IL 2 production was 60, 30, and 22% after a low dose (0.1 mg/kg) of prednisolone phosphate, prednisone, or prednisolone phthalate, respectively. After the low dose, only minimal changes in the percentages of the OKT4+ and OKT8+ cells were detectable, whereas after the high dose of all three steroids the ratio of OKT4+ to the OKT8+ cells dropped, the decline being more pronounced after prednisolone phosphate than after prednisolone phthalate or prednisone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗