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Biomedical subjects

R L Edwards

Publications and source records attributed to R L Edwards.

At least 73 records · Page 4Linked to original sources
PubMed1984

The effect of serum on monocyte tissue factor generation.

Human monocytes generate the procoagulant tissue factor (MTF) following exposure to a variety of immune stimuli in vitro. The generation of MTF is modified by T cells, lymphokines, and immunoregulatory lipoproteins, and recent studies have shown that MTF can be activated in an immune-specific manner following exposure to antigen. We have examined the role of serum factors in the regulation of MTF generation. Low concentrations (less than 1%) of heat-inactivated normal human serum greatly enhanced MTF generation in cultures of normal peripheral blood mononuclear cells. The stimulatory effect was observed in cultures of both unstimulated cells and cells exposed to bacterial lipopolysaccharide. Stimulation was not observed at high serum concentrations (greater than 10%) and could not be explained by endotoxin contamination or activation of the assay system. Stimulatory activity was present in plasma and BaSO4-adsorbed plasma as well as autologous and allogeneic serum, was not abolished by removal of serum lipoproteins, and did not require the presence of T cells for its expression. Sera from 28 different normal volunteers were screened for stimulatory activity and demonstrated a wide variation in potency. These results suggest that a potent factor is present in sera that enhances the expression of MTF activity in vitro. This factor is distinct from previously described lipoprotein regulators and may play a role in the initiation of coagulation in both normal hemostasis and pathologic states.

Blood Coagulation Factors↗
PubMed1984

Macrophage procoagulants.

From the preceding exposition it is now clear that the regulation of monocyte/macrophage PCA is dependent upon a complex network of interacting pathways, some of which amplify the response of the monocyte/macrophage, while others inhibit. In all probability many more will emerge. The construct illustrated in Figure 3, therefore, is a simplified view of the two major stimulatory pathways: the T cell-dependent pathway, activated by immune recognition and mediated by lymphokine(s); and the T cell-independent pathway, activated by direct perturbation of monocytes by such stimuli as LPS. At least 2 or 3 different PCAs can be expressed by monocyte/macrophages from different species, depending upon the anatomic site of the origin of the cell and the types of stimuli imposed. Inhibition of PCA expression is accomplished by at least one set of regulatory lipoproteins, and other inhibitory loops may be found. The result of these multiple interactions is the deposition of fibrin on the cell surface or in the surrounding milieu. It is our belief that this close relationship between coagulation reactions and inflammatory reactions, resulting in fibrin deposition, represents a fundamental host defense designed to delimit the inflammatory response. Nevertheless, the precise role of monocyte procoagulants in vivo remains unclear. A number of potential mechanisms exist for activation of coagulation in both inflammatory and neoplastic disorders, and the finding of enhanced monocyte procoagulant activity by no means establishes its importance in physiologic or, pathosphysiologic responses in vivo. Further studies, possibly with agents capable of specific inhibition of monocyte procoagulants in vivo, will be necessary to define the precise importance of these procoagulants in clinical disorders.

Animals↗
PubMed1983

Abnormalities of blood coagulation in patients with cancer. Fibrinopeptide A generation and tumor growth.

Fibrinopeptide A (FPA) levels have been followed sequentially in a three-year study of 50 patients with advanced carcinoma. Evidence for activation of blood coagulation was found in 26 of 43 subjects (60%) at the time of entry into the study. Serial FPA determinations revealed an upward trend which paralleled the progression of clinical disease. Persistent elevation of the FPA level suggested treatment failure and a poor prognosis. Anticoagulation with sodium warfarin significantly reduced the FPA level in subjects with cancer. Short-term anticoagulation with heparin decreased FPA levels in two patients with thromboembolic disease but failed to reduce FPA to the normal range in any of the three patients with cancer so tested. These data suggest that most patients with advanced cancer have evidence for activation of blood coagulation and suggest that serial FPA determinations may be useful in following tumor progression or response to therapy in patients with cancer.

Aged↗
PubMed1983

Luteinizing hormone releasing hormone analogue in treatment of hypergonadotrophic amenorrhoea.

The effect of a luteinizing hormone releasing hormone analogue (HOE 766) was studied in four patients with hypergonadotrophic amenorrhoea (resistant ovary syndrome). After an initial phase of stimulation, there was a uniform and sustained suppression of gonadotrophin concentrations in all the patients during the 20-24 days of treatment, presumably due to down-regulation of the pituitary receptors. One patient ovulated after stopping treatment.

Adult↗
PubMed1983

Expression of procoagulant activity in a human monocyte-like cell line.

Peripheral blood monocytes generate the potent membrane-bound procoagulant TF in response to a number of immune-related stimuli. Although the contribution of the monocyte/macrophage and its soluble mediators to the immune response has been recognized, the role of macrophage procoagulant in the pathogenesis of this response is less certain. Previous studies have suggested that MTF generation is important in the pathogenesis of fibrin deposition in the inflammatory response. In order to pursue this relationship, we have studied the activation of a procoagulant in a human monocyte-like cell line, the U937. The U937 procoagulant has been characterized as TF by the following criteria: the PCA requires factors VII and X for expression; the PCA is not due to serine protease activity; PCA is neutralized by a monospecific antibody to purified bovine TF. The expression of TF in these cells was amplified after stimulation with LPS, a potent activator of peripheral blood MTF expression, and was inhibited by actinomycin D and cycloheximide. Cytosine arabinoside, an inhibitor of cell division, failed to affect U937 TF generation. The U937 cell line appears to be a useful in vitro model for the study of the activation of MTF.

Cell Line↗
PubMed1982

Trenbolone, estradiol-17 beta and estrone levels in plasma and tissues and live weight gains of heifers implanted with trenbolone acetate.

Twenty-four heifers were allotted into three groups of eight heifers each and designated control, long-term (LT) or short-term (ST). Animals in the latter two groups were implanted in the ear with 300 mg trenbolone acetate (TBA) for 99 or 62 d, respectively. Four heifers in each group were subjected to liver and fat biopsy 60 d after initiation of the experiment. At slaughter, which occurred 15 d after retrieval of the implant, liver and fat were also collected. The implant was analyzed for residual trenbolone (TBOH), and tissues were analyzed for TBOH and estradiol-17 beta (E2 beta). Blood samples were taken weekly after implantation and daily for 14 d before and after implantation. All heifers were weighed weekly. The ST heifers gained faster (P less than .05) than the control or the LT heifers, whereas the LT heifers gained similarly to the controls. Plasma levels of TBOH rose to over 900 pg/ml in response to the implantation in both treated groups, but stabilized at a lower level in the ST group than in the LT group. In both groups plasma E2 beta rose to over 7.5 pg/ml in response to TBA implantation; in fact, a regression analysis of E2 beta on TBOH in individual cows showed that the two hormones varied directly. Fat and liver accumulated substantial TBOH during implantation, but it cleared rapidly during the 15 d withdrawal period. Indications from this experiment are that TBA has promise for promoting rate of gain and efficiency of feed utilization in feedlot heifers. No undesirable effects on carcass quality were detected. The drug cleared blood and tissues rapidly after the implant was withdrawn. Further research is needed to determine the most effective implantation schedule. It would be desirable to determine whether a positive response to TBA will occur in animals being finished predominantly on forages.

Adipose Tissue↗
PubMed1982

Mononuclear cell modulation of fibroblast procoagulant activity.

The release of procoagulant material by connective tissue cells as a sequel to cell injury can initiate blood coagulation and may thus play a role in he pathogenesis of inflammatory lesions. Human foreskin fibroblasts were shown to synthesize high levels of the procoagulant TF in vitro. Generation of TF by fibroblasts was inhibited by addition of supernatants of PHA-stimulated human mononuclear cells to fibroblast cultures. The inhibition was independent of supernatant effects on cellular proliferation and was accompanied by up to a 20-fold increases in PGE2 synthesis in the fibroblast cultures. The inhibition of TF generation by MC-SNs was reversed by adding indomethacin to the fibroblast cultures, suggesting that mononuclear cells suppress fibroblast TF generation by stimulation of endogenous fibroblast synthesis of prostaglandin. Regulation of fibroblast PCA by products of immune cells may be important in the pathogenesis of inflammatory lesions.

Cells, Cultured↗
PubMed1981

Studies on a circulating anticoagulant in procainamide-induced lupus erythematosus.

Circulating anticoagulant activity that had at least two distinct mechanisms--one directed against factor XII and one directed against blood thromboplastin (prothrombin activator complex)--developed in a patient with clinical and laboratory evidence of procainamide hydrochloride-induced systemic lupus erythematosus. The anticoagulant activity behaved as a gamma-globulin in chromatographic and electrophoretic analyses, with the majority of activity behaving as an IgM immunoglobulin. Despite markedly abnormal coagulation study results, no clinical bleeding occurred. Anticoagulant activity paralleled clinical and laboratory evidence of the inflammatory disease and improved on discontinuance of procainamide therapy.

Aged↗
PubMed1981

Abnormalities of blood coagulation in patients with cancer. Mononuclear cell tissue factor generation.

Activation of blood coagulation, as characterized by the occurrence of disseminated intravascular coagulation, increased levels of plasma FPA, and the local deposition of fibrin, is common in both experimental animals and patients with malignant tumors. Many mechanisms have been proposed for the mediation of this response to tumors, including tumor-associated proteases, platelet adherence to tumors, surface activation of blood coagulation by tumor cells, and activation of coagulation by tissue factor derived from either tumor tissue or reactive leukocytes. We have investigated the hypothesis that MTF generation may contribute to increased fibrin generation in cancer patients. Plasma FPA levels and in vitro unstimulated MTF generation were measured simultaneously in samples obtained from 35 patients with lung cancer. FPA levels were significantly elevated in these patients as compared to a group of 20 normal volunteers (p = 0.03). Although unstimulated MTF generation showed considerable variability in both the patients and the normal volunteers, a high degree of correlation was observed between simultaneous levels of FPA and MTF regardless of whether MTF was expressed per cell (r = 0.83), per monocyte (r = 0.95), or per volume of peripheral blood (r = 0.96). MTF generation was also significantly decreased in a group of patients receiving sodium warfarin (p less than 0.001). These results suggest a potential role for MTF generation in the activation of blood coagulation in neoplasia and also suggest the possibility that inhibition of MTF generation by warfarin may be partially responsible for the decreased FPA values previously reported in anticoagulated cancer patients.

Aged↗
PubMed1980

Adrenal function in subgroups of the PCO syndrome assessed by a long ACTH test.

Fifteen patients with the polycystic ovarian (PCO) syndrome were classified into Group A (n = 6) and Group B (n = 9) based on their LH responses to LHRH before and at 44 and 92h after administration of oestradiol benzoate. Adrenal function in both groups was assessed by comparing the hormone responses to ACTH (0.5mg twice daily for 4 days) with those obtained in nine normally ovulating women during the early follicular phase of their cycles. In Group A patients there was no significant difference from normals in the serum concentration of dehydroepiandrosterone sulphate (DHAS), 17 alpha-hydroxy-progesterone (17-OHP) or androgens (testosterone and dihydrotestosterone). In contrast, the serum concentrations in Group B were significantly higher (P less than 0.01) for each of these steroids before ACTH, and remained higher at 2 and 4 days for DHAS, but not for the other two steroids. The concentration of oestrone was significantly higher (P less than 0.05) in Group B patients before, and 2 days after, ACTH, while in Group A patients higher concentrations (P less than 0.02) were found only after 2 days. The concentrations of oestradiol, on the other hand, were not different from normal in either group before ACTH and became lower than normal in both groups at 2 days and remained lower at 4 days in Group B. The concentration of cortisol was within the normal range throughout in Group A, but was lower than normal after 4 days in Group B patients (P less than 0.05). The ratios between the sums of concentrations of DHAS to cortisol on days 2 and 4 (P less than 0.001) or 17-OHP to cortisol (P less than 0.05) were elevated in Group B compared with normal subjects. LH, FSH and prolactin values were normal throughout in Group A, but in Group B patients the mean value for LH was significantly elevated before ACTH and at 4 days after ACTH (P less than 0.02).

Adrenal Glands↗
PubMed1980

The role of human T cells (and T cell products) for monocyte tissue factor generation.

Monocytes generate the procoagulant material tissue factor (TF) when mixed mononuclear cell cultures are stimulated with antigens, mitogens, or bacterial endotoxin in vitro. Optimal monocyte TF production has been shown to require the presence of lymphocytes in the culture system. We have investigated the nature of this lymphocyte requirement by stimulating monocytes grown in the presence of varying numbers of T lymphocytes. In addition, some monocytes were grown in the presence of conditioned media prepared from T lymphocyte cultures. The results of these studies have demonstrated two pathways for monocyte TF generation: a relatively T cell-independent pathway that can be stimulated by endotoxin or PPD and a highly T cell-dependent pathway that can be stimulated by PHA. In addition, the lymphocyte requirement for PHA-induced monocyte TF generation may be replaced by conditioned media from T cell cultures.

Cell Adhesion↗
PubMed1979

Oestrogen modulation of gonadotrophin and prolactin release in women with anovulation and their responses to clomiphene.

An LHRH test was performed before and at both 44 and 92 h after the administration of 2.5 mg oestradiol benzoate in eleven patients with hyperprolactinaemia, eight with idiopathic secondary amenorrhoea and seven with oligomenorrhoea. The basal serum hormone concentrations and the responses to LHRH were compared with the same tests performed on ten normal subjects during the early follicular phase of their menstrual cycles (days 4--6). Mean basal concentrations of oestradiol in each group of patients and oestrone in those with hyperprolactinaemia were significantly lower than in the normal subjects. The mean concentration of prolactin in women with secondary amenorrhoea remained lower than in the normal women throught the tests (P less than 0.05). The LH and FSH responses to LHRH before oestrogen in patients with hyperprolactinaemia and of FSH in those with secondary amenorrhoea, were greater than in the normal subjects (P less than 0.001). After oestrogen treatment the responses were similar in all groups except in those with oligomenorrhoea where LH and FSH responses at 44 h (P less than 0.05 and P less than 0.01 respectively) and LH responses at 92 h (P less than 0.01) were lower than in normal controls. The responses at 92 h in all groups were greater than at 44 h (amplification) but the amplification at 92 h and at 44 h compared to the pre-treatment responses, tended to be lower in each group of patients compared to the normal controls. In the hyperprolactinaemic group of patients there was a negative correlation between the basal prolactin concentration and the gonadotrophin amplifications at 92 h (P less than 0.01), and a positive correlation between the basal oestrone levels and the amplifications at 92 h (P less than 0.01). The results of the oestrogen amplification test in eleven of the non-hyperprolactinaemic anovular patients were compared with the ovulatory response to 100 mg clomiphene given for 5 days. Six showed a normal oestrogen amplification and they all ovulated. Two patients failed to show greater amplification at 92 than at 44 h and required human chorionic gonadotrophin (HCG) as well as clomiphene to ovulate. The other three showed a diminished LH amplification at 92 h; they required 200 mg clomiphene and showed a prolonged follicular phase. The responses of the hyperprolactinaemic patients to clomiphene were poor and there was a negative correlation between prolactin concentration and oestrogen production (P less than 0.01). All ten hyperprolactinaemic patients treated with bromocriptine ovulated and eight conceived. The oestrogen amplification test appears to have some value in predicting the subsequent response to clomiphene in non-hyperprolactinaemic anovular women.

Adult↗
PubMed1979

Oestrogen-gonadotrophin feedback abnormalities in hyperprolactinaemic amenorrhoea demonstrated by the response to clomiphene administration.

Clomiphene was administered to 16 patients with elevated serum prolactin levels in doses of 100, 200 and 300 mg/day for five days in succeeding months and total urinary oestrogens estimated on days 0, 5, 8, 12 and 15 following commencement of treatment. The responses were compared with six patients who were amenorrhoeic but had normal serum prolactin levels and absent positive feedback to oestrogen. The increased outputs of oestrogens were similar in the two groups. In the hyperprolactinaemic group 5 out of 16 subjects showed evidence of ovulation whilst the remainder showed a secondary failure of response. Six subjects who failed to ovulate were treated with clomiphene and human chorionic gonadotrophin (HCG) and ovulations were induced in 31 out of 34 treatment cycles but no pregnancies were achieved. The responses to clomiphene therapy in the hyperprolactinaemic subjects were compared to the assessment of positive feedback mechanisms by means of oestrogen provocation and oestrogen amplification tests and good correlation was obtained. Only those with evidence of positive feedback to these tests were likely to ovulate on clomiphene.

Amenorrhea↗
PubMed1979

Mononuclear cell tissue factor: cell of origin and requirements for activation.

Human mononuclear leukocytes generate the procoagulant material tissue factor (TF) following stimulation by endotoxin, mitogens, or antigens in vitro. We have examined tissue-factor generation by mononuclear cell subpopulations prepared in a variety of ways in order to determine the cell of origin of mononuclear cell TF and the conditions necessary for maximal in vitro TF generation. We have also examined the relationship between in vitro TF generation and in vivo or in vitro measures of delayed hypersensitivity in response to identical antigen stimulation. Our results demonstrate that the monocyte is responsible for the bulk of mononuclear cell TF generation in vitro and that adhesion alone is not sufficient stimulation for significant.

Cell Adhesion↗
PubMed1978

Delayed hypersensitivity in man: effects of systemic anticoagulation.

Skin test reactivity, lymphocyte transformation, and mononuclear cell tissue factor generation were evaluated both before and during systemic anticoagulation in 24 volunteers. Anticoagulation with warfarin decreased skin test induration and tissue factor generation, but lymphocyte trnasformation remained unchanged. An intact coagulation mechanism, including tissue factor generation, appears to be important for the development of skin test induration in humans.

Adult↗