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Biomedical subjects

A M Francis

Publications and source records attributed to A M Francis.

11 recordsLinked to original sources
PubMed1993

High molecular weight kininogen potentiates the heparin-accelerated inhibition of plasma kallikrein by antithrombin: role for antithrombin in the regulation of kallikrein.

The effects of previously characterized interactions of high molecular weight kininogen (H-kininogen) with plasma kallikrein and with heparin on the regulation of kallikrein by the heparin-activated inhibitor, antithrombin, were investigated. H-kininogen, at levels sufficient to fully complex kallikrein, greatly potentiated the acceleration of antithrombin inhibition of kallikrein produced by heparin with high affinity for antithrombin. At I = 0.15, pH 7.4, 25 degrees C, kininogen thus maximally increased the heparin enhancement of the second-order rate constant for the antithrombin-kallikrein reaction from 13-fold (1.6 x 10(2) M-1 s-1 to 2.1 x 10(3) M-1 s-1) to 1200-fold (1.9 x 10(5) M-1 s-1). In contrast, H-kininogen had no effect on the antithrombin-kallikrein reaction in the absence of heparin, nor did the protein enhance the rate constants of 1.7 x 10(4) and 3.4 x 10(4) M-1 s-1 for kallikrein reactions with its primary plasma inhibitors C1-inhibitor and alpha 2-macroglobulin, respectively, in the absence or presence of heparin. Consistent with these results, SDS gel electrophoresis of the 125I-labeled kallikrein-inhibitor complexes formed in a mixture of these kallikrein inhibitors at their relative plasma concentrations indicated that antithrombin effectively competed with C1-inhibitor and alpha 2-macroglobulin for kallikrein, accounting for 54% of the total kallikrein complexes, only when both heparin and H-kininogen were present. Similarly, the presence of therapeutic levels of heparin (approximately 1 unit/mL) in normal, factor XII-deficient, and prekallikrein-deficient plasmas enhanced the rate of inactivation of added kallikrein by 2.3-fold and significantly altered the partitioning of radiolabeled kallikrein from predominantly C1-inhibitor and alpha 2-macroglobulin complexes (86-92%) to mostly antithrombin complexes (50-53%). Experiments in antithrombin-deficient and H-kininogen-deficient plasmas confirmed that the enhanced kallikrein inactivation rate and predominant formation of antithrombin-kallikrein complexes in heparinized plasma were dependent on antithrombin and H-kininogen. The contribution of antithrombin to kallikrein inhibition in plasma remained significant (approximately 40-70%) at optimal concentrations of unfractionated or size- and antithrombin affinity-fractionated heparin, in the presence of plasma levels of calcium and zinc ions, at 37 degrees C, and with minimal plasma dilution. These results suggest that antithrombin and H-kininogen may play important roles in the regulation of kallikrein activity in the presence of heparin or heparin-like glycosaminoglycans.

Antithrombins↗
PubMed1993

Parallel mechanisms of high molecular weight kininogen action as a cofactor in kallikrein inactivation and prekallikrein activation reactions.

The mechanism by which high molecular weight kininogen (H-kininogen) potentiates the heparin-accelerated inhibition of plasma kallikrein by antithrombin [Olson, S. T., Sheffer, R., & Francis, A. M. (1993) Biochemistry (preceding paper in this issue)] was investigated at I = 0.15, pH 7.4, 25 degrees C. Single-chain, two-chain, and light-chain, but not heavy-chain, forms of H-kininogen were similarly effective in potentiating the heparin-accelerated antithrombin-kallikrein reaction, indicating that the light-chain region of the protein was responsible for promoting kallikrein inactivation and that cleavage of H-kininogen did not significantly affect this promoting activity. H-kininogen potentiation increased in a saturable manner with increasing kininogen concentration, reflecting a KD (23 +/- 8 nM) similar to that previously measured for H-kininogen binding to kallikrein by equilibrium methods. Both H-kininogen-stimulated and unstimulated heparin rate enhancements initially increased with increasing heparin concentration in a manner corresponding to the saturation of antithrombin with heparin (KD = 10-30 nM). However, at higher heparin concentrations, the stimulated but not the unstimulated heparin rate enhancement decreased in parallel with the saturation of a protein-heparin interaction with a KD (0.4 +/- 0.2 microM) comparable to that directly measured for the H-kininogen-heparin interaction (2.0 +/- 0.2 microM). These results implied that H-kininogen stimulation required the formation of a quaternary complex in which antithrombin and H-kininogen-kallikrein complex were bound to the same heparin chain. In keeping with this interpretation, a synthetic heparin pentasaccharide representing the antithrombin binding sequence accelerated the antithrombin-kallikrein reaction to an extent similar to that of full-length heparin chains containing this sequence, but the pentasaccharide acceleration was not stimulated by H-kininogen. The importance of H-kininogen-kallikrein complex binding to heparin for kininogen stimulation was further indicated from the marked salt dependence of the second-order rate constant for the association of H-kininogen-kallikrein complex but not free kallikrein with antithrombin-heparin complex, under conditions where saturation of the two binary complexes was maintained. Kinetic analyses of antithrombin-kallikrein reactions as a function of the inhibitor concentration indicated that the KD for an initial antithrombin-kallikrein encounter complex was decreased 20-fold by heparin binding to antithrombin and an additional 200-fold by H-kininogen also binding to kallikrein. By contrast, rate constants for the conversion of the encounter complex to a stable complex were comparable for all reactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Heparin↗
PubMed1988

Host and tumor growth and energy substrates in blood of hepatoma-bearing rats receiving high-fat parenteral infusions.

We examined the effects of isocaloric carbohydrate-based TPN vs fat-based TPN on plasma levels of energy substrates and insulin and on growth of Morris Hepatoma 7777 and host animals. Hepatoma-bearing rats fed similar diets ad libitum served as controls. Although no differences in tumor growth were observed, host weight loss was less in parenterally than in orally fed animals. Liver lipid and plasma free fatty acids and triglycerides in tumor-bearing and normal rats infused high-fat TPN were markedly higher than in all other groups, suggesting that this level of lipid infusion exceeds the rate of utilization. Plasma glucose and insulin in tumor-bearing rats infused high-fat TPN were higher than in all other groups, which may indicate insulin resistance. Replacing glucose energy in TPN with lipid does not appear to reduce glucose availability to tumors but does have potentially deleterious effects on the host.

Adipose Tissue↗
PubMed1986

Menopausal estrogen use and the risk of breast cancer.

The relationship between the occurrence of female breast cancer and menopausal estrogen replacement was investigated in a population-based case-control study. One hundred and eighty-three white female residents of King County, Washington (ages 50-74) in whom breast cancer was diagnosed from July, 1977, through August, 1978, were interviewed with respect to reproductive and other factors, with emphasis on the use of estrogen-containing medication. For purposes of comparison, the same data were collected from 531 white female King County residents of the same ages without breast cancer. Use of menopausal estrogens was reported somewhat more commonly among controls than among cases (relative risk = 0.74, 95% confidence interval = 0.51-1.08) and some variation in proportions of users was present between different hysterectomy-oophorectomy subgroups. However, each of these differences could easily have been due to chance. No substantial trends in risk were apparent with increasing duration of use, time since first use, time since last use, or average dose. The findings suggest that in King County no important relationship exists between use of menopausal estrogens and the occurrence of breast cancer.

Aged↗
PubMed1986

Treatment of recurrent anterior dislocation of the shoulder by duToit Staple capsulorrhaphy. Results of long-term follow-up study.

DuToit Staple Capsulorrhaphy was performed on 79 patients during a period of ten and one-half years. Sixty-five patients were followed for an average period of nine years (26 months to ten and one-half years). Separation of the glenoid labrum from the glenoid rim was noted in 94% of the cases. A markedly lax and redundant capsule was noted in 6% of the cases. A bucket-handle tear of the glenoid labrum was noted in 4% of the cases. Fracture of the anterior rim of the glenoid was noted in 6% of the cases. There was one recurrence of dislocation (1.78%); 94% were rated as excellent; 4% were rated good; and 2% were rated poor. Out of 70% of the patients who were participating in athletic activities, 58% returned to athletic activities after surgical repair. Stapling the glenoid labrum to the glenoid is an effective method of treatment of recurrent anterior dislocation of the shoulder.

Adolescent↗
PubMed1984

Using computer graphics to map origin-destination data describing health care delivery systems.

An interactive graphic computer program, called FLOWMAP, is used to examine the referral patterns of cancer patients in western Washington between 1974 and 1978. FLOWMAP allows one to produce several types of maps from origin-destination data easily and inexpensively. Several maps show some of the significant geographic components of the referral of more than 7000 cancer patients among 13 counties over a 5-year period. It is shown that cancer care has become more decentralized during this period. Nine other possible applications of FLOWMAP to issues of concern regarding the delivery of health care are described. Maps produced by FLOWMAP can be expected to cost 1/30 to 1/50 of the cost of comparable manual methods. An Appendix gives some technical detail regarding the use of FLOWMAP and its data requirements.

Computers↗
PubMed1984

Care of patients with colorectal cancer. A comparison of a health maintenance organization and fee-for-service practices.

The presence of a population-based cancer registry in a community with a health maintenance organization (HMO) enabled a detailed, longitudinal comparison to be made of care given for colorectal cancer in an HMO with traditional fee-for-services (FFS) care. An interview survey of 39 HMO and 150 FFS patients was supplemented with data from the cancer registry. Patients seen by the two provider groups were similar with respect to sociodemographic characteristics, severity of disease at diagnosis, and concurrent medical conditions. The HMO patients received more prediagnostic care but did not receive definitive surgical treatment as quickly as the FFS group. There were few differences in care, however, once diagnosis was made; there were no differences in access to care, rates of definitive surgery, chemotherapy, radiation therapy, length of hospitalization, number of follow-up physician visits, and most measures of satisfaction with care. No differences in outcome, including 4-year survival and 1-year health status, were found. HMO patients expressed significantly less concern about the cost of their care. These findings suggest an initial hesitancy to provide definitive care by the HMO but no significant differences in either the process or outcome of care once definitive care is begun.

Colonic Neoplasms↗
PubMed1984

The treatment of chronic slipped capital femoral epiphysis by biplane osteotomy.

Thirty-two biplane osteotomies in thirty patients were performed for the treatment of chronic slipped capital femoral epiphysis during a fourteen-year period at the Jersey City Medical Center. Twenty-seven patients (twenty-nine hips) were followed for two and a half to fourteen years. The correction obtained at surgery was maintained in all of the patients. Although two patients had had narrowing of the hip joint preoperatively and one had narrowing postoperatively, this had resolved at an average of three years postoperatively. Improvement in the range of motion was noted. In twenty patients the limb lengths were equal, in three the involved limb was longer, and in four patients the limb was shorter postoperatively. One patient had a slight subluxation of the femoral head due to an excessive valgus correction at the time of surgery, and one patient had delayed union of the osteotomy site which went on to satisfactory healing. No patients had avascular necrosis of the femoral head or symptoms of degenerative arthritis at follow-up. Preoperative joint-space narrowing did not appear to be a contraindication to this procedure.

Adolescent↗
PubMed1982

Breast cancer in relation to patterns of oral contraceptive use.

A total of 112 white females residents of King County, Washington, aged 35-54 years, who had received a first diagnosis of invasive breast cancer between July 1977 add August 1978, were investigated concerning prior use of oral contraceptives. Their responses were compared with those of a random sample of 469 demographically comparable women from the same population. Overall, oral contraceptive use in cases and controls was similar. However, use of oral contraceptives in preparous women was more common among cases than controls, with the estimated risk of breast cancer associated with such use being 2.2 times that of nonusers (90% confidence interval = 1.1-4.6). This relationship could be explained only in part by the effect of oral contraceptives in postponing or preventing childbirth. The association of breast cancer with use of oral contraceptives prior to ever giving birth has been observed in three studies, including this one, suggesting that the susceptibility of breast tissue to hormonal factors that influence the development of malignancy may be altered by having been exposed to the events of pregnancy.

Adult↗