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Biomedical subjects

G H Goldsmith

Publications and source records attributed to G H Goldsmith.

At least 19 recordsLinked to original sources
PubMed1990

Effect of tumor necrosis factor on the human fibrinolytic system.

We report the effects on the fibrinolytic system of intravenous (IV) recombinant tumor necrosis factor-alpha (rTNF-alpha) infusions in patients with advanced cancers. During a phase I clinical trial of rTNF-alpha, the plasma fibrinolytic system was closely monitored, measuring tissue-type plasminogen activator (tPA) antigen, plasminogen activator (PA) inhibitor activity, and plasma fibrinolytic activity. Thirteen patients with refractory malignancies received 40, 80, or 160 micrograms/m2 rTNF-alpha as 2-hour IV infusions. After a 1-week rest, the same dose was repeated daily for 5 days every 3 weeks for a maximum of four courses. The serum rTNF-alpha levels peaked at the completion of the IV infusion and rapidly declined thereafter, becoming unmeasurable within 1 hour in all patients. rTNF-alpha infusion markedly alters the plasma fibrinolytic system. During the 2-hour infusion, significant increases in the tPA antigen and plasma fibrinolytic activity were seen. After the infusion, PA inhibitor activity increased, neutralizing the plasma fibrinolytic activity. The increase in PA inhibitor activity was maximal 6 hours after the onset of the rTNF-alpha infusion. Fibrinolytic properties returned to pretreatment values within 24 hours. Daily rTNF-alpha infusions caused changes in plasma tPA antigen and PA inhibitor similar to those of single infusions. We conclude from these observations that the administration of rTNF-alpha in vivo to cancer patients causes profound alterations of endothelial cell-derived components of the fibrinolytic system.

Antigens↗
PubMed1989

Modulation of polymorphonuclear leukocyte microbicidal activity and oxidative metabolism by fibrinogen degradation products D and E.

Fibrinogen degradation products (FDP) D and E are typically present in blood of patients with disseminated intravascular coagulation and related conditions in which granulocyte (PMN) defense against bacterial infection may be compromised. This study was intended to determine whether FDP modify PMN functions critical to their bactericidal activity. Incubation of human PMN and Escherichia coli with 50-100 micrograms/ml FDP did not affect phagocytosis, but reduced by greater than 90% the cells' ability to inhibit bacterial colony growth compared with control PMN incubated with albumin or fibrinogen. FDP (10-100 micrograms/ml) inhibited PMN O2- release and chemotaxis stimulated by FMLP by 17-50% (P less than 0.005) and 41% (P less than 0.01), respectively. Fragment E3, and not fragment D1, was primarily responsible for inhibition of FMLP-induced PMN O2- release. Phorbol myristate acetate (10 ng/ml), 1-oleoyl-2-acetylglycerol (10(-6) M), AA (4.2 x 10(-5) M), and zymosan-activated serum-stimulated PMN O2- release were also decreased 37-63% by FDP compared with control protein. There are at least two mechanisms by which FDP may impair PMN responses. With respect to FMLP, FDP (16-100 micrograms/ml) inhibited specific binding to the cell surface over a ligand concentration range of 1.4-85 nM [3H]FMLP. In contrast, FDP did not effect the extent of phorbol ester binding to PMN but blocked activation of protein kinase C. These data suggest that elevated plasma FDP inhibit several PMN functions critical to the bactericidal role of these inflammatory cells.

Adult↗
PubMed1988

Uric acid nephrolithiasis and acute renal failure secondary to streptozotocin nephrotoxicity.

Uric acid nephrolithiasis developed in a 75-year-old man who had received a large cumulative dose of streptozotocin for treatment of metastatic islet cell carcinoma of the pancreas. Oligoanuric renal failure mediated by massive intraureteral uric acid deposits occurred despite normal serum concentrations of uric acid. This case implicates the uricosuric effects of streptozotocin in the pathogenesis of uric acid nephropathy and suggests that renal uric acid excretion should be monitored routinely in patients receiving large cumulative doses of this drug.

Acute Kidney Injury↗
PubMed1988

Primary pulmonary hypertension in patients with classic hemophilia.

Five patients with classic hemophilia were found to have primary pulmonary hypertension, a disorder not previously recognized in this population. All patients had had their coagulation disorder treated for 10 years or more with self-administered lyophilized concentrates of factor VIII, and all had antibodies to human immunodeficiency virus (HIV). Primary pulmonary hypertension was confirmed by histologic means at autopsy in one patient and by lung biopsy findings in another. In the other three patients, the findings are in agreement with this diagnosis. No patient had underlying cardiac or pulmonary disease, or clinical or pathologic evidence of collagen-vascular disease, vasculitis, parasitic disorders, hemoglobinopathy, or exposure to anorexigenic agents. Whether the primary pulmonary hypertension was related to treatment with lyophilized factor VIII, or to the presence of antibodies to HIV, or both, is unknown.

Adult↗
PubMed1988

Neutrophil adhesive dysfunction in diabetes mellitus; the role of cellular and plasma factors.

We examined neutrophil adherence to bovine aortic endothelial cells in 26 patients with diabetes compared with age- and sex-matched controls. The adherence of chromium 51-labeled neutrophils from patients with diabetes in the basal state and after incubation with phorbol myristate acetate (PMA) but not N-formyl-methionyl-leucyl-phenylalanine (FMLP) was decreased significantly. A subset of 16 of 26 patients demonstrated highly significant decreases in basal adhesion. No significant correlation was found between defective adherence and metabolic control as assessed by plasma glucose level (range 44 to 508 mg/dl) and hemoglobin A1 level (range 7.7% to 17.1%) at the time of study. Plasma from patients with diabetes increased adherence of both diabetic and control neutrophils in the basal state. The adherence-augmenting factor in diabetic plasma was found to be nonfilterable and partially heat labile and to manifest the characteristics of a protein. The adhesive effects of diabetic plasma were mediated through alterations in endothelium rather than neutrophils. Diabetic neutrophil aggregation induced by PMA, FMLP, and calcium ionophore was normal in all patients examined, regardless of the aggregating agent used. Fibronectin release in the basal state and after stimulation with FMLP was found to be comparable in diabetic and control neutrophils. These studies demonstrated intrinsic adhesive dysfunction of diabetic neutrophils and a factor or factors in diabetic plasma that enhanced adherence to endothelium. These cellular and humoral factors may act together to prevent tissue emigration of neutrophils and may contribute to the pathogenesis and susceptibility of infection in diabetes.

Adult↗
PubMed1987

Escalating doses of sequential methotrexate and 5-fluorouracil, doxorubicin, and vincristine for the treatment of metastatic breast cancer.

Antitumor efficacy of sequential methotrexate, 5-fluorouracil, and mid-cycle doxorubicin regimens has been established in advanced gastric cancer. Based on similar theoretical kinetic considerations, we treated 15 women with metastatic breast cancer with a five-drug nonalkylating agent regimen. Six of 14 evaluable patients had an objective response. Three patients achieved a complete remission (duration 9, 14, 19+ months), and 3 attained a partial remission (duration 2, 3, 6 months). Hematologic toxicity was significant, with 8 patients developing moderate to severe (ECOG grade 3 or 4) toxicity. Although significant antitumor activity with this nonalkylating agent regimen was observed, hematologic toxicity was considerable and limits the usefulness of this regimen in its present schedule.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Bovine coronary artery endothelium: in vitro culture and production of plasminogen activator.

A new method for isolation and culture of endothelial cells from bovine coronary artery (BCoAEC) is presented. This method involves in situ perfusion and digestion of main coronary arteries with a collagenase solution. The isolated cells were cultured and maintained through many cell passages in Dulbecco's Modified Eagle's Medium supplemented with fetal bovine serum derived from either whole blood or plasma. Confirmation of these cells' endothelial origin was obtained by demonstration of typical morphologic and growth characteristics of endothelium, immunofluorescent staining with antibodies to von Willebrand factor (Factor VIII: vWF), and measurement of plasminogen activator (PA). In addition, production of PA was inhibited by enzymatically active thrombin as has been previously described with bovine aortic endothelial cells in culture.

Animals↗
PubMed1986

Studies on a circulating anticoagulant inhibiting factor XI in a patient with congenital deficiency and carcinoma of the prostate.

An inhibitor of plasma thromboplastin antecedent (PTA, factor XI), measured in coagulant and radioimmunoassays, was detected in a 60-year-old man with carcinoma of the prostate who had no evidence of a bleeding tendency. Family studies indicated that the patient was either a homozygote or a heterozygote for hereditary factor XI deficiency. In contrast to earlier described patients with factor XI deficiency in whom inhibitors were detected, the patient was unaware of having been transfused with blood or blood products at any time before the discovery of the inhibitor. The inhibitor of factor XI in the patient's plasma appeared to be predominantly in the IgG4 fraction and to be directed at a locus on the factor XI molecule other than the active site; it did not block the amidolytic properties of activated factor XI (XIa). Rather, it appeared to block adsorption of factor XI to negatively charged surfaces. The inhibitor interfered with measurement of other components of the intrinsic pathway of thrombin formation, perhaps explaining the low titres of other coagulation factors of the intrinsic system reported in patients with strong inhibitors directed against factor XI.

Factor XI↗
PubMed1985

Metal and phospholipid binding properties of partially carboxylated human prothrombin variants.

To study the specific role of gamma-carboxyglutamic acid (Gla) residues in prothrombin, we have isolated a series of partially carboxylated prothrombin variants from a patient with a hereditary defect in vitamin K-dependent carboxylation (Goldsmith, G. H., Pence, R. E., Ratnoff, O. D., Adelstein, D. A., and Furie, B. (1982) J. Clin. Invest. 69, 1253-1260). The three variant prothrombins, purified by DEAE-Sephacel, immunoaffinity chromatography, and preparative gel electrophoresis, were indistinguishable from prothrombin in molecular weight, amino acid composition, and NH2-terminal amino acid sequence, with the exception of Gla residues. Variant prothrombin 1, with 8 Gla residues, had 66% of the coagulant activity of prothrombin, one high affinity metal-binding site (Kd = 15 nM), and three lower affinity sites (Kd = 2.7 microM); prothrombin contained two high affinity (36 nM) and four lower affinity sites (Kd = 1 microM). Ca(II) induced a 23% decrease in the intrinsic fluorescence of variant prothrombin 1 fragment 1, compared to a 35% decrease in that of prothrombin fragment 1. The phospholipid binding activity of variant prothrombin 1 was 44% that of prothrombin. Variant prothrombin 2 and variant prothrombin 3, with 4 and 6 Gla residues, respectively, had about 5% of prothrombin coagulant activity and a single high affinity and two lower affinity metal-binding sites and exhibited no phospholipid binding activity. Variant prothrombin 3 fragment 1 and variant prothrombin 2 fragment 1 demonstrated 18 and 13% of Ca(II)-induced fluorescence quenching, respectively. Abnormal prothrombin, with 1 Gla residue, had 8% of prothrombin coagulant activity, a single lower affinity (1 microM) metal-binding site, and 13% Ca(II)-induced fluorescence quenching of the fragment 1 species and did not bind to phospholipid. These results indicate that Gla residues define the metal binding properties of prothrombin. Most, if not all, of the Gla residues are required for complete prothrombin function, and the prothrombin coagulant activity correlates to the phospholipid binding activity of the prothrombin species.

Amino Acid Sequence↗
PubMed1985

Inhibitors of plasma thromboplastin antecedent (factor XI): studies on mechanism of inhibition.

Acquired inhibitors of plasma thromboplastin antecedent (PTA) have been described in several recent studies, which collectively emphasize the heterogeneity of PTA functions that are impaired by this class of circulating anticoagulants. To clarify whether acquired inhibitors of PTA exhibit inhibitory properties that vary widely from one patient to the next, IgG inhibitors from four patients were isolated. The effect of these inhibitors on the binding of PTA to glass, the activation of kaolin-bound PTA, the coagulant activity of both kaolin-bound and fluid phase activated PTA (aPTA), and the enzymatic activity of aPTA against a low molecular weight substrate was quantified. The relative inhibition of these individual components of PTA activation and function by the four anticoagulants was quite similar. The results indicate that the principal binding sites for acquired inhibitors of PTA are PTA domains involved with surface binding and conversion of PTA to aPTA, with less effective steric impairment of aPTA enzymatic activity.

Adult↗
PubMed1985

A monoclonal antibody that inhibits activation of human Hageman factor (factor XII).

A monoclonal antibody to human Hageman factor (HF, factor XII) was derived from BALB/c mouse spleen cells fused with NS-1 mouse myeloma cells. This antibody, purified from ascites fluid, reacted with HF to inhibit the activation of HF, purified or in normal pooled plasma, as measured by a coagulation assay. The antibody did not inhibit the coagulant activity of activated HF. The antibody also inhibited the generation of amidolytic activity in HF-ellagic acid mixtures, but failed to inhibit the amidolytic properties of the carboxy-terminal fragment of HF (HFf). Amidolytic activity, absent in an HF-monoclonal antibody mixture, was generated upon treatment with insoluble trypsin. Monoclonal antibody, bound to CNBr Sepharose 4B gel (Pharmacia Fine Chemicals, Piscataway, NJ), reversibly bound HF in plasma or in buffer, without activating it. HF was then eluted with 4 mol/L guanidine HCI. The passage of 125I-labeled HF enzymatically cleaved by trypsin through a column of monoclonal antibody-CNBr Sepharose 4B gel resulted in flow-through of HFf with a molecular weight (mol wt) of 30,000 and HF fragments of mol wt 12,000. Elution with 4 mol/L guanidine HCI yielded several HF fragments (mol wt 80,000, 52,000, and 40,000) but not HFf. These data suggest that the single determinant recognized by the murine monoclonal antibody is not on HFf, but rather on the amino-terminal fragment thought to be involved in the binding activity of HF. The monoclonal anti-HF bound to CNBr-activated Sepharose 4B gel could be used to artificially deplete plasma samples of HF.

Animals↗
PubMed1979

Inhibitory spectrum of alpha 2-plasmin inhibitor.

alpha 2-Plasmin inhibitor (alpha 2PI) has been recently characterized as a fast-reacting inhibitor of plasmin in human plasma and appears to play an important role in the regulation of fibrinolysis in vivo. We have studied the effect of purified alpha 2PI upon various proteases participating in human blood coagulation and kinin generation. At physiological concentration (50 microgram/ml), alpha 2PI inhibited the clot-promoting and prekallikrein-activating activity of Hageman factor fragments, the amidolytic, kininogenase, and clot-promoting activities of plasma kallikrein, and the clot-promoting properties of activated plasma thromboplastin antecedent (PTA, Factor XIa) and thrombin. alpha 2PI had minimal inhibitory effect on surface-bound activated PTA and activated Stuart factor (Factor Xa). alpha 2PI did not inhibit the activity of activated Christmas factor (Factor IXa) or urinary kallikrein. Heparin (1.5-2.0 units/ml) did not enhance the inhibitory function of alpha 2PI. These results suggest that, like other plasma protease inhibitors, alpha 2PI possesses a broad in vitro spectrum of inhibitory properties.

Blood Coagulation Factors↗
PubMed1979

Platelets and surface-mediated clotting activity.

In contrast to previously reported studies, no evidence could be adduced for the activation of Hageman factor (factor XII) by platelets, whether or not these cells had been incubated with adenosine diphosphate (ADP).

Adenosine Diphosphate↗
PubMed1978

The activation of plasminogen by Hageman factor (Factor XII) and Hageman factor fragments.

Activation of plasminogen through surface-mediated reactions is well recognized. In the presence of kaolin, purified Hageman factor (Factor XII) changed plasminogen to plasmin, as assayed upon a synthetic amide substrate and by fibrinolysis. Kinetic studies suggested an enzymatic action of Hageman factor upon its substrate, plasminogen. Hageman factor fragments, at a protein concentration equivalent to whole Hageman factor, activated plasminogen to a lesser extent. These protein preparations were not contaminated with other agents implicated in surface-mediated fibrinolysis. Diisopropyl fluorophosphate treatment of plasminogen did not inhibit its activation by Hageman factor. These studies indicate that Hageman factor has a hitherto unsuspected function, the direct activation of plasminogen.

Amides↗
PubMed1978

Human plasma prekallikrein (Fletcher factor) clotting activity and antigen in health and disease.

Human plasma prekallikrein (Fletcher factor) clotting activity and antigen levels have been examined in various clinical conditions. Prekallikrein antigen was measured by a newly developed, specific, and sensitive radioimmunoassay. The assay had no demonstrable cross-reactivity with human urinary kallikrein nor, in the species tested, animal plasma prekallikrein. This assay was able to measure plasma kallikrein after its biological functions had been inactivated by plasma inhibitors. Normal human pooled plasma contained approximately 50 microgram/ml prekallikrein. Quantitative measurement of plasma prekallikrein was possible for concentrations as low as 0.3% of that of normal pooled plasma. A good correlation (correlation coefficient = 0.71) existed between titers of plasma prekallikrein measured by Fletcher factor clotting assays and radioimmunoassays among 40 normal subjects. Both prekallikrein clotting activity and antigen were significantly reduced in plasmas of patients with advanced hepatic cirrhosis or DIC. Prekallikrein activity and antigen were mildly decreased in plasmas or serums of patients with chronic renal failure and nephrotic syndrome but were normal in those of patients under treatment with warfarin or suffering from SLE, rheumatoid arthritis, sarcoidosis, or HANE. Human cord serum contained a lower titer of prekallikrein antigen than adult serum. Strenuous physical exercise did not significantly change plasma prekallikrein levels.

Animals↗
PubMed1977

Activation of protein mediators of inflammation and evidence for endotoxemia in Borrelia recurrentis infection.

Fifteen patients with Borrelia recurrentis infection were studied to evaluate the role of certain plasma proteins and endotoxin in the pathophysiology of both the acute illness and the Jarisch-Herxheimer-like reaction. The causative spirochetes disappeared from the blood during the Jarisch-Herxheimer-like reaction, which occurred about 2 hours after antibiotic therapy. The mean titers of Hageman factor, plasma prekallikrein and serum hemolytic complement activity were decreased at the time of admission and 2 hours after treatment, and rose to normal values during convalescence. Serum properdin titers were decreased in 14 patients at the time of admission, in 12 patients 2 hours after treatment, and in none during convalescence. The frequency of elevated levels of fibrinogen-related antigens increased from three patients at the time of admission to 12 patients 2 hours after treatment. Results of plasma limulus tests for endotoxin-like material were positive in 11 patients at the time of admission and in 13 patients 2 hours after treatment. These findings demonstrated that Hageman factor, prekallikrein and proteins of the complement system are activated in B. recurrentis infection and that endotoxin may play a role in both the acute illness and in the development of the Jarisch-Herxheimer-like reaction after treatment.

Adolescent↗