The coagulation-kinin pathway of human plasma.
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Angioedema↗
Biomedical subjects
M Silverberg
Publications and source records attributed to M Silverberg.
Study of the effect of high molecular weight kininogen upon the fluid-phase inactivation of kallikrein by C1 inhibitor.
Plasma kallikrein and factor XIa circulate bound to high molecular weight kininogen, and such binding has been reported to protect these enzymes from inactivation by their respective inhibitors. However, this observation is controversial, and the effect of high molecular weight kininogen upon the interaction between kallikrein and C1 inhibitor (C1-INH) has been questioned. We have re-evaluated this reaction and studied the rate of inhibition of kallikrein by C1-INH in the presence and absence of high molecular weight kininogen. The second-order rate constant of inhibition of kallikrein by C1-INH was unaffected by saturating concentrations of high molecular weight kininogen. Our results suggest that although high molecular weight kininogen clearly augments the rate of formation of kallikrein and other enzymes of the contact activation pathway, it has no effect on the rate of enzyme inhibition by C1-INH.
Complement C1 Inactivator Proteins↗
The intrinsic coagulation/kinin pathway--the classical complement pathway and their interactions.
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Blood Coagulation Factors↗
Use of polyglycolic acid mesh to confine particulate hydroxylapatite for augmentation of bone in the rat.
A preliminary report of the use of polyglycolic acid (PGA) mesh to contain particulate nonresorbable hydroxylapatite (HA) used for augmentation of bone in rats is presented. PGA mesh tubes, approximately 2 mm in diameter and 5 mm in length, were fabricated, filled with HA, and placed in surgically created subperiosteal pockets against the medial cortex of the tibia in rats. Specimens were obtained at two, six, 12, and 18 weeks. The results showed that when the HA was contained within the PGA mesh, severe displacement of particles was prevented and greater HA augmentation was possible. Absorption of the mesh took place between six and 12 weeks, after which the histologic features were the same as those seen when HA was implanted alone. Grossly, the implants appeared to hold firmly to bone even two weeks after implantation. A new, more efficacious delivery system is proposed for the augmentation of atrophic alveolar ridges using HA contained within PGA mesh tubes.
Alveolar Ridge Augmentation↗
The effect of C1 inhibitor upon Hageman factor autoactivation.
Using components purified from human plasma, we have examined the effects of C1 inhibitor (C1 INH), the primary inhibitor of activated Hageman Factor (HFa) and Hageman factor fragment (HFf), on Hageman Factor (HF) autoactivation. When Hageman factor was exposed to a negatively charged surface, provided by either a glass cuvette or dextran sulfate, the addition of C1 INH gave a dose-dependent inhibition of the activity observed. The ability of C1 INH to decrease the maximal enzymatic activity generated was markedly temperature dependent with inhibition increasing as the temperature was raised from 4 degrees C to 37 degrees C. Although the rates of both autoactivation and inhibition were decreased at lower temperatures (4 degrees C), the latter rate was more sensitive to temperature modulation. When HF (final concentration 1 mumol/L) was incubated with C1 INH (0.54, 1.07, and 2.14 mumol/L) in the absence of an initiating surface, no increases in enzymatic activity were observed for up to 48 hours regardless of the C1 INH concentration. However, SDS polyacrylamide gel electrophoresis of the incubation mixture revealed that HF autodigestion had occurred by 48 hours despite the presence of C1 INH. In addition, the appearance of a new band suggested that a complex had been formed between the inhibitor and activated HF. Our findings indicate that C1 INH does not prevent HF autoactivation but rather inactivates the products of HF autodigestion.
Complement C1 Inactivator Proteins↗
The IgE-dependent release of a Hageman factor cleaving factor from human lung.
Passively sensitized human lung fragments were shown to release a protease by an IgE-dependent mechanism which can cleave human Hageman factor (Coagulation Factor XII). This enzyme, lung Hageman factor cleaving factor, was partially purified by ion exchange chromatography and gel filtration and was shown to be a serine protease with an apparent molecular weight of 12,000-13,000. This protease appears to be unrelated to any known activator of Hageman factor by molecular weight and inhibition profile and was shown to be distinct from an IgE-dependent prekallikrein activator, as well as the kininogenase activity defined as basophil kallikrein of anaphylaxis. Although it appears marginally capable of activating Hageman factor, it rapidly cleaves and inactivates the activated form so that the net effect is a loss of activatable Hageman factor. The result suggests that diminished levels of Hageman factor that may be seen associated with IgE-dependent reactions can be due to digestion and depletion rather than activation, and other criteria for activation of the contact system must be employed.
Antigens↗
Peripheral neuropathy in Crohn's disease patients treated with metronidazole.
Thirteen pediatric patients with Crohn's disease, aged 12-22 yr, were studied to assess the prevalence of peripheral neuropathy due to oral metronidazole. After 4-11 mo of therapy, 11 of 13 patients (85%) had a sensory peripheral neuropathy, determined by abnormal neurologic examinations or reduced nerve conduction velocities, or both. Only 6 of the 11 patients were symptomatic. Nine of 11 patients with peripheral neuropathy had their metronidazole discontinued and 2 had the dose reduced to less than 10 mg/kg X day. Follow-up evaluations of the 9 patients whose metronidazole had been discontinued 5.5-13 mo earlier demonstrated complete resolution of the peripheral neuropathy in 5, improvement in 3, and no change in 1. In the 2 patients whose metronidazole dose was reduced, 1 showed worsening and 1 showed complete resolution of the neuropathy after 10-12 mo of continued therapy.
Administration, Oral↗
Quantitative assays of pharmacologic aerosols used in studying asthma.
To more nearly accurately quantitate the dose of pharmacologic agents delivered to human and animal airways via aerosols, we have developed a monodisperse aerosol containing either methacholine or histamine that permits a light scattering device (tyndallometry) to measure accurately the quantity of inspired and expired particles. These aerosols (described in previous studies) are simultaneously tagged with a radioactive label (technetium 99m) to permit the use of external gamma camera imaging. Present work focuses on the development of assay techniques to measure the quantity of methacholine delivered in these aerosols. The lack of specific radioimmune or radioenzyme assays coupled with the cross-reaction of organic contaminants with conventional chemical reagents for measuring methacholine required the development of separative techniques to isolate the methacholine from the organic aerosol contaminants. With aqueous extraction and column separation we have been able to completely isolate the methacholine from these contaminants. This allows the application of standard spectrophotometric assays for methacholine to quantitate the methacholine in the resulting solution. These separative techniques will permit the use of these aerosols in quantitative studies of airway reactivity.
Aerosols↗
Linear growth following surgery in children and adolescents with Crohn's disease: relationship to pubertal status.
Studies of the effect of surgery on growth failure in adolescents with Crohn's disease have revealed conflicting data. To better determine the role of surgery for growth delay, growth data from 26 patients with Crohn's disease with intestinal resections and/or ileostomies were reviewed, 3 of whom had surgery twice. Operations were performed on 14 Tanner Stage I, 1 Tanner II, 1 Tanner III, and 13 Tanner IV or V patients. In the prepubertal group, 13 of the 14 had growth impairment, only one of whom had surgery primarily for that growth failure. One year after operation, 11 of 13 Tanner I growth failure patients experienced an increase in height velocity of 5.38 +/- 1.18 cm/yr (mean +/- SE;P less than 0.01); 9/11 achieved normal height velocity for Tanner I. Two attained their preillness height percentiles at one year follow-up, while 5 patients attained their preillness height percentiles 2.5 to 10 years following surgery. Of the four who failed to achieve normal height velocity, 3 had early recurrence of active disease. The Tanner Stage II and III patients both had growth failure, and both had a growth spurt following surgery. Of those who were Tanner Stage IV or V at the time of surgery, 5 of 13 had growth failure. Following surgery, none had an increase in height velocity. These data suggest that when patients with Crohn's disease and growth failure are prepubertal and surgery is performed primarily because of failure of medical therapy and/or other complications, a postoperative growth spurt may be expected within one year.
Adolescent↗
Magnesium metabolism studies in children with chronic inflammatory disease of the bowel.
Magnesium metabolism was studied in seven patients with severe chronic inflammatory disease of the bowel (CIDB), and in 20 children without intestinal pathology. Four of the CIDB patients had ulcerative colitis and three had granulomatous disease of the bowel. All had diarrhea as well as other gastrointestinal complaints for 1 to 6 years prior to the study. All were being treated with sulfasalazine and were also receiving corticosteroids intermittently. All but one had had intestinal surgery. Basal plasma and urine were obtained in all patients and, if surgery was performed, a piece of muscle was excised. The CIDB patients received an intravenous magnesium infusion of 2 mEq/kg/day for 4 days, 2 days postsurgery. Electrocardiograms were recorded throughout the study. The mean basal plasma magnesium levels were reduced in CIDB patients as compared with controls. Mild hypomagnesemia was observed in six of seven CIDB patients. The mean basal urine excretion of magnesium was also reduced in CIDB patients, but the muscle concentrations of this element were similar to controls. Basal hypomagnesuria was present in only two of the three patients with granulomatous disease and in one patient with ulcerative colitis. The three patients with granulomatous disease excreted minimal amounts of magnesium in the urine during intravenous administration of this ion. A positive magnesium balance persisted throughout the 4-day period of infusion. In contrast, only two of the four patients with ulcerative colitis had magnesium retention during the first day of intravenous administration, and all four had negative magnesium balances thereafter. The data suggest that hypomagnesemia in CIDB patients may occur with or without magnesium deficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Activation of factor XII-dependent pathways in human plasma by hematin and protoporphyrin.
Intravenous administration of hematin is effective in the treatment of acute exacerbations of the inducible porphyrias. In the course of such treatment, coagulopathies have occurred that are characterized by prolongation of prothrombin time, partial thromboplastin time, and formation of fibrin split products. In experiments in vitro with normal human plasma, we observed that hematin and protoporphyrin activated Factor XII-dependent pathways of coagulation and fibrinolysis, and that they generated kallikrein activity. Incubation of protoporphyrin with purified Factor XII resulted in activation as measured by amidolysis of a chromogenic substrate. Neither coproporphyrin, uroporphyrin, delta-aminolevulinic acid, porphobilinogen, or bilirubin activated Factor XII-dependent pathways. Exposure of serum containing added uroporphyrin, coproporphyrin, and protoporphyrin, but not hematin, to ultraviolet light (405 nm) resulted in activation of the classical pathway of the complement system. On the other hand, exposure of plasma containing uroporphyrin or coproporphyrin to ultraviolet light did not result in activation of Factor XII-dependent pathways.
Animals↗
Acute hepatitis--A, B, NANB and delta.
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Acute Disease↗
Perianal disease in children and adolescents with Crohn's disease.
The clinical and pathological features of perianal disease in children and adolescents with Crohn's disease have been delineated. Of the 149 patients (mean age 12.1 yr, range 0.75-21 yr, 68% male), 73 (49%) had perianal disease including 51 with fissures and tags, 10 with fistulas, and 12 with abscesses. Ileocolitis was seen in 68% of all patients and in 75% of patients with perianal disease (p greater than 0.10). Rectal inflammation was present in 94% of patients with fistulas or abscesses, or both, versus 63% of all patients without perianal disease (p less than 0.025). Anorectal granulomata were found in 47% of fistula/abscess patients versus 9% of non-perianal disease patients (p less than 0.05). A variety of medical regimens failed to consistently affect these lesions favorably. Four of 10 patients with fistulas healed after 1-5 yr of intermittent discharge. Nine of 12 patients with abscesses required surgical drainage, and 50% subsequently developed chronic fistulas. Granulomata were equally distributed between those patients who healed and those who developed chronic fistulas. Although an important cause of morbidity in childhood Crohn's disease, perianal disease is not progressively destructive in the majority of patients.
Abscess↗
The effect of surfactants on the interaction of factor XII with surfaces.
Factor XII (Hageman factor) binds irreversibly to plastic as well as glass surfaces. In dilute solution this leads to significant losses of protein onto the walls of tubes, etc. This could be prevented most efficiently by the presence of surfactants in solution. Rinsing the surfaces after contact with the protein, or precoating the surfaces were less effective. Triton X-100 was found to be non-denaturing and effective at concentrations as low as 0.001%. In its presence higher specific activities were obtained in spectrophotometric assay. The autoactivation of factor XII exposed to glass was inhibited but not prevented by Triton X-100. Similar effects on the binding and assay of (Pre) kallikrein were also found.
Detergents↗
Perioperative modification of the morris pin splint.
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Bone Nails↗
Mechanisms of activation of the classical pathway of complement by Hageman factor fragment.
The mechanism by which a fragment of activated Hageman factor (HFf) activates the classical pathway of complement in serum or platelet-poor plasma has been further delineated. When serum or platelet-poor plasma was incubated with various concentrations of HFf, the total complement hemolytic activity was reduced in a dose-dependent manner. This activation appears to be due to the direct interaction of HFf with macromolecular C1, since incubation of purified C1 with HFf resulted in dissociation of the subunits with concomitant reduction of C1r antigenicity that is indicative of C1 activation. HFf-dependent activation was prevented by prior treatment of HFf with the active site-directed inhibitor, H-D-proline-phenylalanine-arginine chloromethyl ketone or with a specific inhibitor of activated HF derived from corn. Incubation of HFf with highly purified C1r also resulted in activation of C1r as assessed directly using a synthetic substrate or indirectly by activation of C1s and consumption of C2. However, incubation of HFf with highly purified C1s resulted in formation of activated C1s (C1s-) but this was less efficient than HFf activation of C1r. We therefore conclude that activation of C1 in macromolecular C1 is the result of HFf conversion of C1r to C1r; activation of C1s then occurs primarily by C-1r and to a lesser degree by the direct action of HFf.
Amino Acid Chloromethyl Ketones↗
Initiation of contact activation of human plasma.
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Binding Sites↗
Use of high-dose oral methotrexate sequenced at 24 hours with 5-FU: a clinical toxicity study.
Twenty-three patients with advanced carcinoma were treated with 131 courses of high-dose oral methotrexate (MTX), sequenced at 24 hours with 5-FU iv and subsequent leucovorin rescue. The 30% incidence of toxicity was predominantly mild to moderate mucositis and myelosuppression. Trough and peak serum MTX levels demonstrated that micromolar concentrations were sustained greater than 24 hours. Toxicity correlated with shorter re-treatment intervals and not with serum MTX levels. This regimen can be safely and conveniently administered to an outpatient population and deserves further assessment in phase II trials.
Breast Neoplasms↗