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Biomedical subjects

K A Shastri

Publications and source records attributed to K A Shastri.

14 recordsLinked to original sources
PubMed1997

Complement activation by heparin-protamine complexes during cardiopulmonary bypass: effect of C4A null allele.

OBJECTIVES: The first objective was to determine the effect of inherited differences in the classic pathway complement protein C4 on complement activation by heparin-protamine complexes in cardiac surgery. Specifically, we hypothesized that patients with heterozygous C4A null phenotype (A0BB), who have decreased amounts of C4A, may have increased complement activation because of reduced clearance of heparin-protamine complexes. The second objective was to determine whether heparin-protamine-induced complement activation correlated with postoperative pulmonary shunt fractions. METHODS: C4 typing was performed by agarose gel immunofixation and crossed immunoelectrophoresis. Complement activation was measured by radioimmunoassay of C3a and C4a before cardiopulmonary bypass, after bypass, and after protamine infusion. Shunt fractions were calculated from blood gases. RESULTS: Of the 79 patients, 18 expressed heterozygous C4A null allele (A0BB), 16 had heterozygous C4B null allele (AAB0), three had homozygous C4B null alleles (AA00), and the rest expressed both C4A and C4B alleles (AABB). Patients with heterozygous C4A null allele had significantly increased plasma levels of C4a after protamine neutralization of heparin (C4a of 2862 +/- 375 ng/ml; mean +/- standard error of the mean) when compared with patients with normal expression of C4 alleles (AABB) (C4a of 1580 +/- 141 ng/ml) or heterozygous C4B null allele (C4a 1526 +/- 208 ng/ml). Pulmonary shunt fractions obtained after the operation correlated with the classic pathway complement activation by heparin-protamine complexes, but not with alternative pathway complement activation during cardiopulmonary bypass. CONCLUSIONS: Patients with heterozygous C4A null phenotype have increased complement activation by heparin-protamine complexes during cardiac operations, possibly because of their defective clearance. The classic pathway complement activation by heparin-protamine interaction correlates with postoperative pulmonary shunt fractions.

Alleles↗
PubMed1997

Diving decompression fails to activate complement.

The present study evaluated complement activation during decompression after air dives in a hyperbaric chamber. Intravascular bubbles were quantified by Doppler ultrasound scoring. Eighteen subjects completed 92 dives, of which 74 produced bubbles. Complement activation was assessed by plasma C3a des Arg and red-cell-bound C3d before and after each dive. These parameters of in vivo complement activation failed to show significant activation. In vitro complement activation susceptibility tests on pre-dive sera were performed to explore their association with in vivo complement activation and intravascular bubbles. Such tests failed to identify a distinct complement-sensitive group and did not correlate with in vivo complement activation during the dives and/or intravascular bubble appearance. Two subjects developed decompression sickness but were not different from the rest of the group regarding in vitro complement sensitivity or complement activation during dives.

Adult↗
PubMed1997

Missed opportunities: ALT and anti-HBc as surrogate tests for hepatitis.

ALT and anti-HBc came into use in the US as surrogate tests for non-A, non-B hepatitis by 1986-1987, generally using cutoffs at 50-60 IU/L. We studied the usefulness of anti-HBc, and of ALT at different cutoffs as surrogate tests for hepatitis C virus, recording and analyzing the ALT, anti-HBc, HBsAg, and RIBA results of 175 non-autologous blood donations in 1993 and 1994 that had positive second generation screening tests for anti-HCV. ALT levels of 1014 blood donations also were studied. Only 93 of 175 anti-HCV-positive donations were RIBA positive. Of these, anti-HBc would have excluded 23%, an ALT cutoff at 60 IU/L would have excluded 42% and an ALT cutoff at 40 IU/L would have excluded 70% (plus 5.6% of all donations). Both tests together would have been better than either alone. No tests for HBsAg were positive. ALT and anti-HBc clearly were useful surrogate tests for hepatitis C. If they had been used sooner and with lower ALT cutoffs, many people would have avoided post-transfusion hepatitis in the years before anti-HCV testing was available.

Alanine Transaminase↗
PubMed1993

Autoimmune neutropenia.

There have been several new developments in the field of autoimmune neutropenia over the past decade. Neutropenia caused by antibodies directed against granulocyte precursor cells, the oligoclonal nature of antineutrophil antibodies, and the expanding knowledge of neutrophil antigens, particularly in relationship to autoantibodies, are exciting new areas of investigation. Knowledge has also been advanced in the effector mechanisms of neutrophil autoantibodies and the effect of autoantibodies on the neutrophil function. In addition, some clinical syndromes of immune neutropenia have been better defined over the past decade, such as autoimmune neutropenia of infancy and chronic idiopathic neutropenia in adults. The past decade also saw interesting developments in the treatment of immune neutropenia, particularly in the use of gammaglobulin preparations and more recently in the advent of hematopoietic growth factors. This review focuses on these newer aspects of autoimmune neutropenia.

Animals↗
PubMed1991

Light chain composition of serum granulocyte binding immunoglobulins.

Serum granulocyte binding IgG, IgM, and the light chain composition of granulocyte binding immunoglobulins were measured in 58 adult subjects, including 8 normal individuals, 6 with Felty syndrome, 6 with chronic idiopathic neutropenia, 32 with B-cell chronic lymphocytic leukemia (CLL), and 6 with multiple myeloma. An abnormal kappa/lambda ratio of granulocyte binding immunoglobulins was detected in 12 of 32 patients with CLL. Neutropenia in patients with CLL did not correlate with an abnormal kappa/lambda ratio or excess granulocyte binding IgG, but did correlate with granulocyte binding IgM (P less than 0.02). Eight of the 12 patients (5 with chronic idiopathic neutropenia and 3 with Felty syndrome) with an immune neutropenia without underlying neoplastic disorder had light chain restricted granulocyte binding immunoglobulins. Of all patients' sera with light chain restriction, 76% were of lambda light chain isotype. Thus, the frequent detection of light chain restriction of granulocyte binding immunoglobulins is not a reflection of malignancy but is suggestive of the somatic mutation of immunoglobulin light chain genes.

Felty Syndrome↗
PubMed1991

Complement activation by artificial blood substitute Fluosol: in vitro and in vivo studies.

A perfluorocarbon blood substitute, Fluosol, is undergoing clinical trials as an adjunct to chemotherapy. The adverse effects associated with its administration have been postulated to result from complement activation. When gel electrophoresis and Western blotting of Fluosol are used after its incubation with serum, activated C3 and factors Bb and H are bound to the Fluosol particles in a time-dependent fashion, which suggests that complement activation with Fluosol, as does that with zymosan, occurs on the surface of the particles. Paradoxically, it is found, both by the measurement of Fluosol-bound C3d and by fluid-phase C5a, that lower concentrations of Fluosol cause greater amounts of complement activation, which suggests a complex interaction of activators and inhibitors that changes as the available surface area is decreased. Studies performed with bystander red cell-bound C3d demonstrated in vivo complement activation occurring in six patients receiving Fluosol as an adjunct to chemotherapy for colon cancer. In two patients, there was a marked increase in red cell-bound C3d after Fluosol infusion; these two patients also developed adverse reactions during Fluosol infusion. These studies suggest that the Fluosol surface plays a major role in the initiation and regulation of complement activation that is seen during Fluosol infusion.

Adenocarcinoma↗
PubMed1991

In vitro activation of human complement by nitrogen bubbles.

Complement activation may be responsible for some of the symptoms of decompression sickness. In the present study, complement activation was studied by exposing human sera with or without red blood cells to nitrogen bubbles. Nitrogen bubbles activated human complement as measured by generation of the fluid-phase, complement-split product C5a des Arg. In addition, we found that complement activation continued after exposure to bubbles was stopped. This continued complement activation may explain the failure of recompression treatment in some patients. Complement activation induced by nitrogen bubbles in human sera was enhanced when red cells were present. Red cells may be able to provide a stable membrane surface on which complement activation by bubbles can occur more efficiently. Complement activation by nitrogen bubbles in serum also led to the binding of activated C3 to red cells. Quantitation of bystander red-cell-bound C3d may allow the assessment of complement activation occurring by nitrogen bubbles in individuals undergoing decompression.

Complement Activation↗
PubMed1991

Idiopathic neutropenia: antineutrophil antibodies and clinical correlations.

PURPOSE: The present study was done to evaluate the clinical characteristics of a large series of adult patients with chronic idiopathic neutropenia, and correlate the presence of antineutrophil antibodies, their class (IgG or IgM), and their ability to fix complement with clinical parameters, including other hemocytopenias, splenomegaly, and infections. PATIENTS AND METHODS: One hundred twenty-one adult patients with chronic idiopathic neutropenia were studied. Serum neutrophil-binding antibodies were measured using paraformaldehyde-fixed granulocytes (PFGs) from normal volunteers as target cells. 125I-labeled staphylococcal protein A was used to detect IgG antibodies while IgM antibodies were detected by using 125I-labeled mouse monoclonal anti-IgM antibody. Sera containing antineutrophil antibodies were tested for their ability to fix complement on donor PFGs by using 125I-labeled monoclonal antibody to the third component of complement. RESULTS: Of the 121 patients with chronic idiopathic neutropenia, 71 patients had isolated neutropenia, while 50 had neutropenia combined with either anemia and/or thrombocytopenia. Among the 71 patients with isolated neutropenia, there were 51 females (72%), compared with 28 females (56%) among the 50 patients with combined hemocytopenias (p = 0.083). Patients with multiple hemocytopenias were significantly older (p less than 0.01), were more likely to demonstrate splenomegaly (p = 0.001), and may have had more infectious complications. From all the patients, 36% of sera were shown to have antineutrophil antibodies, with a non-significant trend for these to be found more frequently in patients with multiple hemocytopenias. Sera with mixed IgG-IgM antineutrophil antibodies were significantly more likely to fix complement than those with isolated IgG or IgM antibodies, and among the patients with antineutrophil antibodies, complement-fixing antibodies were significantly associated with multiple hemocytopenias. Splenomegaly was significantly associated both with antineutrophil antibodies (p = 0.008) and with infections (p = 0.007). Antineutrophil antibodies were not associated with infections. CONCLUSIONS: Approximately one third of adult patients with idiopathic neutropenia have IgG and/or IgM antineutrophil antibodies demonstrable in their serum. There is a subset of patients with idiopathic neutropenia with multiple hemocytopenias who tend to be older, less likely to show female predominance, more likely to have splenomegaly and infections, and more likely to have antineutrophil antibodies, especially mixed IgG-IgM and complement-fixing antibodies.

Adult↗
PubMed1990

Acquired factor VIII inhibitor with squamous cell cancer of the epiglottis.

A 73-year-old woman developed an acquired factor VIII inhibitor in association with squamous cell carcinoma of the epiglottis. The inhibitor was an IgG antibody that reacted with factor VIII in vitro and in vivo. Intravenous gamma-globulin therapy was successful in reducing the inhibitor so that curative surgery could be undertaken. With surgical resection of the tumor the inhibitor did not recur. The relevance of this type of coagulation disorder to the surgical management of the patient's head and neck cancer is discussed.

Aged↗
PubMed1988

Effect of RBCs on the activation of human complement by heparin-protamine complexes.

Complement activation on red cells by heparin-protamine complexes was studied by using whole human serum. C3 bound to red cells was measured by radiolabeled monoclonal antibody to C3, and fluid-phase C5a was determined by radioimmunoassay. Heparin and protamine in clinically relevant concentrations caused the binding of C3 to red cell membranes, and the measurement of C3 binding provided a sensitive indicator of complement activation produced by these complexes. Complement activation by these reagents occurred at concentration ratios of protamine and heparin at which protamine neutralized the anticoagulant effect of heparin. Heparin-protamine complexes appeared to bind to red cells and produce complement activation by the classic pathway. C5a generation with heparin-protamine complexes in serum was greatly enhanced in the presence of red cells and increased with increasing red cell concentration. This enhancement of complement activation in the presence of red cells was also seen as measured by depletion of available C3 hemolytic complement units in the fluid phase. Thus red cells seem to play an important role in activation of complement by heparin-protamine complexes.

Complement Activation↗
PubMedDate not supplied

In vitro activation of human complement by polyacrilonitrile dialyzer membrane assayed by complement binding to bystander red cells.

Quantitation of complement activation by polyacrilonitrile (PAN) dialyzer membrane is complicated by the high adsorptive capacity of the membrane for fluid phase anaphylotoxins. Assays for these anaphylotoxins, therefore, underestimate the degree of complement activation produced by this membrane. Alternative methods of measuring in vitro complement activation by the PAN and Cuprophan membranes were explored by incubating normal human erythrocytes with the membranes in the presence of serum. This led to deposition of C3d on these "innocent bystander" red cells, and provided an independent parameter for measuring complement activation. The PAN membrane caused significantly more C3d deposition on red cells, and thus more complement activation than Cuprophan. The possible significance of complement activation by PAN membrane, in consideration of its property of binding the resultant anaphylotoxins, is discussed.

Acrylic Resins↗
PubMedDate not supplied

Neutrophil lactoferrin release during open heart surgery is unrelated to complement activation.

The relationship between neutrophil activation and complement activation during open heart surgery was evaluated by measuring plasma lactoferrin and C3a des Arg (C3a) in 30 adult patients undergoing coronary artery surgery. Measurements were made before induction of anesthesia, before cardiopulmonary bypass, at the end of bypass, and 10 min after protamine infusion. Changes in the measured parameters thus reflected activation during the three distinct phases of cardiac surgery: pre cardiopulmonary bypass, the bypass phase, and the heparin neutralization phase. A major rise in lactoferrin occurred in the pre bypass period, from 99 +/- 13 (mean +/- SEM) to 647 +/- 48 ng/ml (p < 0.001). During this time, C3a levels did not rise significantly (384 +/- 22 to 439 +/- 36 ng/ml). The bypass procedure resulted in a rise of both lactoferrin and C3a levels, with lactoferrin reaching 1,092 +/- 69 ng/ml and C3a increasing to 1,884 +/- 179 ng/ml after bypass (p < 0.001 for both). In individual patients, however, the changes in lactoferrin during bypass did not correlate with changes in C3a levels (r = -0.06). After protamine infusion, C3a levels reached 3,301 +/- 324 ng/ml, while the plasma lactoferrin levels declined to 522 +/- 57 ng/ml. Thus, during open heart surgery, neutrophil activation, as measured by plasma lactoferrin concentration, does not correlate with complement activation resulting from the bypass procedure or the protamine neutralization of heparin. The potential clinical relevance of the neutrophil granular release of lactoferrin is discussed.

Complement Activation↗