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Biomedical subjects

J Crawford

Publications and source records attributed to J Crawford.

At least 19 recordsLinked to original sources
PubMed1992

Effect of diacylglycerols on the activity of cobra venom, bee venom, and pig pancreatic phospholipases A2.

The effects of a series of diacylglycerols (DAGs) with varying acyl chain lengths and degree of unsaturation on the activity of cobra venom, bee venom, and pig pancreatic phospholipases A2 (PL-A2S) were studied using two lipid substrates: dipalmitoylphosphatidylcholine (DPPC) or bovine liver phosphatidylcholine (BL-PC). The activities of the phospholipases critically depended on the chain length and degree of unsaturation of the added DAGs and on the chemical composition of the substrate. The effects of DAGs on cobra or bee venom PL-A2S were similar, but significantly different from the pig pancreatic PL-A2. The data, taken together with our previous NMR studies on physicochemical effects of these DAGs on lipid bilayer structure [De Boeck, H., & Zidovetzki, R. (1989) Biochemistry 28, 7439; (1992) Biochemistry 31, 623], allowed detailed correlation of the type of a bilayer perturbation induced by DAG with the activation or inhibition of the phospholipase on the same system. In general, the activation of the phospholipases correlated with the DAG-induced defects of the lipid bilayer structure. The results, however, argue against general designation of DAGs as "activators" or "inhibitors" of PL-A2S. Thus, for example, diolein activated phospholipases with the BL-PC lipid substrate, but inhibited them with the DPPC substrate. Dihexanoylglycerol and dioctanoylglycerol inhibited pig pancreatic PL-A2 with both lipid substrates and inhibited cobra or been venom PL-A2 with the DPPC substrate, but activated the latter two enzymes with the BL-PC substrate. Longer-chain DAGs (C greater than 12), which induce lateral phase separation of the bilayers into the regions of different fluidities, activated all PL-A2S with both lipid substrates.(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1992

Phase II study of intravenous idarubicin in unfavorable non-Hodgkin's lymphoma.

Idarubicin, a new analogue of daunorubicin, was administered i.v. at a dose of 15 mg/m2 to 31 previously treated patients with unfavorable non-Hodgkin's lymphoma. Clinical characteristics included median age, 69 years; performance status, 1; and prior chemotherapeutic regimens, 1. Twenty of the patients were relapsing after prior therapy and 11 were refractory; 29 had received prior anthracycline or anthracenedione. Responses were observed in 43% of patient (3 complete remission and 10 partial remission) with a median duration of 10+ months (2-29+ months). Idarubicin was well tolerated with nonhematological toxicities (nausea/vomiting, mucositis, and anorexia) seen in less than 50% of patients. Median hematological values during the first cycle for this dosage included WBC, 1,300/mm3; platelets, 129,000/mm3; and hemoglobin, 10.9 mg/dl. With dose escalation, hematological toxicity was dose limiting. Symptomatic cardiac toxicity was observed in one patient who had received maximum dose doxorubicin and radiotherapy. Median values for the cardiac ejection fraction during the full course of therapy for the entire group of patients were 0.62 (initial) and 0.60 (final). Idarubicin in i.v. form is an active drug in previously treated patients with unfavorable non-Hodgkin's lymphoma.

Adult↗
PubMed1992

Modulation of O6-alkylguanine-DNA alkyltransferase-mediated carmustine resistance using streptozotocin: a phase I trial.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) resistance may be mediated by repair of chloroethylated guanine before stable cross-linking occurs. Guanine adducts may be repaired by the enzyme O6-alkylguanine-DNA alkyltransferase (O6-AGAT). Such repair irreversibly inactivates O6-AGAT. Streptozotocin (STZ) forms adducts at the O6 position of guanine; repair of these adducts consumes O6-AGAT. In vivo STZ potentiates BCNU cytotoxicity. The purpose of this trial was to determine the maximum tolerated dose of BCNU that can be administered together with STZ. The STZ dose was 500 mg/m2/day for 4 days and was not escalated. BCNU was given 4 h after the third dose of STZ at a starting dose of 75 mg/m2. A total of 43 patients were entered in the study. There were 4 dose escalations, reaching a maximum tolerated BCNU dose of 175 mg/m2. At this dose, thrombocytopenia was the dose-limiting toxicity (one patient, 25-49 x 10(9)/liter; 2 patients, less than 25 x 10(9)/liter); neutropenia was less severe (2 patients, 2.0-3.9 x 10(9)/liter, 1 patient, 1.0-1.9 x 10(9)/liter). Two other commonly seen toxicities were elevations in the serum alkaline phosphatase and mild elevations in the serum creatinine. Peripheral blood lymphocyte O6-AGAT levels decreased from a mean of 212 fmol/mg protein pretherapy to 8.2 fmol/mg protein on day 3 prior to BCNU (P = 0.03). Three partial responses were seen. There were no therapy-related fatalities, and toxicity was easily managed. This study established that 150 mg of BCNU can be administered safely together with STZ, 500 mg/m2/day for 4 days. Additional studies are required to determine whether O6-AGAT-mediated BCNU resistance is suppressed.

Adult↗
PubMed1992

Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group.

PURPOSE: The trial was undertaken to determine (1) the relative efficacy/toxicity of two commonly used combination chemotherapy regimens in patients with extensive small-cell lung cancer (SCLC) and (2) whether the rapid alternation of these two regimens could provide superior therapeutic results compared with either regimen alone. PATIENTS AND METHODS: In this phase III trial, 437 eligible patients were stratified by performance status (PS) and sex and were randomly assigned to receive either 12 weeks of cisplatin and etoposide (EP); 18 weeks of cyclophosphamide, doxorubicin, and vincristine (CAV); or 18 weeks of alternation of these two regimens (CAV/EP). RESULTS: There were no significant differences in treatment outcome for EP, CAV, or CAV/EP in terms of response rate (61%, 51%, 59%, respectively), complete response rate (10%, 7%, 7%, respectively), or median survival (8.6 months, 8.3 months, 8.1 months, respectively), with a non-statistically significant trend toward a longer median time to progression with alternating therapy (4.3 months, 4.0 months, 5.2 months, respectively). Crossover second-line chemotherapy given at progression produced low response rates and short survival, regardless of the regimen used. Myelosuppression was the dose-limiting toxicity for all patients, although the pattern and severity differed among the treatment arms. CONCLUSIONS: The combination regimens EP and CAV can be considered equivalently effective induction therapies in extensive SCLC, and these two regimens are, to some degree, crossresistant. Alternating therapy provides no therapeutic advantage compared with the use of either of these regimens alone and should not be considered as standard treatment in this clinical setting.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Colony-stimulating factors: clinical applications.

Recombinant human colony-stimulating factors (CSFs) have potential for wide use in the areas of oncology and infectious disease. Granulocyte CSF and granulocyte-macrophage CSF currently are approved for use in the treatment of neutropenia associated with standard-dose cancer chemotherapy and bone marrow transplantation, respectively. Other settings in which these agents have shown promise are dose-intensive chemotherapy, enhancement of progenitor cell support, primary and acquired neutropenias, myelodysplasia, aplastic anemia, and cytopenias associated with human immunodeficiency virus infection or myelosuppressive therapies for such infection or related conditions. Clinical findings in these areas are encouraging, and potential exists for additional applications of the CSFs.

Anemia, Aplastic↗
PubMed1991

Reduction by granulocyte colony-stimulating factor of fever and neutropenia induced by chemotherapy in patients with small-cell lung cancer.

BACKGROUND: Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. METHODS: Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, less than 1.0 x 10(9) per liter, with a temperature greater than or equal to 38.2 degrees C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21-day cycle. RESULTS: The safety of the study treatment could be evaluated in 207 of the 211 patients assigned to either drug, and its efficacy in 199. At least one episode of fever with neutropenia occurred in 77 percent of the placebo group, as compared with 40 percent of the G-CSF group (P less than 0.001). Over all cycles of chemotherapy, the median duration of grade IV neutropenia (absolute neutrophil count, less than 0.5 x 10(9) per liter) was six days with placebo as compared with one day with G-CSF. During cycles of blinded treatment, the number of days of treatment with intravenous antibiotics, the number of days of hospitalization, and the incidence of confirmed infections were reduced by approximately 50 percent when G-CSF was given, as compared with placebo. Mild-to-moderate medullary bone pain occurred in 20 percent of the patients receiving G-CSF. CONCLUSIONS: The use of G-CSF as an adjunct to chemotherapy in patients with small-cell cancer of the lung was well tolerated and led to reductions in the incidence of fever with neutropenia and culture-confirmed infections; in the incidence, duration, and severity of grade IV neutropenia; and in the total number of days of treatment with intravenous antibiotics and days of hospitalization.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

The diagnosis of acute viral hepatitis A or B by microparticle enzyme immunoassay.

The traditional approach to the diagnosis of viral hepatitis has been to collect a serum sample and to test it for the presence of hepatitis B surface antigen (HBsAg), IgM to the core of HBV (anti-HBc IgM) and IgM to HAV (anti-HAV IgM) by solid phase radio- or enzyme immunoassays. Microparticle enzyme immunoassay technology (IMx-Abbott Laboratories) has been introduced as an automated carousel system for the detection of these markers. A side-by-side, blinded comparison of IMx to current IA was performed for HBsAg on 659 specimens submitted from March to July 1990, of which 72 (10.8%) were positive by AUSRIA (Abbott RIA for HBsAg) and 2 of these were discordant in IMx. Both were near the cutoff and by confirmatory testing one was positive and the other negative. Forty three percent (25/58) of frozen stored sera tested for anti-HBc IgM, by IMx, were positive by EIA (Corzyme M). One specimen near the cutoff was negative by EIA but weakly positive by IMx. Anti-HAV IgM was found in 21.8% (46/211) of sera with 100% correlation by IMx. Thus IMx had the following percent sensitivies and specificities: HBsAg; 98.6, 99.9; anti-HBc IgM; 100, 99.9; anti-HAV IgM; 100, 100. The test set-up times for the 3 markers in the IMx were similar to the RIA and EIA. The turnover time was 45 min for a full IMx carousel compared to: AUSRIA-short incubation (4 h), or long incubation (14 h); Corzyme M-short (4.75 h) or long (20 h); anti-HAV IgM (23 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Automation↗
PubMed1991

Anti-inflammatory effects of pentoxifylline in claudication.

We measured neutrophil elastase/alpha 1 proteinase inhibitor complex (E/alpha) levels by ELISA in plasma samples drawn from 19 patients with claudication, before and at 1 and 2 months after initiation of pentoxifylline (PTF), 400 mg. p.o. tid. Plasma E/alpha levels declined in all eight patients whose initial values were more than 300 ng elastase per ml. Whole blood viscosity (wbv) was reduced by two months' treatment in 12 of 14 patients tested. The relative change in wbv was significantly related to the relative change in E/alpha (R2 = 0.8), for patients with elevated initial E/alpha levels, suggesting a common or related mechanism for the two effects. Plasma crosslinked fibrin D-dimer fragments (XDP) measured by ELISA as indicators of coagulation activity were lower compared to pretreatment levels in 9 of 10 samples drawn when symptoms were improved on PTF, whereas they were increased in 6 of 9 samples drawn when symptoms were worse or unchanged. Plasma viscosity, C-reactive protein and alpha 1-acid-glycoprotein did not change significantly with PTF treatment. Together these findings are consistent with the possibility that reduced microvascular neutrophil activation and coagulation play a role in the clinical efficacy of PTF in intermittent claudication.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Measurements of the G-/F-actin equilibrium in ADP-stimulated human platelets.

The amounts of the different forms of actin (G-actin, F-actin) can be measured biochemically following lysis of the cells by the DNase I inhibition assay. The existing methodology for studying G-actin in unstimulated platelets was found to be inappropriate for studies during ADP-induced platelet activation. However, this problem was overcome by a simple modification of the procedure in which formaldehyde was added to the buffer used to lyse the activated platelets. Using this modification the G-actin values obtained immediately after lysis did not change during storage of the lysates on ice for more than 30 minutes. The results show rapid conversion of G-actin to F-actin in association with the shape change during ADP-stimulated activation. Examination of unstimulated platelets using the modified procedure enabled identification of a pool of actin that is rapidly dissociated to G-actin in the absence of formaldehyde, the existence of which had not previously been recognised.

Actins↗
PubMed1990

Correlation between erythrocyte CR1 reduction and other blood proteinase markers in patients with malignant and inflammatory disorders.

Erythrocyte CR1, a C3b/C4b-binding complement-regulatory protein, is sensitive to proteolysis in vitro. To test the hypothesis that in vivo erythrocyte CR1 reduction results from intravascular proteinase activities, we used enzyme-linked immunosorbent assays to measure gamma-crosslinked fibrin degradation products (D-dimers) as indicators of coagulation/fibrinolytic activity, and complexes of neutrophil elastase with alpha 1 proteinase inhibitor (E/A) as indicators of neutrophil enzyme release in malignant and inflammatory disorders. Erythrocyte CR1, measured by monoclonal anti-CR1 antibody binding, was inversely related to disease activity and blood proteinase markers. Levels of erythrocyte CR1 were significantly lower for patients with active versus remittent squamous and small cell lung cancers, Hodgkin's and diffuse large cell lymphomas, and acute myelogenous leukemias. In patients with active thoracic cancers, elevated D-dimer levels correlated with reduction of CR1. In patients with rheumatoid arthritis, CR1 reduction was correlated with elevated levels of elastase complexes. Our findings substantiate the relationship of acquired CR1 reduction to the activity of certain diseases and provide circumstantial support for the hypothesis that erythrocyte CR1 is lost to proteolysis in vivo. Although heritable differences in CR1 expression reduce the interpretability of single measurements of erythrocyte CR1 levels, disease-associated CR1 reduction may be a useful indicator of disorders with chronically increased blood proteinase activity.

Adult↗
PubMed1990

Stimulus-specific effects of pentoxifylline on neutrophil CR3 expression, degranulation, and superoxide production.

The effects of pentoxifylline (Trental) on human neutrophil CR3 up-modulation, degranulation, and superoxide production were studied. We used the chemotactic peptide fMLP and the phorbol ester PMA as soluble stimuli, and beta-glucan particles as a CR3-specific solid phase stimulus of neutrophil superoxide production. Since neutrophils have adenosine A2 receptors, we compared effects of pentoxifylline to effects of adenosine, and we also looked at the effect of cytochalasin B, which breaks up actin filaments. Pentoxifylline inhibited both CR3 up-modulation and degranulation of myeloperoxidase and lysozyme. Pentoxifylline is a more potent inhibitor of fMLP- compared to PMA-induced degranulation, and is especially potent against superoxide production. While pentoxifylline is less potent than adenosine in its inhibition of fMLP-induced superoxide production, it is more potent in its inhibition of PMA- and beta-glucan particle-stimulated superoxide production. Cytochalasin B, which enhances degranulation and fMLP-stimulated superoxide production, was found to inhibit beta-glucan particle-stimulated superoxide production. These findings are consistent with the hypothesis that pentoxifylline can affect both the cytoskeletal architecture of unstimulated neutrophils and the activation and responses of neutrophils which involve actin polymerization and receptor-cytoskeletal interactions.

Adenosine↗
PubMed1990

The possible use of a spallation neutron source for neutron capture therapy with epithermal neutrons.

Spallation is induced in a heavy material by 72-MeV protons. The resulting neutrons can be characterized by an evaporation spectrum with a peak energy of less than 2 MeV. The neutrons are moderated in two steps: first in iron and then in carbon. Results from neutron fluence measurements in a perspex phantom placed close to the moderator are presented. Monte Carlo calculations of neutron fluence in a water phantom are also presented under some chosen configurations of spallation source and moderator. The calculations and measurements are in good agreement and show that, for proton currents of less than 0.5 mA, useful thermal-neutron fluences are attainable in the depth of the brain. However, the dose contribution from the unavoidable gamma background component has not been included in the present investigation.

Boron↗
PubMed1990

Development of multiple monoclonal serum immunoglobulins (multiclonal gammopathy) following both HLA-identical unfractionated and T cell-depleted haploidentical bone marrow transplantation in severe combined immunodeficiency.

We have identified five patients with severe combined immunodeficiency (SCID) who developed multiple monoclonal serum immunoglobulin components (multiclonal gammopathy) following bone marrow transplantation. Four patients received haploidentical bone marrow stem cells depleted of T cells and other mature marrow cells by soy lectin agglutination and/or sheep erythrocyte rosetting. One patient received unfractionated HLA-identical bone marrow. Twenty-one distinct paraproteins were detected: 14 IgG, 5 IgM, and 2 IgA, all containing either kappa or lambda light chains. In the haploidentical stem-cell recipients, these monoclonal immunoglobulins appeared immediately prior to, or concomitant with, a rise in T-cell numbers and function. Resolution or diminution of this multiclonal gammopathy occurred as T-cell function was established. Posttransplant karyotypic analyses revealed PHA-stimulated T cells to be of donor origin in all patients. Karyotyping of B-cell lines posttransplantation revealed them to be 100% donor in the patient receiving unfractionated HLA-identical marrow and 100% host (1/4), 100% donor (1/4), mixed (1/4), or not tested (1/4) in the patients receiving haploidentical marrow stem cells. There was no evidence of Epstein-Barr virus (EBV) infection in any of the patients. All patients are currently alive and well. Immunoglobulin synthesis is normal in the patient who received the HLA-identical marrow but remains below normal in the four patients who received T cell-depleted haploidentical stem cells. The posttransplantation development of monoclonal immunoglobulins in the absence of EBV infection did not adversely affect the outcome of either HLA-identical marrow or haploidentical stem-cell grafting.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Protein Electrophoresis↗
PubMed1990

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy.

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodgkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients (p less than 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients (p less than 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recurred with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality therapy patients developed acute leukemia.

Antineoplastic Combined Chemotherapy Protocols↗