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Biomedical subjects

D H Cowan

Publications and source records attributed to D H Cowan.

At least 19 recordsLinked to original sources
PubMed1992

Progress and survival factors in acute non lymphocytic leukemia. A 15 year analysis.

We analyzed a population of adults with acute non lymphocytic leukemia (ANLL) treated from 1972-1989 to identify prognostic factors and the influence of therapy over time. To 179 patients treated at Sunnybrook Medical Centre (SMC) were added 114 patients from published patient series from Princess Margaret Hospital (PMH) all treated during that period. All PMH and 98 SMC patients received one of three remission induction protocols: CAV (cyclophosphamide, cytosine arabinoside [ara-C], vincristine) 1973-1976 (n = 46); ACT (Adriamycin, ara-C +/- 6-thioguanine) 1976-1983 (n = 83); high dose ara-C and corticosteroids 1983-1987 (n = 83). The remainder either received supportive therapy only or minimally toxic therapy (e.g., low dose ara-C, 6-mercaptopurine) due to presenting complications such as advanced age, severe concurrent medical condition, or most recently at SMC only, mitoxanthrone and ara-C, and were excluded from analysis. Responses obtained at the two institutions were identical, no survival advantage of any particular protocol was seen. Overall median survival was 8.5 months for patients treated on protocol and 20 months for those entering complete remission. Patients treated with supportive or minimally toxic therapy (n = 76) had a median survival of less than two months. In multivariate analysis, the only important factors for survival were complete response to initial therapy; complete response to second induction therapy following either first relapse (n = 89) or lack of complete response to first therapy (n = 15); and normal cytogenetic analysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1979

Platelet interaction with synthetic copolypeptide films.

Kinetic and equilibrium studies of blood platelet binding to copolypeptide films show that attachment and serotonin release are not dependent upon the composition of the copolypeptide. Data may be explained by postulating that platelets frequently collide elastically with the surface but leave behind material that modifies subsequent behavior. Similarly, material released from platelets adsorbs at the interface and the extent of attachment and serotonin release are modified and controlled by these adsorbed species. Basically, if the platelet is exposed to a clean surface, its collision with the surface leads to activation and release. In the presence of inert protein, the collision is cushioned by the protein and platelets do not attach or release to any extent. Finally, if protein (or other entities) released from the platelet provide attachment sites, then attachment occurs without release. It is postulated that the behavior of platelets at surfaces is controlled by these interrelated processes.

Biocompatible Materials↗
PubMed1979

Migration of human vascular endothelial and smooth muscle cells.

Migration of endothelial and smooth muscle cells was studied in vitro by measuring the increase in surface area at specific time intervals of confluent cell colonies advancing under agarose gels that contained both Morgan's medium 199 and variuos types of sera. First passage cultures of endothelial cells or 3 to 6 passage smooth muscle cells were plated into wells punched in agarose gels, at a seeding density of 50,000 cells per well. At zero time the size of the cell colonies was 35.4 sq. mm. +/- standard error 0.1. Irradiation (1500 rads) did not affect the expansion of the cell colonies although 3H-thymidine uptake was inhibited. Endothelial cells migrated under the agarose gels concentrically as contiguous sheets. When exposed to either 20 per cent platelet-poor plasma serum, platelet-rich plasma serum, or whole blood serum, the average increase in surface area was approximately 9 sq. mm. per day. In contrast, arterial smooth muscle cell colonies expanded with an increment of approximately 9 sq. mm. per day when exposed to 10 per cent platelet-poor plasma serum but 12 sq. mm. per day when exposed to 10 per cent platelet-rich plasma serum (p less than 0.001). Platelet factors also had stimulatory effects on the migration of venous smooth muscle cells. Cytochalasin B, dibutyryl cyclic AMP, and theophylline inhibited the migration of both endothelial and smooth muscle cells, but the latter responded more to the inhibitory effects of all three agents. It is concluded that in contrast to vascular smooth muscle, endothelial cells do not require platelet factors for migration and are less responsive to specific inhibitors affecting cell movement.

Blood Platelets↗
PubMed1978

Abnormal platelet aggregation in severe combined immunodeficiency disease with adenosine deaminase deficiency.

The platelets from a boy with adenosine deaminase deficiency-severe combined immunodeficiency disease (ADA-SCID) showed markedly subnormal aggregation in response to collagen and ADP. In contrast with normal platelets, ATP, AMP and adenosine had little effect in inhibiting ADP-induced aggregation of ADA-SCID platelets. These observations suggest that altered adenosine metabolism exists in ADA-SCID platelets.

Adenosine Deaminase↗
PubMed1976

Platelet aggregation as a sign of septicemia in thermal injury. A prospective study.

Serial measurements of coagulation activity, platelet counts, and platelet aggregation were done in patients with full-thickness burns involving 25% or more of body surface area to detect specific changes that might correlate with the onset of septicemia. Mean and maximal values for prothrombin time, partial thromboplastin time, thrombin time, activities of factor V and factor VIII, and concentrations of fibrinogen and fibrinogen-related antigens observed in the presence of bacterial septicemia did not differ significantly from those observed in the absence of septicemia. Mean platelet counts were significantly less with sepsis, but values in individual subjects were not indicative of the presence of septicemia. By contrast, platelet aggregation in response to adenosine diphosphate, epinephrine, and collagen always became severely abnormal with the onset of septicemia but not in the absence of sepsis.

Anti-Bacterial Agents↗
PubMed1976

The use of oral BCG in the treatment or metastatic malignant melanoma.

This study assess the effects of oral BCG, as a single agent, on tumor progression and on cell-mediated immune function in patients with metastatic malignant melanoma. Thirty patients were studied including 22 with measurable metastatic lesions and 8 with no detectable disease, following treatment of metastases by surgery, radiotherapy, or 5-(3, 3-dimethyl-1 -triazeno)-imidazole-4-carboxamide (DTIC; DIC). Oral BCG was given in doses of 120--240 mg, 1--3 times per week for periods ranging from 9 to 80 weeks and to total doses of from 1.2 to 20.1 gm. Patients were assessed by direct measurements of tumor mass, PPD skin test and in vitro blastogenic responses to PPD PHA. Of the 22 patient with measureable disease, 19 showed tumor progression and none showed regression of any lesion. Of the 8 without apparent disease, 5 remained stable and 3 had tumor recurrence. Of the total group of 30 patients, 8 showed some increased sensitivity to skin testing with PPD. Of 19 tested, 3 showed an increased PPD response in vitro, while 3 showed a decreased response. Six of 20 tested showed an increased PHA response in vitro. Oral BCG alone was not effective as an antitumor agent in patients with metastatic malignant melanoma.

Adult↗
PubMed1976

A comparison of granulopoiesis in culture from blood and marrow cells of nonleukemic individuals and patients with acute leukemia.

The objective of this study was to compare the concentration of committed granulopoietic progenitor cells (CFU-C) in marrow and blood. For individuals without leukemia, a highly significant correlation was observed between the concentration of CFU-C obtained from the two sites. However, CFU-C in blood had a slower sedimentation velocity than that reported for marrow and were found not to be in the DNA synthetic phase of the cycle using the tritiated thymidine suicide tehcnique. In patients with acute leukemia, no correlation was observed between concentrations of CFU-C in marrow and peripheral blood, regardless of whether the patients were newly diagnosed, in remission, or in relapse. We concluded that studies of the peripheral blood do not yield the same information in respect to granulopoietic progenitor cells as do studies of the marrow.

Blood Sedimentation↗
PubMed1975

The influence of ascorbic acid on platelet structure and function.

To determine the effect on platelet behavior of transient exposure of platelets to ascorbic acid, studies of platelet function and ultrastructure were done before exposure to ascorbic acid at pH 6.5, during exposure to pH 6.5, and after restoration of pH to pre-acidification levels. The effect of ascorbic acid (A.A.) was compared to that of HCl and citric acid (C.A.). ADP- and collagen-induced aggregation of normal platelets were significantly impaired by both A.A. and C.A. but were less affected by HCl. The release of 14C-serotonin was significantly reduced by each agent. The ultrastructure of normal platelets brought to pH 6.5 by A.A. was normal. After neutralization, there was marked dilatation of the open channel system and loss of the disc shape. When platelets were brought to pH 6.5 by A.A., then neutralized, the aggregates which formed after stimulation by ADP or collagen were smaller than normal, the platelets were less closely approximated, and degranulation was less complete. The data show that exposure of platelets to ascorbic acid for short intervals impairs their function when measured after restoration of pH to levels compatible with maximal responses. Platelet survival studies using autologous platelets labelled with 51Cr in the presence or absence of ascorbic acid showed that the recovery of normal platelets was unaffected by ascorbic acid, whereas recovery of platelets from patients with idiopathic thrombocytopenic purpura, idiopathic thrombocythemia, and alcohol-related thrombocytopenia was markedly reduced. The injury resulting from the use of ascorbic acid in preparing platelets for studies of platelet survival in patients with disorders affecting platelets may impair the recovery of the cells, resulting in artifactual changes in the survival studies.

Adenosine Diphosphate↗
PubMed1975

Acute leukemia in adults: assessment of remission induction with combination chemotherapy by clinical and cell-culture criteria.

Remission induction was assessed by clinical and cell-culture criteria for 65 patients with acute myelogenous leukemia (AML), 11 patients with chronic myelogenous leukemia (CML) in blast crisis and 19 patients with acute lymphoblastic leukemia (ALL). Cyclophosphamide, cytosine arabinoside and vincristine (CAV) therapy resulted in complete remission in 23 of 50 previously untreated patients with AML and in 3 of the 11 patients with CML. Fourteen patients with ALL responded to vincristine-prednisone induction therapy and two to induction therapy with CAV. The median duration of survival of the responding patients was 2.2 years, compared with 4 months for the patients who did not respond to treatment. Granulopoietic colony formation, assessed by assay of colony-forming units dependent on colony-stimulating activity in culture (CFU-C), was abnormal in 37 of 42 bone marrow aspirates from patients with AML before treatement. CFU-C concentration increased when leukocyte-conditioned medium (LCM) was added to the cultures; 13 cultures had normal or elevated CFU-C concentration with LCM. Marrow cells of patients with ALL or CML in blast crisis demonstrated a similar pattern. Serial studies of marrow CFU-C concentration of 31 patients with AML demonstrated a change to a normal pattern with successful remission induction. Results of this study suggest that administration of purified LCM to leukemic patients might increase granulocyte production from potential but unstimulated granulopoietic precursors. This therapy would lessen the probability of death from infection during remission induction.

Acute Disease↗
PubMed1975

Studies on the platelet defect in alcoholism.

Platelet ultrastructure, protein composition, and adenine nucleotide metabolism were studied in patients ingesting ethanol to elucidate the mechanism of ethanol-induced changes in platelet function and survival. Serial measurements were made in 2 patients who maintained blood ethanol levels in excess of 300 mg/100 ml for 3 to 4 weeks. No major changes in structure or metabolism were detected in platelets from the patient whose platelet counts remained stable during the ingestion period. By contrast, the development of thrombocytopenia in the other patient was associated with significantly reduced intracellular ADP, increased ATP/ADP ratio, decreased release of ADP, increased specific radioactivity of intracellular ATP and ADP, and increased formation of hypoxanthine. Additionally, platelets from this patient varied markedly in size, contained giant granules, and possessed a poorly defined microtubular system. After stimulation with ADP or collagen, centripetal granule migration was retarded, and the aggregates formed were small and loose. Several large proteins were absent from the supernatant fraction of sonicated platelets from the thrombocytopenic patient. Exposure of normal platelets to ethanol in vitro resulted in no detectable change in platelet ultrastructure. The data indicate that the ethanol-related abnormalities of platelet function are due in part to subnormal amounts of intracellular ADP and a deficit in the storage pool of ADP. Additionally, the results suggest that impairment in the release mechanism to the observed defect in the release reaction.

Adenine↗
PubMed1975

Occurrence of hepatitis and hepatitis B surface antigen in adult patients with acute leukemia.

Fifty-eight adult patients with acute leukemia were screened at the onset of the disease for hepatitis B antigen (HBSAg) in the serum, and during the course of the disease for the development of hepatitis B. One patient had a positive test for HBSAg by the radioimmunoassay technique only at the time leukemia was diagnosed; this patient had received transfusions some years before. In six patients icteric hepatitis B developed; five recovered completely and one died of leukemia during the course of hepatitis. All patients in whom hepatitis developed had received transfusions as a part of supportive therapy for leukemia. The hepatitis risk for patients who received transfusions of blood found to be negative for HBSAg by counterimmunoelectrophoresis was 0.26 percent per unit of blood administered.

Acute Disease↗
PubMed1975

The effects of polyanions on NBT Reductions hexose monophosphate shunt activity, and ultrastructure of polymorphonuclear leukocytes.

Heparin causes enhanced nitroblue tetrazolium (NBT) reduction by polymorphonuclear leukocytes (PMN's). To determine the mechanism of this stimulation, samples of 1 to 3 x 10(7) PMN's were incubated with various concentrations of heparin, chondroitin sulfate A (CSA), and chondroitin sulfate B (CSB), with and without NBT. The effect of the polyanions (PA) on PMN hexose monophosphate shunt (HMPS) activity was determined by the production of 14CO2 from glucose-1-14C by the leukocytes. NBT reduction was evaluated histochemically and spectrophotometrically at 515 mmu. Samples of PMN's in heparin and heparin-NBT mixtures were examined by electron microscopy after various incubation periods. Increased NBT reductions by PMN's was found when leukocytes were incubated with heparin, CSA, and CSB, but these compounds had no effect on the HMPS activity of PMN's unless NBT was added. Electron microscopy of samples that contained heparin-NBT revealed an insoluble complex that was phagocytosed by the leukocytes. The stimulation of PMN oxidative metabolism and NBT reduction that follows incubation with PA-NBT appears to be directly related to ingestion of this particulate complex by the leukocytes.

Carbon Dioxide↗
PubMed1975

The platelet defect in leukemia. Platelet ultrastructure, adenine nucleotide metabolism, and the release reaction.

The ultrastructure and adenine nucleotide metabolism of platelets from patients with acute leukemia were studied to elucidate possible mechanisms for the platelet dysfunction observed in this clinical setting. Nonstimulated (resting) platelets from leukemic patients varied greatly in size; exhibited marked variation in the number of alpha granules present per cell; had poorly delineated circumferential bands of microtubules; and often grossly dilated open channel systems or cytoplasmic vacuolization. The intracellular concentrations of ATP and ADP were significantly below normal, and the specific radioactivity of ATP and ADP of nonstimulated platelets in leukemia was equivalent to or exceeded that seen in stimulated normal platelets. Addition of ADP or collagen to platelets from leukemic patients was followed by retarded and incomplete shape change, delayed and incomplete centripetal migration of subcellular organelles, impaired degranulation, and the formation of loose aggregates composed of relatively few platelets. Stimulation of "leukemic" platelets with collagen led to the release of significantly subnormal amounts of ATP and ADP and no significant change in the specific radioactivity of the intracellular nucleotides. In contrast to the results in normal platelets, the conversion of ATP to inosine monophosphate and hypoxanthine in platelets in leukemia failed to increase significantly with collagen stimulation. The results indicate that abnormalities exist in the storage pool of adenine nucleotides and the release mechanism of platelets in acute leukemia. These defects appear to contribute to an impairment in the release reaction in these platelets. Many of the ultrastructural and metabolic defects seen in acute leukemia occur in platelets in preleukemia.

Adenine Nucleotides↗
PubMed1975

Structural-functional relationships in platelets in acute leukemia and related disorders.

Platelet ultrastructure and adenine nucleotide metabolism were studied in acute leukemia in order to elucidate mechanisms for the functional defects of platelets in this clinical setting. A number of structural defects were observed: (1) giant platelets, (2) marked variability in the number and size of cytoplasmic granules, (3) dilatation of the open channel system, (4) cytoplasmic vacuolization, and (5) poorly delineated microtubular system. Metabolic defects included reduced cellular concentrations of ATP and ADP and selective reduction of the storage pool (non-metabolic) nucleotides. Stimulation of platelets was associated with delayed and incomplete granule migration, reduced degranulation, subnormal release of ATP and ADP, and poor platelet aggregate formation. The structural and metabolic defects observed indicate abnormalities exist in the contractile mechanism and the release reaction of platelets in acute leukemia which partly explain the functional defects reported previously. Platelets from patients with pre-leukemic states share some of the structural and metabolic defects seen in acute leukemia. The defects are less uniform consistent with a lesser degree of functional impairment than seen in acute leukemia. Studies of megakaryocytic ultrastructure suggest that the structural defects seen in acute leukemia and pre-leukemia may arise in the late stages of megakaryocyte maturation.

Adenine Nucleotides↗