[Hereditary thrombogenic defects in the national family registry].
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Blood Coagulation Disorders↗
Biomedical subjects
S Schulman
Publications and source records attributed to S Schulman.
Combination chemotherapy and systemic irradiation consolidation for poor prognosis breast cancer.
Seventy patients with poor prognosis, metastatic breast cancer were treated with FUVAC induction chemotherapy (5-fluorouracil, vinblastine, Adriamycin [doxorubicin] and cyclophosphamide). Consolidation therapy was given to 30 of 48 responders (63%), of whom 23 received sequential hemibody irradiation (HBI) at 8 cGy, corrected in the upper half for lung transmission. Seven received high dose cyclophosphamide and total body irradiation (TBI) with subsequent infusion of stored, cryopreserved autologous bone marrow. The response rate to induction therapy was 71% (complete [CR] in 21%). The median survival for all patients entered in this study is 12 months. With consolidation, one CR patient who received cyclophosphamide and TBI is disease free at 20+ months, off all treatment, while HBI did not produce longterm remissions. Of 17 partial response (PR) patients, two of 12 improved to CR with HBI, and one of five improved with cyclophosphamide plus TBI, but all ultimately relapsed. The main toxicity of sequential HBI was myelosuppression, with prolonged thrombocytopenia in 13%; only one case of radiation pneumonitis occurred (3%). Cyclophosphamide and TBI produced temporary, reversible marrow aplasia without other major toxicity. We recommend further investigation of Cytoxan (Bristol Myers Oncology Division, Evansville, IN) and TBI for breast cancer patients in remission after chemotherapy.
Antineoplastic Combined Chemotherapy Protocols↗
DDAVP-induced correction of prolonged bleeding time in patients with congenital platelet function defects.
In 37 patients with prolonged bleeding time, where thrombocytopenia, von Willebrand's disease or deficiency of other coagulation factors could be excluded, we have evaluated the effect of a DDAVP-infusion (0.2 ug/kg) together with tranexamic acid (10 mg/kg). Patients with acquired impairment of primary hemostasis were not included, except two cases where this could have been a contributing factor. The bleeding time was completely normalized in 27 cases and partially corrected in three more patients. The predominant feature among those, who did not respond, was a pattern compatible with thrombasthenia or cyclooxygenase deficiency, as assessed by platelet aggregation studies. Among the patients, in whom DDAVP was effective, this drug was thereafter successfully used as an alternative to blood products in 8 cases during and after surgery or delivery.
Adolescent↗
HIV infection in a defined population of Swedish haemophiliacs.
The results of a clinical follow-up of 124 Swedish patients with haemophilia A and B or severe form of von Willebrand's disease are reported, especially with regard to HIV infection and complications thereof. 44 of the patients were anti-HIV positive. In this group there was an increasing prevalence of lymphadenopathy (18 cases), diarrhoea and fungal infections. 10 patients had generalized persistent lymphadenopathy. Platelet counts were significantly lower and IgG, IgA and IgM levels significantly higher than in the anti-HIV negative group. Oligoclonal protein bands in the gammaglobulin region were found in 8 of the anti-HIV positive patients. The vast majority of these changes have appeared during the past year, and 1-5 years after seroconversion. Presently 22/44 (50%) anti-HIV positive haemophiliacs have at least one symptom related to this infection. Most of the clinical complications have been possible to treat or to mitigate so far.
AIDS-Related Complex↗
Dextran density gradient purification of Plasmodium sporozoites.
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Animals↗
In vitro invasion of host cells by Plasmodium berghei sporozoites in serum-free medium.
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Animals↗
Long-term sequelae of calf vein thrombosis treated with heparin or low-dose streptokinase.
A prospective randomized study was performed to investigate the long-term sequelae of calf vein thrombosis (CVT) and correlate them to the success of the initial treatment. Thirty-six patients with symptomatic CVT, verified by venography, were treated with heparin or low-dose streptokinase (SK) combined with low-dose heparin. Venography was repeated after 1 week, and long-term follow-up was performed clinically and with foot volumetry after an average of 5 years. Since the low-dose SK regimen led to serious hemorrhagic side-effects in a parallel study, the present investigation was discontinued prematurely. The thrombolysis achieved was greater with SK but, since the initial thrombi were somewhat larger in this group, no significant difference in the average size of the thrombi after therapy could be displayed between the groups. The long-term sequelae and results of foot volumetry were also equal. Signs or symptoms of venous insufficiency were found in 37%, and foot volumetry showed deep venous insufficiency in 26% of the cases. There was a correlation between the hemodynamic change, as assessed by foot volumetry, and the venographic severity. This relation was stronger for the size of the thrombus after treatment than for the initial size. Thus, it seems important to limit the extent of a CVT in order to minimize the long-term sequelae, but administration of SK is not justified due to side-effects.
Acute Disease↗
Plasmodium berghei sporozoite invasion is blocked in vitro by sporozoite-immobilizing antibodies.
A monoclonal antibody directed against the circumsporozoite protein on the surface of Plasmodium berghei sporozoites inhibited sporozoite motility in vitro. These immobilized sporozoites could adhere to but not invade target cultured cells. Other sporozoite-immobilizing agents also inhibited sporozoite invasion into cultured cells and did not prevent sporozoite adherence. These results indicate that sporozoite invasiveness is associated with sporozoite motility. Thus, the immobilizing effect of this antibody could explain its functional activity against sporozoite invasion in vivo.
Adhesiveness↗
Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.
The metabolism of pentose-phosphate was investigated in Plasmodium falciparum-infected normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient human red blood cells in vitro. 5'-Phosphoribosyl-1-pyrophosphate (PRPP) content of infected normal red blood cells was increased 50-60-fold at the parasite trophozoite growth stage over that of uninfected cells. The PRPP increment in infected G6PD-deficient cells at comparable stage and parasitemia was only 40% of the value in normal infected cells. Red blood cell PRPP synthetase activity did not change during the growth cycle of the parasite and was similar in both normal and G6PD-deficient cells. Reduced glutathione (GSH) content of G6PD-deficient cells under conditions of culture fell to low or undetectable levels. These low levels of GSH were shown to inhibit the function of red blood cell PRPP synthetase, which requires GSH for full activity. Measurements of the incorporation of 1-14C or 6-14C selectively labeled glucose into parasite nucleic acids revealed that in normal infected red cells, approximately 20% of the pentose was produced via the oxidation of glucose-6-phosphate, whereas in infected G6PD-deficient cells (Mediterranean type), none of the pentose was produced via the oxidative pathway. It is concluded that the low level of reduced GSH found in G6PD deficiency and the resultant partial inhibition of PRPP synthetase together with the missing oxidative pathway for ribose phosphate production can account fully for the reduced parasite growth rate in G6PD-deficient red blood cells described previously. Of these two mechanisms, the predominant one is the impaired PRPP synthetase activity due to low GSH levels in enzyme-deficient red blood cells. The contribution to the ribose-phosphate pool by the hexose monophosphate shunt is relatively minor. A co-existing oxidative stress (which is often hypothesized to mediate the destruction of parasitized red blood cells) is not required to explain growth inhibition in this scheme and does not represent the most straight-forward explanation of the data described in this report.
DNA Replication↗
Transmission of HIV infection to heterosexual partners but not to household contacts of seropositive haemophiliacs.
The prevalence of HIV antibodies in 44 heterosexual female partners and 56 nonsexual family household contacts of 61 HIV seropositive haemophiliacs (41 adults and 20 children or adolescents) was determined to evaluate the risk of transmission of HIV infection. HIV antibodies were determined by enzyme-linked immunosorbent assay and positive reactions were confirmed by Western blotting. HIV antibodies were demonstrated in 4/40 (10%) regular heterosexual partners of 40 seropositive patients with haemophilia A. Four temporary heterosexual partners of one additional seropositive haemophiliac were seronegative. 56 nonsexual household contacts including 30 parents, 13 siblings and 13 children of 29 seropositive haemophiliacs were all negative for HIV antibodies. Thus transmission of HIV occurred from seropositive haemophiliacs to their heterosexual partners but not to nonsexual household contacts.
Acquired Immunodeficiency Syndrome↗
Rhoptry secretion of membranous whorls by Plasmodium falciparum merozoites.
Multilamellar membranous whorls were localized, by electron microscopy, in elements of the rhoptry-microneme complex from glutaraldehyde-tannic acid (TA)-fixed merozoites of the human malarial parasite, Plasmodium falciparum. These multilaminate structures, which have a dark line-to-dark line periodicity of approximately 5 nm, were also found in the nuclear envelope and closely apposed to the external surface of merozoites. Segmented schizonts, which contain intracellular merozoites, often showed membranous whorls within their parasitophorous vacuoles and closely apposed to the external surface of the parasitophorous vacuole membrane. Whorls were not found in trophozoites, immature schizonts, and uninfected erythrocytes. Most rhoptries in merozoites fixed in glutaraldehyde-TA were electron-lucent whereas rhoptries fixed in glutaraldehyde alone were electron-dense. Some merozoites fixed in glutaraldehyde-TA had both an electron-dense and an electron-lucent rhoptry. These findings suggest that TA induces the premature extrusion of rhoptry materials. Our findings support previous suggestions in the literature that phospholipid materials secreted from merozoite rhoptries are involved in merozoite interaction with host erythrocytes.
Animals↗
Malarial pigment-dependent error in the estimation of hemoglobin content in Plasmodium falciparum-infected red cells: implications for metabolic and biochemical studies of the erythrocytic phases of malaria.
Measurements of mean corpuscular hemoglobin (MCH) in Plasmodium falciparum-infected red cells cultured in vitro revealed that malarial pigment (hemozoin) interferes with a true estimate of the actual hemoglobin content in Drabkin's reagent. When the hemozoin pigment was removed by passage of the lysate over a Biorex 70 column, a lower MCH value was obtained which allowed one to estimate that, under these conditions, the parasite consumes about 25% of the red cell's initial hemoglobin. Because spectrophotometric examinations of infected red cell lysates in Drabkin's reagent detect the unchanging heme content of infected red cells (hemoglobin + hemozoin), it can be used for expressing enzymatic activity or metabolite content. Results agree with simultaneous measurements on a per cell basis. However, it is suggested that instead of per gram hemoglobin, the activity should be stated as per mmole (or mumole) heme pigment. The ability to estimate accurately the consumption of intracellular hemoglobin will be useful in metabolic and pharmacologic studies of the parasite/red cell interaction.
Cells, Cultured↗
Combined alkylators and multiple-site irradiation for extensive small cell lung cancer: a Southwest Oncology Group Study.
The Southwest Oncology Group performed a study for patients with extensive small cell lung cancer in which two hypotheses were tested: that combined alkylating agents for induction might improve the initial response rate; and that multiple-site, involved-field consolidation with irradiation in patients with response to chemotherapy might further improve response quality and duration. A regimen of combined alkylating agents plus vincristine [carmustine, thiotepa, vincristine, and cyclophosphamide (BTOC)] was compared to our standard program of cyclophosphamide, doxorubicin, and vincristine (CAV). Patients with bone marrow metastases and/or disseminated bone metastases were randomized to BTOC or CAV as initial induction therapy, but received no multiple-field irradiation afterward. Among 189 such patients, the overall response rates were similar (48% to BTOC and 61% to CAV, with complete remission in 5% and 15%, respectively). Toxic effects were also comparative, with 23% sustaining life-threatening or fatal complications on BTOC and 16% on CAV. Median survival (5.9 and 7 months for BTOC and CAV, respectively) and overall survival were not different, and are superimposable upon our previously reported results with CAV alone. For patients with no evidence of bone marrow involvement and no metastases identified beyond the confines of ipsilateral hemithorax, liver, and brain, the plan of therapy consisted of induction chemotherapy (BTOC or CAV) every 3 weeks for three cycles, followed by multiple-field irradiation consolidation to sites of prior involvement. Among 239 such patients, response rates to therapy initiated with BTOC and CAV were also similar: 54% for BTOC and 62% for CAV, with complete response in 16% and 13%, respectively. However, the program of BTOC followed by multiple-site irradiation was associated with a higher incidence of severe or life-threatening thrombocytopenia (23% versus 8% for CAV), accounted for almost entirely by patients receiving hepatic irradiation after chemotherapy, among whom the incidence of this complication (grade 3 or 4) was 76% and 14%, respectively. Other toxic effects, including granulocytopenia, were comparable. With the exception of thrombocytopenia in the cited subgroup, multiple-field irradiation consolidation proved feasible and tolerable, with improved quality of response evident after its initiation in 24% of 135 patients. However, a similar proportion developed disease progression during or shortly after radiation therapy, and the median survival of patients who received irradiation was only 9 months (7 months from the start of consolidation).(ABSTRACT TRUNCATED AT 400 WORDS)
Antineoplastic Combined Chemotherapy Protocols↗
Pathways for the reduction of oxidized glutathione in the Plasmodium falciparum-infected erythrocyte: can parasite enzymes replace host red cell glucose-6-phosphate dehydrogenase?
Plasmodium falciparum-infected human red cells possess at least two pathways for the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH): (1) the glucose-6-phosphate dehydrogenase (G6PD) pathway and (2) the glutamate dehydrogenase (GD) pathway using glutamate as a substrate. Uninfected erythrocytes lack the GD pathway. The NADPH generated can be used to reduce oxidized glutathione (GSSG), which accumulates in the presence of an oxidative stress. In red cell G6PD deficiency, this pathway is reduced or absent, and the host cells as well as the parasites within them are vulnerable to oxidant stress. In view of the presence of the GD pathway in parasitized red cells and the recent description of a parasite-derived G6PD enzyme, we have asked whether the pathways for the reduction of GSSG provided by the parasite can substitute for the host G6PD in red cells deficient in G6PD activity. We have devised a functional assay in which the reduction rate of GSSG is monitored in the presence of buffered infected or control red cell lysates and substrates. Infected G6PD-deficient erythrocytes were obtained from in vitro cultures after a single prior growth cycle of the parasites in G6PD deficient cells to eliminate contaminating normal red cells. The results show that only parasitized red cells can reduce GSSG via the GD pathway. In parasitized G6PD Mediterranean red cells (completely G6PD-deficient), there is a detectable GSSG reduction via the G6PD pathway, not found in uninfected lysates from the same individual. In G6PD A- (African type, featuring partial deficiency), a small increment in the G6PD-dependent reduction of GSSG can also be detected. However, when compared to G6PD normal red cells, the activities from the parasite-derived pathways are small and could not be considered substitutes for normal host enzyme activity. It is concluded that while the plasmodium provides additional pathways for the generation of NADPH that may serve its own metabolic needs, the host red cells and hence the parasite itself remain vulnerable to oxidant stress.
Erythrocytes↗
Thrombolysis and fibrinolytic parameters during heparin treatment of deep vein thrombosis.
Thirty-nine patients with symptomatic, venographically verified deep vein thrombosis (DVT) were studied during treatment with heparin in order to investigate the correlation between the venographic changes and parameters of heparin therapy or fibrinolytic components. Venograms were scored with a 40-grade scale, and after one week a significant improvement with an average reduction of the thrombi of 17% was observed. No statistically significant correlation was found between reduction of thrombus size and duration of heparin treatment, total amount of heparin administered, mean levels of APTT, plasmin-alpha 2-antiplasmin complex (PAP), tissue plasminogen activator (t-PA) antigen or t-PA-inhibitor. Only a short history of the thrombus was significantly correlated to thrombolysis. The concentrations of PAP and t-PA-inhibitor were not influenced, while that of t-PA antigen showed a significant increase during heparin infusion. Even if statistically significant correlations were not obtained, the patients with pronounced thrombolytic effect had high PAP-levels. Furthermore, patients with high t-PA-inhibitor levels had no lysis. The results suggest, that also other factors than plasminogen dependent fibrinolysis are of importance for the thrombolytic effect.
Blood Coagulation Tests↗
Relationship between thromboembolic complications and intensity of treatment during long-term prophylaxis with oral anticoagulants following DVT.
The frequency of thromboembolic recurrencies during secondary prophylaxis after DVT was retrospectively studied and related to the intensity of the oral anticoagulation. All patients receiving oral anticoagulation after DVT at our hospital during April 1972-May 1980 were studied. Treatment was given to 596 patients for 724 thrombotic events for a total of 4450 months. Thirty-six thromboembolic complications, all objectively verified, occurred. Patients with cancer had complications throughout the entire range of anticoagulation. Patients without neoplastic disease (15 events) never had complications below a prothrombin complex level of 27% as assessed with Simplastin A, corresponding to a BCT-ratio of 1.9. This study confirms, that the lower limit of the therapeutic range, determined by the risk of thromboembolic complications, should be set at a Simplastin A-level of approx. 25% corresponding to BCT 2.0.
Administration, Oral↗
The duration of oral anticoagulation after deep vein thrombosis. A randomized study.
Eighty patients with deep vein thrombosis (DVT) were randomized between our routine duration of oral anticoagulation and 50% reduction thereof, in order to evaluate whether shorter therapy could be given without increased risks. The study was stratified, so that 20 patients with the 1st episode of DVT caused by a temporary risk factor were treated for 1.5 or 3 months, 40 patients with the 1st episode of DVT caused by a permanent risk factor for 3 or 6 months, and 20 patients with the 2nd episode of DVT for 6 or 12 months. When warfarin therapy was discontinued, the patients were followed by means of venous occlusion plethysmography every 3 months for 1 year, and clinically for 15-27 months in the different subgroups. Thromboembolic complications were registered and verified by venography and perfusion lung scan. We could not detect any difference between the groups. The rate of rethrombosis and embolism during 12 and 24 months after cessation of anticoagulant therapy was 8 and 10%, respectively, among the patients with reduced duration of treatment and 8 and 14%, respectively, among those with regular duration. One fatal, warfarin-induced hemorrhage occurred. It is important to reduce unnecessary extension of oral anticoagulation after DVT in order to minimize the negative side-effects without increasing the recurrence rate. More extensive trials should be performed to confirm our results and define the optimal duration of treatment.
Adult↗
Stage-dependent toxicity of N-acetyl-glucosamine to Plasmodium falciparum.
The effects of N-acetyl-glucosamine on growth of synchronized cultures of Plasmodium falciparum were assessed by morphological observations and by measurement of parasite incorporation of 3H-hypoxanthine. Inhibition of 3H-hypoxanthine incorporation was more marked during the later stages of the erythrocytic cycle. At concentrations of the sugar below 20 mM, however, the deleterious effects were mainly a result of failure of released merozoites to invade erythrocytes, rather than a failure of schizonts to mature or release merozoites. These results are compatible with the hypothesis that a lectin-like substance on the merozoite interacts with a surface glycoprotein on the red cell and that sugar residues on this glycoprotein may be involved in this recognition.
Acetylglucosamine↗