Factors that affect human hemopoiesis are produced by T-cell growth factor dependent and independent cultured T-cell leukemia-lymphoma cells

Some laboratory results and clinical situations suggest that human T cells may be important in the regulation of growth of hematopoietic cells. Since the discovery of T-cell growth factor (TCGF), systems are now available for the long-term specific in vitro propagation of mature normal or neoplastic human T cells, providing an opportunity to study the influence of T cells on hematopoiesis. Recently, 24 cell lines from patients with cutaneous T-cell lymphoma (CTCL) and T-cell acute lymphoblastic leukemia (T-ALL) were grown with TCGF and then assessed for release of humoral factors that affect hematopoiesis. Conditioned media (CM) from these cell lines were tested for erythroid burst- promoting activity (BPA) and granulocyte colony-stimulating activity (CSA). BPA was detected in CM from 3/6 cultures of T-ALL patients and 4/6 CTCL cultures. CSA was found in the CM from 6/8 cultures of T-ALL patients, 7/12 CTCL cultures, and 3/4 CTCL cell lines that become independent of exogenous TCGF for growth. The CSA from several of the neoplastic T-cell cultures stimulated high levels of eosinophil colonies, a possible source of the eosinophilia seen in these patients. The ability of continuously proliferating human T lymphocytes, which retain functional specificity and responsiveness to normal humoral regulation, to produce factors that directly or indirectly stimulate myeloid and erythroid colony formation lends further credence to the role of T lymphocytes in regulating hematopoiesis.     

High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy

Seventy-five patients with resistant acute leukemia or lymphoma received high-dose cyclophosphamide and etoposide to explore the activity of this combination in resistant hematologic malignancies, and to determine the maximum doses of these drugs that can be combined without bone marrow transplantation. Etoposide was administered over 29 to 69 hours by continuous infusion corresponding to total doses of 1.8 g/m2 to 4.8 g/m2. Cyclophosphamide, 50 mg/kg/d, was administered on 3 or 4 consecutive days total 150 to 200 mg/kg ideal body weight). At all dose levels myelosuppression was severe but reversible. Mucosal toxicity was dose-limiting with the maximum tolerated dose level combining etoposide 4.2 g/m2 with cyclophosphamide 200 mg/kg. Continuous etoposide infusion produced stable plasma levels that were lower than would be achieved after administration by short intravenous infusion, and this could explain our ability to escalate etoposide above the previously reported maximum tolerated dose. There were 28 complete (35%) and 12 partial (16%) responses. Median duration of complete response (CR) was 3.5 months (range 1.1 to 20+). Seventeen of 40 patients (42%) with acute myelogenous leukemia (AML) achieved CR, including 6 of 20 (30%) with high-dose cytosine arabinoside resistance. We conclude that bone marrow transplantation is not required after maximum tolerated doses of etoposide and cyclophosphamide. This regimen is active in resistant hematologic neoplasms, and the occurrence of CR in patients with high-dose cytosine arabinoside-resistant AML indicates a lack of complete cross-resistance between these regimens.     

Anemia of the Belgrade rat: evidence for defective membrane transport of iron

The mechanisms underlying the impaired utilization of transferrin-bound iron by erythroid cells in the anemia of the Belgrade laboratory rat were investigated using reticulocytes from homozygous anemic animals and transferrin labeled with 59Fe and 125I. The results were compared with those obtained using reticulocytes from phenylhydrazine-treated rats and iron-deficient rats. Each step in the iron uptake mechanism was investigated, ie, transferrin-receptor interaction, transferrin endocytosis, iron release from transferrin, and transferrin exocytosis. Although there were quantitative differences, no fundamental difference was found in any of the abovementioned aspects of cellular function when the reticulocytes from Belgrade rats were compared with those from iron-deficient animals. The basic defect in the Belgrade reticulocytes must therefore reside in subsequent steps in iron uptake, after it is released from transferrin within endocytotic vesicles, ie, in the mechanism by which it is transferred across the lining membrane of the vesicles into the cell cytosol. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) of reticulocyte ghosts extracts demonstrated a prominent protein band of mol wt 69,000 that was absent or present only in low concentration extracts from the other two types of reticulocytes. This may be a result of the genetic defect.     

Effectiveness of methyl-GAG (methylglyoxal-bis[guanylhydrazone]) in patients with advanced malignant lymphoma

We treated 51 patients with advanced malignant lymphoma refractory to conventional therapy with methyl-glyoxal-bis(guanylhydrazone) (methyl- GAG) at doses ranging from 400 to 800 mg/sq m. Therapy was started on a weekly schedule and was switched to every other week in responding patients at the onset of toxicity. Partial responses were observed in 6 of 13 evaluable patients with Hodgkin's disease (46%), 5 of 10 patients with diffuse poorly differentiated lymphocytic lymphoma (50%), 2 of 4 patients with nodular poorly differentiated lymphocytic lymphoma (50%), and 3 of 13 patients with diffuse histiocytic lymphoma (23%). Two of six patients with mycosis fungoides showed objective improvement in cutaneous disease. Toxicity was generally mild and included muscular weakness, myalgia, mucositis, and diarrhea; two patients developed bronchospasm following drug infusions. We conclude that methyl-GAG has major antitumor activity when administered on this schedule to patients with advanced malignant lymphoma. The low degree of toxicity, unique mechanism of action, and minimal myelosuppressive effects suggest that methyl-GAG will prove useful in future trials of combination chemotherapy regimens for the treatment of lymphoma.     

Cardiovascular risk factors and blood pressure in a primary care unit: Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD)

OBJECTIVES: The presence of cardiovascular risk factors in children may be important in the development of atherosclerosis in adulthood. Adequate control of blood pressure is a cornerstone in atherosclerosis prevention. The aim of the Yugoslav Study of the Precursors of Atherosclerosis in School Children (YUSAD) was to identify risk factors for elevated blood pressure in school children. METHODS: The YUSAD study is a multicentre follow-up study comprised of two cross-sectional surveys conducted five years apart. At baseline, 10-year-old children (3226 boys and 3074 girls [n=6300]) were randomly selected during periodical visits to primary health care centres. The risk factors measured were heart rate, weight, body mass index (BMI), waist-to-hip ratio, grade point average and current smoking status. RESULTS: Significant age and sex differences were identified in systolic blood pressure, diastolic blood pressure and all investigated independent variables. In a multivariate analysis, diastolic blood pressure in 10-year-old boys was directly and significantly related to total cholesterol and height, whereas it was inversely related to weight. At follow-up, in the multivariate model, only BMI was a significant predictor of diastolic blood pressure in boys. In girls at baseline in the multivariate regression analysis, the only significant predictor of diastolic blood pressure was total cholesterol. In 15-year-old girls, diastolic blood pressure was significantly and directly related to BMI and heart rate, whereas it was inversely related to weight. For both 10- and 15-year-old male and female participants, none of the variables by multivariate analysis were a significant predictor of systolic blood pressure. CONCLUSIONS: Age, sex, heart rate, cholesterol and weight are the most important predictors of blood pressure in school children.     

A common polymorphism in the brain-derived neurotrophic factor gene in patients with adult-onset primary focal and segmental dystonia

Brain-derived neurotrophic factor (BDNF) modulates neuroplasticity. A functional polymorphism [Val66Met (G196A)] in BDNF has been reported to modify cortical plasticity in humans. Physiologic investigations have revealed that dystonia might be a consequence of the pathologic plasticity of the sensorimotor cortex. We aimed to investigate the role of the Val66Met polymorphism in a cohort of Serbian patients with adult-onset primary focal and segmental dystonia (PTD). One hundred and forty-nine patients with primary adult-onset PTD, 194 patients with Parkinson’s disease (PD), and 366 healthy control subjects were recruited for the study. Patients with PTD and PD, as well as healthy controls had a similar distribution of genotypes and allele frequencies. There was no any significant difference in the allelic distribution at the Val66Met SNP of the BDNF gene among patients with adult-onset PTD, PD, and healthy volunteers from the same geographic areas. In addition, the presence of the Met allele did not influence the clinical characteristics of PTD patients. Patients with the Met variant did not differ by age at onset, number of affected regions, and efficacy of a sensory trick. Met66Met is not associated with an increased risk of dystonia.     

Outcome of patients with atrial fibrillation after intravenous thrombolysis for cerebral ischaemia

The question of whether i.v. rt-PA is beneficial in patients with ischaemic stroke and atrial fibrillation (AF) remains unresolved. Our objective was to evaluate the outcome of patients with AF who received i.v. rt-PA for stroke in the registries of Lille (France) and Belgrade (Serbia). End-points were poor outcome [modified Rankin Scale (mRS) 3–6], and symptomatic haemorrhagic transformation (sHT) according to ECASS3. Of 734 consecutive patients, 155 (21.2 %) had AF. The unadjusted comparison found patients with AF to be 12 years older, more likely to be women, to have hypertension, and baseline INR > 1.2, and less likely to be smokers. They had higher baseline NIHSS scores, diastolic blood pressure, and serum glucose concentrations, and lower platelet counts. They did not differ for sHT (5.8 vs. 5.5 %; p = 0.893), but they more frequently had poor outcomes (52.3 vs. 35.2 %; p < 0.001) and death (21.9 vs. 9.0 %; p < 0.001). The only independent predictor of sHT was baseline NIHSS (_adjOR 1.05 per 1 point increase; 95 % CI 1.01–1.10). Independent variables associated with poor outcome were age (_adjOR 1.04 for 1 year increase; 95 % CI 1.03–1.06), baseline NIHSS (_adjOR 1.17 per 1 point increase; 95 % CI 1.13–1.21), and sHT (_adjOR 47.6; 95 % CI 10.2–250) but not AF. In patients treated with i.v. rt-PA for cerebral ischaemia, those with AF have worse outcomes because they are older and have more severe strokes at admission. This result suggests that we should focus on prevention and research of more aggressive strategies at the acute stage.