Leukokinetic Studies. VII. Morphology of the Bone Marrow and Blood of Dogs Given Vinblastine Sulfate

The effect of a single injection of vinblastine sulfate was studied in 50mongrel dogs. Nine of 34 dogs given 0.2 mg./Kg. of VLB died with gastrointestinal toxicity and the mortality rate increased as the dosage of VLB wasincreased. The morphologic pattern of leukocyte suppression and recovery inthe bone marrow and blood was studied in detail in surviving animals.

The cells of the bone marrow were markedly affected by VLB. Within 4hours there was an increase in the number of cells in metaphase and, by day1, virtually all proliferating leukocytes and erythrocytes had disappeared. Anorderly repopulation of the bone marrow followed.

The neutrophils, eosinophils, lymphocytes and monocytes of the blood wereall markedly altered in concentration after VLB. Each type of cell first decreased to abnormally small numbers and then increased to abnormally largenumbers in the blood. The curve of disappearance from and reappearance inthe blood differed for each cell type.

The changes in blood neutrophil number and morphology were correlatedwith changes in the blood neutrophil precursor cells of the marrow. The following conclusions were reached concerning the neutrophils and the assumptions implicit to these conclusions were detailed.

1. In the dog, the marrow contains enough post-mitotic granulocytes toreplace those lost from the blood for at least 3 to 4 days.

2. The release of mature neutrophils from the bone marrow is a functionof the rate at which blood neutrophils are lost and proceeds normally evenwhen the marrow granulocyte reserve is partially depleted.

Submitted on March 27, 1963 Accepted on August 20, 1963     

HELICOBACTER PYLORI-SPECIFIC TUMOUR-INFILTRATING T CELLS PROVIDE CONTACT DEPENDENT HELP FOR THE GROWTH OF MALIGNANT B CELLS IN LOW-GRADE GASTRIC LYMPHOMA OF MUCOSA-ASSOCIATED LYMPHOID TISSUE

Previous studies have shown that tumour cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue (MALT) type proliferate in vitro in response to heat-killed whole cell preparations of Helicobacter pylori , but only in the presence of tumour-infiltrating T cells. This response is strain-specific in that the tumours studied responded optimally to different strains of H. pylori . It was unclear from these studies, however, whether the ability to recognize the specific stimulating strains of H. pylori was a property of the tumour cells or the tumour-infiltrating T cells. This study shows that whereas the tumour cells do not respond to H. pylori , both freshly isolated tumour-infiltrating T cells and a T cell line derived from these cells proliferate in response to stimulating strains of H. pylori . T cells from the spleen of one of the patients do not share this property. These results suggest that B-cell proliferation in cases of low-grade gastric lymphoma of MALT type in vitro in response to H. pylori is due to recognition of H. pylori by tumour-infiltrating T cells, which in turn provide help for tumour cell proliferation. The observations provide an explanation for properties of gastric MALT-type lymphoma, such as regression following eradication of H. pylori and the tendency of the tumour to remain localized to the primary site.     

Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta‐analysis

Summary. Background: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease.Objectives: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence‐based guidelines.Patients/Methods: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least 3 months of follow‐up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model.Results: Four thousand four hundred and forty‐two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83–1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61–1.75). Minor bleeding, from a 1748‐patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13–2.00).Conclusions: This meta‐analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.     

EFFECT OF CORTISOL TREATMENT ON HORMONAL RELATIONSHIPS IN CONGENITAL ADRENAL HYPERPLASIA

The temporal relationship between administration of cortisol and serum 17α-hydroxyprogesterone was investigated in five patients aged 9-19 years with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. There was marked variability in the 17α-hydroxyprogesterone response (determined hourly for 24 h) of individual patients to administration of cortisol. Mean concentration was less than 0.030 μmol/l in one patient but 0.519μ mol/l in another. Levels were higher in all patients while off treatment, and were greatest in those with salt-losing adrenal hyperplasia. Growth hormone secretion was not suppressed by treatment with cortisol. Withdrawal of cortisol for 3 days resulted in a significant decrease in the mean serum FSH/LH ratio and a rise in serum testosterone in all subjects. Episodic release of gonadotrophins persisted in the adolescent patients.