Normal cellular counterparts of B cell chronic lymphocytic leukemia

In an attempt to compare B cell chronic lymphocytic leukemia (B-CLL) with its normal cellular counterpart, the cell surface phenotype of 100 cases of B-CLL was determined by using a panel of monoclonal antibodies (MoAbs) directed against B cell-restricted and -associated antigens. The majority of B-CLL cells expressed Ia, B4 (CD19), B1 (CD20), B2 (CD21), surface immunoglobulin (sIg), and T1 (CD5) but lacked C3b (CD35) receptors. In contrast, the overwhelming majority of small unstimulated B cells expressed Ia, B4, B1, B2, sIg, and C3b receptors but lacked detectable T1. Small numbers of weakly sIg+ cells could be identified in peripheral blood and tonsil that coexpressed the B1 and T1 antigens. Approximately 16% of fetal splenocytes coexpressed B1, T1, weak sIg, B2, and Ia but lacked C3b receptors and therefore closely resembled most B-CLL cells. With the phenotypic differences between the majority of small unstimulated B cells and B-CLL cells, we examined normal in vitro activated B cells and B-CLL cells for the expression of B cell-restricted and -associated activation antigens. Of 20 cases examined, virtually all expressed B5, and approximately 50% of the cases expressed interleukin-2 receptors (IL-2R) and Blast-1. Normal B cells were activated with either anti-Ig or 12-0-tetradecanoylphorbol- beta-acetate (TPA) and then were examined for coexpression of B1, T1, and the B cell activation antigens B5 and IL-2R. Only cells activated with TPA coexpressed B1 and T1 as well as B5 and IL-2R. B cells activated with either anti-Ig or TPA proliferated in the presence of IL- 2, whereas B-CLL cells did not, although they all expressed the identical 60-kilodalton proteins by immunoprecipitation. These studies are consistent with the notion that B-CLL resembles several minor subpopulations of normal B cells including a population of B cells that are activated in vitro directly through the protein kinase C pathway.     

Immunologic heterogeneity of diffuse large cell lymphoma

The cellular lineage of 57 diffuse large-cell lymphomas (DLCLs) was determined using a panel of monoclonal antibodies directed against lineage-restricted and -associated T, B, and monocyte antigens. The majority (82%) were of B cell lineage as determined by the expression of sig and/or B1, with the remaining 16% being of T cell lineage and 2%, of monocyte-myeloid lineage. By the expression of other B cell- restricted and -associated antigens, two major and two minor subgroups could be identified. These subgroups expressed the following phenotypes: (1) B1+B4+sIG+B2- (51%); (2) B1+B4+sIg+B2+ (29%); (3) B1+B4+sIg-B2+ (10%); and (4) B1+B4-sIg+B2- (10)%. The morphology of transformed lymphocytes, the weak to absent expression of the early B cell antigens B2 and sIgD, and the absence of the late B cell differentiation antigens PCA-1 and PC-1 suggested that these tumors were the neoplastic counterparts of normal B cells at the mid-stages of differentiation. Further support for the notion that B-DLCLs correspond to transformed B lymphocytes was concluded from the observation that B cells could be identified in normal spleen that expressed the cell surface phenotype and morphological appearance of the majority of B- DLCLs.     

Colony-forming cell proliferation: a rapid and sensitive assay system for murine granulocyte and macrophage colony-stimulating factors

A microculture assay for murine granulocyte-macrophage colony- stimulating factor (GM-CSF) has been developed using fetal liver GM colony-forming cells (CFC) isolated by fluorescence-activated cell sorting. These GM-CFC are free of mature hemopoietic cells, such as granulocytes and macrophages, which may interfere with direct assays for GM-CSF. The assay procedure allows the quantitation of GM-CSF within 48 hr by measuring the number of cells produced from 50 GM-CFC in microcultures (15 microliter). The assay is particularly simple to set up and score and yet, because of the reduced volumes, this assay is still capable of detecting 0.2 pg (i.e., 0.2 U) of GM-CSF within 48 hr, i.e., 100 times less GM-CSF than the conventional soft agar assay. By allowing the microcultures to develop for 7 days, the extra proliferation allows a further tenfold increase in the sensitivity of CSF detection. The time and cost of setting up hundreds of GM-CSF assays for fractions from chromatographic columns, e.g., reverse phase high performance liquid chromatography, is reduced by at least five- fold. Enough GM-CFC can be isolated and stored frozen in one afternoon to provide sufficient cells for the daily assay of 200 samples of GM- CSF for several months. Microassay results for several sources of GM- CSF at different stages of purification are compared to the results obtained from the soft agar assay.     

Early life and later determinants of adult disease: a 50 year follow-up study of the Newcastle Thousand Families cohort

The relative contribution of socioeconomic, behavioural and biological factors operating in fetal and infant life, childhood and adulthood to risk for cardiovascular disease, respiratory diseases and non-insulin-dependent diabetes in middle age has become an important research issue. All 1142 babies born in Newcastle upon Tyne in May and June 1947 were recruited into a prospective cohort study of child health (the ‘Thousand Families’ study) and followed in great detail to the age of 15 y, with a brief further follow up at age 22 y. Children from poorer families were at greatest risk of severe respiratory tract infection in infancy. Children from professional and managerial families were on average taller and heavier throughout childhood than those from semi- and unskilled manual social classes. Repeated infections in early childhood greatly increased the risk of developing chronic respiratory disease by age 15 y. This paper outlines a new investigation designed to trace surviving members of this cohort and to chart the relationships between their socioeconomic circumstances, lifestyles, experiences and health from birth through to the present day. Existing data on socioeconomic circumstances and infections in infancy and childhood, infant nutrition, birthweight and physical development to age 22 y will be linked to information gained from a new study. This comprises a postal questionnaire survey of study members' adult health, socioeconomic circumstances and lifestyle, and a hospital based clinical examination including heart and lung function, glucose tolerance, blood lipids and anthropometric measurements at age 49–51 y. Out of a target sample of 979 people for whom sufficient data are available on the first year of life, 866 (88%) have been traced and 649 are still resident in the North of England. Those study members who have been traced are highly representative of the original cohort. The Thousand Families cohort provides a unique opportunity for detailed epidemiological study because of the wealth of data available on infant and childhood socioeconomic and family circumstances, all of which was collected prospectively. In addition, there has been comparatively little loss to follow-up since 1948.     

Structure-activity relationships of antineoplastic agents in multidrug resistance

Clinical resistance to many antineoplastic agents is a major cause of treatment failure. The well-documented phenomenon addressed as multidrug resistance (MDR) allows cells to withstand exposure to lethal doses of drugs with dissimilar chemical structures, modes of action, and physicochemical properties. In one of the earliest studies on MDR, Biedler and Riehm in an attempt to explain the cross-resistance profile of actinomycin D resistant Chinese hamster cells suggested that molecular weight was an important determinant. Our statistical analysis of their data validates their claim and indeed strongly demonstrates that cross resistance is enhanced by the increased size and hydrophobicity of the antitumor agent. Our preliminary studies with methotrexate-resistant L1210 cells indicates that cross resistance is increased in the case of moderate-sized, hydrophilic drugs. These two studies and others suggest that current chemotherapy regimens may be improved by treating resistant cells with antineoplastic agents displaying physicochemical characteristics opposite to that of the original inducing agent.     

Superficial- and deep-tissue temperature increases in anesthetized dogs during exposure to high specific absorption rates in a 1.5-T MR imager

Superficial- and deep-tissue heating was measured in five dogs during high-specific-absorption-rate radiofrequency (RF) irradiation to see whether significant temperature changes could be produced by a 1.5-T clinical magnetic resonance imager. The RF power output employed was 6.3 times that required for routine imaging. Temperature probes were placed in both deep and superficial tissues, and temperatures were recorded before, during, and after exposure. In each dog, there was a linear temperature increase of several degrees during RF exposure; the maximal average change was 4.6 degrees C in the urinary bladder. The temperature increase was slightly greater in deep tissues than in superficial tissues. The calculated specific absorption rate, based on the temperature change, averaged 7.9 W/kg for all five dogs. These findings argue for continued caution in the design and operation of imagers capable of high specific absorption rates, particularly when they are used for imaging infants or patients with altered thermoregulatory capability.