A method of clinical staging of chronic lymphocytic leukemia (CLL) has been proposed which is based on the concept that CLL is a disease of progressive accumulation of nonfunctioning lymphocytes: stage O, bone marrow and blood lymphocytosis only; stage 1, lymphocytosis with enlarged nodes; stage II, lymphocytosis with enlarged spleen or liver or both; stage III, lymphocytosis with anemia; and stage IV:lymphocytosis with thrombocytopenia. Analysis of 125 patients. in the present series showed the following median survival times (in months) from diagnosis: stage 0, is greater than 150; stage I 101; stage II, 71; stage III, 19; stage IV, 19, The median survival for the entire series was 71 mo. The prognostic significance of the stage remained even after adjustment was made for age and sex. However, both sex and age were shown to be poor predictors of survival after adjustment for stage. The method of staging proved to be a reliable predictor of survival whether used at diagnosis or during the course of the disease. The proposed staging system was an equally accurate indicator for survival when applied to two other previously published studies of large series of patients.

The turnover of DNA and histones in the livers and brains of mice has been determined. These mice had been exposed to constant levels of tritiated water from conception until they were 8 months old. At this point, exposure to tritium was discontinued, and the tritium remaining in DNA and histones was measured at various intervals afterward. The half-lives calculated for these components (with 95% confidence limits given in parentheses) were 117 (85-188) days for liver histone, 318 (241-466) days for liver DNA, It is generally agreed that histone synthesis is closely coupled to DNA synthesis in somatic cells and that the turnover of histones within a tissue is very slow compared to that of other nuclear or cytoplasmic proteins (1, 2). Whether this slow tissue turnover is solely due to cell turnover within the tissue or is in part due to histone turnover within intact cells is at present controversial. Piha et al (3) measured the rate of loss of label from brain and liver histones of mice given '4C-labeled lysine in embryo and concluded that all of the observed histone turnover could be accounted for by cell turnover. On the other hand, Hempel et al (4) measured the rate of incorporation of 3H-labeled methionine into the histones of the adult cat kidney and concluded that histone turnover was rapid and almost entirely due to turnover within the living cell.At the heart ofthis controversy is the magnitude ofcell turnover in these tissues. Piha et aL (3) estimated cell turnover from DNA turnover reported by others. Hempel et al. (4) considered cell turnover in the adult cat kidney to be negligible because very few labeled cells were seen in autoradiographs of these tissues taken after injection of tritiated thymidine. However, values for DNA turnover reported in the literature are not reliable. They are based on relatively few measurements and vary by orders of magnitude. The finding of negligible cell proliferation in adult cat kidneys conflicts with findings of significant incorporation ofDNA precursors in adult mouse kidneys (5) and suggests that the autoradiographic findings might be artifacts.The question ofwhether there is histone turnover within the living cell has important implications relating to the stability of the nucleosome, the basic unit of organization of DNA and histone within the chromosome. Complete lack ofturnover implies that the nucleosome is rigid and inert, whereas significant turnover suggests a flexible, dynamic structure. To help resolve this question, we have determined the rate ofboth histone and DNA turnover in mouse brain and liver. These measurements were made on mice that had been exposed to constant levels of tritiated water from conception until 8 months old. They are based on the rate of loss of tritium from DNA and histones after discontinuing exposure of these mice to tritiated water. MATERIALS AND METHODSThe procedures used here have been described in detail elsewhere (6). Mice were obtained from litters born to parents maintained on tritiated drinking water (3.0 ,AC...

The distribution of tritium among the amino acids of serum proteins in mice chronically exposed to tritiated water was determined by ion exchange chromatography of the protein hydrolysate. The specific activity of nonexchangeable tritium in these amino acids relative to the specific activity of tritium in the tissue water of mice ranged from 0.04 for phenylalanine and threonine to 1.0 for glycine and alanine. Since tritium from tissue water can enter the nonexchangeable positions of amino acids only as the result of metabolic processing, the relative specific activity of tritium in each amino acid is an indicator of the extent of such processing. The tritium content of tyrosine and all the amino acids required in the diet for survival is quite low, except for histidine, and can be entirely accounted for by transamination or, in the case of methionine, by transmethylation. The tritium content of the other amino acids is too high to result from such minor processing and must reflect primarily the fraction synthesized de novo. The implications of these findings with respect to the radiobiological consequences of a diet containing tritiated proteins are discussed.

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1. Following administration of H3-thymidine to 15 patients with a variety of hemopoietic conditions, the emergence and the pattern of labeling of neutrophilic granulocytes were studied in peripheral blood leukocytic concentrates. The hematologic diagnosis included five in which the hemopoiesis appeared to be in a steady state equilibrium at the time of study, three with various types of leukemia, one with lymphosarcoma, two with multiple myeloma, one with myelofibrosis, two with pernicious anemia (once before and once after therapy) and two with bacterial infections. 2. The emergence time of neutrophilic segmented granulocytes (time from H3-thymidine injection to the first appearance of labeled segmented forms in the peripheral blood) was found to vary in steady state equilibrium from 96 to 144 hours. It was shortened to 48 hours in two instances with bacterial infection. This was interpreted as indicating a faster than normal nuclear maturation with normal or delayed cytoplasmic maturation (dissociation in nuclear and cytoplasmic maturation). 3. The number of segments of neutrophilic granulocytes was found to be unrelated to cell age as had been hypothesized by Arneth many years ago. However, bandforms were found in the circulation about 24 hours earlier than segmented forms, suggesting that they are younger and that some are acceptable to the blood while others continue to mature to segmented forms. Pelgeroid cells with round or bilobed nuclei found in one case of subleukemic myelocytic leukemia were found to emerge simultaneously 132 hours after H3-thymidine injection. This suggests that both types are identical in their degree of maturation. Thus the cells with round nuclei are not band forms but result possibly from a delayed nuclear maturation. 4. In patients studied for at least 2 weeks, characteristic undulations of the labeling indices of the segmented granulocytes were found. If the sampling intervals were 24 hours, peaks were found 6 days apart, the second peak being about half of the labeling index of the first. If the sample interval was shorter, a finer structure was observed with undulations showing peak intervals of 2-3 days. Although the significance is obscure at present, the constancy of the findings suggest that there may be a constant input of cells with the index of labeling varying due to some synchrony of the precursor population(s). Alternative explanations are discussed.