Hemopoietic Disorders Research Articles

Induction of myeloid leukaemia by whole-body single exposure of CBA male mice to x-rays

A curvilinear dose response of myeloid leukaemia induction in the CBA male mouse was obtained after single whole-body X-irradiation at about 3 months of age. This strain has a very low spontaneous incidence of the disease and no cases were found in the unirradiated controls. The incidence was independent of dose rate over the range used (4.2-552 rad/min). Diagnosis required histopathological examination of various body tissues, the gross anatomical changes being easily confused with other haemopoietic disorders, but a few cases were recognized in life from blood samples. Curve-fitting to various models based on theories of radiocarcinogenic mechanism is described.

Separation of Functionally Distinct Human Granulocyte-Macrophage Colony-Stimulating Factors

AbstractHuman placental conditioned medium (HPCM) contains colony-stimulating factors (CSFs) required for the growth in vitro of neutrophilic granulocyte-macrophage (GM) and eosinophilic (EO) progenitor cells from human bone marrow. Fractionation of CSFs in HPCM was achieved by manipulation of the elution conditions on a column of phenyl-Sepharose. After equilibration of the phenyl-Sepharose column at high ionic strength (1M ammonium sulfate), all of the CSF bound; one species of GM-CSF (α) and all of the elutable EO-CSF were eluted from the column simply by reducing the salt concentration, whereas the second species of GM-CSF (β) was free of EO-CSF and was eluted only by increasing the concentration of ethylene glycol in the elution buffer. The two GM-CSFs were functionally distinct. GM-CSFα preferentially stimulated colony formation by day 14 of culture, and there was a decreased proportion of neutrophil colonies and increased proportion of macrophage colonies as the strength of the stimulus was decreased; GM-CSFβ, on the other hand, preferentially stimulated colony formation by day 7 of culture, and the proportion of neutrophil colonies was high (average 80%) and independent of the concentration of GM-CSFβ. GM-CSFα and GM-CSFβ were indistinguishable on the basis of apparent molecular size on gel filtration columns (molecular weight 30,000), charge properties on isoelectric focusing beds (isoelectric point, 4.9), and were not related to each other as a sialoglycoprotein is related to its asialo form. Adherent cell removal of the target bone marrow cells (to remove colony-stimulating cells) suggested that both GM-CSFs acted directly rather than by stimulating the production of GM-CSF. Mixing and titration experiments indicated that the differences in functional specificities of the two GM-CSFs (and the lack of EO-CSF associated with GM-CSFβ) were not due to the presence of specific inhibitory molecules or lower absolute levels of CSF in one fraction relative to the other. These two species of GM-CSF should be useful in separately enumerating subpopulations of different GM-progenitor cells in human hemopoietic disorders.

Separation of functionally distinct human granulocyte-macrophage colony- stimulating factors

Human placental conditioned medium (HPCM) contans colony-stimulating factors (CSFs) required for the growth in vitro of neutrophilic granulocyte-macrophage (GM) and eosinophilic (EO) progenitor cells from human bone marrow. Fractionation of CSFs in HPCM was achieved by manipulation of the elution conditions on a column of phenyl-Sepharose. After equilibration of the phenyl-Sepharose column at high ionic strength (1 M ammonium sulfate), all of the CSF bound; one species of GM-CSF (alpha) and all of the elutable EO-CSF were eluted from the column simply by reducing the salt concentration, whereas the second species of GM-CSF (beta) was free of EO-CSF and was eluted only by increasing the concentration of tehylene glycol in the elution buffer. The two GM-CSFs were functionally distinct. GM-CSF alpha preferentially stimulated colony formation by day 14 of culture, and there was a decreased proportion of neutrophil colonies and increased proportion of macrophage colonies as the strength of the stimulus was decreased; GM- CSF beta, on the other hand, preferentially stimulated colony formation by day 7 of culture, and the proportion of neutrophil colonies was high (average 80%) and independent of the concentration of GM-CSF beta. GM- CSF alpha and GM-CSF beta were indistinguishable on the basis of apparent molecular size on tel filtration columns (molecular weight 30,000), charge properties on isoelectric focusing beds (isoelectric point, 4.9), and were not related to each other as a sialoglycoprotein is related to its asialo form. Adherent cell removal of the target bone marrow cells (to remove colony-stimulating cells) suggested that both GM-CSFs acted directly rather than by stimulating the production of GM- CSF. Mixing and titration experiments indicated that the differences in functional specificities of the two GM-CSFs (and the lack of EO-CSF associated with GM-CSF beta) were not due to the presence of specific inhibitory molecules or lower absolute levels of CSF in one fraction relative to the other. These two species of GM-CSF should be useful in separately enumerating subpopulations of different GM-progenitor cells inhuman hemopoietic disorders.

Phenotypic characterisation of a unique non-T, non-B acute lymphoblastic leukaemia cell line

MANY human lymphoblastoid cell lines have been established from subjects with different haemopoietic disorders as well as from normal individuals1–3. In most cases the inability to identify the precise origin of cells which have been established has limited the usefulness of these lines, especially those derived from leukaemic donors. Although there are a few important exceptions to this generalisation (2, 3, 4 and see below) it is significant that no lines have been established from the common form of acute lymphoblastic leukaemia (ALL) which is usually referred to as ‘null’ cell or ‘non-T, non-B’ ALL (refs 5–7). We describe here the establishment of a lymphoid cell line, Reh, derived from an acute lymphocytic leukaemia where the leukaemic identity of established cells is supported by kinetic data, chromosome markers and detection of leukaemia associated antigens and enzymes.

Chronic myeloid leukemia: physical and functional similarities to acute leukemia

Blast crisis, closely resembling acute leukemia, is the usual terminal event in chronic myeloid leukemia. Using physical (“fingerprint”) and cultural (colony-forming) methods, we have demonstrated distinctive patterns in the stable phase of chronic myeloid leukemia and in blast crisis. An unusual fingerprint alteration preceding the onset of the terminal phase is noted, and cell culture perturbation is evident at different stages of the disease. Our findings indicate that the application of these methods to the study of hemopoietic disorders is valid, and suggest that the use of such techniques may allow a better understanding of the complex cellular events occurring in the course of chronic myeloid leukemia.

Chronic Myeloid Leukemia: Physical and Functional Similarities to Acute Leukemia

Blast crisis, closely resembling acute leukemia, is the usual terminal event in chronic myeloid leukemia. Using physical ("fingerprint") and cultural (colony-forming) methods, we have demonstrated distinctive patterns in the stable phase of chronic myeloid leukemia and in blast crisis. An unusual fingerprint alteration preceding the onset of the terminal phase is noted, and cell culture perturbation is evident at different stages of the disease. Our findings indicate that the application of these methods to the study of hemopoietic disorders is valid, and suggest that the use of such techniques may allow a better understanding of the complex cellular events occurring in the course of chronic myeloid leukemia.

The Clinical Features of Chronic Granulocytic Leukaemia

SUMMARY Some textbook descriptions seem to imply that the symptoms, physical signs and haematological findings in patients with CGL conform to a stereotype. Although many patients do in fact correspond to the textbook picture, there are less common presentations and some thoroughly atypical presentations. The ability to establish the diagnosis of CGL by cytogenetic studies has demonstrated that some new cases have haematological features which do not even remotely resemble the classical stereotype. In CGL more than in any other neoplasm, there is a very high response rate to a single treatment (busulphan) and, during the chronic phase of the disease, treated patients are notable for their almost uniform good health and normal haematological values. However, even here, patients vary in the degree to which they manifest the adverse effects of therapy; complications vary from undetectable to crippling and even lethal. When CGL departs from its chronic phase, the number of clinical and haematological pictures which may develop is apparently limitless. The older descriptions of ‘blastic crisis’ encompassed but one end of a remarkable spectrum of acute, subacute and chronic haemopoietic disorders. At this stage of its evolution, CGL may mimic any of the myeloproliferative disorders, most of the acute leukaemias, and even the malignant lymphomas. Thus what may appear on first acquaintance to be a relatively straightforward disease has so many subtleties that as experience increases, the physician’s feeling of familiarity with CGL tends to diminish rather than increase.

Social class and morbidity in clinically treated alcoholics

The lifetime physical disease profiles of 122 lower and 724 middle class non-skid row alcoholics admitted to an inpatient treatment facility were compared to further clarify the significance of social class as a determinant of morbidity in alcoholics. The overall severity of physical disease and the frequency of all recorded lifetime illness diagnoses were greater in the lower than in the middle class. The former experienced more trauma, genitourinary disorders, venereal disease and malnutrition, as well as small excesses of respiratory and nervous system disorders. There were no class differences in the lifetime frequencies of liver and biliary tract, gastrointestinal, cardiovascular, endocrine and metabolic, integumentary, locomotor and haemopoietic disorders, or in the incidences of a number of disease entities including acute brain syndromes and chronic brain damage. The drinking patterns of the classes were similar, but the average duration of hazardous drinking was longer and the average current consumption was greater in the lower class. There were no class differences, however, in the average duration of hazardous drinking before the first occurrence of certain diseases. The referral sources of the classes were significantly different. Possible explanations for the differences between the findings of this and earlier studies are discussed.

In Vitro Regulation of Granulopoiesis in Human Leukemia: Application of an Assay for Colony-inhibiting Cells

We describe two assays to detect the action of colony-inhibiting cells. In the first assay, we used a simple density separation technique to remove dense neutrophils (PMN) from suspensions of blood and of bone marrow cells prior to culture in semisolid agar. Conditions were arranged to ensure that control suspensions of unseparated cells and test suspensions of buoyant mononuclear cells differed only in their content of neutrophils. The control and test suspensions contained equal numbers of mononuclear cells (and granulocyte precursors). Colony (and cluster) formation was invariably enhanced in neutrophil-depleted cultures of normal cells. In the second assay, dense PMN, treated by an adherence separation procedure, were recovered, and the non-adherent dense PMN were added back to PMN-depleted cultures. A reproducible dose-related decrease in colony (and cluster) formation to basal levels resulted. The inhibitory effect was identical when the PMN were added directly to the culture (overlayer) or to the underlayer. In PMN-depleted cultures obtained from patients with leukemia and other hemopoietic disorders, neither colony nor cluster formation was enhanced, and sometimes it was reduced. When we compared the effect of adding patient and normal non-adherent PMN to target cultures of normal and patient PMN-depleted cells, some leukemic PMN were noninhibitory. Our results suggest that abnormalities of cellular interactions in vitro detected in the first assay may have more than one explanation, as shown when they are subjected to the closer scrutiny possible with the second assay.

In vitro regulation of granulopoiesis in human leukemia: application of an assay for colony-inhibiting cells

We describe two assays to detect the action of colony-inhibiting cells. In the first assay, we used a simple density separation technique to remove dense neutrophils (PMN) from suspensions of blood and of bone marrow cells prior to culture in semisolid agar. Conditions were arranged to ensure that control suspensions of unseparated cells and test suspensions of buoyant mononuclear cells differed only in their content of neutrophils. The control and test suspensions contained equal numbers of mononuclear cells (and granulocyte precursors). Colony (and cluster) formation was invariably enhanced in neutrophil-depleted cultures of normal cells. In the second assay, dense PMN, treated by an adherence separation procedure, were recovered, and the non-adherent dense PMN were added back to PMN-depleted cultures. A reproducible dose- related decrease in colony (and cluster) formation to basal levels resulted. The inhibitory effect was identical when the PMN were added directly to the culture (overlayer) or to the underlayer. In PMN- depleted cultures obtained from patients with leukemia and other hemopoietic disorders, neither colony nor cluster formation was enhanced, and sometimes it was reduced. When we compared the effect of adding patient and normal non-adherent PMN to target cultures of normal and patient PMN-depleted cells, some leukemic PMN were noninhibitory. Our results suggest that abnormalities of cellular interactions in vitro detected in the first assay may have more than one explanation, as shown when they are subjected to the closer scrutiny possible with the second assay.

Vincristine therapy in malignant glioma recurrencies.

Nine patients were exposed to intravenous Vincristine sulphate therapy because of malignant glioma (glioblastoma, medulloblastoma) relapses. VCR was administered in single doses of 0.02 to 0.05 mg/kg and in a total amount of 11–22 mg. In the major part of the patients the repeated application of radiotherapy and of other chemotherapeutical agents previously used was contraindicated before the onset of VCR therapy. Irreversible toxic effect did not occur and haemopoietic disorders were not developing in the course of the therapy. The neurotoxicity recorded manifested primarily in loss of reflexes.

HAEMOPOIETIC DEFECTS IN MICE INFECTED WITH LYMPHOCYTIC CHORIOMENINGITIS VIRUS

In the preceding report (3) experiments were described which suggested the occurrence of haemopoietic disorders in mice infected with the LCM virus. Immunological disorders associated with the LCM virus infections of mice are well‐known. It was considered that both haemopoietic and immunological defects might be caused by some virus‐induced interference with the stem cells in the infected mice. Attempts were therefore made to estimate the numbers and the function of stem cells in mice infected with the LCM virus. Haemopoietic colony assays were employed, and both acutely infected mice and persistent, tolerant virus carriers were examined. The findings suggested a decrease in colony‐forming stem cells in the bone marrow during the acute infection. However, the most striking observation in the acutely infected mice was of a profound inhibition of the colony‐forming response of stem cells in these animals. The influences exerted upon the stem cell response seemed to be quite specific, in that the response of immunocompetent cells was almost unimpaired when examined at the same time. The inhibition was not caused by a direct viral effect upon the stem cells, nor by any immune‐mediated damage. Experiments with the adult, persistent, tolerant virus carriers indicated that the haemopoietic colony formation was not inhibited in these mice despite a pronounced viraemia. However, their numbers of colony‐forming stem cells amounted to about fifty per cent of the normal values and seemed to agree with their relative increase in sensitivity to X‐rays. It is suggested that virus‐induced interference with the function of haemopoietic stem cells plays a central role for the tolerogen effects of the LCM virus.

Haemopoietic defects in mice infected with lymphocytic choriomeningitis virus. 1. The enhanced x-ray sensitivity of virus infected mice.

Seemingly paradoxical observations were made with mice exposed to infections with the LCM virus and treatment with X‐rays. The X‐irradiation could afford a beneficial effect upon the cource of the viral infection or cause a serious aggravation. The beneficial effect was associated with X‐ray treatment given prior to the inoculation of virus. This pre‐irradiation effectively prevented an antiviral immune response and protected mice against lethal intracerebral challenges with the virus. However, doses of X‐rays which were sublethal for normal mice provoked a lethal disease when given to mice previously inoculated with the virus. Fatal outcomes were observed with persistent, tolerant virus carriers and with i. p. infected adult mice, that is, in cases of normally inapparent LCM virus infections. The X‐ray induced deaths were apparently not related to any enhanced growth of the virus in the irradiated mice. Clinical findings and reconstitution experiments strongly indicated that the striking increase in the sensitivity to X‐rays was caused by a haemopoietic defect in the LCM virus infected mice. The nature of this haemopoietic disorder is not readily explained. Thus several observations made it unlikely that the LCM virus had any direct damaging effect upon the haemopoietic cells. Moreover, the findings with the persistent, tolerant virus carriers provided evidence against any immunopathological basis of the disorder.

Diagnostic value of the serum lysozyme (Muramidase) level

Serum lysozyme concentrations were assayed in a variety of haemopoietic disorders. Abnormal lysozyme levels were found to be associated with disorders of specific haemopoietic cell lines, and the investigation was directed particularly toward evaluating the usefulness of the enzyme level in the diagnosis of marrow dyscrasias where diagnosis on morphological grounds was in doubt, such as in the 'preleukaemic' state. Chronic myeloid leukaemia and myelofibrosis were both found to be associated with elevated serum lysozyme levels (30-120 μg./ml.). This occurred in myelofibrosis despite peripheral pancytopenia, suggesting that ineffective myelopoiesis might occur in this condition. Cytologically distinct myelomonocytic leukaemias were associated with high levels of lysozyme (164-180 μg./ml.); however, several cases of acute leukaemia with predominantly myeloblastic or promyelocytic features had significantly elevated levels. Therefore leukaemias with increased lysozyme were not restricted to one morphological category. Enzyme levels in these patients accurately reflected the response of the leukaemic marrow infiltration to therapy and provided a more reliable index of progress than peripheral blood examination. Monocytosis in bacterial infections produced marginally elevated lysozyme levels which were thus considerably lower than in leukaemic states. Despite the marked monocytosis in infectious mononucleosis the level was less than in bacterial infections. The assay was of value in certain cases of marrow dyscrasia as an early index of leukaemic transformation. While enzyme levels were normal in uncomplicated refractory sideroblastic anaemia, in 3 cases elevated serum lysozyme heralded the onset of overt myelomonocytic leukaemia or a myeloproliferative disorder with a leukaemoid peripheral blood picture.

The occurrence of the i antigenand elevated fetal hemoglobin in hemopoietic disorders

The occurrence of the i antigenand elevated fetal hemoglobin in hemopoietic disorders

Morphology of hemopoiesis in the human embryo in comparison with postfetal hemopoietic disorders

Morphology of hemopoiesis in the human embryo in comparison with postfetal hemopoietic disorders

Eunuchoid Habitus Associated with Sickle-Cell Anemia and the Sickling Trait

HEMATOLOGIC interest in sickle-cell anemia and the sickling trait has offered an opportunity to examine and study numerous subjects of this peculiar hemopoietic disorder. Since its recognition by Herrick in 1910, considerable clinical evidence has been recorded appertaining to its hemopathology and its associated bone changes. Little if any recognition, however, has been accorded the abnormal statural configuration of its subjects, which feature will be discussed in this report. Data on the statural characteristics of 32 Afro-American subjects are cited, 30 of whom had sickle-cell anemia. Of the remaining two, one showed the sickling trait only and another had an anemia without the sickling phenomenon but is included because of consanguinity to one of the patients in the sickle-cell anemia series. In only eight instances was it possible to examine other members of the patients' family. Since this number of families would be statistically insignificant, likewise a statistic on familial incidence of either the sickling phenomenon or any other coexistent anomaly would be vitiated.

Book Reviews

Book Reviews The Medals of the United States Army Medical Department and Medals Honoring Army Medical Officers. By Edgar Erskine Hume. The American Numismatic Society. New York. 1942Clinical Hematology. By Maxwell M. Wintrobe, M.D., Ph.D. Associate in Medicine, Johns Hopkins University; Associate Physician, Johns Hopkins Hospital; and Physician-in-Charge, Clinic for Nutritional, Gastro-Intestinal and Hemopoietic Disorders, Baltimore, Maryland. 792 pages with 167 engravings and 7 colored plates. Philadelphia: Lea & Febiger, 1942. Price $10.00.ÉTudes Sur Les Amputations Et Desarticulations Les Membres. By P. Huard. Surgeon to Colonial Forces, Professor of Anatomy and Operative Surgery at the Superior School of Medicine of Indo-China; National Associate of the Academy of Surgery. Paper cover. Pp. 686. Paris: Masson & Cie. —Hanoi, French Indo-China. G. Tau-pin & Cie. 1940.Encephalitis, A Clinical Study. By Josephine B. Neal, M.D. New York: Grime and Stratton, 1942. Pp. 521.Diseases of Women. 9th Edition. By Harry Sturgeon Crossen, M.D., F.A.C.S. and Robert James Crossen, A.B., M.D., St. Louis, Mo.: The C. V. Mosby Company, Price $12.50.The Delaware Continentals, 1776–1783. By Christopher L. Ward. Wilmington: Historical Society of Delaware. Price $3.75.Roentgen Diagnosis of the Extremities and Spine (enlarged first edition), Annals of Roentgenology—Vol. 17, by Albert B. Ferguson, M.D., formerly Director of Roentgenology, N. Y. Orthopedic Hospital and Instructor in Orthopedic Surgery, College of Physicians and Surgeons, Columbia University. 462 pages, 560 figures, Paul B. Hoeber, Inc., N.Y., Price $12.00.Synopsis of the Preparation and Aftercare of Surgical Patients. By Hugh C. Ilgenfritz, A.B., M.D. Instructor in Surgery, Louisiana State University School of Medicine; Visiting Surgeon, Charity Hospital of Louisiana at New Orleans. And Rawley M. Penick, Jr., Ph.B., M.D., F.A.C.S. Professor of Clinical Surgery, Louisiana State University School of Medicine; Visiting Surgeon, Charity Hospital of Louisiana at New Orleans. With Foreword by Urban Maes, M.D., D.Sc., F.A.C.S. Professor of Surgery and Director of the Department, Louisiana State University School of Medicine; Senior Visiting Surgeon, Charity Hospital of Louisiana at New Orleans; Consulting Surgeon, Touro Infirmary. 532 pages. The C. V. Mosby Company. St. Louis, Missouri. 1941. Price $5.00.The 1941 Year Book of Industrial and Orthopedic Surgery. Edited by Charles F. Painter, M.D., Orthopedic Surgeon to the Massachusetts Women's Hospital and Beth Israel Hospital, Boston. The Year Book Publishers, Inc., Chicago, 1941. 432 pages with 353 figures, $3.Nutritional Deficiencies. By John B. Youmans, A.B., M.S., M.D. Philadelphia: J. B. Lippincott Co. 1941. Price $5.00.Textbook of Clinical Parasitology. By David L. Belding. New York: D. Appleton-Century Co., Inc., 890 pp. 1942. $8.50.Diseases of the Skin (fourth edition, 1942). By Frank Crozer Knowles, M.D., Edward F. Corson, M.D., and Henry B. Decker, M.D., Philadelphia, Pa.: Lea and Febiger. Price $7.00.Army Posts and Towns. By Charles J. Sullivan. New Edition. Los Angeles, California: Haynes Corporation. Price $3.00.Handbook of Anaesthetics. By Ross and Fairlie, 5th Edition, 1940, a William Wood Book, Williams & Wilkins, Baltimore, Maryland. Three hundred and sixtyfour pages and one hundred and four illustrations. Revised by R. J. Minnitt, Trinity College, Cambridge, M.D. (Liverpool), D.A. (R.C.P. & S. England) Lecturer in Anaesthesia, University of Liverpool; Director of Anaesthetics, David Lewis Northern Hospital, Liverpool; Honorary, Anaesthetist, Liverpool Royal Infirmary and Liverpool Maternity Hospital. Price $4.00, Cloth bound. James M. Phalen, James M. Phalen Search for other works by this author on: Oxford Academic Google Scholar Hugh R. Gilmore, Jr., Hugh R. Gilmore, Jr. Search for other works by this author on: Oxford Academic Google Scholar G. M. Blech, G. M. Blech Search for other works by this author on: Oxford Academic Google Scholar J. M. Caldwell, Jr., J. M. Caldwell, Jr. Search for other works by this author on: Oxford Academic Google Scholar P. E. Duggins, P. E. Duggins Search for other works by this author on: Oxford Academic Google Scholar A. A. de Lorimier, A. A. de Lorimier Search for other works by this author on: Oxford Academic Google Scholar James H. Forsee, James H. Forsee Search for other works by this author on: Oxford Academic Google Scholar E. A. Coates, Jr., E. A. Coates, Jr. Search for other works by this author on: Oxford Academic Google Scholar H. P. Marvin, H. P. Marvin Search for other works by this author on: Oxford Academic Google Scholar Alfred Golden, Alfred Golden Search for other works by this author on: Oxford Academic Google Scholar ... Show more J. C. Kimbrough, J. C. Kimbrough Search for other works by this author on: Oxford Academic Google Scholar C. L. Baird C. L. Baird Search for other works by this author on: Oxford Academic Google Scholar The Military Surgeon, Volume 91, Issue 4, October 1942, Pages 491–498, https://doi.org/10.1093/milmed/91.4.491a Published: 01 October 1942