ALBERT

Description: 1. Further studies contrasting the effect of varying doses of 4-amino-N10-methyl-PGA on a resistant variant (Ak4R) of transplanted mouse leukemia Ak4 have been reported. 2. The usual therapeutic dosage of 4-amino-N10-methyl-PGA prevented the increase in total leukocytes, delayed the visceral infiltration, and increased survival time in the Ak4 strain but was without effect in strain Ak4R. 3. In the Ak4 leukemic mice with high leukocyte counts a marked drop within twenty-four hours could be demonstrated after a single dose of 3 mg./Kg. of this drug. With the Ak4R strain there was sufficient resistance so that a dose of at least 25 mg. Kg. was needed to show the marked leukopenia in twenty-four hours. 4. The Ak4R strain was as sensitive as the Ak4 to the leukotoxic effects of 2,6-diaminopurine. This drug also was effective in prolonging the survival time of mice with Ak4R leukemia.

Description: Each of 4 dogs was given two successive transfusions of incompatible dog erythrocytes at intervals of ninety or one hundred and twenty minutes. Measurements were made of the concentration of hemoglobin, complement and isoantibody in the plasma or serum of the recipients and of the rate of disappearance of the donated cells labeled with radioactive iron. In each experiment the donated red corpuscles were destroyed much more slowly after the second transfusion than after the first, and the hemoglobinemia produced by the first transfusion was not appreciably augmented by the second transfusion. The successive transfusions at short intervals were considered nearly equivalent to single large transfusions but permitted separate study of the effects produced. The rate of hemolysis was influenced by the initial titers of both antibody and complement. In dogs with high antibody titer, available complement appeared to limit the rate of destruction of incompatible donated cells. In the presence of adequate complement the rate of hemolysis was limited by the disappearance of antibody when the initial titer of antibody was low. Limitation of the degree of hemoglobinemia due to limitation of the rate of destruction of transfused incompatible erythrocytes and the rather efficient clearance of plasma hemoglobin explains in part the failure of some hemolytic transfusion reactions to produce severe or fatal renal damage. It is emphasized that most investigations of hemoglobinuric nephrosis in animals have dealt with the injection of hemoglobin solutions which resulted in hemoglobinemia of much greater intensity than it has been possible to produce by transfusion of large volumes of incompatible red corpuscles.

Description: 1. Normal gastric juice (intrinsic factor) and vitamin B12 together form a thermolabile hemopoietic factor which ripens megaloblasts in vitro, both gastric juice and B12 alone being inactive. 2. The hemopoietic factor in normal serum which ripens megaloblasts in vitro also appears to be thermolabile, heating to 56 C. for 2 hours destroying some of its activity. 3. The relationship of these factors is discussed and an extra-gastric as well as a gastric source of intrinsic factor is postulated.

Description: Differential Diagnosis. An unresponsive anemia associated with a leukoerythroblastic peripheral blood picture may be seen in such varying clinical conditions as carcinomatosis, leukemia in early phase, Hodgkin’s disease, toxic aplastic anemia, hemolytic anemia, myelosclerosis, myeloma, syphilis, tuberculosis, lipoidosis, Leishmaniasis and infective hepatitis. From the clinical course of the disease and routine methods of investigation, the majority of these diseases could be excluded. It was soon apparent from the appearance of the marrow and the result of the marrow culture that this disease was to be regarded as a primary blood dyscrasia. There is a group of such dyscrasias which is characterized by abnormalities in both erythro- and leukopoiesis. All gradations between erythremic myelosis (Copelli,2 Guglielmo,3 Leitner et al.6) and myeloblastic leukemia may occur. The case here described is neither one of erythremic myelosis nor one of acute leukemia. Heilmeyer and Schöner5 describe a true chronic erythroblastosis of adults which, however, is accompanied by a leukocytosis, never present in this case. Several transitional cases, where there is neither a predominant erythroblastic nor a proponderating myeloblastic hyperplasia, have been reported. In these there is, however, evidence of a neoplastic hyperplasia of both erythroid and myeloid tissue. Such cases have been described by Penati,10 Moeschlin,7 Moeschlin and Rohr,8 Rohr,11 Harvier et al.,4 and Stahel.12 The course of six months in the present case resembles that of Moeschlin.7 It is of academic interest to differentiate between a true aplastic anemia, an aplastic initial phase of leukemia and the mixed neoplastic forms of the erythroleukemic group. Etythroblasts in cases of this group frequenfly show "megaloid" changes (as do those in acute leukemia). A series of transitional forms from normoblasts to megaloblasts through "megaloid" forms may be seen. This could be due to a relative deficiency in nutritive factors consequent on the abnormal cellular proliferation. Similarly in many types of acute leukemia this type of cell, when cultured in normal serum, reverts to the normal maturation rate and morphology of the normoblast. So do the cells of aplastic anemia, where the ultimate defect is further removed. When, however, an abnormal normoblastic maturation rate is found, a qualitative, probably neoplastic, change in the nature of these cells is suggested, since the same changes may be found in the myeloid series in cases of myeloid leukemia. Hence marrow culture may prove of diagnostic value in differentiating these somewhat allied conditions. This case is one of progressive, irresponsive anemia with a peripheral leukoerythroblastosis, and bone marrow showing a considerably lowered leukoerythrogenetic ratio with a relative myeloid predominance of early forms and of atypical blast cells (paramyeloblasts). Culture of the bone marrow established that the rate of maturation of both the erythroid and myeloid tissue was abnormal, although the defect was more marked in the erythroid series. On these findings a diagnosis of erythroleukemia seems justified. Since this report, 2 similar cases investigated by marrow culture have shown comparable maturation abnormalities.

Description: 1. A general description is given of the known effects of a series of allelic genes, W, Wv, w,, which are responsible for varying degrees of a macrocytic anemia as well as for differences in viability, gonad development and intensity and location of hair pigment. A summary is given of previous investigations into the basic nature of these anemias. 2. The mean erythrocyte count for each genotype is given for sixteen day embryos, and for zero day, two weeks and four weeks after birth. All determinations are based on comparisons of normal and anemic littermates. 3. A detailed description is given of the methods used to obtain blood samples from embryos. In all three severely affected genotypes the anemia is already well established at the sixteenth day of embryonic life. 4. In each interval thereafter, some increase in erythrocyte level is found in all genotypes. All genotypes, normal and anemic, made approximately the same relative increase during each time interval, indicating the same relative response to the physiologic stimulus of the individual’s growth. 5. Certain genotypes are lethal at particular stages. It is suggested that these deaths are due to a failure of blood formation to reach the absolute level necessary for continued development and resistance to minor noxious stimuli at these critical periods of rapid growth. 6. Certain other factors possibly affecting blood formation or survival were tested. The presence, absence or degree of anemia of the mother were found to have no effect on the erythrocyte level of newborn young of the slightly anemic Wvw genotype. Continuing injections of diluted whole blood into extremely anemic WWs led to survival for more than 100 days. Two WW individuals survived spontaneously to seven months, indicating that there are influences, as yet unanalyzed, which can lift even this genotype to a level where it can produce sufficient erythrocytes to maintain itself for a considerable period.

Description: 1. The hemoglobin concentration in the cord blood of infants affected with hemolytic disease is very closely related to their chance of survival. If the hemoglobin concentration is plotted against the chance of survival, a sigmoid curve is obtained. Probit analysis can be applied and the results of treatment can then be summarized in terms of the severity of the cases treated. For example, in the present series the cord hemoglobin concentration corresponding to a 50 per cent chance of survival was 8.09 Gm./100 ml. 2. Application of probit analysis makes it possible to compare results obtained in different centers, for due allowance is made for any difference in severity in the cases included in the different series. 3. In the present series, despite uniform treatment (exchange transfusion), over-all mortality fell from 37 percent in 1947 and 1948 to 3 per cent in 1950. It is shown that this can be entirely explained by a decrease in the number of severely affected infants. 4. Predictions of survival based on the cord hemoglobin concentration and cord bilirubin concentration combined are not significantly better than predictions based on cord hemoglobin concentration alone. 5. Infants with positive direct Coombs tests whose cord hemoglobin concentrations exceed 15.5 Gm./100 ml. have some risk (approximately 1 in 12) of developing kernicterus, if untreated.

Description: 1. By simultaneously sampling venous and arterial blood by cardiac catheterization or vessel cannulation, the number of leukocytes entering and leaving the lungs was observed in 12 patients on 14 occasions. 2. The intravenous administration of histamine phosphate in doses of 0.1 to 0.3 mg. (as base) over 10 to 60 seconds, was accompanied by a prompt decrease in leukocyte number in the arterial blood 20 to 60 seconds before the venous white cell count fell. This was interpreted as demonstrating that the leukocytes were removed from tine peripheral blood in the pulmonary circulation. The granulocytic series appeared to be more involved in the leukopenia, although a similar but less apparent change was noted in the agranulocytes. 3. The leukopenia persisted for 40 to 180 seconds following which the arterial leukocyte count exceeded that in the venous blood indicating a return of leukocytes from the lungs into the peripheral circulation. 4. The intravenous administration of histamine also resulted in an immediate decrease in clotting time as determined both by glass and siliconed tube technics. 5. The intravenous injection of histamine affords a relatively simple technic to study one type of leukocyte removal mechanism present in the pulmonary circulation.

Description: 1. Detailed hematologic observations, bone marrow aspirations and blood volume determinations were made on 20 patients with rheumatoid arthritis and allied disorders before, during and after the administration of either ACTH or cortisone. 2. Significant reticulocytosis occurred in every patient during therapy, but its magnitude was poorly correlated with either the initial degree of anemia or subsequent increase in circulating red cell mass. 3. There was an increase in hematocrit and total circulating red cell mass of all anemic patients who responded clinically to either ACTH or cortisone. There was little or no improvement of anemia when the clinical response was poor. 4. Polycythemia did not occur in any patient during prolonged therapy or with repeated courses of either ACTH or cortisone. 5. Hemodilution and hemoconcentration were much more profound during and after ACTH administration than they were with cortisone. 6. Bone marrow studies revealed moderate depression of the erythroid series before treatment. At the end of therapy erythroid elements were normal. 7. Significant polymorphonuclear leukocytosis occurred its all patients during therapy while lymphopenia was inconstant and unsustained. Circulating eosinophils were depressed more with ACTH than with cortisone treatment. 8. Before treatment eosinophils and their precursors were present in the bone marrow its normal or increased numbers. During therapy the number of these cells was unchanged in the marrow, even when there was profound peripheral eosinopenia 9. The role of ACTH and cortisone in the physiologic mechanism of hematopoiesis is discussed. 10. The improvement in the anemia associated with inflammatory disease in response to ACTH or cortisone therapy probably is a reflection of the control of the underlying disease rather than a primary "stimulation" of the bone marrow.

Description: 1. Bitches with erythrocytes lacking the canine A factor were immunized with intravenous injections of A-positive dog cells and mated with A-positive sires. ll A-positive pups born to such dams developed hemolytic disease provided they suckled the immunized dam during the first day of life. There was no evidence of transplacental isoimmunization or of transfer of antibody across the placenta from mother to pup. Anti-A could not be demonstrated in the blood of pups at birth and was not acquired by pups that first suckled an immunized bitch after the first day of life. A-positive pups born to a non-immunized bitch developed hemolytic disease after suckling an immunized foster dam on the day of birth. 2. Of 24 affected A-positive pups, 3 were sacrificed, 9 died within three days of birth and 12 recovered, 2 with the aid of transfusions of A-negative blood. Autopsies revealed varying degrees of hepatomegaly, splenomegaly, erythroid hyperplasia of the bone marrow, extra-medullary erythropoiesis, and questionable evidence of specific injury of the nerve cells of the basal nuclei of the brain. 3. The degree of anemia in the A-positive pups varied widely, the minimum hematocrit for the group being 10 per cent at forty-eight hours after birth. Erythroblastosis, reticulocytosis and spherocytosis were noted in most of the severely affected pups and osmotic fragility of the red cells was substantially increased in all of the A-positive pups exposed to anti-A. 4. The concentration of bilirubin in the serum of most of the affected pups was only slightly increased. The relatively small increases in serum bilirubin, compared with those in hemolytic disease of human infants, are presumably attributable to the unusual capacity of the dog liver for excreting bilirubin. 5. The red cells of all affected A-positive pups gave antiglobulin (Coombs) reactions and in surviving pups the cells were agglutinable in antiglobulin rabbit serum for as long as twenty-two days in A pups and sixty-five days in A’ pups. The degree of reactivity with antiglobulin serum was not correlated with the severity of the hemolytic process. Erythrocytes of the very mildly affected A’ pups were strongly agglutinated by antiglobulin serum but showed no definite sphering and only slight increase in osmotic fragility. 6. Serum of the 20 A-negative litter mates examined in this study contained anti-A for periods as long as thirty-two days while the red cells of these pups remained normal. A few of the A-positive pups also had anti-A in the serum. The in vitro behavior of anti-A in the pups’ sera was identical with that of anti-A in the maternal sera. 7. Twelve C-positive pups in 2 litters born to bitches immunized against the canine C factor showed no evidence of hemolytic disease. 8. Hemolytic disease of newborn dogs is compared with that of human infants and the need for further investigation of certain aspects of the disorder in both species is stressed.