ALBERT

Description: Production by normal human erythrocytes of a substrate for cholinesterase has been demonstrated. At body temperature, the formation and hydrolysis of the cholinesterase substrate is delicately controlled. At lowered temperatures, 0 to -1.5 C., production of cholinesterase substrate greatly exceeds its hydrolysis. The quantity of cholinesterase substrate capable of exerting its influence governs the quantity of dextrose converted to lactic acid by the erythrocyte under anaerobic conditions. The observations corroborate and extend the suggestion of Lindvig, Greig, and Peterson that cholinesterase is part of a cellular system governing erythrocyte permeability. The balance between production and hydrolysis of cholinesterase substrate at low temperature exhibits the same undulating fluctuations during red cell storage that have been noted for other erythrocyte metabolic functions.

Description: The clotting time of human and rat plasma was found to increase markedly after exposure to mushroom tyrosinase. The main, but not exclusive, effect of tyrosinase on the clotting system seems to be on fibrinogen, since the inactivating effect of tyrosinase can be greatly reduced by the subsequent addition of excess fibrinogen just before the clotting time of the plasma is measured. No evidence was found for any major effect of tyrosinase on any of the other components of plasma considered with the possible exception of prothrombin. Purified prothrombin is susceptible while prothrombin in plasma or serum is refractory to tyrosinase.

Description: The phagocytic activity of polymorphonuclear leukocytes from irradiated rats was studied over a period of thirteen days following 550 r total body x-irradiation. Leukocytes from irradiated rats showed slightly increased phagocytosis of plague bacilli during the first six days after irradiation, but on statistical analysis this increase proved to be insignificant. From the seventh to the thirteenth day after irradiation, these cells showed a markedly reduced capacity to phagocytose plague bacilli. Phagocytic studies on suspensions of normal cells in plasma from irradiated animals and on cells from irradiated animals in normal plasma showed that the deficient phagocytosis during the second week following irradiation was due mainly to a defect in the polymorphonuclear leukocytes themselves, though the fact that the addition of normal plasma to cells from irradiated animals did increase their phagocytic capacity by a small but definite degree suggests that there is also a defect in the plasma of irradiated animals.

Description: 1. An example of the new anti-Rh serum, anti-f, is described. 2. It is shown that anti-c and anti-e sera may contain anti-f. 3. The significance of the antigen f is discussed in terms of its genetics and practical importance.

Description: White blood cells from peripheral blood and bone marrow have been sectioned for study in the electron microscope. Methods of fixation and handling are described. Most of the usual blood cell types have been tentatively identified, and their fine structure is described. The high resolving power of the electron microscope promises to reveal details previously unsuspected, as well as to extend and clarify existing knowledge concerning the cytology of blood cells, both normal and pathologic. Ultra-thin sectioning, while still a very difficult art, appears to be the best method currently available for visualizing the fine structure of white blood cells, which would otherwise be too thick for penetration by the electron beam. Conditions of satisfactory fixation and dehydration are extremely critical, and care must be exercised in the interpretation of all results in order to separate gross fixation artifacts from the finer precipitation of protoplasmic material which may approximate a true picture of the living cell.

Description: 1. Leukemia, like other malignant tumors, has long been observed to occur more frequently among members of certain families than in the average population. This observation has been made not only in chickens, mice, and cattle, but also in humans. 2. Direct experimental evidence is now available suggesting that at least in chickens and mice, leukemia is caused by a filterable, submicroscopic agent, presumably a virus, transmitted from one generation to another directly through the embryos. 3. Although no experimental evidence is yet available concerning the nature of leukemia in cattle and in humans, the possibility should be considered that, as in chickens and mice, leukemia in other species may also be caused by a transmissible agent. In cattle, numerous observations have been made of leukemia developing in several members of the same family, in two or three successive generations. In humans, one case has been published in which three, and perhaps four, out of seven, and another in which five out of eight, siblings died from leukemia ; other observers have recorded leukemia developing in three successive generations in man. 4. The familial occurrence of leukemia and other malignant tumors in man and other species, could be explained by the following working hypothesis: there may exist a group of submicroscopic, cell-free oncogenic agents, individually distinct (some causing leukemia, others causing different malignant tumors), transmitted directly through the germinal cells from one generation to another. These agents would usually exist in an inactive form; in such a form, these agents would be frugal and moderate in their requirements, causing no apparent harm to their carrier hosts. Occasionally, however, prompted by as yet obscure but presumably varied trigger stimuli, these hitherto masked agents might change into formidable pathogens. Activated oncogenic agents would cause rapid multiplication of cells harboring them, resulting in the development of leukemia or other malignant new growth, and usually sealing the fate of their carrier hosts. Since, however, the activation of the oncogenic agent would usually occur in middle-aged hosts, the survival of the agent would have been already assured, the transmission of the agent to the host’s offspring occurring prior to the activation of the agent. Leukemia and other malignant tumors would therefore be essentially egg-borne virus diseases, like many other parasitic virus diseases of plants, insects, and birds. 5. On the basis of this working hypothesis, one could therefore regard the development of leukemia, or that of another malignant tumor, as the result of activation, frequently merely accidental, of an oncogenic agent, hitherto, masked, and carried by the host since birth. Since in many, perhaps in most, instances, the oncogenic agents would never become activated (though they would continue being transmitted from one generation to another), only now and then would leukemia, or another malignant new growth, develop in some of the members of certain families. Such instances, however, would usually be separated by one, two, or three generations of healthy individuals. 6. Since, therefore, two cases of leukemia (or other malignant tumors) representing successive links in the generation-to-generation transmission of the hypothetic virus in humans might frequently be separated by a century or two, the tracing of the epidemic course of the oncogenic agents in man would be extremely difficult, if at all possible, unless accurate records of cause of death would become available covering a sufficient number of successive generations. 7. Should this working hypothesis prove to be true, it would then follow that the number of individuals suffering from leukemia, or other tumors, would represent only a fraction of those actually carrying the seeds of either disease.

Description: 1. A survey was undertaken to determine the incidence of the sickle cell trait among two thousand one hundred and sixteen Jamaican children and adults of different racial groups. The following positives were found: average Jamaican children (Afro-Caucasian mixtures) 5.7 per cent; population of rural Jamaican village 3.9 per cent; Maroon schoolchildren 3.6 per cent; East Indian schoolchildren 0.7 per cent; Chinese children and adults 0 per cent; Caucasian schoolchildren 0 per cent; Caucasaian (Jamaican German) schoolchildren 0 per cent. 2. In the group of one thousand and sixty-seven average Jamaican children, no significant difference could be found between the different age-groups (i.e. infants, younger children, older children), or between the predominantly African and lesser Afro-Caucasian mixtures. 3. The incidence of the sickle cell trait in the other West Indian islands is noted. 4. The possible spread of the sickle cell trait from India to Africa, and its present uneven distribution in Africa is discussed.

Description: Five patients with far-advanced Hodgkin’s disease and with evidence of hematopoietic failure were treated by splenectomy in order to determine whether: (1) the course of the disease could be modified, (2) the hematologic picture improved, and (3) responsiveness to nitrogen mustard or x-ray therapy restored. These patients showed a transient slight improvement in their hematologic status, but the course of the disease possibly was accelerated, and the patients all died within thirteen weeks, without showing renewed suitability or increased responsiveness to therapy. On the basis of our data and a review of thirty cases from the literature, it is concluded that splenectomy is not a useful procedure its Hodgkin’s disease, except for certain specific indications. These may be: (1) an apparently solitary splenic tumor; (2) acquired hemolytic anemia, although this process may be better controlled in some cases by treating the underlying Hodgkin’s disease with x-rays, nitrogen mustard, or triethylene melamine ; (3) thrombocytopenic purpura, which appears to be more profound than is to be expected from the severity and extent of Hodgkin’s disease; and (4) hypersplenism. Hematopoietic depression in the vast majority of patients with Hodgkin’s disease, however, cannot be attributed to splenic overactivity or malfunction.

Description: Extensive studies were performed on four cases from three unrelated kindreds with a familial hemolytic syndrome not associated with any significant red cell anomaly (hereditary nonspherocytic hemolytic disease). These cases were compared with similar ones already reported in the literature. 1. Hereditary nonspherocytic hemolytic disease appears to be transmitted as a Mendelian dominant. Frequently the gene responsible for the condition seems to have low expressivity. In some cases, the hereditary mechanism may be due to inheritance of a recessive gene from each parent. The basic erythrocytic defect responsible for the condition is unknown. In view of various clinical and hematologic findings, it is likely that hereditary nonspherocytic hemolytic disease may be a group of diseases involving more than one mechanism. 2. All criteria of hemolytic anemia (erythroid hyperplasia of the bone marrow, reticulocytosis, hyperbilirubinemia, increased fecal urobilinogen, rapid turnover of tracer iron in the plasma) were satisfied. 3. Red cell survival time studies revealed an intraerythrocytic defect with a mean life span of twelve to seventeen days. Normal red cells transfused into the patients under study survived normally. Anemia was normochromic and normocytic or macrocytic; it varied from mild to severe. 4. Osmotic and mechanical fragility of the red cells was normal. Osmotic and mechanical fragility tests after incubation at 37 C. for 24 hours in some showed a mild increase compared with normal controls. Autohemolysis of incubated oxalated blood was not marked and varied from case to case. 5. The electrophoretic mobility of hemoglobin from the patients was that of normal adult hemoglobin. Small increases of fetal hemoglobin were seen in several cases. 6. In contrast to the histologic findings in hereditary spherocytosis the splenic pulp was not congested, but hemosiderin deposits were heavy. Liver biopsy specimens showed deposits of hemosiderin in parenchymal and Kupffer cells. 7. Splenectomy did not arrest the hemolytic process. Mild improvement was seen in one case. In most cases the operation is of no value. 8. Diagnostic difficulties may be encountered with mild cases of hereditary spherocytosis. Examination of rouleaux in fresh blood and an osmotic fragility test in 0.65 per cent sodium chloride after incubation usually establishes the differential diagnosis. The condition may present clinically as hemolytic disease of the newborn and must be differentiated from erythroblastosis due to Rh or other blood group incompatibilities. Other hereditary hemolytic diseases such as sickle cell anemia, Cooley’s anemia, hereditary spherocytosis, and hereditary hemolytic elliptocytosis are easily ruled out by their typical clinical and hematologic manifestations. When a family study is negative or cannot be done, a red cell survival time determination may be necessary to rule out acquired hemolytic anemia with a negative Coombs test. Some cases that have been diagnosed as constitutional hyperbilirubinemia (familial nonhemolytic jaundice) may actually represent mild hereditary nonspherocytic hemolytic disease.

Description: This paper deals with basic problems of glucocorticoid eosinopenia and of regulations within the eosinophile cell system. The effects of glucocorticoids on single regulatory factors of this system, such as eosinotactic stimuli, eosinopoiesis, life span and rate of removal of eosinophils, are discussed in detail. Eosinophilopoiesis is not influenced by glucocorticoids. This finding, added to the observation that blocking the reticuloendothelial system suppresses the glucocorticoid eosinopenia and that these compounds have no eosinolytic properties in vitro, speaks against the contention that the eosinopenic effect of the glucocorticoids is actually due to a direct lytic effect on the eosinophils. A distributional shift of eosinophils in vascular sectors functioning as blood depots, or a migration into tissues can be abandoned as explanations of glucocorticoid eosinopenia. The hypothesis of a fixation at sites of physiologic demand is certainly not a valid explanation of glucocorticoid eosinopenia, since glucocorticoids suppress the eosinotactic stimuli. Blocking experiments of the RES show that the rate of disappearance of the eosinophils is a resultant of the functional condition of the RES and of the sum of the eosinopenic stimuli. On the basis of our investigations we arrive at the conclusion that glucocorticoid eosinopenia depends upon an inhibition of the release of mature eosinophils from the bone marrow and upon an increased destruction of eosinophils in the reticuloendothelial system. The level of the original eosinophilia, that is to say, the percentage of young forms with a long life expectancy, determines the degree of eosinopenia attained by a single application of glucocorticoid and the time lapse before aneosinophilia develops under continuous glucocorticoid administration.

Description: 1. The ten cases of leukemia occurring among 3480 atomic bomb survivors in this study present convincing evidence of the high incidence of leukemia in atomic bomb survivors. 2. In all but one case blood studies were carried out prior to the development of pathognomonic features of leukemia. One case of reticulum cell leukemia was encountered on routine examination in a preclinical stage but with primitive or blast cells in the peripheral blood smears. 3. Of the ten cases, seven were acute or subacute leukemia and three were chronic myelogenous leukemia. 4. Observations on the acute cases of leukemia were of limited value because of the long interval in most cases between routine blood studies and the development of leukemia. However, in one case, examination ten weeks before clinical onset revealed no hematologic or physical findings suggestive of leukemia. 5. In contrast to acute leukemia, the long preclinical stage in two cases of chronic myelogenous leukemia allowed repeated hematologic and biochemical studies which were of considerable interest. 6. In these cases the long latent period and prolonged preclinical course were similar to those reported in cases of chronic myelogenous leukemia occurring spontaneously and following exposure to x-ray and other forms of radioactivity. 7. In the preclinical stage, disturbances in the red cells and platelets as well as leukocytosis with immature neutrophilic granulocytes were noted. The consistent presence of increased numbers of basophils, many of them atypical, was an outstanding feature of the peripheral blood smears in early myelogenous leukemia. 8. In two cases of preclinical myelogenous leukemia, studies on the separated leukocytes of the peripheral blood gave extremely low values for alkaline phosphatase. 9. Certain features of chronic myelogenous leukemia following irradiation suggest that the disorder may be due to a loss of growth-promoting or regulating factors.

Description: The absorption and utilization of radioactive iron has been studied in sixteen patients with steatorrhea and a control group of twelve patients with hypochromic anemia without steatorrhea and three subjects without anemia. The patients with idiopathic steatorrhea showed a poor absorption of the test dose given by mouth. This is in keeping with their poor clinical response to oral treatment with iron. There is some evidence to suggest that poor absorption in such patients may not be the sole factor involved in the development of the anemia.

Description: During the winter and spring of 1952-53 a survey of hemoglobin values was made in Halifax among 1308 male subjects 6 to 98 years of age, and 1424 female subjects 6 to 94 years of age. Among children 6 to 14 years old the values increased from about 13 to about 14 Gm. per 100 ml. of blood, and there were essentially no differences between the sexes. The average value for both the boys and the girls was 13.5 Gm. In girls between 14 and 20 years of age the hemoglobin values decreased slightly, reaching about 13 Gm. per 100 ml. In boys of corresponding ages there was an increase to about 15 Gm. In both sexes these values were attained at about 20 years of age, and remained characteristic of the third decade of life. They were essentially the lowest and the highest shown respectively by the female and the male subjects of any age group. Hemoglobin values in men between 20 and 60 years of age were typically 14.5 to 15 Gm. per 100 ml., the higher values tending to occur among the younger men. After the fifth decade there were progressive and marked decreases to an average of 12.4 in men between 80 and 90 years of age. In women from 20 years of age onward the average hemoglobin values remained near 13 Gm. per 100 ml.

Description: 1. The simultaneous occurrence of a benign thymoma and a severe anemia which failed to respond to therapy with recognized hematopoietic agents has been observed in two adult female patients. 2. Reports of seven other patients with a similar association of thymoma and refractory anemia have been found and the, salient features of these cases are summarized. 3. Possible explanations of the simultaneous occurrence of these two unusual conditions are discussed. 4. It is suggested that the thymus gland or tumors of the thymus may be etiologically responsible for certain cases of refractory anemia.

Description: Observations were made on the changes in volume, osmotic fragility, and cation contents of red cells incubated in serum at 37 C. for 24 and 48 hours. The results show that spontaneous autohemolysis is not due to progressive swelling of the cells, but is probably due to degenerative changes in the cell membranes. On incubation, normal red cells increase in volume during the first 24 hours due to a gain in sodium and water; the cells lose potassium but at a slower rate than they gain sodium. During the second 24 hours of incubation the loss in potassium exceeds the gain in sodium and the cells shrink to near their original volume. These cation changes and the autohemolysis are greatly reduced if glucose is present throughout the 48 hours of incubation. Red cells from several different types of congenital hemolytic anemia were also studied; important deviations from the normal pattern were observed. In hereditary spherocytosis the rates of autohemolysis, of increase in osmotic fragility, and of potassium loss are greater than normal. The continued presence of glucose during incubation markedly retarded these changes. In hereditary elliptocytosis trait the red cells behaved normally on incubation. In one case of elliptocytosis with hemolytic anemia, autohemolysis was normal but there was an increased potassium loss. In another patient with hemolytic anemia and increased osmotic fragility autohemolysis was greatly increased. In all these cases of elliptocytosis, glucose reduced the autohemolysis moderately but not to a normal degree. Four cases of congenital nonspherocytic hemolytic anemia were studied. In two patients (type 1) autohemolysis, osmotic fragility and cation changes on incubation were normal; glucose had a normal effect on the fragility and cation changes, but only slightly reduced the autohemolysis. In the two other patients (type 2) autohemolysis, increase in osmotic fragility, and loss of potassium were markedly increased. Glucose did not retard any of these changes and it was found that the cells were unable to utilize glucose at the normal rate.

Description: Blood was obtained from patients who were divided into four groups: (A) euthyroid, (B) untreated hyperthyroid, (C) iodine-treated hyperthyroid and (D) hypothyroid. The erythrocytes from each patient group were washed and resuspended in Krebs-phosphate solution for study by the Warburg respirometric technic. When the erythrocytes obtained from patient groups B, C and D are compared with group A (control), a +92 per cent, +23 per cent and -15 per cent change is noted, respectively, in their mean QOO2 values when QOO2 values for erythrocytes for each patient in each patient group (excluding group C) are plotted relative to their respective serum PBI concentration (µg. per cent), a curve of exponential order appears to be the curve of best probable fit for these data. The mean QOO2 value for the iodine-treated hyperthyroid group falls on the ordinate of this curve (fig. 1) between the euthyroid and untreated hyperthyroid groups, though the mean serum PBI value (abscissa), of course, has no meaning for this group.

Description: A nontuberculous, lymphocytic meningitis with a low C.S.F. sugar level may be confused with a tuberculous meningitis. Additional diagnostic help may be obtained from examination of the blood. The blood pictures of twelve patients with tuberculous meningitis were compared with those from ten patients with a nontuberculous, nonbacterial lymphocytic meningitis, four of whom had low C.S.F. sugar levels. These ten patients appeared clinically to be suffering from the same disease and only the serum complement fixation test for lymphocytic choriomeningitis showed them to be a heterogeneous group. The main differences in the blood were (1) a uniformly low total white cell count in the benign meningitis group as opposed to a widely varying total white cell count in tuberculous meningitis; (2) a lower percentage count of polymorphs in the benign lymphocytic meningitis group; (3) the presence of atypical plasma cells in nine of the ten patients in the benign, lymphocytic meningitis group. Two of the patients with benign meningitis, who had repeatedly given negative Paul-Bunnell tests showed a blood picture indistinguishable from that of glandular fever. Although these atypical plasma cells are not specific for lymphocytic choriomeningitis or for virus diseases in general, they were found in no case of tuberculous meningitis. The presence of these cells is therefore of considerable aid in excluding a diagnosis of tuberculous meningitis.