ALBERT

Description: 1. Intravenous nicotinic acid produces an immediate and marked neutropenia, which disappears within 15 minutes. The lymphocytes frequently show a slight reduction; but the red cell count, hematocrit and platelet count reveal no significant variation. 2. This response was similar in splenectomized and nonsplenectomized subjects. 3. In 2 patients with leukemia the white cell count was reduced in 5 minutes by nicotinic acid from 177,800 to 146,400 and 73,300 to 33,600. 4. The mechanism of the granulocytopenia after nicotinic acid is discussed in relation to its vasodilatation action and the distribution of leukocytes in the vascular system. This concept is outlined in table 5.

Description: In normal and pathologic plasma cells of the bone marrow, a specific filamentous structure of the cytoplasm has been revealed by electron microscopy. The significance of this structure is briefly discussed.

Description: A patient with chronic myelogenous leukemia developed anemia with evidence of increased red cell destruction. After anemia had persisted for eleven months in spite of 49 blood transfusions, splenectomy was performed. The hemolysis subsided and her health remained good during the following thirty months.

Description: The sedimentation differential agglutination technic is a modification of the Ashby method by means of which the concentration of immunologically distinct erythrocytes in a mixture can be determined by observing their volume after agglutination and subsequent sedimentation. The method has been applied to the determination of the efficiency of replacement transfusions, the survival of red cells after blood transfusion, and has afforded a method for the determination of production of erythrocytes under certain conditions. The results indicate an almost complete inhibition of erythropoiesis and the frequent presence of excessively rapid hemolysis in "blast" leukemias. In a number of instances in which simultaneous measurements by the sedimentation differential agglutination and radioactive phosphorus technics were made, good correspondence between the two methods was observed.

Description: 1. During the third winter campaign in Korea, the hematologic reaction to wounding was studied in thirty-seven casualties at the time of initial resuscitation. 2. Of particular interest was the effect of massive transfusions of stored blood. The results of storage of blood—high plasma hemoglobin and potassium, low labile factor activity, nonviable platelets and leukocytes—had little deleterious effect on patients who received as much as 20 to 30 pints in less than six hours. The loss of transfused red cells because of nonviability was no more than expected. 3. At the time of resuscitation and shortly thereafter, there was a remarkable loss of circulating red cell mass in patients with wounds that involved much tissue destruction. It is believed that the loss was due to hemolysis but the mechanism is unknown. The loss of red cells may be so rapid that a patient with bilateral traumatic amputation of the legs and an adequate hemostasis would become severely anemic if one hesitated to use large, rapid transfusions. Patients with severe shock whose wounds involved less tissue damage (lacerated colon, for example) did not destroy red cells in this fashion. After moderate transfusions such patients often became polycythemic. Transfusions had to be carried out rather gingerly because of a tendency to develop signs of congestion. 4. During the early days of recuperation from severe wounds the patients often tended to become anemic. The anemia appeared to be the result of hemolytic processes plus a relative inhibition of red cell formation. 5. Universal donor blood, group O, was used in all transfusions. In patients who are not group O the massive transfusions resulted in the virtual replacement by red cells of another group. The patient’s plasma sometimes contained antibodies against red cells of his hereditary blood group. Gradual hemolysis of native red cells by transfused antibodies was observed. This was not a clinical hemolytic reaction and did not appear to be detrimental to the patient. The presence of the foreign antibodies made it impossible in some cases to crossmatch the patient with blood of his hereditary group and suggested a source of danger in attempting such transfusions. After transfusion with the universal donor blood has begun, it is recommended that no change be made to blood of another group until at least two weeks have elapsed. 6. No incompatible transfusion reactions were encountered. Several hemoclastic reactions may have been caused by gross contamination of the blood stream from the site of wounds or from the peritoneal cavity.

Description: The fluctuating capacity of stored erythrocytes to release gas when suspended in the presence of dextrose in Krebs-Ringer bicarbonate solution in an atmosphere of 5 per cent CO2-95 per cent N2 is demonstrated. A not dissimilar fluctuation of the cholinesterase activity of the stored cells is reported. Possible seasonal variation in the state of red cells is suggested. Some implications of these observations for erythrocyte storage are suggested.

Description: 1. The 50 per cent complement levels in thirty-three normal newborn infants and twenty-three infants with D (Rh0)-hemolytic disease were determined. 2. No statistically significant difference in complement values was found between the two groups. 3. In vitro tests with ten anti-D (Rh0) sera demonstrated that there was no fixation of human complement.

Description: 1. A case is presented of a Negro woman with Mediterranean anemia who developed megaloblastic anemia of pregnancy in each of three pregnancies. 2. The possibility that Mediterranean anemia predisposes to the development of pernicious anemia of pregnancy is discussed. 3. With megaloblastic erythropoiesis, anemia became more severe, but the characteristic red cell hypochromia of Mediterranean disease was masked. 4. Purified liver extract failed to protect against the development of megaloblastic anemia of pregnancy but folic acid produced a satisfactory therapeutic response.

Description: The concentration of vitamin B12 in blood serum and its excretion in the urine were assayed by the E. coli mutant technic in two patients after total gastrectomy and by use of the more sensitive Euglena gracilis method in four cases of pernicious anemia in relapse and 1 case of well controlled nutritional macrocytic anemia. Following parenteral administration of 100 µg. vitamin B12 intramuscularly to two patients with total gastrectomy, much higher blood levels were observed within the first few hours than those reported by others under similar circumstances in normals. Following oral administration of vitamin B12 together with a potent intrinsic factor concentrate from hog stomach, a rise in blood levels of vitamin B12 was observed in patients with pernicious anemia. The normal serum levels of vitamin B12 could not be maintained, however, for the entire duration of the oral treatment, in spite of the apparent hematologic and clinical remission. The urinary output of vitamin B12 was in all instances less than 0.5 per cent of the total dose of vitamin B12 ingested during the experimental period, in spite of an optimal or suboptimal hematopoietic response obtained. A similar situation existed in patients with total gastrectomy, as well as in the patient with controlled macrocytic nutritional anemia, when vitamin B12 was ingested alone or with intrinsic factor concentrate. The intensity of the obtained hematopoietic response in patients with pernicious anemia indicates the absorption of much larger amounts of vitamin B12 from the intestine than is indicated by the total urinary output of vitamin B12; therefore the anchorage and retention of a large part of vitamin B12 in the storage depots of the body after its absorption from the intestine must occur. A sharp increase in the urinary output of vitamin B12 was observed during or immediately following the hematopoietic response in all patients with pernicious anemia treated orally with vitamin B12 and intrinsic factor concentrate, i.e., coincident with or immediately following the reticulocyte peak in blood. Similar observation was reported by the authors in the previous series of investigations. Of many possible interpretations of this finding, the most plausible appears to be the metabolic release of free vitamin B12 from its complex binding in the body during hyperactivity of the hematopoietic organs and its escape through the kidneys.

Description: The failure to devise a satisfactory means of adjusting all sedimentation rates to a standard cell volume, together with a critical analysis of the results of other investigators, casts serious doubt on the validity of any such correction charts. Two formulae are presented by means of which the sedimentation rate of a given sample of blood can be predicted on the basis of the plasma/cell ratio and plasma proteins concentrations. One formula utilizes the results of saltingout analysis of plasma proteins, the other those of electrophoretic analysis of serum proteins. The most influential factors in determininsg sedimentation rate are plasma/cell ratio, fibrinogen, alpha-2 globulin, and gamma globulin. The results suggest that the effective concentrations of the plasma proteins are most adequately expressed as concentrations per unit of cell volume. Addition of purified protein fractions (fibrinogen, gamma globulin, and albumin) to the blood in vitro confirm the findings from the statistical studies and suggest a direct cause and effect relationship between the concentration of these proteins and the rate of erythrocyte sedimentation. Determination of the erythrocyte sedimentation rate cannot give, per se, any clue as to the level of any one of the responsible factors. An appreciation of the multiple factors involved is essential for an adequate interpretation of the clinical significance of a sedimentation rate determination.

Description: A case of chronic erythremic myelosis (Di Guglielmo) is presented; the diagnosis was established by clinical, hematologic, and pathologic data. The peculiar characteristics of this particular case are discussed, as well as the differential diagnosis from hemolytic anemia and acute leukemia.

Description: 1. Thrombi were produced in the marginal vein of the ear of rabbits with the use of either thrombin or sodium morrhuate. Sodium morrhuate was found to be most dependable. 2. Plasmin given intravenously with an average dose of 10 to 15 ml. per Kg. was effective in producing a complete intravascular lysis in all instances where the thrombus was less than 24 hours old, and a partial or total lysis in the great majority of animals with thrombi over 24 hours old. This lysis took place within 1 to 2 hours after the injection of plasmin. 3. The intravenous use of plasmin is shown in rabbits to be nonlethal and nontoxic.

Description: In rats whose intestinal or thoracic duct lymph was drained externally for several days, lymphopenia occurred. Large numbers of cells were collected in the lymph each day, as many, apparently, from the intestinal lymph alone as from the thoracic duct. Hepatic lymph contributed relatively few cells. Augmentation of lymph flow decreased the concentration of cells in the lymph but did not affect the total number of cells collected each day. Fasting for several days likewise did not decrease the first day’s output. With each day’s lymph flow, however, the daily output of cells spontaneously decreased. The decrease was not prevented by the intravenous injection of fresh lymph or of fresh rat plasma in large amounts. In view of this unexplained effect, one must be cautious in interpreting the results of experiments on the lymph lymphocyte.

Description: Red cell stroma has not been prepared free of iron and/or hemoglobin. It is not certain whether the iron is a contaminant or an essential constituent of the stroma. Extensive washing does not eliminate iron from the stroma but does cause loss of the stroma constituents, protein and lipid. Red cell stroma protein is increased in anemia due to blood loss in the dog, on the average in severe anemia, almost twice the figures recorded in the pooled normal samples of red cell stroma. Lipid fractions under the same conditions show minor fluctuations: approximately 90 per cent of total lipids in the red cells are recovered in the stroma by these methods. The technic for isolation and fractionation of dog erythrocyte stroma is described. Analyses made from the same blood sample by 3 different workers give comparable results. Red cell stroma deserves careful study in controlled experimental conditions.

Description: 1. A method is described whereby accurate hematocrit values can be made from 0.1 ml. blood using equipment which can be made easily and cheaply. 2. Under controlled conditions, a correction factor can be used to convert hematocrit determinations on citrated blood to standard Wintrobe values. Under our experimental conditions the factor is 1.10.

Description: By means of fractional denaturation, it is possible to follow the progress of alkaline degradation of resistant hemoglobins. A characteristic pattern was established for the fetal compound. The alkali resistant hemoglobin fractions in Mediterranean anemia and in some acquired hematologic conditions (acute leukemia and chronic aregenerative anemia) behaved like the fetal pigment. In sickle cell anemia only 4 out of 11 specimens were found to have fetal hemoglobin, whereas the others seem to have a fetal-like compound. Similarly, in 2 members of one family with hereditary spherocytosis, the resistant pigment was also fetal-like. The significance of these findings for the hypothesis that the resistant hemoglobin fractions in these disorders represent either a continuation or a reactivation of the production of the embryonic pigment is discussed.

Description: 1. Eosinophilia has been produced experimentally in guinea pigs by the injection of extracts of Ascaris suum and histamine, the accompanying histologic changes, particularly the distribution of eosinophils, being noted. 2. The tissues of guinea pigs suffering from a natural eosinophilia have been studied and compared with those of experimental eosinophilia. 3. From these findings a path has been traced which, it is suggested, the eosinophil follows in its course through the body. 4. The function of the eosinophil has been discussed and the hypothesis advanced that its function is the carriage of histamine or a histamine-like toxic material for inactivation. 5. This viewpoint has been considered in relation to the occurrence in man of eosinophilia including eosinophilic infiltration of the lungs.

Description: The separations of polymorphonuclear leukocytes from lymphocytes and erythrocytes has been accomplished by employing a method which takes advantage of their density differentials. During a single centrifugations the lymphocytes accumulate at a plasma-albumin interface (albumin I, density = 1.065 to 1.085), the polymorphonuclear leukocytes accumulate at an albumin I-albumin II interface (albumin II, density = 1.094) and the erythrocytes pass to the base of the Wintrobe tube. The yields are over 90 per cent pure cell types. All layers are isosmotic with blood.

Description: It has been found that marked erythrophagocytosis occurred when the buffy coats of 3 patients with idiopathic acquired hemolytic anemia were incubated at 37 C. for one hour. It is suggested that this technic may be used as another in vitro method of demonstrating abnormalities of the red cells in patients with acquired hemolytic anemia, as well as other conditions in which there is damage or alteration of the red cells.

Description: A single injection of cysteine (950 mg. per Kg., I.V.) 5 minutes before total-body exposure of rats to x-rays (800 r) significantly modified the radiation-induced hematologic changes. Depression of the heterophils, lymphocytes, and erythrocytes was less severe and recovery more rapid. The hematologic observations are consistent with the thesis that cysteine reduces the biological effectiveness of the radiation.

Description: (1) Seventeen cases of acute leukemia with Auer bodies have been reported. Studies were carried out on 7 cases of acute monocytic leukemia and 3 cases of subacute myelogenous leukemia. (2) Histochemical studies showed the Auer bodies to be oxidase, peroxidase, and periodic acid-Schiff positive; sudanophilic, slightly metachromatic and to give positive tests for acetal lipids and ribonucleic acid. (3) The Auer bodies were negative for acid and alkaline phosphatase, lipase, glycogen, desoxyribonucleic acid and were non-birefringent. (4) A change in the chemical nature of the Auer body from an acid condition to a more neutral state was noted. This change corresponded with the changes of the normal cytoplasmic granulation of the myelocytes and monocytes during maturation. (5) The effects of cellular movements, trauma, and temperature changes upon the Auer bodies were studied. (6) Several leukemic cells, containing Auer bodies, were studied during the process of mitosis. (7) A theory as to the formation and disintegration of the Auer bodies has been presented.

Description: 1. In 9 patients with various types of megaloblastic anemia responding to treatment with vitamin B12, folic acid or liver extract, no significant deviations from the normal amounts of total or polymerized DNA were observed in the nuclei of red blood cells in marrow smears. 2. During the maturation of megaloblasts in the bone marrow there is a gradual loss of nuclear DNA. 3. This pattern is quantitatively and qualitatively similar for normal marrow and for that of pernicious anemia in relapse and after treatment.

Description: 1. Small differences in the antigenic structures of human normal adult hemoglobin and sickle cell anemia hemoglobin were found to exist. A difference in the serologic behavior of these two hemoglobins attributable to a factor other than that of antigenic specificity was also demonstrated. This factor is thought to pertain to differences in the physicochemical properties of the 2 hemoglobins. 2. Rabbit antiserums failed to show a difference in antigenic specificity, but with chicken antiserums a difference was clearly demonstrated when the in vitro reactions were performed under conditions which produced maximal precipitation. Results suggest that these 2 hemoglobins have a predominance of common antigenic determinants but a small number that are unique for each of the types. 3. Relatively large differences in specificity were found to exist between fetal hemoglobin and adult hemoglobin which suggest that only a few antigenic groups are shared in common by the 2 types. 4. The second, minor hemoglobin in patients with sickle cell anemia was shown to have an antigenic specificity that was either identical with or very similar to that of fetal hemoglobin.

Description: Antisera were produced against guinea pig and mouse blood platelets, guinea pig and mouse spleen, mouse bone marrow, spleen, marrow plus spleen ("antireticulocytotoxic" serum), aqueous fraction of guinea pig adipose tissue rich in nonmuscular blood vessels, guinea pig choroid plexi rich in capillaries, whole guinea pig blood vessels, guinea pig smooth muscle, whole guinea pig blood vessel antiserum absorbed with guinea pig smooth muscle, and dog vascular endothelium. In all cases except the last named there were positive agglutinin and/or complement fixation titers, which were slightly enhanced anamnestically by whole adrenal cortical extract, but not by "Lipoadrenal" extract presumably high in "carbohydrate" factor. In no case was there a nonthrombocytopenic vascular purpura produced in vivo except by the anti-vascular endothelium serum. These preliminary observations are considered to confirm and extend observations made in previous reports in Japanese language periodicals, which are reviewed.

Description: In a study of three subjects with incoagulable blood due to congenital afibrinogenemia, information is presented regarding some basic aspects of coagulation independent, of the fibrinogen-fibrin conversion mechanism. The following facts have been established: (1) Shortly after the blood is exposed to glass, the earliest detectable changes are morphologic alteration in the platelets and their progressive agglutination and lysis. (2) Almost in parallel, plasma antihemophilic activity, originally normal, declines rapidly and practically disappears. (3) Also within minutes, SPCA evolves from its precursor in a normal manner. (4) Acglobulin is rapidly consumed. (5) These changes are well along before detectable amounts of prothrombin have disappeared. (6) Prothrombin consumption proceeds at normal velocity, or slightly faster than normal. (7) Thrombin addition to afibrinogenemic plasma induces platelet agglutination, but this does not occur when thrombin is mixed with platelets alone. (8) The "natural" antithrombic activity of afibrinogenemic plasma is normal. (9) The heparin co-factor of antithrombic activity was demonstrable. (10) Quantitative data were obtained relating the one-stage prothrombin time with the fibrinogen concentration. The theoretic and practical implications of the observations are discussed.

Description: 1. A case of hemoglobinemia and hemoglobinuria with recovery following incomplete drowning is presented. 2. The pathogenesis of the intravascular hemolysis is discussed.

Description: 1. The administration of 20 mg. of folic acid daily to a group of 26 normal subjects and to a group of 22 subjects with some form of anemia other than pernicious anemia for a period of six to twelve months was not harmful to the central nervous system. 2. Pre-existent neurologic changes in both groups of patients were not altered during the period of treatment with folic acid. 3. Hematologic variations in both groups were not significant during the period of treatment. 4. A sense of well being and a diminished incidence of upper respiratory infections were reported by many of the normal subjects to whom folic acid was administered.

Description: 1. Folic acid, when administered alone, did not prevent the development or progression of subacute combined degeneration in 12 of 22 patients receiving this agent for from twelve to twenty-five months. 2. One patient with total gastrectomy and a macrocytic anemia developed subacute combined degeneration after five months of folic acid therapy. 3. Neurologic disease did not develop in 6 pernicious anemia patients treated with folic acid and liver extract for three and one-half to thirty-nine months. 4. In 10 pernicious anemia patients with good nutrition, neurologic relapses did not progress when liver extract or vitamin B12 therapy was instituted, even though folic acid therapy was continued. In 2 patients with abnormal nutrition and complicating organic abnormalities, nervous system disease progressed after institution of liver extract therapy. 5. Our observations are best explained by the theory that the hematologic and neurologic manifestations of pernicious anemia and other macrocytic anemias associated with gastro-intestinal tract pathology and inadequate nutrition are due to a deficiency of more than one substance. The administration of folic acid may improve the hematologic status but induce a deficiency of another substance or substances, e.g., vitamin B12, which are essential for the maintenance of a normal blood picture and the integrity of the central nervous system. This deficiency will eventually result in the development of a suboptimal blood picture or subacute combined degeneration of the spinal cord, or both. 6. The hematologic status of patients with pernicious anemia is not maintained in a more satisfactory state by supplementation of liver extract or vitamin B12 therapy with folic acid. 7. Folic acid therapy did not produce neurologic disease in patients with iron deficiency anemia who had free gastric hydrochloric acid in their gastric secretions and presumably sufficient intrinsic factor. It did not influence response to ferrous sulfate therapy. 8. Patients with sprue, nutritional macrocytic anemia and other macrocytic anemias associated with gastro-intestinal tract pathology who are treated with folic acid should also be given supplemental liver extract or vitamin B12 to insure against the development of nervous system disease.

Description: 1. When the sera of pernicious anemia patients or controls were heated at 100 C. for 30 minutes, they developed the ability to support the growth of L. leichmannii by virtue of some substance other than vitamin B12. It seemed likely, however, that following the administration of the vitamin, such heating also liberated free B12 in the serum from a combined form. 2. The L. leichmannii assay did not appear to be satisfactory for showing possible difference in the levels of vitamin B12 in the urines or sera of pernicious anemia patients and controls. 3. Parenterally administered vitamin B12 did not cause any measurable rise in the serum level of folic acid or citrovorum factor in pernicious anemia patients or controls. 4. The synthetic folic acid conjugates pteroyldiglutamic acid and pteroyltriglutamic acid appeared in the sera and urines of pernicious anemia patients as pteroylglutamic acid or some related substance with folic acid activity for S. faecalis. 5. Orally administered citrovorum factor appeared to be largely converted by the gastric juice to folic acid if free hydrochloric acid was present. When administered parenterally, however, citrovorum factor was excreted in the urine largely unchanged.

Description: Vitamin B12 in doses of 500 to 3000 µg. was given by mouth or by rectum to patients with megaloblastic anemia due to B12 deficiency and to normal subjects. Its absorption was studied by following the hematologic response and/or the changes in serum and urinary B12 concentrations by microbiologic assay with Euglena gracilis var. bacillaris. After oral doses of 1000 to 3000 µg. of B12 there was a definite but variable hematologic response in the thirty-five patients. The serum B12 concentrations, measured in eighteen of these patients, increased in the first twenty-four hours after the dose. The urinary excretion of B12 increased in fifteen out of sixteen patients, but the average amount excreted was only one quarter of that excreted after intramuscular injections producing comparable hematologic responses. The lower urinary excretion after the oral doses was associated with a lower total and uncombined B12 concentration in the serum. In the majority of patients serum B12 concentrations and urinary B12 excretion reached a maximum in the first six hours after the dose. After oral doses of 3000 µg. there was a rise in serum and urinary B12 in three out of four normal subjects. After doses of 500 µg., there was an increase in the serum B12 concentrations of two normal subjects and of one out of two patients with megaloblastic anemia, but there was no change in urinary B12 excretion. After rectal doses of 1000 or 3000 µg. there was evidence of absorption of the vitamin in seven out of eight patients with pernicious anemia.

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: 1. Twenty patients with pernicious anemia were treated under rigidly controlled conditions by administering small oral doses of vitamin B12 in combination with intrinsic factor containing mucinous materials processed from the hog stomach. This study was undertaken in view of our earlier observation concerning the relationship of one of the mucin fractions of the human stomach (glandular mucoprotein) to Castle’s intrinsic factor. The following sources of intrinsic factor from animal stomach were used: (a) commercial gastric mucin; (b) acetic acid extracts of hog pyloric mucosa; (c) mucinous materials precipitated by acetone or by saturation with ammonium sulfate from hydrochloric acid extracts of the hog pyloric mucosa; (d) mucous fractions obtained by further fractionation in the electroconvection apparatus of the above mucinous materials precipitated with ammonium sulfate; (e) an intrinsic factor concentrate from the hog stomach in combination with small doses of vitamin B12, processed under the trade name of Bifacton. 2. Results obtained in this study indicate the feasibility of attaining complete clinical remission and suboptimal or optimal hematopoietic responses in patients with pernicious anemia in relapse when small daily doses (below 20 µg.) of vitamin B12 are given orally in combination with mucinous materials processed by various technics from the hog stomach and containing intrinsic factor. The provisions are that: (1) the doses of both vitamin B12 and intrinsic factor containing materials be adequate and optimal in regard to their mutual ratio; (2) the process involved in processing intrinsic factor containing materials not impair their activity and yield a product sufficiently concentrated. 3. The hematopoietic responses and clinical remissions obtained in six cases of pernicious anemia with Bifacton (vitamin B12 with intrinsic factor concentrate) in different batches were uniform in our hands. The doses employed were marginal, in order to detect differences in potency, and although the reticulocyte responses were frequently suboptimal and protracted, the increases in red cells were roughly equivalent to those obtained with daily administration of approximately 1 unit of a standard oral antianemia preparation. Bifacton is supplied in strikingly smaller dosages than the standard liver or stomach oral preparations, and is fully active in a total daily oral dose of about 50 mg. of intrinsic factor concentrate with 15 µg. vitamin B12. 4. Preliminary studies on two patients with pernicious anemia tend to indicate that the administration of massive single oral doses of Bifacton repeated at intervals of one week may imitate even more closely the results of parenteral treatment with injectable liver concentrates or vitamin B12 than does the administration of this concentrate in small daily doses. The single dose of Bifacton which was given once a week to one of these patients contained 150 µg. vitamin B12 with approximately 250 mg. of intrinsic factor concentrate. Five consecutive single doses administered at intervals of from seven to ten days induced a complete clinical and hematologic remission. 5. The studies on two patients with pernicious anemia indicate that Bifacton is resistant to boiling and that it preserves its hematopoietic activity after being boiled in water for from thirty to forty-five minutes at 95 to 100°C. This suggests either that the intrinsic factor of the animal stomach becomes thermostable after the interaction in vitro with vitamin B12, or that the product of this binding is thermostable under conditions described. 6. The data reported here indicate that various extraction and precipitation procedures may be applied to hog stomach tissue to obtain materials which will exhibit definite intrinsic factor activity in patients with pernicious anemia. Although at present some such extracts are active orally in such small doses as from 40 to 50 mg. per day, still further refinement appears to be possible.

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: Blood smears of 27 cases of hemolytic disease of the newborn were studied intensively for erythrophagocytes. In 25 cases, the smears were positive for this phenomenon. In a control series of 30 normal newborn infants, these cells were not found. Prolonged search and optimum magnification of the smears were important factors in determining the presence or absence of erythrophagocytes in the cases under study.

Description: A case is reported of a probably familial hyperglobulinemia in a 44 year old woman with a circulating anticoagulant, antagonistic to the initial phase of the coagulation, most likely to the antihemophilic globulin. The anticoagulant factor was separated by means of salt precipitation and by electrophoresis. It was shown to be identical with one of the patient's pathologic gamma globulins. There is no reason to suppose an isoimmunization process. The coagulation defect is therefore assumed to be a secondary phenomenon to the patient's probably familial protein disturbance. Dysproteinemia has been observed in hemophilia-like diseases several times but the etiologic connection between the coagulation anomaly and the protein disease has not been previously established. On the other hand, even serious dysproteinemias seem rarely to be complicated by a circulating anticoagulant. A connection between the sedimentation rate and the coagulation of the blood was further shown to be present in our patient.

Description: A method is described for studying the incorporation of radioactive amino acids by leukemic leukocytes in vitro. The effects of time of incubation, concentration of amino acid, temperature, pH, oxygen tension, electrolytes, and glucose concentration on the uptake of S35 L-cystine and S35 L-methionine were studied. The in vitro incorporation of these amino acids appears to be an active process and not solely dependent upon simple diffusion. Reproducible results were obtained under constant conditions. The methods are suitable for studying possible therapeutic agents as well as biochemical abnormalities of leukemic leukocytes.

Description: 1. A simple method for distinguishing between prothrombin and prothrombin conversion accelerators has been described. 2. A deficiency in prothrombin conversion accelerators in the early days after major surgical operations has been observed.

Description: A 59 year old woman with chronic rheumatoid arthritis of twenty years' duration developed chronic granulocytopenia and excessive susceptibility to infection. Mild anemia and symptomless thrombocytopenia were also present. Eight marrow punctures over two and one half years all showed what appeared to be maturation arrest affecting the neutrophils so that segmented polymorphs alone were reduced in number. Throughout this period no form of therapy, including a five day course of ACTH, was effective in promoting normal granulopoiesis; only at the end of this period did the spleen become palpable. Splenectomy resulted in complete symptomatic cure which has been maintained for one year but hematologic cure was not fully obtained. It is believed that this case of splenic neutropenia is really an exaggerated form of Felty's syndrome for the literature shows that malignant neutropenia is not rare in this disease. Furthermore analysis of the literature on splenic neutropenia reveals other cases of an essentially similar nature and the suggestion is put forward that Felty's syndrome may be a fairly common cause of what has been regarded as primary splenic neutropenia. The possible integration of these findings with the immunologic leukopenic mechanism of Moeschlin is briefly discussed.

Description: 1. A successful method of treatment of chronic leg ulcers associated with Mediterranean anemia, employing streptokinase-streptodornase in carboxymethylcellulose jelly, is presented.

Description: One hundred ninety-three cultures of marrows were studied for the presence of fungi. Many of the cases studied had one or more of the classical conditions of histoplasmosis, such as anemia, leukopenia, splenomegaly, hepatomegaly, irregular elevations in temperature, pulmonary disease, and generalized lymphadenopathy. Histoplasma capsulatum was found in only one case. Considering the high incidence of histoplasmin reactors in this locality, it appears that routine cultures of the marrow for Histoplasma capsulatum have little value in histoplasmosis case findings.

Description: 1. Of 76 bone marrow cultures in pediatric patients with a variety of hematologic abnormalities, 5 (6.5 per cent) yielded H. capsulatum. 2. Methods used and brief case reports were described. 3. In 2 of the 5 cases with histoplasmosis, organisms were observed on direct examination of the marrow and cultures were only of confirmatory value. 4. In the remaining 3 patients with histoplasmosis, direct examination of marrow showed no features which distinguished them from the 71 negatives. In these 3 bone marrow culture was the only means by which diagnosis could be established. 5. In no instance in which a negative bone marrow culture for H. capsulatum was obtained, was histoplasmosis diagnosed by other methods. 6. We are of the opinion that while routine marrow culture for H. capsulatum is of little value in adults, it is of considerable value for case finding in infants and children.

Description: 1. Seventy patients with acute leukemia were treated with various folic acid antagonists. Sixty-five survived for a sufficient length of time to evaluate the effect of the therapeutic agents. Types of leukemia observed included 38 cases of acute lymphatic leukemia, 23 patients with acute monocytic leukemia and 4 with the acute myelogenous type of leukemia. 2. The best results, both clinically and hematologically, were obtained in acute lymphatic leukemia. Although the most satisfactory results were observed in the youngest age group, excellent remissions were produced in older individuals. Of 65 cases observed, an excellent clinical and hematologic remission was observed in 11 patients, a partial emission in 19 subjects, and no response in 35 individuals. 3. When a response occurred, a rater definite hematologic pattern was noted. An increased platelet count in most instances was the first evidence of regeneration and occurred in about the third or fourth week. The neutrophilic polymorphonuclear leukocytes began to regenerate at about the same time and an increase in their number was followed by a rise in the erythrocyte count. 4. Observations of the bone marrow indicated that although excellent clinical and hematologic remissions might occur, primitive leukemic cells were still present. In some instances megaloblasts were observed in addition to a peripheral macrocytosis and anisocytosis of erythrocytes. 5. Toxic manifestations were common. These included glossitis, ulceration of the oral cavity, nausea, vomiting, diarrhea and alopecia. In one instance there was ulceration of the entire gastro-intestinal tract, including the esophagus and colon. Hematologic toxic reactions included thrombocytopenia, leukopenia and anemia. Aplasia of marrow tissue was observed in 1 instance. In many instances the margin of safety between a toxic reaction and death was indeed small. 6. It should be emphasized that in no instance has a cure of leukemia resulted from treatment with a folic acid antagonist although prolonged remissions have occurred.

Description: Hematologic studies have been made on 935 randomly selected "control" (nonirradiated) Japanese residing in Kure, Japan, as part of an investigation on the irradiated survivors of the Hiroshima atomic bomb. An analysis of the findings with respect to age and sex indicated that there were a number of divergences from the usual Caucasian expectancies. Associated with a slight anemia in those over puberty there is a progressive increase in the mean size and hemoglobin content of the erythrocyte with increasing age, more pronounced in the male. The hemoglobin concentration in the cells is apparently reduced. The leukocyte counts decrease with increasing age and all mean values are somewhat elevated. Plasma protein levels as determined by the copper sulfate specific gravity method are higher than Caucasian normals. Reticulocyte counts are not unusual. It has been emphasized that this "control" series does not consist entirely of normal healthy individuals, but that a considerable amount of disease is represented especially in regard to parasitic infestation. Also there is an appreciable nutritional imbalance present in the population. These two factors are probably of greatest significance in the interpretation of the observed divergences from Caucasian expectancies, but in view of the complexity of influences and inadequate data relative to each individual studied interpretations must be guarded.

Description: Levels of adenine nucleotides in the blood were determined, using an enzymatic spectrophotometric method. The levels were determined for a large group of normal persons and a larger group of patients chronically ill from a variety of malignant and degenerative diseases. The values for adenyl nucleotides were usually normal; a tendency to increased concentration occurred chiefly in anemia. The varying degrees of increased concentration could not be related to the severity of the anemia or to physical alteration of the red cell. There was probably some relationship to an altered metabolism within the red cell—possibly glycolysis—which in turn might be linked to changes in concentration of electrolytes of the red blood cell, a fact observed in anemia.

Description: 1. The concentration of acid soluble phosphorus, lipid phosphorus and nucleic acid phosphorus was determined in the red cells and polymorphonuclear leukocytes of the rabbit. The concentration of acid soluble phosphorus was of the same order in both types of cells, but there was more lipid phosphorus and nucleic acid phosphorus in the polymorphonuclear leukocytes than in the red cell. Over 80 per cent of the nucleic acid in white cells was of the desoxypentose type. 2. Immature cells were produced in the peripheral blood stream of rabbits either by the administration of phenylhydrazine or by successive bleedings. Either treatment caused a fall in the concentration of hemoglobin, the red cell count and the hematocrit with an increase in the mean corpuscular hemoglobin. There was also an increase in the concentration of acid soluble phosphorus and lipid phosphorus and a great increase in the concentration of nucleic acid phosphorus which was coincident with the increase in number of immature cells as judged by the reticulocyte count. Almost all of the excess nucleic acid was of the pentose type. 3. The basophilia of the immature cells disappeared after treatment with ribonuclease or after hydrolysis with normal hydrochloric acid. Desoxyribonuclease was without effect. 4. These results suggest that the basophilic substance of the immature rabbit red cell, and presumably the reticulum of the reticulocyte, is of cytoplasmic rather than nuclear origin.

Description: 1. The amount of free coproporphyrin and protoporphyrin its the erythrocytes of twenty normal male subjects was found to be 0.76 ± 0.26 and 31.3 ± 11.9 µg./100 ml. of packed RBC, respectively. In ten normal female subjects the values were 0.71 ± 0.23 and 44.6 ± 19.6 µg./100 ml. of packed RBC, respectively. 2. In eighteen male patients with chronic infection, mean values of 1.53 ± 0.61 µg./100 ml. of packed RBC for free erythrocyte coproporphyrin and 181.2 ± 90.6 µg./100 ml. of packed RBC for free erythrocyte protoporphyrin were found.

Description: A case of dual sensitization to the rh'' (E) and hr' (c) factors which was detected antenatally has been presented. The rh'' (E) antibodies probably were caused by a previous blood transfusion which may also have been responsible for the initial stimulation to the hr' (c) antibodies. The subsequent hr' (c) antibodies can be attributed to the hr' (c) factor present in the patient’s three children. In this study the enzyme-treated red blood cell and the antiglobulin tests were more sensitive than the plasma-albumin test in the detection of the antibodies.

Description: In 2 cases of chronic hemolytic anemia with erythrocyte fragility to cold and acid, although the abnormality resides in the red blood cells, serum, whether from the patients or from normal controls, is necessary for the hemolysis. Complement is most likely not responsible for the serum hemolytic activity, because the latter, while similar to complement in certain properties, may be completely dissociated from it. From human serum the euglobulin separated by CO2 and sodium sulphate and the pseudoglobulin I obtained by sodium sulphate precipitation possess hemolytic activity for the cells of the patient and not those of the control. The hemolytic activity of these globulin fractions is increased by chilling and by addition of acid. It is inhibited by serum pseudoglobulin II and albumin. Guinea pig serum aids human serum in its hemolytic activity on susceptible human cells. This augmenting effect of the guinea pig serum is not due to its complement content, nor due to its hetero-hemolysin for all human erythrocyte. In view of the data presented in this and the preceding papers, a new syndrome is suggested which can be clearly differentiated from paroxysmal cold hemoglobinuria and from paroxysmal nocturnal hemoglobinuria.

Description: In the article entitled "Analytical Review: The Interpretation of Red Cell Survival Curves," by A. C. Dornhorst (Blood 6: 1284-1292, 1951), an error in Equation 2, page 1285 occurred. Equation 2 should read: See PDF for Equation

Description: Sublingual administration of crystalline vitamin B12 in daily doses of 25 µg for ten consecutive days failed to induce clinical or hematologic remissions in 5 patients with tropical sprue.

Description: Experiments are described which attempt to define the relation of methemoglobin to hemolysis. A comparison was made in vitro of the resistance of erythrocytes containing chiefly oxyhemoglobin or methemoglobin to hemolysis by saponin, hypotonic saline, bile salts and lysolecithin. These data are interpreted to indicate that intracorpuscular methemoglobin does not alter the resistance of erythrocytes to hemolysis by these lysins, although there are certain peculiarities in the results with bile salts and lysolecithin. In the case of bile salts and lysolecithin, oxyhemoglobin or methemoglobin may have an equal or different inhibitory effect on hemolysis depending upon the conditions of pH and temperature. Chronic methemoglobinemia in dogs maintained by the administration of sodium nitrite does not produce an anemia. These data suggest that the formation of methemoglobin is an independent effect and not a part of the hemolytic action of certain chemical agents.

Description: Hemolysates of human erythrocytes begin to liberate inorganic phosphate as soon as they are lysed. In most cases the process takes place most rapidly at pH 9, but some preparations are about equally active over the entire range from pH 5 to pH 9. The process ceases after incubation for twenty-four hours at 37 C. Hemolysates of human erythrocytes decompose sodium β glycerophosphate and calcium hexose diphosphate about equally. For both substrates there is a well defined maximum of activity at pH 6.0. No other maxima were observed over the range from pH 4 to pH 9. There is some evidence that erythrocytes from patients with various types of anemia liberate more inorganic phosphate when lysed than do those from normal individuals.

Description: Quantitative changes in two serum anti-proteases in several types of adult leukemia are described. High anti-chymotrypsin and low anti-rennin concentrations were observed in the acute leukemias while the reverse was found in chronic forms of the disease. The relationship between the enzyme inhibitors and disease activity in leukemia is similar to that reported in cancer patients.

Description: 1. The fifth known case of Cooley’s anemia in a Chinese child is reported. Death occurred following a febrile illness which was thought to be mumps encephalitis. Autopsy findings were consistent with this diagnosis and with Cooley’s anemia. 2. The remainder of the family showed the characteristic blood findings of Cooley’s trait.

Description: 1. Saccharated ferric oxide in colloidal suspension was administered intravenously on 17 occasions to 13 patients in doses of 100 to 1,000 mg. A prompt arterial leukopenia, followed within 30 to 90 seconds by a similar fall in the venous blood, was observed in all patients who received more than 200 mg. of iron. This leukopenia involved all white cell types. 2. The magnitude of the fall in leukocytes was directly proportional to the amount of material injected, and independent of the rate of injection under the conditions of the study. 3. There was no significant change in the platelet number in arterial or venous blood of 4 patients. In 2 patients an increased clotting power of venous blood containing large amounts of iron was observed only during the period of injection. 4. The colloidal nature of the material is probably the responsible factor in producing the leukopenia.

Description: Five patients with active Hodgkin’s disease were treated for a period varying from four to eighteen days with an antiguanine preparation, guanazolo (5-amino-7-hydroxy-1H-v-triazolo[d]pyrimidine) with a total dosage of 400 mg. to 800 mg. intramuscularly. No therapeutic effect was observed. The only toxic manifestations were pain and tenderness at the site of injection in 4 of the 5 cases. The effect of guanazolo on tissue cultures of an involved node was tested. No inhibition of growth was observed, thus paralleling the lack of in vivo effect.

Description: 1. Six animals (cats) were subjected to four whole body irradiation exposures over a period of one and one-half years. Irradiation dosage was 200 r to the whole body, an amount producing severe hematopoietic abnormalities in the cat. Irradiation in each case was immediately preceded by a large phlebotomy, so that functional impairment of erythropoiesis resulting from irradiation could be assessed in terms of a defective regeneration of erythrocytes. The effect of multiple radiation exposures could also be evaluated for each animal in terms of its prior response to phlebotomy and irradiation. The effects of repeated exposures on the leukocytes could likewise be assessed by means of the comparative leukocyte regeneration curves. 2. Little evidence of permanent functional damage of erythropoietic tissue by repeated exposures under the conditions of this experiment were observed. Erythrocyte and hemoglobin regeneration patterns were very similar from one exposure to another. However, hemoglobin regeneration was slightly slower after the fourth and last irradiation. Whether this represents encroachment on marrow reserve by multiple irradiations or whether it was an artifact resulting from iron deficiency cannot be said with certainty. Multiple exposures exerted little apparent effect on the leukocyte regeneration curves. 3. After recovery from the fourth irradiation, the percentage of mononuclear leukocytes was somewhat less than that prior to the first. 4. It is concluded that while repeated irradiation insults under the conditions of our experiment probably result in hidden damage even in the presence of apparent complete recovery, this damage is so subtle that it is difficult to detect by the tests of marrow reserve employed in this study.

Description: 1. Case reports are presented of 5 cases of acute infectious lymphocytosis in siblings, ages 2¼-10 years. Symptoms included diarrhea, abdominal pain, vomiting, fever and cough. There was an absolute lymphocytosis lasting about three weeks. All of the cases had elevated eosinophil counts during the course of the disease. Four of the 5 had an eosinophilia lasting several months. 2. The clinical features are reviewed. 3. The morphology of the lymphocytes is discussed in detail.

Description: 1. A series of 212 cases of acute leukemia classified according sex and age is presented. Fifty-eight out of 212 were diagnosed by means of phase contrast microscopy. 2. In addition to this personal series, other series collected from the literature tile reviewed. These include both acute and chronic leukemia. 3. The thorough analysis of maximal frequency of the disease according to age, shows that there is, in the course of life, an inverse relation between lymphoid and myeloid leukemias as to the period of life in which they appear. This relation favors the view that a particular ratio of equilibrium must exist between the two systems: lymphoid and myeloid. 4. It is suggested that such an equilibrium might depend upon endocrine factors.

Description: 1. The oral administration of a single or two consecutive daily doses of chloroform to dogs, induced hypoprothrombinemia and lowered the fibrinogen level. Both changes from the normal were most marked 48 hours after chloroform administration. By resting the dogs about 2 weeks between trials comparable reductions in the plasma prothrombin and fibrinogen levels were realized. 2. When caffeine, theobromine, theophylline and adenine were given orally to dogs prior to the oral administration of chloroform and continuing for five consecutive days, the hypoprothrombinemia was either markedly reduced or completely prevented. Creatine, creatinine, guanidine or uracil also afforded some protection. Guanine, xanthine, arginine, allantoin, uric acid or urea gave practically no protection. 3. Caffeine, theobromine, theophylline and adenine also prevented a reduction in the plasma fibrinogen level during chloroform intoxication. Uracil and guanidine showed some protective action, while creatine, creatinine, guanine, xanthine, uric acid, allantoin, urea and arginine gave no detectable protection. 4. Liver injury from the chloroform, as reflected by the bromsulfalein test and icteric plasma, was readily detectable when the methylxanthines or adenine were given with the chloroform, even though no change in prothrombin or fibrinogen level was apparent. 5. It appears that a definite relationship exists between the purine bases (caffeine, theobromine, theophylline and adenine) and the specific function of the liver to elaborate plasma prothrombin and fibrinogen. The capacity of the liver to synthesize prothrombin apparently can be affected independently of other normal functions.