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Ferritin in serum was quantitated by radioimmunoassay to determine the usefulness of this assay in reflecting iron stores during normal development and in the diagnosis of iron deficiency and iron overload in infants and children. In the adult, serum ferritin has been reported to correspond to the magnitude of iron stores throughout a wide range. In 573 normal infants and children, we found the concentration of serum ferritin to parallel known changes in iron stores during development. The median serum ferritin concentration was 101 ng/ml at birth, rose to 356 ng/ml at 1 mo of age, and then fell rapidly to a median value near 30 ng/ml (95% confidence limits: 7-142 ng/ml) between 6 mo and 15 yr of age. In the adult, median concentrations diverged according to sex, 39 ng/ml in the female and 140 ng/ml in the male. In 13 children with iron-deficiency anemia, the serum ferritin concentration was 9 ng/ml or less. Overlap with the normal population was small, and no conditions were found to give "false" low values. In children with β-thalassemia major and sickle cell anemia, median values were elevated to 850 and 160 ng/ml, respectively. Possibly misleading, elevated values were obtained in some patients with acute infection and in acute lymphoblastic leukemia. The serum ferritin assay promises to be a useful tool in the evaluation of iron status, particularly in children.

1. 1. A comparative study of serum lipoprotein profiles of twelve different Old and New World primate species indicated a wide inter- and intra-species variaton. The lipoprotein profile in chimps was the closest to that observed in man. 2. 2. α-Lipoprotein was the predominant lipoprotein class in the majority of the species studied, while pre-β-lipoprotein constituted only a minor component. Old World primates in general had lower levels of β-lipoprotein than others. 3. 3. These observations suggest that serum lipoprotein profiles reflect significant metabolic differences and will be useful in determining inter- and intra-species susceptibility to atherosclerosis.

Measurements were carried out on mice of various ages of some haematological values in the circulatinng blood (number of erythrocytes, leukocytes, platelets; mean erythrocytic volume; haematocrit; haemoglobin) and of some cellular parameters in the bone-marrow and the spleen (total number of cells; transplantibility; total number of haemopoietic stem-cells). Although in some cases significant statistical correlations were found as a function of age, the changes appear biologically of doubtful significance. It is concluded that the potential for division and differentiation of the haemopoietic cells is probably greatly in excess of that required to support the life of the animal and that the problem of ageing must therefore be solved at the cellular rather than at the whole-body level.

1. A survey of the incidence of abnormal hemoglobins in different racial groups distributed over the island of Puerto Rico was performed. The relation of the rate of destruction of red cells to the presence of abnormal hemoglobin patterns in the affected population was also studied. 2. The abnormal hemoglobins were classified by the difference in paper electrophoretic mobility. Fetal hemoglobin was measured by its resistance to alkaline denaturation. The red cell life span was determined by measuring the survival of erythrocytes labelled with radioactive sodium chromate. 3. A total of 2,089 inhabitants were studied. There were 1,487 white subjects and 602 Negroes. Forty-two individuals were found to harbor abnormal hemoglobins. All but one were Negroes or Negroid of African descent, and their relative numbers agreed closely with the geographical distribution of ethnic groups in the island. Abnormal hemoglobins were found in 2.01 per cent of the entire series of 2,089 persons, but in those considered Negroes or Negroids the incidence of abnormal hemoglobins was 6.8 per cent. Of the 42 persons showing abnormal hemoglobins, thirty-four or 81 per cent, had hemoglobin S; only two of these had sickle cell anemia. The incidence of the sickle cell trait among the Puerto Rican Negro population was 5.2 per cent; and the incidence of hemoglobin S disease among those harboring the trait was 5.9 per cent. Eight, or 19 per cent of the abnormal cases had hemoglobin C; only one of these had hemoglobin C disease with clinical hemolytic anemia. The incidence of the hemoglobin C trait among the Puerto Rican Negro population is 1.3 per cent; and the incidence of hemoglobin C disease among those harboring the trait may reach 12.5 per cent. 4. All 42 cases harboring abnormal hemoglobins showed very small quantities of fetal or alkali-resistant hemoglobin ranging from 0.45 per cent to 3.25 per cent, averaging 1.12 per cent. 5. The "apparent" half-life of the red blood cells was found to be 10 days in sickle cell anemia, 7 days in SC disease, 20.6 days in cases of hemoglobin SA, 18.5 days in one case of hemoglobin C disease and 21.5 days in 2 cases of the combination CA. The normal "apparent" half-life in our laboratory is 24.5 days.

1. Different sulfonamides were tested to ascertain their effect in producing the characteristic symptoms of acute PGA deficiency in rats fed on synthetic diets. Sulfasuxidine (1 per cent) and the less soluble phthalylsulfathiazole (1 per cent) were equally effective. Sulfathiazole in 1 per cent concentration produced a hemolytic anemia not reversible by PGA or whole liver powder. In a 0.5 per cent concentration it was also effective, but in view of its toxicity, the less soluble sulfonamides were to be preferred. A mixture of 0.5 per cent sulfathiazole and 0.5 per cent sulfadiazine was extremely toxic and produced a hemolytic anemia. Sulfaguanidine was toxic at 1 per cent concentration. 2. When intermittent small doses of PGA were given to PGA-deficient rats to prolong their life from 45 up to 155 days, 1 per cent sulfasuxidine or phthalylsulfathiazole, or 0.5 per cent sulfathiazole were equally efficient in producing regularly a macrocytic normochromic anemia. 3. The response of PGA-deficient rats to single doses of PGA has been studied and an assay procedure has been suggested which uses the weight increase and duration of cure as the measure of the response. The W.B.C. and reticulocyte response can also be used as a qualitative indication of PGA activity. 4. Of the substances tested by this procedure, vitamin B12, purified pernicious anemia preparations, ascorbic acid and xanthopterin showed no PGA activity. A commercial yeast preparation and Teropterin were found to possess biologic activity comparable with that found by other workers in assays on chicks.

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.

1. Determinations of the oxygen content and the oxygen unsaturation of the venous blood have been performed on patients with varying amounts of hemoglobin. 2. The oxygen unsaturation of the venous blood is independent of the oxygen capacity, unless the latter is reduced below the normal value for oxygen unsaturation (about 5 volumes per cent). In a polycythemic patient, for example, with 33.4 volumes per cent oxygen capacity (181 per cent hemoglobin), the venous oxygen content was. 28 volumes per cent, giving an unsaturation of 5.4 volumes per cent. Similarly, in an anemic patient with only 6.7 volumes per cent oxygen capacity (36 per cent hemoglobin), the venous oxygen was 1.5, giving an unsaturation of 5.2 volumes per cent. This means that the tissues extract from the blood all the oxygen they need with apparently equal readiness, regardless of whether the extraction leaves a great oxygen reserve in the blood as in polycythemia, or practically no reserve as in anemia. 3. The results seem to show that the resting organism does not increase its circulation until all the reserve oxygen is used. This means that the resting anemic organism does not need or use any compensation for its anemia until the hemoglobin has sunk below 30 per cent. Below that value the organism increases the blood flow in order to secure to the tissues the normal amount of oxygen.

The hemoglobin catabolism during the development and during the disappearance of polycythemia induced by hypoxia was studied by measuring the total circulating hemoglobin and the daily bile pigment excretion in bile-fistula dogs before, during, and after prolonged periods of exposure to 20,000 feet simulated altitude. 1. The inscreased erythropoiesis during the first weeks of altitude exposure was accompanied by a signiflcant increase in bile pigment output. The possible sources of this pigment excretion are discussed. 2. The life spans of the red cells during altitude exposure was found to be about 115 days. No differences were observed in the longevity of the cells in animals at ground level and at altitude. 3. The normalization of the polycythemic blood levels took place within six to eight weeks after returns to ground level, and was achieved by the combined effect of a depressed erythropoiesis and of an increased blood destruction. The increase in red cell destruction observed under these conditions demonstrates the existence of an "active" mechanism of blood destrunction by which the organism is able to destroy normal blood cells before their life span is exhausted. This increased red cell destruction, however, accounted for only 21 to 39 per cent of the hemoglobin which disappeared from circulation after return to ground level. The major part of the normalization of altitude polycythemia was brought about by a temporary depression of erythropoiesis which was estimated to amount to 30 or 40 per cent of the normal cell production in the six weeks after the discontinuation of the altitude exposure.

Methemoglobinemia is unusually frequent in Alaskan Eskimos and Indians in whom 15 confirmed cases in a population of about 20,000 are known. It appears to be due to the absence of a factor in red cells which mediates the reduction of methemoglobin by reduced pyridine nucleotides. This anomaly is probably inherited as a recessive trait. The amount of methemoglobin present at any one time in these persons is variable, depending on some environmental influence. The evidence suggests that this environmental influence is the dietary intake of ascorbic acid.

Low-density lipoprotein levels have been determined in 1109 men and 745 women from a New Zealand urban population. Particular care was taken to obtain adequate samples from either extremity of the age range, 15–71 years and over. High molecular weight Dextran Sulphate was employed as the polyanion in a turbidometric method for low-density lipoprotein assay. A logarithmic normal distribution of low-density lipoprotein levels was found in the total population sample, and in sub-groups selected according to age and sex. The changes in mean low-density lipoprotein level with age showed differing patterns between the sexes. Possible explanations for the logarithmic normal distribution are discussed. It is suggested that the differences between mean low-density lipoprotein values in men and women may be a reflection of differing hormonal patterns operating over successive decades.

A congenital familial chronic hemolytic anemia not conforming to the known types was observed in 3 members of a French-Canadian family. The erythrocytes were normochromic, normocytic to macrocytic, and had normal osmotic and mechanical fragility. Spherocytosis. elliptocytosis and sickling were absent but a moderate degree of ovalocytosis was present in many of the patients’ red corpuscles. No acid hemolysis could be demonstrated. The survival of erythrocytes transfused from one of the patients to a normal recipient was significantly shortened, whereas normal erythrocytes transfused into 2 of the patients survived normally, indicating an intracorpuscular defect. Clinically the condition was characterized by jaundice, hepatosplenomegaly, osseous changes, and a tendency toward the development of mongoloid facies. Typical hemolytic crises have been absent. Despite moderately severe anemia there has been remarkably little interference with normal childhood activity.

1. "Inclusion bodies," distinguishable from the Howell-Jolly bodies, were observed in the red blood cells of a patient with a severe refractory fatal anemia, who had been receiving erythrol tetranitrate over a period of one year. 2. "Bodies" with similar staining characteristics were reproduced in cats with large oral doses of erythrol tetranitrate and other nitrates. These were generally accompanied by a temporary fall in the red cell count, followed by recovery upon withdrawal of the drug.

The family history, case history and genealogy of a 6 year old girl suffering from a chronic hemolytic anemia is presented. The disease, resulting from her inheritance of both the gene for sickle trait and that for thalassemia trait, is compared to a similar case in a 38 year old male reported by Powell, et al. To date the child has had no clinical evidence of an hemolytic anemia, except for an enlarged spleen. Hematologically, however, all findings indicate the presence of a brisk hemolytic process. Electrophoretic analysis of the patienst’s hemoglobin reveals a unique pattern intermediate between the usual sickle cell trait and sickle anemia patterns.

Two cases of hypochromic anemia with erythronormoblastic marrows and giant stab-cells are reported. Both cases deteriorated when only on iron treatment; the first responded to pyridoxine therapy and the second to nicotinic acid. Neither of the patients had diarrhea or steatorrhea and all were on the normal tropical hospital diet, similar to that given to the other patients who responded to iron therapy alone. The patients were under our constant control and were in the hospital from three to four weeks and had no other treatment. The diet of these two patients before they entered hospital did not appear to differ from that of other Africans with whom we have been dealing. The presence of G.S.C. in the marrow is in our opinion associated with a deficiency of folic acid, due either to malabsorption following the anemia or low intake associated with poor appetite. In many cases G.S.C. disappear during treatment with iron alone, perhaps due to improvement in absorption or appetite. In others supplementary folic acid is necessary.31,32,34 Bone marrow biopsy done in eight other cases of pellagra showed no giant stab-cells and the marrow was normal except for an increase in plasma cells and eosinophils. We do not think that pyridoxine or nicotinic acid were responsible for their presence in these cases, since giant stab-cells are found in all megaloblastic anemias and in some cases of hypochromic anemia, as well as in other conditions where there is no evidence of either pyridoxine or nicotinic acid deficiency. There was nothing significant about the serum proteins which were within normal range; the albumin globulin ratio was, however, reversed in both patients (tables 1 and 2) and remained so on discharge from hospital. This reversed A/G ratio is common in many Africans and Indians, is not related to anemia and may be associated with diet or be genetically determined.31-32,35,36 Until the exhibition of pyridoxine and nicotinic acid the patients were making no progress, but afterwards they made an uninterrupted cure and were discharged from the hospital feeling well. The reticulocytosis was the expected one for the blood count and hemoglobin level, and as will be seen from figures 1 and 2 did not occur until after either pyridoxine or nicotinic acid had been given. As in Dinning’s and Day’s pyridoxine deficient rats we also found in our pyridoxine-treated patients that there were increased R.B.C. counts and low hemoglobins with the mean corposcular hemoglobin of 20γγg. and 17 γγg. In eight other cases of typical pellagra there was, however, no sign of anemia at all, the hemoglobin range being between 15 to 16 Gm. per 100 ml. At this altitude (6,000 feet) "pure" iron deficient anemia is rather rare32 and it was no surprise to us that these two cases failed to respond to iron therapy alone and that they needed other factors. Pyridoxine appears in some way to be associated with hemopoiesis. Its absence does not in all cases give rise to anemia but sometimes produces abnormalites in red and white cell maturation and hemoglobin production in man and animals. The role of nicotinic acid in hemopoiesis is obscure. We realize that two swallows do not make a summer, and we have no idea how important a part pyridoxine and nicotinic acid play in hemopoiesis. Since, however, such pyridoxine and nicotinic acid-responding cases are rather infrequent we thought it worthwhile to record these two cases.

Iron depletion is considered to be present when staining of bone marrow fragments for hemosiderin gives a negative result; anemia may be absent in that case. Several other methods of investigation which can render iron depletion probable are discussed. Iron depletion without anemia, especially in infants and women, seems to be quite common in affluent societies such as exist in North America and Western Europe. In these cases it is often transient, as is illustrated with some examples. It is also shown that in males who have been gastrectomized usually no anemia arises although iron depletion frequently develops. Women with iron depletion in the reproductive age, however, run a rather great risk of developing irondeficiency anemia because of menstrual blood loss and pregnancies. In iron depletion without anemia, a decrease of iron-containing enzymes has been found in some tissues; it has not been demonstrated, however, that this decrease has any pathological significance. Neither has it been shown that iron depletion as such causes clinical symptoms. Until now no practical methods have been developed to artificially enrich food elements satisfactorily with iron. At present the best way to prevent iron-deficiency anemia in women, particularly in pregnancy, seems to be to strive for a well-balanced diet with an adequate amount of iron-rich constituents. In pregnancy, however, regular controls of the blood picture remain necessary to ensure early diagnosis and adequate treatment of anemia.

Studies have been presented on blood, bone marrow, coagulation and their relation to mortality in guinea pigs exposed to 200, 400 and 600 r total body x-irradiation. The initial responses of the blood and bone marrow were remarkably similar for the 3 doses of x-irradiation (ranging from LD10 to LD100). Marked differences among the dosages were noted in regeneration which occurred earliest after 200 r, later after 400 r and not at all after 600 r. Once started, regeneration was equally active after 200 and 400 r. A coagulation defect, closely related to thrombocytopenia, was observed in the 6 to 13 day period following all doses of irradiation. An additional clotting defect, characterized by increases in the prothrombin time and heparin clotting time, was noted at 4 and 24 hours following all 3 doses of irradiation. The etiology of this defect requires further evaluation. The pattern of hemorrhage, evaluated in various tissues by a semiquantitative scoring method, revealed that hemorrhage was most prominent in the 9 to 13 day period after exposure, and was closely related to thrombocytopenia. As the dose of x-ray increased, hemorrhage tended to become more protracted and severe and involved more organs. Hemorrhage disappeared rapidly as platelet formation returned in the recovery period. Hemorrhage was the chief factor in the severity and incidence of anemia after irradiation.

A case of interaction of the genes for hemoglobin C and "high fetal" has been reported, with an incomplete family study. The "high F" gene seems to behave as a dominant one. A discussion of the relationship, if any, with this disease to "classical" C-thalassemia was presented. The evidence is inconclusive, but this case does not fit the picture of C-thalassemia as previously reported and is considered to be a separate condition.

1. The titers of the isoagglutinins anti-A and anti-B in pregnant women at term do not differ significantly from the isoagglutinin titers in normal male adult blood donors. This indicates that pregnancy itself does not ordinarily stimulate a rise in isoagglutinin titer. 2. The frequency of incompatible blood groups in the infants of 31 mothers with toxemia of pregnancy was slightly higher (29 per cent) than that in a series of 166 infants of mothers without toxemia (22.3 per cent), but the difference was not statistically significant. 3. Of 37 normal mothers whose infants had blood groups incompatible with theirs, 9 were found to have a significant rise in isoagglutinin titer one week post partum. An appreciable rise in isoagglutinin titer occurred under similar circumstances in 6 of 9 mothers with toxemia. The series are too small to permit definite conclusions regarding the significance of this in relation to toxemia. However, there appears to be no doubt that under certain circumstances parturition can stimulate a rise in the maternal isoagglutinin titer. 4. No correlation was found between the occurrence of Rh incompatibility and toxemia of pregnancy. 5. The data obtained furnish additional evidence to support the theory of multiple allelic genes of heredity of the Rh blood types and also Race and Taylor’s theory of inheritance of the Hr factor.

Young rats on a diet low in phosphorus can be protected from rickets by irradiations with sunlight for about 15 minutes daily. In the winter months, however, this degree of light was found insufficient. The effective rays of the sun, in the intensities studied, did not penetrate window glass. They manifested some protective value after reflection from a smooth white surface. Irradiation of a few minutes with the rays of the mercury vapor lamp suffices to protect rats against rickets. This is true likewise of the rays from the carbon arc lamp. A standard protective dose of radiation can be formulated for rats on a standard diet. Light is able to prevent the occurrence of rickets in rats fed a rickets-producing diet characterized either by a low phosphorus and high calcium content, or a high phosphorus and low calcium content. Moderate variations in temperature do not alter the effective action of light rays. Pigmentation of the skin markedly lessens their effect, as demonstrated by the failure of a standard dose to protect black rats.

DFP32 or Cr51 red cell survival studies were performed in 39 patients with hematologic disorders. In each case the erythrocyte life span was also determined using the C14-labeled glycine technic. Good agreement was found between the survival data obtained by the DFP32 and the glycine method. The red cell Cr51 T½ failed to reflect moderate shortening of red cell survival in a significant number of cases when a 25 day half-time was taken as the lower limit of normal. The occasional discrepancy between the erythrocyte life spans obtained with labeled glycine and the Cr51 halftime is probably the result of the limitations of the prevalent method of Cr51 data analysis and of the wide range of Cr51 elution rates in disease. Because of its simplicity and reliability, the DFP32 technics appears to be the method of choice for the determination of red cell survival.

The increase in phagocytic function of neutrophiles of mice was measured during the progressive development of anemia due to blood loss. The animals were bled from the tail, 2 per cent of total body weight being removed twice weekly for nine bleedings. Phagocytosis was 161 per cent of normal at the end of this period, and the erythrocyte totals and hemoglobin values were approximately two thirds of normal. The anemic mice were infected intraperitoneally with a suspension of Salmonella typhimurium and their survival rate was compared with normal mice similarly infected. Twenty-eight of 63 anemic mice survived and 14 of 63 normal mice survived. In a second experiment, mice were subjected to bleeding every third day for nine bleedings, and were then infected along with a control group. One half of the anemic animals were bled for three additional bleedings after the infection. Two of 48 control animals survived, 5 of 47 anemic mice, additionally bled, survived, and 19 of 47 anemic mice, not bled after infection, survived. This suggests that the increase in phagocytosis that accompanies anemia may be, at least in part, responsible for the increased resistance to infection.

Assuming the typical colon bacillus and the typical typhoid bacillus to represent the types of this group that present the greatest divergences in biological peculiarities, we conclude, as others also have done, that there is a series of closely related forms that may be regarded as intermediate or transitional and which serve to establish a biological relationship, either near or remote, between these two typical members. From our own studies we are inclined to regard the typical colon bacillus as the type of this group, for the reason that its functional equilibrium, as observed in the intestine, is so permanent a quality that it may readily be perpetuated under what is ordinarily regarded as favorable artificial circumstances, and that with the continuance of such conditions there is no conspicuous tendency on the part of this organism to deviate from what we regard as its norm; whereas, on the other hand, with all the other members of this group with which we have worked, there is not only a lack of uniformity in the adjustment of the functions, but such as exists is readily disturbed under artificial environment; though it must be borne in mind that even with the typical colon bacillus we have also shown functional modifications to be possible under particular conditions. When the members of the colon group are cultivated under circumstances favorable to the development of both the function of fermentation and that of proteolysis, fermentation invariably takes precedence and no evidence of proteolysis is manifested until after fermentation has ceased. The cultivation of all the members of the colon group under circumstances that favor the development of one function, viz. that of proteolysis, at the expense of another, viz. that of fermentation, results first in an apparent increase of vigor; but this is of temporary duration and is quickly followed by the decline and death of the cell. The result of this increased activity of the proteolytic function is the formation of much larger amounts of indol by typical colon cultures than has ever been obtained by us by any other method. By the method of experimentation through which we were enabled to accentuate the proteolytic activity of the typical colon bacillus, as caused by an increase of indol formation, we have also induced the function of indol formation not only in atypical colon bacilli that had been devoid of it, but in every specimen of typical typhoid bacilli to which we had access as well. We feel justified in regarding one of the differential tests between the typhoid and colon bacillus, namely that of indol formation on the part of the latter and the absence of this function from the former, as of questionable value, for the reason, as shown above, that by particular methods of cultivation indol production has been shown to accompany the development of a number of specimens that we have every reason to regard as genuine typhoid bacilli. As a result of our own experiments, together with the observations of others, there can be no doubt that the bacillus coli communis at times possesses pathogenic properties, and that by artificial methods of treatment it may often be brought from a condition of benignity to one of virulence. The spleen of a typhoid patient has always been regarded as the only trustworthy source from which to obtain the typical typhoid bacillus. While we believe this to be true, still our investigations show that other members of the colon group may also be present in this viscus; in fact, from such spleens we have isolated practically all of the varieties of this group with which we are acquainted. From our experience, the value of the serum test for the differentiation of typhoid and colon bacilli would seem to be questionable. We are inclined, however, to attribute the irregularities recorded above as due more to the method of application than to defects of the principles involved; for, as stated, by the use of dried blood, as in our experiments, it is not possible to make the test with constant and accurate, or even approximately accurate, dilutions of the serum. Our irregularities may be in part due to this defect. We therefore lay less stress upon this than upon the other features of our work.

1. A hemophilia-like disease acquired during the first pregnancy of a young woman, is described. 2. The clotting abnormality was caused by a circulating anticoagulant which, in all probability, inhibited the antihemophilic globulin. 3. The anticoagulant was demonstrated in the patient's second child during his first two and one-half months of life. 4. The transplacental transfer of the anticoagulant and the analogy of this condition to hemophilia (resistant to therapy) following iso-immunization against antihemophilic globulin, strongly suggest that an immunologic mechanism accounts for the development of this abnormality. 5. The patient recovered eighteen months after her second delivery and sixteen months after x-ray sterilization. The possible relation between endocrine factors and recovery is discussed.

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.

Two adult patients with sickle cell anemia of blood group A and A2B respectively, received sufficient transfusions of group O blood to maintain nearly normal hemoglobin concentrations for 4 months or longer. Serial samples of the erythrocytes of each recipient were obtained by agglutination with anti-A (and anti-B) serum. The proportion of Hb F in the agglutinated erythrocytes was determined. Early in the transfusion period, a marked rise in the proportion of Hb F was noted. This rise was attributed to prolonged survival of erythrocytes which contained larger proportions of Hb F. In the later part of the transfusion period, the proportion of fetal hemoglobin declined to pre-transfusion levels or below. However, significant amounts of fetal hemoglobin in the erythrocytes of each patient were demonstrated throughout the period of study, and Fe59 incorporation into Hb F in vivo was demonstrated in one patient after 4 months of transfusion therapy. Under the conditions of these studies, synthesis of Hb F continued despite prolonged correction of the anemia. A decline in the proportion of Hb F in the erythrocytes of one patient after 5 months of transfusions suggested that Hb F synthesis may ultimately be depressed by transfusions. It was suggested that the proportion of fetal hemoglobin observed in the erythrocytes might in certain diseases reflect the degree of anemia present many months before.

Leukoagglutinins were shown to occur in sera from nontransfused gravid Negro, Caucasian and Asian women. Investigations into the relationship of parity to the incidence of leukoagglutinins indicated that two pregnancies were usually required before leukoagglutinins became demonstrable in the gravid women. In their second pregnancies, 13 of 68 women (19 per cent) possessed leukoagglutinins. In families with two children, the leukocytes of both offspring contained the potential antigenic stimulus for leukoagglutinin production. In this series with increasing parity, the proportion of women immunized did not significantly differ. The significance of the frequent leukocyte sensitization was discussed. Leukoagglutinins persisted in the sera of parous women for varying periods of time after parturition. The antibodies of 16 of 31 women could still be identified in their sera three years after delivery. The distribution of potentially stimulating leukocyte antigens in the offspring of two large families provided suggestive evidence that the formation of leukoagglutinins had persisted in the two women for eight years after sensitization. The leukoagglutinins found in gravid women had numerous specificities. Eighteen of the 40 specificities (agglutination patterns) of leukoagglutinins were observed in the sera of other women. With increasing time after delivery, the specificity of leukoagglutinating sera tended to become narrower than the serum sample obtained at parturition.

Serial studies revealed characteristic changes in the peripheral blood of infants with erythroblastosis fetalis. In the presence of elevated nucleated red cells and reticulocytosis, replacement transfusion brought about a momentary decline to normal levels followed by a second rise during the succeeding three days before the values returned to low levels. Platelet counts diminished within a day after replacement and only gradually rose toward normal after approximately three days. Such a picture was not seen in the mildly affected babies who did not receive replacement therapy, in whom the platelet values varied. Within the first three months in both groups anemia developed in the presence of little evidence of compensating marrow activity. After a decline of the hemoglobin to an average level of 7.6 Gm. per cent, erythropoiesis became adequate for return to normal levels. This hypoplastic defect could not be correlated with any other parameter of the disease. Abnormalities were noted in the osmotic and mechanical fragility of the red cells in this disease. The major population of cells was found to be more susceptible to osmotic stress while the limits of hemolysis were within the normal range. The osmotic curves of the blood of those patients who were not transfused returned to normal within 4 weeks. Mechanical fragility of the red cells was increased in a significant number, and this abnormality was observed until the time when minimal hemoglobin values were reached. There was no correlation of these variations in fragility with other laboratory or clinical manifestations of the disease.

Profound, transient neutropenia is observed early in hemodialysis. The present studies were performed during 11 twin-coil dialyses in eight patients with chronic renal failure to determine if the rapid recovery reflects remobilization of sequestered neutrophils and/or if marrow reserves are utilized. In five studies, in vitro cell tagging with diisopropylfluorophosphate-32P (DF 32P) and reinfusion were performed 4-6 hr before routine hemodialysis. In all 11 studies a marked decrease of the absolute neutrophil count occurred within 15 min of starting blood return from the coil. In nine studies carried on over a sufficient period of time, a rebound of the neutrophil count to levels significantly higher than the highest control counts occurred by 1½-3½ hr after starting dialysis. In the radioactive studies during the rebound phase, most or all of the expected number of labeled neutrophils returned to the circulation, but simultaneously in all cases a large number of extra unlabeled neutrophils appeared in circulation. Since there are two sources for additional circulating neutrophils—the marginated pool and the marrow reserves—and since the marginated pool under the study conditions would be expected to have the same specific radioactivity as the circulating pool, the data are consistent with the hypothesis that there was an immediate marrow response to neutropenia.

The blood picture of 100 patients with Addison’s disease was analyzed. Under basal conditions, there was a tendency toward lymphocytosis and neutropenia. Under stress, the blood picture remained fixed. The impaired ability of those patients to show leucocytosis and lymphopenia is attributable to their impaired adrenal function. While large doses of desoxycorticosterone and maintenance doses of adrenal extract had no effect on the blood picture, 17-oxysteroids produce both neutrophilia and lymphopenia. The anemia present in Addison’s disease is normocytic and normochromic.

Clinical, hematologic and genetic data on 28 cases of hereditary spherocytosis are presented for the purpose of characterizing this disorder as completely as possible. On the basis of this experience it is recommended that the following typical laboratory findings be sought in establishing a diagnosis in suspected cases: (1) Presence of spherocytes or abnormally thick red cells in peripheral blood; (2) greater than normal osmotic fragility of the red cells; in cases in which the fragility of fresh cells is not significantly increased, determinations should be made after sterile incubation of the blood at body temperature for 24 hours; (3) greater than normal mechanical fragility of freshly drawn red cells; (4) negative antiglobulin (Coombs) test; (5) greater than normal lysis of the red cells during sterile incubation at body temperature for 48 hours; and (6) presence of similar abnormalities in relatives. Abnormality of the erythrocyte persisted in all of the 11 patients in this series followed one or more years after splenectomy. An unusual case of chronic hemolytic anemia is described but not included in the numbered series because (1) both parents were hematologically normal and (2) spherocytosis and abnormally great osmotic and mechanical fragility and autohemolysis could not be demonstrated after the fifth postoperative month. Classification of this case is deferred pending further experience. Demonstration in a parent, sibling or offspring of red cells showing the afore-mentioned abnormalities is necessary for an unequivocal diagnosis, but this requirement cannot always be met because relatives may not be available for examination. Moreover, when parents and/or several siblings are examined without positive findings, low gene expressivity, gene mutation and illegitimacy may be considered as explanations. Evidence is cited to suggest the possibility of a low degree of penetrance or expression in some cases and to illustrate the need for still more sensitive laboratory tests that might aid in diagnosis of the mildest forms of this disease. The lower incidence of spherocytosis in siblings of propositi than in offspring of propositi is cited as evidence bearing on the theory of gene mutation in some propositi. A simplified "qualitative" test of osmotic fragility of incubated red cells is described.

1. The results of investigations upon some aspects of anemia in rheumatoid arthritis are reported and discussed. 2. The anemia was essentially normocytic and hypochromic, the mean corpuscular volume being usually normal and the mean corpuscular hemoglobin content and concentration usually reduced. Anemia was more pronounced in the presence of very active disease. 3. Undue hemolysis was not of importance. 4. The myelogram showed no gross abnormality but suggested impaired maturation of normoblasts and retarded hemoglobin formation. 5. The blood and plasma volumes were not essentially abnormal, though the frequent asthenic habitus and loss of weight might produce apparently exalted values in terms of body weight. In the more anemic cases, changes common to many anemias were found, viz., normal plasma volume with decreased corpuscle and whole blood volume. 6. The plasma iron concentration was usually reduced; subnormal values were invariable in cases with very active disease or marked anemia. 7. The iron-binding capacity of the serum might be raised by iron deficiency or slightly reduced but not enough to be a factor in producing or maintaining anemia. 8. As judged by changes in the plasma iron, intestinal absorption of iron after a single maximal therapeutic dose was variable. Some cases showed the excellent absorption and therapeutic response characteristic of simple iron deficiency. Others gave strong presumptive evidence of impaired absorption.

1. The hemorrhagic syndrome of acute radiation illness in goats and swine has been described. This syndrome is predominantly a result of a combination of "increased vascular fragility" and thrombopenia. Infrequently, a blood coagulalation defect characterized by a prolonged clotting time due to a circulating anticoagulant with heparin-like properties appears, thus confirming under some conditions in goats and swine the work of Allen on "heparinemia" in irradiated dogs. 2. The prolonged blood coagulation time appeared only in fatally irradiated goats and swine. 3. Evidence was presented suggesting that serum fibrinolysins may have been activated. 4. It is concluded on the basis of this work and that of others that a hemorrhagic syndrome can develop in irradiated dogs, goats, swine, rats, chickens and guinea pigs without the appearance of a prolonged clotting time and without a detectible "heparinemia." The biologically most universal phenomena observed in the hemorrhagic syndrome of radiation illness appear to be: (a) increased vascular fragility, (b) thrombopenia, and (c) ulcerations. ACKNOWLEDGMENTS The author is highly indebted to Captain R. H. Draeger, MC, USN, officer in charge; Captain Shields Warren, MC, USNR, executive officer; Commander, John L. Tullis, MC, USN, pathologist, Naval Medical Research Section Operation Crossroads for guidance and assistance in all phases of this work, and to Dr. George V. LeRoy for having kindly edited this paper and given valuable suggestions.

Two severe hemolytic crises, in a month’s period, were induced by primaquine in a glucose-6-phosphate dehydrogenase deficient Sardinian male. Young red blood cells tagged with Fe59 10 to 16 days earlier were destroyed in the second hemolytic episode. The implications of these experiments on the nature of drug-induced hemolysis in Caucasians are briefly discussed.

The effect of RBC hemolysates on the recovery from anemia due to blood removal was studied in four dogs. For that purpose each dog was bled on two occasions to obtain similar degrees of anemia, and the erythrocytic production was measured during the 14- to 18-day lapse following each bleeding. A 2- to 3-month interval was allowed between bleedings. The erythrocytic production was evaluated by Cr51 determinations of the circulating erythrocyte volume (EV) after each bleeding and at the end of the 14- to 18-day lapse. During the control study, the dogs received iron intramuscularly and saline intraperitoneally; the latter was substituted by hemolyzed RBC during the test study. The erythrocytic production, in terms of ml. of EV gained per Kg. and per day, in every animal was higher during the test study: 1.126 to 2.411 (mean, 1.568) times the production of the same dog during the control study. The results furnish strong evidence that the products of erythrocytic destruction have an enhancing effect on the recovery of anemia induced by bleedings in dogs.

A woman with a history of thrombocytopenic purpura occurring approximately every twenty-eight days was studied extensively on the Metabolic Research Ward. The patient had been treated previously with splenectomy and hystero-oophorectomy without improvement. The cyclical nature of her thrombocytopenia was documented by repeated hematologic observations. Endocrinologic studies demonstrated no evidence of ovarian activity or cyclical variations in adrenal activity. Urinary gonadotropins (FSH) fell coincident with the fall in platelets and suggest that cyclical pituitary function might be related in some way. The exact etiologic mechanisms, however, were not disclosed by this study.

1. Three siblings with Hb H thalassemia disease have been observed in a family in which 17 members from 3 generations have been examined. Four additional family members have α-thalassemia minor. 2. A genetic examination of the family provides further evidence for the theory that Hb H thalassemia disease is due to the interaction of the α-thalassemia gene and another "silent" gene which, however, does appear to produce minor morphologic abnormalities when present alone. 3. Reevaluation of the effects of splenectomy indicate that this procedure may be of significant benefit only in the more severe cases of Hb H disease.

1. Geographic, clinical and genetic data of 35 new cases of microdrepanocytic disease are presented. 2. These data suggest that sickle cell trait and microdrepanocytic disease are not infrequent in the eastern district of Sicily, perhaps with some small foci of sicklemic subjects. 3. The clinical history of adult patients and the personal examination of some cases of microdrepanocytic disease in children show the existence of mild forms of the disease and of forms appearing late in life. 4. From the clinical viewpoint, this series shows several interesting findings in the patients with microdrepanocytic disease: painful osteoarticular crises are inconstantly present; splenomegaly may undergo a spontaneous lessening during the course of the disease, analogous to that which occurs in sickle cell anemia; in women with microdrepanocytic disease miscarriages are frequent and successful pregnancies and births are extremely rare. 5. Hematologic studies reveal hypochromic anemia, leukocytosis, nucleated erythrocytes in the circulating blood, marked abnormalities in the morphology of the erythrocytes, and decreased cell fragility to hypotonic saline. 6. Genetic studies of the new cases again show the simultaneous presence in the patients with microdrepanocytic disease of the genes responsible for microcythemia and sickle cell trait.

A method for determining erythrocyte cholinesterase titers on small samples of whole blood is described in detail. The method is one which requires little special equipment and can be used by any competent technician. Data for erythrocyte cholinesterase are presented on a group of 101 normal adults, and it is shown that the observed data fit the normal distribution. Eighteen children, aged three months to ten years, all had values within the adult distribution, and the mean value was the same as that for adults. Seven newborn babies all had values at or below the lower limit for adults.

Megaloblastosis has been produced in young guinea pigs by feeding them purified diets deficient its pteroylglutamic acid (PGA) or vitamin B12 or both. The withholding of ascorbic acid from the diet did not produce megaloblastosis but it greatly enhanced its development when PGA was also withheld. Spontaneous remission took place in several instances. The possible role of growth of the animal and changes in the bacterial flora of the gastrointestinal tract has been discussed. Bacteriologic studies appeared to indicate a possible interrelationship between the occurrence of Escherichia coli in the stools of guinea pigs consuming deficient diets and the development of megaloblastosis. Diarrhea and infections are considered important in the pathogenesis of megaloblastic anemia but infections were not observed in animals of the present study. However, diarrhea was a prominent feature and appeared to be a factor associated with megaloblastosis. Anemia was usually present in association with megaloblastosis; however, megaloblastosis of a mild degree appearing in some of the animals fed the diets deficient in PGA or vitamin B12 was not accompanied by anemia. When ascorbic acid was withheld in addition, then anemia always developed. A dimorphic picture of macrocytosis and microcytosis was found most commonly in the peripheral blood of animals with megaloblastosis. This has been explained on the basis of regenerative macrocytosis or as a disturbance of the maturation of erythrocytes in such deficiencies. Data obtained from peripheral blood are not a reliable indicator of megaloblastosis, nor is the clinical condition of the animal indicative of the pathologic state. One animal which had been fed a diet deficient in vitamin B12 and PGA and which showed megaloblasts in its bone marrow was given injections of vitamin B12. The megaloblastosis was corrected but the animal died on the sixteenth day of treatment. Two animals fed diets deficient in PGA and ascorbic acid were subsequently given injections of PGA and ascorbic acid. The results demonstrated that administration of ascorbic acid alone did not interrupt the development of severe megaloblastosis in the continuing absence of PGA. When PGA was given, reticuocytosis then ensued and there was a reversal of megaloblastic erythropoiesis.

Induced hypothermia in the 13-lined ground squirrel Citellus t. tridecemlineatus profoundly affected an infection with Hymenolepis citelli (Cestoda). Effects noted on growth and development were as follows: size, weight, proglottid differentiation, and gametogenesis were significantly retarded; polysaccharide and protein concentrations were reduced; and alcohol-soluble sugar concentration was increased. Less than 6% of the cestodes established themselves in squirrels if hypothermia was induced within 72 hr postinoculation. Also adult cestodes were destrobilated 3–4 weeks after the onset of hypothermia, but the scoleces remained in about 50% of the hosts at the end of 6 months of host hypothermia.

In the normal individual the amount of iron absorbed and lost from the body each day is exceedingly small. There are certain periods during life when body iron requirements are increased; the most important of these is infancy. Here, existing iron stores are rapidly depleted, and a deficient diet can soon produce iron deficiency. Once a full complement of body iron has been accrued, the adult is independent of iron intake and becomes iron deficient only through blood loss. In the production of iron deficiency, iron stores are exhausted before anemia appears. If any question in diagnosis from usual laboratory tests exists, the direct. examination of marrow for hemosiderin will establish the diagnosis. It is of obvious importance to confirm the diagnosis by specific therapy and to determine the cause of the iron depletion. Response to oral iron is highly predictable and failure of response usually in dictates a mistaken diagnosis. In a small but significant group of patients, either unable to take iron because of gastrointestinal symptoms, unable to absorb iron, or in need of iron reserves, parenteral administration of iron has distinct advantages. The saccharated oxide of iron is an effective preparation for this purpose.

During an electrophoretic study of the hemoglobin from 150 persons belonging to the Eti-Turk community, two individuals with hemoglobin E trait and one case of sickle-cell-hemoglobin E disease were discovered. The results of this investigation combined with those of other electrophoretic studies performed previously in this community indicate that the incidence of hemoglobin E among Eti-Turks is 1.37 per cent. The importance of the occurrence of hemoglobin E in this community has been discussed, and a possible relationship between Eti-Turks and some people of India has been postulated.

As a further test of the theory of tropin action proposed in the preceding paper artificial surfaces have been prepared, and have been found to be phagocytized according to prediction from the theory. Protein was adsorbed on collodion particles according to the technique of F. S. Jones. These particles were then agglutinated and prepared for phagocytosis by the corresponding protein precipitin sera. The precipitating, agglutinating, surface and tropin effects for each serum or serum globulin fraction have been found to be in satisfactory quantitative correspondence. All of these effects were serologically specific; all remained almost unaffected by inactivation of the immune sera for 30 minutes at 56°C. or by washing of the particles after sensitization. The surfaces of particles maximally sensitized by homologous rabbit immune serum or one of its globulin fractions have shown certain characteristic properties, i.e., they were cohesive, had wetting properties characteristic for protein, and were isoelectric at pH. 5.5 to 5.8. The same set of properties were found for immune precipitate in the zone of maximal precipitation. The same properties have also been found for maximally sensitized acid-fast bacteria, and for maximally sensitized sheep erythrocytes. These results indicate, we believe, that precipitation, agglutination, the surface changes and increased phagocytosis are all consequences of one underlying phenomenon. This phenomenon is the specific chemcal combination with, and deposit on the surface of the antigen of antibody protein. The several serological reactions then follow as consequences of the properties of the sensitized surface and of the special environing conditions. The antibody is contained in the globulin fractions of immune serum, and appears to be a globulin with physico-chemical differences from normal serum globulin.