The megaloblastic hematopoiesis in a variety of clinical and experimental conditions such as 6 cases of pernicious anemia, 5 liver cirrhosis, 6 hemolytic anemia, 48 leukemia, 2 malignant diseases treated with Cytosine Arabinoside (CA), and dogs and rats receiving CA, Methotrexate (MTX) and 6-Mercaptopurine (6-MP) was investigated from the two standpoints of hematologic and cytogenetic studies. The results are as follows.
A small percentage of megaloblasts or megaloblastoid cells in the bone marrow aspirates from patients with leukemia, severe liver cirrhosis and hemolytic anemia were also observed. There was some relationship between the concentration of plasma folate and the appearance rate of megaloblastoid cells in leukemia and hemolytic anemia. These cells were also observed in a high percentage in the bone marrow from patients treated with CA, appearing 5 hours after administration of CA. In the bone marrow aspirates from dogs receiving CA, MTX and 6-MP, megaloblastoid cells appeared 12 hours after administration and disappeared on the 5th day. These megaloblastoid cells in various conditions described above were PAS negative.
The presence of hypersegmented neutrophils in the bone marrow and peripheral blood is one of the characteristic features in pernicious anemia, of which a small percentage was found in the conditions described in the preceding paragraph. However, it disappeared very slowly as compared with megaloblasts or megaloblastoid cells. Similar findings were also observed in dogs receiving CA, MTX and 6-MP. Especially, it is of great interest that hypersegmented neutrophils in the dog bone marrow appeared as early as 6 hours after the administration of these agents, suggesting the direct action of these agents on the granulocytic series. Further studies may provide an answer to these results.
Abnormalities such as breakage, centromeric spreading and elongation in the direct bone marrow cytogenetic preparations from patients with pernicious anemia were observed. Similar chromosome abnormalities in structures were observed in the bone marrow of two patients with malignant diseases treated with CA. In the rats receiving CA there was seen a high incidence of chromosome abnormalities within 24 hours. These chromosome abnormalities disappeared rapidly after a specific therapy or cessation of CA. And no stable chromosome abnormalities was observed. These results suggest that the chromosome abnormalities in the conditions described above do not develope any kind of abnormal clone.

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Increased thymidine kinase activity has been found in the bone marrow cells of 5 cases of megaloblastic anemia caused by vitamin B₁₂ deficiency. This increased enzyme activity has been considered to be caused by a decreased dTTP pool within the vitamin B₁₂ deficient bone marrow cells.
Apparent suppression of the bone marrow cell thymidine kinase activity in vitro by dTTP, as well as increased thymidine kinase activity in the hematopoietic cells of the phenylhydrazine mouse injected an with 5-fluorounracil, which were observed in our present experiments, were considered to support the above speculations of the induction of the thymidine kinase activity by decreased dTTP pool.
In spite of the increase in the thymidine kinase activity, incorporation of the ³H-thymidine into DNA was apparently decreased in vitamin B₁₂ deficient bone marrow cells. This decrease in the incorporation, in the presence of the increased thymidine kinase activity, was explained by a decrease in the DNA polymerase activity which was observed in the present study in a patient with B₁₂ deficiency megaloblastic bone marrow cells.
In the rats made vitamin B₁₂ deficient by feeding deficient diet, DNA synthesis in bone marrow, thymus, and spleen cells were markedly decreased as compared to normal rats. RNA and heme synthesis were not altered by B₁₂ deficiency.
These findings in the DNA synthesis in lymphatic cells were discussed in relation to immunological abnormalities observed in pernicious anemia.

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It is well known that defective B₁₂ absorption is of prime importance among the causes of anemias due to B₁₂ deficiency and is represented by pernicious anemia. Not less important than defective B₁₂ absorption is the disturbed B₁₂ metabolism, which is not infrequently observed in advanced liver damages. Since B₁₂ is required to be converted to 5,6-dimethyl-benzimidazolyl cobamide coenzyme, DBCC, an active form of B₁₂, prior to its utilization, it is reasonably assumed that B₁₂ deficiency, latent or manifest, might result from the disturbance of the conversion, irrespective of B₁₂ absorption. This disturbed B₁₂ metabolism can be rather readily detected by increased urinary methylmalonic acid (MMA) excretion. The increased excretion takes place in the absence or dimunition of DBCC in the body, which is, as an apoenzyme for methylmalonyl CoA isomerase, essential for catabolizing methylmalonyl CoA to succinyl CoA. Therefore, inversely, the increase of urinary MMA points to the presence of B₁₂ deficiency. Based on this fact, an attempt was made to study the correlation between anemias under various diseased states and disturbed B₁₂ metabolism by measuring the urinary MMA. As a result, a significant increase in urinary MMA was observed in cases of myeloid leukemia, aplastic anemia, hemolytic anemia, iron deficiency anemia, systemic lupus erythematosus, Hodgkin's disease, malignancies such as cancer of the stomach and liver cirrhosis, thereby suggesting the presence of the deranged B₁₂ metabolism in these diseased states and its possible participation in part in developing anemias. The mechanism of the disturbed B₁₂ metabolism is not known yet, however. In contrast, no case of lymphoid leukemia showed the increase of MMA.
Thus, it was revealed that anemias, seemingly not related to B₁₂ deficiency, can be at least in part induced by latent B₁₂ deficiency due to deranged B₁₂ metabolism under diseased states and this derangement can be detected by the measurement of urinary MMA excretion. In other words the measurement can serve as a valuable means for the detection of latent B₁₂ deficiency due to disturbed B₁₂ metabolism. Meanwhile, although abnormally increased urinary MMA was found to occur in pernicious anemia, postgastrectomy anemia and anemia associated with blind loop syndrome, the implication of the increase is quite different from that in above-mentioned diseases in that blood B₁₂ concentration and B₁₂ absorption are usually normal, because, in the former, as reflected by B₁₂ absorption test, main cause is the defect in B₁₂ absorption from the gut, but the ability to convert absorbed B₁₂ to DBCC is well preserved.

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In Addison-Biermer megaloblastic anemia the hematological response following administration of anti-pernicious agents occurs as follows: erythroblasts in the bone marrow further increase and return to normal level after 7-17 days; megaloblasts begin to decrease in number within 24 hours and quickly decrease in number as well as in size, and disappear within 8 days; the reticulocyte crisis occurs within a week; on the other hand, anemia recovers gradually and becomes normochromic or hypochromic. The improvement of subjective symptoms appears more slowly in cases receiving oral adoministration therapy than in cases receiving parenteral therapy. In a case receiving an intramuscular single injection of 1,000 μg of hydroxocobalamin subjective symptoms began to improve 24 hours after injection and the remission continued for more than three months. In a case receiving oral doses of 1,500 μg per day of hydroxocobalamin subjective symptoms began to improve a week after beginning of the administration but remission has been kept for four years by oral doses of only 500 μg every three days. Satisfactory remission has continued for several years without any specific therapy in some cases. In another case keeping laboratory remission, sensory disturbances have not been completely improved by any preparation of vitamin B₁₂. The course to remission reveals a nearly similar pattern in all cases but there are variations in the course of maintenance, so the schedule of maintenance therapy should be made case by case.
Megaloblastic anemia in pregnancy shows spontaneous remission in many cases but the anemia will be improve quickly by administration of anti-pernicious agents.
In some of the cases with agastric macrocytic anemia sufficient administration of vitamin B₁₂ is effective not only on hematological findings but also on other various symptoms.
No significant differences between cyanocobalamin, hydroxocobalamin, cobamide coenzyme and methylcobalamin were seen in hematological responses when large doses were used, and no adverse effects were noted.

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1. Case report No. 1.: A case of megaloblastic anemia due to anticonvulsants was reported. He had been administered diphenylhydantoin and phenobarbital for 5 months.
2. The results of examination of the 68 patients receiving anticonvulsants: Slightly hyperchromic or normochromic anemia was seen in 31%. Macrocytosis (MCV over 100 μ³, MCD over 8 μ) detected in 20∼25%. After the administration of 5 mg of folic acid for a month, macrocytosis disappeared.
3. Case report No. 2.: A case of megeloblastic anemia of puerperium was reported. She developed anemia one month after delivery. She obtained improvement of anemia shortly after the admission without specific treatment. This hematologic recovery was considered due to the difference between her diet at home and the hospital diet.
4. The results of the examination of about 100 pregnant women: Blood counts, serum iron, vitamin B₁₂ and folic acid were followed at 13, 25, 36 weeks of the gestation and one month after delivery. Approximately half of these women showed anemia which was predominantly hypochromic and microcytic. Decreased serum iron were seen commonly at antenatal weeks. Vitamin B₁₂ also declined as pregnancy progressed. Low serum folate levels were seen frequently as pregnancy came near the term. As macrocytosis was not seen in these women, we considered that the sign of folic acid deficiency was masked by iron deficiency state.
5. Folic acid contents of two hospital diets.: After cooking, free folate was estimated without treating with the chicken pancreas extract. Total folate was assayed after conjugase treatment. Hospital A: Free folate 108 (63∼178) μg/day, total folate 422 (216∼688) μg/day. Hospital B: Free folate 138 (129∼165) μg/day, total folate 351 (306∼403) μg/day.
6. Conclusion: Folic acid deficiency anemia has been thought to be rare condition in Japan. In this study we could find that subclinical folic acid deficiency does exists among those who were receiving anticonvulsants and pregnant women. But the assay of the hospital diets suggests that Japanese diet contain enough amounts of folic acid. This explains the rarity of folic acid deficiency anemia in Japan. Many additioning factors such as infection, malnutrition, malabsorption should be necessary for manifestation of the megaloblastic anemia.

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Repeated intramuscular injection of folic acid and ceruloplasmin results in appearance of erythropoietic activity in rabbit plasma as early as the fifth day after the injection. Although the combined use of folic acid and ceruloplasmin increased activity in blood, folic acid or ceruloplasmin alone; Vitamin B₁₂ and ceruloplasmin; or Vitamin B₁₂ alone failed to increase activity in blood. These value of Fe⁵⁹ incorporation rate were two to three times that of the control. This activity can be shown at any time after one week following the intramuscular injection. This activity was not increased by substituting γ-globulin for ceruloplasmin which seems to suggest that ceruloplasmin has some role in the formation of erythropoietic activity. Erythropoietic activity described above was assayed by measuring the incorporation of Fe⁵⁹ into peripheral red blood cells of pure strain Wistar rats.
Incorporation of Fe⁵⁹ into protoporphyrin was markedly accelerated in the presence of N⁵-methyltetrahydrofolic acid and ceruloplasmin. Its incorporation rate increased in parallel with the amount of N⁵-methyltetrahydrofolic acid. Ceruloplasmin; N⁵-methyl tetrahydrofolic acid; tetrahydrofolic acid; or folic acid alone have only slight and somewhat variable activity in iron incorporation, while copper iron has no activity.
In hypoplastic anemia, serum ceruloplasmin levels were ranged from 10 mg./dl. to 60 mg./dl.. Gendel recommended a trial of folic acid using large doses over a long period of time. It is inferred that administration of folic acid using large doses is effective in the case of hypoplastic anemia with high serum ceruloplasmin level over 40 mg./dl..

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In this Symposium the authors report on our recent findings on the mechanism of intrinsic factor (IF) in relation to absorption and subsquent transport of vitamin B₁₂.
Using ⁵⁷Co-labeled and ¹⁴C labeled (in the upper ligand) DBCC and methyl-B₁₂ in rats, as well as in vitro with purified hog IF, it was found that DBCC molecule is more protected by IF than CH₃-B₁₂ from light and in intestinal environment. At the moment these coenzymes were absorbed with the aid of IF, they were found to be in their original chemical forms, suggesting a protective action of IF for these unstable coenzyme B₁₂. B₁₂ was bound to non-IF binder in the intestine in the absence of IF, and such B₁₂ was not absorbed without the presence of large quantities of IF. Thus, IF has another function of competing with an inhibitory binder in the intestinal lumen for B₁₂.
We then attempted to isolate the so-called “receptor” by solubilizing the ileal mucosa with pH 9.9 bicarbonate-carbonate buffer, sea-sand grinding, taking ultracentrifuged supernatant and by Bio-Gel filtration. After oral feeding of B₁₂-⁵⁷Co to rats and extracting ileal mucosa as above, we obtained a fraction of a much larger molecular size than IF-B₁₂ in the presence of Ca⁺⁺. The same fraction was obtained in vitro by incubation of mucosal extract with IF-B₁₂. This peak disappeared after treatment of EDTA. Intestinal washing after oral feeding of B₁₂-⁵⁷Co lacked this peak. When the absorption of B₁₂-⁵⁷Co bound to this fraction was tested, it was found to be almost as good as IF-B₁₂, suggesting that calcium bridge between the receptor and IF is weak in the intestine. These data strongly suggest that a recepter-IF-B₁₂ complex was separated with Bio-Gel filtration, and solubilization of receptor was achieved with alkali treatment.

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The informations on the pathogenesis of pernicious anemia have been accumulated, more in detail, by the correlative findings by gastric biopsy, direct intrinsic factor assay and intrinsic factor antibody detection. The author studied the pre-pernicious anemia states, in comparison with pernicious anemia, in special reference to gastric histology, intrinsic factor secretion, V B₁₂ absorption and some imunologic abnormarities including anti-intrinsic factor antibodies.
The summarized findings were as follows.
1. The decrease in intrinsic factor secretion (after augmented histamine stimulation) reflects the extents of gastric atrophic lesion (progressive glandular disappearance followed by intestinal metaplasia). The ratio of intrinsic factor B₁₂ binder to total VB₁₂ binders in gastric juice was found a reliable index for the extent of gastric atrophic lesion.
2. The severe deficiency or, rather, abolishment in intrinsic factor secretion was found in pernicious anemia and in some cases with atrophic gastritis, as well. In cases with atrophic gastritis, intrinsic factor-non-related B₁₂ binders, frequently increased, whech decreased, in contrast, in pernicious anemia.
3. VB₁₂ absorption by hepatic uptake test (double or triple isotope method by Weiseberg & Glass) and in guinea pig intestinal mucosa homogenates (GPIMH assay) are closely correlated with intrinsic factor concentration, the ratio of intrinsic factor to total B₁₂ binders in gastric juice, rather than with one hour output of intrinsic factor under the augmented histamine test.
4. Absorption tests by rado-B₁₂ are related to resting secretion of intrinsic factor, gastrointestinal mobility and intestinal phase of VB₁₂ absorption, neverthless the direct assay of intrinsic factor reflects directly the secretory reserve of gastric intrinsic factor relating the gastric histology.
5. In absorption of VB₁₂, intrinsic factor is suggested not to be absorbed (observations by ⁵¹CrCl₂ & ⁵⁷CoB₁₂ double labelled human and hog intrinsic factor), is competitively inhibited by intrinsic factor-non-related VB₁₂ binder in gastric juice (results by GPIMH assay) and is imunochemically inhibited by anti-intrinsic factor antibody in gastric juice (observations by GPIMH assay and whole body counting of auto serum ingetion).
6. Severe atrophic gastritis and, especially when coexisted with anti-intrinsic factor antibody, is the possible candidate for pernicious anemia. Two case reports were made on such conditions. One case was 52 y.o., female, with hyperthyroidism, glycosuria and bronchial asthma, and the other was 62 y.o., female, with diabetes mellitus and gastric polyposis. No or slight anemia was found, respectively. In the former case, low plasma VB₁₂ leves (132 μμg/ml Euglena method), shorted biological half life of ⁶⁰CoB₁₂ (333 days) and sparse megaloblastoid cells in bone marrow observed. Both cases were diagnosed as latent pernicious anemia (Callender et al., Schiller et al.).

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Serum transcobalamin determinations were made on 138 normal control sera and on 206 various pathologic sera obtained from cases with carcinoma, anemia, leukemia. cirrhosis of the liver and miscellaneous diseases. Serum B₁₂ concentrations were determined by the method of Lau et al., unsaturated B₁₂ binding capacity by the method of Gottlieb et al. At the same time, determinations of serum iron and total iron binding capacity, electrophoretic fractionation on cellulose acetate strips were carried out in parallel.
The normal range for the serum B₁₂, UB₁₂BC and TB₁₂BC were as follows: B₁₂, 126-1155 pg/ml with a mean of 518 pg/ml, UB₁₂BC, 266-1484 pg/ml, with a mean of 884 pg/ml and TB₁₂BC, 655-2619 pg/ml with a mean of 1408 pg/ml, respectively. A significant increase of B₁₂ and UB₁₂BC was observed in cases with carcinomas and moderate increases were noted in various infectious diseases. In chronic myelogenous leukemia, serum transcobalamin levels increased to 2 to 5 fold of the normal value. The transcobalamin values were compared with different parameters and the following correlation coefficients were obtained: RBC (r=-0.08) WBC (r=0.696): Total protein (r=0.162): Albumin (r=-0.060): α₁-glob. (r=0.336): α₂-glob. (r=0.275): β-glob. (r=-0.033): γ-glob. (r=0.174); TIBC (r=-0.009) B₁₂ vs UBBC (r=-0.196), respectively.
Transcobalamins were separated by the use of various fractionation techniques such as gel filtration on Sephadex G-200, DEAE cellulose column chromatography and electrofocusing. The pI s of TC-I were more acidic comparing to those of TC-II, and the presence of marked microheterogeneity in both transcobalamin fractions was confirmed.

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Intrinsic Factor (IF) antibody, parietal cell (PC) antibody, gastric secretion, histology of gastric mucosa and effect of prednisolone therapy were studied in order to investigate pathogenic significance of IF antibody in pernicious anemia (PA). 40 cases of PA, 416 cases which are subject to have atrophic gastritis and 217 cases of control were examined.
PC antibody was positive in 90% of PA, however significant number of other diseases which tend to have atrophic gastritis have also positive PC antibody, compared with control. PC antibody was examined in 97 cases except for PA by biopsy of gastric mucosa, but PC antibody did not have meaningful relation between its titer and the nature or the degree of gastritis. And there was no relation among PC antibody titer, acid secretion and IF secretion.
Concerning IF antibody, 55% of PA were positive in blocking antibody, but out of 633 cases excluding PA, the only one had positive blocking antibody and this case had hyperfunction of thyroid gland and revealed marked diminished secretion of IF, which was quite similar to PA.
When gastric mucosa of 18 PA and 1 hyperthyroidism were examined microscopically, all the cases which showed marked intestinal metaplasia of gastric mucosa had had no blocking antibody.
8 of 27 PA revealed positive blocking antibody in gastric juice. When IF and blocking antibody were separated by acidifing gastric juice of PA with HCl, appearance of IF activity was proved in gastric juice of 5 PA.
The effect of long term prednisolone therapy had been studied in 9 cases of PA, 5 cases of simple atrophic gastritis and 2 caces of total gastrectomy. During prednisolone treatment, 4 cases showed improvement of Schilling test, and simultaneously regeneration of perietal cells, elevation of IF activity and diminution of circulating blocking antibody. 3 of above 4 cases were proved to have positive circulating blocking antibody, the rest of them was the case in which IF activity appeared in gastric juice after HCl treatment. There were no significant change of tests in 5 cases which revealed negative blocking antibody in spite of prednisolone administration. No appreciable effect was also seen to all atrophic gastritis and gastrectomised cases. PC antibody titer remained same.
From these results, it is considered that PC antibody is one of autoimmune phenomena which is not concerned with the pathologenesis of PA. However blocking antibody is thought to be related to disturbance of IF secretion in AP.

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The present study was undertaken to quantity the human gastric intrinsic factor (IF) with charcoal radioimmunoassay using heterologus antisera against human IF instead of anti-IF autoantibody (PA-A-IF) from the patients with pernicious anemia (PA).
For this purpose, purification of the human gastric IF was performed. A large amount of lyophilized gastric juice was dissolved in small amount of pH 9.0 borate buffer solution, and then fractionated with Sephadex G 200 and DEAE cellulose chromatography. B₁₂ binding capacity of each fraction, before and after adding to it PA-A-IF, was determined by the method of Gottlieb et al. The fractions, with great B₁₂ binding capacity and which strikingly reduces its capacity after adding PA-A-IF, was concentrated and used for immunization as IF antigen. Guiner pigs were used as immune animals for preparation of anti-IF antisera, because their serum showed remarkably lower unsaturated B₁₂ binding capacity than a rabbit's serum.
The antisera thus prepared (GP-A-IF) showed antibody activities which were similar to the type I blocking and the type II binding antibody found in the patients with PA. No evidence were found about the existence of antibody activities against non-IF binder in these antisera.
The amount of human gastric IF determined by charcoal radioimmunoassay using GP-A-IF was generally equal to that determined using PA-A-IF.
In further experiments, IF-B₁₂ complex was fractionated by the same method from gastric juice presaturated with a small amount of ⁵⁷CoB₁₂ and excess amount of non-radioactive CN-B₁₂. Guinea pigs were immunized with this IFB₁₂ complex (GP-A-IFB₁₂) in order to compare antigenic activities of IF alone with those of IFB₁₂ complex.
These GP-A-IFB₁₂ also revealed the same two types of antibody activities as were observed in the patient's serum, but showed a tendency that was weaker in the type I antibody and stronger in the type II than GP-A-IF.

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Since ALA synthetase which is the limiting factor for heme synthesis requires pyridoxal phosphate as coenzyme, it has been accepted that a lack of vitamin B₆ may cause hypochromic anemia in some experimental animals.
In this experiment, microcytic hypochromic anemia was induced in rats by feeding vitamin B₆ deficient diet containig desoxypyridoxine for 8 weeks.
As the syntheses of DNA, RNA and protein were not impaired in pyridoxine deficient rats, the setting of erythroblast compartment was thought to be possible using karyometry.
In the bone marrow of this pyridoxine deficient anemia, the increase in sideroblast and the decrease in Kl/8 population were detected, corresponding to the suppression of %RIU and the production of hypochromic microcytes respectively.
The determination of heme content in erythroblast was carried out by use of microspectrophotometer (UMSP-1). Though active heme synthesis was observed in control rats, it was markedly inhibited in vitamin B₆ deficiency.
Finally, changes in content and synthesis of heme in each compartment were studied following the injection of pyridoxal phosphate.
As the result of these experiments, it was confirmed that immature erythroblasts immediately responded to pyridoxal phosphate increased heme content but mature erythroblasts, especially Kl/8, showed no reactability.
So, the increase in heme content in Kl/8 which is recognized long after the stimulation of pyridoxal phosphate may be due to the transport of hemoglobin previously produced and accumulated in precursor cells.
Considering these data, some hypotheses concerning with the production of ALA synthetase in situ were described.

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The etiology and pathogenesis of pyridoxine-responsive anemia (PRA) were briefly discussed on the basis of literature survey and our own observations. It is apparent that, in the majority of patients, the conditions are not due to the dietary deficiency, but due to some more basic metabolic abnormality in hemoglobin formation, which could make the corresponding enzyme system dependent upon vitamin B₆. The enzyme defect found in PRA may not be uniform, but may be variable. Horrigan and Harris classified PRA into two groups, i.e. classic form and non-classic form. In the former, the hemopoiesis is strictly dependent upon the administration of vitamin B₆, and other hematinics (Fe, Vit. B₁₂, folic acid) are without effect. In the latter, however, some responses may follow the administration of other hematinics especially folic acld. We have reported two cases of non-classic form of PRA, responding to both vit. B₆ and folic acid. Investigations on the folate metabolism in these two cases revealed that the primary metabolic defects could be deficiencies of formiminotransferase and N⁵-methyl-tetrahydrofolate transferase respectively, leading to the impaired nucleic acid synthesis in each case.

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Fifty five cases of pyridoxine responsive anemia in literature including two of my cases were analyzed and the variety of the blood pictures, clinical findings and responses to pyridoxine in these cases were compared with the prototype of Harris's case which was first reported in 1956. As a result of the analysis, it appears unlikely that the pathogenesis was a single defiiciency of pyridoxine in the usual sense, and it seems that basic factor is an insufficiency or defect of the pyridoxine dependent enzym associated with unknown factors.
It is for this reason that pyridoxine dependent anemia syndrome, more fiitting term than pyridoxine responsive anemia, should be chosen and might be divided into seven groups as follows; (1) pyridoxine responsive hyperferremic state (in other words, prepyridoxine responsive anemia state, no hematological disorder except for hyperferremic state with effective pyridoxine). (2) congenital pyridoxine responsive anemia (four cases in literature suspected). (3) familiar pyridoxine responsive anemia (heredity may be proved). (4) Pyridoxine deficiency anemia (pyridoxine deficiency will be proved and associated with pyridoxine deficiency syndrome such as neurological or dermatological abnormality). (5) pyridoxine responsive anemia (pyridoxine deficiency may not be proved, but pyridoxine is helpful). (6) combined pyridoxine responsive anemia (although pyridoxine is effective, combined or single use with Vit. C, folic acid, liver extract, testosterone and tryptophane may also be favorable). (7) drug induced pyridoxine responsive anemia (due to INAH, desoxypyridoxine, cycloserine and penicillamine).

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The investigations were carried out to clarify the relationship between Vitamin E and anemia in adults and the following results were obtained:
1. Seventy-eight cases of idiopathic hypochromic anemia (0.87±0.12 mg per 100 ml), fifteen cases of iron deficiency anemia with splenomegaly (0.88±0.16 mg per 100 ml) and three cases of hereditary spherocytosis (0.75±0.12 mg per 100 ml) showed lower levels of serum Vitamin E than one hundred healthy adults (1.25±0.12 mg per 100 ml).
2. Before iron therapy, seventeen cases of idiopathic hypochromic anemia showed a significantly higher level of C 16:0(palmitic) and C 18:0(stearic) content, and a significantly lower level of C 18:1(oleic) and C 18:2(linoleic) content of the serum fatty acid composition in comparison with healthy adults.
Following iron therapy, serum Vitamin E and C 16:0, C 18:0, C 18:1 and C 18:2 content of the serum fatty acid composition returned to normal level.
3. Six cases of iron deficiency anemia with palpoble splenomegaly also showed significantly higher level of C 16:0 and C 18:0 content, and a significantly lower level of C 18:1 and C 18:2 content of the serum fatty acid composition before treatment.
Three cases of iron deficiency anemia with palpoble splenomegaly responded to iron therapy and evinced excellent recovery from anemia and lessening of splenomegaly all three showed simila rchanges in serum Vitamin E and serum fatty acid composition following iron therapy as in cases of idiopathic hypochromic anemia.
4. In cases with insufficient recovery from idiopathic hypochromic anemia following iron therapy, lesser increase of serum Vitamin E was observed.
In a case with insufficient recovery from idiopathic hypochromic anemia following iron therapy alone, further increase of hemoglobin level was observed following combination therapy with iron and Vitamin E.

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Electronic counting of platelets by the method of Bull and his associates has been experimented and applied to the routine use. The basic method can be modified in that the separation of platelets from red blood cells alternatively achieved by centrifugation at the optimal speed and timing.
The influences by contact with glass surface, suspension in the oxalated saline and whole blood storage in cold or at room temperature were evaluated, and found not to be the limiting factors of the method.
The count by electronic method has been found to be in a good correlation with that enumerated by Brecher-Cronkite method (r=1.049).
The results presented demonstrate that precision and reproducibility of the electronic method is far superior to that of the visual methods. Furthermore, the larger number of the samples can be handled by the electronic method in shorter time than by the visual enumerations.
It is concluded that the electronic counting of platelets is feasible and of a method of choice in the service-oriented, clinical hematology laboratory.

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A very rare variant of benign monoclonal gammopathy found in a 70-year-old male patient with silicosis was presented.
Immunoelectrophoretic studies on his serum disclosed the presence of two paraproteins in γ-globulin area both of which proved to be IgG and type L. After the purified M-components were reduced, alkylated and then decomposed, they were subjected to disc electrophoresis. The results showed that each of the two paraproteins proved to be homogenous immunoglobulin and have light chain different in mobility on electrophoresis, respectively.
The problem, whether the paraproteins here reported were derived from one clone or two different clones, remains unsolved.

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Two families of congenital factor VII deficiency were described.
The propositus of the first family was 35-year-old female, who was admitted for anemia. Spontaneous epistaxis, limited to her youth, was main hemorrhagic symptom. The patient delivered two normal children without unusual bleeding. On admission, the physical examination revealed no abnormalities except for the presence of iron deficiency anemia. Results of liver function tests were normal. Coagulation data confirmed the diagnosis of pure factor VII deficiency. Her factor VII complex level was 5% of normal and factor X level was 100%. There was no history of bleeding in her family. However, her daughter was discovered to have factor VII deficiency. Her factor VII complex level was 27% and factor X level was 75%. Factor VII levels of father, three half siblings, husband and son of the propositus were within normal limits.
The propositus of the second family was 25-year-old female, who was admitted complaining of spontaneous nose bleeding, gum bleeding, subcutaneous hemorrhage and menorrhagia. The patient was hospitalized for right oophorectomy at the age af 22. The hematoma in the right ovary was found, however, no unusual bleeding was noted either during surgery or in the postoperative period. On admission, she appeared healthy except for a few ecchymoses. Liver function chemistries were normal. Laboratory data demonstrated factor VII deficiency with increased vascular fragility. Her factor VII complex level was 17% and factor X level was 80%. Mixture of this patient's plasma with that of the propositus of the first family did not result in shortening of the long one-stage prothrombin time, proving an identical deficiency in these patients. The family history revealed that the patient's paternal grandfather were siblings. One brother of the propositus, his daughter and grandmother on the father's side of the porpositus had bleeding tendency. Neither of her parents nor any other family members had any bleeding episodes. Coagulation studies on the brother of the propositus revealed that he had factor VII deficiency. His factor VII complex level was 12% and factor X level was 105%. Factor VII level of the other family members could not be measured.

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We found a case of analbuminemia, the first case in Japan and presumably the third in the world following the original report of Bennhold in 1954.
The patient was an unmarried twenty-one-year-old male. His parents were cousins. An episode of unconsciousness occurred during a march on July 26, 1969, followed by sever frontal headache, nausea and vomiting, and he was admitted to the Kure Kyosai Hospital on August 16, 1969. Since August 15, 1969 moderately elevated body temperature and right upper abdominal pains were observed. Analbuminemia unexpectedly was noticed by separax electrophoresis on August 18, 1969. The total serum protein was 4.2 gm. per 100 ml. and a fractionation revealed no albumin, 12.8 percent α₁-globulin, 25.6 percent α₂-globulin, 29.1 percent β-glbulin and 32.6 percent γ-globulin. No precicitation arc of albumin was observed on agar immunoelectrophoresis using antiwhole human serum-rabbit serum. No A component (4.5 S) was detected by analytical ultracentrifugation at 51,200 rpm, and G (7.0 S), M (19.3S) and X (3.5S) components were the major components of his serum protein. The laboratory findings including urine and feces examinations, blood chemistry, peripheral blood pictures, sternal puncture, liver biopsy and X-ray films of the chest and upper gastrointestinal series were within normal limits expect for high serum ammonia level, cholesterolemia, lipoproteinemia and eosinophilia. Repeated cultures of arterial blood were negative.
The other members of his family showed normal albumin levels. The kinetics study of ¹²⁵I-albumin is in progress.

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A case of acute leukemia preceded by aplastic anemia following the administration of chloramphenicol was reported.
One-year-ten-month old female with chief complaint of fever and pallor, was diagnosed as aplastic anemia on the basis of hematologic and physical findings. Treatment was started with steroid hormone and discontinued upon remisson. Few episodes of the similar course were repeated. Six months after starting the treatment, the diagnosis of acute leukemia was established due to the appearence of abnormal white cells in the peripheral blood and bone marrow.
Her general condition took downhill after the establishment of diagnosis and expired three months later. Autopsy fiindings revealed infiltration of leukemic cells in the various organs.
At the onset of disease and during the period of pre-leukemic course apparently, no difference was seen on the clinical and hematlogic findings as compared with those of aplastic anemia.
The relationship of leukemia and aplastic anemia following the administration of chloramphenicol was discussed.

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Although many authors have commented on the frequency of parenchymal infiltration of the kidneys in leukemia, such a case as with strikingly enlarged kidneys is rare, and there has to date been no systematic study of kidney function during the course of leukemia.
This paper reports a case of 12-year-old boy with acute leukemia accompanied by enlarged kidneys and gross impairment of renal function.
On the first admission, Feb. 27, 1967, his main symptoms were non-tender enlargement of the bilateral cervical lymph nodes and of the hilar lymph nodes on a chest film. The liver, spleen and kidneys were not palpable. Evidence of leukemia was not revealed except the bone marrow smears. A cervical lymph node biopsy was verified as “malignant lymphoma”. A total of 700 r in air was given over the bilateral enlarged cervical nodes, and cervical, hilar nodes markedly reduced. And then, both steroids and 6-mercaptopurine, for the treatment of aleukemic leukemia, were given to the patient with prominent improvement. No significant proteinuria was noted. The phenolsulfonphthalein test revealed 23 per cent excretion of injected dye in 15 minutes and 65 percent total in 2 hours. Renal plasma flow in the renal clearance test was slightly diminished. The decrease in RPF was significantly greater than that in GFR. The serum level of nonprotein nitrogen was 26.5 mg/dl.
The patient was in good health until June, 1967, when he developed a right facial palsy, the second time enlargement of hilar lymph nodes and obvious hepatosplenomegaly. In the peripheral blood and bone marrow, vacuolated immature leukemic cells were seen. An intravenous urograms demonstrated very large bilateral homogeneous masses compatible with enlarged kidneys, and the collecting system was faintly visualized on either side. The phenolsulfonphthalein test showed 0.5 per cent in 15 minutes and 17.0 per cent total in 2 hours. The glomerular filtration rate was greatly reduced to 7 ml per minute, and the renal plasma flow was also reduced to 27 ml per minute. Thus the filtration fraction was reduced. The serum level of nonprotein nitrogen was elevated to 124.6 mg/dl. as a passing phenomenon. The radiohippuran renogram showed non-functioning type which pointed out serious functional loss of kidneys. A large volume of dilute urine and low specific gravity of the urine were observed. Hematuria and proteinuria were not seen. Besides, in liver function test, there was correlation with the extent of the reduction of renal function. The SGOT, SPGT and LDH were over normal limits.
The patient died of intestinal bleeding on Sept. 12, 1967. The relations between renal involvement and the appearance of vocuolated leukemic cells in the blood and bone marrow smears are to be noted.

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The patient was twenty-one-year-old female who had considerable promylocytes in her peripheral blood and bone marrow.
She noticed fever and painful ulcer of the anal area at onset, and laboratory examination showed anemia, leukopenia, thrombocytopenia and elevated erythrocyte sedimentation rate with no bleeding tendency. She had remission temporarily by adrenocorticosteroid and antiplasmin, and five months later the relapse occurred. On autopsy, microscopic examination revealed extensive infiltration of promyelocytes in bone marrow, spleen, liver and lung, and infectious foci in these organs except bone marrow.
Comparison with the features of Hillestad's acute promyelocytic leukemia was discussed.

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