A 38-year-old female patient with prolonged eosinophilia, accompanied by an appearance of monoclonal IgA gammopathy during the course, was reported. Patient showed recurrent episodes of fever, skin lesions and edematous changes of the face and limbs with oliguria. Laboratory examinations revealed leucocytosis with a marked increase of eosinophils up to 50% in the peripheral blood, an elevation of serum immunoglobulin levels, including IgE, with an appearance of monoclonal IgA (κ-type). On the other hand, there was a decrease of the complements. The biopsy specimen from the skin lesion also disclosed marked infiltration of eosinophils in the subcutaneous tissue.
From these clinical and laboratory findings, it was postulated that the eosinophilia might be related to an allergic reaction, or in other words, with an immune reaction caused by an unknown etiology. The relationship between the immunological reactions and the eosinophilotactic factors appearing in the literature was reviewed, stress being laid upon possible antigens, antibodies and the rôle complements. The presentday significance of the Eosinopoietin (Komiya) should be re-emphasized.

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The thalassemia syndrome is a group of entities which are clinically characterized by hypochromic, microcytic anemia and genetically determined by depression of hemoglobin synthesis. The thalassemia has a decreased rate of synthesis of one or more globin chains of hemoglobin, and is classified according to the globin chain involved. Thus, there are the α, β, δ, γ and δβ thalassemia.
The cilnical and laboratory features of main forms of thalassemia are now well defined and are summarized in Table 1. In common types of thalassemia, especially in β and δβ thalassemia, individuals who carry one thalassemia gene and one normal gene (heterozygotes) are relatively mildly affected (thalassemia traet or thalassemia minor). Individuals who inherited two similar or identical thalassemia gene (homozygotes) suffer from a severe impairment of hemoglobin synthesis (thalassemia major).
In thalassemia, primary genetic defect might be led to decrease or alteration of messenger RNA that directs the synthesis of globin chains. In this review, recent progresses in molecular pathology of thalassemia, such as a decreased or defective messenger RNA, are discussed.

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Recent advances in the research of RNA metabolism in human leukemic cells were introduced in this report.
Two methods were found, one of which is the fractionation of RNA used the techniques of sucrose density gradient analysis or polyacrylamide gel electrophoresis. The other is the reports related to RNA synthesis in the transcription of DNA.
Rapidly labelled macromolecular RNA was obtained from leukemic cells and is necessary to study the metabolic pattern and biological role of newly synthesized RNA.
The transcription of chromatin or characterization of DNA dependent RNA polymerase were different in leukemic cells from normal leukocytes.

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76 cases of leukemoid reaction, 39 males and 37 females, were collected from April 1960 to March 1963 at National Tokyo First Hospital.
1. Age distribution ranged from 1 day to 75 years of age without any apparent peak.
2. Type of leukemoid reaction: 74 cases of CML type; 1, CLL type and monocytic type.
3. The background disease: 24 cases of infections disease, 19 cases of malignancies, 12 cases of immaturity and dyspesia, 7 cases of collagen diseases, 6 cases of blood disease excluding leukemias, 3 cases of nephrosis, 2 cases of bleeding, 2 cases of postoperations and 1 case of acute yellow liver atrophy.
4. W. B. C. ranged from 2700 to 82,000 cmm.
5. Erythroblasts were observed in the peripheral blood in 29 cases.
6. Myelogram of most cases revealed hyperplasia. but 4 cases revealed hypoplasia.
7. Pathological examination of bone marrow and spleens disclosed dilated sinusoid with loose or broken argyrophile fibers of the wall, and so the adjacent hyperplastic areas of hemopoiesis.
8. The mean mortality of 76 cases of leukemoid reaction was 29.7%.

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Daunorubicin, 1 mg/kg by rapid intravenous infusion daily for 7 consecutive days, was given 7 cases with previously untreated acute promyelocytic leukemia. In order to prevent the possible exacerbation of disseminated intravascular coagulation due to a sudden release of procoagulant from abnormal promyelocytes damaged by the potent antileukemic drug, heparin was administered intravenously at daily doses of 150 mg concurrently with chemotherapy.
Complete remission occurred in 4 cases. Maintenance therapy consisting of 6 to 9 intravenous injections of daunorubicin at 7-day intervals followed by oral 6-mercapto purine at daily doses of 100 mg was given to these patients. Remissions lasted 27, 30, 68 and 128 weeks. There has been no sign of relapse in the latter two cases. up to the time of this report. The most serious side effects of treatment were severe neutropenia and thrombocytopenia lasting for 2 to 3 weeks after initiation of the therapy, necessitating an intensive antibiotic therapy and platelet transfusion. Fibrinogen level rose after instituting administration of heparin in 2 of the 4 patients treated successfully, while it temporarily decreased in the remaining 2 cases and started to increase first when the mass of abnormal promyelocytes diminished. In none of the cases the bleeding tendency was intensified during heparin administration.
Three patients died of intracranial hemorrhage after treatment for 1,4 and 5 days, respectively. The possibility that heparin gave rise to the fatal hemorrhage in these patients cannot entirely be excluded. It is noteworthy, however, that remission was not produced in any of 11 cases treated at our clinic with various antileukemic agents other than daunorubicin before the introduction of the present protocol, and that 6 of 7 patients in this group without combined use of heparin died also of intracranial hemorrhage with a median survival of 8 days after the establishment of diagnosis.

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The nonspecific immunologic function was studied on the children with leukemias and malignancies. Antibodies against D. P. T. vaccine, measles, and varicella viruses were demonstrated above infectious threshold in almost all sera of these children, who had been vaccinated or infected before the onset of the disease.
Secondary humoral responses to these antigens were well retained in these children at any stages of the disease, whereas the primary responses were disturbed or delayed in most leukemic children and some of the children with malignancies at the onset of the disease.
This suggested that function of antigen processing or its information to B-cells might be involved in these children.
The cellular immunities, such as PPD and DNCB reaction, whether secondary or primary, were in variably disturbed in children both with leukemias and malignancies at the onset of the disease. Reaction turned positive whenever remission was induced. It was stressed PPD reaction correlated well to the clinical status, and the reaction could be used as an indicator for the evaluation of clinical status. Positive reaction turned negative when or before the relapse occurred in these patients, in spite of monthly repeated BCG vaccination.
The posibility of vaccinating live measles and varicella virus vaccine was also discussed.

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Four hundred and fourty five cases of malignancies of children in Chugoku and Shikoku District in Japan were observed for these 4 years.
The ratio male to female was 265:180 (1.47:1.00).
In the classification with reference to age, the greatest number was under 1 year old, 76 cases; next, 2-3 years, 63; 1-2 years, 50; 3-4 years, 48; 4-5 years, 36 and so on, namely, two thirds of cases were under 5 years old.
About the observation of classification of diseases, the greatest number of cases was acute leukemia, it showed 50∼60% in average for these 4 years.
The order of percentage of types of leukemia was as follows: ALL 114, AML 73, AL 50, AMOL 11, and so on.
Other 30 cases were diagnosed to have the malignancies in hematopoietic organs.
The caces of malignancies in hematopoietic organs (including leukemia) in total were two thirds of all malignancies in children.
The commonest cause of death of the children of 5-14 years of age was the malignancies.
In general, the antibiotic therapy for malignancies revealed to be more effective in children than in adults.

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Chromosome analyses and histochemical measurements of neutrophil alkaline phosphatase (neutrophil AP) were performed on patients with acute granulocytic leukemia in pre-treatment period.
1. Of 65 cases cytogenetically examined, 35 had chromosome abnormalities in their bone marrow cells. The percentages of cases with hypo-pseudo- or hyper-diploidy were 17.6, 67.6 and 14.8, respectively.
2. Neutrophil AP showed no any constant tendency in acute granulocytic leukemia, ranging from low to high in the activity. According to the AP activity, acute granulocytic leukemia cases were divided into three groups, low (score 0-170, 28 cases), normal (score 171-320, 21 cases) and high (score 321-500, 33 cases).
3. 15 of 28 patients with low AP activity had a common abnormality of translocation between group C and G, t (Cq-; Gq+).
4. Maturation of leukemic cells and abnormalities of nucleus and/or granules of the cells were frequently observed in cases with low neutrophil AP activity and translocation C/G.
Chromosome abnormalities in groups C and G, low activities of neutrophil AP and tendency for maturation of leukemic cells in acute granulocytic leukemia were discussed, comparing with those in chronic granulocytic leukemia.

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Chronic nephritic patients with uremic syndrome accompany very frequently severe anemia and hemorrhagic diathesis.
Renal anemia is likely due to depression of bone marrow erythropoiesis caused by the lack of erythrnpoietin produced by the intensively damaged kidneys. It is, therefore, very difficult to improve renal anemia only by hemodialysis. However, hemorrhagic diathesis mainly due to functional disorders of blood platelets is usually improvd after hemodialysis, because the treatment is capable of removing from the blood uremic toxins responsible for functional disorders of blood platelets. In Japan, many of chronic renal failure patients with severe anemia and uremic syndrome are now being treated on hemodialysis, combined with the administration of erythropoiesis-stimulating substances, such as iron, testosterone or anabolic steroids.
However, it is very desirable to treat them or hemodialysis combined with extrinsic erythropoietin, which might sooner or later become available here, to cover the lack of intrinsic erythropoietin in the blood and stimulate the depressed bone morrow erythropoiesis.

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Trace studies were made on the lymphocyte dynamics in 95 patients with Banti's syndrome 1-15 years after splenectomy and 27 patients which had to be splenectomized due to trauma 1-30 years after splenectomy. An increase in the peripheral white blood cell count due to a marked increase in neutrophils was seen during several days immediately after splenectomy. After more than 3 months, however, lymphocytes increased due to an increase in large lymphocytes. Small lymphocytes were rather few in number. The same tendency as in adults was observed after the elaspse of more than 6 months to several years in 14 young patients who were splenectomized between the aged of 10-20. However, depending on the condition, the reaction of neutrophil increase occurs even several years after splenectomy. Lymphocytes occupied 35.3% of the bone marrow cells with an actual number of 51,000 in cases of more than 1 year after splenectomy on accounts of splenic trauma, indicating an increase in the proportion and actual number. There is no marked change in the serum protein level or γ-globulin pattern.
Splenectomy was carried out in rabbits and rats within 24 hours of birth, and they showed no definite increase in the lymphocyte count.
The mechanism of an increase in the lymphocyte count after splenectomy is still unkown.

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The present paper reports four cases of disseminated intravascular coagulation which were found in fifty autopsy cases with generalized carcinomas. In a female case with pancreatic carcinoma a shock episode occurred suddenly during the course of admission. She had a continuous fever and high level of amylase activity in serum and urine. The diagnosis of DIC was based upon lowered level of platelet count and prolongation of prothrombin time and euglobulin lysis time.
Two patients with gastric carcinoma showed severe microangiopathic hemolytic anemia in association with DIC. Intravascular fibrin strands and direct contact between red cells and tumor cells within the blood vessel were supposed to be the cause of red cell fragmentation. A female patient with gastric carcinoma, showed the thromboembolic episode in finger and toe. The pathological observation included polypoid friable vegetation consisting mainly of fibrin and platelet on the aortic and mitral valves and peripheral vascular thrombosis, characterized as non-bacterial thrombotic endocarditis.
The clinical, laboratory and histopathological findings about these four cases of DIC were discussed.

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Attempts were made to clarify the mechanism and the clinical problems with the pulmonary infarction occurs, from coagulation-fibrinolytic point of view.
1) Consumption of coagulation-fibrinolytic factors was observed at the 3rd to 6th hour after the injection of minced thrombi or Lycopodium spores. With regard to fibrinolytic activity, differences of the response to microembolisation were observed among minced human thrombi, minced rabbit thrombi and Lycopodium spores. Experimental pulmonary infarction could be produced at a high rate through the infusion of blood clots on the 2nd day after the injection of Lycopodium spores, when the coagulation activity was on the highest grade and the fibrinolytic activity was on the lowest grade. We took an interest in the numerical similarity of epidemiological incidence of pulmonary infarction (58% of pulmonary embolism) to the incidence of pulmonary infarction (50 or 56%) obtained from our rabbits experiments through the infusion of blood clots on the 3rd day after the injection of minced thrombi.
2) The coagulation-fibrinolytic pattern in the clinical case tended to be similar to the pattern of rabbits experiments except the pattern of the short time after the infusion of blood clots. Therefore, it was suggested in the clinical case that intravascular coagulation might be already produced before the clinical onset. So that, exsaminations of coagulation-fibrinolytic activity before the clinical onset should be important for clinical treatments.
3) The analysis of coagulation-fibrinolytic activity should be took into the consideration that the examination of the collected venous blood hardly gives the exact information on the local pathological changes.

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We have examined blood coagulation and fibrinolytic activities in about 16 cases of pancreatitis and in 10 cases of normal adults.
In pancreatitis patients plasma fibrinogen level was elevated and P.T.T. shortened. In fibrinolytic system there is no remarkable change in systemic fibrinolytic activities, but EDP was remarkbly elevated in acute stage of pancreatitis.
In comparison beween arterial and venous blood, hypercoagulable state was observed with arterial blood more than with venous blood. And it was specific that Factor XII, XI and VIII in intrinsic coagulation system were elevated.
After injection of pancreozymin Secretin, the elevation of FDP, and decreasement of Fibrinogen and platelet aggregation were found.
From the results mentioned above, we concluded that in pancreatitis patients basic hypercoagulable state was found and at the acute stage intravascular coagulation will be occured.

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The studies on blood coagulation and fibrinolysis were performed in 6 cases with fulminant hepatitis. In addition, 11 cases of fulminant hepatitis, which were autopsied in these 5 years, were exactly observed upon bleeding tendency and microthrombus formation in all organs by microscopic and macroscopic survey. The results could be as follows;
1) Changes of coagulable and fibrinolytic activity. All cases of fulminant hepatitis showed hypocoagulability due to markedly low levels of coagulable activity (above all, prothrombin, Factor V, Factor VII and Factor X). In 5 of 6 cases, levels of fibrinogen were moderately decreased. Elevated levels of FDP by Fi-test were observed in 2 cases.
2) Microsocopic and macroscopic survey on autopsied cases. 3 of 9 cases with fulminant hepatitis were proved to have markedly bleeding tendency and microthrombus formation in the microvessels in various organ. 6 of 9 cases with fulminant hepatitis were observed on fibrin body in the hepatic sinusoid and central vein. Therefore, on the basis of above evidences, we concluded that hemorrhagic diathesis of fulminant hepatitis consists of hypocoagulability due to severe liver necrosis and occasionally added to disseminated intravascular clotting.

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Effect of trans-1-aminomethyl cyclohexane-4-carboxylic acid (AMCHA), 4-(2-carboxyethyl) phenyl-trans-4-aminomethyl cyclohexane carboxylate hydrochloride (DV 1006), Trasylol and heparin on experimentally induced disseminated intravascular coagulation (DIC) by continuous drip infusion of escherichia coli endotoxin was studied in rabbits.
Consumption of fibrinogen during 9-10-hour-infusion of the endotoxin and fibrin deposition in the glomeruli were enhanced by simultaneous infusion of AMCHA (but statistically not significant), DV 1006 (statistically not significant) and Trasylol (statistically significant), and were inhibited by heparin (statiscally not significant).
These experimental findings may be of help in managing DIC in man.

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Three patients with a severe congenital bleeding disorder due to factor XIII (fibrin stabilizing factor) deficiency in three famillies are described.
Case 1. T. K., a male, born in 1933, was first seen by us at the age of 35, because of repeated swellings of the right thigh. There was no hemorrhagic diathesis in his family, and parents were not consanguinous marriage. At the age of 8, he beld excessively after a minor cut on the right 2nd finger. At the age of 17, he developed a hematoma at the right thigh, which necessitated a transfusion of 200 ml of whole blood. Since then he had several episodes of hematoma at the right thigh. At the age of 40, the patient had an episode of intracranial bleeding after trauma. A cryoperecipitate infusion yielded an improvement.
Case 2. Y. M., a male, born in 1955, was first seen at the age of 17, because of flexion disturbance of left leg. There was no consanguinity and no bleeding patient in the family. The patient had an umbilical bleeding for one week shortly after birth. At the age of 7 and 10, he had excessive bleeding after a cut wound on fingers. At the age of 15, a huge muscle hematoma developed at the left thigh after a trauma and he was given 1000 ml of whole blood transfusion. At the age of 17, he had the same trouble on the left thigh. Since then a flexion disturbance of left leg has been developed.
Case 3. K. K., a male, born in 1957, was admitted to our Clinic on July 18, 1973, because of a walking disturbance. There was no bleeding tendency in the family, but his parents were first cousins. On the seventh day of age he had an umbilical bleeding persisting for 2 weeks. Since infancy the patient had presented ecchymoses and subcutaneous hematomas following minor wounds or traumas. At the age of 7, he had an episode of intraabdominal hemorrhage and operated under cover of 600 ml of whole blood transfusion. At 15 and 16 years of age he had recurrent episodes of pain and swelling at the left thigh after trauma. Since then, he has developed a difficulty of walking.
Usual coagulation tests were all normal in these patients. The plasma clots from each subject dissolved completely within a few minutes in 1% monochloroacetic acid (MCA) and dissolved within one hour in 5 M urea solution. When the plasma from case 1 was mixed with a known congenital factor XIII deficient plasma kindly supplyed by Dr. Shirakawa (Hamanomachi Hospital, Fukuoka, Japan) in various proportions, the abnormal solubilities in MCA or urea failed to yield an correction. Mutual correction of the abnormal solubility of clot did not occur among these three patient's plasmas.
The plasma factor XIII activity was 0U/ml in all of them by MCA solubility method using the plasma from case 1 or DEAE-cellulose treated FSF free human fibrinogen solution as substrate. And also, there was an absence of factor XIII activity in these patient's platelets. It was demonstrated that patients with congenital factor XIII deficiency lack a platelet-factor XIII.
The effects of infusions of fibrinogen and cryoprecipitate preparation durated to 11∼20 days. A half life of factor XIII was considered to be 4 days.

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Three cases of plasma cell leukemia are reported. The first patient, 28 year-old male, was admitted to the Meijo Hospital with the complaint of facial and pedal edema and palpitation in November, 1970. Examination revealed an increase of marrow plasma cells and the presence of serum M-componet measuring 2.9 g per cent which was identfied as IgG with κ light chain. Although he responded partially to steroid, myeloma cells in peripheral blood increased up to 23% of total leukocytes with elevation of serum M-component in December, 1971. He responded to melphalan therapy excellently with decrease of M-component and marrow plsma cells and also with disappearance of plasma cells in peripheral blood, and did well until December 1972, when lumbar pain, bleeding tendency and malaise developed. Combined therapy with melphalan and steroid failed to relieve the symptoms and he died of gartrointestinal tract bleeding and uremia with leukemic picture in circulating blood in May, 1973. The second patient, 71 year-old male, was admitted with complaints of generalized pain and anemia. Laboratory and X-ray examination showed marked increase of peripheral leukocytes (60,000/cmm) consisting mainly of small lymphocytoid plasma cells and profuse Bence-Jones proteinuria as well as vertebral collapses (the 9th thoracic and the 1st lumber). He died of renal failure 5 months after the onset of symptom. The third patient, 65 year-old male, was hospitalized because of nausea and vomiting. Immuno electrophoretic analysis demonstrated a formation of M-bow between his serum and anti γ-chain antiserum, and Bence-Jones protein was identifiied as λ-type. Small plasmacytoid cells constituted 30 to 40% of peripheral leukocytes throughout his course. He died of renal failure 3 months after the onset of the diseae.
In all three cases the plasmacytoid cells in peripheral blood were relatively small with diameter of 11-14μ, and large myeloma cells occasionally found in bone marrow in these cases rarely appeared in circulating blood. In contrast, marrow myeloma cells in the majority of non-leukemic cases were large with diameter of more than 15μ suggesting that the size of myeloma cells is one of controlling factors whether the cases with myelomatosis become leukemic or not. In the first case, the presence of lamellar rough surfaced endoplasmic reticulum was demonstrated by electron microscopic study and the production of IgG by immunofluorescent technique, though the circulating plasma cells may be of relatively immature without well-developed cellular organelles.

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