Twelve members of a new series of 1-trialkylmethyl-1-6, 7-dimethoxy-3, 4-dihydroisoquinoline (D type) and eleven analogs of 1-trialkylmethyl-6, 7-dimethoxy isoquinoline (I type) were investigated for their pharmacological properties, with special reference to the toxicity and spasmolytic activity, comparing with papaverine. Along these isoquinoline, 1-methylisoquinoline, 6, 7-dimethoxyisoquinoline and their respective 3, 4-hydrogenated derivatives, were also examined for the elucidation of structure-activity relationship. All the compounds of D type produced a marked inhibitory action on the isolated rabbit intestine. The most potent members were n-tripropyl, ethyl-n-propyl-n-butyl and methyl-ethyl-n-butyl derivatives. Their spasmolytic actions on both barium and histamine contraction of the intestine exceeded those of papaverine, though the effect on acetylcholine spasm was slightly inferior. They were less toxic in mice than in the latter. The intestine inhibitory activity and toxicity of I Type compounds were both smaller than those of D type analogs. The differences between the two types seemed to be related to the solubility. Other smaller components of the papaverine structure, namely, the primitive isoquinoline derivatives were more toxic, but much less spasmolytic than papaverine. In mice toxic doses of all the compounds caused tremors, excitability and convulsions followed by a generalized central depression. Respiratory paralysis may be direct cause of death. Toxic symptoms were generally similar to those in frogs. The stimulant properties were increased by the saturation of the 3, 4-position on the isoquinoline nucleus.

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1. The protein active SH radical in various blood diseases is generally reduced, but it is markedly so especially in leukemia and cancer. Of various leukemias the acute from shows a marked decreasing tendency.
2. As for mucoprotein on the other hand, a markedly high value is shown in leukemia, cancer and Hodgkin's disease, and even in this instance it is extremely high in the acute from of leukemia. On the contrary in other blood diseases the value is either nomal or at a slightly higher level.
3. Therefore, the protein index of Müller is positive in al most all leukemia, cancer and Hodgkin's disease, making it possible to distinguish them distinctly from other diseases.
4. No specal correlation can be found between the proiein active SH radical and mucoprotein on one hand and the liver function and serum protein fractions on the other.
5. Judging the fluctuations in the protein active SH radical and mucoprotein on the basis of results of treatment in blood diseases, there exists clearly a mutual relationship between the fluctuations and clinical symptoms. In other words, in luekemia the fluctuations in the protein active SH radical and mucoprotein are parallel with the fluctuations in the number of immature leucocytes, while in other blood diseascs the fluctuations parallel with the degree of anemia.
6. The protein active SH radical and mucoprotein in experimental anemia fluctuate in parallel with the degree of anemia and they take about the same course.

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1. The serum cholinesterase (ChE) activity in various blood disease generally shows a decreasing tendency, and it is marked in the acute form of leukemia. However, there can be recognized no special correlation between the serum ChE activity and the liver funktion and serum protein fractions. The serum ChE activity in blood diseases reflects well the clinical symptoms.
2. For the determination of the erythrocyte ChE activity in various blood diseases the author studied it by calculating the ChE activity value in a given unit of erythrocyte. As the result it has been found that in general the erythrocyte ChE activity in blood diseases shows an increasing tendency, and such a tendency is most marked in the acute form of leukemia.
3. When the administration of various drugs and blood transfusion prove effective on the fluctuations of the serum ChE activity and erythrocyte ChE activity in the course of treatment, these activities regain the normal level along with the recovery of anemia. The same trend can be recognized even in the experimental anemia.

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Cases of gastric cancer were classified into two types, i.e. the localized and infiltrating ones. Specimens were taken from the cancer and the neighbouring part of it on sides of the greater and the lesser curvatures, and tissue respiration, aerobic and anaerobic glycolysis were investigated with Warburg apparatus.
1) The cancer tissue has decreased tissue respiration and increesed aerobic as well as anaerobic glycolysis compared with the non-cancerous tissue. Neighbouring tissue of the cancer has more similar nature to the cancer than the non-cancerous case.
2) In non-cancerous tissues, there are observed decreased tissue respiration and increased aerobic glycolysis on the side of the lesser curvature compared with the greater.
3) Neighbouring tissue of the cancer has increased aerobic glycolysis on the side of the lesser curvature.
4) In the cancer tissue, both localized and infiltrating types have decreased tissue respiration on the side of the lesser curvatrue. The infiltrating type shows increased aerobic and anaerobic glycolysis on the side of the lesser curvature, while the localized type shows no difference.
5) From these results, it is proved that the cancer tissue has more malignant biochemical nature on the side of the lesser curvature than that of the greater.

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Specimens were taken from the gastric cancer and that of noncancerous stomach on sides of the lesser and the greater curvatures, and 6-phosphogluconate was added to the homogenate of the specimen. Then the pentose-phosphate (p. p.) was measured before and after incubation.
1) P. p. before incubation shows lower level in the cancer case compared with the noncancerous. In both cases, the side of the lesser curvature has less p. p. than that of the greater.
2) The same results are also observed after incubation.
3) The increase of p. p. by incubation is more marked in the cancer case than the noncancerous. In both cases, the in crease is more marked on the side of the lesser curvature than that of the greater.
4) From these results, it is considered that the production as well as the consumption of p. p. are more marked in the cancer tissue than the non-cancerous, and also so on the side of the lesser curvature than that of the greater.

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In the present report are presented the results of the clinical and statistical observations conducted on the hemomyelogram of various leukemias occurring in the Chugoku-Shikoku District, with a special reference to the comparative studies carried on the bone marrow of patients treated in our department, handling the cases in which bone-marrow tissue culture was conducted and those without the tissue culture separately. It is to be noted that chronic lymphocytic leukemia is not included in the present study as the number of such cases was to small.
1. In every leukemia generally immature cells are markedly increased in number; in acute leukemia blast cells occupy the major proportion; and in chronic leukemia young leucocytes in various stages of maturation are mixed.
2. Judging from the hemomyelogram, all cases of monocytic leukemia seems to occupy an intermediate position between acute leukemia and chronic leukemia. Hence it is difficult to divide it definitely as an acute leukemia or a chronic one.
3. It is worthy of attention that monocytic leukemia in the cases given no bone-marrow tissue culture occupies only 9.8 per cent of the total leukemia, whereas the same in the cases given the bone-marrow tissue culture occupies as much as 45.5 per cent of the total leukemia. Namely, it is to be noted that without the bone-marrow tissue culture it is often difficult to diagnose monocytic leukemia correctly and it is often mistaken for other leukemias, especially for acute myelogenous leukemia.

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The author carried out clinical and statistical observations of the peripheral blood picture in various leukemias occurring in the Chugoku-Shikoku District, with a special reference to the comparative study on the two groups treated in our department, namely, the group whose bone marrow was cultured and the other without such a culture finding. However, cases of chronic lymphocytic leukemia are not included in the present statistics as their number was trivial.
1. Hb content and erythrocyte count: The decrease in Hb content and erythrocyte count is most marked in acute myelogenous leukemia, followed by acute lymphocytic leukemia, and it is least in chronic myelogenous leukemia. The decrease in Hb and erythrocytes of monocytic leukemia occupies an intermediate position between the above two.
2. The color index: The color index is comparatively high in acute type while it tends to be lower in chronic type.
3. Leucocyte count: The aleukemic form is greatest in monocytic leukemia followed in descending order of that in acute lymphocytic leukemia and acute myelogenous leukemia, and all of these aleukemic ones occupy more than 1/3 of the total. However, in chronic myelogenous leukemia it is extremely rare to find the aleukemic form.
4. Reticulocyte count: The reticulocyte count in the peripheral blood of leukemia is generally normal or is increased.
5. Platelet count: The platelet count is about at the normal level in chronic myelogenous leukemia, and in some it is increased. However, it is decreased in all other leukemias. In monocytic leukemia it resembles that in acute type.
6. Classification of leucocytes: In acute myelogenous leukemia myeloblasts occupy a greater proportion and also matured leucocytes are quite many. Intermediate immature cells are low in percentage but it is rare not to see any intermediate immature cells. In chronic myelogenous leukemia mature neutrophils are numerous but immature neutrophils are a few in number.
In acute lymphocytic leukemia a high percentage of lymphatic cells accompanied by a marked increase in lymphoblasts can be observed.
In monocytic leukemia intermdiate mature cells are in a low proportion, and monoblasts are less than in acute type, presenting the characteristic intermediate between acute type and chronic type. Namely, monocytic leukemia is an intermediate type between acute leukemia and chronic leukemia, and it is difficult to divide it into acute and chronic types.
7. Relationship between the leucocyte count and leucocyte percentage: On the whole the increase in the number of leucocytes and myeloblast percentage show a mutual relationship. In monocytic leukemia those whose increase in the number of leucocytes is more marked show a greater number of monoblasts, approaching to the acute type.
8. Relationship between the leucocyte count and platelet count: There can be seen no relationship between the leucocyte count and platelet count.
9. Relationship between the leucocyte count and swelling of the spleen and lymph nodes: In acute lymphocytic leukemia the more marked is the increase in the number of leucocytes the greater is the palpitation frequency and the degere of swelling of the spleen and lymph nodes. In chronic myelogenous leukemia the degree of splenomegaly increases along with the increase in the nmnber of leucocytes.

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The author made a comparative study of serum iron and serum copper contents in various leukemias that had been definitely diagnosed by their bone-marrow tissue culture conducted in our department. Simultaneously the author performed the intravenous iron loading tests and the iron-absorption tests with various leukemias, and obtained the following results. However, in the present comparative study on the serum iron and copper, chronic lymphocytic leukemia is excluded as the number of such cases were too small.
1. In comparing the average value of the serum iron content, acute lymphocytic leukemia shows the greatest value, followed by those of acute myelogenous leukemia, monocytic leukemia, and chronic myelogenous leukemia in the descending order mentioned. The serum copper content is greatest in acute lymphocytic leukemia, and in the descending order of monocytic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia.
Judging monocytic leukemia from the standpoint of its serum iron content, this type also proves to be an intermediary type between acute type and chronic type.
2. In the intravenous iron-loading tests and iron-absorption tests of various leukemias the increased content and decreased content in either case proved to be lower. Moreover, the serum copper content by the iron-loading tests shows hardly any change.
3. In the iron-loading tests likewise no difference can be recognized in various types of leukemia.

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Traceable Fe 55 hemin was dissolved in 20% pyridine water solution, then 1-ascorbic acid was reacted in absence of oxygen. Column chromatography was observed on the reaction mixture of each reacting time. Studies were made on the water solution of the divisible absorption layers and following deductions were obtained.
1) Hourly observations of chromatogram were always in 4 layers and their respective colors and distributions were different. Additionally the fouth layer, due to the failure of retaining it in the absorption column in spite of various manipulations attempted, was collected as a gravity flow effluent.
2) Distribution of the total iron was different with respective layer and reacting time, but there was iron which would not dissolve in water due its remaining in the absorption column unber ionic combination and with increased with the reaction progress.
3) Total iron in the first layer was very small i. e. traceable degree and the greater part of it was easily split off iron. Biliverdin was undetectable therefore absorption curve worth mentioning was obtainable.
4) Conversely with the hourly decrease of total iron in the second layer, easily split off iron increased with the reaction progress. The amount of Biliverdin was highest at the end of four hours. In the absorption curve the peak absorptions of 610 mμ was observed right after the initiation of reaction and after one hour which was believed to be due to pyridine-hemichromogen being absorbed.
5) Total iron of the third layer was exceedingly small and most part of it was easily split off iron. The quantity of Biliverdin was highest at the end of fourth hour. Absorption curve was not obtainable.
6) For the fourth layer total iron showed the peak at the end of four hours but the value for the easily split off iron was relatively high throughout and little deflection was observed for all reaction progress. Biliverdin content was highest in this layer and highest at the fourth hour. With reference to the absorption curve at the initial reaction stage 3 maximum peaks of 656, 530 and 500 mμ were observed. This was parallel with protoverdohemochrome. With the progress of reaction this was equal with the 656 mμ of pyridineverdohemochromogen.
7) The quantity of easily split off iron, that of ron just after the addition of hydrochloric acid and so called free iron was parallel but value of easily split of iron content was higher throughout. Moreover the quantity of easly split off iron and Biliverdin quantity did not show parallel relation to each other.
8) Permeating liquid could be observed after 2 hours reaction. The colour of the liquid was light strow at the begining and as the time elapsed brownish tinge increased. Also the quantity of total iron increased with time lapse but notable absorption curve was not obtainable. Presence of Biliverdin could not be proven qualitatively.

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The following deduction were obtained, reacting traceable Fe⁵⁹ hemoglobin solution with 1-ascorbic acid under absence of oxygen, and subsequently observated the formed intermediate products in the column chromatography as the time elapsed.
1) The column stratified into four layers in 4 hours after initial reaction and into 3 layers 8 hours after start of reaction. Colors and distribution of strata differed at corresponding reacton times.
2) Total iron distribution differred with corresponding absorption layer and reaction time.
3) The hourly increase of total iron in the first stratum was due mostly to increase of easily split off iron.
4) Total iron content of second layer was small and hourly change was minute, however at the start of the reaction the presence of easily split off iron was exceedingly large. Although easly split off iron content reduction was fast in comparison with other layers it appeared as though this layer was the initiator of reaction progress.
5) Total iron content was largest in the third layer, but the quantity of easily split off iron was exceedingly small and hourly change was lacking.
6) Against the fast rate of reduction of total iron content of the fourth layer, the easily split off iron increased at a fast rate.
7) Easily split off iron content was always higher than the iron content immediately after the hydrochloric acid addition or so called free iron.
8) The presence of the so called free iron is obvious, but it was not clear whether it was the natural free iron it was due to trichloro-acetic acid.
9) Differing from other layers, the iron in the first layer was harder to ionize.
10) Biliverdin was analysed from all layers but parallel between its content and that of easily split off iron was not recognized.

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In order to see whether or not the liver of different species of animals possesses antigenicity and also to study the significance of senstization with visceral antigens, the visceral specificity of liver antiserum, and the possible visceral disturbances the author carried out serological study on different species of animals (dogs and rabbits) and obtained the following results.
1. The liver of different species of animals possesses antigenicity, aud the serum of the rabbit sensitized with dog liver extract shows a relative visceral specificity in the reaction in vitro between this serum and the extracts of various organs, blood, and serum of the dog.
2. In the blood as well as in various organ tissues of the rabbit sensitized by the extract of dog liver can be detected antibody (liver antibody) as to react with such sentitizing agents.
3. When the serum of the rabbit sensitized with dog liver extract is inoculated into a normal dog, it disturbs the function of the liver and neighboring abdominal organs. Moreover, such a serum accelerates the production of antibody to react especially with the antigen extracted from the dog liver and also it reveals a relative visceral specificity.

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With the purpose to elucidate the in vivo antigenicity of homologous animal organs, especially of the liver, and also to clarify the problem centering around the visceralspecificity and the harful effect of the homologous liver antiserum obtained from the same species of animals sensitized with the homologous animal antigens, the author carried out serological investigations, and obtained the following results.
1. Antigenicity can be recongized in the liver of the same species of animals, but its antibody titer is lower than that of different species of animals; and moreover, the in vivo reactions between such a liver antiserum and various visceral antigens of rabbits reveal a relative visceral specificity.
2. When the same species of animal is sensitized with antigen extracted from the rabbit liver, homologous liver antibody can be detected not only in the circulating blood but also in various organ tissues of the rabbit.
3. When the homologous liver antiserum obtained from the same species of animal sensitized with the antigen extracted from rabbit liver is inoculated into the same species of rabbits, disturbances in the liver and neighboring internal organs can be recognized serologically and functionally. Moreover, the serum of such animals possesses the relative visceral specificity.

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With the use of Atoxyl antibody obtained from the rabbit immunized with Atoxyl labeled egg-white albumin the author traced the changes of Atoxyl in the blood and oragns of the rabbit inoculated with Atoxyl labeled normal rabbit serum and homologus liver antiserum. As the results it has been clarified that the liver antiserum does not reveal absolute visceral specificity but it shows a relative visceralspecificity and also it tends to disturb the liver function.

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The author conducted a series of experiments on Barkan's easily-splitoff iron E and E' and obtained the following results.
1. There are distinct differences between the inhibtory action of carbor mcnoxide and that of inactivated gas on choleglobin liberating iron.
2. In the estimation of E and E' in ten abult males, the average sum of E and E' has been found to be 1.52 mg%, with E' being 0.34 mg%, and E occupies 77.33 per cent of the total. This value is somewhat higher than that of Barkan.
3. In the study of various conditions of reagent, governing the reaction, when the reaction is made to take place at 0°C without any supply of oxygen, it is retarded most markedly, but it is not completely stopped.
4. In the reagent the decomposition progresses from hemoglobin to E and E' but an exact quantitative analysis has been difficult.

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With the purpose to elucidate the properties of the thoracic duct lymph during the production of bile pigment in vivo, the author pursued the changes in the amounts of easily-split-off iron and free iron in lymph and in hemoglobin content by creating thoracic duct fistula in normal dogs, in dogs administered carbon tetrachlorice or in dogs occluded of RES, and then by lording physiological saline solution or hemoglobin solution into the femoral vein or peritoneal vein of these animals, and compared these results with contents in blood. The following are the results.
1. In the normal dogs the content of easily-split-off iron in lymph increases transiently later than that in blood, but the changes in both are somewhat parallet to one another.
2. In the case with liver disorders the increase in the blood easily-split-off iron is slow or undetectable, while on the contrary, the easily-split-off iron in lymph increases slower than in normal animal but distinctly.
3. Since a large quantity of the injected hemoglobin is transferred to lymph in the case with liver disorders, the major portion of easily-split-off iron produced due to the liver disorders, though the amount produced is trivial, seems to be transferred to lymph.
4. In the case occluded of the RES the increase of easily-split-off iron in lymph is slow and small in amount.
5. The easily-split-off iron in lymph is the one produced in the liver from hemoglobin and then transferred to lymph, while the easily-split-off iron in blood is also a portion of the same produced in the liver but transferred directly to blood.

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With the urine of the patient with mechanical jaundice the author isolated direct bilirubins, both ester form and salt form, by the toutine techniques employed in our laboratory, and studied the realtionship between glucuronic acid and these bilirubins.
1. Regardless of the techniques used in isolating direct bilins of salt form the glucuronic acid reaction proves to be always negative.
2 Of the direct bilirubins of ester form, the one isolated by Komuta's precipitation method is negative to the glucuronic acid test.
3. Of direct bilirubins of ester form obtained by the ion-exchange chromatography as well as by butanol extraction method, most of them are positive to the glucuronic acid test but some prove to be negative.
4. By paper and column chromatography it has been possible to isolate from the esterform direct bilirubin fractions positive to glucuronic acid the direct bilirubin that is related to glucuronic acid aside from the ester-form direct bilirubins, but the quantity is trivial.
From these results the existence of bilirubin glucuronide as contended by Billing et al can be understandable, but its quantity is an extremely small portion of the total ester-form bilirubins, and almost all of them prove to be what we in our laboratory call “ester-form direct bilirubins”

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Using the urine obtained from four cases of mechanical jaundice, one case of acute hapatitis, and one case of chronic hepatitis, (cholangiolitis) to the total of six cases and isolating ester-type direct bilirubins by Sakamoto's ion-exchange chromatography, the author studied the bilirubin glucuronide distribution as against the fractions of the entire ester-type bilirubins; and obtained the following restlts.
1. When the distribution of bilirubin giucuronide is calculated on the basis of the quantitative determination of glucuronic acid:
a) The minimum value of bilirubin glucuronide to the entire ester-type bilirubin was zero per cent, the maximum 30-60 per cent, and the average 16-32 per cent.
b) As to the variation by different diseases it was impossible to determine definitely as the number of the cases studied was small.
c) In the case with normal liver function or with a minimal disturbance of the liver, the minimum value was 12.5-25 per cent; the maximum 30-60 per cent; and the average value was 17-38 per cent. In the case with advanced liver disorder the minimum value was zero per cent; the maximum 10.5-21 per cent; and the average 5.5-11 per cent.
2. When the bilirubin glucuronide distribution is calculated from the indirect bilirubin content produced after hydrolysis by alkali:
a) The minimum value is zero per cent; the maximum 38 per cent; and the average was 21 per cent.
b) In the case with normal liver function or with a minimal disorder of the liver the minimum value was 13 per cent; the maximum 38 per cent; and the average value 24 per cent; while in the case with far advanced disorder of the liver the minimum was zero per cent; the maximum 17 per cent; and the average 9 per cent.
3. From these findnings it can be assumed that the direct bilirubins in the jaundice urine, with exception of basic direct bilirubin, belong mostly to what we call the ester-type direct bilirubin in our laboratory, while on the contrary the quantity of bilirubin glucuronide can be found only in a small percentage, and in the case of far advanced disorder of the liver it is sometimes extremely reduced and even disappears completely when compared with the quantity of the so-called ester-type direct bilirubin.

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Using rabbits, guinea pigs, and mice as the test animals, the author studied the production of homologous-liver-antibody and auto-liver-antibody by preparing various organ antigens of these animals and injecting a hypertonic physiological saline solution of these antigens into the liver of respective animals asceptically so as to avoid the sensitization of homologous animals; and obtained the following results.
1. It is possible to produce auto-liver-antibody by injecting homologous-liver-antigen and auto-liver-antigen.
2. These antibodies can combine with homologous- and auto-liver-antigens in vivo.
3. The homologous-liver-antigens and autoantigens have been found to have a specificity to organs, but this is just a matter of comparison. Of the two the specifity of the latter is more marked.

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The author studied clinical significance of auto-liver-antibody in liver diseases and obtained the following results.
1. Auto-iiver-antibody in liver diseases shows decidedly stronger pesitive reaction than in other diseases, and in addition, it presents a higher titer of the antibody. Especially in the liver disease other than infectious hepatitis such as in liver cirrhosis it may be emphasized that the antibody titer is high.
2. Auto-liver-antibody presents a close correlation with the liver functions and liver autopsy picture.
3. Auto-liver-antibody is quite useful for differential diagnosis and prognosis of liver diseases.
4. The mice previously sensitized wth homologous-liver-antigen or by albumin of eggwhite and attacked by Ectromelia virus are clearly at more disadvantage for the infection than in the case of non-sensitized mice. However, the difference between the two groups is not so distinct and the existence of liver-damaging action by the homologous- and auto-liver-antibodies can not be decided definitely.

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With the purpose to see whether or not anamnetic reaction is induced by hormones of the pituitary and adrenal glands and to study its clinical significance, after disappersance of the homologous-liver-antibody and auto-liver-antibody that have been once produced experimentally in animals, the author performed a series of experiments with animals and obtained the following results.
1. Of pituitary and adrenal hormones ACE markedly elicits anamnetic reaction, homologous and at-liver-antibodies, and moreover, it has becoome clear that these antibodies make their appearance in the circulating blood within one to five days of the injection of these hormones.
2. Clinically this fact increases the imporsance of observing the auto-liver-antibody.
3. The use of an appropriate dose of nitrcmin can prevent this anamnetic reaction form occurring.

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To evoke anoxic anoxia 5 vol % oxygen was inhalated. under 2.5% Ravonal anesthesia, to adult healthy dogs, to dogs whose reticuloendothelial system had been blocked and to bilaterally adrenolectomized dogs. After that, blood coagulation time, plasma coagulation time after calcium readdition, prothrombin index, plasma fibrinogen content and blood water content were measured during pure oxygen inhalation as well as 15, 30, and 45 minutes after commencement of anoxia for a comparative study.
1. Blood coagulation time reduced rapidly in normal dogs with development of anoxia. The reduction was slight in dogs with blocked reticuloendothelial system and almost none in bilaterally adrenolectomized dogs.
2. Plasma coagulation time after calcium readdition reduced in healthy dogs with development of anoxia. An almost similar reduction was observed in dogs with blocked reticuloendothelial system. In bilaterally adrenalectomized dogs, however, it was slight in extent.
3. Prothrombin index increased slightly with development of anoxia except in bilaterally adrenolectomized dogs in which the increase was insignificant.
4. Plasma fibrinogen content increased with development of anoxia in any case. The increase was greater in dogs with blocked reticuloendcthelial system than in normal dogs both during pure oxygen inhalation and during anoxia. With bilaterally adrenolectomized dogs, no difference was noticed compared normal dogs.
5. Blood water content decreased with development of anoxia. No influence of blocking of the reticuloendothelial system or bilaterally adrenolectomy was observed.

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The conversion of ¹⁴C-labelled glucose to free amino acids by homogenate of human and rabbit brain was studied by paper chromatgraphy and radioautography with X-ray film. Results were:
1) In both human and rabbit brain glutamine, asparagine, glutamic acid, aspartic acid and γ-aminobutyric acid with radioactivity were derived from ¹⁴C-labelled glucose. Moreover in rabbit brain alanine was also derived.
2) In normal rabbit brain the derived amino acids were investigated. During short incubate time the precoursors such as aspartic acid and glutamic acid appeared quickly and intensively. Next asparagine and glutamine showed up and then alanine and γ-aminobutyric acid were proved.
3) It needed 24 hours for all free amino acids to appear sharply.
4) The optimal pH of this reaction was 8.5-9.0

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The conversion of ¹⁴C-labelled glucose to free amino acids by homogenates of brain tissues from idiopathic epleptics, non-epileptics as well as normal and LCLA rabbits was studied.
1) The turnover of ¹⁴C-labelled glucose to free amino acids in idiopathic epileptic brain was more disturbed than that in non-epileptic brain: to asparagine and glutamine no significant differences wee seen, but especially to gluamic acid it was slightly disturbed and to aspartic acid and γ-aminobutyric acid they were intensively disturbed.
In idiopathic epileptic brain no γ-aminobutyric acid was proved.
2) In one case of focal epileptic brain, the conversion of aspartic acid was more restrained in the focus than in the contrast part.
3) In LCLA rabbit brain, the turnover of free amino acids were generally more disturbed than that by normal one. To glutamine and asparagine no significant difference was found but to glutamic acid it was slightly and to γ-aminobutyric acid it was markedly disturbed.

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With the purpose to elucidate the cause of the increase in substances positive to Donaggio reaction of urine in fatigue the author administered adrenalin chloride (diluted 1, 000-fold), ammon chloride and ACTH to rabbits and induced conditions simulating those irregularities of the body in fatigue. In the observation of their urine the following results were obtained.
1. In the rabbit administered adrenalin chloride the urine Donaggio value reaches its maximum 2-3 hours after the injection and thereafter descending gradually, it returns to normal lever 24 hours afterwards. The amount of urine likewise increases 2-3 hours after the injection, but urine pH does not show any alteration.
2. In the rabbit given oral administration of ammon chloride the urine Donaggio value reaches the maximum six hours after the administration and decreasing gradually thereafter, it returns to normal level after 24 hours. The amount of urine likewise increases 2-6 hours after the administration, substantiating the increase in the content of substance positive to the urine Donaggio reaction being excreted hourly. Urine pH shows the minimum 3-6 hours after the administration.
3. In the rabbit administered ACTH the urine Donaggio value, increasing markedly already one hour after the injection, reaches the maximum value after three hours. Thereafter decreasing rapidly, it returns to normal level after 24 hours. No changes can be recognized in the urine content and pH.
4. In the rabbit not treated with drug the maximum variation in the urine Donaggio value ranges within two, and no marked change can be recognized in the urine content and in pH.
5. In drawing the correlation curve between the urine Donaggio value and the concentration of remnant methylene blue the result obtained aproximately coincides with that reported by Nakayama. Calculating from this curve, the Donaggio vaules can be correctly determined within the limit of error of 1.0±0.1.

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With the use of various stains the author studied Donaggio reaction of urine and obtained the following results.
1. Methylene blue (MB), thionine (TN), crystal violet (CV), fuchsin (FS), and thymol blue (TB) are all applicable for Donaggio reaction.
2. The sensitivity of various stains is in the descending order of TN>FS>CV>TB>MB.
3. MB, TB, and TN are sensitive stains that respond ralatively rapidly to the reaction, whereas CV and FS are the stains that respond to the reaction rather slowly.
4. MB, TN and TB seem to be especially useful stains for the determination of the grade of fatigue by Donaggio reaction with the urine both before and after work.

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In the study on the effects of various salts and pH on Donaggio reaction the author obtained the following results.
1. In the case loaded with 1% table salt solution the Donaggio value is reduced to one half and in the case with 7% salt solution it is decreased to 1/4.
2. As for the effect of ions, Na⁺, K⁺, and Mg⁺ show an in hibitory action on the Donaggio reaction.
3. As for anions Cl^-, SO^-₄ and PO^-₄ likewise show an inhibitory action on the reaction.
4. At pH between 7.4 and 9.0 the Donaggio reaction is strongly postivie while at pH between 5.8 and 3.0 or between 10.0 and 11.0 the reaction is weakly positive. However, at pH under 2.0 and over 12.0 it is negative.

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In the study on the Donaggio values before and after various surgical operations the author obtained the following results.
1. In the appendectomy the average urine Donaggio value before operation is 2, and 18.7 after the operation.
2. In the operation for gastric cancer or gastric ulcers, the average of the urinc Donaggio values before the operation is 10.7 while it is 24.0 after the operation.
3. In the operation for hernia and pile the urine Donaggio values both before and after the operation do not show any difference.

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By making protein degenerant and protein digestive enzyme act on old tuberculin the author performed the tuberculin reaction, and obtained the following results.
1. In loading a strong potassium iodide solution to old tuberculin the tuberculin reaction grows weaker along with an increase in the concentration of potassium iodide. This suggests that free tyrodine radical in the old tuberculin protein is involved in the tuberculin reaction.
2. In loading sodium nitrite to old tuberculin the tuberculin reaction likewise grows weaker with increase in the concentration of sodium nitrite
3. In the addition of formalin to old tuberculin the tuberculin raction is weakened along with increaes in the concentration of formalin solution.
4. When crystalline trypsine is made to act on old tuberculin, the tuberculin reaction is weakened along with lapse in the digestion time.
5. When pepsin is made to act on old tuberculin, the tuberculin reaction is likewise weakened along with lapse in the digestion time.
6. From these results it is deduced that the tuberculin reastion is mainly controlled by tuberculin protein.

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Using the protein, nuclear protein and polysaccharide fractions obtained from old tuberculin by salt analysis or by paperelectrophoresis the author performed the tuberculin reaction and erythrocyte coagulation reaction, and obtained the following results:
1. In the tuberulin reaction conducted in each of the protein, nuclear protein and polysaccharide fractions from old tuberculin the intesnity of the tuberculin reaction has been found in the descending order of protein, nuclear protein, and polysaccharide fractions. In the erythrocyte coagulation reaction the intensity is in the order of polysaccharide, nuclear protein and protein fractions.
2. By the paperelectrophoresis of old tuberculin with ninhybrin reaction phoretic peaks, A, B, C, and D were obtained in the order of phoretic speed. Of them the peak C seems to be dialytic substance.
3. By ammonia silver nitrate reaction two phoretic peaks A' and B' were obtained according to the phoretic speed.
4. After the paperelectrophoresis of old tuberculin and making l cm strips each from the starting point, when the fractions are extracted by physiological saline solution, the further away from the starting point the lighter is the color. Moreover, the tuberculin reaction and erythrocyte coagulation reaction likewise grow weaker as the distance is further away from the starting point, but there seems to be no marked correlation among the three tests.

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The author executed the tuberculin reaction and the paperelectrophoresis of the lung tuberculosis patients after pulmonectomy and also the paperelectrophoresis of the patients' sera, and obtained the following results.
1. Of 16 tuberculosis patients 9 cases (56.2%) showed the weakening in the tuberculin reaction after pulmonectomy, and 5 cases (31.2%) showed a transient weakening of the reaction but a later recovery.
2. When the aqueous solution of old tuberculin is used in the dilution of 1:100, 1:2, 000, and 1:10, 000, the tuberculin reaction after pulmonectomy shows a weakening tendency in 2 cases (11.1%) out of 18 cases; a transient strengthening and a later weakening in 3 cases (16.6%); a transient weakening then a later strengthening in 11 cases (61.1%); and changes obscure in 2 cases (11.1%).
3. In the tuberculin reaction performed after pulmonectomy with the use of old tuberculin aqueous solution diluted 100-fold, 2, 000-fold, and 10, 000-fold the red color area and the concentration of tuberculin solution show a parallel relationship.
4. In the erythrocyte coagulation reaction performed after pulmonectomy those showing a decreasing tendency in the reaction amounted to 54.5 per cent of the total cases; those showing a weakening and a later strengthening tendency amounted to 18.2 per cent; and in 27-3 per cent no clear-cut fluctuation of the reaction.
5. The tuberculin reaction and erythrocyte coagulation values show a parallel relationship.
6. In the results of paperelectrophoresis it has been found that after pulmonectomy serum albumin is decreased; γ-globulin decreases temporarily but later recovers back to the original level; and α- and β-globulins increase transiently, but each fraction recovers to the level before pulmonectomy after three weeks.

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By measuring the oxygen consumption in the sternal bone marrow of various leukemias definitely diagnosed on the basis of their bone-marrow tissue culture, the author obtained the following results.
1. In leukemia the oxygen consumption of 0.2 cc/hr sternal bone marrow shows an increase as compared with that of normal persons, and the degree of this increase differs according to the form of diseases. The grade of such an increase is in the descending order of that in acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, monocytic leukemia and chronic lymphocytic leukemia. Xo₂/K in comparison with that in the normal case is increased in acute myelogenous leukemia and monocytic leukemia, but in chronic myelogenous leukemia it is somewhat decreased, and in acute and chronic lymphocytic leukemia it is markedly decreased. Qo₂ is increased in all leukemia as compared with that of normal case, and its increase is in the descending order of that in monocytic leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, and chronic lymphocytic leukemia.
2. There is a parallel relation between the oxygen consumption, the nucleated cell count, and the immature cell percentage of the bone marrow, and moreover, in chronic myelogenous leukemia at remission due to the treatment the oxygen consumption is also reduced.
3. As for the oxygen consumption of peripheral erythrocytes in chronic myelogenous leukemia it is at the normal level, but in all others it is slightly reduced.

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With the sternal bone marrow obtained from various leukemias definitely diagnosed by their bone-marrow tissue culture the author measured the glycolysis in the sternal bone marrow and obtained the following results.
1. Anaerobic glycolysis of 0.2 cc/hr sternal bone marrow in leukemia is markedly increased as compared with that in normal persons, and the grads of such an increase differs according to the form of diseases. Pointing out the form of leukemias from the greater to the lesser acceleration in the anaerobic glycolysis, they are in the order of acute lymphocytic leukemia, acute myelogenous leukemia, monocytic leukemia, chronic myelogenous leukemia and chronic lymphocytic leukemia.
2. The acceleration of X_M^N₂/K is most marked in acute myelogenous leukemia followed by monocytic leukemia, and in chronic myelogenous leukemia it is close to the normal value, while in lymphocytic leukemia it is less than the normal value. In the case with a higher percentage of immature cells there is an increasing tendency in X_M^N₂/K.
3. With a single exception of chronic lymphocytic leukemia Q_M^N₂ is accelerated in every form of leukemia, and in pointing out the ones with marked acceleration and down they are in the order of acute lymphocytic leukemia, acute myelogenous leukemia, monocytic leukemia, and chronic myelogenous leukemia. Moreover, those with greater number of nucleated cells and a higher percentage of immature cells in bone marrow the value of Q_M^N₂ tends to be greater.
4. The aerobic glycolysis in leukemia does not show any marked difference from that in arachnoiditis adhaesiva, idiopathic ardiaspasmus, diabetes mellitus, hookworm disease, hypoplastic anaemia and Banti's syndrome.
5. The ratio between the oxygen consumption and anaerobic glycolysis (Q_M^N₂/Qo₂), though less than that in malignant tumor, is higher than normal. This increase is especially marked in acute leukemia but slight in chronic leukemia, and in monocytic leukemia it is intermediate between the acute leukemia (myelogenous and lymphocytic) and the chronic leukemia (myelogenous and lymphocytic).
Namely, the anaerobic glycolysis in the leukemic bone marrow is accelerated as compared with that in normal bone marrow, but the grade of such an increase differs according to the form of diseases; and it is most prominent in acute leukemia; relatively slight in chronic leukemia; and it is intermediate between the acute and the chronic in monocytic leukemia.
The value of Q_M^N₂/_O2 indicates that the metabolism of leukemia is intermediate between the normal bone marrow and that in malignant tumor.

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With Warburg's apparatus the author studied the effects of the addition of various antileukemic agents such as nitromin, myleran, 8-azaguanine, 6-mercapurine, prednisolone, ACTH, actinomycin C, and carzinophilin directly to the bone marrow of the femur of normal rabbits, and obtained the following results.
1. Nitromin at the concentration of 10^-1g/dl seems to inhibit the respiration of the bone marrow, and the oxygen consumption every 10 minutes decreases along with laps of the time.
2. Myleran has no effect on the respiration of the bone marrow.
3. 8-azaguanine has likewise no effect on thc respiration of the bone marrow.
4. 6-mereaptopurine at the concentrations of 5×10^-1g/dl and 5×10^-2g/dl seems to inhibit the respiration of the bone marrow.
5. Prednisolone at the concentrations of 2×10^-1g/dl and 2×10^-2g/dl seems to inhibit the respiration of the bone marrow.
6. ACTH at the concentrations of 2×10^-2unit/dl, 2×10unit/dl and 2unit/dl seems to accelerate the respiration of the bone marrow.
7. Actinomycin C at the concentration of 2×10^-5g/dl accelerates the respiration of the bone marrow slightly, but in any other concentration it does not differ from that of the control, suggesting that it does not inhibit the respiration of the bone marrow,
8. Carzinophilin hardly inhibits the respiration of the bone marrow, but at the concentration of 5×10^-4unit/dl every ten minutes the oxygen consumption somewhat tends to decrease along with lapse of the time.
From these it is assumed that nitromin, 6-mereaptopurine and prednisolone at a specific concentration act directly on the bone marrow and inhibit its respiration, but ACTH directly accelerates the respiration of the bone marrow and thus enhances the hematopoietic fucntion.

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In order to investigate the effect of EDTA on the growth of bacteria, EDTA and bivalent metal ion were added to the media in fixed proportion. The growth of Sal. 57 S and Staph. aureus were studied on this madia and the following results were odtained.
1) Sal. 57 S were able to grow on nutrient agar media containing up to 0.008 M EDTA. The rate of growth was the same as the control up to a concentration of 0.006 M EDTA Staph. aureus was able to grow on nutrient agar media containing up to 0.006 M EDTA. The rate of growth of Staph. anreus was the same as to the control up to a concentration of 0.005 M EDTA.
2) After repeated transfers the Sal. 57 S was capable of growing on media containing 0.009 M EDTA. Staph. aureus also showed an ability to grow in higher concentration of EDTA, i. e. 0.0075 M EDTA. The rate of growth of the subcultured organisms mentioned above was the same as the control. However, in higher concentration of EDTA no growth was observed, even with the subcultured organisms.
3) Since the equal mols of EDTA and bivalent ion are equivalent, the excessive mol of EDTA must exist in media in free when mol of bivalent ion was added in smaller amount than mol of EDTA. The auther would express the excessive mol of EDTA as “possible concentration of EDTA”. The relationship between “possible concentration of EDTA” and the growth of organisms was studied having chelated EDTA by Mg⁺⁺ and Fe⁺⁺. By chelation of Mg⁺⁺ the rate of growth of Sal. 57 S was proportional to “possible concentration of EDTA” as well as to “true concentration of EDTA”, that medned the concentration of EDTA added with no chelation. In the same test using Staph aureus the rate of growth was somewhat inferior than expected rate of growth. However, in chelation by Fe⁺⁺ the rate of growth against “possible concentration of EDTA” did not correspond to “true concentration of EDTA”, but the rate was exceedingly inferior.
4) The effect of addition of EDTA to peptone water and bouillon was studied. The growth of Sal. 57 S was gradually decreased by the addition of EDTA, but up to a certain concentration no decrease was observed. The growth of Staph. aureus was completely inhibited at concentrations of 0.004-0.005 M EDTA, but only small concentration was nescessary for partial inhibition. The rate of growth of EDTA resistant bacteria was superior than normal bacteria.
5) The rate of growth of bacteria to a “possible concentration of EDTA” was superior than the rate of growth to a “true concentration of EDTA”. The rate of growth mentioned above was observed in peptone water and bouillon media chelating by Mg⁺⁺.
6) By contrast, normal Sal. 57 S and EDTA resistant Sal. 57 S on metal ion free synthetic media the EDTA resistant bacteria showed marked growth with the addition of only a small amount of Mg⁺⁺.

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Using Sal. 57 S, the auther carried out the investigation on the enzymatic properties of EDTA resistant bacteria grown on EDTA added nutrient agar media in comparison to normal Sal. 57S. The following results were obtained
1) On oxidatinn of glucose, the normal bacteria oxidized it mostly through the EMBDEN-MEYERHOF pathway. But in the EDTA resistant bacteria the oxidaition pathway was supposedly via WARBURG-DICKENS shunt, While there were evidence of passing through the EMBDEN-MEYERHOR pathway to some extent.
2) Further oxidation beyond pyrvate stage was strongly inhibited in EDTA resiseant bacteria.
3) The enzymatic change mentioned above was easily restored to the normal by the shrot time incubation of the organism.
4) It was postulated no change occured in the hydrogen transfer system.

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In order to ascertain the distribution of bacteria introduced into an animal body, the author carried out the further studies on this subject. The movement of bacteria into liver, spleen, kidney and lung was traced by observing the radioactivity of P³² up to 60 hrs. P³² labeled Salmonella 57 S were obtained by culturing the organism in bouillon media for 18 hrs to which P³² was added, and were injected into body of mouse through various pathways. The following results were obtained.
1) The rate of reduction of P³² in various organs was slower in the case of P³² labeled Sal. 57 S than in the case of direct injection of P³² into body. The amount of P³² in the spleen was found to be specially high.
2) The rate of reduction of P³² was much slower in the mice that were previously immunized against organisms. The reduction of radioactivity on the various organs was not observed 30 hrs after injection. The radioactivity on organs were found to be increased in the case of subcutaneous injection after 30 hrs as above. The concentration of P³² was especially high in spleen when the organisms were injected intraperitoneally.

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By amking 1-ascorbic acid and molecular oxygens act upon methemoglobin the author studied the decomposition processes spectrochemically and obtained the following results.
1. In preparing methemoglobin from oxyhemoglobin with sodium nitrite no spectrochemical effect of sodium nitrite can be recognized on methemoglobin.
2. Methemoglobin is reduced to oxyhemoglobin in the presence of 1-ascorbic acid and molecular oxygen and thereafter it shows a similar decomposition processes as observable in the case of oxyhemoglobin.
3. This reaction is affected by molecular oxygens namely, when the quantity of molecular oxygen is large, the speed of the reaction is greater but the production of 670 mμ substance is inhibited; whereas when the quantity of molecualr oxygen is small, the absorption index of 670 mμ and 630 mμ substances is greater.
4. The 670 mμ and 630 mμ substances that are intermediate substances of this reaction are reversible to one another depending upon the quantity of moecular oxygen present.
5. This reaction is affected by the ion concentration; namely, between pH 6.8 and pH 7.7 at pH 7.2 the 670 mμ and 630 mμ substances are produced in the greatest amounts.
6. This reaction is affected by 1-ascorbic acid; namely, with the increase in the amount of ascorbia acid the speed of reaction is accelerated.
7. This reaction is affected also by temperature; namely, with a rise in temperature the reaction is accelerated whereas with a fall in temperature the reaction is retarded.
8. At an eary stage of this reaction dipyrromethen serlies substances are produced by the decomposition of the 670 mμ and 630 mμ substances.

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By studying spectrochemically the decomposition processes of carohemoglobin, oxyhemoglobin, methemoglobin, and carboxyemoglobin in the presence of 1-ascorbic acid and molecular oxygens the author obtained the following results.
1. In the case of carbohemoglobin besides tha already-known absorption peaks of 556 mμ and 430 mμ it shows another absoorption peak at 760 mμ, and its EmM is 1.4-2.0.
2. The absorption curve of the 670 mμ and 630 mμ substances at the time of deoxydation by sodium dithionite and causatic soda show the absorption peak at 618 mμ and 760 mμ.
3. The decomposition of caroxyhemoglobin takes similar decomposition processes as taken by oxyhemoglobin and methemoglobin, producing the 670 mμ and 630 mμ substances. In other words, it seems that caroxyhemoglobin is reduced to hemoglobin by liberating carbon monoxide and then it enters into decomposition processes, and its decomposition is extremely slow as compared with that of oxyhemoglobin and methemoglobin.
4. CO-choleglobin is not an intermediate product of carboxyhemoglobin decomposition but it is produced at the time when choleglobin comes in contact with carbon monoxide.
5. CO-choleglobin is split into carbon monoxide and choleglobin in the presence of 1-ascorbic acid and molecular oxygens.

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By applying direct Coombs' tests on 288 cases of various diseases mainly of liver disease the author obtained the following results.
1. Incomplete antibodies have been detected in 11 cases out of 33 acute hepatitis; in 6 out of 11 serum hepatitis; in 12 of 40 chronic hepatitis; in 10 of 29 liver cirrhosis; in 2 of 9 hepatoma; in 3 cases of acquired hemolytic anemia; in 2 cases of hypoplastic anemia; in one out of 4 essential thrombocytopenic purpura; in one of 6 Schönlein-Henoch's purpura; 2 of 4 Banti's syndrome; one Hodgkin's disease; in 2 lupus erythematodes; in one cancer of pancreas; in 2 ulcerous colitis; and in one of 21 acute and chronic hephritis, to the total of 57 cases.
2. Four cases of posthepatitic syndrome; 2 subacute yellow liver atrophy; one each of amyloid liver, liver-brain syndrome, and liver distomiasis, one each of congenital hemolytic anemia, familial non-hemolytic jaundice, and hemophilia, and one each of chronic lymphocytic leukemia and chronic myelogenous leukemia, 2 rheumatic arthritis, one periarteritisnodosa, 20 cholecystitis, 2 splenic venous thrombosis, 23 cases of gastric and duodenal ulcers, 16 hypertension, 9 diabetes, 4 Basedow's disease, 6 pericarditis lenta, and other 17 cases proved to be negative to direct Coombs' tests.
3. It has been clarified that incomplete antibodies can be detected in various diseases, but the incomplete antibody appears in a relatively high percentage especially in hepatitis and liver cirrhosis. However, even in the cases proved to be positive to Coombs' test the symptoms signifying an increase in hemolysis are often not necessarily distinct. Namely, of 57 cases responding pnsitive to Coombs' tests besides 3 cases of acquired hemolytic anemia, one acute hepatitis, one serum hepatitis, one chronic hepatitis, one liver cirrhosis, 2 hypoplastic anemia, one Banti's syndrome and one Hodkin's disease to the total of 11 cases demonstrated clearly the mechanism of hemolysis. Moreover, those who were suspected of hemolytic anemia amounted to the total of 8 cases; 2 acute hepatitis, 2 chronic hepatitis, one liver cirrhosis, one lupus erythematodes and one cancer of pancreas.
4. It has been clarified that there exists an immuno-hemolytic factor, derived from the so-called auto-immunization, plays an important role in a fair number of cases with the anemia, usually seen in the diseases such as liver, blood, collagen or malignant neoplastic diseases.

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In the study on the correlation between the incomplete antibody (Coombs' antibody) and the liver auto-antibody in liver diseases the author obtained the following results.
1. On 37 cases of acute hepatitis, 11 serum hepatitis, 40 chronic hepatitis; and 29 liver cirrhosis to the total of 117 cases the incomplete antibodies were detected by direct Coombs' tests, and they were divided into Coombs' test positive and negative groups. These two groups were compared as regards hepatomegaly, splenomegaly, the liver function and serum protein picture.
Hepatomegaly and splenomegaly can be frequently found in Coombs' test positive group, and especially splenomegaly shows a marked difference from Coombs' test negative group.
Disturbances in various liver functions such as the serum bilirubin content, serum colloid reaction, bromsulphalein test, urobilinogen reaction in urine are found mostly in Coombs' test positive group.
The serum total protein content is low in Coombs' test positive group, and the serum protein picture shows an increase in γ-globulin in most of the two groups, especially a higher values of β-and γ-globulins in Coombs' test positive group than those in the negative group.
2. In the comparative study on 107 cases of liver diseases with respect to the incomplete antibody and liver auto-antibodv a significant correlation can be recognized between the two antibodies.
When these cases are divided into four groups of those negative to both antibodies, those positive only to the incomplete antibody, those positive only to the liver auto-antibody, and those positive to both antibodies, the grades of the disturbances in the liver function are in the descending order of the incomplete antibody positive group, the liver auto-antibody positive group, and the both-antibody positive group.
3. In infectious hepatitis the incomplete antibody and the liver auto-antibody make their appearance gradually around the second week after the onset of disease and reach the maximum around the first to the second month. However, most of them disappear along with the improvement in clinical symptoms, and in the chronic stage of the sixth month and thereon a high percentage of the antibodies reappear, showing approximately parallel fluctuations between them.
4. In pursuing the order how the two antibodies appeared in those cases whose incomplete antibody and liver auto-antibody had taken comparable course, those showing the incomplete antibody prior to the liver auto-antibody are somewhat greater but there can be observed no fixed tendency.
5. In the serum of liver diseases positive to the liver autoantibody a high proportion of the antibody that responds to the kidneys, the spleen and other viscera can be detected simultaneously.
6. Summing up the above findings, when the liver autoantibody is produced secondarily due to the destruction of the liver tissue, another antibody that responds to visceral tissue other than the liver tissue or to the components of blood seems to be produced simultaneously. Especially in hepatitis and stilly further in the virus infection abnormal changes in vivo antibody producing tissues of the patients induced by such infections seem to be involved in bringing about complicated immuno-serological changes in the body.

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It has been previously confirmed that hemolysin and agglutinin are produced for erythrocytes in the anti-sera of the animals receiving the antigen obtained from the rabbits sensitized with antigens extracted from various viscera. Therefore, with the purpose to study the significance of the mechanism and the in vivo reactions of hemolytic anemia the author induced in various animals by injecting these heterogenous organ antisera, and obtained the following results.
1. When rabbits are sensitized with the physiological saline solution of various organ antigens extracted from such organs as the dog liver, kidneys and spleen, a rise in the antibody titer for the liver as well as a rise in the non-specific antibody titer for the other crgans can be observed. Simultaneously an increase in the hemolysin value and agglutinin value can be recognized.
2. In observing changes in the blood picture of the dogs after the injections of the various organ antisera mentioned above, there has been recongized a picture of an acute hemolytic anemia revealing a decrease in the erythrocyte count, a decrease or a fall in Hb and Ht values, a fall in erythrocyte resistance and an increase in the reticulocyte count.
3. Although no bivalent antibodies such as hemolysin and erythrocyte agglutinin can be detected in the circulation blood of the dogs injected with various organ antisera, the erythrocyte resistance shows a marked fall for a considerably long period of time, and also the dog erythrocytes prove to be positive to direct Coombs' tests.
4. Histologically specific changes of viscera have been demonstrated in the order of the antiserum for the kidneys, antiserum for the liver, and antiserum for the spleen, showing the changes specific to each organ. At the same time the reactions of the reticuloendothelial system in the spleen, liver and lymph nodes are marked, and hemosiderosis can also be recognized, indicating the changes suggestive of in vivo hemolysis.
5. In the animals injected with organ antisera relatively specific disturbances can be recognized in corresponding organs and at the same time an acute hemolytic anemia is induced by hemolysin and erythrocyte agglutinin contained in the organ antisera as one of nonspecific changes. Moreover, it has been clarified that a mono-valent antibody plays a considerably significant role even in such an immuno-hemolytic anemia.

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With the purpose to elucidate the clinical significance of the so-called liver auto-antibody and heterophile antibody by means of Paul-Bunnell's reaction, the author studied histologically 138 cases of liver diseases including infectious hepatitis with liver biopsy specimens; and obtained the following results.
1. Those liver diseases in which the liver auto-antibody can be detected are infectious hepatitis, chronic infectious mononucleosis, and lupus erythematodes, and in addition, there are fatty liver, hepatoler ticular degeneration (Wilson's disease), mechanical jaundice, Banti's syndrom, and hepatoma; and all the liver auto-antibody of them start from necrotic destruction of liver tissue.
2. The liver auto-antibody titer were well correlated with the proliferation of interstitial connective tissue, exsudation in sinusoid, liver cell necrosis, and stellate cell activation, but have poor correlation with the portal cell infiltration and degeneration of liver cells.
3. Active chronic infectious hepatitis that later develops to liver cirrhosis, cholangiolitic hepatitis, and a portion of the chronic infectious hepatitis in which inflammation spreads to portal and periportal region show a high liver auto-antibody titer which persists for a long period of time. However, in such diseases as active chronic epidemic hepatitis or in serum hepatitis (posttransfusion hepatitis), the possibility of the liver auto-antibody becoming an endogenous factor to spread the local tissue changes to wider area is doubtful in the former, but it markedly strong in the latter.
4. It has been confirmed that heterophile antibody is produced by viral infection in infections hepatitis. Especially high agglutination titer can be found in posthepatitic liver cirrhosis and parenchymatous form of chronic infectious hepatitis, and assuming those titer over 40 times to be agglutination positive, it also has patho-histologically a clinical significance.

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1. From the standpoints of the complement fixation reaction and the tissue reaction it has been proven that the liver homologous immunicity can be accomplished in rabbit liver by injecting homologous liver emulsion into the animals without resorting to Freund's adjuvant method.
2. When the liver tissue is rapidly destroyed by injecting an hypertonic physiological saline solution into the liver, the production of liver auto-antibody can clearly be recognized, and the sensitized state with tissue reaction can also be observed.
3. In comparing the tissue reaction in the case sensitized with microsome fraction of homologous liver or homologous liver phosphatid antigen with the reaction observable in the liver injected with homologous liver emulsion, hardly any difference can be seen in the former, while the tissue reactions such as necrosis of liver cells etc. are far more marked in the latter.
4. Although there are few differences in the tissue reaction according to the dosis and the titer of the injected homologous liver antiserum, a cytotoxin-like action and a relative organ specificity were recognized.
5. The mice sensitized with the homologous liver emulsion previously are secondary infected with ectromelia virus, so that serous inflammation of the liver tissue are used to be found additionally, moreover by the sensitization above mentioned the histological changes in the liver tissue of the mice become more stronger.

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In the cases of infectious hepatitis that has a complication of cholecystopathy, the author studied mainly its pathogenesis; and obtained the following results.
1. Out of 138 cases with hepatitis 33 cases (23.9%) had cholecystopathy as the complication.
When these 33 cases are studied histologically by liver biopsy, periacinar form of chronic infectious hepatitis is found in 13 cases (39.3%), occupying the greatest percentage; followed by acute infectious hepatitis in 5 cases (15.2%), parenchymatous form of chronic infectious hepatitis in 4 (12.1%), posthepatitic cirrhosis in 4 (12.1%); and posthepatitic fibrosis in 2 (6.1%).
On the other hand, judging cholecystopathy from various patho-histological forms, cholangiolitic hepatitis in 100%; periacinar form of chronic infectious hepatitis in 43.3%; posthepatitic fibrosis in 28.6%; parenchymatous form of chronic infectious hepatitis in 20%; posthepatitic cirrhosis in 11.9%; and acute infectious hepatitis in 11.8%.
2. Those showing biliary dyskinesia are mainly composed of the form revealing no marked changes in the liver biopsy (so-called posthepatitis syndrome) or the periacinar form of chronic infectious hepatitis.
3. Those having the complication of cholecystitis are more frequently found in acute infectious hepatitis and posthepatitic cirrhosis.
4. Generally even in the liver biopsy at the time of operation the infiltration of round cells and edema formation in portal region are characteristic traits of the common cholecystitis.
5. In the necropsy of infectious hepatitis likewise the liver and gallbladder are affected simultaneously; and the edema formation from the sublayer of mucous membrane to the sublayer of serous membrane and the congestion of capillary blood vessels with cell infiltration are the main common histological changes in the gallbladder.
6. When the antiserum obtained from the rabbit sensitized with dog abdominal organs (liver, gallbladder, duodenum, stomach, and rectal mucous membrane) as the antigen is injected into dogs, allergic cholecystitis can be induced in 100% of the animals with the use of gallbladder antiserum; in 80% with liver antiserum; in 60% with antiserum of rectal mucous membrane; and in 40% each with stomach antiserum or with antiserum of duodenal mucous membrane. In these instances intralobular and portal cell infiltration and edema formation in portal region can also be observed.
7. The characteristic traits of hepatitic cholecystopathy are the edema formation extending from the sublayer of the gallbladder mucous membrane to the sublayer of serous membrane and cell infiltration around blood vessels. As for the pathogenesis there seems to multiple factors; namely, dyscholia due to functional disturbances of the liver, the loss of the gallbladder motility due to invasion of inflammation inducing substances from portal tract through lymph ducts on serous inflammation, and also it is possible to be met with the secondary infection with an increase in the number of intestinal bacteria coexisting, and in some the involvement of allergic inflammation in gallbladder can be recognized.

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As the results of various examinations conducted on 367 patients, suffering from lung tuberculosis and having received dihydrostreptomycin (DHSM.), twenty-seven cases of them, seven percent, revealed the hearing impairment apparently caused by DHSM
The author studied carefully the inter-relationship among such factor as the initial symptoms and the time of the onset of these symptoms, the type and the degree of hearingloss, the total dosage of the drug given to each patient up to the onset of cochlear symptoms, the duration of time elapsed up to the fixation of hearingloss, and the treatment; and obtained the following findings.
1) Tinnitus is an important symptoms in the early stage previous to the appearance of disturbances in hearing.
2) The disturbances in hearing caused by this drug at the early stages are marked in the high tonel level up to 8000 cps. Moreover, it is noticeable that there exists a typical type of hearing impairment, namely the type that decends abruptly just at 8000 cps.
3) The appearance of such disturbances is greatly correlated with individual susceptibility, namely, with his congenital factor.
4) The early discovery of these disturbances can only be attained by frequent and scrutinous examinations of hearing.
5) As for the prognosis of these disturbances, the cessation of the administration of this drug after a relatively early discovery can sometimes improve the conditions though slightly.
6) Though there are hardly any cases whose tinitus as well as the hearingloss have improved after the treatments by VB₁, VA, a decrease or disappearance only of tinitus with a subsequent improvement in subjective hearing has been recognized in some cases.

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With the purpose to determine the pothological changes occurring in the peripheral auditory organs in the animals administered various doses of dihydrostreptmycin, with a special reference to the changes in the spiral ganglion cells, as well as to study the progress after the acute poisoning induced by this drug, the author conducted the present experiments using three groups of guinea pigs, namely, one group inecjected with a large dose of 300 mg dihydrostreptmycin (DHSM) per day, another group injected with an intermediate dose of 200 mg, and still other with a minimal dose of 100 mg. For the investigation of nerve cells the author excised only the modiolus by breaking the cochlear bony shell with a bar and an incision needle under a bright field of binocular microscope and fixed it after one day's decalification. This method employed by author proved to be significantly satisfactory for the determination of the pathological changes in nerve cells.
Histopathological changes
1. When DHSM is injectid intramuscularly, pathological changes are induced in the peripheral auditory nerve, namely, organ of Corti, cochelear nerve fibers and spiral ganglions, but the greatest injury appears in the organ of Corti, especially in inner and outer hair cells.
2. These pathological changes are more marked at the base of the spiral and they grow less severe nearer to the end of the spiral.
3. This method of observing pathological changes of the spiral ganglions by modiolus method greatly improves the accuracy in the determination of such changes, and for this reason it is believed this method to be of a great significance.
4. These pathological changes are considered to be the cause of deafness.
5. The severity of pathological changes does not necessarily parallel with the doses of the drug administered and this seems to be due to some individual differences in the resistance against the drug.
6. As there occurs a degenerative atrophy of the end organs as well as spiral ganglion cells and nerve fibers in the inner ear of those animals either staving or emaciated, it is advisable to exclude those animals that lost more than 20-30 percent of the body weight from such experiment.
7. These pathological changes showed no tendency to recover spontaneously.

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