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A fibroblast-inhibiting agent, chloroquine, used in the treatment of animal tumors led to a reasonably good result, and this approach was extended to the treatment of human cancers. Of histologically proven 54 cases, the drug was effective in 38, ineffective in 15, and unknown in one. It proved to be effective in all the patients who were treated for over 2 months with exception of terminal patients. Of the various malignant tumors treated, excellent therapeutic effects were obtained in patients with carcinoma of the lung and bladder. In the cases where the drug was effective there were a decrease of the size of tumors, fall of serum lactic dehydrogenase, increase of necrosis, inhibition of the stroma, as well as improvement of the symptoms and general condition. As to the mechanisms of the drug action, it would be necessary to consider of its anti-inflammatory and humoral effects upon the host in addition to its inhibitory action on the stromal connective tissue of cancers. The present chloroquine treatment appears to have its indication in inoperable cases, and pre- and post-operative cases, and for the prevention of reccurrence of tumors. Studies are currently in progress in our laboratory to discover more potent fibroblastinhibiting agents and on the combined chemotherapy of chloroquine and other anti-turnor agents. We are indebted to the Department of Urology of our University for the generosity to allow us to use the clinical data on patients with cancer of the urinary bladder.

1. For the purpose to clarify the relationship between the structural change and lipid composition of isolated rat liver mitochondria, lipid composition and swelling rate of mitochondria obtained from the rat of 3'-Me-DAB feeding and raised in cold room are measured, and the following results were obtained. 2. The mitochondria obtained from the liver of 3'-Me-DAB-fed rat and of rat raised in cold room show a low rate of swelling by addition of Na-oleate accompanied by the decrease in highly unsaturated fatty acids (C18:3 and C20:3or 4) and with the increase in saturated fatty acids (C16 and C18). 3. Activation energy for the mitochondrial swelling is about 16.2 Kcal in the mitochondria obtained from normal rat liver, but requires 19.7 Kcal in the mitochondria that show a low rate of swelling. The fatty acid composition, especially in glycerophosphatides which occupy about 80 per cent of total lipids, is a structural component of mitochondrial membrane, undergoes the change from former to latter in the following fashion: C16:0 21.73→32.10, C16:1 3.37→2.96, C18:0 25.0→29.75, C18:1 13.75→17.40, C18:2 23.90→16.0 and C20:3 or 4 12.23→1.79. 4. At the time of low rate swelling of mitochondria isolated from 3'-MeDAB- fed rat liver, there could be observed a marked increase of the acetone soluble lipid (simple lipids) in the total liver lipids and in the fatty acid distribution of the acetone-soluble lipids, oleic acid was markedly increased (0.838→3.81%/dry liver), despite the fact that in the acetone-insoluble fractions or in the mitochondria there are no marked changes in the oleic acid contents (1.84→2.56% or 0.212→0.246%/dry liver).

1. The forms of irritation causing inflammation and pain are reviewed, with reference to the significance of histamine, serotonin and bradykinin and in particular to the interrelationship between inflammation and pain. 2. The various types of experimental pain are reviewed and mention is made of the human and animal analgesia test methods derived from them. 3. More detailed descriptions are given of the analgesia test methods used by us, namely: a) Silver nitrate gonarthritis-pain, rat, in which both strong and weak analgesics with an anti-inflammatory action are effective. b) Phenylquinone-induced abdominal pain, mouse, in which all the analgesics and anti inflammatory agents mentioned in this article are effective in a greater or lesser degree. c) Tail-flick and hot-plate tests, mouse, in which the strong analgesics, the weaker analgesics and the anti-inflammatory agents, with the exception of the salicylates, are effective. d) Dental-pain test, guinea pig, which can be used to demonstrate the activity of the various analgesics, including the salicylates and also colchicine, which is not active in any other test. e) Pressure-pain, mouse, in which only the strong analgesics (narcotics) are effective. 4. The action of a large number of analgesics, anti-inflammatory agents and related drugs in the various analgesia-tests and in acute experimental inflammation is presented in tabular form. 5. It is concluded that the use of several pain and inflammation tests is essential for screening both analgesics for special indications (severe, mild pain, pain due to inflammation, etc.) and universal pain-killing drugs.

We experienced a case of eosinophilic granuloma in soft tissue, and demonstrated its patterns of hydrolytic and oxidative enzymes histochemically. Neutrophils were rich in acid phosphatase and glucose-6-phosphate dehydrogenase. Eosinophils had much acid phosphatase and less other hydrolytic and oxidative enzymes. Lymphocytes showed weak reaction in all enzymes. Lymph follicles and histiocytes or fibrocytes had moderately oxidative enzymes. Small blood vessels and collagen fibers were rich in alkaline phosphatase and had a moderate amount of oxidative enzymes and acid phosphatase.

The swelling-shrinkage and oxidative phosphorylation of rat liver mitochondria affected by 3'-methy1-DAB feeding were observed in correlation with function by the method mentioned, and the following results were obtained: 1. By feeding 3'-methy1-DAB the swelling-shrinkage ability of rat liver mitochondria showed a remarkable alteration reducing in the amplitude. It reduced gradually during the days of feeding, reached the minimum value on 30th day and restored gradually thereafter (in Case 1). 2. ADP/O ratio also decreased by feeding the carcinogen reached the minimum point on 30th day and increased on 38th day showing the similar tendency in the decrease of the swelling-shrinkage amplitude (in Case 1). 3. The mitochondria from the hepatoma, which was induced by 3'-methy1DAB feeding, showed a lower amplitude in swelling-shrinkage with the dropped ADP/O ratio compared with those of mitochondria from liver tissue neighbouring the tumor. 4. The mechanism in the reduction of swelling-shrinkage ability has been discussed in the relation with fatty acid composition of mitochondria which is reported elsewhere. 5. From the above results it is deduced that lowered ability for swellingshrinkage with the reduced oxidative phosphorylation will be somehow related to the mechanism of cancer induction.

An intestinal absorption test with the use of D-xylose has been performed on 19 patients including 3 of acute hepatitis, 7 of chronic hepatitis and 9 of liver cirrhosis, and the following results were obtained. 1) The 5 hr urinary excretion and 2 hr blood level of D-xylose tend to increase in patients of acute and chronic hepatitis with severer disorder of liver functions. 2) The standard deviations of the 5 hr urinary excretion and 2 hr blood level of D-xylose are larger in liver cirrhosis than in the other liver diseases. Those cases having severe disorder of liver functions are found to be diminished in 5 hr urinary excretion and 2 hr blood level of D-xylose. 3) A decrease in the absorption of D-xylose from the small intestine of liver cirrhosis might be caused by the diminished surface area of villi of the small intestine.

Intestinal absorption tests with the use of D-xylose were conducted on 12 healthy Japanese subjects and the following results were obtained. 1) The mean value of the urinary xylose excretion within five hours after an oral administration of 25 g of D-xylose was 8.07 g and standard error of the mean was 0.11. The mean of urinary excretion was higher than most of previous reports. 2) The 5 hr urinary excretion after intravenous administration of 25 g D-xylose in normal subjects was almost equal to that reported by BUTTERWORTH et al. 3) The rate of D-xylose absorption from the intestine of normal Japanese subjects was higher than that in Europe, Canada and U. S. A. 4) The differences in the pattern of the intestinal absorption of D-xylose in normal individuals seemed to originate from different dietary habit continued over the period of many years, especially of carbohydrate contents.

An anatomical study was made to follow the degeneration of fibers by means of Marchi technique in cat after making experimentally lesion in Forel H field. As the results the following conclusions were reached. 1) The ipsilateral distribution of the degenerated granules was in the anterior sigmoid gyrus, caudate nucleus, putamen and globus pallidus, thalamic nuclei medial to the internal medullary lamina, substantia nigra, rubrocerebellar system, medial longitudinal fascicle system, mesencephalic and pontine reticular formation and medial lemniscus. 2) There was also contralateral distribution to the interpositus and dentatus nuclei of the cerebellum via brachium conjunctivum, to globus pallidus via supraoptic commissure, to subthalamic region and substantia nigra via supramammilary commissure, and to red nucleus via tegmental decussaion. 3) The degeneration is so extensive that the Forel H-field seems to be the cross road of the extrapyramidal system in association with brainstem activating system.

Some investigations have been done on the relationships between the swelling-shrinkage change, oxygen consumption and state of oxidation-reduction of pyridine nucleotides of mitochondria, and between the swelling-shrinkage change of mitochondrial structure by Ca2+ and accumlation of Ca45 in rat liver mitochondria. A parallel relationship is observed between the Ca2+ induced swelling and Ca2+ accumulation. Both of them require Pi but not Mg2+, ATP and exogenous respiratory substrates and are inhibited by respiratory inhihitors or uncouplers of oxidative phosphorylation but not by the inhibitors of phosphorylating respiration. In this case the Ca2+ is transported with the phosphate even in ice cold. Even in the presence of antimycin A, moreover, Pi-dependent Ca2+ accumulation and Ca2+ induced swelling can be overcome by addition of ATP, which are inhibited by oligomycin. In the presence of Pi, mitochondria show shrinkage by addition of Ca2+ before the high amplitude swelling, which is closely correlated to the electron ransport chain and phosphorylation process of mitochondria, and the pattern of the mitochondrial shrinkage is quite similar to that observed in the case of respiratory control by ADP in intact mitochondria. This shrinkage of mitochondria is inhibited by respiratory inhibitor or uncoupler of oxidative phosphorylation but not by the inhibitor of phosphorylating respiration. From these data, therefore, it is considerd that the Ca2+ accumulation and Ca2+ induced shrinkage-swelling of mitochondria require the energy of oxidative phosphorylation with respect to the initial step before the oligomycin block.

In order to increase the accuracy of diagnosis in lung cancer, analysis concerning cytological and histological correlation was attempted. The present study consists of 106 patients, who were seen during the past approximately five years and underwent radical surgery to remove tumors completely; mere biopsy specimens were excluded. These patients were 63 years old on the average, 78 males and 28 females, 29 cases of the hilar type (H) and 77 of the peripheral type (P), and 27 and 76 cases of the clinical stage I in H and P, respectively. Histologically, there were 53 adenocarcinomas (Ad), 38 squamous cell carcinomas (Sq), 4 adenosquamous cell carcinomas (Ad + Sq), 5 large cell carcinomas (LCC), and 6 small cell carcinomas (SCC); among them, 3 Ad and 21 Sq in H, and 50 Ad and 17 Sq in P. The overall positive percentages were 65.5 (H) and 26.0 (P) by combination of spontaneous, airsol-induced and Saccomanno's methods, against 96.6 (H) and 72.8 (P) with inclusion of brushing method. 94.8% of Sq in H and 66.7% of Ad and 70.6% of Sq in P were positive by the brushing. A comparative study of these four methods, performed at least once on the same patient, also confirmed the superiority of brushing. Cyto- and histological agreement was 21/21 (100%) for Sq in H, whereas 30/34 (88.2%) for Ad and 13/15 (86.7%) for Sq in P. In conclusion, cyto- and histological findings in H and P corresponded well, and as far as cytology of peripheral type is concerned, a combined method, especially with brushing, is strongly recommended.

The morphological and biological changes in long term culture cells of normal-appearing trigeminal nerves from 2, 8, and 30-day-old S-D rats administered transplacentaLly with 75 mg ENU/kg were examined. After a marked degeneration of cells, crisscross multiple proliferative foci of transformed spindle cells appeared at the 3rd passage culture from 2 and 8-day-old rats, but not form 30-day-old rats. The transformed cells with S-100 protein and basal lamina had Schwann cell characteristics. Transformed spindle cells continued to form a crisscross pattern more than 700 days and some transformed spindle cells became round in shape 3-6 months after the primary culture. These transformed cells were transplantable to newborn S-D rats and the transplanted tumors were histologically similar to those of malignant Schwannoma of trigeminal nerves induced by ENU. Round-shaped transformed cells were more malignant than spindle-shaped cells and produced rapidly growing transplanted tumors. Spontaneous transformation with multinucleated giant cells occurred in one of the control cultures. These results indicate that the sequential changes of ENU-treated trigeminal nerves in vitro were corresponded to developmental changes of malignant Schwannoma in vivo induced by ENU. This system will be useful for analysis of ENU-carcinogenesis.

Activities of intracellular RNase of the liver cytoplasm, normal liver cells exposed to 3'-Me-DAB and heaptoma cells, have been studied in correlation with the contents of RNA and DNA and morphologic changes of the cells with or without treating RNase. The data showed that in hepatoma cells the intracellular acid RNase activity decreases with the decrease of RNA and unchanged DNA contents and alkaline RNase activity. Morphologic observation proved that hepatoma cells show a small low massed vesicular or vacuolar endoplasmic reticulum having ribosomes. For the exposure to RNase the hepatoma cells proved to be much less resistant comparing to normal liver cells. The former lost the granules and was destroyed in its endoplasmic reticulum, whereas the latter retained ribosomes and ER. From these experiments it has been speculated that acid RNase in the cell may be involved in RNA synthesis and alkaline RNase in RNA decompostition, though the effect of the difference in concentration in the case given RNase experimentally can not be neglected.

Der Autor berichtet über seine Erfahrungen durch Beeinflussung der peripheren Zirkulation und NervenzusHinde mit Heacrin (HAH) bei der Behandlung der Facialis-Lähmungen verschiedener Aetiologie und über die diagnostische Möglichkeit, die mit dem von ihm entwickelten Myotonometer, Angio-Myograph, sowie mit Elektro-Hautthermometer. Mit seiner Oxygen-Insuffiziens-Theorie '(0. I. T.) und Behandlungsmethode der generellen Therapie durch Oxygenversorgung der peripheren Zirkulation (G.T.O.P.C.) hat der Autor die Erfolge erkHirt.

A case of postpartum necrosis of the anterior lobe of the pituitary, known as Sheehan's syndrome, is presented. The patient has done well on a combined replacement therapy with cortisone and thyroid. It is hoped that increased awareness will be given to this clinical entity.

The liver glucuronyl transferase (GT) activity and uridine diphosphate glucuronic acid (UDPGA) content in the patients with viral hepatitis were determined using 4-methyl umbelliferone (4-MU) as a glucuronide receptor. The results were as follows: 1. In acute viral hepatitis, the decrease in the GT activity was more remarkable in the later stage of the recovery. In chronic viral hepatitis, the GT activity was decreased in accordance with the increase in the degree of liver injury. Liver UDPGA content was significantly reduced only in postnecrotic cirrhosis. 2. The decrease or injury in the parenchymal liver cells caused a decrease in the liver GT activity. These quantitative reductions in the liver parenchyme were not the only factor for the alteration in the GT activity of the liver. The results of the present study suggested an involvement of a qualitative change in the liver GT activity in human liver injuries, especially in the early stage of acute viral hepatitis; namely, there might be even an activation of the liver GT other than the reduction resulting from the decrease in the liver parenchyme. 3. The decrease in the liver GT activity correlated significantly with the decrease in the salicylamide glucuronide formation in vivo, while the alteration in the liver UDPGA content failed to correlate with that in the glucuronide formation in vivo. It was suggested that the velocity of in vivo UDPGA production rather than the UDPGA content of the liver was as important a rate-limiting factor for the glucuronide formation in vivo as the liver GT activity.

1. An attempt has been made to find the diagnostic criteria for early gastric cancer. It is most important to detect the evidences or suspected features of the malignant growth in incipient stage in order to attain the radical cure by surgical operation. 2. Twelve patients with early gastric cancer (groups A and B) were selected out of 476 patients who had undergone gastrectomy during the past three years in the Okayama Saiseikai General Hospital. The other 6 patients in the "precancerous group" (group C) were also studied, who had abnormal epithelial proliferation in the resected stomach membrane during the same period. 3. The processes of discovery of early cancer have been described. Fairly precise diagnosis can be made in the mucosal carcinoma, but it is not in the ulcer-carcinoma. It was generally difficult to estimate the degree of the malignancy and the extension of the growth preoperatively. 4. The details of the diagnostic aids are as follows. i. Negative occult blood of stool does not always mean the definite diagnostic aid. ii. The malignant gastric change may occur even in non-anacidity. Further investigations should be followed up on gastric ulcer patients if malignant alteration is under the consideration. iii. Minor roentgenological findings, such as the absence or irregularity of mucosal folds, rigid and/or overlapped contour, localized absence or decrease of the peristaltic waves and absence or bow-shaped deformity of the angulus, are of important significance. Such changes should be minutely sought for by X-ray film examination. iv. On gastroscopy and gastrocamera photography, such changes as erosion or irregular granular thickening of the membrane with abnormal reddening and edematous appearance, irregularity of ulcer edge, uneven swelling on ulcer margin with reddening and unsharpness of the edge of adherent coat on ulcer floor, must be noted in the early gastric cancer. v. It is not safe to leave a patient having stomach ulceration under a mere conservative management because it is often quite difficult to dissolve the question of malignancy of the lesion with all sorts of examinations. vi. So far as clinical examinations have indicated malignancy, histological examination must be carried out immediately at the time of operation, even when malignant lesion is absent in inspection and palpation on the exposure of the stomach. vii. On the gross observation of the resected stomach, a particular attention must be paid to erosion, depression or atrophy, irregular granular thickening and abnormal reddening on the restricted areas of the mucosal surface.

An attempt was made to establish the method for the estimation of glucuronide formation in vivo using salicylamide and further to study the alteration in the glucuronide formation in liver disease. The results were as follows: 1. The method for the determination of free salicylamide separately from other conjugates of salicylamide in urine, without involving any hydrolysis of the other conjugates, was presented. When 1 g. of salicylamide was administered to the subjects with or without liver injuries, no free salicylamide was detected by the present method in the urine following the salicylamide administration. 2. The analytical method for the determination of salicylamide glucuronide was also devised by employing a hydrolysis with β-glucuronidase. The ratio of the salicylamide liberated by the enzymatic hydrolysis of the 10-hour urine following the administration of 1 g. of salicylamide to the total salicylamide excreted in the same urine was neither affected by the total recovery of the salicylamide nor by the urine volume. This ratio was thus used as a means of estimating the capacity of the glucuronide formation in vivo, although it was considered that the ratio might be affected to some extent by the competition between the glucuronide and other conjugate formations in vivo. 3. As a result of this salicylamide glucuronide excretion test, it was indicated that the in vivo formation of salicylamide glucuronide in the patients with postnecrotic cirrhosis was slightly decreased compared with that in normal controls.

A purified compound of the activator of glucuronide formation was isolated from a boiled extract of rat liver by charcoal adsorption, ethanol fractionation of barium salts, and finally paper and Dowex-l column chromatographies. The analytical data and the chemical properties of the compound sugggested that the endogenous activator of glucuronide formation in rat liver might be uridine diphosphate N-acetylglucosamine.

1. The objective of this investigation was to test the influence of mammary cancer tissue extract on the induction of various tumors by urethan. Three strains of female mice, Balb/c, Zb and Db, were used in this experiment. 2. It was found that urethan was a multipotential carcinogen in the induction of (a) lung tumor, ovarian hemorrhagic cyst, and hemorrhagic lesions in various tissue in Balb/c mice, (b) lung tumor, hepatoma, leukemia, mammary cancer, Harderian gland tumor and hemorrhagic lesions in various tissues such as spleen, mesenteric lymphnode, liver and ovary in Zb strain, and (c) lung tumor, mediastinal lymphoma, leukemia, hepatoma and hemorrhagic lesions in the liver and ovary in Db mice. 3. Mammary cancer tissue extract seemed to have a promotive effect on the generalization of the mediastinal lymphoma induced by urethan in Db female mice.

The ongm and characteristics in transmission and morphology of spontaneous lymphatic leukemia in a low-leukemic strain C3Hf have been described. The leukemia line is being currently subjected to a vigorous search for the presence of a filtrable leukemia agent.