Skeletal muscle paralysis is a clinical symptom in many cases of nerve injury or brain hemorrhage and it leads to the atrophy of muscles. The structural, biochemical, physiological and pharmacological changes of the denervated muscle might be the important subject of investigation at present. In this article, the experimental results of my colleagues and other many investigators are summarized in special references to the fundamental finding on the denervated muscle.
The most obvious changes in a denervated muscle are weight loss and decrease in fiber diameter of individual muscle fibers. Weight loss and decrease in fiber diameter initially proceed at a rather rapid rate. After 7 weeks' denervation there is a 20 to 30 per cent weight loss in rat anterior tibial muscle. The nuclei of denervated muscle fiber may alter in shape and staining reaction and appear to increase in number. In the muscles denervated for relatively long periods,35 to 200days, fine structural changes in cell membrane were observed. Lamellar arrays of membrane enclosed cristernae were found in fibers denervated for 11 weeks or longer. Lamellar structure may be derived from the element of sarcoplasmic reticulum. Focal dissociation of the basement membrane from the plasma membrane is observed in muscle fibers denervated 11 weeks or longer. The number of myofilament remarkably decreases and Z-zone of myofibril seems to be indistinct. The nuclear membrane is found to be somewhat irregular in contour. Relatively clear areas of sarcoplasm appear in the perinuclear zone and the enlarged sarcotubles. Clamps of mitochondria, lysosomes and vacuoles are seen in the perinuclear area as well as in the interior of the fibers. At a motor-endplate region, the presynaptic membrane and cytoplasma of nerve-ending show degenerative changes and the basement membrane structure in postsynaptic membrane is found to be swelling and clouding in contour.
After nerve section, a reduction of myoglobin content, succinic dehydrogenase and cytochrome oxidase activity occurs in 2 weeks. Myosin-ATPase activity does not decrease in the muscle at a time when there has been a great decline in the succinic dehydrogenase activity of mitochondria of muscle. Sarcolemma-ATPase activity examined by electronmicroscopic method, is found to reduce to the level, leading to the changes of potassium concentration in denervated muscle.
Acetylcholinesterase is localized in the postsynaptic space and also in the axon-Schwann interface. In denervated muscle, a reduced acetylcholinesterase activity may explain the phenomenon of denervation hypersensitivity. There is, however, no parallelism between the reduced acetylcholinesterase activity and the hypersensitivity of muscle to acetylcholine.

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The activity of acid phosphatase (ACPase) in normal rat liver and in the rat liver during the course of carcinogenesis induced by 3'-methyl-4-dimethyl-diaminoazobenzene (3'-MeDAB) was studied ultracytochemically up to 34 weeks. From 24 weeks the hepato-cellular hepatomas could be obtained.
The ACPase activity was positive in lysosomes including cytolysomes in the normal hepatic parenchymal cells. The enzymatic activity in hepatic cells in the early and intermediate stages of carcinogenesis showed some decrease which was reflected in number and size of lysosomes. However, the activity in hepatic cells revealed increase in late stages of carcinogenesis as well as in hepatocellular hepatoma cells. The probable role of the ACPase activity in the azc-dye carcinogenesis was briefly discussed.
Supported by grants from the Anna Fuller Fund, the Jane Coffin Childs Memorial Fund for Medical Research (Project # 196) and the Japanese Government (Gann 94157) administered by Prof. K. Ogawa.

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As a part of a serial study on changes of the activity of various phosphatases during the azo-dye hepato-carcinogenesis, the activity of thiamine pyrophosphatase (TPPase)was observed in the rat liver cells up to 35 weeks. From 24 weeks and after the hepatocellular hepatomas could be obtained. The TPPase activity was positive in the Golgi apparatus and membranes covering bile canaliculi in normal hepatic cells. The weak enzymatic activity was also observed occasionally in the endoplasmic reticulum.
The TPPase activity within the Golgi apparatus per se did not seem to reveal any appreciable changes in morbid cells. However the Golgi apparatus in hepatic cells in the early and intermediate stages of carcinogenesis was rather smaller than the one seen in normal parenchymal cells. The Golgi vesicles and vacuoles were diminished in number also. In some hepatocellular hepatoma, however, the Golgi apparatus was redeveloped approaching to the normal size.
Supported by grants from the Anna Fuller Fund, the Jane Coffin Childs Memorial Fund for Medical Research (Project # 196) and the Japanese Government (Gann #94157) administered by Prof. K. Ogawa.

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Changes of the activity of glucose-6-phosphatase (G-6-Pase) was observed ultracytochemically in the hepatic cells of the male Sprague-Dawley rats treated with 3'-MeDAB up to 35 weeks.
In the normal hepatic parenchymal cells the G-6-Pase activity was positive in the rough-surfaced endoplasmic reticulum (ER), the smooth-surfaced ER including the one around the glycogen area and the transitional elements, and the nuclear envelope. The enzymatic activity was not observed in the Golgi apparatus, coated vesicles, multivesicular bodies and plasma membranes. The endothelial cells and epithelial cells lining the bile duct system did not reveal any enzymatic activity and only the hepatic parenchymal cell showed the enzymatic activity.
It was evident that the enormously proliferated tubular smooth-surfaced ER in the hepatic cells of treated rats was still positive for the G-6-Pase activity. It should be emphasized that this proliferation of the smooth-surfaced ER was evident only in the early and intermediate stages (up to 24 weeks) of the hepatocarcinogenesis. In the hepatocellular hepatoma cells the area of the proliferated smooth-surfaced ER could not be encountered, although in some cells of the early hepatoma remnants of the smooth-surfaced ER could be seen occasionally.
In hepatocellular hepatoma cells, the two types of the cell were observed, that is, the clear cell and the dark cell. In both cells the G-6-Pase was demonstrable, although the enzymatic activity was rather weak and there was quite a degree of cell to cell variation in the activity. In some hepatoma cells an amount of the rough-surfaced ER appeared to be increased, however, generally speaking, there seemed to be cell to cell variation in an amount of the rough-surfaced ER also.
The young proliferated oval cells arising from the cholangiole and the cholangioma cells did not reveal any G-6-Pase activity.
These findings strongly suggest the fact that the hepatocellular hepatoma arises from the hepatic parenchymal cells, while the cholangioma from the oval cells from the cholangiole.
It was of great interest to note that the proliferation of the smooth-surfaced ER did not persist through the carcinogenesis of the hepatocellular hepatoma and was ceased at a certain stage. The hepatoma cells seem to have lost the capacity of the smoothsurfaced ER proliferation. It is highly likely that the hepatic cell turns into a neoplastic cell following the cessation of the smooth-surfaced ER proliferation. In this connection, an elucidation of the mechanism of the biogenesis of the membrane system in the cell warrants a special attention in the field of the cellular mechanism of the hepato-carcinogenesis in the future.
Supported by grants from the Anna Fuller Fund, the Jane Coffin Childs Memorial Fund (Project # 196) and the Japanese Government (Gann # 94157) administered by Prof. K. Ogawa.

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Little information has appeared in the literature with reference to the relationship between inhalation anesthesia and metastatic development.
The current study has been designed to investigate the effect of anesthesia on the development of metastases. Rats having a simulated renal tumor were anesthetized with various anesthetics for 2 hours, and the renal tumor was removed by nephrectomy. Simulated renal tumors were produced following the method devised by Gullino. i. e., small fragments of Walker tumor were implanted into a subcutaneously transplanted renal parenchyma which then was enclosed in a parafilm sac.11 days after tumor inoculation, subcutaneously developed renal tumors were removed under each anesthetic.
Results disclosed that only 10 per cent of rats operated on under nembutal anesthesia had pulumonary metastases, whereas lung metastases were noted in 44 per cent of rats operated on under chloroform. When rats were anesthetized with ether or penthrane the production of pulmonary metastases was 40 per cent and 22 per cent respectively. The rate of lung metastases of the rats anesthetized with fluothane was 0 per cent.
The general conclusion that may be derived from these studies is that inhalation anesthesia with chloroform or ether enhances the development of pulmonary metastases.

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In the second type of experiment, the rats were anesthetized with each anesthetics, and after 2 hours maintenance 5,000,000 cancer cells (AH 130) in suspension were injected into the portal vein. All animals that survived were sacrificed at 2 weeks and postmortem examinations were made immediately, survival time with the hepatic takes were compared among each anesthetic group.
The chloroform anesthesia had the most harmful effect and hepatic takes were noted in 100 per cent of rats. Penthrane fluothane and ether were next in harmful effect, hepatic takes were noted in 90.9 per cent,81.8 per cent and 80 per cent respectively. When anesthesia with nembutal was performed, takes in the liver were noted in 60per cent of rats.
This indicates that inhalation anesthesia with chloroform, ether penthrane or fluothane acts as a marked stimulus for development of liver metastases.

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The effect of dietary amino-acid imbalance on the incidence of metastases and local recurrences following tumor removal was investigated.
The results obtained showed that the incidence of metastases and local recurrence or tumor growth followed different patterns among these diets differing only slightly in amino-acid composition; that is, the supplemetation of 5.9 % casein diets with excess isoleucine, methionine and tryptophan (group 4) or excess methionine (group 2) lowered the incidence of metastasis and local recurrence of tumors.
These results suggest that there is an association between altered amino-acid patterns of a diet and metastatic formation or tumor growth. Here, too, the rate of metastatic formation or tumor growth is amazingly sensitive to the amino-acid pattern of a diet. Further exparimentation is necessary to demonstrate the optimal or critical ratio of dietary amino-acids for decreased metastatic formation.

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A study was made of the effect of lysine and tryptophan added to 18 zein diets on cancer metastases and local recurrence in rats after surgery. Group 6 (6 % lysine and 1.2 % tryptophan added to 18 zein) showed a decrease in local recurrence following removal of Walker tumor and of hepatic takes following intraportal injection of AH 130 cells, and also retardation of tumor growth.
The amino acid composition of zein diets is inadequate following neoplastic surgery, but it can be improved by the addition of missing essential amino acids.
Thus, it is evident that cancer metastasis, local recurrence and tumor growth are sensitively influenced by the dietary amino acid ratio, and that an excess or a lack of certain amino acids may also affect their incidence.
Further experiments are necessary in this search for a dietary amino acid pattern most suitable for the inhibition of metastases and tumor growth.
The author is indebted to Professor M. Oka M. D., Professor M. Yamamoto M. D. and Lecturer A. Ando for guidance.

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