Thirty-four rats were sacrificed periodically from 191th day to 378th day after peroral administration of MNNG. 94 lesions were found in pyloric region of the glandular stomach of rats. Histologically, these lesions were classiffied as follows: 1) Regenerative glandular hyperplasia (34 lesions), 2) Adenomatous glandular hyperplasia (44 lesions), 3) Adenocarcinoma (16 lesions).
The changes of cellular proliferation and differentiation of these lesions were studied by means of the ³H-thymidine radioautography.
1. At the margin of these three types of lesions, the tendency of increase of labelled cells and extension of generative cell zone toward mucosal surface was observed.
2. The regularities of cell proliferation and migration from neck cell to foveolar and surface cell in normal gastric glands were maintained in the regenerative glandular hyperplasia and in the adenomatous glandular hyperplasia but in the adenocarcinoma such normal cell kinetics were lacking.
3. In these three types of lesions, two kinds of different atypical cells were found, namely dark and red cell, which can not be found in normal gastric gland. They were distinguished not only morphologically but also according to the degree of ³H-thymidine uptake. The dark cell has close similarities to the neck cell and red cell to the regenerative or foveolar epitheliar cell. MNNG induced adenocarcinomas were composed of these dark and red cells which had marked cellular and structural atypia. It is suggested that atypical proliferation of the neck cell which is induced by MNNG during repeated injuries and regeneration of gastric mucosa, might develop into the dark and red cell and finally into adenocarcinoma.

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It is considered that endocrine state may be profoundly involved with brain metabolism underlying psychic functions. I have undertaken to study testosterone metabolism in the brain in order to get a basic knowledge about a role of sex hormones, particularly testosterone, playing in psychic function.
In the present investigation, the activity of Δ⁴-3-ketosteroid 5α-oxidoreductase was measured in rat diencephalon, and the effects of central acting drugs were examined on the enzyme activity.
Experimental methods
1. Rats were adrenalectomized and testectomized under Nembutal anaesthesia. One, three, four and six days after the procedure, the activity of Δ⁴-3-ketosteroid 5α-oxidoreductase was determined in rat diencephalon prepared immediately following decapitation. Three days after the operation, another group of rats received intraperitoneal administration of testosterone propionate (1mg/100g. B. W.) and they were killed to determine the enzyme activity in diencephalon.
2. Intact rats had a single i.p. injection of chlorpromazine (4mg/100g. B. W.), diazepam (0.25mg), dipiperon (8mg), methylphenydate (1mg), diphenylhydantoin (5mg), phenobarbital (6mg), caffeine (10mg), methamphetamine (0.6mg), disulfiram (10mg) or normal saline. 4 hours after injection, rats were killed by decapitaion, and both Δ⁴-3-ketosteroid 5α-oxidoreductase activity in diencephalon and plasma testosterone were estimated. Another group of intact rats received repeated i.p. administrations of 1/10 dosis of each drug above mentioned for 14 consecutive days, and the animals were killed 24 hours after the last injection to determine both Δ⁴-3-ketosteroid 5α-oxidoreductase activity in diencephalon and plasma testosterone.
Results
1. The activity of Δ⁴-3-ketosteroid 5α-oxidoreductase was shown to increase gradually until 3 days following adrenalo-testectomy, and then to return to almost normal value. When rats were given testosterone propionate 3 days after adrenalo-testectomy, their enzyme activities in diencephalon fell in to normal range.
2. The activities of Δ⁴-3-ketosteroid 5α-oxidoreductase in diencephalon showed a significant increase (p<0.01) in each group of rats singly administered with carbamazepine, reserpine, diazepam, diphenylhydantoin, phenobarbital or disulfiram, and also a significant increase (p<0.05) in each group given singly methylphenidate, caffeine or methamphetamine. Plasma testosterone showed a decrease in all groups except for diazepam group after a single drug injection.
The enzyme activity in diencephalon showed a significant decrease after repeated drug administrations in disulfiram group (p<0.01) but a significant increase in methamphetamine group (p<0.05). Plasma testosterone showed a tendency for decrease in methamphetamine group but a tendency for increase in disulfiram group.
From the above results, central acting drugs modulating psychic functions were found to act on testosteron-metabolizing enzyme activity. Therefore, it is possible that there exists some relationship between testosterone metabolism in the brain and psychic functions.

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Vesicles induced by using Unguentum Vesicans at the sites of untreated or reactive skins to allergens of healthy individuals were investigated. Vesicles of patients with bronchial asthma were investigated only at the untreated skins. The numbers of basophilic and eosinophilic leucocyte in the exudate obtained from these vesicles were examined. The results were as follows.
1) The numbers of the total white cells in the exudate were found higher in the vesicular fluid of the patients with bronchial asthma than in that of the healthy individuals.
2) Larger numbers of basophils and eosinophils were found in vesicular fluid of the patients with bronchial asthma than in that of healthy individuals. And, the increase of these cells in numbers were conspicuously observed in the positive immediate-type skin reaction of the healthy individuals.
3) There was no relationship between the numbers of these cells in peripheral blood and in the vesicle.

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Vesicular exudate was produced by the application of Unguentum Vesicans on the skin which was treated with various allergenic extracts. The exudate was than examined for the presence of basophils and eosinophils in 134 patients with bronchial asthma. The results were as follows.
1) Larger numbers of total white cells in the vesicle were seen at the sites of the skin test than at the untreated skin sites.
2) A slightly larger number of basophils and eosinophils was found in the vesicular fluid at the sites of skin, which demonstrated a positive immediate-type reaction, than in the sites of negative to an allergen.
3) Basophils appeared in relatively higher rate in the fluid of positive reaction to candida or ragweed than to house dust. A tendency of eosinophil migration into such vesicular lesions was about the same as basophil migration, although statistically not significant.
4) Basophils and eosinophils in the vesicular fluid with positive reaction using higher concentration of candida or house dust extract showed more increase than using lower concentration. It was found that both cells increased clearly around the concentration of house dust at the end point of the skin.
5) There was a relationship between basophil numbers in peripheral blood and those in the skin vesicles. In the cases with basophils in peripheral blood more than 65/cmm, basophil migration at the sites of skin lesions showed clear increase compared with the cases less than 65/cmm. Similar tendency was also found in eosinophils.
A negative correlation between serum IgE level and intravesicular appearance rate of basophils was observed.
6) Among the patients with occupational asthma induced by inhalation of timber dust of Chinese quince or Rosewood and by inhalation of Buckwheat, basophils and eosinophils appeared in large numbers at the sites of a positive immediate skin reaction to the special allergen.
7) This study demonstrated that basophils as well as eosinophils can easily migrate from the blood vessels into extravascular tissues at sites of allergic reactions, especially in reaginic hypersensitivity. Both basophils and eosinophils or either cell alone appeared in large numbers at sites of positive immediate reactions if allergens were specific in individual cases.
The skin vesicle technique discribed above may be of a great use for detecting allergens and evaluating allergic disease states.

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The appearance of basophils and eosinophils at the sites of late or delayed skin reaction was examined in 34 bronchial asthmatics. Using guinea pigs, basophils at the site of cutaneous basophil hypersensitivity were observed with electron microscopy. The results were as follows.
1) The numbers of basophils and eosinophils increased significantly at the sites of positive delayed skin reaction to PPD and various allergens. Furthermore, the above phenomenon was much more conspicuous and significant at the sites of positive late reactions than of negative ones.
2) The appearance of basophils showed two peaks, i. e., at 30 minutes and 6 hours, after intradermal allergen injection. Eosinophils appeared at 6 hours in the peak.
3) In the cutaneous basophil hypersensitivity, migrating basophils and eosinophils were observed around the blood vessels in the hypodermis of guinea pigs.
Electron microscopic observations demonstrated that basophils showed exocytotic degranulations were sometimes phagocytized by macrophages.

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The effects of various heavy metal ions such as Hg²⁺, Cd²⁺, Cu²⁺ and Zn²⁺ on mitochondrial membrane were investigated and the following results were obtained;
1) Hg²⁺, Cd²⁺, Cu²⁺ and Zn²⁺ released the potassium ion from the mitochondria with the increasing level of an affinity to SH compounds.
2) The release of K⁺ by Cd²⁺ and Zn²⁺ was inhibited in the presence of Mg²⁺, but the release of K⁺ by Hg²⁺ and Cu²⁺ was not affected.
3) In the presence of ImM DTT, the release of K⁺ by all of these metal ions was completely inhibited.
4) The K⁺ release by Hg²⁺ and Cu²⁺ was inhibited by DTNB or PCMB which bound prefencially the thiol component of membrane protein, but the release by Cd²⁺ and Zn²⁺ was not inhibited by these reagents.
5) The release of K⁺ decoupled the oxidative phosphorylation by treatment of the heavy metal ions.

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The effects of organic mercury compounds on the biomembrane were studied with specific reference to the K⁺ compartment and the following results were obtained.
1) PhMC, PhMA, and MMC had effects of decoupling action on the oxidative phosphorylation, and PCMB inhibited the ADP-stimulated respiration, and mercury chloride inhibited the respiration.
2) On the red blood cell and mitochondrial membrane, these organic mercury compounds induced the K⁺ release in the order of HgCl₂ PhMC PhMA MMC PCMB.
4) It is suggested that the liophilic nature of organic mercury compounds plays an important role in the reaction of K⁺ release.

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The mutual effects of Cd²⁺ and ruthenium red on rat liver mitochondrial energy transfer reaction are described. In results, ruthenium red recovered the depression of the oxidative phosphorylation induced by Cd²⁺. Ruthenium red suppressed the K⁺ release induced by Cd²⁺. As the binding site of the Cd²⁺ have other than the binding site of ruthenium red, the site of ruthenium red is greatly related with the inhibitory effect of Cd²⁺ and this site is similar to the binding site of Ca²⁺.

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The effects of ruthenium red (RR) on the K⁺ release induced by Cd²⁺ and on the binding of Cd²⁺ with mitochondrial membrane were examined and the following results were obtained.
1) The K⁺ release of mitochondria induced by Cd²⁺ was inhibited by the compounds which had the affinity to the Ca²⁺-binding site, in the order of RR, procaine.
2) Binding of Cd²⁺ with mitochondrial membrane was inhibited by RR.

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COP, a new alloy for surgical implants, has been evaluated biologically and clinically for its application to orthopaedic field.
1) Biological evaluation
a) Tissue culture: Discs 3.5mm in diameter, 1mm in thickness were made with SMo, Vitallium and COP. Also same sized disc was made with copper. The cells used for culture were ME cells (mouse embryonal fibroblasts) in culture passage of the 86th generation. These test discs were sterilized by supersonication, placed in flasks and TD 15 culture bottles, then ME cells were placed in each vessel and cultured separately with these four discs. Citotoxity of the four metals was determined by observing the growth of fibroblasts in the presence of these metals. Vitallium, SMo and COP are found to be noncytotoxic, however copper is found to be highly cytotoxic.
b) Experiment with rabbits: Small plates were made with SMo, Vitallium and COP as materials and embedded in dorsal subcutaneous tissue of rabbits. Tissue reactions around these materials were examined with the lapse of time. Kirschner's wire 2mm in diameter was also inserted intramedullaryly into the rabbit femur and similar examinations were carried out. Furthermore, small sections of SMo and COP wires 1mm in length were made, embedded in the rabbit knee joint and similarly examined. The results showed no abnormal findings in the tissues in these three series except for fibrous reactions around materials.
2) Clinical evaluation
284 AO type plates and 255 Jewett nail-plates which were made with COP have been applied for fracture fixation. Also 250 AOI plates which were made with SMo have been used for the same time of period. From the assessment of fracures healing, bone union in all fracures has been progressed smoothly without any abnormal reactions around metals either SMo or COP. X-ray examination revealed no abnormalities such as abnormal callus formation or bone absorption around the COP material.
Therefore it is concluded that trial plates and screws made with COP are excellent and can be extensively used as attested to by experimental and clinical results in comparison with other conventional surgical implants available on the market.

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Using phytohemagglutinin (PHA) and/or Antilymphocyte serum (ATS) that are considered to act only on T-lymphocytes, a study was made of the effects of these substances on pleque forming cells (PFC) for sheep red cells in spleen of mice and the antitumor activity of cancer-bearing mice as well as the blastformation rate of mouse lymphocytes against PHA in vitro, and the following results were obtained.
1) From the fact that PFC proliferate in the presence of PHA but they decrease in number in the presence of ATS, PFC seem to be under the control of T-cells.
2) As the antitumor effects of cancer-bearing mouse lymphocytes is enhanced by PHA but it is decreased by ATS, it may be said that T-cells play a leading role in the antitumor immunity as efector cells.
3) Since MIF activity of cancer-bearing mouse is decreased markedly by ATS, it seems that T-cells play the most important role in producing MIF.
4) Since the blastformation rate of mouse lymphocytes against PHA decreases in the presence of ATS, it may be assumed that the lymphocytes undergoing blastformation are T-cells.
Various roles of T-cells are now being clacified, while the present experiment is a step toward the clacification of such roles.

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When we perform a learning experiment using the avoidance training by putting mouse, as an experimental animal in a jump-box, standard deviation becomes larger than we expect among individuals of the same strain, even though we use the inbred strain.
We select male and female of ddN strain mouse. When these mice jump-up within 3 seconds after a conditioned stimulus in more than 20 times out of the first 60 trials, we let them mate. Through 7 generations by brother and sister matings we have improved genetic selection; male and female mice show the reaction in more than 15 times of the first 30 trials. Then, we let them mate. Comparing with the ealier generation of inbred mouse, the standard deviation in the 10th generation (ddN-F10) becomes smaller. And no remarkable differences in male and female on the avoidance ability are noticed.
We also study on comparing the formation of learning by avoidance training and the shortand long-term memories of the reactions after training between the ddN-F10 strain and following inbred strains, i.e., C3H, DBA, C57-BL, RF, AKR, C58, D103, C6, and CBA. AKR, ddN-F10, DBA, C58, and C3H learned fastest, whereas RF, D103, C6, and CBA strains learned slowest. As to the long-term memory, ddN-F10, DBA, C58, C57-BL, and C3H perform superior to RF and D103. Except for the ddN-F10, other strains show a large standard deviation.
In conclusion, we can establish laboratory mice using the avoidance learning for genetic improvement.

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The investigation was carried out on 82 pregnant women with firm diagnoses of cardiac disease, who delivered 84 infants, including two cases of twin pregnancies, during a six and a half year period from January 1971 through June 1977 at the Obstetrical Floor of National Fukuyama Hospital. As a result;
(1) In 39 cases (47.6%), diagnosis was rheumatic heart disease, and 30 cases (36.6%) had congenital heart disease. Other 13 cases (15.9%) were associated with miscellaneous heart disease.
(2) According to functional classifications of the New York Heart Association, 74 cases (90.2%) was evaluated as either Class I or II, and other 8 cases (9.8%) was either Class III or IV.
(3) Five cases (6.1%) developed cardiac insufficiencies; one case at home, one case during hospitalization and repeatedly during cesarean section, and three cases during labors.
(4) Two women (2.4%) resulted in fatal outcome. One case with mitral stenosis, who was poorly managed by a general physician and developed pulmonary edema at home, died immediately after emergent admission and delivery of dead fetus at the 29th gestational week. One case with patent ductus arteriosus died 5 months after recovery from cardiac arrest due to a massive hemorrhage from placenta previa during cesarean section.
(5) As pregnancy complications, nine cases (11.0%) had premature deliveries, two cases (2.4%) with breech presentations, two cases (2.4%) with twin pregnancies, and two cases (2.4%) developed severe toxemia of pregnancy.
(6) Seventy six infants (90.5%) were delivered vaginally; 31 cases (36.9%) by either vacuum extractions or forceps deliveries, and two cases (2.4%) by breech extractions. Cesarean sections were performed on 6 cases (7.3%), however, only one case (1.2%) was for cardiac reason.
(7) Perinatal mortality rate was 1.2% due to fore mentioned intrauterine fetal death.
(8) As perinatal morbidities, 8 cases (9.5%) was IUGR, 5 cases (6.0%) with SFD, 3 cases (3.6%) with asphyxia neonatorum, 4 cases (4.8%) with respiratory insufficiencies, and one case (1.2%) had congenital heart disease.
Modern management of cardiac disease in pregnancy was also discussed.

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The exercise electrocardiogram was studied in the patients with atrial fibrillation who were presumably free of hyperthyroidism, severe pulmonary disease or valvular disease. Thirtyone patients with atrial fibrillation, 25 male and 6 female, were subjected to a double Master's two-step exercise test.
Seventeen out of thirty-one patients (54.8%) had abnormal electrocardiograms (positive test) according to our criteria after the double two-step test. Heart rate responding to the exercise increased much more than controls reported previously form our laboratory. It was assumed that in atrial fibrillation, an abnormally excess response of heart rate to exercise caused a marked rise in myocardial oxygen demands according to an increase in cardiac work and a decrease in effective coronary perfusion time. Furthermore, atrial fibrillation, probably absolutely irregular ventricular rate, might decrease coronary flow reserve responding to increase in oxygen demand.
These suggest that abnormal hemodynamic responses to the exercise result in positive test even in the cases without coronary artery disease.

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Amount of exposure of air pollutants to three persons (A, B and C) lived in different places and life times was measured by personal air sampler.
The results obtained as follows.
1) Amount of dust exposed to A showed the highest level among A, B and C, as A was stayed at business room in which atmosphere showed high level of dust for 6-7 hours.
2) The amount of NO₂ exposed to C showed the highest level, as C was exposed to atmosphere on places and traffic roads, showing high level of NO₂ derived from industry and measured by monitoring station, and from the exhaust.
3) Amount of air pollutants exposed to B showed the lowest level of air pollutants, as B stayed in the room with windows opened and was exposed to atmosphere of the lowest level of air pollutants at his measuring days.
4) From above results, it was estimated that the amounts of air pollutants exposed to each persons could be measured by personal sampler.

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Glycolytic enzymes: glucose-6-phosphate dehydrogenase, 6-phospho-gluconate dehydrogenase, lactate dehydrogenase and pyruvate kinase, of DMBA-induced mammary carcinoma, Shionogi Carcinoma 115 and Shionogi carcinoma 42. Glycolytic activities of these tissues were examined after hormonal ablation, administration of hormones and anti-hormonal drug. Enzymic activity of hormone dependent tumor was rised by administration of dependent hormones.

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Glycolytic enzyme activities of human breast cancer was studied on age, menopausal status, T, N, Stage and pathology in benign and malignant tumor. Influences on incubation with additional hormones also were studied. Mastopathy, benign tumor and breast cancer showed varied enzymic activity. High enzymic activity was observed in breast cancer tissue, but the enzymic activity was not paralleled with tumor size. Enzymic activity changed by incubation with additional hormones. Pre menopausal state, T₁, negative lymph node metastasis, Stage I tissues were elevated enzymic activity. Post menopausal state, T₃, positive lymph node metastasis, and Stage III tissues were decreased enzymic activity.

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Patterns of chronic gastritis accompanied with other gastroduodenal diseases were studied histopathologically. Totally 220 cases of the resected stomach included 38 duodenal ulcer, 40 gastric ulcer, 87 early gastric cancer (34 undifferentiated and 53 differentiated type) and 55 advanced gastric cancer.
Following results were obtained:
1) Degree of glandular atrophy and intestinal metaplasia increased as the patients became older. These mucosal changes spreaded usually from the antrum to the body.
2) Proliferation of lymph follicles and reactive cell-infiltration (lymphcytes, plasmacells, polymorphonuclear leucocytes and eosinophilis) were most frequently seen in the area of atrophic changes, and extended from the antrum to the body with increasing ages.
3) Fibrosis and hypertrophy of the muscularis mucosa increased with the progress of atrophic changes and also patient's year.
4) Atrophic changes were more prominent in the case of gastric ulcer than in the duodenal ulcer, if the patient's ages were same, and were also more significant in the case of differentiated type of early gastric cancer than in the undifferentiated type. Moreover, atrophic changes were not significantly different in the case of gastric ulcer and the undifferentiated type of early cancer, and also in differentiated early cancer and advanced gastric cancer.
5) In the antral mucosa, the degree of proliferation of lymph follicles and reactive cell-infiltration were most prominent in the case of duodenal ulcer, then gastric ulcer, undifferentiated type of early cancer and differentiated type. In the body-mucosa, these findings were seen in vice versa.
6) Fibrosis and hypertrophy of the muscularis mucosa, either at the antrum or the gastric body, were most significant in the case of differentiated type of early cancer, then gastric ulcer, undifferentiated type of early cancer and duodenal ulcer.
7) From these facts, the words of “Attendant Gastritis” seem to be unsuitable, because atrophic changes preced with developing various gastric diseases (ulcer, polyp and cancer).
8) From the findings of proliferation of lymph follicle, cell-infiltration, fibrosis and hypertrophy of the muscularis mucosa, these chronic gastritis seemed to be induced by inflammation.

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Morphological changes of DMBA-induced rat mammary tumors were observed following administration of prolactin and estradiol-17 β or nafoxidine (anti-estrogen agent), and bilateral adreno-ovariectomy.
1) Following combined administration of prolactin 1 I.U./day and estradiol-17β2μg/day, all tumors demonstrated increase in volume. Their morphological changes were hypertrophy of tumor cells, increase of nucleo-cytoplasmic ratio, development of intracytoplasmic orgnelles, increase of free ribosomes and narrowing of the stroma. In addition, some tumors demonstrated marked secretion of fatty droplets and protein granules.
2) Following administration of nafoxidine 100μg/day, 90% of the tumors showed diminution in volume. Their morphological changes were smaller tumor cells in size, disappearance of mitotic figures, maldevelopment of intracytoplasmic organelles, decrease of free ribosomes, development of the basement membrane and marked proliferation of fibrosis in the stroma. On the other hand, myoepithelial cells demonstrated the least influences by anti-estrogen agent.
3) Following bilateral adreno-ovariectomy, 76.9% of the tumors showed diminution in volume. Their morphological changes were necrotic changes of tumor cells represented by appearance of lysosomes and autophagic vacuoles. Myoepithelial cells remained relatively well and surrounded necrotic lesions. However, at last they disappeared and epithelial components of tumors were replaced by stromal components.

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The clinical history, laboratory data, and hypothalamic-pituitary-axis were investigated in 8 patients with Sheehan's syndrome.
2 patients had panhypopituitarism while 6 patients had selective pituitary deficiencies.
Hypothalamic-pituitary-adrenal-axis in 2 patients with Sheehan's syndrome was impaired when the response to metopirone, but not to insulin-induced hypoglycemia.
The interpretation of this difference is complicated in secondary hypothyroidism, and better preserved in the response to metopirone than to insulin-induced-hypoglycemia.
The imbalance of LH and FSH response to LHRH in 2 cases (a blunted LH response in the presence of normal FSH response) may account for the complication of secondary hypothyroidism.
The variety of Sheehan's syndrome was observed, for example that one case without history of postpartum hemorrhage or shock, and others with pregnancy after onset of Sheehan's syndrome.
The duration of illness at the time of diagnosis ranged from 1.5 years to 11 years with an average of 6.5 years.
In the future, a follow-up investigation of women with the history of postpartum hemorrhage or shock is necessary.

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