An assay for exophthalmogenic factor in sera of exophthalmic euthyroid and hyperthyroid patients and some hormone preparations was performed by the method based on measurement of the percent increase in intercorneal distance of gold fish following the intracoelomical administration of the test material.
Out of nine normal adults examined, the sera of seven showed a trace of exophthalmogenic response, but the sera of two males exhibited abnormally high response.
In nine exophthalmic hyperthyroidism, three non-exophthalmic hyperthyroidism and one moderately severe exophthalmic euthyroidism and one non-exphthalmic simple goiter a correlation was observed between each couple of exophthalmos grade, serum exophthalmogenic response, serum TSH level and protein bound iodine (PBI) level : the exophthulmos grade correlated significantly with the serum exophthalmic response, but not with the serum TSH level or PBI level.
As regards exophthalmos, gold fish responded well to the administration of thyrotrophic preparation and beef anterior pituitary extract, but scarcely to gonadotrophin, adrenocorticotrophin, cortisone, testosterone, estradiol and thyroxine. Enhancing effect of ACTH on exophthalmos produced by TSH was not marked.
It was postulated that exophthalmogenic factor, originating from anterior pituitary, existed in human sera, and increased in some patients with exophthalmos, but was not TSH. itself.
The serum TSH concentration in rabbits under various experimental conditions was investigated by the in vitro method based on inorganic I¹³¹ release of beef thyroid tissue. The following results were obtained.
1) The mean serum TSH level in 20 normal rabbits was 1.9±1.1 milli JS u/ml, and the level of TSH in serum circulating in the internal jugular vein was higher than that in serum obtained from peripheral systemic vein.
2) The serum TSH level decreased markedly 24 hours after hypophysectomy.
3) Ninety-six hours after thyroidectomy the content of TSH in the serum increased to more than 10 milli JS u/ml.
4) Within 12 hours after the administration of 1-thyroxine (T₄) or 1-3 : 5 : 3'-triiodothyronine (T₃), the serum TSH activities fell below the lower limit available for the assay method. The inhibition of TSH secretion by T₄ appeared rather gradually but lasted longer than that of T₃. However, it was observed in either occasion that the serum TSH activity was elevated transiently and then returned to the initial level again ; this change was regarded as a “rebound phenomenon”.
5) The TSH level in rabbit sera increased with some variations following the medication of mer-cazole (1-methyl-2-mercaptoimidazole), and decreased gradually to the initial level in 1-2 weeks after the cessation of the administration of mercazole.
6) Exogenous TSH, when administered intravenously, disappeared rapidly from the sera of normal rabbits, but somewhat slowly in the rabbits treated with mercazole or carbon tetrachloride.

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In certain diseases or stresses, it was reported that the increased levels of mucoproteins in serum and increased excretions of urinary mucoproteins were observed. However, very little has been known regarding the relationship between mucoproteins in serum and urine. In this paper, Donaggio-active mucoproteins in serum and urine were estimated by Ishihara's methods and the following results were obtained.
1. Levels of serum mucoproteins in 118 cases of tuberculosis, 4 cases of exsudative pleuritis, 3 cases of pneumonia, 12 cases of cancer, and 9 cases of gastric ulcer were higher than those levels of 23 cases of healthy subjects.
2. Donaggio-active mucoprotein levels in serum were correlated well with 24-hour-excretions of Donaggio-active mucoproteins in 45 cases.
3. No diurnal variations of Donaggio-active mucoproteins in serum were observed in 6 cases of healthy subjects and one case of far advanced tuberculosis, while obvious diurnal variations were observed in urinary Donaggio-active mucoproteins.
4. No daily variations of Donaggio-active mucoproteins in serum were observed in a healthy sub-ject and a patient with far advanced tuberculosis, however daily urinary outputs of mucoproteins were exhibited considerable variations.
5. In 3 cases of healthy subjects, administrations of ACTH gel (40 Armour units) induced a significant increase of Donaggio-active mucoproteins in urine, while levels of Donaggio-active mucoproteins in serum didn't response even to ACTH.
6. Five healthy males are subjected to observe the effect of hydrocortisone. Levels of mucoproteins in serum of 3 cases were elevated following oral administration of hydrocortisone, and no changes were shown in urinary excretions of Donaggio-active mucoproteins. Levels of Donaggio-active mucoproteins in serum of remaining 2 cases were not elevated, and excretions of Donaggio-active mucoproteins in urine were increased significantly.
7. The effects of surgical operation were investigated on 5 cases of gastric ulcer, one case of gastroduodenal ulcer and 2 cases of osteosynthesis. Postoperative levels of Donaggio-active mucoproteins in serum were constant in 4 cases, elevated in 2 cases and indefinitely variable in remaining 2 cases. However Donaggio-active mucoproteins in urine were remarkably increased after operation in all cases.
8. Muscular exercises were performed using bicycle ergometer in 5 healthy subjects. Except one case, muscular exercise didn't affect the levels of Donaggio-active mucoproteins in serum, while excretions of Donaggio-active mucoproteins in urine were increased significantly. In a case excluded, the levels of Donaggio-active mucoproteins in urine was less than those of 4 cases.
In general, Donaggio-active mucoproteins in serum were shown high levels in patients with tuberculosis, pneumonia and cancer. Enhanced excretions of Donaggio-active mucoproteins in urine were also concomitant occurence in these cases. Following administration of ACTH and in such stressed conditions as surgical operation and muscular exercise, Donaggio-active mucoproteins in serum were kept relatively constant, while the outputs of Donaggio-active mucoproteins in urine were increased significantly.
It is of interest to note, in conclusion, that there are distinguishable patterns in the changes of mucoproteins in blood and urine between “stress” and certain diseases where some abnormalities in mucoprotein metabolism have been reported.

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It has been established that anterior pituitary TSH plays a major role in the regulation of thyroid function.
Besides this humoral factor, however, possibility of regulation through autonomic nervous system has been debated, without reaching a definite conclusion as yet. Many reports appeared on the augmentation of thyroid hormone secretion by the stimulation of the cervical sympathetic nerve. Effect of vagal stimulation on thyroid secretion, on the other hand, has scarecely been studied. The author therefore attempted to investigate the effect of vagal stimulation on thyroid function using radioactive iodine.
Dogs were injected with 100 microcuries of I¹³¹ 5 or 6 days prior to the experiments. Polyethylene catheters were inserted into each of the thyroid veins to obtain blood samples continuously. PBI¹³¹ in the thyroidal venous blood was precipitated by TCA and the radioactivity counted in a welltype scintillation counter. Electrical stimulation of the nodose ganglion of the vagus was performed to determine the effect on PBI¹³¹. At the end of each experiment, 2 USP units of TSH were injected intravenously to check whether the polyethylene catheter had been correctly inserted into the thyroidal vein, and, moreover, to determine the reactivity of the thyroid gland to this hormone.
Following results were obtained.
1) Control group : The upper limit of critical region for the significant increase was calculated from the degree of spontaneous fluctuations of PBI¹³¹ in 10 experiments without any stimulation as follows ; PBI¹³¹ concentration 1.49 times the pre-stimulation level, and PBI¹³¹ output 1.29 times.
2) Group with stimulation of unilateral nodose ganglion : In 13 out of 14 cases, PBI¹³¹ concent-ration increased from 1.60 to 4.84 times the pre-stimulation level, while PBI¹³¹ output increased from 1.59 to 5.42 times in all 14 cases.
3) Group with partial section of vago-accessory myelencephalic rootlets of the vagus nerve followed by stimulation of the ipsilateral nodose ganglion 2 weeks later :
a) Section of AM and AH (AM rootlets contain chiefly fibers for stomach and intestine, while AH rootlets chiefly the cardioinhibitory fibers.) : PM¹³¹ concentration increased form 1.60 to 3.99 times, while PBI¹³¹ output increased from 1.61 to 4.22 times in all 6 cases.
b) Group with section of main stem (V rootlets) of vagus nerve : Neither concentration nor output of PBI¹³¹ increased in 5 out of 6 cases.
c) Group with section of cranial 2/3 of main stem V : PBI¹³¹ concentration increased 2.12 times, output 2.17 times in one case.
4) Group with extirpation of the cranial, caudal and stellate ganglia of the cervical, sympathetic nerve followed by stimulation of ipsilateral nodose ganglion 2 weeks later : In 5 out of 7 cases, PBI¹³¹ concentration increased from 1.60 to 4.73 times, while output increased from 1.88 to 3.61 times in all 7 cases.
Stimulation of unilateral nodose ganglion fascilitated the secretion of thyroid hormone bilaterally, the increase in the ipsilatetal thyroid being always more pronounced. Such PBI¹³¹ response to ner-vous stimulation, characterized by the prompt increase within 15 minutes, was in a sharp contrast with the response to intravenous TSH which always took more than 15 minutes for its appearance. From these results it was concluded that, neural regulation of thyroid hormone secretion mostly depends on fibers passing the main stem V among the original rootlets of vagus nerve, in addition to the already known cervical sympathetic nerves. Concerning the thyroidal blood flow, tendency of slight increase was observed in the group of vagal stimulation, and a marked increase in the post-sympathectomy vagal stimulation group, in contrast to the tendency of decrease in response to the sympathetic stimulation.

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In order to obtain some informations about adrenal cortical activity in diabetics, I have observed the changes of glucocorticoids activity measured by urinary excretion of total 17-hydroxycorticosteroids (17-OHCS) in the course of the treatment of diabetics. Following results were obtained.
1. Of 22 uncontrolled diabetics, not associated with diabetic ketosis and coma, 5 patients showed normal excretion of urinary 17-OHCS and 17 patients showed increased excretion of urinary 17-OHCS.
2. Urinary 17-OHCS excretion was intimately correlated to the severity of diabetes.
3. When diabetic states were controlled by insulin in 14 patients, 10 patients showed normal excretion of urinary 17-OHCS and 4 patients showed slightly increased excretion of urinary 17-OHCS. But urinary excretion of 17-OHCS in controlled state was lower than it before treatment in each case.
4. By sulfonylurea therapy urinary excretion of 17-OHCS did not show decreasing tendency when diabetic states were well controlled.
5. In the patients with cardiovascular complications, urinary excretion of 17-OHCS was lower than it of the patients without complications. This seemed to be attributable to the some severe patients who were found in uncomplicated patients.
6. A patient with hyperthyroidism and 3 patients with acromegaly were all severe diabetic patients and showed highly increased excretion of urinary 17-OHCS before treatment. But urinary excretion of 17-OHCS decreased remarkably when the former treated by insulin and antithyroidal drug and the latter by insulin.
7. 3 patients with diabetic ketosis and 3 with diabetic coma, those were considered to be the most severe state of diabetes, showed the most increased excretion of urinary 17-OHCS in all cases. Nevertheless, they decreased after recovery by insulin therapy.
From these findings it may be concluded that adrenal cortical hyperactivity in diabetic patients is a derangement secondarily to the metabolic disturbances of diabetes mellitus, and insulin therapy is preferable to sulfonylurea therapy. No significant differences are found in adrenal cortical activity between the patients with cardiovascular complications and the patients without complications. But it is suspected that hyperadrenocorticism, when it persisted in long period, may play an important role on the pathogenesis of the cardiovascular complications.

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Although numerous investigations on metabolic disturbances in diabetes mellitus have been made, little is known of abnormalities of protein metabolism especially of amino acid metabolism in diabetics.
As the first step to clarify metabolic disturbances of amino acids in diabetes mellitus, urinary amino acid excretion was investigated. Comparing amino acid patterns of normal subjects with those of diabetics, the author gained following results :
(1) Urinary amino acid excretion is decresed in diabetics especially those with ketoacidosis.
(2) Excretion of lysine, arginine, histidine, threonine are strikingly decreased.
(3) Decreased amino acid excretion is recovered to a normal range by administration of insulin, bnt not by other therapeutics.

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In present investigation, the maintenance test of ACTH was performed in order to elucidate the mode of action of this principle to the adrenal cortex as determined by the cytological observation. In the first group, the hypophysectomized male adult rats of Wistar strain were sacrificed at the 5th, 10th, 14th and 30th postoperative day as the control. The second group consisting of hypophysectomized rats was subcutaneously injected with ACTH 2.5mg/day/rat from the next day for 5, 10, 14, 30 days respectively. Each day-subgroup of hypophysectomized control consisted of 2-6 rats and hypophysectomized administered day-subgroup consisted of 2-3 rats. Materials removed immediately after the decapitation were fixed with Levi's solution and the paraffin sections obtained were stained with Heidenhain's iron hematoxylin. In preceding paper (1957) the author appointed the automacity of zona glomerulosa which may be responsible for the hyperactivity induced by the hypophysectomy, because of the fascicle formation and the accumulation of proteinic stainable granules within the cell-bodies. Present cytological alterations in the adrenal cortices following the hypophysectomy were reconcile in general with the descriptions in foregoing article, so a references is to be made to those data in it.
The adrenal gland weight could in no cases recover from the severe reduction following the hypophysectomy by means of the administration of ACTH ; further the decline in size of whole adrenal cortex was not reverted. However, it was learned that the salient histological feature showing the integral retraction from the atrophy of the adrenal cortex was apparent owing to our detail observations.
Five to 7 days after the withdrawal, zona glomerulosa elongated, in which there were a number of the glomeruli consisting of the numerous cells with obscure contour which were burdened with the abundant fat granules. By the administration the zone became to provide the fasciculata appearance whose cells included a majority of stainable granules instead of fat droplets. In the 10th, 14th and 30th postoperative day, the zone was subject to acquir the thorough fasciculata appearance and to obtain the broad extension amounting to 1/2 to 2/3 of the whole size of the adrenal cortex. This may be involved in a sign of active participation in secretory facility. The prolonged administra-tion of ACTH for corresponding days shortened conversely the width of zona glomerulosa, increased the number of stainable granules in its cells and made the glomeruli regenerated with the consequent unequivocal restitution beyond the normal level. The response in zona glomerulosa was inter-preted as the atrophy rather resembling caused by the chronic stress. We could neither recognize the clear-cut mitosis there nor the metamorphosis of fibrocytes in capsule to cortex cells.
The transitional zone constantly hypertrophied up to the 5th or 10th day, and thereafter it gradually declined in size and finally disappeared. The injection of ACTH for less than 10 days was in fact capable to make the inanition in this zone which had hypertrophied apparently, in spite of much supression in reacting capacity in advancing postoperative days more than 10 days.
The zona fasciculata was contracted without an exception in hypophysectomized control group ; its constituent cells fell into an atrophy ; the cell arrangement forming fasciculata was reliably irre-gullar ; most of them included abundant huge fat droplets. The administration failed to prevent the atrophy and subsequent disorder in cell distribution, notwithstanding the precise improvement so far as the internal structure of the cells is concerned. For example, the administration for 5 to 10 days increased conspicuously the number of the proteinic stainable granules. Since the augementation in number of them is consistent with the pattern of the adrenal cortex cells of the animals exposed by the persistent stressful agents,

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The hypophysectomized rats of Wistar strain receiving an operation in 60-90th postnatal day respectively were injected with ACTH and GH alternatively or in combination. The adrenal cortex of these animals was histologically examined in comparing it to that in control hypophysectomized rats and the results were as follows :
A decided conclusion was not obtained as to the changes in weight of adrenal cortex, since the number of experimental animals was small, and the value presented was complicated with the animal difference. But the organ body weight ratio shows that the adrenal gland surely decreases in weight by the hypophysectomy, but cannot be recovered from the reduction by means of the maintenance test of ACTH (2.5 mg/day for 7, 10 days) or GH (2 mg/day for 7 days), and of the repair test of ACTH (the same dose for 5 days) or ACTH and GH in combination (the same dose for 5 days), begun from the 6th day after the removal. Therefore ACTH and GH would be uneffective to allow the animals to recover the loss of organ weight, so far as this admistration method is concerned.
However, it was informed in present research that the hormones are able to modify the histological changes induced by the hypophysectomy. The control hypophysectomized rats (7th day) provided the partially broadened zona glomerulosa in which the cells containing a lot of fat granules arrange fascicularly without a formation of glomerulum. The transitional zone became thicker, representing a layer of the package of nuclei. The cell-strands in zona fasciculata were irregular in general, slender, anastomosed one another and atrophic in some degree. Their cell-bodies were submitted to be rich in fat granules instead of proteinic stainable granules. The cortex cells at the vicinity of medulla surrounded by the multiplied connective tissue were usually flat in shape. The finding in the 10th day after the removal resembled in many respects that of the 7th day, but tended to be shown as the more pronounced changes. When the hypophysectomized rats were administered for 7-10 days with ACTH, the zonation of adrenal cortex was precisely altered, although the whole thickness of it was not recovered. The elongation of cell fascicules in zona fasciculata presses the zona glomerulosa on the capsule. The disappearance of the transitional zone resulted in the mutual transformation between atrophic zona glomerulosa and broad zona fasciculata, where the former no longer consisted of independent glomeruli. The superficial area of adrenal cortex was scanty of fat granules, whereas full of stainable granules (stained with iron-hematoxylin). Despite the atrophic pattern and irregularity of fasciculata cell-strands was not restituted by the administration of ACTH, it was fairly demonstrated that the gross fused fat droplets decreased in number within the cellbodies, in addition the stainable granules increased. This fact may show that the improvement in the internal cell stracture fellow the replacement therapy. Also the connective tissue near the medulla became thoroughly indistinct. As above mentioned, ACTH is expected to have the sweeping ability of some obstacles in intracellular hormone synthesis by the hypophysectomy, and at least the changes by ACTH was akin, beyond the recovery, to the pattern of elevation in function of cortical cells, as is seen in intact rats exposed by the stressful stimuli.
The repair test by ACTH showed the same improvement as by its maintenance test. Of course, the betterment may be restricted to zonation and cell internal structures in connection with the metabolic amelioration, but was not involved in the hyperplasia of cotical cells.
In the event of repeated injections of GH for 7 days (maintenance test) to the hypophysectomized rats, the symptom of the ablation is almost irrecoverable. The changes is not utterly reconcile with the findings of hypophysectomized untreated group,

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The author investigated the erythrocyte respiration in left ventricle blood of endocrine eviscerated rabbit and the effect of different hormone upon it. Oxygen consumption was measured by means of the direct Warburg's method, and coefficient of respiration was calculated.
The results were summarized as followings.
(1) In the experimental hyperthyroidism by the thyradin injection, QO₂ of erythrocyte is remarkably enhanced, but QCo₂ does not show any variation.
(2) On the other hand, in the experimental hypothyroidism by bilateral thyroidectomy, the erythrocyte respiration decreases after long times. (about thirty days).
(3) By the injection of cortisone acetate, QO₂ does not show any variation distinctly, but QCo₂ and RQ are suppressed.
(4) By the injection of desoxycorticosterone acetate, the erythrocyte respiration is remarkably suppressed.
(5) By the bilateral adrenalectomy, the erythrocyte respiration decreases remarkably.
(6) When a small quantity of testosterone propionate was injected on the male rabbits, the erythrocyte respiration is enhanced, but on the female this tendency is not distinct.
(7) By the extirpation of the testicles, the erythrocyte respiration decreases after long time. (about fifty days).
(8) When a small quantity of estradiol benzoate was injected, the erythrocyte respiration is suppressed. Especially, this tendency is remarkable on the males.
(9) By the extirpation of the ovaries, the erythrocyte respiration was not influenced after long time. (about fifty days).
(10) From the overmentioned results, I can presume that the erythrocyte respiration was influenced by endocrine functions excepting the effects of the blood regeneration showed by the variations of reticulocyte count.

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1) The author investigated about the measurement of serum insulin activity, on the basis of Gemmill's observation, that the isolated rat diaphgram uptakes glucose in the glucose containing solution and the glucose uptake is increased by the addition of insulin to the solution.
2) Wistar strain rats were bred about for 7 days with solid food (Oriental Co. made) under the condition of temperature 22±5°C, and were abstained from the food for 15 hours before experiment.
3) These rats were sacrificed by decapitation, and the diaphragms were immediately removed, each of them were dissected in 4 pieces. So-called “quartardiaphragm technique of pooled method” was used for this investigation.
4) Phosphate buffer solution containing 200mg/dl. sugar was used for medium. For the incubator, the author used the manometer flask of Warburg's apparatus. The flask contains one-fourth of diaphragm, medium and 95-100% O₂, incubated for 75 minutes at 38°C, 90 rounds shaking per minute.
5) Glucose uptake of diaphgram per 1 gram (dry weight) in the medium before and after incu-bation, the mean values of four quartardiaphgrams from four rats were used. This value means basal uptake.
The difference between glucose uptake in the medium containing test solution and basal uptake means extraglucose uptake. When used insulin solution of known concentration to medium, this difference called as “insulin effect”.
6) It became clear from the experiment, that the relation between insulin effect (Y) and insulin.concentration (X) could be expressed by means of next equation.
log Y=3/10 log X + log 40
7) Insulin value (insulin activity in sera) in normal subjects and diabetic patients, resulted as follows.
normal subjects 0.339±0.08 mu/ml.
diabetic patients 0.125±0.115mu/ml.
normal rabbits 0.355±0.125mu/ml.
alloxan diabetic rabbits 0.00 -082mu/ml.
normal dogs 0.158±0.032mu/ml.
pancreatectomized dogs 0.00-<0.01 mu/ml.
these values were the averages of 5-10 cases.
8) The remainings of injected insulin in blood of diabetic patients retarded than those by normal bodies, and moreover, these insulin in blood still retained its activity. Same results were obtained from the experimental diabetic animals.
9) Glucose uptake and insulin effect of the diaphragm from alloxanized rat decreased than those of controls.
10) From the result described in 7), 8), and 9) the author proved that insulin in blood decreased on diabetic patients, and diabetes mellitus is not caused by decreasing of activated insulin, but rather by decreasing of insulin utilizing ability.
11) Glucagon decreases glucose uptake and insulin activity in peripheral tissues, and so it acts as insulin inhibitor.

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