The angiotension I-converting enzyme in normal human urine was partially purified with ammonium surfate (3.2M), DEAE-Cellulose ion exchange chromatography (0-0.5M NaCl gradient), and Sephadex G 200 gel filtration. The enzyme was separated into three forms which had different molecular weights of 700000, 290000 and 40000, respectively. The enzymic biochemical characteristics of these three enzymes, however, were identical with regard to their inhibitory effects (bradykinin potentiator c, arg-pro-pro, o-phenanthroline and EDTA), Cl^- dependency, optimal pH (8.3) and temperature (37°C), and Km value (2.3mM).
The enzymic activity was determined in five normal subjects in three conditions of dietary sodium intake (51,153 and 340mEq for 5 days, respectively). The enzymic activity correlated well with the concentration of the excreted sodium (r= 0.87, p<0.001). There was no significant relation between the enzymic excretion and the concentration of the excreted potassium, nor between the activity and the creatinine excretion.
It is suggested that the origin of urinary angiotensin I-converting enzyme is the kidney, and that the enzyme might regulate sodium excretion in cooperation with renal kallikreinkinin system.

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To study the role of volume factors in the pathogenesis of hypertension, total blood volume (TBV) was determined in 43 patients with essential hypertension, 10 with primary aldosteronim, 5 with Cushing's syndrome, 5 with renovascular hypertension and 23 agematched normotensives.
The radioisotope (¹³¹I) labeled plasma tracer technique was employed under conditions of constant sodium intake (200mEq/day).
The TBV values obtained were expressed as % normal against the predicted values according to the formulae of Fujita and his co-workers.
The results were as follows :
(1) TBV was increased in patients with primary aldosteronism.
(2) In essential hypertensive patients, with either normal or low plasma renin activity, TBV was normal.
(3) There was no increment of TBV in patients with Cushing's syndrome.
These results suggest that expanded intravascular volume plays a major role in the mechanism of hypertension with suppressed plasma renin activity in primary aldosteronism, whereas other unknown factors may be related to the causes of hypertension in patients with essential hypertension and Cushing's syndrome.

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The prognostic significance of both the triiodothyronine (T₃) suppression test and the detectability of thyroid stimulating immunoglobulins in patients with Graves' disease who had been treated with antithyroid drugs was evaluated.
Eighty-three patients underwent a T₃ suppression test after having been euthyroid for at least 6 months. In 33 patients, the human thyroid stimulator (HTS) was assayed by measuring cyclic AMP increase in cultured thyroid adenoma cells, and TSH-binding inhibitor immunoglobulins (TBII) were measured by using the radioreceptor assay of TSH. Among 43 patients who had discontinued the drug treatment, 37 patients were under observation for 6-42 months.
When a fall in 30-minute thyroid ^99m TcO₄^-uptake of 50% or more after T₃ administration was defined as positive suppression, the relapse rate was 30% in non-suppressive cases and 26% in suppressive cases. The relapse rate was lower in cases whose pre-suppression uptake was less than 3.0% (3 out of 17 patients) or in cases whose uptake after T₃ administration was less than 0.8% (1 out of 9 patients).
Of 15 patients with negative suppression, 5 (33.3%) were positive in HTS and 4 (26.7%) were positive in TBII. On the other hand, two (11.1%) each of 18 patients with positive suppression were positive in HTS and TBII respectively. Neither HTS nor TBII had been detected at the cessation of therapy in any of the 12 patients who remained euthyroid during the follow-up period. On the other hand, four (44.4%) out of 9 patients who relapsed had been positive in either HTS or TBII. Thus the Graves' disease specific immunoglobulins were found to be significantly associated with the relapse of the disease (p<0.05).
The above data indicates that regardless of the suppressibility of ^99mTcO₄^-uptake after T₃ administration, the rate of recurrence is high when the uptake after T₃ is more than 0.9% and/or when either HTS or TBII are positive.

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We described a 12 7/12-year-old boy presenting the syndrome of insulin resistance and acanthosis nigricans Type A..
Insulin levels at fasting state and after glucose loading were 149 ± 63/μU/ml (mean ± SD) and over 1000W/ml, respectively, while fasting levels of blood glucose were 77.7 ± 8.9mg/dl (mean ± SD). A marked resistance to exogenous insulin was observed. Circulating levels of insulin antagonists such as growth hormone, cortisol and glucagon, were within the normal range. Proinsulin was less than 5% of the total radioimmunoassayable insulin. Insulin antibody and anti-receptor antibody were not detected. Insulin binding to mononuclear cells was decreased to about 50% of controls. Analysis of membrane receptors demonstrated the normal average affinity, dissociation kinetics and negative cooperativity with a decreased number of receptors. After two days fasting, plasma IRI levels decreased to 27/μU/ml, however insulin binding kinetics were not affected. This might suggesting that the receptor decrease was not secondary to hyperinsulinemia.
These findings indicate that a decreased number of receptors was one of the causes for insulin resistance in the patient.

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In the computer algorithms of the bedside-type artificial beta cell system developed originally in the First Department of Medicine, Osaka University Medical School, insulin is infused in a proportional plus derivative control action to blood glucose concentrations in order to simulate the insulin secretion of healthy subjects. With this system the perfect physiological normalization of circadian profiles of blood glucose in diabetics has been established. However, in order to apply this artificial beta cell thus developed to diabetics in various conditions, such as those who have low insulin sensitivity, those who have supernormal insulin sensitivity, or brittle diabetics whose insulin sensitivity may change unpredictably, it is necessary to manually change parameters, deciding insulin infusion rate for the adaptive control of blood glucose in accordance with the individual ability to regulate blood glucose recognized after the specific period of its application.
To cope with these situations, the author has developed a computer algorithm for the adaptive control of blood glucose, in which appropriate values of the parameters determining the rate of insulin infusion were established automatically on a moment-to-moment basis proportional to the changes in the ability of the subject to regulate blood glucose.
First, as the marker of insulin sensitivity seen in normal situations, the projected rate of change in blood glucose [ΔBGp (t)] against blood glucose was determined by analyzing the relationship between the rate of change in blood glucose concentrations and blood glucose concentrations during declines from the peak values after 50 or 100g oral glucose loads in healthy subjects.Second, under glycemic regulation with the artificial beta cell, the real rate of change in blood glucose concentrations in each diabetic subject [ΔBG (t)] was calculated, and the index of insulin sensitivity was then estimated from the difference between ABG (t) and ΔBGp (t). According to the calculated insulin sensitivity, the computer automatically reset the parameters which regulated the insulin infusion rate.
To fulfil the performance of software in the system, a filter system which could eliminate the noises generated from blood glucose sensors was included. The refractory period, in which the parameters should not be changed, was also provided in order to compensate the time-delay of the insulin action on blood glucose regulation.
Validation of these algorithms was performed in diabetic ketotic or ketoacidotic animals and patients.
Hyperglycemic depancreatized dogs were made to have protracted ketosis or keto-acidosis by constant iv infusion of sodium 3-hydroxybutyrate or 3-hydroxybutyric acid, respectively. Then blood glucose regulations were attempted with the aid of the artificial beta cell. In 5 ketotic or 5 ketoacidotic dogs, under the control of the artificial beta cell in which parameters regulating the rate of insulin infusion were fixed, the rate of fall in glycemia was smaller than that in 5 non-ketotic depancreatized dogs, showing that insulin resistance does exist in protracted ketosis or ketoacidosis.
With the algorithm of self-adaptive control, the parameters were automatically changed several times in response to calculated insulin sensitivity; therefore, an adaptive blood glucose regulation which was indistinguishable from that in non-ketotic dogs was established. It was revealed that, for the adaptive blood glucose control, plasma concentrations of insulin should be raised to more than 33/μU/ml or 64μU/ml in protracted ketosis or ketoacidosis, respectively.
Almost identical results were obtained clinically when the bedside-type artificial beta cell with the self-adaptive control algorithm was applied to 4 diabetic ketotic and 2 diabetic ketoacidotic patients.
In summary,

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Extensive studies have recently been conducted on the expression of hormone actions, especially on its mechanisms. Sutherland, et al. identified the function of C-AMP as an intracellular messenger of peptide hormones. Recent studies by several investigators including ours have concluded that the role of C-GMP and calcium are as important as that of C-AMP. In this report we present our findings on the role of Ca ions in the acceleration of steroid production in isolated porcine cells of the corpora lutea. (1) The incubation time needed to compare the production of progesterone and that of C-AMP is at least 120 mins. (2) Production rates of both C-AMP and progesterone in the presence of HCG were maximum at 10^-7g/ml HCG. Inclusion of Ca ions in the medium increases this production rate. (3) When Ca ions are included in the medium, the accelerated rate of progesterone production takes on its highest value at 1.2mM Ca. (4) Verapamil and cycloheximide inhibit the production of progesterone. (5) The binding capacity of ¹²⁵I-HCG combined with corpora lutea cells is independent of the Ca concentration in the medium. (6) Ca uptake into corpora lutea cells increases according to the concentration of HCG until it reaches a plateau at 10^-7g/ml HCG. This acceleration by HCG is affected by Ca and is remarkably inhibited by verapamil.
These results indicate the important role of Ca ions in the acceleration of progesterone production compared to that of C-AMP.

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Uterine estrogen receptors (ER) of the rat during pregnancy and postpartal lactation were assayed. Both the cytoplasmic and nuclear ER were determined by the controlled pore glass (CPG) method as previously described in detail.
The cytoplasmic ER level slightly decreased as pregnancy advanced and then increased remarkably during postpartal lactation, with a tendency to decrease at 5 weeks of lactation when the estrous cycle could have recurred despite the nursing behavior of the rats. On the other hand, no remarkable difference in nuclear ER was noted during pregnancy and lactation. A high concentration of plasma progesterone could have reduced the translocation of the cytoplasmic ER to the nucleus and the replenishment of the cytoplasmic ER, despite a high concentration of plasma estrogen during pregnancy.
In order to keep an environment of a high plasma concentration of estrogen similar to that of pregnancy, a long-acting estrogen (estradiol dipropionate) was injected in to the proestrous rats. The cytoplasmic ER rapidly translocated to the nucleus, followed by a prolonged maintenance of a low cytoplasmic and a high nuclear ER level until 7 days, with a gradual replenishment of the cytoplasmic ER and a gradual decline of the nuclear ER thereafter.
A translocation of the cytoplasmic ER to the nucleus, similarly seen in the hysterectonized-adult rats treated with estradiol, was noted in the rats injected with estradiol at 3 weeks of lactation. In general, low estrogen and high prolactin may be held in plasma during lactation.
These results indicate that the fluctuation of uterine ER simply depends on the plasma level of estrogen during pregnancy and postpartal lactation in rats.

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Although CB-154 has been reported to be effective in the treatment of patients with normo-prolactinemic amenorrhea as well as those with hyperprolactinemic amenorrhea, the precise mechanism concerning its ovulation-inducing effect remains to be established. Several investigators declared that the prolactin (PRL) -lowering effect of CB-154 is responsible for the induction of ovulation, and others reported its direct action to the ovaries. However, a direct central action of CB-154, independent of its PRL-suppressing effect, on the LHRHgonadotropin releasing system has not been ruled out. On the other hand, some evidences have indicated that exogenously administered estrogen fails to produce a positive feedback effect on LH release in patients with hyperprolactinemic amenorrhea and early puerperal women. Therefore, the purpose of the present study was to evaluate the effect of CB-154 on the positive feedback mechanism of estrogen in amenorrheic patients with or without hyperprolactinemia and women in early puerperium. In addition, we investigated the influence of a high circulating PRL level on estrogen feedback action and gonadal function in the experimental model of artificial hyperprolactinemia induced by metoclopramide (MCP), a dopamine receptor antagonist, in normal cycling women. Serum PRL, LH, FSH, 17β-estradiol (E₂), progesterone (P) and dehydroepiandrosterone-sulfate (DHAS) were measured by radioimmunoassy.
1) Normal cycling women (n = 6) and three groups of amenorrheic patients who were diagnosed as having Chiari-Frommel syndrome (n = 7), idiopathic hyperprolactinemic amenorrhea without clinically demonstrable pituitary tumor (n = 7) and normoprolactinemic secondary amenorrhea without polycystic ovary syndrome (n = 8), respectively, were selected. Twenty mg of conjugated estrogens (Premarin) was injected intravenously to these subjects 7-9 days (D 7-9) from the onset of menstruation or withdrawal bleeding. Blood samples were taken at 0, 24, 48 and 72 hours after Premarin injection. Changes in serum LH levels following the Premarin injection were expressed as percent net changes from the basal level.
After the Premarin injection, the initial suppression of LH (negative feedback) was observed 24 hr later, followed by a rebound increase of LH (positive feedback) reaching about +200% above pre-injection values 48-72 hr later in normal women, though no rebound increase after the Premarin injection was recognized in three groups of amenorrheic patients. This impaired estrogen-induced LH release was not significantly different among the three groups of patients. The daily administration of 2.5mg of CB-154 brought about the restoration of the positive feedback effect of estrogen, accompanied by a significant decrease of PRL levels and occurrence of ovulation and/or menstruation in all groups of patients. No significant correlation between the decrement of PRL and the improvement of the positive feedback response was observed in any of the amenorrheic patients during the CB-154 treatment.
2) None of the 4 lactating women who wished to cease lactation showed a LHreleasing response following a Premarin injection at about one month post partum, however, the response was restored and menstruation occurred with a significant fall of serum PRL levels and cessation of lactation after the daily administration of 5mg of CB-154 for about one month, though the other 4 lactating women without CB-154 treatment continued to lack the response at the same period of puerperium.
3) The daily administration of 30mg of MCP for 1-3 months resulted in sustained hyperprolactinemia throughout the experiment in 6 normal cycling women. Serum PRL levels rose about 10-fold greater than pretreatment values, but the results of a Premarin provocation test on D 7-9 were unchanged before and during MCP treatment. Moreover,

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