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An atrophic right kidney located in the pelvic cavity associated with an ectopic ureter was completely removed from a 4-year-old girl by laparoscopic surgery. There were no serious complications during the operation or the postoperative period. The light shining from the tip of a fine fiberscope inserted into the ureter was used to delineate this structure during laparoscopic surgery.

From August 1989 through September 1991 we performed percutaneous nephrostomy under ultrasonic guidance in 26 kidneys of 25 patients. We also indwelled double pigtail ureteral stents by endoscopy in 14 kidneys of 13 patients. No patients died because of renal failure. The survival was dependent on progression of primary disease and performance status. Neither significant nor life-threatening complications were encountered. The difference in the improvement of renal function between nephrostomy group and stent group was not statistically significant. Although the indwelling ureteral stent method requires no external drainage bag, this method has certain drawback such as occasional obstruction of stent. Especially in poor risk patients, percutaneous nephrostomy technique seems to be better than placement of double pigtail ureteral stent in the treatment of postrenal failure secondary to malignancies.

Primary tumor in the ureteral stump is rare. A 66-year-old woman visited our hospital because of microscopic hematuria. She had undergone right nephrectomy for the contracted kidney 36 years ago. Intravenous pyelography and cystoscopy showed no positive findings for hematuria. But urine cytology indicated class V. The flexible ureterorenoscopy disclosed a nonpapillary sessile tumor in the ureteral stump. We also did the biopsy of the tumor under the direct vision before open surgery. The specimen showed transitional cell carcinoma, grade 3. The ureteral stump was successfully removed. The flexible ureterorenoscopy was most useful for the diagnosis in this case.

To elucidate the relationship between cyclosporine (Cs) nephrotoxicity and renal blood flow (RBF), we carried our experiments using rats. Adult male Wistar strain rats each weighing about 100 g were used. Rats were divided into 2 groups; the Cs group (Cs 50 mg/kg/day was intraperitoneally given for 10 consecutive days) and the control group (normal saline solution for 10 consecutive days). The renal cortical blood flow was measured in each group by electrolytic hydrogen gas clearance method. We also carried out renal angiography with barium sulfate (BaSO4). Then we measured blood vessel area/renal sagittal section area ratio and the diameter of interlobar arteries. The Cs group showed a significant decrease of renal cortical blood flow compared with the control group. On the other hand there was no significant change in renal angiogram. In conclusion, Cs decreased renal cortical blood flow. We suppose that vascular resistance increased following afferent arteriolopathy caused by Cs administration.

Urinary incontinence among institutionalized elderly were analyzed from clinical and social viewpoints. The patient group included 25 males and 107 females with an average age of 78 years (ranged from 66 to 92). They had neither highly impaired performance status nor severe dementia. Forty-nine of them (37%) underwent urological examination. Urge incontinence was common among male patients, while urge, stress or mixed incontinence were prevalent in female patients. Thirty-six per cent of the patients had to use pads, diapers and others for their incontinence, while other needed no special protection for their incontinence. Incontinence caused limitation of social activity in 30% of the patients. Many causal factors were assumed for incontinence in elderly; weakness of the pelvic muscles, urinary tract infection, cerebrovascular disorders, neurological disorders and prior pelvic surgery. Prostatic carcinoma or urethral stricture caused overflow incontinence in a few patients. Diuretics or tranquilizers appeared to lead incontinence in some patients. Nine of 18 patients undergoing cystometry had overactive detrusor. Majority of the incontinent elderly showed no intention to visit clinics. Therefore, it recommended to keep staffs in elderly institutions as well as elderly themselves informed that incontinence in the elderly should be treated, which in turn improves the quality of life.

To elucidate the relationship between Cyclosporine (Cs) induced nephrotoxicity and juxtaglomerular (JG) apparatus, we carried out biochemical and morphological experiments using mice. Adult male ICR strain mice weighing about 40 g were used. The mice were divided into 2 groups: the Cs group (Cs 50 mg/kg/day was orally given for 14 consecutive days) and the control group (olive oil for 14 days). Urine was stored for 24 hours on the day 0, 7 and 14 and urine volume and concentrations of urinary creatinine (u-Cr) and urinary potassium (u-K) were measured in each group. All the mice were sacrificed and examined on the 15th day. Concentrations of serum creatinine (s-Cr), serum potassium (s-K), plasma renin activity (PRA), plasma aldosterone (Ald) were noted in each group. The kidneys were also examined histologically with light and electron microscopes. The Cs group showed significant increases of s-K, PRA and Ald and a significant decrease of creatinine clearance compared with the control group. Histologically, the Cs group demonstrated focal vacuolar changes in the proximal tubular cells and an increase in the number of granules in the JG cells. Each granule of the Cs group was larger than that of the control group. Cs certainly stimulates the renin-angiotensin-aldosterone system and causes consequently a secondary aldosteronism.

Prevalence of micturition problems among 1,023 institutionalized elderly was surveyed by a questionnaire. The reply was obtained from 821 elderly (80.3%) including 276 males and 545 females with ages averaged 77 years (range 61 to 96 years). They had neither highly impaired performance status nor severe dementia. Micturition problems were complained by 38% of male responders, where micturition difficulty was the most common. On the other hand, 23% of female responders answered having micturition problems and urinary frequency was the most common. One hundred and twenty-four of total responders (15%) replied to have urinary incontinence; 8% in men and 19% in women. Over half of patients with marked objective incontinence denied its presence or refused to answer. Seventy-one per cent of the incontinent elderly had no intention to receive medical care. From the above facts, it seems that many elderly have micturition problems and the incidence of urinary incontinence is latently higher than complained at survey.

The binding of CRH-binding protein (CRH-BP) in plasma to labeled human CRH has been examined in patients with hypothalamic-pituitary-adrenal disorders. Compared with that in normal subjects, CRH-BP binding decreased in patients with Cushing's syndrome of pituitary or adrenal origin and in patients who were treated with a high dose of glucocorticoids over a long period of time. On the other hand, CRH-BP binding increased in patients with Addison's disease or hypopituitarism. In patients with Addison's disease, the high level of CRH-BP binding fell to the control level after glucocorticoid replacement. In patients with Cushing's syndrome, CRH-BP binding gradually increased and reached the higher level about 1 yr after surgery. Thereafter, it returned to the control level. There was a good negative correlation between the levels of plasma cortisol and CRH-BP binding in patients with Cushing's syndrome before and after surgery. A Scatchard analysis of CRH-BP binding in patients with Cushing's syndrome and in normal subjects showed that the binding affinity was similar in both groups, but that the number of binding sites was low in patients with Cushing's syndrome. These results suggest that in human plasma, glucocorticoids decrease CRH-BP binding. This seems to be caused by a decrease in the concentration of CRH-BP in the plasma of patients with hypercortisolemia.

Bladder and urethral functions were evaluated urodynamically in 114 patients with lumbar disorders including prolapsed lumbar intervertebral disc (66 patients), lumbar canal stenosis (19 patients), lumbar spondylolysis and/or spondylolisthesis (21 patients), lumbar spondylosis deformans (5 patients) and ossification of the yellow ligament of the lumbar spine (3 patients). The patients consisted of 88 males and 26 females with an average age of 47 years (range 17 to 73 years). Symptomatic organic infravesical obstruction was excluded by physical and radiographic examination. Cystometry revealed preoperative neurogenic bladder in 23 patients (20%); normal detrusor with overactive sphincter in 2 (9%), underactive in 8 (36%), overactive in 5 (23%) and equivocal in 7 (32%). One patient not receiving cystometry revealed abnormal uroflowmetry with 140 ml residual urine. Twenty of them underwent electromyographic examination of the external sphincter and 15 (75%) had an overactive sphincter. Nine (39%) of them complained no urological symptoms. Neurogenic bladder seemed to highly associate in those having abnormal tendon reflex in the lower extremities, decreased bulbocavernosus reflex and sensory disturbance in the perineal area, but there was no statistical significance. Of twenty-three neurogenic bladder patients, eighteen underwent a lumbar vertebral operation and fifteen received postoperative urodynamic evaluation. Uroflowmetry was improved in more than half of the patients within 3 months after the operation and cystometry was normalized in 4 of 7 patients who underwent cystometry over 6 months after the operation. Preoperative overactive detrusor remained unchanged in two of three patients who underwent cystometry over 6 months after the operation.

To examine the effect of interleukin-1 (IL-1) on CRF and POMC gene expression, recombinant human IL-1 alpha and -beta were ip injected in rats. The plasma ACTH level showed a dose-related increase at 2 h after the injection of 0.5 and 2 micrograms IL-1 alpha and -beta, and also showed a sustained increase from 1 h until 5 h after the injection of 2 micrograms of IL-1 beta. CRF contents in the medial basal hypothalamus and ACTH contents in the anterior pituitary (AP) decreased at 2 h after the injection of 2 micrograms of IL-1 alpha and -beta, and such decreased levels were maintained until 5 h after the injection of 2 micrograms of IL-1 beta. The levels of CRF mRNA in the hypothalamus and POMC mRNA in AP significantly increased 3 h after the injection of 2 micrograms IL-1 alpha and -beta, and these levels were still higher at 5 h after the injection of 2 micrograms of IL-1 beta compared with those of the control. There was no significant change in the ACTH content and POMC mRNA levels in the intermediate-posterior pituitary or the hypothalamus or in the CRF contents and CRF mRNA levels in the cerebral cortex. These results indicate that acute administration of IL-1 alpha and -beta stimulates gene expression of hypothalamic CRF and CRF release, which causes the stimulation of ACTH release and POMC gene expression in AP.

During the 7 years from 1980 to 1986, 2860 cases of bladder tumors were registered in the Tokai Urological Cancer Registry. Among the 2860 cases, 2304 cases were selected from the registered cases for the present study. The 5-year relative (actual) survival rates were 73.8% (61.9%) of all patients; 48.9% (42.4%) in those with malignant neoplasma of urinary bladder excluding transitional cell carcinoma; 48.8% (41/3%) in those with mixed tumor. In patients with transitional cell carcinoma, the 5-year relative (actual survival rates were 93.7% (78.8%) for G1, 87.2% (74.1%) for G2 and 47.3% (38.9%) for G3. As to staging, the 5-year survival rates were 101.9% (88.0%), 87.6% (75.3%), 57.9% (47.8%), 33.7% (28.2%) and 6.1% (5.0%) in patients with stage of Ta, T1, T2, T3 and T4, respectively. The tumors with muscle infiltration and high grade malignancy obviously deteriorated patients' survival. The 5-year relative (actual) survival rate for patients treated with TUR was 98.1% (82.2%). As to grading, the 5-year survival rates were 102.2% (86.6%) for G1, 104.3% (88.3%) for G2 and 56.9% (48.3%) for G3. The 5-year survival rates of those with Ta, T1 and T2 were 103.9% (89.7%), 96.0% (82.6) and 61.1% (49.1%), respectively. The 5-year relative (actual) survival rate for patients undergoing total cystectomy was 62.4% (52.3%). In those patients, the 5-year survival rates were 96.7% (80.9%) for G1, 63.6% (55.7%) for G2 and 55.4% (47.1%) for G3. As to staging, the 5-year survival rates were 102.3% (90.6%), 77.8% (68.2%), 56.3% (47.9%), 41.8% (34.9%) and 15.2% (13.1%) in patients with stage of Ta, T1, T2, T3 and T4, respectively. The 3 and 5-year relative (actual) survival rates in patients with advanced bladder tumors were 5.3% (4.8%) and 0.87% (0.73%), respectively.

To examine the effects of the cAMP-independent protein kinase-C system and interleukin-1 (IL-1) on secretion of ACTH and POMC gene expression in cultured rat anterior pituitary (AP) cells, AP cells were incubated with CRF, 8-bromo-cAMP, arginine vasopressin, angiotensin II, norepinephrine, and phorbol 12-myristate 13-acetate. After 15 h of incubation, CRF and 8-bromo-cAMP increased both ACTH release and the POMC mRNA level. Arginine vasopressin, angiotensin II, norepinephrine, or phorbol 12-myristate 13-acetate stimulated ACTH release but failed to increase basal or CRF-stimulated POMC mRNA levels. Human recombinant IL-1 alpha and -beta increased neither ACTH release nor POMC mRNA levels after 3 h of incubation. After 15 h of incubation, 100 pM to 10 nM IL-1 alpha and -beta increased ACTH release. However, POMC mRNA levels were significantly elevated only by 10 pM IL-1 beta. These results suggest that the CRF-cAMP system plays a major role in both ACTH release and expression of the POMC gene in AP cells, but the cAMP-independent protein kinase-C system contributes only to ACTH release; that acute stimulation of ACTH release from AP with IL-1 administration is not due to direct action of IL-1 at the pituitary level; that chronic exposure of AP cells to IL-1 alpha or -beta can stimulate ACTH release; and that the direct effects of IL-1 alpha and -beta on POMC gene expression, if any, seem to be minimal.

The fundamental examination on the measurement of proopiomelanocortin (POMC) mRNA levels in cultured rat anterior pituitary (AP) cells was studied. In addition, the detailed study on time- and dose-related effects of corticotropin-releasing factor (CRF) and dexamethasone on the level of POMC mRNA in AP cells in vitro was examined. Basal levels of POMC mRNA in AP cells cultured with serum initially declined after 1-day culture, gradually increased and reached a peak after 3-day culture, and then slightly decreased after 4- and 5-day culture. These mRNA levels after 3-day culture did not change through subsequent 15-hr incubation without serum. CRF treatment caused a time- and dose-dependent increase in POMC mRNA levels. The minimum effective dose of CRF was 0.1 nM for 15-hr incubation. The significant increase in POMC mRNA levels was observed after 3 hrs of 1 nM CRF treatment with a 2-fold elevation seen after 15 hrs of exposure. Dexamethasone treatment caused a dose-dependent decrease in POMC mRNA levels in AP cells. The minimum effective dose was 0.1 microgram/ml and such mRNA levels did not decrease until 15 hrs of exposure.

Spina bifida accompanied with neurogenic bladder in a woman who lived to be 81 years old was reported. Owing to spina bifida (paralyzed below L4), she suffered from urinary incontinence and gait disturbance. Since childhood, she had voided by Credé's maneuver and used a diaper for urinary incontinence. At the age of 56 years old, cystostomy operation was performed for incontinence. After that, she was free from incontinence. The main reason for her longevity was supposed to be the fact that she could accept good medical care and warm family support. Finally she died of lower abdominal carcinoma.

To study the effect of acute stress on ACTH secretion and synthesis in rat pituitary and hypothalamus, ACTH content and POMC mRNA levels (measured by use of Northern blot analysis) in these tissues as well as the levels of ACTH in plasma and those of CRF in the hypothalamus were determined after insulin-induced hypoglycemia. Plasma ACTH levels increased at 30 and 60 min. ACTH levels in the anterior pituitary lobe (AP) decreased at 30 min, and then returned to control levels at 60 min. No change was seen in the intermediate-posterior pituitary (IP) or the hypothalamus after insulin injection. CRF levels decreased at 30 and 60 min, then returned to control levels at 90 min in the medial basal hypothalamus, including the median eminence. Hybridization with a cDNA probe revealed a single size class of POMC mRNA in AP, IP, and hypothalamus, and the size of POMC mRNA in these tissues did not change during the experimental period. POMC mRNA levels in AP increased at 60 min and reached a peak at 120 min, but those in IP and hypothalamus did not change. These results suggest that 1) insulin-induced hypoglycemia stimulates both secretion and synthesis of ACTH (at least by increasing POMC mRNA levels) in the AP, and 2) the levels of ACTH and POMC mRNA in the IP and hypothalamus are not affected by insulin-induced hypoglycemia.

Human corticotropin-releasing factor-binding protein (hCRF-BP), a 38,000 dalton protein, specifically binds hCRF in plasma. CRF-BP-CRF complex adsorbed to concanavalin-A-Sepharose and its Mr decreased after treatment with endoglycosidase H or glycopeptidase A. The binding of CRF-BP to CRF decreased after treatment with endoglycosidase H. These results indicate that the CRF-BP is a glycoprotein that contains asparagine N-linked-type oligosaccharides, and such oligosaccharide chains are important for CRF-BP binding.

Effects of acetylcholine (Ach) and gamma-aminobutyric acid (GABA) on immunoreactive corticotropin-releasing factor (CRF) release from the rat hypothalamus were examined using a rat hypothalamic perifusion system and a rat CRF RIA in vitro. Ach stimulated CRF release in a dose-dependent manner (1 pM-1 nM). One nM Ach-induced CRF release was inhibited by atropine in a dose-dependent manner (1-100 nM), but was inhibited by only a high concentration (100 nM) of hexamethonium. In addition, such Ach-induced CRF release was inhibited by norepinephrine. GABA did not influence basal CRF release. These results suggest that Ach stimulates CRF release mainly through muscarinic receptors at least under our conditions.

Plasma immunoreactive corticotropin-releasing factor (I-CRF) levels were determined by using a human CRF radioimmunoassay and an immunoaffinity procedure. The basal plasma I-CRF level in normal subjects was 6 +/- 0.5 pg/ml (mean +/- SD). We found that most plasma I-CRF levels were affected by stress, negative feedback, and circadian rhythm. Basal I-CRF levels were high in patients with Addison's disease, Nelson's syndrome, hypopituitarism stemming from pituitary macroadenoma, and CRF- and adrenocorticotropic hormone-producing tumors. A very low, but significant, amount of I-CRF was detected (1-3 pg/ml) in patients with Cushing's syndrome, in corticosteroid-treated patients, and in a patient with hypothalamic hypopituitarism. These results suggest that a major component of plasma I-CRF is of hypothalamic origin, however, other extrahypothalamic tissues cannot be ruled out as a minor source of plasma I-CRF.

Effects of catecholamines on immunoreactive corticotropin-releasing factor (I-CRF) release from the rat hypothalamus were examined using a rat hypothalamic perifusion system and a rat CRF RIA in vitro. Norepinephrine had a potent inhibitory effect on I-CRF release in a dose-dependent manner at 0.1 nM-1 microM concentrations, but dopamine did not. This inhibitory effect of norepinephrine was completely blocked by propranolol, but only partially blocked by phentolamine. Isoproterenol also had a potent inhibitory effect at 0.01-100 nM concentrations, and a high dose of phenylephrine (10 nM) inhibited I-CRF release. Clonidine did not influence I-CRF release. These results suggest that norepinephrine inhibits I-CRF release mainly through the beta-adrenergic receptor and partially through the alpha 1-receptor.

The effects of corticotropin-releasing hormone (CRH) and dexamethasone on proopiomelanocortin (POMC) mRNA levels in cultured pituitary adenoma cells were studied in 10 patients with Cushing's disease. As a control, POMC mRNA levels in cells from nonadenomatous tissues were examined in four patients. Human POMC mRNA in the cells was analyzed by Northern blot hybridization. Human POMC DNA probe hybridized with only a single size class of RNA (approximately 1,200 nucleotides) from the adenoma and nonadenoma cells of each patient. The size of POMC mRNA did not change through the culture or after incubation with CRH or dexamethasone. CRH increased POMC mRNA levels in these cells in a dose- and time-dependent manner. The minimum concentration of CRH required to elevate POMC mRNA levels in these cells exposed for 15 h was 0.1 nM. The minimum duration of 1 nM CRH treatment required to increase these levels was 3 h under our conditions. Inhibitory effects of 1 and 10 micrograms/dl dexamethasone on ACTH release and POMC mRNA levels in nonadenoma cells were greater than those in adenoma cells. These results suggest the following: (a) that the mRNA in cultured pituitary adenoma cells is qualitatively the same as that in vivo; (b) that responses of mRNA levels to CRH are time- and dose-dependent; and (c) that adenoma cells resist the inhibitory effect of dexamethasone on POMC mRNA levels and ACTH release.

Recently, a new antibiotic of cephamycins, cefmetazole (CMZ) has been developed. In our clinic, CMZ was used to examine its clinical effect and adverse reactions, and the results were herein reported. The CMZ was administered to 8 patients for the prevention of postoperative infections, 7 with genitourinary infections and 1 with maxillitis complicated with uremia. For these patients, a daily dose of 1 to 6 g of CMZ was intravenously given for a period of 4 to 12 days. Among the 8 patients who received CMZ for the prevention of postoperative infections, there were 1 case with urinary tract infection, 1 with wound infection and 2 with fever of over 38 degrees C, but they had no serious infections. In the clinical observations on 3 cases with pyelonephritis, the CMZ showed marked effectiveness in 2 cases and effectiveness in 1 case. It must be noted that CMZ was proved to be markedly effective for pyelonephritis caused by Serratia marcescens. In the cases with acute epididymitis and prostatitis, a good effect of CMZ was obtained. Similarly in the case with maxillitis complicated with uremia, the maxillitis was improved by the effect of CMZ and hemodialysis. No cases with hepatic or renal dysfunction were observed after using CMZ. It is concluded that satisfactory effect of CMZ was obtained clinically.

Allylestrenol at the daily dose of 50 mg was administered to 45 patients with benign prostatic hypertrophy. The treatment was performed for more than 12 weeks in 40 patients, and improvements, marked and moderate, were observed in 22 patients (55%) in the overall judgement. As side effects of this drug, decrease of potency was observed in 3 cases, decrease of libido in 1 case, pigmentation on breasts in 2 cases, palpitation in 2 cases, short breath in 1 case, and gastrointestinal symptoms in 1 case. However, these side effects were not serious. Our trial suggests that the treatment of benign prostatic hypertrophy with allylestrenol can be useful in urological clinics.

Effects of ACTH and ACTH fragments on immunoreactive corticotropin-releasing factor (I-CRF) release were examined by utilizing rat hypothalamic perifusion system and a rat CRF RIA. ACTH-(1-39) had a dose-related inhibitory effect on I-CRF release. Mean percent inhibition of I-CRF release was 52, 55, 49, 30 and less than 5 percent by ACTH-(1-39), ACTH-(1-24), alpha-MSH and ACTH-(18-39) at 2.2 nM concentrations, respectively. These results suggest the presence of a negative short-loop feedback mechanism, and also that the active core is contained within the ACTH-(1-17) structure.

Two types of operative fiberoptic nephroureteroscopes were developed with the cooperation of the Olympus Optical Company mainly to remove the upper urinary tract calculi. Removal of the renal and upper ureteral stones was attempted in nine cases. The ureter was dilated with olive tip, balloon and Teflon dilators alone or in combination. The combination of balloon and Teflon dilators seemed the most promising. As a result of ureteral dilation, operative fiberoptic nephroureteroscopes, 4.5 mm and 3.5 mm in diameter, could be passed into the ureter in all the cases and the stones could be visualized clearly. Four of the 7 upper ureteral stones and 1 of the 2 pelvic stones could be removed. The success ratio was 56%. The method of stone removal still requires improvement. At present, application of the operative fiberoptic nephroureteroscope is indicated for upper ureteral and renal stones less than 1.0 cm in diameter. With the improved techniques of stone removal using this fiberscope, the indications of extracorporeal shock-wave lithotripsy or percutaneous nephrolithotripsy will probably be greatly reduced in the near future.

We investigated the effects of serotonin, cyproheptadine and reserpine on corticotropin-releasing factor (CRF) release from the rat hypothalamus, and the effect of cyproheptadine on CRF-induced adrenocorticotropic hormone (ACTH) secretion from the anterior pituitary (AP) in vitro using a perifusion system for rat hypothalami and AP, and a rat CRF radioimmunoassay. Cyproheptadine, 10(-8) M, had a direct inhibitory effect on both basal and 10(-9) M CRF-induced ACTH secretion from the rat AP in vitro. In addition, 10(-9)-10(-7) M cyproheptadine inhibited basal CRF release in a dose-dependent fashion, and also suppressed serotonin- and KCl-induced CRF release. Conversely, 10(-9)-10(-7) M reserpine failed to influence CRF release from the rat hypothalamus. These results indicate that a serotonergic mechanism may be involved in the CRF-releasing mechanism, and inhibition of depolarization-dependent calcium entry into cells and/or nerve endings. In addition an anti-serotonergic mechanism is involved in the inhibitory action of cyproheptadine.

A human plasma CRH-binding protein (CRH-BP) was identified and characterized by chemical cross-linking of 125I-Tyr-hCRH to human plasma using disuccinimidyl suberate. The apparent mol wt of the cross-linked complex determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography was approximately 43,000. The mol wt was slightly lower in the nonreduced state, suggesting the presence of intramolecular disulfide bonds. Subtracting the mol wt of 125I-Tyr-CRH, the BP appeared to have a mol wt of approximately 38,000. Binding was specific since the appearance of the 43,000 dalton band was not affected by unlabeled ACTH, vasopressin, serum albumin, or gamma-globulin, but was inhibited by unlabeled hCRH dose dependently. Pretreatment of plasma with 0.1 mol/L HCl, 0.01 mol/L NaOH, 10 mmol/L dithiothreitol, or trypsin before cross-linking abolished its ability to bind 125I-Tyr-hCRH. Rat, rabbit, or goat plasma or human cerebrospinal fluid did not bind 125I-Tyr-CRH. It is unlikely that CRH-BP is a CRH receptor, because the estimated mol wt of the CRH-BP is smaller than the reported size of CRH receptors, and the CRH-BP did not bind to ovine CRH. The binding of 125I-Tyr-CRH to CRH-BP decreased in the third trimester of pregnancy, when plasma CRH levels were markedly elevated. However, after dissociating endogenous CRH from the CRH-BP, the binding was almost the same as in nonpregnant subjects. In addition, CRH-BP inhibited CRH-induced ACTH secretion from cultured rat anterior pituitary cells. We conclude that most of the increased plasma CRH found in pregnant women is bound to CRH-BP, and so is inactive, therefore plasma ACTH levels do not increase to above the normal range.

Corticotropin-releasing hormone (CRH) levels in the human plasma and cerebrospinal fluid (CSF), and those in the rat hypothalamus, peripheral and hypophyseal portal plasma were studied by a specific h/r CRH RIA and an immunoaffinity procedure. CRH levels in the plasma and CSF were low in patients with hypercortisolemia and those with hypothalamic hypopituitarism, but high in patients with hypocortisolemia except for patients with hypothalamic hypopituitarism. Plasma CRH responded to insulin-induced hypoglycemia (ITT) those with Addison's disease and those with primary hypopituitarism, but not in patients with Cushing's syndrome or in patients with hypothalamic hypopituitarism. The results suggest that the major component of plasma CRH may be of hypothalamic origin, but other extrahypothalamic tissues cannot be ruled out as minor sources of plasma CRH. In addition, the measurement of CRH levels in the plasma and CSF seems to be of value in evaluating the hypothalamic function. The short negative feedback mechanism regulating CRH release was demonstrated in humans and rats. In the absence of the long negative feedback control of ACTH secretion by glucocorticoids, ACTH originating from the pituitary may regulate ACTH secretion form the pituitary through inhibition of CRH release.

To study the effect of acute stress on CRF release and synthesis in rat hypothalamus, ACTH levels in plasma, CRF contents in the median eminence (ME), and CRF mRNA levels in the hypothalamus without ME and cerebral cortex were determined after insulin-induced hypoglycemia. Plasma ACTH levels increased at 30 and 60 min, while ME CRF content decreased at 30 and 60 min, then returned to the control level at 90 min. Hybridization with a cRNA probe revealed a single size class of CRF mRNA in the hypothalamus and cerebral cortex (approximately 1300 nucleotides), and the size of CRF mRNA in these tissues did not change during the experimental period. CRF mRNA levels in the hypothalamus increased to 130% of the control value at 30 min and reached a peak (186% of the control value) at 120 min, but these levels in the cerebral cortex did not change. These results suggest that insulin-induced hypoglycemia stimulates CRF synthesis by increasing CRF mRNA levels in the hypothalamus as well as CRF release, and that release and synthesis of CRF in the cerebral cortex are independent of those in the hypothalamus.

Plasma CRH levels are considerably higher in women during the third trimester of pregnancy than in non-pregnant women. Most of plasma CRH in pregnant women is bound to CRH-binding protein (CRH-BP). To gain further insight into CRH physiology during pregnancy, we measured the responses of plasma ACTH and cortisol and the changes in bound and free forms of CRH in plasma after human CRH administration (2 micrograms/kg) in five pregnant (39-40 weeks of pregnancy) and five nonpregnant women. The mean basal plasma ACTH and cortisol levels in the pregnant women were higher than those in the nonpregnant women. However, the maximum increments in plasma ACTH and cortisol levels and the integrated ACTH and cortisol responses, after subtraction of the basal levels after CRH administration, were similar in the two groups. The plasma CRH half-time in the pregnant group was similar to that in the nonpregnant group. The mean basal plasma CRH level in the nonpregnant women was 1.5 +/- 0.2 (+/- SE) pmol/L, and that in the pregnant women was 360 +/- 35 pmol/L. On gel filtration chromatography, almost all of the CRH in the plasma was protein bound (320 +/- 30 pmol/L) in the pregnant women; no CRH peaks were detected in nonpregnant women because of the low plasma CRH levels. After CRH administration, the level of the bound form of plasma CRH was highest at 5 min, and then declined to a plateau at 15 min and 30 min in the pregnant women. In the nonpregnant women, protein-bound CRH also was highest at 5 min, but it progressively declined thereafter. The disappearance rate of the bound CRH in plasma from the nonpregnant women was similar to that of the second compartment of the plasma decay curves of the free CRH from both groups. We conclude that the plasma ACTH and cortisol responses to exogenous CRH are similar in pregnant and nonpregnant women, the effect of CRH-BP on the disappearance of plasma CRH is minimal, and plasma CRH-BP in pregnant women has the capacity to bind additional CRH.

To study possible adrenergic modulation of pituitary-adrenal responses to insulin-induced hypoglycemia and CRH we examined the effect of nonselective alpha-blockade (phentolamine) and nonselective beta-blockade (propranolol) on plasma ACTH, cortisol, and vasopressin (AVP) responses to hypoglycemia and CRH in five normal men. Infusion of propranolol or phentolamine did not alter basal plasma ACTH or cortisol levels. The propranolol infusion enhanced the stimulatory effect of hypoglycemia on ACTH, cortisol, and AVP secretion and also enhanced the stimulatory effect of CRH on ACTH and cortisol secretion. Infusion of phentolamine inhibited hypoglycemia-induced ACTH and AVP secretion, but had no effect on the stimulatory effect of CRH on ACTH and cortisol secretion. The increments of plasma ACTH and cortisol induced by an almost maximal dose of CRH (1 microgram/kg) were smaller than those induced by hypoglycemia. The propranolol-induced enhancement of the ACTH response to hypoglycemia was almost the same as the ACTH response to CRH alone. From these results we conclude that propranolol may act at the pituitary level to enhance CRH action, rather than AVP action, and that the ACTH response to hypoglycemia may be mediated by hypothalamic alpha-adrenergic activation.

In 46 patients treated with PNL in our hospital, the intervals from PNL to removal of a catheter indwelled in the nephrostomy were studied. The intervals were longer in the cases with ureteral stones than those with renal stones probably because of the different degrees of obstruction. To investigate the degree and the interval of upper urinary tract obstruction after PNL, Pressure-flow Studies were performed every or every other day after PNL in 5 cases with renal stones and 5 cases with ureteral stones, selected from 46 cases. In Pressure-flow Studies, intrapelvic pressures were measured while saline mixed with pigment was being dripping at a rate of 5 ml/min into the renal pelvis through the nephrostomy catheter. Saline initially reached into the urinary bladder at an average of 4.8 days after PNL (range 3 to 7 days) with a mean intrapelvic pressure of 37.6 cmH2O (range 28 to 52 cmH2O) in the cases with renal stones and at an average of 9.2 days (range 7 to 12 days) with a mean intrapelvic pressure of 27.0 cmH2O (range 9 to 43 cmH2O) in the cases with ureteral stones. Pressure-flow Studies were performed again a few days after the initial passage of saline into the urinary bladder in 2 of 10 cases. The intrapelvic pressures, 16 cmH2O and 13 cmH2O, respectively, several days after the initial passage of saline were lower than those, 35 cmH2O and 43 cmH2O, respectively, at the initial passage of saline. Therefore, it was likely that the proper interval of indwelling catheter after PNL was about 7 to 8 days, in the cases with renal stones and about 11 to 12 days in the cases with ureteral stones.

Flomoxef (6315-S, FMOX), a new oxacephem antibiotic was studied clinically in 27 patients with complicated urinary tract infections. FMOX was intravenously administered at a dose of 1.0 g twice daily for 5 days. Clinical effect of FMOX on patients with complicated urinary tract infections were excellent in 11.5%, moderate in 57.7% and overall clinical efficacy rate was 69.2%. During the treatment with FMOX, urticaria was observed in 1 case. In laboratory tests, a decrease of RBC, Hb and Ht in 1 case, a decrease of WBC in 1 case and an elevation of GPT in another case were observed. But these abnormal values were slight and transient.

In order to study the effect of Bestatin on superficial bladder cancer, the drug was used in combination with hyperthermia and Peplomycin therapy. The study was made using the following 2 groups. Group 1; Hyperthermic treatment with Peplomycin was used in 6 cases of bladder cancer. Group 2; Bestatin was given in combination with hyperthermia and Peplomycin in 15 cases of bladder cancer. As a result, complete or partial regression was obtained in 1 and 5 cases in Groups 1 and 2 respectively. Therefore, the combined use of Peplomycin and Bestatin in hyperthermic treatment for superficial bladder cancer appeared to be effective. Degeneration of tumor cells, irregularity of tumor structure, interstitial edema, fibrosis and cell infiltration were observed in the surgical specimens taken from effective cases, although the mechanism of action of Bestatin on tumors was clearly demonstrated upon histological examination.