In an experimental study undertaken to elucidate the mechanism whereby Adriamycin (ADM), an anticancer antibiotic, instilled into the bladder, produces its side-effects, normal adult dogs with bilateral ureterostomy were treated with intravesically instilled ADM and subsequently were investigated for the time course of ADM concentration in blood, urine and tissues of various organs as well as histopathological changes in the bladder mucosa. In a separate experiment conducted as a basic approach to the drug effect on bladder tumors, human bladder tumor tissues were exposed to ³H-thymidine (³H-TdR) and ³H-ADM and then the incorporation of these tritiated compounds into tumor tissues was determined by autoradiography.
1) Concentrations of ADM in blood, urine and tissues
ADM was instilled into the bladder of the animals at the following 4 different concentrations: Group 1 (Nos. 1-3), 10mg ADM/10ml physiological saline (1000mcg/ml); Group 2 (Nos. 4-6), 20mg ADM/ 10ml physiological saline (2000mcg/ml); Group 3 (No. 7), 100mg ADM/10ml physiological saline (10000mcg/ml); Group 4, (No. 8) 20mg ADM/10ml physiological saline (2000mcg/ml) preceded by a 100mg/kg intravenous dose of cyclophosphamide given 48 hours before surgical treatment (ureterostomy). In Groups 1 and 2 the experiment was performed with a different retained time and a different time of animal killing. Tissue levels of ADM were measured by determining the intensity of fluorescence. Blood levels of ADM were relatively low, but Case No. 7 showed considerably higher values than the cases in the other groups and Case No. 8 also exhibited higher values as compared with other cases receiving the drug at the same concentration. Urinary levels of the drug were somewhat higher than blood levels. Concerning tissue levels of ADM in the bladder, the level in mucosa is higher than that in muscular layer except No. 1. Levels of ADM in tissues other than bladder tissues became higher as the duration of exposure to the drug became longer. Moreover, the data suggested that the dynamics of blood levels yielded after systemic uptake of the drug from the bladder is similar to that observed following the intravenous administration of the drug.
2) Histological changes (bladder mucosa)
Case with a 6-hr. exposure to 2000mcg/ml ADM demonstrated shedding of epithelial elements of the bladder and marked edema as well as infiltration by neutrophils of the submucosa, changes comparable to those observed with 10-hr. exposure to the drug. These findings suggest the possibility that even in the intact bladder prolonged exposure to a concentration of 2000mcg/ml of ADM might induce noticeable histological changes in the bladder mucosa. Histological changes in the bladder mucosa were more conspicuous in Case No. 8 than in other cases exposed to the same concentration of ADM and still more marked in Case No. 7. From these facts the maximum safe concentration of ADM for bladder instillation is estimated to be 2000mcg/ml.
3) Autoradiography
The uptake of ³H-ADM by the bladder mucosa was demonstrated to be complete in all cases with the labeling index being invariably 100% irrespective of the presence or absence of bladder tumor and also independent of its grade.
A study of the uptake of the tritiated compounds by bladder tumor following its 30-min. incubation in a medium added with cold ADM at the same concentration as ³H-ADM 1μCi/ml revealed that whereas the tissue content of ³H-TdR was low as compared with control level, the incorporation of ³H-ADM was totally unaffected, the labeling index thus being 100%. These findings suggest that the cellular uptake of ADM might be independent of the condition of cells.

View full abstract

The studies reported here were undertaken to relate ureteral blood flow to ureteral peristalsis activity during diuresis. Twenty-eight dogs weighing 13 to 23kg were anesthetized with Thiopental and the ureter was exteriorized transperitoneally. Ureteral peristalsis was continuously recorded by electromyography and intraureteral pressure measurement. Diuresis was induced by an intravenous administration of Furosemide (1mg/kg). Urine was collected every 5min. through a catheter (2mm in outer diameter: 1mm in inner diameter) placed in the lower ureter, and the ureteral stroke volume was estimated.
Ureteral intramural PO₂, an index of ureteral blood flow, was continuously measured by using Yagi's polarographic oxygen electrode of an enameled copper wire 300μ in diameter implanted in the ureteral intramural tissues. Changes in the polarographic amplitudes during diuresis were expressed as 100 of the prediuretic level.
The results obtained were as follows:
1. The mean increment of the ureteral intramural PO₂ during 100% oxygen breathing was 197 (115-660). Thus, the Yagi's polarographic PO₂ measurement was proved to be a useful tool for monitoring ureteral intramural PO₂ in situ.
2. The increase in ureteral intramural PO₂ during oxygen breathing was accompanied by no change in ureteral peristalsis activity.
3. Three type of ureteral response to diuresis were observed:
1) Type I, frequent and persistent peristalsis, 2) Type II, frequent, but short-lived peristalsis, and 3) Type III, no remarkable change in peristalsis.
Regardless of the types of response the ureteral stroke volume was increased. The ureteral stroke volume was lowest in the first type and largest in the second type.
These results suggest that an increase in the urine transport is due to either an increase in the frequency of peristalsis or an increased urine volume per peristalsis, or both.
4. The first, the second and the third type of ureteric response had the mean ureteral intramural PO₂ values of 110±4, 91±8, and 98±4, respectively, which represent no important difference. And also they do not differ significantly from the prediuretic value.
These findings suggeset the ureteral intramural microcirculation remained unchanged during the ureteral peristalsis activity.

View full abstract

The purpose of this study was to determine if ureteral microcirculation is influenced by a ureteral surgery. Twenty dogs weighing 11 to 24kg were anesthetized with Thiopental and the mid-ureter was exteriorized transperitoneally. Surgery was done at different sites of the ureter: Exp. I, transection at the ureterovesical junction (U. V. J.); Exp. II, transection at ureteropelvic junction (U. P. J.); Exp. III, transections at both the U. P. J. and U. V. J.; and Exp. IV, transections at both the U. P. J. and U. V. J., combined with detachment of the whole ureter from its supporting tissues.
Ureteral intramural PO₂, an index of ureteral blood flow, was continuously monitored by using the Yagi's polarographic oxygen electrode of an enameled copper wire 300μ, in diameter implanted in the ureteral intramural tissues. Changes in the polarographic amplitudes following surgery were expressed as 100 of the preoperative level.
The results obtained were as follows:
1. In all cases the ureteral intramural PO₂ was significantly decreased in the ureters receiving a surgical stress.
The mean values of the ureteral intramural PO₂ were 80±18, 79±24, and 72±22 in the Exp. I, II and III, respectively.
The most striking reduction of the ureteral intramural PO₂(42±27) was observed in the Exp. IV, in which transections were made at the U. P. J. and U. V. J., combined with detachment of the whole ureter from its supporting tissues.
2. These results indicate that the ureter receives a significant amount of blood supply from three distinct areas, i. e., the pelvic, vesical and periureteric areas. It is also suggested that ureteral microcirculation can be maintained sufficiently if one of these routes of blood supply is kept intact.

View full abstract

Hydrostatic pressure treatment proposed by Helmstein was applied on 4 cases with contracted bladder caused by non-cancerous lesion with succesful and fruitful results. Those cases with interstitial cystitis and tuberculous contracted bladder responded quite well to the therapy showing increase in bladder capacity as well as decrease of cystalgia.

View full abstract

Since Bricker popularized the use of an isolated heal segment as a bladder substitute, the ileal conduit is the most widely accepted mode of supravesical urinary diversion. The most techniques of this satisfactory procedure today create free ileoureteral reflux which has been viewed with less concern than vesicoureteral or coloureteral reflux, for the ileal conduit has been considered as a low pressure and none reservoir system.
However, in recent years serious long term problems such as pyelonephritis, calculous formation, and the renal deterioration without apparent urinary obstruction have been reported. Clinical and experimental considerations indicate the reflux of infected urine to the kidney as the etiology of these late complications. Therefore, the ureteroileal anastomosis preventing reflux without causing obstruction will give great contribution to reduce long term renal complications.
From this point of view, as an ideal model to prevent the ureteral reflux, the ureterovesical junction was studied in the fetuses and the post-reimplanted intravesical ureter during micturition to search for the primary factor to prevent the vesicoureteral reflux. The results were as follows.
1) The ureterovesical junctions in human fetuses from 11 to 27 weeks of age were studied histologically. Anatomical relationships and origins of the periureteral sheaths, intravesical ureteral muscles, and trigonal muscles were shown. The superficial periureteral sheath arising from the vesical wall was not the source of the trigonal muscles; the deep periureteral sheath arising from the intravesical ureteral wall formed the deep trigonal muscles. The muscles of the intravesical ureter were differentiated longitudinaly and formed the superficial trigonal muscles. The development of the two trigonal muscles-superficial and deep-depends on the development of the deep periureteral sheath and the intravesical ureteral muscles. From the findings that both trigonal muscles are present in fetuses compared with both periureteral sheaths or intravessical ureteral muscles in the latest stage, the ability to maintain the valve mechamism in the ureterovesical junction in the human fetus is based on the periureteral sheaths and intravesical ureter-not on the trigone.
2) Serial radiographic observation of the bladder in which two silver clips were placed at the vesical serosal sides of the orifice and the new ureterovesical joint during the Politano-Leadbetter's reimplantation was done through the full to empty. The results were that although the trigone did not become shorter as with the normal at the time of status change from the full to voiding, the intravesical ureteral length which was indicated by the two silver clips, was doubled with complete protection of the reflux through this procedure.
From these results, namely that the primary factor to prevent the reflux is the intravesical ureter, the new technique of the ureteroileal anastomosis was devised in an attempt to prevent the ileoureteral reflux without causing obstruction and performed in 20 ureters of 11 patients with pelvic malignancies.
Satisfactory results with no serious operative complications, no episodes of pyelonephritic attack, and no renal deteriorations have been obtained in not only normal but also dilated ureters with this technique. In addition the ureteroileal junction created with this technique was demonstrated radiographically and histologically.

View full abstract

For the purpose of analyzing intrapenial hemodynamics in connection with physiological erection, I performed experiments with Xe-133 infused directly into the corpus cavernosum of 8 cases with no trouble on erection and ejaculation, and 40 cases with complaints of impotence. Its dissappearance rate was traced to obtain a declining curve showing Xe-133 clearance. In 47 of the 48 cases, a visual sexual stimulation (V.S.S.) was supplied to induce erection physiologically and changes in their Xe-133 curves were observed.
The curves of Xe-133 declined very gently at the time of non-erection in all 48 cases, with the intrapenial blood flow calculated from the curves ranging 0.5-6.5ml/100g/min, with a mean of 2.31ml/100g/min. Of the 47 cases receiving the V.S.S., the 21 with complete erections registered a marked fall in the Xe-133 curves after V.S.S., with the intrapenial blood flow increasing to 15.4-57.6ml/100g/min (mean 31.61ml/100g/min). Also in the 13 cases with incomplete erection in response to the V.S.S., the Xe133 curves evidently fell, showing an increase in intrapenial blood flow after V.S.S., 5.8-16.4ml/100g/min (mean 11.90ml/100g/min). In the 13 cases with no sign of erection what so ever in response to the V.S.S., the Xe-133 curve and intrapenial blood flow before and after V.S.S. showed no evident change. These results have led us to conclude that human penial erection is not solely attributable to intrapenial blood stagnation, as evidenced by vigorous increases in blood in flow into the penis erection and accompanying increases in the outflow of blood from the penis as well. Our findings seem to indicate that physiologically, erection is possible independent of the blockage of venous return circulation.

View full abstract

Parasympathetic drugs have been conventionally used for nonsurgical treatment of a patient with neurogenic bladder dysfunction containing a large volume of residual urine. However, it has often been observed that the use of parasympathetic stimulants for treatment of neurogenic bladder dysfunction is not constantly effective. On the other hand, various reports have recently appeared indicating significant effectiveness of phenoxybenzamine (POB) on the neurogenic bladder dysfunction. Effects of POB continue 6 weeks or so. Because of tolerance and orthostatic hypotenstion due to this drug, administration of the drug has to be stopped. Recently, 6-OHDA was developed as adrenergic depletor. Therefore, the present study was performed on the effects of 6-OHDA on the adrenergic terminal in the bladder neck and proximal urethra.
The following results were obtained:
1) Local administration of 6-OHDAA to the rabbit bladder neck and proximal urethra resulted in selective and almost complete disappearance of norepinephrine fluorescence intensity in adrenergic nerve terminals of the injected site.
2) The effects of 6-OHDA were found for 2 months in the lower dosage (1mg/kg) group and, in the higher dosage (10-50mg/kg) group, the fluorescence intensity was lower than that of the control group even after 5 months. Throughout the experimental periods, reduction in the fluorescence of the right auricular appendage was not observed in the rabbits treated with lower dose of 6-OHDA.
3) Urethral pressure profile (UPP) studies were performed on the female dog urethra, which was resected of external urethral sphincter with binocular microscope leaving mucous membrane. Maximum pressure of UPP measured in this model went down gradually with stepwise increase in bladder volume. Following β-blockade, this urethra iresponse was effectively obliterated.
4) Chemical sympathectomy of the dog bladder neck and proximal urethra in this model by local injection of 6-OHDA showed an increase in maximum pressure of UPP obtained by vesical distension.

View full abstract

The Effects of 6-Hydroxydopamine (6-OHDA) was studied on 18 patients, of whom 12 patients with upper motor neuron lesion and six patients with lower motor neuron lesion, suffering from neurogenic bladder with high residual urine. Local injection of 6-OHDA (1mg/kg) was performed cystoscopically at 3, 6, 9 and 12 o'clock positions around proximal urethra throughout the perineum. Cystogram, Cystometrograms and Phenoxybenzamine test (improvement in voiding pattern or reduction of maximum urethral pressure using urethral pressure profile studies) were carried out in each patient.
The following results were obtained:
1) Improvement of voiding pattern was obtained in 10 patients.
2) The achievement of bladder emptying was mainly due to increases of the bladder pressure and was partially related with alpha-adrenolytic effect of chemical sympathectomy by local administration of 6-OHDA, in view of cystograms cystometrograms and phenoxybenzamine test.
3) In 13 patients, blood pressure rose temporarily at the time of injection but, it was restored shortly after treatment. Vesico-ureteral reflux was observed in four patients after local administration of 6-OHDA. Three of them recovered after two months without special therapy. Massive hematuria was observed in two cases. No other significant complications were noted.

View full abstract

The response of the urethra to various autonomic stimulants was investigated in 39 individuals whose urethra were either structurally or innervatorily variable. Only the urethra of the chronically denervated bladder responded to α-stimulation with a uniform supersensitivity of 10mmHg or more of the rise above the control in urethral pressure. This supersensitivity to α-stimulation was abolished by preliminary administration of regitine, while it was not affected by either arfonad or buscopana. Supersensitivity to cholinergic stimulation seen in a few instances appears to be a result of its weak nicotinic action on the intramural ganglia whereby catecholamine was liberated via the short adrenergic system and effected on the α-receptor, because preliminary administration of regitine or arfonad and not buscopan abolished this response. These appear to afford substantial neuropharmacological evidence to the recently evolving concept of peculiar innervatory pattern of the urinary sympathetic system where it is characterized by 1) duality with parasympathetic system, 2) intrinsic short neuron system and 3) a system of modulating parasympathetic postganglionic synapse in relation to the short neuron, and to the significant contribution of α-adrenergics to the function of the urethra inclusive of the rhabdosphincter. The mechanism of the supersensitivity was speculated.

View full abstract

We have performed 20 urethroplastics for posterior urethral strictures between April 1966 and November 1977.
1) There was no danger of urethral necrosis in our pull through method, even if the urethra was, mobilized up to the penoscrotal angle.
2) Urethrogram does not always reveal the true length of the urethral defect, because contraction of the corpus spongiosum makes a longer defect on X-ray than the true defect.
3) The limit of pull through method based on urethrogram was longer than 6cm of urethral defect in the first operation and longer than 5cm in the reoperation.
4) Every effort must be made to avoid impairing the bladder neck, because preservation of bladder neck is only way to be continent of urine in posterior urethral injury.
5) Suprapubic cystostomy should be performed in the patient with pelvic fracture as first aid and urethroplasty should be done as a secondary operation.

View full abstract

A silicone gel prosthesis, reported by Kaufman in 1973 for the urinary anti-incontinence operation, has been implanted in 3 patients.
Case 1: An 8-year-old boy complained of continuous dribbling of urine owing to congenital malformation of the external sphincter. The postoperative distension of prosthesis following the implantation was performed in 2 occasions with 7 ml of contrast medium. The maximum urethral pressure is presently 52mmHg and the result is good.
Case 2: A 27-year-old man with a traumatic urethral rupture. The silicone gel prosthesis was implanted after transurethral resection of massive fibrosis at the posterior and bulbous urethra. The postoperative infusion of 8ml contrast medium failed to increase the maximum urethral pressure above 30mmHg. A penile clamp is necessitated; poor result.
Case 3: A 42-year-old man with a traumatic urethral rupture. The sling operation at the anterior urethra was previously attempted in vain using the fascia of rectus muscle. The postoperative distension of prosthesis with 10ml of contrast medium following the implantation was not sufficient to prevent the incontinence completely. The amplitude of the maximum urethral pressure remained at 28mmHg; poor result.
While the immediate postoperative results were excellent in all cases, the compression effect started to deteriorate in about one week after operation. The fall of compression strength had to be compensated by the infusion of contrast medium up to 10ml. It is speculated that the dissipation of local edema and/or elongation of ischiocavernosus muscle and Dacron-velour straps are responsible for this change. The present results, 8 to 20 months later, are 1 good and 2 poor.
A thorough urodynamic investigation on the lower urinary tract should be considered for all patients before and after the operation. The urethral pressure profilometry is quite of use to evaluate both the remaining urethral sphincter function preoperatively and the strength of urethral compression attained by prosthesis postoperatively. A patient who has shown the fibrotic degeneration at the site of bulbous urethra cannot be a candidate for this operation, since the scar tissue with a high elastic constant prevents the urethral lumen to be occluded completely with this prosthesis. Urinary flowmetry and urethrocystography are also of value to investigate the functional and organic alterations caused by the implantation of prosthesis.

View full abstract

In total of 22, 954 patients who were seen at the Department of Urology, the University of Tokyo during the period of 1969 to 1976, 15, 998 had urological diseases, the number of urological diseases definitely diagnosed being 16, 789. They consisted of congenital anomalies (9.5%), tuberculosis (2.0%), venereal disease (1.2%), non-specific infection and inflammation (25.8%), neoplasms (15.9%), calculi (15.2%), foreign bodies (0.2%), trauma (1.0%), infertility (4.9%), adrenal diseases (0.6%) and others (23.7%). Sex and age distributions and etiologic factors in the diseases were determined.

View full abstract

Five children with pelvic embryonal rhabdomyosarcoma were seen at this hospital between October, 1965 and September, 1977.
The primary site of tumor was the bladder in 3 cases (2 boys and 1 girl) and the vagina in 2 cases. (Table 1). Three girls died postoperatively. First case died of local recurrence 4 months postoperatively. Second case died 4 and a half years postoperatively due to acute myelogenic leukemia and there was neither local recurrence nor distant metastases at autopsy. Third case died of local recurrence and pulmonary metastases 17 months postoperatively. Two boys are now free of tumor for 37 months and 4 months respectively after radical treatment.
Recently, aggressive coordinated treatment with surgery, radiotherapy and cyclic combination chemotherapy has been used in many medical facilities and survival rate has been increased. We hererin discussed briefly the usefulness of the aggressive coordinated treatment from literature.

View full abstract