Stimulatory action of mitemcinal (GM-611), an acid-resistant non-peptide motilin receptor agonist, on colonic motor activity and defecation: spontaneous and mitemcinal-induced giant migrating contractions during defecation in dogs.

The aim of this study was to characterize giant migrating contractions (GMCs) during spontaneous defecation in dogs and to investigate the effect of mitemcinal (an orally active and highly acid-resistant motilin receptor agonist) on colonic motility to assess the possibility of using it for the treatment of colonic motility disorders. To assess colonic motility, strain-gauge force transducers were implanted on the gastrointestinal tract of five dogs, and the behaviour of the dogs was monitored with a noctovision-video camera system. The effect of mitemcinal (0, 3, 10 or 30 mg per dog) and sennoside (300 mg per dog) on colonic motility was assessed 24 h after oral administration. During a 39-day period, the starting point of most of the 140 GMCs was between the transverse colon and the descending colon, but some variation was observed. In the daytime, the GMCs originated from somewhat more proximal positions than at night. Mitemcinal caused an increase in the GMC-index (integration of contractile amplitude and duration) and proximal translocation of the GMC starting point, but did not cause an increase in the number of defecations 12 h after administration. Sennoside, however, caused a significant increase in the number of defecations, an increase in the GMC-index, and prolongation of the duration of GMCs. The GMC starting point in the canine colon varied during spontaneous defecation. Mitemcinal was a potent prokinetic drug to mimic a spontaneous defecation compared with sennoside. Mitemcinal evacuates more intestinal luminal contents during the defecation than does sennoside.

Calculation of biliary atresia prognostic index using a multivariate linear model.

The purpose of this study was to determine the relative value of liver function markers in predicting the magnitude of morbidity and to develop a quantitative estimate of the prognostic risk using a multivariate regression model in patients who have been operated on for biliary atresia. The study sample consisted of 37 patients who had undergone a Kasai portoenterostomy; the jaundice disappeared in 32 and persisted in five. A computer-based stepwise regression procedure produced the linear predictive models by the equation: biliary atresia prognostic index (BAPI) = 9.2 Cu:Zn + 1.0 ZTT + 3.2 TB - 0.05 ChE + 9.9 for infants under 1 year of age, and BAPI = 10.3 Cu:Zn + 0.8 ZTT + 0.03 GGTP - 0.12 ChE + 25.6 for children over 1 year of age. In validation of these models, the indexes fluctuated from -17 to 122, and the degree of morbidity increased linearly with the increase in BAPI. Postoperatively the patients were classified into four categories according to the dynamics of their postoperative course: A (BAPI < 25), successful cases that should not require liver transplantation (40.5%); B (25 < or = BAPI < or = 50), improved cases that have extended survival with their native liver (29.7%); C (50 < BAPI < or = 75), cases that improved in terms of disappearance of jaundice but ultimately will require liver transplantation (8.1%); and D (BAPI > 75), cases that require early referral for transplantation (21.6%). (The percentages indicate the distribution rate of patients at the time of final follow-up evaluation.) These models allow quantification of the risk of morbidity from progressive liver cirrhosis in the individual patient, permitting the clinician to consider whether such patients should be considered for liver transplantation.

Sacroperineal anorectoplasty using intraoperative ultrasonography: a preliminary report.

Intraoperative ultrasonography (US) was applied to sacroperineal anorectoplasty for the purpose of making a pull-through tunnel under visual guidance. Intraoperative US images the horizontal plane of the muscle complex and the tip of the forceps, which is placed at the entrance of the tunnel (ie, the space anterior to the puborectalis sling), ready to penetrate the muscle complex. A surgeon can thus penetrate the center of the muscle by confirming the relation between the muscle and forceps on the US screen. Postoperative computed tomography of four patients on whom this technique was applied demonstrated that the rectum was pulled through the exact center of the puborectalis and external sphincter muscles.

Comparison of cardiac actions of doxorubicin, pirarubicin and aclarubicin in isolated guinea-pig heart.

The cardiac actions of doxorubicin were compared with those of pirarubicin and aclarubicin to understand the mechanisms responsible for differences in cardiotoxic effects of anthracycline agents. In left atrial muscle preparations obtained from guinea-pig heart and stimulated at 2 Hz, anthracyclines produced positive inotropic effects. The magnitude of the effect was pirarubicin > doxorubicin > aclarubicin. The order for depression of potentiated postrest contraction and prolongation of the time to peak twitch tension was doxorubicin > pirarubicin > aclarubicin. Drug washout following a 2-h incubation with 100 microM doxorubicin prevented a further increase in the time to peak twitch tension, caused a marked recovery of depressed potentiated postrest contractions, and augmented the positive inotropic effect. Pirarubicin and doxorubicin, but not aclarubicin, caused a parallel rightward shift of the dose-response curve for the negative inotropic effect of acetylcholine. The potency of inhibition of [3H]quinuclidinyl benzilate binding was pirarubicin > doxorubicin > aclarubicin. These results indicate that three anthracycline anticancer agents share similar effects on cardiac muscle contractility and on muscarinic acetylcholine receptors. The actions of aclarubicin were weak compared to those of doxorubicin or pirarubicin. Increases in the time to peak twitch tension and the depression of potentiated postrest contraction are apparently mediated by mechanisms different from those responsible for the positive inotropic effects or antagonism at muscarinic acetylcholine receptors.

[Surgical treatment of tracheobronchial lesions in children].

A total of 16 cases of tracheal and bronchial lesions such as bronchial tumor (4 cases), aspirated foreign body (5 cases), and tracheo-bronchial stenosis (7 cases) were surgically treated at the National Children's Hospital from 1965 to 1990. A mucoepidermoid tumor was excised via bronchotomy. Pulmonary lobectomy was indicated for another 2 mucoepidermoid tumors which arose from the middle and lower lobe bronchus. Pneumonectomy was indicated for a leiomyoma located at the stem of the left bronchus and showed extensive invasion into the bronchial wall. It is important to accurately diagnose the location and extent of the tumor by performing intraoperative bronchoscopy, bronchotomy, frozen section examination in order to avoid unnecessary pulmonary resection. Three aspirated foreign bodies (2 marking needles and a peanut) were removed via bronchotomy. Right lower lobectomy was performed in a patient who received an accidental injection of barium sulfate into the right lower bronchus. The barium remained for more than one year and caused recurrent pneumonia. A radiolucent toy plate aspirated into the left main bronchus of a 3-year-old girl was overlooked for more than 3 years. Suppurative changes of the left lung necessitated pneumonectomy. Tracheal resection with end-to-end anastomosis was carried out successfully in a 5-year-old patient suffering from segmental fibrogranulous stenosis of the mid-trachea. Extensive congenital stenosis in 6 patients was repaired by costal cartilage autograft, with a 67% mortality rate. Treatment of the associated cardiac anomalies and the possible postoperative complications such as anastomotic leakage, restenosis, exuberant granulation, and tracheomalacia are the major problems associated with this type of tracheoplasty.

Effectiveness of an intussusceptive antireflux valve to prevent ascending cholangitis after hepatic portojejunostomy in biliary atresia.

An intussusceptive antireflux valve was created in the Roux-en-Y loop at the same time as the hepatic portojejunostomy (Kasai procedure) for the purpose of preventing ascending cholangitis in 14 new cases of biliary atresia and in 6 long-term survivors of the Kasai operation after episodes of ascending cholangitis. Ascending cholangitis did not develop in any of the 13 new patients who showed bile outflow following a modified Kasai procedure with antireflux valve nor in 5 of 6 patients who had secondary valve implementation. Postmortem examination of a patient with a valve who died 2 years 3 months after surgery showed that the structure of the valve was intact and that the valve still was quite effective as an antireflux mechanism.

Digital imaging system for recording rapid changes in intracellular Ca2+ concentrations triggered by electrical stimulation of cardiac myocytes.

To examine the origin and spreading of the Ca2+ transient following electrical stimulation of isolated myocyte, a system capable of recording intracellular Ca2+ distribution with sufficient temporal and spatial resolution was constructed. The system consists of a fluorescence microscope with computer-controlled pulse illumination and a digital image analyzer. The results with this new equipment show that the Ca2+ transient originates from one or a few points within a myocyte, and spreads throughout the cell. During the initial 60-msec period, the distribution of Ca2+ within a myocyte was not uniform. The system may be used for better understanding of the excitation-contraction coupling mechanism occurring within a cardiac myocyte or of changes in intracellular Ca2+ concentrations in other cells in which Ca2+ plays a crucial role in signal transduction.

Delayed puberty in girls having biliary atresia.

Biliary atresia patients have several problems even after undergoing successful Kasai operation. Fourteen female patients have been followed for over 12 years after successful Kasai original portoenterostomy procedures. The oldest patient is 21 years of age. All patients are jaundice-free, but 10 patients have a history of esophageal varices and/or hypersplenism. Five patients complain of menstrual disorders. The average age of menarche was delayed 1 year, 9 months, compared with Japanese controls. Two cases of 11 (18.2%) presented primary amenorrhea after 14 years, 6 months, which is mean + 2SD of Japanese controls. Four cases of 11 (36.4%) showed secondary amenorrhea. Unestablished menstrual cycles after 2 years of menarche were observed in two patients of nine (22.2%). Four cases had regular menstruation. Five patients showed delay in the development of pubic hair and breasts. Six patients showed atypical body height velocity pattern that showed no peaking, and one patient showed no growth spurt. All the patients with amenorrhea had portal hypertension. In hormonal evaluation, the patients with menstruation showed normal or slightly good reaction of luteinizing hormone and follicle stimulating hormone in the luteinizing hormone-releasing hormone test, having normal to high estradiol levels. The patients with menstrual abnormality showed overreaction of LH, having normal estradiol levels.

[Early complications after hepatic porto-jejunostomy in biliary atresia].

Postoperative complications which developed within three years after hepatic porto-jejunostomy (Kasai's operation) in 126 patients of biliary atresia were analyzed. Ascending cholangitis developed in 47 of 97 bile excreted patients. The excretion of bile ceased in another 18 patients without any symptom of cholangitis. Adhesive ileus, bleeding from the porta hepatis, wound dehiscence, and anastomotic leak developed less frequently. The mortality rate of the patients with these complications, especially with cholangitis or with cessation of the bile excretion, was extremely high; twenty nine (62%) out of 47 patients with cholangitis, and 14(78%) out of 18 patients with cessation of the bile excretion died. On the other hand, the mortality rate in 24 patients with bile excretion but without any postoperative complication was only 8% (2 patients). An intussusception type antireflux valve in the Roux-en-Y loop was effective for preventing cholangitis; cholangitis developed in none of 8 patients with an anti-reflux valve, whereas cholangitis developed in 25(48%) of recent 52 patients without a valve.

Effects of Ca2+ on the sodium pump observed in cardiac myocytes isolated from guinea pigs.

It is presently unknown whether Ca2+ plays a role in the physiological control of Na+/K+-ATPase or sodium pump activity. Because the enzyme is exposed to markedly different intra- and extracellular Ca2+ concentrations, tissue homogenates or purified enzyme preparations may not provide pertinent information regarding this question. Therefore, the effects of Ca2+ on the sodium pump were examined with studies of [3H]ouabain binding and 86Rb+ uptake using viable myocytes isolated from guinea-pig heart and apparently maintaining ion gradients. In the presence of K+, a reduction of the extracellular Ca2+ increased specific [3H]ouabain binding observed at apparent binding equilibria: a half-maximal stimulation was observed when extracellular Ca2+ was lowered to about 50 microM. The change in [3H]ouabain binding was caused by a change in the number of binding sites accessible by ouabain instead of a change in their affinity for the glycoside. Ouabain-sensitive 86Rb+ uptake was increased by a reduction of extracellular Ca2+ concentration. Benzocaine in concentrations reported to reduce the rate of Na+ influx failed to influence the inhibitory effect of Ca2+ on glycoside binding. When [3H]ouabain binding was at equilibrium, the addition of Ca2+ decreased and that of EGTA increased the glycoside binding. Mn2+, which does not penetrate the cell membrane, had effects similar to Ca2+. In the absence of K+, cells lose their tolerance to Ca2+. Reducing Ca2+ concentration prevented the loss of rod-shaped cells but failed to affect specific [3H]ouabain binding observed in the absence of K+. These results indicate that a large change in extracellular Ca2+ directly affects the sodium pump in cardiac myocytes isolated from guinea pigs.

Radiologic evaluation of surgical resectability in abdominal neuroblastoma.

To assess the resectability of abdominal neuroblastoma, three parameters were framed in the lateral view aortogram: AV index, AS index, and AS angle. AV index is the ratio of the maximum distance between the aorta/spinal column and the height of the fourth lumbar vertebral body (HV). AS index is the ratio of the maximum distance between the aorta/superior mesenteric artery (SMA) and the HV. AS angle is the angle between the aorta and SMA. Thirty-four aortograms from 21 patients with abdominal neuroblastoma were reviewed, and these parameters were measured in each of the aortograms. Radical resection of the tumor was achieved in ten of 12 patients (83%) with an AV index less than 0.5; however, radical resection was performed in only three of 12 patients (25%) with an AV index greater than or equal to 0.5. The AV index was less than 0.5 in ten of 13 patients (77%) undergoing radical resection. On the other hand, resection was delayed in all ten patients with an AV index greater than or equal to 0.5. Radical resection was achieved in 12 of 14 patients (86%) when the AS index was less than 1.0, but in only one of ten patients (10%) with an AS index greater than or equal to 1.0. Also, the AS index was less than 1.0 in 12 of 13 patients (92%) with radical resection. However, surgery was postponed in all ten patients with an AS index greater than or equal to 1.0. There appeared to be no significant relation between resectability and AS angle. The AV and AS indexes, which are derived from lateral view aortograms, seem to be useful parameters in assessing the resectability of abdominal neuroblastoma.

Doxorubicin: mechanism of cardiodepressant actions in guinea pigs.

The clinical use of doxorubicin is frequently limited by its depressant effects on cardiac muscle, presumably resulting from alterations of Ca2+ movements. Therefore, the modification of various Ca2+ pools that contribute to cardiac contraction was assessed from developed tension observed in isolated atrial muscle preparations incubated at 31 degrees C and stimulated at 0.5 Hz. Doxorubicin (100 or 200 microM) caused a transient positive inotropic effect followed by a sustained and marked negative effect, prolonged the time to peak twitch tension and decreased the rate of relaxation. Potentiated posttest contraction was depressed to a greater extent compared with contractions observed at 0.5-Hz stimulation. After a 3-hr exposure to doxorubicin, effects of ryanodine to depress developed tension observed in preparations stimulated at 0.5 Hz were markedly smaller, indicating a reduced contribution of the ryanodine-sensitive Ca2+ pool to contractile activation. In atrial muscle preparations obtained from guinea pigs treated for 10 days with doxorubicin (total dose 5 mg/kg iv), similar results as above were observed. Moreover, a longer quiescent period was required to attain the maximal posttest contraction. These results indicate that an acute or subacute exposure to doxorubicin impairs the function of the cardiac sarcoplasmic reticulum.

Comparison of [3H]ouabain binding sites in intact cells and cell homogenates: apparent lack of glycoside receptors unrelated to sarcolemmal Na+, K+-ATPase in guinea-pig heart.

In intact heart muscle cells incubated in a physiological solution, i.e. under the condition in which the cardiac glycosides produce pharmacological and toxicological effects, receptors for these actions of the glycosides should be available to ouabain. In cell homogenates, [3H]ouabain binding observed in the presence of Mg2+ and inorganic phosphate represents binding of the glycoside to Na+, K+-ATPase. Therefore, numbers of these two types of [3H]ouabain binding sites were compared using viable myocyte preparations obtained from ventricular muscle of guinea-pig heart. The number of ouabain binding sites observed in viable myocytes in the absence of Ca2+ and K+ was not different from the number of ouabain binding sites on Na+, K+-ATPase observed with sodium dodecylsulfate-treated homogenates prepared from isolated myocytes. These results do not support the hypothesis that there are receptors for the pharmacological or toxic actions of ouabain other than those that are associated with sarcolemmal Na+, K+-ATPase.

Cardiodepressant actions of the orally active male contraceptive, gossypol, in guinea-pig heart muscle.

We have previously shown that gossypol has direct actions on isolated atrial muscle preparations. The possible mechanisms responsible for the transient positive and sustained negative inotropic effects of gossypol were examined under conditions that modify Ca2+ pools involved in contractile activation. In Langendorff preparations obtained from guinea-pig or rat heart, gossypol produced marked negative inotropic and arrhythmogenic effects but failed to produce a positive inotropic effect. Langendorff preparations were significantly more sensitive than atrial muscle preparations. In atrial muscle preparations, the negative inotropic effect of gossypol was not specific to utilization of superficial or intracellular Ca2+ pools; force-staircase phenomenon observed between 0.5 and 3 Hz, contractions elicited by slow action potentials in partially depolarized muscle, the inotropic effect of extracellular Ca2+ and potentiated post-rest contractions were all suppressed by gossypol to the similar extent. Low external Na+ concentrations abolished the positive inotropic effect of gossypol without affecting the negative inotropic effect. A low extracellular Ca2+ concentration enhanced the transient positive inotropic effect and delayed development of the negative inotropic effect. Simultaneous reduction of extracellular Na+ and Ca2+ concentrations abolished the positive inotropic effect and enhanced the negative inotropic effect. Gossypol inhibited ATP-dependent Ca2+ uptake by sarcolemmal vesicles obtained from dog heart. These results indicate that the actions of gossypol on cardiac muscle is not specific to utilization of either the superficial or intracellular Ca2+ pools involved in contractile activation.

The use of computerized tomography to evaluate anorectal anomalies.

Computerized tomography (CT) was applied to various types of anorectal anomalies to directly image the anal sphincters. In normal cases and low type anomalies, CT demonstrated clear images of the puborectal muscle and external sphincters. Among high type anomalies, the distribution of sphincter muscle in patients with rectovesical fistula is totally different from that seen in patients with rectourethral fistula. In the latter, the puborectal muscle is attached not only around urethra, but also around the distal part of the blind rectum; external sphincters are present as a mass beneath the perineum. In the rectovesical fistula, however, the puborectal muscle cannot be identified and the external sphincters exist only as a string-like structure. CT done postoperatively identified two different causes for incontinence. In one type, the pull-through colon missed the sphincteric musculature, and in the other, sphincters were markedly hypoplastic. CT, therefore, provides adequate imaging to determine the type of operation needed to correct the abnormality.

[Our new operative method for high-type anorectal malformations based on the histological studies].

From 1971 onwards we have been examining the anatomy and histology of sphincter components in patients with several anorectal malformation who died of associated anomalies. These histological studies demonstrated that not only puborectal muscle but also the superficial and deep external sphincters exist, even in the high type anomalies, and that the mass of external sphincter is located above the anal dimple. Moreover, the inner circular muscle of rectum is thickened at the level of the closest part to the fistula. Based on our histological studies, we devised our new operation to use all the sphincter musculature effectively for the newly reconstructed anal canal. Our new surgical procedure is clearly different from Kiese wetter-Rehbein's method in that the puborectal muscle is penetrated from the outside of rectal wall and might be damaged, since puborectal muscle is attached to the blind pouch of rectum. Moreover, the puborectal muscle and the external sphincters can be easily identified by electrical stimulation under direct vision from extended sacroperineal approach. And the colon can be pulled exactly through the centre of the external sphincters and puborectal muscle under direct vision without causing any damage to these important sphincters, unlike Pena's operation.

Abdomino-extended sacroperineal approach in high-type anorectal malformation--and a new operative method.

From 1971 onwards we have been examining the anatomy and histology of sphincter components in patients with several anorectal malformation who died of associated anomalies. These histological studies demonstrated that not only puborectal muscle but also the superficial and deep external sphincters exist, even in the high type anomalies, and that the mass of external sphincter is located above the anal dimple. Moreover, the inner circular muscle of rectum is thickened at the level of the closest part of the fistula. Based on our histological studies, we devised our new operation to use all the sphincter musculature effectively for the newly reconstructed anal canal. Our new surgical procedure is clearly different from Kiesewetter-Rehbein's method in that the puborectal muscle is penetrated from the outside of rectal wall and might be damaged, since puborectal muscle is attached to the blind pouch of rectum. Moreover, the puborectal muscle and the external sphincters can be easily identified by electrical stimulation under direct vision from extended sacroperineal approach. And the colon can be pulled exactly through the centre of the external sphincters and puborectal muscle under direct vision without causing any damage to these important sphincters, unlike Pena's operation.