Non-prostanoid thromboxane A2 receptor antagonists with a dibenzoxepin ring system. 2.

A series of 11-[2-(1-benzimidazolyl)ethylidene]-6,11-dihydrodibenz[b,e]oxep in-2- carboxylic acid derivatives and related compounds were synthesized and found to be potent TXA2/PGH2 receptor antagonists. Each compound synthesized was tested for its ability to displace [3H]U-46619 binding from guinea pig platelet TXA2/PGH2 receptors. Structure-activity relationship studies revealed that the following key elements were required for enhanced activities: (1) an (E)-2-(1-benzimidazolyl)ethylidene side chain in the 11-position of the dibenzoxepin ring system and (2) a carboxyl group in the 2-position of the dibenzoxepin ring system. The studies also indicated that the TXA2/PGH2 receptor binding affinities of this series of compounds in guinea pig platelet were poorly correlated with those in human platelet. Introduction of substituent(s) to the benzimidazole moiety was effective and sodium (E)-11-[2-(5,6-dimethyl-1-benzimidazolyl)ethylidene]- 6,11-dihydrodibenz[b,e]oxepin-2-carboxylate monohydrate (57) recorded the highest affinity for human platelet TXA2/PGH2 receptor with a K(i) value of 1.2 +/- 0.14 nM. It demonstrated potent inhibitory effects on U-46619-induced guinea pig platelet aggregation (in vitro and ex vivo) and human platelet aggregation (in vitro). Compound 57, now designated as KW-3635, is a novel, orally active, and specific TXA2/PGH2 receptor antagonist with neither TXA2/PGH2 receptor agonistic nor TXA2 synthase inhibitory effects. It is now under clinical evaluation.     

Evaluation of image-diagnosing methods of enlarged parathyroid glands in chronic renal failure

Three noninvasive image-diagnosing methods, computed tomography (CT), scintigraphy with²⁰¹T1C1 and^99mTcO_h4 ^–, and ultrasonography (US), were preoperatively performed on 50 patients with chronic renal failure and secondary hyperparathyroidism who underwent total parathyroidectomy and parathyroid autograft. The detection rates of the 3 methods on the 191 excised parathyroid glands were compared according to weight and location. CT detected 57.1% of all glands and 78.6% of 103 glands weighing over 500 mg. Scintigraphy detected 51.8% and 75.7%, and US detected 42.4% and 53.4%, respectively. The detection rate of upper glands was best with CT at 58.9% and 89.1%; that of lower glands was best with scintigraphy at 65.3% and 80.4%. Although the combination of the 3 methods diagnosed 69.6% and 89.5%, CT and scintigraphy, the best 2 combinations, visualized 67.5% and 88.3%.

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Resumen Tres métodos diagnósticos no invasivos, la tomografía computadorizada (TC), la centelleografía con²⁰¹T1C1 y^99mTcO₄ y la ultrasonografía (US) fueron realizados preoperatoriamente en 50 pacientes con falla renal crónica e hiperparatiroidismo secundario sometidos a paratiroidectomía y autotransplante paratiroideo. Las tasas de detección de los 3 métodos fueron comparados sobre las 191 glándulas paratiroideas resecadas en relación a los pesos y a los sitios de ubicación. La TC detectó el 57.1% del total de glándulas y el 78.6% de aquellas glándulas (103) con pesos superiores a 500 mg. La centelleografía detectó 51.8% y 75.7%, y la US 42.4% y 53.4% respectivamente. La tasa de detección para las glándulas superiores fue optima con TC, con 58.9% y 89.1%; la de las glándulas inferiores fue óptima con centelleografía, con 65.3% y 80.4%. Aunque la combinación de los 3 metodos diagnosticó el 69.6% y 89.5%, la TC y la centelleografía, la mejor de las combinaciones, visualizó el 67.5% y el 88.3% respectivamente.

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Résumé Trois méthodes d'imagerie non invasives, la tomodensitométrie, la scintigraphie (avec T1C1²¹⁰ et TcO₄ ^99m), et l'ultrasonographie ont été pratiquées avant l'intervention chez 50 malades qui présentaient une insuffisance rénale chronique compliquée d'hyperparathyroïdisme secondaire et qui furent traités par parathyroïdectomie totale et autogreffe parathyroïdienne. Les taux de détection de ces 3 méthodes concernant 191 glandes parathyroïdes réséquées ont été évalués en fonction du poids et du siège des lésions. La tomodensitométrie a permis de découvrir 57.1% de toutes les glandes et 78.6% des glandes dont le poids dépassait 500 mg; la scintigraphie 51.8% et 75.7%; l'ultrasonographie 42.4% et 53.4%. Le taux de détection des glandes supérieures fut plus élevé avec la tomodensitométrie: 58.9% et 89.1%; celui des glandes inférieures le fut avec la scintigraphie: 65.3% et 80.4%. Si la combinaison des 3 méthodes permet le diagnostic dans 69.6% et 89.5% des cas la tomodensitométrie associée seulement à la scintigraphie donne des résultats très voisins, les taux respectifs étant de 67.5% et de 88.3%.

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Presented at the International Association of Endocrine Surgeons in Paris, September 1985.     

A case-control study of breast cancer among Japanese women: with special reference to family history and reproductive and dietary factors

Summary To study the effects of family history and reproductive, anthropometric, and dietary factors on the risk of breast cancer among low risk populations, we conducted a hospital-based case-control study involving 908 patients with breast cancer and their matched controls, in Japan. A positive family history of breast cancer significantly increased the risk of breast cancer (odds ratio = 1.52, 95% confidence interval: 1.14–2.03). The risk further increased with increasing number of family members affected. Obesity, single marital status, fewer births, a late childbirth, and less consumption of green-yellow vegetables and dairy products were also associated with an increased risk of breast cancer. These associations were independent in multivariate analyses. There was no increase in risk associated with consumption of high fat foods. When analyzed by menopausal status, the association with family history of breast cancer, especially in the first degree of relatives, was more evident for premenopausal breast cancer. The associations with obesity and lower consumption of dairy products were more pronounced for postmenopausal breast cancer, while those with lower parity and single marital status were stronger for premenopausal breast cancer.     

Local cerebral blood flow measured by stable xenon CT during fentanyl-diazepam anesthesia

We assessed the local cerebral blood flow (LCBF) in 40 patients under fentanyl-diazepam anesthesia. The measurement of LCBF was made using 50%–70% stable xenon with 20 min of inhalation interval and a shuttle method for computed tomography imaging. All patients were anesthetized with 5.95±1.76 μg·kg⁻¹ fentanyl and 0.22±0.07 mg·kg⁻¹ diazepam under mechanical ventilation during CBF measurement. The values and distribution of LCBF on non-affected hemisphere appeared to be unaltered by fentanyldiazepam anesthesia. We also assessed the cerebral carbon dioxide reactivity in 6 patients. The cerebral carbon dioxide reactivity, expressed as percentage change in LCBF per unit change in arterial carbon dioxide partial pressure, was 5.39±1.07, and there were no significant differences of reactivity among regions studied. In conclusion, we showed reference values of LCBF and carbon dioxide reactivity, measured by stable xenon-enhanced computed tomography, in patients under fentanyl-diazepam anesthesia. Carbon dioxide reactivity was preserved in all regions including gray matter, white matter, and basal ganglia.     

Case of ruptured gastroduodenal arterial pseudoaneurysm with penetration to the duodenum, successfully treated with transcatheter arterial embolization]

A 77-year-old man, who underwent segmental pancreatectomy for intraductal papillary mucinous adenoma in 2001, was referred to our hospital with complaints of hematemesis and melena on January, 2004. Emergency upper gastrointestinal endoscopy showed a pulsating submucosal protrusion in the duodenal bulb, which was identified as a gastroduodenal arterial aneurysm measuring 1.5cm on abdominal CT imaging. Transcatheter arterial embolization of the aneurysm with metallic coils was successfully performed. Periodically repeated endoscopic examination has revealed the coils protruding into the duodenal lumen without any serious complication.     

Acute pulmonary embolism after cerebral infarction associated with a mobile thrombus in the ascending aorta

Although the causes of stroke are diverse, thromboembolism due to a mobile aortic thrombus is rare. We describe a surgical case of acute massive pulmonary embolism after critical cerebral infarction associated with a mobile ascending aortic thrombus in a 52-year-old woman. Concomitant surgical removal of the aortic thrombus and pulmonary embolectomy was performed successfully, and the patient has been stable without recurrent thromboembolic complications after 18 months of follow-up.     

Lobular carcinoma of the male breast--a case report]

Lobular carcinoma of the male breast is very rare, because lobules do not exist in the male mammary gland. Seven cases of lobular carcinoma of the male breast have been reported in Europe and U.S.A., although no case in Japan. We encountered a very rare case of the lobular carcinoma of 74-year-old male breast. Histopathological examinations of both primary tumor and recurrent tumors of the skin led to the diagnosis of lobular carcinoma.     

Development and Initial Testing of a Permanently Implantable Centrifugal Pump

Abstract: To be able to salvage heart failure patients, the need for an economical permanent ventricular assist device is increasing. To meet this increasing demand, a miniaturized centrifugal blood pump has been developed as a permanently implantable device. The Gyro permanently implantable model (PI-601) incorporates a sealless design with a blood stagnation free structure. The pump impeller is magnetically coupled to the driver magnet in a sealless manner. This pump is atraumatic and antithrombogenic and incorporates a double pivot bearing system. A miniaturized actuator was utilized in this system in collaboration with the University of Vienna. The priming volume of this pump is 20 ml. The overall size of the pump actuator package is 53 mm in height and 65 mm in diameter, 145 ml of displacement volume, and 305 g in weight. Testing to date has included in vitro hydraulic performance and hemolysis. This pump can provide 5 L/min against a 110 mm Hg total pressure head at 2,000 rpm and 8 Limin against 150 mm Hg at 2,500 rpm. The normalized index of hemo-lysis (NIH) value of this pump was 0.0028 g/100 L at 5 Limin against 100 mm Hg. A preliminary anatomical study revealed the possibility of the implantability of 2 such systems in biventricular bypass at a preperitoneal location. This system is feasible for use as a permanently implantable biventricular assist device.     

AUGMENTED ENDOGENOUS NITRIC OXIDE PRODUCTION IN PARTIAL PORTAL VEIN-LIGATED RATS

1. Endothelium-derived nitric oxide (NO) is a potent vasodilator. Because the body oxidizes it to nitrate ions, NO₃-, measurement of the serum concentration and the urinary excretion of NO₃- may be an index for endogenous NO. We investigated the role of NO on hyperdynamic circulation in cirrhotic and partial portal vein-ligated rats by measuring NO₃. 2. Liver cirrhosis was induced by administration of thioacetamide. Systemic and splanchnic haemodynamics and splenic-systemic shunting were determined by tracer microspheres. The concentration of NO₃- was measured by using high-performance liquid chromatography with an anion-column. 3. We found that systemic and splanchnic hyperdynamic circulation existed to almost the same extent in cirrhotic and in portal vein-ligated rats as compared to the controls and sham-operated rats, respectively. Splenic-systemic shunting was markedly greater in portal vein-ligated rats than in cirrhotic rats. 4. Serum NO₃- levels and urinary excretion of NO₃- in cirrhotic rats tended to increase as compared to the controls. On the other hand, the levels in portal vein-ligated rats were significantly increased as compared to those of the sham-operated rats, and were significantly and negatively correlated to the splanchnic arterial resistance and total vascular resistance. The amount of urinary excretion of NO₃- significantly correlated to splenic-systemic shunting (r = 0.61, P<0.05) only in portal vein-ligated rats. 5. We suggest that these high levels of NO₃- in portal vein-ligated rats relate to the extensive formation of porto-collateral vasculature or acute changes in systemic and splanchnic haemodynamics due to portal vein-ligation.     

Synchronous pulmonary atypical adenomatous hyperplasia and metastatic osteosarcoma in a young female

A 17-year-old female underwent metastasectomy of three synchronous lesions in the bilateral lungs under the diagnosis of metastatic osteosarcoma, however, one of them was found to be atypical adenomatous hyperplasia (AAH). Since AAH is very rare among young people, a careful evaluation of high-resolution computed tomographic image is important in determining the operative indications and procedures in patients with multiple metastatic tumors.