Peroxisome proliferator-activated receptor delta (PPARdelta), a novel target site for drug discovery in metabolic syndrome.

The development of new treatments for metabolic syndrome is urgent project for decreasing the prevalence of coronary heart disease and diabetes mellitus in the advanced countries. Peroxisome proliferator-activated receptor (PPAR)alpha and gamma agonists have shed light on the treatment of hypertriglyceridemia and type 2 diabetes mellitus, respectively. Among PPARs, analysis of the PPARdelta functions is lagging behind because specific PPARdelta agonists have not been developed. The appearance of new PPARdelta agonists is brightening the prospects for elucidating the physiological role of PPARdelta. PPARdelta is a new target for the treatment of metabolic syndrome. In particular, the fact that fatty acid oxidation and energy dissipation in skeletal muscle and adipose tissue by PPARdelta agonists lead to improved lipid profile, reduced adiposity and insulin sensitivity is a breakthrough. It seems that treatment of PPARdelta agonists operate similarly to the caloric restriction and prolonged exercise. We suggest that the physiological role of PPARdelta may be an indicator for switching from glucose metabolism to fatty acid metabolism. To receive new benefits of PPARdelta agonists against metabolic syndrome by increasing fatty acid consumption in skeletal muscle and adipose tissue, we need to unveil more details on the functions of PPARdelta itself and its agonists in the future.     

Intrapulmonary metastasis developing eighteen years after complete resection of thymoma

We present a case of intrapulmonary metastasis developing 18 years after complete resection of thymoma. An 8 mm nodule in the lower lobe of the left lung was noted on chest X-ray in a 76-year-old woman who had undergone complete resection of Masaoka’s stage II thymoma 18 years earlier. Since the nodule grew to 17 mm during a 2-year follow-up, wedge resection was performed. The lesion was histologically diagnosed as an intrapulmonary metastasis from thymoma. Extremely late recurrence after complete resection of thymoma is discussed.     

Activation of protein kinase C and nicotinamide adenine dinucleotide phosphate oxidase in leukocytes of spontaneously hypertensive rats.

The involvement of oxidative stress in polymorphonuclear leukocytes (PMN) in the pathogenesis of hypertension remains to be elucidated. We analyzed the generation of reactive oxygen species (ROS) by the circulating and peritoneally infiltrating PMN from spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Flow cytometric analysis revealed that ROS generation by PMN from SHR was higher than that from WKY before (at 6 weeks of age) and after (at 16 weeks of age) the onset of hypertension. In vivo, ROS generation by PMN from SHR, but not that by PMN from WKY, was significantly suppressed by 10-week treatment with 50 mg/kg/day carvedilol, and this treatment did not affect blood pressure. Western blotting analysis revealed that protein kinase C alpha (PKCalpha), but not PKCbetaI or betaII, was activated more strongly in PMN from SHR than in PMN from WKY. Furthermore, expression of p47phox of nicotinamide adenine dinucleotide phosphate oxidase, but not of p67phox, in PMN from SHR was higher than that in PMN from WKY. These results suggest that ROS generation by PMN is principally enhanced in SHR through activation of PKCalpha and p47phox.     

Clinical significance of associated nodular lesions of the adrenal in patients with aldosteronoma

Thirty-seven patients with primary aldosteronism were treated by unilateral total adrenalectomy during a 7-year period (1981–1987). The 37 patients were classified into 3 groups on the basis of adrenal pathology: unilateral solitary adenoma, 23 cases (group 1); unilateral adenomas, 3 cases (group 2); and adenoma with multiple macro- or microscopic nodules, 11 cases (group 3). The preoperative conditions of the patients (age, duration of hypertension, plasma renin activity, plasma aldosterone concentration, and serum potassium concentration), postoperative sequential changes of hormone levels, and outcome of hypertension were compared among the groups in order to determine whether the differences of adrenal pathology would affect the postoperative course. The preoperative parameters excluding age at surgery did not differ significantly among the 3 groups. The mean age in group 3, however, was slightly higher than in groups 1 and 2 (47.8 versus 42.8 versus 42.7 years). Postoperative hormonal changes were also similar, particularly in groups 1 and 3, staying within the normal range throughout the follow-up period (mean, 31 months; range, 3–86 months). However, postoperative improvement of hypertension showed marked differences, being significantl retarded in patients with multinodular lesions (group 3), about half of whom remained hypertensive even after 1 year. Nodular lesions other than adenoma(s) were, therefore, thought not to contribute to hormonal excess but to result from intractable hypertension.

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Resumen Treinta y siete pacientes con aldosteronismo primario fueron tratados mediante adrenalectomía total unilateral en un período de 7 años (1981–1987). Los 37 pacientes fueron clasificados en 3 grupos con base en la patología adrenal: adenoma solitario unilateral, 23 casos (grupo I); adenomas unilaterales, 3 casos (grupo 2); y adenoma con múltiples macro-o micronódulos, 11 casos (grupo 3). Las condiciones preoperatorias de los pacientes (edad, duración de la hipertensión, actividad de renina plasmática, concentración plasmática de aldosterona, y concentración sérica de potasio), los cambios postoperatorios secuenciales en los niveles hormonales, y el resultado de la hipertensión fueron comparados en los 3 grupos, con el objeto de determinar si las diferencias en la patología adrenal podrían afectar la evolución postoperatoria. Los parámetros preoperatorios, excluyendo la edad en el momento de la cirugía, no diferieron significativamente en los 3 grupos. La edad promedio en el grupo 3, sin embargo, fue ligeramente superior en los grupos 1 y 2 (47.8 versus 42.8 versus 42.7 años).Los cambios hormonales postoperatorios también fueron similares, particularmente en los grupos 1 y 3, manteniéndose dentro del rango normal a través del seguimiento (promedio, 31 meses; rango, 3–86). Sin embargo, la mejoría postoperatoria de la hipertensión exhibió diferencias marcadas, con aparación significativamente tardía en pacientes con lesiones nodulares (grupo 3); aproximadamente la mitad de éstos permanecieron hipertensos aún después de un año. Por consiguiente, se piensa que las lesiones nodulares diferentes del adenoma(s) no contribuyen al exceso hormonal sino que resultan de la hipertensión intratable.

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Résumé Trente-sept patients ayant un hyperaldostéronisme primaire ont eu une surrénalectomie totale unilatérale entre 1981 et 1987. Ces 37 patients ont été classés en 3 groupes selon la pathologie surrénalienne: adénome solitaire unilatéral, 23 cas (groupe 1); adénome unilatéral, 3 cas (groupe 2); et adénome avec nodules micro ou macroscopiques multiples, 11 cas (groupe 3). On a comparé les données préopératoires (âge, durée de l'hypertension, activité rénine plasmatique, concentration d'aldostérone plasmatique et kaliémie), les changements hormonaux postopératoires, et l'évolution de l'hypertension afin de déterminer si des différences de pathologie surrénalienne peuvent influencer l'évolution postopératoire. Les paramètres préopératoires (excepté l'âge) ne différaient pas de façon significative parmi les 3 groupes. L'âge moyen était plus élevé dans le groupe 3 que dans les groupes 1 et 2 (47.8 versus 42.8 versus 42.7 ans).Les variations hormonales postopératoires étaient également similaires, surtout dans les groupes 1 et 3, restant dans les limites de la normale pendant la période de suivi (moyenne, 31 mois; extrêmes, 3 à 86 mois). Cependant l'amélioration de l'hypertension postopératoire était différente, retardée de façon significative chez les patients ayant des lésions multinodulaires (groupe 3), la moitié d'entre eux restant hypertendus après un an. Les lésions nodulaires, étant donné que les adénomes ne donnent pas d'hypersécrétion hormonale, peuvent traduire plutôt une hypertension prolongée.

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Presented at the International Association of Endocrine Surgeons in Toronto, Ontario, Canada, September, 1989.     

Study on the lymphatic flow of the lower gastric region for radical lymphadenectomy in advanced lower gastric cancer

A prognosis of patients with a curative resected advanced cancer of the lower gastric region was worse than that of the other region of the stomach. The 5 year survival rate was only 47.3%. One of the main reasons was that a rate of lymph node recurrence was higher. In this point of view, we studied on lymphatic flow of the lower gastric region using an activated carbon particle (CH40). Lymph nodes were stained black soon after the injection of CH40 into the lower gastric wall at laparotomy. The black stained rate of an each regional lymph node was as follows. 3. 58%, 4. 17%, 5. 50%, 6. 25%, 1. 21%, 7. 58%, 8. 83%, 9. 58%, 11. 17% and 12. 33% in case of injection into the greater curvature and and 4. 31%, 6. 100%, 8. 25%, 9. 25%, 14V and 56% in case of injection into the lesser curvature. The stained rate was relatively high in 12 and 14V lymph node which we had not routinely dissected. The rates of lymph nodes stained black were related to those of cancer metastasis. The results suggest that lymphadenectomy of 12 for the cancer at the lesser curvature and that of 14V for the cancer at the greater curvature might make a prognosis of lower gastric cancer better.     

Effects of gender on prognosis of patients with known or suspected coronary artery disease undergoing contrast-enhanced dobutamine stress echocardiography.

BACKGROUND: Gender differences in the predictors of outcome among patients with known or suspected coronary artery disease (CAD) undergoing contrast-enhanced dobutamine stress echocardiography (CE-DSE) have not been completely determined. METHODS AND RESULTS: Follow-up (30+/-17 months) data for 581 men and 309 women with known or suspected CAD who underwent CE-DSE (mean age: 66 years) were obtained. Hard cardiac events included cardiac death and nonfatal myocardial infarction. Total cardiac events included hard cardiac events, unstable angina, congestive heart failure, and late revascularization (>3 months). Cardiac events occurred in 123 male and 50 female patients. Positive results for CE-DSE were associated with worse prognosis in both men and women (2-year total event free rate: 73.5% vs 88.2% in men, p<0.0001, 80.3% vs 91.3% in women, p<0.01). Addition of CE-DSE results, including abnormal left ventricular end-systolic volume response and left ventricular ejection fraction at peak stress <50%, to the clinical and rest echocardiography model provided incremental information for predicting total cardiac events (increase in chi-square value for the model from 60 to 72, p<0.001) in men and (increase in chi-square value for the model from 17 to 32, p<0.001) in women. CONCLUSIONS: CE-DSE provides incremental information for predicting future cardiac events in both men and women.