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.     

Functional and immunohistochemical studies of cultured rat microglia

We studied functional and immunohistochemical characteristics of cultured rat microglia. Unstimulated microglia did not proliferate. Microglia stimulated with LCM (L929 conditioned medium: colony stimulating factor-1) had proliferative activity and increased acid phosphatase activity. LPS (lipopolysaccharide) and IFN gamma (interferon-gamma) but did not affect proliferative activity. Immunohistochemically, RCA-1 lectin and GS-1 lectin, which react to beta-D-galactose and alpha-D-galactose respectively, strongly reacted to the cytoplasm and membrane of unstimulated microglia. After stimulation with LCM, microglia elongated processes and decreased response to these lectins. On the other hand, microglia stimulated with LCM showed increased reactivity to monoclonal antibody of vimentin. Microglia stimulated with LPS had round shape and had response to these lectins and vimentin. Microglia stimulated with IFN gamma had adhesive activity and weakly stained with these lectins but not with vimentin. ED-1 (monoclonal antibody of rat monocytes/macrophages) reacted to unstimulated and stimulated microglia. In flow cytometry, unstimulated microglia expressed OX-18 (MHC class I) and W3/25 (CD4) antigen. After stimulation with IFN gamma, microglia were induced to express these antigens. CD4 antigen is a marker of helper/inducer T cells and thought to be a receptor of HIV. The results that microglia had CD4 antigen which was further induced with IFN gamma are important to investigate infection of the CNS with HIV. OX-6 (Ia) antigen was induced with IFN gamma. This indicates that the microglia plays a central role in the CNS immune reaction. These characteristics of cultured rat microglia provide useful informations to investigate the pathogenesis of the CNS disorders.     

Locally applied cilostazol suppresses neointimal hyperplasia and medial thickening in a vein graft model.

BACKGROUND: Pathological changes in vein grafts begin immediately after arterial circulation is applied to the grafts. Chemical mediator stimulation and mechanical strain induce neointimal hyperplasia and medial thickening of the vein grafts, resulting in their failure. We investigated the inhibitory effect of locally applied cilostazol, an inhibitor of cyclic adenosine monophosphate phosphodiesterase III, on neointimal hyperplasia and medial thickening of the grafts. METHODS AND RESULTS: We established a distal anastomotic stricture model of femoral vein-abdominal aorta interposition grafting in rats. In this model, neointimal hyperplasia was observed not only at the distal anastomotic sites, but also in the graft body at postoperative day 14 and was markedly progressed at day 28. A strong expression of tenascin-C was found in the media and neointima of the graft body. In the grafts around which cilostazol was administered locally using Pluronic gel, neointimal hyperplasia was significantly suppressed compared with control grafts treated with the gel alone, with the mean neointimal cross-sectional area reduced by 87.1% for the graft body and by 78.9% for the distal anastomotic sites and mean medial cross-sectional area of the graft body reduced by 54.2% at day 28 versus the control. Cilostazol treatment decreased cell proliferation and the number of tenascin-C-producing cells seen by in situ hybridization, but the expression of tenascin-C protein was not suppressed. CONCLUSION: We concluded that a single perivascular application of cilostazol inhibits neointimal hyperplasia and medial thickening of vein grafts in a rat model.     

Intravesical instillation therapy with bacillus Calmette-Guérin for superficial bladder cancer: Study of the mechanism of bacillus Calmette-Guérin immunotherapy

AIM: In order to clarify the initial step of the mechanism by which bacillus Calmette-Guérin (BCG) exhibits antitumor activity via the immune response induced in the bladder submucosa after intravesical BCG therapy for human bladder cancer, various cytokines secreted in the urine after BCG instillation were measured. METHODS: After transurethral resection of bladder cancer, a 6-week course of BCG instillation was performed. At the first and sixth weeks' dosings, spontaneously excreted urine was collected before and 4, 8, and 24 h after BCG instillation. The urinary cytokines were determined by Sandwich enzyme-linked immunosorbent assay using monoclonal antibodies against granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1beta, IL-8, interferon (IFN)-gamma, and IL-12. RESULTS: After the BCG therapy, various cytokines, such as GM-CSF, TNF-alpha, G-CSF, IL-1beta, IL-8, IFN-gamma, and IL-12 were secreted, comprising the immune response cascade. The mean urinary excretions of GM-CSF and TNF-alpha 4 h after the sixth week's instillation were significantly higher than the pre-instillation levels. There were no significant increases in the urinary IFN-gamma or IL-12 levels between 4 and 24 h after the sixth week's instillation. The TNF-alpha level 4 h after the sixth week's instillation had a strong tendency towards the absence of recurrence, with a mean follow-up of 54.1 months. The Kaplan-Meier curve showed the 2, 5, and 10-year recurrence-free survival rates were 72.4%, 65.8%, and 56.4%, respectively. CONCLUSIONS: We suggested that the urinary levels of TNF-alpha might be essential in antitumor activity after BCG therapy and might play an important role in the prevention of bladder tumor recurrence.     

Detection of urinary polyamine by a new enzymatic differential assay. (II). Comparison with conventional method

A new method of determining urinary polyamine concentration was compared with other techniques, namely, high pressure liquid chromatography (HPLC) and a polyamine test-enzyme kit. The values obtained by the new method, HPLC, and polyamine test-enzyme kit correlated well for all the fractions: diamine, spermidine and spermine. The correlation between the new method and the polyamine test-enzyme kit gave r = 0.9702, y = 1.1359x + 5.1266 (n = 48).     

Pharmacodynamic Modeling for Change of Locomotor Activity by Methylphenidate in Rats

Purpose. The locomotive activity changes after intravenous (i.v.) administration of methylphenidate (MPD) in rats were pharmacodynamically analyzed. Methods. MPD concentration in plasma, MPD concentration and dopamine (DA) level in striatal dialysate collected by microdialysis method, and the locomotor activity after i.v. administration of MPD (2, 5 and 10 mg/kg doses) were used for the analysis. Results. The transport of MPD from plasma to the interstitial fluid in the brain could be expressed by the linear two-compartment model. The clockwise hysteresis between the MPD concentration and the DA level in the dialysate could be explained by the pharmacodynamic model considering Michaelis-Menten type reuptake process of the extracellular DA into the terminal of the dopaminergic nerve and its competitive inhibition by the extracellular MPD. The inhibition constant (K_i) of MPD for DA reuptake was estimated to be 41.3 ± 73.8 nM (mean ± SE), which was closely consistent with the in vitro value after correction with dialysis recovery. The relationship between DA level in dialysate and locomotor activity was expressed by the Emax model considering two contrary effects, hyperkinesia and stereotypy. The bi-phasic locomotor activity-time profiles after high dose of MPD could be represented by this model. Conclusions. The developed model made it possible to explain the tolerance in DA increase and the complicated locomotive change induced by MPD, and may be useful for other DA reuptake inhibitors, such as amphetamine and methamphetamine.     

Interobserver and interstudy variability of myocardial blood flow and flow-reserve measurements with nitrogen 13 ammonia-labeled positron emission tomography

Background  

Experimental studies have shown that positron emission tomography (PET) with ¹³N-labeled ammonia provides accurate quantification of regional myocardial blood flow (MBF) under rest and stress conditions. To establish the clinical utility of this method, the interobserver variability and the temporal variability of serial measurements of blood flow and coronary flow reserve (CFR) must be known. This study investigated the interobserver and temporal reproducibility of ¹³N-labeled PET for measurement of MBF and CFR.