Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.

Recent studies have suggested that aldosterone plays a role in the pathogenesis of renal injury. In this study, we investigated whether local angiotensin II (Ang II) activity contributes to the progression of renal injury in aldosterone/salt-induced hypertensive rats. Uninephrectomized rats were treated with 1% NaCl in a drinking solution and one of the following combinations for 6 weeks: vehicle (2% ethanol, s.c.; n=9), aldosterone (0.75 mug/h, s.c.; n=8), aldosterone+Ang II type 1 receptor blocker olmesartan (10 mg/kg/day, p.o.; n=8), or aldosterone+olmesartan (100 mg/kg/day, p.o.; n=9). Aldosterone/salt-treated hypertensive rats exhibited severe proteinuria and renal injury characterized by glomerular sclerosis and tubulointerstitial fibrosis. Aldosterone/salt-induced renal injury was associated with augmented expression of angiotensin converting enzyme and Ang II levels in the renal cortex and medullary tissues. Renal cortical and medullary mRNA expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) as well as the collagen contents were increased in aldosterone/salt-treated hypertensive rats. Treatment with olmesartan (10 or 100 mg/kg/day) had no effect on blood pressure but attenuated proteinuria in a dose-dependent manner. Olmesartan at 10 mg/kg/day tended to decrease renal cortical and medullary Ang II levels, TGF-beta and CTGF expression, and collagen contents; however, these changes were not significant. On the other hand, an ultrahigh dose of olmesartan (100 mg/kg/day) significantly decreased these values and ameliorated renal injury. These data suggest that augmented local Ang II activity contributes, at least partially, to the progression of aldosterone/salt-dependent renal injury.     

Long-term results of open reduction for residual subluxation in congenital dislocation of the hip: A new open reduction method involving 360° circumferential capsulotomy

We report satisfactory results with a new operative treatment, conducted via an extensive anterolateral approach, involving 360 degree circumferential capsulotomy, for residual subluxation in congenital dislocation of the hip (CDH). Long-term radiographic results of this procedure (group A) were compared retrospectively with the results of partial capsulotomy (group B), which preserved the posteroinferior joint capsule. The mean center edge angle in group A (22.5°) was greater than that in group B (16.0°). Satisfactory results were achieved in 11 of 15 hips (73%) (Severin class I or II) in group A, and in 5 of 12 hips (42%) in group B. These results suggest that whole circumferential capsulotomy can remove obstacles to complete reduction, and that acetabular development can be expected in hips reduced by the procedure, without the performance of innominate osteotomy. We believe that our technique is a useful alternative for the treatment of residual subluxation in CDH.     

Macular oscillatory potentials in humans

Studies of the focal macular electroretinogram (ERG) have been made with special reference to oscillatory potentials (OPs) by using a fundus monitoring system in humans. Human macular OPs consist of 3 to 4 wavelets (mean peak interval, approximately 6.5 msec). The distribution of OPs in relation to those in a- and b-waves was studied. The amplitudes of a-waves, b-waves, and OPs of the upper macula were significantly larger than those of the lower macula. The distribution of OPs is relatively sparse in the fovea, becoming more dense than the a- and b-waves from the fovea toward the parafovea, and differing even more toward the perifovea. There was no statistical difference of amplitude in a- and b-waves between nasal and temporal macula. The amplitude of OPs in the temporal macula, however, was significantly larger than in the nasal macula. In some macular diseases, such as diabetic maculopathy, cystoid macular edema, or the convalescent stage of central serous chorioretinopathy, macular OPs were selectively reduced, leaving the a- and b-waves intact. Macular OPs can provide a new aspect of macular function and can be a sensitive indicator to assess that function in macular diseases.     

Statistical evaluation of determinants of progression of superficial bladder cancer by proportional hazards model

To evaluate clinical and pathological factors present at the initial consultation which affect disease progression, we reviewed data from 223 patients with superficial bladder cancer (pTa and pT1) who were initially treated at Nagoya University Hospital between January 1973 and December 1987. The factors included in the present analysis were age, sex, symptoms, interval between initial symptoms and first consultation, location of tumor, size, number, endoscopic shape, histological pattern of growth, grade and stage. The median duration of the follow-up after initial treatment was 46 months. Of the 223 patients, 17 died: 8 (3.6%) of bladder cancer and the remaining 9 (4.0%) of unrelated causes. Disease progression developed in 12 patients (5.4%): muscle invasion of the bladder wall in 11 and lung metastasis in one. The interval between initial treatment and progression ranged from 4 to 108 months, with a median of 11.5 months. Of the 12 patients, 9 (75%) had disease progression within 2 years. Progression was significantly associated with poor prognosis (p less than 0.001): the 5-year actuarial survival rates were 47.1% and 92.8% in patients with and without progression, respectively. Univariate analysis by Cox's proportional hazards model demonstrated that characteristics such as irritative bladder symptoms, higher-grade tumors, invasion into lamina propria, and nonpapillary growth seen at initial consultation were significantly related to disease progression. Cox's proportional hazards model produced hazard ratios of 10.2 in irritative bladder symptoms (yes vs. no), 6.3 in histological grade (grade 3 vs. grades 0-2), 4.9 in stage (pT1 vs. pTa), and 4.7 in pattern of growth (papillary vs. nonpapillary).(ABSTRACT TRUNCATED AT 250 WORDS)     

Association of Vascular Endothelial Growth Factor Expression with Tumor Angiogenesis and with Early Relapse in Primary Breast Cancer

Angiogenesis is an independent prognostic indicator in breast cancer. In this report, the relationship between expression of vascular endothclial growth factor (VEGF; a selective mitogen for endothelial cells) and the microvessel density was examined in 103 primary breast cancers. The expression of VEGF was evaluated by immunocytochemical staining using anti-VEGF antibody. The microvessel density, which was determined by immunostaining for factor VIII antigen, in VEGF-rich tumors was clearly higher than that in VEGF-poor tumors ( P <0.01). There was a good correlation between VEGF expression and the increment of microvessel density. Furthermore, postoperative survey demonstrated that the relapse-free survival rate of VEGF-rich tumors was significantly worse than that of VEGF-poor tumors. It was suggested that the expression of VEGF is closely associated with the promotion of angiogenesis and with early relapse in primary breast cancer.     

Vasodilator effects of C-type natriuretic peptide on cerebral arterioles in rats

The vasodilator effects of C-type natriuretic peptide (CNP) were investigated in isolated rat cerebral arterioles. CNP caused dose-dependent vasodilation, maximally by 10.0±2.2% at 10⁻⁶ M. The median effective concentration (EC₅₀) was 5.2×10⁻¹⁰ M. In contrast, atrial natriuretic peptide and B-type natriuretic peptide, other members of the natriuretic peptide family, produced little or no vasodilation. Pretreatment with methylene blue (10⁻⁴ M) abolished CNP-induced vasodilation, whereas pretreatment with N^G-monomethyl-

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-arginine or indomethacin did not inhibit vasodilation. Thus, CNP is suggested to cause significant vasodilation in cerebral arterioles via a cyclic guanosine monophosphate-dependent mechanism. © 1997 Elsevier Science B.V. All rights reserved.     

Effects of nitric oxide synthase inhibitors on gastric alkaline secretion in rats.

The effects of NG-nitro-L-arginine methyl ester (L-NAME), the nitric oxide (NO) synthase inhibitor, on gastric HCO3- secretion were examined in anesthetized rats. Intravenous administration of L-NAME (1, 2.5, 5 mg/kg) increased HCO3- secretion in a dose-related manner. This effect of L-NAME was mimicked by NG-mono-methyl-L-arginine (50 mg/kg, i.v.) and was antagonized significantly by concurrent administration of L-arginine but not D-arginine (200 mg/kg, i.v.). These results indicate that gastric HCO3- secretion is stimulated by inhibition of NO biosynthesis.     

Gyrate atrophy of the choroid and retina: 15 Japanese patients.

We examined 15 Japanese patients who had gyrate atrophy of the choroid and retina with hyperornithinaemia. Their visual acuities fell to 0.2 or worse in the second or third decade of life. Myopia developed late in the first decade, and the refractions decreased to -10 or -15 dioptres at age 20. Tunnel vision developed at approximately age 20. Our results suggested that the visual functions of Japanese patients were worse in the third decade or later than similarly affected Finnish patients.     

Pseudopolymorphism and phase stability in four solid forms of (6R,7R)-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo - [4,2,0]oct-2-ene-2-carboxylate (E1040)

(6R,7R)-7-[2-(5-Amino-1,2,4-thiadiazol-3-yl)-(Z)-2-methoxy- iminoacetamid]-3- [(4-carbamoyl-1-quinuclidinio)methyl]-8-oxo-5-thia-1-azabicyclo [4,2,0]oct-2-ene-2-carboxylate (1; E1040) was isolated as alpha-(decahydrate), beta-(pentahydrate), and gamma-form (anhydrate) crystals and the X-ray amorphous form. The relationship between the pseudopolymorphic crystal forms of this compound and water content was studied by X-ray diffractometry, coulometric moisture analysis, thermal analysis, and hygroscopic and vacuum-freeze-drying experiments. The phase transition of crystalline 1 clearly indicated the effect of water content on dehydration. During dehydration, hydrated alpha-form (decahydrate) crystals and beta-form (pentahydrate) crystals became anhydrate gamma-form crystals, with the diffraction angle shifting toward shorter spacing accompanied by line broadening. These results indicate conversion of hydrate 1 crystals to the anhydrous form and contraction of the crystal lattice. It was estimated that the decahydrate (alpha-form) crystals contain 8 mol/mol crystal water and 2 mol/mol adhesion water, and that the pentahydrate (beta-form) crystals contain 4 mol/mol crystal water and 1 mol/mol adhesion water. These estimates were made by comparing the data from equilibrium hydration experiments and vacuum-freeze-drying experiments. It thus follows that gamma-form crystals are anhydrate and the X-ray amorphous form exists in either the hydrous or anhydrous form.