[A Case Diagnosed as Iatrogenic Vesical Tuberculosis 4 Years after Intravesical Immunotherapy Using Bacillus Calmette-Guérin (BCG) for the Treatment of Bladder Carcinoma].

We report a case of iatrogenic vesical tuberculosis diagnosed 4 years after intravesical immunotherapy using Bacillus Calmette- Guérin (BCG) for the treatment of bladder carcinoma. A 72-year-old man underwent a transurethral resection (TUR) of multiple noninvasive urothelial carcinomas and intravesical BCG infusion (40 mg/week) for 7 weeks to prevent the recurrence of bladder carcinoma. BCG infusion therapy was terminated because of the appearance of Reiter's syndrome, including arthritis of the left toe joint, conjunctivitis and non-gonococcal urethritis as complications. The patient suffered from repeated cystitis, bladder atrophy and urethral stenosis. The cystitis improved with the administration of antibiotics (Levofloxacin) but persisted without a complete cure. Four years later, a cystoscopy revealed mucosal erosion and a white coating. An acid-fast bacteria examination of a urine sample using bacteria incubation and DNA PCR revealed the presence of Mycobacterium bovis. Finally, anti-tuberculosis therapy (INH＋REP＋EB) was initiated after the patient was diagnosed as having iatrogenic bladder tuberculosis resulting from BCG immunotherapy. The tuberculosis bacteria subsequently disappeared from the urine samples, and the gross appearance of the bladder mucosa improved. Bladder carcinoma has not recurred to date. Intravesical BCG infusion therapy has a good anti-tumor effect and can help prevent tumor recurrence after TUR therapy in case of noninvasive bladder carcinoma. However, there is a risk of severe complications arising from the BCG infusion. In the present case, an adequate bacteria examination was not performed, even though antibiotics were repeatedly administered for cystitis. In particular, the patient was not tested for the presence of acid-fast bacteria for 4 years after the intravesical BCG infusion therapy. Furthermore, among patients who received anti-bacteria therapy for repeated cystitis after BCG infusion, a bacteria examination including bacteria incubation, was not ordered in 19 out of 30 cases treated at our hospital over the past 5 years. In conclusion, bacteria examination, including tests for acid-fast bacteria, should be immediately performed when repeated and/or persistent cystitis occurs after BCG infusion therapy.

Pregnancy and delivery in women with renovascular hypertension due to multiple intrarenal microaneurysms: a report of two cases.

We herein report two cases of pregnant women who had chronic hypertension caused by renovascular hypertension due to multiple intrarenal microaneurysms from unknown causes, who had similar clinical courses. During the first pregnancy, both women developed uncontrollable severe hypertension that finally led to superimposed preeclampsia; however, during the second pregnancy, the blood pressure was controlled well, and the clinical courses were uneventful. These cases suggest that an uneventful term delivery may be achieved with adequate blood pressure control in pregnant women with chronic hypertension caused by renovascular hypertension, and a prior eventful clinical course of delivery does not affect the subsequent clinical course.

Knockout of endothelin-1 in vascular endothelial cells protects against insulin resistance induced by high-salt diet in mice.

The increased plasma Endothelin-1 (ET-1) level has been associated with development of insulin resistance in obese and hypertensive patients. However, the underlying mechanism remains elusive. Here we investigate the potential role of endothelial cell-derived ET-1 in mediating insulin resistance induced by high-salt diet. To address this issue, we used vascular endothelial cell-specific ET-1 knockout (VEETKO) mice and its littermates fed with a high-salt diet containing 8% NaCl for 3 weeks, and evaluated the metabolic parameters. High-salt diet increased systolic blood pressure similarly in both genotypes. We observed impairment of glucose tolerance in control mice despite comparable increase of serum insulin concentration with VEETKO mice. We further found that VEETKO mice showed preservation of circulating adiponectin level - an adipokine with insulin-sensitizing property - and prevention of the upregulation of the pro-inflammatory adipokine TNF-α, which lead towards better insulin sensitivity. These results provide evidence that blockade of endothelin signaling may be proven beneficial in preventing high-salt induced insulin resistance.

Endothelial cell-derived endothelin-1 promotes cardiac fibrosis in diabetic hearts through stimulation of endothelial-to-mesenchymal transition.

BACKGROUND: Persistently high plasma endothelin-1 (ET-1) levels in diabetic patients have been associated with the development of cardiac fibrosis, which results from the deposition of extracellular matrix and fibroblast recruitment from an as-yet unknown source. The underlying mechanism, however, remains elusive. Here, we hypothesize that ET-1 might contribute to the accumulation of cardiac fibroblasts through an endothelial-to-mesenchymal transition in diabetic hearts. METHODS AND RESULTS: We induced diabetes mellitus in vascular endothelial cell-specific ET-1 knockout [ET-1(f/f);Tie2-Cre (+)] mice and their wild-type littermates using the toxin streptozotocin. Gene expression and histological and functional parameters were examined at 8, 24, and 36 weeks after the induction of diabetes mellitus. Diabetes mellitus increased cardiac ET-1 expression in wild-type mice, leading to mitochondrial disruption and myofibril disarray through the generation of superoxide. Diabetic mice also showed impairment of cardiac microvascularization and a decrease in cardiac vascular endothelial growth factor expression. ET-1 further promotes cardiac fibrosis and heart failure through the accumulation of fibroblasts via endothelial-to-mesenchymal transition. All of these features were abolished in ET-1(f/f);Tie2-Cre (+) hearts. Targeted ET-1 gene silencing by small interfering RNA in cultured human endothelial cells ameliorated high glucose-induced phenotypic transition and acquisition of a fibroblast marker through the inhibition of transforming growth factor-beta signaling activation and preservation of the endothelial cell-to-cell contact regulator VE-cadherin. CONCLUSIONS: These results provide new insights suggesting that diabetes mellitus-induced cardiac fibrosis is associated with the emergence of fibroblasts from endothelial cells and that this endothelial-to-mesenchymal transition process is stimulated by ET-1. Targeting endothelial cell-derived ET-1 might be beneficial in the prevention of diabetic cardiomyopathy.

Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation.

AIMS: Although endothelin-1 (ET-1) has been suggested to contribute to the pathogenesis of neointima formation and atherosclerosis, the individual roles of ET-1 derived from certain cell types in this disease remain unclear. In this study, we determined the role of vascular endothelial ET-1 on vascular inflammation and neointima formation using vascular endothelial ET-1-knockout [ET-1(f/f); Tie2-Cre (+)] mice. METHODS AND RESULTS: Intimal hyperplasia was induced by complete ligation of the left carotid artery in 12-week-old male ET-1(f/f);Tie2-Cre (+) mice (n = 35) and the wild-type (WT) littermates (n = 34). Following this intervention, neointima formation was reduced in ET-1(f/f);Tie2-Cre (+) mice compared with the WT mice, independent of the difference in blood pressure. This reduction was associated with a decrease in inflammatory cell recruitment to the vessel wall, which was accompanied by reduced expression levels of endothelial adhesion molecules as well as chemokines and a decrease in vascular smooth muscle cell proliferation. CONCLUSION: The results of our study provide direct evidence for the role of vascular endothelial ET-1 in mediating vascular inflammation and neointima formation following vascular injury in addition to promoting vasoconstriction and cell proliferation. Furthermore, this study suggests a strategy for the efficient design of ET receptor antagonists with targeted inhibition of ET-1 signalling in vascular endothelial cells.

Obesity-induced upregulation of myocardial endothelin-1 expression is mediated by leptin.

Several studies have shown that leptin, the product of the obese gene, may link obesity with cardiovascular diseases, and in particular with cardiac hypertrophy. In vitro studies suggest that the mechanism by which leptin causes cardiac hypertrophy involves the upregulation of endogenous endothelin-1 (ET-1), a potent vasoconstrictor and mitogen. Whether obesity-associated hyperleptinemia causes an increase in myocardial ET-1 expression in vivo remains unclear. To address this issue, we fed mice with a high-fat diet and analyzed serum levels of ET-1 and ET-1 mRNA in the heart. We found that in mice fed a high-fat diet, serum ET-1, myocardial ET-1, leptin and leptin receptor mRNA were all elevated. In contrast, in leptin-deficient obese (ob/ob) mice, both serum and myocardial ET-1 levels were not higher than in wild type mice. These findings suggest that upregulation of myocardial ET-1 by obesity is mediated by leptin.