We recently characterized male DahlS.Z-Lepr fa /Lepr fa (Dahl salt-sensitive (DS)/obese) rats, which were established from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome (MetS). We have now investigated cardiac pathophysiology and metabolic changes in female DS/obese rats in comparison with homozygous lean female littermates (DahlS.Z-Lepr + /Lepr + , or DS/lean, rats). Animals were maintained on a normal diet and were subjected to echocardiography followed by various pathological analyses at 15 weeks of age. Systolic blood pressure was significantly higher in female DS/obese rats than in DS/lean females at 12 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 15 weeks. Body weight, as well as visceral and subcutaneous fat mass were significantly increased in DS/obese rats, which also manifested left ventricular (LV) diastolic dysfunction and marked LV hypertrophy and fibrosis. In addition, myocardial oxidative stress and inflammation were increased in DS/obese rats compared with DS/lean rats. Serum insulin and triglyceride levels as well as the ratio of low-density lipoprotein-to high-density lipoprotein-cholesterol levels were markedly elevated in DS/obese rats, whereas fasting serum glucose concentrations were similar in the two rat strains. The phenotype of female DS/obese rats is similar to that of MetS in humans. These animals also develop salt-sensitive hypertension and LV diastolic dysfunction as well as LV hypertrophy and fibrosis, and these changes are associated with increased cardiac oxidative stress and inflammation. Keywords: cardiac hypertrophy; diastolic dysfunction; metabolic syndrome; myocardial fibrosis; salt-sensitive hypertension INTRODUCTION Metabolic syndrome (MetS), a complex of highly debilitating disorders including hypertension, diabetes mellitus and dyslipidemia, is associated with the development of visceral obesity. 1 Adipocytes in visceral fat of obese humans secrete a variety of biological agents that are known as adipocytokines and include proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-6 as well as angiotensinogen and leptin. 2 Recent studies have revealed intricate interactions among adipocytes, the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) that contribute to the disturbed metabolic state associated with obesity. 3 Indeed, adipose tissue is thought to have an important role in the development of both hypertension and other complications related to insulin resistance. Activation of the RAAS and associated oxidative stress can result in mitochondrial abnormalities, altered bioenergetics and the accumulation of lipids in the heart, and thereby increase susceptibility to metabolic cardiomyopathy. 4

Calorie restriction (CR) can modulate the features of obesity-related metabolic and cardiovascular diseases. We have recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. DS/obese rats develop hypertension and manifest left ventricular remodeling and diastolic dysfunction, as well as increased cardiac oxidative stress and inflammation. We have now investigated the effects of CR on cardiac pathophysiology in DS/obese rats. DS/obese rats were fed either normal laboratory chow ad libitum or a calorie-restricted diet (65% of the average food intake for ad libitum) from 9 to 13 weeks. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+) or DS/lean) littermates served as controls. CR reduced body weight in both DS/obese and DS/lean rats, as well as attenuated the development of hypertension in DS/obese rats without affecting blood pressure in DS/lean rats. CR also reduced body fat content, ameliorated left ventricular hypertrophy, fibrosis, and diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats. In addition, it increased serum adiponectin concentration, as well as downregulated the expression of angiotensin-converting enzyme and angiotensin II type 1A receptor genes in the heart of DS/obese rats. Our results thus show that CR attenuated obesity and hypertension, as well as left ventricular remodeling and diastolic dysfunction in DS/obese rats, with these latter effects being associated with reduced cardiac oxidative stress and inflammation.

Objectives: To evaluate a clinical pathway of discharge on postoperative day 3 for the tension-free vaginal mesh (TVM) procedure in patients with pelvic organ prolapse (POP). Methods: Between May 2006 and December 2007, 305 consecutive women with POP quantification stage 3 or 4 were planned to undergo the TVM procedure in a single general hospital. Excluding five patients with concomitant hysterectomy, a pathway (removal of the indwelling urethral catheter on the next morning, discharge on postoperative day 3) was applied to the remaining 300 patients. The perioperative complications and postoperative hospitalization were prospectively evaluated in this case series. Results: Perioperative complications were: bladder injury (11 cases, 3.7%), vaginal wall hematoma (two cases, 0.7%), rectal injury (one case, 0.3%) and temporary hydronephrosis (one case, 0.3%). None needed blood transfusion. The indwelling urethral catheters were removed on the next morning as in the pathway in 287 cases (95.6%), and none required clean intermittent catheterization at home. Postoperative hospitalization was within 3 days in 280 cases (93.3%). The six cases (2.0%) with longer hospitalization were due to complications (two cases of bladder injury, one of rectal injury, one of blood loss over 200 mL, one of temporary urinary retention, and one of hydronephrosis). Two patients were re-hospitalized within one month due to vaginal bleeding or gluteal pain. Conclusions: Patients generally accepted the pathway of discharge on postoperative day 3 in spite of the Japanese culture preferring a longer hospital stay.

Objective:The DahlS.Z-Leprfa/Leprfa (DS/obese) rat strain was established from a cross between Dahl salt-sensitive rats and Zucker fatty (fa/fa) rats, the latter of which harbor a missense mutation in the leptin receptor gene (Lepr). We examined whether DS/obese rats might be a suitable animal model of metabolic syndrome in humans.Methods:The systemic pathophysiological and metabolic characteristics of DS/obese rats were determined and compared with those of homozygous lean littermates, namely, DahlS.Z-Lepr+/Lepr+ (DS/lean) rats.Results:Systolic blood pressure was higher in DS/obese rats fed a normal diet than in DS/lean rats at 11 weeks of age and thereafter. The survival rate of DS/obese rats was significantly lower than that of DS/lean rats at 18 weeks. Body weight, visceral and subcutaneous fat mass, as well as heart, kidney and liver weights, were increased in DS/obese rats at 18 weeks compared with DS/lean rats. Serum low-density lipoprotein (LDL)-cholesterol, triglyceride and insulin concentrations, as well as the ratio of LDL-cholesterol to high-density lipoprotein-cholesterol levels, were increased in DS/obese rats, whereas serum glucose concentration did not differ significantly between DS/obese and DS/lean rats. Creatinine clearance was decreased and urinary protein content was increased in DS/obese rats, which also manifested lipid accumulation in the liver and elevation of serum alanine aminotransferase levels.Conclusion:These results show that the phenotype of DS/obese rats is similar to that of humans with metabolic syndrome, and that these animals may thus be an appropriate model for this condition.

BackgroundMetabolic syndrome (MetS) enhances salt sensitivity of blood pressure and is an important risk factor for cardiovascular disease. The effects of dietary salt restriction on cardiac pathology associated with metabolic syndrome remain unclear.Methods and ResultsWe investigated whether dietary salt restriction might ameliorate cardiac injury in DahlS.Z‐Leprfa/Leprfa (DS/obese) rats, which are derived from a cross between Dahl salt‐sensitive and Zucker rats and represent a model of metabolic syndrome. DS/obese rats were fed a normal‐salt (0.36% NaCl in chow) or low‐salt (0.0466% NaCl in chow) diet from 9 weeks of age and were compared with similarly treated homozygous lean littermates (DahlS.Z‐Lepr+/Lepr+, or DS/lean rats). DS/obese rats fed the normal‐salt diet progressively developed hypertension and showed left ventricular hypertrophy, fibrosis, and diastolic dysfunction at 15 weeks. Dietary salt restriction attenuated all of these changes in DS/obese rats. The levels of cardiac oxidative stress and inflammation and the expression of cardiac renin–angiotensin–aldosterone system genes were increased in DS/obese rats fed the normal‐salt diet, and dietary salt restriction downregulated these parameters in both DS/obese and DS/lean rats. In addition, dietary salt restriction attenuated the increase in visceral adipose tissue inflammation and the decrease in insulin signaling apparent in DS/obese rats without reducing body weight or visceral adipocyte size. Dietary salt restriction did not alter fasting serum glucose levels but it markedly decreased the fasting serum insulin concentration in DS/obese rats.ConclusionsDietary salt restriction not only prevents hypertension and cardiac injury but also ameliorates insulin resistance, without reducing obesity, in this model of metabolic syndrome.

We reviewed 41 cases of transitional cell carcinoma of the renal pelvis and ureter with special reference to the coexistence or subsequent development of bladder cancer. Bladder cancer was associated with an upper urinary tract neoplasm in 20 of the 41 cases (48 per cent). Most of these patients (15 of 20) were treated by radical total cystectomy of 1-stage nephroureterocystectomy. The incidence of ureteral stump cancer after nephrectomy alone or incomplete nephroureterectomy was 64 per cent (7 of 11 patients). Twelve surgically removed specimens of the renal pelvis, ureter and/or bladder were examined extensively for the histological association of pre-neoplastic disease, such as atypical hyperplasia and carcinoma in situ. Every specimen had these changes of the urothelium adjacent to and remote from obvious tumors.

A clinical and pathological analysis was done on 87 autopsy cases of carcinoma of the bladder. Of the 87 cases 68 were men and 19 were women, with a mean age of 64 years. The average survival time was 39 months from the onset of symptoms to death. The patients with multiple tumors had a longer average survival time than the patients with single tumors (51 compared to 40 months), and the average survival times were definitely more favorable for men than for women (43 compared to 23 months). Histological examination revealed transitional cell carcinoma in 77 patients, squamous cell carcinoma in 4, vesical adenocarcinoma in 3 and urachal adenocarcinoma in 3. Squamous cell carcinoma and vesical adenocarcinoma seemed to be more malignant neoplasms. Metastasis was noted in 58 of 87 cases (66.7 per cent) and occurred most frequently in lymph nodes (37.9 per cent), liver (29.9 per cent), lungs (29.9 per cent) and bones (24.1 per cent). Of the 87 cases of bladder carcinoma 11 had primary carcinoma in organs other than the bladder.

Cilnidipine attenuated LV fibrosis and diastolic dysfunction as well as LV concentricity to a greater extent than did amlodipine in Dahl salt-sensitive rats. The superior cardioprotective action of cilnidipine is likely attributable, at least in part, to the greater antioxidant and anti-inflammatory effects associated with inhibition of cardiac RAS gene expression observed with this drug.