Optimal allogeneic islet dose for transplantation in insulin-dependent diabetic Macaca fascicularis monkeys.

Many groups are working to improve the results of clinical allogeneic islet transplantation in a primate model. However, few studies have focused on the optimal islet dose for achieving normal glycemia without exogenous insulin after transplantation in primate models or on the relationship between rejection and islet amyloid polypeptide (IAPP) expression. We evaluated the dose (10,000, 20,000, and > 25,000 islet equivalents (IEQ)/kg) needed to achieve normal glycemia without exogenous insulin after transplantation using eleven cynomolgus monkeys, and we analyzed the characteristics exhibited in the islets after transplantation. 10,000 IEQ/kg (N = 2) failed to control blood glucose level, despite injection with the highest dose of exogenous insulin, and 20,000 IEQ/kg group (N = 5) achieved unstable control, with a high insulin requirement. However, 25,000 IEQ/kg (N = 4) achieved normal glycemia without exogenous insulin and maintained it for more than 60 days. Immunohistochemistry results from staining islets found in liver biopsies indicated that as the number of transplanted islets decreased, the amount of IAPP accumulation within the islets increased, which accelerated CD3+ T cell infiltration. In conclusion, the optimal transplantation dose for achieving a normal glycemia without exogenous insulin in our cynomolgus monkey model was > 25,000 IEQ/kg, and the accumulation of IAPP early after transplantation, which depends on the transplanted islet dose, can be considered one factor in rejection.

Integrated whole liver histologic analysis of the allogeneic islet distribution and characteristics in a nonhuman primate model.

The most obvious method to observe transplanted islets in the liver is direct biopsy, but the distribution and location of the best biopsy site in the recipient's liver are poorly understood. Islets transplanted into the whole liver of five diabetic cynomolgus monkeys that underwent insulin-independent survival for an extended period of time after allo-islet transplantation were analyzed for characteristics and distribution tendency. The liver was divided into segments (S1-S8), and immunohistochemistry analysis was performed to estimate the diameter, beta cell area, and islet location. Islets were more distributed in S2 depending on tissue size; however, the number of islets per tissue size was high in S1 and S8. Statistical analysis revealed that the characteristics of islets in S1 and S8 were relatively similar to other segments despite various transplanted islet dosages and survival times. In conclusion, S1, which exhibited high islet density and reflected the overall characteristics of transplanted islets, can be considered to be a reasonable candidate for a liver biopsy site in this monkey model. The findings obtained from the five monkey livers with similar anatomical features to human liver can be used as a reference for monitoring transplanted islets after clinical islet transplantation.

Enhanced effect of human mesenchymal stem cells expressing human TNF-αR-Fc and HO-1 gene on porcine islet xenotransplantation in humanized mice.

BACKGROUND: Porcine islet xenotransplantation is considered an attractive alternative treatment for type 1 diabetes mellitus. However, it is largely limited because of initial rejection due to Instant Blood-Mediated Inflammatory Reaction (IBMIR), oxidative stress, and inflammatory responses. Recently, soluble tumor necrosis factor-ɑ receptor type I (sTNF-αR) and heme oxygenase (HO)-1 genes (HO-1/sTNF-αR) have been shown to improve the viability and functionality of porcine islets after transplantation. METHODS: In this study, genetically modified mesenchymal stem cells (MSCs) expressing the HO-1/sTNF-αR genes (HO-1/sTNF-αR-MSC) were developed using an adenoviral system, and porcine islet viability and function were confirmed by in vitro tests such as GSIS, AO/PI, and the ADP/ATP ratio after coculturing with HO-1/sTNF-αR-MSCs. Subsequently, isolated porcine islets were transplanted underneath the kidney capsule of diabetic humanized mice without MSCs, with MSCs or with HO-1/sTNF-αR-MSCs. RESULTS: According to the results, the HO-1/sTNF-αR-MSC-treated group exhibited improved survival of porcine islets and could reverse hyperglycemia more than porcine islets not treated with MSCs or islets cotransplanted with MSCs. Moreover, the HO-1/sTNF-αR-MSC group maintained its morphological characteristics and the insulin secretion pattern of transplanted porcine islets similar to endogenous islets in immunocompetent humanized mice. CONCLUSIONS: Our results suggest that HO-1/sTNF-αR-MSCs are efficient tools for porcine islet xenotransplantation, and this study may provide basic information for pre-clinical animal models and future clinical trials of porcine islet xenotransplantation.

Men with Hypertension are More Likely to Have Severe Lower Urinary Tract Symptoms and Large Prostate Volume.

OBJECTIVE: Patients with lower urinary tract symptoms (LUTS) have a higher prevalence of cardiovascular disease. We evaluated the correlation between LUTS and cardiovascular risk factors in men presenting with benign prostatic hyperplasia (BPH). METHODS: We retrospectively reviewed the medical records of 295 men with transurethral resection of the prostate for the treatment of BPH and LUTS. Risk factors for cardiovascular disease included: hypertension, diabetes mellitus (DM), smoking, and dyslipidemia. The severity of LUTS measured by the International Prostatic Symptom Score (IPSS), prostate volume, prostate specific antigen (PSA), maximal urinary flow rate (Qmax), and postvoid residual urine (PVR) in subjects with or without cardiovascular risk factors were compared. RESULTS: IPSS-total (22.9 ± 7.8 vs. 21.2 ± 7.3, P = 0.01) and obstructive symptom score (13.3 ± 5.2 vs. 11.9 ± 4.7, P = 0.01) was significantly different between men with hypertension and without cardiovascular risk factors. There was no significant difference of variables between subjects with DM, smoking or dyslipidemia and without cardiovascular risk factors. In the Pearson correlation, the systolic and diastolic blood pressure (BP) were related with prostate volume (r = 0.138, P = 0.040; r = 0.163, P = 0.020), IPSS-total (r = 0.139, P = 0.043; r = 0.138, P = 0.043), and an obstructive symptom score (r = 0.168, P = 0.014; r = 0.143, P = 0.037), respectively. CONCLUSIONS: Men with hypertension are more likely to have a higher IPSS and large prostate volume than men without hypertension. This finding implicates a pathophysiological association between hypertension and LUTS, and the need to manage comorbid symptoms simultaneously.

Predictors of intravesical recurrence after radical nephroureterectomy for upper urinary tract urothelial carcinoma: an inflammation-based prognostic score.

PURPOSE: Systemic inflammatory responses, which are defined in terms of the Glasgow prognostic score (GPS), have been reported to be independent predictors of unfavorable outcomes in various human cancers. We assessed the utility of the GPS as a predictor of intravesical recurrence after radical nephroureterectomy (RNU) in upper urinary tract carcinoma (UTUC). MATERIALS AND METHODS: We collected data for 147 UTUC patients with no previous history of bladder cancer who underwent RNU from 2004 to 2012. Associations between perioperative clinicopathological variables and intravesical recurrence were analyzed by using univariate and multivariate Cox regression models. RESULTS: Overall, 71 of 147 patients (48%) developed intravesical recurrence, including 21 patients (30%) diagnosed with synchronous bladder tumor. In the univariate analysis, performance status, diabetes mellitus (DM), serum albumin, C-reactive protein, GPS, and synchronous bladder tumor were associated with intravesical recurrence. In the multivariate analysis, performance status (hazard ratio [HR], 2.33; 95% confidence interval [CI], 1.41-3.85; p=0.001), DM (HR, 2.04; 95% CI, 1.21-3.41; p=0.007), cortical thinning (HR, 2.01; 95% CI, 1.08-3.71; p=0.026), and GPS (score of 1: HR, 6.86; 95% CI, 3.69-12.7; p=0.001; score of 2: HR, 5.96; 95% CI, 3.10-11.4; p=0.001) were independent predictors of intravesical recurrence. CONCLUSIONS: Our results suggest that the GPS as well as performance status, DM, and cortical thinning are associated with intravesical recurrence after RNU. Thus, more careful follow-up, coupled with postoperative intravesical therapy to avoid bladder recurrence, should be considered in these patients.

Predicting factors for stent failure-free survival in patients with a malignant ureteral obstruction managed with ureteral stents.

PURPOSE: To determine predictive factors for stent failure-free survival in patients treated with a retrograde ureteral stent for a malignant ureteral obstruction. MATERIALS AND METHODS: We retrospectively reviewed 71 patients who underwent insertion of a cystoscopic ureteral stent due to a malignant ureteral obstruction between May 2004 and June 2011. Performance status, type of cancer, hydronephrosis grade, location of the obstruction, presence of bladder invasion, C-reactive protein (CRP), serum albumin, and inflammation-based prognostic score (Glasgow prognostic score, GPS) were assessed using a Cox proportional regression hazard model as predicting factors for stent failure. RESULTS: A univariate analysis indicted that hypoalbuminemia (<3.5 g/dL; hazard ratio [HR], 2.43; 95% confidence interval [CI], 1.21 to 4.86; p=0.012), elevated CRP (≥1 mg/dL; HR, 4.79; 95% CI, 2.0 to 11.1; p=0.001), and presence of a distal ureter obstruction (HR, 3.27; 95% CI, 1.19 to 8.95; p=0.021) were associated with stent failure-free survival. A multivariate analysis revealed that the presence of a mid and lower ureteral obstruction (HR, 3.27; 95% CI, 1.19 to 8.95; p=0.007), GPS ≥1 (HR, 7.22; 95% CI, 2.89 to 18.0; p=0.001), and elevated serum creatinine before ureteral stent placement (>1.2 mg/dL; HR, 2.16; 95% CI, 1.02 to 4.57; p=0.044) were associated with stent failure-free survival. CONCLUSIONS: A mid or lower ureteral obstruction, GPS ≥1, and serum creatinine before ureteral stent insertion >1.2 mg/dL were unfavorable predictors of stent failure-free survival. These factors may help urologists predict survival time.