Synthesis and permeation behavior of membranes from segmented multiblock copolymers containing poly(ethylene oxide) and poly(β-benzyl L-aspartate) blocks

Novel segmented multiblock copolymers ( 7 ) were synthesized by linking poly(ethylene oxide) (PEO) blocks with poly(β-benzyl L -aspartate)(PBLA) blocks via urethane and urea bonds, which were formed by the reaction of 4,4′-methylenediphenyl isocyanate ( 5 ) with the terminal hydroxyl groups of α-hydro-ω-hydroxypoly(oxyethylene) ( 4 ) and the terminal amino groups of poly(β-benzyl L -aspartate)-block-iminohexamethyleneimino-block-poly(β-benzyl L -aspartate) ( 3 ) [prepared from 1,6-hexanediamine ( 1 ) and β-benzyl L -aspartate N-carboxy anhydride ( 2 )], respectively. Membranes with various water contents were obtained from these copolymers by changing the lengths of the PEO and PBLA segments. The study of the permeation of 1-phenyl-1,2-ethanediol, vitamin B₁₂ and myoglobin through the membranes showed a high dependency of the permeability on the molecular weight of the solutes.     

Metachromatic leukodystrophy caused by a partial cerebroside sulfatase defect

A patient with neuropathy and myopathy since infancy but whose neuropathy had been stable for a number of years showed a profound deficiency of arylsulfatase A in leukocytes and urine. Urine contained material that stained metachromatically and cochromatographed with cerebroside sulfate. In contrast, cultured fibroblasts contained about 10-20% of normal arylsulfatase A with properties identical to properties of normal fibroblast enzyme, except that it showed no cerebroside sulfatase activity. Growing fibroblasts in the cerebroside sulfate loading test had an attenuated rate of sulfatide hydrolysis. A re-examination of the cerebroside sulfatase reaction revealed that while only limited hydrolysis occurred with low concentrations of taurodeoxycholate or cholate (type I activation), significant hydrolysis of the natural substrate did take place with high concentrations of cholate (type II activation). This suggests that there is a partial cerebroside sulfatase defect in this atypical form of metachromatic leukodystrophy.     

Histological evidence of the altered distribution of osteocytes and bone matrix synthesis in klotho-deficient mice

Mice homozygous for klotho gene deletion are well established aging models as they mimic certain aspects of human senescence e.g. osteoporosis. Induced senescence may affect cellular functions and alter the histological properties of the extracellular matrices. The present study examined the histological and ultrastructural features of osteocytes and the surrounding bone matrix in klotho-deficient mice. As expected, osteoblasts showed a flattened shape with a weak immunoreactivity for alkaline phosphatase, and the bone matrix contained many empty osteocytic lacunae. The walls of both normal and empty lacunae were intensely immunopositive for osteopontin and dentin matrix protein-1, but featured an inconsistent immunoreactivity for osteocalcin and type I collagen. Not surprisingly, TUNEL-positivity, indicative of apoptosis, was found in many osteoblasts, osteocytes, and bone marrow cells of the klotho-deficient mice. In transmission electron microscopy, an amorphous matrix containing non-collagenous organic materials was recognizable around osteoblasts and in the osteocytic lacunae. Some osteoblasts on the bone surface featured these amorphous materials in vacuoles associated with their trans-Golgi network, indicating that, under klotho-deficient conditions, they synthesize and secrete the non-collagenous structures. Some osteocytes displayed pyknosis or degenerative traits. Thus, our findings provide histological evidence that klotho gene deletion influences the spatial distribution of osteocytes and the synthesis of bone matrix proteins in addition to the accelerated aging of bone cells.     

Maternal Quercetin Consumption during Pregnancy May Help Regulate Total Cholesterol/HDL-Cholesterol Ratio without Effect on Cholesterol Levels in Male Progeny Consuming High-Fat Diet

Quercetin has been shown to have anti-obesity effects, but it is unknown whether these effects can be transmitted from mothers to their progeny. In this study, we investigated whether maternal quercetin consumption during pregnancy has a protective effect on high-fat diet–induced hyper lipid levels and overweight in progeny. Female mice consumed a control diet or a diet containing 1.0% quercetin during breeding. The male progeny were then divided into four groups that were (1) sacrificed at postnatal day 3; (2) born to dams fed the control diet and also fed the control diet (C-C), (3) born to dams fed the control diet and then fed a 30% high-fat diet (C-HF), or (4) born to dams fed the Q-diet and then fed the HF diet (Q-HF). Maternal consumption of quercetin did not affect body weight or blood lipid parameters in either dams or neonates at postnatal day 3. After 13 weeks, the Q-HF group exhibited greater body and liver weights, and higher blood cholesterol levels than the C-HF group. However, the total cholesterol/ high density lipoprotein (HDL)-cholesterol ratios in the Q-HF and C-C groups remained similar. In conclusion, maternal quercetin consumption does not appear to protect the next generation from high-fat diet–induced hyper cholesterol level in the blood and liver, and consequently overweight, but may help regulate the total cholesterol/HDL-cholesterol ratio.     

Pig kidney xenotransplantation: Progress toward clinical trials

Pig organ xenotransplantation offers a solution to the shortage of deceased human organs for transplantation. The pathobiological response to a pig xenograft is complex, involving antibody, complement, coagulation, inflammatory, and cellular responses. To overcome these barriers, genetic manipulation of the organ‐source pigs has largely been directed to two major aims—(a) deletion of expression of the known carbohydrate xenoantigens against which humans have natural (preformed) antibodies, and (b) transgenic expression of human protective proteins, for example, complement‐ and coagulation‐regulatory proteins. Conventional (FDA‐approved) immunosuppressive therapy is unsuccessful in preventing an adaptive immune response to pig cells, but blockade of the CD40:CD154 costimulation pathway is successful. Survival of genetically engineered pig kidneys in immunosuppressed nonhuman primates can now be measured in months. Non‐immunological aspects, for example, pig renal function, a hypovolemia syndrome, and rapid growth of the pig kidney after transplantation, are briefly discussed. We suggest that patients on the wait‐list for a deceased human kidney graft who are unlikely to receive one due to long waiting times are those for whom kidney xenotransplantation might first be considered. The potential risk of infection, public attitudes to xenotransplantation, and ethical, regulatory, and financial aspects are briefly addressed.     

Impact of chronic kidney disease on oncological outcomes in patients with high-risk non-muscle-invasive bladder cancer who underwent adjuvant bacillus Calmette-Guérin therapy

ObjectivesTo investigate the impact of chronic kidney disease (CKD) on oncological outcomes in patients with high-risk non-muscle invasive bladder cancer (NMIBC) who underwent adjuvant induction bacillus Calmette-Guérin (BCG) therapy after transurethral resection of bladder tumor (TURBT).Materials and MethodsWe conducted a multi-institutional retrospective study assessing 209 patients with high-risk NMIBC who underwent TURBT and subsequent adjuvant induction BCG therapy from December 1998 to April 2019. Patients were divided into 2 groups: those with preoperative estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73 m² (non-CKD group), and those with eGFR < 60 ml/min/1.73 m² (CKD group). Primary endpoints were intravesical recurrence-free survival (RFS) and muscle-invasive bladder cancer (MIBC)-free survival. Background-adjusted multivariate analyses with the inverse probability of treatment weighting (IPTW) method using the propensity score were performed to evaluate the impact of CKD on intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. Moreover, multivariable analyses were performed to assess the impact of CKD on intravesical recurrence and MIBC progression, adjusting for the competing risk of death using the Fine-Gray competing risk regression model.ResultsMedian age and follow-up period after TURBT were 72 years and 45 months, respectively. Of 209 patients, 71 (34%) were diagnosed with CKD before TURBT. Background-adjusted multivariate analyses with the IPTW method indicated that CKD was significantly associated with shorter intravesical RFS, MIBC-free survival, metastasis-free survival, cancer-specific survival, and overall survival. In the Fine-Gray competing risk regression model, CKD showed significantly higher probabilities of intravesical recurrence and MIBC progression, with an adjusted subdistribution hazard ratio of 1.886 (95% confidence interval 1.069–3.330, P = 0.028) and 3.740 (95% confidence interval 1.060–13.20, P = 0.040), respectively.ConclusionsCKD presents a risk factor of poor oncological outcomes in patients with high-risk NMIBC who underwent adjuvant induction BCG therapy after TURBT.     

The effect of frailty on the quality of life and lower urinary symptoms following robot-assisted radical prostatectomy: A longitudinal analysis (FRARP-QL Study)

ObjectivesWe aimed to evaluate the effect of frailty on health-related quality-of-life (HRQOL) and lower urinary symptoms (LUTS) following robot-assisted radical prostatectomy (RARP) in patients with prostate cancer (CaP).Materials and MethodsWe longitudinally evaluated geriatric 8 (G8), HRQOL, and LUTS for 12 months in 118 patients with RARP from January 2017 to April 2020. Patients were divided into frail (G8 ≤14) and nonfrail (G8 >14) groups. We compared the effect of frailty on HRQOL and LUTS between the frail and nonfrail groups before and 12 months after RARP.ResultsThe median age of patients was 68 years. The number of patients in the frail and nonfrail groups were 41 and 77, respectively. No significant difference in patients’ background was observed between the groups, except for the presence of cardiovascular disease (22% vs. 7.8%, P = 0.041). There was no significant difference in HRQOLs and LUTS between the groups at baseline. Similarly, HRQOLs, LUTS, and pad-free continence rates were not significantly different between the groups at 12 months after RARP. In the nonfrail group, LUTS at 12 months following RARP significantly improved compared to those at the baseline, but it did not significantly improve in the frail group. Multivariable logistic regression analysis demonstrated that frailty was not significantly associated with LUTS worsening.ConclusionsFrailty was not significantly associated with the worsening of HRQOL, LUTS, and pad-free continence rates in patients treated with RARP.     

Prognostic significance of the Ki67 index and programmed death-ligand 1 expression after radical cystectomy in patients with muscle-invasive bladder cancer

ObjectivesTo investigate the association between Ki67 index and programmed death-ligand 1 (PD-L1) expression in muscle-invasive bladder cancer (MIBC) patients after RC.Materials and MethodsWe retrospectively evaluated 262 MIBC patients treated with RC between April 2004 and April 2020. The impact of Ki67 index and PD-L1 expression on prognosis was evaluated by univariate Cox regression analysis. In addition, a pathomolecular risk score, including Ki67 and PD-L1, was developed to predict prognosis and pathological factors. We also evaluated the link between the Ki67 index and PD-L1 under the IL-6 stimulation in the bladder cancer cell lines of T24 and 5637 cells.ResultsThe median age and follow-up period was 69 years and 52 months, respectively. Ki67 index and PD-L1 expression were significantly associated with tumor recurrence. Univariate Cox regression analysis showed that pT3–4, mixed histology, lymphovascular invasion positive (LVI+), pN+, Ki67-high (>17%), and PD-L1+ were significantly associated with recurrence-free survival (RFS). The pathomolecular risk score was developed using resection margin+ (1 point), mixed histology (1 point), LVI+ (1 point), pN+ (1 point), and Ki67-high (1 point). RFS and overall survival were significantly shorter in patients with higher pathomolecular risk scores (>1) than in those with lower risk scores (≤1). Cell proliferation was significantly increased in the T24 and 5637 cells under the IL-6 stimulation, while PD-L1 expression was not.ConclusionsA significant effect of Ki67-high and PD-L1 expression on poor prognosis was observed in patients with MIBC. Further studies are necessary to elucidate the precise mechanisms of cell proliferation and PD-L1 expression in patients with MIBC.     

Adjuvant heparinization before manipulation of artery reduces early failure in primary arteriovenous fistula for end-stage renal disease patients

Clinical and Experimental Nephrology - Arteriovenous fistula (AVF) is the most preferred vascular access for hemodialysis patients, and early failure of AVF is one of the most avoidable...