Comparative outcomes of flexible ureteroscopy and mini-percutaneous nephrolithotomy for pediatric kidney stones larger than 2 cm.

OBJECTIVES: To compare the outcomes of flexible ureteroscopy and mini-percutaneous nephrolithotomy for pediatric kidney stones larger than 2 cm and to show the learning curves for the two procedures. METHODS: A prospectively managed database containing pediatric patients with kidney stones larger than 2 cm from June 2014 to October 2019 was analyzed. The primary outcomes were the efficacy and safety of flexible ureteroscopy and mini-percutaneous nephrolithotomy. Data on patient demographics, treatment details, stone-free rate, and complication rate were collected and compared. Learning curves were generated to estimate the effect of the surgeon's experience on surgical outcomes. RESULTS: The final analysis included 113 pediatric patients who underwent surgery for kidney stones on a total of 126 sides. The stone-free rates for mini-percutaneous nephrolithotomy and flexible ureteroscopy were 80.9% (34/42) and 79.7% (67/84), respectively (P = 0.19). The complication rates for mini-percutaneous nephrolithotomy and flexible ureteroscopy were 52.5% (21/40) and 27.4% (27/73), respectively (P = 0.01). When stone mass was considered, the stone-free rates for mini-percutaneous nephrolithotomy and flexible ureteroscopy for stones with a high mass (>5000 HU*cm2 ) were 83.3% (20/24) and 55.5% (10/18), respectively (P = 0.04). The learning curves showed that the stone-free rates for both mini-percutaneous nephrolithotomy and flexible ureteroscopy increased with the accumulation of cases. A higher stone-free rate could be achieved after approximately 20 mini-percutaneous nephrolithotomy cases and after approximately 50 flexible ureteroscopy cases. CONCLUSIONS: Flexible ureteroscopy has an acceptable stone-free rate and a lower complication rate than mini-percutaneous nephrolithotomy when treating pediatric kidney stones larger than 2 cm. Mini-percutaneous nephrolithotomy is more applicable to stones with a high mass. The stone-free rates achieved after both mini-percutaneous nephrolithotomy and flexible ureteroscopy could be improved with number of cases accumulated.

Nomograms predicting the outcomes of endoscopic treatments for pediatric upper urinary tract calculi.

OBJECTIVES: To demonstrate the efficacy and safety of mini-percutaneous nephrolithotomy, micro-percutaneous nephrolithotomy, and flexible ureteroscopy for pediatric upper urinary tract calculi and to develop nomograms predicting surgical outcomes. METHODS: A prospectively managed database containing children who were diagnosed with upper urinary tract calculi and treated with mini-percutaneous nephrolithotomy, micro-percutaneous nephrolithotomy, and flexible ureteroscopy between June 2014 and April 2019 was analysed. Patient demographics, intraoperative data, stone characteristics, stone-free rate, and complication rate were analysed and compared. Nomograms predicting the postoperative stone-free rate and complication rate were established based on predictors, and internal validation was performed. Calibration curves and decision curves were generated to assess the predictive efficacy and clinical benefit. RESULTS: Forty-three children underwent mini-percutaneous nephrolithotomy on 56 sides in 47 operations, 30 children underwent micro-percutaneous nephrolithotomy on 30 sides in 30 operations, and 275 children underwent flexible ureteroscopy on 320 sides in 288 operations. The stone-free rates were 88.5% (282/320) for flexible ureteroscopy, 89.3% (50/56) for mini-percutaneous nephrolithotomy, and 90.0% (27/30) for micro-percutaneous nephrolithotomy (P = 0.94). And the complication rates were 19.8% (57/288), 36.2% (17/47), and 33.3% (10/30), respectively (P = 0.02). Nomograms based on stone characteristics, operation duration, and the physical condition of the child were shown to have good discrimination and calibration. The area under the curve of the models was 81% for stone-free rate and 73% for complication rate. The calibration curves showed that the nomogram might underestimate the probability of stone-free rate when the threshold was below 82% and might overestimate the risk of complication rate when the threshold was over 25%. The decision curves demonstrated that the Capital Medical University nomograms improved clinical risk prediction against threshold probabilities of stone-free rate ≤20% and complication rate ≤10%. CONCLUSIONS: Both the percutaneous nephrolithotomy and flexible ureteroscopy procedures could have acceptable stone-free rates when treating pediatric stones. The Capital Medical University nomograms performed well in helping to predict stone-free and complication rates.

SIRT1 suppresses self-renewal of adult hippocampal neural stem cells.

The balance between self-renewal and differentiation of adult neural stem cells (aNSCs) is essential for the maintenance of the aNSC reservoir and the continuous supply of new neurons, but how this balance is fine-tuned in the adult brain is not fully understood. Here, we investigate the role of SIRT1, an important metabolic sensor and epigenetic repressor, in regulating adult hippocampal neurogenesis in mice. We found that there was an increase in SIRT1 expression during aNSC differentiation. In Sirt1 knockout (KO) mice, as well as in brain-specific and inducible stem cell-specific conditional KO mice, the proliferation and self-renewal rates of aNSCs in vivo were elevated. Proliferation and self-renewal rates of aNSCs and adult neural progenitor cells (aNPCs) were also elevated in neurospheres derived from Sirt1 KO mice and were suppressed by the SIRT1 agonist resveratrol in neurospheres from wild-type mice. In cultured neurospheres, 2-deoxy-D-glucose-induced metabolic stress suppressed aNSC/aNPC proliferation, and this effect was mediated in part by elevating SIRT1 activity. Microarray and biochemical analysis of neurospheres suggested an inhibitory effect of SIRT1 on Notch signaling in aNSCs/aNPCs. Inhibition of Notch signaling by a γ-secretase inhibitor also largely abolished the increased aNSC/aNPC proliferation caused by Sirt1 deletion. Together, these findings indicate that SIRT1 is an important regulator of aNSC/aNPC self-renewal and a potential mediator of the effect of metabolic changes.

Protein kinase LKB1 regulates polarized dendrite formation of adult hippocampal newborn neurons.

Adult-born granule cells in the dentate gyrus of the rodent hippocampus are important for memory formation and mood regulation, but the cellular mechanism underlying their polarized development, a process critical for their incorporation into functional circuits, remains unknown. We found that deletion of the serine-threonine protein kinase LKB1 or overexpression of dominant-negative LKB1 reduced the polarized initiation of the primary dendrite from the soma and disrupted its oriented growth toward the molecular layer. This abnormality correlated with the dispersion of Golgi apparatus that normally accumulated at the base and within the initial segment of the primary dendrite, and was mimicked by disrupting Golgi organization via altering the expression of Golgi structural proteins GM130 or GRASP65. Thus, besides its known function in axon formation in embryonic pyramidal neurons, LKB1 plays an additional role in regulating polarized dendrite morphogenesis in adult-born granule cells in the hippocampus.

Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system.

In the central nervous system (CNS) of adult mammals, neurogenesis occurs in only two restricted areas, the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Isolation of multipotent progenitor cells from other CNS regions suggests that their neurogenic potential is dictated by local environmental cues. Here, we report that astrocytes in areas outside of the SGZ and SVZ of adult mice express high levels of ephrin-A2 and -A3, which present an inhibitory niche, negatively regulating neural progenitor cell growth. Adult mice lacking both ephrin-A2 and -A3 display active ongoing neurogenesis throughout the CNS. These findings suggest that neural cell replacement therapies for neurodegeneration or injury in the adult CNS may be achieved by manipulating ephrin signaling pathways.

alpha-Aminoadipate induces progenitor cell properties of Müller glia in adult mice.

PURPOSE: Retinal Müller glia in higher vertebrates have been reported to possess progenitor cell properties and the ability to generate new neurons after injury. This study was conducted to determine the signals that can activate this dormant capacity of Müller glia in adult mice, by studying their behavior during glutamate stimulation. METHODS: Various concentrations of glutamate and its analogue alpha-aminoadipate, which specifically binds Müller glia, were injected subretinally in adult mice. Proliferating retinal cells were labeled by subretinal injection of 5'-bromo-2'-deoxyuridine (BrdU) followed by immunohistochemistry. Müller cell fates were analyzed in retinal sections by using double immunolabeling with primary antibodies against Müller and other retina-specific cell markers. The effects of glutamate and alpha-aminoadipate were also determined in purified Müller cell cultures. RESULTS: Although high levels of glutamate induce retinal damage, subtoxic levels of glutamate directly stimulate Müller glia to re-enter the cell cycle and induce neurogenesis in vivo and in purified Müller cell cultures. alpha-Aminoadipate, which selectively target glial cells, also induced expression of progenitor cell markers by Müller cells in vitro or stimulated Müller cell migration to the outer nuclear layer (ONL) and to differentiate into photoreceptors in vivo. CONCLUSIONS: Mature Müller glia in adult mice can be induced to dedifferentiate, migrate, and generate new retinal neurons and photoreceptor cells by alpha-aminoadipate or glutamate signaling. The results of this study suggest a novel potential strategy for treating retinal neurodegeneration, including retinitis pigmentosa and age-related macular degeneration, without transplanting exogenous cells.