Cerebral organoids are three-dimensional nerve cultures induced by embryonic stem cells(ESCs)or induced pluripotent stem cells(iPSCs)that mimic the structure and function of human brain.With the continuous optimization of cerebral organoid culture technology and the combination with emerging technologies such as organ transplantation,gene editing and organoids-on-chip,complex brain tissue structures such as functional vascular structures and neural circuits have been produced,which provides new methods and ideas for studying human brain development and diseases.This article reviews the latest advances in brain organoid technology,describes its application in neurological diseases and advances in stroke modeling and transplantation treatment.

Post-stroke cognitive impairment(PSCI)is mainly manifested as learning and memory disorders.Highly enriched RNA m6A methylation modification in mammalian brain is involved in glial cell-mediated neuroinflammation.Given that neuroinflammation is the main mechanism for neural damage and spatial and memory impairment of PSCI,it is speculated that RNA m6A methylation modification can regulate the inflammatory response of glial cells after stroke to improve PSCI.This review summarizes and analyzes the role of RNA m6A methylation modification in the development of PSCI and analyzes its detailed mechanism of regulating glial cell-mediated inflammation,which will provide reference for researchers in this field.

BACKGROUND:Long non-coding RNAs(lncRNAs),as important regulators of the inflammatory response,are involved in the immune-inflammation-brain crosstalk mechanism after ischemic stroke and have the potential to become a therapeutic agent for neurological dysfunction after ischemic stroke. OBJECTIVE:To analyze and summarize the molecular mechanism of lncRNA acting on glial cells involved in the neuroimmuno-inflammatory cascade response after ischemic stroke and the associated signaling pathways,pointing out that lncRNAs have the potential to regulate inflammation after ischemic stroke. METHODS:PubMed was searched using the search terms of"ischemic stroke,long non-coding RNA,neuroinflammation,immune function,signal pathway,microglia,astrocytes,oligodendrocyte,mechanism,"and 63 relevant documents were finally included for review. RESULTS AND CONCLUSION:In the early stage of ischemic stroke,the death of nerve cells due to ischemia and hypoxia activates the innate immune response of the brain,promoting the secretion of inflammatory factors and inducing blood-brain barrier damage and a series of inflammatory cascades responses.As an important pathogenesis factor in ischemic stroke,the neuroimmuno-inflammatory cascade has been proved to seriously affect the prognosis of patients with ischemic stroke,and it needs to be suppressed promptly in the early stage.Neuroinflammation after ischemic stroke usually induces abnormal expression of a large number of lncRNAs that mediate a series of neuro-immune-inflammatory crosstalk mechanisms through regulating the polarization of microglia,astrocytes and oligodendrocytes to exert post-stroke neuroprotective effects.LncRNAs,as important regulatory factors of the inflammatory response,inhibit the neuroimmuno-inflammatory cascade response after ischemic stroke through regulating nuclear factor-κB,lncRNA-miRNA-mRNA axis,Rho-ROCK,MAPK,AKT,ERK and other signaling pathways to effectively improve neurological impairment after ischemic stroke.Most of experimental studies on the interaction between lncRNAs and ischemic stroke are based on a middle cerebral artery occlusion model or a cerebral ischemia-reperfusion injury model,but no clinical trials have been conducted.Therefore,it remains to be further explored about whether lncRNAs can be safely applied in clinical practice.At present,there are many therapeutic drugs for the treatment of ischemic stroke,but there are relatively few studies on the application of lncRNAs,exosomes and other transplantation technologies for the treatment of ischemic stroke using tissue engineering technology,which need to be further explored.lncRNA has become an important target for the treatment of ischemic stroke with its relative stability and high specificity.In future studies,more types of inflammatory lncRNAs that function under ischemic-hypoxia conditions should continue to be explored,in order to provide new research directions for the treatment of neuroinflammation after ischemic stroke.

Post-stroke cognitive impairment(PSCI)is a common complication after stroke,which significantly affects quality of life.However,the pathogenesis has not been fully explained.Increasing evidence has shown that the mechanism of programmed cell death(PCD)is related to PSCI,including apoptosis,necroptosis,pyroptosis,PANoptosis,parthanatos,and ferroptosis.Therefore,it is crucial to clearly understand the various mechanisms of PCD and their relationship with PSCI,and to elucidate the role of PCD in PSCI pathogenesis.The article reviews six PCD pathways related to PSCI,summarizes their mechanisms of action in PSCI,and elucidates the possible crosstalk among pathways to provide a basis for clinical targeting of regulatory factors in the PCD pathway for PSCI treatment.

Objective:To explore the cerebral cortical mechanism of intravesical electrical stimulation (IVES) on neurogenic underactive bladder (UAB).Methods:A prospective study was conducted on healthy subjects (HS) recruited in our center and patients with neurogenic UAB treated with IVES from March 2022 to June 2023 were included. HS inclusion criteria: females aged 18-60 years; the 72-hour voiding diary was normal; the urine volume was 200-400 ml, and the free urine flow rate > 20 ml/s. HS exclusion criteria: urinary and neurological related disorders; major diseases of all systems of the body; cognitive dysfunction. Inclusion criteria for UAB patients: females aged 18-60 years; neurogenic UAB due to incomplete spinal cord injury (grade D or E) with a duration of > 3 months; previous routine use of intermittent catheterization, or indication of intermittent catheterization (residual urine accounts for > 40% of functional bladder capacity). Exclusion criteria for UAB patients: decreased bladder compliance on urodynamic examination; symptomatic urinary tract infection; concomitant hydronephrosis, vesicoureteral reflux or renal insufficiency (serum creatinine greater than 1.5 times of the normal upper limit); bladder tumors; neurological related diseases; pregnant or trying to conceive; a pacemaker or defibrillator has been implanted in the body. At baseline, the 24-hour voiding diary, residual urine, voiding efficiency, first sensation of bladder filling volume and American Urological Association Symptom Index Quality of Life scores(AUA-SI-QOL)were recorded, and the resting state-functional near-infrared spectroscopy scans of the prefrontal cortex was completed in the bladder emptying state and the strong desire to void stage. The UAB group was re-evaluated after completing 20 IVES treatments. Improvement in residual urine > 50% was defined as success of IVES treatment. The differences in functional connectivity in the prefrontal lobe between the successful UAB group before and after IVES and between the successful UAB group and the HS group were compared.Results:A total of 16 HS and 18 UAB patients were included. Eleven UAB patients were successfully treated by IVES, and 7 UAB patients were failed. Compared with pre-treatment, the post-treatment residual urine volume [90.0(50.0, 120.0) ml vs. 210.0(110.0, 300.0) ml], 24-h intermittent catheterization [3.0(2.0, 4.0) times vs. 4.0(3.0, 4.0) times], first sensation of bladder filling volume [275.0(245.0, 280.0) ml vs. 295.0 (290.0, 315.0) ml] and AUA-SI-QOL score [2.0 (2.0, 3.0) vs. 4.0 (4.0, 4.0)] of the successful UAB group were significantly lower ( P<0.05), and the voiding efficiency [75.0% (69.0%, 85.0%) vs. 42.0% (35.0%, 77.0%)] was significantly higher ( P< 0.05). Before IVES, the successful UAB group compared with the HS group, internal prefrontal functional connectivity was significantly attenuated in the bladder emptying state involving 5 brain regions: bilateral dorsolateral prefrontal cortex (DLPFC), bilateral frontopolar area, and left pars triangularis. And in the strong desire to void stage significantly attenuated involving 4 brain regions: bilateral DLPFC and bilateral frontopolar area. In the successful UAB group after IVES compared with the HS group, internal prefrontal functional connectivity was significantly attenuated in the bladder emptying state involving 2 brain regions: left pars triangularis and left DLPFC. And in the strong desire to void stage involving 4 brain regions: left DLPFC, right frontopolar area, the left pars opercularis Broca's area, and the left pars triangularis. After IVES in the successful UAB group compared with pretreatment, prefrontal internal functional connectivity was significantly enhanced in the bladder emptying state involving 4 brain regions: bilateral DLPFC and bilateral frontopolar area, and in the strong desire to void stage involving 4 brain regions: bilateral DLPFC, bilateral frontopolar area. Conclusions:Significant enhancement of functional connectivity within the prefrontal lobes (bilateral DLPFC and bilateral frontopolar area) may be the cortical mechanism of IVES for neurogenic UAB.

Objective:The purpose of this study was to explore the critical values of monitored indexes of perioperative major adverse cardiac events(MACE), so as to take effective prevention and treatment measures in time to maintain the stability of perioperative cardiac function to further improve the perioperative safety of elderly patients with biliary diseases.Methods:The clinical data of 246 elderly patients with biliary diseases in our hospital from May 2016 to February 2022 were collected.According to whether MACE occurred during the perioperative period, they were divided into the MACE group and the non-MACE group.The differences of clinical data, the monitoring indexes of postoperative cardiac function, and the coagulation function between the two groups were compared and analyzed.Logistic regression was used to analyze the independent risk factors of perioperative MACE, the cut-off value of the receiver operating characteristic(ROC)curve was calculated, and the Logistic multivariate prediction model was established.Results:In the MACE compared with the non-MACE group, age, postoperative complications and mortality, postoperative hospital stay, and the levels of postoperative high sensitivity troponin-I(Hs-TnI), creatine kinase isoenzyme(CK-MB), myoglobin(MYO), B-type natriuretic peptide(BNP), and D-dimer(D-D)were significantly increased(all P<0.05). Multivariate Logistic regression showed that postoperative BNP and D-D were two independent risk factors for perioperative MACE, and their cut-off values in the ROC curve were 382.65 pg/mL and 0.975mg/L respectively.The Logistic multivariate prediction model established by the Logistic regression equation was P= ex/(1+ ex), X=-5.710+ 0.003X 1+ 0.811X 2, where X 1 was the postoperative BNP level and X 2 was the postoperative D-D level.The accuracy, specificity and sensitivity of this prediction model for predicting perioperative MACE were 96.3%(237/246), 100.0%(235/235), and 18.2%(2/11). Conclusions:The Logistic multivariate prediction model established in this study can effectively predict the occurrence of perioperative MACE in elderly patients.Postoperative BNP and D-D were two independent risk factors for perioperative MACE.The cut-off values of BNP and D-D in the ROC curve could be used as critical values for monitoring perioperative MACE.Therefore, it is of great clinical significance to take effective prevention and treatment measures in time to maintain the stability of perioperative cardiac function, and further improve the perioperative safety of elderly patients with biliary diseases.

Purpose: The aim of this study was to explore the mechanisms of central brain action in patients with neurogenic underactive bladder (UAB) treated with intravesical electrical stimulation (IVES). Methods: We prospectively recruited patients with neurogenic UAB who chose to receive IVES treatment and healthy subjects (HS). At baseline, the following data were obtained: a 72-hour voiding diary; measurements of postvoid residual urine (PVR), voiding efficiency (VE) and first sensation of bladder filling (FS); American Urological Association Symptom Index Quality of Life (AUA-SI-QOL) scores, and functional near-infrared spectroscopy scans of the prefrontal cortex in the voiding stage. All UAB patients were re-evaluated for these indices after completing 4 weeks of IVES. A >50% improvement in PVR was defined as successful IVES treatment. Prefrontal activity was analyzed using the NIRS_KIT software, corrected with the false discovery rate (P<0.05). Statistical analysis was performed using IBM SPSS Statistics ver. 22.0, and P<0.05 was considered statistically significant. Results: Eighteen UAB patients and 16 HS were included. IVES treatment was successful in 11 UAB patients and failed in 7. The PVR, VE, 24-hour clean intermittent catheterization, FS volume, and AUA-SI-QOL scores of the UAB group significantly improved after successful IVES treatment. BA9 (right dorsolateral prefrontal cortex [DLPFC]) and BA10 (right frontal pole) were significantly activated after successful IVES, and no significant difference was found between the successful group and HS group after IVES. Before IVES, BA10 (right frontal pole) was significantly deactivated in the failed group compared with the successful group. Conclusions The possible central mechanism of IVES treatment for neurogenic UAB is that IVES reactivates the right DLPFC and right frontal pole.

Objective:Evaluate the influence of different pressure transmission media of urodynamic water filled catheter(WFC) and air charged catheter(ACC) on the pressure measurement results to determine whether they can be used interchangeably.Methods:The results of 2 147 patients who underwent urodynamic examination in our hospital from January 2014 to December 2020 were retrospectively analyzed. A total of 2 538 times of bladder manometry data were obtained, including 1 299 times in WFC group, 856 times in male and 443 times in female, aged 37(24, 50)years, course of disease 1.2(0.4, 5.0) years, 1 130 times in neurogenic bladder(NB)and 169 times in non-neurogenic bladder(N-NB); In ACC group, there were 1 239 times, 773 times for male and 466 times for female, with age of 37(24, 55)years, course of disease of 1.5(0.5, 6.0)years, 1 040 times for Nb and 199 times for N-NB. There was no significant difference in baseline data of general clinical data between the two groups. The intravesical pressure(Pves), intra-abdominal pressure(Pabd)and detrusor pressure(Pdet) of WFC and ACC patients during filling and urination were analyzed. For traumatic spinal cord injury(SCI) and idiopathic patients, the two sets of pressure measurement data were analyzed separately. Nonparametric test and Chi-square test were used to compare the Pves, Pabd, and Pdet recorded by the two manometry catheters before, at the end and after urination, the maximum detrusor pressure at DO(Pdet.max-DO), and the maximum detrusor pressure during spontaneous urination (Pdet. max) and the detrusor pressure (Pdet.Qmax) corresponding to the maximum urine flow rate, the maximum urethral pressure (MUP) and the maximum urethral closure pressure (MUCP) during resting urethral pressure profile, and the initial cough Pdet signal pattern (typeⅠ, typeⅡand typeⅢ).Results:Regardless of the cause, the Pabd values measured by ACC were significantly higher than WFC before filling, end filling and after voiding[18(10, 26)cmH 2O vs.15(11, 21)cmH 2O; 23(16, 31)cmH 2O vs. 20(14, 26)cmH 2O; 23(15, 31)cmH 2O vs.18(12, 24)cmH 2O], and Pdet were significantly lower than WFC[0(0, 0) cmH 2O vs. 0(0, 1)cmH 2O; 5(1, 13)cmH 2O vs. 9(4, 17)cmH 2O; 6(1, 12)cmH 2O vs. 7(3, 14)cmH 2O]. In the initial cough state, Pves and Pabd increase value were also significantly lower than that of WFC [22(12, 36)cmH 2O vs. 23(14, 38)cmH 2O; 20(10, 33)cmH 2O vs. 21(12, 36)cmH 2O]. The Pves measured by ACC was also significantly higher than WFC before filling and after voiding[18(10, 27)cmH 2O vs. 16(11, 21)cmH 2O; 30(22, 39)cmH 2O vs. 26(20, 36)cmH 2O]. Maximum urethral pressure (MUP) and maximum urethral closure pressure (MUCP) measured by ACC were significantly higher than WFC [91(69, 118)cmH 2O vs.81(64, 106)cmH 2O; 77(55, 103)cmH 2O vs. 68(48, 91)cmH 2O], and there were no significant differences in Pdet.max-DO、Pdet.max和Pdet.Qmax. For patients with traumatic SCI, the Pves measured by ACC was significantly higher than WFC before filling[15(10, 24)cmH 2O vs. 14(10, 20)cmH 2O], and only MUP was significantly higher than WFC in the measurement of urethral pressure[95(71, 119)cmH 2O vs. 85(65, 112)cmH 2O], and there were no significant differences in Pdet.max-DO, Pdet.max, Pdet.Qmax and MUCP. For idiopathic patients, Pves measured by ACC before filling and after urination were significantly higher than WFC[25(20, 29)cmH 2O vs. 18(11, 23)cmH 2O; 35(29, 44)cmH 2O vs. 28(20, 38)cmH 2O], while Pdet.max-DO, Pdet.max, Pdet.Q max, MUP and MUCP were not significantly different in different pressure measurement systems. For the comparison of the initial cough Pdet signal pattern, ACC is easier to detect type Ⅰ, and WFC is easier to detect type Ⅱ and type Ⅲ. Conclusions:Compared with WFC, ACC measured higher Pves and Pabd and lower Pdet in resting state, and lower Pves and Pabd in initial cough state. The pressure values and signal pattern measured by WFC and ACC are not completely consistent, so they cannot be used interchangeably.

Objective:To explore the efficacy and safety of intravesical electrical stimulation (IVES) combined with a training for bladder motor and sensory dysfunction in the treatment of neurogenic underactive bladder(UAB).Methods:A prospective, single-blind, randomized controlled trial was used to study neurogenic UAB patients admitted to the China Rehabilitation Research Center from October 2019 to May 2021. Inclusive criteria included age≥18 years old, the patients who have been diagnosed as neurogenic UAB and the course of disease being more than 3 months; patients who have been undergone intermittent catheterization to empty the bladder or patients indicated for intermittent catheterization (post-void residual urine accounts for more than 40% of the functional bladder volume), voluntary signing of written informed consent, able to communicate well with researchers and comply with the requirements of the whole trial, and the patient not undergoing any treatment other than oral medication before IVES. Exclusion criteria included patients with low bladder compliance by urodynamic examination(<20 ml/cmH 2O), patients with mechanical outflow obstruction, patients with complete spinal cord injury, the patients with symptomatic urinary tract infection which was not cured, patients with hydronephrosis or bladder-ureteral reflux, patients with renal insufficiency(serum creatinine greater than 1.5 times of the upper limit of normality), patients with malignant tumors of the bladder or prostate, overactive bladder, Alzheimer's disease, brain atrophy, acute cerebrovascular disease, or cognitive impairment, patients who were pregnant or planning to be pregnant, bladder mucosa injury, patients with pacemakers or defibrillators, those who participated in other clinical trials 3 months before the study, and other circumstances that the researcher consider it is not suitable to be involved in this study. The patients were randomly divided into experimental group and control group according to the ratio of 1∶1. The experimental group used conventional transurethral insertion of bipolar catheter electrodes for IVES combined with bladder motor and sensory dysfunction training, and the control group underwent IVES with open circuit combined with bladder motor and sensory dysfunction training. The stimulation parameters of the two groups were two-way square wave, 1-30 mA intensity, 10-20 Hz frequency, 200 μs pulse width, once a day, lasting 30 minutes for each treatment, and for continuous 20 working days. The post-void residual urine, voiding efficiency, 24-hour intermittent catheterization times, first sensation of bladder filling volume and American Urological Association Symptom Index Quality of Life(AUA-SI-QOL) scores were recorded before and at the end of treatment. The adverse events during the treatment were recorded. Results:Fifty-two patients were selected and 50 patients completed the trial, including 26 patients in the experimental group and 24 patients in the control group. Before treatment, there were no significant differences in gender[16(male)/10(female)vs.13(male)/11(female), P=0.598], age [(40.7±13.5)years vs.(38.5±12.3)years, P=0.543], course of disease[0.71(0.42, 1.63)years vs.0.79(0.42, 1.50)years, P=0.695], post-void residual urine[300(193, 400)ml vs.325(178, 380)ml, P=0.724], voiding efficiency[17%(0, 47.8)% vs.21%(0, 38.0)%, P=0.960], 24-hour intermittent catheterization times[4(2, 4)vs.3(2, 4), P=0.692], first sensation volume during bladder filling[(325.8±74.3)ml vs.(307.5±75.0)ml, P=0.391] or AUA-SI-QOL scores[5(4, 5)vs.4(4, 5), P=0.313] between the experimental group and the control group. At the end of treatment, the post-void residual urine, first sensation volume during bladder filling and AUA-SI-QOL scores of the experimental group were significantly lower than those of the control group [250(40, 350)ml vs.300(200, 390)ml, P=0.034; (276.5±68.8)ml vs.(315.4±67.3)ml, P=0.049; 4(2, 4)vs.4(3, 5), P=0.024], and the voiding efficiency was significantly higher than that of the control group[33%(14.5, 84.5)% vs.18%(0, 35.8)%, P=0.041], but there was no significant difference in the number of 24-hour intermittent catheterization between the two groups [3(1, 4)vs.3(2, 4), P=0.174]. In the control group, there were no significant changes in post-void residual urine, voiding efficiency, 24-hour intermittent catheterization times, first sensation volume during bladder filling and AUA-SI-QOL scores before and after treatment [325(178, 380)ml vs.300(200, 390)ml, P=0.832; 21%(0, 38.0)% vs.18%(0, 35.8)%, P=0.943; 3(2, 4)vs.3(2, 4), P=0.239; (307.5±75.0)ml vs.(315.4±67.3)ml, P=0.257; 4(4, 5)vs.4(3, 5), P=0.157]. In the experimental group, there were significant improvements in post-void residual urine, voiding efficiency, 24-hour intermittent catheterization times, first sensation volume during bladder filling and AUA-SI-QOL scores before and after treatment [300(193, 400)ml vs.250(40, 350)ml, P<0.001; 17%(0, 47.8)% vs.33%(14.5, 84.5)%, P<0.001; 4(2, 4)vs.3(1, 4), P=0.011; (325.8±74.3)ml vs.(276.5±68.8)ml, P<0.001; 5(4, 5)vs.4(2, 4), P<0.001]. During the treatment period, 1 case of abdominal discomfort occurred in the experimental group and 1 case of urethral discomfort in the control group. After adjusting the stimulation intensity and catheter position, the discomfort disappeared without other serious adverse events. Conclusions:IVES combined with bladder motor sensory dysfunction training can not only effectively improve the bladder emptying efficiency and bladder sensation in patients with neurogenic UAB, but also be safe and easy to operate.

Purpose: The present study determined the effects of saphenous nerve stimulation (SNS) at different stimulation frequencies on bladder reflex and explored a possible action mechanism of tibial nerve stimulation (TNS) on bladder activity in cats. Methods: Two bipolar nerve cuff electrodes were implanted on the saphenous nerve and the contralateral tibial nerve in 13 cats, respectively. Multiple cystometrograms were obtained to determine the effects of single SNS at different frequencies and that of combined SNS and TNS on the micturition reflex by infusing normal saline. Results: SNS at 1 Hz significantly reduced the bladder capacity (BC) to 59.8%±7.7% and 59.3%±5.8% of the control level at the intensity threshold (T) and 2T, respectively (P<0.05), while that at 20 Hz significantly increased the BC to 130.6%±4.2% of the control level at 6T (P<0.05). The TNS and SNS at 20 Hz did not significantly change the BCs at 1T (P>0.05), while combined stimulation at 1T significantly increased the BC to 122.7%±1.9% of the control level and induced an inhibitory effect which was similar to that TNS at 2T. Conclusions The current study revealed that SNS reduced and increased BC depending on different stimulation frequencies. The combined SNS and TNS maximized the clinical efficacy at a low intensity. Also, SNS may be a potential therapeutic mechanism of TNS.