Water-avoidance stress aggravates prostatic inflammation in a murine model of chronic prostatitis.

OBJECTIVES: To date, few studies have considered the influence of psychological factors on chronic prostatitis (PRO) models. Here, we aimed to refine a murine PRO model combining chemically induced prostatitis with psychological stress. METHODS: A total of 40 mice were randomly divided into four groups: normal control (NC) group, PRO group, water avoidance stress (WAS) group, and PRO + WAS group. Ten mice were assigned to each group: five for cystometrograms (CMGs) and five for von Frey testing and histological analysis. PRO was induced through a prostatic injection of 10% paraformaldehyde. The WAS mice were placed on the middle platform for 1 h per day for 10 consecutive days. RESULTS: The results of the von Frey test demonstrated that both WAS and PRO induced bladder hyperalgesia in mice, and the WAS + PRO group showed significant pelvic pain symptoms either. The CMG results suggested that the PRO group, the WAS group, and the PRO + WAS group all exhibited bladder overactivity, presented as a shortened micturition interval and decreased threshold pressure evoking bladder contraction. The symptoms of the PRO group and the PRO + WAS group were more severe than those of the WAS group. The tissue staining results indicated that WAS itself caused only mild prostatic inflammation but could significantly aggravate chemical-induced prostatic inflammation, as well as the total number of mast cells and proportion of activated mast cells. CONCLUSIONS: Our refined murine PRO model could manifest persistent bladder overactivity, pelvic hyperalgesia and prostatic inflammation. WAS could induce mild prostatic inflammation and aggravate primary prostatic inflammation.

Endogenous Zinc-Ion-Triggered In Situ Gelation Enables Zn Capture to Reprogram Benign Hyperplastic Prostate Microenvironment and Shrink Prostate.

Benign prostatic hyperplasia (BPH) as the leading cause of urination disorder is still a refractory disease, and there have no satisfied drugs or treatment protocols yet. With identifying excessive Zn2+ , inflammation, and oxidative stress as the etiology of aberrant hyperplasia, an injectable sodium alginate (SA) and glycyrrhizic acid (GA)-interconnected hydrogels (SAGA) featuring Zn2+ -triggered in situ gelation are developed to load lonidamine for reprogramming prostate microenvironment and treating BPH. Herein, SAGA hydrogels can crosslink with Zn2+ in BPH via coordination chelation and switch free Zn2+ to bound ones, consequently alleviating Zn2+ -arisen inflammation and glycolysis. Beyond capturing Zn2+ , GA with intrinsic immunoregulatory property can also alleviate local inflammation and scavenge reactive oxygen species (ROS). Intriguingly, Zn2+ chelation-bridged interconnection in SAGA enhances its mechanical property and regulates the degradation rate to enable continuous lonidamine release, favoring hyperplastic acini apoptosis and further inhibiting glycolysis. These multiple actions cooperatively reprogram BPH microenvironment to alleviate characteristic symptoms of BPH and shrink prostate. RNA sequencing reveals that chemotaxis, glycolysis, and tumor necrosis factor (TNF) inflammation-related pathways associated with M1-like phenotype polarization are discerned as the action rationales of such endogenous Zn2+ -triggered in situ hydrogels, providing a candidate avenue to treat BPH.

[Electrophysiological appropriateness technique based on TCM meridian theory for postoperative pain after urethral reconstruction: A real-world study].

OBJECTIVE: To investigate the clinical efficacy of electrophysiological appropriateness technique (EAT) therapy based on the traditional Chinese medicine (TCM) meridian theory in managing postoperative pain after urethral reconstruction surgery. METHODS: Using the real-world study approach, we enrolled 61 male patients undergoing urethral reconstruction and divided them into a control group (n = 30) and an observation group (n = 31), the former receiving patient-controlled intravenous analgesia (PCIA), while the latter PCIA plus EAT at 4 pairs of acupoints (Hegu, Neiguan, Zusanli and Sanyinjiao bilaterally) and the Ashi point, with 100 mg tramadol hydrochloride given orally as remedial analgesia in both groups in case of postoperative Visual Analogue Scale (VAS) score ≥4. We compared the VAS scores at 4, 12, 24 and 48 hours postoperatively, the dose of cumulative fentanyl used at 48 hours, the number of cases needing remedial analgesia, the time to first flatus and the incidence of adverse reactions between the two groups of patients. RESULTS: The VAS scores were markedly lower in the observation than in the control group at 4, 12, 24 and 48 hours after surgery (P < 0.05), with statistically significant differences in time-dependent effect and interactive effect (P < 0.05). Significant reduction was observed in the doses of cumulative fentanyl (P < 0.05) and remedial tramadol analgesia (P < 0.05), time to first flatus (P < 0.05), and incidence of adverse reactions (P < 0.05) in the observation group in comparison with the controls. CONCLUSION: Electrophysiological therapy based on the TCM meridian theory can safely and effectively alleviate postoperative pain after urethral reconstruction, reduce opioid consumption, and decrease adverse events.

A comparative study of two single-stage oral mucosal substitution urethroplasty (Kulkarni and Asopa) in the surgical treatments of lichen sclerosus urethral strictures.

Long-segment lichen sclerosus (LS) urethral stricture is a challenge for urologists. Limited data are available for surgeons to make a surgical decision between Kulkarni and Asopa urethroplasty. In this retrospective study, we investigated the outcomes of these two procedures in patients with LS urethral stricture. Between January 2015 and December 2020, 77 patients with LS urethral stricture underwent Kulkarni and Asopa procedures for urethroplasty in the Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (Shanghai, China). Of the 77 patients, 42 (54.5%) underwent the Asopa procedure and 35 (45.5%) underwent the Kulkarni procedure. The overall complication rate was 34.2% in the Kulkarni group and 19.0% in the Asopa group, and no difference was observed ( P = 0.105). Among the complications, no statistical difference was observed in the incidence of urethral stricture recurrence ( P = 0.724) or glans dehiscence ( P = 0.246) except for postoperative meatus stenosis ( P = 0.020). However, the recurrence-free survival rate between the two procedures was significantly different ( P = 0.016). Cox survival analysis showed that antiplatelet/anticoagulant therapy use ( P = 0.020), diabetes ( P = 0.003), current/former smoking ( P = 0.019), coronary heart disease ( P < 0.001), and stricture length ( P = 0.028) may lead to a higher hazard ratio of complications. Even so, these two techniques can still provide acceptable results with their own advantages in the surgical treatment of LS urethral strictures. The surgical alternative should be considered comprehensively according to the patient characteristics and surgeon preferences. Moreover, our results showed that antiplatelet/anticoagulant therapy use, diabetes, coronary heart disease, current/former smoking, and stricture length may be contributing factors of complications. Therefore, patients with LS are advised to undergo early interventions for better therapeutic effects.

Therapeutic effects of p38 mitogen-activated protein kinase inhibition on hyperexcitability of capsaicin sensitive bladder afferent neurons in mice with spinal cord injury.

AIMS: Nerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice. MAIN METHODS: We used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 µg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neuron to capsaicin was evaluated. KEY FINDINGS: In capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K+ (KA) and sustained delayed rectifier-type K+ (KDR) currents were significantly reduced by SCI. The reduction of KA, but not KDR, current density was reversed by the treatment with p38 MAPK inhibitor. SIGNIFICANCE: P38 MAPK plays an important role in hyperexcitability of capsaicin-sensitive bladder afferent neurons due to the reduction in KA channel activity in SCI mice.

A Modified Bilateral Scrotal Flap for Penile Skin Defect Repair.

Skin shortages and scar contractures are common complications following penile trauma and tumor surgery, resulting in significant pain and erectile dysfunction. Currently, skin grafts and scrotal flaps are widely used to reconstruct skin shortages. However, various limitations still exist; for instance, the skin graft may cause severe scarring in patients, and the traditional scrotal flap usually requires a two-stage procedure due to the large skin defect. To treat the shortage of foreskin, a modified bilateral scrotal pedicled flap is used. In this procedure, flaps located on each side of the midline of the scrotum, which was pedicled from the anterior scrotal artery, are harvested. Subsequently, these bilateral scrotal flaps, like a butterfly, can successfully cover the foreskin defect. In this study, seven patients underwent this procedure, and satisfactory outcomes were obtained. Only two patients developed necrosis in some small areas of the flaps, which were recovered after wound care. Postoperative penile length significantly increased compared to the preoperative status in both flaccid and erectile states. We believe that modified bilateral scrotal flaps are a simple and effective solution to penile skin shortages and scar contractures.

Nerve growth factor-mediated Na+ channel plasticity of bladder afferent neurons in mice with spinal cord injury.

AIM: To investigate the effect of nerve growth factor (NGF) neutralization on Na+ channel plasticity of bladder afferent neurons in mice with spinal cord injury (SCI). MAIN METHODS: Female C57/BL6 mice were randomly divided into spinal intact (SI) group, SCI group and SCI + NGF-Ab group. SCI was induced by spinal cord transection at the Th8/9 level. In SCI + NGF-Ab group, anti-NGF antibodies (10 µg·kg-1 per hour) were continuously administered for 2 weeks using osmotic pumps. Bladder afferent neurons were labelled with Fluoro­gold (FG) injected into the bladder wall. L6-S1 dorsal root ganglion (DRG) neurons were dissociated and whole-cell patch clamp recordings were performed on FG-labelled neurons. Expression of Nav1.7 and Nav1.8 was examined by immunofluorescent staining. KEY FINDINGS: Whole-cell patch clamp recordings showed that TTX only partially inhibited action potentials (AP) and Na+ currents of bladder afferent neurons in SI mice, but it almost completely inhibited them in SCI mice. Total and TTX-sensitive Na+ currents were increased and TTX-resistant currents were decreased in bladder afferent neurons from SCI mice vs. SI mice. These changes in SCI mice were significantly reversed by NGF-antibody treatment. Immunostaining results showed the increased and decreased levels of Nav1.7 and Nav1.8, respectively, in FG-labelled bladder afferent neurons in SCI mice vs. SI mice, which was significantly reversed in SCI + NGF-Ab mice. SIGNIFICANCE: NGF mediates the Na+ channel plasticity with a shift from TTX-resistant Nav1.8 to TTX-sensitive Nav1.7 in bladder afferent neurons, which could be a possible underlying mechanism of bladder afferent hyperexcitability and detrusor overactivity after SCI.

A Lipid-Nanosphere-Small MyoD Activating RNA-Bladder Acellular Matrix Graft Scaffold [NP(saMyoD)/BAMG] Facilitates Rat Injured Bladder Muscle Repair and Regeneration [NP(saMyoD)/BAMG].

BACKGROUND: Bladder tissue engineering is an excellent alternative to conventional gastrointestinal bladder enlargement in the treatment of various acquired and congenital bladder abnormalities. We constructed a nanosphere-small MyoD activating RNA-bladder acellular matrix graft scaffold NP(saMyoD)/BAMG inoculated with adipose-derived stem cells (ADSC) to explore its effect on smooth muscle regeneration and bladder repair function in a rat augmentation model. METHODS: We performed many biotechniques, such as reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot, MTT assay, HE staining, masson staining, and immunohistochemistry in our study. Lipid nanospheres were transfected into rat ADSCs after encapsulate saRNA-MyoD as an introduction vector. Lipid nanospheres encapsulated with saRNA-MyoD were transfected into rat ADSCs. The functional transfected rat ADSCs were called ADSC-NP(saMyoD). Then, Rat models were divided into four groups: sham group, ADSC-BAMG group, ADSC-NP(saMyoD)/BAMG group, and ADSC-NP(saMyoD)/SF(VEGF)/BAMG group. Finally, we compared the bladder function of different models by detecting the bladder histology, bladder capacity, smooth muscle function in each group. RESULTS: RT-PCR and Western blot results showed that ADSCs transfected with NP(saMyoD) could induce high expression of α-SMA, SM22α, and Desmin. At the same time, MTT analysis showed that NP(saMyoD) did not affect the activity of ADSC cells, suggesting little toxicity. HE staining and immunohistochemistry indicated that the rat bladder repair effect (smooth muscle function, bladder capacities) was better in the ADSC-NP(saMyoD)/BAMG group, ADSC-NP(saMyoD)/SF(VEGF)/BAMG group than in the control group. CONCLUSIONS: Taken together, our results demonstrate that the NP(saMyoD)/SF(VEGF)/BAMG scaffold seeded with ADSCs could promote bladder morphological regeneration and improved bladder urinary function. This strategy of ADSC-NP(saMyoD)/SF(VEGF)/BAMG may has a potential to repair bladder defects in the future.

The role of prostaglandin and E series prostaglandin receptor type 4 receptors in the development of bladder overactivity in a rat model of chemically induced prostatic inflammation.

OBJECTIVES: To evaluate, using a rat model of non-bacterial prostatic inflammation, the prostaglandin production and expression profiles of E-series prostaglandin (EP) receptor subtypes, which are reportedly implicated in the development of overactive bladder, in the bladder mucosa, and to investigate the effect of EP receptor type 4 (EP4) blockade on bladder overactivity after prostatic inflammation. METHODS: Male Sprague-Dawley rats were used. Prostatic inflammation was induced by formalin injection (5%; 50 µL per lobe) into the bilateral ventral lobes of the prostate. At 10 days after induction of prostatic inflammation or vehicle injection, bladder tissues from the deeply anaesthetized rats were harvested and separated into mucosal and detrusor layers. Then, prostaglandin E2 (PGE2) concentrations and protein levels of PGE2 receptors (EP1-4) in the bladder mucosa and detrusor were measured by ELISA and Western blotting, respectively. In separate groups of control and formalin-treated rats, awake cystometry was performed to evaluate the changes in bladder activity after prostatic inflammation. In addition, the effect of intravesical administration of a selective EP4 antagonist (ONO-AE3-208; 30 µm) on bladder activity was evaluated in control rats and rats with prostatic inflammation. RESULTS: PGE2 concentration and protein levels of EP4, but not other EP receptor subtypes, in the bladder mucosa and detrusor layers were significantly increased in formalin-injected rats vs vehicle-injected control rats. In cystometry, rats with prostatic inflammation exhibited a significant decrease in intercontraction intervals (ICIs) compared with control rats. Intravesical application of ONO-AE3-208 (30 µm), but not vehicle application, significantly increased ICIs in rats with prostatic inflammation, whereas ONO-AE3-208 at this concentration did not significantly affect any cystometric values in control rats. CONCLUSIONS: Because intravesical administration of an EP4 antagonist effectively improved bladder overactivity after prostatic inflammation, EP4 activation, along with increased PGE2 production in the bladder mucosa, seems to be an important contributing factor to bladder overactivity induced by prostatic inflammation. Thus, blockade of EP4 in the bladder could be a therapeutic approach to male lower urinary tract symptoms attributable to benign prostatic hyperplasia with prostatic inflammation.

Long-lasting bladder overactivity and bladder afferent hyperexcitability in rats with chemically-induced prostatic inflammation.

BACKGROUND: Benign prostatic hyperplasia (BPH) is one of the major causes of lower urinary tract symptoms (LUTS), including storage LUTS such as urinary frequency and urgency. Recently, a growing number of clinical studies indicate that prostatic inflammation could be an important pathophysiological mechanism inducing storage LUTS in patients with BPH. Here we aimed to investigate whether nonbacterial prostatic inflammation in a rat model induced by intraprostatic formalin injection can lead to long-lasting bladder overactivity and changes in bladder afferent neuron excitability. METHODS: Male Sprague-Dawley rats were divided into four groups (n = 12 each): normal control group, 1-week prostatic inflammation group, 4-week inflammation group, and 8-week inflammation group. Prostatic inflammation was induced by formalin (10%; 50 µL per lobe) injection into bilateral ventral lobes of the prostate. Voiding behavior was evaluated in metabolic cages for each group. Ventral lobes of the prostate and the bladder were then removed for hematoxylin and eosin (HE) staining to evaluate inflammation levels. Continuous cystometrograms (CMG) were recorded to measure intercontraction intervals (ICI) and voided volume per micturition. Whole-cell patch clamp recordings were performed on dissociated bladder afferent neurons labeled by fluorogold injected into the bladder wall, to examine the electrophysiological properties. RESULTS: Results of metabolic cage measurements showed that formalin-treated rats exhibited significantly (P < 0.05) increases in micturition episodes/12 hours and decrease in voided volume per micturition at every time point post injection. Continuous CMG illustrated the significant ( P < 0.05) higher number of nonvoiding contractions per void and shorter ICI in formalin-treated rats compared with control rats. HE staining showed significant prostatic inflammation, which declined gradually, in prostate tissues of formalin-induced rats. In patch clamp recordings, capsaicin-sensitive bladder afferent neurons from rats with prostatic inflammation had significantly ( P < 0.05) lower thresholds for spike activation and a "multiple" firing pattern compared with control rats at every time point post injection. CONCLUSIONS: Formalin-induced prostatic inflammation can lead to long-lasting bladder overactivity in association with bladder afferent neuron hyperexcitability. This long-lasting model could be a useful tool for the study of inflammation-related aspects of male LUTS pathophysiology.

Streptozotocin-induced diabetes causes upregulation of serotonin (5-HT)2A/C receptors in lumbosacral cord motoneurons and down regulation of serotonergic paraneurons in the urethra.

Lower urinary tract (LUT) dysfunction is the most common complication of diabetes mellitus (DM). An involvement of the 5-HT2A receptor in spinal micturition control has been demonstrated in urethane anaesthetized DM rats in which i.v. administration of the 5-HT2A/2C receptor agonist 2,5-methoxy-4-iodoamphetamine (DOI), stimulated high frequency oscillations (HFOs) and improved micturition. However, the mechanisms involved in these effects are not completely understood. The present work showed that 5-HT2A and -2C receptors were upregulated in lumbosacral cord motoneurons, and the number of serotonergic paraneurons were downregulated in the urethra in DM group. The importance of the downregulation of urethral paraneurons in DM remains to be elucidated but may be related to the reduced urethral sensation caused by the disease. We suggest that targets of 5-HT receptor agonists for improvement of voiding function may be found both in the LUT and lumbosacral spinal cord.

Bladder overactivity and afferent hyperexcitability induced by prostate-to-bladder cross-sensitization in rats with prostatic inflammation.

KEY POINTS: There is clinical evidence showing that prostatic inflammation contributes to overactive bladder symptoms in male patients; however, little is known about the underlying mechanisms In this study, we investigated the mechanism that prostatic inflammation causes detrusor overactivity by using a rat model of chemically induced prostatic inflammation. We observed a significant number of dorsal root ganglion neurons with dichotomized afferents innervating both prostate and bladder. We also found that prostatic inflammation induces bladder overactivity and urothelial NGF overexpression in the bladder, both dependent on activation of the pelvic nerve, as well as changes in ion channel expression and hyperexcitability of bladder afferent neurons. These results indicate that the prostate-to-bladder cross-sensitization through primary afferent pathways in the pelvic nerve, which contain dichotomized afferents, could be an important mechanism contributing to bladder overactivity and afferent hyperexcitability induced by prostatic inflammation. ABSTRACT: Prostatic inflammation is reportedly an important factor inducing lower urinary tract symptoms (LUTS) including urinary frequency, urgency and incontinence in patients with benign prostatic hyperplasia (BPH). However, the underlying mechanisms inducing bladder dysfunction after prostatic inflammation are not well clarified. We therefore investigated the effects of prostatic inflammation on bladder activity and afferent function using a rat model of non-bacterial prostatic inflammation. We demonstrated that bladder overactivity, evident as decreased voided volume and shorter intercontraction intervals in cystometry, was observed in rats with prostatic inflammation versus controls. Tissue inflammation, evident as increased myeloperoxidase activity, and IL-1α, IL-1ß, and IL-6 levels inside the prostate, but not in the bladder, following intraprostatic formalin injection induced an increase in NGF expression in the bladder urothelium, which depended on activation of the pelvic nerve. A significant proportion (18-19%) of dorsal root ganglion neurons were double labelled by dye tracers injected into either bladder or prostate. In rats with prostatic inflammation, TRPV1, TRPA1 and P2X2 increased, and Kv1.4, a potassium channel α-subunit that can form A-type potassium (KA ) channels, decreased at mRNA levels in bladder afferent and double-labelled neurons vs. non-labelled neurons, and slow KA current density decreased in association with hyperexcitability of these neurons. Collectively, non-bacterial inflammation localized in the prostate induces bladder overactivity and enhances bladder afferent function. Thus, prostate-to-bladder afferent cross-sensitization through primary afferents in the pelvic nerve, which contain dichotomized afferents, could underlie storage LUTS in symptomatic BPH with prostatic inflammation.

The serotonin (5-hydroxytryptamine) 5-HT7 receptor is up-regulated in Onuf's nucleus in rats with chronic spinal cord injury.

OBJECTIVES: To examine the effect of intrathecal (i.t.) serotonin (5-hydroxytryptamine) 5-HT7 agonist administration on voiding function in the urethane-anesthetised rat, and the change in 5-HT7 receptor (5-HT7 R) expression in the lumbosacral cord Onuf's nucleus after spinal cord injury (SCI). MATERIALS AND METHODS: In all, 32 female Sprague-Dawley (SD) rats were equally divided into a spinally intact (SI) group and SCI group (n = 16 each). At 8 weeks after transection, half of the rats underwent continuous cystometry under urethane anaesthesia, and the 5-HT7 R-selective agonist LP44 was given (i.t.). The remaining rats were used for pseudorabies (PRV) retrograde tracing, immunofluorescence, and Western Blot. RESULTS: LP44 administered i.t. had no effect in the SI rats. In SCI rats, LP44 (1-30 µg/kg) induced significant dose-dependent increases in micturition volume, voiding efficiency, number of high-frequency oscillations per micturition; and decreases in residual volume, bladder capacity, peak bladder pressure, threshold pressure and non-voiding contractions. The 5-HT7 R antagonist, SB-269970 (10 µg/kg), partially reversed LP44-induced changes. Using PRV retrograde tracing and immunofluorescence, 5-HT7 Rs were found in the L6-S1 spinal cord Onuf's nucleus in both SI and SCI rats, but the expression was significantly greater in the SCI rats. Western blot showed significantly more 5-HT7 Rs in the ventral L6-S1 spinal cord in SCI rats. CONCLUSION: A 5-HT7 R agonist, given i.t., improved voiding efficiency in urethane-anesthetised SCI rats, and the 5-HT7 R was significantly up-regulated in the lumbosacral cord Onuf's nucleus. If valid for humans, these findings suggest that the 5-HT7 R could be a target for therapeutic interventions.

Effect of 5-HT2A receptor antagonist ketanserin on micturition in male rats.

OBJECTIVES: This study aimed to investigate the effects of ketanserin on micturition mediated via the 5-HT2A receptor in the motoneuron nucleus of the Lumbosacral cord, as reflected in high frequency oscillations (HFOs) of intravesical pressure and the external urethral sphincter electromyogram (EUS-EMG) in anesthetized male rats. METHODS：: Male Sprague-Dawley rats were used. Cystometry and EUS-EMG were performed in all rats under urethane anesthesia to examine the variations after successive intrathecal (i.t.) administration of various doses of ketanserin into the lumbosacral cord. Immunofluorescence staining and Western blotting were made to observe the distribution of 5-HT2 A and -2C receptors in the lumbosacral cord motor neurons. RESULTS: Compared to the controls, ketanserin-treated rats showed a declined trend of dose-dependent manner in the HFOs, in accordance with the variation of EUS-EMG, while decreased micturition volume, voiding efficiency, and increased post-void residual volume was only observed at the dose of 0.1 mg/kg. The effects of ketanserin on the HFO and EUS-EMG activity were partially or completely reversed by the 5-HT2A/2C receptor agonist, DOI. Meanwhile, immunofluorescence staining and Western blot analysis showed that immunoreactivity of 5-HT2A receptor was higher than that of 5-HT2C, labeling in the lumbosacral cord motoneurons. CONCLUSIONS: The intrathecally administrated 5-HT2A receptor antagonist ketanserin can weaken the EUS bursting activity, decrease HFOs, and reduce voiding efficiency as dose dependently. The effects of ketanserin on micturition may be mainly mediated via the 5-HT2A receptors in the motoneuron nucleus of the lumbosacral cord.

Therapeutic Potential of Human Adipose-Derived Stem Cell Exosomes in Stress Urinary Incontinence - An in Vitro and in Vivo Study.

BACKGROUND/AIMS: To evaluate whether local injection of exosomes derived from human adipose-derived stem cells (hADSCs) facilitates recovery of stress urinary incontinence (SUI) in a rat model. METHODS: For the in vitro study, a Cell Counting Kit-8 (CCK-8) array and proteomic analysis were performed. For the in vivo study, female rats were divided into four groups: sham, SUI, adipose-derived stem cell (ADSC), and exosomes (n = 12 each). The SUI model was generated by pudendal nerve transection and vaginal dilation. Vehicle, hADSCs, or exosomes were injected into the peripheral urethra. After 2, 4, and 8 weeks, the rats underwent cystometrography and leak point pressure (LPP) testing, and tissues were harvested for histochemical analyses. RESULTS: The CCK-8 experiment demonstrated that ADSC-derived exosomes could enhance the growth of skeletal muscle and Schwann cell lines in a dose-dependent manner. Proteomic analysis revealed that ADSC-derived exosomes contained various proteins of different signaling pathways. Some of these proteins are associated with the PI3K-Akt, Jak-STAT, and Wnt pathways, which are related to skeletal muscle and nerve regeneration and proliferation. In vivo experiments illustrated that rats of the exosome group had higher bladder capacity and LPP, and had more striated muscle fibers and peripheral nerve fibers in the urethra than rats of the SUI group. Both urethral function and histology of rats in the exosome group were slightly better than those in the ADSC group. CONCLUSIONS: Local injection of hADSC-derived exosomes improved functional and histological recovery after SUI.

Efficacy of different spinal nerve roots for neuromodulation of micturition reflex in rats.

Electrical stimulation of peripheral nerves controlling the bladder is an alternative, nondestructive medical treatment for urinary incontinence and retention. In this study, we aimed to identify the most efficient sensory and motor spinal nerve roots involved in the micturition reflex. Unilateral L5-S2 dorsal and ventral roots were electrically stimulated, and bladder reflex contractions were recorded under isovolumetric conditions. Repeated stimulation of the L6 and S1 dorsal roots not only abolished bladder reflex contractions but also induced a poststimulation inhibitory effect, whereas repeated stimulation of the L5 and S2 dorsal roots had no effect. Only the L6 ventral root directly caused bladder contraction when ventral roots L5-S2 were stimulated in sequence. Upon retrograde tracing using pseudorabies virus (PRV), the sacral parasympathetic nucleus of the L6 segment had more PRV-positive cells than the other segments, though the S1 segment of the dorsal root ganglia had the highest density of PRV-positive neurons. These results suggest the L6 ventral root is most efficient in producing detrusor muscle contraction, and the S1 dorsal root best inhibits the micturition reflex.

Chronic spinal cord injury causes upregulation of serotonin (5-HT)2A and 5-HT2C receptors in lumbosacral cord motoneurons.

OBJECTIVES: To investigate whether the voiding dysfunction caused by spinal cord injury (SCI) in rats can be improved by i.v. administration of the serotonin (5-HT)2A/2C receptor agonist 2,5-dimethoxy-4-iodophenyl-2-aminopropanehydrochloride (DOI), and to discuss whether the mechanism can be ascribed to 5-HT2A and 5-HT 2C receptor upregulation in lumbosacral cord motoneurons. MATERIALS AND METHODS: Female Sprague-Dawley rats were divided into two groups (SCI group vs normal control [NC] group). Under urethane anaesthesia, cystometry was performed to examine the variation in urodynamic variables before and after successive intrathecal (i.t.) administration of various doses of DOI into the lumbosacral cord. Changes in 5-HT2A and -2C receptors in the lumbosacral cord were also investigated using immunohistochemical staining and Western blot analysis. RESULTS: Compared with NC rats, the SCI rats had higher bladder capacity and post-void residual urine volume, and lower voiding efficiency. After SCI, DOI improved voiding efficiency, probably via external urethral sphincter (EUS) activity. Immunohistochemical staining and Western blot analysis showed that 5-HT2A and -2C receptors were upregulated in lumbosacral cord motoneurons. CONCLUSION: In rats with SCI, DOI can improve voiding efficiency; this may be attributable to 5-HT2A and -2C receptor upregulation in lumbosacral cord motoneurons controlling EUS activity.

Is repeat Botulinum Toxin A injection valuable for neurogenic detrusor overactivity-A systematic review and meta-analysis.

AIM: To investigate the value of repeat botulinum toxin A (BTX-A) injections in patients with neurogenic detrusor overactivity (NDO). METHODS: We searched the PubMed, EMBASE, and EBSCO databases for articles published until June 2016. Studies that reported the efficacy and safety of repeat BTX-A injections for adult patients with NDO were eligible. The effect size for each outcome was calculated as the standardized mean difference ± standard error and 95% confidence interval, and was graded as small, >0.2; moderate, >0.5; or large, >0.8. The outcomes included maximum cystometric capacity (MCC), maximum detrusor pressure (MDP), reflex volume (RV), bladder compliance (BC), quality of life (QOL), and injection interval. Descriptive reviews were performed for urinary incontinence (UI) and adverse events (AEs). RESULTS: Eighteen studies involving 1533 patients whose level of evidence ranged from 3 to 4 were included in this study. We noted non-significant changes in MCC, MDP, RV, and BC between the first and last injections. Patients who had received ≤4 injections were found to have stable QOL improvements after the first and last injections, whereas patients who had received ≥5 injections were found to have a significant decrease in QOL after the last injection. No significant differences in injection intervals were noted after repeat BTX-A injections, and the repeat injection failure rate was low. CONCLUSION: Our study demonstrated that repeat BTX-A injections allow sustained improvements in patients with NDO. The rate of AEs was stable and low. However, additional high-quality, large-scale, and long-term trials are necessary to establish the efficacy and safety of ≥5 repeat BTX-A injections.

The Characteristics of the Transitional Zone in Prostate Growth With Age.

OBJECTIVE: To investigate the age-related growth variation in prostatic parameters by transrectal ultrasound with a simultaneous evaluation of the transitional zone measurements in different prostate volumes. METHODS: A retrospective study of 2001 subjects derived from the outpatient clinic at our institution (Shanghai Jiao Tong University Affiliated Sixth People's Hospital in Shanghai) who were diagnosed with benign prostatic hyperplasia (BPH) and prostatitis was reviewed. All subjects were evaluated by the International Prostatic Symptom Score and transrectal ultrasound of the prostate. Statistical analysis was conducted between prostatic parameters and age. RESULTS: The prostate volume, index, length, and width of transitional zone were the parameters most closely associated with increasing age. Notably, the transitional zone measurements showed a significant difference among individuals greater than 50 years old. Moreover, the fastest increasing rate of prostatic parameters was found to be between the ages of 50 and 69. Additionally, we also discovered that the difference between transitional zone parameters and different prostate volumes varies along with increasing age. CONCLUSION: These results suggest that transitional zone growth is the main contributor to total prostate growth, especially at the ages of 50-69, which may elucidate the higher incidence of the lower urinary tract symptoms from BPH. In view of the increasing rate of transitional zone and the level of total prostate volume, further research is needed to identify the underlying mechanism for such differences in prostate growth.