Development of opioid-induced hyperalgesia depends on reactive astrocytes controlled by Wnt5a signaling.

Opioids are the frontline analgesics for managing various types of pain. Paradoxically, repeated use of opioid analgesics may cause an exacerbated pain state known as opioid-induced hyperalgesia (OIH), which significantly contributes to dose escalation and consequently opioid overdose. Neuronal malplasticity in pain circuits has been the predominant proposed mechanism of OIH expression. Although glial cells are known to become reactive in OIH animal models, their biological contribution to OIH remains to be defined and their activation mechanism remains to be elucidated. Here, we show that reactive astrocytes (a.k.a. astrogliosis) are critical for OIH development in both male and female mice. Genetic reduction of astrogliosis inhibited the expression of OIH and morphine-induced neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We found that Wnt5a is a neuron-to-astrocyte signal that is required for morphine-induced astrogliosis. Conditional knock-out of Wnt5a in neurons or its co-receptor ROR2 in astrocytes blocked not only morphine-induced astrogliosis but also OIH and NCP. Furthermore, we showed that the Wnt5a-ROR2 signaling-dependent astrogliosis contributes to OIH via inflammasome-regulated IL-1ß. Our results reveal an important role of morphine-induced astrogliosis in OIH pathogenesis and elucidate a neuron-to-astrocyte intercellular Wnt signaling pathway that controls the astrogliosis.

Extracellular vesicles derived from mesenchymal stem cells alleviate neuroinflammation and mechanical allodynia in interstitial cystitis rats by inhibiting NLRP3 inflammasome activation.

BACKGROUND: Neuroinflammation in spinal dorsal horn (SDH) plays an important role in the pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS). Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) exert potent anti-inflammatory activities in the treatment of various diseases. This study aimed to determine the therapeutic effects of MSC-EVs on IC and furtherly investigate the potential mechanism to attenuate neuroinflammation. METHODS: Female IC rat model was established by intraperitoneal injection of cyclophosphamide (50 mg/kg, every 3 days for 3 doses). Inhibition of NLRP3 inflammasome was performed by intraperitoneal injection of MCC950 (10 mg/kg). MSC-EVs were isolated from the culture supernatants of human umbilical cord derived MSCs using ultracentrifugation, and then injected intrathecally into IC rats (20 µg in 10 µl PBS, every other day for 3 doses). Suprapubic mechanical allodynia was assessed using up-down method with von Frey filaments, and micturition frequency was examined by urodynamics. The expression of NLRP3 inflammasome components (NLRP3 and Caspase-1), glial cell markers (IBA-1 and GFAP), proinflammatory cytokines (TNF-α, IL-1ß, IL-6 and IL-18) and TLR4/NF-κB signal pathway (TLR4, p65 NK-κB and phospho-p65 NK-κB) in L6-S1 SDH was measured by Western blot analysis. The cellular localization of NLRP3 in SDH was detected using immunofluorescence co-staining. RESULTS: NLRP3 inflammasome was activated in neurons in SDH of IC rats. NLRP3 inflammasome activation contributed to activation of glial cells and process of spinal neuroinflammation in IC rats, and was related to suprapubic mechanical allodynia and frequent micturition. Intrathecal injection of MSC-EVs alleviated suprapubic mechanical allodynia and frequent micturition in IC rats, restrained activation of glial cells and attenuated neuroinflammation in SDH. In addition, MSC-EV treatment significantly inhibited activation of both NLRP3 inflammasomes and TLR4/NF-κB signal pathway. CONCLUSIONS: NLRP3 inflammasome activation is involved in the neuroinflammation of IC. Intrathecal injection of MSC-EVs alleviates neuroinflammation and mechanical allodynia in IC by inhibiting the activation of NLRP3 inflammasome, and TLR4/NF-κB signal pathway may be the potential regulatory target.

Metallopolymer Particle Engineering via Etching of Boronate Polymers toward High-Performance Overall Water Splitting Catalysts.

Metallopolymers combine the property features of both metallic compounds and organic polymers, representing a typical direction for the design of high-performance hybrid materials. Here, a highly adaptive etching method to create pores and cavities in the metallopolymer particles is established. Starting from boronate polymer (BP) and inorganic@BP core-shell particles, porous, hollow, and yolk-shell metallopolymer particles can be fabricated, respectively. By taking advantage of the easy control over composition and pore/cavity structure, these metallopolymer particles provide a universal platform for the fabrication of nitrogen, boron co-doped carbon nanocomposites loaded with metals (M-NBCs). The as-prepared M-NBCs exhibit remarkable catalytic activities toward oxygen evolution reaction and hydrogen evolution reaction. An alkaline overall water splitting cell assembled by using M-NBCs as the anode and cathode can be driven by a single AAA battery. The proposed strategy for the construction of metallopolymer composites may enlighten for the design of complex hybrid nanomaterials.

Notch1 Signaling Contributes to Mechanical Allodynia Associated with Cyclophosphamide-Induced Cystitis by Promoting Microglia Activation and Neuroinflammation.

AIMS: Notch1 signaling regulates microglia activation, which promotes neuroinflammation. Neuroinflammation plays an essential role in various kinds of pain sensation, including bladder-related pain in bladder pain syndrome/interstitial cystitis (BPS/IC). However, the impact of Notch1 signaling on mechanical allodynia in cyclophosphamide- (CYP-) induced cystitis is unclear. This study is aimed at determining whether and how Notch1 signaling modulates mechanical allodynia of CYP-induced cystitis. METHODS: CYP was peritoneally injected to establish a bladder pain syndrome/interstitial cystitis (BPS/IC) rat model. A γ-secretase inhibitor, DAPT, was intrathecally injected to modulate Notch1 signaling indirectly. Mechanical withdrawal threshold in the lower abdomen was measured with von Frey filaments using the up-down method. The expression of Notch1 signaling, Iba-1, OX-42, TNF-α, and IL-1ß in the L6-S1 spinal dorsal horn (SDH) was measured with Western blotting analysis and immunofluorescence staining. RESULTS: Notch1 and Notch intracellular domain (NICD) were both upregulated in the SDH of the cystitis group. Moreover, the expression of Notch1 and NICD was negatively correlated with the mechanical withdrawal threshold of the cystitis rats. Furthermore, treatment with DAPT attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of TNF-α and IL-1ß. CONCLUSION: Notch1 signaling contributes to mechanical allodynia associated with CYP-induced cystitis by promoting microglia activation and neuroinflammation. Our study showed that inhibition of Notch1 signaling might have therapeutic value for treating pain symptoms in BPS/IC.

Online Public Attention Toward Premature Ejaculation in Mainland China: Infodemiology Study Using the Baidu Index.

BACKGROUND: Premature ejaculation (PE) is one of the most described psychosocial stress and sexual complaints worldwide. Previous investigations have focused predominantly on the prospective identification of cases that meet researchers' specific criteria. The genuine demand from patients with regard to information on PE and related issues may thus be neglected. OBJECTIVE: This study aims to examine the online search trend and user demand related to PE on a national and regional scale using the dominant major search engine in mainland China. METHODS: The Baidu Index was queried using the PE-related terms for the period of January 2011 to December 2020. The search volume for each term was recorded to analyze the search trend and demographic distributions. For user interest, the demand and trend data were collected and analyzed. RESULTS: Of the 36 available PE search keywords, 4 PE searching topics were identified. The Baidu Search Index for each PE topic varied from 46.30% (86,840,487/187,558,154) to 6.40% (12,009,307/187,558,154). The annual percent change (APC) for the complaint topic was 48.80% (P<.001) for 2011 to 2014 and -16.82% (P<.001) for 2014 to 2020. The APC for the inquiry topic was 16.21% (P=.41) for 2011 to 2014 and -11.00% (P<.001) for 2014 to 2020. For the prognosis topic, the annual APC was 11.18% (P<.001) for 2011 to 2017 and -19.86% (P<.001) for 2017 to 2020. For the treatment topic, the annual APC was 14.04% (P<.001) for 2011 to 2016 and -38.83% (P<.001) for 2016 to 2020. The age distribution of those searching for topics related to PE showed that the population aged 20 to 40 years comprised nearly 70% of the total search inquiries (second was 17.95% in the age group younger than 19 years). People from East China made over 50% of the total search queries. CONCLUSIONS: The fluctuating online popularity of PE searches reflects the real-time population demands. It may help medical professionals better understand population interest, population concerns, regional variations, and gender differences on a nationwide scale and make disease-specific health care policies. The internet search data could be more reliable when the insufficient and lagging registry data are completed.

BDNF promotes activation of astrocytes and microglia contributing to neuroinflammation and mechanical allodynia in cyclophosphamide-induced cystitis.

BACKGROUND: Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) often grieve over a low quality of life brought about by chronic pain. In our previous studies, we determined that neuroinflammation of the spinal dorsal horn (SDH) was associated with mechanisms of interstitial cystitis. Moreover, it has been shown that brain-derived neurotrophic factor (BDNF) participates in the regulation of neuroinflammation and pathological pain through BDNF-TrkB signaling; however, whether it plays a role in cyclophosphamide (CYP)-induced cystitis remains unclear. This study aimed to confirm whether BDNF-TrkB signaling modulates neuroinflammation and mechanical allodynia in CYP-induced cystitis and determine how it occurs. METHODS: Systemic intraperitoneal injection of CYP was performed to establish a rat cystitis model. BDNF-TrkB signaling was modulated by intraperitoneal injection of the TrkB receptor antagonist, ANA-12, or intrathecal injection of exogenous BDNF. Mechanical allodynia in the suprapubic region was assessed using the von Frey filaments test. The expression of BDNF, TrkB, p-TrkB, Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the L6-S1 SDH was measured by Western blotting and immunofluorescence analysis. RESULTS: BDNF-TrkB signaling was upregulated significantly in the SDH after CYP was injected. Similarly, the expressions of Iba1, GFAP, p-p38, p-JNK, IL-1ß, and TNF-α in the SDH were all upregulated. Treatment with ANA-12 could attenuate mechanical allodynia, restrain activation of astrocytes and microglia and alleviate neuroinflammation. Besides, the intrathecal injection of exogenous BDNF further decreased the mechanical withdrawal threshold, promoted activation of astrocytes and microglia, and increased the release of TNF-α and IL-1ß in the SDH of our CYP-induced cystitis model. CONCLUSIONS: In our CYP-induced cystitis model, BDNF promoted the activation of astrocytes and microglia to release TNF-α and IL-1ß, aggravating neuroinflammation and leading to mechanical allodynia through BDNF-TrkB-p38/JNK signaling.

Normalization of magnesium deficiency attenuated mechanical allodynia, depressive-like behaviors, and memory deficits associated with cyclophosphamide-induced cystitis by inhibiting TNF-α/NF-κB signaling in female rats.

BACKGROUND: Bladder-related pain symptoms in patients with bladder pain syndrome/interstitial cystitis (BPS/IC) are often accompanied by depression and memory deficits. Magnesium deficiency contributes to neuroinflammation and is associated with pain, depression, and memory deficits. Neuroinflammation is involved in the mechanical allodynia of cyclophosphamide (CYP)-induced cystitis. Magnesium-L-Threonate (L-TAMS) supplementation can attenuate neuroinflammation. This study aimed to determine whether and how L-TAMS influences mechanical allodynia and accompanying depressive symptoms and memory deficits in CYP-induced cystitis. METHODS: Injection of CYP (50 mg/kg, intraperitoneally, every 3 days for 3 doses) was used to establish a rat model of BPS/IC. L-TAMS was administered in drinking water (604 mg·kg-1·day-1). Mechanical allodynia in the lower abdomen was assessed with von Frey filaments using the up-down method. Forced swim test (FST) and sucrose preference test (SPT) were used to measure depressive-like behaviors. Novel object recognition test (NORT) was used to detect short-term memory function. Concentrations of Mg2+ in serum and cerebrospinal fluid (CSF) were measured by calmagite chronometry. Western blot and immunofluorescence staining measured the expression of tumor necrosis factor-α/nuclear factor-κB (TNF-α/NF-κB), interleukin-1ß (IL-1ß), and N-methyl-D-aspartate receptor type 2B subunit (NR2B) of the N-methyl-D-aspartate receptor in the L6-S1 spinal dorsal horn (SDH) and hippocampus. RESULTS: Free Mg2+ was reduced in the serum and CSF of the CYP-induced cystitis rats on days 8, 12, and 20 after the first CYP injection. Magnesium deficiency in the serum and CSF correlated with the mechanical withdrawal threshold, depressive-like behaviors, and short-term memory deficits (STMD). Oral application of L-TAMS prevented magnesium deficiency and attenuated mechanical allodynia (n = 14) and normalized depressive-like behaviors (n = 10) and STMD (n = 10). The upregulation of TNF-α/NF-κB signaling and IL-1ß in the L6-S1 SDH or hippocampus was reversed by L-TAMS. The change in NR2B expression in the SDH and hippocampus in the cystitis model was normalized by L-TAMS. CONCLUSIONS: Normalization of magnesium deficiency by L-TAMS attenuated mechanical allodynia, depressive-like behaviors, and STMD in the CYP-induced cystitis model via inhibition of TNF-α/NF-κВ signaling and normalization of NR2B expression. Our study provides evidence that L-TAMS may have therapeutic value for treating pain and comorbid depression or memory deficits in BPS/IC patients.

Neuregulin-1-ErbB signaling promotes microglia activation contributing to mechanical allodynia of cyclophosphamide-induced cystitis.

AIMS: Central sensitization playsimportant roles in cyclophosphamide (CYP)-induced cystitis. In addition, as a visceral pain, CYP-induced chronic pain shares common pathophysiological mechanisms with neuropathic pain. Previous studies demonstrated that neuregulin-1 (Nrg1)-ErbB signaling contributes to neuropathic pain, but whether and how this signaling influences mechanical allodynia in CYP-induced cystitis is unclear. This study aimed to determine whether and how Nrg1-ErbB signaling modulates mechanical allodynia in a CYP-induced cystitis rat model. METHODS: Systemic injection with CYP was used to establish a rat model of bladder pain syndrome/interstitial cystitis (BPS/IC). An irreversible ErbB family receptor inhibitor, PD168393, and exogenous Nrg1 were intrathecally injected to modulate Nrg1-ErbB signaling. Mechanical allodynia in the lower abdomen was assessed with von-Frey filaments using the up-down method. Western blot analysis and immunofluorescence staining were used to measure the expression of Nrg1-ErbB signaling, Iba-1, p-p38, and IL-1ß in the L6-S1 spinal dorsal horn (SDH). RESULTS: We observed upregulation of Nrg1-ErbB signaling as well as overexpression of the microglia activation markers Iba-1 and p-p38 and the proinflammatory factor, interleukin-1ß (IL-1ß), in the SDH of the cystitis group. Further, treatment with PD168393 attenuated mechanical allodynia in CYP-induced cystitis and inhibited microglia activation, leading to decreased production of IL-1ß. The inhibitor PD168393 reversed the algesic effect of exogenous Nrg1 on the cystitis model. CONCLUSIONS: Nrg1-ErbB signaling may promote microglia activation, contributing to mechanical allodynia of CYP-induced cystitis. Our study showed that modulation of Nrg1-ErbB signaling may have therapeutic value for treating pain symptoms in BPS/IC.

The Self-Retaining Barbed Suture for Parenchymal Repair in Laparoscopic Partial Nephrectomy: A Systematic Review and Meta-Analysis.

Objectives. The warm ischemia time (WIT) is key to successful laparoscopic partial nephrectomy (LPN). The aim of this study was to perform a meta-analysis comparing the self-retaining barbed suture (SRBS) with a non-SRBS for parenchymal repair during LPN. Methods. A systematic search of PubMed, Scopus, and the Cochrane Library was performed up to March 2018. Inclusion criteria for this study were randomized controlled trials (RCTs) and observational comparative studies assessing the SRBS and non-SRBS for parenchymal repair during LPN. Outcomes of interest included WIT, complications, overall operative time, estimated blood loss, length of hospital stay, and change of renal function. Results. One RCT and 7 retrospective studies were identified, which included a total of 461 cases. Compared with the non-SRBS, use of the SRBS for parenchymal repair during LPN was associated with shorter WIT (P < .00001), shorter overall operative time (P < .00001), lower estimated blood loss (P = .02), and better renal function preservation (P = .001). There was no significant difference between the SRBS and non-SRBS with regard to complications (P = .08) and length of hospital stay (P = .25). Conclusions. The SRBS for parenchymal repair during LPN can significantly shorten the WIT and overall operative time, decrease blood loss, and preserve renal function.

Umbilical cord-derived mesenchymal stem cells alleviated inflammation and inhibited apoptosis in interstitial cystitis via AKT/mTOR signaling pathway.

Interstitial cystitis (IC) is a bladder syndrome characterized by pelvic pain and urinary frequency without infection or other identifiable pathology. There are no effective treatments to cure IC. This study investigated the effects of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) injection on IC rat model. Furthermore, we used a coculture system to find the possible molecular mechanism on the human uroepithelial cells (SV-HUC-1), which was the cell model of IC. A rat model of IC was established via systemic injection with cyclophosphamide (CYP) and a cell model of IC was induced by being exposed to tumor necrosis factor (TNF)-α (10 ng/ml). After one week, UC-MSCs injection significantly ameliorated the bladder voiding function in IC rat model. And the Histo- and immunohistochemical analyses showed that UC-MSCs can repair impaired bladder, reduce mast cell infiltration and inhibit apoptosis of urothelium. ELISA results showed that UC-MSCs can decrease IL-1ß, IL-6 and TNF-α in bladder. In the coculture system, UC-MSCs can promote proliferation of impaired SV-HUC-1 cells, and inhibit apoptosis. However, while knocked down EGF secreted by UC-MSCs with siRNA, the effects would be weaken. Western blot showed that UC-MSCs increase protein expression levels of p-AKT and p-mTOR in SV-HUC-1 cells, and decrease the levels of cleaved caspase-3. Taken together, we provide evidence that UC-MSCs therapy can successfully alleviate IC in a preclinical animal Model and cell model by alleviating inflammation, promoting proliferation and inhibiting apoptosis. In addition, we demonstrate that the AKT/mTOR signaling pathway was activated.

Utility of Fluorescence In Situ Hybridization (FISH) to Sub-Classify Low-Grade Urothelial Carcinoma for Prognostication.

BACKGROUND Fluorescence in situ hybridization (FISH) is used widely to detect cancer levels, but its value in urothelial carcinoma remains unclear. The aim of this study was to use FISH to examine the urine specimens of low-grade urothelial carcinoma (UC) patients to determine the possibility of sub-classifying the prognosis of UC. MATERIAL AND METHODS We diagnosed 107 patients with low-grade UC using a UroVysion kit to detect chromosomes 3, 7, 17, and P16 in the urine. An average 46.6-month follow-up completed in January 2016 combined with the clinical follow-up data were evaluated with Spearman's correlation analysis to analyze the aberration of chromosomes in relation to the prognostication. Univariate and multivariate analysis using the Mantel-Cox log-rank test for overall, cancer-specific, and disease-free survival were used to determine the prognostic significance of CSP7/CSP17 and CSP3/GLPp16. RESULTS In the 107 samples, 84 showed positive reaction in the FISH test. Furthermore, CSP7/CSP17 was found to be significantly related with age, tumor size, T stage, and tumor numbers, but not in CSP3/GLPp16. In addition, Kaplan-Meier analysis and Cox proportional hazards regression revealed a significant negative correlation between CSP7/CSP17 and survival, while CSP3/GLPp16 showed no significantly differences. CONCLUSIONS CSP7/CSP17 positivity on FISH test appears to play a critical role in low-grade UC and may be considered as a high-risk and prognosis factor.

Spinal astrocytic activation contributes to mechanical allodynia in a rat model of cyclophosphamide-induced cystitis.

BACKGROUND: Previous studies have demonstrated that glial cells play an important role in the generation and maintenance of neuropathic pain. Activated glial cells produce numerous mediators such as proinflammatory cytokines that facilitate neuronal activity and synaptic plasticity. Similarly, bladder pain syndrome/interstitial cystitis shares many characteristics of neuropathic pain. However, related report on the involvement of spinal glia in bladder pain syndrome/interstitial cystitis-associated pathological pain and the underlying mechanisms are still lacking. The present study investigated spinal glial activation and underlying molecular mechanisms in a rat model of bladder pain syndrome/interstitial cystitis. RESULTS: A rat model of bladder pain syndrome/interstitial cystitis was established via systemic injection with cyclophosphamide. Mechanical allodynia was tested with von Frey monofilaments and up-down method. Moreover, Western blots and double immunofluorescence were used to detect the expression and location of glial fibrillary acidic protein, OX42/Iba1, P-P38, NeuN, interleukin (IL)-1ß, phosphorylation of N-methyl-D-aspartate receptor 1 (P-NR1), and IL-1 receptor I (IL-1RI) in the L6-S1 spinal cord. We found that glial fibrillary acidic protein rather than OX42/Iba1 or P-P38 was significantly increased in the spinal cord of cyclophosphamide-induced cystitis. L-alpha-aminoadipate but not minocycline markedly attenuated the allodynia. Furthermore, we found that spinal IL-1ß was dramatically increased in cyclophosphamide-induced cystitis, and activated astrocytes were the only source of IL-1ß release, which contributed to allodynia in cystitis rats. Besides, spinal P-NR1 was statistically increased in cyclophosphamide-induced cystitis and only localized in IL-1RI positive neurons in spinal dorsal horn. Additionally, NR antagonist significantly attenuated the cystitis-induced pain. Interestingly, the time course of the P-NR1 expression paralleled to that of IL-1ß or glial fibrillary acidic protein. CONCLUSIONS: Our results demonstrated that astrocytic activation but not microglial activation contributed to the allodynia in cyclophosphamide-induced cystitis and IL-1ß released from astrocytes might bind to its endogenous receptor on the neurons inducing the phosphorylation of NR1 subunit, leading to sensory neuronal hyperexcitability and pathological pain.

Gp120 in the pathogenesis of human immunodeficiency virus-associated pain.

OBJECTIVE: Chronic pain is a common neurological comorbidity of human immunodeficiency virus (HIV)-1 infection, but the etiological cause remains elusive. The objective of this study was to identify the HIV-1 causal factor that critically contributes to the pathogenesis of HIV-associated pain. METHODS: We first compared the levels of HIV-1 proteins in postmortem tissues of the spinal cord dorsal horn (SDH) from HIV-1/acquired immunodeficiency syndrome patients who developed chronic pain (pain-positive HIV-1 patients) and HIV-1 patients who did not develop chronic pain (pain-negative HIV-1 patients). Then we used the HIV-1 protein that was specifically increased in the pain-positive patients to generate mouse models. Finally, we performed comparative analyses on the pathological changes in the models and the HIV-1 patients. RESULTS: We found that HIV-1 gp120 was significantly higher in pain-positive HIV-1 patients (vs pain-negative HIV-1 patients). This finding suggested that gp120 was a potential causal factor of the HIV-associated pain. To test this hypothesis, we used a mouse model generated by intrathecal injection of gp120 and compared the pathologies of the model and the pain-positive human HIV-1 patients. The results showed that the mouse model and pain-positive human HIV-1 patients developed extensive similarities in their pathological phenotypes, including pain behaviors, peripheral neuropathy, glial reactivation, synapse degeneration, and aberrant activation of pain-related signaling pathways in the SDH. INTERPRETATION: Our findings suggest that gp120 may critically contribute to the pathogenesis of HIV-associated pain.

Increased severity of inflammation correlates with elevated expression of TRPV1 nerve fibers and nerve growth factor on interstitial cystitis/bladder pain syndrome.

OBJECTIVES: Although evidence supports a role for inflammation in interstitial cystitis/bladder pain syndrome (IC/BPS), the mechanism remains unknown. We determined whether inflammation causes an elevated expression of nerve growth factor (NGF) and transient receptor potential vanilloid receptor subtype 1 (TRPV1) and correlated them with the symptoms. METHODS: Bladder biopsies were obtained from 53 IC/BPS patients and 27 controls, and hematoxylin and eosin staining, immunostaining and Western blotting were performed to detect inflammation, TRPV1-immunoreactive and PGP9.5-immunoreactive nerve fibers, and NGF, respectively. Symptoms were assessed using the Pelvic Pain/Urgency/Frequency (PUF) questionnaire and pain visual analogue scale scores. Suburothelial nerve fiber density was quantified and correlated with PUF scores. RESULTS: Increased severity of inflammation was correlated with a higher TRPV1-immunoreactive nerve fiber density (r = 0.4113, p = 0.0024) and higher NGF levels (r = 0.3775, p = 0.0052). Suburothelial TRPV1-immunoreactive nerve fiber density was significantly correlated with pain scores and urgency scores (r = 0.3320, p = 0.0145 and r = 0.3823, p = 0.0039, respectively). PGP9.5-immunoreactive nerve fibers were significantly increased in IC/BPS (p = 0.0193) and had a positive relationship with inflammation severity (r = 0.6138, p < 0.0001). CONCLUSIONS: Our study revealed increased severity of inflammation correlated with a higher expression of TRPV1-immunoreactive nerve fibers and NGF in IC/BPS and correlated with clinical symptoms.

Associations Between Serum Estrogen Levels and Urinary Incontinence in Women: A Cross-sectional Analysis of NHANES 2013 to 2016.

OBJECTIVE: To explore the relationship between serum estrogen levels and urinary incontinence in a nationally representative female population. MATERIALS AND METHODS: We included women who had serum estradiol measurements and self-reported urinary incontinence problems in the 2013-2016 National Health and Nutrition Examination Survey cycles. A weighted multivariable logistic regression model was used to determine the association between urinary incontinence and serum estrogen levels after adjusting for age, race, Body Mass Index, diabetes, venipuncture, hypertension, poverty-to-income ratio, smoking, marital status, alcohol use, education, and menopause. RESULT: A total of 4114 individuals were ultimately included in our study. Of these women, 1200 (29.17%) complained of urge urinary incontinence (UUI), 1674 (40.69%) complained of stress urinary incontinence (SUI), 730 (17.74%) complained of mixed urinary incontinence (MUI). Women in the lowest quartile of serum estrogen were more likely to complain of UUI compared to those in the highest quartile (OR=1.885; 95% CI=1.042-3.412, P = .039). No association was noted between serum estrogen levels and SUI or MUI. CONCLUSION: Our study shows a significant association between low serum estrogen level and the increased likelihood of UUI in women. Further research is required to validate our findings, elucidate the physiological mechanisms that underlie them, and assess potential therapeutic implications.

Associations between serum testosterone levels and overactive bladder in women: a cross-sectional research of NHANES 2011 to 2016.

PURPOSE: Androgen receptors are expressed in the pelvic floor and lower urinary tract. However, the association between serum testosterone and overactive bladder (OAB) in women remains unclear. This study aimed to investigate their association in a nationally representative population. METHODS: In this cross-sectional study, we collected data on female participants older than 20 years with serum total testosterone measurements and OAB questionnaires from the 2011-2016 National Health and Nutrition Examination Survey (NHANES). Survey-weighted logistic regression models were used to analyze the relationship between testosterone and OAB in women. RESULTS: Data on 4991 women was analyzed in this study, of whom 25.9% had OAB symptoms. Women with lower serum testosterone had an increased frequency of urge urinary incontinence and nocturia compared to participants with enough testosterone. The multivariate logistic models showed that those women with a testosterone level less than 18.5 ng/dL had significantly higher odds of OAB compared to those with a testosterone level greater than 18.5 ng/dL [OR 95% CI = 1.271 (1.073-1.505), P = 0.0076]. Separate interaction analyses revealed no significant effect of age, BMI, diabetes, education, alcohol use and menopause on the association between serum testosterone and OAB. Sensitivity analyses demonstrated that additional variables (depression, stroke and stress urinary incontinence) had no significant effect on this relationship. CONCLUSIONS: Low serum testosterone is associated with an increased likelihood of OAB in women. This supports the potential therapeutic role of testosterone supplementation in women with OAB. Given the direct and indirect effects of testosterone on the pelvic floor and lower urinary tract, a potential mechanism for this relationship can be further explored in translational studies.

Electrically weldable conductive elastomers.

Flexible and stretchable electronic devices are subject to failure because of vulnerable circuit interconnections. We develop a low-voltage (1.5 to 4.5 V) and rapid (as low as 5 s) electric welding strategy to integrate both rigid electronic components and soft sensors in flexible circuits under ambient conditions. This is achieved through the design of conductive elastomers composed of borate ester polymers and conductive fillers, which can be self-welded and generate welding effects to various materials including metals, hydrogels, and other conductive elastomers. The welding effect is generated through the electrochemical reaction-triggered exposure of interfacial adhesive promotors or the cleavage/reformation of dynamic bonds. Our strategy can ensure both mechanical compliance and conductivity at the circuit interfaces and easily produce welding strengths in the kilopascal to megapascal range. The as-designed conductive elastomers in combination with the electric welding technique provide a robust platform for constructing standalone flexible and stretchable electronic devices that are detachable and assemblable on demand.

Spatiotemporal release of non-nucleotide STING agonist and AKT inhibitor from implantable 3D-printed scaffold for amplified cancer immunotherapy.

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

Supine lithotomy versus prone position in minimally invasive percutaneous nephrolithotomy for upper urinary tract calculi.

OBJECTIVE: To compare operative time, safety and effectiveness of minimally invasive percutaneous nephrolithotomy (MPCNL) in the supine lithotomy versus prone position. METHODS: Between January 2008 and December 2010, a total of 109 consecutive patients with upper urinary tract calculi were enrolled and randomly divided into group A (53 patients, supine lithotomy position) and group B (56 patients, prone position). The MPCNL procedures were performed under the guidance of real-time grayscale ultrasound system. The preoperative characteristics, intraoperative and postoperative parameters were analyzed and compared. RESULTS: All patients were successfully operated. There was no significant difference between the two groups in stone-free rate (group A 90.1 vs. group B 87.5%, p = 0.45), mean blood loss, number of access tracts, calyx puncture, mean hospital stay (group A 6 ± 1.1 vs. group B 6 ± 1.5 days, p = 0.38) and complications. But the operative time was significantly shortened in supine lithotomy position (group A 56 ± 15 vs. group B 86 ± 23 min, p < 0.001). CONCLUSIONS: The effectiveness and safety of the supine lithotomy position for MPCNL were similar to the prone position. However, the supine lithotomy position has an important advantage of reducing the operative time. The supine lithotomy position could be a good choice to perform MPCNL.