Preliminary analysis of stimulation parameters for sacral neuromodulation in different indications: a multicenter retrospective cohort study from China.

BACKGROUND: Sacral neuromodulation (SNM) is an effective approach for treating lower urinary tract dysfunction (LUTD), and stimulation programming is essential for successful treatment. However, research on SNM programming for various indications is limited. Thus, the authors aimed to determine whether there were differences in the stimulation parameters for different SNM indications and the appropriate programming recommendations. MATERIALS AND METHODS: Clinical data were retrospectively collected from patients with LUTD who underwent SNM and completed internal pulse generator implantation. The parameters with the highest patient satisfaction or the most symptom improvement during the test period were considered optimal and used to set the programming after internal pulse generator implantation. RESULTS: After screening, 282 patients were enrolled and categorized into four groups based on the following indications: refractory overactive bladder (OAB) ( n =61), neurogenic lower urinary tract dysfunction (nLUTD) ( n =162), interstitial cystitis/painful bladder syndrome (IC/BPS) ( n =24), and idiopathic nonobstructive urinary retention (NOUR) ( n =35). When analyzing the optimal stimulus parameters, disparities in the stimulation amplitude and pulse frequency were noted among the four groups. The stimulation amplitude in the nLUTD group was higher than that in the idiopathic NOUR group ( P =0.013). Differences in pulse frequency were observed between the refractory OAB and nLUTD groups ( P <0.001) and between the refractory OAB and idiopathic NOUR groups ( P =0.001). No differences in the electrode configuration or pulse width settings existed among the four groups. CONCLUSIONS: The stimulation parameters for SNM varied among the different indications. For the initial programming of stage I, most patients are recommended to start with stimulation amplitudes below 2 V, although patients with nLUTD may benefit from higher amplitudes. A standard pulse width of 210 µs is recommended for all patients. However, for individuals experiencing nLUTD or idiopathic NOUR, the pulse frequency can begin above the standard 14 Hz but not exceed 50 Hz.

Sacral neuromodulation remote programming in patients with refractory lower urinary tract dysfunction: China's experience during the COVID-19 pandemic.

Objectives: Sacral neuromodulation is an effective, minimally invasive treatment for refractory lower urinary tract dysfunction. However, regular postoperative programming is crucial for the maintenance of the curative effects of electronic sacral stimulator devices. The outbreak of coronavirus disease 2019 (COVID-19) limited the ability of practitioners to perform traditional face-to-face programming of these stimulators. Therefore, this study aimed to evaluate the application of remote programming technology for sacral neuromodulation during the COVID-19 pandemic in China. Materials and methods: We retrospectively collected data including baseline and programming information of all patients with lower urinary tract dysfunction who underwent sacral neuromodulation remote programming in China after the outbreak of COVID-19 (i.e., December 2019). The patients also completed a self-designed telephone questionnaire on the subject. Results: A total of 51 patients from 16 centers were included. They underwent 180 total remote programming visits, and 118, 2, 25, and 54 voltage, current, pulse width, and frequency adjustments, respectively, were performed. Additionally, remote switching on and off was performed 8 times; impedance test, 54 times; and stimulation contact replacement, 25 times. The demand for remote programming was the highest during the first 6 months of sacral neuromodulation (average, 2.39 times per person). In total, 36 out of the 51 patients completed the questionnaire survey. Of these, all indicated that they chose remote programming to minimize unnecessary travel because they had been affected by COVID-19. The questionnaire also showed that remote programming could reduce the number of patient visits to the hospital, save time, reduce financial costs, and would be easy for patients to master. All surveyed patients indicated that they were satisfied with remote programming and were willing to recommend it to other patients. Conclusion: Remote programming for sacral neuromodulation is feasible, effective, safe, and highly recommended by patients with refractory lower urinary tract dysfunction. Remote programming technology has great development and application potential in the post-pandemic era.

Differences in patterns of metabolic abnormality and metabolic syndrome between early-onset and adult-onset first-episode drug-naive schizophrenia patients.

Although metabolic abnormalities and metabolic syndrome (MetS) often occur in schizophrenia, few studies have investigated them in early-onset schizophrenia (EOS) patients. To our knowledge, this was the first to compare clinical correlates of metabolic abnormalities between first-episode drug-naïve (FEDN) EOS and adult-onset schizophrenia (AOS) patients. A total of 489 Chinese FEDN schizophrenia patients (116 EOS and 373 AOS) and 451 healthy controls were recruited in this cross-sectional study. Blood pressure, waist circumference (WC), Body mass index (BMI), total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), glucose, hemoglobin A1c (HbA1c), insulin and insulin resistance were measured. The Positive and Negative Syndrome Scale (PANSS) was applied to evaluate the clinical symptoms of schizophrenia patients, and higher scores on PANSS indicate increased severity. EOS patients had lower rates of: MetS, elevated WC, hypertriglyceridemia, hypercholesterolemia, and hyper-LDLC than EOS patients (all p < 0.05). In EOS patients, WC was positively associated with PANSS general psychopathology score (p = 0.04). In AOS patients, WC (p = 0.01; p = 0.02) and glucose (p < 0.001; p < 0.001) were positively associated with PANSS general psychopathology and total score. HOMA-IR was positively associated with PANSS total score (p = 0.04). Systolic BP, triglycerides and HDLC were main contributors to MetS in AOS (all p < 0.05), but not in EOS. BMI was a risk factor of MetS in EOS, while BMI and HOMA-IR were risk factors of MetS in AOS (all p < 0.05). Our results indicate differences in metabolic abnormalities patterns, risk factors and their association with clinical characteristics between Chinese EOS and AOS patients. DATA AVAILABILITY STATEMENT: The datasets that support the findings of this study are not publically available due to ongoing analyses for further publications, but are available from the corresponding author X.Z. upon reasonable request.

Smoking Affects the Patterns of Metabolic Disorders and Metabolic Syndrome in Patients With First-Episode Drug-Naive Schizophrenia: A Large Sample Study Based on the Chinese Han Population.

OBJECTIVE: Although metabolic disorders and smoking are common in schizophrenia, few studies have investigated the effects of smoking on metabolic disorders or metabolic syndrome (MetS) in schizophrenia patients, especially in first-episode drug-naïve (FEDN) patients. We sought to investigate the differences in metabolic disorders and MetS between smoking and nonsmoking FEDN schizophrenia patients. METHODS: A total of 428 FEDN schizophrenia patients and 435 controls were recruited. Blood pressure, waist circumference, body mass index (BMI), lipid profiles, and glucose metabolism were measured. The psychopathology was evaluated by Positive and Negative Syndrome Scale. RESULTS: FEDN schizophrenia patients had a higher smoking rate than controls (23.8% vs 14.0%, P < .001). After adjusting for confounding variables, the prevalence of MetS, overweight, hypertension, hypertriglyceridemia, elevated insulin, and insulin resistance in smoking patients was higher than those in nonsmoking patients, while overweight and hypertension were higher in the smoking controls than in nonsmoking controls (all P < .05). In smoking patients, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS, while in nonsmoking patients, waist circumference, systolic blood pressure, triglyceridemia, high-density lipoprotein cholesterol, and fasting blood glucose were the main contributing components to MetS. In smoking patients, BMI and homeostatic model assessment for insulin resistance were associated factors of MetS (both P < .05). In nonsmoking patients, sex, BMI, insulin, and homeostatic model assessment for insulin resistance were associated factors of MetS (all P < .05). CONCLUSIONS: Our study indicates that smoking schizophrenia patients have a higher prevalence of MetS and metabolic disorders than nonsmoking patients. Moreover, smoking and nonsmoking patients have different contributing components and associated factors for MetS.

Neuronal Dual Leucine Zipper Kinase Mediates Inflammatory and Nociceptive Responses in Cyclophosphamide-Induced Cystitis.

Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is implicated in neuropathic pain. We hypothesized that neuronal DLK is involved in the regulation of inflammation and nociceptive behavior in cystitis. Mice deficient in DLK in sensory neurons (cKO) were generated by crossing DLK floxed mice with mice expressing Cre recombinase under Advillin promoter. Cystitis was induced by cyclophosphamide (CYP) administration in mice. Nociceptive behavior, bladder inflammation, and pathology were assessed following cystitis induction in control and cKO mice. The role of DLK in CYP-induced cystitis was further determined by pharmacological inhibition of DLK with GNE-3511. Deletion of neuronal DLK attenuated CYP-induced pain-like nociceptive behavior and suppressed histamine release from mast cells, neuronal activation in the spinal cord, and bladder pathology. Mice deficient in neuronal DLK also showed reduced inflammation induced by CYP and reduced c-Jun activation in the dorsal root ganglia (DRG). Pharmacological inhibition of DLK with GNE-3511 recapitulated the effects of neuronal DLK depletion in CYP treatment mice. Our study suggests that DLK is a potential target for the treatment of neuropathic pain and bladder pathology associated with cystitis.

Neuromodulation of the Pudendal Nerve Assisted by 3D Printed: A New Method of Neuromodulation for Lower Urinary Tract Dysfunction.

Electrical stimulation of peripheral nerves by implanted electrodes is an effective treatment for certain pelvic floor diseases. As well as intravesical electrical stimulation, this predominantly includes stimulation of the sacral nerve, tibial nerve, and pudendal nerve. The pudendal nerve is one of the main nerves that stimulate pelvic floor muscles, external urethral meatus, and the anal sphincter and pelvic organs, and it may have effects on frequent urination, urgency, dysuria, and perineal pain. It is difficult to locate because of its anatomical course, however, leading to difficulties fixing the electrode, which increases the difficulty of pudendal nerve electrical stimulation in clinical practice. In the current study 3D printed navigation was used to solve these problems. Combined with autopsy data and patient pelvic and nerve data, a personalized design was generated. Neural modulation of the pudendal nerve was achieved by implanting the lead with the guidance of 3D printed navigation. 3D printed navigation can maximize the phase II conversion rate, reduce the difficulty of surgery, shorten the operation time, reduce damage to additional organs and blood vessels, and increase the accuracy of electrode implantation, and it can be performed while the patient is awake. It is an accurate, reversible, efficient, and minimally invasive surgery.

[Efficacy of electroacupuncture nerve stimulation therapy for interstitial cystitis/bladder pain syndrome].

OBJECTIVE: To explore the clinical efficacy of electroacupuncture nerve stimulation therapy (ENST) for interstitial cystitis/painful bladder syndrome (IC/PBS). METHODS: A total of 68 patients with IC/PBS were randomly divided into an observation group and a control group, 34 cases in each one. The patients in the observation group were treated with ENST; abdominal four acupoints and sacral four acupoints were connected with a pair of electrodes and treated alternately every other day. The ENST was given 50 min per times, three times a week for 3 months. The patients in the control group were treated with perfusion therapy of four-medication combination (heparin sodinm, lidocaine, sodium bicarbonate, gentamicin sulfate), twice a week for the first 6-8 weeks, followed by twice per month for 3 months. The infusion fluid remained for 1 h before discharging. The O' Leary-Sant score, including interstitial cystitis symptom index (ICSI) and interstitial cystitis problem index (ICPI), 24 h urination frequency, visual analogue scale (VAS) and maximum bladder volume were observed before treatment and treatment of 1 month, 3 months and 6 months after treatment respectively; the adverse events during the treatment were also recorded. RESULTS: Compared before treatment, the O'Leary-Sant score (ICSI, ICPI), 24 h urination frequency, VAS and maximum bladder volume in the two groups were improved after 1, 3 months treatment and 6 months after treatment (all P<0.05). The scores of ICSI, ICPI, VAS and 24 h urination frequency in the observation group were significantly lower than those in the control group (P<0.05). The maximum bladder volume in the observation group was significantly higher than that in the control group (P<0.05). Six months after treatment, the total effective rate in the observation group was 87.5% (28/32), which was higher than 69.7% (23/33) in the control group (P<0.01). No significant adverse events occurred during the treatment. CONCLUSION: ENST could effectively relieve the clinical symptoms of IC/PBS, but its long-term efficacy needs further observation.

Microrna-139-5p inhibits epithelial-mesenchymal transition and fibrosis in post-menopausal women with interstitial cystitis by targeting LPAR4 via the PI3K/Akt signaling pathway.

The study explores whether miR-139-5p targeting LPAR4 affects epithelial-mesenchymal transition (EMT) and fibrosis in post-menopausal women with interstitial cystitis (IC) via the PI3K/Akt signaling pathway. Bladder tissues of IC and normal bladder tissues were collected. The pathology of bladder tissues was observed by HE, Masson and Picrosirius red staining. LPAR4 positive expression rate were determined by IHC. ELISA was performed to detect the levels of IL-6, IL-8, IL-10, and TNF-α. Rat IC models were randomized into seven different groups. miR-139-5p, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, P13K, Akt, E-cadherin, N-cadherin, Vimentin, TGF-ß1, and CTGF expression were determined by RT-qPCR and Western blotting. Dual luciferase reporter gene assay verified that LPAR4 is a target gene of miR-139-5p. Fibrosis was a pathological manifestation of IC. The IC group showed higher LPAR4, PI3K, Akt, p-PI3K, p-Akt, N-cadherin, Vimentin, TGF-ß1, and CTGF expression but lower miR-139-5p and E-cadherin expression than the normal group. The levels of IL-6, IL-8, IL-10, and TNF-α expression decreased while HB-EGF increased in the IC group in comparison of the normal group. Compared with the blank and NC groups, E-cadherin expression was increased in the miR-139-5p mimic and siRNA-LPAR4 groups, while LPAR4, PI3K, Akt, p-P13K, p-Akt, N-cadherin, Vimentin, TGF-ß1, and CTGF expression were decreased. An opposite trend was found in the miR-139-5p inhibitor group. The miR-139-5p decreased in the miR-139-5p inhibitor + siRNA-LPAR4 and miR-139-5p inhibitor + wortmannin groups. Conclusively, miR-139-5p targeting LPAR4 inhibits EMT and fibrosis in post-menopausal IC women through the PI3K/Akt signaling pathway.

Inhibition of microRNA-214 promotes epithelial-mesenchymal transition process and induces interstitial cystitis in postmenopausal women by upregulating Mfn2.

Our study aims to investigate the roles that microRNA-214 (miR-214) plays in the epithelial mesenchymal transition (EMT) process and the development of interstitial cystitis (IC) in postmenopausal women by targeting Mitofusin 2 (Mfn2). IC bladder tissues and adjacent normal bladder tissues were collected from postmenopausal women. Immunohistochemistry (IHC) staining was conducted. The target relationship between miR-214 and Mfn2 was determined by a dual luciferase reporter gene assay. Adipose-derived mesenchymal stem cells (ADMSCs) were extracted from postmenopausal rats and assigned to the blank, mimics, miR-214 inhibitors, mimics negative control (NC), inhibitors NC, Mfn2 siRNA, miR-214 inhibitors and Mfn2 siRNA groups. Exosomes secreted by transfected ADMSCs were instilled into the bladders of postmenopausal rats. The expression of miR-214 and Mfn2 mRNA and EMT markers was assessed by qRT-PCR and western blotting. It was confirmed that Mfn2 was the target gene of miR-214 in IC. Compared with the normal bladder tissues, miR-214 decreased, but Mfn2 increased in IC bladder tissues. Compared with the blank group, the expression of miR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein increased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein decreased in the miR-214 mimics and Mfn2 groups. The expression of MiR-214 and the expression levels of N-cadherin, Fibronectin, Twist1, Snail and Vimentin mRNA and protein decreased, whereas the expression levels of Mfn2, E-cadherin and ZO-1 mRNA and protein increased in the miR-214 inhibitors group. Our findings indicate that the inhibition of miR-214 promotes the EMT process and contributes to bladder wall fibrosis by up-regulating Mfn2, thus leading to the occurrence of IC in postmenopausal women.