Electroacupuncture attenuates nociceptive behaviors in a mouse model of cancer pain.

Pain is a major symptom in cancer patients, and cancer-induced bone pain (CIBP) is the most common type of moderate and severe cancer-related pain. The current available analgesic treatments for CIBP have adverse effects as well as limited therapeutic effects. Acupuncture is proved effective in pain management as a safe alternative therapy. We evaluated the analgesic effect of acupuncture in treatment of cancer pain and try to explore the underlying analgesic mechanisms. Nude mice were inoculated with cancer cells into the left distal femur to establish cancer pain model. Electroacupuncture (EA) treatment was applied for the xenograft animals. Pain behaviors of mice were evaluated, followed by the detections of neuropeptide-related and inflammation-related indicators in peripheral and central levels. EA treatment alleviated cancer-induced pain behaviors covering mechanical allodynia, thermal hyperalgesia and spontaneous pain, and also down-regulated immunofluorescence expressions of neuropeptide CGRP and p75 in the skin of affected plantar area in xenograft mice, and inhibited expressions of overexpressed neuropeptide-related and inflammation-related protein in the lumbar spinal cord of xenograft mice. Overall, our findings suggest that EA treatment ameliorated cancer-induced pain behaviors in the mouse xenograft model of cancer pain, possibly through inhibiting the expressions of neuropeptide-related and inflammation-related protein in central level following tumor cell xenografts.

Molecular Determinants for the High-Affinity Blockade of Human Ether-à-go-go-Related Gene K + Channel by Tolterodine.

ABSTRACT: Tolterodine is a first-line antimuscarinic drug used to treat overactive bladder. Adverse cardiac effects including tachycardia and palpitations have been observed, presumably because of its inhibition of the human ether-à-go-go-related gene (hERG) K + channel. However, the molecular mechanism of hERG channel inhibition by tolterodine is largely unclear. In this study, we performed molecular docking to identify potential binding sites of tolterodine in hERG channel, and two-microelectrode voltage-clamp to record the currents of hERG and its mutants expressed in Xenopus oocytes. The results of computational modeling demonstrated that phenylalanine at position 656 (F656) and tyrosine at position 652 (Y652) on the S6 helix of hERG channel are the most favorable binding residues of tolterodine, which was validated by electrophysiological recordings on Y652A and F656A hERG mutants. The Y652A and F656A mutations decreased inhibitory potency of tolterodine 345-fold and 126-fold, respectively. The Y652A mutation significantly altered the voltage dependence of channel inhibition by tolterodine. For both the wild-type and the mutant channels, tolterodine reduced the currents in a time-dependent manner, and the blockade occurred with the channel activated. Tolterodine did not interfere with hERG channel deactivation, whereas channel inactivation greatly impaired its blocking effect. The inhibition of hERG channel by tolterodine is independent of its action on muscarinic acetylcholine receptors. In conclusion, tolterodine is an open-state blocker of hERG K + channel with nanomolar potency. Y652 and F656, 2 aromatic residues on the inner S6 helix, are responsible for the high-affinity binding of tolterodine to hERG channel.

Application of an individualized and reassemblable 3D printing navigation template for accurate puncture during sacral neuromodulation.

OBJECTIVE: To evaluate the feasibility and safety of an individualized and reassemblable three-dimensional (3D) printing navigation template for making accurate punctures during sacral neuromodulation (SNM). METHODS: From July 2016 to July 2017, 24 patients undergoing SNM were enrolled. Conventional X-ray guidance was used in the control group, which included 14 patients, while the 3D printing template was used in the experimental group, which included 10 patients. The number of punctures, the average puncture time, the exposure to X-ray, the adjustment time during the operation and the testing of the SNM device, the infection and haemorrhage rate, and the implantable pulse generator (IPG) implantation rates were compared between the two groups. RESULTS: In total, 24 patients successfully underwent stage I. When comparing the control group and the experimental group, the number of punctures were 9.6 ± 7.7 and 1.5 ± 0.7, respectively; the average puncture times were 35.4 ± 14.6 and 4.1 ± 2.2 min, respectively; and the X-ray exposure levels were 8.37 ± 4.83 mAs and 2.34 ± 0.54 mAs, respectively. No postoperative complications were reported in either group. The IPG implantation rates were not different between the two groups. CONCLUSION: The 3D printing template for SNM can help us to perform accurate and quick punctures into the target sacral foramina, reduce X-ray exposure, and shorten the operation time. For patients with obesity, sacral variation, sacral bone fractures or losses and for patients who are unable to tolerate the prone position during operation, use of the 3D printing template is recommended.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization.

Background: Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. Objective: This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. Methods: We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. Results: We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (ß=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (ß=-0.127), showed an indirect effect on infertility mediated by SUA (ß=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Conclusion: Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

Causal pathways in preeclampsia: a Mendelian randomization study in European populations.

Purpose: Our study utilizes Mendelian Randomization (MR) to explore the causal relationships between a range of risk factors and preeclampsia, a major contributor to maternal and perinatal morbidity and mortality. Methods: Employing the Inverse Variance Weighting (IVW) approach, we conducted a comprehensive multi-exposure MR study analyzing genetic variants linked to 25 risk factors including metabolic disorders, circulating lipid levels, immune and inflammatory responses, lifestyle choices, and bone metabolism. We applied rigorous statistical techniques such as sensitivity analyses, Cochran's Q test, MR Egger regression, funnel plots, and leave-one-out sensitivity analysis to address potential biases like pleiotropy and population stratification. Results: Our analysis included 267,242 individuals, focusing on European ancestries and involving 2,355 patients with preeclampsia. We identified strong genetic associations linking increased preeclampsia risk with factors such as hyperthyroidism, BMI, type 2 diabetes, and elevated serum uric acid levels. Conversely, no significant causal links were found with gestational diabetes, total cholesterol, sleep duration, and bone mineral density, suggesting areas for further investigation. A notable finding was the causal relationship between systemic lupus erythematosus and increased preeclampsia risk, highlighting the significant role of immune and inflammatory responses. Conclusion: This extensive MR study sheds light on the complex etiology of preeclampsia, underscoring the causal impact of specific metabolic, lipid, immune, lifestyle, and bone metabolism factors. Our findings advocate for a multidimensional approach to better understand and manage preeclampsia, paving the way for future research to develop targeted preventive and therapeutic strategies.

Acupuncture treatment of acute urinary retention caused by varicella-zoster virus through by combining the mechanism of sacral neuromodulation: A rare case report.

RATIONALE: Urinary dysfunction triggered by varicella-zoster virus (VZV) attacking the nervous system seriously affects the quality of life of patients and may even cause irreversible damage to the urinary system. This a 62-year-old man with acute urinary retention triggered by VZV, who was cured after acupuncture treatment. The rational application of acupuncture therapy to promote the recovery of bladder contraction function can effectively relieve the symptoms of dysuria, shorten the course of the disease. PATIENT CONCERNS: Symptoms included dysuria and distension of the bladder area secondary to postherpetic herpes zoster, with significant pressure and pain in his lower abdomen, accompanied by cutaneous herpes distributed over the sacral region. DIAGNOSES: The case was diagnosed as acute urinary retention (Neurogenic Bladder). Ancillary tests include urodynamic examination, Doppler ultrasound, urodynamic tests are the preferred diagnostic method and suggest: no contraction of the detrusor muscle is seen during voiding, and voiding occurs in an The absence of abdominal pressure-assisted micturition and repeated attempts to pass urine suggests detrusor weakness; residual urine suggests a severe bladder emptying disorder. Doppler ultrasound suggested overfilling of the bladder, and 1153 mL of residual urine was seen in the bladder after voiding. INTERVENTIONS: The patient developed sacral herpes and dysuria and was treated with oral antiviral drugs on the 12th day of illness. But his urinary difficulty did not improve but gradually worsened, resulting in acute urinary retention, and he then turned to the acupuncture treatment, innovative approach combined the mechanism of action of sacral neuromodulation with traditional Chinese medicine theory. OUTCOMES: The duration of acupuncture treatment totaled 12 weeks; he was able to urinate on her own and her symptoms completely disappeared. No other adverse and unintended events occurred during treatment. LESSONS: This study demonstrates that acupuncture is safe and effective in the treatment of acute urinary retention caused by VZV, which is worth recommending as a conservative treatment. Moreover, we found that the early intervention and full-term treatment with acupuncture is particularly important, provided that the right key acupoints are selected.

Causal effects of circulating lipids and lipid-lowering drugs on the risk of urinary stones: a Mendelian randomization study.

Background: Previous studies have yielded conflicting findings regarding the association between circulating lipids and lipid-lowering drugs with urinary stones, and the causal relationship between the two remains inconclusive. Objective: This study aimed to assess the causal relationship between circulating lipids (Triglycerides [TG], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], apolipoprotein A [APOA], apolipoprotein B [APOB] and Pure hypercholesterolaemia), lipid-lowering drugs (HMGCR [HMG-CoA reductase] inhibitors and PCSK9[Proprotein Convertase Subtilisin/Kexin Type 9] inhibitors) and the risk of urinary stones, using genetic data. Methods: Genetic instrumental variables (GIVs) for circulating lipids and lipid-lowering drugs were obtained from the UK Biobank and existing literature. Outcome data were extracted from a genetic association database with 3,625 urinary stone cases and 459,308 controls. Two-sample MR analysis, employing the TwoSampleMR software package in R 4.2.3, was conducted to assess the associations between multiple exposures. The primary outcome was determined using the inverse variance weighted (IVW) method for the causal relationship between exposure and outcome, while additional methods such as MR-Egger, weighted median, simple mode, and weighted mode were utilized as supplementary analyses. Robustness of the Mendelian Randomization (MR) analysis results was assessed through leave-one-out analysis and funnel plots. Results: The MR analysis revealed a significant association between elevated TG levels per 1 standard deviation and the occurrence of urinary stones (odds ratio [OR]: 1.002, 95% confidence interval [CI]: 1.000-1.003, P = 0.010). However, no significant association was observed between factors other than TG exposure and the risk of urinary stone occurrence across all methods(LDL-C: [OR], 1.001; 95% [CI], 1.000-1.003, P=0.132;HDL-C: [OR], 0.999; 95% [CI], 0.998-1.000, P=0.151;APOA:[OR] being 1.000 (95% [CI], 0.999-1.001, P=0.721;APOB: [OR] of 1.001 (95% [CI], 1.000-1.002, P=0.058;Pure hypercholesterolaemia: [OR] of 1.015 (95% [CI], 0.976-1.055, P=0.455) and lipid-lowering drugs (HMGCR inhibitors: [OR], 0.997; 95% [CI], 0.990-1.003, P=0.301 and PCSK9 inhibitors:[OR], 1.002; 95% [CI], 1.000-1.005, P=0.099). Conclusion: Our findings provide conclusive evidence supporting a causal relationship between an increased risk of urinary stones and elevated serum TG levels. However, we did not find a significant association between urinary stone occurrence and the levels of LDL-C, HDL-C, APOA, APOB, Pure hypercholesterolaemia and lipid-lowering drugs.

Study of mirabegron and solifenacin in the improvement of catheter-related bladder discomfort in patients undergoing transurethral resection: A case-control study.

BACKGROUND: The goal of this study was to see if using mirabegron, solifenacin, or placebo may help patients with transurethral resection avoid catheter-related bladder discomfort (CRBD). METHODS: Patients who underwent transurethral surgery and were given a catheter for 3 days after surgery were chosen for this study. The enrolled patients were separated into 3 groups: mirabegron (M), solifenacin (S), and a blank control group (C). All patients had their overactive bladder symptoms score (OABSS) and blood pressure checked before surgery. The CRBD, blood pressure, and heart rate were measured at 6, 24, 48, and 72 hours after surgery. The OABSS and side effects were documented on the 7th day. RESULTS: The 104 patients in this trial were randomized into 3 groups at random: M, S, and C. The ultimate follow-up was completed by 99 patients, including 33 in group M, 33 in group S, and 33 in group C. The OABSS, CRBD, and blood pressure in groups M and S were similar before and after surgery (P > .05). Groups M and S performed much better on the OABSS and CRBD than group C (P < .05). There were no significant differences in blood pressure between the 3 groups (P > .05). There were no significant differences in the occurrences of new onset dry mouth (P = .84) or constipation (P = .64) among the 3 groups. CONCLUSION: Mirabegron is comparable to solifenacin as an alternative for the prevention of CRBD, making it a viable option for CRBD prevention.

[Efficacy and safety of body-insulated acupuncture needle for electrical stimulation at rabbit scia-tic nerve trunk].

OBJECTIVE: To evaluate the efficacy and safety of electrical stimulation at the rabbit sciatic nerve trunk with the body-insulated acupuncture needle whose body is painted with insulating material. METHODS: Eighteen male New Zealand rabbits were randomized into the body-insulated acupuncture needle (BIAN), the general acupuncture needle (GAN), and the blank control groups，with 6 rabbits in each group. The rats'sciatic nerve trunks in BIAN and GAN groups were stimulated by electroacupuncture with the body-insulated acupuncture needle (only allowing the uncoated needle handle and tip to conduct electricity) and the general acupuncture needle, separately. The current intensity was recorded when regular plantarflexion reflexes (sciatic nerve effector reflexes) were observed in the rabbit's foot. The pathological changes of the sciatic nerve at the acupuncture site were observed by H.E. staining, and the ultrastructural changes of the sciatic nerve trunk were observed by transmission electron microscope. RESULTS: The intensity of the current causing the regular plantar flexion reflection in BIAN group (ï¼»0.29±0.07ï¼½ mA) was significantly lower than that in the GAN group(ï¼»0.86±0.08ï¼½ mA, P<0.01). H.E. staining revealed nerve axon degeneration, forming eosinophilic bodies, nerve fiber edema, and focal loss of myelin sheath in the GAN group. While the nerve fiber damage was not obvious, and axons were only degenerated in a few areas in the BIAN group. Transmission electron microscopy observations showed that the nerve myelin sheath structure was separated, the layers were arranged disorderly and bubbled in the GAN group. while the nerve myelin sheath structure of the BIAN group was normal, and it presents a concentric circle-like light and dark lamellar structure, with fewer myelin vacuoles and fissures, only a small part of the mitochondria, microfilaments, and microtubules of the nerve axons were abnormal, and the overall vacuole-like degeneration was significantly reduced, with few of the myelinated fibers were slightly degenerated, and axonal disease was not obvious. CONCLUSION: Insulated acupuncture needle is more accurate and safer than ordinary acupuncture needle for electrical stimulation of rabbit sciatic nerve trunk, and the required electric current intensity is smaller.

Using electroacupuncture with optimized acupoint positioning to predict the efficacy of sacral neuromodulation of refractory overactive bladder: A case report.

RATIONALE: Overactive bladder (OAB) is a common disease in the female urinary system. Refractory OAB is an indication for sacral neuromodulation (SNM) therapy, which was approved by the Food and Drug Administration (FDA) of the United States. However, SNM does not alleviate the clinical symptoms in all refractory OAB cases. Patients are required to undergo an SNM stage 1 operation, a traumatic and costly procedure, to evaluate the clinical efficacy of the treatment. If the procedure is predicted to likely be ineffective, the patient has to bear the physical and economic losses. Here, we report a patient with a 3-year course of refractory urge urinary incontinence who was treated with electroacupuncture according to traditional Chinese medicine (TCM). PATIENT CONCERNS: The patient was 73 years old and had frequent urination and urge urinary incontinence for 3 years; she had 24 to 30 counts of urination per day and 7 to 9 counts of urge incontinence. The patient was treated with multiple TCM and Western medicines and therapies. The TCM treatment consisted of several patented Chinese medicines and TCM decoctions. The Western medication comprised mainly antibiotics, alpha receptor antagonists, and muscarinic receptor antagonists. The treatment effect was unsatisfactory, and there was no apparent alleviation of symptoms; therefore, she underwent electroacupuncture. DIAGNOSIS: Refractory OAB. INTERVENTIONS: The patient received 30 days of TCM-based electroacupuncture with optimized acupoint positioning, which comprised a total of 10 sessions (1 electroacupuncture session every 2 days) targeting the bilateral Zhongliao and Sanyinjiao acupoints. After treatment, the patient experienced a good therapeutic outcome. OUTCOMES: After 30 days of electroacupuncture treatment, the average daily count of urination in 5 days decreased from 29.3 per day before treatment to 19.8 after treatment, and the average count of urge incontinence decreased from 9.3 before treatment to 5.8 after treatment. However, good prognosis was not stable. After careful consideration, the patient accepted SNM treatment, which greatly alleviated the symptoms of frequent urination and urge incontinence. The patient received follow-up visits for 2 years, during which she manifested stable curative effects. LESSONS: The optimized positioning at the Zhongliao acupoint improves the accuracy of acupuncture. Accurate electroacupuncture alleviates the symptoms of refractory OAB by stimulating the Zhongliao and Sanyinjiao acupoints, as the underlying mechanisms are similar to those of SNM. Therefore, it is possible to use electroacupuncture to estimate the therapeutic effect of SNM, thereby providing a reference for patients and clinicians to determine whether SNM treatment will be effective.

Application of Internet+-based Tsinghua PINS Remote Tech to improve sacral neuromodulation programming procedure.

OBJECTIVE: To explore the feasibility and safety of the Tsinghua PINS Remote Tech to facilitate sacral neuromodulation programming procedure. METHOD: For 22 patients who had previously participated in the phase III clinical trial for treating overactive bladder with the Tsinghua PINS sacral neuromodulation system during several Hospital, PINS Remote Tech was applied to perform postoperative parameter adjustment in order to evaluate the safety and reliability of this new technique. Telephone surveys on Remote Tech-related questionnaires were also conducted. RESULTS: 17/22 patients underwent 26 parameter adjustments, average adjustment frequency was 1.53 times per person; the average adjustment time was 23.4 ± 5.1 min (15-32 min). The total effective rate of the Remote control was 14/17 (82.3%). 7/17 (41.1%) patients' symptoms recurrence due to not knowing how to handle patient controller, these patients were instructed on how to use it correctly through Remote Tech even without reprogramming it. Other 10 patients received reprogramming. There was no discomfort during and after parameter adjustment. The questionnaire survey showed that the remote technology saved patients' time and lowered financial costs, significantly improved patient satisfaction. All patients expressed their willingness to recommend it to other patients. CONCLUSION: The PINS Remote Tech can significantly reduce the financial cost and provide a remote reprogram control service that is as safe and reliable as outpatient program control.

Sanjin tablets for acute uncomplicated lower urinary tract infection (syndrome of dampness-heat in the lower jiao): protocol for randomized, double-blind, double-dummy, parallel control of positive drug, multicenter clinical trial.

BACKGROUND: Acute uncomplicated lower urinary tract infection (UTI) is one of the most common bacterial infections. Patients usually present with dysuria, urinary urgency, urinary frequency, and suprapubic pain or tenderness. Approximately 150 million people are diagnosed with UTI each year worldwide. The high recurrence rate of lower UTI is a common problem of clinical treatment. The misuse of antibiotics has led to the emergence of a number of resistant bacterial strains. Thus, traditional Chinese medicine is considered as an alternative option for treating acute uncomplicated lower UTI. Thus, this study aims to evaluate the efficacy and safety of Sanjin tablets (SJT) for the treatment of acute uncomplicated lower UTI, explore whether SJT can reduce or substitute the use of antibiotics, and reduce the recurrence rate in the treatment of acute uncomplicated lower UTI. METHODS/DESIGN: In this study, a randomized, double-blind, double-dummy, parallel control of positive drug, multicenter clinical study will be established. A total of 252 patients with acute uncomplicated lower UTI (syndrome of dampness-heat in the lower jiao) will be randomly allocated in the ratio of 1:1:1 to three groups: experimental group; control group 1; and control group 2. The experimental group receives Sanjin tablets plus levofloxacin tablets (LT) placebo; the control group 1 receives LT plus SJT placebo; and the control group 2 receives SJT plus LT on the first five days, SJT plus LT placebo on the last two days. Each group will be treated for seven days and followed-up 1-2 times. The primary outcome measures of effective rate and recurrence rate are symptoms. Secondary outcome measures of effective rate and recurrence rate are the urine leukocytes, bacteriology examination, and safety assessment. Outcomes will be assessed at baseline and after treatment. DISCUSSION: This study protocol will provide the research data of efficacy and safety of SJT for the treatment of acute uncomplicated lower UTI. The first aim is to determine whether Sanjin tablets can reduce the use of antibiotics; the second aim is to determine whether Sanjin tablets can substitute the use of antibiotics. The recurrence rate will be assessed after cured to determine whether SJT can reduce the recurrence rate. The results of this study will improve the rational use of drugs, especially the rational application of antibiotics. It will also enable safety evaluation from laboratory indices and adverse events, which will provide reliable evidence for clinical treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03658291 . Registered on 4 September 2018.

Sphenopalatine ganglion stimulation with one acupuncture needle for moderate-severe persistent allergic rhinitis: study protocol for a multicenter randomized controlled trial.

BACKGROUND: Allergic rhinitis is a symptomatic allergic disease of the nose that affects 10 to 20% of the global population. Chinese otolaryngologists use one acupuncture needle to stimulate the sphenopalatine ganglion because of its potential advantages for treating moderate-severe persistent allergic rhinitis compared with traditional Chinese acupuncture (verum acupuncture); however, little evidence is available to support the wide clinical use thus far. Therefore, we propose a protocol for a parallel, multicenter, assessor-blinded, randomized controlled trial to evaluate sphenopalatine ganglion stimulation with one acupuncture needle compared to verum acupuncture for treatment of moderate-severe persistent allergic rhinitis. METHODS: In the trial, 96 patients previously diagnosed with moderate-severe persistent allergic rhinitis and meeting all inclusion criteria will be allocated to one of two equal therapeutic groups by using a computer-generated randomization list. The interventional group will receive sphenopalatine ganglion stimulation with one acupuncture needle for 4 weeks (once or twice weekly, total four to eight sessions); attending physicians will decide whether the second session is required in a week by examining signs and symptoms. The control group will receive individualized verum acupuncture for 4 weeks (twice weekly, total eight sessions). Follow-up evaluations will be performed 1 month later. The primary outcome measure is the change in the total nasal symptom score from the baseline to week 4. The secondary outcome measures include onset time and duration of effectiveness in every session, change in number of days with moderate-severe persistent allergic rhinitis from the baseline to week 8, change in total immunoglobulin E level and eosinophil count in venous blood from the baseline to week 4, change in Rhinoconjunctivitis Quality of Life Questionnaire score from the baseline to week 4, and clinical waiting time. DISCUSSION: The trial should provide evidence for the benefits of sphenopalatine ganglion stimulation with one acupuncture needle for treating moderate-severe persistent allergic rhinitis, including better change in total nasal symptom score, faster onset time, longer duration of effectiveness, and shorter treatment time. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN21980724 (registered on 27 March 2014).