Activation of voltage-gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats

<p>Abstract</p> <p>Background</p> <p>Temporomandibular disorders (TMDs) are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassium KCNQ/Kv7 channels (M-current), suggesting that specific activation of M-current might be beneficial for TMD pain.</p> <p>Results</p> <p>In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-current, and investigated the effect of retigabine on inflammation of the temporomandibular joint (TMJ) induced by complete Freund's adjuvant (CFA) in rats. The results show that the head withdrawal threshold for escape from mechanical stimulation applied to facial skin over the TMJ in inflamed rats was significantly lower than that in control rats. Administration of centrally acting M-channel opener retigabine (2.5 and 7.5 mg/kg) can dose-dependently raise the head withdrawal threshold of mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 mg/kg). Food intake is known to be negatively associated with TMJ inflammation. Food intake was increased significantly by the administration of retigabine (2.5 and 7.5 mg/kg), and this effect was reversed by XE991 (3 mg/kg). Furthermore, intracerebralventricular injection of retigabine further confirmed the analgesic effect of central retigabine on inflammatory TMJ.</p> <p>Conclusions</p> <p>Our findings indicate that central sensitization is involved in inflammatory TMJ pain and pharmacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels may have therapeutic potential for TMDs.</p

The novel role of LDHA/LDHB in the prognostic value and tumor-immune infiltration in clear cell renal cell carcinoma

Lactate dehydrogenase (LDH) is a crucial glycolytic enzyme which mediates the metabolic plasticity of cancer cells, however its clinical significance in renal cell carcinoma (RCC) is poorly understood. Herein, we examined the prognostic significance of the two primary components of LDH, i.e., LDHA and LDHB, in clear cell RCC (ccRCC) patients and further explored their association with immune infiltration in ccRCC. In this study, the expression levels of LDHA and LDHB were examined in ccRCC and adjacent normal tissues by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, and western blotting (WB) analyses, and their prognostic values were estimated in 150 ccRCC and 30 adjacent normal tissues by immunohistochemistry (IHC) analysis. The relationship to immune infiltration of LDHA and LDHB genes was further investigated using tumor immune estimation resource 2 (TIMER2) and Tumor-Immune System Interactions and DrugBank (TISIDB) databases, respectively. Public databases and WB analyses demonstrated higher LDHA and lower LDHB in ccRCC than in non-tumor tissues. IHC analysis revealed that LDHA and LDHB expression profiles were significantly associated with tumor grade, stage, size, and overall survival (OS). Univariate survival analysis displayed that high grade, advanced stage, large tumor, metastasis, high LDHA, and low LDHB expression were significantly associated with a poorer OS, and multivariate analysis revealed tumor stage and LDHB were identified as independent predictors for OS in patients with ccRCC. Further TIMER2 and TISIDB analyses demonstrated that LDHA and LDHB expression was significantly related to multiple immune cells and immune inhibitors in over 500 ccRCC patients. These findings revealed that LDHB was an independent favorable predictor, and LDHA and LDHB correlated with tumor immune infiltrates in ccRCC patients, which indicated LDHA/LDHB could be implicated in the tumorigenesis of ccRCC and might be potential therapeutic targets for patients with ccRCC

High HIV Incidence Among Men Who Have Sex With Men in 8 Chinese Cities: Results From a Trial.

BACKGROUND: In China, while the overall HIV prevalence has been decreasing within key populations, the epidemic among men who have sex with men (MSM) is still on the rise. This study aims to assess the HIV incidence rate and identify driving forces of HIV seroconversion among MSM in a closed cohort. METHODS: This study is a secondary analysis of a large trial of HIV testing promotion among Chinese MSM in 2016-2017. Sexual behaviors, HIV testing activities, and HIV serostatus were measured at baseline and follow-up every 3 months. HIV seroconversion in this study was defined as a self-reported HIV-positive test result. Participants who reported testing for HIV at least twice during different follow-up periods were included. Subgroup analysis and Cox regression were used to examine the correlates with HIV seroconversion. RESULTS: Overall, 347 participants were included in this study, with a mean age of 25.3 ± 6.1, and 71.2% were migrants. The sociodemographic characteristics of the included participants were similar to the rest of the participants in the trial (n = 1034); 7.2% (25/347) of participants seroconverted during the study period, resulting in an incidence rate of 15.56/100 person-years. In subgroup analysis, the HIV incidence rate was higher among migrants than nonmigrants (incidence rate ratio, 1.26; 95% confidence interval [CI], 0.47-3.87). In the time-dependent Cox regression model, bisexual MSM had a higher risk of contracting HIV than gay men (adjusted hazard ratio, 2.19; 95% CI, 1.02-4.72). CONCLUSIONS: Our findings suggest a high HIV incidence rate among Chinese MSM. Further expansion of pre-exposure prophylaxis and other effective HIV prevention interventions are urgently needed

Pay-it-forward gonorrhea and chlamydia testing among men who have sex with men in China:a study protocol for a three-arm cluster randomized controlled trial

BACKGROUND: Gonorrhea and chlamydia testing rates are poor among Chinese men who have sex with men (MSM). A quasi-experimental study suggested that a pay-it-forward strategy increased dual gonorrhea/chlamydia testing among MSM. Pay-it-forward offers an individual a gift (e.g., a free test) and then asks the same person if they would like to give a gift to another person. This article reports the protocol of a randomized controlled trial to evaluate dual gonorrhea/chlamydia test uptake and other outcomes among MSM in three arms - a pay-it-forward arm, a pay-what-you-want arm, and a standard of care arm. METHODS: Three hundred MSM will be recruited at three HIV testing sites in Guangzhou and Beijing. Testing sites include two hospital-based MSM sexually transmitted diseases clinics and one MSM community-based organization. Eligible participants will be born biologically male, aged 16 years or older, reporting previous anal sex with another man, having never participated in the pay-it-forward program, without previous gonorrhea and chlamydia testing in the past 12 months, and residing in China. Following a cluster randomized design, every cluster of ten participants will be randomly allocated into one of three arms: (1) a pay-it-forward arm in which men are offered free gonorrhea and chlamydia testing and then asked whether they would like to donate ("pay it forward") toward testing for future testers; (2) a pay-what-you-want arm in which men are offered free testing and told to decide how much to pay after receiving the test; (3) a standard of care arm in which men can pay the full price for dual gonorrhoea and chlamydia testing. The primary outcome is dual gonorrhoea/chlamydia testing as verified by administrative records. Secondary outcomes include incremental cost per test, incremental cost per diagnosis, community connectedness, and social cohesion. Primary outcome will be calculated for each arm using intention-to-treat and compared using one-sided 95% confidence intervals with a margin of 20% increase defined as superiority. DISCUSSION: This study will examine the pay-it-forward strategy in comparison to the standard of care in improving test uptake for gonorrhea and chlamydia. We will leverage the cluster randomized controlled trial to provide scientific evidence on the potential effect of pay-it-forward. Findings from this study will shed light on novel intervention methods for increasing preventive health service utilization and innovate ways to finance it among communities. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03741725 . Registered on 12 November 2018

The role of Tyro 3 subfamily receptors in the regulation of hemostasis and megakaryocytopoiesis

Background and Objectives The molecular mechanisms regulating megakaryocytopoiesis and hemostasis remain largely unknown. The Tyro 3 subfamily of receptor tyrosine kinases (RTK), which is composed of three members (Tyro 3, Axl and Mer), plays important roles in various tissues, such as those in the nervous, immune and reproductive systems. Here, we investigate the roles of the Tyro 3 RTK subfamily in regulating megakaryocytopoiesis and hemostasis.Design and Methods Single, double, and triple knock-out mice for the three Tyro 3 RTK were used in the study. Bleeding time, platelet count, megakaryocyte count, megakaryocyte ploidy, rate of proplatelet formation, platelet aggregation and ATP release were used as criteria to evaluate hemostasis, megakaryocytopoiesis and platelet function.Results Mice lacking all three receptors had impaired hemostasis and mild thrombocytopenia, which may be due to platelet dysfunction and defective megakaryocytopoiesis. Mice lacking different combinations of two receptors of the Tyro 3 RTK subfamily had normal platelet counts in peripheral blood, but exhibited impaired hemostasis and platelet function. Although knock-out mice for any single receptor had normal hemostasis and megakaryocytopoiesis, they exhibited a mild platelet dysfunction.Interpretation and Conclusions The Tyro 3 RTK subfamily plays important roles in regulating hemostasis, megakaryocytopoiesis and platelet function

Pay-it-forward gonorrhoea and chlamydia testing among men who have sex with men in China:a randomised controlled trial

BACKGROUND: WHO recommends that men who have sex with men (MSM) receive gonorrhoea and chlamydia testing, but many evidence-based preventive services are unaffordable. The pay-it-forward strategy offers an individual a gift (eg, a test for sexually transmitted diseases) and then asks whether they would like to give a gift (eg, a future test) to another person. This study examined the effectiveness of a pay-it-forward programme to increase gonorrhoea and chlamydia testing among MSM in China. METHODS: We did a randomised controlled superiority trial at three HIV testing sites run by MSM community-based organisations in Guangzhou and Beijing, China. We included MSM aged 16 years or older who were seeking HIV testing and met indications for gonorrhoea and chlamydia testing. Restricted randomisation was done using computer-generated permuted blocks. 30 groups were randomised into three arms (1:1:1): a pay-it-forward arm in which men were offered free gonorrhoea and chlamydia testing and then asked whether they would like to donate for testing of prospective participants, a pay-what-you-want arm in which men were offered free testing and given the option to pay any desired amount for the test, and a standard-of-care arm in which testing was offered at ¥150 (US$22). There was no masking to arm assignment. The primary outcome was gonorrhoea and chlamydia test uptake ascertained by administrative records. We used generalised estimating equations to estimate intervention effects with one-sided 95% CIs and a prespecified superiority margin of 20%. The trial is registered with ClinicalTrials.gov, NCT03741725. FINDINGS: Between Dec 8, 2018, and Jan 19, 2019, 301 men were recruited and included in the analysis. 101 were randomly assigned to the pay-it-forward group, 100 to the pay-what-you-want group, and 100 to the standard-of-care group. Test uptake for gonorrhoea and chlamydia was 56% (57 of 101 participants) in the pay-it-forward arm, 46% (46 of 100 participants) in the pay-what-you-want arm, and 18% (18 of 100 participants) in the standard-of-care arm. The estimated difference in test uptake between the pay-it-forward and standard-of-care group was 38·4% (95% CI lower bound 28·4%). Among men in the pay-it-forward arm, 54 of 57 (95%) chose to donate to support testing for others. INTERPRETATION: The pay-it-forward strategy can increase gonorrhoea and chlamydia testing uptake among Chinese MSM and could be a useful tool for scaling up preventive services that carry a mandatory fee. FUNDING: US National Institute of Health; Special Programme for Research and Training in Tropical Diseases, sponsored by UNICEF, UNDP, World Bank, and WHO; the National Key Research and Development Program of China; Doris Duke Charitable Foundation; and Social Entrepreneurship to Spur Health

Adolescent and non-consensual anal sexual debut among Chinese men who have sex with men: a cross-sectional study.

BACKGROUND: Adolescent sexual debut and non-consensual sex have been linked to higher sexual risk and STI infection in adulthood among men who have sex with men (MSM) in high-income countries. This study aimed to examine adolescent and non-consensual anal sexual debut among Chinese MSM and to evaluate factors associated with adolescent sexual debut and non-consensual anal sex. METHODS: A cross-sectional study was conducted recently among Chinese men assigned male sex at birth, ≥18 years old, and who had ever engaged in anal sex with a man. Participants answered questions regarding socio-demographics, condomless sex, age at anal sexual debut with a man, and whether the first anal sex was consensual. Factors associated with an adolescent sexual debut (< 18 years old) and non-consensual sex at sexual debut were evaluated. We defined adolescent sexual debut as having anal sex with another man at 17 years old or younger, and the participants were asked whether their first male-to-male anal sex was non-consensual. RESULTS: Overall, 2031 eligible men completed the survey. The mean age of sexual debut was 20.7 (SD = 4.3) years old. 17.6% (358/2031) of men reported adolescent sexual debut, and 5.0% (101/2031) reported a non-consensual sexual debut. The adolescent sexual debut was associated with having more male sexual partners (adjusted OR 1.10, 95% CI 1.06-1.15) and condomless anal sex in the last three months (AOR = 1.71, 95% CI 1.34-2.18). MSM whose sexual debut was non-consensual were more likely to have condomless anal sex (AOR = 1.76, 95% CI 1.17-2.66), and to have reported an adolescent sexual debut (AOR = 2.72, 95% CI 1.75-4.21). CONCLUSIONS: Many Chinese MSM reported adolescent sexual debut and non-consensual sex, both of which are associated with sexual risk behaviors and drive STI transmission. These findings highlight the need for designing tailored interventions for MSM who experienced adolescent sexual debut and non-consensual sex at debut

Sexual Health Influencer Distribution of HIV/Syphilis Self-Tests Among Men Who Have Sex With Men in China: Secondary Analysis to Inform Community-Based Interventions.

BACKGROUND: Social network-based strategies can expand HIV/syphilis self-tests among men who have sex with men (MSM). Sexual health influencers are individuals who are particularly capable of spreading information about HIV and other sexually transmitted infections (STIs) within their social networks. However, it remains unknown whether a sexual health influencer can encourage their peers to self-test for HIV/syphilis. OBJECTIVE: The aims of this study were to examine the impact of MSM sexual health influencers on improving HIV/syphilis self-test uptake within their social networks compared to that of nonsexual health influencers. METHODS: In Zhuhai, China, men 16 years or older, born biologically male, who reported ever having had sex with a man, and applying for HIV/syphilis self-tests were enrolled online as indexes and encouraged to distribute self-tests to individuals (alters) in their social network. Indexes scoring >3 on a sexual health influencer scale were considered to be sexual health influencers (Cronbach α=.87). The primary outcome was the mean number of alters encouraged to test per index for sexual health influencers compared with the number encouraged by noninfluencers. RESULTS: Participants included 371 indexes and 278 alters. Among indexes, 77 (20.8%) were sexual health influencers and 294 (79.2%) were noninfluencers. On average, each sexual health influencer successfully encouraged 1.66 alters to self-test compared to 0.51 alters encouraged by each noninfluencer (adjusted rate ratio 2.07, 95% CI 1.59-2.69). More sexual health influencers disclosed their sexual orientation (80.5% vs 67.3%, P=.02) and were community-based organization volunteers (18.2% vs 2.7%, P<.001) than noninfluencers. More alters of sexual health influencers came from a rural area (45.5% vs 23.8%, P<.001), had below-college education (57.7% vs 37.1%, P<.001), and had multiple casual male sexual partners in the past 6 months (25.2% vs 11.9%, P<.001). CONCLUSIONS: Being a sexual health influencer was associated with encouraging more alters with less testing access to self-test for HIV/syphilis. Sexual health influencers can be engaged as seeds to expand HIV/syphilis testing coverage