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Background This study aimed to evaluate the clinical efficacy of femoral head and neck fenestration combined with autologous bone mixed with β-tricalcium phosphate porous bioceramic bone (light bulb procedure) through Orthopdische Chirurgie München approach (OCM approach) for pre-collapse non-traumatic osteonecrosis of the femoral head(ONFH). Methods The clinical data of 47 patients (47 hips) with ONFH were retrospectively reviewed. The Harris hip score (HHS) was used to evaluate the clinical outcomes. Imaging was assessed by X-ray. Clinical failure was defined as postoperative total hip arthroplasty (THA) or the HHS was poor ( Results All the 47 hips were followed up for 24–58 months, with an average of 45 months. The Harris score (76.29 ± 10.38) at the last follow-up was significantly higher than the preoperative HHS (64.45 ± 2.93) (P P P Conclusions The head and neck fenestration and bone grafting via the OCM approach in the treatment of non-traumatic ONFH in the pre-collapse stage can achieve good clinical outcomes. 25(OH)D deficient patients and ARCO IIIA patients had a higher failure rate of bone graft using this approach.

BACKGROUND The effect of remote monitoring (RM) in atrial arrhythmia detection, stroke reduction, and anticoagulation therapy remains unknown, particularly for patients with implantable or wearable cardiac devices.Methods and Results:We performed a systematic review and meta-analysis to evaluate the role of RM in atrial arrhythmia detection, stroke reduction and anticoagulation therapeutic intervention. Online databases were queried to include randomized controlled trials comparing detection of atrial arrhythmia and stroke risk between patients undergoing RM and those receiving in-office (IO) follow-up. Outcomes and complications of RM-guided anticoagulation therapy and conventional therapy in patients with atrial fibrillation were also reviewed. A total of 16 studies were included. Compared with patients receiving IO follow-up, patients undergoing RM had a significantly higher detection rate of atrial arrhythmia (risk ratio [RR], 1.363; 95% confidence interval [CI], 1.147-1.619), and a lower risk of stroke (RR, 0.539; 95% CI, 0.301-0.936). The higher rate of atrial arrhythmia was only noted in patients with wearable devices (RR, 4.070; 95% CI, 2.408-6.877), and the lower risk of stroke was only noted in patients with cardiovascular implantable electronic devices (CIED) (RR, 0.513; 95% CI, 0.265-0.996). CONCLUSIONS RM is effective for atrial arrhythmia detection in patients using wearable devices and for reducing the risk of stroke in patients with CIED.

An improved reconfigurable Doherty power amplifier (DPA) structure with extended bandwidth is presented. A traditional DPA structure is often used to expand the output power back-off (OBO) range by using three transistors, and the peaking amplifiers work in the same frequency band. In this modified structure, the carrier amplifier works in the whole frequency band of $f_{1}$ – $f_{3}$ , and two peaking amplifiers work in $f_{1}$ – $f_{2}$ and $f_{2}$ – $f_{3}$ , respectively ( $f_{1} ). In addition, switches are applied in power divider and power combining networks in order to switch peaking amplifier between frequency bands. A 1.8–3.4-GHz DPA has been demonstrated utilizing such a modified structure, and the frequency band is divided into two parts, which are 1.8–2.7 GHz and 2.7–3.4 GHz. The measured results show that 7.2–11.2 dB of saturated gain, 42.2–43.9 dBm of peaking output power, 45%–62.3% and 36.7%–48.5% of drain efficiency at peaking power levels and 6-dB OBO are delivered.

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, the genetic and phenotypic heterogeneity of the illness has hampered the discovery of its genetic determinants. In this study, in an independent Han Chinese sample (1824 MDD cases and 3031 controls), we conducted replication analyses of two genetic loci highlighted in a previous Chinese MDD genome-wide association study (GWAS), and confirmed the significant association of a single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Besides, in independent Han Chinese postmortem brain and peripheral blood samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies.

Background The purpose of the current study was to evaluate whether radiation dose‐volume metrics to technetium‐99m (99mTc) sulfur colloid single‐photon emission tomography (SPET)‐defined active bone marrow (ABM) subregions can more accurately predict acute hematologic toxicity in locally advanced cervical cancer patients who receive chemoradiotherapy than conventional dosimetric parameters. Methods and materials Thirty‐nine patients with stage IB2‐III cervical cancer who underwent 99mTc sulfur colloid SPET imaging before treatment with cisplatin‐based chemoradiation between January 2017 and March 2018 were analyzed. The total bone marrow (TBM) volume was defined as the external contours of all bones within the vertebral bodies from L4 to the coccyx, the pelvic bones, and the proximal femoral heads. The ABM volume was defined by SPET as the subregion of TBM with a nuclide uptake value greater than or equal to the mean total body nuclide uptake value. Student's t test was used to test for statistical significance between TBM and ABM dose‐volume metrics. Receiver operating characteristic (ROC) curves were generated to compare the predictors of grade 3 or higher (grade 3+) hematologic toxicity. Results The mean ABM‐V40 (23.22% ± 7.65%) and ABM‐V30 (45.28% ± 9.20%) were significantly lower than the mean TBM‐V40 (33.06% ± 6.72%) and TBM‐V30 (53.08% ± 7.77%), respectively (t = 5.78, P = .001) (t = 4.13, P = .001). The ABM volume (46.5%, AUC = 0.875, P = .001), and ABM‐V40 (>23.5%, AUC = 0.858, P = .001) can predict the occurrence of grade 3+ hematologic toxicity. Among patients with an ABM volume 387.5 cm3. Conclusions The ABM volume (, The mean ABM‐V40 and ABM‐V30 were decreased by 9.84% and 7.8%, respectively, compared with mean TBM‐V40 and TBM‐V30. ABM volume (AUC = 0.928), ABM‐V30 (AUC = 0.875), and ABM‐V40 (AUC = 0.858) can predict the occurrence of grade 3 or higher (grade 3+) hematologic toxicity. ABM volume (

STUDY DESIGN Retrospective longitudinal cohort study. OBJECTIVE To investigate the incidence and risk of axial spondyloarthritis (axSpA) in patients with scoliosis in Taiwan. SUMMARY OF BACKGROUND DATA Scoliosis and axSpA causes back pain which reduces quality of life in many patients. Both scoliosis and axSpA had attracted numerous research attention, but the association between the two was hardly known. METHODS In this retrospective study, the data of 25,566 patients were obtained from Taiwan's National Health Insurance Research Database. We identified patients diagnosed with scoliosis and included them in the study cohort. We included age- and sex-matched patients without scoliosis in the control cohort. The total follow-up period was 7 years. Cox proportional hazards models were used to analyze the retrieved data. Hazard ratios (HRs) and adjusted HRs were calculated. RESULTS The study and control cohorts included 4261 and 21,305 patients, respectively. The incidences of axSpA were 141 and 46 per 100,000 person-years in the study and control cohorts, respectively. The crude HRs and adjusted HRs for patients with scoliosis were 2.98 (95% confidence interval, 1.87-4.73; P

Background Psychological stress, which is associated with poor sleep quality, has a profound effect on the gut microbiome. To better elucidate the gut microbiome changes associated with psychological stress, we measured levels of stress and sleep quality among the healthy stool donors recruited through a national campaign, and further assessed their relationship with the gut microbiome. Methods The gut microbial composition of 272 adults residing in Singapore was determined by 16S rRNA V3-V4 amplicon sequencing. Stress and distress levels of participants were assessed using the Perceived Stress Scale (PSS) and Kessler Psychological Distress Scale (K10) respectively, while sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). Multivariate statistical data analyses were conducted to explore the link between the gut microbiome, stress, distress and sleep quality. Results A significant proportion of stool donors exhibited low distress (84.2%) levels. However, nearly one-third of participants reported high-stress levels (33.5%) and poor sleep quality (44.8%) (IDDF2021-ABS-0165 Figure A. Stacked bar plot showing the number of participants under each category of (i) K10 , (ii) PSS and (iii) PSQI). The overall variation in the gut microbiome composition amongst stool donors was predominantly dependent on age and body mass index (BMI), rather than psychosocial stress and sleep quality (IDDF2021-ABS-0165 Figure B. PERMANOVA results of main factors in this study). However, four microbial features (i.e., Streptococcus, Erysipelotrichaceae UCG-003, Sutterella and Parabacteroides) were found to be positively associated with severe distress, of which Erysipelotrichaceae UCG-003 was more abundant in both distressed and stressed donors (DESeq2, p Conclusions One-third of the participants exhibited high stress/distress levels and almost half poor sleep. In this study, we identified several bacterial genera that are significantly altered in the gut microbiome of stressed individuals, with Erysipelotrichaceae UCG-003 being consistently increased across people with high stress and severe distress levels. Erysipelotrichaceae UCG-003 was previously reported to be elevated in individuals with sleep deprivation. Our findings also suggest the need to factor for stress and sleep quality when studying the gut microbiome of healthy individuals.

Skeletal muscle (SM) weakness occurs in hypothyroidism and resistance to thyroid hormone α (RTHα) syndrome. However, the cell signaling and molecular mechanism(s) underlying muscle weakness under these conditions is not well understood. We thus examined the role of thyroid hormone receptor α (TRα), the predominant TR isoform in SM, on autophagy, mitochondrial biogenesis, and metabolism to demonstrate the molecular mechanism(s) underlying muscle weakness in these two conditions. Two genetic mouse models were used in this study: TRα1PV/+ mice, which express the mutant Thra1PV gene ubiquitously, and SM-TRα1L400R/+ mice, which express TRα1L400R in a muscle-specific manner. Gastrocnemius muscle from TRα1PV/+, SM-TRα1L400R/+, and their control mice was harvested for analyses. We demonstrated that loss of TRα1 signaling in gastrocnemius muscle from both the genetic mouse models led to decreased autophagy as evidenced by accumulation of p62 and decreased expression of lysosomal markers (lysosomal-associated membrane protein [LAMP]-1 and LAMP-2) and lysosomal proteases (cathepsin B and cathepsin D). The expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), mitochondrial transcription factor A (TFAM), and estrogen-related receptor α (ERRα), key factors contributing to mitochondrial biogenesis as well as mitochondrial proteins, were decreased, suggesting that there was reduced mitochondrial biogenesis due to the expression of mutant TRα1. Transcriptomic and metabolomic analyses of SM suggested that lipid catabolism was impaired and was associated with decreased acylcarnitines and tricarboxylic acid cycle intermediates in the SM from the mouse line expressing SM-specific mutant TRα1. Our results provide new insight into TRα1-mediated cell signaling, molecular, and metabolic changes that occur in SM when TR action is impaired.

Carpal tunnel syndrome (CTS) refers to the symptoms and signs caused by the compression of the median nerve in the carpal tunnel. It can be treated by corticosteroid injection into the carpal tunnel. Two methods for injection have been employed, namely ultrasound-guided and landmark-guided injection. This systematic review and meta-analysis was conducted to compare these methods in terms of several outcomes. Randomized controlled trials (RCTs) were identified, and data collection was completed on 7 October 7, 2020. Results for continuous variables are expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). Analyses were performed using RevMan 5.3 software. The analysis included eight RCTs published between 2013 and 2019 with a total of 448 patients. Ultrasound-guided injection yielded more favorable results for the Boston Carpal Tunnel Syndrome Questionnaire, Symptom Severity Scale [SMD = −0.49, 95% CI (−0.74, −0.25), P < 0.0001], Boston Carpal Tunnel Syndrome Questionnaire, Functional Status Scale [SMD = −0.24, 95% CI (−0.42, −0.06), P = 0.01], distal motor latency [SMD = −0.36, 95% CI (−0.70, −0.02), P = 0.04], and compound muscle action potential [SMD = 0.38, 95% CI (0.16, 0.61), P = 0.0008] . Ultrasound-guided corticosteroid injection is recommended for patients with CTS.

BackgroundThis study aimed to evaluate the clinical efficacy of autologous bone mixed with tricalcium phosphate porous bioceramic bone grafting via Orthopdische Chirurgie München approach (OCM approach) with fenestration of the femoral head-neck in patients with pre-collapse non-traumatic osteonecrosis of the femoral head (ONFH).MethodsThe clinical data of 47 patients (47 hips) with ONFH were retrospectively reviewed. The Harris hip score (HHS) was used to evaluate the clinical outcomes. Imaging was assessed by X-ray. Clinical failure was defined as postoperative total hip arthroplasty (THA) or the HHS was poor (

In order to overcome the problem that the accuracy of privacy information mining in the existing privacy data encryption methods of student archives is lower than that of encryption security, this paper proposes a privacy information encryption method in student archives based on blockchain technology. In order to improve the effectiveness and security of encryption, singular value decomposition (SVD) method is used to mine the privacy information in students' archives. Based on the results of privacy information mining, combined with chaotic encryption technology in blockchain, the encryption function of privacy information in student archives is constructed to complete the encryption of privacy information in student archives. Experimental results show that, compared with the traditional encryption method, this method can effectively improve the accuracy of privacy information mining, and has high encryption security.

3D printing of silicone elastomers with the direct ink writing (DIW) process has demonstrated great potential in areas as diverse as flexible electronics, medical devices, and soft robotics. However, most of current silicones are not printable because of their low viscosity and long curing time. The lack of systematic research on materials, devices, and processes during printing makes it a huge challenge to apply the DIW process more deeply and widely. In this report, aiming at the dilemmas in materials, devices, and processes, we proposed a comprehensive guide for printing highly stretchable silicone. Specifically, to improve the printability of silicone elastomers, nanosilica was added as a rheology modifier without sacrificing any stretching ability. To effectively control print speed and accuracy, a theoretical model was built and verified. With this strategy, silicone elastomers with different mechanical properties can all be printed and can realize infinite time and high speed printing (>25 mm/s) while maintaining accuracy. Here, super-stretchable silicone that can be stretched to 2000% was printed for the first time, and complex structures can be printed with high quality. For further demonstration, prosthetic nose, data glove capable of detecting fingers' movement, and artificial muscle that can lift objects were printed directly. We believe that this work could provide a guide for further work using the DIW process to print soft matters in a wide range of application scenarios.

Background: Serum total 25-hydroxyvitamin D (25[OH]D) and physical activity (PA) both play important roles in maternal–fetal health. However, a high prevalence of vitamin D and PA insufficiency has been observed in women of childbearing age. Active transportation may increase overall PA levels and potentially boost serum 25(OH)D levels. Methods: Data from the National Health and Nutrition Examination Survey between 2007 and 2014 were used. A total of 5601 women aged 18–49 years were included. Transportation PA (TPA) was quantified as metabolic equivalents of task and serum 25(OH)D levels was measured. Multivariable logistic regression models adjusted for potential confounders were conducted. Results: The corresponding adjusted odds ratios associated with vitamin D insufficiency (1000 MET minutes per week of TPA, respectively, compared with no TPA. Using vitamin D deficiency (Conclusions: A moderate level of TPA is related to lower odds of suboptimal vitamin D status among women of childbearing age.

BACKGROUND: Inflammatory bowel disease, including ulcerative colitis and Crohn’s disease, is characterized by chronic inflammation that could be a risk factor for extraintestinal cancer. The aim of this study is to evaluate whether inflammatory bowel disease is related to the risk of lower urinary tract tumors. METHODS: A systematical research was performed on various medical databases including PubMed, the Cochrane Library, Embase and Web of Science from inception to April 2020. Data were independently extracted by two reviewers. The Newcastle-Ottawa Scale and the Oxford Centre for Evidence-Based Medicine criteria were used to assess the quality of included articles. The analysis was completed by STATA version 14.2. RESULTS: Six hundred and twelve of records were initially identified and 16 studies were included in the final analysis. In general, inflammatory bowel disease patients were not at increased risk of prostate cancer, bladder cancer and male genital cancer. In the subgroup analysis, Crohn’s disease patients seemed to have borderline increased risk of prostate cancer [standardized incidence ratio: 1.05; 95% confidence interval (CI): 0.90–1.21; I(2)=15.1%] and bladder cancer (standardized incidence ratio: 1.19; 95% CI: 0.94–1.44; I(2)=0.0%), and ulcerative colitis patients seemed to have borderline increased risk of prostate cancer (standardized incidence ratio: 1.13; 95% CI: 0.93–1.33; I(2)=73.5%). CONCLUSIONS: Inflammatory bowel disease did not significantly increase the risk of prostate cancer, bladder cancer and male genital cancer. Crohn’s disease patients seemed to have a higher risk of prostate cancer and bladder cancer, and ulcerative colitis patients seemed to have a higher risk of prostate cancer. ulcerative colitis patients in East Asian countries have significantly increased prostate cancer risk.

BackgroundThe gaps between evidence-based recommendations and real-world practice for management of chronic obstructive pulmonary disease (COPD) have been poorly characterised. We aimed to describe the progress of patients with COPD through the cascade of care.MethodsWe performed five systematic reviews and meta-analyses of observational studies evaluating the diagnosis and treatment of patients with COPD. We searched MEDLINE, Embase, CINAHL, Global Health, and the Cochrane Library for studies, published between January 2000 and December 2018, that reported data on the following five main components of patient care: diagnosis using spirometry, pharmacotherapy, smoking cessation, vaccination, and pulmonary rehabilitation. A random effects model was used to identify the proportion of patients with COPD completing each step in the cascade.FindingsWe identified 18, 32, 15, 48, and 36 studies for diagnosis, pharmacotherapy, smoking cessation, vaccination, and pulmonary rehabilitation components, respectively. Major gaps in the cascade included: assignment of a diagnosis of COPD among people with airflow obstruction and respiratory symptoms (29·7% [95% CI 13·1 – 54·3%]), adherence to maintenance inhalers up to 12 months (proportion of days covered: 30·9% [95% CI 18·3 – 47·1%]; medication possession ratio: 29·7% [95% CI 20·3 – 41·3%]), vaccination against S.pneumoniae (37·9% [95% CI 24·9 – 53·0%]), and referral for pulmonary rehabilitation (20·4% [95% CI 9·2 – 39·3%]).InterpretationSubstantial gaps were identified between evidence and practice for patients along the cascade of care for COPD. Further policies and actions are needed to address these gaps and reduce the global burden of COPD.FundingAustralian National Health and Medical Research Council.

Lymphoblastic lymphoma (LBL) is a relatively rare but highly aggressive type of non-Hodgkin lymphoma (NHL), most of which have T-cell origin (T-LBL) [1]. The disease progresses rapidly and often tr...

Previous studies have included a limited number of randomized controlled trials (RCTs) and compared limited parameters after treatment with imidafenacin and other anticholinergic drugs (ADs) for overactive bladder syndrome (OAB), and controversy about the superiority of these ADs still remains. We aim to update the evidence and provide better clinical guidance. A systematic search of PubMed, Embase, ClinicalTrial.gov and Cochrane Library Central Register of Controlled Trials was conducted from January 2007 to April 2019. Meta-analysis of all published RCTs comparing imidafenacin with other ADs in patients with OAB was performed. The primary outcomes were the changes in OAB symptoms and OAB symptom score (OABSS). Secondary outcomes included adverse events (AEs) and the dropout rate related to AEs. A total of 6 studies including 7 RCTs involving 1430 patients with mean follow-up of 23.43 weeks were included. All ADs improved OAB symptoms. Regarding efficacy, these drugs had similar efficacy in voids, urgency episodes, urgency incontinence episodes, incontinence episodes and OABSS. However, imidafenacin performed better in the reduction of nocturia episodes (MD = –0.24, 95% CI –0.44 to –0.04, P = 0.02). Moreover, imidafenacin was associated with a statistically lower dry mouth rate (RR = 0.87, 95% CI 0.75–1.00, P = 0.04), lower constipation rate (RR = 0.68, 95% CI 0.50–0.93, P = 0.01) and lower AE-related withdrawal rate (RR = 0.51, 95% CI 0.29–0.89, P = 0.02). There was no significant difference in terms of other complications. In conclusion, imidafenacin was comparable to other ADs in the treatment of OAB. Moreover, imidafenacin presented a lower dry mouth rate, lower constipation rate and higher adherence and persistence.

The emergence of nanotechnology has greatly impacted our daily lives. Multiple products, including cosmetics, pharmaceuticals, electronics and food, are produced with incorporation of nanomaterials (NMs). Nanotechnology has yielded many promising benefits, yet, there remains much uncertainty about the hazards of NMs to humans. Hence, it is important to ensure safety of the users. Although many in vitro and in vivo studies have been carried out on the potential toxicity generated by NMs in food, its effects on the microRNA genome (miRNome) involved in the regulation of gene expression have been poorly understood. Therefore, this review focuses on the types of commonly used NMs (containing silicon dioxide, titanium dioxide, silver or zinc oxide) in food products and their potential toxic effects, including how NMs can induce epigenetic toxicity mediated via altered miRNA expression.

By combining the new superposition principle of linear elasticity used in discrete dislocation plasticity and the recently available solution of the elastic displacement and stress fields due to a polygonal dislocation loop within an anisotropic homogeneous full-space, the anisotropic elastic fields induced by a 3D polygonal prismatic dislocation loop (PPDL) in bimaterials of spherical shells are obtained. The location and orientation of the PPDLs with respect to the fixed reference coordinate system are arbitrary. Factors influencing the interfacial elastic fields, such as the size of the PPDLs, the thickness of the inner-layer and lastly the mismatch of crystallographic orientations of the adjacent layers are investigated in detail. The present model has two distinct features of easy extensibility to planar or nonplanar multilayered polycrystalline models and the ease of numerical implementation for parallel programming.

An anisotropic distribution dislocation loop model is proposed for simulation of nanoindentation of single crystals based on the recently available solution of the elastic displacement and stress fields due to a polygonal dislocation within an anisotropic homogeneous half-space ( Chu et al., 2012 ). The present investigation is a direct extension of the approach established by Mura et al. (1989) , and its recent application to triangular dislocation loop model ( Muraishi, 2013 ), which is only capable of describing the indentation processes of isotropic materials, thus ruling out the possibility of characterizing the nanoindentation of elastically anisotropic single crystals. By following the procedure of Mura et al. (1989) , we adopt square and triangular prismatic dislocation loops (PDLs) as building blocks with Burgers vectors normal to the free surface to simulate the Vickers and Berkovich indentation, respectively. However, we place all the prismatic dislocation loops within a semi-ellipsoidal volume rather than a semi-spherical region as adopted by Mura et al. (1989) after analyzing the existing simulation results based on dislocation density formulation ( Huang et al., 2000 ). The nanoindentation is performed in [001] and [111] crystallographic directions employing Vickers and Berkovich indenters, respectively, and different magnitude of pile-up, sink-in and spring-back is observed in different directions, clearly demonstrating the effects of elastic anisotropy of the indented single crystals on nanoindentation, hence a further improvement of the original model of Mura et al. (1989) .

Electroacupuncture is beneficial for the recovery of spinal cord injury, but the underlying mechanism is unclear. The Rho/Rho-associated kinase (ROCK) signaling pathway regulates the actin cytoskeleton by controlling the adhesive and migratory behaviors of cells that could inhibit neurite regrowth after neural injury and consequently hinder the recovery from spinal cord injury. Therefore, we hypothesized electroacupuncture could affect the Rho/ROCK signaling pathway to promote the recovery of spinal cord injury. In our experiments, the spinal cord injury in adult Sprague-Dawley rats was caused by an impact device. Those rats were subjected to electroacupuncture at Yaoyangguan (GV3), Dazhui (GV14), Zusanli (ST36) and Ciliao (BL32) and/or monosialoganglioside treatment. Behavioral scores revealed that the hindlimb motor functions improved with those treatments. Real-time quantitative polymerase chain reaction, fluorescence in situ hybridization and western blot assay showed that electroacupuncture suppressed the mRNA and protein expression of Rho-A and Rho-associated kinase II (ROCKII) of injured spinal cord. Although monosialoganglioside promoted the recovery of hindlimb motor function, monosialoganglioside did not affect the expression of Rho-A and ROCKII. However, electroacupuncture combined with monosialoganglioside did not further improve the motor function or suppress the expression of Rho-A and ROCKII. Our data suggested that the electroacupuncture could specifically inhibit the activation of the Rho/ROCK signaling pathway thus partially contributing to the repair of injured spinal cord. Monosialoganglioside could promote the motor function but did not suppress expression of RhoA and ROCKII. There was no synergistic effect of electroacupuncture combined with monosialoganglioside.

Dislocations in a finite medium bring about image stresses. These image stresses play important roles in the dislocation behavior in finite sized systems such as thin films. Since the ratio of surface to volume is higher for thin films than for bulk materials, dislocation behaviors in thin films are greatly different from those in a corresponding infinite medium, which make it necessary to take into account the effects of free surfaces on the evolution of dislocations in thin films. In the investigations[4, 5], image stresses in an elastic cylinder and thin films are calculated by employing a Fourier transform (FFT) approach and isotropically elastic fields due to dislocations are adopted in their formulation. However, most crystals are anisotropic, and the anisotropic ratio changes with environment physical parameters, such as the temperature, moisture, electron field, magnetic field. A theorem based on anisotropic Stroh’s formula for calculating the image stress of infinite straight dislocations in anisotropic bicrystals has been developed by Barnett and Lothe[6]. Wu et al.[3] recently also make use of the FFT technique to investigate the general dislocation image stresses of cubic thin films, thus extending the formalism by Weinberger et al.[4,5] from isotropic to anisotropic thin films. It is clear that for the assumed in-plane elastic fields to be periodically defined within an unbounded region is an essential and indispensable prerequisite for the above FFT-based approach to be effectively implemented, thus ruling out the possibility of its being employed to analyse image stresses in bounded and/or voided thin cubic films. Our motivation here is then to make an further extension by first calculating the anisotropic elastic fields of dislocation loops in an unbounded thin film with cavities and then invoking FEM and the principle of superposition to seek the image stress solution.

Background Vitamin D supplementation is recommended for patients with multiple sclerosis (MS). However, a recent meta-analysis based on low-quality trials suggested no evidence of supplementation benefit. A systematic review and meta-analysis of high-quality observational cohort studies should provide us further evidences. Methods MEDLINE, EMBASE, and WEB-of-SCIENCE databases were systematically searched to identify eligible studies published before October 2018. Prospective cohort studies assessing the associations of serum 25(OH)D levels with MS relapses, radiological inflammatory lesions, or changes in expanded disability status scale in adults (≥18 years) with MS were included. Pooled RRs were calculated using fixed-effect or random-effects model depending on heterogeneity. Results Thirteen studies and 3498 patients were included. Each 25 nmol/L increase in serum 25(OH)D levels was associated with a reduction in (1) clinical relapse rate [RR = 0.90; 95% confidence interval (CI) = 0.83–0.99], (2) gadolinium-enhancing lesions (RR = 0.69; 95% CI = 0.60–0.79), (3) new/enlarging T2 lesions (RR = 0.86; 95% CI = 0.77–0.95), and (4) new active lesions (RR = 0.81; 95% CI = 0.74–0.89) in the magnetic resonance imaging(MRI). Conclusions Serum 25(OH)D levels are associated with a modest decrease in relapse rate and radiological inflammatory activities in patients with MS. The association with disability worsening remains inconclusive.

Background To investigate the relationship between an increase in the pre- and post-operative mean platelet volume (MPV) and superficial femoral artery in-stent restenosis (ISR) rate. Methods and results We recruited patients that underwent superficial femoral artery stenting for lower extremity arteriosclerosis obliterans at our hospital from March 2015 to March 2018. All patients gave venous blood three days before and following implantation. Doppler ultrasound, computed tomography angiography or digital subtraction angiography were used for regular follow-up examination. Logistic regression was used to identify predictors of ISR after superficial femoral artery stenting. We enrolled 173 patients, of which 34 (19.6%) were determined as having ISR for a mean of 8.9 ± 2.7 months (3–12 months). Neutrophil count, neutrophil ratio, lymphocyte ratio and platelet count pre-implantation, and platelet count and MPV after stent implantation, and the pre- and post-operative mean platelet volume difference (MPVD) and mean platelet volume difference ratio (MPVDR) were all statistically different when comparing the ISR and non-restenosis groups (p P P P Conclusions An increase in pre- and post-operative MPV was correlated with the occurrence of superficial femoral artery ISR.

Purpose Previous study included limited number of randomized controlled trials (RCTs) and compared limited parameters post the treatment of imidafenacin and other anticholinergic drugs (ADs) for overactive bladder syndrome (OAB) and controversy about the superiority of those ADs still remains. We aim to update the evidence and provide better clinical guidance. Methods A systematic search in PubMed, Embase, ClinicalTrial.gov, and Cochrane Library Central Register of Controlled Trials was conducted from January 2007 to April 2019. Meta-analysis of all published RCTs comparing imidafenacin with other ADs in patients with OAB was performed. The primary outcomes were the changes in OAB symptoms and OAB Symptom Score (OABSS). Secondary outcomes included adverse events (AEs) and dropout rate related to AEs. Results A total of 6 studies including 7 RCTs involving 1,430 patients with mean follow-up of 23.43 weeks were included. All ADs improved OAB symptoms. In regard to efficacy, those drugs had similar efficacy in voids, urgency episodes, urgency incontinence episodes, incontinence episodes and in OABSS. However, Imidafenacin had a better performance in the reduction of nocturia episodes (MD=-0.24, 95%CI -0.44 to-0.04, P=0.02). Moreover, Imidafenacin was associated with statistically lower dry mouth rate (RR=0.87, 95%CI 0.75-1.00, P=0.04), lower constipation rate (RR=0.68, 95%CI 0.50-0.93, P=0.01) and lower AE-related withdrawal rate (RR=0.51, 95%CI 0.29-0.89, P=0.02). There was no significant difference in terms of other complications. Conclusions In conclusion, Imidafenacin was comparable with other ADs in the treatment of OAB. Moreover, imidafenacin presented lower dry mouth rate, lower constipation rate and higher adherence and persistence.

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, its genetic and phenotypic heterogeneity has hampered successful discovery of its genetic determinants. In this study, we conducted replication analyses of genetic loci highlighted in a previous Chinese MDD genome-wide association studies (GWAS) in an independent Han Chinese sample (1,824 MDD cases and 3,031 controls), and have confirmed the significant association between MDD and a previous highlighted single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Further, in two independent Han Chinese postmortem brain samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81722019 to M.L., 31701133 to X.X., 81825009 to W.Y., 81571313 to W.Y.); Yunnan Applied Basic Research Projects (2018FB051 to X.X.); National Key RD the medical and health science and technology project in Zhejiang (2018KY721 to D.S.Z.); the Major Science and Technology Projects in Ningbo, Zhejiang Province, China (2017C510012); the Medical Science and Technology Project in Ningbo, Zhejiang Province, China (2017A10). Xiao Xiao was also supported by the Chinese Academy of Sciences Western Light Program, and Youth Innovation Promotion Association, CAS. Ming Li was also supported by CAS Pioneer Hundred Talents Program and the 1000 Young Talents Program. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All the protocols and methods were approved by the institutional review board of Kunming Institute of Zoology, Chinese Academy of Sciences, and the ethics committees of all participating hospitals and universities. Written informed consents from all participants were obtained prior to the study.

Liver cancer, which is the second leading cause of tumor-associated mortality, is of great concern worldwide due to its resistance to chemotherapeutic drugs. Transcatheter arterial chemoembolization (TACE) has previously been used as a treatment for unresectable liver tumors in China; however, the response to TACE treatment differs between patients. It has been reported that hepatitis B virus (HBV)-as sociated tumors are less sensitive to TACE treatment compared with non-HBV-associated liver cancer. Previous studies have demonstrated that exosomes serve a crucial role in hepatic carcinoma chemoresistance. We therefore hypothesized that HBV may modulate chemosensitivity via exosomes. The aim of the present study was to investigate how exosomes affect chemoresistance by assessing their role in chaperone-mediated autophagy (CMA)-dependent chemoresistance in HBV-associated liver cancer. Iconography data from HBV-positive and HBV-negative patients with hepatic carcinoma receiving TACE treatment were assessed, and it was revealed that the tumor volume was decreased in the patients with non-HBV-associated liver cancer compared with that in the patients with HBV-associated tumors following TACE therapy. Furthermore, it was revealed that exosomes from HBV-infected liver cancer cells were able to downregulate cell apoptosis when treated with oxaliplatin compared with exosomes from normal HepG2 cells. Furthermore, the results demonstrated that HBV-associated exosomes modulate cell death via activating the CMA pathway, and its key molecule, lysosome-associated membrane protein (Lamp2a), was also upregulated. Lamp2a-knockdown was also found to reverse anti-apoptotic effects in liver cancer. Taken together, the results of the present study suggest that chemoresistance in patients with HBV-associated hepatic tumors may be mediated by exosomes, and thus may provide a basis for the development of novel treatment strategies for chemoresistant liver cancer.

Objective The aim of the study is to explore the incidence and the risks associated with major osteoporotic fractures, all-cause mortality with osteoporotic fractures and the effect of the psychiatric drug exposure in patients with schizophrenia during a 10-year follow-up period. Methods Two nationwide cohorts were selected from the Taiwan National Health Insurance Research Database (NHIRD) consisting of 30,335 patients with schizophrenia (age ≥ 40 years) and 121,340 age- and sex-matched control participants without schizophrenia. The psychiatric proportion of days covered (PDC) is an indicator of the intensity of drug exposure in patients with schizophrenia. The incidence and risk factors of major osteoporotic fractures were calculated for both cohorts. Additionally, the patient survival rate after major osteoporotic fractures was also calculated. Results During a 10-year follow-up period, 1677 (5.53%) schizophrenia and 4257 (3.51%) control subjects had major osteoporotic fractures (P 0.1 showed a significantly higher incidence of major osteoporotic fractures than did the non-schizophrenia controls; however, those with a psychiatric PDC ≤ 0.1 did not. After adjustment, the psychiatric PDC was significantly and independently associated with the risk of major osteoporotic fractures except some medical morbidities but the schizophrenia diagnosis was not. In addition, among all 5934 patients with major osteoporotic fracture, the adjusted mortality hazard ratio for psychiatric PDC was 1.92 (95% CI = 1.63–2.26). Conclusions Patients with schizophrenia are at a higher risk for major osteoporotic fractures than the general population and also have a higher mortality rate due to major osteoporotic fractures. These findings may be caused by psychiatric drug use rather than schizophrenia, which suggests that directions can be taken in future studies.

The development of automotive technology has become increasingly important for preventing car accidents. Hence, as a basic research of driver assistance systems, a novel control method has been proposed for steering support. In particular, the stability and limitation of such a system is investigated for the safe and comfortable drive. First, the particle swarm optimisation (PSO)-based algorithm is used to search the optimal feedback gain under practical constraints for achieving tracking control. Moreover, to reduce the convergence time further, the PSO algorithm is combined with the technique of quantum computing. Simulation results indicate that the proposed feedback controller based on quantum PSO has the ability to provide efficient computational performance for trajectory tracking and stabilisation.

Evidence indicates that type 2 diabetes may stimulate the initiation and progression of several types of cancer. Metformin, a drug most commonly used to treat type 2 diabetes, may inhibit cancer cell growth and reduce the risk of cancer. However, evidence of the antitumor effects of metformin on ovarian cancer is still limited. In this study, we retrospectively examined the effects of metformin on ovarian cancer patients with diabetes at our institution. We identified 568 consecutive patients who were newly diagnosed with ovarian cancer and treated between January 2011 and March 2014. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage I to IV epithelial ovarian, fallopian, or peritoneal cancer were included. Patients with type 1 diabetes, incomplete records (including medication records) and any other cancer before their ovarian cancer diagnosis, as well as those diagnosed with diabetes more than 6 months after their ovarian cancer diagnosis, were excluded. Out of 568 patients, 48 (8.5%) patients with type 2 diabetes continuously used metformin, 34 (5.9%) patients with type 2 diabetes did not take metformin, 22 (3.9%) patients with type 2 diabetes discontinued metformin, and 464 (81.7%) ovarian cancer patients were nondiabetic controls. Longer progression-free survival (PFS) and overall survival (OS) were observed in ovarian cancer patients with diabetes who were taking metformin than in diabetic patients not taking metformin, diabetic patients who discontinued metformin, and nondiabetic ovarian cancer patients (P = .001). After adjusting for possible confounders, metformin use was associated with a lower risk for disease relapse [hazard ratio (HR) = 0.34; 95% confidence interval (CI): 0.27–0.67; P

Objective To explore how post-acute care (PAC) for stroke patients delivered by per-diem payment system in varying hospitalization paths affects medical care utilization and functional status. Design, setting and patients A longitudinal prospective cohort study of 181 acute stroke patients in a southern Taiwan hospital and patients were separated into two groups: patients transferred from regional hospitals (group 1) and patients referred from medical centers (group 2). Intervention The intervention was a hospital based, function oriented, 3- to 12-weeks rehabilitative PAC intervention for patients with cerebrovascular diseases. Measurements Barthal Index, Functional Oral Intake Scale, Instrumental Activities of Daily Living Scale, EuroQoL Quality of Life Scale, and Berg Balance Scale. Results The average duration between day of stroke onset and day of admission to PAC ward was significantly (P < 0.001) shorter in group 1 (9.88 days) compared to group 2 (17.11 days). The average duration of PAC was also significantly (P < 0.01) shorter in group 1 (25.51 days) compared to group 2 (34.11 days). Finally, the average cost of PAC under per-diem payment was significantly lower (P < 0.01) in group 1 (US$2637) compared to group 2 (US$3450). Functional status significantly (P < 0.05) improved in patients who had received rehabilitative PAC. However, functional status did not significantly differ between the two groups. Conclusions The most effective way to reduce the costs of PAC for stroke patients is to minimize the duration of their hospital stay before transfer to rehabilitative PAC. Because it substantially reduces medical costs, rehabilitative PAC should be considered standard care for stroke patients.

Guillain-Barré syndrome is classified into acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy. Whereas autoantibodies to GM1 or GD1a induce the development of acute motor axonal neuropathy, pathogenic autoantibodies have yet to be identified in acute inflammatory demyelinating polyneuropathy and chronic inflammatory demyelinating polyneuropathy. This review highlights the importance of autoantibodies to peripheral nerve proteins in the physiopathology of acute and chronic inflammatory demyelinating polyneuropathies. Moreover, we listed up other potential antigens, which may become helpful biomarkers for acquired, dysimmune demyelinating neuropathies based on their critical functions during myelination and their implications in hereditary demyelinating neuropathies.

Currently, cloud computing is experiencing the rapid development. However, cloud migration is firstly required for the adaptation of some application systems to new cloud computing environments. Consequently, theories and strategies of the cloud migration research have emerged to be hot spots. In spite of the availability of many successful economic plans and technical schemes in this field, few guiding plans with wide applicability have been devised based on the migration of the private clouds. This paper summarized the technical principles and the general methods of the private clouds migration, and summed up a common method for private cloud migration. Subsequently, a specific case of migration from an enterprise system to the Eucalyptus cloud environment was completed based on proposed method, which indicated the feasibility and validity of this method. At last, through the analysis of system performances based on different migration methods, some technical suggestions for further development of the performances are also given in this paper.

This paper proposes a new bi-directional evolutionary structural optimization (BESO) method with draw direction constraints. Draw direction constraints, defined by required manufacturing process, are achieved by modifying element removal/addition criteria such that elements are removed from the top surface of the draw direction to the inner design domain. The optimized design with draw direction constraints is free from hollow or closed cavity geometries which are infeasible for manufacturing. A stiffness design of a motor front cover is carried out to show the ability of the proposed method in practical mechanical design problems.

With the progress of smart grid building, the trend of load of diversity has become increasingly apparent. Under the condition of load of diversity, considering synthetically from multiple factors including electricity consumption, energy cost, environmental protection and comprehensive user’s satisfactory, the coordination and optimization model of user’s electricity energy efficiency is made up of four objective functions, including the minimum electricity consumption, energy cost, emission of 14CO2"> and the maximum comprehensive user’s satisfactory. The coordination and optimization of user’s electricity energy efficiency is melted into the use time allocation of electricity systems, to select the right electricity behavior to implement optimization of user’s electricity energy efficiency.

We propose a scheme for generation of a nonlinear coherent state (NCS) of a mechanical resonator (MR) in an optomechanical micro-cavity, in which a two-level quantum dot (QD) and the microcavity are respectively driven by a strong laser and a weak laser. This microcavity can be engineered within a photonic band-gap (PBG) material. By properly tuning the frequency of the weak driving field, two-photon blockade phenomenon occurs. The QD-cavity subsystem can evolve into a dark state due to the damping of the microcavity and the elimination of the decay rate of the QD at selected frequencies in the PBG material. In this situation, the phonon mode of the MR can be prepared into a NCS, which is a non-classical state and possesses the sub-Poisson statistics. We also demonstrate the Wigner function of the NCS, which negativity implies its non-classicality.

To coordinate research efforts in psychiatric genetics in China, a group of Chinese and foreign investigators have established an annual “Summit on Chinese Psychiatric Genetics” to present their latest research and discuss the current state and future directions of this field. To date, two Summits have been held, the first in Changsha in April, 2014, and the second in Kunming in April, 2015. The consensus of roundtable discussions held at these meetings is that psychiatric genetics in China is in need of new policies to promote collaborations aimed at creating a framework for genetic research appropriate for the Chinese population: relying solely on Caucasian population-based studies may result in missed opportunities to diagnose and treat psychiatric disorders. In addition, participants agree on the importance of promoting collaborations and data sharing in areas where China has especially strong resources, such as advanced facilities for non-human primate studies and traditional Chinese medicine: areas that may also provide overseas investigators with unique research opportunities. In this paper, we present an overview of the current state of psychiatric genetics research in China, with emphasis on genome-level studies, and describe challenges and opportunities for future advances, particularly at the dawn of “precision medicine.” Together, we call on administrative bodies, funding agencies, the research community, and the public at large for increased support for research on the genetic basis of psychiatric disorders in the Chinese population. In our opinion, increased public awareness and effective collaborative research hold the keys to the future of psychiatric genetics in China.

In this article, we propose a new boundary method based on support vector domain description (SVDD) for multiclass classification problems. By utilizing the boundary around a class of data constructed by the SVDD, a new boundary distance measure, which gives the distance between a test object and the boundary around a class of data, can be determined by locating the nearest boundary point to the test object with the help of the geometrical interpretation of inner product. To decide which class the test object belongs to, a minimum distance classification is then carried out. Experimental results show that our method is robust to issues such as outliers and class imbalance, and overall it can achieve a comparable or better performance than other support vector-based classifiers for multiclass classification problems.

Inhibitors of epidermal growth factor receptor (EGFR), including tyrosine kinase inhibitors (TKIs), present significant clinical benefits in the treatment of non-small cell lung cancer (NSCLC), particularly in patients with an EGFR mutation. However, TKI treatment also results in unwanted cutaneous toxic side effects, such as a skin rash. Eyelash trichomegaly is rarely reported as a side effect; however, it causes cosmetic issues or eyeball irritation in patients, which may result in the early termination of TKI treatment. Therefore, although TKI-induced eyelash trichomegaly is rare, it should be considered carefully by lung cancer physicians. The present study reported a case of erlotinib-induced eyelash trichomegaly in a 65-year-old Chinese female patient suffering from NSCLC with an EGFR mutation. To the best of our knowledge, this is the first reported case of erlotinib-induced trichomegaly in a Chinese patient.

The Mental Health Act (MHA) in Taiwan was developed in 1990 to protect patients. It was introduced to provide legislative recognition that people with mental illness have rights to reasonable treatment. After a few minor modifications and a substantial revision in 2007, the revised version was formally enacted on July 4, 2008. According to the newly developed regulations, in addition to an evaluation by two designated certificated psychiatrists within two days, whether a patient requires compulsory hospitalization will also be reviewed and decided by the committee --Psychiatric Disease Mandatory Assessment and Community Care Review Committee---of mandatory evaluation within five days and the maximum length of an order is 60 days. Since the 2007 version of the Mental Health Act was implemented, the number of the patients with mandatory hospitalizations was significantly reduced by 77%, corresponding to a decrease from 3,129 in 2006 and 3,171 in 2007 to 728 in 2014. Only 1.46% of these individuals were compulsorily hospitalized, which is significantly lower than the 6-58% in the United States and Europe. The human rights of patients in mental health care were further protected, which is a substantial achievement in mental health care!

Noxious stimuli inhibit inflammation by activating neuroendocrine stress axes, an effect that is potently attenuated by ongoing activity in subdiaphragmatic vagal afferents. Because this vagal afferent activity is carried in the coeliac and coeliac accessory branches of the subdiaphragmatic vagus, we tested the hypothesis that the activity arises from vagal afferents that innervate a proximal segment of the gastrointestinal tract. Surgical removal of the duodenum, but not the stomach, produces a marked (six orders of magnitude) leftward shift in the dose–response curve for intraplantar capsaicin-induced inhibition of synovial plasma extravasation induced by the potent inflammatory mediator bradykinin, in the knee joint; this is similar in magnitude to the inhibition produced by subdiaphragmatic or by coeliac plus coeliac accessory branch vagotomy. Fasting, to unload mechanically sensitive polymodal afferents in the proximal gastrointestinal tract, produces a similar leftward shift in the dose–response curve for the inhibitory effect of capsaicin, an effect that is reversed by balloon distension in the duodenum in fasted rats, while balloon distension postvagotomy had no effect. These results suggest that activation of mechanically sensitive vagal afferents in the duodenum contributes vagal afferent activity that modulates neuroendocrine control of the inflammatory response.

In male rats, activity in subdiaphragmatic vagal afferents modulates nociception via an adrenal medulla-dependent mechanism. Because both the vagus and adrenal medullae are sexually dimorphic, we evaluated vagotomy-induced changes in mechanical nociceptive threshold and inflammatory hyperalgesia in female rats and compared them to those previously reported in male rats. We have found that (1) mechanical nociceptive threshold is lower in female rats than in male rats, perhaps because of tonic release of adrenal medullary factors in female rats; (2) mechanical nociceptive threshold in female rats is influenced to a lesser degree by activity in the subdiaphragmatic vagus; (3) vagotomy-induced enhancement of bradykinin hyperalgesia is greater in female rats; (4) in female rats, in contrast to male rats, celiac plus celiac accessory branch vagotomy failed to fully account for the enhancement of bradykinin hyperalgesia in complete subdiaphragmatic vagotomy; and (5) in female rats, in contrast to male rats, adrenal medullectomy plus subdiaphragmatic vagotomy only partially (approximately 30%) reversed the effect of vagotomy on bradykinin hyperalgesia. These findings demonstrate sexual dimorphism in the modulation of both mechanical nociceptive threshold and bradykinin-induced hyperalgesia by activity in subdiaphragmatic vagal afferents as well as the adrenal medulla.

Vagal afferent activity modulates mechanical nociceptive threshold and inflammatory mediator-induced hyperalgesia, effects that are mediated by the adrenal medulla. To evaluate the role of epinephrine, the major hormone released from the adrenal medulla, the beta2-adrenergic receptor antagonist ICI 118,551 was chronically administered to vagotomized rats and epinephrine to normal rats. In vagotomized rats, chronic administration of ICI 118,551 markedly attenuated vagotomy-induced enhancement of bradykinin hyperalgesia but had no effect on nociceptive threshold. In normal rats, chronic epinephrine had the opposite effect, enhancing bradykinin hyperalgesia. Like vagotomy-, epinephrine-induced enhancement of hyperalgesia developed slowly, taking 14 days to reach its peak. Vagotomy induced a chronic elevation in plasma concentrations of epinephrine. We suggest that ongoing activity in vagal afferents inhibits the release of epinephrine from the adrenal medulla. Chronically elevated levels of epinephrine, occurring after vagotomy, desensitize peripheral beta2-adrenergic receptors and lead to enhancement of bradykinin hyperalgesia. The ability of prolonged elevated plasma levels of epinephrine to sensitize bradykinin receptors could contribute to chronic generalized pain syndromes.

Recently we have found that inhibition of bradykinin-induced synovial plasma extravasation by transcutaneous electrical stimulation at strengths which excite unmyelinated afferent axons is mediated by the hypothalamo-pituitary-adrenal axis. Here we tested whether stimulation of nociceptors in the rat paw by intradermally injected capsaicin inhibits bradykinin-induced synovial plasma extravasation and whether this inhibition is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. Furthermore, we tested whether inhibition of bradykinin-induced plasma extravasation generated by intraperitoneally injected capsaicin, which preferentially excites visceral afferents, is mediated by the hypothalamo-pituitary-adrenal or sympatho-adrenal axis. We used normal rats, subdiaphragmatically vagotomized rats, rats with denervated adrenal medullae and rats with acutely transected spinal cords at the segmental levels T1/T2 or T12/L1. Injection of capsaicin into the plantar or palmar surface of the paws produced a depression of bradykinin-induced plasma extravasation. The inhibition elicited from the forepaw was larger than that from the hindpaw. The inhibition of bradykinin-induced plasma extravasation elicited from both paws was potentiated by subdiaphragmatic vagotomy. Denervation of the adrenal medullae abolished the inhibitory effect of intradermal capsaicin in vagus-intact and in vagotomized animals. After spinalization at the segmental level T1/T2, capsaicin injected into the forepaw did not depress bradykinin-induced plasma extravasation either in vagus-intact or in vagotomized animals. Capsaicin injected into the hindpaw in these spinalized animals produced a small depression. After spinalization at the segmental level T12/L1 no depression was produced by capsaicin injected into the hindpaw. Depression of bradykinin-induced plasma extravasation generated by intraperitoneal injection of capsaicin in vagus-intact and in vagotomized animals was also abolished or attenuated after denervation of the adrenal medullae. This shows that this depression was also largely dependent on the activation of the sympatho-adrenal system. We conclude that depression of bradykinin-induced plasma extravasation during stimulation of nociceptors by capsaicin is mediated predominantly by the sympathoadrenal pathway. This finding differs from the inhibitory mechanism of depression of bradykinin-induced plasma extravasation generated by cutaneous electrical stimulation, which is mediated by the hypothalamo-pituitary-adrenal axis.

We have recently shown that subdiaphragmatic vagotomy enhances bradykinin-induced hyperalgesic behavior and decreases baseline paw withdrawal threshold to mechanical stimulation of the hindpaw skin in rats by a peripheral mechanism. To elucidate the underlying mechanism, we studied whether lesions of efferent neuroendocrine pathways could prevent or reverse the potentiating effect of vagotomy. In groups of sham-vagotomized or vagotomized rats, we surgically removed or denervated the adrenal medulla. Bradykinin was injected intradermally into the skin of the dorsal surface of the rat hindpaw. Threshold of paw withdrawal to mechanical stimulation of the skin was measured.Vagotomy induced a decrease in mechanical baseline paw withdrawal threshold and enhancement of bradykinin-induced mechanical hyperalgesic behavior, both of which were maintained over the 5 week testing period. Adrenal enucleation or denervation of the adrenal gland by suprarenal ganglionectomy prevented vagotomy-induced decrease in baseline paw withdrawal threshold and enhancement of bradykinin-induced hyperalgesia. In animals that had a demonstrated decrease in baseline paw withdrawal threshold and enhancement of bradykinin-induced hyperalgesia 2 weeks after vagotomy, additional denervation of the adrenal medulla significantly reversed these effects over a 3 week period.These results imply that both the decrease in baseline paw withdrawal threshold and enhancement of bradykinin-induced hyperalgesic behavior after vagotomy are dependent on a hormonal signal released from the adrenal medulla and suggest a novel mechanism of sensitization of cutaneous nociceptors.

Miao, Frederick Jia-Pei, Wilfrid Jänig, Paul G. Green, and Jon D. Levine. Inhibition of bradykinin-induced plasma extravasation produced by noxious cutaneous and visceral stimuli and its modulation by vagal activity. J. Neurophysiol. 78: 1285–1292, 1997. Intrathecally applied nicotine reduces bradykinin-induced plasma extravasation (BK-induced PE) in the rat knee joint. This depression is mediated by the hypothalamo-pituitary-adrenal (HPA) axis and is enhanced by interruption of impulse traffic in afferents of the abdominal vagus nerve. Like intrathecal nicotine, electrical stimulation of unmyelinated cutaneous fibers also depresses BK-induced PE, which is also dependent on an intact HPA axis. In this study, we investigated whether the inhibitory effect of intrathecal nicotine can be mimicked by noxious stimulation of skin and of viscera. Furthermore we determined whether this depression is potentiated after subdiaphragmatic vagotomy. Stimulation of visceral afferents in the peritoneum, by intraperitoneal capsaicin injection, dose-dependently decreased BK-induced PE. The capsaicin dose-response function was shifted by 1.5–2 orders of magnitude to the left after vagotomy. Stimulation of visceral afferents in the urinary bladder by capsaicin also dose-dependently reduced BK-induced PE, which similarly was potentiated after vagotomy. Transcutaneous stimulation of unmyelinated nociceptive afferents from the plantar skin of the paw depressed BK-induced PE. This depression had a threshold of ∼0.25 Hz and was maximal at a stimulation frequency of ∼1 Hz. After subdiaphragmatic vagotomy, the stimulus response function shifted to the left and the inhibition was significantly larger than in control, in the range of 0.125–1 Hz stimulation. These results show that noxious stimulation of skin and viscera depressed BK-induced PE and that such depression was potentiated after subdiaphragmatic vagotomy in a manner similar to that of intrathecally applied nicotine. Based on these observations, we hypothesize that intrathecal nicotine depresses BK-induced PE by exciting spinal nociceptive neurons or the central projections of nociceptive primary afferent neurons.