BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People

ObjectiveTo observe the mechanism of chronic psychological stress aggravating idiopathic pulmonary fibrosis （IPF） in rats and the regulatory effect of Xiaoyaosan. MethodSixty SD rats were acclimatized for one week and then randomly divided into five groups： sham operation group， IPF group， IPF and depression model group， pirfenidone group， and pirfenidone + Xiaoyaosan group， with 12 rats in each group. The IPF group was induced by intratracheal instillation of bleomycin （5 mg·kg^-1） and administered 0.9% sodium chloride solution intragastrically. The model group was induced with bleomycin （5 mg·kg^-1） combined with chronic unpredictable mild stress to establish a rat model of IPF and depression and administered 0.9% sodium chloride solution intragastrically. Concurrently， the pirfenidone group was administered pirfenidone aqueous solution （50 mg·kg^-1） intragastrically， and the pirfenidone + Xiaoyaosan group was administered pirfenidone aqueous solution （50 mg·kg^-1） and Xiaoyaosan decoction （19.27 g·kg^-1） intragastrically. The experiment lasted for four weeks. Various parameters， including body weight， food intake， sucrose consumption rate， open field behavior， lung function， lung coefficient， pathological changes in lung tissue， and hydroxyproline （HYP） content were compared among the groups. Enzyme-linked immunosorbent assay （ELISA） was used to measure serum cortisol （CORT）， corticotropin-releasing hormone （CRH）， adrenocorticotropic hormone （ACTH） levels， and serotonin （5-HT） levels in serum and hippocampus. The levels of interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factor-α （TNF-α） in serum and lung tissue were also measured. Real-time fluorescence quantitative polymerase chain reaction （Real-time PCR） was employed to determine the mRNA expression of IL-1β， TNF-α， IL-6， p38 mitogen-activated protein kinase （p38 MAPK）， and nuclear transcription factor-κB p65 （NF-κB p65） in lung tissue. Western blot was used to detect the expression of proteins related to the p38 MAPK/NF-κB signaling pathway. ResultCompared with the normal group， IPF and depression model group showed slow weight gain， reduced food intake， decreased sucrose consumption rate， reduced total distance and average speed of movement in the open field test， weakened lung function， increased lung coefficient （P<0.01）， significant inflammatory cell infiltration in lung tissue by hematoxylin-eosin （HE） staining， collagen fiber deposition by Masson staining， and increased HYP content （P<0.01）. There were elevated levels of serum CORT， CRH， and ACTH （P<0.05， P<0.01）， increased protein and mRNA levels of IL-1β， IL-6， and TNF-α in serum and lung tissue， decreased 5-HT levels in serum and hippocampus， and increased relative expression of p-p38 MAPK and p-NF-κB p65 proteins in lung tissue （P<0.01）. Compared with the IPF and depression model group， the depression and IPF of rats in the pirfenidone + Xiaoyaosan group were effectively ameliorated， as evidenced by faster weight gain， increased food intake and sucrose consumption rate， increased total distance and average speed of movement in the open field test， enhanced lung function， reduced lung coefficient （P<0.01）， decreased inflammatory cell infiltration by HE staining， reduced collagen fiber deposition by Masson staining in lung tissue， and decreased HYP content （P<0.01）. Decreased serum CORT， CRH， and ACTH levels （P<0.05， P<0.01）， decreased protein and mRNA levels of IL-1β， IL-6， and TNF-α in serum and lung tissue （P<0.05， P<0.01）， increased 5-HT levels in serum and hippocampus （P<0.05， P<0.01）， and decreased relative expression of p-p38 MAPK and p-NF-κB p65 proteins in lung tissue were also noted （P<0.05， P<0.01）， with the effects of Xiaoyaosan + pirfenidone being more significant. ConclusionChronic unpredictable stress exacerbates the progression of IPF in rats. The combination of Xiaoyaosan and pirfenidone not only improves depressive-like behavior but also alleviates pulmonary fibrosis， potentially through the regulation of the p38 MAPK/NF-κB signaling pathway and inhibition of excessive expression of inflammatory factors.

Tripterygium wilfordii is widely used in the treatment of immune system disease and has a remarkable curative effect. Triptolide and Tripterygium glycosides are the most commonly used active ingredients in clinical practice， but their treatment window is narrow and there are many side effects. The damage involves the reproductive system， blood system， cardiovascular system， digestive system， etc. Based on clinical observations and literature summaries， the symptoms of adverse reactions mostly occur in the digestive system （liver and gastrointestinal tract）. Relevant scholars have launched a lot of studies of the manifestations of liver injury induced by T. wilfordii and the mechanism of liver injury. The mechanism is mainly related to liver cell apoptosis， induction of oxidative stress， immune injury， excessive autophagy of liver cells， abnormal fatty acid metabolism， and abnormal enzyme metabolism in liver tissues. This article reviewed and summarized relevant literature on gastrointestinal injury caused by T. wilfordii， but there are few studies on the manifestations and mechanisms of adverse reactions， which still need further research by scholars. In addition， this article also summarized the research on how to reduce toxicity and enhance efficacy of prescriptions prepared from T. wilfordii in the digestive system， mainly involving compatibility with western medicines （Methotrexate， Leflunomide， Iguratimod， etc.）， use along or combination with Chinese medicines （single Chinese medicine， Chinese medicine monomers， and Chinese medicine compounds）， acupuncture and moxibustion （electroacupuncture and moxibustion）， dosage form improvement （glycol plastid gel， self-dissolving microneedle， solid lipid nanoparticles， gastric floating sustained-release capsules， etc.）， processing （steaming， stir-frying， radish seed processing， money grass processing， licorice processing， etc.）， and other methods to reduce toxicity. To sum up， this article analyzed the manifestations， mechanisms， and methods of reducing toxicity and enhancing efficacy of T. wilfordii-induced liver injury and gastrointestinal injury by sorting out relevant literature， in order to provide a reference for the clinical application of T. wilfordii and some research ideas for the future in-depth study of T. wilfordii-induced digestive system injury.

Xiaoyaosan， a classical prescription for mental disorder recorded in Formulary of the Bureau of Taiping People's Welfare Pharmacy（《太平惠民合剂局方》）， is composed of Bupleuri Radix， Angelicae Sinensis Radix， Paeoniae Radix Alba， Atractylodis Macrocephalae Rhizoma， Poria， Zingiberis Rhizoma Praeparatum， Menthae Haplocalycis Herba， and Glycyrrhizae Radix Et Rhizoma Praeparata Cum Melle. Clinical practices and experiments have proved that it can be used for primary depression， anxiety， as well as the depression induced by various somatic disorders， such as gynecological diseases， internal diseases， and digestive system diseases， as evidenced the improvement of Hamilton depression rating scale score， self-rating depression scale score， etc. Xiaoyaosan has been verified to be remarkably effective， with high compliance and no obvious adverse reactions in patients. Xiaoyaosan mainly acts on monoamine neurotransmitters 5-hydroxytryptamine （5-HT）， norepinephrine （NE）， and dopamine （DA）， adrenocorticotropic hormone （ACTH） and corticosterone （CORT） in hypothalamic-pituitary-adrenal axis， pro-inflammatory cytokines interleukin-1β （IL-1β）， interleukin-6 （IL-6）， and tumor necrosis factored （TNF）-α， and orexin， ghrelin， and leptin in intestinal microecology and brain-gut axis， to regulate the neurobiochemical mechanism， endocrine mechanism， immune mechanism， and abnormal brain structure， thereby preventing and alleviating depression. However， the antidepressant mechanism of Xiaoyaosan needs to be further discussed. Through literature research， this paper analyzes the clinical application and basic mechanism of Xiaoyaosan in the treatment of depression， which is expected to serve as a reference for the application of this prescription in the clinical prevention and treatment of depression and improvement of the quality of life of patients， and further research on the antidepressant mechanism of Xiaoyaosan.

Objective:To understand the influencing factors of death of epidemic Japanese encephalitis (EJE) cases in Longnan City of Gansu Province.Methods:In the EJE Monitoring Information Report Management System of the Chinese Disease Prevention and Control Information System, data on EJE cases with onset from 2014 to 2018 and current address in Longnan City were derived. An "Individual Questionnaire of Epidemic Japanese Encephalitis in Longnan City" was designed, retrospective study was conducted on enrolled cases, their information on demographic data, consultation, onset, clinical classification, and chronic underlying diseases were collected, characteristics of EJE cases and death-related factors were analyzed.Results:From 2014 to 2018, a total of 260 EJE cases were reported in Longnan City, and 259 cases completed the questionnaire. Among them, 70 cases (27.0%) were aged ≥60 years old, 67 cases (25.9%) were severe and extremely severe, and 55 cases (21.2%) had chronic underlying diseases. Among 259 EJE cases, 46 cases died, with a fatality rate of 17.8%. After multivariate unconditional logistic regression analysis, age ≥60 years old [odds ratio ( OR)=2.667, 95% confidence interval ( CI): 1.140-6.237], severe and extremely severe ( OR = 2.762, 61.820, 95% CI: 1.053-7.091, 5.149-742.239), and chronic underlying diseases ( OR = 2.489, 95% CI: 1.038-5.964) were risk factors for death in EJE cases. Conclusions:The influencing factors of death of EJE cases in Longnan City are age, clinical classification and chronic underlying diseases. Therefore, we should focus on patients over 60 years old, clinically classified as severe or extremely severe, and suffering from chronic underlying diseases, and strengthen the immunization of EJE vaccine for key populations.

Objective To explore the effect of oxaliplatin combined with S-1 ( SOX ) chemotherapy on the resection of ad-vanced gastric cancer.Methods Twenty patients with advanced gastric cancer, who first underwent oxaliplatin combined with S-1 chemotherapy and then received surgery, were recruited as the combined treatment group, while another 20 surgical patients with ad-vanced gastric cancer who did not have chemotherapy were assigned as the control group.The surgical resection rate, the number of postoperative lymphatic node metastasis and the average length of stay in the hospital were compared between the patients of the 2 groups.Results The surgical resection rate in the 20 patients of the combined treatment group was as high as 95%, while that of the control group was just 70%.Statistical significance could be found, when comparisons were made between them(P<0.05).There were statistical differences in the number of postoperative lymphatic node metastasis and the average length of stay, when comparisons were made between the combined treatment group and the control group(P<0.05).Conclusion The application of combined chemo-therapy with oxaliplatin and S-1 before surgery could achieve better clinical therapeutic effects.

Objective To investigate effect of single anterior decompression and fusion for pinching cervical spondylosis myelopathy.Methods 82 patients with pinching cervical spondylosis myelopathy,treated with single anterior decompression and fusion,were analyzed,including 43 males and 39 females,with an average age of 54.4 years (range,33-79 years).Occupying rate,anterior occupying rate and posterior occupying rate were measured on pre- and post-operative midsagittal MRIs.Multiple regression analysis was performed between preoperative occupying rate,intervertebral space height,postoperative imaging changes and neural function recovery.Results All patients were followed up for an average of 25.8 months (range,9-72 months).Significant differences were found between pre- and postoperative Japanese Orthopaedic Association (JOA) scores,anterior occupying rate,posterior occupying rate,and intervertebral space height,respectively.Pre- and post-operative posterior occupying rate was averagely 29.0％±10.5％ and 19.9％+11.6％,respectively,and improvement rate of posterior occupying rate was 9.0％±6.1％.Regression analysis found that preoperative intervertebral space height did not relate to posterior occupying rate,while preoperative posterior occupying rate related to improvement rate of posterior occupying rate.JOA scores improved significantly after operation in patients with preoperative posterior occupying rate between 20％ and 40％.However,the decompression results were poor in patients with preoperative posterior occupying rate ≥40％.Conclusion Anterior decompression and fusion can achieve satisfactory results in patients with pinching cervical spondylotic myelopathy.For patients with preoperative posterior occupying rate between 20％ and 40％,the decompression results are better.

To formulate clinical guidelines of diagnosis,syndrome differentiation,and standard treatment for children's tic disorder based on both domestic & foreign researching progress and our own many years researching results.We hope to provide reference for traditional Chinese medicine standardized treatment of children's tic disorder.

Objectiye To measure longitudinal (T1) and transverse (T2 ) relaxation time of metabolites in m. soleus (SOL) and m. tibialis anterior TA of healthy volunteers at 3.0 T through 1H-MRS and optimize measurement protocols. Methods Altogether 24 healthy volunteers were recruited in the study. All subjects signed a letter of informed consent. After divided into 2 groups randomly by the table of random number, 1H-MRS measurements with stimulated echo acquisition mode (STEAM) sequence were undertaken in SOL and TA separately. Progressive saturation method was used for T1 measurement. Spectra with 8 different TRs (770,900,1000, 1100,1200,1500,2000 and 3000ms ) were acquired with TE=20 ms.T2 time was measured by changing TE. Altogether 8 TEs (20,30,45,60,90,135,200 and 270 ms) were used with TR = 3000 ms. Metabolites' concentration was calculated through T1 and T2 correction using water as internal reference. The t test was used for statisties. Results Altogether 22 groups of data were gained ( 12 for SOL, 10 for TA ) . T1 value of water, Creatine-CH3 ( Cr3 ), Trimethyl amonium ( TMA ),extramyocellular lipid (EMCL) and intramyocellular lipid (IMCL) in SOL were ( 1384. 0 ± 36. 9 ),( 1064. 0 ± 167.0), (964. 2 ± 144. 0 ), ( 373.0 ± 46. 8 ), ( 374. 7 ± 20. 6) ms respectively and T2 value were (26.5 ±1.2), (100.2±19.3), (149. 1 ±32.7), (81.4±5.2), (84.7±4.2) ms. InTA T1 value of water, Cr3, TMA, EMCL, and IMCL were ( 1307. 0 ± 24.4), (945.7 ± 132. 0), (968.3 ± 127. 0),(372. 7 ± 39. 2), (412. 8 ±80. 2) ms respectively and T2 value were (27. 1 ± 0. 9), (135.3 ± 18. 2 ),(62.1 ± 6. 0), ( 84. 3 ± 4. 0 ), ( 90. 7 ± 3.2 ) ms. After corrected by the calculated relaxation times, the concentrations of Cr3 in SOL and TA were (33. 1 ± 3.7) and (31.7 ± 3. 1 ) mmol/kg respectively, TMA (35.2±3.2) and (32.9 ±5.2) mmol/kg, EMCL (12.2 ±5.0) and (8.9 ±4.9) mmol/kg, IMCL (9. 0 ± 2. 4) and (3.0 ± 0. 8 ) mmoL/kg. IMCL in TA was much lower than SOL with statistical significant ( t = 8. 044, P < 0. 01 ), the difference between other metabolites were not statistically significant( t = 0. 926,1. 264, 1. 542, P > 0. 05 ) . Conclusions Accurate relaxation time was measured at 3.0 T of the metabolites in skeletal muscles of healthy adult human. After corrected by the relaxation times, the absolute concentrations calculated were consistent with the reported results. Quantitative knowledge of muscle NMR relaxation time was a prerequisite for absolute quantification of metabolites using the 1H-MRS and also was useful for optimizing measurement protocols.

Objective To demonstrate the feasibility of DTI in human calf with body phased-array coil and surface coil of spine as receiving coil on 3 T system, and to optimize the parameters of sequence, including slice thickness and b-value. Methods Fifteen healthy volunteers were recruited in this study and randomly divided into three groups. The DTI sequence for head was performed on calf in the first group (5 cases), and the sequence parameters were optimized based on the deficits of the raw and the post-processed DTI images. Then, different slice thickness were applied in the senond group (5 eases) to optimize the slice thickness, and this optimized parameter with the highest score based on quality of the post-processed DTI images was applied in the next step. Finally, different b values were applied in the last group to optimize this parameters. The b value with the highest score based on the quality of the pest-processed was the proper one. Results Three problems existed in the raw and the pest-processed images, when the DTI sequence for brain was used for the calf. First, the SNR of raw images is extremely low. Second, the muscle were unclear on the image with parts of signal lose, especially in the anterior tibialis muscle. Finally, the artifacts due to chemical shift and ghost are quite serious. The scores for muscle display quality with slice thickness of 4 mm , 5 mm and 6 mm were (7.0±0. 0), (8.6±0. 9) and (9.0±0. 0) score respectively, the signal less scores were (5.0±0. 0) and ( 12. 8±2. 6) and ( 13. 8±2. 2) score respectively, and the general score were (22. 0±0. 0) and (30. 1±3.8) and (31.0±4. 1 ) score respectively. The differences of above scores were significant among different slice thickness (F-value were 21. 000 and 30. 544 and 12. 390 respectively, P <0. 05 ). The muscle displaying quality, signal loss and general scores were lowest in group with 4 mm slice thickness (q-value were 4. 896.6. 120,6. 327,7. 138,3. 863 and 4. 043, P < 0. 05 ) o The scores of muscle display quality, signal loss and general for b =400 s/mm2 were (9. 0±0. 0), ( 14. 0± 2. 2 ) and ( 33.0±2. 2 ) score respectively, which were lower than those with b = 800 s/ram2 [(7.0±0.0), (6.2±2.2), (21.8±3.4) score] and b=1000 s/mm2[(7.0±0.0), (5.0±0.0), (20.6±2.2) score] (q-value were 3.873,3.873,6.650,7.672,7. 101 and 5.917, P <0.05)o The scores of muscle displaying quality, signal loss and general for b =600 s/mm2 were (8.2±1.1 ), ( 13.0± 2. 3) and ( 30. 8±3. 8 ) score respectively, which were higher than those with b = 800 s/mm2 and b= 1000 s/nun2 (q-value were 3.873, 3.873, 5.797, 6.820, 5.326 and 5.917, P <0.05).There is no significant difference between b = 600 s/ram2 and 400 s/ram2 ( q-value were 2. 582 and 0. 852 and 1. 775, P > 0. 05 ). Conclusion Our preliminary findings indicate that it is feasible to perform DTI on human calf with 3 T MR. With body phased-array coil and surface coil of spine as receiving coil, the DTI sequence were optimized to acquire enough SNB with slice thickness of 5 mm and b-value of 400 s/mm2.