The ventral anterior (VA) nucleus of the thalamus is a major target of the basal ganglia and is closely associated with the pathogenesis of Parkinson's disease (PD). Notably, the VA receives direct innervation from the hypothalamic histaminergic system. However, its role in PD remains unknown. Here, we assessed the contribution of histamine to VA neuronal activity and PD motor deficits. Functional magnetic resonance imaging showed reduced VA activity in PD patients. Optogenetic activation of VA neurons or histaminergic afferents significantly alleviated motor deficits in 6-OHDA-induced PD rats. Furthermore, histamine excited VA neurons via H1 and H2 receptors and their coupled hyperpolarization-activated cyclic nucleotide-gated channels, inward-rectifier K⁺ channels, or Ca²⁺-activated K⁺ channels. These results demonstrate that histaminergic afferents actively compensate for Parkinsonian motor deficits by biasing VA activity. These findings suggest that targeting VA histamine receptors and downstream ion channels may be a potential therapeutic strategy for PD motor dysfunction.
Animals ; Histamine/metabolism* ; Male ; Oxidopamine/toxicity* ; Rats ; Ventral Thalamic Nuclei/physiopathology* ; Rats, Sprague-Dawley ; Disease Models, Animal ; Parkinson Disease/metabolism* ; Neurons/physiology* ; Humans ; Optogenetics

Objective: To examine the prevalence and trend of tobacco and e-cigarettes uses and identify the influencing factors for smoking behavior in junior middle school students in Shanghai, and provide data support and scientific basis for the development of tobacco control intervention strategy in adolescents. Methods: Multi-stage stratified random sampling method was used to select junior middle school students in 8 districts and 10 districts in Shanghai in 2013 and in 2019 respectively. Information about tobacco and e-cigarettes uses in the students were collected by using self-administrated questionnaire. The prevalence of tobacco and e-cigarettes uses were calculated, the difference between two years was compared with χ² test. The influencing factors were identified by multivariate logistic regression analysis. Results: In 2019, the current smoking rate was 0.6% in junior middle school students in Shanghai, and the smoking attempt rate was 2.9%, both were lower than the levels in 2013 (0.7% and 6.9%). The current use rate of e-cigarettes was 0.6% in 2019,with no significant change compared with 2013 (0.6%). The proportion of the students who had heard of e-cigarettes in 2019 (78.4%) was higher than that in 2013 (47.2%). In 2019, the second-hand smoke (SHS) exposure rate at home, in both indoor and outdoor public places and on public transportations was 72.5%, which was slightly lower than the level in 2013 (73.0%), the differences were all significant (P<0.05). In 2019, the students seeing close friend smoking (OR=27.381, 95%CI: 12.037-62.287), seeing someone smoking in school (OR=2.477, 95%CI: 1.155-5.312), believing that SHS may not be harmful (OR=8.471, 95%CI: 1.464-49.005) had higher possibility of smoking. Being aged ≥15 years (compared with being aged ≤12 years, OR=8.688, 95%CI: 1.922-39.266), exposure to SHS in outdoor public place (OR=8.608, 95%CI: 1.048-70.692), close friend smoking (OR=8.115, 95%CI: 1.754-37.545) were positively associated with e-cigarettes use, and believing that smoking results in uncomfortable social contact [compared with believing that smoking results in comfortable social contact (OR=0.105,95%CI: 0.018-0.615)] were negatively associated with e-cigarettes use, the difference was significant (P<0.05). Conclusion: The prevalence of tobacco and e-cigarette uses in junior middle school students in Shanghai remained at a low level in recent years. The SHS exposure rate in junior middle school students is high. Smoking behavior of junior middle school students is closely related to personal attitude and awareness of tobacco, exposure to SHS, peer smoking and the situation of tobacco control in schools. Prevention and intervention should be carried out from multi-dimensions to effectively protect teenagers from tobacco hazards.
Adolescent ; China/epidemiology* ; Electronic Nicotine Delivery Systems ; Humans ; Prevalence ; Students ; Tobacco ; Tobacco Smoke Pollution

Objective:To observe the effect of oxymatrine （OM） combined with bevacizumab （ BV ） on the proliferation， invasion， and migration of breast cancer MCF-7 cells and explore the mechanism of OM in regulating BV-induced epithelial-mesenchymal transition （EMT） based on the Wnt/β-catenin signaling pathway. Method:The effect of different concentrations of OM（0， 0.5， 1.0， 2.0， 4.0， 8.0， 16.0 mmol·L^-1）and BV（0， 0.25×10^-4， 0.50×10^-4， 1.00×10^-4， 2.00×10^-4， 4.00×10^-4， and 8.00×10^-4 mmol·L^-1）on the proliferation of MCF-7 cells were detected by cell counting kit-8（CCK-8）assay. The effect of OM（4.0 mmol·L^-1） combined with BV（2.00×10^-4 mmol·L^-1）on the invasion and migration of MCF-7 cells were observed in transwell and scratch repair tests. Western blot was conducted to investigate the effect of OM（4.0 mmol·L^-1）combined with BV （2.00×10^-4 mmol·L^-1） on proliferation-related proteins in MCF-7 cells， followed by the detection of the expression levels of Wnt/β-catenin signaling pathway- and EMT-related proteins. Result:Compared with the blank group， OM （2.0，4.0，8.0，16.0 mmol·L^-1） inhibited the proliferation of MCF-7 cells in a concentration-dependent manner （P<0.01）， while BV did not show the inhibitory effect against the proliferation of MCF-7 cells. The inhibitory effect of the combination of the two drugs on the proliferation of MCF-7 cells was not significantly different from that of OM. Compared with the blank group， OM significantly reduced the migration distance of MCF-7 cells and the number of invaded cells（P<0.01）， while BV increased the migration distance of MCF-7 cells and the number of invaded cells （P<0.05，P<0.01）. Compared with BV， its combination with OM significantly inhibited the invasion and migration of MCF-7 cells induced by BV （P<0.01）. Compared with the blank group， both OM and the combined medication obviously inhibited the phosphorylation of proliferation-related protein kinase B（Akt） and extracellular-signal-regulated protein kinase 1/2 （ERK1/2）in MCF-7 cells （P<0.01） and down-regulated the protein expression levels of β-catenin， proto-oncogene （c-Myc）， CD44， and G₁/S-specific cyclin D₁ in Wnt/β-catenin signaling pathway （P<0.05，P<0.01）. Besides， OM and the combination of two drugs both significantly reduced the protein expression levels of calcium-dependent cell adhesion protein N-cadherin and Vimentin in EMT， whereas increased the expression of calcium-dependent cell adhesion protein E-cadherin（P<0.01）. However， the expression of the above-mentioned proteins in the BV group was reversed （P<0.05，P<0.01）. Conclusion:After the combination with BV， OM plays an anti-breast cancer role by effectively inhibiting the activation of Wnt/β-catenin pathway induced by BV and reversing EMT.

With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.

Objective To investigate the correlation between the severity of alcoholic fatty liver disease and the amount of fat in the abdominal cavity and the serum inflammatory factor IL-18 and IL-8. Methods From October 2016 to October 2017,one hundred and twenty patients with AFLD in the First Hospital of Hebei Medical University were divided into light,medium,heavy groups according to the severity of fatty lesions by color Doppler Ultrasound. There were 40 mild patients,50 moderate patients and 30 severe patients. Forty healthy subjects were selected as controls. All the participants underwent CT scanning. The intra-abdominal fat area (VAT),abdominal subcutaneous fat area (SAT) and total abdominal fat area (TA) were measured. The liver function was measured by biochemical analyzer and enzyme-linked immunoassay (ELISA). (ELSIA) IL-18 was detected and IL-8 was detected by radioimmunoassay. Results The VAT of the healthy control group and the mild,medium and severe AFLD group were (70. 28±10. 19),(114. 38 ± 9. 97),(146. 73±10. 19),(163. 38±12. 69) cm2. The TA of the healthy control group and the mild, medium and severe AFLD group were ( 256. 72± 34. 56),( 332. 19 ± 33. 28),( 387. 49± 32. 28),( 478. 19 ±31. 02) cm2. The SAT of the healthy control group and the light,medium and severe AFLD group were (156. 23±28. 19),(203. 43±27. 12),(246. 19±26. 89),(271. 19 ±27. 94) cm2,respectively. Aspartate aminotransferase (AST) of the healthy control group and the mild,medium and severe AFLD group were (18. 50±1. 12),(23. 50±1. 21),(25. 50±1. 24),(29. 50± 1. 43) U/L. Alanine aminotransferase (ALT) of the healthy control group and the light, medium and severe AFLD group were ( 18. 50 ± 2. 14), ( 26. 50 ±2. 22),(35. 50±2. 34),(38. 50±2. 11) U/L. γ-glutamyltransferaseof the healthy control group and the light,medium and severe AFLD group were ( 16. 50 ± 2. 11), ( 32. 50 ± 2. 23), ( 47. 50 ± 2. 31), ( 48. 00 ±2. 43) U/L,respectively. Compared with the healthy control group,VAT,TA,SAT,AST,ALT andγ-GT in the light,medium and heavy AFLD group showed statistically significant differences ( P＜0. 05) . Compared with the mild AFLD group, VAT, TA, SAT, AST, ALT and γ-GT in the medium and heavy AFLD group showed statistically significant differences ( P＜0. 05) . Compared with the moderate AFLD group,the VAT, TA,SAT, AST, ALT, and γ-GT of the severe AFLD group showed statistically significant differences ( P＜0. 05). The data of the three AFLD groups showed that the concentration of all indicators were increasing as the severity of fat deepened. IL-18 of the healthy control group and the light,medium and severe AFLD group were (45. 67±4. 51),(52. 18±5. 09),(59. 87±4. 98),(64. 18±5. 12) ng/L; IL-8 of the healthy control group and the light, medium and severe AFLD group were ( 78. 92 ± 5. 07), ( 115. 62 ± 4. 89), ( 223. 76 ± 6. 78),(286. 42±7. 02) g/L. Compared with every group,IL-18 and IL-8 of light,medium and severe AFLD group showed statistically significant differences (F＝1035. 67,2. 93×105,P＜0. 001); compared with mild AFLD group,IL-18 and IL-8 of medium and heavy group showed statistically significant differences;compared with moderate AFLD group,IL-18 and IL-8 of severe group AFLD showed statistically significant differences ( P＜0. 001) . The levels of inflammatory factors IL-18 and IL-8 increased with the severity of steatosis. The severity of AFLD was significantly positively correlated with VAT,TA,SAT,IL-18 and IL-8 ( r 0. 415(P＜0. 001), 0. 435 ( P＜0. 001), 0. 512 ( P＜0. 001), 0. 274 ( P＜0. 001 ), 0. 689 ( P ＜0. 001). Conclusion Fat control is an important measure to prevent AFLD. IL-18 and IL-8 can reflect the severity of liver injury in AFLD and have important significance in judging prognosis.

Objective:To investigate the clinical effects of scalp acupuncture combined with cognitive therapy on cognitive impairment after traumatic brain injury. Methods:From June, 2016 to October, 2017, 60 patients with cognitive impairment after traumatic brain injury were randomly divided into scalp acupuncture group (n = 20), cognitive training group (n = 20) and combined group (n = 20), who accepted their own therapies for 40 times. They were assessed with Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and modified Barthel Index (MBI) before and after treatment. Results:All the groups improved in the scores of MMSE, MoCA and MBI after treatment (F > 21.923, P < 0.001), which were the best in the combined group (F > 3.423, P < 0.05). Conclusion:Combination of scalp acupuncture and cognitive training is more effective on cognitive impairment after traumatic brain injury.

Objective To investigate the role of triggering receptor expressed on myeloid cells 1 (TREM1)in rats with neuropathic pain and its possible mechanism.Methods Forty-eight male a-dult Sprague-Dawley rats,weighing 220-300 g,were successfully placed intrathecal catheters,and then randomly divided into 4 groups (n=1 2 ):sham operation group (group S),neuropathic pain group (group CCI),TREM1 shRNA group (group RNAi)and negative lentivirus group (group Vi-rus).The neuropathic pain was induced by chronic sciatic nerve compression injury (CCI).In group RNAi,30 μl pGLVU6/RFP/Puro-shRNA (1×109IU/ml)was injected intrathecally 1 week before modeling.Group Virus was injected with 30 μl negative lentivirus,whereas group CCI and group S with equal amount of normal saline.MWT and TWL were measured 1 day before (baseline)and 1,3, 7,14 day after modeling.When behavioral test finished,the expression levels of TREM1,TLR4, MyD88,IκBαand p-NF-κB p65 in spinal cord were determined by Western blot.Whereas the mRNA expression levels of IL-1β,TNF-αand IL-6 in spinal cord were measured by RT-PCR.Results Com-pared with group S,the expression levels of TREM1 in groups CCI and Virus significantly increased (P<0.05).While compared with group CCI,the TREM1 expression of group RNAi in spinal cord significantly decreased (P<0.05).Compared with group S,MWT and TWL of groups CCI,Virus and RNAi after modeling and the expression of IκBαsignificantly decreased (P<0.05),whereas the expression of TLR4,MyD88,p-NF-κB p65 increased significantly (P<0.05),as well as the expres-sion of IL-1β,TNFαand IL-6 mRNA (P<0.05).Compared with group CCI,the MWT and TWL of group RNAi after modeling and the expression of IκBαremarkably increased (P<0.05),whereas the expression of TLR4,MyD88 and p-NF-κB p65 in the spinal cord remarkably decreased (P<0.05), as well as the expression of IL-1β,TNF-αand IL-6 mRNA (P<0.05).Conclusion TREM1 knock-down can alleviate neuropathic pain,the underlying mechanism might be the inhibition of TLR4/MyD88/NF-κB signaling pathway.

AIM:To evaluate 23G vitrectomy for macular edema in eyes with retinal vein occlusion (RVO) combined with vitreoretinal traction (VMT) or epiretinal membrane (ERM).METHODS:Totally 22 patients (22 eyes) diagnosed with macular edema of RVO combined with VMT or ERM were retrospectively analyzed.Twelve cases performed with 23G vitrectomy together with peeling of inner limiting membrane (ILM) and/or ERM were considered as the observation group or intervention group.Ten cases without vitrectomy were recruited as control group.The best corrected visual acuity (BCVA) and central retinal thickness (CRT) at baseline, 1, 3 and 6mo were recorded and compared.RESULTS:At baseline, the difference of BCVA and CRT between observation group and control group was not statistically significant (P=0.645, 0.206).After vitrectomy, the BCVA and CRT of RVO patients in observation group were significantly improved compared with baseline at each follow-up (F=2.895, P=0.048;F=16.431, P<0.01).However, the BCVA and CRT in control group remained the same as baseline at every follow-up.Moreover, the BCVA and CRT in observation group were much better than that in control group at both 3 and 6mo after vitrectomy.However, the BCVA and CRT between two groups were not significantly different at 1mo postoperatively.CONCLUSION:The 23G vitrectomy could markedly improve BCVA and reduce CRT in RVO patients with macular edema combined with VMT and/or ERM.

Objective To understand the changing resistance proifle ofProteus,Serratia,Citrobacter,Morganella andProvidencia in hospitals across China according to the data from CHINET Antimicrobial Resistance Surveillance Program 2005-2014.Methods Antimicrobial susceptibility was tested by using Kirby-Bauer method or automatic minimum inhibitory concentration determination according to a uniifed protocol.Results A total of 21 663 clinical isolates were collected from January 2005 to December 2014. The proportion ofProteus andSerratia isolates increased with time from 1.41% in 2005 to 2.09% in 2014, and from 0.99% in 2005 to 1.28% in 2014 among all the isolates. No change was found for the proportion ofCitrobacter,Morganella, orProvidencia. Less than 10% of theProteus isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, ceftazidime, cefoxitin, amikacin and tigecycline. Less than 10% of theSerratia isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, amikacin and tigecycline. Less than 20% of theCitrobacter isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, amikacin and tigecycline. Less than 10% of theMorganella isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, amikacin and tigecycline. Less than 20% of theProvidencia isolates were resistant to cefoperazone-sulbactam, piperacillin-tazobactam, cefepime, cefoxitin and tigecycline.Conclusions The antibiotic resistance ofProteus,Serratia, Citrobacter,Morganella andProvidencia isolates in hospitals across China is growing during the period from 2005 to 2014. Strengthening infection control and rational antibiotic use are effective to slow the growth of drug resistance.

Objective To investigate the distribution and antibiotic resistance proifle of clinicalEnterobacter isolates using the data from CHINET during the period from 2005 through 2014.Methods A total of 20 558 clinical strains ofEnterobacter spp. were collected from 2005 to 2014 in CHINET Antimicrobial Resistance Surveillance Program. Antimicrobial susceptibility testing was performed with Kirby-Bauer or minimum inhibitory concentration method. The results were analyzed according to CLSI 2014 breakpoints.ResultsEnterobacter cloacae andEnterobacter aerogenes accounted for 71.1% (14 617/20558) and 20.1% (4 129/20 558) of all theEnterobacterisolates, respectively. The proportion ofEnterobacter spp. increased with time from 3.5% in 2005 to 4.3% in 2014. The main source of the isolates was respiratory tract, accounting for 55.2% (11 358/20 558). More than 90% of theEnterobacterisolates were resistant to cefazolin and cefoxitin, but less than 30% of the strains were resistant to cefepime, piperacillin-tazobactam, cefoperazone-sulbactam, amikacin, gentamicin, ciprolfoxacin, meropenem, imipenem and ertapenem. TheEnterobacterisolates showed a trend of declining resistance to most antibiotics except ertapenem and meropenem. The resistance proifle ofEnterobacterisolates varied with departments where they were isolated. The strains from ICU and Department of Surgery were relatively more resistant to antibiotics. The prevalence of multi-drug resistant (MDR) strains was decreasing, but the prevalence of carbapenem-resistantEnterobacter (CRE, resistant to any of imipenem, meropenem or ertapenem) was increasing. The MDR and CRE strains were primarily isolated from ICU and Department of Surgery. At least 30% of the MDREnterobacter strains were resistant to any of the antimicrobial agents tested except meropenem, imipenem and ertapenem and at least 35% of the CRE strains were resistant to any of the antimicrobial agents tested except amikacin and ciprolfoxacin.Conclusions TheEnterobacter isolates in CHINET Antimicrobial Resistance Surveillance Program showed decreasing resistance to most of the antimicrobial agents tested since 2011, but the prevalence of CRE strains increased progressively. Effective measures should be carried out to prevent the spread of CRE strains in hospitals.