The pathogenesis of multiple sclerosis ( MS) involves alterations to multiple pathways and processes, which represent a significant challenge for developing more-effective therapies.In MS, abnormalities have been identified in several cytokine-signaling pathways, as well as those of other immune receptors.Among the downstream molecules implicated are Jak/Stat, NF-κb, ERK1/2, p38 or Jun/Fos, current MS drugs target some of these pathways.This article will with the aid of the latest research results of systems biology approaches that study pathway dysregulation in the process of MS development, targeting these relevant MS-signaling pathways, offers the opportunity to accelerate the development of novel individual or combination therapies for the future of new drug research.

Objective To investigate the epidemiology of drug-resistant tuberculosis (TB) in five rural counties of eastern China and analyze the biological,demographic and social risk factors.Methods Subjects of this study were all the diagnosed TB patients registered in the five study sites in Shandong Province,Jiangsu Province and Zhejiang Province during one year of 2008- 2009.Questionnaire interview was conducted in all the subjects to acquire the socio-demographic and clinical information.Sputum samples were collected for culturing and isolating of Mycobacterium tuberculosis (M.TB) strains.All the M.TB isolates were further tested for the susceptibility to first-line drugs including rifampin,isoniazid,ethambutol and strepomycin by proportion method.Mantel-Haenszel chi-square test,Fisher's exact test,ANOVA and nonconditional Logistic regression modeling were applied for data analysis.Results Among the total 380 M.TB isolates,105 were resistant to at least one of the first-line drugs.The total drug resistant TB prevalence was 27.6％.Multidrug-resistant tuberculosis (MDR-TB) was observed in 8.4％ of newly treated TB patients,whereas it was 23.3％in previously treated TB patients.After adjusted by county,gender and age of the subjects,multivariate analysis showed that previous treatment history (OR=3.900,95％CI: 1.737-8.704),tuberculosis cavity (OR - 1.987,95 ％ CI: 1.001 - 3.942) were independent factors influencing the occurrence of MDR-TB.Conclusions The prevalence of drug resistant TB in rural area of eastern China is relatively low compared with the average level in China,while it is still higher than the global average level.The present study highlights that TB patients with previous treatment history,cavitaryTB are correlated with MDR-TB,and elderly patients are at high risk of MDR-TB.

OBJECTIVE:To provide reference for the construction and development of hospital modernization pharmacy in Chi-na,and to promote the application of pharmacy automation system in hospital. METHODS:By introducing the change of pharma-cy management due to the debugging and application of outpatient pharmacy automation system(rapid dispensing machine,intelli-gent access machine)in our hospital,the problems of automation system and countermeasures were put forward,and the effects of automation system in our hospital were evaluated. RESULTS:With the application of automation system,the pharmacy layout was adjusted,the drugs in the machine was debugged and optimized,the procedure on adding drugs and stocktaking drugs were im-proved,the reasonable scheduling work in outpatient pharmacy was worked,the complete management plan on validity of drugs was established;referring to the problems of automation system,the procedures of adding drugs by rapid dispensing machine and intelligent access machine were formulated as well as related working guide. The adding and delivering drug failure emergency han-dling procedure of rapid dispensing machine,intelligent access machine failure emergency handling procedure were formulated ac-cording to the possible fault of automation system. Related index evaluation showed that automation system was applied and continu-ously improved,which reduced labor intensity(step count of pharmacists adding drug decreased from 5 634.6 steps/day to 4 087.8 steps/day);the work efficiency was improved greatly(the number of prescriptions increased from 226.55 sheets/h to 311.55 sheets/h during rush hours);the work error was reduced(the number of dispensing internal error decreased from 54.75 items/week to 21.50 items/week). CONCLUSIONS:After appling the automation system in outpatient pharmacy,the drug dispensing and staff manage-ment has been standardized,and it become the hospital pharmacy development inevitable trend. But it is suggested to adjust and op-timize the automation system continuously so as to exert its maximal efficacy.

Diabetic SD rats were established by injection of streptozotocin,and were divided into normal blood sugar control group(NC),diabetic control group(DM),and the insulin treatment group(IDM).12 weeks later,the maximum rates of increasing and decreasing pressure in left ventricle were both decreased in DM group(P＜ 0.05),and those in IDM group were higher than those in DM group(P＜0.05).Regional myocardial blood flow in DM group was lower than that in NC group [(3.39 ± 0.48 vs 3.90 ± 0.45) ml · g-1 · min-1,P＜ 0.05],and that in IDM group was higher than that in DM group [(4.46 ± 0.52 vs 3.39 ± 0.48) ml · g-1 · min-1,P＜0.05].The capillary density ratio in DM group was lower than that of NC group [0.429 ± 0.091 vs 0.545 ± 0.082,P＜0.05],but that in IDM group was higher than DM group [0.494 ± 0.076 vs 0.429 ± 0.091,P＜0.05].VEGF and Ang-1 expression in DM group were the highest in 3 groups (P＜0.05).Insulin therapy may improve the angiogenesis and myocardial blood flow in diabetic rats with cardiomyopathy.

Objective To investigate the growth inhibition and DNA damage of energized fusion protein anti-CD20(Fab)-LDM on B JAB cells in vitro.Methods The binding activity of fusion protein anti-CD20 (Fab)-LDP to B JAB cells was studied by flow cytometry and confocal laser scanning microscopy.MTT assay was used to study the energized fusion protein anti-CD20(Fab)-LDM on cell growth of B JAB cells.Comet assay was employed to detect DNA damage in B JAB cells.The cell growth cycle of BJAB was analyzed by FACS.Results The recombinant fusion protein anti-CD20 (Fab)-LDP possessed an significant target affinity towarded BJAB cells.The energized fusion protein anti-CD20(Fab)-LDM showed obvious inhibition on proliferation,as well as induced potent DNA damage in B JAB cells in vitro compared with lidamycin.B JAB cells treated with energized fusion protein anti-CD20 (Fab)-LDM showed S phase cell cycle.Conclusion The energized fusion protein anti-CD20 (Fab)-LDM could target binding to BJAB cells and significantly inhibit the proliferation of B JAB cells by inducing DNA damage and S phase arrest.

Objective To evaluate the antitumor effects of interferon (IFN)γ-endostatin based gene radiotherapy in a metastatic breast tumor model of mice, and to elucidate the possible mechanisms involved. Methods Murine mammary adenocarcinoma 4T1 cells transfected with pEgr-IFN-γ and pEgrendostatin plasmids were irradiated with 2-20 Gy of X-rays. IFN-γ and endostatin levels in the culture supernatants were measured. Female BALB/c mice were inoculated with 1 × 105 of 4T1 cells by mammary fat pad injection, and divided randomly into control, empty vector, gene therapy (pEgr-IFN-γ and pEgrendostatin), radiotherapy, and combined gene-radiotherapy groups. Tumor/body weight ratio, lung metastases, and survival of the tumor-bearing mice were observed. Splenic cytotoxic T-lymphocyte (CTL)and natural killer (NK) cell activity and intratumor microvessel density were also assessed. Results Irradiation significantly enhanced the section of IFN-γ and endostatin from the transfected 4T1 cells.Compared with gene therapy or radiotherapy alone, combined gene-radiotherapy resulted in the maximal attenuation in tumor growth rate, lung metastases and increased survival. The activities of CTL and NK cells were significantly enhanced and intratumor microvessel density reduced ( t = 2. 120-22.140, P ＜ 0.05 ).Conclusions IFN-γ-endostatin-based gene-radiotherapy could provide a potential antitumor effect in a murine metastatic breast tumor model, which may be related to IFN-γ-stimulated CTL and NK cell activation, and endostatin-induced antiangiogenic activity. Gene-radiotherapy could serve as a neoadjuvant therapy for the locally advanced breast cancer.

Objective To establish a real-time quantitative polymerase chain reaction (qPCR) assay for B-cell lymphoblastic leukemia according to individualized and specific immunoglobulin gene rearrangements in leukemia cells, and to use it for the monitoring of minimal residual disease (MRD) of B-cell lymphocytic leukemia. Methods The immunoglobulin gene rearrangements of bone marrow samples from 15 cases of B-cell lymphoblastic leukemia were analyzed with a validated European BIOMED-2 system, and the individualized and specific qPCR-based quantification of leukemic immunoglobulin gene rearrangements was established. Results Unique and specific gene rearrangements of immunoglobulin light and heavy chains were identified in 14 cases and Ig-qPCR based on these gene rearrangements had a sensitivity of 10-5 and high specificity which met the international criteria in 10 patients. Leukemia MRD quantification with immunoglobulin gene rearrangement-based qPCR was similar as compared with other MRD detection methods. Conclusion Immunoglobulin gene rearrangement-based leukemia MRD quantification is feasible, sensitive, specific, precise and much valuable for clinical decision of treatments in B-cell lymphoblastic leukemia.

Objective To evaluate the changes in the expression of spinal divalent metal transporter 1 (DMT1) during remifentanil-induced hyperalgesia in a rat model of incisional pain.Methods Thirtytwo male Sprague-Dawley rats,weighing 240-260 g,aged 2-3 months,were randomly divided into 4 groups (n =8 each) using a random number table:control group (group C),incisional pain group (group I),remifentanil group (group R),and incisional pain + remifentanil group (group I+R).In group C,normal saline was infused for 60 min at a rate of 0.1 ml · kg-1 · min-1.A 1-cm longitudinal incision was made through skin,fascia and muscle of the plantar aspect of the left hindpaw in sevoflurane-anesthetized rats,and normal saline was infused intravenously for 60 min at a rate of 1.0 μg · kg-1 · min-1 at the same time in group I.In group R,remifentanil was infused for 60 min at a rate of 1.0 μg · kg 1 · min-1 In group I+R,the model of incisional pain was established,and remifentanil was simultaneously infused for 60 min at a rate of 1.0 μg · kg-1 · min-1.At 24 h before normal saline or remifentanil infusion and 6,24 and 48 h after the end of infusion (T0-3),the mechanical paw withdrawal threshold (MWT) and thermal paw withdrawal latency (TWL) were measured.All the rats wcrc sacrificed after the last measurement of pain thresholds,and the spinal cord was removed for determination of DMT1 with/without iron-responsive element [DMT1 (+)IRE and DMT1 (-)IRE] expression (by Western blot analysis and immunohistochemistry).Results Compared with group C,the MWT was significantly decreased,and the TWL was significantly shortened at T1-3,and the expression of spinal DMT1 (-) IRE was significantly up-regulated in I,R and I+R groups (P＜0.05).Compared with I and R groups,the MWT was significantly decreased,and TWL was significantly shortened at T1-3,and the expression of spinal DMT1 (-) IRE was significantly upregulated in group I+R (P＜0.05).There was no significant difference in the expression of spinal DMT1 (+) IRE between the four groups (P＞ 0.05).Conclusion Spinal DMT1 (-)IRE activation may be involved in the mechanism underlying remifentanil-induced hyperalgesia in a rat model of incisional pain.

Objective To investigate the value of contrast-enhanced ultrasound(CEUS) to diagnose thyroid nodules with different calcifications,and analyze its correlation with age and gender.Methods The image characteristics of high frequency ultrasound and pathological results of 522 patients with calcified thyroid nodules were analyzed retrospectively.CEUS enhancement patterns of different age and gender were observed and compared.Results There were no malignant nodules in patients under the age of 10.In the group of male and female,malignant nodules patients constituted the highest proportion between 40-49years old and a minimal proportion between 10-19 years old.The CEUS for weak enhancement with micro calcifications were mostly malignant nodules;the high or equal enhancement with macrocalcifications were mostly benign nodules.But a part of micro calcifications in young women patients (20 to 29 years old) with high or equal enhancement were mostly malignant nodules.Conclusions The CEUS for weak enhancement with microcalcifications are mostly malignant nodules,but a part of microcalcifications in young women patients (20 to 29 years old) with high or equal enhancement are mostly malignant nodules.

Objective To evaluate volume doubling time (VDT) and net mass doubling time of tumor (nMDT) of pulmonary pure ground glass nodules (PGGN) of different pathological types and to investigate whether VDT and nMDT can help to differentiate invasive pulmonary adenocarcinomas from minimally invasive adenocarcinomas and preinvasive lesions.Methods Fifty-one pathologically confirmed pGGNs in 46 patients were retrospectively evaluated,in whom at least two HRCT scans were obtained preoperatively (median scan times,3 times;range,2-6 times) with 1-month or longer follow-up interval (median follow-up interval,251 days;range,30-1 552 days).According to the rechecked results of the postoperative pathological section,51 pGGNs were divided into two groups:group A,invasive adenocarcinoma (IAC),30 pGGNs (58.8％);group B,21 pGGNs (41.2％),including 8 minimally invasive adenocarcinoma (MIA),7 adenocarcinomas in situ (AIS) and 6 atypical adenomatous hyperplasia (AAH).The volume,cumulative percentage of volume growth and VDTs of pGGNs were automatically acquired by Lung VCAR (advantage windows 4.6,GE HealthCare).Subsequently,the mass,cumulative percentage of mass growth and nMDTs of pGGNs were calculated.The count data and measurement data between two groups were compared using Fisher exact probability and Mann-Whitney U test,respectively.A pairwise comparision were performed by using Wilcoxon signed-rank test.Subsequently,the receiver operating characteristic (ROC) curve was used to determine the optimal cut-off values of VDT and nMDT for the differential diagnosis of IAC and MIA/AIS/AAH,and calculated the area under the curve (AUC).Results The median VDT and nMDT of 51 pGGNs were 1 854.11 days (range,165.22—+∞ days) and 1 138.45 days (range,95.92—+ ∞ days),respectively.The median nMDT was shorter than the median VDT,and the difference was significant (Z=-2.444,P=-0.O15).The median VDTs of IAC and MIA/AIS/AAH were 847.07 days (165.22—+∞ days) and 4 460.09 days (691.14—+∞ days),respectively.The median nMDTs of IAC,MIA/AIS/AAH were 769.93 days (95.92—+∞ days) and 3814.77 days (611.56—+∞ days),respectively.The median VDT and nMDT of IAC were significantly shorter than those of MIA/AIS/AAH (Z=-3.443,-3.860,P＜ 0.01,respectively).Differentiating IAC from MIA/AIS/AAH,the optimal cutoff value of VDT was 2095.86 days (sensitivity,71.4％;specificity,80.0％),the optimal cutoff value of nMDT was 1 169.77 days (sensitivity,81.0％;specificity,76.7％).Conclusions In pulmonary pGGNs,IAC showed significantly shorter VDT and nMDT than MIA/AIS/AAH.When VDT is shorter than 2 095.86 days or nMDT is shorter than 1 169.77 days,IAC is suggested.