A series of new coumarin-based benzotriazole derivatives were successfully synthesized via a multi-step sequence of cyclization, etherification and N-alkylation, and were confirmed by 1H NMR, IR, MS spectra as well as elemental analyses. All these synthesized coumarin compounds were evaluated for in vitro antimicrobial activities against four Gram-positive bacteria, four Gram-negative bacteria and three fungi by two fold serial dilution technique. The bioactive assay showed that all these prepared coumarin benzotriazoles could inhibit the growth of the tested bacterial and fungal strains. Title compounds 11a-11e and 13a-13c were more active than chloromycin on Proteus vulgaris ATCC 6896. Coumarin benzotriazoles 11a and 11b displayed comparable antibacterial efficacy against Staphylococcus aureus ATCC 25923 and Micrococcus luteus ATCC 4698 in comparison with reference drug chloromycin. Compared to fluconazole, compounds 11a-11d displayed stronger inhibition on Aspergillus fumigatus ATCC 96918. Moreover, coumarin-based benzotriazoles in combination with antibacterial chloromycin or antifungal fluconazole, showed notable antimicrobial efficacy with less dosage and broader antimicrobial spectrum. More importantly, fluconazole-insensitive A. fumigatus and methicillin-resistant Staphylococcus aureus N 315 (MRSA) were sensitive to these combined drugs.

Objective To evaluate antimicrobial activity of fosfomycin combined with tigecycline against Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae and study the mechanism of drug resistance to fosfomycin. Methods Broth microdilution method was used to independently determine the minimum inhibitory concentrations (MIC)of fosfomycin and tigecycline against 42 Klebsiella pneumoniae isolates (including 20 KPC-producing and 22 KPC non-producing isolates).Checkerboard design method was applied to evaluate combined effect of different concentrations on antimicrobial susceptibility and calculate the fractional inhibitory concentration index (FICI).FICI=MICfosfomycin joint/MICfosfomycin monotherapy +MICtigecycline joint/MICtigecycline monotherapy .Related interpretation criteria were as following:FICI≤0.5 means synergy;0.5 2 means antagonism.The fosfomycin resistant genes in KPC-producing Klebsiella pneumoniae isolates were screened.The data were analyzed by t test.Results Antimicrobial susceptibility testing results indicated the fosfomycin and tigecycline susceptibility rates in KPC-producing isolates were 35 .0%(7/20)and 70.0% (14/20 ),respectively.The susceptibility rates of drug combination increased to 50.0% (10/20 )and 95 .0% (19/20 ),respectively,with both MIC decreased.MIC of tigecycline decreased significantly after combination therapy and showed a statistical significance compared with the MIC of monotherapy (t = - 2.596,P = 0.013 ),whereas there was no significant difference between single and combined therapy of fosfomycin (t=-1 .274,P =0.211).FICI indicated that a total of 60.0%isolates showed synergy and additive effects between two antimicrobial agents,followed by indifference (40.0%),but there was no antagonism effect.Among 22 KPC non-producing isolates,there were 54.5 %showing indifference effects,followed by additive (31 .8%)and synergy (13.6%)effects.No antagonism effect was found.The study also identified two isolates with fosA resistant gene which located on the same plasmid as well as the bla KPC gene.The plasmid sizes in the two isolates were 138.9 kb and 104.5 kb, respectively.Conclusions KPC-producing Klebsiella pneumoniae are more susceptible to tigecycline. Combined use of two antimicrobial agents mainly exerts synergy and additive effect rather than antagonism,which may suggest the combination therapy strategy could inhibit the activity of KPC-producing Klebsiella pneumoniae .

Objective To observe the clinical effect of treating Alzheimer's disease (AD) using transcranial magnetic stimulation.Methods One hundred and ninety-six patients with Alzheimer's disease were randomly divided into an observation group and a control group,each of 98.The observation group was given transcranial magnetic stimulation of the left and right dorsolateral frontal lobes of the brain and simultaneously given "8-shaped" coil stimulation.The stimulation intensity was 80％ of the motor threshold with a sequence of 2 s of stimulation at 5 Hz and 30 s rest for 30 min in each session.There were two sessions a day for 28 days.The control group was treated with identical pseudo-stimulation.Moreover,both groups were treated with intravenous injections of 20 ml of Ginkgo biloba extract dissolved in 250 ml of sodium chloride,or in the control group a glucose injection,one daily for two weeks.Before and after the treatment,the cognition,behavior and neuropsychological symptoms of both groups were evaluated using the mini mental state examination scale (MMSE),the AD rating scale (ADAS-cog),the activity of daily living (ADL) scale,a neuropsychiatric questionnaire (NPI) and an AD behavioral pathology rating scale (BEHAVE-AD) to compare the clinical effects.Results There were no significant differences in the groups' average scores on any of the evaluations before the treatment.After the treatment,the average MMSE and ADAS-cog scores in both groups had improved significantly,but with significantly greater improvement in the observation group.After the treatment,the average ADL,NPI and BEHAVE-AD scores of the observation group and the average ADL score of the control group were significantly lower than before the treatment.No significant differences were observed in the average NPI and BEHAVE-AD scores of the control group.After the intervention,the average ADL,NPI and BEHAVE-AD scores in the observation group were significantly lower than those of the control group.The total effectiveness rate of the observation group (90.8％) was significantly higher than that of the control group (62.2％).Conclusion Transcranial magnetic stimulation can significantly improve the cognitive,behavioral and neuropsychological status of patients with Alzheimer's disease.

Objective: To investigate the levels of vitamin D and the correlation between DPN and vitamin D in elderly patients with diabetic peripheral neuropathy(DPN). Methods: A total of 849 patients aged 60 years and over admitted into endocrinology department from June 2016 to September 2017 were enrolled in this retrospective case-control study.According to DPN diagnostic criteria, patients were divided into the non-DPN group(n=542)and the DPN group(n=307). The 25(OH)-vitamin D[25(OH)D]level and blood biochemical parameters were determined and compared between the two groups.The risk factors for DPN were analyzed using logistic regression analysis and plotting receiver operating characteristic(ROC)curves. Results: The mean of serum 25(OH)D level in the 849 patients was 43.9±19.4 nmol/L.Serum 25(OH)D level was lower in the DPN patients than in the non-DPN patients[(40.9±20.4)nmol/L vs.(45.7±18.6)nmol/L, P<0.05]. The incidence of 25(OH)D deficiency was higher in the DPN group than in the non-DPN group(72.3% or 222/307 vs. 64.6% or 350/542, P<0.05). Binary logistic regression analysis indicated that 25(OH)D was a protective factor for DPN(OR=0.980, 95% CI: 0.964~0.995, P<0.05)and the disease duration was a risk factor for DPN(OR=1.048, 95% CI: 1.027~1.070, P<0.001). ROC analysis indicated that the diagnostic cut-off value of serum 25(OH)D for predicting DPN was 37.5nmol/L, with a Youden index of 0.17, sensitivity of 0.65 and specificity of 0.52. Conclusions The 25(OH)D level is much lower in diabetic patients, especially in DPN patients.Higher 25(OH)VD level might be a protective factor for DPN, and vitamin D might be one of potential biomarkers for DPN in diabetic patients.