Alzheimer′s disease(AD)is a major form of neurodegenerative disease. Due to the lack of effective treatment for AD,drug discovery is imminent,and genomics has become a driving force for the drug discovery. Genomic studies of AD involve sever?al aspects,such as large-scale studies on the genetic risk,brain transcriptome studies,and epigenetic studies. Notable progress has been made in genomic studies of AD,which has facilitated the drug discovery. In the meantime,biomarkers for early diagnosis includ?ing those from peripheral blood have emerged as a major research topic because early detection and intervention are the prominent task for the moment. Research progress in this field will be briefly reviewed. Because of the vast heterogeneity in AD pathogenesis ,genom?ics will also provide strong support for precision medicine in the future.

Objective To develop a HPLC-MS/MS method for determination of Tacrolimus(FK506) in bone marrow trans plant patient,and explore the relationship of HPLC-MS/MS with CMIA and Elecsys in the measurement of FK506 blood drug concentration,and provide reliable basis for clinical rational use of monitoring method in FK506 blood drug concentra tion.Methods The separation was performed on a Ultimate xB-C18 column with a mobile phase of water (containing 2 mmol/L ammonium acetate and 0.1 ml/dl formic acid) and methanol (containing 0.1 ml/dl formic acid).The way of eluting was gradient.Mass spectrum detection method was ESI positive ion mode and the MRM transitions of FK506 m/z 821.5～ 768.5 and Ascomycin m/z 809.4～756.4.Selected part of the whole blood samples of FK506 in bone marrow transplant patient and respectively were tested by HPLC/MS/MS method,CMIA method and Elecsys method.Then,three methods for the detection of FK506 density were compared.Results The standard curve of FK506 was linear over the range of 0.5～50 ng/ml,Y=0.228X-0.003 08 (r=0.999 0).FK506 blood concentrations were not significantly different in HPLC/MS/MS method,CMIA method and Elecsys method.Conclusion The HPLC-MS/MS method in the detection of FK506 was established and can be used for monitoring of whole blood concentration of FK506 in bone marrow transplant patients.

Objective To develop a HPLC-MS/MS methodfor determination of cyclosporin A(CSA)and AM1 in bone marrow transplant patient,and explore the relationship of CSA and its main metabolite AM1 within individual and between individuals,and provide reliable basis for clinical rational use of monitoring in CSA blood drug concentration.Methods CSD was used as internal standard,and whole blood samples were treated with internal standard methanol precipitated protein.The column was Ultimate XB-C18 with a column temperature of 65 ℃ and the mobile phase was eluted with 0.1％ of formic acid and 2 mmol/L ammonium acetate in water and methanol containing 0.1％ formic acid.The mass spectrometry was detected by electrospray ion trap positive ion mode,MRM scanning,monitoring CSA 1219.9 to 1203.1 m/z,AM1 1236.1 to 1219.1 m/z,CSD 1234.0 to 1217.0 m/z.Results The concentration of CSA was linear in the range of 16 to 1600 ng/mL,Y=0.0143X+0.0213(r=0.9976).The concentration of AM1 was linear in the range of 10～1000 ng/mL,Y=0.00363X-0.00528(r=0.9973).The ratio of CSA to AM1 (AM1/CSA) between individual ranged from 32％ to 356％.The ratio of CSA to AM1 within indiviolual(AM1/CSA) ranged from 27 ％ to 147 ％.Conclusion HPLC-MS/MS method for the simultaneous detection of CSA and AM1 was established.The variation of CSA exists in the bone marrow transplant patient between individuals and within individual;the HPLC-MS/MS method can be used for monitoring of whole blood concentration of CSA in bone marrow transplant patients.

Objective To develop a HPLC-MS/MS method for determination of Imatinib and Dasatinib in CML patient,and make it used in clinic trial.Methods The separation was performed on a Ultimate XB-C18 column with a mobile phase of water(containing 2 mmol/L ammonium acetate and 0.1 ml/dl formic acid)and methanol(containing 0.1 ml/dl formic acid). The way of eluting was gradient.Mass spectrum detection method was ESI positive ion mode and monitoring Imatinib m/z 494.5>394.3 and Dasatinib m/z 488.3>401.3.Results The standard curve of Imatinib was linear over the range of 0.05~7.5 μg/ml,Y =5.6×105 X+5× 103 (R =0.999 8).Thestandard curve of Dasatinib was linear over the range of 5~250 ng/ml,Y =211X+66.6(R=0.999 6).The relative recovery was among the range of 90%~107%.RSDs of intra-and inter-day validation were less than 10%.Conlusion This method is convenient,accurate and rapid,and can be used for the deter-mination of Imatinib and Dasatinib in clinic test.

Objective To study the protein expression levels of matrix metalloproteinases (MMPs)and their inhibitors in bone tissues of rat femoral head and to explore the relationship between necrosis of femoral head and glucocorticoid.Methods Twenty healthy adult SD rats were randomly divided into glucocorticoid group and control group,with 10 rats in each.Glucocorticoid group was treated with intramuscular injection of hydrocortisone twice a week.The control group received normal saline of the same volume.Four weeks later,bone tissues of left femoral head were collected from each group of rats for HE determination of femoral head necrosis.The expressions of matrix metalloproteinase-1 (MMP-1 ), matrix metalloproteinase-2 (MMP-2 ), tissue inhibitor of matrix metalloproteinase-1 (TIMP-1 ),and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2 )at mRNA and protein levels were detected by RT-PCR and Western blot techniques,respectively.Results The expressions of MMP-1 and MMP-2 at mRNA and protein levels were higher in glucocorticoid group than those in the control group. However,TIMP-1 and TIMP-2 gene and protein expression levels were lower in glucocorticoid group (all P<0.05). Conclusion The expressions of MMPs in bone tissues of rat femoral head in early necrosis were increased,but their inhibitors had decreased expressions. We can draw the conclusion that glucocorticoid-induced necrosis of femoral head may be related to its regulation of the expression levels of MMPs and their related inhibitors.

Objective To observe the effect of two reverse pedicle flap repaired soft tissue defect of the finger.Methods From April,2011 to March,2015,46 patients were randomly divided into two groups.Twenty-eight cases were performed by dorsal metacarpal artery flaps with cutaneous branches as pedicle and the 18 cases were performed by reverse the proper palmar digital artery dorsal branches island flap.The complication,survival rate,hand function and appearance were analyzed.Results The dorsal metacarpal artery flaps with cutaneous branches as pedicle and reverse the proper palmar digital artery dorsal branches island flap were an average follow-up of 18 and 15 months,all flaps survived.For fingertip defects,8 cases were repaired with as pedicle as the dorsal metacarpal artery flaps with cutaneous branches as pedicle while 16 cases were repaired with reverse the proper palmar digital artery dorsal branches island flap.Among them,complication included 2 cases of early venous congestion and 2 cases of superficial skin necrosis.One case of reverse the digital artery dorsal branches island flap blistered;the flap sensibility was good recovery.The two-point discrimination testing of dorsal metacarpal artery flaps with cutaneous branches as pedicle was from 6.0 to 9.0 mm (average of 7.1 ± 0.5 mm);the two-point discrimination testing of dorsal metacarpal artery flaps with cutaneous branches as pedicle was from 4.0 to 7.0 mm (average of 5.2 ± 0.4 mm),but there were differences in two-point discrimination and there was statistically significant (P ＜ 0.05).There was no significant difference between the two groups each finger interphalangeal joint activity compared with the healthy side.The study found that 10 cases of dorsal metacarpal artery flaps appearance was 5 mm higher than normal skin and 1 patient of reverse the digital artery dorsal branches island flap appearance was 5 mm higher than normal skin,the difference was statistically significant (P ＜ 0.05),the latter was better than the former,especially repaired fingertip defect.Conclusion Dorsal metacarpal artery flaps with cutaneous branches as pedicle and reverse the proper palmar digital artery dorsal branches island flap were safe and reliable,it is the ideal flap finger defects.For finger fingertip defect repaired reverse the proper palmar digital artery dorsal branches island flap is superior dorsal metacarpal artery flaps with cutaneous branches as pedicle.

This study examined the association of problem behavior with neurotransmitter deficiency in adolescents, which would provide new insights into behavioral problems. A total of 1259 students of the seventh grade from 4 middle schools in Wuhan city located in the central China were recruited. With the approval of school and parents, they were invited to complete the Youth Self-Report (YSR) questionnaire and Symptom Scale of Neurotransmitter Deficiency (SSND) questionnaire. Pearson's bivariate correlation analysis showed that the correlation coefficients between each subscale of YSR and SSND ranged from 0.24 to 0.61 with all P<0.01. Canonical correlation analysis indicated that anxiety/depression was interrelated with insufficiency of GABA and 5-HT; aggressive behavior was associated with inadequate GABA; famine of DA influenced the attention problems. It was concluded that neurotransmitter deficiency may cause a series of behavioral and mental problems.

Objective To investigate the effect of exercise on the recovery of locomotor and neurological function in rats after incomplete spinal cord injury (SCI). Methods Ninety-five male Sprague Dawley rats were randomly divided into a control group, a training group (including subgroups which received training for 1 week, 2 weeks, 3 weeks and 4 weeks) and a sham operation group. The control and training groups were administered an SCI model at the T_(10) level by extradural compression using a modified Allen's stall with a damage energy of 40 g-cm. These rats were loosely restrained and given partial weight-bearing treadmill training 5min/time, twice a day for 1-4 weeks. Locomotor and neurological function were evaluated with inclined plane tests, modified Tarlov scores, the Basso-Beattie-Bresnahan scale and spinal cord somatosensory evoked potential (SCSEP) before injury and at different time points thereafter. Results Locomotor function improved significantly at different time points during the train-ing, and significantly better than in the control group. In the rats trained for 2-4 weeks, SCSEP latency shortened sig-nificantly compared to the control group. The latency shortened gradually with longer exercise. Conclusions Exer-cise with partial weight support may improve locomotor and neurological function. The improvements are correlated closely with the duration of the training.

Alzheimer Disease ; metabolism ; Amyloid ; chemistry ; metabolism ; Amyloid beta-Protein Precursor ; chemistry ; metabolism ; Dimerization ; Humans ; Hydrogen Bonding ; Protein Binding ; Protein Folding ; Protein Structure, Quaternary ; Protein Structure, Secondary ; Protein Structure, Tertiary

Objective To observe the effect of psoralen on the proliferation of osteoblasts induced by alcohol, thus to explore the mechanism of psoralen in preventing and treating alcohol-induced osteoporosis. Methods The osteoblasts separated from neonatal rat skull were identified by alkaline phosphatase (ALP) staining method. The in-vitro confirmed osteoblasts were randomly divided into 4 groups, namely blank control group, alcohol group (model group), psoralen group, and psoralen plus alcohol group. The alcohol-induced osteoblast proliferation in various groups was determined by methyl thiazolyl tetrazolium (MTT) method. Results Compared with the blank control group, the alcohol-induced osteoblast proliferation at culturing hour 24, 48, 72, 96 in alcoholgroup was significantly decreased (P<0.05), and the proliferation in psoralen group at various time points only showed an increasing trend, the differences being statistically insignificant (P>0.05). Compared with the alcohol group, osteoblast proliferation at culturing hour 24 in psoralen plus alcohol group was significantly increased (P <0.05) , but the differences of osteoblast proliferation at culturing hour 48, 72, 96 h between the two groups were insignificant (P > 0.05). Conclusion Psoralen has certain effect on promoting alcohol-induced osteoblast proliferation in vitro.