tralateral parietal lobe. Conclusions CIMT can improve the patients' upper-limb function effectively. The constraint-induced movement of the affected arm during CIMT appears to induce cortical reorganization and compensation as measured by fMRL

Action Potentials ; drug effects ; Animals ; CA1 Region, Hippocampal ; cytology ; Drug Antagonism ; Male ; Neurons ; drug effects ; Pentylenetetrazole ; pharmacology ; Propofol ; pharmacology ; Rats ; Rats, Wistar ; Synaptic Transmission ; drug effects

Small molecule covalent inhibitors, or called as irreversible inhibitors, are a type of inhibitors that exert their biological functions by irreversibly binding to target through covalent bonds. Compared with non-covalent inhibitors, covalent inhibitors have obvious advantages in bioactivity. Nevertheless, these agents may also exhibit larger toxicity once off-target effects arise. This "double-edged swords" property often leads drug researchers to avoid attaching them. In recent years, some problems such as drug resistance are difficult to be solved with reversible inhibitors leading researchers to pay more attention on the covalent inhibitors. In this review, we shall make a short summary to the recent research progress of covalent inhibitors and the interaction modes between covalent inhibitors and their target protein residues.
Amino Acids ; chemistry ; Antineoplastic Agents ; chemical synthesis ; chemistry ; therapeutic use ; Antiviral Agents ; chemical synthesis ; chemistry ; therapeutic use ; Drug Discovery ; Drug Resistance ; Enzyme Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Hepatitis C ; drug therapy ; Humans ; Molecular Structure ; Neoplasms ; drug therapy ; Protein Binding ; Protein Kinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; Serine Proteinase Inhibitors ; chemical synthesis ; chemistry ; therapeutic use

Objective:To explore the correlation between the characteristics of contrast-enhanced sonography of intraoperative glioblastoma multiform (GBM) and molecular markers of isocitrate dehydrogenase-1(IDH1).Methods:A retrospective analysis were performed in 30 patients who underwent neurosurgery and pathologically confirmed to be GBM at Beijing Tiantan Hospital from May 2018 to April 2019. All neurosurgical glioblastoma patients after craniotomy underwent conventional ultrasound and contrast-enhanced ultrasound(CEUS) guided navigation. The characteristics of the ultrasound imaging (whether the tumor involves the structure of the corpus callosum, the clarity of the tumor boundary after enhanced ultrasound and whether the tumor has necrotic areas with enhanced ultrasound images) were analyzed. The ratio between tumor necrosis area and whole tumor area (N/W) was measured, and the correlation with IDH1 gene expression was analyzed.Results:There were statistical differences in clarity of tumor boundary after CEUS and tumor necrosis after CEUS between positive IDH1 and negative IDH1 groups(all P<0.05). The positive expression of IDH1 was negatively correlated with the N/W area of the contrast-enhanced ultrasound mode( r=-0.756, P<0.05), suggesting that the expression level of IDH1 gene was negatively correlated with the area of tumor necrosis. Conclusions:Ultrasound contrast agent examination can more accurately distinguish the active proliferation area, hemorrhagic necrosis area and peripheral edema area of glioblastoma. Accurately identifying the extent of tumor necrosis area through ultrasound contrast agent examination can predict expression of IDH1.

Objective:To prepare superparamagnetic iron oxide(SPIO) nanoparticles and to observe its acute toxicity on mice,so as to pave a way for further study on its long-term toxicity and on its role as a carrier in magnetic resonance gene imaging.Methods: The SPIO nanoparticle was obtained by means of co-precipitation,and its physical and chemical parameters were determined by transmission electron microscope,atomic force microscope,and 1.5 T super conduct MR,etc.According to the administration pathway and doses of SPIO,90 mice were divided into oral administration(with a total dose of 2 104.8 mg/kg and a volume of 40 ml/kg,n=30),intravenous injection(a total dose of 438.5 mg/kg and a volume of 25 ml/kg,n=30) and intraperitoneal injection(with a total dose 1 578.6 mg/kg and a volume of 30 ml/kg,n=30) groups.Another 10 mice in each group receiving the same dose of normal saline via the same pathway served as the controls(n=10).The general condition,the major serologic parameters,and the pathological changes of major organs were observed 14 d after administration in each group.Results: We have successfully prepared SPIO,and its core component was Fe3O4 crystal,with a size of 20-35 nm,a T2 relaxivity of 0.155?106 mol-1?sec-1,a specific saturated magnetization of 68.395 68 emu/g,and a retentivity of 21.463 74 Gs.There was no death of mice during the observation.There was no significant difference in serological parameters between mice of different groups and between each experiment group and their corresponding control group.No edema,degeneration and necrosis were seen in the liver,spleen,kidney,heart,and lungs by H-E staining and marrow by Wright staining;only a few blue particles were observed in the liver and spleen in the administration groups by Prussian blue staining,none observed in the control groups.Conclusion: SPIO prepared in the present study meets the requirement of MR imaging,with no acute toxicity to mice,and warrants further study for future MR gene imaging.

Background Posterior capsular opacification (PCO) following the extracapsular extract of cataract is associated with the proliferation and migration of residual lens epithelial cells (LECs).Study showed that the incidence of PCO is higher in diabetic patients than those of non-diabetes.So if insulin-like growth factor-1 (IGF-1) participates in the pathogenesis of PCO deserve research.Objective This study was to explore the active mechanism of IGF-1/IGF-1 receptor (IGF-1 R) system in the migration of LECs and offer theoretical basis for clinical prevention and treatment of PCO.Methods Human lens epithelial cell lines (HLEC-B3) were cultured and passaged in DMEM.The cells were identified using fluorescence immunocytometry.IGF-1 with the concentrations of 0,30,90 μg/L were added into the medium separately for 48 hours.The numbers of migrated cells were calculated by Transwell test.The cells were cultured in DMEM containing 0,1.5,30,60,90 μg/L IGF-1,and the expressions of IGF-1 Rα and IGF-1Rβ in the cells were assayed and compared by Western bolt.Results The cultured showed the positive response for α-crystallin anibody with red fluorescence in the cellular membrane.Twelve hours after Transwell incubation,the number of migrated cells (Median) was 0(0,1),10(10,11) and 29(27,31) in the 0 μg/L IGF-1 group,30 μg/L IGF-1 group and 90 μg/L IGF-1 group,respectively,showing a significant difference among the 3 groups (Z=12.610,P=0.002).The number of migrated cells in the 30 μg/L IGF-1 group and 90 μg/L IGF-1 group was significantly more than that of the 0 μg/L IGF-1 group (both at P =0.008),and the number of migrated cells in the 90 μg/L IGF-1 group was significantly more than that of the 30 μg/L IGF-1group (P =0.009).Western blot assay showed that the expressions of IGF-1Rα and IGF-1Rβ in the cells were significantly different among the 0,1.5,30,60,90 μg/L IGF-1 groups (F=63.700,130.530,both P =0.000).The expressions of IGF-1 Rα and IGF-1Rβ were gradually elevated as increase of IGF-1 doses when then concentration of IGF-1 was ＞ 30 μg/L,with significant differences among the different concentrations groups (all at P＜0.05).Conclusions IGF-1 can upregulate the expressions of IGF-1R in HLEC-B3 cells in vitro in a dose-dependent manner.Also,IGF-1 enhances the migration ability of HLEC-B3 cells.These results suggest that activation of IGF-1/IGF-1R system may be associated with the pathogenesis of PCO.

Objective To investigate the evidence of cortical reorganization in stroke hemiplegia treated with constraint-induced movement therapy(CIMT)by fMRI.Methods Five patients with chronic stroke were evaluated with the Action Research Arm Test(ARAT).The functional MRI(fMRI)was performed on a 3.0-T MRI with echo-planar imaging.The subjects were required to finish the finger-tapping task and undergo fMRI before and after CIMT.A block design was used for the inspection.Results After CIMT,the function of upper limb(sick side)of patients improved significantly assessed by ARAT(P<0.001),and cortical reorganization was found on fMRI.Conclusion CIMT can improve motor function of upper limb of chronic stroke patients with hemiplegia and induce cortical reorganization as measured by fMRI.

Deflazacort (DFZ, a prodrug) is well absorbed and rapidly metabolized into the active metabolite 21-hydroxydeflazacort (21-OH DFZ) after oral administration. The aim of this study is to evaluate the pharmacokinetic properties of 21-OH DFZ in healthy Chinese volunteers after a single and multiple oral administration of DFZ tablets under fed condition. Twelve volunteers (six males and six females) were administered a single dose of 6 mg or 12 mg or 24 mg of DFZ in three different periods separately, according to the 3 x 3 Latin square design. Between each administration period there was a washout period of one week. The multiple-dose study of 12 mg dose DFZ per day for 7 consecutive days was started after a 1 w washout period when the single-dose study completed. The pharmacokinetic parameters of 21-OH DFZ after the single oral administration of 6 mg, 12 mg and 24 mg DFZ tablets were as follows: (37.7 +/- 11.6), (61.5 +/- 17.7) and (123 +/- 23) ng x mL(-1) for C(max); (1.90 +/- 0.32), (1.96 +/- 0.27) and (2.13 +/- 0.34) h for t1/2; (96.6 +/- 25.9), (190 +/- 44) and (422 +/- 107) ng x h x mL(-1) for AUC(0-14 h), respectively. After the multiple dose administration, the mean plasma concentration at steady-state C(av) was (7.00 +/- 1.66) ng x mL(-1) and the degree of plasma concentration fluctuation DF was 7.7 +/- 1.2. The results showed that the pharmacokinetic characteristics of 21-OH DFZ in healthy Chinese volunteers were linear over the dose range of 6 to 24 mg. No significant gender differences were found in the pharmacokinetics of 21-OH DFZ in healthy Chinese volunteers. After the multiple dose administration of 12 mg DFZ for 7 d, no accumulation of 21-OH DFZ in healthy Chinese volunteers was observed.
Administration, Oral ; Area Under Curve ; Asian Continental Ancestry Group ; Female ; Healthy Volunteers ; Humans ; Male ; Pregnenediones ; pharmacokinetics ; Tablets

Objective To investigate the efficacy of combined monitoring of motor evoked potentials with transcranial electrical stimulation (TES-MEP),somatosensory evoked potentials (SEP) and spontaneous electromyo-graphy (s-EMG) in tuberculosis surgery involving the thoracic,lumbar and sacral vertebrae.Methods Twenty-seven patients with tuberculosis of the thoracic vertebrae (T2-L2) received intra-operative SEP and TES-MEP monito-ring.Combined SEP,TES-MEP and spontaneous EMG monitoring were employed in 11 patients with tuberculosis of the lumbar or/and sacral vertebrae (L3-S1).SEP and TES-MEP were used to precisely observe the status of the sen-sory and motor pathways; s-EMG responses were used to more accurately localize nerve root irritation.ResuIts (1) SEP monitoring was successful in all of the operations.TES-MEPs were successfully monitored in 35 of them (92.1％).Combined motor and sensory monitoring was successfully achieved in 35 cases (92.1％).Abnormal SEPs were observed in 3 cases (7.9％),while abnormal MEPs were observed in 11 cases (28.9％).Abnormality in both the SEP and TES-MEP occurred in 2 cases (5.3％).There were 9 cases (23.7％) where the SEPs were nor-mal and the TES-MEPs were abnormal.In only 1 case (2.6％) was the SEP normal and the MEP abnormal.The false negative rate was 0％ with combined SEP and TES-MEP monitoring,while the false positive rate was 5.3％.There were 2 cases complicated by post-operative neurological deficits.(2) Spontaneous EMG monitoring can accu-rately determine the functioning of lumbar nerve roots during lumbar or lumbosacral tuberculosis surgery.Among 5 cases where EMG responses were observed,4 cases occurred during the spinal canal and nerve root decompression,1 case occurred in the orthopedic reset phase.Conclusions (1) During tuberculosis surgery involving thoracic,lumbar or sacral vertebrae,combined monitoring of SEPs and TES-MEPs can reflect the physiological and pathological condition of the spinal cord after ruling out interfering factors.This can improve monitoring and help assure the safety of lumbar surgery.(2) Intra-operative s-EMG monitoring can accurately reveal nerve root function in real time,help-ing to avert nerve root injury in lumbar and lumbosacral tuberculosis surgery.

Alcohol-Related Disorders ; metabolism ; Animals ; Benzofurans ; pharmacology ; Glutamic Acid ; metabolism ; Hippocampus ; drug effects ; metabolism ; Male ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; metabolism