Multimodal study on cerebral functional imaging under sleep deprivation / 中华核医学与分子影像杂志

Objective:To reveal the specific region location of brain function injury after sleep deprivation by exploring cerebral glucose metabolism and blood perfusion changes and the correlation between them in healthy volunteers of sleep deprivation.Methods:From January 2019 to December 2019, a total of 17 healthy volunteers (8 males, 9 females; age (22.5±1.7) years) from People′s Hospital of Zhengzhou University were enrolled prospectively. All patients accepted MRI three-dimensional (3D) arterial spin labeling (ASL) and 18F-FDG PET/CT scanning at 2 h after normal sleep and after sleep deprivation of 24 h. Statistical parametric mapping (SPM) software was used for image processing, and brain metabolism and perfusion differences activation graphs before and after sleep deprivation were obtained respectively. Then the common activated brain regions were obtained as ROI. The cerebral blood flow (CBF) and the SUV ratio (SUVR; the cerebellum was the reference area) were calculated. Pearson correlation analysis and paired t test were used for data analysis. Results:The cerebral metabolism and perfusion of the subjects after sleep deprivation were reduced, and the abnormal brain areas were similar. Brain areas with reduced metabolism were more than those with reduced perfusion. The brain areas with reduced metabolism and perfusion after sleep deprivation were commonly in the frontal lobe, temporal lobe, parietal lobe, etc. The CBF and SUVR value of left dorsolateral frontal gyrus after sleep deprivation were correlated ( r=0.58, P=0.014). The mean CBF value ((46.32±7.39) ml·100 g -1·min -1) and SUVR value (1.46±0.04) of whole brain after sleep deprivation were lower than those before sleep deprivation ((54.91±6.51) ml·100 g -1·min -1, 1.53±0.06; t values: -2.67, -3.72, P values: 0.012, 0.001). Conclusions:The specific region′s location of brain function injury after sleep deprivation is preliminarily revealed. 18F-FDG PET/CT was more sensitive than 3D-ASL for brain function research of sleep deprivation and left dorsolateral frontal gyrus may be a key responsible functional region in subjects of sleep deprivation.

Survey on the status quo and training needs of general practitioner job-transfer training program in Hebei Province / 中华全科医师杂志

Objective:To investigate the status quo and training needs of general practitioner (GP) job-transfer training program in Hebei Province.Methods:An online survey with self-designed questionnaire was conducted on May 2019 through WeChat among 165 trainees in the General Practice Training Center of Hebei Province. A total of 165 questionnaires were distributed and 149 were valid with an effective rate of 90.3%. The contents of the questionnaire included the basic information of the trainees, the evaluation of the current training, and the needs of the GPs′ job-transfer training.Results:Among 149 participants, there were 131 (87.9%)from the secondary hospitals or above, 146(98.0%)with bachelor′s degree or above, and 128 (85.9%)with intermediate or above professional titles. The survey showed that 72.0%(67/93)thought the main reasons affecting participation in the training were busy work load and insufficient personnel, the main problems of training were too short training duration(45.2%, 42/93), the not focused training contents(38.7%, 36/93) and lack of practice(37.6%, 35/93). In the 149 trainees, 136(91.3%) thought that the most important contents should be standardized diagnosis and treatment of common diseases; 104(69.8%), 118(79.2%), 115(77.2%) and 98(65.8%) considered that the knowledge of prevention and health-protection, first aid, latest progress and chronic disease management were needed for training; 110(73.8%)and 80(53.7%)thought the mastery of clinical practice and basic theory were needed. And 57.7% (86/149)of the trainees believed that research training was needed, and there was significant difference in the demand for research training among participants from different work units and with different professional titles (χ 2=15.371,10.625,all P<0.05). The accepted training methods were case study(53.7%, 81/149) and practical work(37.6%, 56/149). For training duration, 43.6% (65/149) thought it should not exceed 6 months and 56.4% (84/149) preferred more than 1 year; there was a significant difference in demanded training duration among trainees from different work units, with different education background and professional titles (χ 2=16.225,6.243,25.966, all P<0.05). Conclusion:We need a multi-channel and multi-level training model to establish a better job-transfer training system for general practitioners, in order to meet different training needs and to improve the effectiveness of the training.

Correlation between cerebral striatal dopamine D 2 receptors non-displaceable binding potential and functional connectivity in patients with major depressive disorder / 中华行为医学与脑科学杂志

Objective:To study the correlation between changes of cerebral striatal dopamine D 2 receptors non-displaceable binding potential (BP ND), functional connectivity (FC) and clinical symptoms in patients with first-episode major depressive disorder (MDD), by 11C-Raclopride PET/CT and resting state fMRI (rs-fMRI). Methods:Thirty-eight first-episode depression patients (MDD group) and forty healthy volunteers (control group) matched with age, gender and years of education were selected. All subjects were scored with Hamilton depression scale (24 versions) before enrollment.All the subjects underwent cerebral 11C-Raclopride PET/CT and rs-fMRI in resting state. MIAKAT and DPARSF were used to analyze BP ND of cerebral striatal dopamine D 2 receptors and FC of striatum and the whole brain in subjects, respectively. Changes of striatal dopamine D 2 receptors BP ND and striatum and the whole brain FC of MDD were analyzed, and correlations among BP ND, FC and Hamilton depression rating scale were calculated by Rest 1.8 and SPSS 20.0. Results:Compared with the control group, BP ND of bilateral caudate nucleus and putamen dopamine D 2 receptors in the MDD group were decreased(left caudate nucleus: 1.16±0.37 vs 1.48±0.39, right caudate nucleus: 1.21±0.31 vs 1.62±0.48, left putamen: 1.73±0.47 vs 2.21±0.66, right putamen: 1.79±0.46 vs 2.17±0.65, t=3.66, -4.42, -3.68, -2.91, all P<0.001). Besides, FC of left caudate nucleus and left medial prefrontal lobes(4.38±1.31, 2.35±0.48), left caudate nucleus and left middle frontal gyrus(3.36±1.11, 1.64±0.56), left caudate nucleus and left superior frontal gyrus(3.14±0.78, 1.64±0.53), left putamen and left medial prefrontal lobes(4.10±1.42, 2.42±0.64, t=6.82, P<0.05), right caudate nucleus and right medial prefrontal lobes (4.32±1.30, 2.33±0.63, t=8.51, P<0.05), right putamen and right medial prefrontal lobes(3.77±1.25, 2.31±0.63, t=6.49, P<0.05)in the MDD group were increased.FC of left putamen and left anterior cingulate(1.60±0.55, 2.68±0.84, t=-6.76, P<0.05), right caudate nucleus and right amygdala (1.67±0.57, 3.46±0.64, t=-8.27, P<0.05) in the MDD group were decreased. Furthermore, there were significant negative correlations between D 2 receptors BP ND of bilateral striatum and FC of the same lateral striatum and medial prefrontal lobes ( r=-0.66, -0.50, -0.67, -0.47, all P<0.05). In MDD group, FC in left caudate nucleus and left medial prefrontal lobe were positively correlated with total score of Hamilton depression scale and anxiety somatization( r=0.55, 0.68, P<0.001). FC in left putamen and left medial prefrontal cortex were positively correlated with cognitive impairment and retardation ( r=0.37, 0.40, P=0.021, 0.001). FC of right caudate nucleus and right medial prefrontal lobe were positively correlated with Hamilton depression scale total score and anxiety somatization ( r=0.52, 0.67, all P<0.001). FC in right putamen and right medial prefrontal cortex was positively correlated with cognitive impairment ( r=0.50, P=0.002). Conclusion:The abnormal BP ND of cerebral striatal dopamine D 2 receptor of patients with first-episode depression is related to the abnormal activity of dopamine reward circuit related neurons in patients with MDD, which was related to clinical symptoms of depression. It may be involved in the pathogenesis of depression.

Changes of dopamine D2 receptor in patients with insomnia and its clinical significance / 中华核医学与分子影像杂志

Objective To explore the changes of dopamine D2 receptor in dopamine pathway in in-somnia patients and discuss its clinical significance. Methods From January 2016 to December 2016, 15 patients with insomnia (1 male, 14 females, age:(44.3±8.6) years) and 15 gender-/age-matched-healthy volunteers (control group;3 males, 12 females, age:(40.5±9.0) years) were included to undergo resting brain 11C-Raclopride PET/CT imaging. The D2 receptor binding potential (BPND) of the dopamine pathway was calculated by molecular imaging and kinetic analysis toolbox ( MIAKAT) software. The BP ND , Hamilton depression scale ( HAMD) , transient and graphics memory scale results were compared with two-sample t test and Mann-Whitney u test between the two groups. Pearson correlation analysis was used to evaluate the correlation between BPND(nucleus accumbens, caudate nucleus, putamen) and Pittsburgh sleep quality in-dex ( PSQI) , HAMD, course of disease, transient memory and graphical memory scale scores in the patient group. Results The BP ND in bilateral putamen, nucleus accumbens and left caudate nucleus of patients was lower than that of controls( left putamen:z=-2.717, right putamen:z=-2.883, both P<0.01;left nu-cleus accumbens:t=-2.269, right nucleus accumbens:t=-2.410, both P<0.05;left caudate nucleus:t=-2.632,P<0. 05), but the BPND level of right caudate nucleus was not significantly different(z=-0.850, P>0.05) . The scores of HAMD in the patient group were higher than those in control group ( t=10. 273, P<0. 01), while the scores of instantaneous memory (t=-4.888, P<0.01) and graphical memory scale (t=-2.624, P<0.05) were lower. There were significant negative correlations between the BP ND of bilateral nucleus ac-cumbens, caudate nucleus and putamen and the course of insomnia in the patient group ( r range:-0.761 to-0.682, all P<0.01) . Conclusion Patients with insomnia have abnormal neurotransmitter system of dopa-mine D2 and it may play a role in the pathogenesis of insomnia.

Effect of Xiaoqinglong Decoction on the expression of TSLP in airway epithelial cells of asthmatic model mice / 重庆医学

Objective To study the effect of Xiaoqinglong Decoction on the expression of TSLP in airway epithelial cells of asthmatic model mice.Methods Thirty healthy female BALB/C mice were divided into the blank control group,asthma model group and Xiaoqinglong Decoction group,10 cases in each group.The each group adopted corresponding intervention measures. Then the bronchial and lung tissues were taken.The expression level of bronchial TSLP was detected by immunofluorescence,and the expression level of TSLP mRNA and protein in lung tissue was detected by qRT-PCR and Western Blot.Results The mouse bronchial epithelial cell membrane TSLP staining was strongly positive in the asthma model group,which was weakly positive in the Xiaoqinglong Decoction group and negative in the blank control group.Compared with the asthma model group,mice lung tissue TSLP mRNA expression level in the Xiaoqinglong Decoction group and blank control group was decreased(P<0.05),the Xiaoqin-glong Decoction group was slightly higher than the blank control group,but the inter-group difference was not statistically signifi-cant(P>0.05).The expression level of lung tissue TSLP protein in the Xiaoqinglong Decoction group and blank control group was lower than that in the asthma model group(P<0.05),the Xiaoqinglong Decoction group was slightly higher than the blank control group,but the inter-group difference was not statistically significant(P>0.05).Conclusion Xiaoqinglong decoction has obvious inhibiting effect on the expression of TSLP in airway epithelial cells of asthmatic model mice.

Multi-modal imaging study of striatal dopamine D2receptors binding potential and brain regional homogeneity in patients with first-episode major depressive disorder / 中华放射学杂志

Objective To explore the correlation between changes of striatal dopamine D2receptors non-displaceable binding potential (BPND) in 11C-Raclopride PET-CT and brain regional homogeneity (ReHo) derived from resting state functional MRI (fMRI) in patients with first-episode major depressive disorder (MDD) . Methods Patients with first-episode MDD and age and sex matched healthy volunteers accepted brain 11C-Raclopride PET-CT and resting state fMRI. MIAKAT based on MATLAB and Rest 1.8 were used to calculate BPNDof brain dopamine D2receptors and brain ReHo, respectively. Changes of striatal dopamine D2receptors BPNDand brain ReHo values were analyzed by paired-sample t test and two independent sample t-test, and Pearson correlation analysis was used to analyze the correlation between BPNDand ReHo. Results Twenty patients with first-episode MDD were enrolled as MDD group, and 20 healthy volunteers as the control group. The two groups were all right-handed, and there were no statistical differences for age (t =1.33,P=0.19)and gender(χ2=0.10,P=0.75). Compared with the control group, the ReHo in MDD patients increased in the bilateral striatum (caudate nucleus and putamen), bilateral medial prefrontal lobes, and right thalamic (27 to 56 voxels, P＜0.05) and decreased in the left middle frontal gyrus, the left anterior cingulate, the left hippocampal and the right amygdala (21 to 35 voxels, P＜0.05). In addition, compared with the control group, BPNDof bilateral caudate nucleus and putamen dopamine D2receptors in the MDD group were decreased (t=－4.41 to －3.13, P＜0.05). Furthermore, there was a negative correlation between D2 receptors BPNDand ReHo of bilateral caudate nucleus and putamen (r=－0.81 to－0.62, P＜0.05). And there was a negative correlation between ReHo of the bilateral medial prefrontal lobes and BPNDof the same lateral caudate nucleus and putamen D2receptors in the MDD group (r=－0.86 to－0.52, P＜0.05). Besides, ReHo of the left middle frontal gyrus, right thalamic, left anterior cingulate, left hippocampal and right amygdala had no correlation with the D2receptors BPNDof the striatum in the MDD group (－0.27 to 0.39, P＞0.05). Conclusion There were abnormal levels of dopamine neurotransmitter in the cerebral striatum regions and abnormal brain activities in the brain region associated with dopamine reward circuit in the first-episode MDD patients, and there was a correlation between the two abnormalities.

Establishment and application of a TNF-α humanized mouse model of Listeria monocytogenes infection / 中国比较医学杂志

Objective TNF-α monoclonal antibody drugs are widely used to treat conditions such as rheumatic arthritis and ankylosing spondylitis. On the other hand, it is also a wide concern that the application of these drugs may increase the susceptibility of patients to infections such as tuberculosis and listeriosis. The aim of this study was to establish a mouse model of Listeria monocytogenes infection and to evaluate the effect of TNF-α monoclonal antibody on the host susceptibility to this infection. Methods Six SPF 14-week old female C57BL/6 mice and 12 SPF 14-week old female TNF-α humanized mice were injected with saline or adalimumab intravenously, and challenged with intraperitoneal injection of 104 CFU Listeria monocytogenes 24 h later. After one day or 4 days, the mice were sacrificed to examine the pathological lesions and the bacterial load in the spleen and liver. Results Four days after infection, the area of microabscess in the liver tissues was significantly increased in the adalimumab-treated group. The bacterial load in the spleen and liver tissues of the adalimumab-treated group was significantly higher than that of the C57BL/6 mouse control group and TNF-α humanized mouse control group (P ＜ 0. 05). However, the distribution of macrophages in the liver tissues and B cells in the spleen tissues were similar among groups. Conclusions TNF-α plays an important role in the host immune responses to Listeria monocytogenes infection. After the intervention with TNF-α monoclonal antibody, the progress of host disease is significantly exacerbated.

Blockage of macrophage-mediated PD1/PD-L1 pathways inhibits tuberculosis relapse in mice / 中国比较医学杂志

Objective To study the immune intervention effect and mechanism of blockage of macrophage-mediated PD1 /PD-L1 pathways with functional PD-L1(programmed cell death ligand-1,PD-L1)monoclonal antibody upon tuberculosis(TB)relapse in mice. Methods Female C57BL/6 mice were infected by tail vein injection of 106CFU M. tuberculosis H37Rv to obtain active TB infection. Two weeks postinfection, the mice in different groups were administered isoniazid(10 mg/kg)(group ISO)and isoniazid combined with PD-L1 monoclonal antibody(50 μg/each)(group ISO+PD-L1)respectively,continued for four weeks to obtain latent infection. The subsequent relapse was monitored. Among the treatment groups,the TB relapse was induced by TNF-α antibody(50 ug/each)for four weeks from the beginning of latent stage. At each scheduled time point, bacterial loads and pathological changes in the lung, spleen and liver were quantitatively analyzed,thereby,the in vivo intervention effect of PD-L1 monoclonal antibody on tuberculosis recurrence in mice was revealed. The in vitro experiment was further explored whether knock-down the expression of PD-L1 on the infected macrophages could accerlate the macrophage apoptosis. Results The bacterial burden reached 3-4 Lg(CFU/mL),and granuloma lesions were extensive in the lung, spleen and liver in the all infected groups, which appeared as active TB stage at 2nd week postinfection. After treated,the bacterial burden of the lung,spleen and liver was decreased, and the pathological lesions alleviated in the group ISO and group ISO+PD-L1, compared with the model control group, showing significant differences, but there was no significant difference between the two treatment groups. However, compared with the group ISO,the group ISO+PD-L1 had a significantly lower bacterial load and milder pathological lesions during the relapse period. Futhermore, knock-down the expression of PD-L1 on macrophages with anti-PD-L1 or PD-L1-siRNA promoted apoptosis in macrophages. Conclusions Blockade of the PD1/PD-L1 pathway by PD-L1 functional antibody can inhibit TB relapse in mice,and knock-down the expression of PD-L1 on macrophages or PD1/PD-L1 pathway with functional antibody can promote apoptosis in macrophages,which together indicate that PD-L1 blockage can effectively promote isoniazid treatment of TB and remarkably inhibit the recurrence of TB in mice.

Lentiviral vector-mediated somatostatin overexpression suppresses seizures induced in hippocampal kindled rats / 中华行为医学与脑科学杂志

Objective To explore the effect of lentiviral vector-mediated somatostatin (SST) expression on seizures induced by hippocampal kindling in rats.Methods Adult Sprague-Dawley rats were randomly divided into the sham group (Sham),epilepsy group (EP),Lenti-pSyn-EGFP (LV-EGFP) group and Lenti-pSyn-SST-2A-EGFP (LV-SST) group.The rats in LV-EGFP group were subsequently electrically hippocampal kindled and LV-EGFP (5 μl) was injected into dentate gyrus (DG).The rats in LV-SST group were kindled and LV-SST (5 μl) was injected into the dentate gyrus (DG),medial entorhinal cortex (MEC) or amygdala (Amy).Seizure severity was evaluated and immunohistochemical staining was employed to detect the expression of SST,neuron specific nuclear protein (NeuN) and microtubule associated protein 2 (MAP2).Results The current values to the first stage V seizure of LV-SST (DG) group,LV-SST (MEC) group or LV-SST (Amy) group ((143.8±3.8)μA,(142.5±4.1)μA,(142.5±5.3) μA,respectively) were significantly increased compared with that of epilepsy (EP) group ((136.3±5.3)μA),and V stage current values of LV-SST groups in each stimulation day were higher than that of EP group except the fifth stimulation day (P<0.05).After kindling,SST expression and NeuN-positive neurons of EP group and LV-SST groups were less than that of Sham group in CA1,CA3 and DG.SST and NeuN neurons loss in LV-SST groups were less than that of EP group (P<0.05) and MAP2 immunohistochemistry stainings in LV-SST groups were higher than that in EP group.Conclusion Lentiviral vector-mediated somatostatin expression suppresses seizures and can rescue the neuronal damage of seizure induced by kindling in hippocampus,which may provide a new method of gene therapy for temporal lobe epilepsy.

Non-displaceable binding potential changes of striatal dopamine D2 receptors in patients with first-episode major depressive disorder and the correlation with clinical features / 中华核医学与分子影像杂志

Objective To observe non-displaceable binding potential (BPND) changes of striatal dopamine D2 receptors(SDDR) in patients with first-episode major depressive disorder (MDD) using 11C-Raclopride PET/CT,and to analyze the relationship between BPND and Hamilton rating scale for depression (HAM-D).Methods From December 2014 to December 2015,patients with first-episode MDD and age/gender-matched healthy controls underwent brain MRI and 11C-Raclopride PET/CT in this prospective study.BPND of bilateral SDDR was calculated by molecular imaging and kinetic analysis toolbox (MIAKAT).BPND changes of bilateral SDDR and their relationship with HAM-D score were analyzed.Paired t test,two-sample t test and Pearson correlation analysis were used.Results A total of 20 MDD patients (8 males,12 females,average age: (32.80±9.76) years) and 20 healthy controls (9 males,11 females,average age:(29.25±6.93) years) were enrolled in this study.The 11C-Raclopride uptake in brain tissue of the MDD group and control group were mainly distributed in bilateral striatum,and very few 11C-Raclopride was distributed in bilateral cerebral cortex and cerebellum.In MDD group,the BPND level of bilateral SDDR had no statistical differences(t values: 0.69,0.35,both P>0.05),and similar results were found in the control group(t values: 0.28,0.24,both P>0.05).Compared with the control group,however,the MDD group had lower BPND level of bilateral SDDR(t values: 3.13-4.41,all P<0.05).The BPND of bilateral caudate nucleus and/or putamen D2 receptors was correlated with HAM-D total score,anxiety/somatization factor score,cognitive impairment factor score,retardation factor score and sleep disturbance factor score(r values: from-0.688 to-0.453,all P<0.05).Conclusions The binding potential of SDDR in patients with first-episode MDD is declined,and the BPND level of SDDR is correlated with symptoms of depression.The abnormality of SDDR may be an important molecular mechanism of the abnormality of midbrain-striatal dopamine reward circuits in MDD patients.

Effects of lentiviral delivery in different brain regions on transfection of rat dentate gyrus neurons / 中华行为医学与脑科学杂志

Objective To explore the effect of lentiviral delivery green fluorescent protein in different brain regions on the transfection of dentate gyrus neurons.Methods Lenti-pSyn-EGFP was stereotaxic injected into dentate gyrus (DG),Cornu Ammonis 1 (CAl) of hippocampus and medial entorhinal cortex (EC) of rats.All animals were perfused with 4％ paraformaldehyde.Their brains were cut into 30 μm sections which were performed with Nissl fluorescent staining.Results The resuts showed that the GFP positive cells in DG area of DG,CA1,EC,DG-EC groups were (18.0± 1.0),(17.0±0.6),(17.3±0.6),(18.3±0.6) respectively,and there was no statistical difference among each group(P＞0.05).Conclusion Lentivirus delivery in EC and CA1 both can transfect DG neurons.This is a useful method to transfect dentate gyrus neurons instead of injecting lentivirus into DG directly and avoid the lesion of DG.

Association of NEDD4 gene polymorphisms with schizophrenia and its clinical characteristics in Chinese Han population / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To assess the association of neural precursor cell expressed developmentally down-regulated 4 (NEDD4) with schizophrenia.</p><p><b>METHODS</b>Five single nucleotide polymorphisms (SNPs) of the NEDD4 gene were genotyped by TaqMan SNP genotyping assay in an independent sample of 464 individuals with schizophrenia and 487 healthy controls from eastern Han Chinese population. Clinical data were collected with a general information questionnaire and Positive and Negative Syndrome Scale (PANSS).</p><p><b>RESULTS</b>Frequencies of rs3088077 (allelic: χ2=18.024, P=0.000; genotypic: χ2=16.634, P=0.000), rs7162435 (allelic: χ2=6.771, P=0.009; genotypic: χ2=7.352, P=0.025) and rs2303579 (allelic: χ2=11.253, P=0.001; genotypic: χ2=12.248, P=0.002) were found to be significant different between the two groups. Moreover, TT of rs7162435 was significantly correlated with scores of factors of excitement and hostility (14.53±3.925, F=3.551, P=0.029).</p><p><b>CONCLUSION</b>rs3088077, rs7162435 and rs2303579 of the NEDD4 gene may be associated with schizophrenia. Moreover, the TT genotype of rs7162435 may increase the severity of excitement and hostility. Our results may provide a clue for delineating the connection between the glutamate hypothesis of schizophrenia and ubiquitination.</p>

Influences of Polyethylene Glycol6000 on the Solubility of m-Nisoldipine / 医药导报

Objective To investigate the influences of polyethylene glycol on the solubility and in vitro dissolution of m-nisoldipine,which could provide guidance for chosing formulations of m-nisoldipine. Methods Solid dispersions of m-nisoldipine were prepared by solvent-melting method with polyethylene glycol6000 matrix. DSC and XRD spectroscopy were applied to identify the solid dispersions. The solubility and in vitro dissolution were detected by UV spectroscopy. Results The DSC and XRD map were different from the crude drug and their physical mixtures. The dissolution rates(13,15,17) were faster(35. 31%,38. 71%,41. 48%) than that of the crude drug(26. 80%),and the dissolution rates of the solid dispersions in the same ratio were higher than the physical mixtures. Conclusion DSC analysis indicated that eutectic compounds were produced by the m-nisoldipine and polyethylene glycol,in which polyethylene glycol6000 acts as a carrier. The solubility and in vitro dissolution of m-nisoldipine can be increased.