Chronic modafinil therapy ameliorates depressive-like behavior, spatial memory and hippocampal plasticity impairments, and sleep-wake changes in a surgical mouse model of menopause.

Depression, cognitive deficits, and sleep disturbances are common and often severe in menopausal women. Hormone replacement cannot effectively alleviate these symptoms and sometimes elicits life-threatening adverse reactions. Exploring effective therapies to target psychological problems is urgently needed. In this work, we developed a mouse model of menopause by bilateral ovariectomies (OVXs) and investigated whether menopausal mental symptoms can be ameliorated by psychostimulant modafinil (MOD) as well as explored the underlying mechanisms. At ~3 weeks after OVXs, mice got daily intraperitoneal administrations of MOD at the beginning of the active phase. Several behavioral tests and electroencephalogram (EEG) recordings were conducted. Electrophysiological and immunohistochemical experiments were carried out to evaluate the synaptic plasticity and neurogenesis, respectively. We found that chronic MOD administration in OVX mice significantly decreased immobility time. The spatial memory performance of OVX mice improved significantly in response to MOD administration in the Morris water-maze test. The OVX mice were characterized by an attenuation of hippocampal synaptic transmission and synaptic long-term potentiation and had fewer 5-ethynyl-2'-deoxyuridine-labeled cells in the dentate gyrus, which were restored after MOD administration. Antagonists of dopamine D1 and D2 receptors and GABAA receptor agonists were involved in MOD-exerted anti-depressant actions and augments of hippocampal neurogenesis in OVX mice. Moreover, night-dosed MOD therapy significantly promoted the night-time delta-band EEG power during wakefulness and the day-time rapid eye movement sleep amount, which were significantly reduced by OVXs. Collectively, these findings suggest that MOD is a promising therapeutic candidate for menopausal women.

The Rostromedial Tegmental Nucleus: Anatomical Studies and Roles in Sleep and Substance Addictions in Rats and Mice.

The rostromedial tegmental nucleus (RMTg), a brake of the dopamine system, is specifically activated by aversive stimuli, such as foot shock. It is principally composed of gamma-aminobutyric acid neurons. However, there is no exact location of the RMTg on the brain stereotaxic atlas. The RMTg can be defined by c-Fos staining elicited by psychostimulants, the position of retrograde-labeled neurons stained by injections into the ventral tegmental area (VTA), the terminal field formed by axons from the lateral habenula, and some molecular markers identified as specifically expressed in the RMTg such as FoxP1. The RMTg receives a broad range of inputs and produces diverse outputs, which indicates that the RMTg has multiple functions. First, the RMTg plays an essential role for non-rapid eye movement sleep. Additionally, the RMTg serves a vital role in response to addiction. Opiates increase the firing rates of dopaminergic neurons in the VTA by acting on µ-opioid receptors on RMTg neurons and their terminals inside the VTA. In this review, we summarize the recent research advances on the anatomical location of the RMTg in rats and mice, its projections, and its regulation of sleep-wake behavior and addiction.

Crosstalk network among multiple inflammatory mediators in liver fibrosis.

Liver fibrosis is the common pathological basis of all chronic liver diseases, and is the necessary stage for the progression of chronic liver disease to cirrhosis. As one of pathogenic factors, inflammation plays a predominant role in liver fibrosis via communication and interaction between inflammatory cells, cytokines, and the related signaling pathways. Damaged hepatocytes induce an increase in pro-inflammatory factors, thereby inducing the development of inflammation. In addition, it has been reported that inflammatory response related signaling pathway is the main signal transduction pathway for the development of liver fibrosis. The crosstalk regulatory network leads to hepatic stellate cell activation and proinflammatory cytokine production, which in turn initiate the fibrotic response. Compared with the past, the research on the pathogenesis of liver fibrosis has been greatly developed. However, the liver fibrosis mechanism is complex and many pathways involved need to be further studied. This review mainly focuses on the crosstalk regulatory network among inflammatory cells, cytokines, and the related signaling pathways in the pathogenesis of chronic inflammatory liver diseases. Moreover, we also summarize the recent studies on the mechanisms underlying liver fibrosis and clinical efforts on the targeted therapies against the fibrotic response.

Differential diagnosis of Helicobacter pylori-associated gastritis with the linked-color imaging score.

BACKGROUND: Helicobacter pylori (H. pylori) infection in gastric mucosa is the main risk factor for gastric cancer. The purpose of this study was to assess the value of the linked-color imaging (LCI) score for the identification of H. pylori-associated gastritis. METHODS: A total of 358 patients were enrolled in the study. H. pylori was positive in 127 cases and negative in 231 cases. Redness of fundus glands, granular erosion, purple mucus (+) and mucus lake turbidity were investigated by the LCI mode of endoscopy. Logistic regression was used to screen the observation indexes and their relative partial regression coefficients, which were helpful for the differential diagnosis of H. pylori infection. Then, each observation index was scored according to the partial regression coefficient. RESULTS: Using a total scores of 3.5 as the cut-off value, the sensitivity and specificity were 83.8% and 99.5%, respectively, for the differential diagnosis of H. pylori gastritis. The area under the curve was 95.3%. CONCLUSIONS: The LCI score showed high sensitivity and specificity for the differential diagnosis of H. pylori-associated gastritis and is an effective method for identifying H. pylori infection in gastric mucosa.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

Investigation of TCM Constitutions and Lifestyles of Subjects with Positive Tumor Marker Screening / 中国中医药信息杂志

Objective To explore the differences of TCM constitutions and lifestyles among the subjects with positive tumor marker screening and those with normal tumor marker screening. Methods Totally 245 subjects with positive tumor marker screening from September 2014 to December 2017 in Weihai area were selected as the observation group and 300 subjects with normal tumor marker screening were selected as the control group. Field questionnaire was used to investigate TCM constitutions and lifestyles. Results In the observation group, the ratio of constitution of yin-yang harmony was significantly lower than the control group, with statistical significance (χ2=207.483, P＜0.001). The ratios of constitution of phlegm-dampness, constitution of blood stasis, constitution of qi deficiency and constitution of qi stagnation were significantly higher than the control group, with statistical significance (P＜0.05). There was statistical significance between the 2 groups in irregular rest, heavy drinking, regular smoking, lack of exercise, irregular diet and partial eclipse (P＜0.05). CEA, a positive indicator of tumor markers in the observation group, was commonly found in constitution of phlegm-dampness (40.43％) and constitution of qi deficiency (22.70％); CA199 was commonly found in constitution of qi stagnation (38.71％) and constitution of qi deficiency (24.19％); AFP was commonly found in constitution of blood stasis (38.46％) and constitution of qi deficiency (23.08％); CA125 was commonly found in constitution of blood stasis (33.33％) and constitution of qi stagnation (19.05％); CYFRA21-1 was commonly found in constitution of phlegm-dampness (54.55％) and constitution of qi deficiency (22.73％); PSA was commonly found in constitution of phlegm-dampness (61.52％) and constitution of damp-heat (23.08％). Conclusion Effectively controling the distribution of TCM constitutions of subjects with positive tumor marker screening in Weihai area and understanding the influence of lifestyles on tumor markers can provide guidance for clinical improvement of patients' biased constitutions and reduction of positive indicators of tumor markers.

The differentiatial diagnostic value of 99Tcm-MIBI SPECT combined with localizable CT imaging in oxygen intervention for lung lesions / 中华核医学杂志

Objective To investigate the differentiatial diagnostic value of 99Tcm-methoxyisobutylisonitrile ( MIBI ) SPECT combined with localizable CT in the evaluation of oxygen intervention for suspicious lung lesions,and to establish a cost-effective imaging modality in the detection of malignant lung lesions.Methods From September 2008 to March 2009,47 consecutive patients with suspicious malignant lung lesions underwent 99Tcm-MIBI SPECT/CT prospectively. Patients with suspicious pneumonia were treated with antibiotics for about 4 d before imaging. All patients were cannulized with a nostril tube for oxygen inhalation before 99Tc-MIBI injection. SPECT combined with localizable CT of the chest was performed at 10 min and 2 h after 99Tcm-MIBI injection. The uptake ratios of lesion to contralateral normal lung parenchyma(early uptake ratio:EUR and delayed uptake ratio:DUR) were compared using independent-samples ttest. In addition,the diagnostic efficiency of uptake ratios of lung lesions was analyzed with receiver operating characteristic (ROC) curve. Results Forty-seven patients ( primary lung cancers:32,metastatic tumors of the lung:4,benign lung diseases:11 ) had 51 lung lesions,including 39 malignant and 12 benign lung lesions. The sensitivity,specificity,accuracy,positive predictive value (PPV),and negative predictive value (NPV) were 94.9% (37/39),83.3% ( 10/12),92.2% (47/51),94.9% (37/39) and 83.3% ( 10/12),respectively. The EUR of malignant lesions was 2.95 ± 1.16,whereas of benign lesions was 1.43 ±0.33. The DUR of the malignant lesions was 3.19 ± 1.74,whereas of benign lesions was 1.60 ±0.32. Both EUR and DUR were significantly different between malignant and benign lung lesions,respectively (t= -4.44,-3.12,respectively,both P＜0.01). The ROC curve showed that EUR value ≥1.625 provided the sensitivity of 97.4% (38/39) and specificity of 83.3% (10/12); DUR value ≥ 1.75provided the sensitivity of 94.9% (37/39) and specificity of 83.3% (10/12). Conclusion 99Tcm-MIBI SPECT combined with localizable CT imaging in oxygen intervention has a potential value in differentiating malignant from benign lung lesions.

[Construction of VEGF recombinant plasmid pcDNA/V and its expression in model rats with acute myocardial ischemia].

The cDNA encoding human Vascular Endothelial Growth Factor 165 (VEGF165) was amplified using RT-PCR from human tonsil tissue and cloned into eukaryotic expression vector pcDNA3.1 (+). The recombinant plasmid pcDNA/V was transferred into 293 cells mediated by liposome and the cells stably expressing VEGF were selected under the pressure of G418. ELISA and Western blotting demonstrated that the eukaryotic expression vector pcDNA/V was successfully constructed and its corresponding protein could be expressed efficiently in vitro. Chick Charioallantoic Membrane (CAM) bioassay showed that recombinant protein has biological activity of hVEGF. Model rats with acute myocardial ischemia were used to further study the expression of VEGFin vivo. The model rats were divided randomly into three groups: control group, pcDNA3.1 (+) group and pcDNA/V group. 50microL naked plasmid DNA or saline was intramyocardially injected at three sites into the border zone of infarction. The hearts of rats were excised and fixed histologically, then the infarction sizes were studied by immunohistochemical staining and electron microscope after four weeks. Immunohistochemical staining for VEGF appeared to be negative in control and pcDNA3.1 (+) groups. In pcDNA/V group, myocardial cells in infarction border zone showed positive staining for VEGF in cytoplasm. Ultrastructural anaylsis showed that there were visible hyperplasia of vascular endothilium in pcDNA/V group. The control and pcDNA3.1 (+) groups showed less capillary hyperplasia. In this study, VEGF165 gene was successfully cloned and its protein expressed in vitro and in vivo was of bioactivity, which provides a basis for the further study of biological functions of human VEGF.