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Fatigue refers to the manifestation of disorders in the process of carrying out or maintaining random activities， which can be regarded as an independent disease or as a symptom in a variety of chronic diseases. The high incidence of fatigue has seriously affected people's physical and mental health， and the prevention and treatment of fatigue has become an important problem to be solved urgently. The pathogenesis of fatigue mainly includes energy consumpation， accumulation of metabolites， abnormal secretion of neurotransmitters， decline of mitochondrial function， dysfunction of hypothalamus pituitary adrenal axis， etc. At present， there is no unified understanding about the pathogenesis of fatigue at home and abroad. The gene research of fatigue is the current research frontier. Gene expression profiling provides a new method for the study of the mechanism of fatigue. The combination of gene chip technology and traditional Chinese medicine（TCM） theory is expected to bring a breakthrough in the study of the pathogenesis of fatigue. In the study of fatigue gene chip， messenger RNA（mRNA） and microRNA（miRNA） are the common research objects， but few explorations are focused on the gene expression rule of fatigue by a specific signaling pathway and the effective regulation targets of TCM for treating fatigue. In recent years， the dysfunction of reward and inhibition mechanism in the central nervous system has become a research hotspot. In particular， gamma amino butyric acid （GABA） and dopamine （DA） have attracted much attention as the main substances of inhibition and reward mechanism， respectively. GABA and DA are used as inhibition and reward mechanisms to maintain the balance， and the body will not feel fatigue. Once the balance is broken， the fatigue will be formed. At the same time， DA and GABA receptors can also regulate cyclic adenosine monophosphate signaling pathway（cAMP） to affect fatigue. The research on key genes in GABA/DA balance mechanism and related cAMP signaling pathway by gene chip technology is expected to reveal the pathogenesis of fatigue in depth. The gene chip method is used to detect the changes of key genes in GABA/DA pathway and the related cAMP signaling pathway in the fatigue population and the normal population， so as to further explore the pathogenesis of fatigue. In this paper， the key genes in GABA/DA balance mechanism and cAMP signaling pathway related to fatigue were summarized by using the review method， so as to provide the basis for further study on the pathogenesis of fatigue and effective prevention and treatment from the perspective of genetics.
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Objective To research ketogenic diet(KD) adjustment for the balance of helper T cell subsets in peripheral blood of children with refractory epilepsy (CRE).Methods Forty-two CRE children admitted to Children's Hospital Affiliated to Zhengzhou University from January 2015 to May 2016 were retrospectively analyzed.All the CRE patients were treated with KD,and the data before and after treatment were collected.During the same period,40 healthy children were taken as the healthy control group.The changes of the compositions of helper T cells 17(Thl7),regulatory T cells (Treg) and helper T cells 1 (Th1) in each group were recorded.Meanwhile,m RNA expression of Th17,Treg and Th1 related factors were detected,and plasma levels of inflammatory cytokines were analyzed before and after treatment.Results There were less Treg cells [(1.75 ± 0.53) ％] in children with CRE compared with the healthy control group [(3.97 ± 0.28)％],but more Th1[(12.25 ± 1.03)％] and Th17 cells [(2.89 ±0.68)％]compared with the healthy control group [(7.75 ± 2.42) ％,(1.86 ± 0.57) ％] (t =23.542,11.049,7.415,all P ＜0.05).The mRNA expression of interleukin-17A (IL-17A),gamma-interferon (IFN-γ),in the CRE group before treatment [(2.46 ± 0.75) × 10-4,(1.48 ± 0.64) × 10-2],were significantly higher than those in the healthy control group [(0.91 ±0.24) × 10-4,(0.47 ±0.11) × 10-2].The mRNA expression levels of cytotoxic T lymphocyte associated antigen 4 (CTLA-4) and tumor necrosis factor receptor (GITR) in the pre-treatment group of CRE children[(20.02 ± 6.57) × 10-2;(12.42 ± 6.46) × 10-5] were significantly lower than the healthy control group [(26.57 ± 6.75) × 10-2;(16.31 ± 4.18) × 10-5];the difference was statistically significant (F =4.697,5.232,4.981,3.872,all P ＜ 0.05).After treatment,mRNA expression levels of IL-17A [(1.20 ± 0.44) × 10-4],IFN-γ[(0.7 ±0.41) × 10-2],CTLA-4 [(10.72 ±2.99) × 10-2] and GITR [(6.04 ±2.51) × 10-5] were significantly decreased compared with the level of pre-treatment group [(2.46 ± 0.75) × 10-4,(1.48 ± 0.64) × 10-2,(20.02 ±6.57) × 1 0-2,(12.42 ± 6.46) × 10-5,p ＜ 0.05].The levels of IL-17 A,IFN-γ,Cyclooxygenases-2 (COX-2)and Prostaglandin F2α (PGF2α) in children with CRE the level of pre-treatment group [(26.52 ± 6.17) ng/L,(11.19 ± 3.15) ng/L,(2.14 ± 1.31) ng/L,(205.74 ± 32.30) ng/L] were significantly higher than those in the healthy control group [(13.93 ± 2.98) ng/L,(8.87 ± 1.09) ng/L,(1.04 ± 0.33) ng/L,(109.80 ± 38.74) ng/L](F=5.361,3.987,3.654,11.370,all P ＜ 0.05).The levels of IL-17A [(18.48 ± 6.18) ng/L],IFN-γ[(9.54±1.42) ng/L],COX-2 [(1.46 ±0.72) ng/L] and PGF2α[(126.13±13.07) ng/L]in CRE children were reduced after KD adjustment [(26.52 ± 6.17) ng/L,(1 1.19 ± 3.15) ng/L,(2.14 ± 1.31) ng/L,(205.74 ±32.30) ng/L],and the differences were statistically significant (all P ＜ 0.05).Conclusions KD adjustment may have a beneficial effect on balance of peripheral blood in children with CRE.KD adjustment is positively correlated with the level of factors related to Th cells and inflammatory cytokines.
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OBJECTIVE: To figure out the balance mechanism between brand-name drugs and generic drugs in American drug review. METHODS: This paper reviewed FDA laws and regulations, domestic and foreign literature to retrospect the basis of generic development and explore the brand-name drug companies' action to prevent generic competition. RESULTS AND CONCLUSION: The abbreviate new drug application, patent challenge and market exclusivity in the Hatch-Waxman Act were the basis of generic development. Brand-name drug companies prevented competition by occupying the market, refusing to provide samples, submitting citizen petitions to extend generic drug review time and extending the patent term and market exclusivity of brand-name drugs. The United States legislated and amended relevant laws and regulations, adjusted the generic drug user fee to maintain the stability of the balance, which is worthy of further research.
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Objective To investigate the inhibition of metformin on corneal neovascularization in rats following alkali burn.Methods Totally 48 SD rats (48 eyes)were randomly divided into three groups,and they were negative control group (n =6),in which the controls were left untreated,normal saline group(n =21),rats treated with intraperitoneal injection of equivalent saline,and metformin group (n =21),rats subjected to intraperitoneal injection of 120 mg · kg-1 metformin every day.The expression of vascular endothelial growth factor (VEGF),VEGF receptors (Flk1,Flt1) and thrombospondin 1 (TSP1) protein in corneal tissue were detected by Western blot,while RT-PCR was used to detect the expression of VEGF,Flk1,Flt1 and TSP1 mRNA in corneal tissue.Then the morphological structure of cornea was observed by HE staining.Resuits The area of neovascularization in metformin group was smaller than that of the normal saline group on day 5,7,14 after administration (all P ＜0.01).And there was interaction in the both groups with different treatment methods at different time points (F=147.32,P =0.000).The expression of Flk-1 protein in the metformin group was lower than that of the normal saline group,whereas the relative expression of TSP-1 protein was higher than that of the normal saline group (all P ＜ 0.01).The expression of VEGF,Flk-1 and Flt-1 mRNA in the metformin group was lower than those of the normal saline group,but the expression of TSP-1 mRNA was higher than that of the normal saline group (all P ＜0.01).HE staining showed that the degree of corneal edema,the inflammatory response and the number of new blood vessels in the metformin group were significantly alleviated compared with normal saline group.Conclusion Metformin can inhibit the progress of corneal neovascularization in SD rats.