Objective To explore the associations of the genetic polymorphisms of cytochrome P450, family 2, subfamily D, polypeptide 6 (CYP2D6) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) with early-onset severe pre-eclampsia and the efficacy of labetalol therapy. Methods Totally 105 gravidas diagnosed with early-onset severe pre-eclampsia (experimental group) and 103 healthy gravidas (control group) were recruited from Beijing Obstetrics and Gynecology Hospital between August 2013 and July 2016. Labetalol was given to control blood pressures in gravidas with early-onset severe pre-eclampsia. If labetalol administration alone did not exceed the mean dose (100 mg, one dose per eight hours) and effectively controlled the blood pressures, it would be considered to be valid (n=75), otherwise it would be viewed as an invalid treatment. Genotype and allele frequencies of CYP2C9 gene (rs1057910 and rs4918758) and CYP2D6 gene (rs1065852, rs28371725, rs35742686 and rs3892097) in the gravidas were analyzed by TaqMan probe polymerase chain reaction. Differences in the genotype and allele frequencies were compared between the experimental and control groups, and the valid and invalid labetalol treatment groups. Chi-square test, analysis of variance and LSD test were used as statistical methods. Results The gravidas in both experimental and control groups were AA genotype in CYP2C9 gene rs1057910, TT genotype in CYP2D6 gene rs35742686 and CC genotype in CYP2D6 gene rs3892097. Frequencies of CC and CT genotypes in CYP2D6 gene rs28371725 in the experimental group were higher than those in the control group [18.1% (19/105) vs 14.6% (15/103);56.2% (59/105) vs 42.7% (44/103); χ2=6.707], and higher C allele frequency in CYP2D6 gene rs28371725 was also observed in the experimental group [46.2% (97/210) vs 35.9% (74/206), χ2=4.529] (all P<0.05). No statistical differences in maternal age, diastolic pressure, body mass index before pregnancy, serum triglyceride, creatinine and neonatal birth weight were observed among women with CC, CT or TT genotype of CYP2D6 gene rs28371725 in the experimental group (all P>0.05). Compared with the gravidas with CT or TT genotype of CYP2D6 gene rs28371725, those with CC genotype had longer gestational age [(32.5±2.1) vs (29.5±1.8) and (29.8±2.2) weeks] and higher plasma albumin [(27.2±9.3) vs (20.3±10.4) and (22.5±7.4) g/L], but lower systolic pressure and 24 hours urine protein (LSD test, all P<0.05). The G allele frequency in CYP2D6 gene rs1065852 in invalid labetalol treatment group was higher than that in valid labetalol treatment group [93.3% (56/60) vs 76.0% (114/150), χ2=8.351, P=0.004]. Conclusions The polymorphism of CYP2D6 gene rs28371725 may be associated with early-onset severe pre-eclampsia, and the allele of G in CYP2D6 gene rs1065852 may be associated with the efficacy of labetalol in treatment of early-onset severe pre-eclampsia.

Objective To study the effect of lentiviral vector of MicroRNA-126 on survival differentiation of mesenchymal stem cells under ischemic condition.Methods Lentiviral vector of MicroRNA-126 was constructed and then transfected into mouse mesenchymal stem cells (MSCs).Flow detection was used to detect transfection ability and synthesis of collagen type Ⅰ.ELISA was used to detect osteocalcin,Insulin-like growth factor 1 (IGF-1) and transforming growth factor-β (TGF-β) in cell culture supernatant.Mandibular bone defect model was constructed and then injected the hydrogel mixed with MSCs.After 48h,the survival rate and proportion of differentiation into osteoblasts was determined.Results Flow results showed lentiviral vector of MicroRNA-126 could transfected into MSCs.ELISA results showed that MicroRNA-126 lentiviral vector transfected MSCs secreted more bone gla protein and IGF-1 and TGF-β,which increased by 1.43,1.87 and 2.63 times compared with the control virus treated group.Animal experiments showed the number of stem cells survived in the MicroRNA-126 group was 4.56 times that of the control group and the percentage of MSC differentiation into osteoblasts was 75％,which is 3.95 times more than that in the control group.Conclusion The research shows that lentiviral vector of MicroRNA-126 could maintain MSCs survival and differentiation under ischemic condition.

Background:Based on the effect of seasonal changes on human visceral function,this study investigated the impact of seasonal photoperiod of the pineal body on hypothalamic-pituitary-adrenal axis-hippo-campal-receptor in rats,aiming to reveal the mechanism by which pineal gland melatonin regulates the seasonal secretion of hippocampal neurotransmitters.Methods:Vernal equinox,summer solstice,autumn equinox,and winter solstice were selected as four experimental time points,and rats were randomly divided into normal control group,sham operation group,and pinealectomized group.The seasonal changes in corticotropin-releasing hormone(CRH),adrenocorticotropic hormone(ACTH),corticosterone,hypothalamic melatonin receptor(MTR),and hippocampal corticosterone receptor(CORTR)were examined by enzyme-linked immunosorbent assay.Results:Comparing the same group between different seasons,we showed that in the normal control group,CRH,ACTH,corticosterone,and MTR were higher,while CORTR was lower in autumn and winter than in spring(all P＜.05).Compared with the normal control group,the pinealectomized group showed higher levels of corticosterone(P=.01),MTR(P=.01),and CORTR(P=.03)during spring;reduced levels of MTR and CORTR(both P＜.001)during summer;higher levels of ACTH(P=.001)and MTR(P＜.001),and lower levels of CRH(P=.001),corticosterone(P＜.001),and CORTR(P=.003)during autumn;and lower levels of CRH(P＜.001)and MTR(P=.004),and higher level of ACTH(P＜.001)in winter.Conclusions:Seasonal photoperiod acts on the pineal gland to secrete different levels of melatonin,resulting in seasonal changes in the hypothalamic-pituitary-adrenal axis-hippocampal-receptor,which may be the pathophysiological basis for the onset of seasonal affective disorder.

Background: Based on the theory of"five Zang-organs corresponding to the seasons"in traditional Chinese medicine (TCM), physiological functions including emotions vary with the seasons. We aimed to investigate the seasonal photoperiod effects of melatonin (MT) released from the pineal gland on the MT receptor (MTR)-Gs/Gi-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP response element-binding protein (CREB) signaling pathway in the hippocampus.Methods: Rats were divided into three groups: control, operation (surgery with pineal gland removal), and pseudo-operation groups (same surgery as operation group but without removing pineal gland), and fed at specific time across the four seasons. The levels of MTR, adenylate cyclase (AC), cAMP, PKA, and CREB in the hippocampus were analyzed using ELISA. The concentrations of Gs and Gi were analyzed using Western blot. The expression of CREB mRNA was detected by PCR. Results: For intragroup comparisons, compared with spring, the levels of Gs/Gi in the control group were higher in summer, autumn, and winter (P=.009 in summer;P<.001 in autumn and winter);the levels of MTR, cAMP, PKA, and CREB in the control group were significantly higher in autumn and winter than in spring (all P<.001). The levels of MTR, cAMP, PKA, and CREB in each season were significantly lower in the operation group than in the control group (all P < .05). Significant differences were noted in Gs/Gi levels between the operation group and control group in spring, autumn, and winter (all P<.05). Conclusion: Our findings suggest that MTR-Gs/Gi-cAMP-PKA-CREB signaling pathway is involved in the seasonal photoperiod effects of the pineal gland on the hippocampus and may underpin seasonal changes in emotions. It can support the prevention and treatment of the seasonal onset of mental dis-orders, and enrich the theory of"five Zang-organs corresponding to the seasons".

This paper systematically analyzed the understanding of qi from the perspectives of matter， energy， information and relationship reality， introduced the original holistic principle of systematic traditional Chinese medicine （TCM）， and considered the latest research results of qi （three-layer material theory）， trying to optimize the structure framework of the qi theoretical system and exhibit the occurrence and development rules of original qi. It emphasizes the hierarchical order of qi transformation following the original holistic principle， and takes this to guide the clinical understanding of “qi diseases”， helping doctors grasp the basic pathogenesis of the disease， that is abnormal qi movement， and helping them establish the awareness of providing systematic TCM treatment to patients by taking qi regulation as the key. At the same time， it discusses people within the structure of time and space， and points out that the treatment of diseases must comply with the principle of “the harmony of heaven， earth， and human beings”.

Objective: To investigate the effect of incisor retraction on three-dimensional morphology of upper airway and fluid dynamics in class Ⅰ adult patients with bimaxillary protrusion. Methods: Thirty class Ⅰ patients with bimaxillary protrusion that received fixed orthodontic treatment in Department of Stomatology, The First Affiliated Hospital of Wenzhou Medical University from January 2011 to September 2014 were selected using random number table. All the patients were treated with extraction of four first premolars and retraction of anterior teeth using implant anchorage. Cone-beam CT (CBCT) scans were performed before and after incisor retraction for all patients. The CBCT data of the upper airway were constructed using Mimics 16.0, and the flow field characteristics inside the upper airway were simulated using Ansys 14.0. The changes of volume (V), mean cross-sectional area (mCSA), maximum lateral diameters/maximum anteroposterior diameters (LP/AP) of cross section, the maximum pressure of airflow (P_max), the minimum pressure of airflow (P_min) and pressure drop (△P) of nasopharynx, oropharynx and hypopharynx before and after incisor retraction were measured and compared using paired t test. The correlation between the variation of △P in the most significant pharyngeal part and the morphological variables after incisor retraction was analyzed using Pearson correlation test. Results: No statistical differences were observed in the morphology and flow field in nasopharynx before and after incisor retraction (P>0.05). Before incisor retraction, the oropharyngeal volume and mCSA were (7 580±622) mm³ and (217±40) mm², respectively, and the hypopharyngeal volume and mCSA were (2 564±162) mm³, and (239±43) mm², respectively. After incisor retraction, the volumes of oropharynx and hypopharynx were (6 885±601) mm³ and (2 535±156) mm³, respectively, and mCSA of oropharynx and hypopharynx were (197±37) mm² and (236±42) mm², respectively. The volume and mCSA of oropharynx and hypopharynx were significantly decreased after incisor retraction (P<0.05). The greatest changes in pharyngeal volume and mCSA occurred in the oropharynx. In addition, the LP/AP of oropharynx after incisor retraction was changed from 1.9±0.6 to 2.1±0.7, which was significantly increased compared with the levels before incisor retraction (P<0.05). After simulation of pharyngeal airflow, the oropharyngeal P_min, hypopharyngeal P_max and P_min were (-13.7±4.3), (-8.3±3.8) and (-42.8±9.5) Pa, respectively, whereas the values turned to (-16.4±6.5), (-11.9±3.6) and (-46.0±11.0) Pa, respectively after incisor retraction, which was significantly reduced (P<0.05). △P of oropharynx was significantly increased from (42.7±10.1) Pa to (45.2±13.0) Pa after incisor retraction (P<0.05) and the variation of oropharyngeal △P was negatively correlated with the variation of V and mCSA in oropharynx before and after incisor retraction (r=-0.681, P=0.001; r=-0.844, P=0.000). Conclusions The oropharynx was constricted and the pharyngeal resistance was increased after incisor retraction in adult class Ⅰ patients with bimaxillary protrusion. A comprehensive and systematic evaluation of the pharyngeal morphology and ventilatory function were very important for making a scientific and rational clinical treatment plan.

Objective: To describe the distribution and drug resistance of pathogens at hematology department of Jiangsu Province from 2014 to 2015 to provide reference for empirical anti-infection treatment. Methods: Pathogens were from hematology department of 26 tertiary hospitals in Jiangsu Province from 2014 to 2015. Antimicrobial susceptibility testing was carried out according to a unified protocol using Kirby-Bauer method or agar dilution method. Collection of drug susceptibility results and corresponding patient data were analyzed. Results: The separated pathogens amounted to 4 306. Gram-negative bacteria accounted for 64.26%, while the proportions of gram-positive bacteria and funguses were 26.99% and 8.75% respectively. Common gram-negative bacteria were Escherichia coli (20.48%) , Klebsiella pneumonia (15.40%) , Pseudomonas aeruginosa (8.50%) , Acinetobacter baumannii (5.04%) and Stenotropho-monas maltophilia (3.41%) respectively. CRE amounted to 123 (6.68%) . Common gram-positive bacteria were Staphylococcus aureus (4.92%) , Staphylococcus hominis (4.88%) and Staphylococcus epidermidis (4.71%) respectively. Candida albicans were the main fungus which accounted for 5.43%. The rates of Escherichia coli and Klebsiella pneumonia resistant to carbapenems were 3.5%-6.1% and 5.0%-6.3% respectively. The rates of Pseudomonas aeruginosa resistant to tobramycin and amikacin were 3.2% and 3.3% respectively. The resistant rates of Acinetobacter baumannii towards tobramycin and cefoperazone/sulbactam were both 19.2%. The rates of Stenotrophomonas maltophilia resistant to minocycline and sulfamethoxazole were 3.5% and 9.3% respectively. The rates of Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis resistant wards vancomycin were 0, 6.4% and 1.4% respectively; also, the rates of them resistant to linezolid were 1.2%, 0 and 1.6% respectively; in addition, the rates of them resistant to teicoplanin were 2.8%, 14.3% and 8.0% respectively. Furthermore, MRSA accounted for 39.15% (83/212) . Conclusions Pathogens were mainly gram-negative bacteria. CRE accounted for 6.68%. The rates of Escherichia coli and Klebsiella pneumonia resistant to carbapenems were lower compared with other antibacterial agents. The rates of gram-positive bacteria resistant to vancomycin, linezolid and teicoplanin were still low. MRSA accounted for 39.15%.

There are different views on the theory of “spleen governs time”， which is still a hot spot in the study of Zangxiang （藏象） theory. Based on Zangxiang time-space view， it is found that the thinking mode of the spleen governing time theory follows space-time logic. It is believed that the different time views of the spleen governing time are all formed based on the space view that the spleen belongs to earth and resides in the center， and the zang time theory is developed with the unified time and space logic. Guided by Zangxiang time-space view， the origin of the spleen belonging to earth and residing in the center is traced， and the theoretical connotation and its clinical application of spleen governing time under different time-space logic are explored with reference to the four season and five zang theory， five season and five zang theory， six season and six zang theory， and eight season and eight zang theory.

Metformin is the most common first-line oral hypoglycemic drug ，but there are large individual differences in pharmacokinetic parameters and pharmacodynamics during clinical use. The dosage of some patients should be adjusted to achieve satisfactory therapeutic effect. Pharmacokinetic parameters of metformin are affected by many factors ，including respects of transporter gene polymorphism ，drug interaction ，intestinal flora ，plateau hypoxia and physiological function and so on. In order to guide the clinical individualized use of metformin ，this study reviews the research progress on the influencing factors of metformin pharmacokinetics.

OBJECTIVES: Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM). METHODS: A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups. RESULTS: The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T_1/2), area under the curve (AUC), time to reach maximum concentration (T_max). Compared with the control group, AUC was increased by 23.5%, T_max and T_1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population. CONCLUSIONS Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.
Humans ; Diabetes Mellitus, Type 2/drug therapy* ; Metformin/therapeutic use* ; Acidosis, Lactic ; Tandem Mass Spectrometry ; Hypoxia ; Glucose