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1.  Estradiol accelerates the effects of fluoxetine on serotonin 1A receptor signaling 
Psychoneuroendocrinology  2012;38(7):1145-1157.
A major problem with current anti-depressant therapy is that it takes on average 6–7 weeks for remission. Since desensitization of serotonin (5-HT)1A receptor signaling contributes to the anti-depressive response, acceleration of the desensitization may reduce this delay in response to antidepressants. The purpose of the present study was to test the hypothesis that estradiol accelerates fluoxetine-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the hypothalamus (PVN) of rats, via alterations in components of the 5-HT1A receptor signaling pathway. Ovariectomized rats were injected with estradiol and/or fluoxetine, then adrenocorticotropic hormone (ACTH) and oxytocin responses to a 5-HT1A receptor agonist (+)8-hydroxy-2-dipropylaminotetralin (8-OH-DPAT) were examined to assess the function of 5-HT1A receptors in the PVN. Treatment with estradiol for either 2 or 7 days or fluoxetine for 2 days produced at most a partial desensitization of 5-HT1A receptor signaling, whereas 7 days of fluoxetine produced full desensitization. Combined treatment with estradiol and fluoxetine for 2 days produced nearly a full desensitization, demonstrating an accelerated response compared to either treatment alone. With two days of combined treatments, estradiol prevented the fluoxetine-induced increase in 5-HT1A receptor protein, which could contribute to the more rapid to the desensitization. Furthermore, EB treatment for 2 days decreased the abundance of the 35 kD Gαz protein which could contribute to the desensitization response. We found two isoforms of Gαz proteins with molecular mass of 35 and 33 kD, which differentially distributed in the detergent resistant microdomain (DRM) and in Triton X-100 soluble membrane region, respectively. The 35 kD Gαz proteins in the DRM can be sumoylated by SUMO1. Stimulation of 5-HT1A receptors with 8-OH-DPAT increases the sumoylation of Gαz proteins and reduces the 33 kD Gαz proteins, suggesting that these responses may be related to the desensitization of 5-HT1A receptors. Treatment with estradiol for 2 days also reduced the levels of the G-protein coupled estrogen receptor GPR30, possibly limiting to the ability of estradiol to produce only a partial desensitization response. These data provide evidence that estradiol may be effective as a short-term adjuvant to SSRIs to accelerate the onset of therapeutic effects.
PMCID: PMC3610798  PMID: 23219224
SSRIs; GPR30; Gαz; oxytocin; ACTH; sumoylation; detergent resistant microdomain; lipid raft; 5-HT1A receptors
2.  Clinical significance of expression of tissue factor and tissue factor pathway inhibitor in ulcerative colitis 
AIM: To investigate the clinical significance of expression of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in ulcerative colitis (UC).
METHODS: Thirty UC specimens taken by colonoscopy from patients with active UC treated at the Department of Pathology, Central Hospital Affiliated to Shenyang Medical College from February 2010 to January 2012 were included in an experimental group, and 30 normal colon tissue samples taken by colonoscopy from non-UC patients were included in a control group. Expression of TF and TFPI in UC and normal colon tissue samples was detected by immunohistochemistry.
RESULTS: The positive rate of TF in UC was significantly higher than that in normal colon tissue (63% vs 33%, χ2 = 5.41, P < 0.05). The positive rate of TFPI in UC was also significantly higher than that in normal colon tissue (43% vs 17%, χ2 = 5.08, P < 0.05).
CONCLUSION: Positive rates of TF and TFPI expression in UC are significantly higher than those in normal colon tissue. TF and TFPI may play an important role in the pathogenesis of UC.
PMCID: PMC4064091  PMID: 24966616
Ulcerative colitis; Tissue factor; Tissue factor pathway inhibitor
3.  Subtype of Dietary Fat in Relation to Risk of Hodgkin Lymphoma: A Population-based Case-Control Study in Connecticut and Massachusetts 
Cancer causes & control : CCC  2013;24(3):485-494.
Few epidemiological studies have examined the relationship between dietary fat, which may affect immune function, and risk of Hodgkin lymphoma (HL). The aim of this study was to test the hypothesis that high dietary intake of fat and specific subtypes of fat is associated with the risk of HL among 486 HL cases and 630 population-based controls recruited between 1997–2000 in Connecticut and Massachusetts. Unconditional logistic regression was used to calculate odds ratios (OR) and 95 % confidence intervals (CIs) stratified by age and gender. Among younger adults, HL risk was significantly and positively associated with higher intake of saturated fat (ORs for increasing quartiles= 1.3, 1.8, and 2.1; p trend = 0.04), and negatively associated with higher intake of monounsaturated fat (ORs for increasing quartiles= 0.5, 0.5, and 0.4; p trend = 0.03), after adjustment for potential confounders including lifestyle and other dietary factors. The associations with saturated fat (ORs for increasing quartile = 2.4, 3.2, and 4.4; p trend < 0.01) and monounsaturated fat (ORs for increasing quartile= 0.3, 0.6, and 0.3; p trend = 0.04) were most apparent in younger women, whereas there was no significant association between intake of total fat or any type of fat and risk of HL in older females or younger or older males. These findings show that the associations between dietary fat and risk of HL may vary by gender and age, and require confirmation in other populations.
PMCID: PMC4044911  PMID: 23314676
Hodgkin lymphoma; dietary fat; saturated fat; monounsaturated fat
4.  VP292 of White spot syndrome virus Interacts with VP26 
Indian Journal of Virology  2012;24(1):54-58.
Interactions between virus structural proteins are suggested to be crucial for virus assembly. Many steps in the process of white spot syndrome virus (WSSV) assembly and maturation remain unclear. In this paper, we discovered a new interaction of WSSV VP292. Temporal-transcription analysis showed that VP292 is expressed in the late stage of WSSV infection. Western blot and matrix-assisted laser desorption ionization MS assays showed that VP292 interacts with VP26, a major envelope protein. Far-western blot provided further evidence for interaction between VP292 and VP26. These results collectively demonstrated that VP292 anchors to the envelope through interaction with VP26.
PMCID: PMC3650189  PMID: 24426258
White spot syndrome virus; VP292; Characterization; Interact; VP26
5.  Complement activation in pediatric patients with recurrent acute otitis media 
Otitis media (OM) is one of the most common childhood diseases. The relative contribution of complement activation in protection and pathogenesis during OM remains largely unknown. The purpose of this study was to investigate the beneficial and pathogenic contributions of complement activation in the middle ear of pediatric patients with recurrent acute otitis media (rAOM), and therefore to provide a rational approach to prevent sequelae of OM such as hearing loss.
Twenty children undergoing pressure equalization tube placement with or without adenoidectomy for rAOM were enrolled in the study. Bacterial cultures, enzyme-linked immunosorbent assay (ELISA) for complement components and cytokines and western blot for complement activation were performed on middle ear effusion (MEE) and serum samples. The levels of complement C3a, C5a and sC5-b9 in MEEs and serum samples were compared. The levels of these factors were also examined in regards to length of episode. Pearson’s correlation coefficients were calculated on variables between C5a and IL-6 or IL-8. Complement gene expression in human middle ear epithelial (HMEE) cells induced by otopathogens was evaluated. Data were analyzed with Student’s t test or the Mann-Whitney rank sum test. In all cases, a P value of <0.05 was set as the measure of significance.
Our data demonstrated that the complement classical/lectin, alternative and terminal pathways were activated in the middle ear of children with rAOM. Increased complement components of C3a, C5a and sC5-b9 in MEEs were detected in patients with the episode lasting more than six weeks. There was a strong correlation between C5a and IL-6 or IL-8 in the MEEs. Additionally, otopathogens induced enhanced gene expression of factor B and C3 in HMEE cells, which is beneficial for host defense against invading pathogens.
Our studies provided important new insights on how complement activation contributes to inflammatory process during rAOM. Knowledge of the activity of the complement pathway in patients with rAOM may stimulate the development of new strategies to prevent middle ear inflammatory tissue destruction by directing treatment to specific pathways within the complement cascade.
PMCID: PMC3660544  PMID: 23537925
otitis media; complement activation; factor B; C3; C5a; cytokine
6.  A mechanically-induced colon cancer cell population shows increased metastatic potential 
Molecular Cancer  2014;13:131.
Metastasis accounts for the majority of deaths from cancer. Although tumor microenvironment has been shown to have a significant impact on the initiation and/or promotion of metastasis, the mechanism remains elusive. We previously reported that HCT-8 colon cancer cells underwent a phenotypic transition from an adhesive epithelial type (E-cell) to a rounded dissociated type (R-cell) via soft substrate culture, which resembled the initiation of metastasis. The objective of current study was to investigate the molecular and metabolic mechanisms of the E-R transition.
Global gene expressions of HCT-8 E and R cells were measured by RNA Sequencing (RNA-seq); and the results were further confirmed by real-time PCR. Reactive oxygen species (ROS), anoikis resistance, enzyme activity of aldehyde dehydrogenase 3 family, member A1 (ALDH3A1), and in vitro invasion assay were tested on both E and R cells. The deformability of HCT-8 E and R cells was measured by atomic force microscopy (AFM). To study the in vivo invasiveness of two cell types, athymic nude mice were intra-splenically injected with HCT-8 E or R cells and sacrificed after 9 weeks. Incidences of tumor development and metastasis were histologically evaluated and analyzed with Fisher’s exact test.
Besides HCT-8, E-R transition on soft substrates was also seen in three other cancer cell lines (HCT116, SW480 colon and DU145 prostate cancer). The expression of some genes, such as ALDH3A1, TNS4, CLDN2, and AKR1B10, which are known to play important roles in cancer cell migration, invasion, proliferation and apoptosis, were increased in HCT-8 R cells. R cells also showed higher ALDH3A1 enzyme activity, higher ROS, higher anoikis resistance, and higher softness than E cells. More importantly, in vitro assay and in vivo animal models revealed that HCT-8 R cells were more invasive than E cells.
Our comprehensive comparison of HCT-8 E and R cells revealed differences of molecular, phenotypical, and mechanical signatures between the two cell types. To our knowledge, this is the first study that explores the molecular mechanism of E-R transition, which may greatly increase our understanding of the mechanisms of cancer mechanical microenvironment and initiation of cancer metastasis.
PMCID: PMC4072622  PMID: 24884630
In vitro cancer microenvironment; Metastasis; Mechanotransduction; Cancer biomarkers; Invasiveness; Polyacrylamide hydrogel
7.  Stereoselective activity of 2-(4-amino-3-chloro-5- trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride to improve the pulmonary function in asthma 
Biomedical Reports  2014;2(4):539-544.
Asthma is a chronic airway disease that is characterized by significantly exacerbated bronchospasms and marked inflammation of the airways. Although the etiology of asthma remains to be determined, genetic predisposition is one of the factors involved. β2-agonists compounds may serve as options for the treatment of bronchial asthma. The aim of the present study was to investigate the effects of 2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride (SPFF) and its enantiomers with regard to improving asthmatic pulmonary function and selective binding to β2-adrenergic receptor. The bronchoconstrictor action of histamine in guinea pigs was conducted and the results demonstrated that (−)SPFF and (±)SPFF could significantly inhibit the increase of bronchoconstriction induced by histamine, while (+)SPFF did not show an effect. Inflammatory mediator release from allergic lung tissues was determined and it was found that (±)SPFF showed the highest activity among all the tested compounds, while the efficacy of (−)SPFF was similar to that of (+)SPFF. SPFF and its enantiomers stimulated cyclic adenosine monophosphate (cAMP) production in the asthmatic lung tissues examined, showing that asthmatic lung tissues had a significant cAMP enhancement in response to (−)SPFF and (±)SPFF compared with (+)SPFF. Cardiac contractility of the right atria was assessed in the guinea pigs to establish the receptor selectivity of the compounds. The results indicated that all the compounds had high affinities to the β2 receptor. In conclusion, with regards to asthmatic pulmonary function improvement, (−)SPFF was more efficient as compared to (+)SPFF, while no significant difference was observed for the receptor selectivity of (−)SPFF and (+)SPFF.
PMCID: PMC4051474
β2 agonist; SPFF; enantiomer; pulmonary function; receptor-selectivity; asthma
8.  A Novel DFNA36 Mutation in TMC1 Orthologous to the Beethoven (Bth) Mouse Associated with Autosomal Dominant Hearing Loss in a Chinese Family 
PLoS ONE  2014;9(5):e97064.
Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.
PMCID: PMC4020765  PMID: 24827932
9.  Molecular identification of Theileria parasites of northwestern Chinese Cervidae 
Parasites & Vectors  2014;7:225.
Theileria and Babesia protozoan parasites are transmitted mainly by tick vectors. These parasites cause heavy economic losses to the live-stock industry, as well as affecting the health of wild animals in parasite-endemic areas. Identification of infectious agents in wild animals is not only crucial for species preservation, but also provides valuable information on parasite epidemiology. Here, we conducted a molecular surveillance study in Northwestern China to assess the prevalence of blood pathogens in cervids.
PCR analysis and microscopic evaluation of blood smears to detect Theileria- and Babesia-related diseases in Cervidae were conducted, in which 22 blood samples from red deer (n = 22) in Qilian Mountain and 20 from sika deer (n = 20) in Long Mountain were collected and tested for the presence of Theileria and Babesia. The 18S rRNA gene was amplified, and selected polymerase chain reaction (PCR)-positive samples were sequenced for species identification.
PCR revealed that 9.1% of the Qilian Mountain samples and 20% of the Long Mountain samples were positive for Theileria uilenbergi; 90.09% of the Qilian Mountain samples (n = 22) were positive for T. capreoli, but all of the Long Mountain samples (n = 20) were negative for T. capreoli; no other Theileria or Babesia species were found. PCR showed that T. uilenbergi and T. capreoli were present in red deer in Qilian Mountain, while only T. uilenbergi was found in sika Deer in Long Mountain. The 18S rRNA gene sequences were aligned against the corresponding GenBank sequences of known isolates of Theileria and Babesia and subjected to phylogenetic analysis. The phylogenetic tree showed that the newly isolated Theileria spp. could be classified as belonging to two clades: one group belonged to the same clade as T. uilenbergi, the other to a clade containing T. capreoli.
Our results provide important data to increase understanding of the epidemiology of Cervidae theileriosis, and will assist with the implementation of measures to control theileriosis transmission to Cervidae and small ruminants in central China.
PMCID: PMC4029935  PMID: 24885179
Theileria and Babesia; Molecular detection; Cervid; PCR; Northwestern China
10.  c-kit+ Cardiac Stem Cells Alleviate Post-Myocardial Infarction Left Ventricular Dysfunction Despite Poor Engraftment and Negligible Retention in the Recipient Heart 
PLoS ONE  2014;9(5):e96725.
Although transplantation of c-kit+ cardiac stem cells (CSCs) has been shown to alleviate left ventricular (LV) dysfunction induced by myocardial infarction (MI), the number of exogenous CSCs remaining in the recipient heart following transplantation and their mechanism of action remain unclear. We have previously developed a highly sensitive and accurate method to quantify the absolute number of male murine CSCs in female recipient organs after transplantation. In the present study, we used this method to monitor the number of donor CSCs in the recipient heart after intracoronary infusion. Female mice underwent a 60-min coronary occlusion followed by reperfusion; 2 days later, 100,000 c-kit+/lin- syngeneic male mouse CSCs were infused intracoronarily. Only 12.7% of the male CSCs present in the heart immediately (5 min) after infusion were still present in the heart at 24 h, and their number declined rapidly thereafter. By 35 days after infusion, only ∼1,000 male CSCs were found in the heart. Significant numbers of male CSCs were found in the lungs and kidneys, but only in the first 24 h. The number of CSCs in the lungs increased between 5 min and 24 h after infusion, indicating recirculation of CSCs initially retained in other organs. Despite the low retention and rapid disappearance of CSCs from the recipient heart, intracoronary delivery of CSCs significantly improved LV function at 35 days (Millar catheter). These results suggest that direct differentiation of CSCs alone cannot account for the beneficial effects of CSCs on LV function; therefore, paracrine effects must be the major mechanism. The demonstration that functional improvement is dissociated from survival of transplanted cells has major implications for our understanding of cell therapy. In addition, this new quantitative method of stem cell measurement will be useful in testing approaches of enhancing CSC engraftment and survival after transplantation.
PMCID: PMC4013035  PMID: 24806457
11.  Validation of an Algorithm to Estimate Gestational Age in Electronic Health Plan Databases 
To validate an algorithm that uses delivery date and diagnosis codes to define gestational age at birth in electronic health plan databases.
Using data from 225,384 live born deliveries among women aged 15–45 years in 2001–2007 within 8 of the 11 health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program, we compared 1) the algorithm-derived gestational age versus the “gold-standard” gestational age obtained from the infant birth certificate files; and 2) the prenatal exposure status of two antidepressants (fluoxetine and sertraline) and two antibiotics (amoxicillin and azithromycin) as determined by the algorithm-derived versus the gold-standard gestational age.
The mean algorithm-derived gestational age at birth was lower than the mean obtained from the birth certificate files among singleton deliveries (267.9 versus 273.5 days) but not among multiple-gestation deliveries (253.9 versus 252.6 days). The algorithm-derived prenatal exposure to the antidepressants had a sensitivity and a positive predictive value (PPV) of ≥95%, and a specificity and a negative predictive value (NPV) of almost 100%. Sensitivity and PPV were both ≥90%, and specificity and NPV were both >99% for the antibiotics.
A gestational age algorithm based upon electronic health plan data correctly classified medication exposure status in most live born deliveries, but misclassification may be higher for drugs typically used for short durations.
PMCID: PMC3644383  PMID: 23335117
algorithm; database; gestational age; maternal exposure; pregnancy; validation studies
12.  A Highly Sensitive and Accurate Method to Quantify Absolute Numbers of c-kit+ Cardiac Stem Cells Following Transplantation in Mice 
Basic research in cardiology  2013;108(3):346.
Although transplantation of c-kit+ cardiac stem cells (CSCs) alleviates post-myocardial infarction left ventricular dysfunction, there are no reliable methods that enable measurement of the absolute number of CSCs that persist in the recipient heart. To overcome this limitation, we developed a highly sensitive and accurate method to quantify the absolute number of murine CSCs after transplantation. This method has two unique features: i) real-time PCR-based detection of a novel male-specific, multiple-copy gene, Rbmy, which significantly increases the sensitivity of detection of male donor cells in a female recipient, and ii) an internal standard, which permits quantification of the absolute number of CSCs as well as the total number of cells in the recipient organ. Female C57BL/6 mice underwent coronary occlusion and reperfusion; 2 days later, 105 male mouse CSCs were injected intramyocardially. Tissues were analyzed by real-time PCR at serial time points. In the risk region, >75% of CSCs present at 5 min were lost in the ensuing 24 h; only 7.6±2.1% of the CSCs present at 5 min could still be found at 7 days after transplantation and only 2.8±0.5% (i.e., 1,224±230 cells/heart) at 35 days. Thus, even after direct intramyocardial injection, the total number of CSCs that remain in the murine heart is minimal (at 24 h, ~10% of the cells injected; at 35 days, ~1%). This new quantitative method of stem cell detection, which enables measurement of absolute cell number, should be useful to optimize cell-based therapies, not only for CSCs but also for other stem cells and other organs.
PMCID: PMC3684056  PMID: 23549981
Stem cells; Stem cell therapy; Myocardial infarction; Quantitative PCR
13.  Squalene Synthase As a Target for Chagas Disease Therapeutics 
PLoS Pathogens  2014;10(5):e1004114.
Trypanosomatid parasites are the causative agents of many neglected tropical diseases and there is currently considerable interest in targeting endogenous sterol biosynthesis in these organisms as a route to the development of novel anti-infective drugs. Here, we report the first x-ray crystallographic structures of the enzyme squalene synthase (SQS) from a trypanosomatid parasite, Trypanosoma cruzi, the causative agent of Chagas disease. We obtained five structures of T. cruzi SQS and eight structures of human SQS with four classes of inhibitors: the substrate-analog S-thiolo-farnesyl diphosphate, the quinuclidines E5700 and ER119884, several lipophilic bisphosphonates, and the thiocyanate WC-9, with the structures of the two very potent quinuclidines suggesting strategies for selective inhibitor development. We also show that the lipophilic bisphosphonates have low nM activity against T. cruzi and inhibit endogenous sterol biosynthesis and that E5700 acts synergistically with the azole drug, posaconazole. The determination of the structures of trypanosomatid and human SQS enzymes with a diverse set of inhibitors active in cells provides insights into SQS inhibition, of interest in the context of the development of drugs against Chagas disease.
Author Summary
Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and affects eight million individuals, primarily in Latin America. Currently there is no cure for chronic T. cruzi infections. Unlike humans, this parasite use a variety of sterols (e.g. ergosterol, 24-ethyl-cholesta-5,7,22-trien-3 beta ol, and its 22-dihydro analogs), rather than cholesterol in their cell membranes, so inhibiting endogenous sterol biosynthesis is an important therapeutic target. Here, we report the first structure of the parasite's squalene synthase, which catalyzes the first committed step in sterol biosynthesis, as well as the structures of a broad range of squalene synthase inhibitors active against the clinically relevant intracellular stages, opening the way to new approaches to treating this neglected tropical disease.
PMCID: PMC4006925  PMID: 24789335
14.  Cu-doped ZnO nanorod arrays: the effects of copper precursor and concentration 
Nanoscale Research Letters  2014;9(1):199.
Cu-doped ZnO nanorods have been grown at 90°C for 90 min onto a quartz substrate pre-coated with a ZnO seed layer using a hydrothermal method. The influence of copper (Cu) precursor and concentration on the structural, morphological, and optical properties of ZnO nanorods was investigated. X-ray diffraction analysis revealed that the nanorods grown are highly crystalline with a hexagonal wurtzite crystal structure grown along the c-axis. The lattice strain is found to be compressive for all samples, where a minimum compressive strain of −0.114% was obtained when 1 at.% Cu was added from Cu(NO3)2. Scanning electron microscopy was used to investigate morphologies and the diameters of the grown nanorods. The morphological properties of the Cu-doped ZnO nanorods were influenced significantly by the presence of Cu impurities. Near-band edge (NBE) and a broad blue-green emission bands at around 378 and 545 nm, respectively, were observed in the photoluminescence spectra for all samples. The transmittance characteristics showed a slight increase in the visible range, where the total transmittance increased from approximately 80% for the nanorods doped with Cu(CH3COO)2 to approximately 90% for the nanorods that were doped with Cu(NO3)2.
PMCID: PMC4011776  PMID: 24855460
Zinc oxide; Nanostructures; Doping; Hydrothermal crystal growth; Photoluminescence
15.  Correlation of measured and calculated serum osmolality during mannitol or hypertonic saline infusion in patients after craniotomy: a study protocol and statistical analysis plan for a randomised controlled trial 
BMJ Open  2014;4(4):e004921.
Brain oedema is a major complication after craniotomy. Hyperosmolar agents have been used as the medical treatment for this condition. Measurement and estimation of serum osmolality during hyperosmolar agent infusion is of clinical importance to evaluate clinical efficacy, adjust dosage and avoid side effects. However, several studies have shown that calculated serum osmolality may lead to a systematic bias compared with direct measurement. In the present study, mannitol or hypertonic saline (HS) will be used in patients after elective craniotomy. We aim to determine the accuracy of serum osmolality estimation during the application of hyperosmolar agent.
Methods and analysis
The study is a prospective, randomised, double-blinded, controlled, parallel-group design. Adult patients requiring the use of hyperosmolar agents for the prevention or treatment of postoperative brain oedema are enrolled and assigned randomly to one of the two treatment study groups, labelled as ‘M group’ and ‘HS group’. Patients in the M and HS groups receive intravenous infusion of 125 mL of either 20% mannitol or 3.1% sodium chloride solution, respectively. Data will be collected immediately before the infusion of study agents, 15, 30, 60, 120, 240 and 360 min after the start of infusion of experimental agents, which includes serum osmolality, concentration of serum sodium, potassium, urea and glucose. Serum osmolality will be measured by means of freezing point depression. Estimated serum osmolality will also be calculated by using four formulas published previously. Osmole gap is calculated as the difference between the measured and the estimated values. The primary endpoint is the correlation of measured and estimated serum osmolality during hyperosmolar agent infusion.
Ethics and dissemination
The study was approved by the International Review Board (IRB) of Beijing Tiantan Hospital, Capital Medical University. Study findings will be disseminated through peer-reviewed publications and conference presentations.
Trial registration number identifier: NCT02037815.
PMCID: PMC4010815  PMID: 24760352
16.  Immobilised Histidine Tagged β2-Adrenoceptor Oriented by a Diazonium Salt Reaction and Its Application in Exploring Drug-Protein Interaction Using Ephedrine and Pseudoephedrine as Probes 
PLoS ONE  2014;9(4):e94955.
A new oriented method using a diazonium salt reaction was developed for linking β2-adrenoceptor (β2-AR) on the surface of macroporous silica gel. Stationary phase containing the immobilised receptor was used to investigate the interaction between β2-AR and ephedrine plus pseudoephedrine by zonal elution. The isotherms of the two drugs best fit the Langmuir model. Only one type of binding site was found for ephedrine and pseudoephedrine targeting β2-AR. At 37 °C, the association constants during the binding were (5.94±0.05)×103/M for ephedrine and (3.80±0.02) ×103/M for pseudoephedrine, with the binding sites of (8.92±0.06) ×10−4 M. Thermodynamic studies showed that the binding of the two compounds to β2-AR was a spontaneous reaction with exothermal processes. The ΔGθ, ΔHθ and ΔSθ for the interaction between ephedrine and β2-AR were −(22.33±0.04) kJ/mol, −(6.51±0.69) kJ/mol and 50.94±0.31 J/mol·K, respectively. For the binding of pseudoephedrine to the receptor, these values were −(21.17±0.02) kJ/mol, −(7.48±0.56) kJ/mol and 44.13±0.01 J/mol·K. Electrostatic interaction proved to be the driving force during the binding of the two drugs to β2-AR. The proposed immobilised method will have great potential for attaching protein to solid substrates and realizing the interactions between proteins and drugs.
PMCID: PMC3991622  PMID: 24747442
18.  A unified intermediate and mechanism for soot combustion on potassium-supported oxides 
Scientific Reports  2014;4:4725.
The soot combustion mechanism over potassium-supported oxides (MgO, CeO2 and ZrO2) was studied to clarify the active sites and discover unified reaction intermediates in this typical gas-solid-solid catalytic reaction. The catalytically active sites were identified as free K+ rather than K2CO3, which can activate gaseous oxygen. The active oxygen spills over to soot and forms a common intermediate, ketene, before it was further oxidized into the end product CO2. The existence of ketene species was confirmed by density functional theory (DFT) calculations. The oxygen spillover mechanism is proposed, which is explained as an electron transfer from soot to gaseous oxygen through the active K+ sites. The latter mechanism is confirmed for the first time since it was put forward in 1950, not only by ultraviolet photoelectron spectroscopy (UPS) results but also by semi-empirical theoretical calculations.
PMCID: PMC3989558  PMID: 24740213
19.  Acupuncture at local and distal points for chronic shoulder pain: study protocol for a randomized controlled trial 
Trials  2014;15:130.
Chronic shoulder pain (CSP) is the third most common type of musculoskeletal pain. It has a major impact on health-related quality of life. In Chinese medicine, CSP is considered one of the conditions most amenable to treatment with acupuncture. The purpose of this study is to evaluate the efficacy of local acupoints in combination with distal acupoints in pain relief and shoulder function improvement in CSP patients.
This is a multicenter, single blind, factorial randomized controlled clinical trial. A total of 164 participants will be randomly allocated to four different groups: Group A will receive acupuncture at local acupoints in combination with distal acupoint. Group B will receive acupuncture at local acupoints in combination with distal non-acupoint. Group C will receive acupuncture at local non-acupoints in combination with distal acupoint. Group D will receive acupuncture at local non-acupoints in combination with distal non-acupoint. Each group will receive 12 treatments of acupuncture one to three times per week for six weeks in total. The primary outcome is shoulder pain intensity, which is graded using a 100 -mm Visual Analogue Scale. The assessment is at baseline (before treatment initiation), 6 weeks after the first acupuncture, 10 weeks after the first acupuncture and 18 weeks after the first acupuncture.
This trial will be helpful in identifying whether acupuncture at local acupoints in combination with distal acupoints may be more effective than needling points separately.
Trial registration
International Standard Randomized Controlled Trial Number Register: ISRCTN61861069 (
PMCID: PMC4012183  PMID: 24742182
20.  Intratumoral injection of cisplatin in various concentrations of ethanol for cisplatin-resistant lung tumors 
Molecular and Clinical Oncology  2014;2(4):491-496.
Cisplatin [cis-diammineplatinum dichloride (DDP)] resistance is a major limitation in the treatment of lung cancer. We previously demonstrated that DDP dissolved in 5% ethanol (5% ethanol-DDP) injected intratumorally was able to eradicate DDP-resistant lung tumors and prolong survival, as 5% ethanol improved DDP delivery to the tumor. The present study aimed to investigate the efficacy of DDP in various concentrations of ethanol and determine the optimal ethanol concentration in which DDP exhibits optimal efficacy in reducing tumor volume and prolonging survival. The efficiency of DDP dissolved in 2, 5, 10, 20 and 50% ethanol (v/v) in DDP-resistant A549/DDP lung tumor-bearing Balb/C nude mice was investigated. Tumor growth and survival were evaluated in all the treatment groups. Microvessel density in xenograft tumor tissues was measured by immunohistochemistry. Our results revealed that 5% ethanol-DDP exhibited the highest efficiency in reducing tumor volume and prolonging survival among all the investigated ethanol-DDP combinations. We found that 5% ethanol-DDP produced the most significant inhibition of tumor angiogenesis among all the remaining ethanol-DDP combinations, while treatment with ethanol alone increased tumor angiogenesis. In conclusion, 5% ethanol-DDP produced the strongest tumor growth inhibition and longest survival among all the investigated ethanol-DDP combinations, possibly providing a novel therapeutic strategy for improving the survival of patients with DDP-resistant lung cancer. The potent inhibition of tumor angiogenesis by 5% ethanol-DDP may be one of the mechanisms underlying its superior efficiency.
PMCID: PMC4051566  PMID: 24940482
lung cancer; cisplatin; ethanol; cisplatin resistance
21.  Acupuncture Promotes Angiogenesis after Myocardial Ischemia through H3K9 Acetylation Regulation at VEGF Gene 
PLoS ONE  2014;9(4):e94604.
Acupuncture exerts cardioprotective effects on several types of cardiac injuries, especially myocardial ischemia (MI), but the mechanisms have not yet been well elucidated. Angiogenesis mediated by VEGF gene expression and its modification through histone acetylation has been considered a target in treating myocardial ischemia. This study aims to exam whether modulation of angiogenesis through H3K9 acetylation regulation at VEGF gene is one possible cardioprotective mechanism of acupuncture.
We generated rat MI models by ligating the left anterior descending coronary artery and applied electroacupuncture (EA) treatment at the Neiguan (PC6) acupoint. Our results showed that acupuncture reversed the S-T segment change, reduced Q-wave area, decreased CK, CK-MB, LDH levels, mitigated myocardial remodeling, and promoted microvessel formation in the MI heart. RNA-seq analysis showed that VEGF-induced angiogenesis signaling was involved in the modulation of EA. Western blot results verified that the protein expressions of VEGF, Ras, phospho-p44/42 MAPK, phospho-p38 MAPK, phospho-SAPK/JNK and Akt, were all elevated significantly by EA treatment in the MI heart. Furthermore, increased H3K9 acetylation was also observed according with the VEGF. ChIP assay confirmed that EA treatment could notably stimulate the recruitment of H3K9ace at the VEGF promoter.
Our study demonstrates for the first time that acupuncture can effectively up-regulate VEGF expression through H3K9 acetylation modification directly at the VEGF promoter and hence activate VEGF-induced angiogenesis in rat MI models. We employed high throughput sequencing in this study and, for the first time, generated genome-wide gene expression profiles both in the rat MI model and in acupuncture treatment.
PMCID: PMC3983235  PMID: 24722278
22.  The association of body mass index with the risk of type 2 diabetes: a case–control study nested in an electronic health records system in the United States 
Obesity is a known risk factor for type 2 diabetes (T2D). We conducted a case–control study to assess the association between body mass index (BMI) and the risk of being diagnosed with T2D in the United States.
We selected adults (≥ 18 years old) who were diagnosed with T2D (defined by ICD-9-CM diagnosis codes or use of anti-diabetic medications) between January 2004 and October 2011 (“cases”) from an electronic health records database provided by an integrated health system in the Middle Atlantic region. Twice as many individuals enrolled in the health system without a T2D diagnosis during the study period (“controls”) were selected based on age, sex, history of cardiac comorbidities or hyperinflammatory state (defined by C-reactive protein and erythrocyte sedimentation rate), and use of psychiatric or beta blocker medications. BMI was measured during one year prior to the first observed T2D diagnosis (for cases) or a randomly assigned date (for controls); individuals with no BMI measure or BMI < 18.5 kg/m2 were excluded. We assessed the impact of increased BMI (overweight: 25–29.9 kg/m2; Obesity Class I: 30–34.9 kg/m2; Obesity Class II: 35–39.9 kg/m2; Obesity Class III: ≥40 kg/m2), relative to normal BMI (18.5–24.9 kg/m2), on a T2D diagnosis using odds ratios (OR) and relative risks (RR) estimated from multiple logistic regression results.
We included 12,179 cases (mean age: 55, 43% male) and 25,177 controls (mean age: 56, 45% male). We found a positive association between BMI and the risk of a T2D diagnosis. The strength of this association increased with BMI category (RR [95% confidence interval]: overweight, 1.5 [1.4–1.6]; Obesity Class I, 2.5 [2.3–2.6]; Obesity Class II, 3.6 [3.4–3.8]; Obesity Class III, 5.1 [4.7–5.5]).
BMI is strongly and independently associated with the risk of being diagnosed with T2D. The incremental association of BMI category on the risk of T2D is stronger for people with a higher BMI relative to people with a lower BMI.
PMCID: PMC3976458  PMID: 24694251
Obesity; Risk of type 2 diabetes; Electronic health records
23.  Prevalence and trends in the use of antipsychotic medications during pregnancy in the U.S., 2001–2007: A population-based study of 585,615 deliveries 
Archives of women's mental health  2013;16(2):149-157.
To estimate the prevalence of and temporal trends in prenatal antipsychotic medication use within a cohort of pregnant women in the U.S.
We identified live born deliveries to women aged 15–45 years in 2001–2007 from 11 U.S. health plans participating in the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). We ascertained prenatal exposure to antipsychotics from health plan pharmacy dispensing files, gestational age from linked infant birth certificate files, and ICD-9-CM diagnosis codes from health plan claims files. We calculated the prevalence of prenatal use of atypical and typical antipsychotics according to year of delivery, trimester of pregnancy, and mental health diagnosis.
Among 585,615 qualifying deliveries, 4,223 (0.72%) were to women who received an atypical antipsychotic and 548 (0.09%) were to women receiving a typical antipsychotic any time from 60 days before pregnancy through delivery. There was a 2.5-fold increase in atypical antipsychotic use during the study period, from 0.33% (95% confidence interval: 0.29%, 0.37%) in 2001 to 0.82% (0.76%, 0.88%) in 2007, while the use of typical antipsychotics remained stable. Depression was the most common mental health diagnosis among deliveries to women with atypical antipsychotic use (63%), followed by bipolar disorder (43%) and schizophrenia (13%).
The number and proportion of pregnancies exposed to atypical antipsychotics has increased dramatically in recent years. Studies are needed to examine the comparative safety and effectiveness of these medications relative to other therapeutic options in pregnancy.
PMCID: PMC3715880  PMID: 23389622
Antipsychotics; database; pregnancy; prevalence
24.  Absorption, Distribution and Pathological Injury in Mice Due to Ricin Poisoning Via the Alimentary Pathway 
The aim of this work was to investigate the potential interactions between intestinal absorbance and ricin poisoning. The Caco-2 cell monolayer and everted intestinal sac (VEIS) models were used. The distribution of ricin in CD-1 mice intoxicated with 0.1 mg/kg of ricin intragastrically was determined by immunohistochemistry. The results showed that ricin could not transfer across the healthy Caco-2 cell monolayer within three hours after poisoning. However, it could pass through the everted rat intestinal wall after 0.5 h of incubation. The toxin in the liver, spleen, lungs and kidneys of mice could be detected as early as 1 h after intoxication. The pathological results were in accordance with the cytotoxicities of ricin in Caco-2, HepG 2, H1299 and MDCK cells, indicating that though no significant symptom in mice could be observed within 3 h after ricin intoxication, important tissues, especially the kidneys, were being injured by the toxin and that the injuries were progressing.
PMCID: PMC4000076  PMID: 24791070
ricin; immunohistochemistry; alimentary poisoning
25.  Effects of Chronic Electroacupuncture on Depression- and Anxiety-Like Behaviors in Rats with Chronic Neuropathic Pain 
Growing evidence indicates that chronic neuropathic pain is frequently accompanied by an array of psychiatric diseases, such as depression and anxiety. Electroacupuncture (EA), as one therapy of traditional Chinese medicine, has displayed potent antidepressant-like effects in numerous clinical studies. The present study was designed to examine the possible effects of EA on the depressive and anxiety disorders induced by neuropathic pain. A classic rat model of neuropathic pain was produced by chronic constriction injury (CCI) of the sciatic nerve. EA was performed on acupoints “Bai-Hui” (GV20) and unilateral “Yang-Ling-Quan” (GB34). The antidepressive and anxiolytic effects of EA treatment were analyzed using the forced swimming test (FST) and the elevated plus maze (EPM) test, respectively. CCI resulted in remarkable depression- and anxiety-like behaviors, whereas the chronic EA treatment significantly improved the behavioral deficits of CCI rats. Moreover, the phosphorylation level of the NMDA receptor type 1 (NR1) subunit was decreased in the hippocampus of CCI rats. Intriguingly, continuous EA treatment effectively blocked this decrease in the levels of pNR1. These results suggested that EA has antidepressive and anxiolytic effects on rats with neuropathic pain and that this might be associated with restoring the phosphorylation of NR1 in the hippocampus.
PMCID: PMC3984799  PMID: 24795763

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