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1.  Rosuvastatin attenuates contrast-induced nephropathy through modulation of nitric oxide, inflammatory responses, oxidative stress and apoptosis in diabetic male rats 
Contrast-induced nephropathy (CIN) is an important cause of acute renal failure. We observe the effect of rosuvastatin on preventing CIN in diabetic rats in current study.
Diabetic rats were then divided into five groups: 1 diabetic rats (D), 2 diabetic rats + contrast media (DCM), 3 diabetic rats + rosuvastatin (DR), 4 diabetic rats + contrast media + rosuvastatin (DRCM), 5 non-diabetic rat control (NDCM). Contrast-induced nephropathy was induced by intravenous injection a single dose of indomethacin (10 mg/kg), double doses of N-nitro-L-arginine methyl ester (10 mg/kg) and a single dose of high-osmolar contrast medium meglumine amidotrizoate (6 ml/kg). DR and DRCM group rats were treated with rosuvastatin (10 mg/kg/day) by gavage for 5 days. At the end of treatment, the experimental groups were sacrificed, and their renal tissues were investigated histopathologically beside assessments of functional activities, nitric oxide metabolites, and oxidative stress and apoptic markers.
After 6 days, serum creatinine and urine microprotein were increased, and creatinine clearance, kidney nitrite were decreased in DCM rats compared with NDCM, D, DR and DRCM groups. Histopathology scores in group DCM were increased compared with groups NDCM, D and DR, but lower in group DRCM than in group DCM (p < 0.01). Kidney thiobarbituric acid-reacting substances (TBARS), serum malondialdehyde (MDA), and serum protein carbonyl content (PCC) were increased, and serum thiol was decreased in the DCM group compared with groups NDCM, D and DR; however, these results were reversed in group DRCM compared with group DCM. Both expression of IL-6, TNF-α and the percentage of apoptotic cells were increased in group DCM than in groups NDCM, D and DR, but they were decreased in group DRCM than in group DCM. The expression of phospho-p38, cleaved capase-3, and the Bax/Bcl-2 ratio, were increased in group DCM than in groups NDCM, D and DR, but were decreased in group DRCM than in group DCM.
Our study demonstrated that rosuvastatin treatment attenuated both inflammatory processes and apoptosis and inhibited oxidative stress and the p38 MAPK pathway in a diabetic rat model in the setting of CIN.
PMCID: PMC4329210
Diabetic; Contrast-induced nephropathy (CIN); Rosuvastatin
3.  Effects of nerve growth factor on nerve regeneration after corneal nerve damage 
The study aims to determine the relation between the effects of mouse nerve growth factor (mNGF) and nerve regeneration after corneal surgery nerve damage. Mechanical nerve injury animal model was established by LASIK (the excimer laser keratomileusis) surgery in 12 Belgian rabbits. mNGF and the balanced salt solution (BBS) were alternatively administered in the left and right eye two times every day for 8 weeks. The morphous and growth of the sub-basal nerve plexus and superficial stroma were observed by in vivo confocal microscopy at the end of weeks 1, 2, 4 and 8 after the surgery. The animal model is successfully established. The morphology and density of corneal nerve have been observed and demonstrated by confocal microscopy. A systematic administration of mNGF can significantly promote the nerve regeneration at the end of weeks 1, 2, 4 and 8, which comparing to the administration of balanced salt solution (P < 0.05). mNGF has effect on sub-basal nerve plexus and superficial stroma after corneal nerve damage which is caused by LASIK. The experimental results suggested that the mNGF may solve the problem of dry eye after LASIK.
PMCID: PMC4276247  PMID: 25550989
mNGF; LASIK; confocal microscopy; dry eye
4.  MeCP2 Phosphorylation Limits Psychostimulant-Induced Behavioral and Neuronal Plasticity 
The Journal of Neuroscience  2014;34(13):4519-4527.
The methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictive-like behaviors was unknown. Here we show that MeCP2 Ser421Ala knock-in mice display both a reduced threshold for the induction of locomotor sensitization by investigator-administered amphetamine and enhanced behavioral sensitivity to the reinforcing properties of self-administered cocaine. These behavioral differences were accompanied in the knock-in mice by changes in medium spiny neuron intrinsic excitability and nucleus accumbens gene expression typically observed in association with repeated exposure to these drugs. These data show that phosphorylation of MeCP2 at Ser421 functions to limit the circuit plasticities in the nucleus accumbens that underlie addictive-like behaviors.
PMCID: PMC3965780  PMID: 24671997
MeCP2; nucleus accumbens; psychostimulants; intrinsic excitability; GABAergic interneurons; cocaine self-administration
5.  Intra-Voxel Incoherent Motion MRI in Rodent Model of Diethylnitrosamine-Induced Liver Fibrosis 
Magnetic resonance imaging  2013;31(6):1017-1021.
Rationale and Objectives
To compare the apparent diffusion coefficient (ADC) and the perfusion fraction measured by intra-voxel incoherent motion (IVIM) Magnetic Resonance Imaging (MRI) with liver fibrosis degrees in a rodent model.
Materials and Methods
All experiments received approval from our institutional animal care and use committee. Liver fibrosis was induced in 17 rats by oral gavage with diethylnitrosamine. Diffusion Weighted MRI was the performed and 8 gradient factors (0, 50, 100, 150, 200, 300, 400 and 500 sec/mm2) were acquired. The values of ADC, true diffusion coefficient D and perfusion fraction f were measured based on Li Bihan’s method. The percentage of liver fibrosis was assessed via quantitative analysis of Masson trichrome staining using an average of 30 fields per section. The MRI measurements were compared to the histological fibrotic grade to evaluate the correlation between them.
ADC contained the contribution of diffusion and perfusion. The ADC and f values decreased significantly with the increasing fibrosis level (correlation coefficient: ADC: ρ = −0.781, p < 0.001; f: ρ = −0.720, p = 0.001); but D was poorly correlated with fibrosis level (ρ = −0.502, p = 0.040).
The hepatic ADC and the perfusion fraction f were significantly correlated with the liver fibrosis level; however, D was not. This might suggest that hepatic perfusion is altered during the progression of hepatic fibrosis.
PMCID: PMC3676695  PMID: 23598061
Intra-Voxel Incoherent Motion; Diffusion weighted MRI; liver fibrosis
6.  The Impact of Secondary Lymphedema after Head and Neck Cancer Treatment on Symptoms, Functional Status, and Quality Of Life 
Head & neck  2012;35(7):1026-1035.
Lymphedema may disrupt local function and affect quality of life (QOL) in patients with head and neck cancer. The study aim was to examine the associations among severity of internal and external lymphedema, symptoms, functional status, and QOL in patients with head and neck cancer.
The sample included 103 patients who were ≥3 months post head and neck cancer treatment. Variables assessed included severity of internal and external lymphedema, physical/psychological symptoms, functional status, and QOL.
Severity of internal and external lymphedema was associated with physical symptoms and psychological symptoms. Patients with more severe external lymphedema were more likely to have a decrease in neck left/right rotation. The combined effects of external and internal lymphedema severity were associated with hearing impairment and decreased QOL.
Lymphedema severity correlates with symptom burden, functional status, and QOL in patients post head and neck cancer treatment.
PMCID: PMC4017911  PMID: 22791550
Head and neck cancer; Lymphedema; Symptom; Functional Status; Quality of life (QOL)
7.  A neonatal gnotobiotic pig model of human enterovirus 71 infection and associated immune responses 
Vaccine development and pathogenesis studies for human enterovirus 71 are limited by a lack of suitable animal models. Here, we report the development of a novel neonatal gnotobiotic pig model using the non-pig-adapted neurovirulent human enterovirus 71 strain BJ110, which has a C4 genotype. Porcine small intestinal epithelial cells, peripheral blood mononuclear cells and neural cells were infected in vitro. Oral and combined oral–nasal infection of 5-day-old neonatal gnotobiotic pigs with 5×108 fluorescence forming units (FFU) resulted in shedding up to 18 days post-infection, with viral titers in rectal swab samples peaking at 2.22×108 viral RNA copies/mL. Viral capsid proteins were detected in enterocytes within the small intestines on post-infection days (PIDs) 7 and 14. Additionally, viral RNA was detected in intestinal and extra-intestinal tissues, including the central nervous system, the lung and cardiac muscle. The infected neonatal gnotobiotic pigs developed fever, forelimb weakness, rapid breathing and some hand, foot and mouth disease symptoms. Flow cytometry analysis revealed increased frequencies of both CD4+ and CD8+ IFN-γ-producing T cells in the brain and the blood on PID 14, but reduced frequencies were observed in the lung. Furthermore, high titers of serum virus-neutralizing antibodies were generated in both orally and combined oral–nasally infected pigs on PIDs 7, 14, 21 and 28. Together, these results demonstrate that neonatal gnotobiotic pigs represent a novel animal model for evaluating vaccines for human enterovirus 71 and for understanding the pathogenesis of this virus and the associated immune responses.
PMCID: PMC4051366
adaptive immune responses; animal model; human enterovirus 71; neonatal gnotobiotic pigs; pathogenesis; vaccine evaluation
8.  Identification of four novel serum protein biomarkers in sepsis patients encoded by target genes of sepsis-related miRNAs 
Clinical Science (London, England : 1979)  2014;126(Pt 12):857-867.
The goal of the present study was to identify novel protein biomarkers from the target genes of six serum miRNAs that we identified previously in patients with sepsis. The target genes were predicted by bioinformatics analysis; the levels of the respective proteins in the sera of patients with sepsis were detected by ELISA. ACVR2A (activin A receptor, type IIA), FOXO1 (forkhead box O1), IHH (Indian hedgehog), STK4 (serine/threonine kinase 4) and DUSP3 (dual specificity phosphatase 3) were predicted to be the targets of the six miRNAs, and their encoded proteins were used for biomarker identification. Levels of ACVR2A (P<0.01) and FOXO1 (P<0.01) were significantly different among normal controls, patients with sepsis, patients with severe sepsis and patients with septic shock. Furthermore, levels of ACVR2A (P=0.025), FOXO1 (P<0.001), IHH (P=0.001) and STK4 (P=0.001) were differentially expressed in survivors and non-survivors. DUSP3 levels were not significantly different between any groups. Conjoin analysis of the four differentially expressed proteins showed that the area under the curve of the predictive probabilities was 0.875 [95% CI (confidence interval): 0.785–0.965], which was higher than the SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. When the value of predictive probabilities was 0.449, the four proteins yielded a sensitivity of 68% and a specificity of 91%. Dynamic changes in ACVR2A, FOXO1 and IHH levels showed differential expression between survivors and non-survivors at all time points. On the basis of a combined analysis of the four identified proteins, their predictive value of 28-day mortality of patients with sepsis was better than the SOFA or APACHE II scores.
Four novel protein biomarkers encoded by the miRNA target genes were identified for patients with sepsis. The combined analysis of the four proteins indicated that their predictive value for sepsis prognosis was better than the values for the SOFA score and APACHE II score.
PMCID: PMC4202716  PMID: 24303815
ACVR2A (activin A receptor; type IIA); FOXO1 (forkhead box O1); IHH (Indian hedgehog); miRNA; sepsis; STK4 (serine/threonine kinase 4); ACVR2A, activin A receptor, type IIA; AIC, Akaike information criterion; APACHE II, Acute Physiology and Chronic Health Evaluation II; AUC, area under the curve; CI, confidence interval; CRP, C-reactive protein; DUSP3, dual specificity phosphatase 3; FOXO1, forkhead box O1; FRS2, factor receptor substrate 2; GO, Gene Ontology; ICU, intensive care unit; IHH, Indian hedgehog; IL-6, interleukin 6; IL-18, interleukin 18; KEGG, Kyoto Encyclopedia of Genes and Genomes; PCT, procalcitonin; ROC, receiver operating characteristic; SLC4A4, solute carrier family 4, member 4; SOFA, Sequential Organ Failure Assessment; STK4, serine/threonine kinase 4; TGF-β, transforming growth factor-β
9.  Adenoviruses Associated with Acute Diarrhea in Children in Beijing, China 
PLoS ONE  2014;9(2):e88791.
Adenoviruses have been recognized as important causal pathogens of community-acquired diarrhea (CAD) among children, but their role in hospital-acquired diarrhea (HAD) is not well-understood. Hospitalized children with acute diarrhea and children who visited the outpatient department due to diarrhea were investigated from 2011 to 2012. Adenovirus was detected in stool specimens by PCR and further characterized by sequencing and phylogenetic analysis. SPSS software (version 19.0) was used for statistical analyses. A total of 2233 diarrheal children were enrolled in this study; this sample was comprised of 1371 hospitalized children, including 885 with CAD (IP-CAD) and 486 with HAD, and 862 outpatients with CAD (OP-CAD). Among these 2,233 patients, adenovirus was detected in 219 cases (9.8%). The positive rates for adenovirus were significantly different between the IP-CAD (9.3%), HAD (13.8%) and OP-CAD (8.1%) cases (X2 = 11.76, p = 0.003). The positive rate of adenovirus was lower in infants under six months of age compared to the positive rates in the other age groups. Of the 219 of adenovirus positive patients, 91 (41.6%) were identified as having serotype 41. Although enteric adenovirus (group F) was the most frequently detected adenovirus among children with either CAD or HAD, the role of non-enteric adenoviruses, especially the adenovirus 31 type (19.7%), cannot be ignored in diarrheal children.
PMCID: PMC3923065  PMID: 24533149
10.  Analysis of the severity and prognosis assessment of aged patients with community-acquired pneumonia: a retrospective study 
Journal of Thoracic Disease  2013;5(5):626-633.
Community-acquired pneumonia (CAP) is a prevalent and potentially life-threatening infection, and has poor prognosis in aged patients. The objective of this study was to compare the potential of admission N-terminal pro B-type natriuretic peptide (proBNP) levels and scoring models [CURB-65, Pneumonia Severity Index (PSI), and Acute Physiology and Chronic Health Evaluation (APACHE) II scores] to predict outcomes for aged patients with CAP admitted to Intensive Care Unit (ICU), and to explore the prognostic factors.
Clinical data of the patients were collected retrospectively, whose CURB-65, PSI, APACHE II scores were calculated and in whom measurements of proBNP was performed. The outcomes of interest were severity evaluation, prediction of need for mechanical ventilation and 28-day mortality. Receiver operating characteristic (ROC) curve was conducted to predict the assessment ability of proBNP and scoring models on different outcomes, and the logistic regression analysis was performed to screen factors affecting prognosis.
240 patients were enrolled, with the mean age of 75±8 years old. Admission levels of NT-proBNP, scoring models were significantly higher in SCAP patients, MV group, and non-survivors compared to non-SCAP patients, no-MV group, and 28-day survivors, respectively (P<0.001). PSI had the highest area under the curve (AUC) and specificity for the three outcomes considered (AUC: 0.868 and specificity: 0.906 for 28-day mortality, AUC: 0.864 and specificity: 0.831 for requirement of MV, and AUC: 0.888 and specificity: 0.894 for severity evaluation). NT-proBNP had the highest sensitivity of 0.987 and 0.903 on prediction of mortality and need for MV. And APACHE II scoring model with the highest sensitivity of 0.890 was used to evaluate severity. Logistic regression analysis showed that the odd ratio (OR) of systolic blood pressure, PSI, and APACHE II scores were 0.886, 1.019, and 1.249.
PSI scores was the best indicator in predicting different clinical outcomes of aged patients with CAP among the proBNP and three scoring systems. Systolic blood pressure might be as a protective factor for prognosis while PSI and APACHE II scores as risk factors for prognosis of aged patients with CAP.
PMCID: PMC3815733  PMID: 24255776
Aged; community-acquired pneumonia (CAP); severity; prognosis
11.  Genetic Variation in Attachment Glycoprotein Genes of Human Respiratory Syncytial Virus Subgroups A and B in Children in Recent Five Consecutive Years 
PLoS ONE  2013;8(9):e75020.
Human respiratory syncytial virus (HRSV) outranks other viral agents as the cause of respiratory tract diseases in children worldwide. Molecular epidemiological study of the virus provides useful information for the development of globally effective vaccine. We investigated the circulating pattern and genetic variation in the attachment glycoprotein genes of HRSV in Beijing during 5 consecutive seasons from 2007 to 2012. Out of 19,942 tested specimens, 3,160 (15.8%) were HRSV antigen-positive. The incidence of HRSV infection in males was significantly higher than in females. Of the total 723 (23.1%) randomly selected HRSV antigen-positive samples, 462 (63.9%) and 239 (33.1%) samples were identified as subgroup A and B, respectively. Subgroups A and B co-circulated in the 5 consecutive HRSV seasons, which showed a shifting mixed pattern of subgroup dominance. Complete G gene sequences were obtained from 190 HRSV-A and 72 HRSV-B by PCR for phylogenetic analysis. Although 4 new genotypes, NA3 and NA4 for HRSV-A and BA-C and CB1 for HRSV-B, were identified here, they were not predominant; NA1 and BA9 were the prevailing HRSV-A and -B genotypes, respectively. We provide the first report of a 9 consecutive nucleotide insertion in 3 CB1 genotype strains. One Beijing strain of ON1 genotype with a 72 nucleotide insertion was found among samples collected in February 2012. The reversion of codon states in glycosylation sites to previous ones were found from HRSV strains in this study, suggesting an immune-escape strategy of this important virus.
PMCID: PMC3775769  PMID: 24069376
12.  Control of Respiratory Motion by Hypnosis Intervention during Radiotherapy of Lung Cancer I 
BioMed Research International  2013;2013:574934.
The uncertain position of lung tumor during radiotherapy compromises the treatment effect. To effectively control respiratory motion during radiotherapy of lung cancer without any side effects, a novel control scheme, hypnosis, has been introduced in lung cancer treatment. In order to verify the suggested method, six volunteers were selected with a wide range of distribution of age, weight, and chest circumference. A set of experiments have been conducted for each volunteer, under the guidance of the professional hypnotist. All the experiments were repeated in the same environmental condition. The amplitude of respiration has been recorded under the normal state and hypnosis, respectively. Experimental results show that the respiration motion of volunteers in hypnosis has smaller and more stable amplitudes than in normal state. That implies that the hypnosis intervention can be an alternative way for respiratory control, which can effectively reduce the respiratory amplitude and increase the stability of respiratory cycle. The proposed method will find useful application in image-guided radiotherapy.
PMCID: PMC3777187  PMID: 24093100
13.  Improved Survival and Reduced Phenotypic Severity Following AAV9/MECP2 Gene Transfer to Neonatal and Juvenile Male Mecp2 Knockout Mice 
Typical Rett syndrome (RTT) is a pediatric disorder caused by loss-of-function mutations in the MECP2 gene. The demonstrated reversibility of RTT-like phenotypes in mice suggests that MECP2 gene replacement is a potential therapeutic option in patients. We report improvements in survival and phenotypic severity in Mecp2-null male mice after neonatal intracranial delivery of a single-stranded (ss) AAV9/CBA-MECP2 vector. Median survival was 16.6 weeks for MECP2-treated versus 9.3 weeks for GFP-treated mice. ssAAV9/CBA-MECP2-treated mice also showed significant improvement in the phenotype severity score, in locomotor function and in exploratory activity, as well as a normalization of neuronal nuclear volume in transduced cells. Wild-type mice receiving neonatal injections of the same ssAAV9/CBA-MECP2 vector did not show any significant deficits, suggesting a tolerance for modest MeCP2 overexpression. To test a MECP2 gene replacement approach in a manner more relevant for human translation, a self-complementary AAV vector designed to drive MeCP2 expression from a fragment of the Mecp2 promoter was injected intravenously into juvenile (4-5 week-old) Mecp2-null mice. While the brain transduction efficiency in juvenile mice was low (~2-4% of neurons), modest improvements in survival were still observed. These results support the concept of MECP2 gene therapy for RTT.
PMCID: PMC3536818  PMID: 23011033
AAV; Gene Therapy; MeCP2; Rett Syndrome
14.  Effects of Vitamin B6 Therapy for Sepsis Patients with Linezolid-Associated Cytopenias: A Retrospective Study☆ 
The common adverse effects of linezolid for treating septic patients with gram-positive cocci is anemia and thrombocytopenia, which limit its clinical application.
We determined the effects of vitamin B6 adjunctive therapy on linezolid-associated cytopenias, and retrospectively studied 75 septic patients who received at least 7 days of linezolid treatment.
Patients were divided into a linezolid treatment group (LTG; n = 41) that received linezolid only and a combination treatment group (CTG; n = 34) that received both linezolid and vitamin B6. Each group was further subdivided into those with sepsis and those with severe sepsis. Each patient had red blood cell (RBC), hemoglobin (Hb), hematocrit (Hct), and platelet (PLT) measurements at baseline (day 0) and every other day for 2 weeks during treatment; these parameters were compared between the groups and assessed for time-dependent trends.
For patients in the LTG, RBC, Hb, and Hct values showed statistically significant reductions over time, and these values were lower compared with the values in the CTG. The CTG also showed downward trends, except on the first day of treatment. The PLT count also decreased in both groups. Patients with severe sepsis had lower PLT counts in both treatment groups compared with the septic patients.
Septic patients who received a combination treatment of linezolid and vitamin B6 might show positive effects for linezolid-associated reductions in some hematologic parameters (RBC, Hb, and Hct). This combined treatment might also slow PLT reduction, which was more evident in patients with severe sepsis. identifier: NCT01295801.
PMCID: PMC3862191  PMID: 24385027
linezolid; linezolid-associated cytopenias; sepsis; vitamin B6
15.  Entecavir plus adefovir rescue therapy for chronic hepatitis B patients after multiple treatment failures in real-life practice 
Virology Journal  2013;10:162.
To evaluate the efficacy and safety of Entecavir (ETV) plus adefovir (ADV) for chronic hepatitis B (CHB) patients after multiple nucleos(t)ide analogue (NAs) failure treatment.
Hepatitis B e antigen (HBeAg)-positive patients who had a suboptimal response or developed resistance to two or more previous NAs treatments were included, and all subjects were treated with ETV in combination with ADV for ≥ 24 months. Complete virologic response (CVR) was defined as an undetectability of serum hepatitis B virus (HBV) DNA level during treatment. Safety assessment was based on the increasing of serum creatinine and creatine kinase levels.
A total of 45 eligible patients were included. Twenty-five patients had been treated with lamivudine (LAM) or telbivudine (LdT) and developed genotypic resistance. Resistance to ADV was present in 18 patients and 4 patients had a suboptimal response to ETV. Two patients had a resistance to both LAM and ADV. The cumulative probabilities of CVR at 12 and 24 months of ETV + ADV treatment were 88.9% (40/45) and 97.8% (44/45), respectively. Although one patient failed to achieve CVR, its serum HBV DNA level decreased by 3.3 log copies/mL after 24 months of combination therapy. The cumulative probability of HBeAg seroconversion was 15.6% (7/45) and 26.7% (12/45) at 12 and 24 months of treatment, respectively. History of prior exposure to specific NAs did not make a difference to ETV + ADV treatment outcome. There were no significant adverse events related to ETV + ADV therapy observed in the study subjects.
ETV + ADV can be used as an effective and safe rescue therapy in patients after multiple NA therapy failures, especially in the areas where tenofovir is not yet available.
PMCID: PMC3680075  PMID: 23706010
Chronic hepatitis B; Multiple failures; Resistance; Combination therapy; Entecavir; Adefovir
16.  Inhibition of preadipocyte differentiation and adipogenesis by zinc‐α2‐glycoprotein treatment in 3T3‐L1 cells 
Zinc‐α2‐glycoprotein (ZAG) is associated with the loss of adipose tissue in cancer cachexia, and has recently been proposed to be a candidate factor in the regulation of bodyweight. The aim of the study was to investigate the effects of ZAG on the proliferation and differentiation of 3T3‐L1 preadipocytes.
Materials and Methods
3‐(4,5‐Dimethylthiazol‐2‐yl) 2,5‐diphenyl tetrazolium bromide (MTT) spectrophotometry, Oil Red O staining, intracellular triglyceride assays, real‐time quantitative reverse transcription polymerase chain reaction and transient transfection methods were used to explore the action of ZAG.
Ectopic ZAG expression significantly stimulates 3T3‐L1 cells proliferation in a dose‐ and time‐dependent manner. The maximum influence of ZAG on proliferation was 1.43‐fold higher than what was observed in control cells. This effect was observed 144 h after transfection with 0.16 μg of murine ZAG (mZAG) plasmid (P < 0.001). The intracellular lipids content in mZAG over‐expressing cells were decreased as much as 37% when compared with the control cells after differentiation (P < 0.05, P < 0.01). The messenger ribonucleic acid levels of peroxisome proliferators‐activated receptor‐γ (PPARγ), CCAAT enhancer‐binding protein‐α (C/EBPα) and the critical lipogenic gene, fatty acid synthase (FAS), are also downregulated by up to 50% in fully differentiated ZAG‐treated adipocytes. ZAG suppresses FAS messenger ribonucleic acid expression by reducing FAS promoter activity.
Zinc‐α2‐glycoprotein stimulates the proliferation and inhibits the differentiation of 3T3‐L1 murine preadipocytes. The inhibitory action of ZAG on cell differentiation might be a result of the attenuation of the expression of PPARγ, C/EBPα and the lipogenic‐specific enzyme FAS by reducing FAS promoter activity.
PMCID: PMC4015661  PMID: 24843663
3T3‐L1 preadipocytes; Differentiation; Zinc‐α2‐glycoprotein
17.  Nanoporous CREG-Eluting Stent Attenuates In-Stent Neointimal Formation in Porcine Coronary Arteries 
PLoS ONE  2013;8(4):e60735.
The goal of this study was to evaluate the efficacy of a nanoporous CREG-eluting stent (CREGES) in inhibiting neointimal formation in a porcine coronary model.
In vitro proliferation assays were performed using isolated human endothelial and smooth muscle cells to investigate the cell-specific pharmacokinetic effects of CREG and sirolimus. We implanted CREGES, control sirolimus-eluting stents (SES) or bare metal stents (BMS) into pig coronary arteries. Histology and immunohistochemistry were performed to assess the efficacy of CREGES in inhibiting neointimal formation.
CREG and sirolimus inhibited in vitro vascular smooth muscle cell proliferation to a similar degree. Interestingly, human endothelial cell proliferation was only significantly inhibited by sirolimus and was increased by CREG. CREGES attenuated neointimal formation after 4 weeks in porcine coronary model compared with BMS. No differences were found in the injury and inflammation scores among the groups. Scanning electron microscopy and CD31 staining by immunohistochemistry demonstrated an accelerated reendothelialization in the CREGES group compared with the SES or BMS control groups.
The current study suggests that CREGES reduces neointimal formation, promotes reendothelialization in porcine coronary stent model.
PMCID: PMC3616099  PMID: 23573278
18.  Expression of WNT-5a and ROR2 correlates with disease severity in osteosarcoma 
Molecular Medicine Reports  2012;5(4):1033-1036.
Osteosarcoma, a common malignancy primarily affecting children, generally has a poor prognosis. Novel diagnostic, prognostic and therapeutic markers are required to ameliorate the negative outcomes of this disease. We investigated two potential markers, WNT-5a and ROR2, which are hypothesized to dysregulate WNT signaling pathways to promote tumorigenesis in other types of cancer. We investigated WNT-5a and ROR2 expression using immunohistochemistry in 42 osteosarcoma and 12 osteochondroma specimens, and compared the expression of these proteins with one another as well as with clinicopathological parameters. WNT-5a was detected in 34/42 (81.0%) cases and ROR2 was detected in 31/42 (73.8%) cases, significantly higher than in osteochondroma (16.7 and 25.0%, respectively; both P<0.05). Expression of these proteins was positively correlated (r=0.552, P<0.05). Furthermore, expression of WNT-5a and ROR2 was both correlated with Enneking surgical stage and tumor metastasis (P<0.05), but not with patient gender, age or pathological type. Thus, WNT-5a and ROR2 were more highly expressed in more severe disease states, and therefore may play a coordinated role in the occurrence and progression of osteosarcoma.
PMCID: PMC3493076  PMID: 22293903
osteosarcoma; Wnt-5a; Ror2; immunohistochemistry; clinicopathological parameter
20.  Identification of Novel Biomarkers for Sepsis Prognosis via Urinary Proteomic Analysis Using iTRAQ Labeling and 2D-LC-MS/MS 
PLoS ONE  2013;8(1):e54237.
Sepsis is the major cause of death for critically ill patients. Recent progress in proteomics permits a thorough characterization of the mechanisms associated with critical illness. The purpose of this study was to screen potential biomarkers for early prognostic assessment of patients with sepsis.
For the discovery stage, 30 sepsis patients with different prognoses were selected. Urinary proteins were identified using isobaric tags for relative and absolute quantitation (iTRAQ) coupled with LC-MS/MS. Mass spec instrument analysis were performed with Mascot software and the International Protein Index (IPI); bioinformatic analyses were used by the algorithm of set and the Gene Ontology (GO) Database. For the verification stage, the study involved another 54 sepsis-hospitalized patients, with equal numbers of patients in survivor and non-survivor groups based on 28-day survival. Differentially expressed proteins were verified by Western Blot.
A total of 232 unique proteins were identified. Proteins that were differentially expressed were further analyzed based on the pathophysiology of sepsis and biomathematics. For sepsis prognosis, five proteins were significantly up-regulated: selenium binding protein-1, heparan sulfate proteoglycan-2, alpha-1-B glycoprotein, haptoglobin, and lipocalin; two proteins were significantly down-regulated: lysosome-associated membrane proteins-1 and dipeptidyl peptidase-4. Based on gene ontology clustering, these proteins were associated with the biological processes of lipid homeostasis, cartilage development, iron ion transport, and certain metabolic processes. Urinary LAMP-1 was down-regulated, consistent with the Western Blot validation.
This study provides the proteomic analysis of urine to identify prognostic biomarkers of sepsis. The seven identified proteins provide insight into the mechanism of sepsis. Low urinary LAMP-1 levels may be useful for early prognostic assessment of sepsis.
Trial Registration NCT01493492
PMCID: PMC3553154  PMID: 23372690
21.  Voices from the Shadows: Living with Lymphedema 
Cancer nursing  2012;35(1):E18-E26.
Breast cancer survivors with lymphedema face a lifetime of stressful physical and emotional symptoms and challenging self-care demands. An in-depth understanding of the perceptions and feelings surrounding life with lymphedema is critical to developing effective supportive care approaches.
To explore perceptions and feelings related to lymphedema in breast cancer survivors.
The expressive writings of 39 individuals were evaluated for this descriptive qualitative study. Data were analyzed using conventional content analysis.
Qualitative analyses produced four major themes: (1) marginalization and minimization; (2) multiplying losses; (3) yearning to return to normal; (4) uplifting resources. Sub-themes for each major theme were also identified.
The lymphedema experiences of breast cancer survivors reveal perceptions of marginalization from healthcare providers who are not well informed about lymphedema management and minimize its impact. Multiple distressing losses confront these patients on a daily basis, including body image disturbances, loss of functionality and control over time, permanent uncertainty, and adverse effects on relationships. The daily challenges of lymphedema often result in cumulative frustration and resentment that contribute to failure to perform self-care. Normalcy has been lost, never to return. These women find solace, encouragement and hope to meet the challenges of lymphedema through support from others and their spiritual beliefs.
Implication for Practice
Healthcare providers need greater awareness of the physical and psychosocial effects of lymphedema in breast cancer survivors. Nurses have unique opportunities to serve as advocates for reducing perceived marginalization and promoting effective self-care and other activities that promote psychological well-being and reduce physical deterioration.
PMCID: PMC3172392  PMID: 21558848
Lymphedema; Breast Cancer; Marginalization; Psychosocial Stress; Cancer Treatment Late-effects; Qualitative Research; Women’s Health
22.  Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin 
Neuropsychopharmacology  2011;37(2):321-337.
Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional- and cell-type specificity of pMeCP2 induction. The D1-class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D2-class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NET-knockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region- and cell-type specific pMeCP2 in the CNS.
PMCID: PMC3242304  PMID: 21956448
MeCP2; monoamine transporters; signal transduction; dopamine; serotonin; nucleus accumbens; dopamine; serotonin; neuropharmacology; signal transduction; MeCP2; monoamine transporters; nucleus accumbens
23.  Clinical Presentations, Antiplatelet Strategies and Prognosis of Patients with Stent Thrombosis: An Observational Study of 140 Patients 
PLoS ONE  2012;7(10):e48520.
Until now there has been scarce evidence regarding an optimal antiplatelet strategy and clinical outcomes for patients who had suffered from stent thrombosis (ST).
Methods and Results
140 patients who suffered from stent thrombosis were prospectively registered. Patients received dual (aspirin and 150 mg clopidogrel, N = 66) or triple (additional cilostazol, N = 74) antiplatelet therapy at the physician’s discretion. Thereafter platelet reactivity and one year clinical outcomes were analyzed. The primary outcome included the composite of cardiac death, non-fatal myocardial infarction (MI) or stroke at one year,which developed in 41 (29.3%) patients, consisting of 31 (22.1%) cardiac death, 9 (6.4%) non-fatal MI and 1 (1.4%) stroke. Recurrent definite and probable ST according to ARC definition was observed in 8 (5.7%) and 14 (10.0%) patients, respectively. Triple therapy was associated with significantly lower platelet reactivities (50.2±17.8, % vs. 59.6±17.2, %, P = 0.002) compared to high dose dual antiplatelet therapy. However, the incidence of primary events (24.3% vs. 34.8%, P = 0.172) did not differ between triple and dual antiplatelet therapies. High on-treatment platelet reactivity (HR: 8.35, 95% CI: 2.234∼30.867, P = 0.002) and diabetes (HR: 3.732, 95% CI: 1.353∼10.298, P = 0.011) were independent predictors of primary events.
Patients who suffered from stent thrombosis have a poor prognosis even after revascularization with intensive antiplatelet therapy. Triple antiplatelet therapy was more effective in reducing on-treatment platelet reactivity, compared to high dose dual antiplatelet therapy.
PMCID: PMC3485366  PMID: 23119044
24.  Maternal Mortality in Henan Province, China: Changes between 1996 and 2009 
PLoS ONE  2012;7(10):e47153.
Maternal deaths occur mostly in developing countries and the majority of them are preventable. This study analyzes changes in maternal mortality and related causes in Henan Province, China, between 1996 and 2009, in an attempt to provide a reliable basis for introducing effective interventions to reduce the maternal mortality ratio (MMR), part of the fifth Millennium Development Goal.
Methods and Findings
This population-based maternal mortality survey in Henan Province was carried out from 1996 to 2009. Basic information was obtained from the health care network for women and children and the vital statistics system, from specially trained monitoring personnel in 25 selected monitoring sites and by household survey in each case of maternal death. This data was subsequently reported to the Henan Provincial Maternal and Child Healthcare Hospital. The total MMR in Henan Province declined by 78.4%, from 80.1 per 100 000 live births in 1996 to 17.3 per 100 000 live births in 2009. The decline was more pronounced in rural than in urban areas. The most common causes of maternal death during this period were obstetric hemorrhage (43.8%), pregnancy-induced hypertension (15.8%), amniotic fluid embolism (13.9%) and heart disease (8.0%). The MMR was higher in rural areas with lower income, less education and poorer health care.
There was a remarkable decrease in the MMR in Henan Province between 1996 and 2009 mainly in the rural areas and MMR due to direct obstetric causes such as obstetric hemorrhage. This study indicates that improving the health care network for women, training of obstetric staff at basic-level units, promoting maternal education, and increasing household income are important interventional strategies to reduce the MMR further.
PMCID: PMC3470574  PMID: 23071740
25.  Genome Sequencing of Five Shewanella baltica Strains Recovered from the Oxic-Anoxic Interface of the Baltic Sea 
Journal of Bacteriology  2012;194(5):1236.
Here we describe five Shewanella baltica genomes recovered from the same sample, as well as 12 years apart from the same sampling station. These genomes expand the collection of previously sequenced S. baltica strains and represent a valuable resource for assessing the role of environmental settings on genome adaptation.
PMCID: PMC3294791  PMID: 22328742

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