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1.  Ultrasonic Modeling and Hydrophone Measurements of Dual Divergent Transducers for Wearable Therapeutic Ultrasound Device 
This paper models and experimentally measures the acoustic interference from two low intensity 3MHz continuous ultrasound transducers of the sam® wearable ultrasound device. Resulting data show that placement configuration, which dictates interference depth, and frequency phase variation are the main factors to acoustic pressure distribution. Mathematical analysis reveals that the acoustic pressure distribution from continuous ultrasound is modulated by near field variations at shallow tissue depths. This observation is useful in the application of sam® and in the further research of its therapeutic benefits.
doi:10.1109/EMBC.2014.6943652
PMCID: PMC4313554  PMID: 25570020
2.  The effects of psychological interventions on depression and anxiety among Chinese adults with cancer: a meta-analysis of randomized controlled studies 
BMC Cancer  2014;14(1):956.
Background
Our previous studies found the high prevalence of depression and anxiety among Chinese cancer patients, and many empirical studies have been conducted to evaluate the effects of psychological interventions on depression and anxiety among Chinese cancer patients. This study aimed to conduct a meta-analysis in order to assess the effects of psychological interventions on depression and anxiety in Chinese adults with cancer.
Methods
The four most comprehensive Chinese academic database- CNKI, Wanfang, Vip and CBM databases-were searched from their inception until January 2014. PubMed and Web of Science (SCIE) were also searched from their inception until January 2014 without language restrictions, and an internet search was used. Randomized controlled studies assessing the effects of psychological interventions on depression and anxiety among Chinese adults with cancer were analyzed. Study selection and appraisal were conducted independently by three authors. The pooled random-effects estimates of standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated. Moderator analysis (meta-regression and subgroup analysis) was used to explore reasons for heterogeneity.
Results
We retrieved 147 studies (covering 14,039 patients) that reported 253 experimental-control comparisons. The random effects model showed a significant large effect size for depression (SMD = 1.199, p < 0.001; 95% CI = 1.095-1.303) and anxiety (SMD = 1.298, p < 0.001; 95% CI = 1.187-1.408). Cumulative meta-analysis indicated that sufficient evidence had accumulated since 2000–2001 to confirm the statistically significant effectiveness of psychological interventions on depression and anxiety in Chinese cancer patients. Moderating effects were found for caner type, patients’ selection, intervention format and questionnaires used. In studies that included lung cancer, preselected patients with clear signs of depression/anxiety, adopted individual intervention and used State-Trait Anxiety Inventory (STAI), the effect sizes were larger.
Conclusions
We concluded that psychological interventions in Chinese cancer patients have large effects on depression and anxiety. The findings support that an adequate system should be set up to provide routine psychological interventions for cancer patients in Chinese medical settings. However, because of some clear limitations (heterogeneity and publication bias), these results should be interpreted with caution.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-956) contains supplementary material, which is available to authorized users.
doi:10.1186/1471-2407-14-956
PMCID: PMC4301929  PMID: 25510213
Psychological intervention; Ddepression; Anxiety; Chinese adults with cancer; Meta-analysis
3.  Netrin-1 overexpression promotes white matter repairing and remodeling after focal cerebral ischemia in mice 
Damage of oligodendrocytes after ischemia has negative impact on white matter integrity and neuronal function. In this work, we explore whether Netrin-1 (NT-1) overexpression facilitates white matter repairing and remodeling. Adult CD-1 mice received stereotactic injection of adeno-associated virus carrying NT-1 gene (AAV-NT-1). One week after gene transfer, mice underwent 60 minutes of middle cerebral artery occlusion. The effect of NT-1 on neural function was evaluated by neurobehavioral tests. Proliferated oligodendrocyte progenitor cells (OPCs), newly matured oligodendrocytes, and remyelination were semi-quantified by immunohistochemistry. The role of NT-1 in oligodendrogenesis was further explored by examining specific NT-1 receptors and their function. Netrin-1 overexpression was detected in neurons and astrocytes 2 weeks after AAV-NT-1 gene transfer and significantly improved the neurobehavioral outcomes compared with the control (P<0.05). In comparison with the control, proliferated OPCs, newly matured oligodendrocytes, and remyelination were greatly increased in the ipsilateral hemisphere of AAV-NT-1-transduced mice. Furthermore, both NT-1 receptors deleted in colorectal carcinoma and UNC5H2 were expressed on OPCs whereas only UNC5H2 was expressed in myelinated axons. Our study indicated that NT-1 promoted OPC proliferation, differentiation, and increased remyelination, suggesting that NT-1 is a promising factor for white matter repairing and remodeling after ischemia.
doi:10.1038/jcbfm.2013.150
PMCID: PMC3851901  PMID: 23963365
ischemia; netrin-1; oligodendrocyte progenitor cells; remyelination; white matter
4.  Higher Fibrinogen Level is Independently Linked with the Presence and Severity of New-Onset Coronary Atherosclerosis among Han Chinese Population 
PLoS ONE  2014;9(11):e113460.
Background
Fibrinogen is a coagulation/inflammatory biomarker strongly associated with atherogenesis. However, no data is currently available regarding the association of fibrinogen level with the presence and severity of new-onset coronary atherosclerosis assessed by Gensini score (GS), particularly in Han Chinese with a large sample size.
Methods and Results
We studied 2288 consecutive, new-onset subjects undergoing coronary angiography with angina-like chest pain. Clinical and laboratory data were collected. Coronary stenotic lesions were considered to be the incidence of coronary atherosclerosis. The severity of coronary stenosis was determined by the GS system. Data indicated that patients with high GS had significantly elevated fibrinogen level (p<0.001). The prevalence and severity of coronary atherosclerosis were dramatically increased according to fibrinogen tertiles. Spearman correlation analysis revealed a positive association between fibrinogen level and GS (r = 0.138, p<0.001). Multivariate logistic regression analysis demonstrated that plasma fibrinogen level was independently associated with high GS (OR = 1.275, 95% CI 1.082–1.502, p = 0.004) after adjusting for potential confounders. Moreover, fibrinogen level was also independently related to the presence of coronary atherosclerosis (fibrinogen tertile 2: OR = 1.192, 95% CI 0.889–1.598, p = 0.241; tertile 3: OR = 2.003, 95% CI 1.383–2.903, p <0.001) and high GS (fibrinogen tertile 2: OR = 1.079, 95% CI 0.833–1.397, p = 0.565; tertile 3: OR = 1.524, 95% CI 1.155–2.011, p = 0.003) in a dose-dependent manner. Receiver-operating characteristic curve analysis showed that the best fibrinogen cut-off value for predicting the severity of coronary stenosis was 3.21 g/L.
Conclusions
Higher fibrinogen level is independently linked with the presence and severity of new-onset coronary atherosclerosis in Han Chinese population.
doi:10.1371/journal.pone.0113460
PMCID: PMC4245131  PMID: 25426943
5.  Policosanol Attenuates Statin-Induced Increases in Serum Proprotein Convertase Subtilisin/Kexin Type 9 When Combined with Atorvastatin 
Objective. Statin treatment alone has been demonstrated to significantly increase plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The effect of policosanol combined with statin on PCSK9 is unknown. Methods. Protocol I: 26 patients with atherosclerosis were randomly assigned to receive either atorvastatin 20 mg/d or policosanol 20 mg/d + atorvastatin 20 mg/d for 8 weeks. Protocol II: 15 healthy volunteers were randomly assigned to either policosanol 20 mg/d or a control group for 12 weeks. Serum levels of PCSK9 were determined at day 0 and the end of each protocol. Results. Protocol I: atorvastatin 20 mg/d significantly increased serum PCSK9 level by 39.4% (256 ± 84 ng/mL versus 357 ± 101 ng/mL, P = 0.002). However, policosanol 20 mg/d + atorvastatin 20 mg/d increased serum PCSK9 level by only 17.4% without statistical significance (264 ± 60 ng/mL versus 310 ± 86 ng/mL, P = 0.184). Protocol II: there was a trend toward decreasing serum PCSK9 levels in the policosanol group (289 ± 71 ng/mL versus 235 ± 46 ng/mL, P = 0.069). Conclusion. Policosanol combined with statin attenuated the statin-induced increase in serum PCSK9 levels. This finding indicates that policosanol might have a modest effect of lowering serum PCSK9 levels.
doi:10.1155/2014/926087
PMCID: PMC4247936  PMID: 25478000
6.  Advances in treatment of ulcerative colitis with herbs: From bench to bedside 
World Journal of Gastroenterology : WJG  2014;20(39):14099-14104.
Ulcerative colitis (UC), an idiopathic inflammatory disorder in the colon, has become a clinical challenge, owing to the increasing incidence and poor prognosis. The conventional treatments for UC including aminosalicylates, corticosteroids, and immunosuppressants, induce remission in only half of patients. Meanwhile, the treatments often come with serious side effects which can be life-threatening. Herbal medicine, one of the most common traditional Chinese medicine modalities, has been introduced for centuries into clinical treatment of many human diseases such as infections and functional disorders. Recently, the potential effectiveness of herbs has been suggested as the treatment of UC, as shown by a variety of clinical trials and experimental studies. The herbs reported in the literature include aloe vera gel, butyrate, tormentil extracts, wheat grass juice, and curcumin. In the review, bioactivity of the herbs and their involvement in UC treatment are discussed.
doi:10.3748/wjg.v20.i39.14099
PMCID: PMC4202341  PMID: 25339799
Inflammatory bowel disease; Herbs; Herb medicine; Ulcerative colitis; Therapy; Safety
7.  Metformin attenuates blood-brain barrier disruption in mice following middle cerebral artery occlusion 
Background
Metformin, a widely used hypoglycemic drug, reduces stroke incidence and alleviates chronic inflammation in clinical trials. However, the effect of metformin in ischemic stroke is unclear. Here, we investigated the effect of metformin on ischemic stroke in mice and further explored the possible underlying mechanisms.
Methods
Ninety-eight adult male CD-1 mice underwent 90-minute transient middle cerebral artery occlusion (tMCAO). Metformin (200 mg/kg) was administrated for up to 14 days. Neurobehavioral outcomes, brain infarct volume, inflammatory factors, blood-brain barrier (BBB) permeability and AMPK signaling pathways were evaluated following tMCAO. Oxygen glucose deprivation was performed on bEND.3 cells to explore the mechanisms of metformin in inhibiting inflammatory signaling pathways.
Results
Infarct volume was reduced in metformin-treated mice compared to the control group following tMCAO (P < 0.05). Neurobehavioral outcomes were greatly improved in metformin-treated mice (P < 0.05). MPO+ cells, Gr1+ cells, MPO activity and BBB permeability were decreased after metformin administration (P < 0.05). In addition, metformin activated AMPK phosphorylation, inhibited NF-κB activation, down-regulated cytokine (IL-1β, IL-6, TNF-α) and ICAM-1 expression following tMCAO (P < 0.05). Furthermore, metformin activated AMPK signaling pathway and alleviated oxygen-glucose deprivation-induced ICAM-1 expression in bEND.3 cells (P < 0.05). Compound C, a selective AMPK inhibitor, eliminated this promotional effect.
Conclusions
Metformin down-regulated ICAM-1 in an AMPK-dependent manner, which could effectively prevent ischemia-induced brain injury by alleviating neutrophil infiltration, suggesting that metformin is a promising therapeutic agent in stroke therapy.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-014-0177-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-014-0177-4
PMCID: PMC4201919  PMID: 25315906
Blood-brain barrier; ICAM-1; Inflammation; Ischemic stroke; Metformin
8.  Intraocular Pressure and Associations in Children. The Gobi Desert Children Eye Study 
PLoS ONE  2014;9(10):e109355.
Purpose
To assess the intraocular pressure (IOP) and its association in children in a population living in an oasis in the Gobi Desert.
Methods
The cross-sectional school-based study included all schools in the Ejina region. The children underwent an ophthalmic examination, non-contact tonometry and measurement of blood pressure and body height and weight.
Results
Out of eligible 1911 children, 1565 (81.9%) children with a mean age of 11.9±3.5 years (range: 6–21 years) participated. Mean spherical refractive error was −1.58±2.00 diopters. In multivariate analysis, higher IOP (right eye) was associated with younger age (P<0.001; standardized coefficient beta: −0.13; regression coefficient B: −0.13; 95% Confidence interval (CI):−0.18, −0.07), higher diastolic blood pressure (P<0.001;beta:0.13;B:0.05;95%CI:0.03,0.07), higher corneal refractive power (P<0.001;beta:0.11;B:0.23;95%CI:0.12,0.34), more myopic refractive error (P = 0.035;beta: −0.06;B: −0.10;95%CI: −0.19, −0.001), and Han Chinese ethnicity of the father (P = 0.03;beta:0.06;B:0.42;95%CI:0.04,0.89). If age and diastolic blood pressure were dropped, higher IOP was associated with higher estimated cerebrospinal fluid pressure (CSFP) (P<0.001;beta:0.09; B:0.13;95%CI:0.06,0.21) after adjusting for higher corneal refractive power (P<0.001) and Han Chinese ethnicity of the father (P = 0.04). Correspondingly, higher IOP of the left eye was associated with younger age (P<0.001;beta: −0.15;B: −0.16;95%CI: −0.21, −0.10), female gender (P<0.001;beta:0.09;B:0.65;95%CI:0.30,1.01), higher corneal refractive power (P<0.001;beta:0.08;B:0.19;95%CI:0.06,0.32), more myopic refractive error (P = 0.03;beta: −0.06;B: −0.12;95%CI: −0.22, −0.01), and higher estimated CSFP (P<0.001;beta:0.11;B:0.17;95%CI:0.09,0.24).
Conclusions
In school children, higher IOP was associated with steeper corneal curvature and with younger age and higher blood pressure, or alternatively, with higher estimated CSFP. Corneal curvature radius should be included in the correction of IOP measurements. The potential association between IOP and CSFP as also assumed in adults may warrant further research.
doi:10.1371/journal.pone.0109355
PMCID: PMC4190171  PMID: 25295855
9.  Clinical features of coronary artery ectasia in the elderly 
Objective
To investigate the incidence, imaging and clinical characteristics in elderly patients with coronary artery ectasia (CAE).
Methods
A retrospective analysis was conducted on patients with CAE who underwent coronary angiography between January 2006 and December 2012. According to age, the enrolled patients were divided into two groups (elderly group, age ≥ 65 years; non-elderly group, age < 65 years). The clinical feature, imaging characteristics and the 5-year survival rate of the two groups were compared.
Results
The prevalence of CAE in elderly patients was 0.33%. Patients in elderly group were found to have significantly higher proportion of female (30.1% vs. 10.1%, P < 0.001), three-vessel disease (60.5% vs. 45.2%, P = 0.003) and localized ectasia (55.0% vs. 40.2%, P = 0.003). In addition, body mass index (20.90 ± 2.71 kg/m2 vs. 22.31 ± 2.98 kg/m2, P < 0.001) and percentage of current smokers (45.0% vs. 64.6%, P < 0.001) were significantly lower in elderly group. Cumulative survival curves demonstrated reduced 5-year cumulative survival at the follow-up in the elderly group compared with the non-elderly group (88.0% vs. 96.0%, P = 0.002). But the 5-year event free survival rate failed to show a significant difference between the two groups (31.0% vs. 35.0%, P = 0.311).
Conclusion
The prevalence of CAE in elderly patients was 0.33%, which was about 1/3 of the entire numbers of CAE patients. There were significant differences between the elderly and the non-elderly patients with CAE in terms of coronary artery disease risk factors and coronary artery ectatic characteristics. CAE might be associated with increased mortality risk in the elderly.
doi:10.11909/j.issn.1671-5411.2014.03.012
PMCID: PMC4178508  PMID: 25278965
Coronary artery ectasia; Elderly patients; Clinical feature
10.  Comparative analysis of diosgenin in Dioscorea species and related medicinal plants by UPLC-DAD-MS 
BMC Biochemistry  2014;15:19.
Background
Dioscorea is a genus of flowering plants, and some Dioscorea species are known and used as a source for the steroidal sapogenin diosgenin. To screen potential resource from Dioscorea species and related medicinal plants for diosgenin extraction, a rapid method to compare the contents of diosgenin in various plants is crucial.
Results
An ultra-performance liquid chromatography (UPLC) coupled with diode array detection (DAD) and electrospray ionization mass spectrometry (ESI-MS) method was developed for identification and determination of diosgenin in various plants. A comprehensive validation of the developed method was conducted. Twenty-four batches of plant samples from four Dioscorea species, one Smilax species and two Heterosmilax species were analyzed by using the developed method.
The present method presented good sensitivity, precision and accuracy. Diosgenin was found in three Dioscorea species and one Heterosmilax species, namely D. zingiberensis, D. septemloba, D. collettii and H. yunnanensis.
Conclusion
The method is suitable for the screening of diosgenin resources from plants. D. zingiberensis is an important resource for diosgenin harvesting.
doi:10.1186/1471-2091-15-19
PMCID: PMC4131487  PMID: 25107333
Diosgenin; UPLC-DAD-MS; Dioscorea; Medicinal plants; Quality evaluation
11.  In Vitro Anti-Influenza Virus Activities of a New Lignan Glycoside from the Latex of Calotropis gigantea 
PLoS ONE  2014;9(8):e104544.
A new lignan glycoside, (+)-pinoresinol 4-O-[6″-O-vanilloyl]-β-d-glucopyranoside (1) and two known phenolic compounds, 6′-O-vanilloyltachioside (2) and 6′-O-vanilloylisotachioside (3) were isolated from the latex of Calotropis gigantea (Asclepiadaceae). The structure of the new compound was elucidated by using spectroscopic and chemical methods. Three isolates (1–3) and one authentic compound, (+)-pinoresinol 4-O-β-d-glucopyranoside, were screened for A/PR/8/34 (H1N1) inhibitory activity by cytopathic effect (CPE) inhibition assay on MDCK cells. Compound 1 showed inhibitory activity against A/PR/8/34 (H1N1). In sharp contrast, the other three compounds (2, 3 and (+)-pinoresinol 4-O-β-d-glucopyranoside) did not show such activity. An analysis of structure-activity relationship between 1 and (+)-pinoresinol 4-O-β-d-glucopyranoside revealed that the presence of a vanilloyl group in the sugar moiety of 1 is crucial for its anti-influenza virus activity. Compound 1 was further evaluated for in vitro inhibitory activities against a panel of human and avian influenza viruses by CPE inhibition assay. It showed inhibitory effect against human influenza viruses in both subtypes A and B (IC50 values around 13.4–39.8 µM with SI values of 3.7–11.4), while had no effect on avian influenza viruses. Its antiviral activity against human influenza viruses subtype A was further confirmed by plaque reduction assay. The time course assay indicated that 1 exerts its antiviral activity at the early stage of viral replication. A mechanistic study showed that 1 efficiently inhibited influenza virus-induced activation of NF-κB pathway in a dose-dependent manner, but had no effect on virus-induced activation of Raf/MEK/ERK pathway. Further studies demonstrated that nuclear translocation of transcription factor NF-κB induced by influenza virus was significantly blocked by 1, meanwhile, nuclear export of viral ribonucleoproteins was also effectively inhibited. These findings suggest that this new lignan glycoside from Calotropis gigantea, may have therapeutic potential in influenza virus infection through inhibition of NF-κB pathway and viral ribonucleoproteins nuclear export.
doi:10.1371/journal.pone.0104544
PMCID: PMC4125211  PMID: 25102000
12.  Characterization and Evolutionary Implications of the Triad Asp-Xxx-Glu in Group II Phosphopantetheinyl Transferases 
PLoS ONE  2014;9(7):e103031.
Phosphopantetheinyl transferases (PPTases), which play an essential role in both primary and secondary metabolism, are magnesium binding enzymes. In this study, we characterized the magnesium binding residues of all known group II PPTases by biochemical and evolutionary analysis. Our results suggested that group II PPTases could be classified into two subgroups, two-magnesium-binding-residue-PPTases containing the triad Asp-Xxx-Glu and three-magnesium-binding-residue-PPTases containing the triad Asp-Glu-Glu. Mutations of two three-magnesium-binding-residue-PPTases and one two-magnesium-binding-residue-PPTase indicate that the first and the third residues in the triads are essential to activities; the second residues in the triads are non-essential. Although variations of the second residues in the triad Asp-Xxx-Glu exist throughout the whole phylogenetic tree, the second residues are conserved in animals, plants, algae, and most prokaryotes, respectively. Evolutionary analysis suggests that: the animal group II PPTases may originate from one common ancestor; the plant two-magnesium-binding-residue-PPTases may originate from one common ancestor; the plant three-magnesium-binding-residue-PPTases may derive from horizontal gene transfer from prokaryotes.
doi:10.1371/journal.pone.0103031
PMCID: PMC4103896  PMID: 25036863
13.  Relationship of Glycated Hemoglobin Levels with Myocardial Injury following Elective Percutaneous Coronary Intervention in Patients with Type 2 Diabetes Mellitus 
PLoS ONE  2014;9(7):e101719.
Background
Glycated hemoglobin (HbA1c) predicts clinical cardiovascular disease or cardiovascular mortality. However, the relationship between HbA1c and myocardial injury following elective percutaneous coronary intervention (PCI) in patients with type 2 diabetes mellitus (DM) has not been investigated.
Objectives
The study sought to assess the relationship between HbA1c and myocardial injury following elective PCI in patients with type 2 DM.
Methods
We studied a cohort of consecutive 994 diabetic patients with coronary artery disease (CAD) undergoing elective PCI. Periprocedural myocardial injury was evaluated by analysis of troponin I (cTnI). The association between preprocedural HbA1c levels and the peak values of cTnI within 24 hours after PCI was evaluated.
Results
Peak postprocedural cTnI >1×upper limit of normal (ULN), >3×ULN and >5×ULN were detected in 543 (54.6%), 337 (33.9%) and 245 (24.6%) respectively. In the multivariate model, higher HbA1c levels were associated with less risk of postprocedural cTnI >1×ULN (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.76–0.95; P = 0.005). There was a trend that higher HbA1c levels were associated with less risk of postprocedural cTnI >3×ULN (OR, 0.90; 95% CI, 0.81–1.02; P = 0.088). HbA1c was not associated with the risk of postprocedural cTnI elevation above 5×ULN (OR, 0.95; 95% CI, 0.84–1.08; P = 0.411).
Conclusions
The present study provided the first line of evidence that higher preprocedural HbA1c levels were associated with less risk of myocardial injury following elective PCI in diabetic patients.
doi:10.1371/journal.pone.0101719
PMCID: PMC4079566  PMID: 24988213
14.  Surgical Strategy for Isolated Caudate Lobectomy: Experience with 16 Cases 
HPB Surgery  2014;2014:983684.
Introduction. Surgical resection is the most effective treatment for neoplasm in the caudate lobe. Isolated caudate lobectomy is still a challenge for hepatobiliary surgeons. No widely accepted surgical strategy for the procedure has been developed yet. Objective. To get a better understanding of isolated caudate lobectomy and to optimize the procedure. Materials and Methods. 16 cases of isolated caudate lobectomy were reviewed to summarize the surgical experience. Results. All the 16 cases of isolated caudate lobectomy were carried out successfully, among which left side approach was adopted in two cases (12.5%), right side approach in three cases (18.75%), and both sides approach in 11 cases (68.75%). No severe complications occurred. Conclusion. The majority of neoplasms confined to the caudate lobe can be resected safely by left and right side approach with proper anatomic surgical procedure, usually in the sequence of mobilization, outflow control, inflow control, and division of the hepatic parenchyma. Fully mobilizing the caudate lobe from the inferior vena cava (IVC) is of great importance. Division of the retrohepatic ligament and the venous ligament facilitated the procedure.
doi:10.1155/2014/983684
PMCID: PMC4102013  PMID: 25100899
15.  Neurovascular Recovery via Cotransplanted Neural and Vascular Progenitors Leads to Improved Functional Restoration after Ischemic Stroke in Rats 
Stem Cell Reports  2014;3(1):101-114.
Summary
The concept of the “neurovascular unit,” emphasizing the interactions between neural and vascular components in the brain, raised the notion that neural progenitor cell (NPC) transplantation therapy aimed at neural repair may be insufficient for the treatment of ischemic stroke. Here, we demonstrate that enhanced neurovascular recovery via cotransplantation of NPCs and embryonic stem cell-derived vascular progenitor cells (VPCs) in a rat stroke model is correlated with improved functional recovery after stroke. We found that cotransplantation promoted the survival, migration, differentiation, and maturation of neuronal and vascular cells derived from the cotransplanted progenitors. Furthermore, it triggered an increased generation of VEGF-, BDNF-, and IGF1-expressing neural cells derived from the grafted NPCs. Consistently, compared with transplantation of NPCs alone, cotransplantation more effectively improved the neurobehavioral deficits and attenuated the infarct volume. Thus, cotransplantation of NPCs and VPCs represents a more effective therapeutic strategy for the treatment of stroke than transplantation of NPCs alone.
Highlights
•Neural and vascular progenitor cell cotransplantation therapy for ischemic stroke•Better neurovascular recovery by cotransplanted progenitor cells in the infarct area•Better infarction reduction and functional restoration by cotransplantation•Neurovascular recovery likely mediated by neural production of growth/trophic factors
Gao, Yang, and colleagues demonstrate a more favorable neurovascular recovery and functional restoration after cotransplantation of neural progenitor cells (NPCs) and embryonic stem cell-derived vascular progenitor cells than after transplantation of NPCs alone in a rat stroke model. Cotransplantation not only reciprocally enhances the survival and differentiation of the transplanted progenitors but also preserves the host brain from further degeneration, likely by increasing neural production of VEGF, BDNF, and IGF1.
doi:10.1016/j.stemcr.2014.05.012
PMCID: PMC4110773  PMID: 25068125
16.  Glycosylated hemoglobin A1c as a marker predicting the severity of coronary artery disease and early outcome in patients with stable angina 
Background
Glycosylated hemoglobin A1C (HbA1c) has been widely recognized as a marker for predicting the severity of diabetes mellitus (DM) and several cardiovascular diseases. However, whether HbA1c could predict the severity and clinical outcomes in patients with stable coronary artery disease (CAD) remains largely unknown. We determine relationship of HbA1c with severity and outcome in patients with stable CAD.
Methods
We enrolled 1433 patients with stable angina who underwent coronary angiography and were followed up for an average 12 months. The patients were classified into three groups by tertiles of baseline HbA1c level (low group <5.7%, n = 483; intermediate group 5.7 - 6.3%, n = 512; high group >6.3%, n = 438). The relationships between the plasma HbA1c and severity of CAD and early clinical outcomes were evaluated.
Results
High HbA1c was associated with three-vessel disease. Area under the receivers operating characteristic curve (AUC = 0.67, 95% CI: 0.63-0.71, P < 0.001) and multivariate logistic regression analysis suggested that HbA1C was an independent predictor of severity of CAD (OR = 1.60, 95% CI: 1.29-1.99, P < 0.001) even after adjusting for gender, age, risk factor of CAD, lipid profile and fasting blood glucose. During follow-up, 133 patients underwent pre-specified outcomes. After adjusting for multiple variables in the Cox regression model, HbA1C remained to be an independent predictor of poor prognosis (HR = 1.28, 95% CI: 1.12-1.45, P < 0.001).
Conclusions
We concluded that high level of baseline HbA1c appeared to be an independent predictor for the severity of CAD and poor outcome in patients with stable CAD.
doi:10.1186/1476-511X-13-89
PMCID: PMC4070346  PMID: 24884794
Hemoglobin A1c; Stable angina pectoris; Coronary artery disease; Outcome
17.  Epidemic and virulence characteristic of Shigella spp. with extended-spectrum cephalosporin resistance in Xiaoshan District, Hangzhou, China 
BMC Infectious Diseases  2014;14:260.
Background
Shigellae have become increasingly resistant to the extended-spectrum cephalosporin (ESC) worldwide and pose a great challenge to anti-infection treatment options. The purpose of this study was to determine the resistance, cephalosporin resistance mechanisms, virulence characteristic and genotype of ESC-resistant Shigella.
Methods
From 2008 to 2012, Shigella isolates collected from diarrhea patients were detected for antibiotics sensitivity by disk diffusion, cephalosporin resistance determinants and virulence genes using polymerase chain reaction (PCR) and genotyping through enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR).
Results
A total of 356 Shigella isolates were gathered, and 198 (55.6%, 58 S. flexneri and 140 S. sonnei) were resistant to ESC. All ESC-resistant isolates were susceptible to imipenem, and only 0.5% isolate was resistant to piperacillin/tazobactam. ESC-resistant S. flexneri showed high degrees of resistance to ampicillin (100%), ampicillin/sulbactam (96.6%), piperacillin (100%), trimethoprim/sulfamethoxazole (74.1%), ciprofloxacin (74.1%), levofloxacin (53.4%), ceftazidime (58.6%) and cefepime (58.6%). ESC-resistant S. sonnei exhibited high resistance rates to ampicillin (100%), piperacillin (100%) and trimethoprim/sulfamethoxazole (96.4%). Cephalosporin resistance genes were confirmed in 184 ESC-resistant isolates. blaCTX-M types (91.8%, mainly blaCTX-M-14, blaCTX-M-15 and blaCTX-M-57) were most prevalent, followed by blaOXA-30 (26.3%). Over 99.0% ESC-resistant isolates harbored virulence genes ial, ipaH, virA and sen. However, set1 were more prevalent in ESC-resistant S. flexneri isolates than in S. sonnei isolates. ERIC-PCR results showed that 2 and 3 main genotypes were detected in ESC-resistant S. flexneri and S. sonnei, respectively.
Conclusion
Our findings indicated that a high prevalence of ESC-resistant Shigella mediated mainly by blaCTX-M with stronger resistance and virulence, and the existence of specific clones responsible for these Shigella infection in the region studied.
doi:10.1186/1471-2334-14-260
PMCID: PMC4229937  PMID: 24886028
Shigella; Extended-spectrum cephalosporin; Resistance; Cephalosporin resistance mechanism; Virulence markers; Genotyping
18.  The Inhibitory Effect of Somatostatin Receptor Activation on Bee Venom-Evoked Nociceptive Behavior and pCREB Expression in Rats 
BioMed Research International  2014;2014:251785.
The present study examined nociceptive behaviors and the expression of phosphorylated cAMP response element-binding protein (pCREB) in the dorsal horn of the lumbar spinal cord and the dorsal root ganglion (DRG) evoked by bee venom (BV). The effect of intraplantar preapplication of the somatostatin analog octreotide on nociceptive behaviors and pCREB expression was also examined. Subcutaneous injection of BV into the rat unilateral hindpaw pad induced significant spontaneous nociceptive behaviors, primary mechanical allodynia, primary thermal hyperalgesia, and mirror-thermal hyperalgesia, as well as an increase in pCREB expression in the lumbar spinal dorsal horn and DRG. Octreotide pretreatment significantly attenuated the BV-induced lifting/licking response and mechanical allodynia. Local injection of octreotide also significantly reduced pCREB expression in the lumbar spinal dorsal horn and DRG. Furthermore, pretreatment with cyclosomatostatin, a somatostatin receptor antagonist, reversed the octreotide-induced inhibition of the lifting/licking response, mechanical allodynia, and the expression of pCREB. These results suggest that BV can induce nociceptive responses and somatostatin receptors are involved in mediating the antinociception, which provides new evidence for peripheral analgesic action of somatostatin in an inflammatory pain state.
doi:10.1155/2014/251785
PMCID: PMC4033427  PMID: 24895558
19.  Impact of admission triglyceride for early outcome in diabetic patients with stable coronary artery disease 
Background
The role of triglyceride (TG) in predicting the outcomes in diabetic patients with coronary artery disease (CAD) has not been well investigated.
Methods
A total of 329 cases with stable angina pectoris (SAP) were prospectively enrolled and followed up for an average of 12 months. They were classified into the two groups according to the cut-off values of predicting early outcome of fasting TG level (low group <1.2 mmol/L, n = 103; High group ≥1.2 mmol/L, n = 226). The relationship between the TG levels and early outcomes were evaluated.
Results
High TG group showed severer lipid profile and elevated inflammatory markers. During an average of 12-month follow-up, 47 out of 329 patients suffered from pre-specified outcomes. Area under the receivers operating characteristic curve suggested that TG, similar to serum Hemoglobin A1C (HbA1C), was a significant predictor of early outcome for diabetic patients with SAP (P = 0.002). In Cox regression models, after adjusted age, gender, body mass index, other lipid parameters, fasting blood glucose, high sensitivity C-reactive protein, neutrophil count and HbA1C, TG remained as an independent predictor of adverse prognosis.
Conclusions
High level of fasting TG (≥1.2 mmol/L) was an independent predictor for early outcome of diabetic patients with SAP as like as HBA1c and number of affected coronary arteries in the era of revascularization and statin therapeutics.
doi:10.1186/1476-511X-13-73
PMCID: PMC4013537  PMID: 24766776
Triglyceride; Hemoglobin A1C; Stable angina pectoris; Coronary artery disease; Outcome
20.  Increase of circulating miR-223 and insulin-like growth factor-1 is associated with the pathogenesis of acute ischemic stroke in patients 
BMC Neurology  2014;14:77.
Background
The relationship between circulating microRNA-223 and pathogenesis of acute ischemic stroke is unknown. Here we investigated the roles and possible targets of circulating microRNA-223 in human ischemic stroke within the first 72 hours.
Methods
Blood samples were collected from patients within 72 hours after cerebral ischemia (n = 79) and compared with healthy control samples (n = 75). The level of possible downstream factors of microRNA-223 including insulin-like growth factor-1, insulin-like growth factor-1 receptor and interleukin-6 was examined by ELISA assay. The relationship between the microRNA-223 level and NIHSS scores, TOAST subtypes, and infarct volume was analyzed respectively. In addition, twelve adult male CD-1 mice underwent middle cerebral artery occlusion using the suture technique. Circulating blood and brain tissue in the ischemic ipsilateral hemisphere were collected at 24 hours after middle cerebral artery occlusion. microRNA-223 was detected by real-time polymerase chain reactions.
Results
microRNA-223 levels in the circulating blood of acute ischemic stroke patients were greatly increased compared to the control (p < 0.05). microRNA-223, which were negatively correlated with NIHSS scores (r = −0.531, p < 0.01) and infarct volume (r = −0.265, p = 0.039), was significantly up-regulated in large artery and small artery strokes. The plasma level of insulin-like growth factor-1 was positively associated with that of microRNA-223 (r = 0.205, p = 0.022). Moreover, microRNA-223 in blood and brain were positively correlated (r = 0.834, p < 0.05), and they were up-regulated significantly in mice that underwent middle cerebral artery occlusion (p < 0.05).
Conclusions
Our results suggest that microRNA-223 is associated with acute ischemic stroke and possibly plays a role in stroke through up-regulating growth factor such as insulin-like growth factor-1 gene.
doi:10.1186/1471-2377-14-77
PMCID: PMC4234389  PMID: 24708646
Human; Ischemia; microRNA-223; Stroke
21.  Association of Fibrinogen with Severity of Stable Coronary Artery Disease in Patients with Type 2 Diabetic Mellitus 
Disease Markers  2014;2014:485687.
Background. Some studies have suggested a relation of plasma fibrinogen to the severity of coronary artery disease (CAD). However, whether plasma fibrinogen can predict the presence and severity of CAD in patients with diabetes mellitus has not been determined. Methods. A total of consecutive 373 diabetic patients with typical angina pectoris who received coronary angiography were enrolled and classified into three groups by tertiles of Gensini score (GS, low group <8; intermediate group 8~28; high group >28). The relationship between fibrinogen and GS was evaluated. Results. There were correlations of fibrinogen with hemoglobin A1c, C-reactive protein, and GS (r = 0.17, r = 0.52, and r = 0.21, resp.; all P < 0.001). Area under the receivers operating characteristic curve of fibrinogen was 0.62 (95% CI 0.56–0.68, P < 0.001) for predicting a high GS. Multivariate analysis suggested that plasma fibrinogen was an independent predictor of a high GS for diabetic patients (OR = 1.40, 95% CI 1.04–1.88, and P = 0.026) after adjusting for traditional risk factors of CAD. Conclusions. The present data indicated that plasma fibrinogen, a readily measurable systematic inflammatory marker, appeared to be an independent predictor for the severity of CAD in diabetic patients.
doi:10.1155/2014/485687
PMCID: PMC3997864  PMID: 24803720
22.  Significance of red cell distribution width measurement for the patients with isolated coronary artery ectasia 
Background
Red cell distribution width (RDW) has been recognized as a novel marker for several cardiovascular diseases. The aim of this study was to evaluate the association between RDW levels and the presence of isolated coronary artery ectasia (CAE).
Methods
We studied 414 subjects including 113 patients with isolated CAE (Group A), 144 patients with coronary artery disease (CAD, group B) and 157 angiographically normal controls (group C). Baseline clinical characteristics and laboratory findings including RDW were compared among three groups.
Results
The levels of RDW were significantly higher in group A and B compared with that in group C (12.97 ± 1.4 and 12.88 ± 1.0 vs 12.34 ± 0.9, p = 0.020) while no difference was found between CAE and CAD (p = 0.17). Additionally, the levels of CRP were also higher in patients with CAE and CAD compared with normal controls (0.26 ± 0.14 mg/L, 0.31 ± 0.27 mg/L vs 0.20 ± 0.06 mg/L, p = 0.04). The multivariate analysis indicated that RDW and CRP were the independent variables most strongly associated with the presence of isolated CAE and CAD. There was a positive correlation between levels of RDW and CRP in patients with isolated CAE (γ=0.532, p = 0.001).
Conclusions
Our data suggested that RDW may be a useful marker and independent predictor for the presence of isolated CAE.
doi:10.1186/1479-5876-12-62
PMCID: PMC3975450  PMID: 24606910
Red cell distribution width; Coronary artery ectasia; Coronary artery disease; C-reactive protein
23.  Relation of Leukocytes and Its Subsets Counts with the Severity of Stable Coronary Artery Disease in Patients with Diabetic Mellitus 
PLoS ONE  2014;9(3):e90663.
Background
Both coronary artery disease (CAD) and diabetes mellitus (DM) are associated with inflammation. However, whether and which leukocytes can predict the presence and extent of CAD in patients with DM has not been investigated. The aim of the present study was to examine the association of leukocyte and its subsets counts with the severity of CAD in patients with DM.
Methods and Findings
Three hundred and seventy-three diabetic patients who were scheduled for coronary angiography due to typical stable angina pectoris were enrolled in this study. They were classified into the three groups according to tertiles of Gensini score (GS, low group <8, n = 143; intermediate group 8∼28, n = 109; high group >28, n = 121). The relationship between the leukocyte and its subsets counts with the severity of CAD were evaluated. The data indicated that there were significant correlations between leukocyte and neutrophil counts with GS (r = 0.154 and 0.156, respectively, all P<0.003 for Pearson's correlation). Similarly, area under the receivers operating characteristic curve of leukocyte and neutrophil counts were 0.61 and 0.60 respectively (95%CI: 0.55–0.67, all P = 0.001) for predicting high GS. Multivariate logistic regression analysis demonstrated that leukocyte count was an independent predictor for high GS patients with DM (OR = 1.20, 95%CI 1.03–1.39, P = 0.023) after adjusting for conventional risk factors of CAD.
Conclusions
Compared with its subsets, leukocyte count appeared to be an independent predictor for the severity of CAD and the optimal cut-off value for predicting high GS (>28 points) was 5.0×109 cells/L in diabetic patients.
doi:10.1371/journal.pone.0090663
PMCID: PMC3944194  PMID: 24599246
24.  Therapeutic Benefit of Bone Marrow–Derived Endothelial Progenitor Cell Transplantation after Experimental Aneurysm Embolization with Coil in Rats 
PLoS ONE  2014;9(2):e90069.
Aneurysm embolization with coil is now widely used clinically. However, the recurrence of aneurysms after embolization has always plagued neurosurgeons because the endothelial layer of the aneurysm neck loses its integrity after being embolized by coil. Bone marrow–derived endothelial progenitor cells (BM-EPCs) could be incorporated into injured endothelium and differentiate into mature endothelial cells during vascular repairing processes. The aim of our study is to explore the effects of BM-EPCs on aneurysm repairing and remodeling in a rat embolization model of abdominal aortic aneurysm. BM-EPC proliferation, migration and tube formation were not affected by super-paramagnetic iron oxide nanoparticle (SPIO) labeling compared to the controls (p>0.05). The number of SPIO-labeled cells greatly increased in EPC transplanted rats compared to that of phosphate buffered saline treated rats. SPIO-labeled EPC (SPIO-EPC) are mainly located in the aneurysm neck and surrounded by fibrous tissue. A histology study showed that the aneurysm orifice was closed with neointima and the aneurysm was filled with newly formed fibrous tissue. The SPIO-EPC accumulated in the aneurysm neck, which accelerated focal fibrous tissue remodeling, suggesting that BM-EPCs play a crucial role in repairing and remodeling the aneurysm neck orifice.
doi:10.1371/journal.pone.0090069
PMCID: PMC3938595  PMID: 24587209
25.  AMPK Inhibition Blocks ROS-NFκB Signaling and Attenuates Endotoxemia-Induced Liver Injury 
PLoS ONE  2014;9(1):e86881.
Background
AMP-activated protein kinase (AMPK) is an important enzyme in regulation of cellular energy homeostasis. We have previously shown that AMPK activation by 5-aminoimidazole-4-carboxamide (AICAR) results in suppression of immune responses, indicating the pivotal role of AMPK in immune regulation. However, the cellular mechanism underpinning AMPK inhibition on immune response remains largely to be elucidated. The study aimed to investigate the effects of AMPK inhibition on reactive oxygen species (ROS)-nuclear factor κB (NFκB) signaling and endotoxemia-induced liver injury.
Methodology/Principal Findings
RAW 264.7 cells were pretreated with AMPK activator or inhibitor, followed by LPS challenge. In addition, LPS was injected intraperitoneally into mice to induce systemic inflammation. The parameters of liver injury and immune responses were determined, and survival of mice was monitored respectively. LPS challenge in RAW 264.7 cells resulted in AMPK activation which was then inhibited by compound C treatment. Both AMPK activation by AICAR or inhibition by compound C diminished LPS-induced ROS generation, inhibited phosphorylation of IKK, IκB, and NFκB p65, and consequently, decreased TNF production of RAW 264.7 cells. AICAR or compound C treatment decreased ALT, AST, and TNF levels in serum, reduced CD68 expression and MPO activity in liver tissue of mice with endotoxemia. Moreover, AICAR or compound C treatment improved survival of endotoxemic mice.
Conclusions
AICAR or compound C treatment attenuates LPS-induced ROS-NFκB signaling, immune responses and liver injury. Strategies to activate or inhibit AMPK signaling may provide alternatives to the current clinical approaches to inhibit immune responses of endotoxemia.
doi:10.1371/journal.pone.0086881
PMCID: PMC3901729  PMID: 24475189

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