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1.  The equity of China’s emergency medical services from 2010–2014 
Background
With the depth development of health care system reform in China, emergency medical services (EMS) is confronted with challenges as well as opportunities. This study aimed to analyze the equity of China’s EMS needs, utilization, and resources distribution, and put forward proposal to improve the equity.
Method
Three emergency needs indicators (mortality rate of cardiovascular and cerebrovascular diseases, harm, and digestive system disease), two utilization indicators (emergency outpatient visits and rate of utilization) and one resource allocation indicator (number of EMS facilities) were collected after the review of the China Statistical Yearbook and the National Disease Surveillance System. Next, EMS related indicators were compared among 31 provinces from the eastern, central, and western regions of the country. Concentration Index (CI) were used to measure the equity of EMS needs and utilization among the western, central, and eastern regions. The Gini coefficient of demographic and geographic distribution of facilities represented the equity of resource allocation.
Result
During 2010–2014, the CI of cardiovascular and cerebrovascular disease mortality changed from positive to negative, which indicates that the concentrated trend transferred from richer regions to the poorer area. Injury mortality (CI: range from − 0.1241to −0.1504) and digestive disease mortality (CI: range from − 0.1921 to − 0.2279) consistently concentrated in the poorer region, and the inequity among regions became more obviously year-by-year. The utilization of EMS (CI: range from 0.1074 to 0.0824) showed an improvement; however, the inequity reduced gradually. The EMS facilities distribution by population (Gini coefficient: range from 0.0922 to 0.1200) showed high equitability but the EMS facilities distribution by geography (Gini coefficient: range from 0.0922 to 0.1200) suggested a huge gap between regions because the Gini coefficients were greater than 0.5 in the past 5 years.
Conclusion
There are some inequities of needs, utilization, and resource allocation in the China EMS. The government needs to stick to the principle of increasing investment in poorer regions, perfecting ambulance configuration and improving health workers’ professional skills to improve the equity and quality of EMS.
doi:10.1186/s12939-016-0507-5
PMCID: PMC5225518  PMID: 28077150
Emergency medical services; Equity; China
2.  Insights into the Mechanistic Basis of Plasmid-Mediated Colistin Resistance from Crystal Structures of the Catalytic Domain of MCR-1 
Scientific Reports  2017;7:39392.
The polymixin colistin is a “last line” antibiotic against extensively-resistant Gram-negative bacteria. Recently, the mcr-1 gene was identified as a plasmid-mediated resistance mechanism in human and animal Enterobacteriaceae, with a wide geographical distribution and many producer strains resistant to multiple other antibiotics. mcr-1 encodes a membrane-bound enzyme catalysing phosphoethanolamine transfer onto bacterial lipid A. Here we present crystal structures revealing the MCR-1 periplasmic, catalytic domain to be a zinc metalloprotein with an alkaline phosphatase/sulphatase fold containing three disulphide bonds. One structure captures a phosphorylated form representing the first intermediate in the transfer reaction. Mutation of residues implicated in zinc or phosphoethanolamine binding, or catalytic activity, restores colistin susceptibility of recombinant E. coli. Zinc deprivation reduces colistin MICs in MCR-1-producing laboratory, environmental, animal and human E. coli. Conversely, over-expression of the disulphide isomerase DsbA increases the colistin MIC of laboratory E. coli. Preliminary density functional theory calculations on cluster models suggest a single zinc ion may be sufficient to support phosphoethanolamine transfer. These data demonstrate the importance of zinc and disulphide bonds to MCR-1 activity, suggest that assays under zinc-limiting conditions represent a route to phenotypic identification of MCR-1 producing E. coli, and identify key features of the likely catalytic mechanism.
doi:10.1038/srep39392
PMCID: PMC5216409  PMID: 28059088
3.  RNA virus receptor Rig-I monitors gut microbiota and inhibits colitis-associated colorectal cancer 
Background
Retinoic acid-inducible gene-I (Rig-I) is an intracellular viral RNA receptor, which specifically recognizes double-stranded viral RNA initiating antiviral innate immunity. Increasing evidences showed that Rig-I had broader roles in antibacterial immunity and cancer protection. However, the potential roles and mechanisms of Rig-I in gut flora regulation and colorectal cancer (CRC) progression remain unclear.
Methods
Immunohistochemistry was performed to detect Rig-I protein in 38 pairs of CRC tissue and matched adjacent mucosa, and immunofluorescence and western blot were also used to detect Rig-I protein expression in AOM/DSS-induced mice CRC samples. High-throughput sequencing was conducted to evaluate gut microbiota changes in Rig-I-deficient mice. Immunofluorescence and flow cytometry were used to detect IgA expression. Additionally, real-time quantitative PCR was performed to detect RNA expression in mouse intestines and cultured cells, and western blot was used to detect phosphorylation of STAT3 in IL-6-stimulated B cell line.
Results
Rig-I was downregulated in human and mouse CRC samples and Rig-I-deficient mice were more susceptible to AOM/DSS-induced colitis-associated colorectal cancer (CAC). Furthermore, Rig-I-deficient mice displayed gut microbiota disturbance compared to wild type mice. IgA, Reg3γ and Pdcd1 levels were decreased in intestines of Rig-I-deficient mice. Phosphorylation of STAT3 in IL-6-stimulated 1B4B6 was decreased.
Conclusion
Rig-I could regulate gut microbiota through regulating IgA and IL6-STAT3-dependent Reg3γ expression. Besides, Rig-I could inhibit CRC progression.
Electronic supplementary material
The online version of this article (doi:10.1186/s13046-016-0471-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s13046-016-0471-3
PMCID: PMC5217425  PMID: 28057020
Rig-I; Gut microbiota; Colorectal cancer; Mouse model; High-throughput sequencing
4.  Atrial fibrillation in patients hospitalized with acute myocardial infarction: analysis of the china acute myocardial infarction (CAMI) registry 
Background
The incidence, clinical outcomes and antithrombotic treatment spectrum of atrial fibrillation (AF) in patients hospitalized with acute myocardial infarction (AMI) have not been well studied in Chinese population.
Methods
Twenty-six thousand five hundred ninety-two consecutive patients diagnosed with AMI were enrolled in CAMI registry from January 2013 to September 2014. After excluding 343 patients with uncertain AF status and 1,591 patients transferred out during hospitalization, 24,658 patients were finally included in this study and involved in analysis.
Results
In the CAMI registry, 740 (3.0%) patients were recorded with AF prevalence during hospitalization. Higher-risk baseline clinical profile was observed in patients with AF. These patients were less likely to receive reperfusion/revascularization than those without AF. The in-hospital mortality (including death and treatment withdrawal) was significantly higher in patients with AF than that of without AF (25.2% vs. 7.2%, respectively; p < 0.01). The case of composite of adverse events was similar, which included death, treatment withdrawal, re-infarction, heart failure or stroke (42.1% vs. 16.0%, p <0.01). In multivariate logistic regression analysis, AF was an independent predictor for in-hospital mortality (odds ratio, 1.88; 95% confidence interval: 1.27–2.78) and the composite of adverse events (odds ratio, 2.11; 95% CI: 1.63–2.72). Only 5.1% of patients with AF were treated with warfarin, and 1.7% were treated with both warfarin and dual antiplatelet therapy.
Conclusions
The analysis was based on the CAMI registry in China. The patients hospitalized for AMI who developed AF were at significantly higher risk for in-hospital mortality and other adverse events. However, the anticoagulants including warfarin have been largely underused post hospital discharge.
Trial registration
Clinical Trial Registration: Identifier: NCT01874691.
doi:10.1186/s12872-016-0442-9
PMCID: PMC5210261  PMID: 28052755
Atrial fibrillation; Acute myocardial infarction; Hospital mortality; Anticoagulation treatment
5.  Venous thromboembolism after oral and maxillofacial oncologic surgery: Report and analysis of 14 cases in Chinese population 
Background
Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism (PE) is a leading cause of death in cancer patients. The aim of this study was to explore the potential risk factor of VTE in oral and maxillofacial oncological surgery.
Material and Methods
The data of patients who received operation in our institution were gathered in this retrospective study. A diagnosis of VTE was screened and confirmed by computer tomography angiography (CTA) of pulmonary artery or ultrasonography examination of lower extremity. Medical history and all perioperative details were analyzed.
Results
14 patients were diagnosed as VTE, including 6 cases of PE, 7 cases of DVT, 1case of DVT and PE. The mean age of these patients was 62.07 years. Reconstruction was performed in 12 patients of these cases, most of which were diagnosed as malignance. Mean length of surgery was 8.74 hours, and lower extremity deep venous cannula (DVC) was performed in all these patients.
Conclusions
We analyzed several characters of oral and maxillofacial surgery and suggested pay attention to lower extremity DVC which had a high correlation with DVT according to our data.
Key words:Venous thromboembolism, pulmonary embolism, deep vein thrombosis, oral and maxillofacial surgery.
doi:10.4317/medoral.21399
PMCID: PMC5217489  PMID: 27918738
6.  A LGG-derived protein promotes IgA production through up-regulation of APRIL expression in intestinal epithelial cells 
Mucosal immunology  2016;10.1038/mi.2016.57.
p40, a Lactobacillus rhamnosus GG (LGG)-derived protein, transactivates epidermal growth factor receptor (EGFR) in intestinal epithelial cells, leading to amelioration of intestinal injury and inflammation. To elucidate mechanisms by which p40 regulates mucosal immunity to prevent inflammation, this study aimed to determine the effects and mechanisms of p40 on regulation of a proliferation-inducing ligand (APRIL) expression in intestinal epithelial cells for promoting IgA production. p40 up-regulated April gene expression and protein production in mouse small intestine epithelial (MSIE) cells, which were inhibited by blocking EGFR expression and kinase activity. Enteroids from Egfrfl/fl , but not Egfrfl/fl-Vil-Cre mice with EGFR specifically deleted in intestinal epithelial cells, exhibited increased April gene expression by p40 treatment. p40-conditioned media from MSIE cells increased B cell class switching to IgA+ cells and IgA production, which was suppressed by APRIL receptor neutralizing antibodies. Treatment of B cells with p40 did not show any effects on IgA production. p40 treatment increased April gene expression and protein production in small intestinal epithelial cells, fecal IgA levels, IgA+B220+, IgA+CD19+, and IgA+ plasma cells in lamina propria of Egfrfl/fl, but not Egfrfl/fl-Vil-Cre mice. Thus, p40 up-regulates EGFR-dependent APRIL production in intestinal epithelial cells, which may contribute to promoting IgA production.
doi:10.1038/mi.2016.57
PMCID: PMC5199635  PMID: 27353252
APRIL; B cell; epidermal growth factor receptor; IgA; intestinal epithelial cell; Lactobacillus GG; p40
7.  Cryptosporidium parvum infection attenuates the ex vivo propagation of murine intestinal enteroids 
Physiological Reports  2016;4(24):e13060.
Abstract
Cryptosporidium, a ubiquitous coccidian protozoan parasite that infects the gastrointestinal epithelium and other mucosal surfaces, is an important opportunistic pathogen for immunocompromised individuals and a common cause of diarrhea in young children in the developing countries. One of the pathological hallmarks of intestinal cryptosporidiosis is villous atrophy, which results in a shorter height of intestinal villi. Here, we investigated the effects of Cryptosporidium infection on intestinal epithelial growth, using an ex vivo model of intestinal cryptosporidiosis employing enteroids from mice. We detected infection of enteroids isolated from immunocompetent adult and neonatal mice after ex vivo exposure to Cryptosporidium sporozoites. We observed a significant inhibition of enteroid propagation following infection. Intriguingly, we identified a decreased expression level of intestinal stem cell markers in enteroids following C. parvum infection. We further measured the expression levels of several Wnt antagonists or agonists in infected enteroids, as induction of the Wnt/β‐catenin activation is a key factor for intestinal stem cell function. We detected a markedly increased level of the Dickkopf‐related protein 1 and decreased level of the Wnt family member 5a in enteroids after infection. The low density lipoprotein receptor‐related protein 5, one of the Wnt co‐receptors, is downregulated in the infected enteroids. In addition, increased apoptotic cell death and cell senescence were observed in the infected enteroids. Our results demonstrate a significant inhibitory effect of Cryptosporidium infection on the ex vivo propagation of enteroids from mice, providing additional insights into the impact of Cryptosporidium infection on intestinal epithelial growth.
doi:10.14814/phy2.13060
PMCID: PMC5210379  PMID: 28039407
C. parvum; cryptosporidiosis; cytokines; enteroids; intestine; Lgr5; mice; neonatal; stem cells
8.  Negative Life Events and Antenatal Depression among Pregnant Women in Rural China: The Role of Negative Automatic Thoughts 
PLoS ONE  2016;11(12):e0167597.
Background
Few studies have looked at the relationship between psychological and the mental health status of pregnant women in rural China. The current study aims to explore the potential mediating effect of negative automatic thoughts between negative life events and antenatal depression.
Methods
Data were collected in June 2012 and October 2012. 495 rural pregnant women were interviewed. Depressive symptoms were measured by the Edinburgh postnatal depression scale, stresses of pregnancy were measured by the pregnancy pressure scale, negative automatic thoughts were measured by the automatic thoughts questionnaire, and negative life events were measured by the life events scale for pregnant women. We used logistic regression and path analysis to test the mediating effect.
Results
The prevalence of antenatal depression was 13.7%. In the logistic regression, the only socio-demographic and health behavior factor significantly related to antenatal depression was sleep quality. Negative life events were not associated with depression in the fully adjusted model. Path analysis showed that the eventual direct and general effects of negative automatic thoughts were 0.39 and 0.51, which were larger than the effects of negative life events.
Conclusions
This study suggested that there was a potentially significant mediating effect of negative automatic thoughts. Pregnant women who had lower scores of negative automatic thoughts were more likely to suffer less from negative life events which might lead to antenatal depression.
doi:10.1371/journal.pone.0167597
PMCID: PMC5157981  PMID: 27977715
9.  Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway 
Scientific Reports  2016;6:38979.
Osteoarthritis is a disease with inflammatory and catabolic imbalance in cartilage. Dihydroartemisinin (DHA), a natural and safe anti-malarial agent, has been reported to inhibit inflammation, but its effects on chondrocytes have yet to be elucidated. We investigated the effects of DHA on catabolism in chondrocytes. Viability of SD rats chondrocytes was analyzed. Autophagy levels were determined via expression of autophagic markers LC3 and ATG5, GFP-LC3 analysis, acridine orange staining, and electron microscopy. ATG5 siRNA induced autophagic inhibition. Catabolic gene and chemokine expression was evaluated using qPCR. The NF-κB inhibitor SM7368 and p65 over-expression were used to analyze the role of NF-κB pathway in autophagic activation. A concentration of 1 μM DHA without cytotoxicity increased LC3-II and ATG5 levels as well as autophagosomal numbers in chondrocytes. DHA inhibited TNF-α-induced expression of MMP-3 and -9, ADAMTS5, CCL-2 and -5, and CXCL1, which was reversed by autophagic inhibition. TNF-α-stimulated nuclear translocation and degradation of the p65 and IκBα proteins, respectively, were attenuated in DHA-treated chondrocytes. NF-κB inhibition activated autophagy in TNF-α-treated chondrocytes, but p65 over-expression reduced the autophagic response to DHA. These results indicate that DHA might suppress the levels of catabolic and inflammatory factors in chondrocytes by promoting autophagy via NF-κB pathway inhibition.
doi:10.1038/srep38979
PMCID: PMC5150254  PMID: 27941926
10.  Metallothionein Prevents Age-Associated Cardiomyopathy via Inhibiting NF-κB Pathway Activation and Associated Nitrative Damage to 2-OGD 
Antioxidants & Redox Signaling  2016;25(17):936-952.
Abstract
Aims: Cardiac-specific metallothionein (MT) overexpression extends lifespan, but the mechanism underlying the effect of MT protection against age-associated cardiovascular diseases (CVD) remains elusive. To elucidate this, male wild-type and two lines of MT-transgenic (MT-TG) mice, MM and MT-1 (cardiac-specific overexpressing MT about 10- and 80-fold, respectively) at three representative ages (2–3, 9–10, and 18–20 months), were utilized. A stable human MT2A overexpressing cardiomyocytes (H9c2MT7) was also introduced.
Results: Histomorphology and echocardiographic analysis revealed that age-associated cardiac hypertrophy, remodeling, and dysfunction were ameliorated in MT-TG mice. Also, aging-accompanied NF-κB activation, characterized by increased nuclear p65 translocation, elevated DNA-binding activity, and upregulation of inflammatory cytokines, was largely attenuated by MT overexpression. Treatment of H9c2 cardiomyocytes with tumor necrosis factor-α (TNF-α), which mimicked an inflammatory environment, significantly increased NF-κB activity, and some age-related phenotypes appeared. The NF-κB activation was further proved to be pivotal for both age-associated and TNF-α-induced nitrative damage to cardiac 2-oxoglutarate dehydrogenase (2-OGD) by virtue of NF-κB p65 gene silencing. MT inhibited NF-κB activation and associated nitrative damage to cardiac 2-OGD in both old MT-TG hearts and TNF-α-treated H9c2MT7 cardiomyocytes; these protective effects were abolished in H9c2MT7 cardiomyocytes by MT-specific gene silencing.
Innovation and Conclusion: Together, these findings indicate that the protective effects of MT against age-associated CVD can be attributed mainly to its role in NF-κB inhibition and resultant alleviation of nitrative damage to 2-OGD. Antioxid. Redox Signal. 25, 936–952.
doi:10.1089/ars.2016.6648
PMCID: PMC5144888  PMID: 27477335
nitrative damage; metallothionein; 2-oxoglutarate dehydrogenase; inflammation; age-associated cardiovascular diseases
11.  Prediction of cancer progression in a group of 73 gastric cancer patients by circulating cell-free DNA 
BMC Cancer  2016;16:943.
Background
Circulating cell-free DNA (ccf-DNA) in plasma may contain both specific and non-specific of tumor markers. The concentration and integrity of ccf-DNA may be clinical useful for detecting and predicting cancer progression.
Methods
Plasma samples from 40 healthy controls and 73 patients with gastric cancers (two stage 0, 17 stage I, 11 stage II, 33 stage III, and 10 stage IV according to American Joint Committee on Cancer stage) were assessed respectively. qPCR targeting the Alu repeats was performed using two different sets of primers amplifying the long and short segments. DNA integrity was calculated as a ratio of the long to the short fragments of Alu repeats.
Results
Plasma DNA concentration was significantly higher in patients with stage III and IV gastric cancers than in healthy controls (p = 0.028 and 0.029 respectively). The receiver operating characteristic (ROC) curve for discriminating patients with stage III and IV gastric cancers from healthy controls had an area under the curve (AUC) of 0.744 (95% CI, 0.64 to 0.85). Circulating cell-free DNA concentration increased within 21 days following surgery and dropped by 3 months after surgery.
Conclusions
Concentration of ccf-DNA is a promising molecular marker for assessing gastric cancer progression.
Trial registration
Current Controlled Trials ChiCTR-DDT-12002848, 8 October 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-016-2977-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12885-016-2977-7
PMCID: PMC5148873  PMID: 27938352
Gastric cancer; Circulating cell-free DNA; DNA integrity; Alu-qPCR
12.  Treatment for Spontaneous Intracranial Dissecting Aneurysms in Childhood: A Retrospective Study of 26 Cases 
Objective
This study aimed to assess the clinicoradiological features and treatment outcomes of intracranial dissecting aneurysms (IDAs) in childhood.
Methods
We conducted a retrospective study of pediatric patients who were treated for spontaneous IDAs in our institute between January 2010 and December 2015. The clinical presentation, aneurysm characteristics, treatment modality, and outcome were studied.
Results
We studied 26 pediatric patients (mean age, 13.4 years; range, 4–18 years) with 31 IDAs who comprised 6.9% of all IDA patients treated during the same period. Seventeen (65.4%) patients were males, and nine (34.6%) were females. The incidence of large (≥10 mm in size) or giant aneurysms (≥25 mm in size) was 65.5%. Twenty-one (80.8%) patients underwent endovascular or surgical treatment and five (19.2%) received conservative treatment. Perioperative complications occurred in three patients, in whom two eventually recovered completely with a Glasgow Outcome Scale (GOS) score of 5 and one partially recovered with a GOS score 4. Overall, 25 (96.2%) patients had a favorable outcome and one (3.8%) had an unfavorable outcome at a mean follow-up of 22.8 months (range, 6–60 months).
Conclusion
Pediatric IDAs are rare. In this series, endovascular management was a relatively safe and effective method of treatment for pediatric IDAs. However, continued follow-up is required because of the possibility of aneurysm recurrence and de novo aneurysm formation after treatment.
doi:10.3389/fneur.2016.00224
PMCID: PMC5138241  PMID: 27999562
intracranial aneurysm; pediatrics; dissection; intervention; treatment
13.  Suppression of Immunotherapy on Group 2 Innate Lymphoid Cells in Allergic Rhinitis 
Chinese Medical Journal  2016;129(23):2824-2828.
Background:
Group 2 innate lymphoid cells (ILC2s) are regarded as a novel population of lineage-negative cells that induce innate Type 2 responses by producing the critical Th2-type cytokines interleukin (IL)-5 and IL-13. ILC2s as key players in the development of allergic rhinitis (AR) have been proved, however, the effect of subcutaneous immunotherapy (SCIT) with dermatophagoides pteronyssinus extract (Der p-SCIT) on ILC2s in AR patients is not clear. This study aimed to investigate the response of ILC2s of peripheral blood in house dust mites (HDM)-sensitized Chinese patients with AR who received SCIT with Der P extract.
Methods:
Seven healthy controls without symptoms of AR who had negative reactions to any of the allergens from skin-prick testing, nine patients diagnosed with persistent AR according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines, and 24 AR patients who received Der p-SCIT for 1.0–3.5 years were recruited for the study. ILC2s in the peripheral blood were evaluated using flow cytometry. The severity of their symptoms of all participants was rated based on the Total 5 symptom score.
Results:
Among 40 participants, 9 AR patients were assigned to the untreated group, 24 AR patients receiving Der p-SCIT were assigned to the immunotherapy group, and 7 healthy controls without symptoms of AR were assigned to healthy control group. The mean Total 5 symptom score of immunotherapy group was significantly lower than that of untreated group (4.3 ± 1.4 vs. 10.1 ± 2.5, P < 0.001). Similarly, the levels of ILC2s in the peripheral blood of immunotherapy group were significantly reduced compared with that in untreated group (P < 0.001), but were not significantly different from healthy controls (P = 0.775). Further subgroup analysis based on the duration of SCIT therapy (1.0–2.0 years [SCIT1-2], 2.0–3.0 years [SCIT2-3], and 3.0–3.5 years [SCIT3-3.5]) showed that the percentage of ILC2s was not significantly different between SCIT1-2, SCIT2-3, and SCIT3-3.5 groups (SCIT1-2 vs. SCIT2-3: P = 0.268; SCIT1-2 vs. SCIT3-3.5: P = 0.635; and SCIT2-3 vs. SCIT3-3.5: P = 0.787).
Conclusions:
The present study highlighted the suppression of Der p-SCIT on ILC2s in HDM-AR patients. ILC2s identified in peripheral blood can be used as an effective biomarker for Der p-SCIT.
doi:10.4103/0366-6999.194642
PMCID: PMC5146790  PMID: 27900996
Allergic Rhinitis; Group 2 Innate Lymphoid Cell; House Dust Mite; Immunotherapy
14.  MicroRNA-29b is a therapeutic target in cerebral ischemia associated with aquaporin 4 
MicroRNA-29b (miR-29b) is involved in regulating ischemia process, but the molecular mechanism is unclear. In this work, we explored the function of miR-29b in cerebral ischemia. The level of miR-29b in white blood cells was evaluated in patients and mice after ischemic stroke. Brain infarct volume and National Institute of Health stroke scale (NIHSS) scores were analyzed to determine the relationship between miR-29b expression and the severity of stroke. The relationship of miR-29b and aquaporin-4 (AQP4) was further studied in mice. We found that miR-29b was significantly downregulated in stroke patients (P<0.05). MiR-29b level negatively associated with NIHSS scores (r=−0.349, P<0.01) and brain infarct volume (r=−0.321, P<0.05). In ischemic mice, miR-29b in the brain and blood were both downregulated (r=0.723, P<0.05). MiR-29b overexpression reduced infarct volume (49.50±6.55 versus 35.48±2.28 mm3, P<0.05), edema (164±4% versus 108±4%, P<0.05), and blood–brain barrier (BBB) disruption compared with controls (15±9% versus 7±3%, P<0.05). Aquaporin-4 expression greatly decreased after miR-29b overexpression (28±7% versus 11±3%, P<0.05). Dual-luciferase reporter system showed that AQP-4 was the direct target of miR-29b (P<0.05). We concluded that miR-29b could potentially predict stroke outcomes as a novel circulating biomarker, and miR-29b overexpression reduced BBB disruption after ischemic stroke via downregulating AQP-4.
doi:10.1038/jcbfm.2015.156
PMCID: PMC4671118  PMID: 26126866
aquaporin-4; human; ischemia; microRNA-29b; stroke
15.  Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy 
Stem Cells Translational Medicine  2015;4(12):1425-1435.
In this study, bone marrow-derived mesenchymal stem cells (BMSCs) were indirectly cocultured with neonatal rat ventricular cardiomyocytes in vitro or intramyocardially transplanted into hypertrophic hearts in vivo. The results showed that isoproterenol-induced typical hypertrophic characteristics of cardiomyocytes were prevented by BMSCs in the coculture model in vitro and after BMSC transplantation in vivo, providing the first evidence for the treatment of myocardial hypertrophy using BMSCs.
Bone marrow-derived mesenchymal stem cells (BMSCs) have emerged as a promising therapeutic strategy for cardiovascular disease. However, there is no evidence so far that BMSCs can heal pathological myocardial hypertrophy. In this study, BMSCs were indirectly cocultured with neonatal rat ventricular cardiomyocytes (NRVCs) in vitro or intramyocardially transplanted into hypertrophic hearts in vivo. The results showed that isoproterenol (ISO)-induced typical hypertrophic characteristics of cardiomyocytes were prevented by BMSCs in the coculture model in vitro and after BMSC transplantation in vivo. Furthermore, activation of the Ca2+/calcineurin/nuclear factor of activated T cells cytoplasmic 3 (NFATc3) hypertrophic pathway in NRVCs was abrogated in the presence of BMSCs both in vitro and in vivo. Interestingly, inhibition of vascular endothelial growth factor (VEGF) release from BMSCs, but not basic fibroblast growth factor and insulin-like growth factor 1, abolished the protective effects of BMSCs on cardiomyocyte hypertrophy. Consistently, VEGF administration attenuated ISO-induced enlargement of cellular size; the upregulation of atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain expression; and the activation of Ca2+/calcineurin/NFATc3 hypertrophic pathways, and these pathways can be abrogated by blocking VEGFR-1 in cardiomyocytes, indicating that VEGF receptor 1 is involved in the antihypertrophic role of VEGF. We further found that the ample VEGF secretion contributing to the antihypertrophic effects of BMSCs originates from the crosstalk of BMSCs and cardiac cells but not BMSCs or cardiomyocytes alone. Interplay of mesenchymal stem cells with cardiomyocytes produced synergistic effects on VEGF release. In summary, crosstalk between mesenchymal stem cells and cardiomyocytes contributes to the inhibition of myocardial hypertrophy via inhibiting Ca2+/calcineurin/NFATc3 hypertrophic pathways in cardiac cells. These results provide the first evidence for the treatment of myocardial hypertrophy using BMSCs.
Significance
This study found that mesenchymal stem cells may crosstalk with cardiomyocytes, which causes a synergistic vascular endothelial growth factor (VEGF) release from both kinds of cells and then inhibits pathological cardiac remodeling following hypertrophic stimulation in cardiomyocytes in vitro and in vivo. Blockage of VEGF release from bone marrow-derived mesenchymal stem cells (BMSCs) abolishes the antihypertrophic actions of BMSCs in vitro and in vivo. On the contrary, VEGF administration attenuates hypertrophic signaling of calcineurin/ nuclear factor of activated T cell cytoplasmic 3 signal pathways. This study provides the first evidence for the treatment of myocardial hypertrophy using BMSCs.
doi:10.5966/sctm.2015-0032
PMCID: PMC4675503  PMID: 26586774
Mesenchymal stem cell; Cardiomyocyte; Crosstalk; Hypertrophy; Remodeling
16.  High Glucose/High Lipids Impair Vascular Adiponectin Function via Inhibition of Caveolin-1/AdipoR1 Signalsome Formation 
Reduced levels of adiponectin (APN) contribute to cardiovascular injury in the diabetic population. Recent studies demonstrate elevated circulating APN levels are associated with endothelial dysfunction during pre-diabetes, suggesting the development of APN resistance. However, mechanisms leading to, and the role of, vascular APN resistance in endothelial dysfunction remain unidentified. The current study determined whether diabetes cause endothelial APN resistance, and by what mechanisms. Under high glucose/high lipids (HG/HL), APN-stimulated nitric oxide production by HUVEC was decreased, phosphorylation of eNOS, AMPK, and Akt was attenuated (P<0.01), and APN’s anti-TNFα effect was blunted (P<0.01). APN receptor expression remained normal, whereas Cav1 expression was reduced in HG/HL cells (P<0.01). The AdipoR1/Cav1 signaling complex was dissociated in HG/HL cells. Knock-down of Cav1 inhibited APN’s anti-oxidative and anti-inflammatory actions. Conversely, preventing HG/HL-induced Cav1 downregulation by Cav1 overexpression preserved APN signaling in HG/HL cells. Knock-in of a wild type Cav1 in Cav1 knock-down cells restored caveolae structure and rescued APN signaling. In contrast, knock-in of a mutated Cav1 scaffolding domain restored caveolae structure, but failed to rescue APN signaling in Cav1 knock-down cells. Finally, AdipoR1/Cav1 interaction was significantly reduced in diabetic vascular tissue, and the vasorelaxative response to APN was impaired in diabetic animals. The current study demonstrates for the first time the interaction between AdipoR1 and Cav1 is critical for adiponectin-mediated vascular signaling. The AdipoR1/Cav1 interaction is adversely affected by HG/HL, due largely to reduced Cav1 expression, supporting a potential mechanism for the development of APN resistance, contributing to diabetic endothelial dysfunction.
Graphical abstract
doi:10.1016/j.freeradbiomed.2015.09.005
PMCID: PMC4684768  PMID: 26453924
Caveolin; Adiponectin; Vascular Injury; Endothelial Function
17.  Cerebral Perfusion and Gray Matter Changes Associated With Chemotherapy-Induced Peripheral Neuropathy 
Journal of Clinical Oncology  2015;34(7):677-683.
Purpose
To investigate the longitudinal relationship between chemotherapy-induced peripheral neuropathy (CIPN) symptoms (sx) and brain perfusion changes in patients with breast cancer. Interaction of CIPN-sx perfusion effects with known chemotherapy-associated gray matter density decrease was also assessed to elucidate the relationship between CIPN and previously reported cancer treatment–related brain structural changes.
Methods
Patients with breast cancer treated with (n = 24) or without (n = 23) chemotherapy underwent clinical examination and brain magnetic resonance imaging at the following three time points: before treatment (baseline), 1 month after treatment completion, and 1 year after the 1-month assessment. CIPN-sx were evaluated with the self-reported Functional Assessment of Cancer Therapy/Gynecologic Oncology Group–Neurotoxicity four-item sensory-specific scale. Perfusion and gray matter density were assessed using voxel-based pulsed arterial spin labeling and morphometric analyses and tested for association with CIPN-sx in the patients who received chemotherapy.
Results
Patients who received chemotherapy reported significantly increased CIPN-sx from baseline to 1 month, with partial recovery by 1 year (P < .001). CIPN-sx increase from baseline to 1 month was significantly greater for patients who received chemotherapy compared with those who did not (P = .001). At 1 month, neuroimaging showed that for the group that received chemotherapy, CIPN-sx were positively associated with cerebral perfusion in the right superior frontal gyrus and cingulate gyrus, regions associated with pain processing (P < .001). Longitudinal magnetic resonance imaging analysis in the group receiving chemotherapy indicated that CIPN-sx and associated perfusion changes from baseline to 1 month were also positively correlated with gray matter density change (P < .005).
Conclusion
Peripheral neuropathy symptoms after systemic chemotherapy for breast cancer are associated with changes in cerebral perfusion and gray matter. The specific mechanisms warrant further investigation given the potential diagnostic and therapeutic implications.
doi:10.1200/JCO.2015.62.1276
PMCID: PMC4822503  PMID: 26527786
18.  Rhein and rhubarb similarly protect the blood-brain barrier after experimental traumatic brain injury via gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 signaling pathway 
Scientific Reports  2016;6:37098.
Oxidative stress chiefly contributes to the disruption of the BBB following traumatic brain injury (TBI). The Chinese herbal medicine rhubarb is a promising antioxidant in treating TBI. Here we performed in vivo and in vitro experiments to determine whether rhubarb and its absorbed bioactive compound protected the BBB after TBI by increasing ZO-1 expression through inhibition of gp91phox subunit of NADPH oxidase/ROS/ERK/MMP-9 pathway. Rats were subjected to the controlled cortical impact (CCI) model, and primary rat cortical astrocytes were exposed to scratch-wound model. The liquid chromatography with tandem mass spectrometry method showed that rhein was the compound absorbed in the brains of CCI rats after rhubarb administration. The wet-dry weights and Evans blue measurements revealed that rhubarb and rhein ameliorated BBB damage and brain edema in CCI rats. Western blots showed that rhubarb and rhein downregulated GFAP in vitro. RT-PCR, immunohistochemistry, Western blot and dichlorodihydrofluorescein diacetate analysis indicated that rhubarb prevented activation of gp91phox subunit of NADPH oxidase induced ROS production, subsequently inhibited ERK/MMP-9 pathway in vivo and in vitro. Interestingly, rhein and rhubarb similarly protected the BBB by inhibiting this signaling cascade. The results provide a novel herbal medicine to protect BBB following TBI via an antioxidative molecular mechanism.
doi:10.1038/srep37098
PMCID: PMC5128794  PMID: 27901023
19.  CCL5/RANTES contributes to hypothalamic insulin signaling for systemic insulin responsiveness through CCR5 
Scientific Reports  2016;6:37659.
Many neurodegenerative diseases are accompanied by metabolic disorders. CCL5/RANTES, and its receptor CCR5 are known to contribute to neuronal function as well as to metabolic disorders such as type 2 diabetes mellitus, obesity, atherosclerosis and metabolic changes after HIV infection. Herein, we found that the lack of CCR5 or CCL5 in mice impaired regulation of energy metabolism in hypothalamus. Immunostaining and co-immunoprecipitation revealed the specific expression of CCR5, associated with insulin receptors, in the hypothalamic arcuate nucleus (ARC). Both ex vivo stimulation and in vitro tissue culture studies demonstrated that the activation of insulin, and PI3K-Akt pathways were impaired in CCR5 and CCL5 deficient hypothalamus. The inhibitory phosphorylation of insulin response substrate-1 at Ser302 (IRS-1S302) but not IRS-2, by insulin was markedly increased in CCR5 and CCL5 deficient animals. Elevating CCR5/CCL5 activity induced GLUT4 membrane translocation and reduced phospho-IRS-1S302 through AMPKα-S6 Kinase. Blocking CCR5 using the antagonist, MetCCL5, abolished the de-phosphorylation of IRS-1S302 and insulin signal activation. In addition, intracerebroventricular delivery of MetCCL5 interrupted hypothalamic insulin signaling and elicited peripheral insulin responsiveness and glucose intolerance. Taken together, our data suggest that CCR5 regulates insulin signaling in hypothalamus which contributes to systemic insulin sensitivity and glucose metabolism.
doi:10.1038/srep37659
PMCID: PMC5127185  PMID: 27898058
20.  Combination of transcatheter arterial chemoembolization and CT-guided percutaneous segment ablation for hepatocellular carcinoma therapy 
Medicine  2016;95(47):e5422.
Abstract
Treatment option for liver cancer patients with large tumor >5 cm and/or portal vein tumor thrombosis is very limited. New treatment strategy is badly needed. Our study is to determine the safety and treatment efficacy of a new minimally invasive treatment strategy—liver segment thermal ablation.
Late-stage hepatocellular carcinoma patients were included and treated with percutaneous ablation to destroy the entire tumor-containing liver segment to reduce reoccurrence and prolong survival. Transcatheter arterial chemoembolization was used before ablation to label tumor margin. The patients were followed up routinely.
The patients were followed up for 8 to 95 months. Mean overall survival (OS) (n = 6) was 21.5 months (range 8–95). For patients in BCLC stage B (n = 2), average OS was 16 months; for those in stage C (n = 4), mean OS was 25 months (range 15–95). Out of all 6 patients, 2 reoccurred within 1 year, and 1 reoccurred after 13 months postoperatively. The average alpha-fetoprotein was dropped from 1153.69 to 41.22 μg/L postoperatively. No severe intra or postoperative complications were observed.
Our preliminary data indicated that transcatheter arterial chemoembolization + segment ablation is safe and benefits survival significantly for late-stage hepatocellular carcinoma patients. A prospective multicenter, randomized trial comparing focal and segment ablation is now ongoing in China (Trial Registry Number, ChiCTR-TRC-12002786).
doi:10.1097/MD.0000000000005422
PMCID: PMC5134874  PMID: 27893681
ablation; hepatocellular carcinoma; percutaneous; segment; survival
21.  Impact of acute kidney injury on coagulation in adult minimal change nephropathy 
Medicine  2016;95(46):e5366.
Abstract
A hypercoagulable state exists in patients with nephrotic syndrome (NS), which more easily leads to venous thromboembolism (VTE). However, whether acute kidney injury (AKI), a common complication of NS, affects the hypercoagulable state and VTE has rarely been elucidated. In this study, we aimed to explore coagulation changes and analyze relevant influencing factors in NS-AKI patients.
A total of 269 consecutive NS patients with minimal change disease (MCD) between 2011 and 2016 were included in this observational study. Ninety-one cases were in the AKI group and 178 cases in the non-AKI group. The 1:1 propensity score matching (PSM) method was applied to match the baseline information. The coagulation biomarkers were compared, and the thrombosis events were recorded. Linear correlation was performed to detect any relation between D-dimer and clinical data.
The PSM method gave matched pairs of 88 MCD patients with AKI and non-AKI patients, resulting in no differences in baseline information. The D-dimer, fibrinogen, and thromboelastography parameters maximum amplitude (MA), G values of the MCD-AKI patients were significantly higher than the levels of the MCD patients without AKI (D-dimer: 1.8 [1.0, 3.3] vs 1.1 [0.6, 1.7] mg/L, P < 0.001; fibrinogen: 7.0±2.0 vs 6.5 ± 1.4 g/L, P = 0.036; MA: 74.6 ± 5.0 vs 70.5 ± 5.3 mm, P = 0.020; G: 15.7 ± 5.3 vs 12.5 ± 3.3, P = 0.034). For the MCD patients, the serum creatinine, white blood cell count, and interleukin-6 levels in the patients with D-dimers >1 mg/L were significantly higher than those of patients with D-dimers ≤1 mg/L. The correlation analysis showed that the D-dimer level was correlated with serum creatinine, white blood cell count, and interleukin-6 (r = 0.410, P =  < 0.001; r = 0.248, P =  < 0.001; r = 0.306, P =  < 0.001, respectively). Five deep vein thrombosis events occurred in the AKI group and 1 pulmonary embolism event occurred in the non-AKI group after adjusting the propensity score value. AKI appeared to have an association with higher incidence of VTE, but the difference was not statistically significant (RR: 4.9, 95% CI: 0.6–42.7, P = 0.154).
The MCD-NS patients complicated with AKI had a more severe hypercoagulable state, which might be associated with the active inflammation of AKI that mediated activation of the coagulation system.
doi:10.1097/MD.0000000000005366
PMCID: PMC5120924  PMID: 27861367
acute kidney injury; coagulation; minimal change disease; nephrotic syndrome; thromboembolic events
22.  Electroacupuncture for reproductive hormone levels in patients with diminished ovarian reserve: a prospective observational study 
Acupuncture in Medicine  2016;34(5):386-391.
Background
Effective methods for the treatment of reproductive dysfunction are limited. Previous studies have reported that acupuncture can modulate female hormone levels, improve menstrual disorders, alleviate depression and improve pregnancy rates. However, studies of acupuncture for diminished ovarian reserve (DOR) are lacking.
Objective
To carry out a prospective observational study aimed at assessing the effect of EA on the reproductive hormone levels of patients with DOR seeking fertility support and consider its safety.
Methods
Eligible patients with DOR received EA for 12 weeks: five times a week for 4 weeks followed by three times a week for 8 weeks. The primary outcome was the change in mean follicle-stimulating hormone (FSH) level at week 12. Mean luteinising hormone (LH) and serum oestradiol (E2) levels, FSH/LH ratios and symptom scale scores were simultaneously observed.
Results
Twenty-one patients with DOR were included in the final analysis. Mean FSH levels fell from 19.33±9.47 mIU/mL at baseline to 10.58±6.34 mIU/mL at week 12 and 11.25±6.68 mIU/mL at week 24. Change in mean FSH from baseline was −8.75±11.13 mIU/mL at week 12 (p=0.002) and −8.08±9.56 mIU/mL at week 24 (p=0.001). Mean E2 and LH levels, FSH/LH ratios and irritability scores were improved at weeks 12 and/or 24. Approximately 30% patients reported subjective increases in menstrual volume after treatment.
Conclusions
EA may modulate reproductive hormone levels and the effects seem to persist for at least 12 weeks after treatment with no significant side effects. EA may improve the ovarian reserve of patients with DOR, though further research is needed.
Trial registration number
NCT02229604; Results.
doi:10.1136/acupmed-2015-011014
PMCID: PMC5099178  PMID: 27177929
COMPLEMENTARY MEDICINE; GYNAECOLOGY
23.  DDR1 promotes E-cadherin stability via inhibition of integrin-β1-Src activation-mediated E-cadherin endocytosis 
Scientific Reports  2016;6:36336.
Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase of collagen, is primarily expressed in epithelial cells. Activation of DDR1 stabilises E-cadherin located on the cell membrane; however, the detailed mechanism of DDR1-stabilised E-cadherin remains unclear. We performed DDR1 knockdown (Sh-DDR1) on Mardin-Darby canine kidney cells to investigate the mechanism of DDR1-stabilised E-cadherin. Sh-DDR1 decreased junctional localisation, increased endocytosis of E-cadherin, and increased physical interactions between E-cadherin and clathrin. Treatment of the dynamin inhibitor Dyngo 4a suppressed Sh-DDR1-induced E-cadherin endocytosis. In addition, the phosphorylation level of Src tyrosine 418 was increased in Sh-DDR1 cell junctions, and inhibition of Src activity decreased Sh-DDR1-induced E-cadherin endocytosis. To characterise the molecular mechanisms, blocking integrin β1 decreased Src activity and E-cadherin junctional localisation in Sh-DDR1 cells. Photoconversion results showed that inhibition of Src activity rescued E-cadherin membrane stability and that inhibition of integrin β1-Src signalling decreased stress fibres and rescued E-cadherin membrane stability in Sh-DDR1 cells. Taken together, DDR1 stabilised membrane localisation of E-cadherin by inhibiting the integrin β1-Src-mediated clathrin-dependent endocytosis pathway.
doi:10.1038/srep36336
PMCID: PMC5099905  PMID: 27824116
24.  Independent Prognostic Value of High-sensitivity C-reactive Protein in Patients with Coronary Artery Ectasia 
Chinese Medical Journal  2016;129(21):2582-2588.
Background:
Despite its severity, coronary artery ectasia (CAE) is still poorly understood. High-sensitivity C-reactive protein (hs-CRP) has been recognized as a prognostic factor in some cardiovascular diseases but not assessed in CAE. The aim of this observational study was to investigate the prognostic value of hs-CRP in CAE.
Methods:
Our analysis evaluated the effect of the baseline hs-CRP on cardiovascular events (CVs) (cardiac death and nonfetal myocardial infarction) in consecutively enrolled stable CAE patients. We used the Cox proportional hazards regression models to examine the association between baseline hs-CRP level and follow-up CVs in CAE. The net reclassification improvement and integrated discrimination improvement (IDI) of hs-CRP were also assessed.
Results:
We obtained the follow-up results of 540 patients over a median follow-up period of 36 (37.41 ± 15.88) months. The multivariable Cox analysis showed that the hs-CRP was a significant predictor of adverse outcomes in CAE (hazard ratio [HR]: 2.99, 95% confidence interval [CI]: 1.31–6.81, P = 0.0091). In Kaplan–Meier analysis, the group with hs-CRP >3 mg/L had a lower cumulative 66-month event-free survival rate (log-rank test for trend, P = 0.0235) and a higher risk of CVs (HR = 2.66, 95% CI: 1.22–5.77, P = 0.0140) than the group with hs-CRP ≤3 mg/L. Hs-CRP added predictive information beyond that given by the baseline model comprising the classical risk factors (P value for IDI = 0.0330).
Conclusions:
A higher level of hs-CRP was independently associated with cardiac death and nonfatal myocardial infarction in CAE patients. The hs-CRP level may therefore provide prognostic information for the risk stratification of CAE patients.
doi:10.4103/0366-6999.192778
PMCID: PMC5125337  PMID: 27779165
C-reactive Protein; Coronary Artery Ectasia; Coronary Heart Disease; Prognosis
25.  Maintained Individual Data Distributed Likelihood Estimation (MIDDLE) 
Multivariate behavioral research  2015;50(6):706-720.
Maintained Individual Data Distributed Likelihood Estimation (MIDDLE) is a novel paradigm for research in the behavioral, social, and health sciences. The MIDDLE approach is based on the seemingly-impossible idea that data can be privately maintained by participants and never revealed to researchers, while still enabling statistical models to be fit and scientific hypotheses tested. MIDDLE rests on the assumption that participant data should belong to, be controlled by, and remain in the possession of the participants themselves. Distributed likelihood estimation refers to fitting statistical models by sending an objective function and vector of parameters to each participants’ personal device (e.g., smartphone, tablet, computer), where the likelihood of that individual’s data is calculated locally. Only the likelihood value is returned to the central optimizer. The optimizer aggregates likelihood values from responding participants and chooses new vectors of parameters until the model converges. A MIDDLE study provides significantly greater privacy for participants, automatic management of opt-in and opt-out consent, lower cost for the researcher and funding institute, and faster determination of results. Furthermore, if a participant opts into several studies simultaneously and opts into data sharing, these studies automatically have access to individual-level longitudinal data linked across all studies.
doi:10.1080/00273171.2015.1094387
PMCID: PMC4804354  PMID: 26717128

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