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1.  Effect of Intravenous Iron Supplementation on Acute Mountain Sickness: A Preliminary Randomized Controlled Study 
The aim of this study was to assess the role of intravenous iron supplementation in the prevention of AMS.
This was a randomized, double-blinded, placebo-controlled study. Forty-one (n=41) healthy Chinese low-altitude inhabitants living in Beijing, China (altitude of about 50 meters) were randomly assigned into intravenous iron supplementation (ISS group; n=21) and placebo (CON group; n=20) groups. Participants in the ISS group received iron sucrose supplement (200 mg) before flying to Lhasa, China (altitude of 4300 meters). Acute mountain sickness (AMS) severity was assessed with the Lake Louise scoring (LLS) system within 5 days after landing on the plateau (at high altitude). Routine check-ups, clinical biochemistry, and blood tests were performed before departure and 24 h after arrival.
A total of 38 participants completed the study (ISS group: n=19; CON group: n=19). The rate of subjects with AMS (LLS>3) was lower in the ISS group compared with the CON group, but no significant differences were obtained (P>0.05). There were no differences in patients’ baseline characteristics. The physiological indices were similar in both groups except for serum iron concentrations (19.44±10.02 vs. 85.10±26.78 μmol/L) and transferrin saturation rates (28.20±12.14 vs. 68.34±33.12%), which were significantly higher in the ISS group (P<0.05). Finally, heart rate was identified as a contributing factor of LLS.
These preliminary findings suggest that intravenous iron supplementation has no significant protective effect on AMS in healthy Chinese low-altitude inhabitants.
PMCID: PMC4515939  PMID: 26175087
Administration, Intravenous; Altitude Sickness; Randomized Controlled Trial
2.  Alterations of Bacteroides sp., Neisseria sp., Actinomyces sp., and Streptococcus sp. populations in the oropharyngeal microbiome are associated with liver cirrhosis and pneumonia 
BMC Infectious Diseases  2015;15:239.
The microbiomes of humans are associated with liver and lung inflammation. We identified and verified alterations of the oropharyngeal microbiome and assessed their association with cirrhosis and pneumonia.
Study components were as follows: (1) determination of the temporal stability of the oropharyngeal microbiome; (2) identification of oropharyngeal microbial variation in 90 subjects; (3) quantitative identification of disease-associated bacteria. DNAs enriched in bacterial sequences were produced from low-biomass oropharyngeal swabs using whole genome amplification and were analyzed using denaturing gradient gel electrophoresis analysis.
Whole genome amplification combined with denaturing gradient gel electrophoresis analysis monitored successfully oropharyngeal microbial variations and showed that the composition of each subject’s oropharyngeal microbiome remained relatively stable during the follow-up. The microbial composition of cirrhotic patients with pneumonia differed from those of others and clustered together in subgroup analysis. Further, species richness and the value of Shannon’s diversity and evenness index increased significantly in patients with cirrhosis and pneumonia versus others (p < 0.001, versus healthy controls; p < 0.01, versus cirrhotic patients without pneumonia). Moreover, we identified variants of Bacteroides, Eubacterium, Lachnospiraceae, Neisseria, Actinomyces, and Streptococcus through phylogenetic analysis. Quantitative polymerase chain reaction assays revealed that the populations of Bacteroides, Neisseria, and Actinomycetes increased, while that of Streptococcus decreased in cirrhotic patients with pneumonia versus others (p < 0.001, versus Healthy controls; p < 0.01, versus cirrhotic patients without pneumonia).
Alterations of Bacteroides, Neisseria, Actinomyces, and Streptococcus populations in the oropharyngeal microbiome were associated with liver cirrhosis and pneumonia.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-015-0977-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4477430  PMID: 26099252
Whole genome amplification (WGA); Oropharyngeal microbiome; Pneumonia; Cirrhosis; Denaturing gradient gel electrophoresis (DGGE)
3.  Engineered chromosome-based genetic mapping establishes a 3.7-Mb critical genomic region for Down syndrome-associated heart defects in mice 
Human genetics  2013;133(6):743-753.
Trisomy 21 (Down syndrome, DS) is the most common human genetic anomaly associated with heart defects. Based on evolutionary conservation, DS-associated heart defects have been modeled in mice. By generating and analyzing mouse mutants carrying different genomic rearrangements in human chromosome 21 (Hsa21) syntenic regions, we found the triplication of the Tiam1-Kcnj6 region on mouse chromosome 16 (Mmu16) resulted in DS-related cardiovascular abnormalities. In this study, we developed two tandem duplications spanning the Tiam1-Kcnj6 genomic region on Mmu16 using recombinase-mediated genome engineering, Dp(16)3Yey and Dp(16)4Yey, spanning the 2.1Mb Tiam1-Il10rb and 3.7Mb Ifnar1-Kcnj6 regions, respectively. We found that Dp(16)4Yey/+, but not Dp(16)3Yey/+, led to heart defects, suggesting the triplication of the Ifnar1-Kcnj6 region is sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(16)4Yey/+ embryos showed that the Hsa21 gene orthologs located within the duplicated interval were expressed at the elevated levels, reflecting the consequences of the gene dosage alterations. Therefore, we have identified a 3.7Mb genomic region, the smallest critical genomic region, for DS-associated heart defects, and our results should set the stage for the final step to establish the identities of the causal gene(s), whose elevated expression(s) directly underlie this major DS phenotype.
PMCID: PMC4024075  PMID: 24362460
Down syndrome; trisomy 21; heart defects - congenital; chromosome engineering; mouse models for human genetic disease; genetic mapping
4.  Associations Between Serum-Intact Parathyroid Hormone, Serum 25-Hydroxyvitamin D, Oral Vitamin D Analogs and Metabolic Syndrome in Peritoneal Dialysis Patients: A Multi-Center Cross-Sectional Study 
♦ Introduction: Although previous studies have suggested associations between serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25(OH)D) and metabolic syndrome (MS) in the general population, these associations are still uncharacterized in peritoneal dialysis (PD) patients.
♦ Methods: In total, 837 prevalent PD patients from 5 centers in China were enrolled between April 1, 2011 and November 1, 2011. The demographic data, biochemical parameters and medical records were collected, except for serum 25(OH)D which was measured in 347 of 837 patients. The definition of MS was modified from National Cholesterol Education Program Third Adult Treatment Panel (NCEP-ATPIII).
♦ Results: 55.4% of 837 patients were found to have MS. The median concentration of iPTH, 25(OH)D and doses of oral vitamin D analogs for participants with MS was significantly lower than those without MS. The iPTH, 25(OH)D values and doses of vitamin D analogs were all associated with one or more components of MS. After multivariate adjustment, low serum iPTH values and oral vitamin D analogs, rather than serum 25(OH)D, were significantly associated with the presence of MS, abnormal fasting blood glucose (FBG) and high-density lipoprotein cholesterol (HDL-C). Compared to iPTH < 130pg/mL, iPTH 130-585 pg/mL and > 585pg/mL were associated with a lower risk of MS with adjusted odds ratio (OR) of 0.59 and 0.33, respectively. Taking vitamin D analogs was also associated with a lower risk of MS with adjusted OR of 0.55.
♦ Conclusions: Serum iPTH and the use of active vitamin D supplements rather than serum 25(OH)D were independently associated with the presence of MS in patients on PD.
PMCID: PMC4079492  PMID: 24497582
Metabolic syndrome; parathyroid hormone; peritoneal dialysis; vitamin D
5.  Transverse False Tendons in the Left Ventricular Cavity Are Associated with Early Repolarization 
PLoS ONE  2015;10(5):e0125173.
Left ventricular false tendons (LVFTs) are related to precordial murmurs, ventricular arrhythmias and some repolarization abnormalities. Early repolarization (ER) is a specific type of repolarization abnormality.
The aim of the present study was to investigate the relationship between LVFTs and ER.
This study retrospectively included 99 consecutive healthy subjects and 33 patients with ER. Early repolarization was defined as an elevation of the QRS-ST junction of >0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching. Each participant was examined using echocardiography with second harmonic imaging, and the attachments of the LVFTs were recorded.
A total of 93 LVFTs were present in 82 (83%) of the 99 healthy subjects. Of these 93 LVFTs, the majority (79/93, or 84.9%) were longitudinal-type LVFTs, which originated from the basal interventricular septum (IVS) and progressed toward the apical segment of the left ventricular free wall. There were significant differences in the positioning of the LVFTs between the ER patients and control (P < 0.0001). LVFTs between mid-IVS to the middle of the LV free wall were found more common in patients with ER compared with control subjects (47.5% vs. 6.5%, P < 0.0001). In the ER group, LVFTs between the basal IVS to the apical segment of LV free wall were only identified in 21% of the LVFTs, compared to a value of 84.9% for the control group (P < 0.0001). The distribution of LVFT trends in the ER group was also significantly different from that in the control group (P < 0.05).
LVFTs are commonly visualized using echocardiography. An LVFT from the basal IVS to the apical segment of the left ventricular free wall may be a normal anatomical structure in the left ventricular cavity. On the contrary, transverse false tendons in the left ventricular cavity may be associated with ER.
PMCID: PMC4416704  PMID: 25933440
6.  Plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women 
To investigate the associations of the plasma homocysteine levels with the alterations in arterial stiffness in a community-based cohort. The gender differences in these associations were examined.
We evaluated the relationship between plasma homocysteine levels to three measures of vascular function [carotid-femoral pulse wave velocity (CF-PWV), carotid-ankle PWV (CA-PWV) and heart rate corrected augmentation index (AI)] in 1680 participants (mean age: 61.5 years; 709 men, 971 women) from communities of Beijing, China.
In univariate analysis, plasma homocysteine levels was positively related to the CF-PWV (r = 0.211, P < 0.0001) and CA-PWV (r = 0.148, P < 0.0001), whereas inversely associated with AI (r = −0.052, P = 0.016). In multiple linear regression models adjusting for covariants, plasma homocysteine remained positively related to the CF-PWV (standardized β = 0.065, P = 0.007) in total cases. When the groups of men and women were examined separately, plasma homocysteine remained positively associated with the CF-PWV (standardized β = 0.082, P = 0.023) in men, whereas the relations between homocysteine and any of the arterial stiffness indices were not further present in women.
In Chinese population, plasma homocysteine levels are independently associated with alterations of large artery stiffness in men but not in women.
PMCID: PMC4460168  PMID: 26089849
Arterial stiffness; Gender differences; Homocysteine; Pulse wave velocity
7.  Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA) 
Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100 nM), in a cell line with doxycycline-inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA.
PMCID: PMC4242414  PMID: 24472523
Gonadotropin-releasing hormone receptor (GnRHR); adrenal aldosterone-producing adenoma (APA); CYP11B2; aldosterone
8.  Predictors of Percutaneous Catheter Drainage (PCD) after Abdominal Paracentesis Drainage (APD) in Patients with Moderately Severe or Severe Acute Pancreatitis along with Fluid Collections 
PLoS ONE  2015;10(2):e0115348.
Although we previously demonstrated abdominal paracentesis drainage (APD) preceding percutaneous catheter drainage (PCD) as the central step for treating patients with moderately severe (MSAP) or severe acute pancreatitis (SAP), the predictors leading to PCD after APD have not been studied.
Consecutive patients with MSAP or SAP were recruited between June 2011 and June 2013. As a step-up approach, all patients initially received medical management, later underwent ultrasound-guided APD before PCD, if necessary, followed by endoscopic necrosectomy through the path formed by PCD. APD primarily targeted fluid in the abdominal or pelvic cavities, whereas PCD aimed at (peri)pancreatic fluid.
Of the 92 enrolled patients, 40 were managed with APD alone and 52 received PCD after APD (14 required necrosectomy after initial PCD). The overall mortality was 6.5%. Univariate analysis showed that among the 20 selected parameters, 13 factors significantly affected PCD intervention after APD. Multivariate analysis revealed that infected (peri)pancreatic collections (P = -0.001), maximum extent of necrosis of more than 30% of the pancreas (P = -0.024), size of the largest necrotic peri(pancreatic) collection (P = -0.007), and reduction of (peri)pancreatic fluid collections by <50% after APD (P = -0.008) were all independent predictors of PCD.
Infected (peri)pancreatic collections, a largest necrotic peri(pancreatic) collection of more than 100 ml, and reduction of (peri)pancreatic fluid collections by <50% after APD could effectively predict the need for PCD in the early course of the disease.
PMCID: PMC4319763  PMID: 25659143
9.  The predictive capacity and additional prognostic power of N-terminal pro-B-type natriuretic peptide in Chinese elderly with chronic heart failure 
This study was conducted to research the prognostic utility of N-terminal pro-B-type natriuretic peptide (NT-proBNP), compare the utility of the Seattle Heart Failure Score (SHFS) with NT-proBNP, develop a risk-evaluation model based on NT-proBNP, assess the associations of NT-proBNP with patient characteristics, and screen for decisive factors of NT-proBNP in Chinese elderly with chronic heart failure (CHF).
Patients and methods
There were 306 patients (≥60 years) with CHF chosen as study subjects. Each one received an assessment of NT-proBNP on serum. The end point was all-cause mortality during a mean follow-up period of 471 days.
Subjects had a median age of 85 (60–100) years, a median NT-proBNP of 1,743.4 pg/mL, and a median SHFS of 1.87. During the follow-up period, 104 deaths occurred. NT-proBNP was significantly related to mortality (odds ratio 1.603, 95% confidence interval 1.407–1.826; P<0.001) and the significance persisted after full adjustment (odds ratio 1.282, 95% confidence interval 1.103–1.489; P=0.001). Age, New York Heart Association class IV CHF, plasma albumin, and neutrophils/lymphocytes were also independent predictors for mortality (P<0.05 for all). NT-proBNP and the SHFS showed similar predictive capacities (0.736 versus 0.796, P=0.105). The addition of NT-proBNP to the SHFS (0.818 versus 0.796, P=0.168) generated marginal growth in the c-statistic. The model based on NT-proBNP consisting of all selected predictors in this study, including age, New York Heart Association class IV CHF, plasma albumin, neutrophils/lymphocytes, and NT-proBNP, had a moderately higher c-statistic compared with the SHFS (0.846 versus 0.796, P=0.066). NT-proBNP was bound with the SHFS (r=0.500, P<0.001). Characteristics regarding general condition, inflammation, and cardiac and renal function were the decisive factors of NT-proBNP (P<0.05 for all).
As a comprehensive representation of the patient characteristics described earlier, NT-proBNP values provided significant prognostic power similar to the SHFS in Chinese elderly with CHF. A novel model based on NT-proBNP could offer help for risk stratification.
PMCID: PMC4315566  PMID: 25670892
NT-proBNP; prognosis; chronic heart failure; elderly
Spironolactone and eplerenone are widely used as mineralocorticoid antagonists. Spironolactone has several nonspecific actions including inhibition of androgen receptor and steroid hormone biosynthesis. While studies have shown that eplerenone does not exhibit nonspecific actions on androgen receptor, its effects on steroid hormone production have not been reported. Herein, the effects of eplerenone (0.1 to 30 µM) and spironolactone (0.1 to 30 µM) on steroid production were examined in human adrenocortical H295R cells. Spironolactone inhibited basal production of cortisol (91%) and aldosterone (53%). Treatment of H295R cells with angiotensin II (Ang II) for 24 h increased aldosterone production by 11-fold. Spironolactone inhibited Ang II stimulation of aldosterone production by 80%. Addition of pregnenolone increased aldosterone (9-fold) and cortisol (3-fold) production. Spironolactone inhibited pregnenolone metabolism to aldosterone (67%) and cortisol (74%). The inhibitory effects of spironolactone occurred at concentrations far higher than those needed to block mineralocorticoid receptor, suggesting an action directly on the enzymes involved in steroid production. In contrast, eplerenone did not inhibit basal, Ang II, forskolin, pregnenolone-stimulated cortisol or aldosterone production. Together, these data demonstrate that opposed to spironolactone, pharmacologic concentrations of eplerenone do not inhibit adrenal cell aldosterone or cortisol production.
PMCID: PMC4277847  PMID: 18819053
aldosterone; cortisol; angiotensin; mineralocorticoid receptor blocker; steroid
11.  Association between resting heart rate and N-terminal pro-brain natriuretic peptide in a community-based population study in Beijing 
N-terminal pro-brain natriuretic peptide (NT-proBNP) is associated with an increased risk of cardiac insufficiency, which possibly leads to heart failure. However, the relationship between resting heart rate and NT-proBNP is unclear.
This study focuses on this relativity between resting heart rate and plasma NT-proBNP levels in a surveyed community-based population.
We evaluated the relativity between resting heart rate and plasma levels of NT-proBNP in 1,567 participants (mean age 61.0 years, range 21–96 years) from a community-based population in Beijing, People’s Republic of China.
In patients with high resting heart rate (≥75 beats/min), NT-proBNP was higher than in those having low resting heart rate (<75 beats/min). In multiple linear stepwise regression analysis, plasma NT-proBNP was associated with resting heart rate (partial correlation coefficient, 0.82; 95% confidence interval, 0.18–1.51; P=0.011). A subsequent subgroup analysis revealed that the association between resting heart rate and plasma NT-proBNP was strengthened in subjects over 60 years old (partial correlation coefficient 1.28; 95% confidence interval, 0.49–2.36; P=0.031); while the relativity between resting heart rate and plasma NT-proBNP was not emerged in the younger subgroup (<60 years old).
Resting heart rate was associated with plasma NT-proBNP in the elderly, which indicated a relationship between resting heart rate and cardiac function damage.
PMCID: PMC4279610  PMID: 25565787
resting heart rate; N-terminal pro-brain natriuretic peptide; epidemiology; cardiac function; relationship
12.  CD24 activates the NLRP3 inflammasome through c-Src kinase activity in a model of the lining epithelium of inflamed periodontal tissues 
Chronic periodontitis is characterized by perturbation of the epithelial attachment to the tooth with subsequent migration of the lining epithelium and formation of a cleft or pocket. This non-keratinized lining epithelium provides initial responses to bacterial products by signalling through receptors of innate immunity to activate inflammasome pathways. These comprise an intracellular network of regulatory and effector molecules leading to synthesis and activation of pro-inflammatory cytokines. Conversely, CD24 is characteristically strongly expressed by the pocket epithelium and is reported to function as an important negative regulator for danger signals, protecting tissues from excessive leukocyte activity. The objective of the study was to determine the impact of ligation of CD24 on expression of inflammasome components. An epithelial mimic of pocket epithelium was used to evaluate activation of the NLRP3 inflammasome pathway. Surprisingly, antibody ligation of CD24 enhanced expression of NLRP3 together with co-activators ASC and caspase-1 resulting in burst release of activated interleukin (IL)-18. Potent product inhibition was detected with IL-18 suppressing expression of NLRP3, ASC, and caspase-1. Scant distribution of these products within pocket epithelium compared with healthy gingival attachment provided indication of potential cycling of NLRP3 inflammasome expression. As subjects with mild chronic periodontitis have increased titres of serum antibodies auto-reactive with CD24 compared with those of subjects with severe periodontitis, a molecular mechanism for regulated expression of the NLRP3 inflammasome mediated by c-Src kinase activity, is proposed. This pathway could be regionally disrupted by products of pathogenic bacteria with profound downregulation in the dysbiosis associated with severe disease.
PMCID: PMC4386918  PMID: 25866631
CD24; inflammasome; NLRP3; periodontitis
13.  The Association of Homocysteine with Metabolic Syndrome in a Community-Dwelling Population: Homocysteine Might Be Concomitant with Metabolic Syndrome 
PLoS ONE  2014;9(11):e113148.
Elevated plasma total homocysteine (tHcy) and metabolic syndrome (MetS) are both associated with cardiovascular disease, but the association between tHcy and MetS is not well characterized. The aim of this study was to determine the relationship between tHcy and MetS.
To further estimate the time-dependent association of tHcy and MetS, we analyzed the tHcy level and MetS in 1499 subjects from a 4.8-year longitudinal study in Beijing, People’s Republic of China.
In multiple linear regression analysis, baseline tHcy levels associated with age, BMI, SBP, DBP, LDL-C and Cr independently over 4.8-years follow-up; age, BMI, SBP, DBP and Cr were found to be associated with tHcy levels independently at the end of follow-up. Logistic regression analysis showed that there was no association between the baseline tHcy level and MetS over the 4.8-year follow-up (odds ratio (OR), 1.32; 95% confidence interval (CI), 0.79–2.19; P = 0.282); rather, there was an association only with hypertension as a MetS component (OR, 1.53; 95% CI, 1.06–2.21; P = 0.024). tHcy levels were associated with MetS at both cross-sectional baseline (OR, 1.38; 95% CI, 1.02–1.88; P = 0.038) and cross-sectional follow-up (OR, 1.60; 95% CI, 1.02–2.50; P = 0.041). The tHcy levels of MetS subjects were higher than those of non-MetS subjects at both cross-sectional baseline (19.35±7.92 µmol/L vs. 17.45±6.70 µmol/L, respectively; P = 0.001) and cross-sectional follow-up (18.95±7.15 µmol/L vs. 17.11±5.98 µmol/L, respectively; P = 0.02).
The tHcy level was not predictive of the incidence of MetS; however, it may be a risk factor for hypertension as a MetS component. Furthermore, tHcy levels were associated with MetS at cross-sectional baseline and follow-up, which suggests that a higher level of tHcy might be concomitant with MetS.
PMCID: PMC4234666  PMID: 25401978
14.  Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages 
PLoS ONE  2014;9(11):e112953.
In a previous study, activation of the peroxisome proliferator–activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ - induced protective effect was unclear.
Materials and Methods
A chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regularory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM).
T cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival.
PPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects.
PMCID: PMC4226585  PMID: 25383620
15.  Improving heart function by modulating myocardiocyte autophagy: a possible novel mechanism for cardiovascular protection of high-density lipoprotein 
High-density lipoprotein (HDL) has been shown to confer cardiovascular protection in clinical and epidemiologic studies. Emerging evidence suggests that many of the cardioprotective functions of HDL may be due to the phospholipid sphingosine-1-phosphate (S1P).
Presentation of the hypothesis
HDL-S1P binds to S1P receptors in the heart, activating PI3K/Akt signaling and myocyte survival. PI3K/Akt is a classic signaling modulator of autophagy. Excessive autophagy due to cell death and cardiomyocyte loss may contribute to impaired heart function during pressure overload-induced heart failure. Therefore, we hypothesize that HDL-S1P may suppress excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling. Further, reconstituted HDL (including S1P) may protect heart function during pressure overload-induced heart failure.
Testing the hypothesis
We will design the following experiments to test this hypothesis. (1) We will treat cells and mice with PI-3 kinase inhibitors to examine if HDL-S1P downregulates expression of Autophagy-related genes (ATGs) and proteins via activation of PI3K/Akt signaling. (2) We will use siRNA against S1P receptors or inhibitors of S1P receptors to determine which types of S1P receptors participate in this mechanism. (3) We will also examine if reconstituted HDL (including S1P) improves heart function during pressure overload-induced heart failure by suppressing excessive autophagy of cardiomyocytes through activation of PI3K/Akt signaling.
Implications of the hypothesis
Understanding the autophagy signaling pathway modulated by HDL-S1P will make a major contribution to the field by identifying a novel mechanism for cardiovascular protection of high-density lipoprotein. Further, using reconstituted HDL to improve heart function would provide a novel therapeutic approach for pressure overload–induced heart failure.
PMCID: PMC4216853  PMID: 25339382
Autophagy; Reconstituted high-density lipoprotein; Sphingosine-1-phosphate; Heart function
16.  Early decrease in carotid plaque lipid content as assessed by magnetic resonance imaging during treatment of rosuvastatin 
Statin therapy has shown to deplete atherosclerotic plaque lipid content and induce plaque regression. However, how early the plaque lipid depletion can occur with low-density lipoprotein cholesterol (LDL-C) lowering in humans in vivo has not been fully described.
We enrolled 43 lipid treatment naïve subjects with asymptomatic carotid atherosclerosis and LDL-C ≥ 100 and ≤ 250 mg/dl. Rosuvastatin 5–20 mg/day was used to lower LDL-C levels to < 80 mg/dl. Lipid profile and carotid MRI scans were obtained at baseline, 3, 12, and 24 months. Carotid plaque lipid-rich necrotic core (LRNC) and plaque burden were measured and compared between baseline and during treatment.
Among the 32 subjects who completed the study, at 3 months, an average dose of rosuvastatin of 11 mg/day lowered LDL-C levels by 47% (125.2 ± 24.4 mg/dl vs. 66.7 ± 17.3 mg/dl, p < 0.001). There were no statistically significant changes in total wall volume, percent wall volume or lumen volume. However, LRNC volume was significantly decreased by 7.9 mm3, a reduction of 7.3% (111.5 ± 104.2 mm3 vs. 103.6 ± 95.8 mm3, p = 0.044). Similarly, % LRNC was also significantly decreased from 18.9 ± 11.9% to 17.9 ± 11.5% (p = 0.02) at 3 months. Both LRNC volume and % LRNC continued to decrease moderately at 12 and 24 months, although this trend was not significant.
Among a small number of lipid treatment naïve subjects, rosuvastatin therapy may induce a rapid and lasting decrease in carotid plaque lipid content as assessed by MRI.
Trial registration
ClinicalTrials.Gov numbers NCT00885872
PMCID: PMC4107586  PMID: 25022285
Atherosclerosis; Plaque lipid content; Statin; Magnetic resonance imaging
17.  Relationship of Arterial Compliance and Blood Pressure with Microalbuminuria and Mildly Decreased Glomerular Filtration Rate: A Chinese Community-Based Analysis 
PLoS ONE  2014;9(6):e101013.
This analysis is designed to determine the prevalence of microalbuminuria (MAU) and mildly decreased glomerular filtration rate (GFR); to investigate the association of augmentation index (AIx), central blood pressure (cBP) and peripheral blood pressure (pBP) with MAU and mildly decreased GFR; and to compare the association strength of cBP and pBP with MAU and mildly decreased GFR.
This community-based analysis included 2071 Chinese residents. Urine albumin-to-creatinine ratio (UACR), GFR, and pulse wave measurements were performed. UACR of 30–299 mg/g and GFR of 60–89 ml/min/1.73 m2 were identified as MAU and mildly decreased GFR.
The prevalence of MAU and mildly decreased GFR was 21.3% and 33.2%. The AIx, cBP and pBP were significantly higher in participants with MAU compared with those without MAU, and in participants with mildly decreased GFR compared with those without mildly decreased GFR (all P<0.001). After participants were categorized into four subgroups based on the presence or absence of MAU and mildly decreased GFR, Aix, cBP and pBP progressively increased from the subgroup without both of MAU and mildly decreased GFR to the subgroups with either one of them, and arrived at top in the subgroup with both of them (all P<0.001). Compared with the reference category without MAU and mildly decreased GFR, the odd ratio values significantly increased from the category with either one of MAU and mildly decreased GFR to the category with both of them (all P<0.001). The AIx, cBP and pBP were all independently associated with MAU and mildly decreased GFR after full adjustment (all P<0.05), and the association strength of MAU and mildly decreased GFR with cBP was similar to those with pBP.
In Chinese community-dwelling population, there was a high prevalence of MAU and mildly decreased GFR. The AIx, cBP and pBP were all independently associated with MAU and mildly decreased GFR; meanwhile, cBP did not exhibit stronger association with MAU and mildly decreased GFR compared with pBP.
PMCID: PMC4071047  PMID: 24963717
18.  HBsAg as an important predictor of HBeAg seroconversion following antiviral treatment for HBeAg-positive chronic hepatitis B patients 
Serum quantitative hepatitis B surface antigen (HBsAg) levels may be an important predictor of hepatitis B e antigen (HBeAg) seroconversion (SC) in HBeAg-positive chronic hepatitis B (CHB) patients during antiviral treatment. The pattern of HBsAg variation in CHB patients either with or without SC following tenofovir disoproxil fumarate (TDF) treatment is not clearly understood.
Twenty patients with full experimental data were enrolled, and liver biochemistry, serum HBV DNA, and circulating CD4+CD25+ regulatory T cell (Treg) levels were determined at baseline and every 12weeks after the initiation of TDF treatment (for a total of 96weeks). In addition, the relationship between HBsAg or HBeAg and alanine aminotransferase (ALT), HBV DNA and Treg levels in SC and non-SC patients was analyzed.
In all, 9 patients had undergone HBeAg seroconversion by week 72 of TDF treatment, and biochemical and virological indexes and Treg percentages declined to normal levels. Furthermore, the positive correlation between HBsAg and ALT, HBV DNA and Treg levels was significant for SC patients, but not for non-SC patients. However, for HBeAg, significant positive correlations were or not observed for both SC and non-SC patients.
The quantitation of HBsAg is a more useful indicator than HBeAg for distinguishing SC and non-SC patients during TDF treatment. Moreover, HBsAg may be related to immune regulatory property of CHB patients during antiviral treatment.
PMCID: PMC4230803  PMID: 24962263
Chronic hepatitis B; Antiviral treatment; HBsAg quantitation; HBeAg seroconversion; Prognostic indicator
19.  The Associations between the Family Education and Mortality of Patients on Peritoneal Dialysis 
PLoS ONE  2014;9(5):e95894.
To investigate whether education level of family members predicts all-cause and cardiovascular death and initial-episode peritonitis in patients on peritoneal dialysis (PD).
A total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic, socioeconomic and laboratory data of patients and the education level of all family members were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of all-cause and cardiovascular mortality, and initial-episode peritonitis with adjustments for recognized traditional factors.
There were no significant differences in baseline characteristics between patients with (n = 1752) and without (n = 512) complete education information. According to the highest education level of patients' family, included 1752 patients were divided into four groups, i.e. elementary or lower (15%), middle (27%), high (24%) and more than high school (34%). The family highest education (using elementary school or lower group as reference, hazard ratio and 95% confidence interval of middle school group, high school group and more than high school group was 0.68[0.48–0.96], 0.64[0.45–0.91], 0.66[0.48–0.91], respectively) rather than their average education level or patients' or spouse's education was significantly associated with the higher mortality. Neither patients' nor family education level did correlate to the risk for cardiovascular death or initial-episode peritonitis.
Family members' education level was found to be a novel predictor of PD outcome. Family, as the main source of health care providers, should be paid more attention in our practice.
PMCID: PMC4010396  PMID: 24797080
20.  Association between serum homocysteine and arterial stiffness in elderly: a community-based study 
Arterial stiffness and homocysteine are both powerful predictors of cardiovascular disease, especially in older populations. Previous studies have investigated the association of homocysteine with arterial stiffness in human subjects, while the relationship between homocysteine and arterial stiffness in the elderly is still indefinite. The current study examined the association of homocysteine with arterial stiffness in Chinese community-based elderly persons.
We related serum levels of homocysteine to two measures of arterial stiffness (carotid-femoral pulse wave velocity (PWV) and carotid-radial PWV) in 780 participants (46.3% men, mean age 71.9 years (ranging 65–96 years old)) from two communities of Beijing, China. Arterial stiffness was measured within two days of the time of biomarker measurement.
In multiple-adjusted models, homocysteine levels were strongly associated with the carotid-femoral PWV (standardized β = 0.13, P < 0.001), even after adjustment for classical risk factors of cardiovascular disease. The association is also stronger when the carotid-femoral PWV is elevated above normal, whereas no significant association with homocysteine was observed for carotid-radial PWV.
In Chinese elderly persons, serum homocysteine levels are associated with alterations of aortic stiffness.
PMCID: PMC3981981  PMID: 24748879
The elderly; Homocysteine; Arterial stiffness; Pulse wave velocity
21.  Different types of atrial fibrillation, renal function, and mortality in elderly Chinese patients with coronary artery disease 
Atrial fibrillation (AF) is the most common arrhythmia in patients with chronic kidney disease (CKD), and the combined prevalence of these two disorders increases as the population ages. Both AF and CKD have risk factors for development of each other and eventual mortality. However, the relationship between different types of AF, CKD, and mortality remains unclear, especially in elderly Chinese patients with coronary artery disease.
This study comprised 1,050 patients of median age 86 (60–104) years with coronary artery disease. The end point was all-cause death during a mean follow-up of 417 days.
Of 219 patients identified to have AF, 128 had paroxysmal type, 44 had persistent type, and 47 had permanent type. After adjusting for confounders, the estimated glomerular filtration rate was lower and the prevalence of CKD was higher in patients with permanent AF but not in those with paroxysmal or persistent AF. During follow-up, 106 non-CKD patients and 112 CKD patients died; mortality was significantly higher in CKD patients with AF than in those without AF (36 [40.9%] versus 76 [26.8%]), but not in patients without CKD (17 [13.0%] versus 89 [16.3%]). In patients with CKD, paroxysmal AF was independently associated with higher mortality after adjustment but not persistent or permanent AF. No type of AF had an independent association with mortality in patients without CKD.
All types of AF had a high prevalence. Permanent AF was independently associated with an increased prevalence of CKD and a decreased estimated glomerular filtration rate. Paroxysmal AF was an independent risk factor for survival in patients with CKD but not in those without CKD.
PMCID: PMC3933252  PMID: 24600210
atrial fibrillation; chronic kidney disease; coronary artery disease; Chinese; elderly; mortality
22.  Plasma Homocysteine Is Associated with Aortic Arterial Stiffness but not Wave Reflection in Chinese Hypertensive Subjects 
PLoS ONE  2014;9(1):e85938.
Elevated plasma total homocysteine (tHcy) acts synergistically with hypertension to exert a multiplicative effect on cardiovascular diseases risk. The aim of this study was to determine the relationship between tHcy concentration and blood pressure, and to evaluate the role of plasma tHcy in arterial stiffness and wave reflection in hypertension.
In this cross-sectional study, a community-based sample of 1680 subjects (mean age 61.6 years) was classified into four groups according to tHcy level (<21.6 vs. ≥21.6 µmol/l) and blood pressure (hypertensive vs. normotensive). Levels of plasma tHcy and other biochemical parameters (e.g., lipids, glucose) were determined. Central arterial blood pressure, reflected pressure wave, and carotid-femoral pulse wave velocity (cf-PWV) were assessed by tonometry within 2 days of obtaining the blood specimen.
Neither peripheral nor central blood pressure differed according to tHcy levels in normotensive and hypertensive subjects. Differences in cf-PWV according to tHcy were observed only in hypertensive subjects; differences in cf-PWV in normotensive subjects were not significant after adjusting for confounding factors. Central augmentation index did not differ according to tHcy level in either normotensive or hypertensive subjects. Results of univariate analysis revealed significant correlations between blood pressure parameters and tHcy concentration only among normotensive subjects; however, these correlations were not significant in a partial correlation analysis. Results of multiple regression analysis showed that plasma tHcy levels were independently correlated with cf-PWV in hypertensive subjects (β = 0.713, P = 0.004). The independent relationship between tHcy and central augmentation index was not significant by further multiple analyses in normotensive or hypertensive individuals.
Plasma tHcy level is strongly and independently correlated with arterial stiffness measured as cf-PWV only in hypertensive subjects. Thus, hypertension is a major link between tHcy and aortic arterial stiffness.
PMCID: PMC3903502  PMID: 24475061
23.  Xuezhikang Therapy Increases miR-33 Expression in Patients with Low HDL-C Levels 
Disease Markers  2014;2014:781780.
Background. MicroRNA-33a and -b (miR-33a/b) have been revealed to be posttranscriptional regulators of HDL metabolism. Xuezhikang (XZK) is a marked natural HDL-raising polypill. We aim to evaluate the effects of XZK on the expression of circulating miR-33a/b in patients with low plasma HDL-C levels. Methods. A total of 42 participating patients with low baseline levels of HDL cholesterol were assigned to receive an XZK capsule, 600 mg twice daily for 6 months. The expression of circulating miR-33a/b was detected at baseline and after XZK therapy measured with quantitative reverse-transcription (RT) polymerase chain reaction (PCR). Results. The mean (SD) HDL-C level after XZK treatment was 1.19 (0.13) mmol/L, representing an increase of 11.2% from baseline (P < 0.001). Q-PCR analysis of plasma miRNAs revealed an increase in relative miR-33a/b expression with XZK treatment. The miR-33a expression was raised from 0.81 to 1.73 (P = 0.012); miR-33b expression was increased from 1.2 to 2.75 (P < 0.001). The changes of miR-33a and miR-33b were inversely related to the posttreatment LDL-C levels (r = −0.37, P = 0.019; r = −0.33, P = 0.035, resp.). Conclusion. In patients with low HDL-C levels, XZK therapy raised plasma levels of miR-33a and miR-33b, which may inhibit cellular cholesterol export and limit the HDL-raising effect of XZK.
PMCID: PMC3925606  PMID: 24591767
24.  The abilities of new anthropometric indices in identifying cardiometabolic abnormalities, and influence of residence area and lifestyle on these anthropometric indices in a Chinese community-dwelling population 
The study aimed to investigate the prevalence of overweight, obesity, and cardiometabolic abnormalities, the influence of residence area, occupation, and lifestyle on new anthropometric indices, and the relationship between anthropometric indices and cardiometabolic abnormalities in a Chinese community-dwelling population.
The study included 4,868 residents through a large health check-up program in Beijing.
Overall obesity existed in 22.2% of men and 28.1% of women. 67.1% of men and 65.2% of women were overweight. 65.99% of men and 65.97% of women had central obesity. Residents of rural areas, manual workers, and smokers had significantly higher anthropometric indices. The power of each anthropometric index varied for identifying different cardiometabolic abnormalities, and the ability of the waist-to-height ratio to identify participants with greater than one or two cardiometabolic abnormalities was optimal. The appropriate cut-off values of all anthropometric indices for cardiometabolic abnormalities were obtained.
Overweight is common for both sexes in the People’s Republic of China, as are general and central obesity. Residents of rural areas, manual workers, and smokers have significantly higher anthropometric indices. Waist-to-height ratio has the ability to reflect the compound risk of different cardiometabolic abnormalities and the greatest potential to be widely applied in clinical practice.
PMCID: PMC3897240  PMID: 24477219
anthropometric indices; residence area; lifestyle; cardiometabolic abnormalities; Chinese community-dwelling population
25.  The Associations of Uric Acid, Cardiovascular and All-Cause Mortality in Peritoneal Dialysis Patients 
PLoS ONE  2014;9(1):e82342.
To investigate whether uric acid (UA) is an independent predictor of cardiovascular (CV) and all-cause mortality in peritoneal dialysis (PD) patients after controlling for recognized CV risk factors.
A total of 2264 patients on chronic PD were collected from seven centers affiliated with the Socioeconomic Status on the Outcome of Peritoneal Dialysis (SSOP) Study. All demographic and laboratory data were recorded at baseline. Multivariate Cox regression was used to calculate the hazard ratio (HR) of CV and all-cause mortality with adjustments for recognized traditional and uremia-related CV factors.
There were no significant differences in baseline characteristics between patients with (n = 2193) and without (n = 71) UA measured. Each 1 mg/dL of increase in UA was associated with higher all-cause mortality with 1.05(1.00∼1.10) of HR and higher CV mortality with 1.12 (1.05∼1.20) of HR after adjusting for age, gender and center size. The highest gender-specific tertile of UA predicted higher all-cause mortality with 1.23(1.00∼1.52) of HR and higher CV mortality with 1.69 (1.21∼2.38) of HR after adjusting for age, gender and center size. The predictive value of UA was stronger in patients younger than 65 years without CV disease or diabetes at baseline. The prognostic value of UA as both continuous and categorical variable weakened or disappeared after further adjusted for uremia-related and traditional CV risk factors.
The prognostic value of UA in CV and all-cause mortality was weak in PD patients generally, which was confounded by uremia-related and traditional CV risk factors.
PMCID: PMC3885378  PMID: 24416142

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