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1.  Can Serum Surfactant Protein D or CC-Chemokine Ligand 18 Predict Outcome of Interstitial Lung Disease in Patients with Early Systemic Sclerosis? 
The Journal of rheumatology  2013;40(7):1114-1120.
To examine the predictive significance of 2 pneumoproteins, surfactant protein D (SP-D) and CC-chemokine ligand 18 (CCL18), for the course of systemic sclerosis (SSc)-related interstitial lung disease.
The pneumoproteins were determined in the baseline plasma samples of 266 patients with early SSc enrolled in the GENISOS observational cohort. They also were measured in 83 followup patient samples. Pulmonary function tests were obtained annually. The primary outcome was decline in forced vital capacity (FVC percentage predicted) over time. The predictive significance for longterm change in FVC was investigated by a joint analysis of longitudinal measurements (sequentially obtained FVC percentage predicted) and survival data.
SP-D and CCL18 levels were both higher in patients with SSc than in matched controls (p < 0.001 and p = 0.015, respectively). Baseline SP-D levels correlated with lower concomitantly obtained FVC (r = −0.27, p < 0.001), but did not predict the short-term decline in FVC at 1 year followup visit or its longterm decline rate. CCL18 showed a significant correlation with steeper short-term decline in FVC (p = 0.049), but was not a predictor of its longterm decline rate. Similarly, a composite score of SP-D and CCL18 was a significant predictor of short-term decline in FVC but did not predict its longterm decline rate. Further, the longitudinal change in these 2 pneumoproteins did not correlate with the concomitant percentage change in FVC.
SP-D correlated with concomitantly obtained FVC, while CCL18 was a predictor of short-term decline in FVC. However, neither SP-D nor CCL18 was a longterm predictor of FVC course in patients with early SSc.
PMCID: PMC3728890  PMID: 23588945
2.  Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility 
Annals of the rheumatic diseases  2012;72(7):10.1136/annrheumdis-2012-202357.
The interleukin 2 (IL-2) and interleukin 21 (IL-21) locus at chromosome 4q27 has been associated with several autoimmune diseases, and both genes are related to immune system functions. The aim of this study was to evaluate the role of the IL-2/IL-21 locus in systemic sclerosis (SSc).
Patients and methods
The case control study included 4493 SSc Caucasian patients and 5856 healthy controls from eight Caucasian populations (Spain, Germany, The Netherlands, USA, Italy, Sweden, UK and Norway). Four single nucleotide polymorphisms (rs2069762, rs6822844, rs6835457 and rs907715) were genotyped using TaqMan allelic discrimination assays.
We observed evidence of association of the rs6822844 and rs907715 variants with global SSc (pc=6.6E-4 and pc=7.2E-3, respectively). Similar statistically significant associations were observed for the limited cutaneous form of the disease. The conditional regression analysis suggested that the most likely genetic variation responsible for the association was the rs6822844 polymorphism. Consistently, the rs2069762A-rs6822844T-rs6835457G-rs907715T allelic combination showed evidence of association with SSc and limited cutaneous SSc subtype (pc=1.7E-03 and pc=8E-4, respectively).
These results suggested that the IL-2/IL-21 locus influences the genetic susceptibility to SSc. Moreover, this study provided further support for the IL-2/IL-21 locus as a common genetic factor in autoimmune diseases.
PMCID: PMC3887514  PMID: 23172754
3.  Therapeutic Effect of TSG-6 Engineered iPSC-Derived MSCs on Experimental Periodontitis in Rats: A Pilot Study 
PLoS ONE  2014;9(6):e100285.
We derived mesenchymal stem cells (MSCs) from rat induced pluripotent stem cells (iPSCs) and transduced them with tumor necrosis factor alpha-stimulated gene-6 (TSG-6), to test whether TSG-6 overexpression would boost the therapeutic effects of iPSC-derived MSCs in experimental periodontitis.
A total of 30 female Sprague-Dawley (SD) rats were randomly divided into four groups: healthy control group (Group-N, n = 5), untreated periodontitis group (Group-P, n = 5), iPS-MSCs-treated and iPSC-MSCs/TSG-6-treated periodontitis groups (Group-P1 and P2, n = 10 per group). Experimental periodontitis was established by ligature and infection with Porphyromonas gingivalis around the maxillae first molar bilaterally. MSC-like cells were generated from rat iPSCs, and transducted with TSG-6. iPSC-MSCs or iPSC-MSCs/TSG-6 were administrated to rats in Group-P1 or P2 intravenously and topically, once a week for three weeks. Blood samples were obtained one week post-injection for the analysis of serum pro-inflammatory cytokines. All animals were killed 3 months post-treatment; maxillae were then dissected for histological analysis, tartrate-resistant acid phosphatase (TRAP) staining, and morphological analysis of alveolar bone loss.
Administration of iPSC-MSC/TSG-6 significantly decreased serum levels of IL-1β and TNF-α in the Group-P2 rats (65.78 pg/ml and 0.56 pg/ml) compared with those in Group-P (168.31 pg/ml and 1.15 pg/ml respectively) (p<0.05). Both alveolar bone loss and the number of TRAP-positive osteoclasts showed a significant decrease in rats that received iPSC-MSC/TSG-6 treatment compared to untreated rats in Group-P (p<0.05),
We demonstrated that overexpression of TSG-6 in rat iPSC-derived MSCs were capable of decreasing inflammation in experimental periodontitis and inhibiting alveolar bone resorption. This may potentially serve as an alternative stem-cell-based approach in the treatment and regeneration of periodontal tissues.
PMCID: PMC4076279  PMID: 24979372
4.  Association between Copy Number Variations HLA-DQA1 and Ankylosing Spondylitis in Chinese Han population 
Genes and immunity  2013;14(8):10.1038/gene.2013.46.
Ankylosing spondylitis (AS) is a chronic inflammatory disease with complex genetic traits. Multiple sequence variations have been associated with AS, but explained only a proportion of heritability. The studies herein aimed to explore potential associations between genomic copy number variation (CNV) and AS of Han Chinese. Five AS patients were examined with the high-density comparative genomic hybridization (CGH) microarrays in the first screen test for AS associated CNVs. A total of 533 AS patients and 792 unrelated controls were examined in confirmation studies with the AccuCopy assays. A significant association was observed between the CNV of the HLA-DQA1 and AS. Comparing with controls, AS patients showed an aberrant copy number (CN), and significantly increased number of patients had more than 2 copies of the HLA-DQA1. Therefore, CNV of the HLA-DQA1 may play an important role in susceptibility to AS in Han Chinese population.
PMCID: PMC3855587  PMID: 24048351
5.  The Contribution of Qualitative CEUS to the Determination of Malignancy in Adnexal Masses, Indeterminate on Conventional US – A Multicenter Study 
PLoS ONE  2014;9(4):e93843.
The aim of this study is to evaluate the efficacy of qualitative analysis of contrast-enhanced ultrasound (CEUS) in discrimination of adnexal masses which were undetermined by conventional ultrasound (US). A total of 120 patients underwent transabdominal CEUS. The initial enhancement time and intensity compared with the uterine myometrium, contrast agent distribution patterns and dynamic changes of enhancement were assessed. The sensitivity (Sen), specificity (Spe), positive predictive value (PPV), negative predictive value (NPV), accuracy (ACC) and Youden’s index were calculated for contrast variables. The gold standard was the histological diagnosis. There were 48 malignant tumors and 72 benign tumors. The enhancement features of malignant masses were different from benign ones. Earlier or simultaneous enhancement with inhomogeneous enhancement yielded the highest capability in differential diagnosis, and Sen, Spe, PPV, NPV, ACC, Youden’s index was 89.6%, 97.2%, 93.2%, 95.6%, 93.3%, and 0.88, respectively. The qualitative evaluation of CEUS is useful in the differential diagnosis of adnexal masses where conventional US is indeterminate.
PMCID: PMC3988034  PMID: 24736589
6.  Reduction of left ventricular longitudinal global and segmental systolic functions in patients with hypertrophic cardiomyopathy: Study of two-dimensional tissue motion annular displacement 
The early detection of abnormal left ventricular systolic functions in patients with hypertrophic cardiomyopathy (HCM) remains a challenge. The aim of this study was to identify a novel method for the assessment of left ventricular systolic function in patients with HCM. A total of 65 patients with HCM were included in this study. The patients were divided into obstructive HCM (HOCM; 16 cases) and non-obstructive HCM (NOHCM; 49 cases) groups. The healthy control group comprised 48 participants. Two-dimensional (2D) speckle-tracking technology was used to measure the left ventricular global and segmental longitudinal strains and mitral annular displacement (MADs). Compared with healthy control group, the six segmental strains and the global strain of the left ventricle (LSglobal) increased while six segmental MADs and MADglobal of the mitral annulus decreased in the HOCM and NOHCM groups (P<0.05). In addition, the six segmental MADs of the mitral annulus were significantly negatively correlated with the six segmental strains of the left ventricle (r=−0.744 to −0.647, P<0.001). MADglobal was significantly negatively correlated with LSglobal (r=−0.857, P<0.001). The tissue motion annular displacement (TMAD) at the midpoint was significantly negatively correlated with LSglobal (r=−0.871, P<0.001). The 2D TMAD technique of measuring MAD was feasible and practically approachable for rapidly evaluating the left ventricular longitudinal global and segmental systolic functions of patients with HCM.
PMCID: PMC4043569  PMID: 24926326
echocardiography; hypertrophic cardiomyopathy; left ventricular function; two-dimensional strain; tissue motion annular displacement
7.  Association of HLA-DPB1 with Scleroderma and Its Clinical Features in Chinese Population 
PLoS ONE  2014;9(1):e87363.
Human leukocyte antigen DPB1 was reported to contain singly nucleotide polymorphisms conferring the strongest susceptibility to systemic sclerosis in Korean population. However, associations of specific DPB1 alleles with SSc vary in different ethnic populations. The aim of this study was to profile DPB1 alleles in Chinese population and to identify specific DPB1 alleles in association with SSc and clinical and serological features of SSc in Han Chinese. A cohort containing 338 patients with SSc and 480 gender-matched and unrelated controls were examined in the study. The HLA-DPB1 genotyping was performed with sequence-based typing method. Exact p-values were obtained (Fisher's test) from 2×2 tables of allele counts or allele carriers and disease status. Thirty eight DPB1 alleles were found in the cohort. DPB1*05:01 was the most common allele in this cohort. DPB1*03:01 and *13:01 were significantly increased in SSc. DPB1*13:01 association had already been described in other ethnic populations, whereas DPB1*03:01 was specific to Han Chinese patients with SSc. In addition, comparisons between SSc subsets indicated that patients carrying DPB1*03:01 were more likely to develop pulmonary fibrosis, DPB1*04 carriers were increased in SSc patients with anti-centromere autoantibodies and in contrast, SSc patients with homozygous DPB1*05:01 showed an opposite association with marginal significance.
PMCID: PMC3909094  PMID: 24498086
8.  Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci 
Nature genetics  2013;45(7):730-738.
Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.
PMCID: PMC3757343  PMID: 23749187
9.  Clinical and serological features of systemic sclerosis in a Chinese cohort 
Clinical rheumatology  2012;32(5):617-621.
Our goal was to study the prevalence of systemic sclerosis (SSc) subtypes, autoantibody profile, and pulmonary fibrosis in a large group of Han Chinese. Chinese SSc patients (n=419) were recruited from a multicenter study including hospitals and outpatient clinics in China. All patients met the American College of Rheumatology classification criteria for SSc. Anti-topoisomerase (ATA), anti-centromere (ACA), anti- RNA polymerase III (anti-RNAP3), and anti-U1- ribonucleoprotein (anti-U1RNP) were detected utilizing commercially available kits. The clinical and autoantibody information in Chinese patients was compared to that in the US Caucasian patients (n=834), recruited from the Genetics versus Environment in Scleroderma Outcome Study and Scleroderma Family Registry. Chi-square test was utilized for the abovementioned comparisons. Chinese patients showed 40.3 % limited (lcSSc) and 59.7 % diffuse (dcSSc) forms of SSc. ATA was found in 59.9 %, ACA in 13.4 %, anti-RNAP3 in 1.3 %, and anti-U1RNP in 18 % of Chinese SSc patients. Compared to US patients (65.1 % lcSSc, 34.9 % dcSSc, ATA in 18.7 %, ACA in 32.4 %, anti-RNAP3 in 17.4 %, and anti-U1RNP in 2.8 %), Chinese SSc patients are significantly higher in dcSSc and the frequencies of ATA and anti-U1RNP, but lower in ACA and anti-RNAP3. In addition, pulmonary fibrosis was observed in 78 % Chinese SSc patients and was strongly associated with the presence of ATA. The present study represents the first report of SSc features in a large group of Chinese patients. Clinical subtypes and the frequencies of SSc-related autoantibodies in Chinese SSc patients are significantly different from those in SSc patients of the US Caucasian descent.
PMCID: PMC3734856  PMID: 23271609
Anti-centromere antibody; Anti-topoisomerase antibody; Autoantibodies; Pulmonary fibrosis; Systemic sclerosis
10.  2-Hy­droxy-N′-methyl-5-nitro­benzohydrazide 
In the title compound, C8H9N3O4, there are two mol­ecules in the asymmetric unit, one of which is in the zwitterionic form. The zwitterion contains an intra­molecular N—H⋯O hydrogen bond and the other mol­ecule contains both an intra­molecular N—H⋯O and an intra­molecular O—H⋯O hydrogen bond. In the crystal, N—H⋯O and N—H⋯N hydrogen bonds link the mol­ecules, formimg a two-dimensional network parallel to (10-1).
PMCID: PMC3793794  PMID: 24109381
11.  Estrogen Status Alters Tissue Distribution and Metabolism of Selenium in Female Rats1,2 
A reported association between estrogen and selenium status may be important in the regulation of selenium metabolism. In this study the effect of estrogen status on the metabolism of orally administered 75Se-selenite and tissue selenium status was investigated. Female Sprague Dawley rats were bilaterally ovariectomized at 7 weeks of age and implanted with either a placebo pellet (OVX) or pellet containing estradiol (OVX+E2), or were sham operated (Sham). At 12 weeks of age, 60 μCi of 75Se as selenite was orally administered to OVX and OVX+E2 rats. Blood and organs were collected 1, 3, 6, and 24h after dosing. Estrogen status was associated with time dependent differences in distribution of 75Se in plasma, RBC, liver, heart, kidney, spleen, brain, and thymus and incorporation of 75Se into plasma selenoprotein P (Sepp1) and glutathione peroxidase (GPx). Estrogen-treatment also significantly increased selenium concentration and GPx activity in plasma, liver, and brain, selenium concentration in RBC, and hepatic Sepp1 and GPx1 mRNA. These results suggest that estrogen status affects tissue distribution of selenium by modulating Sepp1 as this protein plays a central role in selenium transport.
PMCID: PMC3178707  PMID: 21684133
selenium; estrogen; selenoprotein P; glutathione peroxidase; ovariectomized rats
12.  Neoadjuvant rh-endostatin, docetaxel and epirubicin for breast cancer: efficacy and safety in a prospective, randomized, phase II study 
BMC Cancer  2013;13:248.
Recombinant human endostatin (rh-endostatin) is a novel antiangiogenesis drug developed in China. Previous experiments have shown that rh-endostatin can inhibit the proliferation and migration of endothelial cells and some types of tumor cells. In this study, we evaluated the efficacy and safety profiles of combination therapy of rh-endostatin and neoadjuvant chemotherapy for breast cancer patients in a prospective, randomized, controlled, phase II trial.
Sixty-eight patients with core-biopsy confirmed breast cancer were allocated randomly to two groups to receive 3 cycles of intravenous administration of either neoadjuvant DE (docetaxel: 75 mg/m2, d1, epirubicin: 75 mg/m2, d1, every 3 weeks), or neoadjuvant DE combined with rh-endostatin (7.5 mg/m2, d1-d14, every 3 weeks). The primary end point was clinical response based upon Response Evaluation Criteria in Solid Tumors, and the secondary end point was safety and quality of life.
All patients were assessable for toxicity and 64 (94.2%) were assessable for efficacy evaluation. The objective response rate was 67.7% for chemotherapy (n = 31) and 90.9% for rh-endostatin plus chemotherapy (n = 33) (P = 0.021). A retrospective subset analysis revealed that rh-endostatin was more effective in premenopausal patients and patients with ECOG score of zero (P = 0.002 and P = 0.049, respectively). Five patients in the rh-endostatin plus chemotherapy arm achieved pathologic complete response compared with 2 in the chemotherapy arm (P = 0.428). No significant difference was identified in quality of life score and side effects (P > 0.05).
The combination of rh-endostatin with chemotherapy produced a higher tumor response rate without increasing toxicity in breast cancer patients.
Trial registration Identifier, NCT00604435
PMCID: PMC3664086  PMID: 23693018
Breast cancer; Recombinant human endostatin; Neoadjuvant chemotherapy; Clinical trial
13.  Interleukin-22 Inhibits Bleomycin-Induced Pulmonary Fibrosis 
Mediators of Inflammation  2013;2013:209179.
Pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Recent insight has suggested that early injury/inflammation of alveolar epithelial cells could lead to dysregulation of tissue repair driven by multiple cytokines. Although dysregulation of interleukin- (IL-) 22 is involved in various pulmonary pathophysiological processes, the role of IL-22 in fibrotic lung diseases is still unclear and needs to be further addressed. Here we investigated the effect of IL-22 on alveolar epithelial cells in the bleomycin- (BLM-) induced pulmonary fibrosis. BLM-treated mice showed significantly decreased level of IL-22 in the lung. IL-22 produced γδT cells were also decreased significantly both in the tissues of lungs and spleens. Administration of recombinant human IL-22 to alveolar epithelial cell line A549 cells ameliorated epithelial to mesenchymal transition (EMT) and partially reversed the impaired cell viability induced by BLM. Furthermore, blockage of IL-22 deteriorated pulmonary fibrosis, with elevated EMT marker (α-smooth muscle actin (α-SMA)) and overactivated Smad2. Our results indicate that IL-22 may play a protective role in the development of BLM-induced pulmonary fibrosis and may suggest IL-22 as a novel immunotherapy tool in treating pulmonary fibrosis.
PMCID: PMC3588191  PMID: 23476100
14.  Inflammatory Cells in Tissues of Gout Patients and Their Correlations with Comorbidities 
The major pathological finding of gout is the deposition of monosodium urate monohydrate (MSU) crystals with inflammatory infiltrate in the tissue. There have been many reports of in vitro analysis of inflammatory mechanism and comorbidities in gout. However, the associations of immune response cells and comorbidities of gout have not been well documented. Our studies aimed to examine the immune cell types and quantity in gout tissues, and to define the association of individual cell type with comorbidities.
Surgically resected or biopsied tissues from 48 patients diagnosed as gout were used for this study. Cell count was performed on Hemotoxylin and Eosin stained sections for macrophages, plasma cells, neutrophils and on immunostained slides for T and B lymphocytes.
Hyperlipidemia, hypertension and diabetes mellitus were seen in 70.8%, 87.5% and 37.5% of patients, respectively. There were 35.6% and 37.8% of patients who admitted history of smoking and alcohol intake, respectively. Mean serum uric acid level was 8.5 mg/dl. The average body mass index was 30.1 kg/m2. H&E stained tissue sections demonstrated the crystalline deposits rimmed by palisading multinucleated giant cells, macrophages, neutrophils, plasma cells, T and B cells. Significant correlations between the clinical features and tissue inflammatory cells were observed in hyperlipidemia with number of T cells (p = 0.0363), hypertension with number of T cells and B cells (p = 0.0138 and 0.0033, respectively), diabetes mellitus with macrophages (p = 0.0016), and uric acid level with giant cells (p = 0.0088).
Comorbidity factors including hyperlipidemia, hypertension and diabetes are significantly associated with the inflammatory cells in the tissues.
PMCID: PMC3681035  PMID: 23802027
Gout; mononucleated macrophages; multinucleated giant cells; T-cells; B-cells; uric acid; comorbidities.
15.  Profiling of HLA-B Alleles for Association Studies with Ankylosing Spondylitis in the Chinese Population 
Human leucocyte antigen (HLA) B*27 is a susceptibility allele to ankylosing spondylitis (AS). However, major AS-associated subtypes of HLA-B*27 and other HLA-B alleles vary in different ethnic populations. Herein, we examined HLA-B alleles in a total of 360 AS patients and 350 controls of Chinese Han ancestry. The HLA-B genotyping was performed with sequence-based typing (SBT) method. Six HLA-B*27 subtypes B*27:04, B*27:05, B*27:07, B*27:08, B*27:10 and B*27:15 were observed in the cohorts. HLA-B*27:04:01 and -B*27:05:02 appeared significantly increased in AS patients, which indicated as two major susceptibility alleles to AS. Homozygous B*27 was observed only in AS patients. There are 30 HLA-B alleles identified in the studies. HLA-B*15, especially B*15:01:01:01, appeared as the major allele type in the Chinese controls. Some common HLA-B alleles such as HLA-B*15, B*13, B*46 and B*51 were significantly reduced in Chinese AS patients. In conclusion, the studies profiled the HLA-B alleles, and identified major susceptibility subtypes of B27 to AS in Han Chinese population
PMCID: PMC3778539  PMID: 24062861
Ankylosing spondylitis (AS); HLA-B27; Chinese Han.
16.  Anti-Fibrillarin Antibody in African American Patients with Systemic Sclerosis: Immunogenetics, Clinical Features, and Survival Analysis 
The Journal of rheumatology  2011;38(8):1622-1630.
Anti-U3-RNP or anti-fibrillarin antibodies (AFA) are detected more frequently among African American (AA) patients with systemic sclerosis (SSc) compared to other ethnic groups and are associated with distinct clinical features. The current study examines the immunogenetic, clinical, and survival correlates of AFA in a large group of AA patients with SSc.
Overall, 278 AA SSc patients and 328 unaffected AA controls were enrolled from three North American cohorts. Clinical features, autoantibody profile, and HLA-class-II genotyping were captured. To compare the clinical manifestations, relevant clinical features were adjusted for disease duration. The Cox proportional hazards regression was used to determine the effect of AFA on survival.
Fifty (18.5%) AA patients had AFA. After Bonferroni correction, HLA-DRB1*08:04 was associated with AFA, compared to unaffected AA controls (OR=11.5, p<0.0001) and AFA negative SSc patients (OR=5.2, p=0.0002). AFA positive AA patients had younger age of disease onset, higher frequency of digital ulcers, diarrhea, pericarditis, higher Medsger Perivascular and lower Lung Severity Indices (p=0.004, p=0.014, p=0.019, p=0.092, p=0.006, and p=0.016, respectively). After adjustment for age at enrollment, AFA positive patients did not have different survival compared with patients without AFA (p=0.493).
These findings demonstrate strong association between AFA and HLA-DRB1*08:04 allele in AA patients with SSc. Moreover, AA SSc patients with AFA had younger age of onset, higher frequency of digital ulcers, pericarditis, and severe lower gastrointestinal involvement, but less severe lung involvement compared to AA patients without AFA. However, presence of AFA did not change survival.
PMCID: PMC3149738  PMID: 21572159
Scleroderma; GENISOS; anti-U3-RNP; digital ulcer; HLA DRB1; and Scleroderma Family Registry
17.  Impact of Dry Eye Syndrome on Vision-Related Quality of Life in a Non-Clinic-Based General Population 
BMC Ophthalmology  2012;12:22.
Dry eye syndrome (DES) is a common ocular disorder occurring in general population. The purpose of this study is to evaluate the impact of DES on vision-related quality of life (QoL) in a non-clinic-based general population.
This population-based cross-sectional study enrolled subjects older than 40 years, who took part in an epidemiological study on dry eye in Sanle Community, Shanghai. Apart from the collection of sociodemographics, dry eye symptoms, and other clinical data, a Chinese version of the 25-item National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) was administered to all subjects. Comparisons of the NEI VFQ-25 subscale item scores and composite score were made among subgroups divided according to the presence of dry eye symptoms or signs. Multivariate regression analysis was performed to investigate the relationship between the clinical variables and the VFQ-25 composite score.
A total of 229 participants were enrolled in the study, with an average age of (60.7 ±10.1) years old. Majority of these participants were female (59.8 %, 137/229). The total DES symptom scores (TDSS) in subjects either with definite DES or only with dry eye symptoms were significantly higher (F = 60.331, P < 0.001). The values of tear break-up time (TBUT) and Schirmer test were significantly lower in participants with DES and those with dry eye signs only (F = 55.158 and 40.778, P < 0.001). The composite score of the NEI VFQ-25 was significantly lower in subjects with DES (F = 4.901, P = 0.003). Moreover, the subscale scores of ocular pain and mental health were significantly lower in those with either DES or dry eye symptoms only (F = 10.962 and 7.362 respectively, both P < 0.001). The multiple regression analysis showed that the TDSS had a significant negative correlation with the VFQ-25 composite score as well as with the subscale score for ocular pain and mental health, even after the adjustment of all other factors (all P < 0.01).
The symptoms of dry eye are associated with an adverse impact on vision-related QoL in non-clinic-based general population, which is mainly represented as more ocular pain and discomfort, and impaired mental health as well. Apart from clinical examination, it is also important to refer to subjective symptoms and QoL scores when assessing the severity of DES.
PMCID: PMC3437197  PMID: 22799274
Dry eye syndrome; NEI VFQ-25; Visual quality of life
18.  Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci 
Nature genetics  2010;42(2):123-127.
To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10−800), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 × 10−19) and 21q22 (rs2242944; P = 8.3 × 10−20), as well as in the genes ANTXR2 (rs4333130; P = 9.3 × 10−8) and IL1R2 (rs2310173; P = 4.8 × 10−7). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 × 10−14) and ERAP1 (rs27434; P = 5.3 × 10−12). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.
PMCID: PMC3224997  PMID: 20062062
19.  Decreased catalytic function with altered sumoylation of DNA topoisomerase I in the nuclei of scleroderma fibroblasts 
Arthritis Research & Therapy  2011;13(4):R128.
Sumoylation is involved in nucleolus-nucleoplasm transport of DNA topoisomerase I (topo I), which may associate with changes of cellular and topo I functions. Skin fibroblasts of patients with systemic sclerosis (SSc) exhibit profibrotic cellular changes. The aims of this study were to examine the catalytic function and sumoylation of topo I in the nuclei of SSc fibroblasts, a major cell type involved in the fibrotic process.
Eleven pairs of fibroblast strains obtained from nonlesional skin biopsies of SSc patients and age/sex/ethnicity-matched normal controls were examined for catalytic function of nuclear topo I. Immunoprecipitation (IP)-Western blots were used to examine sumoylation of fibroblast topo I. Real-time quantitative RT-PCR was used to measure transcript levels of SUMO1 and COL1A2 in the fibroblasts.
Topo I in nuclear extracts of SSc fibroblasts generally showed a significantly lower efficiency than that of normal fibroblasts in relaxing equivalent amounts of supercoiled DNA. Increased sumoylation of topo I was clearly observed in 7 of 11 SSc fibroblast strains. Inhibition of SUMO1 with SUMO1 siRNA improved the catalytic efficiency of topo I in the SSc fibroblasts. In contrast, sumoylation of recombinant topo I proteins reduced their catalytic function.
The catalytic function of topo I was decreased in SSc fibroblasts, to which increased sumoylation of topo I may contribute.
PMCID: PMC3239368  PMID: 21827649
20.  Gene and pathway-based second-wave analysis of genome-wide association studies 
Despite the great success of genome-wide association studies (GWAS) in identification of the common genetic variants associated with complex diseases, the current GWAS have focused on single-SNP analysis. However, single-SNP analysis often identifies only a few of the most significant SNPs that account for a small proportion of the genetic variants and offers only a limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis of 13 published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single-SNP analysis, but also detected new genes in which each single SNP conferred a small disease risk; however, their joint actions were implicated in the development of diseases. The results also showed that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases, which were confirmed by a gene-set-rich analysis using gene expression data.
PMCID: PMC2987176  PMID: 19584899
genome-wide association studies; gene and pathway-based analysis; complex diseases; combining P-values; gene-set enrichment analysis
21.  HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis -Genome-wide association study in Koreans with Replication in North Americans 
Arthritis and rheumatism  2009;60(12):3807-3814.
To investigate the most susceptible genetic loci in systemic sclerosis (SSc) with genome-wide association study (GWAS).
A genome-wide association study was performed in 137 patients with systemic sclerosis and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine mapping study, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population.
The SNPs (rs3128930, rs7763822, rs7764491, rs3117230 and rs3128965) of HLA-DPB1 and –DPB2 on chromosome 6 formed a distinctive peak with log p-values (p =8.16 × 10−13) for association with SSc susceptibility. Subtyping analysis of HLA-DPB1 showed that DPB1*1301 (p = 7.61×10−8) and DPB1*0901 (p = 2.56×10−5)were the most susceptible subtypes for SSc in Koreans. In US Caucasians, two pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti-DNA topoisomerase I (p = 7.58 × 10−17/4.84 × 10−16) or anti-centromere autoantibodies (p = 1.12 × 10−3/3.2 × 10−5), respectively.
Our GWAS in Koreans revealed that the region of HLA-DPB1 and –DPB2 contains the most susceptible loci to Korean SSc. The confirmatory studies in US Caucasians indicated that specific SNPs of the HLA-DPB1 and/or –DPB2 were strongly associated with US Caucasian SSc patients who were positive to anti-topoisomerase I or anti-centromere autoantibodies.
PMCID: PMC2829245  PMID: 19950302
Systemic sclerosis; Genome wide association study; HLA-DPB1; Anti-topoisomerase I antibody
22.  Identification of Chemically Sulfated/desulfated Glycosaminoglycans in Contaminated Heparins and Development of a Simple Assay for the Detection of Most Contaminants in Heparin 
Glycobiology insights  2010;2010(2):1-12.
Contaminated heparin was linked to at least 149 deaths and hundreds of adverse reactions. Published report indicates that heparin contaminants were a natural impurity, dermatan sulfate, and a contaminant, oversulfated chondroitin sulfate (OSCS). OSCS was assumed to derive from animal cartilage. By analyzing 26 contaminated heparin lots from different sources, our data indicate that the heparin contaminants were chemically sulfated or chemically sulfated/desulfated glycosaminoglycans (GAGs) consisting of heparan sulfate, chondroitin sulfate, and dermatan sulfate based on monosaccharide quantification, CE, heparin lyase digestion, and liquid chromatography/mass spectrometry analysis. Since currently recommended heparin quality control assays had failed to detect certain heparin contaminants, a simple method that detects most contaminants in heparin was developed. This assay detects specific heparin structures that most contaminants cannot mimic and can be performed in any laboratory equipped with an UV spectrometer.
PMCID: PMC2909132  PMID: 20657729
heparin; contaminants; oversulfated chondroitin sulfate; glycosaminoglycan
23.  Attenuation of fibrosis in vitro and in vivo with SPARC siRNA 
SPARC is a matricellular protein, which, along with other extracellular matrix components including collagens, is commonly over-expressed in fibrotic diseases. The purpose of this study was to examine whether inhibition of SPARC can regulate collagen expression in vitro and in vivo, and subsequently attenuate fibrotic stimulation by bleomycin in mouse skin and lungs.
In in vitro studies, skin fibroblasts obtained from a Tgfbr1 knock-in mouse (TBR1CA; Cre-ER) were transfected with SPARC siRNA. Gene and protein expressions of the Col1a2 and the Ctgf were examined by real-time RT-PCR and Western blotting, respectively. In in vivo studies, C57BL/6 mice were induced for skin and lung fibrosis by bleomycin and followed by SPARC siRNA treatment through subcutaneous injection and intratracheal instillation, respectively. The pathological changes of skin and lungs were assessed by hematoxylin and eosin and Masson's trichrome stains. The expression changes of collagen in the tissues were assessed by real-time RT-PCR and non-crosslinked fibrillar collagen content assays.
SPARC siRNA significantly reduced gene and protein expression of collagen type 1 in fibroblasts obtained from the TBR1CA; Cre-ER mouse that was induced for constitutively active TGF-β receptor I. Skin and lung fibrosis induced by bleomycin was markedly reduced by treatment with SPARC siRNA. The anti-fibrotic effect of SPARC siRNA in vivo was accompanied by an inhibition of Ctgf expression in these same tissues.
Specific inhibition of SPARC effectively reduced fibrotic changes in vitro and in vivo. SPARC inhibition may represent a potential therapeutic approach to fibrotic diseases.
PMCID: PMC2888211  PMID: 20359365
24.  Localized Surface Plasmon Resonance Biosensing with Large Area of Gold Nanoholes Fabricated by Nanosphere Lithography 
Nanoscale Research Letters  2010;5(5):818-822.
Localized surface plasmon resonance (LSPR) has been extensively studied as potential chemical and biological sensing platform due to its high sensitivity to local refractive index change induced by molecule adsorbate. Previous experiments have demonstrated the LSPR generated by gold nanoholes and its biosensing. Here, we realize large uniform area of nanoholes on scale of cm2 on glass substrate by nanosphere lithography which is essential for mass production. The morphology of the nanoholes is characterized using scanning electron microscope and atomic force microscope. The LSPR sensitivity of the nanoholes to local refractive index is measured to be 36 nm/RIU. However, the chip has demonstrated high sensitivity and specificity in biosensing: bovine serum albumin adsorption is detected with LSPR peak redshift of 27 nm, and biotin-streptavidin immunoassay renders a LSPR redshift of 11 nm. This work forms a foundation toward the cost-effective, high-throughput, reliable and robust chip-based LSPR biosensor.
PMCID: PMC2893834  PMID: 20672118
Localized surface plasmon resonance (LSPR); Nanosphere lithography (NSL); Nanohole; Nanoparticles; Biosensing
25.  Localized Surface Plasmon Resonance Biosensing with Large Area of Gold Nanoholes Fabricated by Nanosphere Lithography 
Nanoscale Research Letters  2010;5(5):818-822.
Localized surface plasmon resonance (LSPR) has been extensively studied as potential chemical and biological sensing platform due to its high sensitivity to local refractive index change induced by molecule adsorbate. Previous experiments have demonstrated the LSPR generated by gold nanoholes and its biosensing. Here, we realize large uniform area of nanoholes on scale of cm2 on glass substrate by nanosphere lithography which is essential for mass production. The morphology of the nanoholes is characterized using scanning electron microscope and atomic force microscope. The LSPR sensitivity of the nanoholes to local refractive index is measured to be 36 nm/RIU. However, the chip has demonstrated high sensitivity and specificity in biosensing: bovine serum albumin adsorption is detected with LSPR peak redshift of 27 nm, and biotin-streptavidin immunoassay renders a LSPR redshift of 11 nm. This work forms a foundation toward the cost-effective, high-throughput, reliable and robust chip-based LSPR biosensor.
PMCID: PMC2893834  PMID: 20672118
Localized surface plasmon resonance (LSPR); Nanosphere lithography (NSL); Nanohole; Nanoparticles; Biosensing

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