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1.  Association between the Interaction of Key Genes Involved in Effector T-Cell Pathways and Susceptibility to Developallergic Rhinitis: A Population-Based Case-Control Association Study 
PLoS ONE  2015;10(7):e0131248.
Evidence suggests that interaction between key genes mediating signaling and transcriptional networks involving effector T-cell responses may influence an individual’s susceptibility to develop allergic rhinitis(AR).
The aim of this study was todetermine whether specific interactions between key genes involved in effector T-cell pathways are associated with an individual’s susceptibility to develop AR in Han Chinese subjects.
A cohort of 489 patients with AR and 421 healthy controls was enrolled from the Han Chinese population in Beijing, China. AR was established by questionnaire and clinical examination, and peripheral blood was drawn from all subjects for DNA extraction. A total of 96 single nucleotide polymorphisms (SNPs) in 26 reprehensive candidate genes involved in T helper 1 (Th1), Th2, Th17, Th9 and T regulatory cell pathways were selected from the International Haplotype Mappingdatabase for Han Chinese in Beijing (CHB) population, and IlluminaGoldenGate assay was conducted for SNP genotyping. The PLINK software package was used to perform statistical analyses.
Simple SNP-phenotype association analysis using logistic regression showed SNP rs8193036 in IL17A gene, rs2569254 in IL-12 and rs1898413 in RORα weresignificantlyassociatedwith AR.Simple SNP-phenotype association analysis with genetic models demonstrated thatrs2569254 in IL-12, rs1031508 in STAT4, and rs3741809 in IL-26 were likely to be recessive, rs8193036 in IL17A allelic, rs897200in STAT4 genotypic, and rs1898413 in RORα dominant. Epistasis analyses exhibited that 83 SNPs in 23 genes were significantly interactive; of which 59 interactions/SNP pairs demonstrated OR values higher than 2 or lower than 0.5, and 12 interactions/SNP pairs OR values higher than 4 or lower than 0.25. STAT3, RORα and IL-26, involved in Th17 pathway,were the mostfrequentlyinteractive genes.
This study suggests that interactions between several SNPs in key genes involved in effector T-cell pathways are likely to influence an individual’s susceptibility to develop AR.
PMCID: PMC4510440  PMID: 26196693
2.  TMEM16A-Mediated Mucin Secretion in IL-13-Induced Nasal Epithelial Cells From Chronic Rhinosinusitis Patients 
Chronic rhinosinusitis with nasal polyps (CRSwNP), a mainly Th2 cytokine-mediated disease, often involves mucus secretion. Recent evidence suggests that transmembrane protein 16A (TMEM16A), a calcium-activated Cl- channel (CaCC), can regulate mucus secretion from airway epithelium by transepithelial electrolyte transport and hydration. However, the role of TMEM16A in mucin production/secretion in the airway epithelium is not clear. This study was conducted to determine the role of TMEM16A in mediating mucin secretion in human nasal polyp epithelial cells (HNPECs) induced by IL-13.
Human sinonasal mucosa tissue and dissociated sinonasal epithelium from control subjects and patients with CRSwNP were assessed for the expression of TMEM16A and the secretion of human mucin 5AC (MUC5AC) by immunohistochemistry, Western blot analysis, and enzyme-linked immuno-sorbent assay (ELISA). A model of the Th2 inflammatory environment was created by exposure of primary air-liquid interface (ALI)-cultured HNPECs to interleukin-13 (IL-13) for 14 days, with subsequent assessment of TMEM16A expression in cell lysates by Western blotting and MUC5AC secretion in apical washings of cells by ELISA.
The expressions of TMEM16A and MUC5AC were increased in human nasal polyp tissue and dissociated nasal polyp epithelium. TMEM16A was detected in IL-13-treated HNPECs, specifically in MUC5AC-positive cells but not in ciliated cells. IL-13 treatment increased percentages of TMEM16A-positive cells, MUC5AC-positive cells, and cells coexpressing TMEM16A/MUC5AC, the expression of TMEM16A protein, and the secretion of MUC5AC. T16Ainh-A01, a TMEM16A inhibitor, attenuated these IL-13-induced effects.
The expression of TMEM16A and MUC5AC are increased in CRSwNP, which might be a direct effect of Th2 cytokines present in the sinonasal mucosa in CRSwNP. Down-regulation of TMEM16A expression and MUC5AC secretion in HNPECs by T16Ainh-A01 indicates that TMEM16A might play an important role in mucin secretion in upper airway inflammatory diseases.
PMCID: PMC4446635  PMID: 25749771
Chronic rhinosinusitis with nasal polyps; MUC5AC; mucin secretion; nasal epithelial cells; TMEM16A
3.  The Role of Temporal Envelope and Fine Structure in Mandarin Lexical Tone Perception in Auditory Neuropathy Spectrum Disorder 
PLoS ONE  2015;10(6):e0129710.
Temporal information in a signal can be partitioned into temporal envelope (E) and fine structure (FS). Fine structure is important for lexical tone perception for normal-hearing (NH) listeners, and listeners with sensorineural hearing loss (SNHL) have an impaired ability to use FS in lexical tone perception due to the reduced frequency resolution. The present study was aimed to assess which of the acoustic aspects (E or FS) played a more important role in lexical tone perception in subjects with auditory neuropathy spectrum disorder (ANSD) and to determine whether it was the deficit in temporal resolution or frequency resolution that might lead to more detrimental effects on FS processing in pitch perception. Fifty-eight native Mandarin Chinese-speaking subjects (27 with ANSD, 16 with SNHL, and 15 with NH) were assessed for (1) their ability to recognize lexical tones using acoustic E or FS cues with the “auditory chimera” technique, (2) temporal resolution as measured with temporal gap detection (TGD) threshold, and (3) frequency resolution as measured with the Q10dB values of the psychophysical tuning curves. Overall, 26.5%, 60.2%, and 92.1% of lexical tone responses were consistent with FS cues for tone perception for listeners with ANSD, SNHL, and NH, respectively. The mean TGD threshold was significantly higher for listeners with ANSD (11.9 ms) than for SNHL (4.0 ms; p < 0.001) and NH (3.9 ms; p < 0.001) listeners, with no significant difference between SNHL and NH listeners. In contrast, the mean Q10dB for listeners with SNHL (1.8±0.4) was significantly lower than that for ANSD (3.5±1.0; p < 0.001) and NH (3.4±0.9; p < 0.001) listeners, with no significant difference between ANSD and NH listeners. These results suggest that reduced temporal resolution, as opposed to reduced frequency selectivity, in ANSD subjects leads to greater degradation of FS processing for pitch perception.
PMCID: PMC4459992  PMID: 26052707
4.  CKIP-1 regulates macrophage proliferation by inhibiting TRAF6-mediated Akt activation 
Cell Research  2014;24(6):742-761.
Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage proliferation is promoted by macrophage colony-stimulating factor (M-CSF)-induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2-interacting protein-1 (CKIP-1) as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP-1 was phosphorylated at Serine 342 by constitutively active GSK3β, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degradation of CKIP-1. Upon M-CSF stimulation, Akt is activated by CSF-1R-PI3K and then inactivates GSK3β, leading to the stabilization of CKIP-1 and β-catenin proteins. β-catenin promotes the expression of proliferation genes including cyclin D and c-Myc. CKIP-1 interacts with TRAF6, a ubiquitin ligase required for K63-linked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6-mediated Akt activation. By this means, CKIP-1 inhibits macrophage proliferation specifically at the late stage after M-CSF stimulation. Furthermore, CKIP-1 deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1−/− mice spontaneously develop a macrophage-dominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation.
PMCID: PMC4042176  PMID: 24777252
macrophage proliferation; Akt signaling; TRAF6; GSK3β; CKIP-1
5.  Frequency, Suppressive Capacity, Recruitment and Induction Mechanisms of Regulatory T Cells in Sinonasal Squamous Cell Carcinoma and Nasal Inverted Papilloma 
PLoS ONE  2015;10(5):e0126463.
Sinonasal squamous cell carcinoma (SSCC) and nasal inverted papilloma (NIP) represent the predominant type of malignant and benign tumors in sinonasal tract, respectively. CD4+CD25+Foxp3+ natural regulatory T (Treg) cells might play critical role(s) in the suppression of anti-tumor immune response and thus shed light on tumor progression from benign to malignant.
This study aimed to evaluate the frequency and suppressive capacity of Treg cells in SSCC compared to NIP and further to explore the underlying mechanisms.
Patients and Methods
Frequencies of Treg, Th1 and Th2 cells were evaluated by flow cytometry in tissue homogenate and peripheral blood from 31 SSCC patients, 32 NIP patients and 35 normal controls. Treg cells were tested for regulatory function by co-culture with effector T cells. CCR4 and its ligands, CCL22 and CCL17, were analyzed by flow cytometry and Luminex, respectively. The chemoattractant properties of CCR4/CCL22 and CCR4/CCL17 for Treg cells were assessed using the Boyden chamber technique, to elucidate the potential mechanisms of Treg recruitment in tumor microenvironment. Treg cells induction via TGF-β was assessed with transwells after local CD4+Foxp3+ T cells were assessed by immunohistochemistry and TGF-β concentration was measured by Luminex.
Tumor-infiltrating Treg cells increased significantly from normal to NIP to SSCC (P ≤ 0.001 for normal vs. NIP and P = 0.004 for NIP vs. SSCC). Significantly elevated frequency and enhanced suppression capacity of circulating Treg cells in SSCC were detected compared to NIP and healthy controls, concomitant with Th1 decrease and Th2 increase. Apparently increased CCL22 attracted CCR4-expressing Treg cells to tumor microenvironment in SSCC, compared to NIP. SSCC produced significantly more TGF-β than NIP and thus possessed greater potential for Treg cell induction.
Frequency and suppressive capacity of Treg cells enhanced with progression of malignancy from NIP to SSCC. Circulating Treg cells were recruited to tumor tissue via CCR4/CCL22 signalling, whereas tumor-synthesised TGF-β contributed to induction of peripheral Treg cells.
PMCID: PMC4447263  PMID: 26020249
6.  Analysis of fungal ball rhinosinusitis by culturing fungal clumps under endoscopic surgery 
Objective: This study was designed to investigate the clinical microbiology of fungal ball (FB) rhinosinusitis by culturing fungal clumps collected under endoscopic surgery. Methods: From April to November of 2012, fungal clumps were sampled by endoscopic surgery from patients diagnosed with FB using clinical and histopathological methods. The specimens were subjected to smear microscopy, and cultured for bacteria and fungi analysis. Results: Out of the 81 specimens from 80 patients, 69 (69/81, 85.19%) specimens were detected a mixed infection of bacteria and fungi. However, only 25 (25/81, 30.86%) specimens resulted in fungal growth. There were 12 (12/81, 14.81%) specimens with fungal infections alone. The cultured fungi included 36 strains belonging to five genera, and most of them were Aspergillus spp. (30/36, 83.3%). The cultured bacteria included 94 strains belonging to 16 genera, and the most frequently seen was Staphylococcus spp. (23/94, 35.94%). When it was fungal and Pseudomonas aeruginosa mixed infection, the fungal growth was inhibited (P = 0.002). Conclusion: Patients with fungal ball usually have mixed fungal and bacterial infections. The fungi from these samples are sometimes difficult to culture, which may be the result of the inhibition by bacteria in vitro and in vivo.
PMCID: PMC4483880  PMID: 26131186
Fungal ball; fungal rhinosinusitis; clinical microbiology; microbial culture; mixed infections
7.  Mir-135a enhances cellular proliferation through post-transcriptionally regulating PHLPP2 and FOXO1 in human bladder cancer 
Bladder cancer is the most common malignancy in urinary system and the ninth most common malignancy in the world. MicroRNAs (miRNAs) are small, non-coding RNAs that regulate gene expression by targeted repression of transcription and translation and play essential roles during cancer development. We investigated the expression of miR-135a in bladder cancer and explored its bio-function during bladder cancer progression.
The expression of miR-135a in bladder cancer cells and tissues are performed by using Real-time PCR assay. Cell viability assay (MTT assay), colony formation assay, anchorage-independent growth ability assay and Bromodeoxyuridine labeling and immunofluorescence (BrdUrd) assay are used to examine cell proliferative capacity and tumorigenicity. Flow cytometry analysis is used to determine cell cycle progression. The expressions of p21, p27, CyclinD1, Ki67, PHLPP2 and FOXO1 are measured by Western blotting assay. Luciferase assay is used to confirm whether FOXO1 is the direct target of miR-135a.
miR-135a is upregulated in bladder cancer cells and tissues. Enforced expression of miR-135a promotes bladder cancer cells proliferation, whereas inhibition of miR-135a reverses the function. Furthermore, for the first time we demonstrated PHLPP2 and FOXO1 are direct targets of miR-135a and transcriptionally down-regulated by miR-135a. Suppression of PHLPP2 or FOXO1 by miR-135a, consisted with dysregulation of p21, p27, Cyclin D1 and Ki67, play important roles in bladder cancer progression.
Our study demonstrates that miR-135a promotes cell proliferation in bladder cancer by targeting PHLPP2 and FOXO1, and is performed as an onco-miR.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-015-0438-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4367980  PMID: 25888950
Bladder cancer; miR-135a; PHLPP2; FOXO1; Proliferation
8.  Prevalence of Allergic Rhinitis Among Adults in Urban and Rural Areas of China: A Population-Based Cross-Sectional Survey 
The aim of the present study was to compare the prevalence of self-reported and confirmable allergic rhinitis (AR) with positive skin prick test (SPT) results among adults living in urban and rural areas of China.
Adults from a community in Beijing and a village in Baoding were selected as representative urban and rural dwellers, respectively. All eligible residents were enrolled from the population register and received a face-to-face interview using modified validated questionnaires. Equal sets of randomly selected self-reporting AR-positive and AR-negative participants who responded to the questionnaires were also investigated using skin prick tests.
A total of 803 participants in the rural area and a total of 1,499 participants in the urban area completed the questionnaires, with response rates being 75.9% and 81.5% respectively. The prevalence of self-reported AR of the rural area (19.1%) was significantly higher than that of the urban area (13.5%). The elementary school of educational level increased the risk of having AR (adjusted OR=2.198, 95% CI=1.072-2.236) .The positive SPT rates among subjects with self-reported AR in the rural and urban areas were 32.5% and 53.3%, respectively; the confirmable AR prevalence of 6.2% and 7.2% among the rural and urban adults, respectively.
The prevalence of confirmable AR is similar between rural and urban areas in China, although there is a higher prevalence of self-reported AR in the former.
PMCID: PMC4341336  PMID: 25729622
Allergic rhinitis; prevalence; epidemiology; skin prick test; China
9.  MEK Inhibitor PD-0325901 Overcomes Resistance to CK2 Inhibitor CX-4945 and Exhibits Anti-Tumor Activity in Head and Neck Cancer 
The serine-threonine kinase CK2 exhibits genomic alterations and aberrant overexpression in human head and neck squamous cell carcinomas (HNSCC). Here, we investigated the effects of CK2 inhibitor CX-4945 in human HNSCC cell lines and xenograft models. The IC50's of CX-4945 for 9 UM-SCC cell lines measured by MTT assay ranged from 3.4-11.9 μM. CX-4945 induced cell cycle arrest and cell death measured by DNA flow cytometry, and inhibited prosurvival mediators phospho-AKT and p-S6 in UM-SCC1 and UM-SCC46 cells. CX-4945 decreased NF-κB and Bcl-XL reporter gene activities in both cell lines, but upregulated proapoptotic TP53 and p21 reporter activities, and induced phospho-ERK, AP-1, and IL-8 activity in UM-SCC1 cells. CX-4945 exhibited modest anti-tumor activity in UM-SCC1 xenografts. Tumor immunostaining revealed significant inhibition of PI3K-Akt-mTOR pathway and increased apoptosis marker TUNEL, but also induced p-ERK, c-JUN, JUNB, FOSL1 and proliferation (Ki67) markers, as a possible resistance mechanism. To overcome the drug resistance, we tested MEK inhibitor PD-0325901 (PD-901), which inhibited ERK-AP-1 activation alone and in combination with CX-4945. PD-901 alone displayed significant anti-tumor effects in vivo, and the combination of PD-901 and CX-4945 slightly enhanced anti-tumor activity when compared with PD-901 alone. Immunostaining of tumor specimens after treatment revealed inhibition of p-AKT S129 and p-AKT T308 by CX-4945, and inhibition of p-ERK T202/204 and AP-1 family member FOSL-1 by PD-901. Our study reveals a drug resistance mechanism mediated by the MEK-ERK-AP-1 pathway in HNSCC. MEK inhibitor PD-0325901 is active in HNSCC resistant to CX-4945, meriting further clinical investigation.
PMCID: PMC4366640  PMID: 25798061
CX-4945; CK2 inhibitor; PD-0325901; MEK inhibitor; head and neck cancer.
10.  ICON: chronic rhinosinusitis 
Chronic rhinosinusitis (CRS) is a public health problem that has a significant socio-economic impact. Moreover, the complexity of this disease due to its heterogeneous nature based on the underlying pathophysiology - leading to different disease variants - further complicates our understanding and directions for the most appropriate targeted treatment strategies. Several International/national guidelines/position papers and/or consensus documents are available that present the current knowledge and treatment strategies for CRS. Yet there are many challenges to the management of CRS especially in the case of the more severe and refractory forms of disease. Therefore, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), a collaboration between EAACI, AAAAI, ACAAI, and WAO, has decided to propose an International Consensus (ICON) on Chronic Rhinosinusitis. The purpose of this ICON on CRS is to highlight the key common messages from the existing guidelines, the differences in recommendations as well as the gaps in our current knowledge of CRS, thus providing a concise reference. In this document we discuss the definition of the disease, its relevance, pharmacoeconomics, pathophysiology, phenotypes and endotypes, genetics and risk factors, natural history and co-morbidities as well as clinical manifestations and treatment options in both adults and children comprising pharmacotherapy, surgical interventions and more recent biological approaches. Finally, we have also highlighted the unmet needs that wait to be addressed through future research.
PMCID: PMC4213581  PMID: 25379119
Chronic rhinosinusitis; Pharmacoeconomics; Pathophysiology; Phenotypes; Genetics; Co-morbidities; Treatment; Biologicals; Unmet needs
11.  The Development of Auditory Skills in Young Children with Mondini Dysplasia after Cochlear Implantation 
PLoS ONE  2014;9(9):e108079.
The aim of this study is to survey and compare the development of auditory skills in young children with Mondini dysplasia and profoundly-deaf young children with radiologically normal inner ears over a period of 3 years after cochlear implantation. A total of 545 young children (age 7 to 36 months) with prelingual, severe to profound hearing loss participated in this study. All children received cochlear implantation. Based on whether or not there was a Mondini dysplasia as diagnosed with CT scanning, the subjects were divided into 2 groups: (A) 514 young children with radiologically normal inner ears and (B) 31 young children with Mondini dysplasia. The Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) was used to assess the children's auditory skills that include vocalization changes, spontaneous alerting to sounds in everyday living environments, and the ability to derive meaning from sounds. The assessment was performed prior to surgery and at 1, 3, 6, 9, 12, 24, and 36 months after implant device switch-on. The mean scores for overall auditory skills were not significantly different between groups A and B at pre-surgery, 1, 12, 24, and 36 months post-surgery, but were significantly different at 3, 6, and 9 months post-surgery. The mean scores for all auditory skills in children with Mondini dysplasia showed significant improvement over time. The mean scores for the three subcategories of auditory skills in children with Mondini dysplasia also showed significant differences at pre-surgery, 1, 3, 6, and 9 months, however, there were no significant differences at 12, 24, and 36 months. Overall, the auditory skills of young children with Mondini dysplasia developed rapidly after cochlear implantation, in a similar manner to that of young children with radiologically normal inner ears. Cochlear implantation is an effective intervention for young children with Mondini dysplasia.
PMCID: PMC4172681  PMID: 25247792
12.  Suppression of Cytokine Release by Fluticasone Furoate vs. Mometasone Furoate in Human Nasal Tissue Ex-Vivo 
PLoS ONE  2014;9(4):e93754.
Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse.
To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa.
We used an ex-vivo human nasal mucosal tissue model and employed pre- and post- Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use.
At a fixed concentration of 10−10 M, FF had significantly higher suppressive effects on interferon (IFN)-γ, interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-α, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-α after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF.
The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre- and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use.
PMCID: PMC3977874  PMID: 24710117
13.  Prevalence of Allergic Rhinitis in China 
Allergic rhinitis (AR) is a serious systemic allergic disease, which together with comorbid asthma causes major illness and disability worldwide. Recent epidemiological studies have revealed wide variations in the increasing prevalence of AR and allergies globally, including in China. Despite a markedly higher population than western countries, and a landmass close to Europe in area, little epidemiological data is available on AR in China. Thus, the present study reviewed the prevalence, comorbid allergic diseases, trends and pattern of sensitizing allergens in adults and children suffering from AR in China. Available data indicated that despite variations in the prevalence of AR in different regions of the country, the prevalence of AR has increased in both adults and children over the last 2 decades. Similarly, there has been an increase in a "western"-type lifestyle, industrialization and air pollution over this period, which may have contributed to the increased prevalence of AR observed in China.
PMCID: PMC3936037  PMID: 24587945
Allergic rhinitis; prevalence; China; asthma; allergen; epidemiology; adult; children
14.  Staphylococcal enterotoxin B influences the DNA methylation pattern in nasal polyp tissue: a preliminary study 
Staphylococcal enterotoxins may influence the pro-inflammatory pattern of chronic sinus diseases via epigenetic events. This work intended to investigate the potential of staphylococcal enterotoxin B (SEB) to induce changes in the DNA methylation pattern. Nasal polyp tissue explants were cultured in the presence and absence of SEB; genomic DNA was then isolated and used for whole genome methylation analysis. Results showed that SEB stimulation altered the methylation pattern of gene regions when compared with non stimulated tissue. Data enrichment analysis highlighted two genes: the IKBKB and STAT-5B, both playing a crucial role in T- cell maturation/activation and immune response.
PMCID: PMC3867657  PMID: 24341752
Staphylococcus aureus enterotoxin B; Chronic rhinosinusitis and nasal polyps; DNA methylation; MBD2; Whole genome methylation analysis; Hypermethylation
15.  Assessment of the feasibility and coverage of a modified universal hearing screening protocol for use with newborn babies of migrant workers in Beijing 
BMC Pediatrics  2013;13:116.
Although migrant workers account for the majority of newborns in Beijing, their children are less likely to undergo appropriate universal newborn hearing screening/rescreening (UNHS) than newborns of local non-migrant residents. We hypothesised that this was at least in part due to the inadequacy of the UNHS protocol currently employed for newborn babies, and therefore aimed to modify the protocol to specifically reflect the needs of the migrant population.
A total of 10,983 healthy babies born to migrant mothers between January 2007 and December 2009 at a Beijing public hospital were investigated for hearing abnormalities according to a modified UNHS protocol. This incorporated two additional/optional otoacoustic emissions (OAE) tests at 24–48 hours and 2 months after birth. Infants not passing a screening test were referred to the next test, until any hearing loss was confirmed by the auditory brainstem response (ABR) test.
A total of 98.91% (10983/11104) of all newborn children underwent the initial OAE test, of which 27.22% (2990/10983) failed the test. 1712 of the failed babies underwent the second inpatient OAE test, with739 failing again; thus significantly decreasing the overall positive rate for abnormal hearing from 27.22% to 18.36% ([2990–973 /10983)]; p = 0). Overall, 1147(56.87%) babies underwent the outpatient OAE test again after1-month, of whom 228 failed and were referred for the second outpatient OAE test (i.e. 2.08% (228/10983) referral rate at 1month of age). 141 of these infants underwent the referral test, of whom 103 (73.05%) tested positive again and were referred for a final ABR test for hearing loss (i.e. final referral rate of 1.73% ([228-38/10983] at 2 months of age). Only 54 infants attended the ABR test and 35 (0.32% of the original cohort tested) were diagnosed with abnormal hearing.
Our study shows that it is feasible and practical to achieve high coverage rates for screening hearing loss and decrease the referral rates in newborn babies of migrant workers, using a modification of the currently employed UNHS protocol.
PMCID: PMC3750515  PMID: 23926962
Auditory brainstem response (ABR); Migrant people; Newborn babies; Otoacoustic emissions (OAE); Universal newborn hearing screening (UNHS)
17.  Interaction between IGF-IR and ER Induced by E2 and IGF-I 
PLoS ONE  2013;8(5):e62642.
Estrogen receptor (ER) is a nuclear receptor and the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) is a transmembrane tyrosine kinase receptor. Estrogen and IGF-I are known to have synergistic effects on the growth of breast cancer cells. Recently, non-nuclear effects of ER have been under investigation. To study the mechanism involved in this process, we have used MCF-7 breast cancer cell lines transfected with IGF-IR anti-sense cDNA (SX13, MCF-7SX13) that resulted in 50% reduction of IGF-IR. In MCF-7 cells, estradiol (E2) and IGF-I induced the rapid association of ER to IGF-IR, however, the interaction was abrogated in MCF-7SX13 cells. In addition, NWTB3 cells (NIH3T3 cells overexpressing IGF-IR) were transiently transfected with ERα, the ER-IGF-IR interaction was induced by both E2 and IGF-I. Moreover, ERα regulated the IGF-I signaling pathways through phosphorylation of ERK1/2 and Akt and the interaction of ER-IGF-IR potentiated the cell growth. Finally, E2 and IGF-I stimulated translocation of ER from the nucleus to the cytoplasm. Taken together, these findings reveal that the interaction of the ER and IGF-IR is important for the non-genomic effects of ER.
PMCID: PMC3660452  PMID: 23704881
18.  The effects of vitamins C and B12 on human nasal ciliary beat frequency 
This study was designed to investigate the effects of the vitamins C and B12 on the regulation of human nasal ciliary beat frequency (CBF).
Human nasal mucosa was removed endoscopically and nasal ciliated cell culture was established. Changes of CBF in response to different concentrations of vitamin C or vitamin B12 were quantified by using high-speed (240 frames per second) digital microscopy combined with a beat-by-beat CBF analysis.
At the concentrations of 0.01% and 0.10%, vitamin C induced an initial increase, followed by a gradual decrease of CBF to the baseline level, while 1.00% vitamin C induced a reversible decrease of CBF. Vitamin B12, at the concentrations of 0.01% and 0.10%, did not influence CBF during the 20-min observation period, while a 1.00% vitamin B12 treatment caused a time-dependent but reversible decrease of CBF.
Treatment with vitamin C or vitamin B12 caused a concentration-dependent but reversible decrease of CBF in cultured human nasal epithelial cells. Therefore, it is necessary to choose a concentration that is safe, effective, and non-ciliotoxic when applying these drugs topically in the nasal cavity.
PMCID: PMC3663725  PMID: 23688196
Ciliary beat frequency; Vitamin C; Vitamin B12; Nasal epithelial cell
19.  The Association between Polymorphisms in the MRPL4 and TNF-α Genes and Susceptibility to Allergic Rhinitis 
PLoS ONE  2013;8(3):e57981.
Allergic rhinitis (AR) is a chronic inflammatory disease of the nasal mucosa, involving a complex interaction between genetic and environmental factors. Evidence suggests that polymorphisms in the gene coding for mitochondrial ribosomal protein L4 (MRPL4), located in close proximity to intercellular adhesion molecule-1 (ICAM-1) gene on chromosome location 19p13.2, may influence the risk factor for the development of AR.
The aim of our study was to investigate any association between AR susceptibility and polymorphisms in ICAM-1 gene, as well as associations between AR risk and polymorphisms in MRPL4, nuclear factor-kappaB (NF-κB) and tumor necrosis factor alpha(TNF-α) genes, associated with ICAM-1 expression.
A cohort of 414 patients with AR and 293 healthy controls was enrolled from the Han Chinese population in Beijing, China. Blood was drawn for DNA extraction and total serum immunoglobulin E (IgE). A total of 14 single nucleotide polymorphisms (SNPs) in ICAM-1, NF-κB, TNF-α, and MRPL4 genes were selected using the CHB genotyping data from the International Haplotype Mapping (HapMap) and assessed for differences in frequencies of the alleles and genotypes between the AR patients and control subjects.
TNF-α SNP rs1799964 and MRPL4 SNP rs11668618 were found to occur in significantly greater frequencies in the AR group compared to control group. There were no significant associations between SNPs in NF-κB, ICAM-1 and AR. The SNP-SNP interaction information analysis further indicated that there were no synergistic effects among the selected sets of polymorphisms.
Our results suggest a strong association between AR risk and polymorphisms of MRPL4 and TNF-α genes in Han Chinese population.
PMCID: PMC3589466  PMID: 23472126
20.  Prediction of significant coronary artery disease in patients undergoing operations for rheumatic mitral valve disease 
This study aims to develop a logistic regression model and a simple score system for the prediction of significant coronary artery disease (CAD) in patients undergoing operations for rheumatic mitral valve disease.
A total of 1241 rheumatic patients (mean age 57 ± 6 years), who underwent routine coronary angiography (CAG) before mitral valve operations between 1998 and 2009, was analyzed. To identify low-risk (≤5%) patients, a bootstrap refined logistic regression model on the basis of clinical risk factors was developed, from which an additive model was derived. Receiver operating characteristic (ROC) curves were used to compare discrimination, and precision was quantified by the Hosmer–Lemeshow statistic. Significant coronary atherosclerosis was defined as 50% or more luminal narrowing in one or more major epicardial vessels by means of CAG.
One hundred twenty-seven (10.2%) patients had significant coronary atherosclerosis. Independent predictors of significant CAD include age, male sex, hypertension, angina, smoking, and hypercholesterolemia. Five hundred and fifty patients were designated as low risk according to our logistic regression and additive models. Of these patients, only 6 (1.1%) had single-vessel disease, and none had multivessel disease. Our models proved more efficient than established regression models.
Our logistic regression model could estimate the risk of significant CAD in rheumatic patients undergoing mitral valve operations, while the additive simple score system could reliably identify the low-risk patients in whom routine preoperative angiography might be safely avoided.
PMCID: PMC3241135  PMID: 21641813
Rheumatic heart valve disease; Mitral valve disease; CAD; Risk factor; Logistic regression model
21.  Single nucleotide polymorphisms in thymic stromal lymphopoietin gene are not associated with allergic rhinitis susceptibility in Chinese subjects 
BMC Medical Genetics  2012;13:79.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine, implicated in the development and progression of allergic diseases. Recent studies have demonstrated significantly increased expression and synthesis of TSLPin nasal mucosa of patients with allergic rhinitis (AR), compared with nonallergic control subjects. Also, there is significant correlation between the level of TSLP mRNA and symptom severity in AR patients. In this study, we investigated whether polymorphisms in the TSLP gene were associated with increased risk of AR in the Chinese population.
In a candidate gene association study, we tested 11 single nucleotide polymorphisms (SNPs) in the TSLP gene in 368 AR and 325 control adult Han Chinese subjects from Beijing. The 11 SNPs were selected from the Chinese HapMap genotyping dataset to ensure complete genetic coverage. AR was established by questionnaire and clinical examination, and blood was drawn from all subjects for DNA extraction. The PLINK software package was used to perform statistical testing.
In the single-locus analysis of AR risk, no significant differences in allele and genotype frequencies were found between AR and control subjects. Further logistic regression analyses adjusted for age and gender also failed to reveal significant associations between AR and the selected SNPs. Similarly, analysis stratified by gender, and haplotype or diplotype did not reveal any association with AR risk.
Although TSLP presents itself as a good candidate for contributing to allergy, this study failed to find an association between specific SNPs in the TSLP gene and AR susceptibility in the Han Chinese population.
PMCID: PMC3459694  PMID: 22973903
Allergic rhinitis; Chinese subjects; Genotyping; Thymic stromal lymphopoietin; Single nucleotide polymorphism
22.  Multiple Osteomas in Middle Ear 
Case Reports in Otolaryngology  2012;2012:685932.
Since the first description of middle ear osteomas by Thomas in 1964, only few reports were published within the English literatures (Greinwalid et al., 1998; Shimizu et al., 2003; Cho et al., 2005; and Jang et al., 2009), and only one case of the multiple osteomas in middle ear was described by Kim et al., 2006, which arose from the promontory, lateral semicircular canal, and epitympanum. Here we describe a patient with multiple middle ear osteomas arising from the promontory, incus, Eustachian tube, and bony semicanal of tensor tympani muscle. This patient also contracted the chronic otitis media in the ipsilateral ear. The osteomas were successfully removed by performing type III tympanoplasty in one stage.
PMCID: PMC3420700  PMID: 22928138
23.  Herpes Simplex Virus Type 1 Infection Facilitates Invasion of Staphylococcus aureus into the Nasal Mucosa and Nasal Polyp Tissue 
PLoS ONE  2012;7(6):e39875.
Staphylococcus aureus (S. aureus) plays an important role in the pathogenesis of severe chronic airway disease, such as nasal polyps. However the mechanisms underlying the initiation of damage and/or invasion of the nasal mucosa by S. aureus are not clearly understood. The aim of this study was to investigate the interaction between S. aureus and herpes simplex virus type 1 (HSV1) in the invasion of the nasal mucosa and nasal polyp tissue.
Methodology/Principal Findings
Inferior turbinate and nasal polyp samples were cultured and infected with either HSV1 alone, S. aureus alone or a combination of both. Both in turbinate mucosa and nasal polyp tissue, HSV1, with or without S. aureus incubation, led to focal infection of outer epithelial cells within 48 h, and loss or damage of the epithelium and invasion of HSV1 into the lamina propria within 72 h. After pre-infection with HSV1 for 24 h or 48 h, S. aureus was able to pass the basement membrane and invade the mucosa. Epithelial damage scores were significantly higher for HSV1 and S. aureus co-infected explants compared with control explants or S. aureus only-infected explants, and significantly correlated with HSV1-invasion scores. The epithelial damage scores of nasal polyp tissues were significantly higher than those of inferior turbinate tissues upon HSV1 infection. Consequently, invasion scores of HSV1 of nasal polyp tissues were significantly higher than those of inferior turbinate mucosa in the HSV1 and co-infection groups, and invasion scores of S. aureus of nasal polyp tissues were significantly higher than those of inferior turbinate tissues in the co-infection group.
HSV1 may lead to a significant damage of the nasal epithelium and consequently may facilitate invasion of S. aureus into the nasal mucosa. Nasal polyp tissue is more susceptible to the invasion of HSV1 and epithelial damage by HSV1 compared with inferior turbinate mucosa.
PMCID: PMC3387208  PMID: 22768151
24.  Polymorphisms in RYBP and AOAH Genes Are Associated with Chronic Rhinosinusitis in a Chinese Population: A Replication Study 
PLoS ONE  2012;7(6):e39247.
The development of CRS is believed to be the result of combined interactions between the genetic background of the affected subject and environmental factors.
To replicate and extend our recent findings from genetic association studies in chronic rhinosinusitis (CRS) performed in a Canadian Caucasian population in a Chinese population.
In a case-control replication study, DNA samples were obtained from CRS with (n = 306; CRSwNP) and without (n = 332; CRSsNP) nasal polyps, and controls (n = 315) in a Chinese population. A total of forty-nine single nucleotide polymorphisms (SNPs) selected from previous identified SNPs associated with CRS in Canadian population, and SNPs from the CHB HapMap dataset were individually genotyped.
We identified two SNPs respectively in RYBP (rs4532099, p = 2.15E–06, OR = 2.59) and AOAH (rs4504543, p = 0.0001152, OR = 0.58) significantly associated with whole CRS cohort. Subgroup analysis for the presence of nasal polyps (CRSwNP and CRSsNP) displayed significant association in CRSwNP cohorts regarding to one SNP in RYBP (P = 3.24E–006, OR = 2.76). Evidence of association in the CRSsNP groups in terms of 2 SNPs (AOAH_rs4504543 and RYBP_rs4532099) was detected as well. Stratifying analysis by gender demonstrated that none of the selected SNPs were associated with CRSwNP as well as CRSsNP. Meanwhile 3 SNPs (IL1A_rs17561, P = 0.005778; IL1A_rs1800587, P = 0.009561; IRAK4_rs4251513, P = 0.03837) were associated with serum total IgE level.
These genes are biologically plausible, with roles in regulation of transcription (RYBP) and inflammatory response (AOAH). The present data suggests the potential common genetic basis in the development of CRS in Chinese and Caucasian population.
PMCID: PMC3378692  PMID: 22723975
25.  Cost-effectiveness analysis of neonatal hearing screening program in china: should universal screening be prioritized? 
Neonatal hearing screening (NHS) has been routinely offered as a vital component of early childhood care in developed countries, whereas such a screening program is still at the pilot or preliminary stage as regards its nationwide implementation in developing countries. To provide significant evidence for health policy making in China, this study aims to determine the cost-effectiveness of NHS program implementation in case of eight provinces of China.
A cost-effectiveness model was conducted and all neonates annually born from 2007 to 2009 in eight provinces of China were simulated in this model. The model parameters were estimated from the established databases in the general hospitals or maternal and child health hospitals of these eight provinces, supplemented from the published literature. The model estimated changes in program implementation costs, disability-adjusted life years (DALYs), average cost-effectiveness ratio (ACER), and incremental cost-effectiveness ratio (ICER) for universal screening compared to targeted screening in eight provinces.
Results and discussion
A multivariate sensitivity analysis was performed to determine uncertainty in health effect estimates and cost-effectiveness ratios using a probabilistic modeling technique. Targeted strategy trended to be cost-effective in Guangxi, Jiangxi, Henan, Guangdong, Zhejiang, Hebei, Shandong, and Beijing from the level of 9%, 9%, 8%, 4%, 3%, 7%, 5%, and 2%, respectively; while universal strategy trended to be cost-effective in those provinces from the level of 70%, 70%, 48%, 10%, 8%, 28%, 15%, 4%, respectively. This study showed although there was a huge disparity in the implementation of the NHS program in the surveyed provinces, both universal strategy and targeted strategy showed cost-effectiveness in those relatively developed provinces, while neither of the screening strategy showed cost-effectiveness in those relatively developing provinces. This study also showed that both strategies especially universal strategy achieve a good economic effect in the long term costs.
Universal screening might be considered as the prioritized implementation goal especially in those relatively developed provinces of China as it provides the best health and economic effects, while targeted screening might be temporarily more realistic than universal screening in those relatively developing provinces of China.
PMCID: PMC3353179  PMID: 22510223

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