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author:("Zhang, yingzi")
2.  Contributors to diffusion impairment in HIV-infected persons 
The European respiratory journal  2013;43(1):195-203.
Abnormal diffusing capacity is common in HIV-infected individuals including never smokers. Etiologies for diffusing capacity impairment in HIV are not understood, particularly in those without a history of cigarette smoking.
A cross-sectional analysis of 158 HIV-infected individuals without acute respiratory symptoms or infection to determine associations between a DLCO % predicted and participant demographics, pulmonary spirometric measures (FEV1 and FEV1/FVC), radiographic emphysema (fraction of lung voxels <-950 Hounsfield units), pulmonary vascular/cardiovascular disease (echocardiographic tricuspid regurgitant jet velocity [TRV], N-terminal pro-brain natriuretic peptide), and airway inflammation (induced sputum cell counts), stratified by history of smoking.
Mean DLCO was 65.9% predicted, and 55 (34.8%) participants had a significantly reduced DLCO (<60 % predicted). Lower DLCO % predicted in ever smokers was associated with lower post-bronchodilator FEV1 % predicted (p<0.001) and greater radiographic emphysema (p=0.001). In never smokers, mean (standard deviation) DLCO was 72.7% (13.4%) predicted, and DLCO correlated with post-bronchodilator FEV1 (p=0.02), sputum neutrophils (p=0.03), and sputum lymphocytes (p=0.009), but not radiographic emphysema.
Airway obstruction, emphysema, and inflammation influence DLCO in HIV. Never smokers may have a unique phenotype of diffusing capacity impairment. The interaction of multiple factors may account for the pervasive nature of diffusing capacity impairment in HIV infection.
doi:10.1183/09031936.00157712
PMCID: PMC4023348  PMID: 23429919
HIV; Pulmonary function; Diffusing capacity; AIDS
3.  One-stage partial vertebrectomy, titanium mesh implantation and pedicle screw fixation in the treatment of thoracolumbar burst fractures through a posterior approach 
Clinics  2014;69(12):804-808.
OBJECTIVE:
To analyze the clinical results of a partial vertebrectomy with titanium mesh implantation and pedicle screw fixation using a posterior approach to reconstruct the spine in the treatment of thoracolumbar burst fractures.
METHOD:
From January 2006 to August 2008, 20 patients with severe thoracolumbar fractures were treated.For vertebral bodies associated with one injured intervertebral disk, subtotal vertebrectomy surgery and single-segment fusion were performed. For vertebral bodies with two injured adjacent intervertebral disks, partial vertebrectomy surgery and two-segment fusion were performed.
RESULTS:
All 20 patients were followed up for 12 to 24 months (average of 18 months). There were no complications such as wound infections, hemopneumothorax or abdominal infections in any of the patients. The neurological status of all of the patients was improved by at least one American Spinal Injury Association grade by the last follow-up. The anterior vertebral body height was an average of 50.77% before surgery, 88.51% after surgery and 87.86% at the last follow up; the sagittal Cobb angle was improved, on average, from 26.15° to 5.39° and was 5.90° at the last follow up. The percentage of spinal stenosis was improved, on average, from 26.07% to 4.93%° and was 6.15% at the last follow up. There were significant differences in the anterior vertebral body height pre- and post-surgery and in the sagittal Cobb angle and the percentage of spinal stenosis (p<0) in all patients.
CONCLUSIONS:
This surgical procedure is simple and can accomplish decompression, reduction, fixation and fusion of the spine in one stage. This approach could be widely used in orthopedics.
doi:10.6061/clinics/2014(12)03
PMCID: PMC4286664  PMID: 25627991
Thoracolumbar Burst Fracture; Partial Vertebrectomy; Posterior Approach
5.  Biomarkers in idiopathic pulmonary fibrosis 
Purpose of review
This review examines the recent literature on molecular biomarkers of idiopathic pulmonary fibrosis (IPF). Specific attention is dedicated to the recent studies that identified the genes associated with IPF and the peripheral blood biomarkers that predict outcome in IPF.
Recent findings
Multiple studies attempted to identify diagnostic and predictive biomarkers in IPF. Until recently, these studies were limited in size and lacked replication, but still when taken together provided convincing evidence that changes in blood proteins (KL-6, SP-A, MMP-7, CCL-18, among others) or cells (fibrocytes and T-cell subpopulations) are indicative of the disease presence and outcome. More recently, larger studies have identified gene polymorphisms associated with IPF, as well as protein markers and integrated clinical and molecular prediction rules that accurately predict outcome in patients with IPF.
Summary
The peripheral blood contains disease presence and outcome relevant information, and suggests distinct biologically defined outcome trajectories in patients with IPF. Although recently identified biomarkers should still be validated in multiple clinical contexts, there is sufficient evidence to suggest that collection of peripheral blood biomarkers needs to be incorporated in the design of drug studies and that some of these markers be clinically evaluated in lung transplant prioritization.
doi:10.1097/MCP.0b013e328356d03c
PMCID: PMC4165635  PMID: 22847105
genomics; MMP-7; MUC5b; PCMI; personalized medicine
6.  Fluoroscopic views for safe insertion of lag screws into the posterior column of the acetabulum 
Background
Percutaneous lag screw fixation is an alternative treatment for non-displaced or minimally displaced posterior column fractures. This study aims to explore new fluoroscopic views of the acetabulum for safe percutaneous insertion of posterior column lag screws.
Methods
Axial computed tomography (CT) scans were taken of sixteen embalmed adult cadavers. The axial CT images at the level of the middle height of the acetabulum were selected. The angle (angle α) between the posterior cortex of the posterior column (PCPC) and the line intersecting the axial plane and the coronal plane, and the angle (angle β) between the medial wall and the line intersecting the axial plane and the sagittal plane were identified and measured. Tangential views of the PCPC and medial wall were obtained by referencing the measured angles. A lag screw was inserted into the posterior columns of the sixteen pelvic specimens under fluoroscopic guidance using an iliac oblique view and the two tangential views. CT scans were performed to evaluate the lag screw position. Axial CT images of 52 volunteers were obtained and the angles α and β were measured following the same methods used for the cadaveric specimens.
Results
The angles α and β for the specimens were 29.3±2.8.1 and 8.1±1.4 degrees, respectively. On the tangential view of the PCPC, the posterior cortex appears as a nearly straight line between the lesser and greater sciatic notches. On the tangential view of the medial wall, the medial wall appears as a distinct straight line. Using these radiographic images, the lag screws were inserted into the posterior columns of bony pelvic specimens. Screw placement was confirmed by CT, and found to be fully intraosseous in all cases without any cortical breaches. The angles α and β were 30.4±4.1 and 9.2±1.9 degrees for male volunteers and 28.5±3.7 and 7.7±1.8 degrees for female volunteers, significant difference in these angles between cadaveric specimens and human volunteers.
Conclusion
The tangential views of both the PCPC and medial wall can be obtained following the aforementioned methods The oblique iliac view and the two tangential views enable safe insertion of posterior column lag screws.
doi:10.1186/1471-2474-15-303
PMCID: PMC4169822  PMID: 25224878
Acetabular fracture; Posterior column; Percutaneous fixation; Fluoroscopic view
7.  Autoreactivity to Glucose Regulated Protein 78 Links Emphysema and Osteoporosis in Smokers 
PLoS ONE  2014;9(9):e105066.
Rationale
Emphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders.
Objectives
To discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers.
Methods
Replicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays.
Measurements and Main Results
Circulating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7–5.7, p = 0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7–13.3, p = 0.002), and increased circulating bone metabolites (p = 0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p = 0.0002) and IFN-gamma production (p = 0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p = 0.005) and productions of IL-8, CCL-2, and MMP9 (p = 0.005, 0.007, 0.03, respectively).
Conclusions
Humoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders.
doi:10.1371/journal.pone.0105066
PMCID: PMC4162538  PMID: 25216103
8.  Thrombospondin-1 triggers macrophage IL-10 production and promotes resolution of experimental lung injury 
Mucosal immunology  2013;7(2):440-448.
Mononuclear phagocyte recognition of apoptotic cells triggering suppressive cytokine signaling is a key event in inflammation resolution from injury. Mice deficient in thrombospondin-1 (thbs1−/−), an extracellular matrix glycoprotein that bridges cell-cell interactions, are prone to LPS-induced lung injury and show defective macrophage IL-10 production during the resolution phase of inflammation. Reconstitution of IL-10 rescues thbs1−/− mice from persistent neutrophilic lung inflammation and injury and thbs1−/− alveolar macrophages show defective IL-10 production following intratracheal instillation of apoptotic neutrophils despite intact efferocytosis. Following co-culture with apoptotic neutrophils, thbs1−/− macrophages show a selective defect in IL-10 production whereas PGE2 and TGF-β1 responses remain intact. Full macrophage IL-10 responses require the engagement of thrombospondin-1 structural repeat 2 domain and the macrophage scavenger receptor CD36 LIMP-II Emp sequence homology (CLESH) domain in vitro. Although TSP-1 is not essential for macrophage engulfment of apoptotic neutrophils in vivo, TSP-1 aids in the curtailment of inflammatory responses during the resolution phase of injury in the lungs by providing a means by which apoptotic cells are recognized and trigger optimal IL-10 production by macrophages.
doi:10.1038/mi.2013.63
PMCID: PMC3945733  PMID: 24045574
Thrombospondin-1; Injury Resolution
9.  Sequence of the Essex-Lopresti lesion–a high-speed video documentation and kinematic analysis 
Acta Orthopaedica  2014;85(5):545-546.
doi:10.3109/17453674.2014.949058
PMCID: PMC4164876  PMID: 25140987
10.  Comparison of single and two-tunnel techniques during open treatment of acromioclavicular joint disruption 
BMC Surgery  2014;14:53.
Background
Coracoclavicular (CC) ligament reconstruction with semitendinosus tendon (ST) grafts has become more popular and has achieved relatively good results; however optimal reconstruction technique, single-tunnel or two-tunnel, still remains controversial. This paper is to compare the clinical and radiographic data of allogenous ST grafting with single- or two-tunnel reconstruction techniques of the AC joint.
Methods
The outcomes of 21 consecutive patients who underwent anatomical reduction and ST grafting for AC joint separation were reviewed retrospectively. Patients were divided into two groups: single-tunnel group (11) and two-tunnel group (10). All patients were evaluated clinically and radiographically using a modified UCLA rating scale.
Results
The majority of separations (18 of 21) were Rockwood type V, with one each in type III, IV and VI categories. The overall mean follow-up time was 16 months, and at the time of the latest follow-up, the overall mean UCLA rating score was 14.1 (range 8–20).
The percentage of good-to-excellent outcomes was significantly higher for patients with the two-tunnel technique than for those with the one-tunnel technique (70% vs. 18%, respectively, p = 0.03). Within the single-tunnel group, there was no statistically significant difference in percentage of good-to-excellent outcomes between patients with vs. without tightrope augmentation (17% vs 20%, p > 0.99). Similarly, within the two-tunnel group, there was no significant difference in the percentage of good-to-excellent outcomes between the graft only and augment groups (67% vs. 75%, p > 0.99).
Conclusion
Anatomical reduction of the AC joint and reconstruction CC ligaments are crucial for optimal joint stability and function. Two-tunnel CC reconstruction with an allogenous ST graft provides superior significantly better radiographic and clinical results compared to the single-tunnel reconstruction technique.
doi:10.1186/1471-2482-14-53
PMCID: PMC4139139  PMID: 25127715
Acromioclavicular joint; Single-tunnel; Two-tunnel; Reconstruction; Augmentation
11.  Genetic determinants of haemolysis in sickle cell anaemia 
British journal of haematology  2013;161(2):270-278.
Summary
Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10−07). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r2 = 1) and in strong LD with rs7197554 (r2 = 0·75) and rs13336641 (r2 = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the −∝3·7thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia.
doi:10.1111/bjh.12245
PMCID: PMC4129543  PMID: 23406172
haemolysis; sickle cell anaemia; haemolytic anaemia; genetic analysis; thalassaemia
12.  Pneumocystis jirovecii colonization is associated with enhanced Th1 inflammatory gene expression in lungs of humans with chronic obstructive pulmonary disease 
Microbiology and immunology  2014;58(3):202-211.
Chronic obstructive pulmonary disease (COPD) is a complex disease, the pathogenesis of which remains incompletely understood. Colonization with Pneumocystis jirovecii may play a role in COPD pathogenesis; however, the mechanisms by which such colonization contributes to COPD are unknown. The objective of this study was to determine lung gene expression profiles associated with Pneumocystis colonization in patients with COPD to identify potential key pathways involved in disease pathogenesis. Using COPD lung tissue samples made available through the Lung Tissue Research Consortium (LTRC), Pneumocystis colonization status was determined by nested PCR. Microarray gene expression profiles were performed for each sample and the profiles of colonized and non-colonized samples compared. Overall, 18 participants (8.5%) were Pneumocystis-colonized. Pneumocystis colonization was associated with fold increase in expression of four closely related genes: INF-γ and the three chemokine ligands CXCL9, CXCL10, and CXCL11. These ligands are chemoattractants for the common cognate receptor CXCR3, which is predominantly expressed on activated Th1 T-lymphocytes. Although these ligand–receptor pairs have previously been implicated in COPD pathogenesis, few initiators of ligand expression and subsequent lymphocyte trafficking have been identified: our findings implicate Pneumocystis as a potential trigger. The finding of upregulation of these inflammatory genes in the setting of Pneumocystis colonization sheds light on infectious-immune relationships in COPD.
doi:10.1111/1348-0421.12135
PMCID: PMC4106795  PMID: 24438206
chronic obstructive; microarray; Pneumocystis jirovecii; Pulmonary disease; Th1 cells
13.  Transstyloid Perilunate Fracture-Dislocations of the Carpus, a Review of Two Cases 
Transstyloid perilunate fracture-dislocations of the carpus resulting from a force in an ulnar-to-radial direction are rare injuries. We present two cases of transstyloid perilunate fracture-dislocations of the carpus, one of which dislocated palmarly and was accompanied with fractures of the triquetrum and the ulnar styloid. The treatment algorisms are described and a satisfactory reduction is the goal for optimal functional recovery.
doi:10.1007/s12593-012-0065-z
PMCID: PMC3650169  PMID: 24426669
Fracture dislocation of the carpus; Perilunate; Transstyloid
14.  Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study 
The lancet. Respiratory medicine  2013;1(4):309-317.
Summary
Background
Idiopathic pulmonary fibrosis (IPF) is a devastating disease that probably involves several genetic loci. Several rare genetic variants and one common single nucleotide polymorphism (SNP) of MUC5B have been associated with the disease. Our aim was to identify additional common variants associated with susceptibility and ultimately mortality in IPF.
Methods
First, we did a three-stage genome-wide association study (GWAS): stage one was a discovery GWAS; and stages two and three were independent case-control studies. DNA samples from European-American patients with IPF meeting standard criteria were obtained from several US centres for each stage. Data for European-American control individuals for stage one were gathered from the database of genotypes and phenotypes; additional control individuals were recruited at the University of Pittsburgh to increase the number. For controls in stages two and three, we gathered data for additional sex-matched European-American control individuals who had been recruited in another study. DNA samples from patients and from control individuals were genotyped to identify SNPs associated with IPF. SNPs identified in stage one were carried forward to stage two, and those that achieved genome-wide significance (p<5 × 10−8) in a meta-analysis were carried forward to stage three. Three case series with follow-up data were selected from stages one and two of the GWAS using samples with follow-up data. Mortality analyses were done in these case series to assess the SNPs associated with IPF that had achieved genome-wide significance in the meta-analysis of stages one and two. Finally, we obtained gene-expression profiling data for lungs of patients with IPF from the Lung Genomics Research Consortium and analysed correlation with SNP genotypes.
Findings
In stage one of the GWAS (542 patients with IPF, 542 control individuals matched one-by-one to cases by genetic ancestry estimates), we identified 20 loci. Six SNPs reached genome-wide significance in stage two (544 patients, 687 control individuals): three TOLLIP SNPs (rs111521887, rs5743894, rs5743890) and one MUC5B SNP (rs35705950) at 11p15.5; one MDGA2 SNP (rs7144383) at 14q21.3; and one SPPL2C SNP (rs17690703) at 17q21.31. Stage three (324 patients, 702 control individuals) confirmed the associations for all these SNPs, except for rs7144383. Linkage disequilibrium between the MUC5B SNP (rs35705950) and TOLLIP SNPs (rs111521887 [r2=0.07], rs5743894 [r2=0.16], and rs5743890 [r2=0.01]) was low. 683 patients from the GWAS were included in the mortality analysis. Individuals who developed IPF despite having the protective TOLLIP minor allele of rs5743890 carried an increased mortality risk (meta-analysis with fixed-effect model: hazard ratio 1.72 [95% CI 1.24–2.38]; p=0.0012). TOLLIP expression was decreased by 20% in individuals carrying the minor allele of rs5743890 (p=0.097), 40% in those with the minor allele of rs111521887 (p=3.0 × 10−4), and 50% in those with the minor allele of rs5743894 (p=2.93 × 10−5) compared with homozygous carriers of common alleles for these SNPs.
Interpretation
Novel variants in TOLLIP and SPPL2C are associated with IPF susceptibility. One novel variant of TOLLIP, rs5743890, is also associated with mortality. These associations and the reduced expression of TOLLIP in patients with IPF who carry TOLLIP SNPs emphasise the importance of this gene in the disease.
Funding
National Institutes of Health; National Heart, Lung, and Blood Institute; Pulmonary Fibrosis Foundation; Coalition for Pulmonary Fibrosis; and Instituto de Salud Carlos III.
doi:10.1016/S2213-2600(13)70045-6
PMCID: PMC3894577  PMID: 24429156
15.  Plasma inflammatory mediators associated with bone metabolism in COPD 
COPD  2010;7(3):186-191.
Background
The association of osteoporosis with COPD is well established, but the relationship between systemic inflammatory mediators and bone metabolism has not been explored.
Materials and Methods
Plasma samples from 40 COPD patients awaiting lung transplantation were analyzed for 27 inflammatory mediators using a multiplex protein array. C-telopeptide type I collagen (CTx), a marker of bone resorption, was measured with ELISA, and N-terminal procollagen propeptide (P1NP), a marker of bone formation, was ascertained with a radioimmunoassay. Associations between inflammatory mediators versus CTx and P1NP with adjustments for steroid and bisphosphonate use were determined.
Results
Mean age was 59 years (± 6) and FEV1 was 23.5% (± 8.3%) predicted. Ninety-five percent of the subjects had low bone mineral density measured by dual x-ray absorptiometry (DXA). Tumor necrosis factor alpha and interleukin 4 were positively associated with CTx and P1NP. RANTES and eotaxin were inversely associated with CTx and P1NP. Interleukin 2 and interferon gamma were also directly associated with P1NP.
Conclusions
Biologically plausible systemic mediators are associated with bone metabolism in patients with severe COPD, offering potential insight into risk factors and underlying mechanisms of bone disease. Furthermore, they may be useful in monitoring disease activity, and serve as targets for biological therapy.
doi:10.3109/15412555.2010.482114
PMCID: PMC3985167  PMID: 20486817
Pulmonary disease; chronic obstructive; Osteoporosis; Inflammation; Cytokines
16.  Bony destructive injuries of the calcaneus: long-term results of a minimally invasive procedure followed by early functional exercise: a retrospective study 
BMC Surgery  2014;14:19.
Background
Bony destructive injury of the calcaneus (BDIC) represents one of the most severe comminuted fractures of the calcaneus in which soft tissue coverage remains intact. The features of this injury include a collapsed articular surface, significant widening, severe loss of height and an unrecognisable outline of the calcaneus. This study aims to present the long-term outcomes of BDIC treated in a minimally invasive fashion followed by supervised early exercise.
Methods
Twelve patients with unilateral BDICs were treated at our institution. The main surgical procedures included percutaneous traction and leverage reduction and internal compression fixation with anatomic plates and compression bolts. Early functional exercise was encouraged to mould the subtalar joint. The height, length and width of the calcaneus; Böhler’s and Gissane’s angles; reduction of the articular surfaces; and functional recovery of the affected feet were assessed.
Results
The height, length and width of the calcaneus were substantially restored. The mean Böhler’s and Gissane’s angles of the affected calcaneus were 24.5 and 122.8 degrees, respectively. Five patients regained anatomical or nearly anatomical reduction of their posterior facets. Residual articular displacement of more than 3 mm was noted in three patients. Patients were followed for a mean of 93.9 months. The mean American Orthopaedic Foot and Ankle Society score was 83.8. Nine patients showed excellent or good results. Radiographic evidence of post-traumatic subtalar arthritis was observed in four cases. However, no subtalar arthrodesis was required.
Conclusions
BDICs can be treated effectively with percutaneous reduction and internal compression fixation followed by early active exercise. This protocol resulted in satisfactory radiological and functional outcomes.
doi:10.1186/1471-2482-14-19
PMCID: PMC4021046  PMID: 24725606
Calcaneal fracture; Bony destructive injury; Internal compression fixation; Percutaneous leverage; Early exercise
17.  Patients with Idiopathic Pulmonary Fibrosis with Antibodies to Heat Shock Protein 70 Have Poor Prognoses 
Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations.
Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF.
Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti–heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies.
Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0–8.6; P < 0.0001). HSP70 protein, antigen–antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression.
Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.
doi:10.1164/rccm.201203-0506OC
PMCID: PMC3678112  PMID: 23262513
B cells; T cells; adaptive immunity; interstitial lung disease
18.  Comparative Study of W-Shaped Angular Plate and Reconstruction Plate in Treating Posterior Wall Fractures of the Acetabulum 
PLoS ONE  2014;9(3):e92210.
Objective
This study aims to assess the medium-term results of the reconstruction of posterior wall fractures using a W-shaped acetabular angular plate (WAAP) compared to those fixed using a reconstruction plate.
Methods
Between July 2006 and March 2009, we performed a retrospective study, which collected data for any patient treated for a posterior acetabular wall fracture. At the time of treatment, patients were either treated using a WAAP or a pelvic reconstruction plate. The intraoperative fluoroscopic images for both groups were compared. The quality of reduction and radiological grading were assessed according to the criteria developed by Matta. The clinical assessment was based on a modified Merle d’Aubigne and Postel scoring.
Results
53 patients met the inclusion criteria and were followed up for an average of 38 months. 25 patients were treated with a WAAP (study group), and 28 patients were treated with a pelvic reconstruction plate (control group). The intraoperative fluoroscopic images of the study group confirmed extra-articular screw placement in all cases. In the control group, intra-articular screw placement was observed intraoperatively in 5 patients (17.86%), and the definitive location of the periarticular hardware could not be determined in 4 patients (14.29%) during the operation. The differences between the two groups were statistically significant (p = 0.002). In contrast, the quality of fracture reduction, clinical outcomes, and radiological grading in the study group were not significantly different from those of the control group (p>0.05). The radiographic grade was strongly associated with the clinical outcomes in both the study and control groups (p<0.05).
Conclusion
Reconstruction of posterior wall fractures of the acetabulum using a WAAP can help avoid screw penetration of the hip joint, provide a stable fixation of the posterior wall, and ensure good clinical outcomes.
doi:10.1371/journal.pone.0092210
PMCID: PMC3954867  PMID: 24632754
19.  Cartilage Oligomeric Matrix Protein in Idiopathic Pulmonary Fibrosis 
PLoS ONE  2013;8(12):e83120.
Idiopathic pulmonary fibrosis (IPF) is a progressive and life threatening disease with median survival of 2.5–3 years. The IPF lung is characterized by abnormal lung remodeling, epithelial cell hyperplasia, myofibroblast foci formation, and extracellular matrix deposition. Analysis of gene expression microarray data revealed that cartilage oligomeric matrix protein (COMP), a non-collagenous extracellular matrix protein is among the most significantly up-regulated genes (Fold change 13, p-value <0.05) in IPF lungs. This finding was confirmed at the mRNA level by nCounter® expression analysis in additional 115 IPF lungs and 154 control lungs as well as at the protein level by western blot analysis. Immunohistochemical analysis revealed that COMP was expressed in dense fibrotic regions of IPF lungs and co-localized with vimentin and around pSMAD3 expressing cells. Stimulation of normal human lung fibroblasts with TGF-β1 induced an increase in COMP mRNA and protein expression. Silencing COMP in normal human lung fibroblasts significantly inhibited cell proliferation and negatively impacted the effects of TGF-β1 on COL1A1 and PAI1. COMP protein concentration measured by ELISA assay was significantly increased in serum of IPF patients compared to controls. Analysis of serum COMP concentrations in 23 patients who had prospective blood draws revealed that COMP levels increased in a time dependent fashion and correlated with declines in force vital capacity (FVC). Taken together, our results should encourage more research into the potential use of COMP as a biomarker for disease activity and TGF-β1 activity in patients with IPF. Hence, studies that explore modalities that affect COMP expression, alleviate extracellular matrix rigidity and lung restriction in IPF and interfere with the amplification of TGF-β1 signaling should be persuaded.
doi:10.1371/journal.pone.0083120
PMCID: PMC3869779  PMID: 24376648
20.  Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis 
Nature genetics  2013;45(6):613-620.
We performed a genome-wide association study in non-Hispanic white subjects with fibrotic idiopathic interstitial pneumonias (N=1616) and controls (N=4683); replication was assessed in 876 cases and 1890 controls. We confirmed association with TERT and MUC5B on chromosomes 5p15 and 11p15, respectively, the chromosome 3q26 region near TERC, and identified 7 novel loci (PMeta = 2.4×10−8 to PMeta = 1.1×10−19). The novel loci include FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13), and chromosomal regions 7q22 and 15q14-15. Our results demonstrate that genes involved in host defense, cell-cell adhesion, and DNA repair contribute to the risk of fibrotic IIP.
doi:10.1038/ng.2609
PMCID: PMC3677861  PMID: 23583980
21.  A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation 
Nature immunology  2013;14(5):470-479.
Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in septic subjects and we furthermore identified a hypofunctional Fbxo3 human polymorphism. A small molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several murine disease models. These studies identify a pathway of innate immunity that may characterize subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.
doi:10.1038/ni.2565
PMCID: PMC3631463  PMID: 23542741
22.  The application of central tension plate with sharp hook in the treatment of intra-articular olecranon fracture 
Background
Standard plate fixation can be used to treat intraarticular olecranon fractures with satisfactory functional recovery, but its use is accompanied by implant related complications. This retrospective study reports on the functional outcome of intraarticular olecranon fractures treated with a central tension plate with sharp hook.
Methods
A retrospective review of any patient with an olecranon fracture from August 2007 to December 2008 was conducted. Patients were considered for inclusion in the study if they were treated surgically with a central tension plate with sharp hook. Patients with pathological fractures or previous fractures of the proximal ulna were excluded. The quality of reduction was evaluated using postoperative imaging. The functional recoveries of the affected upper limbs were evaluated postoperatively at regular intervals using the Mayo Elbow Performance (MEP) score and Disability of the Arm, Shoulder and Hand questionnaire (DASH).
Results
Twenty six patients met the study criteria and were included in analysis. There were ten Type IIA, nine Type IIB, four Type IIIA and three Type IIIB fractures according to the Mayo classification system. Thirteen patients exhibited other concomitant fractures at the time of surgery: one patient with a coronoid fracture, two with a fracture of the radial head, and ten with fractures in other bones. Postoperative radiographic assessment revealed an anatomical or nearly anatomical reduction of all olecranon fractures treated. All olecranon fractures healed at an average of 14 weeks (range, 9 to 32 weeks). The patients were followed up for 42 months (range, 32 to 54 months). The mean DASH score was 8.5 (range, 0 to 31.7). The mean MEP score was 93.6 (range, 75 to 100). Based on the MEP score, all patients achieved good or excellent outcomes. No symptomatic plate removal was performed at the time of last follow-up.
Conclusion
The central tension plate with sharp hook closely contours to the osteology of the proximal ulna. Treating intra-articular olecranon fracture with this new plate can achieve good to excellent functional outcome with a high union rate and a low incidence of hardware related complications.
doi:10.1186/1471-2474-14-308
PMCID: PMC4231343  PMID: 24161080
Olecranon; Fracture; Plate fixation; Central tension plate
23.  E2F1 effects on osteoblast differentiation and mineralization are mediated through up-regulation of frizzled-1☆ 
Bone  2013;56(2):234-241.
Frizzled homolog 1 (FZD1) is a transmembrane receptor that mediates Wnt signaling. The transcriptional regulation of FZD1 and the role of FZD1 in osteoblast biology are not well understood. We examined the role of E2F1 in FZD1 promoter activation and osteoblast differentiation and mineralization. A putative E2F1 binding site in the FZD1 promoter region was initially identified in silico and characterized further in Saos2 cells in vitro by chromatin immunoprecipitation (ChIP), electrophoretic mobility shift (EMSA) and promoter reporter assays. Over-expression of E2F1 transactivated the FZD1 promoter and increased endogenous FZD1 mRNA and protein levels in Saos2 cells. Over-expression of E2F1 in Saos2 cells up-regulated osteoblast differentiation markers alkaline phosphatase (ALP), type I collagen α (COL1A), and osteocalcin (OCN). Furthermore, E2F1 over-expression enhanced mineralization of differentiated Saos2 cells, whereas siRNA knockdown of FZD1 diminished the effects of E2F1 on osteoblast mineralization. The effects of E2F1 on FZD1 expression and osteoblast mineralization were further confirmed in normal human FOB osteoblasts. Taken together, our experiments demonstrate a role of E2F1 in osteoblast differentiation and mineralization and suggest that FZD1 is required, in part, for E2F1 regulation of osteoblast mineralization.
doi:10.1016/j.bone.2013.06.019
PMCID: PMC3758927  PMID: 23806799
Frizzled homology1 (FZD1); E2F1; Osteoblasts; Mineralization
24.  Bohler’s angle’s role in assessing the injury severity and functional outcome of internal fixation for displaced intra-articular calcaneal fractures: a retrospective study 
BMC Surgery  2013;13:40.
Background
Controversy exits over the role of Böhler’s angle in assessing the injury severity of displaced intra-articular calcaneal fractures and predicting the functional outcome following internal fixation. This study aims to investigate whether a correlation exists between Böhler’s angle and the injury severity of displaced calcaneal fractures, and between surgical improvement of Böhler’s angle and functional outcome.
Methods
Patients treated operatively for unilateral closed displaced intra-articular calcaneal fractures from January 1, 2004 to March 31, 2008 were identified. The Böhler’s angles of both calcaneus were measured, and the measurement of the uninjured foot was used as its normal control. The difference in the value of Böhler’s angle measured preoperatively or postoperatively between the angle of the injured foot and that of the contralateral calcaneus were calculated, respectively. The change in Böhler’s angle by ratio was calculated by dividing the difference value of Böhler’s angle between bilateral calcaneus by its normal control. The injury severity was assessed according to Sanders classification. The functional outcomes were assessed using American Orthopaedic Foot & Ankle Society hindfoot scores.
Results
274 patients were included into the study with a mean follow-up duration of 71 months. According to Sanders classification, the fracture pattern included 105 type II, 121 type III and 48 type IV fractures. According to American Orthopaedic Foot & Ankle Society hindfoot scoring system, the excellent, good, fair and poor results were achieved in 104, 132, 27, and 11 patients, respectively. The preoperative Böhler’s angle, difference value of Böhler’s angle between bilateral calcaneus, and change in Böhler’s angle by ratio each has a significant correlation with Sanders classification (rs=−0.178, P=0.003; rs=−0.174, P=0.004; rs=−0.172, P=0.005, respectively), however, is not correlated with functional outcome individually. The three postoperative measurements were all found to have a significant correlation with American Orthopaedic Foot & Ankle Society hindfoot scores (rs=0.223, P<0.001; rs=0.224, P<0.001; rs=0.220, P<0.001, respectively). However, these correlations were all weak to low.
Conclusions
There was a significant correlation between preoperative Böhler’s angle and the injury severity of displaced intra-articular calcaneal fractures, but only postoperative Böhler’s angle parameters were found to have a significant correlation with the functional recovery.
doi:10.1186/1471-2482-13-40
PMCID: PMC3849198  PMID: 24330592
Calcaneus; Displaced intra-articular fracture; Böhler’s angle; Functional outcome; Sanders classification
25.  Flexible fixation of syndesmotic diastasis using the assembled bolt-tightrope system 
Background
Syndesmotic diastasis is a common injury. Syndesmotic bolt and tightrope are two of the commonly used methods for the fixation of syndesmotic diastasis. Syndesmotic bolt can be used to reduce and maintain the syndesmosis. However, it cannot permit the normal range of motion of distal tibiofibular joint, especially the rotation of the fibula. Tightrope technique can be used to provide flexible fixation of the syndesmosis. However, it lacks the ability of reducing the syndesmotic diastasis. To combine the advantages of both syndemostic bolt and tightrope techniques and simultaneously avoid the potential disadvantages of both techniques, we designed the assembled bolt-tightrope system (ABTS). The purpose of this study was to evaluate the primary effectiveness of ABTS in treating syndesmotic diastasis.
Methods
From October 2010 to June 2011, patients with syndesmotic diastasis met the inclusion criteria were enrolled into this study and treated with ABTS. Patients were followed up at 2, 6 weeks and 6, 12 months after operation. The functional outcomes were assessed according to the American Orthopedic Foot and Ankle Society (AOFAS) scores at 12 months follow-up. Patients’ satisfaction was evaluated based upon short form-12 (SF-12) health survey questionnaire. The anteroposterior radiographs of the injured ankles were taken, and the medial clear space (MCS), tibiofibular overlap (TFOL), and tibiofibular clear space (TFCS) were measured. All hardwares were routinely removed at 12-month postoperatively. Follow-ups continued. The functional and radiographic assessments were done again at the latest follow-up.
Results
Twelve patients were enrolled into this study, including 8 males and 4 females with a mean age of 39.5 years (range, 26 to 56 years). All patients also sustained ankle fractures. At 12 months follow-up, the mean AOFAS score was 95.4 (range, 85 to 100), and all patients were satisfied with the functional recoveries. The radiographic MCS, TFOL, and TFCS were within the normal range in all patients. After hardware removal, follow-up continued. At the latest follow-up (28 months on average, (range, 25 to 33 months) from internal fixation), the mean AOFAS score was 96.3 (range, 85 to 100), without significant difference with those assessed at 12 months after fixation operations. No syndesmotic diastasis reoccurred based upon the latest radiographic assessment.
Conclusions
ABTS can be used to reduce the syndesmotic diastasis and provide flexible fixation in a minimally invasive fashion. It seems to be an effective alternative technique to treat syndesmotic diastasis.
doi:10.1186/1757-7241-21-71
PMCID: PMC3849036  PMID: 24053432
Syndesmotic diastasis; Tightrope; Syndesmotic bolt; Assembled bolt-tightrope system; Flexible fixation

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