Comparison of bone structure and microstructure in the metacarpal heads between patients with psoriatic arthritis and healthy controls: an HR-pQCT study.

Human cadaveric study has indicated that the metacarpal head (MCH) is intracapsular in location. We hypothesized that exposure to the intra-articular inflammatory milieu in psoriatic arthritis (PsA) will lead to bone loss in the MCH. INTRODUCTION: To compare the bone structure and microstructure in the MCH between patients with PsA and healthy controls by high-resolution peripheral quantitative CT (HR-pQCT), and to ascertain factors associated with bone loss in PsA patients. METHODS: Sixty-two PsA patients without joint destruction and 62 age-, gender-, and body mass index-matched healthy subjects underwent HR-pQCT imaging of the second and third MCH (MCH 2&3). The number and volume of bone erosion and enthesiophytes, as well as volumetric bone mineral density (vBMD) and microstructure at the MCH 2&3, were recorded. Correlation analysis and multivariable linear regression models were used to determine the association of demographic and disease-specific variables with compromised bone structure and microstructure in PsA. RESULTS: At the MCH 2&3, bone erosion (p = 0.003) and enthesiophyte (p = 0.000) volumes in PsA patients were significantly larger than healthy controls. In PsA patients, older age was associated with a larger erosion and enthesiophyte volume. Concerning the mean vBMD and microstructure at the MCH 2&3, PsA patients had significantly lower mean vBMD (average vBMD - 6.9%, trabecular vBMD - 8.8%, peri-trabecular vBMD - 7.7%, meta-trabecular vBMD - 9.8%), trabecular bone volume fraction (- 8.8%), and trabecular thickness (- 8.1%) compared with control subjects. Multivariable regression analysis revealed that older age and a higher C-reactive protein level were associated with trabecular bone loss. CONCLUSIONS: PsA patients had a higher burden of bone damages (erosions and enthesiophytes) and trabecular bone loss compared with healthy control at the MCH. Inflammation contributed to the deterioration in trabecular microstructure in these patients.

MODSIDE: a motif discovery pipeline and similarity detector.

BACKGROUND: Previous studies demonstrate the usefulness of using multiple tools and methods for improving the accuracy of motif detection. Over the past years, numerous motif discovery pipelines have been developed. However, they typically report only the top ranked results either from individual motif finders or from a combination of multiple tools and algorithms. RESULTS: Here we present MODSIDE, a motif discovery pipeline and similarity detector. The pipeline integrated four de novo motif finders: ChIPMunk, MEME, Weeder, and XXmotif. It also incorporated a motif similarity detection tool MOTIFSIM. MODSIDE was designed for delivering not only the predictive results from individual motif finders but also the comparison results for multiple tools. The results include the common significant motifs from multiple tools, the motifs detected by some tools but not by others, and the best matches for each motif in the motif collection of multiple tools. MODSIDE also possesses other useful features for merging similar motifs and clustering motifs into motif trees. CONCLUSIONS: We evaluated MODSIDE and its adopted motif finders on 16 benchmark datasets. The statistical results demonstrate MODSIDE achieves better accuracy than individual motif finders. We also compared MODSIDE with two popular motif discovery pipelines: MEME-ChIP and RSAT peak-motifs. The comparison results reveal MODSIDE attains similar performance as RSAT peak-motifs but better accuracy than MEME-ChIP. In addition, MODSIDE is able to deliver various comparison results that are not offered by MEME-ChIP, RSAT peak-motifs, and other existing motif discovery pipelines.

Performance evaluation for MOTIFSIM.

BACKGROUND: Previous studies show various results obtained from different motif finders for an identical dataset. This is largely due to the fact that these tools use different strategies and possess unique features for discovering the motifs. Hence, using multiple tools and methods has been suggested because the motifs commonly reported by them are more likely to be biologically significant. RESULTS: The common significant motifs from multiple tools can be obtained by using MOTIFSIM tool. In this work, we evaluated the performance of MOTIFSIM in three aspects. First, we compared the pair-wise comparison technique of MOTIFSIM with the un-gapped Smith-Waterman algorithm and four common distance metrics: average Kullback-Leibler, average log-likelihood ratio, Chi-Square distance, and Pearson Correlation Coefficient. Second, we compared the performance of MOTIFSIM with RSAT Matrix-clustering tool for motif clustering. Lastly, we evaluated the performances of nineteen motif finders and the reliability of MOTIFSIM for identifying the common significant motifs from multiple tools. CONCLUSIONS: The pair-wise comparison results reveal that MOTIFSIM attains better performance than the un-gapped Smith-Waterman algorithm and four distance metrics. The clustering results also demonstrate that MOTIFSIM achieves similar or even better performance than RSAT Matrix-clustering. Furthermore, the findings indicate if the motif detection does not require a special tool for detecting a specific type of motif then using multiple motif finders and combining with MOTIFSIM for obtaining the common significant motifs, it improved the results for DNA motif detection.

Current innovations and future challenges of network motif detection.

Network motif detection is the search for statistically overrepresented subgraphs present in a larger target network. They are thought to represent key structure and control mechanisms. Although the problem is exponential in nature, several algorithms and tools have been developed for efficiently detecting network motifs. This work analyzes 11 network motif detection tools and algorithms. Detailed comparisons and insightful directions for using these tools and algorithms are discussed. Key aspects of network motif detection are investigated. Network motif types and common network motifs as well as their biological functions are discussed. Applications of network motifs are also presented. Finally, the challenges, future improvements and future research directions for network motif detection are also discussed.

FG-3019, a Human Monoclonal Antibody Recognizing Connective Tissue Growth Factor, is Subject to Target-Mediated Drug Disposition.

PURPOSE: To evaluate and model the pharmacokinetic and pharmacodynamic behavior in rats of FG-3019, a human monoclonal antibody targeting connective tissue growth factor (CTGF). METHODS: FG-3019, human CTGF (rhCTGF), or the N-terminal domain of rhCTGF were administered intravenously to rats and concentrations of these proteins as well as endogenous CTGF were determined by immunoassays. FG-3019, or (125)I-labeled FG-3019, and human CTGF (rhCTGF) were co-administered to assess the impact of CTGF on the elimination rate and tissue localization of FG-3019, which was further characterized by immunohistochemical analysis. A PK/PD model for target-mediated elimination of FG-3019 was developed to fit the kinetic data. RESULTS: FG-3019 exhibited non-linear pharmacokinetics in rats. Circulating concentrations of the N-terminal half of CTGF increased after dosing with FG-3019, reached maximal levels after 1-5 days, and returned toward baseline levels as FG-3019 cleared from the circulation, whereas the concentration of intact CTGF was unaffected by administration of FG-3019. Co-administration of rhCTGF dramatically enhanced the rate of FG-3019 elimination, redistributing the majority of (125)I-labeled FG-3019 from the blood to the liver, kidney, spleen and adrenal gland. FG-3019 co-administered with CTGF was found along the sinusoids of the liver and adrenal glands, the capillaries of the kidney glomeruli and in the spleen. A pharmacokinetic model for target-mediated elimination of FG-3019 was used to fit the time courses of FG-3019 and endogenous CTGF plasma concentrations, as well as time courses of rhCTGF and rhCTGF N-fragment after intravenous administration of these species. CONCLUSIONS: FG-3019 is subject to target mediated elimination in rats.

Remission of systemic lupus erythematosus disease activity with regulatory cytokine interleukin (IL)-35 in Murphy Roths Large (MRL)/lpr mice.

The immunological mechanisms mediated by regulatory cytokine interleukin (IL)-35 are unclear in systemic lupus erythematosus (SLE). We investigated the frequency of CD4(+) CD25(+) forkhead box protein 3 (FoxP3)(+) regulatory T (Treg ) and IL-10(+) regulatory B (Breg ) cells and related immunoregulatory mechanisms in a female Murphy Roths Large (MRL)/lpr mouse model of spontaneous lupus-like disease, with or without IL-35 treatment. A remission of histopathology characteristics of lupus flare and nephritis was observed in the MRL/lpr mice upon IL-35 treatment. Accordingly, IL-35 and IL-35 receptor subunits (gp130 and IL-12Rß2) and cytokines of MRL/lpr and BALB/c mice (normal controls) were measured. The increased anti-inflammatory cytokines and decreased proinflammatory cytokines were possibly associated with the restoration of Treg and Breg frequency in MRL/lpr mice with IL-35 treatment, compared to phosphate-buffered saline (PBS) treatment. mRNA expressions of Treg -related FoxP3, IL-35 subunit (p35 and EBI3) and soluble IL-35 receptor subunit (gp130 and IL12Rß2) in splenic cells were up-regulated significantly in IL-35-treated mice. Compared with the PBS treatment group, IL-35-treated MRL/lpr mice showed an up-regulation of Treg -related genes and the activation of IL-35-related intracellular Janus kinase/signal transducer and activator of transcription signal pathways, thereby indicating the immunoregulatory role of IL-35 in SLE. These in vivo findings may provide a biochemical basis for further investigation of the regulatory mechanisms of IL-35 for the treatment of autoimmune-mediated inflammation.

Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine, for patients with osteoarthritis of the knee: a multi-site, randomized, double-blind, placebo-controlled phase II clinical trial.

OBJECTIVE: To examine the efficacy and safety of Huo-Luo-Xiao-Ling (HLXL)-Dan, a Traditional Chinese Medicine (TCM), in patients with knee osteoarthritis (OA). DESIGN: A multi-site, randomized, double-blind, placebo-controlled phase II dose-escalation clinical trial was conducted. Eligible patients who fulfilled American College of Rheumatology criteria were randomized to receive either HLXL or placebo. Clinical assessments included measurement of knee pain and function with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), patient global assessment (PGA), and knee pain scores every 2 weeks. A Data and Safety Monitoring Board (DSMB) was established to review the data for ensuring the quality of the trial. RESULTS: In the first stage, 28 participants were randomized to receive either low-dose HLXL-Dan (2400 mg/day) or placebo for 6 weeks. The results showed no statistical difference between the two groups. The study was then re-designed following the recommendation of DSMB. Ninety-two patients were enrolled in the second stage and were randomized to receive either high-dose HLXL-Dan (4000 mg/day for week 1-2, and 5600 mg/day for week 3-8) or placebo for 8 weeks. All outcome assessments showed significant improvements for both groups after 8 weeks but no significant between-group differences. The change (mean ± SD) of WOMAC pain and WOMAC function scores of HLXL and placebo group after 8 weeks were -1.2 ± 1.7 vs -1.4 ± 1.5, and -1.1 ± 1.6 vs -1.3 ± 1.5 respectively. No serious adverse events were reported. CONCLUSION: Although safe to use, an 8-week treatment of HLXL-Dan was not superior to placebo for reduction in pain or functional improvement in patients with knee OA. CLINICAL TRIAL REGISTRATION NUMBER: Clinicaltrials.gov (NCT00755326).

Density, structure, and strength of the distal radius in patients with psoriatic arthritis: the role of inflammation and cardiovascular risk factors.

UNLABELLED: We investigated the densitometric and microstructural features of the distal radius in psoriatic arthritis (PsA) patients using high-resolution peripheral quantitative computed tomography. PsA patients have unique bone microstructural deficits, manifested as lower cortical bone density and higher cortical porosity, which are associated with a propensity to bone fragility. INTRODUCTION: The aim of this study was to investigate the densitometric, geometric, microstructural, and biomechanical features of the distal radius in psoriatic arthritis (PsA) patients. METHODS: This study cohort consisted of 53 PsA patients (24 males and 29 females), with an average age of 53.1 years and 53 gender- and age-matched controls. Areal bone mineral density (aBMD) of the hip, lumbar spine, and ultradistal radius was measured by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed at the distal radius to obtain measures of volumetric BMD (vBMD), microstructure, and derived biomechanical indices. RESULTS: There were no significant between-group differences in aBMD at the femoral neck, total hip, and ultradistal radius, while aBMD at the lumbar spine was significantly higher in patients. The only indices indicating compromised bone quality in PsA patients were related to cortical bone quality. Cortical vBMD were -3.8% significantly lower, while cortical pore volume, porosity index, and pore diameter were 108, 79.5, and 8.6%, respectively, significantly higher in patients. Cortical stress was marginally lower (-1.3%, p = 0.077) in patients with stress significantly more unevenly distributed (4.9%, p = 0.035). Endocortical perimeter and cortical pore volume were significantly higher in patients with vertebral fracture. Deficits in cortical bone quality were associated with indices of disease activity/severity and were more prominent in patients with type 2 diabetes mellitus or hypertension. CONCLUSIONS: There is an intertwined relationship between chronic inflammation, cardiovascular risk factors, and bone loss in PsA. PsA patients seem to have unique bone microstructural deficits which are associated with a propensity to bone fragility.

Cortical thinning and progressive cortical porosity in female patients with systemic lupus erythematosus on long-term glucocorticoids: a 2-year case-control study.

UNLABELLED: In this study, we characterized longitudinal changes of volumetric bone mineral density and cortical and trabecular microstructure at the distal radius using HR-pQCT in female systemic lupus erythematosus (SLE) patients on long-term glucocorticoids. Cortical thinning and increased cortical porosity are the major features of longitudinal microstructural deterioration in SLE patients. INTRODUCTION: The study aims to characterize longitudinal changes of volumetric bone mineral density (vBMD) and bone microstructure at distal radius in female systemic lupus erythematosus (SLE) patients on long-term glucocorticoids. METHODS: This 2-year case-control study consisted of 166 premenopausal subjects (75 SLE patients and 91 controls) and 79 postmenopausal subjects (44 SLE patients and 35 controls). We obtained areal BMD (aBMD) by dual-energy X-ray absorptiometry at multiple skeletal sites and indices of vBMD and microstructure at distal radius by high-resolution peripheral quantitative computed tomography (HR-pQCT) at baseline, 12 and 24 months. RESULTS: In either premenopausal or postmenopausal subjects, changes in aBMD did not differ between patients and controls except that decrease in aBMD at total hip at 24 months in premenopausal patients was significantly higher. In premenopausal subjects, decrease in cortical area (-0.51 vs. -0.06 %, p = 0.039) and thickness (-0.63 vs. 0.02 %, p = 0.031) and increase in cortical porosity (21.7 vs. 7.16 %, p = 0.030) over study period were significantly larger in patients after adjustment of age and body mass index. Decreased in trabecular vBMD was significantly less (-0.63 vs. -2.32 %, p = 0.001) with trabecular microstructure better maintained in patients. In postmenopausal subjects, decrease in cortical vBMD (-2.66 vs. -1.56 %, p = 0.039) and increase in cortical porosity (41.6 vs. 16.3 %, p = 0.021) were significantly higher in patients, and there was no group-wise difference in change of trabecular microstructure. CONCLUSION: Longitudinal microstructural deterioration in SLE is characterized by cortical thinning and increased cortical porosity. Cortical bone is an important source of bone loss in SLE patients on glucocorticoids.

Members of the receptor for advanced glycation end products axis as potential therapeutic targets in patients with lupus nephritis.

The relationship of inflammation and the expression of full-length receptor for advanced glycation end products (flRAGE) on monocytes, plasma levels of RAGE ligand high mobility group box protein 1 (HMGB1), soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) was assessed to elucidate the effect of HMGB1/DNA/RAGE-mediated innate inflammatory responses in patients with lupus nephritis. Cell surface expression of flRAGE was elevated on the monocytes of lupus patients, correlated with plasma HMGB1 levels. Plasma sRAGE level negatively correlated with systemic lupus erythematosus (SLE) disease activity index. Plasma esRAGE level was significantly lower in SLE patients with flare while esRAGE/sRAGE ratio negatively correlated with complement C3 level. HMGB1 alone could moderately induce ex vivo IL-6 production from monocytes, resulting in activation of intracellular p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase and nuclear factor (NF)-κB. Moreover, toll-like receptor-9 ligand together with HMGB1 exhibited a synergistic effect on IL-6 and IL-12p70 secretions and the phosphorylation of p38 MAPK and NF-κB. Therefore, over-expression of flRAGE in lupus may lead to the amplification of RAGE ligands-mediated inflammatory responses through the activation of p38 MAPK and NF-κB. Plasma sRAGE may serve as a potential biomarker for disease activity and a future therapeutic target in SLE.

Aberrant expression of regulatory cytokine IL-35 in patients with systemic lupus erythematosus.

OBJECTIVE: This study characterizes an IL-35-mediated regulatory role in patients with systemic lupus erythematosus (SLE). METHODS: Plasma of SLE patients and healthy controls (HCs) was analyzed for the concentrations of IL-35 and soluble gp130 by using ELISA. mRNA expression of IL-35 subunit (p35 and EBI3) and its receptor (gp130 and IL-12Rß2) in peripheral blood mononuclear cells (PBMCs) was assessed by RT-qPCR. Flow cytometry was performed to evaluate the number of CD4(+)CD25(high)CD127(-)Treg cells and the expression of IL-35 receptor on the CD4+ helper (Th) cells and CD19+ B cells. Plasma collected from SLE patients and HCs was assayed for cytokine and chemokine expression by Luminex multiplex assay. RESULTS: Plasma IL-35 and soluble gp130 levels positively correlated with each other and were significantly higher in patients with severe SLE compared with HCs. Significantly higher levels of inflammatory cytokines/chemokines CCL2, CXCL8, IL-6, interferon (IFN)-γ, IL-10 and IL-17A were observed in plasma of SLE patients than HCs. mRNA levels of IL-35 and its receptor were significantly positively correlated in PBMCs from SLE patients and their levels were higher in SLE than HCs. The increase significantly correlated with changes in SLE Disease Activity Index (SLEDAI) (all p < 0.05). In addition, the number of Treg cells in severe and moderate SLE patients were both significantly lower than HCs, where the ratio of CD4(+)CD25(-)effector T cell %/CD4(+)CD25(high)CD127(-)Treg % was found to be significantly higher in severe SLE patients. Furthermore, the expression of gp130 on CD4+ Th cells and percentage of Tregs were positively correlated with each other, and both were negatively correlated with SLEDAI. CONCLUSION: Our findings indicate that high level of plasma IL-35 in active SLE patients expressed with low level of IL-35 receptor (gp130) on CD4+ Th cells. These data raise the possibility that the level of IL-35 expression in SLE patients is not sufficient to induce the production of CD4(+)CD25(high)CD127(-)Tregs, and subsequently suppress the release of inflammatory cytokines and chemokines upon inflammation.

Dynamic contrast-enhanced imaging of the wrist in rheumatoid arthritis: dedicated low-field (0.25-T) versus high-field (3.0-T) MRI.

OBJECTIVE: To compare the assessment of wrist synovitis severity, synovial volume and synovial perfusion parameters on a dedicated low-field (0.25-T) to that of a high-field (3-T) whole-body MR system in patients with rheumatoid arthritis (RA). METHODS: Twenty-one patients (mean age 50.0 ± 9.8 years) with active RA were recruited prospectively. Dynamic contrast-enhanced MRI examination of the most severely affected wrist was performed at both 0.25 T and 3 T. Three MRI-derived parameters, synovitis severity (RAMRIS grade), synovial volume (ml(3)) and synovial perfusion indices (maximum enhancement and enhancement slope), were compared. RESULTS: Comparing 0.25- and 3-T MRI, there was excellent agreement for semiquantitative assessment (r: 0.80, p < 0.00001) of synovitis (RAMRIS) as well as quantitative assessment (r: 0.94, p < 0.00001) of synovial volume. Good agreement for synovial Emax (r: 0.6, p = 0.002) and fair agreement (r: 0.5, p = 0.02) for synovial Eslope was found. CONCLUSIONS: Imaging of the RA wrist at 0.25 T yields excellent correlation with 3 T with regard to the synovitis activity score (RAMRIS) and synovial volume measurement. Fair to good correlation between low- (0.25-T) and high-field (3-T) MR systems was found for perfusion parameters, being better for Emax than for Eslope.

Incidence of and risk factors for non-vertebral and vertebral fracture in female Chinese patients with systemic lupus erythematosus: a five-year cohort study.

OBJECTIVE: The objective of this paper is to investigate the incidence of both non-vertebral and vertebral fracture in female patients with systemic lupus erythematosus (SLE) and to identify risk factors for incident fracture. METHODS: In a five-year prospective study of 127 female Chinese SLE patients with an average age of 46.9 years (SD: 10.1 years), information on potential risk factors, including demographics, clinical data and bone mineral density (BMD) at lumbar spine and hip by dual-energy X-ray absorptiometry was collected at baseline. At follow-up, participants reported incident non-vertebral fracture during the study period. Semi-quantitative analysis was used to determine incident vertebral fracture on lateral thoracic and lumbar radiographs, defined as any vertebral body graded normal at baseline and at least mildly deformed (20%-25% reduction or more in any vertebral height) at follow-up. RESULTS: Nine incident non-vertebral fractures occurred in eight patients during the study period. Six patients had one or more incident vertebral fractures. The incidence of non-vertebral and vertebral fracture was 1.26 and 0.94 per 100 patient-years, respectively. In multivariate logistic analyses, independent variables associated with incident non-vertebral fracture were duration of glucocorticoid use and prevalent lumbar spine osteoporosis, while risk factors associated with incident vertebral fracture were higher organ damage and prevalent lumbar spine osteoporosis. CONCLUSIONS: The incidence of fracture in SLE patients is lower than the prevalence reported in cross-sectional studies. Lumbar spine BMD appears to have a stronger relationship with incident fracture than hip BMD. This warrants further investigation regarding the optimal site of BMD measurement when predicting fracture risk in SLE patients.

Alterations of bone geometry, density, microarchitecture, and biomechanical properties in systemic lupus erythematosus on long-term glucocorticoid: a case-control study using HR-pQCT.

UNLABELLED: Compared to controls, HR-pQCT at distal radius of SLE patients on chronic glucocorticoid (SLE/GC) revealed reduced bone area, vBMD, deteriorated microarchitecture, and unevenly distributed stresses limited to cortical bone. Despite similar trabecular quality, whole bone strength decreased in patients. These alterations may partly explain high fracture rates in SLE/GC. INTRODUCTION: To assess bone geometric, densitometric, microarchitectural, and biomechanical properties in patients with systemic lupus erythematosus (SLE) on long-term glucocorticoid (GC) (SLE/GC) as compared with healthy controls. METHODS: A total of 180 female SLE patients and 180 healthy controls were in this cross-sectional study to assess areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR-pQCT) and microfinite element analysis (µFEA) was performed at distal radius. RESULTS: In addition to significantly lower aBMD at femoral neck, total hip and lumbar spine, cortical area, average volumetric BMD (vBMD) and cortical vBMD also significantly reduced by 5.3, 5.7, to 1.9 % in SLE patients, respectively. Deteriorations of cortical microarchitecture were pronounced in patients, with 6.3 % reduction in cortical thickness and 13.6 % higher in cortical porosity. Local stresses were more unevenly distributed through cortical bone in patients. SLE/GC patients had decreased whole bone stiffness, estimated failure load, and apparent modulus. Parameters related to trabecular bone density and microarchitecture were comparable between patients and controls. CONCLUSION: In SLE/GC patients, despite a reduction in bone area, vBMD and deteriorated microarchitecture and unevenly distributed stresses limited to the cortical compartment, whole bone strength decreased. HR-pQCT and µFEA were promising in elucidating the potential underlying pathophysiology of bone loss and propensity to fracture in SLE/GC and provide us additional information about alterations of bone quality which might better predict fracture risk beyond aBMD in SLE/GC.

SLE disease per se contributes to deterioration in bone mineral density, microstructure and bone strength.

OBJECTIVE: The objective of this report is to assess the effect of systemic lupus erythematosus (SLE) disease itself on deterioration of bone mineral density (BMD), microstructure and bone strength. METHOD: Thirty age-matched SLE patients on long-term glucocorticoids (GC) (SLE/GC), 30 SLE patients without GC (SLE/non-GC) and 60 healthy controls were examined. Areal BMD (aBMD) was measured by dual-energy X-ray absorptiometry. Bone geometry, volumetric BMD (vBMD), and architectural parameters at the nondominant distal radius were assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT). Bone strength was estimated by HR-pQCT-based micro-finite element analysis. RESULTS: Adjusted for menopausal status and adjusted calcium level, when compared with controls, SLE/non-GC patients had significantly lower aBMD at femoral neck and total hip, and diminished radial total vBMD, cortical area, vBMD and thickness, respectively, by 8.3%, 8%, 2.7% and 9.2%, as well as significant compromised bone strength (stiffness, failure load and apparent modulus) by 8.3%, 9.1% and 9.5%, respectively. Similar alterations were also found in SLE/GC patients when compared to controls. In the premenopausal subgroup analysis, when compared with controls, total hip aBMD and radial cortical area were significantly lower in SLE/non-GC patients, and cortical area and thickness were significantly deficit in SLE/GC patients. However, no significant difference in any bone variables was present between SLE/GC and SLE/non-GC patients in the entire cohort or in the premenopausal subgroup. CONCLUSION: SLE disease per se contributes to the deterioration in bone density, cortical microstructure and bone strength. This might help to explain the considerably higher fracture risk seen in SLE patients.

Anthrax toxin-induced rupture of artificial lipid bilayer membranes.

We demonstrate experimentally that anthrax toxin complexes rupture artificial lipid bilayer membranes when isolated from the blood of infected animals. When the solution pH is temporally acidified to mimic that process in endosomes, recombinant anthrax toxin forms an irreversibly bound complex, which also destabilizes membranes. The results suggest an alternative mechanism for the translocation of anthrax toxin into the cytoplasm.

Effect of 10% and 15% carbamide peroxide on fracture toughness of human dentin in situ.

PURPOSE: Although damage to the structural integrity of the tooth is not usually considered a significant problem associated with tooth bleaching, there have been some reported negative effects of bleaching on dental hard tissues in vitro. More studies are needed to determine whether the observed in vitro effects have practical clinical implications regarding tooth structural durability. OBJECTIVES: This in situ study evaluated the effect of 10% and 15% carbamide peroxide (CP) dental bleach, applied using conventional whitening trays by participants at home, on the fracture toughness of dentin. METHODS: Ninety-one adult volunteers were recruited (n ≈ 30/group). Compact fracture toughness specimens (approximately 4.5 × 4.6 × 1.7 mm) were prepared from the coronal dentin of recently extracted human molars and gamma-radiated. One specimen was fitted into a prepared slot, adjacent to a maxillary premolar, within a custom-made bleaching tray that was made for each adult participant. The participants were instructed to wear the tray containing the dentin specimen with placebo, 10% CP, or 15% CP treatment gel overnight for 14 nights and to store it in artificial saliva when not in use. Pre-bleach and post-bleach tooth color and tooth sensitivity were also evaluated using ranked shade tab values and visual analogue scales (VASs), respectively. Within 24-48 hours after the last bleach session, the dentin specimens were tested for fracture toughness using tensile loading at 10 mm/min. Analysis of variance, Kruskal-Wallis, χ (2) , Tukey's, and Mann-Whitney U tests were used for statistical analysis. The level of significance was set at p<0.05 for all tests, except for the Mann-Whitney U tests, which used a Bonferroni correction for post hoc analyses of the nonparametric data (p<0.017). Results : The placebo, 10% CP, and 15% CP groups contained 30, 31, and 30 participants, respectively. Mean fracture toughness (+ standard deviation) for the placebo, 10% CP, and 15% CP groups were 2.3 ± 0.9, 2.2 ± 0.7, and 2.0 ± 0.5 MPa*m(1/2) respectively. There were no significant differences in mean fracture toughness results among the groups (p=0.241). The tooth sensitivity VAS scores indicated a significantly greater incidence (p=0.000) and degree of tooth sensitivity (p=0.049 for VAS change and p=0.003 for max VAS) in the bleach groups than in the placebo group. The color change results showed generally greater color change in the bleach groups than in the placebo group (p=0.008 for shade guide determination and p=0.000 for colorimeter determination). CONCLUSIONS: There were no significant differences in in situ dentin fracture toughness results among the groups. The results of this study provide some reassurance that dentin is not overtly weakened by the bleaching protocol used in this study. However, the lack of a statistically significant difference cannot be used to state that there is no effect of bleach on dentin fracture toughness.

Effect of Tooth Bleach on Dentin Fatigue Resistance in Situ.

BACKGROUND: Negative effects of bleaching on dentin have previously been reported in vitro. OBJECTIVE: The purpose of this study was to determine the effect of carbamide peroxide bleaching on dentin fatigue resistance using a clinically relevant in situ model. METHODS AND MATERIALS: Following research ethics board approval, 60 human teeth requiring extraction were collected. Sterilized human dentin specimens were cut (1.2x1.2x10 mm) and secured into customized bleaching trays to be used by study participants. Participants were randomly assigned to either bleach (10% carbamide peroxide, n=23) or control (gel without bleach, n=26) treatment groups. Treatment was applied to the bleaching trays and worn overnight by participants for 14 days. After treatment completion, dentin specimens were removed from the bleaching trays and subjected to fatigue testing (10 N, 3 mm/s, 2x105 cycles) while submerged in artificial saliva. Kaplan-Meier survival analysis was conducted to compare the number of cycles to failure during fatigue testing in both groups. A log rank test was run to determine if there were differences in the survival distribution between the two groups (α<0.05). RESULTS: The median number of cycles to failure was 352 ± 202 and 760 ± 644 for the bleach and control groups, respectively. The survival distributions for the two groups were significantly different (p=0.020). Dentin fatigue resistance was significantly lower in the bleach group compared to the control. CONCLUSIONS: Direct bleaching of human dentin using an at-home tray bleaching protocol in situ reduced dentin fatigue resistance. This has implications for tooth fracture risk and longevity.