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Alveolar Bone Resorption (alveolar + bone_resorption)
Selected AbstractsChange in supporting tissue following loss of a permanent maxillary incisor in childrenDENTAL TRAUMATOLOGY, Issue 6 2007Helen D. Rodd Abstract,,, Alveolar bone resorption is an inevitable consequence of tooth loss and may be detrimental to long-term dental aesthetics and function. The aim of the present study was to quantify the degree of tissue resorption following the loss of a permanent incisor in a young population. The study group comprised 11 boys and five girls who all required the extraction of a permanent maxillary central incisor due to trauma-related sequelae. Mean age at tooth loss was 10.8 years. Upper alginate impressions were taken at regular intervals following tooth loss and were cast in yellow dental stone. Study models were sectioned longitudinally through the mid-point of both the maxillary incisor socket and the contra-lateral incisor to provide a thin plaster section. Digital photographs were acquired of the edentulous (A1) and dentate (A2) surfaces of this section and image analysis software was employed to quantify the surface area of both A1 and A2. At 3 months postextraction, mean A1 was 15.7% less than mean A2. By 6 months mean A1 had further reduced and was 25.3% less than that of the corresponding dentate alveolus. However, at subsequent time intervals following tooth extraction (>6 months), tissue loss appeared to stabilise with an overall reduction in tissue area remaining at 22%. This reduction in supporting tissue area was found to be highly statistically significant (P = 0.002, anova). Furthermore, girls appeared to have an overall greater degree of tissue loss than boys (P = 0.015). Further research is indicated to explore factors influencing the degree of tissue loss following incisor extraction and the benefit of therapeutic interventions in limiting this resorption. [source] (-)-Epigallocatechin gallate induces apoptosis, via caspase activation, in osteoclasts differentiated from RAW 264.7 cellsJOURNAL OF PERIODONTAL RESEARCH, Issue 3 2007J.-H. Yun Background and Objective:, Alveolar bone resorption is a characteristic feature of periodontal diseases and involves removal of both the mineral and the organic constituents of the bone matrix, a process mainly carried out by multinucleated osteoclast cells. (-)-Epigallocatechin gallate, the main constituent of green tea polyphenols, has been reported to induce the apoptotic cell death of osteoclasts and to modulate caspase activation in various tumor cells. In the present study, we investigated the inhibitory effect of (-)-epigallocatechin gallate on osteoclast survival and examined if (-)-epigallocatechin gallate mediates osteoclast apoptosis via caspase activation. Material and Methods:, The effect of (-)-epigallocatechin gallate on osteoclast survival was examined by tartrate-resistant acid phosphatase (TRAP) staining in osteoclasts differentiated from RAW 264.7 cells. In addition, we evaluated the apoptosis of osteoclasts by (-)-epigallocatechin gallate using a DNA-fragmentation assay. Involvement of caspase in (-)-epigallocatechin gallate-mediated osteoclast apoptosis was evaluated by treatment with a general caspase inhibitor, Z-VAD-FMK. Moreover, the effect of (-)-epigallocatechin gallate on the activation of caspase-3 was assessed by a colorimetric activity assay and western blotting. Results:, (-)-Epigallocatechin gallate significantly inhibited, in a dose-dependent manner, the survival of osteoclasts differentiated from RAW 264.7 cells and induced the apoptosis of osteoclasts. Treatment with (-)-epigallocatechin gallate resulted in DNA fragmentation and induced the activation of caspase-3 in RAW 264.7 cell-derived osteoclasts. Additional treatment with Z-VAD-FMK suppressed these effects of (-)-epigallocatechin gallate. Conclusion:, From these findings, we could suggest that (-)-epigallocatechin gallate might prevent alveolar bone resorption by inhibiting osteoclast survival through the caspase-mediated apoptosis. [source] Inhibitory effects of green tea polyphenol (,)-epigallocatechin gallate on the expression of matrix metalloproteinase-9 and on the formation of osteoclastsJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2004Jeong-Ho Yun Background:, Alveolar bone resorption is a characteristic feature of periodontal diseases and involves the removal of both the mineral and organic constituents of the bone matrix, which is caused by either multinucleated osteoclast cells or matrix metalloproteinases (MMPs). The gram-negative bacterium, Porphyromonas gingivalis has been reported to stimulate the activity and expression of several groups of MMPs, whereas (,)-epigallocatechin gallate (EGCG), the main constituent of green tea polyphenols, has been reported to have inhibitory effects on the activity and expression of MMPs. Objectives:, In the present study, we investigated the effects of the green tea polyphenol, EGCG, on the gene expression of osteoblast-derived MMP-2, -9 and -13, stimulated by P. gingivalis, and on the formation of osteoclasts. Methods:, The effect of EGCG on the gene expression of MMPs was examined by treating mouse calvarial primary osteoblastic cells with EGCG (20 µm) in the presence of sonicated P. gingivalis extracts. The transcription levels of MMP-2, -9 and -13 were assessed by reverse transcription-polymerase chain reaction (RT-PCR). The effect of EGCG on osteoclast formation was confirmed by tartrate-resistant acid phosphatase (TRAP) staining in a co-culture system of mouse bone marrow cells and calvarial primary osteoblastic cells. Results:, Treatment with the sonicated P. gingivalis extracts stimulated the expression of MMP-9 mRNA and this effect was significantly reduced by EGCG, whereas the transcription levels of MMP-2 and MMP-13 were not affected by either the sonicated P. gingivalis extracts or EGCG. In addition, EGCG significantly inhibited osteoclast formation in the co-culture system at a concentration of 20 µm. Conclusions:, These findings suggest that EGCG may prevent the alveolar bone resorption that occurs in periodontal diseases by inhibiting the expression of MMP-9 in osteoblasts and the formation of osteoclasts. [source] Selective Blockade of Voltage-Gated Potassium Channels Reduces Inflammatory Bone Resorption in Experimental Periodontal Disease,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2004Paloma Valverde Abstract The effects of the potassium channel (Kv1.3) blocker kaliotoxin on T-cell-mediated periodontal bone resorption were examined in rats. Systemic administration of kaliotoxin abrogated the bone resorption in conjunction with decreased RANKL mRNA expression by T-cells in gingival tissue. This study suggests a plausible therapeutic approach for inflammatory bone resorption by targeting Kv1.3. Introduction: Kv1.3 is a critical potassium channel to counterbalance calcium influx at T-cell receptor activation. It is not known if Kv1.3 also regulates RANKL expression by antigen-activated T-cells, and consequently affects in vivo bone resorption mediated by activated T-cells. Materials and Methods:Actinobacillus actinomycetemcomitans 29-kDa outer membrane protein-specific Th1-clone cells were used to evaluate the expression of Kv1.3 (using reverse transcriptase-polymerase chain reaction [RT-PCR] and Western blot analyses) and the effects of the potassium channel blocker kaliotoxin (0,100 nM) on T-cell activation parameters ([3H]thymidine incorporation assays and ELISA) and expression of RANKL and osteoprotegerin (OPG; flow cytometry, Western blot, and RT-PCR analyses). A rat periodontal disease model based on the adoptive transfer of activated 29-kDa outer membrane protein-specific Th1 clone cells was used to analyze the effects of kaliotoxin in T-cell-mediated alveolar bone resorption and RANKL and OPG mRNA expression by gingival T-cells. Stimulated 29-kDa outer membrane protein-specific Th1 clone cells were transferred intravenously on day 0 to all animals used in the study (n = 7 animals per group). Ten micrograms of kaliotoxin were injected subcutaneously twice per day on days 0, 1, 2, and 3, after adoptive transfer of the T-cells. The control group of rats was injected with saline as placebo on the same days as injections for the kaliotoxin-treated group. The MOCP-5 osteoclast precursor cell line was used in co-culture studies with fixed 29-kDa outer membrane protein-specific Th1-clone cells to measure T-cell-derived RANKL-mediated effects on osteoclastogenesis and resorption pit formation assays in vitro. Statistical significance was evaluated by Student's t -test. Results: Kaliotoxin decreased T-cell activation parameters of 29-kDa outer membrane protein-specific Th1 clone cells in vitro and in vivo. Most importantly, kaliotoxin administration resulted in an 84% decrease of the bone resorption induced in the saline-treated control group. T-cells recovered from the gingival tissue of kaliotoxin-treated rats displayed lower ratios of RANKL and OPG mRNA expression than those recovered from the control group. The ratio of RANKL and osteoprotegerin protein expression and induction of RANKL-dependent osteoclastogenesis by the activated T-cells were also markedly decreased after kaliotoxin treatments in vitro. Conclusion: The use of kaliotoxin or other means to block Kv1.3 may constitute a potential intervention therapy to prevent alveolar bone loss in periodontal disease. [source] The temporal expression and localization of extracellular matrix metalloproteinase inducer (EMMPRIN) during the development of perio-dontitis in an animal modelJOURNAL OF PERIODONTAL RESEARCH, Issue 4 2010L. Liu Liu L, Li C, Cai X, Xiang J, Cao Z, Dong W. The temporal expression and localization of extracellular matrix metalloproteinase inducer (EMMPRIN) during the development of periodontitis in an animal model. J Periodont Res 2010; 45: 541,549. © 2010 John Wiley & Sons A/S Background and Objective:, We previously demonstrated extracellular matrix metalloproteinase inducer (EMMPRIN) was associated with the matrix metalloproteinases production of human periodontitis. The aim of this study was to investigate the temporal expression and localization of EMMPRIN during ligature-induced periodontitis in rats. Material and Methods:, Periodontitis was inducd in rats by placing a thread around the cervix of the first mandibular molar. Animals were killed 3, 7, 11, 15 or 21 d after ligation. Mandibles were processed for paraffin sections and stained with hematoxylin and eosin or picrosirius red. The distance from the amelocemental junction to the alveolar crest (ACJ,AC) and the area fraction (Area%) of collagen fibers were measured. EMMPRIN was examined by immunohistochemistry and quantified by positive cell counting. Correlation analyses were then performed. Results:, Histologically, alveolar bone was gradually destroyed from day 3 to 11 and then stabilized. Collagen fibers were slightly dissociated on day 3 and extensively broken on day 7. They were reconstructed from day 11 to 21. EMMPRIN was localized predominantly in infiltrating cells and adjacent fibroblasts in interdental gingiva. The number of EMMPRIN-positive cells increased on day 3, peaked on day 7 and then gradually subsided from day 11 to 21. Statistically, there was a moderate positive correlation regarding the ACJ,AC distance (r = 0.552, p < 0.01) and a strong negative correlation with the Area% of collagen fibers (r = ,0.808, p < 0.01). In gingival epithelium, the immunoreactivity was extremely strong in basal layer cells and sulcular epithelial cells in health. It was greatly enhanced in the inflamed conditions on days 3 and 7. In the interradicular bone, EMMPRIN was localized in the osteoclasts on days 3 and 7, as well as in the osteoblasts from day 11 onwards. Conclusion:, The expression and localization of EMMPRIN are temporally varied during the development of periodontitis. In addition, the inflammation-dependent expression of EMMPRIN might be involved in alveolar bone resorption and collagen breakdown. [source] Topical administration of simvastatin recovers alveolar bone loss in ratsJOURNAL OF PERIODONTAL RESEARCH, Issue 3 2008H. Seto Background and Objective:, Simvastatin, a cholesterol-lowering drug, has been reported to show anabolic effects on bone metabolism. We examined the effects of simvastatin in vitro using cultured rat calvaria cells and in vivo using periodontitis-induced rats. Material and Methods:, Alkaline phosphatase activity and bone nodule formation were measured in cultured rat calvaria cells. Nylon ligature was placed around the maxillary molars of Fischer male rats for 20 d to induce alveolar bone resorption. After ligature removal, simvastatin was topically injected into the buccal gingivae for 70 d and then microcomputed tomography and histological examinations were performed. Results:, Simvastatin maintained high alkaline phosphatase activity and increased bone nodule formation in rat calvaria cells in a dose-dependent manner, showing that simvastatin increased and maintained a high level of osteoblastic function. Microcomputed tomography images revealed that treatment with simvastatin recovered the ligature-induced alveolar bone resorption, showing a 46% reversal of bone height. Histological examination clarified that low-mineralized alveolar bone was formed in simvastatin-treated rats. Conclusion:, These findings demonstrate that simvastatin has the potential to stimulate osteoblastic function and that topical administration of simvastatin may be effective for the recovery of alveolar bone loss in rats. [source] (-)-Epigallocatechin gallate induces apoptosis, via caspase activation, in osteoclasts differentiated from RAW 264.7 cellsJOURNAL OF PERIODONTAL RESEARCH, Issue 3 2007J.-H. Yun Background and Objective:, Alveolar bone resorption is a characteristic feature of periodontal diseases and involves removal of both the mineral and the organic constituents of the bone matrix, a process mainly carried out by multinucleated osteoclast cells. (-)-Epigallocatechin gallate, the main constituent of green tea polyphenols, has been reported to induce the apoptotic cell death of osteoclasts and to modulate caspase activation in various tumor cells. In the present study, we investigated the inhibitory effect of (-)-epigallocatechin gallate on osteoclast survival and examined if (-)-epigallocatechin gallate mediates osteoclast apoptosis via caspase activation. Material and Methods:, The effect of (-)-epigallocatechin gallate on osteoclast survival was examined by tartrate-resistant acid phosphatase (TRAP) staining in osteoclasts differentiated from RAW 264.7 cells. In addition, we evaluated the apoptosis of osteoclasts by (-)-epigallocatechin gallate using a DNA-fragmentation assay. Involvement of caspase in (-)-epigallocatechin gallate-mediated osteoclast apoptosis was evaluated by treatment with a general caspase inhibitor, Z-VAD-FMK. Moreover, the effect of (-)-epigallocatechin gallate on the activation of caspase-3 was assessed by a colorimetric activity assay and western blotting. Results:, (-)-Epigallocatechin gallate significantly inhibited, in a dose-dependent manner, the survival of osteoclasts differentiated from RAW 264.7 cells and induced the apoptosis of osteoclasts. Treatment with (-)-epigallocatechin gallate resulted in DNA fragmentation and induced the activation of caspase-3 in RAW 264.7 cell-derived osteoclasts. Additional treatment with Z-VAD-FMK suppressed these effects of (-)-epigallocatechin gallate. Conclusion:, From these findings, we could suggest that (-)-epigallocatechin gallate might prevent alveolar bone resorption by inhibiting osteoclast survival through the caspase-mediated apoptosis. [source] Milk basic protein increases alveolar bone formation in rat experimental periodontitisJOURNAL OF PERIODONTAL RESEARCH, Issue 1 2007H. Seto Background and Objective:, It is conceivable that the active components extracted from milk whey protein (i.e. milk basic protein, MBP) stimulate bone formation and suppress bone resorption. Periodontitis is characterized by excessive alveolar bone resorption. We examined whether milk basic protein could recover alveolar bone loss in rat experimental periodontitis. Material and Methods:, A nylon ligature was placed around the cervix of molars in 8-wk-old male Fischer rats for 20 d. Then, the ligature was removed and a powder diet containing 0.2 or 1.0% milk basic protein was provided daily for another 45,90 d. On days 45 and 90, the maxillae were extracted and analyzed using microcomputerized tomography (micro-CT), followed by histological analysis. Results:, Micro-CT images showed that alveolar bone resorption was severely induced around the molar by the 20-d ligature procedure. Treatment with high-dose milk basic protein (1.0%) clearly recovered ligature-induced alveolar bone resorption on days 45 and 90, whereas low-dose milk basic protein (0.2%) did not show such a clear effect. Histological examination clarified that the osteoid thickness of alveolar bone was dose dependently increased by milk basic protein treatment for 90 d. Conclusion:, These findings suggest that a systemic administration of milk basic protein may be effective for the recovery of alveolar bone loss in periodontitis. [source] Inhibitory effects of green tea polyphenol (,)-epigallocatechin gallate on the expression of matrix metalloproteinase-9 and on the formation of osteoclastsJOURNAL OF PERIODONTAL RESEARCH, Issue 5 2004Jeong-Ho Yun Background:, Alveolar bone resorption is a characteristic feature of periodontal diseases and involves the removal of both the mineral and organic constituents of the bone matrix, which is caused by either multinucleated osteoclast cells or matrix metalloproteinases (MMPs). The gram-negative bacterium, Porphyromonas gingivalis has been reported to stimulate the activity and expression of several groups of MMPs, whereas (,)-epigallocatechin gallate (EGCG), the main constituent of green tea polyphenols, has been reported to have inhibitory effects on the activity and expression of MMPs. Objectives:, In the present study, we investigated the effects of the green tea polyphenol, EGCG, on the gene expression of osteoblast-derived MMP-2, -9 and -13, stimulated by P. gingivalis, and on the formation of osteoclasts. Methods:, The effect of EGCG on the gene expression of MMPs was examined by treating mouse calvarial primary osteoblastic cells with EGCG (20 µm) in the presence of sonicated P. gingivalis extracts. The transcription levels of MMP-2, -9 and -13 were assessed by reverse transcription-polymerase chain reaction (RT-PCR). The effect of EGCG on osteoclast formation was confirmed by tartrate-resistant acid phosphatase (TRAP) staining in a co-culture system of mouse bone marrow cells and calvarial primary osteoblastic cells. Results:, Treatment with the sonicated P. gingivalis extracts stimulated the expression of MMP-9 mRNA and this effect was significantly reduced by EGCG, whereas the transcription levels of MMP-2 and MMP-13 were not affected by either the sonicated P. gingivalis extracts or EGCG. In addition, EGCG significantly inhibited osteoclast formation in the co-culture system at a concentration of 20 µm. Conclusions:, These findings suggest that EGCG may prevent the alveolar bone resorption that occurs in periodontal diseases by inhibiting the expression of MMP-9 in osteoblasts and the formation of osteoclasts. [source] Molecular characterization of Treponema denticola infection-induced bone and soft tissue transcriptional profilesMOLECULAR ORAL MICROBIOLOGY, Issue 4 2010V. Bakthavatchalu Summary Treponema denticola is associated with subgingival biofilms in adult periodontitis and with acute necrotizing ulcerative gingivitis. However, the molecular mechanisms by which T. denticola impacts periodontal inflammation and alveolar bone resorption remain unclear. Here, we examined changes in the host transcriptional profiles during a T. denticola infection using a murine calvarial model of inflammation and bone resorption. T. denticola was injected into the subcutaneous soft tissue over the calvaria of BALB/c mice for 3 days, after which the soft tissues and the calvarial bones were excised. RNA was isolated and analysed for transcript profiling using Murine GeneChip® arrays. Following T. denticola infection, 2905 and 1234 genes in the infected calvarial bones and soft tissues, respectively, were differentially expressed (P , 0.05). Biological pathways significantly impacted by T. denticola infection in calvarial bone and calvarial tissue included leukocyte transendothelial migration, cell adhesion (immune system) molecules, cell cycle, extracellular matrix,receptor interaction, focal adhesion, B-cell receptor signaling and transforming growth factor-, signaling pathways resulting in proinflammatory, chemotactic effects, and T-cell stimulation. In conclusion, localized T. denticola infection differentially induces transcription of a broad array of host genes, the profiles of which differed between inflamed calvarial bone and soft tissues. [source] Omega-3 fatty acid regulates inflammatory cytokine/mediator messenger RNA expression in Porphyromonas gingivalis -induced experimental periodontal diseaseMOLECULAR ORAL MICROBIOLOGY, Issue 4 2007L. Kesavalu Introduction:,Porphyromonas gingivalis is strongly implicated in the etiology of adult periodontitis by inducing inflammatory cytokines, resulting in gingival and periodontal tissue inflammation and alveolar bone resorption. This study tested the hypothesis that supplementing the diet with omega-3 fatty acid (,-3 FA; i.e. fish oil) would exert anti-inflammatory effects in the gingival tissues of P. gingivalis -infected rats. Methods:, Rats were fed either fish oil or corn oil diets ad libitum for 22 weeks and infected with P. gingivalis strain 381 or strain A7A1-28. After sacrifice, rat gingival tissues were excised and the RNA was isolated and analyzed for proinflammatory mediators [interleukin-1, (IL-1,), tumor necrosis factor-, (TNF-,), IL-6], T helper type 1 and type 2 cytokines [interferon-, (IFN-,), IL-4, IL-10), antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD)], and genes critical for eicosanoid mediator production [cyclo-oxygenase-2 (COX-2), 5-lipoxygenase (5-LO)] by reverse transcription-polymerase chain reaction using rat-specific primers. Results:, Rats on the ,-3 FA diet exhibited decreased proinflammatory cytokine gene expression (IL-1,, TNF-,) and enhanced IFN-,, CAT and SOD messenger RNA expression compared to rats fed a corn oil diet, supporting a diet-induced modulation of host inflammatory reactions. Analyses of alveolar bone resorption in the rats related to gene expression profiles demonstrated significant positive correlations with IL-1,, IL-6 and COX-2 and negative correlations with CAT and SOD. Conclusion:, These findings suggest that diets enriched for ,-3 FA modulate the local gingival inflammatory milieu of the host following oral P. gingivalis infection, which impacts on alveolar bone resorption in rats. [source] Cytokine pattern determines the progression of experimental periodontal disease induced by Actinobacillus actinomycetemcomitans through the modulation of MMPs, RANKL, and their physiological inhibitorsMOLECULAR ORAL MICROBIOLOGY, Issue 1 2006G. P. Garlet Objective:, Inflammatory and immune reactions raised in response to periodontopathogens are thought to trigger periodontal tissue destruction. We therefore investigated the expression of matrix metalloproteinases (MMPs) and the osteoclastogenic factor RANKL (receptor activator of nuclear factor-,B ligand), their respective inhibitors TIMPs (tissue inhibitors of metalloproteinases) and OPG (osteoprotegerin) and their possible correlation with the expression of inflammatory and regulatory cytokines in the course of experimental periodontal disease in mice. Methods:, We characterized the time course of leukocyte migration and alveolar bone loss in C57BL/6 mice infected with Actinobacillus actinomycetemcomitans. Quantitative polymerase chain reaction (RealTime PCR) and ELISA were performed to determine the expression of MMPs, TIMPs, RANKL, OPG and cathepsin K, interleukin-1,, tumor necrosis factor-,, interferon-,, interleukin-12, interleukin-4 and interleukin-10 in periodontal tissue samples harvested throughout the course of experimental disease. Results:, Oral inoculation of A. actinomycetemcomitans results in an intense and widespread migration of leukocytes to the gingival tissues, besides marked alveolar bone resorption. Our data also demonstrate two distinct patterns of MMP/TIMP and RANKL/OPG expression in the course of experimental periodontal disease. The expression of MMPs (MMP-1, 2 and 9) and RANKL was correlated with the expression of interleukin-1,, tumor necrosis factor-, and interferon-,, in a time period characterized by the intense increase of inflammatory reaction and alveolar bone loss. On the other hand, interleukin-4 and interleukin-10 were associated with higher expression of TIMPs (TIMP 1, 2 and 3) and OPG, with a lower expression of MMPs and RANKL, and with reduced rates of increase of cellular infiltration in periodontal tissues and alveolar bone loss. Conclusions:, It is possible that the pattern of cytokines produced in periodontal tissues determines the progression and the severity of experimental periodontal disease, controlling the breakdown of soft and bone tissues through the balance between MMPs/TIMP and RANKL/OPG expression in gingival tissues. [source] Effects of a herbal gel containing carvacrol and chalcones on alveolar bone resorption in rats on experimental periodontitisPHYTOTHERAPY RESEARCH, Issue 4 2008Marco Antonio Botelho Abstract Carvacrol and dimeric chalcones are the respective bioactive components of Lippia sidoides and Myracrodruon urundeuva, popular medicinal plants of Northeastern Brazil with proven antimicrobial and antiinflammatory properties. Periodontal disease is associated with inflammation and microbiological proliferation, thus the study aimed to investigate the effect of a topical gel based on carvacrol and chalcones in the experimental periodontal disease (EPD) in rats. Animals were treated with carvacrol and/or chalcones gel, immediately after EPD induction, three times a day for 11 days. Appropriate controls were included in the study. Animals were weighed daily. They were killed on day 11, the mandibles dissected and alveolar bone loss was measured. The periodontium were examined at histopathology and the neutrophil influx into the gingiva was assayed using myeloperoxidase activity. The bacterial flora were assessed through culture of the gingival tissue. Alveolar bone loss was significantly (p < 0.05) inhibited by combined carvacrol and chalcones gel, compared with the vehicle and non-treated groups. The treatment with the combined gel reduced tissue lesion at histopathology, decreased myeloperoxidase activity in gingival tissue and inhibited the growth of oral microorganisms as well as the weight loss. Carvacrol and chalcones combination gel has a beneficial effect upon EPD in this model. Copyright © 2008 John Wiley & Sons, Ltd. 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