Sclerostin does not play a major role in the pathogenesis of skeletal complications in type 2 diabetes mellitus

In contrast to previously reported elevations in serum sclerostin levels in diabetic patients, the present study shows that the impaired bone microarchitecture and cellular turnover associated with type 2 diabetes mellitus (T2DM)-like conditions in ZDF rats are not correlated with changes in serum and bone sclerostin expression. INTRODUCTION: T2DM is associated with impaired skeletal structure and a higher prevalence of bone fractures. Sclerostin, a negative regulator of bone formation, is elevated in serum of diabetic patients. We aimed to relate changes in bone architecture and cellular activities to sclerostin production in the Zucker diabetic fatty (ZDF) rat. METHODS: Bone density and architecture were measured by micro-CT and bone remodelling by histomorphometry in tibiae and femurs of 14-week-old male ZDF rats and lean Zucker controls (n = 6/group). RESULTS: ZDF rats showed lower trabecular bone mineral density and bone mass compared to controls, due to decreases in bone volume and thickness, along with impaired bone connectivity and cortical bone geometry. Bone remodelling was impaired in diabetic rats, demonstrated by decreased bone formation rate and increased percentage of tartrate-resistant acid phosphatase-positive osteoclastic surfaces. Serum sclerostin levels (ELISA) were higher in ZDF compared to lean rats at 9 weeks (+40 %, p < 0.01), but this difference disappeared as their glucose control deteriorated and by week 14, ZDF rats had lower sclerostin levels than control rats (-44 %, p < 0.0001). Bone sclerostin mRNA (qPCR) and protein (immunohistochemistry) were similar in ZDF, and lean rats at 14 weeks and genotype did not affect the number of empty osteocytic lacunae in cortical and trabecular bone. CONCLUSION: T2DM results in impaired skeletal architecture through altered remodelling pathways, but despite altered serum levels, it does not appear that sclerostin contributes to the deleterious effect of T2DM in rat bone

Parallel plate model for trabecular bone exhibits volume fraction-dependent bias

Unbiased stereological methods were used in conjunction with microcomputed tomographic (micro-CT) scans of human and animal bone to investigate errors created when the parallel plate model was used to calculate morphometric parameters. Bone samples were obtained from the human proximal tibia, canine distal femur, rat tail, and pig spine and scanned in a micro-CT scanner. Trabecular thickness, trabecular spacing, and trabecular number were calculated using the parallel plate model. Direct thickness, and spacing and connectivity density were calculated using unbiased three-dimensional methods. Both thickness and spacing calculated using the plate model were well correlated to the direct three-dimensional measures (r(2) = 0. 77-0.92). The correlation between trabecular number and connectivity density varied greatly (r(2) = 0.41-0.94). Whereas trabecular thickness was consistently underestimated using the plate model, trabecular spacing was underestimated at low volume fractions and overestimated at high volume fractions. Use of the plate model resulted in a volume-dependent bias in measures of thickness and spacing (p < 0.001). This was a result of the fact that samples of low volume fraction were much more "rod-like" than those of the higher volume fraction. Our findings indicate that the plate model provides biased results, especially when populations with different volume fractions are compared. Therefore, we recommend direct thickness measures when three-dimensional data sets are available

Current concepts in osteogenesis imperfecta:bone structure, biomechanics and medical management

The majority of patients with osteogenesis imperfecta (OI) have mutations in the COL1A1 or COL1A2 gene, which has consequences for the composition of the bone matrix and bone architecture. The mutations result in overmodified collagen molecules, thinner collagen fibres and hypermineralization of bone tissue at a bone matrix level. Trabecular bone in OI is characterized by a lower trabecular number and connectivity as well as a lower trabecular thickness and volumetric bone mass. Cortical bone shows a decreased cortical thickness with less mechanical anisotropy and an increased pore percentage as a result of increased osteocyte lacunae and vascular porosity. Most OI patients have mutations at different locations in the COL1 gene. Disease severity in OI is probably partly determined by the nature of the primary collagen defect and its location with respect to the C-terminus of the collagen protein. The overall bone biomechanics result in a relatively weak and brittle structure. Since this is a result of all of the above-mentioned factors as well as their interactions, there is - considerable variation between patients, and accurate prediction on bone strength in the individual patient with OI is difficult. Current treatment of OI focuses on adequate vitamin-D levels and interventions in the bone turnover cycle with bisphosphonates. Bisphosphonates increase bone mineral density, but the evidence on improvement of clinical status remains limited. Effects of newer drugs such as antibodies against RANKL and sclerostin are currently under investigation. This paper was written under the guidance of the Study Group Genetics and Metabolic Diseases of the European Paediatric Orthopaedic Society

Identification of CD8+ T Cell Epitopes in the West Nile Virus Polyprotein by Reverse-Immunology Using NetCTL

West Nile virus (WNV) is a growing threat to public health and a greater understanding of the immune response raised against WNV is important for the development of prophylactic and therapeutic strategies.In a reverse-immunology approach, we used bioinformatics methods to predict WNV-specific CD8(+) T cell epitopes and selected a set of peptides that constitutes maximum coverage of 20 fully-sequenced WNV strains. We then tested these putative epitopes for cellular reactivity in a cohort of WNV-infected patients. We identified 26 new CD8(+) T cell epitopes, which we propose are restricted by 11 different HLA class I alleles. Aiming for optimal coverage of human populations, we suggest that 11 of these new WNV epitopes would be sufficient to cover from 48% to 93% of ethnic populations in various areas of the World.The 26 identified CD8(+) T cell epitopes contribute to our knowledge of the immune response against WNV infection and greatly extend the list of known WNV CD8(+) T cell epitopes. A polytope incorporating these and other epitopes could possibly serve as the basis for a WNV vaccine

Reduced Inflammatory Threshold Indicates Skin Barrier Defect in Transglutaminase 3 Knockout Mice

Recently a transglutaminase 3 knockout (TGM3/KO) mouse was generated that showed impaired hair development, but no gross defects in the epidermal barrier, although increased fragility of isolated corneocytes was demonstrated. Here we investigated the functionality of skin barrier in vivo by percutaneous sensitization to fluorescein-isothiocyanate (FITC) in TGM3/KO (n=64) and C57BL/6 WT mice (n=36). Cutaneous inflammation was evaluated by mouse ear swelling test (MEST), histology, serum IgE levels, and by flow-cytometry from draining lymph nodes. Inflammation induced significant MEST difference (P<0.0001) was detected between KO and WT mice and was supported also by histopathology. A significant increase of CD4+ CD25+ activated T-cells (P<0.01) and elevated serum IgE levels (P<0.05) in KO mice indicated more the development of FITC sensibilization than an irritative reaction. P. acnes induced intracutaneous inflammation showed no difference (P=0.2254) between the reactivity of WT and KO immune system. As in vivo tracer, FITC penetration from skin surface followed by two-photon microscopy demonstrated a more invasive percutaneous penetration in KO mice. The clinically uninvolved skin in TGM3/KO mice showed impaired barrier function and higher susceptibility to FITC sensitization indicating that TGM3 has a significant contribution to the functionally intact cutaneous barrier.Journal of Investigative Dermatology accepted article preview online, 24 July 2013. doi:10.1038/jid.2013.307

Chain of care for patients who have attempted suicide: a follow-up study from Bærum, Norway

<p>Abstract</p> <p>Background</p> <p>Individuals who have attempted suicide are at increased risk of subsequent suicidal behavior. Since 1983, a community-based suicide prevention team has been operating in the municipality of Bærum, Norway. This study aimed to test the effectiveness of the team's interventions in preventing repeated suicide attempts and suicide deaths, as part of a chain of care model for all general hospital treated suicide attempters.</p> <p>Methods</p> <p>Data has been collected consecutively since 1984 and a follow-up was conducted on all individuals admitted to the general hospital after a suicide attempt. The risk of repeated suicide attempt and suicide were comparatively examined in subjects who received assistance from the suicide prevention team in addition to treatment as usual versus those who received treatment as usual only. Logistic regression and Cox regression were used to analyze the data.</p> <p>Results</p> <p>Between January 1984 and December 2007, 1,616 subjects were registered as having attempted suicide; 197 of them (12%) made another attempt within 12 months. Compared to subjects who did not receive assistance from the suicide prevention team, individuals involved in the prevention program did not have a significantly different risk of repeated attempt within 6 months (adjusted <it>OR </it>= 1.08; 95% CI = 0.66-1.74), 12 months (adjusted <it>OR </it>= 0.86; 95% CI = 0.57-1.30), or 5 years (adjusted <it>RR </it>= 0.90; 95% CI = 0.67-1.22) after their first recorded attempt. There was also no difference in risk of suicide (adjusted <it>RR </it>= 0.85; 95% CI = 0.46-1.57). Previous suicide attempts, marital status, and employment status were significantly associated with a repeated suicide attempt within 6 and 12 months (p < 0.05). Alcohol misuse, employment status, and previous suicide attempts were significantly associated with a repeated attempt within 5 years (p < 0.05) while marital status became non-significant (p > 0.05). With each year of age, the risk of suicide increased by 3% (p < 0.05).</p> <p>Conclusions</p> <p>The present study did not find any differences in the risk of fatal and non-fatal suicidal behavior between subjects who received treatment as usual combined with community assistance versus subjects who received only treatment as usual. However, assistance from the community team was mainly offered to attempters who were not receiving sufficient support from treatment as usual and was accepted by 50-60% of those deemed eligible. Thus, obtaining similar outcomes for individuals, all of whom were clinically judged to have different needs, could in itself be considered a desirable result.</p

Rapid response of Helheim Glacier in Greenland to climate variability over the past century

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Geoscience 5 (2012): 37-41, doi:10.1038/ngeo1349.During the early 2000s the Greenland Ice Sheet experienced the largest ice mass loss observed on the instrumental record1, largely as a result of the acceleration, thinning and retreat of major outlet glaciers in West and Southeast Greenland2-5. The quasi-simultaneous change in the glaciers suggests a common climate forcing and increasing air6 and ocean7-8 temperatures have been indicated as potential triggers. Here, we present a new record of calving activity of Helheim Glacier, East Greenland, extending back to c. 1890 AD. This record was obtained by analysing sedimentary deposits from Sermilik Fjord, where Helheim Glacier terminates, and uses the annual deposition of sand grains as a proxy for iceberg discharge. The 120 year long record reveals large fluctuations in calving rates, but that the present high rate was reproduced only in the 1930s. A comparison with climate indices indicates that high calving activity coincides with increased Atlantic Water and decreased Polar Water influence on the shelf, warm summers and a negative phase of the North Atlantic Oscillation. Our analysis provides evidence that Helheim Glacier responds to short-term (3-10 years) large-scale oceanic and atmospheric fluctuations.This study has been supported by Geocenter Denmark in financial support to the SEDIMICE project. CSA was supported by the Danish Council for Independent Research│Nature and Universe (Grant no. 09-064954/FNU). FSt was supported by NSF ARC 0909373 and by WHOI’s Ocean and Climate Change Institute and MHRI was supported by the Danish Agency for Science, Technology and Innovation.2012-06-1

Role of Secreted Conjunctival Mucosal Cytokine and Chemokine Proteins in Different Stages of Trachomatous Disease

Trachoma, a disease of antiquity dating back to the 16th century B.C.E., predominates among developing countries, where it remains the primary cause of preventable blindness worldwide. In trachoma, recurrent Chlamydia trachomatis bacterial infections during childhood are thought to result in inflammation and subsequent conjunctival scarring that can progress to trichiasis (TT; chronic trachoma; inversion of ≥1 eyelash that touches the globe of the eye). The trachomatous follicular grade (TF; active disease) is a self-limiting disease, suggesting the coexistence of protective inflammatory proteins. The trachomatous inflammatory grade (TI; active disease) is more likely to progress to trachomatous scarring (TS; chronic trachoma). To date, there are only a handful of studies that have examined the immune response in trachoma, and these were primarily based on gene expression. Characterizing quantified conjunctival mucosal immune differences for secreted proteins among individuals with no, active, and chronic trachoma may identify protein biomarkers associated with protection versus disease, which would greatly aid our understanding of the immunopathogenesis of trachoma. In this study, we characterized 25 cytokine and chemokine proteins for all trachoma grades. We identified eight cytokines and chemokines as risk factors for chronic trachoma and four as protective. Together, these findings further characterize the immunopathologic responses involved during trachoma, which will likely aid in the design of a vaccine and immunomodulating therapeutics for trachoma