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PubMed | University of Aalborg, Utrecht Institute of Pharmaceutical science, Maastricht University and University of Southern Denmark
Type: Journal Article | Journal: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA | Year: 2016

In the present study, we used national health care databases to estimate fracture incidence rates (IRs) and compared these IRs based on imputed data. We showed that imputation could lead to both over- and underestimation of IRs, and future research should therefore focus on how to improve those imputations.Osteoporosis is a major public health burden through associated (osteoporotic) fractures. In Denmark, the incidence rates (IRs) of hip fracture are widely available. However, there is limited data about other fracture sites. A recent report could only provide imputed IRs, although nationwide data is readily available in electronic healthcare databases. Therefore, our aim was to estimate fracture site-specific IRs for Denmark in 2011 and to compare those to the previously reported imputed data.Data from the Danish National Hospital Discharge Register was used to estimate age- and gender-specific IRs for any fracture as well as for different fracture sites in the Danish population aged 20years and older in 2011. Hip fracture IRs were stratified to sub-sites, and IRs were determined for all hip fractures which were confirmed by surgery.The total number of incident fractures in 2011 was 80,760 (IR 191, 95% confidence interval (CI) 190-192 (per 10,000 person-years)), of which 35,398 (43.8%, IR 171, 95% CI 169-173) occurred in men and 45,362 (56.2%, IR 211, 95% CI 209-213) in women. The majority of the fractures occurred in the population aged 50years and older (n=50,470, IR 249, 95% CI 247-251). The numbers of any hip fracture were lower than the previously imputed estimates, whereas the number of forearm fractures was higher.We showed age- and gender-specific fracture rates for any fracture as well as for different fracture sites. The IRs of most fracture sites increased with age. Estimating the number of fractures for Denmark based on imputation of data from other countries led to both over- and underestimation. Future research should therefore focus on how to improve those imputations as not all countries have nationwide registry data.

PubMed | University of Southampton, Utrecht Institute of Pharmaceutical science, University of Aalborg and Maastricht University
Type: | Journal: British journal of clinical pharmacology | Year: 2016

The aim of the present study was to estimate the effect of incretins on fracture risk in the real-world situation by meta-analysis of the available population-based cohort data. Pubmed and Embase were searched for original articles investigating use of incretin agents, and fracture risk up to December 2015. Adjusted results were extracted and pooled by use of generic inverse variance methods, assuming a random-effects model. Neither current dipeptidyl peptidase 4-inhibitor use nor current glucagon-like peptide 1 receptor agonist use was associated with a decreased risk of fracture: pooled relative risk (pooled RR [95% confidence interval]: 1.02 [0.91-1.13] and 1.03 [0.87-1.22]), respectively. This meta-analysis demonstrated that current use of incretin agents, was not associated with decreased fracture risk. Our findings show the value of representative real-world populations, and the risks associated with suggesting benefits for medications on the basis of safety reporting in randomized controlled trials.

PubMed | St Antonius Hospital, Utrecht Institute of Pharmaceutical science, University of Southampton, Maastricht University and Viecuri MC Venlo
Type: Journal Article | Journal: Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA | Year: 2016

In this retrospective cohort study using the Clinical Practice Research Datalink (CPRD), patients with sarcoidosis have an increased risk of clinical vertebral fractures and when on recent treatment with oral glucocorticoids, also an increased risk of any fractures and osteoporotic fractures.Sarcoidosis is a chronic inflammatory disease, in which fragility fractures have been reported despite normal BMD. The aim of this study was to assess whether patients with sarcoidosis have an increased risk of clinical fractures compared to the general population.A retrospective cohort study was conducted using the CPRD. All patients with a CPRD code for sarcoidosis between January 1987 and September 2012 were included. Cox proportional hazards models were used to derive adjusted relative risks (RRs) of fractures in all sarcoidosis patients compared to matched controls, and within the sarcoidosis group according to use and dose of systemic glucocorticoids.Five thousand seven hundred twenty-two sarcoidosis patients (mean age 48.0years, 51% females, mean follow-up 6.7years) were identified. Compared to 28,704 matched controls, the risk of any fracture was not different in patients with sarcoidosis. However, the risk of clinical vertebral fractures was significantly increased (adj RR 1.77; 95% CI 1.06-2.96) and the risk of non-vertebral fractures was decreased although marginally significant (adj RR 0.87; 95% CI 0.77-0.99). Compared to sarcoidosis patients not taking glucocorticoids, recent use of systemic glucocorticoids was associated with an increased risk of any fracture (adj RR 1.50; 95% CI 1.20-1.89) and of an osteoporotic fracture (adj RR 1.47; 95% CI 1.07-2.02).Patients with sarcoidosis have an increased risk of clinical vertebral fractures, and when using glucocorticoid therapy, an increased risk of any fractures and osteoporotic fractures. In contrast, the risk of non-vertebral fractures maybe decreased. Further investigation is needed to understand the underlying mechanisms of these contrasting effects on fracture risk.

PubMed | Utrecht Institute of Pharmaceutical science, Viecuri Medical Center and Maastricht University
Type: | Journal: Diabetes, obesity & metabolism | Year: 2016

To investigate the association between long-term dipeptidyl peptidase-4 (DPP-4) inhibitor use and risk of fracture among people with type 2 diabetes mellitus (T2DM).A retrospective population-based cohort study, using data from the Clinical Practice Research Datalink database (2007-2015), was conducted. All those (N=328254) with at least one prescription for a non-insulin antidiabetic drug (NIAD), aged 18years at the time of data collection, were included. Cox proportional hazards models were used to estimate the hazard ratios of any fracture, osteoporotic fracture and hip fracture in DPP-4 inhibitor users compared with those using other NIADs. Analyses were stratified by continuous duration of DPP-4 inhibitor use. Time-dependent adjustments were made for age, sex, lifestyle, comorbidity and concomitant drug use.Current use of DPP-4 inhibitors was not associated with risk of any fracture (adjusted hazard ratio [HR] 0.99 [95% confidence interval {CI} 0.93-1.06]) as compared with current other NIAD use. Current use of DPP-4 inhibitors was also not associated with risk of osteoporotic or hip fracture. After stratification by continuous duration of DPP-4 inhibitor use the highest category was not associated with any (>4.0-8.5years of use, adjusted HR 0.99 [95% CI 0.70-1.41]), osteoporotic (>3.0-8.5years of use, adjusted HR 0.75 [95% CI 0.52-1.09]) or hip (>2.0-8.5years of use; adjusted HR 1.24 [95% CI 0.85-1.79]) fracture.Continuous long-term DPP-4 inhibitor use (defined as >4.0-8.5years of DPP-4 inhibitor use for any fracture, >3.0-8.5years for osteoporotic fracture and >2.0-8.5years for hip fracture was not associated with risk of any, osteoporotic or hip fracture. These findings may be of value for clinical decisions regarding treatment of patients with T2DM, especially those at high risk of fracture.

PubMed | Utrecht Institute of Pharmaceutical science and Maastricht University
Type: Journal Article | Journal: Alimentary pharmacology & therapeutics | Year: 2016

Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms remain unclear.To study the association between exposure to these drugs and MC, with attention to time of exposure, duration, dosage and combined exposure, and to test hypotheses on underlying pharmacological mechanisms.A case-control study was conducted using the British Clinical Practice Research Datalink. MC cases (1992-2013) were matched to MC-naive controls on age, sex and GP practice. Drug exposure was stratified according to time of exposure, duration of exposure or dosage. Conditional logistic regression analysis was applied to calculate adjusted odds ratios (AORs).In total, 1211 cases with MC were matched to 6041 controls. Mean age was 63.4 years, with 73.2% being female. Current use of NSAIDs (AOR 1.86, 95% CI 1.39-2.49), PPIs (AOR 3.37, 95% CI 2.77-4.09) or SSRIs (AOR 2.03, 95% CI 1.58-2.61) was associated with MC compared to never or past use. Continuous use for 4-12 months further increased the risk of MC. Strongest associations (fivefold increased risk) were observed for concomitant use of PPIs and NSAIDs. Statins were not associated with MC.Current exposure to NSAIDs, PPIs or SSRIs and prolonged use for 4-12 months increased the risk of MC. Concomitant use of NSAIDs and PPIs showed the highest risk of MC. Acid suppression related dysbiosis may contribute to the PPI effect, which may be exacerbated by NSAID-related side-effects.

PubMed | University Utrecht, University Hospital Frankfurt, University of Würzburg and Utrecht Institute of Pharmaceutical science
Type: Journal Article | Journal: Genes, brain, and behavior | Year: 2016

We recently showed that a genetic polymorphism (rs878886) in the human corticotropin-releasing hormone receptor 1 (CRHR1) is associated with reduced fear-conditioned responses to a threat cue. This is a potentially important finding considering that the failure to acquire fear contingencies can leave an individual in a maladaptive state of more generalized anxiety. Consistent with that idea, the CRHR1-dependent fear acquisition deficit translated into heightened contextual anxiety when taking genetic variability within the serotonin transporter long polymorphic region (5-HTTLPR) into account. To replicate our previous findings, we conducted a replication study in 224 healthy medication-free human subjects using the exact same cue and context virtual reality fear-conditioning procedure as in study by Heitland et al. (2013). In the replication study, consistent with the original findings, CRHR1 rs878886 G-allele carriers showed reduced acquisition of cue-specific fear-conditioned responses compared with C/C homozygotes. Also, in this larger sample the cue acquisition deficit of G-allele carriers translated into heightened contextual anxiety, even independent of 5-HTT gene variation. In contrast to our earlier findings, there was an additional interaction effect of CRHR1 rs878886 and the triallelic 5-HTTLPR/rs25531 variant on cued fear acquisition. In summary, this study replicated the initially reported association of the CRHR1 rs878886 G-allele with cued fear acquisition deficits, albeit with a different pattern of results regarding the interaction with 5-HTT variation. This further supports the notion that the human corticotropin-releasing hormone plays a role in the acquisition of fears.

Siewe B.,Rush University Medical Center | Wallace J.,Rush University Medical Center | Rygielski S.,Rush University Medical Center | Stapleton J.T.,University of Iowa | And 4 more authors.
PLoS ONE | Year: 2014

During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4+ and CD8+ T cells. We have shown that in vitro, IL-10hiPD-L1hi regulatory B cells (Bregs) directly attenuate HIV-specific CD8+-mediated CTL activity. Bregs also modulate APC and CD4+ T cell function; herein we characterize the Breg compartment in uninfected (HIVNEG), HIV-infected ''elite controllers'' (HIVEC), ART-treated (HIVART), and viremic (HIVvir), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIVEC and HIVART subjects exhibit comparable IL-10 expression levels significantly higher than HIVNEG subjects, but significantly lower than HIVVIR subjects. Bregs from HIVEC and HIVART subjects exhibit comparable PD-L1 expression, significantly higher than in HIVVIR and HIVNEG subjects. SAHA-treated Breg-depleted PBMC from HIVEC and HIVART subjects, displayed enhanced CD4+ T-cell proliferation, significant upregulation of antigenpresentation molecules, increased frequency of CD107a+ and HIV-specific CD8+ T cells, associated with efficient elimination of infected CD4+ T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4+ T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4+ T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication. © 2014 Siewe et al.

Bereszczak J.Z.,Utrecht Institute of Pharmaceutical science | Bereszczak J.Z.,Netherlands Proteomics Center | Watts N.R.,U.S. National Institutes of Health | Wingfield P.T.,U.S. National Institutes of Health | And 3 more authors.
Protein Science | Year: 2014

Hepatitis B virus core-antigen (capsid protein) and e-antigen (an immune regulator) have almost complete sequence identity, yet the dimeric proteins (termed Cp149d and Cp(210)149d, respectively) adopt quite distinct quaternary structures. Here we use hydrogen deuterium exchange-mass spectrometry (HDX-MS) to study their structural properties. We detect many regions that differ substantially in their HDX dynamics. Significantly, whilst all regions in Cp(210)149d exchange by EX2-type kinetics, a number of regions in Cp149d were shown to exhibit a mixture of EX2- and EX1-type kinetics, hinting at conformational heterogeneity in these regions. Comparison of the HDX of the free Cp149d with that in assembled capsids (Cp149c) indicated increased resistance to exchange at the C-terminus where the inter-dimer contacts occur. Furthermore, evidence of mixed exchange kinetics were not observed in Cp149c, implying a reduction in flexibility upon capsid formation. Cp(210)149d undergoes a drastic structural change when the intermolecular disulphide bridge is reduced, adopting a Cp149d-like structure, as evidenced by the detected HDX dynamics being more consistent with Cp149d in many, albeit not all, regions. These results demonstrate the highly dynamic nature of these similar proteins. To probe the effect of these structural differences on the resulting antigenicity, we investigated binding of the antibody fragment (Fab E1) that is known to bind a conformational epitope on the four-helix bundle. Whilst Fab E1 binds to Cp149c and Cp149d, it does not bind non-reduced and reduced Cp(210)149d, despite unhindered access to the epitope. These results imply a remarkable sensitivity of this epitope to its structural context. © 2014 The Protein Society.

Dienava-Verdoold I.,Sanquin Research | Boon-Spijker M.G.,Sanquin Research | De Groot P.G.,University Utrecht | Brinkman H.J.M.,Sanquin Research | And 6 more authors.
Journal of Thrombosis and Haemostasis | Year: 2011

Background:Patients with antiphospholipid syndrome (APS) display a heterogeneous population of antibodies with beta2 glycoprotein-1 (β2GP1) as the major antigen. Objectives:We isolated and characterized human mAbs directed against β2GP1 from the immune repertoire of APS patients. Methods:Variable heavy chain repertoires from B cells from two APS patients with anti-β2GP1 antibodies were cloned into the pHEN1-VLrep vector. Constructed full-length IgG antibodies were tested for lupus anticoagulant (LAC) activity and binding to β2GP1 and its domains. Results:Two clones of each patient were selected on the basis of the reactivity of single chain Fv (scFv) fragments displayed on phages towards full-length β2GP1 and its isolated domain I. The affinity of selected antibodies for β2GP1 was lost when transforming from phages to monovalent scFvs, and was regained when antibodies were constructed as complete IgG, indicating a role for bivalency in binding to β2GP1. Both selected clones from patient 2 recognized domain I of β2GP1, and for both clones selected from patient 1, binding required the presence of both domain I and domain II. All mAbs displayed LAC activity in both activated partial thromboplastin time-based and dilute Russell's viper venom test-based clotting assays and in thrombin generation. Conclusions:In this study, we show successful cloning of patient-derived mAbs that require domain I of β2GP1 for binding, and that display LAC activity that is dependent on their affinity for β2GP1. These antibodies can help us to gain more insights into the pathogenesis of APS, and may facilitate standardization of APS diagnosis. © 2011 International Society on Thrombosis and Haemostasis.

Mulder G.E.,Utrecht Institute of Pharmaceutical science | Quarles Van Ufford H.C.,Utrecht Institute of Pharmaceutical science | Van Ameijde J.,Utrecht Institute of Pharmaceutical science | Brouwer A.J.,Utrecht Institute of Pharmaceutical science | And 2 more authors.
Organic and Biomolecular Chemistry | Year: 2013

A diversity of protein surface discontinuous epitope mimics is now rapidly and efficiently accessible. Despite the important role of protein-protein interactions involving discontinuous epitopes in a wide range of diseases, mimicry of discontinuous epitopes using peptide-based molecules remains a major challenge. Using copper(i) catalyzed azide-alkyne cycloaddition (CuAAC), we have developed a general and efficient method for the synthesis of collections of discontinuous epitope mimics. Up to three different cyclic peptides, representing discontinuous epitopes in HIV-gp120, were conjugated to a selection of scaffold molecules. Variation of the scaffold molecule, optimization of the ring size of the cyclic peptides and screening of the resulting libraries for successful protein mimics led to an HIV gp120 mimic with an IC50 value of 1.7 μM. The approach described here provides rapid and highly reproducible access to clean, smart libraries of very complex bio-molecular constructs representing protein mimics for use as synthetic vaccines and beyond. © 2013 The Royal Society of Chemistry.

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