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ID PMID Title PublicationDate abstract
22130109 Independent estimation of the frequency of rare CNVs in the UK population confirms their r 2012 Mar BACKGROUND: Several large, rare chromosomal copy number variants (CNVs) have recently been shown to increase risk for schizophrenia and other neuropsychiatric disorders including autism, ADHD, learning difficulties and epilepsy. AIMS: We wanted to examine the frequencies of these schizophrenia-associated variants in a large sample of individuals with non-psychiatric illnesses to better understand the robustness and specificity of the association with schizophrenia. METHODS: We used Affymetrix 500K microarray data from 10,259 individuals from the UK Wellcome Trust Case Control Consortium (WTCCC) who are affected with six non-psychiatric disorders (coronary artery disease, Crohn's disease, hypertension, rheumatoid arthritis, types 1 and 2 diabetes) to establish the frequencies of nine CNV loci strongly implicated in schizophrenia, and compared them with the previous findings. RESULTS: Deletions at 1q21.1, 3q29, 15q11.2, 15q13.1 and 22q11.2 (VCFS region), and duplications at 16p11.2 were found significantly more often in schizophrenia cases, compared with the WTCCC reference set. Deletions at 17p12 and 17q12, were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples. The frequencies of CNVs in the WTCCC non-psychiatric controls at three of the loci (15q11.2, 16p13.1 and 17p12) were significantly higher than those reported in previous control populations. CONCLUSIONS: The evidence for association with schizophrenia is compelling for six rare CNV loci, while the remaining three require further replication in large studies. Risk at these loci extends to other neurodevelopmental disorders but their involvement in common non-psychiatric disorders should also be investigated.
22127469 (99m)Tc-labeled rituximab for imaging B lymphocyte infiltration in inflammatory autoimmune 2012 Oct PURPOSE: The rationale of the present study was to radiolabel rituximab with 99m-technetium and to image B lymphocytes infiltration in the affected tissues of patients with chronic inflammatory autoimmune diseases, in particular, the candidates to be treated with unlabelled rituximab, in order to provide a rationale for 'evidence-based' therapy. PROCEDURES: Rituximab was labelled with (99m)Tc via 2-ME reduction method. In vitro quality controls of (99m)Tc-rituximab included stability assay, cysteine challenge, SDS-PAGE, immunoreactive fraction assay and competitive binding assay on CD20+ve Burkitt lymphoma-derived cells. For the human pilot study, 350-370 MBq (100 μg) of (99m)Tc-rituximab were injected in 20 patients with different chronic inflammatory autoimmune diseases. Whole body anteroposterior planar scintigraphic images were acquired 6 and 20 h p.i. RESULTS: Rituximab was labelled to a high labelling efficiency (>98%) and specific activity (3515-3700 MBq/mg) with retained biochemical integrity, stability and biological activity. Scintigraphy with (99m)Tc-rituximab in patients showed a rapid and persistent spleen uptake, and the kidney appeared to be a prominent source for the excretion of radioactivity. Inflamed joints showed a variable degree of uptake at 6 h p.i. in patients with rheumatoid arthritis indicating patient variability; similarly, the salivary and lacrimal glands showed variable uptake in patients with Sjögren's syndrome, Behçet's disease and sarcoidosis. Inflammatory disease with particular characteristics showed specific uptake in inflammatory lesions, such as, dermatopolymyositis patients showed moderate to high skin uptake, a sarcoidosis patient showed moderate lung uptake, a Behçet's disease patient showed high oral mucosa uptake and a polychondritis patient showed moderate uptake in neck cartilages. In one patient with systemic lupus erythematosus, we did not find any non-physiological uptake. CONCLUSION: Rituximab can be efficiently labelled with (99m)Tc with high labelling efficiency. The results suggest that this technique might be used to assess B lymphocyte infiltration in affected organs in patients with autoimmune diseases; this may provide a rationale for anti-CD20 therapies.
22105341 Evidence of vitamin D and interferon-β cross-talk in human osteoblasts with 1α,25-dihydr 2012 Sep It is well established that 1α-25-dihydroxyvitamin D3 (1,25D3) regulates osteoblast function and stimulates mineralization by human osteoblasts. The aim of this study was to identify processes underlying the 1,25D3 effects on mineralization. We started with gene expression profiling analyses of differentiating human pre-osteoblast treated with 1,25D3. Bioinformatic analyses showed interferon-related and -regulated genes (ISG) to be overrepresented in the set of 1,25D3-regulated genes. 1,25D3 down-regulated ISGs predominantly during the pre-mineralization period. This pointed to an interaction between the vitamin D and IFN signaling cascades in the regulation of osteoblast function. Separately, 1,25D3 enhances while IFNβ inhibits mineralization. Treatment of human osteoblasts with 1,25D3 and IFNβ showed that 1,25D3 completely overrules the IFNβ inhibition of mineralization. This was supported by analyses of extracellular matrix gene expression, showing a dominant effect of 1,25D3 over the inhibitory effect of IFNβ. We identified processes shared by IFNβ- and 1,25D3-mediated signaling by performing gene expression profiling during early osteoblast differentiation. Bioinformatic analyses revealed that genes being correlated or anti-correlated with interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) were associated with osteoblast proliferation. In conclusion, the current study demonstrates a cross talk between 1,25D3 and IFNβ in osteoblast differentiation and bone formation/mineralization. The interaction is complex and depends on the process but importantly, 1,25D3 stimulation of mineralization is dominant over the inhibitory effect of IFNβ. These observations are of potential clinical relevance considering the impact of the immune system on bone metabolism in conditions such as rheumatoid arthritis.
22075248 Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. 2012 Feb OBJECTIVE: Transsignaling of interleukin (IL)-6 is a central pathway in the pathogenesis of disorders associated with chronic inflammation, such as Crohn disease, rheumatoid arthritis, and inflammatory colon cancer. Notably, IL-6 also represents an independent risk factor for coronary artery disease (CAD) in humans and is crucially involved in vascular inflammatory processes. METHODS AND RESULTS: In the present study, we showed that treatment with a fusion protein of the natural IL-6 transsignaling inhibitor soluble glycoprotein 130 (sgp130) and IgG1-Fc (sgp130Fc) dramatically reduced atherosclerosis in hypercholesterolemic Ldlr(-/-) mice without affecting weight gain and serum lipid levels. Moreover, sgp130Fc treatment even led to a significant regression of advanced atherosclerosis. Mechanistically, endothelial activation and intimal smooth muscle cell infiltration were decreased in sgp130Fc-treated mice, resulting in a marked reduction of monocyte recruitment and subsequent atherosclerotic plaque progression. Of note, patients with CAD exhibited significantly lower plasma levels of endogenous sgp130, suggesting that a compromised counterbalancing of IL-6 transsignaling may contribute to atherogenesis in humans. CONCLUSIONS: These data clarify, for the first time, the critical involvement of, in particular, the transsignaling of IL-6 in CAD and warrant further investigation of sgp130Fc as a novel therapeutic for the treatment of CAD and related diseases.
21985999 Assessing 5-year incidence rates and determinants of osteoporotic fractures in primary car 2012 Jan PURPOSE: To assess the gender and age-related 5-year incidence rates of osteoporotic fractures, and their related predictors, in a primary care setting. METHODS: We obtained information from the Health Search-CSD Longitudinal Patients Database (HSD). This is an Italian General Practice data repository which comprises information given by computer-based patient records of a selected group of over 900 Primary Care Physicians (PCPs). We selected all patients aged 50 to 85 years, who were actively included into the PCP's list at the beginning of the enrolment period (1st January 2002-31st December 2003). We excluded individuals who were registered in the PCPs' list for less than 1 year before the entry date (Index date) into the cohort, as well as those who were diagnosed with Paget disease or malignant neoplasm. Participants were followed up until the occurrence of osteoporotic fracture, one of the exclusion criteria, or the end of the study period. RESULTS: The 5-year rates (per 1000 person-years) of any osteoporotic fracture were 11.56 (95% C.I. 11.33 to 11.77) among females, and 4.91 (95% C.I. 4.75 to 5.07) among males. For hip fractures, the overall incidence rates were 3.23 (95% C.I. 3.11 to 3.34) among females and 1.21 (95% C.I. 1.12 to 1.28) among males, respectively. Advanced age, history of fracture, use of corticosteroids, rheumatoid arthritis, BMI<=20, presence of osteoporosis, gastrointestinal and chronic hepatic disease, depression, chronic obstructive pulmonary disease, use of anticonvulsants and a higher number of co-medications, increased the risk of any osteoporotic fractures. CONCLUSIONS: The use of primary care data confirms a higher incidence of osteoporotic fractures among females vs. males as well as in older individuals. Predictors of osteoporotic fractures were consistent with FRAX® algorithm. Given the clinical utility of a simple score for the assessment of absolute fracture risk among osteoporotic patients, its assessment and validation in the Italian HSD could potentially provide an applicable prediction tool.
23149276 Resurfacing humeral prosthesis: do we really reconstruct the anatomy? 2013 May BACKGROUND: The goal of a resurfacing shoulder arthroplasty is to reproduce the individual's anatomy while preserving the bone stock of the humeral head. This study investigated the hypothesis that resurfacing the humeral prosthesis restores normal glenohumeral relationships and correlates with the final clinical results. MATERIALS AND METHODS: A resurfacing shoulder implant was performed in 61 patients (64 shoulders). Indications were primary osteoarthritis in 26, secondary osteoarthritis in 21, avascular necrosis in 4, rheumatoid arthritis in 4, dysplasia in 4, and for others indications in 5. RESULTS: At an average of 36 months (range, 24-65) of follow-up , the Constant score reached 68 points and the Quick-Disabilities of Arm, Shoulder and Hand score reached 28 points. Preoperative and postoperative radiographic analysis showed a decrease of the humeral head diameter (51 ± 5 vs 48 ± 5 mm) and of the height of the humeral head (21 ± 4 vs 19 ± 2 mm), without modification of the radius of curvature or the height of the center of rotation. The medial humeral offset increased from 3.3 ± 3.5 to 6.4 ± 3 mm and the lateral offset from 6.8 ± 9 to 10.4 ± 9 mm. The implant was mainly in varus postoperatively compared with preoperative values (122° ± 11° vs 134° ± 7°). Postoperative radiographic analysis and at the last follow-up did not show any significant difference, except for the increase of the depth of the glenoid from 4.2 ± 1.4 to 4.9 ± 1.8 mm. CONCLUSIONS: The resurfacing shoulder arthroplasty reproduces the normal anatomy and compensates glenohumeral wear. However, there was a tendency to position the prosthesis in varus because of technical imperfections. With follow-up, medialization of the humerus with glenoid wear was observed and was correlated in some patients with reappearance of pain.
23073294 CD226 Gly307Ser association with multiple autoimmune diseases: a meta-analysis. 2013 Feb BACKGROUND: Recently, there has been increasing evidence shown that a non-synonymous exchange (Gly307Ser/rs763361) of the CD226 gene on chromosome 18q22 is linked to several autoimmune diseases (ADs) including type 1 diabetes (T1D), celiac disease (CED), rheumatoid arthritis (RA), multiple sclerosis (MS), Grave's disease, Wegener's granulomatosis (WG), psoriasis, and primary sicca syndrome (pSS). Taking into consideration that different autoimmune diseases may share some common pathogenic pathways and in order to assess the overall relationship between CD226 Gly307Ser (rs763361) polymorphism and multiple autoimmune diseases, we performed this meta-analysis. METHOD: All eligible case-control studies were searched in the US National Library of Medicine's PubMed and Embase database. Crude odds ratios (OR) with 95% confidence intervals (CI) were conducted to assess the association. RESULTS: 7876 cases and 8558 controls from 7 published studies which were selected from 149 articles identified by a search of the US National Library of Medicine's PubMed and Embase databases for the period up to 25th April 2012. The total OR for ADs associated with the T allele was 1.19 (95%CI=1.12-1.27) by random effects model. Significantly increased risks were also observed in the South American (OR=1.72, 95%CI=1.34-2.20), Asian (OR=1.46, 95%CI=1.01-2.10), and European (OR=1.29, 95%CI=1.07-1.58). Similarly, significant associations were observed in two genetic models (OR=1.41, 95%CI=1.23-1.62 in a codominant model; OR=1.33, 95%CI=1.18-1.50 in a recessive model). CONCLUSION: This meta-analysis provided evidence that CD226 Gly307Ser (rs763361) is significantly associated with the risk of multiple autoimmune diseases.
23057802 Interleukin-7 receptor blockade suppresses adaptive and innate inflammatory responses in e 2012 Oct 12 BACKGROUND: Interleukin-7 (IL-7) acts primarily on T cells to promote their differentiation, survival, and homeostasis. Under disease conditions, IL-7 mediates inflammation through several mechanisms and cell types. In humans, IL-7 and its receptor (IL-7R) are increased in diseases characterized by inflammation such as atherosclerosis, rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel disease. In mice, overexpression of IL-7 results in chronic colitis, and T-cell adoptive transfer studies suggest that memory T cells expressing high amounts of IL-7R drive colitis and are maintained and expanded with IL-7. The studies presented here were undertaken to better understand the contribution of IL-7R in inflammatory bowel disease in which colitis was induced with a bacterial trigger rather than with adoptive transfer. METHODS: We examined the contribution of IL-7R on inflammation and disease development in two models of experimental colitis: Helicobacter bilis (Hb)-induced colitis in immune-sufficient Mdr1a-/- mice and in T- and B-cell-deficient Rag2-/- mice. We used pharmacological blockade of IL-7R to understand the mechanisms involved in IL-7R-mediated inflammatory bowel disease by analyzing immune cell profiles, circulating and colon proteins, and colon gene expression. RESULTS: Treatment of mice with an anti-IL-7R antibody was effective in reducing colitis in Hb-infected Mdr1a-/- mice by reducing T-cell numbers as well as T-cell function. Down regulation of the innate immune response was also detected in Hb-infected Mdr1a-/- mice treated with an anti-IL-7R antibody. In Rag2-/- mice where colitis was triggered by Hb-infection, treatment with an anti-IL-7R antibody controlled innate inflammatory responses by reducing macrophage and dendritic cell numbers and their activity. CONCLUSIONS: Results from our studies showed that inhibition of IL-7R successfully ameliorated inflammation and disease development in Hb-infected mice by controlling the expansion of multiple leukocyte populations, as well as the activity of these immune cells. Our findings demonstrate an important function of IL-7R-driven immunity in experimental colitis and indicate that the therapeutic efficacy of IL-7R blockade involves affecting both adaptive and innate immunity.
22885695 The effect of gene copy number and co-expression of chaperone on production of albumin fus 2012 Nov Interleukin-1 receptor antagonist (IL1ra) is known to treat a number of diseases such as rheumatoid arthritis and type 2 diabetes. However, the biological half-life of IL1ra is very short due to its rapid renal clearance. Our present study aimed to increase the biological half-life of IL1ra through fusion with human serum albumin (HSA), and then augmented expression of the IL1ra and HSA fusion protein (IH) in Pichia pastoris strain by increasing IH gene copy number or was co-expressed with chaperone. By comparing clones containing varying copy numbers of IH fusion gene, it was observed that higher levels of secretory IH fusion protein was produced in strain with higher IH gene copy number. In addition, IH protein yield was further improved after being co-expressed with protein disulfide isomerase (PDI). Conversely, it was significantly decreased (i.e., secretory IH in the culture medium) by co-expression of immunoglobulin binding protein. We have also discussed whether the multi-copy strain and co-expressed of PDI could enhance the levels of other secretory albumin fusion protein (e.g., HSA and human growth hormone fusion protein). Interestingly, the level of this fusion protein was apparently also increased by these approaches. In conclusion, our results have demonstrated that increasing copy number and co-expression of PDI may raise yield of albumin fusion protein in P. pastoris, which might probably contribute to the industry for the development of proteinous drugs.
22792242 Impact of health literacy in patients with chronic musculoskeletal disease--systematic rev 2012 OBJECTIVES: To estimate the prevalence of low health literacy, and evaluate the impact of low health literacy on outcomes in patients with chronic musculoskeletal conditions. DATA SOURCES: We searched Embase, Pubmed, PsycInfo, and CINAHL in January 2011 for relevant studies, restricted to English-language articles. STUDY SELECTION AND DATA EXTRACTION: Studies were included if they measured health literacy and/or reported on the link between outcomes and health literacy levels in patients with osteoporosis, osteoarthritis, or rheumatoid arthritis. We assessed risk of bias from participant selection, methods of measuring health literacy and functional outcomes, missing data, and potential for confounding. DATA SYNTHESIS: We reviewed 1863 citations and judged 8 studies to be relevant. Most were cross-sectional in nature, and five were based in the United States. Diversity in measurements, participant characteristics, and settings meant that results had to be synthesized narratively. Prevalence of low health literacy varied from 7% to 42%. Of the five studies that reported on musculoskeletal outcomes, only one showed an association (unadjusted) between low health literacy and greater pain and limitations in physical functioning. However, other studies, including those with multivariate analyses, found no significant relationship between health literacy and measures of pain or disease specific questionnaires. One clinical trial found short-term improvements in the mental health of patients with musculoskeletal conditions after an intervention to improve health literacy. LIMITATIONS: Most of the studies were cross-sectional in nature, which precludes interpretation of a causal relationship. The sample sizes may not have been sufficiently large to enable detection of significant associations. CONCLUSIONS: The current evidence does not show a consistent association between low health literacy and poorer functional outcomes in patients with chronic musculoskeletal conditions. In the absence of a definite link, efforts to develop interventions to improve health literacy would not necessarily improve health service or patient-related outcomes.
22650377 TNF α signaling beholds thalidomide saga: a review of mechanistic role of TNF-α signalin 2012 Tumor necrosis factor alpha (TNF-α) is a pleiotropic inflammatory cytokine. The cytokine possesses both growth stimulating properties and growth inhibitory processes, and it appears to have self regulatory properties as well. Agents like etanercept and infliximab showed beneficial effects against rheumatoid arthritis by modulationg TNF-α proteins, however, these agents are largely unable to penetrate the blood-brain barrier, which severely limits their use in different conditions. Thalidomide, an inhibitor of TNF-α protein synthesis is readily capable of crossing the blood-brain barrier and thus thalidomide and its analogs are excellent candidates for use in determining the potential value of anti-TNF-α therapies in a variety of diseases. Thalidomide blocks TNF-α expression by different possible mechanisms. Down regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), an essential transcription factor for TNF and other cytokines under thalidomide treatment leads to reduction in the TNF-α expression. Additionally, myeloid differentiation factor 88 (MyD88), an adapter protein regulates the expression of TNF under thalidomide treatment. Thalidomide treatment also leads to destruction of TNF-α mRNA thus, reducing the total expression of TNF-α protein. Thalidomide also targets reactive oxygen species (ROS) and α(1)-acid glycoprotein (AGP) to regulate TNF-α. In the present review, we discuss different possible mechanism that regulates TNF-α under thalidomide treatment. Additionally, we suggest novel strategies for the future targeting combination therapies of thalidomide and its analogs with different other anti-inflammatory drug to curb TNF-α associated diseases.
22479344 Structural insights from binding poses of CCR2 and CCR5 with clinically important antagoni 2012 Chemokine receptors are G protein-coupled receptors that contain seven transmembrane domains. In particular, CCR2 and CCR5 and their ligands have been implicated in the pathophysiology of a number of diseases, including rheumatoid arthritis and multiple sclerosis. Based on their roles in disease, they have been attractive targets for the pharmaceutical industry, and furthermore, targeting both CCR2 and CCR5 can be a useful strategy. Owing to the importance of these receptors, information regarding the binding site is of prime importance. Structural studies have been hampered due to the lack of X-ray crystal structures, and templates with close homologs for comparative modeling. Most of the previous models were based on the bovine rhodopsin and β2-adrenergic receptor. In this study, based on a closer homolog with higher resolution (CXCR4, PDB code: 3ODU 2.5 Å), we constructed three-dimensional models. The main aim of this study was to provide relevant information on binding sites of these receptors. Molecular dynamics simulation was done to refine the homology models and PROCHECK results indicated that the models were reasonable. Here, binding poses were checked with some established inhibitors of high pharmaceutical importance against the modeled receptors. Analysis of interaction modes gave an integrated interpretation with detailed structural information. The binding poses confirmed that the acidic residues Glu291 (CCR2) and Glu283 (CCR5) are important, and we also found some additional residues. Comparisons of binding sites of CCR2/CCR5 were done sequentially and also by docking a potent dual antagonist. Our results can be a starting point for further structure-based drug design.
22386473 Demographic and medical parameters in the development of complex regional pain syndrome ty 2012 Jun Limited data are available on the incidence of complex regional pain syndrome type 1 (CRPS1) and on demographic and medical risk factors for the development of CRPS1. The objective of this study was to investigate the incidence of CRPS1 in patients with a fracture using 3 sets of diagnostic criteria and to evaluate the association between demographic/medical factors and the development of CRPS1 diagnosed with the Harden and Bruehl criteria. A prospective multicenter cohort study of 596 patients (ages 18 years and older) with a single fracture of the wrist, scaphoid, ankle, or metatarsal V, recruited patients from the emergency rooms of 3 Dutch hospitals. Of the 596 participants, 42 (7.0%) were diagnosed with CRPS1 according to the Harden and Bruehl criteria, 289 (48.5%) according to the International Association for the Study of Pain criteria, and 127 (21.3%) according to the criteria of Veldman. An analysis of the medical and demographic differences revealed that patients in whom CRPS1 later developed more often had intra-articular fractures, fracture dislocations, rheumatoid arthritis, or musculoskeletal comorbidities. An ankle fracture, dislocation, and an intra-articular fracture contributed significantly to the prediction of the development of CRPS1. No CRPS1 patients were symptom free at 12 months (T3). At baseline, patients with CRPS1 had significantly more pain than patients without CRPS1 (P<.001). The incidence of the diagnosis of CRPS1 after a single fracture depends to a large extent on the diagnostic criteria used. After a fracture, 7% of the patients developed CRPS1 and none of the patients were free of symptoms at 1-year follow-up.
22294629 Prevalence and significance of previously undiagnosed rheumatic diseases in pregnancy. 2012 Jun OBJECTIVES: The objective of this study was to evaluate the rates of previously undiagnosed rheumatic diseases during the first trimester of pregnancy and their impact on the pregnancy outcome. METHODS: Pregnant women in their first trimester were screened using a two-step approach using a self-administered 10-item questionnaire and subsequent testing for rheumatic autoantibodies (antinuclear antibody, anti-double-stranded DNA, anti-extractable nuclear antigen, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies and lupus anticoagulant) and evaluation by a rheumatologist. Overall, the complications of pregnancy evaluated included fetal loss, pre-eclampsia, gestational diabetes, fetal growth restriction, delivery at less than 34 weeks, neonatal resuscitation and admission to the neonatal intensive care unit. RESULTS: Out of the 2458 women screened, the authors identified 62 (2.5%) women with previously undiagnosed undifferentiated connective tissue disease (UCTD) and 24 (0.98%) women with previously undiagnosed definite systemic rheumatic disease. The prevalences were seven (0.28%) for systemic lupus erythematosus and Sjogren's syndrome, six (0.24%) for rheumatoid arthritis, three (0.12%) for antiphospholipid syndrome and one (0.04%) for systemic sclerosis. In multiple exact logistic regression, after adjustment for potential confounders, the OR of overall complications of pregnancy were 2.81 (95% CI 1.29 to 6.18) in women with UCTD and 4.57 (95% CI 1.57 to 13.57) in those with definite diseases, respectively, compared with asymptomatic controls. CONCLUSIONS: In our population approximately 2.5% and 1% of first trimester pregnant women had a previously undiagnosed UCTD and definite systemic rheumatic disease, respectively. These conditions were associated with significant negative effects on the outcome of pregnancy.
22007982 Crossing the transition chasm: experiences and recommendations for improving transitional 2011 Nov BACKGROUND: Transition from paediatric to adult healthcare has received little attention in the Netherlands. This study aimed to: (i) map experiences with the transfer to adult care of young adults with chronic conditions; and (ii) identify recommendations for transitional care of young adults, their parents and healthcare providers. METHODS: Semi-structured interviews with 24 young adults after transfer (aged 15-22 years; diagnosed with haemophilia, diabetes mellitus, spina bifida, congenital heart disorders, cystic fibrosis, juvenile rheumatoid arthritis or sickle cell disease), 24 parents and 17 healthcare providers. Thematic analysis was performed. RESULTS: Only the haemophilia department offered a structured transition programme, most patients had not been prepared for transition. Experiences and views of patients, parents and professionals mainly overlapped and were condensed into four core themes. Two are related to moving to adult care: (1) 'leaving paediatric care is a logical step'. Leaving familiar surroundings was harder for parents than for young adults who displayed a positive 'wait-and-see' attitude; and (2) 'transition is complicated by cultural gaps between paediatric and adult services'. Young adults and parents felt lost after transfer and recommended their peers 'to be alert and involved'. Providers also recognized the cultural chasm between both services and worried about non-compliance, lost to follow-up and lack of independence. Two other themes indicated priorities for improvement: (3) 'better patient and parent preparation' for differences between healthcare settings and for new roles and responsibilities with respect to self-management; and (4) 'more collaboration and personal links' between paediatric and adult care providers. CONCLUSIONS: Action is required to cross the chasm between paediatric and adult-oriented care. Preparation for transition should start early and focus on strengthening adolescents' independency without undermining parental involvement. Building bridges between services, gaining trust and investing in new personal relations is a challenge for all parties involved: transition is about responding and bonding.
21953287 Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from r 2012 Jun IgG4-related disease (IgG4-RD) is a novel disease entity that includes Mikulicz's disease, autoimmune pancreatitis (AIP), and many other conditions. It is characterized by elevated serum IgG4 levels and abundant IgG4-bearing plasmacyte infiltration of involved organs. We postulated that high levels of serum IgG4 would comprise a useful diagnostic tool, but little information is available about IgG4 in conditions other than IgG4-RD, including rheumatic diseases. Several reports have described cutoff values for serum IgG4 when diagnosing IgG4-RD, but these studies mostly used 135 mg/dL in AIP to differentiate from pancreatic cancer instead of rheumatic and other common diseases. There is no evidence for a cutoff serum IgG4 level of 135 mg/dL for rheumatic diseases and common diseases that are often complicated with rheumatic diseases. The aim of this work was to re-evaluate the usual cutoff serum IgG4 value in AIP (135 mg/dL) that is used to diagnose whole IgG4-RD in the setting of a rheumatic clinic by measuring serum IgG4 levels in IgG4-RD and various disorders. We therefore constructed ROC curves of serum IgG4 levels in 418 patients who attended Sapporo Medical University Hospital due to IgG4-RD and various rheumatic and common disorders. The optimal cut-off value of serum IgG4 for a diagnosis of IgG4-RD was 144 mg/dL, and the sensitivity and specificity were 95.10 and 90.76%, respectively. Levels of serum IgG4 were elevated in IgG4-RD, Churg-Strauss syndrome, multicentric Castleman's disease, eosinophilic disorders, and in some patients with rheumatoid arthritis, systemic sclerosis, chronic hepatitis, and liver cirrhosis. The usual cut-off value of 135 mg/dL in AIP is useful for diagnosing whole IgG4-RD, but high levels of serum IgG4 are sometimes observed in not only IgG4-RD but also other rheumatic and common diseases.
21907987 Osteoporosis is not a risk factor for the development of nonunion: A cohort nested case-co 2011 Dec INTRODUCTION: Osteoporosis (OP) is one of the most prevalent metabolic bone disorders worldwide and it is associated with a higher incidence of fractures. The aim of this study was to identify OP as a risk factor for the development of nonunion. METHODS: In a prospective database all patients aged >50 years with an acute fracture were screened for osteoporosis from September 13, 2004 till February 9, 2009. Bone mineral density measurements (T-scores, Z-scores and absolute values in g/cm(2)) were performed. The selected patients were matched (1:2 ratio) to control patients based on gender, age (±5 years) and type of fracture according to the AO-criteria. Other parameters including diabetes mellitus, corticosteroid use, rheumatoid arthritis, smoking, alcohol use, and body mass index were recorded. Follow-up for the patients in the matched group was at least one year. RESULTS: This study included a total of 1498 patients who were screened for the presence of osteoporosis. In total 40 patients were treated for nonunion. After 1:2 matching this resulted in a total number of 120 patients for analysis. Logistic regression analysis including all covariates in the model demonstrated no correlation between the standardised regression coefficients and the development of nonunion (r(2)=0.10, p=0.6). The patients that developed an atrophic nonunion, according to radiographic results, were analysed separately and compared to matched patients. The presence of osteoporosis, osteopenia and normal bone density and the related independent BMD measurements did not differ significantly between the atrophic nonunion group and the matched controls. CONCLUSION: We conclude that although bone quality may be diminished in the elderly this does not influence the occurrence of nonunion. These results indicate that the use of BMD measurements preoperatively to identify osteoporosis as a possible risk factor of nonunion has no clinical value.
21844205 Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects ag 2011 Aug 29 IL-20 is a proinflammatory cytokine of the IL-10 family that is involved in psoriasis, rheumatoid arthritis, atherosclerosis, and stroke. However, little is known about the role of IL-20 in bone destruction. We explored the function of IL-20 in osteoclastogenesis and the therapeutic potential of anti-IL-20 monoclonal antibody 7E for treating osteoporosis. Higher serum IL-20 levels were detected in patients with osteopenia and osteoporosis and in ovariectomized (OVX) mice. IL-20 mediates osteoclastogenesis by up-regulating the receptor activator of NF-κB (RANK) expression in osteoclast precursor cells and RANK ligand (RANKL) in osteoblasts. 7E treatment completely inhibited osteoclast differentiation induced by macrophage colony-stimulating factor (M-CSF) and RANKL in vitro and protected mice from OVX-induced bone loss in vivo. Furthermore, IL-20R1-deficient mice had significantly higher bone mineral density (BMD) than did wild-type controls. IL-20R1 deficiency also abolished IL-20-induced osteoclastogenesis and increased BMD in OVX mice. We have identified a pivotal role of IL-20 in osteoclast differentiation, and we conclude that anti-IL-20 monoclonal antibody is a potential therapeutic for protecting against osteoporotic bone loss.
21799742 Multidimensional single cell based STAT phosphorylation profiling identifies a novel biosi 2011 INTRODUCTION: Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE), a complex autoimmune disease. Comprehensively quantifying basal STATs phosphorylation and their signaling response to cytokines should help us to better understand the etiology of SLE. METHODS: Phospho-specific flow cytometry was used to measure the basal STAT signaling activation in three immune cell types of peripheral-blood mononuclear cells from 20 lupus patients, 9 rheumatoid arthritis (RA) patients and 13 healthy donors (HDs). A panel of 27 cytokines, including inflammatory cytokines, was measured with Bio-Plex™ Human Cytokine Assays. Serum Prolactin levels were measured with an immunoradiometric assay. STAT signaling responses to inflammatory cytokines (interferon α [IFNα], IFNγ, interleukin 2 [IL2], IL6, and IL10) were also monitored. RESULTS: We observed the basal activation of STAT3 in SLE T cells and monocytes, and the basal activation of STAT5 in SLE T cells and B cells. The SLE samples clustered into two main groups, which were associated with the SLE Disease Activity Index 2000, their erythrocyte sedimentation rate, and their hydroxychloroquine use. The phosphorylation of STAT5 in B cells was associated with cytokines IL2, granulocyte colony-stimulating factor (G-CSF), and IFNγ, whereas serum prolactin affected STAT5 activation in T cells. The responses of STAT1, STAT3, and STAT5 to IFNα were greatly reduced in SLE T cells, B cells, and monocytes, except for the STAT1 response to IFNα in monocytes. The response of STAT3 to IL6 was reduced in SLE T cells. CONCLUSIONS: The basal activation of STATs signaling and reduced response to cytokines may be helpful us to identify the activity and severity of SLE.
21748532 A comparative study of the usefulness of color vision, photostress recovery time, and visu 2011 Aug Ocular toxicity from hydroxychloroquine (HCQ) is rare, but its potential permanence and severity makes it imperative to employ measures and screening protocols to minimize its occurrence. This study was performed to assess the usefulness of color vision, photo stress recovery time (PSRT), and visual evoked potentials (VEP) in early detection of ocular toxicity of HCQ, in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). 86 patients were included in the study and divided into three groups: (1) with history of HCQ use: interventional 1 (Int.1) without fundoscopic changes and Int.2 with fundoscopic changes; and (2) without history of HCQ use, as control. Visual field, color vision, PSRT and VEP results were recorded for all patients and the effect of age, disease duration, treatment duration and cumulative dose of HCQ on each test was assessed in each group. There was a significant relationship among PSRT and age, treatment duration, cumulative dose of HCQ and disease duration (P<0.001 for all). Color vision was normal in all the cases. P100 amplitude was not different between the three groups (P=0.846), but P100 latency was significantly different (P=0.025) and for Int.2 it was greater than the others. The percentage of abnormal visual fields for Int.2 was more than Int.1 and control groups (P=0.002 and P=0.005 respectively), but Int.1 and control groups were not significantly different (P>0.50). In the early stages of maculopathy, P100 latencies of VEP and PSRT are useful predictors of HCQ ocular toxicity. In patients without ocular symptoms and fundoscopic changes, the P100 latency of VEP predicts more precisely than the others.