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Troelsen L.N.,Copenhagen University | Garred P.,Laboratory of Molecular Medicine | Jacobsen S.,Copenhagen University
Journal of Rheumatology | Year: 2010

Objective. Patients with rheumatoid arthritis (RA) have increased overall and cardiovascular mortality. Mannose-binding lectin (MBL) may play differentiated roles in the pathogenesis of RA. We had observed that high serum levels of MBL increased the risk of ischemic heart disease in patients with RA. In this followup study we describe the mortality in a cohort of 229 Danish patients with RA.We examine if previously reported factors and MBL influence the risk of overall death and death due to cardiovascular disease. Methods. Known predictors of RA mortality were assessed. MBL extended genotypes (YA/YA, YA/XA, XA/XA, YA/YO, XA/YO, YO/YO) were determined; MBL serum concentrations were measured. The vital status and causes of death were assessed in a prospective study. Results. The median followup was 10.3 years. The overall risk of death was 4% per year. Comparing mortality in the RA cohort with mortality in an age- and sex-matched cohort based on the general Danish population, we found significantly increased overall mortality [standardized mortality ratio (SMR) 1.5, 95% CI 1.2-1.9, and cardiovascular mortality (SMR 1.7, 95% CI 1.3-2.6)]. In multivariate analysis, significant predictors of overall death were extraarticular manifestations, positive rheumatoid factor, increased C-reactive protein (CRP), poor nutritional state, and serum MBL. Predictors of cardiovascular death were Health Assessment Questionnaire score, increased CRP, poor nutritional state, and the high-producing MBL genotype YA/YA. Conclusion. Both overall and cardiovascular mortality were increased in Danish patients with RA. In our cohort, states of high MBL production and several previously reported factors contributed significantly to this increased risk of overall death and cardiovascular death. The Journal of Rheumatology © 2010. All rights reserved.

Jiang J.,Harvard University | Lazarus M.B.,Harvard University | Pasquina L.,Harvard University | Sliz P.,Harvard University | And 2 more authors.
Nature Chemical Biology | Year: 2012

Glycosyltransferases (Gtfs) catalyze the formation of a diverse array of glycoconjugates. Small-molecule inhibitors to manipulate Gtf activity in cells have long been sought as tools for understanding Gtf function. Success has been limited because of challenges in designing inhibitors that mimic the negatively charged diphosphate substrates. Here we report the mechanism of action of a small molecule that inhibits O-linked N-acetylglucosamine transferase (OGT), an essential human enzyme that modulates cell signaling pathways by catalyzing a unique intracellular post-translational modification, β-O-GlcNAcylation. The molecule contains a five-heteroatom dicarbamate core that functions as a neutral diphosphate mimic. One dicarbamate carbonyl reacts with an essential active site lysine that anchors the diphosphate of the nucleotide-sugar substrate. A nearby cysteine then reacts with the lysine adduct to form a carbonyl crosslink in the OGT active site. Though this unprecedented double-displacement mechanism reflects the unique architecture of the OGT active site, related dicarbamate scaffolds may inhibit other enzymes that bind nucleotide-containing substrates. © 2011 Nature America, Inc. All rights reserved.

Catteruccia M.,Laboratory of Molecular Medicine
Neuromuscular disorders : NMD | Year: 2013

Mutations in dynamin 2 (DNM2) gene cause autosomal dominant centronuclear myopathy and occur in around 50% of patients with centronuclear myopathy. We report clinical, morphological, muscle imaging and genetic data of 10 unrelated Italian patients with centronuclear myopathy related to DNM2 mutations. Our results confirm the clinical heterogeneity of this disease, underlining some peculiar clinical features, such as severe pulmonary impairment and jaw contracture that should be considered in the clinical follow-up of these patients. Muscle MRI showed a distinct pattern of involvement, with predominant involvement of soleus and tibialis anterior in the lower leg muscles, followed by hamstring muscles and adductor magnus at thigh level and gluteus maximus. The detection of three novel DNM2 mutations and the first case of somatic mosaicism further expand the genetic spectrum of the disease. Copyright © 2013 Elsevier B.V. All rights reserved.

Bertini E.,Laboratory of Molecular Medicine | D'Amico A.,Laboratory of Molecular Medicine | Gualandi F.,University of Ferrara | Petrini S.,Confocal Microscopy Core Facility IRCCS Childrens Hospital Bambino Gesu
Seminars in Pediatric Neurology | Year: 2011

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous neuromuscular disorders with onset at birth or in infancy in which the muscle biopsy is compatible with a dystrophic myopathy. In the past 10 years, knowledge of neuromuscular disorders has dramatically increased, particularly with the exponential boost of disclosing the genetic background of CMDs. This review will highlight the clinical description of the most important forms of CMD, paying particular attention to the main keys for diagnostic approach. The diagnosis of CMDs requires the concurrence of expertise in multiple specialties (neurology, morphology, genetics, neuroradiology) available in a few centers worldwide that have achieved sufficient experience with the different CMD subtypes. Currently, molecular diagnosis is of paramount importance not only for phenotype-genotype correlations, genetic and prenatal counseling, and prognosis and aspects of management, but also concerning the imminent availability of clinical trials and treatments. © 2011 Elsevier Inc.

Bay J.T.,Laboratory of Molecular Medicine | Sorensen So.S.,Rigshospitalet | Hansen J.M.,Copenhagen University | Madsen H.O.,Laboratory of Molecular Medicine | Garred P.,Laboratory of Molecular Medicine
Kidney International | Year: 2013

Activation of the complement system is initiated by the alternative, the classical, or the lectin pathway. As the complement system is involved in the pathophysiology of graft rejection after kidney transplantation, we investigated the possible role of mannose-binding lectin in kidney transplantation and the influence of human leukocyte antigen (HLA) immunization on this process. In a prospective study of 544 kidney transplant patients over a follow-up period of 5 years, low serum levels of this lectin at the time of transplantation were found to be significantly associated with decreased 5-year death-censored graft survival (hazard ratio 1.68). Subanalysis showed that this association was confined to non-HLA-immunized patients (hazard ratio 1.93). The strongest association was seen in non-HLA-immunized patients receiving a kidney from a deceased donor (hazard ratio 2.93). No significant association with mannose-binding lectin levels and graft survival were found in HLA-immunized patients. Variant MBL2 genotypes causing low mannose-binding lectin serum concentrations showed the same association pattern. Our findings demonstrate a clear protective role of mannose-binding lectin and thus innate immunity in maintaining kidney graft survival, but these are probably overruled by HLA immunization. © 2012 International Society of Nephrology.

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