Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus

Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented in the 103 SLE patients (mean age 41 ± 13 years, mean disease duration 7 ± 4 years). The percentage of SLE patients with severe MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk

Dynamics of circulating TNF during adalimumab treatment using a drug-tolerant TNF assay

Patients with rheumatoid arthritis (RA) can be successfully treated with tumor necrosis factor (TNF) inhibitors, including the monoclonal antibody adalimumab. Once in remission, a proportion of patients can successfully discontinue treatment, indicating that blocking TNF is no longer required for disease control. To explore the dynamics of circulating TNF during adalimumab treatment, we developed a competition enzyme-linked immunosorbent assay that can quantify TNF in the presence of large amounts of TNF inhibitor, i.e., a “drug-tolerant” assay. In 193 consecutive adalimumab-treated patients with RA, we demonstrated that circulating TNF increased in average of &gt;50-fold upon treatment and reached a stable concentration in time for most patients. A similar increase in TNF was found in 30 healthy volunteers after one dose of adalimumab. This implies that TNF in circulation during anti-TNF treatment is not primarily associated with disease activity. During treatment, TNF was in complex with adalimumab and could be recovered as inactive 3:1 adalimumab-TNF complexes. No quantitative association was found between TNF and adalimumab concentrations. Low TNF concentrations at week 4 were associated with a higher frequency of antidrug antibodies (ADAs) at subsequent time points, less frequent methotrexate use at baseline, and less frequent remission after 52 weeks. Also in healthy volunteers, early low TNF concentrations are associated with ADAs. In conclusion, longitudinal TNF concentrations are mostly stable during adalimumab treatment and may therefore not predict successful treatment discontinuation. However, early low TNF is strongly associated with ADA formation and may be used as timely predictor of nonresponse toward adalimumab treatment.</p

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: The Treat-OA consortium

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genomewide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81×10-5). The C allele conferred a reduced risk of 33% to 41% using a case-control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA

Common genetic variation in the Estrogen Receptor Beta (ESR2) gene and osteoarthritis: results of a meta-analysis

Background: The objective of this study was to examine the relationship between common genetic variation of the ESR2 gene and osteoarthritis.Methods: In the discovery study, the Rotterdam Study-I, 7 single nucleotide polymorphisms (SNPs) were genotyped and tested for association with hip (284 cases, 2772 controls), knee (665 cases, 2075 controls), and hand OA (874 cases, 2184 controls) using an additive model. In the replication stage one SNP (rs1256031) was tested in an additional 2080 hip, 1318 knee and 557 hand OA cases and 4001, 2631 and 1699 controls respectively. Fixed- and random-effects meta-analyses were performed over the complete dataset including 2364 hip, 1983 knee and 1431 hand OA cases and approximately 6000 controls.Results: The C allele of rs1256031 was associated with a 36% increased odds of hip OA in women of the Rotterdam Study-I (OR 1.36, 95% CI 1.08-1.70, p = 0.009). Haplotype analysis and analysis of knee- and hand OA did not give additional information. With the replication studies, the meta-analysis did not show a significant effect of this SNP on hip OA in the total population (OR 1.06, 95% CI 0.99-1.15, p = 0.10). Stratification according to gender did not change the results. In this study, we had 80% power to detect an odds ratio of at least 1.14 for hip OA (α = 0.05).Conclusion: This study showed that common genetic variation in the ESR2 gene is not likely to influence the risk of osteoarthritis with effects smaller than a 13% increase

Morphological changes in diabetic kidney are associated with increased O-GlcNAcylation of cytoskeletal proteins including α-actinin 4

Abstract Purpose The objective of the present study is to identify proteins that change in the extent of the modification with O-linked N-acetylglucosamine (O-GlcNAcylation) in the kidney from diabetic model Goto-Kakizaki (GK) rats, and to discuss the relation between O-GlcNAcylation and the pathological condition in diabetes. Methods O-GlcNAcylated proteins were identified by two-dimensional gel electrophoresis, immunoblotting and peptide mass fingerprinting. The level of O-GlcNAcylation of these proteins was examined by immunoprecipitation, immunoblotting and in situ Proximity Ligation Assay (PLA). Results O-GlcNAcylated proteins that changed significantly in the degree of O-GlcNAcylation were identified as cytoskeletal proteins (α-actin, α-tubulin, α-actinin 4, myosin) and mitochondrial proteins (ATP synthase β, pyruvate carboxylase). The extent of O-GlcNAcylation of the above proteins increased in the diabetic kidney. Immunofluorescence and in situ PLA studies revealed that the levels of O-GlcNAcylation of actin, α-actinin 4 and myosin were significantly increased in the glomerulus and the proximal tubule of the diabetic kidney. Immunoelectron microscopy revealed that immunolabeling of α-actinin 4 is disturbed and increased in the foot process of podocytes of glomerulus and in the microvilli of proximal tubules. Conclusion These results suggest that changes in the O-GlcNAcylation of cytoskeletal proteins are closely associated with the morphological changes in the podocyte foot processes in the glomerulus and in microvilli of proximal tubules in the diabetic kidney. This is the first report to show that α-actinin 4 is O-GlcNAcylated. α-Actinin 4 will be a good marker protein to examine the relation between O-GlcNAcylation and diabetic nephropathy.</p

Afstudeerwerk

Preface In nummer 2 van 2022 introduceerde het Bulletin KNOB een tweejaarlijkse rubriek ‘afstudeerwerk’, waarin de studenten die hadden meegedongen naar de KNOB Stimuleringsprijs 2021 hun onderzoek presenteerden. In dit nummer vindt u de tweede editie van die rubriek. Het bevat samenvattingen van scripties ingezonden voor de KNOB Stimuleringsprijs 2023. De zestien scripties zijn geschreven aan twee Belgische universiteiten (Katholieke Universiteit Leuven en Vrije Universiteit Brussel), vier Nederlandse (Rijksuniversiteit Groningen, Technische Universiteit Delft, Universiteit Utrecht, Universiteit van Amsterdam) en een hogeschool (Inholland Delft). Ze behandelen herkenbare architectuurhistorische thema’s als de negentiendeeeuwse arbeiderswoning, plafondontwerpen van Daniel Marot en historisch glas-in-lood, maar ook aanverwante onderwerpen als de ‘soundscape’ van de kerken van Christopher Wren, archeologisch erfgoed als herinneringsplaats, en – op het snijvlak van de architectuurhistorie en de sociale geschiedenis – de speeltuin tussen 1878 en 1978. De KNOB Stimuleringsprijs leidt tot meer. Het afstudeeronderzoek van Sara Duisters over kunststof gevels resulteerde al in een publicatie in het recente themanummer Post 65. Winnaar van de Stimuleringsprijs 2023 Lara Reyniers schreef voortbouwend op haar afstudeeronderzoek voor het huidige nummer samen met Stephanie Van de Voorde en Ine Wouters een artikel over de omgang met afbraakmaterialen in Brussel in de periode 1860-1940. Daarmee is dit nummer bijna volledig gevuld met het werk van jonge vakgenoten. In de bijdrage van Reyniers et al staan nu eens niet de creatie en bouw van architectuur centraal, maar de afbraak ervan, en dan met name het beleid ten aanzien van het sloopafval. De behandelde periode was er een van grootschalige stedelijke vernieuwing die veel afval opleverde, waaronder puin, bijzondere bouwfragmenten en van alles daar tussenin. Hoe de Brusselse overheid hiermee omging is interessant, zeker ook in het huidige tijdsgewricht, waarin sloop en sloopafval – nu vanuit een duurzaamheidsoogpunt – opnieuw in de aandacht staan. De redactieVoorwoord In nummer 2 van 2022 introduceerde het Bulletin KNOB een tweejaarlijkse rubriek ‘afstudeerwerk’, waarin de studenten die hadden meegedongen naar de KNOB Stimuleringsprijs 2021 hun onderzoek presenteerden. In dit nummer vindt u de tweede editie van die rubriek. Het bevat samenvattingen van scripties ingezonden voor de KNOB Stimuleringsprijs 2023. De zestien scripties zijn geschreven aan twee Belgische universiteiten (Katholieke Universiteit Leuven en Vrije Universiteit Brussel), vier Nederlandse (Rijksuniversiteit Groningen, Technische Universiteit Delft, Universiteit Utrecht, Universiteit van Amsterdam) en een hogeschool (Inholland Delft). Ze behandelen herkenbare architectuurhistorische thema’s als de negentiendeeeuwse arbeiderswoning, plafondontwerpen van Daniel Marot en historisch glas-in-lood, maar ook aanverwante onderwerpen als de ‘soundscape’ van de kerken van Christopher Wren, archeologisch erfgoed als herinneringsplaats, en – op het snijvlak van de architectuurhistorie en de sociale geschiedenis – de speeltuin tussen 1878 en 1978. De KNOB Stimuleringsprijs leidt tot meer. Het afstudeeronderzoek van Sara Duisters over kunststof gevels resulteerde al in een publicatie in het recente themanummer Post 65. Winnaar van de Stimuleringsprijs 2023 Lara Reyniers schreef voortbouwend op haar afstudeeronderzoek voor het huidige nummer samen met Stephanie Van de Voorde en Ine Wouters een artikel over de omgang met afbraakmaterialen in Brussel in de periode 1860-1940. Daarmee is dit nummer bijna volledig gevuld met het werk van jonge vakgenoten. In de bijdrage van Reyniers et al staan nu eens niet de creatie en bouw van architectuur centraal, maar de afbraak ervan, en dan met name het beleid ten aanzien van het sloopafval. De behandelde periode was er een van grootschalige stedelijke vernieuwing die veel afval opleverde, waaronder puin, bijzondere bouwfragmenten en van alles daar tussenin. Hoe de Brusselse overheid hiermee omging is interessant, zeker ook in het huidige tijdsgewricht, waarin sloop en sloopafval – nu vanuit een duurzaamheidsoogpunt – opnieuw in de aandacht staan. De redacti

Positive association between increased popliteal artery vessel wall thickness and generalized osteoarthritis: is OA also part of the metabolic syndrome?

This is the final version of the article. Available from Springer Verlag via the DOI in this record.PURPOSE: The purpose of the study was to determine if a positive association exists between arterial vessel wall thickness and generalized osteoarthritis (OA). Our hypothesis is that generalized OA is another facet of the metabolic syndrome. MATERIALS AND METHODS: The medical ethical review board of our institution approved the study. Written informed consent was obtained from each patient prior to the study. Magnetic resonance (MR) images of the knee were obtained in 42 patients who had been diagnosed with generalized OA at multiple joint sites. Another 27 MR images of the knee were obtained from a matched normal (non-OA) reference population. Vessel wall thickness of the popliteal artery was quantitatively measured by dedicated software. Linear regression models were used to investigate the association between vessel wall thickness and generalized OA. Adjustments were made for age, sex, and body mass index (BMI). Confidence intervals (CI) were computed at the 95% level and a significance level of alpha = 0.05 was used. RESULTS: Patients in the generalized OA population had a significant higher average vessel wall thickness than persons from the normal reference population (p < or = alpha), even when correction was made for sex, age, and BMI. The average vessel wall thickness of the popliteal artery was 1.09 mm in patients with generalized OA, and 0.96 mm in the matched normal reference population. CONCLUSION: The association found between increased popliteal artery vessel wall thickness and generalized osteoarthritis suggests that generalized OA might be another facet of the metabolic syndrome

Illness cognitions in head and neck squamous cell carcinoma: predicting quality of life outcome

Goals of work: This paper presents an observational study of the longitudinal effects of cancer treatment on quality of life (QoL) in patients treated for head and neck squamous cell carcinoma (HNSCC), and evaluated the contribution of patients' baseline illness cognitions to the prediction of QoL 2 years after diagnosis. Patients and methods: One hundred seventy-seven patients eligible for primary treatment for HNSCC completed the Illness Perception Questionnaire-Revised at baseline and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire-30 at baseline, at 1-year and 2-year follow-ups. Main results Compared to baseline, patients reported better emotional functioning at both follow-ups (p<0.001), worse social functioning at 12 months (p<0.05), and better global health