Objective. The repertoire of T cells in patients with rheumatoid arthritis (RA) is characterized by clonal expansion of selected CD4+ T cells, which are autoreactive and lack the expression of the functionally important CD28 molecule. The goal of this study was to determine the contribution of these unusual lymphocytes to the disease process.
Methods. RA patients (n = 108) and normal controls (n = 53) were examined for the expression of CD4+CD28‐ T cells by 2‐color fluorescence‐activated cell sorter analysis. Clinical data were ascertained by retrospective chart review.
Results. The frequencies of CD4+CD28‐ T cells displayed a bimodal distribution, defining carriers and noncarriers in normal subjects and RA patients. In longitudinal studies, the noncarrier and carrier phenotypes were stable over time. Carriers of CD4+CD28‐ T cells accumulated in the RA population (64% versus 45%; P = 0.02). The expansion of CD4+CD28‐ T cells correlated with extraarticular involvement, but not with disease duration, antirheumatic treatment, or severity of joint destruction. The patient subsets with nodular disease (P = 0.02) and rheumatoid organ disease (P = 0.04) had the highest proportion of CD4+CD28‐ T cell carriers. The size of the CD4+CD28‐ compartment correlated with extraarticular progression of RA (P = 0.001 in nodular RA, P = 0.003 in rheumatoid organ disease).
Conclusion. The bimodality of distribution of CD4+CD28‐ T cell frequencies is compatible with genetic control of the generation of these unusual T cells. In RA patients, CD4+CD28‐ T cells are not an epiphenomenon of the disease process, but predispose patients to developing inflammatory lesions in extraarticular tissues.
Oligoclonality is a characteristic feature of CD4+ CD28- T cells which are expanded in some healthy individuals and in the majority of RA patients. The lack of CD28 expression is a common denominator of CD4+, CD8+, and CD4- CD8- T cells prone to develop clonal dominance. The limited TCR diversity of clonal CD4+ CD28- populations in RA patients suggests that these T cells recognize a limited spectrum of antigens. The fact that the majority of individuals with marked expansions and oligoclonality of CD4+ CD28- T cells are RA patients suggests a role for these unusual lymphocytes in the pathogenetic events leading to RA.
Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands, <3 years after their diagnosis. From these, 119 were randomly assigned 1:1 to simvastatin 40 mg (n = 61) or placebo (n = 58), stratified for sex and study site. Primary outcomes were symptom severity and cognition after 12 months of treatment. Depression, symptom subscores, general functioning, metabolic syndrome, movement disorders, and safety were secondary outcomes. Intention to treat analyses were performed using linear mixed models and ANCOVA. No main effect of simvastatin treatment was found on total symptom severity after 12 months of treatment as compared to placebo (X2(1) = 0.01, P = .90). Group differences varied over time (treatment*time X2(4) = 11.2; P = .025), with significantly lower symptom severity in the simvastatin group after 6 months (mean difference = −4.8; P = .021; 95% CI: −8.8 to −0.7) and at 24 months follow-up (mean difference = −4.7; P = .040; 95% CI: −9.3 to −0.2). No main treatment effect was found for cognition (F(1,0.1) = 0.37, P = .55) or secondary outcomes. SAEs occurred more frequently with placebo (19%) than with simvastatin (6.6%). This negative finding corroborates other large scale studies on aspirin, minocycline, and celecoxib that could not replicate positive findings of smaller studies, and suggests that anti-inflammatory augmentation does not improve the clinical presentation of SSD.
The hypothesis of a recent reversal in the eutrophication of the Wadden Sea and the potential of inshore waters in denitrification is explored. Salinity, temperature and nitrate concentrations in the List Tidal Basin (Northern Wadden Sea) have been measured about twice weekly since 1984. Salinity has a clear seasonal cycle with lowest salinities of about 27 in late winter and highest salinities of about 31 in summer. Mean annual deviations from the long-term mean salinity correlate significantly with riverine freshwater discharge. Winter nitrate concentrations are generally high (about 50 lM on average). The major part of the variability is related to salinity (*35%). Temperature had a minor impact (*1%). Superimposed on this, a long-term decrease of about 1 lM per year was found. Together, these processes account for about 45% of the nitrate variability. The long-term decrease of about 2% per year is similar to continental riverine trend in total nitrogen loads. In contrast to the List Tidal Basin, salinity explained more than 90% of nitrate variability in the off-shore German Bight. Salinity (30) normalised winter nitrate data of the German Bight also show a long-term decreasing trend. Most of the List Tidal Basin data are either on or below the nitrate-salinity relation found in the German Bight. This observation suggests that denitrification has a major impact on the winter nitrate concentrations in the Northern Wadden Sea compared to the German Bight. It is hypothesised that a large part of the unexplained variability is related to weather-dependent changes in residence time of tidal water masses in the Wadden Sea and circulation patterns within the German Bight.
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