Adiponectin levels in a large pooled plaque psoriasis study population.

Background: Adiponectin is an adipocyte-secreted protein potentially relevant in the context of cardiometabolic comorbidity of psoriasis patients.Objective: This post-hoc analysis aimed to assess the impact of obesity, metabolic syndrome, psoriasis severity and treatment with secukinumab/etanercept on adiponectin.Methods: Three phase III trials in moderate to severe plaque psoriasis were included. Correlations of Psoriasis Area and Severity Index (PASI), body mass index (BMI), and associated comorbidity with adiponectin levels as well as the impact of secukinumab, etanercept, and placebo were analyzed.Results: Data of 3010 patients were included of whom 71.2% had a BMI >25. Adiponectin levels were significantly higher in patients with lower BMI (r = -0.23; p < .0001) and in patients without metabolic syndrome compared to patients with higher BMI and with metabolic syndrome. PASI score was negatively associated with adiponectin levels (r = -0.065; p = .0004). However, the correlation was extremely weak and thus clinically irrelevant. During treatment with secukinumab or etanercept over 52 weeks adiponectin levels remained stable.Conclusion: Metabolic syndrome and BMI are key determinants of adiponectin levels in psoriasis patients. Psoriasis severity and anti-psoriatic treatment had no relevant impact on adiponectin levels.

Altered glycan accessibility on native immunoglobulin G complexes in early rheumatoid arthritis and its changes during therapy.

The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.

Sweet but dangerous - the role of immunoglobulin G glycosylation in autoimmunity and inflammation.

Glycosylation is well-known to modulate the functional capabilities of immunoglobulin G (IgG)-mediated cellular and humoral responses. Indeed, highly sialylated and desialylated IgG is endowed with anti- and pro-inflammatory activities, respectively, whereas fully deglycosylated IgG is a rather lame duck, with no effector function besides toxin neutralization. Recently, several studies revealed the impact of different glycosylation patterns on the Fc part and Fab fragment of IgG in several autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we provide a synoptic update summarizing the most important aspects of antibody glycosylation, and the current progress in this field. We also discuss the therapeutic options generated by the modification of the glycosylation of IgG in a potential treatment for chronic inflammatory diseases.

Altered glycosylation of complexed native IgG molecules is associated with disease activity of systemic lupus erythematosus.

In addition to the redundancy of the receptors for the Fc portion of immunoglobulins, glycans result in potential ligands for a plethora of lectin receptors found in immune effector cells. Here we analysed the exposure of glycans containing fucosyl residues and the fucosylated tri-mannose N-type core by complexed native IgG in longitudinal serum samples of well-characterized patients with systemic lupus erythematosus. Consecutive serum samples of a cohort of 15 patients with systemic lupus erythematosus during periods of increased disease activity and remission were analysed. All patients fulfilled the 1982 American College of Rheumatology classification criteria. Sera of 15 sex- and age-matched normal healthy blood donors served as controls. The levels and type of glycosylation of complexed random IgG was measured with lectin enzyme-immunosorbent assays. After specifically gathering IgG complexes from sera, biotinylated lectins Aleuria aurantia lectin and Lens culinaris agglutinin were employed to detect IgG-associated fucosyl residues and the fucosylated tri-mannose N-glycan core, respectively. In sandwich-ELISAs, IgG-associated IgM, IgA, C1q, C3c and C-reactive protein (CRP) were detected as candidates for IgG immune complex constituents. We studied associations of the glycan of complexed IgG and disease activity according to the physician's global assessment of disease activity and the systemic lupus erythematosus disease activity index 2000 documented at the moment of blood taking. Our results showed significantly higher levels of Aleuria aurantia lectin and Lens culinaris agglutinin binding sites exposed on IgG complexes of patients with systemic lupus erythematosus than on those of normal healthy blood donors. Disease activity in systemic lupus erythematosus correlated with higher exposure of Aleuria aurantia lectin-reactive fucosyl residues by immobilized IgG complexes. Top levels of Aleuria aurantia lectin-reactivity were found in samples taken during the highest activity of systemic lupus erythematosus. Our results show that native circulating IgG complexes from active systemic lupus erythematosus patients expose fucosyl residues and their glycan core is accessible to soluble lectins. Two putative mechanisms may contribute to the increased exposure of these glycans: (1) the canonical N-glycosylation site of the IgG-CH2 domain; (2) an IgG binding non-IgG molecule, like complement or C-reactive protein. In both cases the complexed IgG may be alternatively targeted to lectin receptors of effector cells, e.g. dendritic cells.

[Nuclear medicine in Europe: education]. / Nuklearmedizin in Europa. Die Ausbildungssituation.

The technical developments that have taken place in the preceding years (PET, hybrid imaging) have changed nuclear medicine. The future cooperation with radiologists will be challenging as well as positioning nuclear medicine in an European context. It can also be expected that education in nuclear medicine will undergo a harmonization process in the states of the European Union. In this paper, we describe how nuclear medicine education is organized in several European countries. We aim to stimulate constructive discussions on the future development of the specialization in nuclear medicine in Germany.

[Procedure guideline for radioiodine therapy and 131iodine whole-body scintigraphy in paediatric patients with differentiated thyroid cancer]. / Verfahrensanweisung zur Radioiodtherapie und 131I-Ganzkörperszintigraphie bei differenzierten Schilddrüsenkarzinomen im Kindes- und Jugendalter.

The procedure guideline for radioiodine ((131)I) therapy and (131)I whole-body scintigraphy of differentiated thyroid cancer in paediatric patients is the counterpart to the procedure guidelines (version 3) for adult patients and specify the interdisciplinary guideline for thyroid cancer of the Deutsche Krebsgesellschaft concerning the nuclear medicine part. Characteristics of thyroid cancer in children are the higher aggressiveness of papillary thyroid cancer, the higher frequency of extrathyroidal extension and of disseminated pulmonary metastases as well as the high risk of local recurrences. Radioiodine therapy is generally recommended in children, the (131)I activity depends on the children's body weight. Radioiodine ablation in children with small papillary cancer (< or =1 cm) should be considered. TSH stimulation is reached two weeks (children) or three weeks (adolescents) after withdrawal of thyroid hormones. Anti-emetic drugs are highly recommended. CT of the chest and examination of pulmonary function are clearly indicated if there is any suspicion on metastases. 3-6 months after (131)I ablation, the (131)I whole-body scintigraphy is highly recommended as lymph node metastases are frequently detected in paediatric patients. Follow-up care should be arranged in shorter intervals than in adults to test the compliance and to adapt dosage of thyroid hormones to the children's body weight. Reference values of fT3 are higher in children than in adults. Evidence is insufficient to describe in which constellation the TSH may be kept within the low normal level. Therefore, TSH suppression is generally recommended.

Guidelines on radioiodine therapy for differentiated thyroid carcinoma: impact on clinical practice.

AIM: For the examination of the impact on clinical practice of the guidelines for differentiated thyroid carcinoma (DTC), treatment data from the ongoing Multicenter Study Differentiated Thyroid Carcinoma (MSDS) were analyzed. PATIENTS, METHODS: Patients were randomized to adjuvant external beam radiotherapy (RTx) or no RTx in addition to standard therapy in TNM stages pT4 pN0/1/x M0/x (UICC, 5th ed. 1997). All patients were to receive the same treatment regimen consisting of thyroidectomy, ablative radioiodine therapy (RIT), and a diagnostic 131I whole-body scintigraphy (WBS) 3-4 months after RIT. RESULTS: Of 339 eligible patients enrolled between January 2000 and March 2004, 273 could be analyzed. Guideline recommendations by the German Society for Nuclear Medicine from 1999 and 1992 were complied with within 28% and 82% with regard to the interval between surgery and RIT (4 vs. 4-6 weeks), in 33% and 84% with regard to 131I activity for RIT (1-3 vs. 1-4 GBq; +/- 10%), and in 16% and 60% with regard to 131I activity for WBS (100-300 vs. 100-400 MBq; +/- 10%). CONCLUSIONS: The 1999 guideline revision appears to have had little impact on clinical practice. Further follow-up will reveal if guideline compliance had an effect on outcomes.

Multicenter study differentiated thyroid carcinoma (MSDS). Diminished acceptance of adjuvant external beam radiotherapy.

AIM: The Multicenter Study Differentiated Thyroid Carcinoma (MSDS) is an ongoing study in Germany, Austria, and Switzerland on the clinical benefit of adjuvant external beam radiotherapy (RTx) for locally invasive differentiated thyroid carcinoma (DTC) in TNM stages pT4 pN0/1/x M0/x (5th ed. 1997). METHODS: MSDS was designed as a prospective randomized trial. Patients receive thyroidectomy, radioiodine therapy (RIT) to ablate the thyroid remnant, and TSH-suppressive L-thyroxine therapy with or without RTx after documented elimination of cervical iodine-131 uptake (http://msds-studie.uni-muenster.de). RESULTS: 311 patients were enrolled between January 2000 and March 2003. 279 patients met the trial's inclusion criteria. 45 consented to randomization, of whom 17 were randomized into treatment arm A (RTx) and 18 into arm B (no RTx). Advised by the trial's independent Data Monitoring and Safety Committee, the MSDS steering committee decided to terminate randomization in April 2003 and continue MSDS as a prospective cohort study. 23 of the 234 patients in the observation arm of the trial were prescribed RTx by their physicians. Thus, 14% of the trial cohort were randomized or assigned to receive RTx (in-tention-to-treat analysis). In contrast, at least 44% of all patients with pT4 papillary DTC in Germany in the nation-wide PCES study underwent RTx in 1996 (p <0.001, chi(2)-test). CONCLUSIONS: Acceptance of external beam RTx as a treatment modality for DTC has receded to a degree that accrual of a sufficient number of patients for a randomized trial has been impossible. Observation of the trial cohort is continued in order to assess clinical event rates with and without RTx and chronic RTx toxicity.

Cytochalasin D as excitation-contraction uncoupler for optically mapping action potentials in wedges of ventricular myocardium.

INTRODUCTION: Cytochalasin D in tissue bath superfusate inhibits the contraction of isolated thin trabeculae from canine right ventricle without affecting the intracellular action potential recorded with glass microelectrode. The purpose of this study was to test whether cytochalasin D could also be used to immobilize perfused wedges of ventricular muscle without affecting the action potential duration or propagation, and also to determine the optimal concentration and time duration of drug in the perfusate. METHODS AND RESULTS: Using a membrane potential sensitive dye, di-4-ANEPPS, and a high-resolution photodiode optical mapping system at a rate of 1,000 frames/sec, we recorded action potentials on the transmural surface of arterially perfused wedges of muscle from the canine left ventricular free wall. We also recorded arterial pulse pressure as a surrogate for tissue contraction. Cytochalasin D at > or = 20 micromol/L in the perfusate for > or = 6 minutes reduced the arterial pulse pressure to approximately one tenth of its initial value and significantly reduced or eliminated motion artifacts in the action potentials. A sustained concentration of 10 micromol/L cytochalasin D in the perfusate prevented contraction from recurring after the tissue was immobilized with an initial concentration of 25 micromol/L. Cytochalasin D had little effect on the action potential duration and on its transmural gradient, and did not slow the transmural velocity of excitation propagation. CONCLUSION: Cytochalasin D can be used to uncouple excitation and contraction in perfused canine cardiac muscle for the fluorescent-optical mapping of action potentials without affecting action potential duration or slowing transmural propagation.

Differential effects of cytochalasin D and 2,3 butanedione monoxime on isometric twitch force and transmembrane action potential in isolated ventricular muscle: implications for optical measurements of cardiac repolarization.

INTRODUCTION: 2,3-Butanedione monoxime (BDM) has been widely used to inhibit contraction during optical recordings of cardiac membrane voltage changes, even though it markedly abbreviates cardiac action potentials. METHODS AND RESULTS: We compared the effects of BDM and of the F-actin disrupter cytochalasin D (cyto D) on isometric twitch force and transmembrane action potentials in isolated canine right ventricular trabeculae superfused with Tyrode's solution (2 mmol/L CaCl2, 37 degrees C) and stimulated at 0.5 Hz. BDM at 10 mmol/L and cyto D at 80 micromol/L were equally effective in reducing peak isometric force to 10%+/-3% (n = 6; mean+/-SEM) and 8%+/-1% (n = 8), respectively. Neither agent significantly altered resting tension. While 10 mmol/L BDM markedly shortened the action potential duration at 90% repolarization (APD90) from 198+/-7 msec to 146+/-9 msec (P < 0.001), 80 micromol/L cyto D had no significant effects on APD90 or on any other action potential parameter. The effects of BDM on peak isometric force and APD were completely reversible after 15 minutes of washout, whereas in the cyto D group contractile force continued to be reduced (13%+/-3%) and action potential characteristics did not show significant changes from control values after a 60-minute period of superfusion with cyto D-free Tyrode's solution. CONCLUSION: We conclude that cyto D should be considered an alternative excitation-contraction uncoupler for optical mapping studies of cardiac repolarization.

Transmembrane voltage changes produced by real and virtual electrodes during monophasic defibrillation shock delivered by an implantable electrode.

INTRODUCTION: Epicardial point stimulation produces nonuniform changes in the transmembrane voltage of surrounding cells with simultaneous occurrence of areas of transient positive and negative polarization. This is the phenomenon of virtual electrode. We sought to characterize the responses of epicardial ventricular tissue to the application of monophasic electric shocks from an internal transvenous implantable cardioverter defibrillator (ICD) lead. METHODS AND RESULTS: Langendorff-perfused rabbit hearts (n = 12) were stained with di-4-ANEPPS. A 9-mm-long distal electrode was placed in the right ventricle. A 6-cm proximal electrode was positioned horizontally 3 cm posteriorly and 1 cm superiorly with respect to the heart. Monophasic anodal and cathodal pulses were produced by discharging a 150-microF capacitor. Shocks were applied either during the plateau phase of an action potential (AP) or during ventricular fibrillation. Leading-edge voltage of the pulse was 50 to 150 V, and the pulse duration was 10 msec. Transmembrane voltage was optically recorded during application of the shock, simultaneously from 256 sites on a 11 x 11 mm area of the anterior right ventricular epicardium directly transmural to the distal electrode. The shock effect was evaluated by determining the difference between the AP affected by the shock and the normal AP. During cathodal stimulation an area of depolarization near the electrode was observed, surrounded by areas of hyperpolarization. The amplitude of polarization gradually decreased in areas far from the electrode. Inverting shock polarity reversed this effect. CONCLUSION: ICD monophasic defibrillation shocks create large dynamically interacting areas of both negative and positive polarization.