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Exercise training has been firmly established as an additional therapeutic strategy in addition to pharmacological and interventional treatment in patients with cardiovascular disease. Benefits for quality of life as well as prognosis have been confirmed for cardiovascular risk factors, ischemic heart disease, after myocardial infarction, in heart failure with preserved as well as reduced ejection fraction, in atrial fibrillation and in patients after catheter-assisted aortic valve implantation (TAVI), with an implantable cardioverter defibrillator (ICD) or with left ventricular assist devices (VAD). Training programs have to be tailored according to the disease, stage of disease, comorbidities, age of the patient, medication as well as exercise capacity. For prescribing exercise mode and intensity, a maximum exercise test has to be performed. Ideally, this is accompanied by spirometry to assess maximum values such as maximum oxygen consumption. Training intensity will then be prescribed according to the optimal training range and maximum training intensity.

Introduction: Intradermal periareolar injection technique for sentinel lymph node biopsy (SLNB) may offer an advantage by including multifocal breast cancer as an additional indication. In May 2008 we changed our standard procedure from peritumoral (PT) to periareolar (PA) injection. We compared the results for corresponding periods before and after the change in procedure. Material and Method: A total of 117 patients (pts.) were investigated the year after we changed our technique; a total of 152 pts were investigated in the reference period 2007. We investigated the identification rates for sentinel lymph nodes (SLN) identified scintigraphically and surgically as well as the rates of metastatic involvement (LN). Results: After PT injection, scintigraphic detection of SLN failed in 5/152 pts., and in a further 10 pts. SLN was not found at surgery. In 7 of 15 pts. in whom SLN was not detected, histology demonstrated nodal involvement. Metastases were found in the SLN of 28 of 137 pts. with successful detection of SLN; no other lymph nodes were affected in 21 of these pts. (75.0 % of pts. with positive SLN detection). With PA injection at least one SLN could always be detected using scintigraphy; only 2/117 SLN could not be found intraoperatively. Metastasis was found in SLN in 34/115 pts.; in 19/34 pts., metastatic involvement was limited to the SLN with no other lymph nodes involved (55.9 % of pts. with positive detection of SLN). Discussion: The detection rate for SLN was significantly higher using PA injection (98.3 % vs. 90.1 %). As axillary dissection was not done in SLN-negative patients, rates of false-negative detection cannot be determined. PA injection not only results in better detection rates, it also offers the advantage that the technique can be performed correctly regardless of tumour localisation.

We have investigated the phenomenon of flow-induced aggregation in highly concentrated colloidal dispersions exposed to strongly converging flow fields. This phenomenon is relevant not only for classical technical operations like coating, pumping or filtration, but also for the application of concentrated suspensions in upcoming processing technologies based on microfluidic devices. A ring-slit device (gap height 10-25 μm), which allows for a variation of flow kinematics in a wide range, has been developed in order to investigate this phenomenon. Various polymer dispersions with different particle surface properties have been used as model systems. Our experiments exclude, that channel clogging is due to retention of pre-existing aggregates, fouling or hydrodynamic bridging. Instead, we demonstrate that clogging of the microchannel is induced by hetero-coagulation between primary colloidal particles and micron-sized impurities present at concentrations on the order of 100-1000 ppm. Clogging can occur even if the diameter of these impurities is less than a tenth of the gap height. Aggregation takes place in the converging flow field at the channel entrance, but not in the shear field within the slit. It can be suppressed by appropriate stabilization of the primary particles., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Recently, there has been increasing evidence that a non-synonymous exchange (Gly307Ser) in the gene for CD226 is linked to several autoimmune diseases including type 1 diabetes, multiple sclerosis (MS), rheumatoid arthritis and Grave's disease. Here we present evidence that this polymorphism also predisposes to Wegener's granulomatosis (WG), an autoimmune condition belonging to the group of ANCA (antineutrophil cytoplasmic autoantibody)-associated vasculitides. We found a significant association of the 307Ser allele in separate panels of 520 Northern German (P=0.016, odds ratio (OR)=1.20) and 122 Southern German (P=0.020, OR=1.37) WG cases compared with 1226 healthy controls. The importance of this single-nucleotide polymorphism in the etiopathology of ANCA-associated vasculitides is supported by similar effect sizes that we found in British WG cases (n=105) and German patients with Churg-Strauss syndrome (n=119), which, however, miss significance level because of the relatively small cohorts available for these rare disorders. Finally, we confirm the association with MS in a cohort of 422 German patients (P=0.011, OR=1.23).

IR/R2PI-spectroscopy has been applied to the electronic ground and electronically excited states of 3-hydroxyflavone (3-HF) and 2-(2-naphthyl)-3-hydroxychromone (2-NHC) in a supersonic jet yielding direct structural information on the educt and product of a proton transfer reaction. We show that IR spectra of the electronically excited states can be recorded subsequent to a photoinduced chemical reaction, in this case a proton transfer. In combination with DFT and TDDFT calculations structural assignments are performed.

Aim: In non-diabetic patients, sympathetic innervation can be preserved even if there is major impairment of myocardial blood supply. Matters may be more complex in diabetic patients because denervation can be caused by cardiac autonomic neuropathy (CAN) or by ischemic injury. Our aim was to determine whether restrictions in myocardial blood supply have a pronounced influence on sympathetic innervation in diabetics and if this effect can be differentiated from CAN., Patients, Methods: We analyzed 20 diabetics with advanced coronary artery disease (CAD) and without known CAN. We determined quantitative myocardial blood flow using (13)N-ammonia-PET, myocardial viability with (18)F-FDG, and cardiac innervation with (11)C-HED. We investigated the relationship between regional HED retention, blood flow, and coronary flow reserve (CFR). Attenuated heart rate response to adenosine was taken as indicator for CAN (HR ratio)., Results: There was minor correlation of segmental stress flow and HED retention (r(2)=0.063, p<0.0001). Correlation improved when stress flow as well as HED retention were normalized to the individual maximum (r(2)=0.162, p<0.0001). In nine patients, a HR ratio <1.2 implicated subclinical CAN. Duration of diabetic disease or glycaemic control (HbA1c) did not correlate with mean HED retention in the viable segments, but with its variation coefficient., Conclusions: As in non-diabetic patients, a slight correlation exists between CFR and sympathetic innervation. The sensitivity of sympathetic nerves to reductions in CFR does not seem to be increased as compared to the results reported for non-diabetics. Besides impaired blood supply, long duration of diabetic disease and bad glycaemic control also seem to impair sympathetic innervation provoking higher heterogeneity.

In this paper the structure of the isolated tetrapeptide model Ac-Leu-Val-Tyr(Me)-NHMe (Leu = leucine, Val = valine, Tyr = tyrosine) is investigated by mass- and isomer-selective IR/UV double resonance spectroscopy. Two isomers of this peptide are observed and in combination with force field, ab initio, and DFT calculations these structures are assigned to folded arrangements presenting two different secondary structure binding motifs: (a) a combined gamma-turn/beta-turn structure and (b) a triple gamma-turn structure, which is described for the first time for an isolated model system in the gas phase.

In this communication we report on the conformational analysis of side-chains in the beta-sheet model system (Ac-Phe-OMe)(2) by applying IR/R2PI (infrared/resonant 2-photon ionisation) spectroscopy in the fingerprint region up to 10 microm, where in order to get information in this spectral region an extension of our new high energy and narrow band-width nanosecond IR laser system is presented.

Inflammatory bowel diseases (IBD) are multifactorial disorders characterised by the host's inability to limit the inflammatory response to luminal antigens. The association of polymorphisms in the CARD15 gene with Crohn's disease (CD) demonstrates the relevance of activated transcription factor NF(kappa)B in mononuclear cells. Interleukin 11 (IL11) mediates anti-inflammatory effects and is able to downregulate LPS-induced NF(kappa)B activation. The IL11 gene is therefore a good candidate involved in genetic predisposition to IBD. To evaluate the role of the IL11 gene in IBD, two polymorphisms, including a dinucleotide repeat in the promoter region, have been genotyped in 222 patients with CD, 152 patients with ulcerative colitis (UC) and 400 healthy controls. PCR-SSCP analysis of the coding region revealed a single polymorphism in exon 4 leading to an amino acid exchange (G335A; R112H), not significantly associated with either disease. Dinucleotide repeat frequencies of the IL11.A1 allele and of IL11.A1 homozygous individuals were significantly increased among the patients with UC (P < 0.002 and (P < 0.003, respectively) but not with CD. Altered expression of IL11 appears to be involved in the genetic predisposition of UC.

Treatment with isotretinoin (13-cis-retinoic acid, 13-cis-RA) is a recent additional option in advanced, otherwise intractable differentiated thyroid cancers. The aim of this study was to evaluate fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the prediction and the monitoring of response to 13-cis-RA therapy. Twenty-one patients with advanced differentiated thyroid cancers were investigated using 18F-FDG PET and iodine-131 whole-body scans before and 3, 6 and 9 months after initiation of 13-cis-RA therapy. After 9 months, 13-cis-RA treatment was discontinued and imaging procedures repeated 3 months later. Average 18F-FDG uptake (SUV) decreased significantly during 13-cis-RA therapy but subsequently increased in five of eight patients after withdrawal of 13-cis-RA. 18F-FDG uptake (SUV) 3 months after onset of 13-cis-RA therapy was significantly lower in patients who developed increased 131I uptake in their tumour sites than in patients with no subsequent increase in 131I uptake. There was no relationship between serum thyroglobulin level on the one hand and simultaneously measured 131I or 18F-FDG uptake on the other hand. There was a tendency towards lower 18F-FDG uptake in tumour manifestations with a better outcome. Therefore, 18F-FDG PET at 3 months after the start of treatment promises to differentiate between those patients who will eventually benefit from 13-cis-RA and those who will not. In conclusion, these data indicate that 18F-FDG PET is a useful tool for the evaluation and monitoring of adjuvant therapy with 13-cis-RA in thyroid cancer.

Background: Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Although genetic factors play an important role in the pathogenesis, little is known about the genes accountable. Immune response to intestinal bacteria seems to be crucial in the pathogenesis of IBD., Methods: To evaluate the role of the CD14 gene in IBD, a functionally relevant polymorphism in the promoter region (T/C at position -159) has been genotyped in 219 patients with Crohn disease (CD), 142 patients with ulcerative colitis (UC) and 410 healthy controls by RFLP analysis., Results: T allele and TT genotype frequencies were found increased in CD patients compared to controls (Pc=0.044 and 0.005, respectively)., Conclusion: An altered immune response to LPS seems to play a role in the genetic predisposition to CD but not to UC.

Studies of resting regional cerebral glucose consumption (rCMRGlc) in nondemented patients with Parkinson's disease (PD) have produced conflicting results, reporting both reduced and normal metabolism in advanced disease and reduced or normal metabolism after dopaminergic therapy. To investigate these issues, [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed in 11 nondemented PD patients with advanced disease and 10 age-matched controls. PD patients were studied after withdrawal of all dopaminergic medication to produce a practically defined off condition, and a second time 1 hour after levodopa, resulting in a clinical on state. Dynamic PET scans and simultaneous arterialised venous blood samples of [(18)F] activity were obtained. A graphical approach was used to generate parametric images of rCMRGlc and statistical parametric mapping to localise significant metabolic changes in PD. Compared with controls, global rCMRGlc was reduced in the on but not in the off condition in PD. In both states, significant regional reductions of glucose uptake were found in the parietal, frontal, temporal cortex, and caudate nucleus. Reductions correlated with the severity of disability in frontal and temporal cortex. Direct comparison between on and off conditions revealed relatively greater reductions of uptake in the ventral/orbital frontal cortex and the thalamus during on. Results suggest that cortical and caudate hypometabolism are common in advanced PD and that caution is mandatory if [(18)F]FDG PET is being used to differentiate advanced PD from dementia and progressive supranuclear palsy where similar reductions are seen. Furthermore, in PD, administration of levodopa is associated with further hypometabolism in orbitofrontal cortex; an area known to be relevant for reversal learning where performance is typically impaired after dopaminergic treatment., (Copyright 2001 Movement Disorder Society.)

Imbalances in the regulation of Th1 and Th2 lymphocytes are crucial in inflammatory bowel diseases. Interleukin-4 is secreted by Th2 lymphocytes and downregulates cytokine production from Th1 lymphocytes. Functionally relevant polymorphisms have been described in the interleukin-4 and the interleukin-4 receptor alpha genes. Association of inflammatory bowel diseases with these polymorphisms has been reported recently suggesting high transcription and enhanced signalling activity in Crohn's disease. Our study, comprising 211 patients with Crohn's disease, 147 patients with ulcerative colitis and 446 healthy controls revealed significant association of Crohn's disease with the -590 T allele of the interleukin-4 gene (P = 0.03). This allele entails reduced expression of IL-4. The reason for these contrasting findings may be discussed in the context of a putatively predisposing allele in linkage disequilibrium with the alleles of the interleukin-4 gene.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg-Strauss syndrome (CSS) are characterized by the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Anti-myeloperoxidase (MPO)-ANCA are a typical feature of MP and CSS, while anti-proteinase 3 (PRTN3)-ANCA are highly specific for WG. Several reports indicate that ANCA may directly contribute to pathological processes, ie, through an increase of adhesivity between polymorphonuclear (PMN) and endothelial cells (EC). PMN interact and endothelium interact via the adhesion cascade (AC). CD18 is a key molecule of the AC, as CD18 defects abrogate the adhesion of PMN and cause leukocyte adhesion deficiency, an immunodeficient trait. We have screened the entire coding and regulatory regions of the CD18 gene. Ten single nucleotide polymorphisms (SNP) were identified, four of them showing significant associations with MPO-ANCA(+) vasculitis. One of these SNP's was localized in an alternate transcription initiation site. This polymorphism may influence CD18 gene expression, resulting in dose-dependent increase in adhesion and consecutively facilitated degranulation and respiratory burst. In this manner the pro-adherent genotype may predispose to MPO-ANCA(+) vasculitis.

Unlabelled: Our objective was to investigate the properties of [1-(11)C]acetate as a quantitative perfusion tracer for myocardial PET studies., Methods: We determined the flow dependence of the effective acetate extraction by a comparison with [(13)N]ammonia in 24 patients at rest (n = 8) and under pharmacologic vasodilation (n = 16). Furthermore, we compared the statistical quality of the perfusion values derived with both tracers. Quantification was based on an irreversible 2-compartment model for [(13)N]ammonia and a reversible 1-compartment model for [1-(11)C]acetate. Area-conserving polar maps were used to determine the correlation between the unidirectional uptake parameters of both tracers on a pixel-by-pixel basis for the whole left ventricular myocardium., Results: A fit of a generalized Renkin-Crone formula to the data yielded the unidirectional acetate extraction fraction E(f) = 1 - 0.64e(-1.20/f). An extraction correction based on this formula led to good quantitative agreement of perfusion values derived with [(13)N]ammonia and [1-(11)C]acetate over the whole observed flow range (average difference of flow values, 3%; correlation coefficient, 0.96). This agreement proved the applicability of acetate as a quantitative perfusion tracer even under stress conditions. An analysis of the statistical properties of the parameter estimates showed, moreover, that statistical errors were reduced by a factor of nearly 2 in comparison with ammonia., Conclusion: [1-(11)C]acetate allows accurate quantification of myocardial perfusion with PET at rest as well as under stress conditions. The use of acetate leads to distinctly improved statistical accuracy for the perfusion estimates in comparison with ammonia. This accuracy facilitates the generation of reliable parametric polar maps, which are especially useful for clinical application of myocardial perfusion quantification.

The frequency of carriers of the alpha1-antitrypsin (alpha1-AT) deficiency allele PI*Z is increased in patients with Wegener's granulomatosis (WG). The polymorphic protease inhibitor (PI) gene is part of a cluster of serine protease inhibitor (serpin) genes (AACT; alpha1-antichymotrypsin, PCI; protein C inhibitor, CBG; corticosteroid binding globulin, PIL; PI-like pseudogene) at chromosome 14q32.1. In this study we investigated whether the serpin gene cluster contributes to the background of Wegener's granulomatosis. Therefore, phenotyping of alpha1-AT was performed and simple tandem repeat polymorphisms (STRP) in the genes for CBG, PI, and PCI as well as two STRP (D14S55 and D14S48) flanking the centromeric and one (D14S51) flanking the telomeric region of the gene cluster were examined in a population of 79 patients with WG and 128 unrelated healthy controls. In WG patients an increased frequency of the PI*Z defective allele is demonstrated as well as a linkage disequilibrium between all members of this gene cluster plus the centromeric and telomeric STRP. These results indicate an involvement of the serpin genes in the pathogenesis of Wegener's granulomatosis and it is possible that other genes located in the vicinity of D14S55 or D14S51 contribute to the genetic background of the disease., (Copyright 2000 Academic Press.)

Objective: Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Genetic factors play an important role in the pathogenesis, but little is known about the accountable genes. Increased secretion of pro-inflammatory cytokines appears crucial in the initiation of the inflammatory response., Methods: To evaluate the role of the IL-6 gene in IBD, a functionally relevant polymorphism in the promoter region (G/C at position -174) has been genotyped in 169 patients with Crohn's disease (CD), 133 patients with ulcerative colitis (UC) and 440 healthy controls by using restriction fragment length polymorphism (RFLP) analysis., Results: No significant differences were apparent in the allele, genotype and carrier frequencies between patients and controls., Conclusion: High secretion of IL-6 does not seem to play a major role in the genetic predisposition to IBD.

Background: Wegener's granulomatosis (WG) is a rare systemic autoimmune disease characterized by small-vessel vasculitis leading to organ damage and the presence of antineutrophil cytoplasmic autoantibodies (ANCAs). ANCAs were shown to be involved in the pathogenesis of the disease by increasing adhesion of polymorphonuclear cells (PMNs) to endothelial cells and through activation of primed PMN. The main autoantigen of ANCA in WG is proteinase 3 (PR3), a neutrophil- and monocyte-derived neutral serine protease. The association of WG with individuals continuously expressing a high level of PR3 on the surface of PMNs suggests that PR3 variants or altered regulation of PR3 expression might be directly involved in the pathogenesis of the disease., Methods: We screened the entire coding and promoter sequences of the PR3 gene for polymorphisms by means of polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). Allelic, genotypic, and haplotype frequencies were compared between 79 WG patients and a cohort of 129 healthy controls., Results: Seven single-nucleotide polymorphisms (SNPs), one amino acid change (Val119Ile), one 84 bp insertion/deletion, and a microsatellite were identified. An association with WG could be demonstrated for the A-564G polymorphism in the PR3 promoter affecting a putative transcription factor-binding site., Conclusions: This study excludes certain PR3 epitope variants as autoantigenic stimuli in WG, since the Val119Ile polymorphism showed no differences between patients and controls. Overexpression of PR3, however, might predispose the patient to the development of autoimmune ANCA-associated vasculitis.

Although genetic predisposition for inflammatory bowel disease (IBD) is well established, little is known about the accountable genes. The pathogenesis of IBD is characterized by an imbalanced activation of Th1- and Th2-lymphocytes. IL-10 represents an anti-inflammatory cytokine which downregulates the production of Th1-derived cytokines. To evaluate the role of the IL-10 gene in IBD, two polymorphisms in the promoter region (G/A at position -1082 and C/A at position -592) were genotyped in 142 patients with Crohn's disease (CD), 104 patients with ulcerative colitis (UC), and 400 healthy controls. Significant differences were not apparent, neither in the allele frequencies of either polymorphism, nor in the haplotype frequencies. Screening of the coding region of the IL-10 gene by polymerase chain reaction--single strand conformation polymorphism (PCR-SSCP) analysis revealed a rare sequence variation in exon 1 leading to an amino acid exchange (G-->A; G15R) in two patients with CD and five healthy controls. Therefore, polymorphisms of the IL-10 gene are not demonstrably involved in the predisposition of IBD in our cohorts of patients.

Intestinal vasculitis caused by persistent measles virus infection of intestinal endothelial cells was described in Crohn's disease. Furthermore, endothelial cell autoantibodies have been demonstrated in inflammatory bowel disease (IBD). Autoantibodies against intestinal endothelial cells were visualized by indirect immunofluorescence in patients with IBD, in their healthy first-degree relatives, in patients with infectious enterocolitis, and in healthy, unrelated controls. In intestinal tissue specimens of 22 antibody-positive IBD patients a search for the measles virus genome was performed. Endothelial cell autoantibodies were significantly more frequent in patients with IBD, in both groups of first-degree relatives, and in patients with infectious enterocolitis than in the healthy controls (P = 0.0002 or less). The measles virus genome was found in none of the intestinal biopsies. Endothelial cell autoantibodies are not a genetic but rather an epigenetic (infectious) marker of disease susceptibility. The expression of these autoantibodies is unlikely to be triggered by a persistent measles virus infection.

Wegener granulomatosis (WG), microscopic polyangiitis (MP), and Churg Strauss syndrome (CSS) are rare systemic autoimmune disorders. Common features are anti-neutrophil cytoplasmic antibodies (ANCA) in patient sera. Whereas WG patients show mainly anti-proteinase 3 ANCA, MP and CSS patients typically present anti-myeloperoxidase (MPO) ANCA. ANCA play an important role in the pathogenesis in the vessel wall by activating polymorphonuclear cells (PMN) and increased adhesivity between PMN and endothelial cells via adhesion molecules. Here we investigated major adhesion molecules as predisposition factors via common polymorphisms in or in the vicinity of the candidate genes ICAM-1, e-selectin, PLAUR, CD11b, and CD18. A restriction fragment-length polymorphism in exon 11 of the CD18 gene was associated with MPO-ANCA(+) systemic vasculitis. Our data indicate that a common variant of the CD18 gene confers increased risk for CSS and MP, supporting that genetic factors are involved in the etiology and pathogenesis of ANCA-associated systemic vasculitides., (Copyright 2000 Academic Press.)

The aim of this study was to demonstrate the necessity of an off-centre uniformity measurement during performance evaluation and acceptance testing of a positron emission tomography (PET) system. To this end, the effect of different methods of geometric arc correction on image uniformity was considered. The arc correction routine of the system software of a particular PET scanner family was tested in computer simulations, phantom measurements and a patient study. Various methods of geometric arc correction--nearest neighbour interpolation, linear interpolation and cubic smoothing spline interpolation--were applied to the same data. Uniformity was evaluated both visually and quantitatively using intensity profiles and regions of interest. The arc correction routine of the PET scanner family produced significant ring artefacts and led to overestimation of tracer uptake by up to 15%. Since uniformity measurements are usually performed using a cylindrical phantom at the centre of the transverse field of view, these artefacts are not detected. In conclusion, the standards for performance evaluation of a PET scanner should be extended by inclusion of an off-centre uniformity measurement at the edge of the transverse field of view. On the basis of our comparison of different methods for geometric arc correction, we suppose that cubic smoothing spline interpolation might improve the relation between statistical noise reduction and spatial resolution as compared with conventional linear interpolation.

Wegener's granulomatosis (WG) and microscopic polyangiitis are systemic autoimmune diseases characterized by the presence of ANCA in the sera of patients. Little is known about the aetiologic factors and genetic predisposition as well as the pathogenesis of these disease entities. A slightly decreased representation of HLA-DRB1*13 and HLA-DQB1*0603 individuals was observed in our cohort of ANCA-associated systemic vasculitis (AASV) patients compared with controls. In addition, HLA-DRB1*04 individuals were over-represented in a subgroup of patients with WG in end-stage renal disease as a result of renal vasculitis. In order to identify other genes relevant for these diseases, we investigated highly polymorphic markers in the vicinity of several immunorelevant genes, i.e. tumour necrosis factor (TNF)alpha, IL-2, IL-5 receptor alpha (IL-5RA), in a group of 102 patients with AASV and compared the representation with controls. Furthermore, functional polymorphisms were directly analysed in the promotor region of TNFalpha as well as in the coding region of the FcgammaIIRA genes. Polymorphisms of the TNFalpha promotor (TNF-308) as well as in the FcgammaIIRA gene were excluded as risk factors for the disease in our cohort. No major phenotype distribution differences were observed between patients and controls for the IL-2 and IL-5RA microsatellites. Most importantly, several haplotypes on chromosome 6p appeared strongly associated with proteinase 3 (PR3)-ANCA+ AASV. Thus, as in other autoimmune diseases, different predisposing factors play differential aetiopathogenic roles in various groups of AASV patients.

CD40 and its ligand CD40L are key players in T cell-B cell interaction and T cell-antigen-presenting cell (APC) interaction. Inhibition of CD40-CD40L interaction leads to severe humoral and cellular immunodeficiency. In this study we examined the presence of soluble CD40 (sCD40) in the serum of haemodialysis (HD) patients, CAPD patients, chronic renal failure (CRF) patients and healthy donors in order to evaluate the possible involvement of CD40 in uraemic immunodeficiency. Soluble CD40 was detected in the serum of healthy donors (n = 41) with a mean of 0.14 +/- 0.12 ng/ml and in the urine of healthy donors with a mean of 1.80 +/- 0.74 ng/ml. Soluble CD40 was highly elevated in all patients with impaired renal function. HD patients (n = 22) had up to 100-fold elevated sCD40 levels with a mean concentration of 8.32 +/- 4.11 ng/ml, whereas CAPD patients (n = 10) had considerably lower levels of sCD40 with a mean of 3.58 +/- 2.40 ng/ml. A strong correlation between sCD40 and serum creatinine levels was noted in CRF patients (n = 66). The highly elevated levels of sCD40 may point to the involvement of CD40 and its ligand CD40L in the clinical manifestation of uraemic immunodeficiency.

Endogenous uveitis is a T cell mediated autoimmune disease leading to impairment of visual acuity. The association of different uveitis entities with HLA-class I antigens and the discovery of antigenic mimicry between a peptide of uveitis-associated HLA-class I antigens and a peptide of retinal autoantigen led to a new hypothesis for the pathogenesis of uveitis. On the basis of this mechanism an open trial of oral tolerance induction with the HLA-peptide B27PD was initiated for nine patients with long lasting, therapy-refractive uveitis. Within 6 weeks of oral peptide treatment all patients responded with a marked decrease of intraocular inflammation, which allowed a reduction of systemic corticosteroids in seven patients. One patient, who suffered from an acute relapse, responded within 2 weeks, followed by an increase of visual acuity. In addition, two patients discontinued azathioprine immediately prior to oral tolerance induction without the occurrence of relapses. Visual acuity remained unchanged or increased in 14 of 16 eyes. One patient did not finish oral peptide treatment. None of these patients experienced any adverse events. It was concluded that the oral application of highly tolerogenic peptides might be a potent approach for the treatment of autoimmune diseases.

Introduction: An association between different HLA-subtypes and ulcerative colitis has been described in various study populations of different ethnic and geographic background. Moreover, a correlation between HLA-DR2 and ulcerative colitis, in particular p-ANCA-positive ulcerative colitis, was reported. Thus, the present study aimed on the correlation of HLA-DRB1* alleles with the presence of p-ANCA and clinical characteristics in individuals of southern german descent., Patients and Methods: The study population comprised 56 patients with ulcerative colitis and 177 healthy controls. HLA-DRB1* alleles were assessed by use of the dot blot method. Autoanti-bodies were visualized by indirect immunofluorescence on ethanol-fixed neutrophils., Results: The allele HLA-DRB1*12 was more frequent in patients with ulcerative colitis (p = 0.01). After correction for the number of alleles tested (n = 16) statistical significance was no longer preserved. A weak association between the presence of HLA-DR5 and the detection of p-ANCA in ulcerative colitis was found (p = 0.0375). After correction for the number of comparisons (n = 10) no associations between HLA-DR antigens and the presence of p-ANCA remained. Furthermore, no significant correlations between clinical characteristics of ulcerative colitis and HLA-DR antigens were detected., Discussion: Genes encoding for HLA-DR antigens are unlikely to have an impact on the heredity and the presence of disease phenotypes of ulcerative colitis in a study population of southern german descent.

Background: The present study was performed to analyse the immunological properties of the autoantigens recognized by autoantibodies against exocrine pancreas (PAb), which have been described in Crohn's disease., Methods: Autoantibodies were detected by indirect immunofluorescence. Inhibition studies were performed by preincubating tissue sections with various glycoproteins and the different fractions obtained in fractioned salt precipitation of pancreas homogenate with ammonium sulphate. Immunoblotting of human pancreas homogenate was conducted using PAb-positive sera., Results: In size exclusion chromatography, the molecular weight of the pancreas autoantigen (PAg) was determined as > 800 kD. In the fractionated salt precipitation, the autoantigen could be detected in fractions I (0-25% ammonium sulphate) and III (50-90% ammonium sulphate). In immunoblotting, a number of protein bands were observed (at 16, 18, 19, 24, 27, 29, 31 and 34 kD), and the binding pattern showed little variation between individual patients., Conclusions: The protein that is recognized by PAb appears to be a large protein complex consisting of several subunits which exhibit reactivity to PAb.

Peritoneal mesothelial cells are considered the predominant source of peritoneal prostanoid formation because they represent the largest resident cell population in the peritoneal cavity. The present study was designed to evaluate the effect of D-glucose, which is widely used in commercially available peritoneal dialysis fluids as an osmotic compound, on the synthesis of prostaglandins in cultured human mesothelial cells (HMC). Analysis of eicosanoid synthesis in HMC by reversed-phase HPLC revealed that 6-keto-PGF1alpha, the spontaneous hydrolysis product of prostacyclin (PGI2), and prostaglandin E2 (PGE2) were the main eicosanoids produced. Addition of D-glucose resulted in a time- and concentration-dependent (30 to 120 mM) increase in PGE2 production in HMC (24 h, 90 mM: 3.9+/-0.5 ng/10(5) cells versus 2.3+/-0.3 in untreated cells; P < 0.05). Mannitol (90 mM) or L-glucose (90 mM). nonmetabolizable osmotic compounds, also led to a significant (P < 0.05) but less intense increase in PGE2 synthesis (3.3+/-0.4 and 3.2+/-0.5 ng/10(5) cells, respectively). Increased PGE2 synthesis was completely blunted by coincubation with the specific protein kinase C (PKC) inhibitor Ro 31-8220 or downregulation of PKC activity by preincubation with phorbol myristate acetate for 16 h. Furthermore, coincubation with PD 98059, an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway, also inhibited increased PGE2 synthesis by D-glucose or mannitol. In contrast, the iso-osmolar glucose polymer icodextrin, which is used as an alternative to D-glucose in peritoneal dialysis solutions, had no effect on PGE2 synthesis. These data indicate that D-glucose and metabolically inert sugars increase PGE2 synthesis in HMC at least in part by hyperosmolarity and that this effect requires activation of PKC and the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway of intracellular signaling.

Introduction: Data about the nature and pathophysiological relevance of the target antigens reacting with perinuclear antineutrophil cytoplasmatic autoantibodies (p-ANCA) in ulcerative colitis are inconsistent and partly conflicting. In the majority of the previous studies only one singular potential target antigen was investigated. The present study aimed on the simultaneous assessment of five different p-ANCA subtypes in patients with ulcerative colitis and attempted to detect reactivity against one of the previously described antigens and to correlate specificity for different target antigens with clinical features of the disease., Methods: Sera from 61 patients with ulcerative colitis and from 56 healthy controls were tested using indirect immunofluorescence and enzyme-linked immunosorbent assays specific for elastase, lactoferrin, cathepsin G, myeloperoxidase and bactericidal permeability increasing protein (BPI). p-ANCA subtypes were correlated with clinical features of ulcerative colitis like disease extent or presence of extraintestinal manifestations. Moreover, a possible correlation to current immunosuppressive therapy was evaluated., Results: In 46% (28/61) of patients with ulcerative colitis and in 4% (2/56) of the controls p-ANCA were detected. p-ANCA subtypes were distributed as follows: 26% (16/61) anti-BPI. 16% (10/61) anticathepsin G, 15% (9/61) antielastase, 7% (4/61) antilactoferrin, 5% (3/61) antimyeloperoxidase. Presence of anticathepsin G antibodies was negatively correlated with immunosuppressive therapy. No further correlations between p-ANCA subtypes and clinical characteristics were observed., Discussion: p-ANCA subtypes in inflammatory bowel disease react with a variety of different target antigens and are not correlated with clinical features of the disease.