Negative association of the chemokine receptor CCR5 d32 polymorphism with systemic inflammatory response, extra-articular symptoms and joint erosion in rheumatoid arthritis

Introduction Chemokines and their receptors control immune cell migration during infections as well as in autoimmune responses. A 32 bp deletion in the gene of the chemokine receptor CCR5 confers protection against HIV infection, but has also been reported to decrease susceptibility to rheumatoid arthritis (RA). The influence of this deletion variant on the clinical course of this autoimmune disease was investigated. Methods Genotyping for CCR5d32 was performed by PCR and subsequent electrophoretic fragment length determination. For the clinical analysis, the following extra-articular manifestations of RA were documented by the rheumatologist following the patient: presence of rheumatoid nodules, major organ vasculitis, pulmonary fibrosis, serositis or a Raynaud's syndrome. All documented CRP levels were analyzed retrospectively, and the last available hand and feet radiographs were analyzed with regards to the presence or absence of erosive disease. Results Analysis of the CCR5 polymorphism in 503 RA patients and in 459 age-matched healthy controls revealed a significantly decreased disease susceptibility for carriers of the CCR5d32 deletion (Odds ratio 0.67, P = 0.0437). Within the RA patient cohort, CCR5d32 was significantly less frequent in patients with extra-articular manifestations compared with those with limited, articular disease (13.2% versus 22.8%, P = 0.0374). In addition, the deletion was associated with significantly lower average CRP levels over time (median 8.85 vs. median 14.1, P = 0.0041) and had a protective effect against the development of erosive disease (OR = 0.40, P = 0.0047). Intriguingly, homozygosity for the RA associated DNASE2 -1066 G allele had an additive effect on the disease susceptibility conferred by the wt allele of CCR5 (OR = 2.24, P = 0.0051 for carrier of both RA associated alleles) Conclusions The presence of CCR5d32 significantly influenced disease susceptibility to and clinical course of RA in a German study population. The protective effect of this deletion, which has been described to lead to a decreased receptor expression in heterozygous patients, underlines the importance of chemokines in the pathogenesis of RA

Feasibility and morbidity of combined hyperthermia and radiochemotherapy in recurrent rectal cancer - Preliminary results

Background: The local recurrence rate of colorectal cancer has been significantly reduced due to the use of combined radiochemotherapy. Despite this improvement regarding locally advanced tumour recurrences, the treatment strategy for pre-treated patients remains difficult and unresolved. Patients and Methods: We analysed treatment and follow-up data of 14 patients with local recurrence of rectal cancer who were treated with radiation therapy (RT), chemotherapy (CT) and regional hyperthermia (RHT) from November 1997 to December 2001. Nine of these patients had received irradiation and CT (=pre-treated patients) in the past. For this group, 30.6-39.6 Gy RT, 5-fluorouracil (5-FU) as a continuous infusion over 5 days per week (350 mg/m(2)/24 h) combined with RHT twice a week was given. The 5 remaining patients (=not pre-treated) received conformal irradiation of 45 Gy with a boost between 9 and 14.4 Gy, combined with continuous infusion of 5-FU on days 1-4, and 29-33 (500 mg/m(2)/24 h), and RHT twice a week. Response to therapy was evaluated by means of computed tomography (CT) or magnetic resonance imaging (MRI) and by clinical follow-up. Results: Among 13 evaluated cases, the overall objective response rate was 54% (5 complete responses, 2 partial responses). At mean follow-up of 13.9 months (range 5-32 months) 7 patients were alive. Conclusion: The therapeutic regimen appears to be active in the treatment of local recurrences of rectal cancer. Larger-scaled studies are needed to evaluate the potency of hyperthermia in this therapeutic strategy

Validation scheme for solar coronal models : Constraints from multi-perspective observations in EUV and white-light

Context. In this paper, we present a validation scheme to investigate the quality of coronal magnetic field models, which is based on comparisons with observational data from multiple sources. Aims. Many of these coronal models may use a range of initial parameters that produce a large number of physically reasonable field configurations. However, that does not mean that these results are reliable and comply with the observations. With an appropriate validation scheme, which is the aim of this work, the quality of a coronal model can be assessed. Methods. The validation scheme was developed with the example of the EUropean Heliospheric FORecasting Information Asset (EUHFORIA) coronal model. For observational comparison, we used extreme ultraviolet and white-light data to detect coronal features on the surface (open magnetic field areas) and off-limb (streamer and loop) structures from multiple perspectives (Earth view and the Solar Terrestrial Relations Observatory - STEREO). The validation scheme can be applied to any coronal model that produces magnetic field line topology. Results. We show its applicability by using the validation scheme on a large set of model configurations, which can be efficiently reduced to an ideal set of parameters that matches best with observational data. Conclusions. We conclude that by using a combined empirical visual classification with a mathematical scheme of topology metrics, a very efficient and objective quality assessment for coronal models can be performed.Peer reviewe

Citizen Empowerment by a Technical Approach for Privacy Enforcement

It is a fundamental right of every natural person to control which personal information is collected, stored and processed by whom, for what purposes and how long. In fact, many (cloud based) services can only be used if the user allows them broad data collection and analysis. Often, users can only decide to either give their data or not to participate in communities. The refusal to provide personal data results in significant drawbacks for social interaction. That is why we believe that there is a need for tools to control one\u27s own data in an easy and effective way as protection against economic interest of global companies and their cloud computing systems (as data collector from apps, mobiles and services). Especially, as nowadays everybody is permanently online using different services and devices, users are often lacking the means to effectively control the access to their private data. Therefore, we present an approach to manage and distribute privacy settings: PRIVACY-AVARE is intended to enable users to centrally determine their data protection preferences and to apply them on different devices. Thus, users gain control over their data when using cloud based services. In this paper, we present the main idea of PRIVACY-AVARE

The contact-mediated response of peripheral-blood monocytes to preactivated T cells is suppressed by serum factors in rheumatoid arthritis

Stimulation of monocytes/macrophages after cell contact with preactivated T cells has been suggested to contribute to the excessive TNF-α production in rheumatoid arthritis (RA). In this study, T cell-contact-dependent TNF-α production by peripheral-blood monocytes in vitro was investigated and found to be significantly lower in treated and untreated patients with RA than in healthy controls. This suppression was not due to a general deficiency of monocytes to respond, because responses to lipopolysaccharide were comparable in patients and controls. In agreement with the pivotal role of TNF-α in RA, T cell-dependent induction of TNF-α in synovial macrophages was fivefold to tenfold higher than in peripheral-blood monocytes from either patients or controls. The decreased response of peripheral-blood monocytes from patients with RA was found to be mediated by inhibitory serum factors, because the addition of patient sera to monocytes from healthy controls suppressed TNF-α response in the co-culture assay. Preincubation of monocytes from healthy controls with RA serum was sufficient to suppress the subsequent TNF-α response in T cell co-cultures, indicating that inhibitory factors do indeed bind to monocyte surfaces, which might represent a regulatory counter-action of the immune system to the long-standing and consuming autoimmune process in RA. There are some indications that apolipoprotein A-1 might be part of this regulatory system

Increased Expression of Cell-Cell Signaling Genes by Stimulated Mononuclear Leukocytes in Patients with Previous Atherothrombotic Stroke A Whole Genome Expression Profile Study

Background/Aims: Inflammation plays an important role in atherosclerosis and stroke. Acute infections are recognized as trigger factors for ischemic stroke. Methods: In this whole genome expression profile study of 15 patients and 15 control subjects, we tested the hypothesis that patients with a history of atherothrombotic stroke show enhanced transcription of inflammatory genes in circulating leukocytes. RNA from unstimulated or lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) was analyzed with Affymetrix U133A GeneChips using a pooling design. Expression of single genes and functional groups of genes was analyzed by global statistical tests. Results: A total of 10,197 probe sets showed positive calls. After correction for multiple testing no single probe set revealed significant differences either without or with LPS stimulation. However, significant global expression differences were found upon LPS stimulation for the group of genes that are involved in cell-cell signaling. Conclusion: LPS stimulation of PBMCs, a condition mimicking bacterial infection, induces differential expression of a group of cell-cell signaling genes in patients with previous atherothrombotic stroke. This finding can be caused by genetic differences between both groups, but acquired risk factors, medication and technical factors may also have contributed to the result. Copyright (C) 2009 S. Karger AG, Base

Comprensión del concepto de triángulo de estudiantes universitarios, en el marco teórico de los registros de representación semiótica

Este artículo hace parte de una investigación que tiene como objetivo la comprensión del concepto de triángulo en estudiantes universitarios desde los registros de representación semióticos y secuencias de enseñanza, mediadas por material físico y entornos informáticos. El marco teórico son los sistemas de representación semiótica, la metodología es de tipo cualitativa, apoyada en una ingeniería didáctica. Los resultados muestran cómo los estudiantes usan situaciones problema, representaciones, conceptos, argumentos, procedimientos y propiedades que configuran el concepto de triángulo. Esto ha permitido concluir que los estudiantes muestran diferencias en las formas de argumentar, demostrar y establecer relaciones entre los elementos matemáticos

Herausforderungen bei der Entwicklung von Anwendungen zum Selbstdatenschutz

Durch zunehmende Vernetzung steigt die Notwendigkeit, Betroffene in der Ausübung ihres Privatsphärenschutzes zu unterstützen. Wenn technische Lösungen dabei in die Integrität urheberrechtlich geschützter Computerprogramme eingreifen oder Geschäftsmodelle „Dienst gegen Daten“ vereiteln, stellt sich die Frage der urheber-und lauterkeitsrechtlichen Bewertung im Spannungsverhältnis zum Selbstdatenschutz. In diesem Beitrag werden die rechtlichen Herausforderungen, auch im Hinblick auf aktuelle Vorschläge der Datenökonomisierung, beleuchtet und mit einem Exkurs zu den Anforderungen der intelligenten Bereitstellung generierter Daten zur Verschleierung persönlicher Informationen abgeschlossen

PRIVACY-AVARE: An approach to manage and distribute privacy settings

Privacy enhancing technologies become increasingly necessary as more and more personal data is collected. Especially, as nowadays everybody is permanently online using different applications and devices, users are often lacking the means to effectively control the access to their private data. Existing approaches provide only isolated solutions for one device and are limited in functionality to control data access. Moreover, existing solutions may not be legally compliant and lack usability, especially for non-experts. Therefore, we present an interdisciplinary approach to manage and distribute privacy settings: PRIVACY-AVARE is intended to enable users to centrally determine their data protection preferences and to apply them globally on different devices (mobiles, tablets, smart homes, cars, ...). In this paper, we present PRIVACY-AVARE by first introducing and discussing main functional and non-functional requirements with a special focus on compliance and usability requirements. Based on this discussion, we then develop a conceptual solution. Finally, we discuss the limitations of our approach and give an outlook

Associations between MTHFR 1793G>A and plasma total homocysteine, folate, and vitamin B12 in kidney transplant recipients

Associations between MTHFR 1793G>A and plasma total homocysteine, folate, and vitamin B12 in kidney transplant recipients.BackgroundCurrently, no evidence is available on the putative associations between a novel single nucleotide polymorphism of the 5,10-methylenetetrahydrofolate reductase gene MTHFR 1793G>A and plasma levels of vitamin B12, folate, or total homocysteine (tHcy).MethodsIn a cross-sectional study of 730 kidney allograft recipients, patients were categorized by MTHFR 1793G>A genotype. In univariate and multivariate linear regression models that allowed the outcome variables vitamin B12, folate, and tHcy plasma levels to follow a gamma distribution, we tested for possible associations of allelic variants of MTHFR 1793G>A and these three dependent variables. As hypothesized in previous work, we specifically evaluated possible effect modification between the MTHFR 1793G>A and 1298A>C mutations on these outcomes.ResultsThe allele frequency for MTHFR 1793G>A was 0.052. Heterozygosity (N = 72) or homozygosity (N = 2) for MTHFR 1793G>A was not independently associated with plasma levels of vitamin B12 (P = 0.33) or tHcy (P = 0.70), but a borderline association with higher folate concentrations was detected (Δfolate = 1.91 nmol/L) (95% CI -0.03 to 3.86 nmol/L) (P = 0.05). Further, we found strong and significant positive interactions between the MTHFR 1793G>A and 1298A>C mutations on vitamin B12 concentrations.ConclusionHigher folate concentrations in kidney transplant recipients with MTHFR 1793GA or 1793AA and markedly higher concentrations of vitamin B12 in patients with combined MTHFR 1793G>A and 1298A>C mutations may contribute to the survival advantage that has been postulated for such patients showing these genotypes