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Objective: To test the reliability of Outcome Measures in Rheumatology Clinical Trials (OMERACT) consensus-based ultrasound definitions for normal and vasculitic temporal and axillary arteries in patients with giant cell arteritis (GCA) and in controls., Methods: A preliminary 1-day meeting and a full 3-day meeting fulfilling OMERACT Ultrasound Group guidelines were held. Temporal and axillary arteries were examined at 2 timepoints by 12 sonographers on 4 patients with GCA and 2 controls. The aim was to test inter- and intrareader reliability for normal findings, halo sign, and compression sign. In both meetings, patients had established GCA. Pathology was more recent in the full meeting, which was preceded by 6 h of training. Scanning time was 15-20 min instead of 10-13 min., Results: In the preliminary exercise, interreader reliabilities were fair to moderate for the overall diagnosis of GCA (Light κ 0.29-0.51), and poor to fair for identifying vasculitis in the respective anatomical segments (Light κ 0.02-0.46). Intrareader reliabilities were moderate (Cohen κ 0.32-0.64). In the main exercise, interreader reliability was good to excellent (Light κ 0.76-0.86) for the overall diagnosis of GCA, and moderate to good (Light κ 0.46-0.71) for identifying vasculitis in the respective anatomical segments. Intrareader reliability was excellent for diagnosis of GCA (Cohen κ 0.91) and good (Cohen κ 0.71-0.80) for the anatomical segments., Conclusion: OMERACT-derived definitions of halo and compression signs of temporal and axillary arteries are reliable in recent-onset GCA if experienced sonographers (> 300 examinations) have 15-20 min for a standardized examination with prior training and apply > 15 MHz probes.

Objectives: To define the elementary ultrasound (US) lesions in giant cell arteritis (GCA) and to evaluate the reliability of the assessment of US lesions according to these definitions in a web-based reliability exercise., Methods: Potential definitions of normal and abnormal US findings of temporal and extracranial large arteries were retrieved by a systematic literature review. As a subsequent step, a structured Delphi exercise was conducted involving an expert panel of the Outcome Measures in Rheumatology (OMERACT) US Large Vessel Vasculitis Group to agree definitions of normal US appearance and key elementary US lesions of vasculitis of temporal and extracranial large arteries. The reliability of these definitions on normal and abnormal blood vessels was tested on 150 still images and videos in a web-based reliability exercise., Results: Twenty-four experts participated in both Delphi rounds. From originally 25 statements, nine definitions were obtained for normal appearance, vasculitis and arteriosclerosis of cranial and extracranial vessels. The 'halo' and 'compression' signs were the key US lesions in GCA. The reliability of the definitions for normal temporal and axillary arteries, the 'halo' sign and the 'compression' sign was excellent with inter-rater agreements of 91-99% and mean kappa values of 0.83-0.98 for both inter-rater and intra-rater reliabilities of all 25 experts., Conclusions: The 'halo' and the 'compression' signs are regarded as the most important US abnormalities for GCA. The inter-rater and intra-rater agreement of the new OMERACT definitions for US lesions in GCA was excellent., Competing Interests: Competing interests: None declared.

Objectives: To summarize and compare the benefits and harms of biological agents used as monotherapy for rheumatoid arthritis (RA) in order to inform decisions for patients who are intolerant to conventional DMARD therapy., Methods: We searched MEDLINE, EMBASE, CENTRAL, and other sources for randomised trials that compared biological monotherapy with methotrexate, placebo, or other biological monotherapies. Primary outcomes were ACR50 and the number of patients who discontinued due to adverse events. Our network meta-analysis was based on mixed-effects logistic regression, including both direct and indirect comparisons of the treatment effects, while preserving the randomised comparisons within each trial. PROSPERO identifier: CRD42012002800., Results: The analysis comprises 28 trials (8602 patients), including all nine biological agents approved for RA. Eight trials included "DMARD-naïve", and 20 "DMARD-Inadequate responder" (DMARD-IR) patients. All agents except anakinra and infliximab were superior (p < 0.05) to placebo (i.e., no DMARD treatment) with regard to ACR50. Etanercept and rituximab were superior to anakinra (p = 0.018 and p = 0.049, respectively). Tocilizumab was superior to adalimumab (p = 0.0082), anakinra (p = 0.0083), certolizumab (p = 0.037), and golimumab (p = 0.049). No differences among etanercept, tocilizumab, and rituximab were found (p > 0.52). However, because rituximab was evaluated in just 40 patients, our confidence in the estimates is limited. When including only DMARD-IR trials, the same statistical pattern emerged; in addition etanercept and tocilizumab were superior to abatacept. At recommended doses, both etanercept and tocilizumab were superior to adalimumab and certolizumab. No statistically significant differences among biological agents were found with respect to discontinuation due to adverse events (p > 0.068)., Conclusions: Evidence from randomised trials suggests that most biological agents are effective as monotherapy. Although our confidence in the estimates is limited, etanercept or tocilizumab may be the optimal choice for most patients who need treatment with biological monotherapy. However, given our limited confidence in the estimates including possibility of bias, it is appropriate to strongly weight patients׳ preferences and values in the final treatment choice., (Copyright © 2017 Elsevier Inc. All rights reserved.)

This study aims to investigate 1-year hand bone loss (HBL 1-year ) in early rheumatoid arthritis (RA) patients treated with a methotrexate (MTX) and intra-articular triamcinolone treat-to-target strategy +/- adalimumab and to determine if HBL 6months is associated with radiographic progression after 2 years. In a clinical trial (OPERA) of 180 treatment-naive early RA patients, bone mineral density (BMD) was estimated from hand radiographs with digital X-ray radiogrammetry (DXR) at baseline, after 6 (n = 90) and 12 months (n = 70) of follow-up. Baseline and 2-year radiographs were scored according to the Sharp/van der Heijde method. Baseline characteristics and HBL 6months (0-6 months changes in DXR-BMD) were investigated as predictors of structural damage by univariate linear (∆ total Sharp/van der Heijde score (TSS) as dependent variable) and logistic (+/-radiographic progression (∆TSS >0) as dependent variable) regression analyses. Variables with p < 0.10 were included in multivariable models. In 70 patients with available HBL 1-year data, HBL 1-year was median (interquartile range (IQR)) -1.9 (-3.3; -0.26 mg/cm 2 ) in the MTX + placebo group and -1.8 (-3.6; 0.06) mg/cm 2 in the MTX + adalimumab group, p = 0.98, Wilcoxon signed-rank. Increased HBL (compared to general population reference values) was found in 26/37 and 23/33 patients in the MTX + placebo and MTX + adalimumab groups, chi-squared = 0.99. In 90 patients with HBL 6months data and 2-year radiographic data, HBL 6months was independently associated with ∆TSS after 2 years (β = -0.086 (95% confidence interval = -0.15; -0.025) TSS unit/mg/cm 2 increase, p = 0.006) but not with presence of radiographic progression (∆TSS >0) (OR 0.96 (0.92-1.0), p = 0.10). In early RA patients treated with a methotrexate-based treat-to-target strategy, the majority of patients had increased HBL 1-year , irrespective of adalimumab; HBL 6months was independently associated with ∆TSS after 2 years.

Objectives: To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses in patients with AS treated with their first tumour necrosis factor-alpha inhibitor (TNFi) therapy in routine care., Methods: Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan-Meier plots, Cox and logistic regression analyses by smoking status (current/never/previous) were calculated for treatment adherence and BASDAI 50%/20 mm-response. Additional stratified analyses were performed for gender and TNFi-type., Results: Of 1576 AS patients included in the study, 1425(90%) had known smoking status (current/never/previous: 43%/41%/16%). The median follow-up time was 2.02 years (IQR 0.69-5.01). At baseline, current smokers compared with never smokers had longer disease duration (4 years (1-12)/2 years (0-10)), higher BASDAI (61 mm (47-73)/58 mm (44-70)), BASFI (53 mm (35-69)/46 mm (31-66)) and BASMI (40 mm (20-60)/30 mm (10-50)) scores (all P < 0.01). Current and previous smokers had shorter treatment adherence than never smokers (current: 2.30 years (1.81-2.79) (median (95% CI)); previous: 2.48 years (1.56-3.40), never: 4.12 years (3.29-4.95)), P < 0.0001). Similar results were found in multivariate analyses (current versus never smokers, HR 1.41 (95% CI 1.21-1.65), P < 0.001), most pronounced among men. Current smokers had poorer 6 months' BASDAI50%/20 mm-response rate than never smokers (42%/58%, P < 0.001). In multivariate analyses, current smokers had lower odds of achieving BASDAI50%/20 mm-response than never smokers, both overall (OR 0.48 (95% CI 0.35-0.65), P < 0.0001) and for the different TNFi-types (adalimumab 0.45 (0.27-0.76)/etanercept 0.24 (0.10-0.61)/infliximab 0.57 (0.34-0.95))., Conclusion: In this study of TNFi-treated AS patients in clinical practice, current and previous smokers had significantly poorer patient-reported outcomes at baseline, shorter treatment adherence and poorer treatment response compared with never smokers., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Autoimmune diseases encompass a plethora of conditions in which the immune system attacks its own tissue, identifying them as foreign. Multiple factors are thought to contribute to the development of immune response to self, including differences in genotypes, hormonal milieu, and environmental factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus was associated with each of the three diseases. Although there was a significant overlap, most loci only occurred in one of the studied disease. Remarkably, within each disease, there was a statistical interaction (synergy) between two loci. Additional synergy between retroviral loci and human lymphocyte antigens is reported for multiple sclerosis. We speculate the possibility that recombinants or mixed viral particles are formed and that the resulting viruses stimulate the innate immune system, thereby initiating the autoimmune response.

Introduction. Colorectal cancer is one of the most frequent cancers in the world and liver metastases are seen in up to 19% of patients with colorectal cancers. Detection of liver metastases is not only vital for sufficient treatment and survival, but also for a better estimation of prognosis. The aim of this study was to evaluate the feasibility of diffusion weighted MRI of the liver as part of a combined MR evaluation of patients with rectal cancers and compare it with the standard preoperative evaluation of the liver with CT. Methods. Consecutive patients diagnosed with rectal cancers were asked to participate in the study. Preoperative CT and diffusion weighted MR (DWMR) were compared to contrast enhanced laparoscopic ultrasound (CELUS). Results. A total of 35 patients were included, 15 patients in Group-1 having the standard CT evaluation of the liver and 20 patients in Group-2 having the standard CT evaluation of the liver and DWMR of the liver. Compared with CELUS, the per-patient sensitivity/specificity was 50/100% for CT, and for DWMR: 100/94% and 100/100% for Reader 1 and 2, respectively. The per-lesion sensitivity of CT and DWMR were 17% and 89%, respectively compared with CELUS. Furthermore, one patient had non-resectable metastases after DWMR despite being diagnosed with resectable metastases after CT. Another patient was diagnosed with multiple liver metastases during CELUS, despite a negative CT-scan. Discussion. DWMR is feasible for preoperative evaluation of liver metastases. The current standard preoperative evaluation with CT-scan results in disadvantages like missed metastases and futile operations. We recommend that patients with rectal cancer, who are scheduled for MR of the rectum, should have a DWMR of the liver performed at the same time.

Objectives: To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy., Methods: All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bDMARD) treatment as monotherapy without concomitant conventional synthetic DMARDs (csDMARDs) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bDMARD monotherapy were calculated., Results: Of the 775 patients on bDMARD monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different bDMARDs, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years., Conclusion: Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csDMARD. Acceptable drug adherence and remission rates were achieved with bDMARDs. With the exception of infliximab, no statistically significant differences were observed between anti-TNFs and biologics with other modes of action., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To assess the frequency of discordance in patient's (PtGA) and physician's (PGA) global assessment, and to investigate whether higher discordance in female patients compared with male patients is associated with the physician's sex in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA)., Methods: PtGA, PGA, and other patient-related variables were retrieved from the Danish DANBIO registry, used nationwide to monitor patients with RA, axSpA, and PsA. A questionnaire was sent to all physicians registering in DANBIO (n = 265) regarding individual physician characteristics including sex and age. Discordance was defined as PtGA > 20 mm higher (or lower) than PGA. First encounters between patients and physicians were analyzed using descriptive statistics and mixed model regression analysis., Results: Ninety physicians (34%) returned the questionnaire and were pairwise matched with 10,282 first patient encounters (8300 patients with RA, 524 axSpA, and 1458 PsA). The frequency of discordant (PtGA > PGA) encounters (not including PGA > PtGA seen in < 2%) in RA, axSpA, and PsA was 49.0%, 48.3%, and 56.5%, respectively. Discordance was more common in female patients with high scores on functional disability, pain, and fatigue across the 3 diseases, whereas it was independent of the physician's sex., Conclusion: In this study on Danish patients with RA, axSpA, and PsA, the PtGA was > 20 mm higher than the PGA in about half of the encounters, and more common in female patients of both female and male physicians. This finding highlights one of the challenges in shared decision making.

Objectives. To study adherence to methotrexate (MTX) and factors of importance thereof in patients with rheumatoid arthritis (RA). Methods. Patients with a hospital diagnosis of RA (ICD10 codes M05.X or M06.X) after January 1, 1997, and aged ≥18 years at the date of first diagnosis/contact, with at least one prescription of MTX (L04AX03), were included. Results. A total of 18,703 (47.6%) patients had ever used MTX among 39,286 with a diagnosis of RA; among the MTX users, 16,503 (88.2%) had filed more than one MTX prescription. The median time from diagnosis to first MTX prescription was 0.66 (IQR 0.26-1.80) years. In those who filed more than one MTX prescription, the mean adherence time for ≥7.5 mg MTX per week was 1,925 (IQR 467-3,056) days for patients treated in private practice versus 1,892 (IQR 452-3,316) days for patients treated in hospital. The main determinants of nonadherence were female gender, younger age, and time from diagnosis to initiation of MTX. Conclusions. Treatment at hospital or in private practice did not influence the adherence to MTX. Nonmodifiable factors of importance were gender and age, while adherence to MTX therapy decreased with time lapse between diagnosis and prescription.

Background: It has been suggested that polymorphisms in Toll-like Receptors (TLRs) are associated with Rheumatoid Arthritis (RA), but the implicated alleles have differed between studies. The aim of this investigation was to explore whether polymorphisms of TLR genes are associated with RA in a predominantly Caucasian population from Denmark using a case-control approach., Findings: DNA samples (3 university hospital outpatient clinics) were obtained from patients with RA (n = 704) and healthy controls (n = 639) in a Danish population. TLR single nucleotide polymorphisms (SNPs) were selected based on the previously reported associations with chronic autoimmune diseases. Genotyping for the TLR SNPs was performed using Sequenom Multiplex technology.We identified one SNP in TLR3, [(rs3775291, P = 0.02, OR (95% CI) 1.31 (1.1087-1.5493)] significantly associated with the whole RA cohort. Subgroup analysis according to IgM rheumatoid factor (RF) and anti-cyclic citrinullated peptide (CCP) status suggested a significant association of sero-negative RA with the rs3775291 A allele and disease activity in this subset., Conclusion: These observations on a RA population of Danish ancestry suggest that variations in the TLR3 locus may be implicated in the pathogenesis of sero-negative RA. Since this TLR3 SNP has previously been associated with systemic lupus erythematous (SLE), the present findings support the notion that TLR3 genetic variants may represent a common risk factor in different chronic inflammatory conditions, including RA and SLE.

Background: The aim of the present study was to evaluate the accuracy of two approaches using magnetic resonance imaging (MRI) or combined ultrasonography (US) and anti-cyclic citrullinated peptide antibody (ACPA) for diagnosis and classification of individuals with established rheumatoid arthritis (RA)., Methods: In 53 individuals from a population-based, cross-sectional study, historic fulfilment of the American College of Rheumatology (ACR) 1987 criteria ("classification") or RA diagnosed by a rheumatologist ("diagnosis") were used as standard references. The sensitivity, specificity and Area under Curve for Receiver Operating Characteristics curves (ROC-area: (sensitivity + specificity)/2) were calculated for "current fulfilment of the ACR 1987 criteria" (list format), "adapted ACR 1987 criteria" (list format, substituting IgM rheumatoid factor with ACPA and clinical joint swelling and erosions on radiography with synovitis and erosions detected by US on a semi-quantitative scale), and RA MRI scoring System (RAMRIS) scores on low-field MRI in the unilateral hand., Results: For the ACR 1987 criteria the ROC-area was 75% (sensitivity/specificity = 50%/100%) (with "classification" as standard reference) and 69% (44%/94%) (with "diagnosis" as standard reference), while for the adapted ACR 1987 criteria it was 86% (75%/97%) (classification) and 82% (72%/91%) (diagnosis). For RAMRIS synovitis score in metacarpophalangeal (MCP) joints only (cut-off ≥5), the ROC-area (sensitivity/specificity) was 78% (62%/94%) (classification) and 85% (69%/100%) (diagnosis), while for the total synovitis score of MCP joints plus wrist (cut-off ≥10) it was 78% (62%/94%) (both classification and diagnosis)., Conclusions: Compared with the ACR 1987 criteria, low-field MRI alone or adapted criteria incorporating US and ACPA increased the correct classification and diagnosis of RA.

Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7)-like cytokine with a pivotal role in development and maintenance of atopic diseases such as allergic asthma and atopic dermatitis. Moreover, recent studies show an involvement of TSLP in the progression of various cancers. TSLP signaling is mediated by the TSLP receptor (TSLPR), a heterodimeric type I cytokine receptor. It consists of the IL-7 receptor alpha chain (IL-7Rα), which is shared with the IL-7 receptor, and the TSLPRα chain as a specific subunit. Blocking signal release by TSLP without affecting IL-7 function is a potentially interesting option for the treatment of atopic diseases or certain tumors. By employing the extracellular domain of human TSLPRα chain (hTSLPRα(ex)) as an antigen, we generated a set of monoclonal antibodies. Several binders to native and/or denatured receptor protein were identified and characterized by cytometry and Western blot analysis. A screen based on a STAT3-driven reporter gene assay in murine pro-B cells expressing a functional hTSLPR yielded two hybridoma clones with specific antagonistic properties towards hTSLP, but not IL-7. Kinetic studies measuring blockade of hTSLP-dependent STAT phosphorylation in a TSLP-responsive cell line revealed an inhibitory constant in the nanomolar range., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: To describe drug survival, disease activity and clinical response in patients with rheumatoid arthritis (RA) treated with abatacept or tocilizumab in routine care, based on prospectively registered observational data from the nationwide Danish DANBIO registry., Methods: 150 Patients with RA treated with abatacept and 178 treated with tocilizumab were identified. Drug survival was investigated. Response data were available in 104 and 97 patients, respectively. Changes in 28-joint Disease Activity Score (DAS28) based on C-reactive protein (CRP) and European League Against Rheumatism (EULAR) response after 24 and 48 weeks were investigated. No direct comparison of drugs was made., Results: Median (IQR) disease duration was 8.5 (3-14)/9 (3-12) years (abatacept/tocilizumab). 95%/93% of patients had previously received one or more tumour necrosis factor inhibitor (TNFi). After 48 weeks, 54%/64% of patients (abatacept/tocilizumab) maintained treatment. Among patients with available response data, DAS28 was 5.3 (4.7-6.1), 3.4 (2.7-4.9) and 3.3 (2.5-4.3) at baseline, weeks 24 and 48, respectively, in the abatacept group and 5.4 (4.7-6.2), 2.9 (2.3-4.0) and 2.5 (1.9-4.5) in the tocilizumab group. At weeks 24 and 48, the remission rates for abatacept/tocilizumab were 19%/39% and 26%/58%, respectively. EULAR good-or-moderate response rates were 70%/88% and 77%/84%, respectively. The decline in DAS28 variables over time appeared similar between drugs, except for CRP, which seemed to decline more rapidly among tocilizumab-treated patients., Conclusions: In patients with RA (≥90% TNFi failures), a good-or-moderate EULAR response was achieved in ≥70% of patients treated with abatacept or tocilizumab for 24 weeks in routine care. Apparent declines in DAS28 variables over time were similar between drugs, except for the more rapid CRP decline among tocilizumab-treated patients, directly caused by interleukin 6 inhibition.

Maraviroc is the first and, so far, the only licensed representative of the class of chemokine receptor type 5 (CCR5) inhibitors used for the treatment of human immunodeficiency virus (HIV) infection. Its safety and efficacy were demonstrated in several clinical trials, and its use was approved in 2007 by the responsible authorities. Some specific issues are correlated with maraviroc and its use. It is the only drug in the antiretroviral armamentarium, which does not interact with the viral enzymes but with a human receptor. Hence, it is able to be long-term effective only if the infecting virus uses, exclusively, the CCR5 receptor. Occurrence and detection of the CCR5 tropism are some of the great challenges of maraviroc use in treatment-experienced patients. Although up to 80% of naive patients harbor CCR5-tropic virus, the occurrence of CXCR4 or other tropisms increases with the duration of HIV infection and treatment. Nonetheless, maraviroc is a potent medication for eligible patients and helps to improve the outcome of antiretroviral treatment (ART) of HIV infection.

CCR5 antagonists are a newly developed class of antiretroviral drugs which inhibit viral entry into the host cell by binding to the predominant HIV coreceptor. Data on the use of these new drugs in treatment-experienced HIV patients are emerging. Clinical trials on maraviroc and vicriviroc in pretreated patients recruited more than 1300 individuals. Interim results of these studies indicate that pretreated patients infected with CCR5-tropic viruses benefit from their use in optimized combination regimens. Maraviroc reduces the HIV-1 viral load in patients with previous triple-class failure by 1.96 log10 copies/ml versus 0.99 log10 copies/ml in placebo; vicriviroc shows potency by dose depending viral decrease of 1.51-1.68 log10 copies/ml compared to 0.29 log10 in placebo. As expected, CCR5 antagonists do not reduce viral load in patients harbouring CXCR4-tropic or dual/mixed tropic viruses. Nevertheless, since a considerable percentage of late-stage HIV patients still bear CCR5-tropic viruses, the use of CCR5 antagonists appears promising in properly selected treatment-experienced patients.

Background and Aims: Restricted physical activity as a consequence of chronic disease or injury is a predictor of functional decline. The aim of this study was to test the hypothesis that a 6- month multidimensional training program would have sustained beneficial effects upon the physiological, functional and psychological condition of old women with a recent history of falls., Methods: Participants were 65 home-dwelling women (70-90 years) identified from hospital records as having had an accidental fall. After assessment of muscle strength, balance performance, walking speed, balance confidence, and physical activity level, the participants were randomly assigned to a control group (n=33) or a training group (n=32), who performed a multidimensional training program including moderate resistance exercise and balance exercise twice weekly for 6 months. Measurements were repeated after 6 and 12 months., Results: Six months of multidimensional training resulted in significant improvements and between-group differences in isometric knee extension strength (p<0.05), trunk extension/ flexion strength (p<0.001), habitual/maximal walking speed (p<0.001) and balance performance (p<0.001). At follow-up, 6 months after intervention, these improvements were preserved in the training group and there was also a significant between- group difference with regard to balance confidence. No between-group differences were found concerning number of falls or physical activity level during the one-year study period., Conclusions: A multi-dimensional training program produced significant improvements in physiological and functional risk factors for falls and disability in women aged 70-90 years with a recent history of falls.

Interleukin-13 (IL-13) is a cytokine with a crucial role in the development of allergic asthma. The IL-13 receptor shares the IL-4Ralpha subunit with the IL-4R system, but contains as a specific component the IL-13Ralpha1 chain. Blocking signal release by IL-13 without affecting IL-4 function is a potentially interesting therapeutical option for the treatment of asthma. Employing genetic immunization, we generated a set of novel monoclonal antibodies to the IL-13Ralpha1 receptor that proved very specific and efficient inhibitors of human IL-13 activity. Receptor binding antibodies were identified by their specific reactivity with both human monocytes and a murine pro-B cell line overexpressing human IL-13Ralpha1 by flow cytometry and cell ELISA. A luciferase reporter cell system based on STAT6-mediated promoter activation in murine Ba/F3 cells was employed to screen the antibodies for IL-13 antagonistic properties. Inhibitory antibody effects were quantified by interference with IL-13-dependent proliferation of TF-1 cells. The capability of blocking IL-13-driven responses of primary, inflammation-relevant cells was tested by Western blot analysis of STAT6 tyrosine phosphorylation and expression of 15-lipoxygenase in monocytes from fresh blood. The most potent inhibitory antibody identified, GM1E7, inhibited IL-13-driven gene activation and cell proliferation in immune cell lines with IC(50) values in the low nanomolar range. Both short-term (STAT6 activation) and long-term (15-LO induction) responses of primary human blood cells to IL-13 were almost entirely blocked, whereas IL-4 effects remained virtually unaffected. GM1E7 is superior to available agents interfering with IL-13 activity in terms of specificity and efficiency and offers potential novel therapeutic perspectives for the treatment of allergic asthma.

Objective: To describe the clinical course and risk factors of death in highly active antiretroviral therapy (HAART)-treated patients with progressive multifocal leukencephalopathy (PML); to evaluate the efficacy of cidofovir in addition to HAART., Methods: Retrospective multicenter cohort study of PML in HIV-1-infected patients. Diagnosis of PML was confirmed by histology or by positive polymerase chain reaction for JC virus (JCV) in cerebrospinal fluid (CSF) or was made by typical radiologic and clinical findings., Results: Thirty-five cases of PML were identified. The diagnosis was made by histology (9 cases), detection of JCV in CSF (17 cases), and by radiologic findings (9 cases). Upon manifestation of PML, 15/35 patients had never received HAART, and 11/35 were on HAART for >6 months (median 1126 days). In 9/35 cases, clinical manifestation of PML occurred within 6 months after initiation of HAART. All patients received HAART after PML diagnosis. After a median follow-up of 553 days (range 28-2694 days), the median survival time was not reached. In 12 patients who were treated concomitantly with cidofovir, cumulative survival was significantly shorter than in patients without cidofovir (P = 0.03). Patients in whom PML was diagnosed while on HAART demonstrated a trend toward a shorter survival than HAART-naive patients (P = 0.15)., Conclusions: PML continues to occur in HIV-1-infected patients even when they are treated with HAART. Patients developing PML on HAART had a trend toward a shorter median survival compared with treatment-naive patients, and cidofovir therapy was not associated with improved survival in this cohort.

Background: Kaposi's sarcoma (KS) remains the most common neoplasm in HIV-infected patients. Human herpesvirus 8 (HHV-8) infection is etiologically associated with KS. Diagnostic procedures with regard to HHV-8 infection are not routinely performed in HIV-infected patients; diagnostic and prognostic value of HHV-8 serology or PCR are unknown in this setting. Epidemiological data concerning HHV-8 infection of HIV-infected patients in Germany are rare., Objectives: To assess prevalence of HHV-8 infection in a cohort of HIV-infected patients with and without KS in Germany and to correlate this to manifestations and clinical course of KS., Study Design: HHV-8 serology was performed in 483 patients in routine care for HIV-infection in northern Germany. HHV-8 DNA was analyzed by PCR in peripheral blood mononuclear cells (PBMC) of 293 patients; in a subgroup multiple samples were analyzed. History and manifestations of KS were recorded., Results: HHV-8 antibodies were detected using IFT in 91% of 33 patients with KS and 52% of 398 patients without KS. In 36 of 293 (12.3%) patients HHV-8 DNA was detected in PBMC. In general, HHV-8 DNA was not continuously detected when multiple samples from the same patient were analyzed. Patients with KS history were more likely to be PCR positive than those without (45.5% versus 7.8%). In patients with active KS HHV-8 DNA was detected more frequently than in patients with disease remission. HHV-8 DNA was not detected in serologically negative patients. However, three patients with KS history in full remission for several years were seronegative., Conclusions: HIV-infected patients were frequently found to be positive for HHV-8 antibodies. The number of patients positive for viral DNA in PBMC was much smaller. Single PCR-examinations were of little value for prognosis, but repeated detection of HHV-8 DNA represents an increased risk of disease activity.

Background: Treatment of Mycosis fungoides (MF) in HIV-infected patients is controversially discoursed. Photodynamic therapy (PDT) after topical sensitization with 5-aminolevulinic acid (5-ALA) is a new and effective modality for treatment of skin malignancies., Objective: In this report we describe, what is, to our knowledge, the first case of a patient with MF through advanced HIV-infection, successfully experiencing topical 5-ALA sensitization and PDT., Methods: 5-ALA ointment was applied to plaques and held in occlusion for 4 hours. PDT was applied using the PDT 1200 irradiation source (Waldmann Medizintechnik System) with 180 J/cm superset 2., Results: Complete remission of MF was achieved, after two completed cycles of photodynamic therapy., Conclusion: MF lesions in the presended case showed a high response to 5-ALA sensitization and PDT. This modality appeared to be very effective in treatment of MF in a HIV-infected patient and could be a valuable treatment option for cutaneous T-cell lymphoma in HIV-infected patients.

Background: HIV-infected patients fail viral load suppression, because resistance against antiretroviral drugs arises or for other reasons. HIV-resistance analyses can aid to achieve effective HAART regimen. Furthermore, clinical benefits from genotyping in study settings are significantly higher for treating physicians, who can include external advice from HIV-experts into HAART switch., Objective: To develop a compiling internet presence to provide expert advice for HAART switch in general practice of HIV-infected individuals after therapy failure. -, Design: A multifactorial (genotyping, drug monitoring, adherence, expert advice) interdisciplinary internet service (www.radata.de) with an associated server hosted database., Patients and Methods: HIV-infected patients after failure to HAART are eligible for registration to the Radata project. Genotyping is performed according to protocols specific for each participating institution. Therapeutic drug monitoring (NNRTIs, PIs) follows setting for drug level detection by mass spectrometry. An adherence self-report is completed by every patient. Clinical documentation is provided by the treating Primary Care Physician. Clinical expert advice for implementation into HAART switch in daily clinical practice for treating physicians is provided by HIV-experts according to data obtained. Clinical and laboratory follow-up visits are scheduled firstly 4 weeks after HAART switch and three monthly afterwards, over a period of one year., Results: Technical resources and a compiling internet presence for generation of resistance analysis based expert advice were developed. Initially, 7 HIV-treatment centres, 7 laboratories and 17 HIV advisors contribute to Radata database project. 15 patients were enrolled during test period. 30 expert advices were generated during the test phase. Expert advice was provided in 6 weeks median for implementation into HAART switch. 13 out of 15 expert advices were implemented into HAART switch by treating Primary Care Physicians., Conclusions: Radata is a novel database concept with features to generate expert advice for implementation into HAART switch of HIV-infected subjects. A test period has shown, that the concept is technically approved to fit all requirements with regard to data collection, evaluation and to generate expert advice for therapy switch in daily clinical practice.

Objective: To explore the significance of HHV-8 viremia in HIV-positive individuals for the risk of developing Kaposi's sarcoma (KS) in the era of highly active antiretroviral therapy., Methods: 237 HIV-positive patients were included in this prospective evaluation and followed over an average duration of 34 months. HHV-8 DNA in peripheral blood mononuclear cells (PBMCs) and CD4-lymphocytes were determined. In addition AIDS-defining conditions and antiretroviral therapy were documented of all participating subjects., Results: HHV-8 DNA was detectable in PBMCs of 12.6% out of all individuals. 53.3% of these patients initially complained about KS, although 9.2% of patients without HHV-8 DNA in PBMCs were found on KS as well. Furthermore, four patients in total were observed with newly developed KS during follow up visits. None of these patients were noted with detectable HHV-8 DNA at their initial evaluation., Conclusions: Prevalence of HHV-8 DNA in PBMCs of subjects in this investigation was quite similar to former investigations. However, new diagnosed KS occurred less frequently than demonstrated in previous studies. All of those observed patients with new KS manifestations were negative for HHV-8 DNA in PBMCs at study entry. This observation differs from earlier studies which have postulated the detection of HHV-8 DNA in PBMCs as a predictive value for development of KS. Due to results as presented, a single HHV-8 DNA test in blood has no predictive value in support of predictability of KS development. With respect toto costs and to a less complicated performance antibody assays should be preferred.

The incidence of AIDS-associated Kaposi's sarcoma has declined since the mid-nineties due to the availability of potent antiretroviral therapy including protease inhibitors. However, Kaposi's sarcoma is still the most common neoplasia in HIV-infected patients. In the pathogenesis of the HIV-associated as well as other forms of this disease an infectious agent seems to play a role, namely the human herpesvirus 8. Even before the discovery of the HIV virus, high levels of an unusual acid-labile form of endogenous interferon alpha were found in patients with AIDS-associated KS. The administration of recombinant interferon alpha evolved as standard therapy for Kaposi's sarcoma in HIV-infected patients with a moderate immunodeficiency in addition to antiretroviral therapy. This investigation monitored the levels of HHV 8 and endogenous interferon in 4 patients with and without Kaposi's sarcoma during the course of HIV-disease. The results of our experiments lead us to two hypotheses: First of all, the pre-therapeutic level of endogenous interferon may be a predictor of the response to an interferon-alpha therapy for HIV-associated Kaposi's sarcoma. Secondly, the determination of HHV 8 DNA in blood of HIV-positive patients may allow conclusions about the risk for the development of Kaposi's sarcoma. However these hypotheses should be tested by monitoring the levels of endogenous interferon and HHV 8 DNA in clinical studies of a greater number of HIV-infected patients.

A CA-repeat polymorphism within the first intron of the interferon (IFN)-gamma gene was analyzed. This polymorphism was recently demonstrated to be associated with insulin-dependent diabetes mellitus (IDDM) in Japanese subjects. We typed 266 IDDM patients and 195 control subjects of Danish Caucasoid origin. No significant differences in allele or genotype frequencies between patients and control were observed. In addition, we typed 168 IDDM and 110 control subjects of Finnish origin. A significant disease association of the studied IFN-gamma allelic pattern was found (p = 0.029). Analysis of data according to HLA-DQB1 susceptibility status did not reveal heterogeneity of risk at the IFN-gamma locus in either of the populations. Fifty-five Danish and 94 Finnish IDDM multiplex families with at least two affected siblings (660 individuals) were typed to test for transmission disequilibrium (TDT). No evidence for overall transmission disequilibrium using either an allele-wise (p = 0.42; combined data) or a genotype-wise analysis (p = 0.21; combined data) could be detected. Thus, the modest significance level observed in the Finnish case-control study and the failure to replicate it by the TDT provide little support for the hypothesis that the IFN-gamma gene microsatellite is associated with IDDM.

1. The purpose of this study was to investigate the effect of fractional meal stimulation on postprandial haemodynamic changes, the possible correlation between these changes and the potential mediating role of circulating catecholamines and insulin. 2. Healthy young subjects were studied before and after ingestion of isocaloric, isovolumetric high-protein, carbohydrate or fat meals (80-85% of total energy), 60 kJ per kg of body weight. Multigated radionuclide cardiography with autologous 99mTc-labelled erythrocytes was performed for assessment of cardiac output, venous occlusion plethysmography to obtain forearm blood flow and Doppler-ultrasonography for portal vein flow. Plasma levels of catecholamines and insulin were determined by radioimmunoassay. 3. Cardiac output increased considerably after each meal, including the control meal (water) with only minor differences in extent and timing. Left ventricular volumes increased after food intake, most pronounced after carbohydrate and protein. Forearm blood flow increased only after carbohydrate and protein. Portal vein flow increased after all meals, especially after fat, but also after the control meal. There was a significant correlation between the increment in cardiac output and changes in forearm and portal vein flow, but no correlation between either haemodynamic response and plasma catecholamines or insulin. 4. Postprandial cardiovascular changes are not substantially different after various isocaloric and isovolumic meal compositions. Gastric distension seems to play a role in the increase in cardiac output, accomplished by ventricular dilatation. These changes seem to some extent to be linked to changes in muscle and splanchnic flow.

Based on studies in spontaneously non-obese diabetic (NOD) mice, it has been suggested that the Mr 65,000 isoform of glutamic acid decarboxylase (GAD65) is of major importance in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In humans, antibodies to GAD65 are present before and at onset of the disease and in vitro T cell reactivity to GAD has also been reported. To further characterize the T cell recognition of GAD65, we incubated peripheral blood mononuclear cells from 45 newly diagnosed IDDM patients with purified recombinant human islet GAD65 and correlated the proliferative response with HLA DR haplotype and the presence of GAD65 autoantibodies. Fifty healthy individuals were studied as controls. Of the patients, 49% showed proliferative responses to GAD65 in contrast to only 4% of the controls. T cell proliferation to GAD65 was significantly more frequent in patients not being HLA DR3/4 heterozygous (19/29, 66%) as compared to HLA DR3/4 heterozygous patients (3/16, 19%) (p < 0.01). The difference was most pronounced in females with 64% (9/14) of the HLA non-DR3/4 patients being positive compared to none (0/6) of the HLA DR3/4 patients (p < 0.05). The overall frequency of GAD65 autoantibodies was 71% (32/45) with a similar distribution between patients with HLA DR3/4 (10/16, 63%) and HLA non-DR 3/4 (22/29, 76%). There was no correlation between levels of the T and B cell responses to GAD65 (r = 0.24). In conclusion, we find a proliferative T cell response to GAD65 in approximately 50% of recent onset IDDM patients and unexpectedly find the majority of responders to be HLA non-DR 3/4 heterozygous patients. No difference was observed in B cell responsiveness between the two HLA groups.

Fifty-five Danish families with two offspring concordant for type 1 diabetes--identified through a nationwide population-based survey, and 57 "true sporadic" cases--matched with familial cases for age at onset, but with no IDDM-affected first-degree relatives and long disease duration, and 110 control subjects were typed for putative genetic susceptibility markers for type 1 diabetes identified from a pathogenetic model. The markers included MHC class I, II and III loci, the manganese superoxide dismutase (MnSOD) locus (chr. 6q), interleukin-1 beta (IL1B), the IL-1 receptor antagonist (IL1RN), and the IL-1 type 1 receptor (IL1RI) loci (each chr. 2q). No significant differences between familial and sporadic cases were found within the MHC region (including the following loci: HLA-DQ, -DR, heat shock protein (HSP) 70, tumour necrosis factor (TNF), HLA-B and -A). In both groups of patients 11% were negative for both DQA1*0301-DQB1*0302 and DQA1*0501-DQB1*0201 genotypes, and 7% of the type 1 diabetics had genotypes unable to encode a susceptibility DQ alpha beta heterodimer. Disease association was found for the IL1RN (p = 0.04) and for the IL1RI (p = 0.03). When comparing controls and only familial cases with type 1 diabetes for the IL1RN polymorphism a difference was observed (p = 0.003). For the IL1B RFLP a trend for difference was observed between familial cases and control subjects (p = 0.046), whereas no differences between sporadic cases and control subjects could be demonstrated neither at the IL1B nor at the IL1RN loci. A difference in the MnSOD pattern was observed between sporadic cases and controls (p = 0.04).

Interleukin 1 (IL-1) is selectively cytotoxic to the insulin producing beta cell of pancreatic islets. This effect may be due to IL-1 induced generation of reactive oxygen species and nitric oxide. Since beta cells contain low amounts of the superoxide radical scavenger enzyme manganese superoxide dismutase (MnSOD), this may leave beta cells more susceptible to IL-1 than other cell types. Genetic variation in the MnSOD locus could reflect differences in scavenger potential. We, therefore, studied possible restriction fragment length polymorphisms (RFLPs) of this locus in patients with insulin-dependent diabetes mellitus (IDDM) (n = 154) and control individuals (n = 178). TaqI revealed a double diallelic RFLP in patients as well as in controls. No overall difference in allelic or genotype frequencies were observed between IDDM patients and control individuals (p = 0.11) and no significant association of any particular RFLP pattern with IDDM was found. Structurally polymorphic MnSOD protein variants with altered activities have been reported. If genetic variation results in MnSOD variants with reduced activities, the MnSOD locus may still be a candidate gene for IDDM susceptibility. Whether the RFLPs reported in this study reflects differences in gene expression level, protein level and/or specific activity of the protein is yet to be studied.

The trafficking of apolipoprotein E-deficient high-density lipoprotein particles and of their component cholesteryl esters in rat hepatocytes was studied. Human high-density lipoprotein 3, labeled with two nondegradable, intracellularly trapped tracers in their apolipoprotein A-I and their cholesteryl esters, were injected into rats, and five subcellular hepatocytic fractions were isolated at various time intervals. In control experiments with homologous lipoproteins, doubly labeled rat high-density lipoproteins depleted of apolipoprotein E were used. In endosomes and lysosomes the two labels were recovered at near unity, indicating that high-density lipoproteins are endocytosed as particles, transported to early and late endosomes and finally subjected to lysosomal degradation. No significant amounts of label were found in receptor-recycling endosomes. In contrast to label of those of low-density lipoproteins, label of component protein and cholesteryl esters of high-density lipoproteins from isolated endosomes floated at different densities in gradient ultracentrifugation, indicating early disintegration of high-density lipoprotein particles. In contrast to the endocytic organelles, in the whole liver, label of high-density lipoprotein-associated cholesteryl esters exceeded the label of high-density lipoprotein-associated apolipoprotein A-I twofold to threefold. This finding is compatible with selective uptake of high-density lipoprotein cholesteryl esters in addition to uptake of high-density lipoprotein particles. The excess cholesteryl esters accumulated in a nonendosomal fraction, whose major proteins differed from the integral proteins of endosomes. These data suggest two distinct intracellular routes of hepatocytic high-density lipoprotein trafficking in vivo. High-density lipoproteins free of apolipoprotein E are internalized intact by hepatocytes, are predominantly transported to early and late endosomes and are finally subjected to lysosomal degradation. High-density lipoprotein particles do not undergo retroendocytosis in hepatocytes. In addition, high-density lipoprotein-associated cholesteryl esters can be taken up by hepatocytes selectively. They, however, accumulate in a nonendosomal, nonlysosomal compartment.

Determining the possible adverse health effects of air pollutants can be complicated by differences in the environmental conditions of temperature and humidity. To evaluate the potentially confounding effects of differences in temperature and humidity, we exposed 8 normal male subjects and 8 male subjects with asthma to the extremes in temperature and humidity that could be maintained in an environmental chamber. We performed serial pulmonary function tests for these subjects before and during 6 hr exposure periods on 5 separate occasions: cold, dry (10 degrees C, 10% relative humidity); cold, humid (10 degrees C, 50% relative humidity); normal ambient (22 degrees C, 40% relative humidity); hot, dry (37 degrees C, 15% relative humidity); and hot, humid (37 degrees C, 60% relative humidity). The exposure period included a 12 min exercise on a cycle ergometer. We found no significant change in spirometry, airways resistance, or diffusing capacity for either group of subjects at rest alone over the 6 hr period of exposure for any exposure condition. However, there were changes in spirometry and airways resistance as a result of the 12 min period of exercise. The subjects with asthma had significant decreases in forced expiratory volume in 1 sec (FEV1) (20-21%) and increases in specific airways resistance when exercising in conditions of cold and dry, cold and humid, and hot and dry. The normal subjects had an average increase in FEV1 of approximately 6% when exercising in the hot and humid conditions. We found significant correlations for the changes in FEV1 with the water content of the exposure conditions for both groups of subjects. We also found that the work performance (expressed as the external work performed divided by the oxygen consumed) was decreased for the subjects in both groups at the conditions of the higher temperature (37 degrees C) compared with the lower temperature (10 degrees C). These results confirm that controlling for the conditions of temperature and humidity is essential in chamber studies, field studies, or epidemiologic evaluations determining the adverse effect of an air pollutant.