No difference in antidepressant prescription in rheumatoid arthritis and controls. Results from a population-based, matched inception cohort.

OBJECTIVE: Depression occurs at least two times more often in rheumatoid arthritis (RA) patients than in controls, but little is known about the treatment of depression in RA. The primary objective of this study was to compare the 1 year period prevalence of antidepressant prescription in patients with RA versus controls. METHOD: We included a retrospective inception cohort of 509 patients with incident RA and 2545 frequency-matched population controls ascertained from 1995 to 2002. The cohort was followed until 31 December 2017 and linked with nationwide Danish registers. From the Danish National Prescription Register, we obtained information on redeemed prescriptions of antidepressants (Anatomical Therapeutic Chemical code N06A). RESULTS: We did not demonstrate significant differences in the 1 year period prevalence ratios and the incidence rate ratios for either antidepressant prescription or the frequency of hospital admissions with depressive episode. The most frequent indication for antidepressant prescription in patients with RA was depression. Cox regression analyses showed no association between RA and antidepressant prescription. CONCLUSION: We found no significant differences in the occurrence of antidepressant prescription in patients with RA versus matched controls. The main indication for antidepressant prescription in RA was depression.

Using multi-event hydrologic and hydraulic signatures from water level sensors to diagnose locations of uncertainty in integrated urban drainage models used in living digital twins.

Digital twins of urban drainage systems require simulation models that can adequately replicate the physical system. All models have their limitations, and it is important to investigate when and where simulation results are acceptable and to communicate the level of performance transparently to end users. This paper first defines a classification of four possible 'locations of uncertainty' in integrated urban drainage models. It then develops a structured framework for identifying and diagnosing various types of errors. This framework compares model outputs with in-sewer water level observations based on hydrologic and hydraulic signatures. The approach is applied on a real case study in Odense, Denmark, with examples from three different system sites: a typical manhole, a small flushing chamber, and an internal overflow structure. This allows diagnosing different model errors ranging from issues in the underlying asset database and missing hydrologic processes to limitations in the model software implementation. Structured use of signatures is promising for continuous, iterative improvements of integrated urban drainage models. It also provides a transparent way to communicate the level of model adequacy to end users.

Beta Decay of Molecular Tritium.

The beta decay of tritium in the form of molecular T_{2} is the basis of sensitive experiments to measure neutrino mass. The final-state electronic, vibrational, and rotational excitations modify the beta spectrum significantly and are obtained from theory. We report measurements of the branching ratios to specific ionization states for the isotopolog HT. Two earlier, concordant measurements gave branching ratios of HT to the bound HHe^{+} ion of 89.5% and 93.2%, in sharp disagreement with the theoretical prediction of 55%-57%, raising concerns about the theory's reliability in neutrino mass experiments. Our result, 56.5(6)%, is compatible with the theoretical expectation and disagrees strongly with the previous measurements.

Increased risk of long-term sickness absence, lower rate of return to work and higher risk of disability pension among people with type 1 and type 2 diabetes mellitus: a Danish retrospective cohort study with up to 17 years' follow-up.

AIM: To evaluate labour market outcomes in type 1 or type 2 diabetes. METHODS: Individuals with type 1 (n = 431) and type 2 diabetes (n = 4047) were identified in Danish national registers from 1994 to 2011 and compared with individuals without diabetes (n = 101 295). Multi-state Cox proportional hazards analyses estimated hazard ratios (HR) with 95% confidence intervals (CI) for transitions between work, sickness absence, unemployment and disability pension. RESULTS: We observed significantly higher HR of sickness absence in type 1 diabetes (women: 1.34, 95% CI 1.12-1.62; men: 1.43, 1.01-2.03) and type 2 diabetes (women: 1.46, 95% CI 1.35-1.58; men: 1.64, 1.46-1.85) compared with people without diabetes. HR of unemployment was higher for men with type 1 diabetes (1.25, 95% CI 1.01-1.53) and women with type 2 diabetes (1.09, 95% CI 1.03-1.16) and men with type 2 diabetes (1.17, 95% CI 1.08-1.27). HR of disability pension was higher in type 1 diabetes (women: 1.90, 95% CI 1.46-2.46; men: 2.09, 1.38-3.18) and type 2 diabetes (women: 1.78, 95% CI 1.62-1.96; men: 2.11, 1.86-2.40). Only women with type 2 diabetes were less likely to return to work from sickness absence (HR 0.91, 95% CI 0.86-0.98) or unemployment (0.89, 95% CI 0.85-0.94). We found no significant difference between the two types of diabetes. Hazard ratios for diabetes regarding unemployment, sickness absence while unemployed and disability pension were significantly higher for men than for women. CONCLUSIONS: Both type 1 and type 2 diabetes affect labour market outcomes, but future studies should also consider comorbidity and social gradient.

Mortality and its predictors in patients with rheumatoid arthritis: a Danish population-based inception cohort study.

OBJECTIVES: To investigate mortality and its predictors in a retrospectively defined population-based rheumatoid arthritis (RA) inception cohort Method: We included patients ascertained with incident RA from a region in the southern part of Denmark from 1995 to 2002. All patients fulfilled the 1987 American College of Rheumatology criteria for RA. The patients were followed from RA classification until death, emigration, or end of follow-up on 31 December 2013. We used personal record linkage with national public registers to obtain information on education, employment, cohabitation, comorbidity, and vital status. RESULTS: The cohort comprised 509 patients, of whom 200 (39%) died during 6079 person-years. The most frequent underlying causes of death were cardiovascular disease (34%), neoplasms (26%), and respiratory disease (12%). In rheumatoid factor (RF)-positive males, the standardized mortality ratio (95% confidence interval) from all causes was 1.47 (1.15-1.88), from cardiovascular disease 1.63 (1.09-2.46), from respiratory disease 2.03 (1.06-3.90), and from neoplasms 2.26 (1.02-5.03) in the age group < 70 years, and 2.45 (1.23-4.90) in the age group > 79 years. On applying Cox models after multiple imputations by chained equations, we found that RF modified the effect of age. Employment status, comorbidity, and gender were independent baseline predictors of subsequent mortality. CONCLUSION: In this cohort, significant excess mortality was confined to RF-positive males. The effect of age was modified by RF, and employment status and comorbidity were independent predictors of mortality.

Interfacial electrostatics of poly(vinylamine hydrochloride), poly(diallyldimethylammonium chloride), poly-l-lysine, and poly-l-arginine interacting with lipid bilayers.

Charge densities of cationic polymers adsorbed to lipid bilayers are estimated from second harmonic generation (SHG) spectroscopy and quartz crystal microbalance with dissipation monitoring (QCM-D) measurements. The systems surveyed included poly(vinylamine hydrochloride) (PVAm), poly(diallyldimethylammonium chloride) (PDADMAC), poly-l-lysine (PLL), and poly-l-arginine (PLR), as well as polyalcohol controls. Upon accounting for the number of positive charges associated with each polyelectrolyte, the binding constants and apparent free energies of adsorption as estimated from SHG data are comparable despite differences in molecular masses and molecular structure, with ΔGads values of -61 ± 2, -58 ± 2, -57 ± 1, -52 ± 2, -52 ± 1 kJ mol-1 for PDADMAC400, PDADMAC100, PVAm, PLL, and PLR, respectively. Moreover, we find charge densities for polymer adlayers of approximately 0.3 C m-2 for poly(diallyldimethylammonium chloride) while those of poly(vinylamine) hydrochloride, poly-l-lysine, and poly-l-arginine are approximately 0.2 C m-2. Time-dependent studies indicate that polycation adsorption to supported lipid bilayers is only partially reversible for most of the polymers explored. Poly(diallyldimethylammonium chloride) does not demonstrate reversible binding even over long timescales (>8 hours).

Galectin-3 is Persistently Increased in Early Rheumatoid Arthritis (RA) and Associates with Anti-CCP Seropositivity and MRI Bone Lesions, While Early Fibrosis Markers Correlate with Disease Activity.

Galectin-3 has been suggested as a pro-inflammatory mediator in animal arthritis and rheumatoid arthritis (RA). We aimed to study the serum level of galectin-3 in patients with newly diagnosed RA and associations with disease profile, Magnetic resonance imaging (MRI) findings and seromarkers of synovial matrix inflammation. One hundred and sixty DMARD naïve patients newly diagnosed with RA were included (CIMESTRA study). Clinical, serological and imaging data were recorded before treatment and at 6 weeks, 3 and 12 months. Galectin-3 and hyaluronan (HYA) were measured by ELISA (R&D and Corgenix, USA), and the N-terminal propeptide of type III collagen (PIIINP) by radioimmunoassay (Orion Diagnostica, Finland). One hundred and nineteen, 87 and 60 blood donors served as controls for galectin-3, HYA and PIIINP, respectively. Baseline galectin-3 was significantly elevated in anti-CCP positive (4.2 µg/l IQR [3.6;6.1]) patients as compared with anti-CCP negatives (4.0 µg/l [2.6;4.9], P = 0.05) and controls (3.8 µg/l [3.0;4.8], P < 0.01). During treatment, galectin-3 remained elevated, but increased transiently with peak values at 6 weeks. Galectin-3 correlated with baseline smoking, anti-CCP, and with MRI erosion score after 1 year of follow-up. HYA and PIIINP were elevated (P < 0.001) irrespective of anti-CCP status and correlated positively with synovitis assessed clinically and by MRI. HYA and PIIINP did not correlate with galectin-3. These observations indicate that HYA and PIIINP mainly reflect expansive synovitis proliferation while galectin-3 is more closely linked to autoimmunity, smoking and joint destructive processes.

Artificial selection on ant female caste ratio uncovers a link between female-biased sex ratios and infection by Wolbachia endosymbionts.

Social insect sex and caste ratios are well-studied targets of evolutionary conflicts, but the heritable factors affecting these traits remain unknown. To elucidate these factors, we carried out a short-term artificial selection study on female caste ratio in the ant Monomorium pharaonis. Across three generations of bidirectional selection, we observed no response for caste ratio, but sex ratios rapidly became more female-biased in the two replicate high selection lines and less female-biased in the two replicate low selection lines. We hypothesized that this rapid divergence for sex ratio was caused by changes in the frequency of infection by the heritable bacterial endosymbiont Wolbachia, because the initial breeding stock varied for Wolbachia infection, and Wolbachia is known to cause female-biased sex ratios in other insects. Consistent with this hypothesis, the proportions of Wolbachia-infected colonies in the selection lines changed rapidly, mirroring the sex ratio changes. Moreover, the estimated effect of Wolbachia on sex ratio (~13% female bias) was similar in colonies before and during artificial selection, indicating that this Wolbachia effect is likely independent of the effects of artificial selection on other heritable factors. Our study provides evidence for the first case of endosymbiont sex ratio manipulation in a social insect.

A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences.

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10(-4)). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7-2.3 for lung cancer (LC; P=4.0 × 10(-4)), chronic obstructive pulmonary disease (COPD; P=9.3 × 10(-4)), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10(-4)), COPD (OR=3.22, P=2.9 × 10(-4)), PAD (OR=3.47, P=9.2 × 10(-3)) and AAA (OR=6.44, P=6.3 × 10(-3)). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10(-5)), particularly for early-onset cases (P=2.1 × 10(-7)). Our results are in agreement with functional studies showing that the human α4ß2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Effect of a treat-to-target strategy based on methotrexate and intra-articular betamethasone with or without additional cyclosporin on MRI-assessed synovitis, osteitis, tenosynovitis, bone erosion, and joint space narrowing in early rheumatoid arthritis: results from a 2-year randomized double-blind placebo-controlled trial (CIMESTRA).

OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect. METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods. RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups. CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.

Estimation of genetic parameters and heterosis for longevity in crossbred Danish dairy cattle.

Crossbreeding has been shown to improve the longevity of dairy cattle in countries across the world. The aim of this study was to estimate heterosis, breed effects, and genetic parameters for longevity in crossbred dairy cattle among Danish Holstein (DH), Danish Red (DR), and Danish Jersey (DJ) breeds. Data were provided from 119 Danish commercial herds that use systematic crossbreeding (i.e., rotational crossbreeding). Additional data from 11 mixed-breed herds with DH and DJ were included to estimate reliable breed effects for DJ. Survival information on 73,741 cows was analyzed with a linear animal model using the artificial insemination-REML algorithm in the DMU package. Five longevity (L) traits were defined: days from first calving until the end of first lactation or culling (L1), days from first calving until the end of second lactation or culling (L2), days from first calving until the end of third lactation or culling (L3), days from first calving until the end of fourth lactation or culling (L4), and days from first calving until the end of fifth lactation or culling (L5). Heritabilities ranged between 0.022 and 0.090. Additive breed effects in units of days were estimated relative to DH for DR as -0.5 (L1), +10.5 (L2), +18.5 (L3), +11.9 (L4), and +28.6 (L5), and corresponding figures for DJ were +2.0, +0.5, +14.2, +27.7, and +44.0. Heterosis effects in L1 were low (1.2%) but favorable in crosses between DH and DR, whereas negative heterosis effects were estimated for crosses between DH and DJ (-2.5%) and DR and DJ (-1.2%). The largest heterosis effects for L2, L3, L4, and L5 were found in DH × DR and were favorable (+3.3, +5.7, +7.7, and +8.5%, respectively). Corresponding figures for heterosis effects in DH × DJ and DR × DJ were favorable as well: +2.3, +4.1, +5.6, and +6.2% in DH × DJ and +3.1, +7.3, +6.9, and +7.2% in DR × DJ. The favorable heterosis effects show that crossbreeding is an efficient tool for improving longevity in Danish dairy cattle.

Improving the energy balance of grass-based anaerobic digestion through combined harvesting and pretreatment.

An important challenge that has to be addressed to achieve sustainable anaerobic digestion of lignocellulosic substrates is the development of energy and cost efficient pretreatment methods. Technologies orientated to simultaneously harvest and mechanically pretreat the biomass at the field could meet these criteria as they can potentially reduce the energy losses. The objective of this study was to elucidate the effect of two full-scale harvesting machines to enhance the biogas production and subsequently, improve energy balance. The performances of Disc-mower and Excoriator were assessed on meadow and cultivated grass silages. The results showed that relatively high methane production can be achieved from meadow and cultivated grass harvested in different seasons. The findings indicated that the bioenergy production can be improved based on the selection of the appropriate harvesting technology. More specifically, Excoriator, which cuts and subsequently applies shearing forces on harvested biomass, enhanced the methane production up to 10% and the overall energy budget was improved proportionally to the driving speed increase.

Regaining familiarity with own body after treatment for operable lung cancer - a qualitative longitudinal exploration.

Little is known about the experiences of operable lung cancer patients during treatment in a clinical setting based on fast-track surgery. The study aimed to explore (1) the embodied meaning of illness in patients with operable lung cancer during treatment to 4 months after surgery and (2) patterns of change over time that may affect the patients' daily lives. Twenty patients referred for lung cancer surgery were interviewed three times, corresponding to potential critical transition points following surgery: hospitalisation; hospital-to-home transition; and resumption of daily life activities. Data collection, analysis and interpretation followed a phenomenological hermeneutical approach inspired by Ricoeur and the theoretical framework was grounded in Merleau-Ponty's phenomenology of perception. The findings reveal the process patients went through in regaining familiarity with their own body after lung cancer treatment. Through the post-operative trajectory the patients' resumption of daily activities involved adjusting to a new awareness of everyday life, physical restrictions and their perception of themselves. The findings are expressed in four sub-themes: (1) perceptions of embodied alterations; (2) transformation of embodied structures in the transition from hospital to home was unexpectedly challenging; (3) embodied perceptions of the intersubjective world; and (4) transforming embodied disruptions into bodily awareness. Patients experienced a smooth treatment trajectory regarding physical consequences of illness and treatment which might be due to the fast-track surgery. Clinicians should be aware of patients' experiences of illness to facilitate patient reconstitution of own identity.

Burden of allergic respiratory disease: a systematic review.

This meta-analysis compared the health-related quality of life (HRQL) of patients with allergic rhinitis (AR) and/or allergic asthma (AA) caused by perennial house dust mite (HDM) versus AR and/or AA caused by seasonal pollen allergy. Following a systematic search, the identified studies used the disease-specific rhinitis quality of life questionnaire or generic instruments (SF-36 and SF-12). Summary estimates obtained by meta-analysis showed that HRQL in patients with perennial HDM allergy was significantly worse than that of patients with seasonal pollen allergy, when measured by both disease-specific and generic HRQL instruments, and was reflected by an impact on both physical and mental health. A systematic review of cost data on AR and AA in selected European countries demonstrated that the majority of the economic burden was indirectly caused by high levels of absenteeism and presenteeism; there was little or no evidence of increasing or decreasing cost trends. Increased awareness of the detrimental effects of AR and/or AA on patients' HRQL and its considerable cost burden might encourage early diagnosis and treatment, in order to minimize the disease burden and ensure beneficial and cost-effective outcomes.

Prenatal exposure to systemic antibacterials and overweight and obesity in Danish schoolchildren: a prevalence study.

BACKGROUND/OBJECTIVE: Prenatal exposure to antibacterials may permanently dysregulate fetal metabolic patterns via epigenetic pathways or by altering maternal microbiota. We examined the association of prenatal exposure to systemic antibacterials with overweight and obesity in schoolchildren. SUBJECTS/METHODS: We conducted a prevalence study among Danish schoolchildren aged 7-16 years using data from routine school anthropometric evaluations conducted during 2002-2013. Prenatal exposure to antibacterials was ascertained by using maternal prescription dispensations and infection-related hospital admissions during pregnancy. We defined overweight and obesity among the children using standard age- and sex-specific cutoffs. We computed sex-specific adjusted prevalence ratios (aPRs) of overweight and obesity associated with exposure to prenatal antibacterials, adjusting for maternal age at delivery, marital status, smoking in pregnancy and multiple gestation; we also stratified the analyses by birth weight. RESULTS: Among 9886 schoolchildren, 3280 (33%) had prenatal exposure to antibacterials. aPRs associated with the exposure were 1.26 (95% confidence interval (CI): 1.10-1.45) for overweight and 1.29 (95% CI: 1.03-1.62) for obesity. Among girls, aPRs were 1.16 (95% CI: 0.95-1.42) for overweight and 1.27 (95% CI: 0.89 to 1.82) for obesity. Among boys, aPRs were 1.37 (95% CI: 1.13-1.66) for overweight and 1.29 (95% CI: 0.96-1.73) for obesity. The aPR for overweight was higher among schoolchildren with birth weight <3500 g (aPR: 1.30, 95% CI: 1.05-1.61) than in schoolchildren with birth weight ⩾3500 g (aPR: 1.18, 95% CI: 0.95-1.46). Inversely, the association for obesity was higher among schoolchildren with birth weight ⩾3500 g (aPR: 1.35, 95% CI: 1.00-1.81) than among those who were <3500 g at birth (aPR: 1.16, 95% CI: 0.82-1.65). CONCLUSIONS: Prenatal exposure to systemic antibacterials is associated with an increased risk of overweight and obesity at school age, and this association varies by birth weight.

Interactions between smoking, increased serum levels of anti-CCP antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis.

OBJECTIVES: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset. METHOD: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity. RESULTS: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes. CONCLUSIONS: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.

Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influence of alendronate and intra-articular glucocorticoid treatment. Post hoc analyses from the CIMESTRA trial.

OBJECTIVES: The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during 1 year of a treat-to-target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)). PATIENTS AND METHODS: A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score ≤0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp-van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients. RESULTS: The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged -2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients (-1.8% and -2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0-19), non-alendronate: 0 (0-18)). CONCLUSIONS: In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression.

Specificity and sensitivity of commercially available assays for glucagon-like peptide-1 (GLP-1): implications for GLP-1 measurements in clinical studies.

AIMS: To evaluate the performances of commercially available glucagon-like peptide-1 (GLP-1) assays and the implications for clinical studies. METHODS: Known concentrations (5-300 pmol/l) of synthetic GLP-1 isoforms (GLP-1 1-36NH2, 7-36NH2, 9-36NH2, 1-37, 7-37 and 9-37) were added to the matrix (assay buffer) supplied with 10 different kits and to human plasma, and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations. Endogenous GLP-1 levels in clinical samples were assessed using three commercial kits. RESULTS: The USCN LIFE assay detected none of the GLP-1 isoforms. The active GLP-1 enzyme-linked immunosorbent assays (ELISAs) from Millipore and DRG appeared identical and were specific for intact GLP-1 in buffer and plasma. The Meso Scale Discovery (MSD) total GLP-1 kit detected all six GLP-1 isoforms, although recovery of non-active forms was incomplete, especially in plasma. Millipore total GLP-1 ELISA kit detected all isoforms in buffer, but mainly amidated forms in plasma. The Alpco, Phoenix and Bio-Rad kits detected only amidated GLP-1, but the Alpco kit had a limited measurement range (30 pmol/l), the Phoenix kit had incomplete recovery in plasma and the Bio-Rad kit was insensitive (detection limit in plasma 40 pmol/l). The pattern of postprandial GLP-1 responses in clinical samples was similar between the kits tested, but the absolute concentrations measured varied. CONCLUSIONS: The specificity and sensitivity of commercially available kits for the analysis of GLP-1 levels vary considerably. This should be taken into account when selecting which assay to use and when comparing data from different studies.

Upregulated baseline plasma CCL19 and CCR7 cell-surface expression on monocytes in early rheumatoid arthritis normalized during treatment and CCL19 correlated with radiographic progression.

OBJECTIVES: The aim of this study was to measure, in early rheumatoid arthritis (RA) patients, the concentration of CC-chemokine ligand 19 (CCL19) in plasma and the cell-surface expression of CC-chemokine receptor 7 (CCR7) on circulating monocytes and CD4+ T lymphocytes and to analyse correlations with disease activity and 5-year radiographic progression. METHOD: In disease-modifying anti-rheumatic drug (DMARD)-naïve RA patients (disease duration < 6 months), we measured plasma CCL19 by enzyme-linked immunosorbent assay (ELISA) (n = 160) and CCR7 cell-surface expression on monocytes and CD4+ T lymphocytes by flow cytometry (n = 40) at baseline and after 1 year of treatment with methotrexate (MTX) or methotrexate+cyclosporin A (MTX/CyA). Radiographic progression was scored by the van der Heijde-modified Total Sharp Score (TSS) from 0 to 5 years. RESULTS: Increased baseline CCL19 (median 85 pg/mL, range 31-1008 pg/mL, p = 0.01) decreased after 1 year (median 31 pg/mL, range 31-1030 pg/mL, p < 0.001) and 5 years (median 31 pg/mL, range 31-247 pg/mL, p < 0.001) to a level below the controls (n = 45) (median 60 pg/mL, range 31-152 pg/mL). Baseline plasma CCL19 levels [p = 0.011, 95% confidence interval (CI) 0.0030-0.0176], anti-cyclic citrullinated peptide (anti-CCP) antibody status (p = 0.002, 95% CI 0.61-2.38), and TSS > 0 at baseline (p < 0.001, 95% CI 1.21-3.16) were independent predictors of 5-year radiographic progression evaluated by multiple logistic regression in contrast to never smoked, C-reactive protein (CRP), gender, age, number of tender (NTJ) and swollen joints (NSJ), and 28-joint Disease Activity Score (DAS28). Increased CCR7 expression on monocytes (p = 0.008) correlated to CRP (p = 0.006, r = 0.52) and normalized (n = 15) after 1 year (p = 0.02). CONCLUSIONS: In DMARD-naïve RA patients, CCL19 plasma level and CCR7 surface expression on monocytes were upregulated and normalized after 1 year of treatment. Increased baseline plasma CCL19 level, anti-CCP antibody status, and TSS > 0 at baseline correlated independently with 5-year radiographic progression.

Using citrate-functionalized TiO2 nanoparticles to study the effect of particle size on zebrafish embryo toxicity.

TiO2 nanoparticles (NPs) are photoactive, potentially producing toxicity in vivo in the presence of sunlight. We have previously demonstrated photodependent toxicity in zebrafish embryos exposed to TiO2 NPs. Here we investigate the effect of particle size on developing zebrafish exposed to 6, 12 and 15 nm citrate-functionalized anatase TiO2 NPs under either simulated sunlight illumination or in the dark. All three sizes of TiO2 NPs caused photo-dependent toxicity. Under simulated sunlight illumination, the acute toxicity of the 6 nm citrate-TiO2 NPs (120 h LC50 of 23.4 mg L(-1)) exceeded that of the 12 and 15 nm citrate-TiO2 NPs. Exposure to 6 nm particles under illumination also caused a higher incidence of developmental defects than the larger particles. These abnormalities included pericardial edema, yolk-sac edema, craniofacial malformation, and opaque yolk. To gain insight into the mechanisms of toxicity, we measured hydroxyl radicals (˙OH) generated by NPs in vitro and reactive oxygen species (ROS) produced in vivo. We found that on a mass basis, smaller particles generated higher levels of ROS both in vitro and in vivo, and the 6 nm citrate-TiO2 NPs induced more oxidative stress than larger particles in the zebrafish embryo. We examined oxidative DNA damage by measuring 8-hydroxydeoxyguanosine in zebrafish exposed to different-sized citrate-TiO2 NPs and found that 6 nm particles caused more DNA damage than did larger particles (12 and 15 nm) under illumination. Our results indicate a photo-dependent toxicity of citrate-TiO2 NPs to zebrafish embryos, with an inverse relationship between particle size and toxicity. Production of more ROS, resulting in more oxidative stress and more DNA damage, represents one possible mechanism of the higher toxicity of smaller citrate-TiO2 NPs. These results highlight the relationship between citrate-TiO2 NP size and toxicity/oxidative stress in developing zebrafish embryos.