Three out of four disease-modifying anti-rheumatic drug-naïve rheumatoid arthritis patients meet 28-joint Disease Activity Score remission at 12 months: results from the FIN-ERA cohort.

OBJECTIVE: To assess what proportion of patients with disease-modifying anti-rheumatic drug (DMARD)-naïve early rheumatoid arthritis (ERA) reach 28-joint Disease Activity Score (DAS28) remission over 1 year, and remission variability across clinics in Finland. METHOD: Patients with DMARD-naïve newly diagnosed inflammatory arthritis were recruited. The proportion of patients in 28-joint Disease Activity Score with three variables (DAS28-3) remission was compared across sites. Repeated measures were analysed using a mixed models approach with appropriate distribution and link function. RESULTS: In total, 611 patients were recruited at five sites: 67% were female; the mean (sd) age was 57 (16) years; 71% and 68% were positive for rheumatoid factor and anti-cyclic citrullinated peptides, respectively; and 23% had radiographic erosions. A total of 506 (83%) fulfilled the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for rheumatoid arthritis for further analyses. DAS28-3 remission was met by 68% and 75% at 3 and 12 months, respectively. The clinical site had no effect on remission when adjusted for confounders. At baseline, 68% used methotrexate-based combination therapy, and 31% used triple therapy with methotrexate, hydroxychloroquine, and sulphasalazine (the Fin-RACo regimen). In multivariate analysis, the only independent predictors of DAS28-3 remission at 12 months were lower baseline DAS28-3 and triple therapy as the initial treatment. CONCLUSION: Three out of four DMARD-naïve ERA patients in Finland are in remission during the first year from the diagnosis. High remission rates were achieved for most patients with the use of conventional synthetic DMARDs in combination. Treatment of DMARD-naïve ERA patients with the FIN-RACo regimen is a predictor of DAS28-3 remission in real-life rheumatology settings.

A hyperparasite affects the population dynamics of a wild plant pathogen.

Assessing the impact of natural enemies of plant and animal pathogens on their host's population dynamics is needed to determine the role of hyperparasites in affecting disease dynamics, and their potential for use in efficient control strategies of pathogens. Here, we focus on the long-term study describing metapopulation dynamics of an obligate pathogen, the powdery mildew (Podosphaera plantaginis) naturally infecting its wild host plant (Plantago lanceolata) in the fragmented landscape of the Åland archipelago (southwest Finland). Regionally, the pathogen persists through a balance of extinctions and colonizations, yet factors affecting extinction rates remain poorly understood. Mycoparasites of the genus Ampelomyces appear as good candidates for testing the role of a hyperparasite, i.e. a parasite of other parasites, in the regulation of their fungal hosts' population dynamics. For this purpose, we first designed a quantitative PCR assay for detection of Ampelomyces spp. in field-collected samples. This newly developed molecular test was then applied to a large-scale sampling within the Åland archipelago, revealing that Ampelomyces is a widespread hyperparasite in this system, with high variability in prevalence among populations. We found that the hyperparasite was more common on leaves where multiple powdery mildew strains coexist, a pattern that may be attributed to differential exposure. Moreover, the prevalence of Ampelomyces at the plant level negatively affected the overwinter survival of its fungal host. We conclude that this hyperparasite may likely impact on its host population dynamics and argue for increased focus on the role of hyperparasites in disease dynamics.

Smokers and non smokers with rheumatoid arthritis have similar clinical status: data from the multinational QUEST-RA database.

OBJECTIVES: To analyse clinical severity/activity of rheumatoid arthritis (RA) according to smoking status. METHODS: The QUEST-RA multinational database reviews patients for Core Data Set measures including 28 swollen and tender joint count, physician global estimate, erythrocyte sedimentation rate (ESR), HAQ-function, pain, and patient global estimate, as well as DAS28, rheumatoid factor (RF), nodules, erosions and number of DMARDs were recorded. Smoking status was assessed by self-report as 'never smoked', 'currently smoking' and 'former smokers'. Patient groups with different smoking status were compared for demographic and RA measures. RESULTS: Among the 7,307 patients with smoking data available, status as 'never smoked,' 'current smoker' and 'former smoker' were reported by 65%, 15% and 20%. Ever smokers were more likely to be RF-positive (OR 1.32;1.17-1.48, p<0.001). Rheumatoid nodules were more frequent in ever smokers (OR 1.41;1.24-1.59, p<0.001). The percentage of patients with erosive arthritis and extra-articular disease was similar in all smoking categories. Mean DAS28 was 4.4 (SD 1.6) in non-smokers vs. 4.0 (SD 1.6) in those who had ever smoked. However, when adjusted by age, sex, disease duration, and country gross domestic product, only ESR remained significantly different among Core Data Set measures (mean 31.7mm in non-smokers vs. 26.8mm in ever smoked category). CONCLUSIONS: RA patients who had ever smoked were more likely to have RF and nodules, but values for other clinical status measures were similar in all smoking categories (never smoked, current smokers and former smokers).

Environmental sustainability assessment from planetary boundaries perspective - A case study of an organic sheep farm in Finland.

Food production processes may have both positive and negative environmental sustainability impacts. This makes decision-making challenging in the transition towards more sustainable food production systems. In this paper, a new method for presenting environmental impacts in the context of planetary boundaries is demonstrated. This will help food and agricultural producers compare the magnitudes of various environmental impacts. The environmental sustainability impacts of an organic sheep farm in the boreal climate zone in Finland are studied herein first using a life cycle assessment method. The results are then normalized and presented in a planetary boundary framework to ascertain the extent of different environmental impacts. The results show that in the planetary boundary context, there are positive impacts of sheep grazing on biosphere integrity (genetic diversity) and biogeochemical flows and negative impacts on climate change, land use or freshwater use. Magnitudes of the impacts greatly dependent on the assumptions made especially regarding biosphere integrity impacts. In the future, it is crucial that decision-making be based on the evaluation of various environmental impacts and that the focus be more on complex sustainability thinking, rather than on one single environmental impact. This research demonstrates that results from a life cycle assessment can be modified and presented in a planetary boundaries context. A planetary boundary framework approach similar to that proposed herein could be further used to identify different environmental sustainability perspectives and to help one better recognize the multifunctional aspects of the ecosystem processes.

Author Correction: Solar superstorm of AD 774 recorded subannually by Arctic tree rings.

The authors became aware of a mistake in the data displayed in Fig. 1 and Supplementary Table 2 of the original version of the Article. Specifically, the 14C production values were printed out in the code before the conversion between the omnidirectional fluence and the flux. As a consequence, the values of the 14C production in Fig. 1 and Supplementary Table 2 were too high by a factor of 4×π = 12.566.. As a result of this, a number of changes have been made to both the PDF and the HTML versions of the Article. A full list of these changes is available online.

Identifying footprints of directional and balancing selection in marine and freshwater three-spined stickleback (Gasterosteus aculeatus) populations.

Natural selection is expected to leave an imprint on the neutral polymorphisms at the adjacent genomic regions of a selected gene. While directional selection tends to reduce within-population genetic diversity and increase among-population differentiation, the reverse is expected under balancing selection. To identify targets of natural selection in the three-spined stickleback (Gasterosteus aculeatus) genome, 103 microsatellite and two indel markers including expressed sequence tags (EST) and quantitative trait loci (QTL)-associated loci, were genotyped in four freshwater and three marine populations. The results indicated that a high proportion of loci (14.7%) might be affected by balancing selection and a lower proportion (2.8%) by directional selection. The strongest signatures of directional selection were detected in a microsatellite locus and two indel markers located in the intronic regions of the Eda-gene coding for the number of lateral plates. Yet, other microsatellite loci previously found to be informative in QTL-mapping studies revealed no signatures of selection. Two novel microsatellite loci (Stn12 and Stn90) located in chromosomes I and VIII, respectively, showed signals of directional selection and might be linked to genomic regions containing gene(s) important for adaptive divergence. Although the coverage of the total genomic content was relatively low, the predominance of balancing selection signals is in agreement with the contention that balancing, rather than directional selection is the predominant mode of selection in the wild.

Genetic evidence for male-biased dispersal in the three-spined stickleback (Gasterosteus aculeatus).

Sex-biased dispersal is capable of generating population structure in nonisolated populations and may affect adaptation processes when selective conditions differ among populations. Intrasexual competition for local resources and/or mating opportunities predicts a male-biased dispersal in polygynous species and a female bias in monogamous species. The patterns of sex-biased dispersal in birds and mammals are well explained by their respective mating systems, but the picture emerging from fish studies is still mixed. Using neutral genetic markers, we investigated whether there is any evidence for sex-biased dispersal among Baltic Sea populations of the three-spined stickleback (Gasterosteus aculeatus). The null hypothesis of non sex-biased dispersal was rejected in favour of male-biased dispersal in this species. As the three-spined stickleback has a polygynous mating system, the observed male bias in dispersal is consistent with the hypothesis that local mate competition might drive the observed pattern. Although more research both on the proximate and ultimate causes behind the observed pattern is needed, our results serve as a first step towards understanding patterns of sex-biased dispersal in this species.

Stability of the upper neck during isometric neck exercises in rheumatoid arthritis patients with atlantoaxial disorders.

OBJECTIVE: To study the effect of isometric neck strength exercises on upper cervical stability in patients with rheumatoid arthritis (RA). METHODS: Twenty patients with a mean (SD) age of 58 (9) years and duration of RA of 27 (10) years volunteered for the study. Lateral radiographs of the cervical spine were taken to measure the current atlantoaxial distance (AAD) in flexion and extension. Maximal isometric neck flexion and extension strength values were measured by a dynamometer. Thereafter, AADs were measured from radiographs taken at 80-90% resistance of maximal strength. RESULTS: According to the full flexion radiographs at baseline, the patients were classified into three groups: eight patients without anterior atlantoaxial subluxation (aAAS) [AAD = 2.1 (2-3) mm], seven with unstable aAAS [AAD = 6.6 (5-8) mm], and five with stable aAAS [AAD = 5.5 (5-7) mm]. During resisted flexion the AAD decreased by 5 (3-7) mm (p<0.001) in the unstable aAAS group, while in the other two groups the changes were minor. During resisted extension the AAD increased by 3 (2-6) mm (p<0.001) in the cases with unstable aAAS only. CONCLUSION: Isometric exercising towards flexion decreases the AAD in cases with unstable aAAS. Submaximal loading of the neck extensors by pushing the back of the head against the resistance even in the neutral position of the cervical spine leads to a decrease in the width of the cervical spine canal and is not recommended in unstable aAAS.

Solar superstorm of AD 774 recorded subannually by Arctic tree rings.

Recently, a rapid increase in radiocarbon (14C) was observed in Japanese tree rings at AD 774/775. Various explanations for the anomaly have been offered, such as a supernova, a γ-ray burst, a cometary impact, or an exceptionally large Solar Particle Event (SPE). However, evidence of the origin and exact timing of the event remains incomplete. In particular, a key issue of latitudinal dependence of the 14C intensity has not been addressed yet. Here, we show that the event was most likely caused by the Sun and occurred during the spring of AD 774. Particularly, the event intensities from various locations show a strong correlation with the latitude, demonstrating a particle-induced 14C poleward increase, in accord with the solar origin of the event. Furthermore, both annual 14C data and carbon cycle modelling, and separate earlywood and latewood 14C measurements, confine the photosynthetic carbon fixation to around the midsummer.

Definitions of remission for rheumatoid arthritis and review of selected clinical cohorts and randomised clinical trials for the rate of remission.

Various definitions of remission in rheumatoid arthritis (RA) have been proposed. The ACR (American College of Rheumatology--formerly ARA, American Rheumatism Association) remission criteria are strict and include nonspecific symptoms such as fatigue. More recently remission according to the Disease Activity Index (DAS) and DAS28 has been described. However, patients who meet the DAS28 remission cut point of < 2.6 may nonetheless have tender and/or swollen joints. The ACR remission criteria are more rigorous than the requirement of DAS28 <2.6. Newer tools for evaluation of RA activity include the Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI), and cut points for remission according to these new indices have been defined. However, all available remission criteria may ignore important aspects of RA, including physical function and radiographic damage.

Remission as the treatment goal--the FIN-RACo trial.

The Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial is the first rheumatoid arthritis (RA) clinical trial in which remission served as the primary outcome measure. This chapter reviews the philosophical background, study design, and results of the FIN-RACo trial. The study showed that a third of patients with active early RA may achieve remission with a combination of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), and prednisolone.

Influence of social background on psychomotor development in the first year of life and its correlation with later intellectual capacity: a prospective cohort study.

The effect of the sex of the child, somatic growth and five family background variables upon psychomotor development during the first year of life was studied by regression analysis in a Northern Finland birth cohort (n = 12 058) for 1966. Children with mental retardation and cerebral palsy were excluded from the series. The significant explanatory variables for the age of learning to stand and to walk without support were gestational age, birth weight, sex and maternal age. The girls and children of young mothers revealed a faster pattern of development. Urban residence enhanced learning to walk with support, an ability which was attained at the same age in both sexes. Female sex was the most powerful explanatory variable for early development of speech, the other significant variable being height at one year, birth weight, low parity of the mother and urban place of the residence. The social class and marital status of the mother proved insignificant for the developmental milestones studied here. The fast learners during their first year of life were superior to the others in their educational capacity at the age of 14 years. The prognosis in this respect was independent of social class.

Mitochondrial DNA phylogeography of the three-spined stickleback (Gasterosteus aculeatus) in Europe-evidence for multiple glacial refugia.

An analysis of mitochondrial DNA sequence variation in 172 three-spined sticklebacks (Gasterosteus aculeatus) sampled across the European distribution range revealed three major evolutionary lineages occupying relatively large and separate geographic areas. The trans-Atlantic lineage comprised of populations spanning from the East Coast of USA to the continental Europe and was basal group to the other European lineages in the phylogeny. The European lineage included populations located in the Western and Eastern Europe, British Isles, Scandinavia as well as some parts of the Mediterranean region. The third lineage was specific to the Black Sea drainages. The within lineage structure was characterized by significant excess of low frequency haplotypes and star-like mtDNA genealogies, which suggest a recent population expansions to the formerly glaciated marine and freshwater environments. A coalescent-based method dated the splits between the major lineages to have occurred during the Saalian and Weichselian glaciations in the late Pleistocene, depending on the molecular clock calibration. The coalescent simulations further indicate high degree of genetic diversity within the lineages and a substantial increase in the genetic diversity in the European lineage relative to the ancestral level. In addition to the three major lineages, the freshwater populations in R. Neretva and L. Skadar in the Adriatic Sea coast region harboured unique and highly divergent haplotypes suggesting long independent histories of these populations. Evidence from mtDNA analyses suggests that these populations deserve a status of an evolutionary significant unit.

Most people over age 50 in the general population do not meet ACR remission criteria or OMERACT minimal disease activity criteria for rheumatoid arthritis.

OBJECTIVE: To analyse the proportion of individuals in the general population over age 50 who do not meet American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA) remission, and OMERACT criteria for minimal disease activity (MDA), and to compare results to RA patients. METHODS: A self-report questionnaire was completed by 1400 community control subjects and 1705 RA patients, including the Health Assessment Questionnaire (HAQ), gradual rating scales for pain, fatigue and global health, duration of morning stiffness and painful joints. The prevalence of 4/6 ACR remission criteria and 4/7 OMERACT criteria for MDA was analysed in community control subjects and patients with RA over age 50. RESULTS: For ACR criteria, 76% of control subjects reported painful joints, 37% morning stiffness, 62% pain and 66% fatigue, vs 94, 65, 84 and 84% of patients with RA. MDA criteria were not met by 64% of control subjects for painful joints, 38% for pain, 45% for global health and 18% for HAQ, vs 89, 60, 69 and 52% of RA patients. The four ACR remission criteria were met by only 15% of control subjects over age 50 and 3% of RA patients, and MDA criteria by 28% of controls and 7% of patients. CONCLUSIONS: The majority of community population over age 50 did not meet criteria for remission or MDA in RA. Although a self-report format may differ from results involving an assessor, the current criteria may not be accurate to identify remission or MDA in people with RA who are older than age 50.

The utility of QTL-Linked markers to detect selective sweeps in natural populations--a case study of the EDA gene and a linked marker in threespine stickleback.

Sequence polymorphisms in coding genes and variability in quantitative trait loci (QTL)-linked markers can be used to uncover the evolutionary mechanisms of traits involved in adaptive processes. We studied sequence variation in the EDA gene and allelic variation in 18 microsatellites - one of which (Gac4174) is linked with the EDA QTL - in low, partially and completely plated morphs from eight threespine stickleback European populations. The results agree with previous studies in that EDA polymorphism is closely related to plate number variation: EDA sequences grouped populations into low and completely plated morphs, whereas microsatellites failed to do so. Furthermore, partially plated fish were heterozygous with respect to the distinctive EDA alleles for completely and low plated morphs, indicating that completely plated morph alleles are not entirely dominant in controlling the expression of lateral plate number. An examination of population differentiation in plate number with quantitative genetic methods revealed that the degree of differentiation exceeded that expected from genetic drift alone (Q(ST) > F(ST)). Our results support the adaptive genetic differentiation of plate morphs and the view that distinctive EDA gene polymorphism occurs in similar sites across the distribution range of this species. Yet, allele frequency differentiation in the Gac4174 microsatellite locus, informative in experimental crosses for plate number variation, did not differ from that of neutral markers and, was therefore unable to detect the signature of natural selection responsible for population divergence.

Contrasting patterns of body shape and neutral genetic divergence in marine and lake populations of threespine sticklebacks.

Comparisons of neutral marker and quantitative trait divergence can provide important insights into the relative roles of natural selection and neutral genetic drift in population differentiation. We investigated phenotypic and genetic differentiation among Fennoscandian threespine stickleback (Gasterosteus aculeatus) populations, and found that the highest degree of differentiation occurred between sea and freshwater habitats. Within habitats, morphological divergence was highest among the different freshwater populations. Pairwise phenotypic and neutral genetic distances among populations were positively correlated, suggesting that genetic drift may have contributed to the morphological differentiation among habitats. On the other hand, the degree of phenotypic differentiation (PST) clearly surpassed the neutral expectation set by FST, suggesting a predominant role for natural selection over genetic drift as an explanation for the observed differentiation. However, separate PST/FST comparisons by habitats revealed that body shape divergence between lake and marine populations, and even among marine populations, can be strongly influenced by natural selection. On the other hand, genetic drift can play an important role in the differentiation among lake populations.

Genetic relationships among marine and freshwater populations of the European three-spined stickleback (Gasterosteus aculeatus) revealed by microsatellites.

To assess the population genetic structure of the three-spined stickleback, Gasterosteus aculeatus, variability at 18 microsatellite loci was examined in 1724 individuals from 74 locations covering most of the species distribution range in Europe. The results revealed high overall degree of differentiation (F(ST) = 0.21) but contrasting level of divergence and genetic variability between habitat types. Marine populations were genetically relatively uniform even across great geographical distances as compared to substantial differentiation among freshwater populations. Analysis of molecular variance indicated low but significant (2.7%) variation in allele frequencies between geographical regions, but a negligible effect of habitat type (0.2%). The phylogenetic pattern was not explained by habitat type, but a weak signal of populations clustering according to geographical or water system origin was found. The results support the view that three-spined stickleback marine ancestors colonized northern European fresh waters during the postglacial marine submergence c. 10,000 years ago, whereas in the Mediterranean region colonization probably dates back to the Pleistocene. The independent origins of river and lake populations indicate that they originate from multiple colonizations rather than sharing common ancestry. In the continuous marine environment, the low degree of differentiation among populations can be explained by gene flow among subpopulations and large effective population size buffering divergence in neutral markers. In contrast, among postglacially established freshwater populations differentiation appears to be driven by genetic drift and isolation. The stepwise mutations appear to have contributed to the population differentiation in the southern part of the three-spined stickleback distribution range.

Muscle strength, pain, and disease activity explain individual subdimensions of the Health Assessment Questionnaire disability index, especially in women with rheumatoid arthritis.

OBJECTIVE: To study the extent to which muscle strength and performance, pain, and disease activity are associated with the total Health Assessment Questionnaire (HAQ) disability index and its subdimensions in male and female patients with rheumatoid arthritis. METHODS: HAQ for functional capacity was completed by 135 patients with rheumatoid arthritis referred for orthopaedic surgery (74% women; mean (SD) age 62 (10) years; disease duration 19 (13) years, 70% positive for rheumatoid factor). Knee extension, trunk extension and flexion, grip strength, walking speed, and sit-to-stand test were measured to mirror physical function. Radiographs of hands and feet, pain, and the modified 28 joint disease activity score (DAS28) were also assessed. RESULTS: Mean total HAQ was 1.08 (0.68) in women and 0.67 (0.70) in men (p = 0.0031). Women had greater disability than men in five of the eight subdimensions of the HAQ. Grip strength was 48%, knee extension strength 46%, trunk extension strength 54%, and trunk flexion strength 43% lower in women than in men. Knee extension strength was inversely correlated with walking time (r = -0.63 (95% confidence interval, -0.73 to -0.51)) and with sit-to-stand test (r = -0.47 (-0.60 to -0.31)). In an ordered logistic regression analysis in female rheumatoid patients, DAS28, pain, knee extension strength, and grip strength were associated with the total HAQ disability index. CONCLUSIONS: Women reported greater disability than men both in the total HAQ and in the majority of its eight subdimensions. In addition to disease activity and pain, muscle strength has a major impact on disability especially in female rheumatoid patients.

High prevalence of asymptomatic cervical spine subluxation in patients with rheumatoid arthritis waiting for orthopaedic surgery.

OBJECTIVE: To study the prevalence of cervical spine subluxation in patients with rheumatoid arthritis waiting for orthopaedic surgery, and symptoms that might be associated with the disorders. METHODS: 194 patients with rheumatoid arthritis were referred for orthopaedic surgery at Jyväskylä Central Hospital, 154 (79%) of whom volunteered for the present study including clinical examination, laboratory tests, radiographs of the cervical spine, hands, and feet, and self report questionnaires. Definition of anterior atlantoaxial subluxation (aAAS) was >3 mm and of subaxial subluxation (SAS)>or=3 mm. Atlantoaxial impaction (AAI) was analysed following to the Sakaguchi-Kauppi method. RESULTS: 67 patients (44%) had cervical spine subluxation or previous surgical fusion. The prevalence of aAAS, AAI, SAS, or previous fusion was 27 (18%), 24 (16%), 29 (19%), and 8 (5%), respectively; 69% of patients with cervical spine subluxations (those with fusions excluded) reported neck pain, compared with 65% of patients without subluxations (p=0.71). The prevalence of occipital, temporal, retro-orbital, and radicular pain in upper extremities was similar in patients with or without cervical spine subluxations (54% v 43%; 17% v 31%; 25% v 24%; 47% v 48%, respectively). However, patients with subluxations were older, had longer disease duration, more active disease, poorer function according to the Health Assessment Questionnaire, and had more often erosive disease. CONCLUSIONS: Asymptomatic cervical spine subluxation is common in patients with rheumatoid arthritis waiting for orthopaedic surgery. Regardless of symptoms, the possibility of cervical spine subluxation in patients with severe rheumatoid arthritis should be considered in preoperative evaluation.