Miracle-dz/UniFAR-FTUs huggingface dataset:
Brief Report: Clinical Trials Aiming to Prevent Rheumatoid Arthritis Cannot Detect Prevention Without Adequate Risk Stratification: A Trial of Methotrexate Versus Placebo in Undifferentiated Arthritis as an Example

Prevention of rheumatoid arthritis (RA) was the aim of several trials in undifferentiated arthritis (UA), with overall negative results. As preparatory work has revealed that only ∼30% of UA patients progress to having RA, we hypothesized that inclusion of patients without imminent RA could lead to false‐negative results. We undertook this study to evaluate this hypothesis by reinvestigating the Probable Rheumatoid Arthritis: Methotrexate versus Placebo Treatment (PROMPT) trial (a 1‐year course of methotrexate [MTX] versus placebo in UA) after excluding patients without a high risk of developing RA.
Anti–Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients

Studies suggest that rheumatoid arthritis (RA)–related autoimmunity is initiated at a mucosal site. However, the factors associated with the mucosal generation of this autoimmunity are unknown, especially in individuals who are at risk of future RA. Therefore, we tested anti–cyclic citrullinated peptide (anti‐CCP) antibodies in the sputum of RA‐free first‐degree relatives (FDRs) of RA patients and patients with classifiable RA.
Loneliness-distress and physician utilization in well-elderly females.

Two samples (N = 112 and 115) of females aged 65–85, recruited from senior centers and groups, were surveyed with respect to the determinants of their use of physician services. The results of the two samples are fairly consistent: (a) Sociodemographic variables are not useful in predicting physician utilization; (b) health status accounts for about 30% of the variance in frequency of visits; (c) psychosocial factors, in particular loneliness-distress, account for an additional 13%–14% of the variance in frequency of visits; (d) when subject to discriminant analysis, health status and psychosocial variables together correctly classify about 60% of the high utilizers (those in the top quarter of the sample in physician visit rate), with a less than 10% false-positive rate.
Eosinophils in the pathogenesis of paediatric severe asthma

Purpose of reviewThe importance and functional contribution of eosinophils to the pathogenesis of severe asthma was questioned when adult studies reported neutrophilic inflammation and Th17 cells were central to disease. Recent findingsEosinophilic inflammation, atopic sensitization and airway remodelling are the hallmark features of severe asthma in children. Contrary to adult reports, neutrophils, Th17 and Th2 cytokines are rarely detected in children with severe disease who are prescribed high-dose steroids. Type 2 innate lymphoid cells (ILCs), which are induced by the epithelial cytokine interleukin (IL)-33, and also release the Th2 cytokines IL-5 and IL-13, have been shown to be important in mediating asthma, and specifically, ILCs have a role in mediating eosinophil homeostasis. A direct link between IL-33, airway remodelling and steroid resistance in paediatric severe asthma suggests the steroid-resistant eosinophilia may be mediated by ILCs rather than classical Th2 lymphocytes. SummaryData from children with severe asthma have shown that findings from adults cannot be translated to children, and that steroid-resistant eosinophilic inflammation appears central to the pathogenesis of paediatric disease. Age-appropriate experimental models and use of airway samples from children are critical to understanding the underlying mechanisms and identifying novel therapeutic targets.
Angular Stable Plates in Lower Cervical Spine Fractures

This study evaluates the results of operative treatment of lower cervical spine injuries stabilised with angular stable plates and screws. It is a retrospective study of anterior spondylodesis carried out to stabilise unstable lower cervical spine injuries. From 1994 to 2001, 131 anterior spondylodeses were performed. One segment was fused in 116 (88.5%) cases and two segments were fused in 15 (11.5%) cases. Preoperative realignment was achieved by halo traction followed by operative decompression and stabilisation. Ruptured discs or fractured vertebral bodies were removed and fusion was performed using tricortical autologous bone grafts with angular stable plates and screw fixation. In 131 cases of anterior spondylodesis, 125 (95.4%) fused solidly in an average of 3.4 months. In 4 (3%) cases pseudarthrosis oc-curred and in 2 (2.5%) cases dislocation of instrumentation was found. All cases of pseudarthrosis required further surgery. Repeated plate breakage occurred in one patient but due to the absence of clinical signs or symptoms of instability no further surgery was performed. In the 2 cases of dislocation of screws and plates, reosteosynthesis resulted in solid fusion. Both of these patients suffered from ankylosing spondylitis. Our results of fusion (95.4%) using angular stable plates and screws are comparable to other results available in the literature. The reason for the occurrence of pseudarthrosis is not clear. Early and over vigorous physical exercise may contribute. In patients with ankylosing spondylitis, reduced bone quality probably caused the dislocation of screws and the resulting non-union.
Mechanisms of immune regulation by IVIG

Purpose of reviewIn the past few years there have been many advances in our understanding of the mechanisms by which intravenous immune globulin (IVIG) modulates immune function in autoimmune disorders. Recent findingsPrevious investigations have focused on the Fc domain of the IgG molecule, and the role of the Fc&ggr;RIIB receptor and the sialylated Fc domain that have been show to mediate the anti-inflammatory effects in certain murine models of autoantibody-mediated diseases. More recent findings have implicated the F(ab’)2 domain in IVIG-induced immune modulation in T-cell-mediated autoimmune disease models in which upregulation of T-regulatory cells and downregulation of the Th17 pathways are important components of this mechanism. The prostaglandin E pathway may be playing a role in the IVIG-induced changes in the T-regulatory pathway. SummaryMany of the mechanisms proposed for the immune-modulating effects of IVIG demonstrate the complexity of immune effector functions in disease processes. Although controversy exists on the role of the Fc&ggr;RIIB receptor and the importance of the sialylated Fc domain in human autoimmune disorders, probably no one single mechanism is responsible for the effects of IVIG in autoimmune and inflammatory diseases. The potential role of the prostaglandin E pathway may offer alternative treatments.
Immunological mechanisms in allergic contact dermatitis

Purpose of reviewAllergic contact dermatitis is a skin disease resulting from an adverse reaction of the immune system to low-molecular-weight organic chemicals or metal ions. This review summarizes recent findings that highlight new details of the complex orchestration of the cellular and molecular immune response to contact allergens. Recent findingsProgress has been made in the characterization of the roles of natural killer T cells, natural killer cells, mast cells and neutrophils, as well as in the elucidation of signaling pathways triggered by contact allergens. Global technologies begin to reveal gene signatures for contact allergen identification and improved diagnostics. SummaryRecent progress in contact allergy research has deepened our understanding of the molecular and cellular pathomechanisms, and opens new avenues towards improved diagnostics and treatments, as well as prevention and risk assessment strategies.
Intestinal Metabolites Are Profoundly Altered in the Context of HLA–B27 Expression and Functionally Modulate Disease in a Rat Model of Spondyloarthritis

HLA–B27–associated spondyloarthritides are associated with an altered intestinal microbiota and bowel inflammation. We undertook this study to identify HLA–B27–dependent changes in both host and microbial metabolites in the HLA–B27/β2‐microglobulin (β2m)–transgenic rat and to determine whether microbiota‐derived metabolites could impact disease in this major model of spondyloarthritis.
Rituximab for Antineutrophil Cytoplasmic Antibody–Associated Vasculitis—Not Everything in the Garden Is Rosy: Comment on the Article by Cortazar et al

1. Erratum. Arthritis Rheumatol 2017;69:2080. 2. Reginster JY, Reiter-Niesert S, Bruyère O, Berenbaum F, Brandi ML, Branco J, et al. Recommendations for an update of the 2010 European regulatory guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis and reflections about related clinically relevant outcomes: expert consensus statement. Osteoarthritis Cartilage 2015;23:2086–93. 3. Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, Rodriguez de la Serna A, Naranjo A, et al. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis 2011;70:1957–62. 4. Herrero-Beaumont G, Marcos ME, S anchez-Pernaute O, Granados R, Ortega L, Montell E, et al. Effect of chondroitin sulphate in a rabbit model of atherosclerosis aggravated by chronic arthritis. Br J Pharmacol 2008;154:843–51. 5. Largo R, Roman-Blas J, Moreno-Rubio J, S anchez-Pernaute O, Mart ınez-Calatrava MJ, Casta~ neda S, et al. Chondroitin sulfate improves synovitis in rabbits with chronic antigen-induced arthritis. Osteoarthritis Cartilage 2010;18 Suppl 1:S17–23. 6. Largo R, Mart ınez-Calatrava MJ, S anchez-Pernaute O, Marcos ME, Moreno-Rubio J, Aparicio C, et al. Effect of a high dose of glucosamine on systemic and tissue inflammation in an experimental model of atherosclerosis aggravated by chronic arthritis. Am J Physiol Heart Circ Physiol 2009;297:H268–76.
Genome‐Wide Association Meta‐Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci

Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)−negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes.
Editorial: Anti–Citrullinated Protein Antibody, Anti–Carbamylated Protein Antibody, and Rheumatoid Arthritis: Azurophilic Granules Sing the Blues

Arginine and lysine are distinguished by their identity as the most cationic (basic) amino acids. They are also the target of many post-translational modifications, e.g. acetylation, citrullination, hydroxylation, methylation, ubiquitination. These modifications are catalyzed by a series of enzymes, presumably to enable a tapestry of functionality by a single protein, including regulation of DNA transcription, repair and replication. Besides their functional roles in normal physiological conditions, some of these protein modifications have been recognized as inflammatory triggers and targets of autoimmune reactions. This article is protected by copyright. All rights reserved.
a-Fetoprotein: Reevaluation

a-Fetoprotein (AFP) is a fetal serum protein (1,2), and its reappearance in mice with hepatoma was demonstrated by Abelev et al. (3) in 1963 and in patients with liver cancer by Tatarinov (4,5) nearly at the same time. The association of raised serum levels of AFP with yolk sac tumors was documented later by Abelev et al. (6) and Masopust et al. (7). Interestingly, Tatarinov (5 , 8) suggested that AFP is a marker of hepatoma on the basis of results obtained with a very small number of patients with this disorder. This was probably possible because AFP is a highly specific and sensitive marker of hepatocellular carcinoma (HCC) as it was shown later by a number of workers. An AFP-positive case of fulminant hepatitis was also found in his early studies using an immunodiffusion technique, and the appearance of AFP in other hepatitis and cirrhosis was reported later in a collaborative study (9) using a similar test system. Development of a sensitive RIA system (10, 11) enabled us to study low levels of AFP in patients with benign liver diseases and malignant tumors of other origins. It is now generally accepted that a considerable number of patients with acute and chronic hepatitis and cirrhosis without malignancy show slight but significant elevations of serum AFP (11-14). Regulatory mechanisms of increased AFP synthesis in hepatic injury and in malignant transformation have been explored at the cellular and molecular levels (15-18). The recognition of raised serum levels of AFP is clinically important because AFP-positive patients with chronic hepatitis and cirrhosis have a high risk of liver-related death (19-20) or development of HCC (14, 21, 22). Currently, serum levels of AFP at the time of hepatoma diagnosis became lower as a result of the advent of advanced imaging and biopsy techniques in the diagnosis of HCC, resulting in a wider overlapping zone of AFP levels between benign and malignant liver diseases. Accordingly, it becomes more important to discriminate between AFP elevation associated with hepatoma evolution and that with hepatitis and cirrhosis alone. Thus the lectin-dependent fractionation of AFP originally described by Brqborowicz, Mackiewicz and Brqborowicz (23) and Miyazaki, Endo and Oda (24) is now an important complementary test in the follow-up of Health Research Center, Kagawa Uniuersity, Takamatsu 760, Japan
Safety, Tolerability, and Pharmacodynamics of ABT‐122, a Tumor Necrosis Factor– and Interleukin‐17–Targeted Dual Variable Domain Immunoglobulin, in Patients With Rheumatoid Arthritis

Tumor necrosis factor (TNF) and interleukin‐17 (IL‐17) independently contribute to the pathophysiology of rheumatoid arthritis (RA). ABT‐122 is a novel dual variable domain immunoglobulin that selectively and simultaneously targets human TNF and IL‐17A. The aim of treatment with ABT‐122 is to evoke a greater clinical response than that achieved by targeting either cytokine alone. This study was undertaken to present the pooled safety, tolerability, and exploratory pharmacodynamics of ABT‐122 based on 2 phase I, placebo‐controlled, multiple ascending‐dose studies in patients with primarily inactive RA.
Sperm competition roles and ejaculate investment in a promiscuous mammal

Theoretical models of sperm competition predict how males should allocate sperm and seminal fluid components to ejaculates according to their mating role (dominant vs. subordinate). Here, we present a detailed analysis of ejaculate expenditure according to male roles in the bank vole (Myodes glareolus). Sperm competition occurs regularly in this species, and dominant males typically achieve higher fertilization success than subordinates. Contrary to theoretical predictions, we found that dominant male bank voles invest more sperm per ejaculate than subordinates, both absolutely and relative to body and testes mass. The testes of dominant males were also absolutely (although not relatively) larger than those of subordinates. However, we found no evidence that subordinate males compensate for lower sperm numbers per ejaculate by increasing ejaculation frequency or sperm velocity. Similarly, we found no evidence for differential investment in copulatory plug size according to male roles in sperm competition, although dominant males had significantly larger seminal vesicles (both absolutely and relative to body mass) compared with subordinates. We conclude that sperm competition roles can have significant but unexpected influences on ejaculate investment in mammals with clearly defined differences in male social status.
Recent advances in environmental controls outside the home setting

Purpose of reviewIt has been well studied that aeroallergen, mold, and airborne pollutant exposure in the inner-city home environment is associated with significant childhood asthma morbidity. Although the home environment has been extensively studied, the school environment is less well understood. Recent findingsIn this article, we discuss the relationship between environmental exposures within the school and daycare environment and pediatric asthma morbidity and novel environmental interventions designed to help mitigate pediatric asthma morbidity. SummaryStudies assessing environmental exposures outside the home environment and interventions to mitigate these exposures have the potential to reduce pediatric asthma morbidity. Further study in this area should focus on the complex cost benefit analyses of environmental interventions outside the home setting, while controlling for the home environment.
Detecting cryptic speciation in the widespread and morphologically conservative carpet chameleon (Furcifer lateralis) of Madagascar

Species delimitation within recently evolved groups can be challenging because species may be difficult to distinguish morphologically. Following the General Lineage Concept, we apply a multiple evidence approach to assess species limits within the carpet chameleon Furcifer lateralis, which is endemic to Madagascar and exported in large numbers for the pet trade. Cryptic speciation within F. lateralis was considered likely because this species (1) has a vast distribution, (2) occupies exceptionally diverse habitats and (3) exhibits subtle regional differences in morphology. Phylogenetic trees reconstructed using nuclear and mitochondrial genes recovered three well‐supported clades corresponding with geography. Morphological results based on canonical variates analysis show that these clades exhibit subtle differences in head casque morphology. Ecological niche modelling results found that these phylogenetic groups also occupy unique environmental space and exhibit patterns of regional endemism typical of other endemic reptiles. Combined, our findings provide diverse yet consistent evidence for the existence of three species. Consequently, we elevate the subspecies F. lateralis major to species rank and name a new species distributed in northern and western Madagascar. Initial ecological divergence, associated with speciation of F. lateralis in humid eastern habitat, fits the Ecographic Constraint model for species diversification in Madagascar. By contrast, the second speciation event provides some support for the Riverine Barrier model, with the Mangoky River possibly causing initial isolation between species. These findings thus support two contrasting models of speciation within closely related species and demonstrate the utility of applying a combined‐evidence approach for detecting cryptic speciation.
Variation in adult sex ratio alters the association between courtship, mating frequency and paternity in the lek‐forming fruitfly Ceratitis capitata

The intensity with which males deliver courtship and the frequency with which they mate are key components of male reproductive success. However, we expect the strength of the relationship between these traits and a male’s overall paternity to be strongly context dependent, for example to be altered significantly by the extent of post‐mating competition. We tested this prediction in a lekking insect, Ceratitis capitata (medfly). We examined the effect of manipulating the sex ratio from male‐ to female‐biased (high and low male competition, respectively) on courtship behaviour, mating frequency and paternity of focal males. Under high male competition, focal males delivered significantly more courtship but gained lower paternity than under lower competition. Paternity was positively associated with mating frequency and small residual testes size. However, the association between mating frequency and paternity was significantly stronger under low competition. We conclude that manipulation of sex ratio significantly altered the predictors of mating success and paternity. The relationship between pre‐ and post‐mating success is therefore plastic and alters according to the prevailing level of competition. The results highlight the importance of post‐copulatory processes in lekking species and illuminate selection pressures placed on insects such as medflies that are mass reared for pest control.
Larval Temperature in Brood Clumps of Bombus Pascuorum (Scop.)

SummaryFor 21 larvae cocoon diameter (4·3 to 8·1 mm) was positively correlated with mean temperature at the fourth instar stage (27·06, SE ± 0·17 to 31·89, SE ± 0·15°C; r = 0·59, P<0·01) and negatively correlated with variation in temperature (coefficient of variation, CV, 2·38 to 4·65; r = −0·53, P<0·05). Larvae located centrally in a brood clump generally experienced higher and more stable temperatures (30·89 ± 0·39°C; CV, 2·77 ± 0·16) than those located peripherally (29·10 ± 0·34°C; CV, 3·26 ± 0·13). Pupal weight was highly correlated with centrally located pupal cocoons of 7·27, SE ± 0·30 mm in diameter and peripheral cocoons of 5·78, SE ± 0·28 mm in diameter (r = 0·95, P<0.001).
The costs of parental care: a meta‐analysis of the trade‐off between parental effort and survival in birds

A fundamental premise of life‐history theory is that organisms that increase current reproductive investment suffer increased mortality. Possibly the most studied life‐history phenotypic relationship is the trade‐off between parental effort and survival. However, evidence supporting this trade‐off is equivocal. Here, we conducted a meta‐analysis to test the generality of this tenet. Using experimental studies that manipulated parental effort in birds, we show that (i) the effect of parental effort on survival was similar across species regardless of phylogeny; (ii) individuals that experienced reduced parental effort had similar survival probabilities than control individuals, regardless of sex; and (iii) males that experienced increased parental effort were less likely to survive than control males, whereas females that experienced increased effort were just as likely to survive as control females. Our results suggest that the trade‐off between parental effort and survival is more complex than previously assumed. Finally, our study provides recommendations of unexplored avenues of future research into life‐history trade‐offs.
Calcium and salinity as selective factors in plate morph evolution of the three‐spined stickleback (Gasterosteus aculeatus)

Identifying the causal factors underlying natural selection remains a key challenge in evolutionary biology. Although the genetic basis for the plate morph evolution of three‐spined stickleback (Gasterosteus aculeatus) is well described, the environmental variables that form the basis for different morphs are not understood. We measured the effects of dissolved calcium and salinity on the growth of sticklebacks with different plate morphs from Scotland and Poland. There was a significant interaction of calcium with plate morph for fish from both regions, with complete morph sticklebacks growing more slowly at low calcium concentrations and low morph sticklebacks showing divergent responses to calcium concentration. A Scottish anadromous population showed evidence of local adaptation to high salinity, which was independent of plate morph. Polish and Scottish populations diverged in their response to salinity, suggesting a difference in osmotic regulation. The results implicate a role for calcium in selecting for plate morph evolution in sticklebacks, possibly as a limiting element in skeletal growth.