Serum level of adiponectin is a surrogate independent biomarker of radiographic disease progression in early rheumatoid arthritis: results from the ESPOIR cohort

Introduction

Adipokines such as adiponectin, leptin, and visfatin/nicotinamide phosphoribosyltransferase (NAMPT) have recently emerged as pro-inflammatory mediators involved in the pathophysiology of rheumatoid arthritis (RA). We aimed to determine whether serum adipokine levels independently predicted early radiographic disease progression in early RA.

Methods

In total, 791 patients were included from the prospective Etude et Suivi des POlyarthrites Indifférenciées Récentes (ESPOIR) cohort who met the American College of Rheumatology-European League Against Rheumatism criteria for RA (n = 632) or had undifferentiated arthritis (UA) (n = 159). Enzyme-linked immunosorbent assay (ELISA) was used to assess baseline serum levels of adiponectin, leptin, and visfatin/NAMPT. In the RA group, we tested the association of serum adipokine levels and (a) baseline radiographic damage and (b) radiographic disease progression, defined as a change >0 or ≥5 in total Sharp-van der Heijde Score (∆SHS) between inclusion and 1 year (∆SHS ≥1 or rapid radiographic progression: ∆SHS ≥5), adjusting for confounders (age, sex, body-mass index, insulin resistance, C-reactive protein level, Disease Activity Score in 28 joints, Health Assessment Questionnaire score, autoantibody status, steroid use, and radiographic evidence of RA damage at inclusion).

Results

Adiponectin level was independently associated with baseline total SHS (adjusted β = 0.12; P = 0.006). It was also associated with ∆SHS ≥1 (adjusted odds ratio (aOR) = 1.84 (1.25 to 2.72)) involving erosive as well as narrowing disease progression (aOR = 1.73 (1.17 to 2.55) and 1.93 (1.04 to 3.57), respectively). Serum adiponectin level predicted ∆SHS ≥5 (aOR = 2.0 (1.14 to 3.52)). Serum leptin level was independently associated only with ∆SHS >0 (aOR = 1.59 (1.05 to 2.42)). Conversely, serum visfatin/NAMPT level and radiographic disease progression were unrelated. Considering the receiver-operated characteristic curves, the best adiponectin cut-offs were 4.14 μg/ml for ∆SHS ≥1 and 6.04 μg/ml for ∆SHS ≥5, with a good specificity (58% and 75% for ∆SHS ≥1 and ∆SHS ≥5, respectively) and high negative predictive values (75% and 92% for ∆SHS ≥1 or ∆SHS ≥5, respectively).

Conclusion

Serum adiponectin level is a simple useful biomarker associated with early radiographic disease progression in early RA, independent of RA-confounding factors and metabolic status.     

Impact of elevated CO2 and increased temperature on Japanese beetle herbivory

To examine how the major elements of global change affect herbivory in agroecosystems, a multifactorial experiment was conducted where soybeans were grown at two levels of carbon dioxide and temperature, including those predicted for 2050, under otherwise normal field conditions. Japanese beetles (Popillia japonica Newman) were enclosed on foliage for 24 h, after which the beetle survivorship, total and per capita leaf consumption, and leaf protease inhibitor activity were measured. The direct effect of temperature on beetle consumption and survivorship also was measured under controlled environmental conditions. No differences in total foliage consumption were observed; however, beetles forced to feed at elevated temperature in the field demonstrated greater per capita consumption and reduced survivorship compared to beetles feeding at ambient temperature. Survivorship was also greater for beetles that consumed foliage grown under elevated CO₂, but there were no interactive effects of CO₂ and temperature, and no differences in leaf chemistry were resolved. Leaf consumption by beetles increased strongly with increasing temperature up to ～37° C, above which increased mortality caused a precipitous decrease in consumption. An empirical model based on the temperature dependence of leaf consumption and flight suggests that the 3.5°C increase in temperature predicted for 2050 will increase the optimal feeding window for the Japanese beetle by 290%. Elevated temperature and CO₂ operating independently have the potential to greatly increase foliage damage to soybean by chewing insects, such as Popillia japonica, potentially affecting crop yields.     

Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia

The goal of this study was to examine the relation of early androgen exposure to sex-typed activities and interests in adolescence. Participants aged 9-19 years included 24 girls and 18 boys with congenital adrenal hyperplasia (CAH) and 16 unaffected sisters and 24 unaffected brothers who served as controls. Using standardized questionnaires, adolescents reported on their participation in sex-typed activities and interest in sex-typed occupations, and parents reported on the adolescents' activities. As hypothesized, girls with CAH showed sex-atypical preferences: increased interest in male-typical activities and careers and reduced interest in female-typical activities and careers compared to the unexposed control girls. These results extend findings of sex-atypical play in young girls with CAH and suggest that the sex-atypical activities and interests of females with CAH reflect direct effects of androgens on the developing brain rather than social responses to virilized genitalia. These results also suggest that population sex differences in activities and interests arise in part from sex differences in early androgens.     

Common intra-articular T cell expansions in patients with reactive arthritis: identical beta-chain junctional sequences and cytotoxicity toward HLA-B27

Spondyloarthropathies constitute a group of autoimmune diseases of special interest because of their tight association with the MHC class I molecule HLA-B27 and the bacterial triggering of some clinical forms called reactive arthritis (ReA). One current hypothesis is the presentation by HLA-B27 of a so-called arthritogenic peptide to T cells. To better focus on the relevant T cell populations within the joint, we performed an extensive beta-chain T cell repertoire analysis of synovial fluid compared with PBL in seven patients, four of whom were characterized as having ReA triggered by Yersinia enterocolitica, Chlamydia trachomatis, or Shigella sonnei. Analysis of the size diversity of the beta-chain complementarity-determining region 3 (CDR3) allowed us to evaluate the degree of T cell clonality in the samples. Oligoclonal T cell expansions were frequently observed in the joint. In one patient, CDR3 amino acid sequences of major expansions using two different BV genes were identical. One dominant T cell expansion and several CDR3 amino acid sequences were identical in two different patients. Furthermore, one sequence was identical with a sequence reported independently in a Salmonella-induced ReA patient. Together, these data indicate a surprisingly high degree of conservation in the T cell responses in recent-onset ReA triggered by different micro-organisms. A CD8+ synovial line expressing shared clonotypes was established and reacted toward several B*2705 lymphoblastoid cell lines, therefore supporting a molecular mimicry phenomenon at the T cell level in the disease mechanism.     

Phenotype matching in wild parsnip and parsnip webworms: causes and consequences

According to the geographic mosaic theory of coevolution, selection intensity in interactions varies across a landscape, forming a selection mosaic; interaction traits match at coevolutionary hotspots where selection is reciprocal and mismatch at coldspots where reciprocity is not a factor. Chemical traits play an important role in the interaction between wild parsnip (Pastinaca sativa) and the parsnip webworm (Depressaria pastinacella). Furanocoumarins, produced as plant defenses, are detoxified by the webworms by cytochrome P450 monooxygenases; significant additive genetic variation exists for both furanocoumarin production in the plant and detoxification in the insect, making these traits available for selection. To test the hypothesis that differences in selection intensity affect the distribution of coevolutionary hotspots and coldspots in this interaction, we examined 20 populations of webworms and wild parsnips in Illinois and Wisconsin that varied in size, extent of infestation, proximity to woods (and potential vertebrate predators), and proximity to a chemically distinct alternate host plant, Heracleum lanatum (cow parsnip). Twelve of 20 populations displayed phenotype matching between plant defense and insect detoxification profiles. Of the eight mismatched populations, a logistic regression model related matching probability to two predictors: the presence of the alternate host and average content of xanthotoxin (one of the five furanocoumarins produced by P. sativa). The odds of mismatching were significantly increased by the presence of the alternate host (odds ratio = 15.4) and by increased xanthotoxin content (odds ratio = 6.053). Parsnips growing near cow parsnip displayed chemical phenotypes that were chemically intermediate between cow parsnip and parsnips growing in isolation. Rapid phenotype matching in this system is likely due in part to differential mortality every season; larvae transferred to a plant 30 m or more from the plant on which they developed tended to experience increased mortality over larvae transferred to another umbel on the same plant on which they had developed, and plant populations that mismatched in 2001 displayed a change in chemical phenotype distribution from the previous year. Trait mixing through gene flow is also a likely factor in determining mismatch frequency. Populations from which webworms were eradicated the previous year were all recolonized; in three of seven of these populations, infestation rates exceeded 90%. Our findings, consistent with the geographic mosaic theory, suggest that the presence of a chemically distinct alternate host plant can affect selection intensity in such a way as to reduce the likelihood of reciprocity in the coevolutionary interaction between wild parsnip and the parsnip webworm.     

Increase in Dickkopf-1 Serum Level in Recent Spondyloarthritis. Data from the DESIR Cohort

Objectives

To investigate DKK-1 and SOST serum levels among patients with recent inflammatory back pain (IBP) fulfilling ASAS criteria for SpA and associated factors.

Methods

The DESIR cohort is a prospective, multicenter French cohort of 708 patients with early IBP (duration >3 months and <3 years) suggestive of AxSpA. DKK-1 and SOST serum levels were assessed at baseline and were compared between the subgroup of patients fulfilling ASAS criteria for SpA (n = 486; 68.6%) and 80 healthy controls.

Results

Mean SOST serum levels were lower in ASAS+ patients than healthy controls (49.21 ± 25.9 vs. 87.8 ± 26 pmol/L; p<0.0001). In multivariate analysis, age (p = 5.4 10⁻⁹), CRP level (p<0.0001) and serum DKK-1 level (p = 0.001) were associated with SOST level. Mean DKK-1 serum levels were higher in axial SpA patients than controls (30.03 ± 15.5 vs. 11.6 ± 4.2 pmol/L; p<0.0001). In multivariate analysis, DKK-1 serum levels were associated with male gender (p = 0.03), CRP level (p = 0.006), SOST serum level (p = 0.002) and presence of sacroiliitis on radiography (p = 0.05). Genetic association testing of 10 SNPs encompassing the DKK-1 locus failed to demonstrate a significant contribution of genetics to control of DKK-1 serum levels.

Conclusions

DKK-1 serum levels were increased and SOST levels were decreased among a large cohort of patients with early axial SpA compared to healthy controls. DKK-1 serum levels were mostly associated with biological inflammation and SOST serum levels.     

A substrate-specific cytochrome P450 monooxygenase, CYP6AB11, from the polyphagous navel orangeworm (Amyelois transitella)

The navel orangeworm Amyelois transitella (Walker) (Lepidoptera: Pyralidae) is a serious pest of many tree crops in California orchards, including almonds, pistachios, walnuts and figs. To understand the molecular mechanisms underlying detoxification of phytochemicals, insecticides and mycotoxins by this species, full-length CYP6AB11 cDNA was isolated from larval midguts using RACE PCR. Phylogenetic analysis of this insect cytochrome P450 monooxygenase established its evolutionary relationship to a P450 that selectively metabolizes imperatorin (a linear furanocoumarin) and myristicin (a natural methylenedioxyphenyl compound) in another lepidopteran species. Metabolic assays conducted with baculovirus-expressed P450 protein, P450 reductase and cytochrome b₅ on 16 compounds, including phytochemicals, mycotoxins, and synthetic pesticides, indicated that CYP6AB11 efficiently metabolizes imperatorin (0.88 pmol/min/pmol P450) and slowly metabolizes piperonyl butoxide (0.11 pmol/min/pmol P450). LC-MS analysis indicated that the imperatorin metabolite is an epoxide generated by oxidation of the double bond in its extended isoprenyl side chain. Predictive structures for CYP6AB11 suggested that its catalytic site contains a doughnut-like constriction over the heme that excludes aromatic rings on substrates and allows only their extended side chains to access the catalytic site. CYP6AB11 can also metabolize the principal insecticide synergist piperonyl butoxide (PBO), a synthetic methylenedioxyphenyl compound, albeit slowly, which raises the possibility that resistance may evolve in this species after exposure to synergists under field conditions.