Natural Variation in Maize Aphid Resistance Is Associated with 2,4-Dihydroxy-7-Methoxy-1,4-Benzoxazin-3-One Glucoside Methyltransferase Activity

Plants differ greatly in their susceptibility to insect herbivory, suggesting both local adaptation and resistance tradeoffs. We used maize (Zea mays) recombinant inbred lines to map a quantitative trait locus (QTL) for the maize leaf aphid (Rhopalosiphum maidis) susceptibility to maize Chromosome 1. Phytochemical analysis revealed that the same locus was also associated with high levels of 2-hydroxy-4,7-dimethoxy-1,4-benzoxazin-3-one glucoside (HDMBOA-Glc) and low levels of 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one glucoside (DIMBOA-Glc). In vitro enzyme assays with candidate genes from the region of the QTL identified three O-methyltransferases (Bx10a-c) that convert DIMBOA-Glc to HDMBOA-Glc. Variation in HDMBOA-Glc production was attributed to a natural CACTA family transposon insertion that inactivates Bx10c in maize lines with low HDMBOA-Glc accumulation. When tested with a population of 26 diverse maize inbred lines, R. maidis produced more progeny on those with high HDMBOA-Glc and low DIMBOA-Glc. Although HDMBOA-Glc was more toxic to R. maidis than DIMBOA-Glc in vitro, BX10c activity and the resulting decline of DIMBOA-Glc upon methylation to HDMBOA-Glc were associated with reduced callose deposition as an aphid defense response in vivo. Thus, a natural transposon insertion appears to mediate an ecologically relevant trade-off between the direct toxicity and defense-inducing properties of maize benzoxazinoids.     

The language of systematics,and the philosophy of ‘total evidence’

This contribution analyses the primacy of classification over generalization, and the philosophy of total evidence that emerges from the relation of homology to character statements. Primary conjectures of homology are basic character statements, i.e. statements that predicate properties of organisms, properties that are instantiated by those organisms and/or their parts. Secondary conjectures of homology are embedded in a second‐level (metalinguistic) discourse that turns on the coherence or incoherence of those basic character statements relative to a hierarchy. The coherence or incoherence of character statements is a logical relation between statements, not a causal (historical) relation between organisms. The choice of the hypothesis of relationships that is supported by the largest set of coherent basic character statements is based on the empirical presupposition that the properties referred to by the set of coherent character statements are grounded in causally efficacious relations of inheritance and ontogeny, and co‐instantiated because they are inherited through common ancestry (Hennig's auxiliary principle). Unless that empirical presupposition is causally grounded, phylogeny reconstruction is of an inherently probabilistic nature, whether under parsimony or other models of analysis. The causal grounding of a coherent set of character statements typically seeks a link between character statements and causally efficacious generative mechanisms for morphological characters (as is defeasibly indicated by topology and connectivity), or secondary structure information for molecular characters.     

Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis

Introduction

Our objective was to determine the interrelationships of interleukin (IL)-6 receptor inhibition with haemoglobin, acute-phase reactants and iron metabolism markers (including hepcidin) in patients with rheumatoid arthritis (RA).

Methods

Data of patients receiving tocilizumab or placebo in the MEASURE study were analysed. We investigated associations at baseline and during tocilizumab treatment among haemoglobin, parameters of haemoglobin and iron homeostasis [ferritin, total iron-binding capacity (TIBC), hepcidin, haptoglobin], IL-6 and acute-phase reactants [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] to identify statistical correlates of rise in haemoglobin level.

Results

At baseline, CRP and haptoglobin were inversely correlated (modestly) with haemoglobin levels. After treatment with tocilizumab, CRP, hepcidin, ferritin and haptoglobin levels fell alongside increases in TIBC and haemoglobin. The falls in CRP, hepcidin and haptoglobin levels in the first 2 weeks correlated with a week 12 rise in TIBC and haemoglobin.

Conclusions

Inflammatory anaemia improves in patients with RA treated with tocilizumab. This improvement correlates with the degree of suppression of systemic inflammation, reduction in hepcidin and haptoglobin and increase in iron-binding capacity. These clinical data provide evidence of a role for IL-6 signalling in the inflammatory anaemia of RA.     

Efficacy of anakinra in gouty arthritis: a retrospective study of 40 cases

Introduction

Gout is a common arthritis that occurs particularly in patients who frequently have associated comorbidities that limit the use of conventional therapies. The main mechanism of crystal-induced inflammation is interleukin-1 production by activation of the inflammasome. We aimed to evaluate the efficacy and tolerance of anakinra in gouty patients.

Methods

We conducted a multicenter retrospective review of patients receiving anakinra for gouty arthritis. We reviewed the response to treatment, adverse events and relapses.

Results

We examined data for 40 gouty patients (32 men; mean age 60.0 ± 13.9 years) receiving anakinra. Mean disease duration was 8.7 ± 8.7 years. All patients showed contraindications to and/or failure of at least two conventional therapies. Most (36; 90%) demonstrated good response to anakinra. Median pain on a 100-mm visual analog scale was rapidly decreased (73.5 (70.0 to 80.0) to 25.0 (20.0 to 32.5) mm, P <0.0001), as was median C-reactive protein (CRP) level (130.5 (55.8 to 238.8) to 16.0 (5.0 to 29.5) mg/l, P <0.0001). After a median follow-up of 7.0 (2.0 to 13.0) months, relapse occurred in 13 patients after a median delay of 15.0 (10.0 to 70.0) days. Seven infectious events, mainly with long-term use of anakinra, were noted.

Conclusions

Anakinra may be efficient in gouty arthritis, is relatively well tolerated with short-term use, and could be a relevant option in managing gouty arthritis when conventional therapies are ineffective or contraindicated. Its long-term use could be limited by infectious complications.     

Predictors of Chikungunya rheumatism: a prognostic survey ancillary to the TELECHIK cohort study

Introduction

Long-lasting relapsing or lingering rheumatic musculoskeletal pain (RMSP) is the hallmark of Chikungunya virus (CHIKV) rheumatism (CHIK-R). Little is known on their prognostic factors. The aim of this prognostic study was to search the determinants of lingering or relapsing RMSP indicative of CHIK-R.

Methods

Three hundred and forty-six infected adults (age ≥ 15 years) having declared RMSP at disease onset were extracted from the TELECHIK cohort study, Reunion island, and analyzed using a multinomial logistic regression model. We also searched for the predictors of CHIKV-specific IgG titres, assessed at the time of a serosurvey, using multiple linear regression analysis.

Results

Of these, 111 (32.1%) reported relapsing RMSP, 150 (43.3%) lingering RMSP, and 85 (24.6%) had fully recovered (reference group) on average two years after acute infection. In the final model controlling for gender, the determinants of relapsing RMSP were the age 45-59 years (adjusted OR: 2.9, 95% CI: 1.0, 8.6) or greater or equal than 60 years (adjusted OR: 10.4, 95% CI: 3.5, 31.1), severe rheumatic involvement (fever, at least six joints plus four other symptoms) at presentation (adjusted OR: 3.6, 95% CI: 1.5, 8.2), and CHIKV-specific IgG titres (adjusted OR: 3.2, 95% CI: 1.8, 5.5, per one unit increase). Prognostic factors for lingering RMSP were age 45-59 years (adjusted OR: 6.4, 95% CI: 1.8, 22.1) or greater or equal than 60 years (adjusted OR: 22.3, 95% CI: 6.3, 78.1), severe initial rheumatic involvement (adjusted OR: 5.5, 95% CI: 2.2, 13.8) and CHIKV-specific IgG titres (adjusted OR: 6.2, 95% CI: 2.8, 13.2, per one unit increase). CHIKV specific IgG titres were positively correlated with age, female gender and the severity of initial rheumatic symptoms.

Conclusions

Our data support the roles of age, severity at presentation and CHIKV specific IgG titres for predicting CHIK-R. By identifying the prognostic value of the humoral immune response of the host, this work also suggest a significant contribution of the adaptive immune response to the physiopathology of CHIK-R and should help to reconsider the paradigm of this chronic infection primarily shifted towards the involvement of the innate immune response.     

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.