Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder

Introduction

Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.

Methods

Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.

Results

Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).

Conclusions

Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.     

Biochemical,Transcriptional and Translational Evidences of the Phenol-meta-Degradation Pathway by the Hyperthermophilic Sulfolobus solfataricus 98/2

Phenol is a widespread pollutant and a model molecule to study the biodegradation of monoaromatic compounds. After a first oxidation step leading to catechol in mesophilic and thermophilic microorganisms, two main routes have been identified depending on the cleavage of the aromatic ring: ortho involving a catechol 1,2 dioxygenase (C12D) and meta involving a catechol 2,3 dioxygenase (C23D). Our work aimed at elucidating the phenol-degradation pathway in the hyperthermophilic archaea Sulfolobus solfataricus 98/2. For this purpose, the strain was cultivated in a fermentor under different substrate and oxygenation conditions. Indeed, reducing dissolved-oxygen concentration allowed slowing down phenol catabolism (specific growth and phenol-consumption rates dropped 55% and 39%, respectively) and thus, evidencing intermediate accumulations in the broth. HPLC/Diode Array Detector and LC-MS analyses on culture samples at low dissolved-oxygen concentration (DOC  =  0.06 mg.L⁻¹) suggested, apart for catechol, the presence of 2-hydroxymuconic acid, 4-oxalocrotonate and 4-hydroxy-2-oxovalerate, three intermediates of the meta route. RT-PCR analysis on oxygenase-coding genes of S. solfataricus 98/2 showed that the gene coding for the C23D was expressed only on phenol. In 2D-DIGE/MALDI-TOF analysis, the C23D was found and identified only on phenol. This set of results allowed us concluding that S. solfataricus 98/2 degrade phenol through the meta route.     

Direct and indirect effects of ocean acidification and warming on a marine plant–herbivore interaction

The impacts of climatic change on organisms depend on the interaction of multiple stressors and how these may affect the interactions among species. Consumer–prey relationships may be altered by changes to the abundance of either species, or by changes to the per capita interaction strength among species. To examine the effects of multiple stressors on a species interaction, we test the direct, interactive effects of ocean warming and lowered pH on an abundant marine herbivore (the amphipod Peramphithoe parmerong), and whether this herbivore is affected indirectly by these stressors altering the palatability of its algal food (Sargassum linearifolium). Both increased temperature and lowered pH independently reduced amphipod survival and growth, with the impacts of temperature outweighing those associated with reduced pH. Amphipods were further affected indirectly by changes to the palatability of their food source. The temperature and pH conditions in which algae were grown interacted to affect algal palatability, with acidified conditions only affecting feeding rates when algae were also grown at elevated temperatures. Feeding rates were largely unaffected by the conditions faced by the herbivore while feeding. These results indicate that, in addition to the direct effects on herbivore abundance, climatic stressors will affect the strength of plant–herbivore interactions by changes to the susceptibility of plant tissues to herbivory.     

Modelling root demography in heterogeneous mountain forests and applications for slope stability analysis

Background and aims

Plant roots provide mechanical cohesion (c _r ) to soil on slopes which are prone to shallow landslides. c _r varies in heterogeneous natural forests due to the spatial, inter- and intra-annual dynamics of root demography. Characterizing root initiation density and mortality, as well as how root growth is influenced by abiotic and biotic factors is essential for exploring a root system’s capacity to reinforce soil.

Methods

In this study, root demography data were monitored using field rhizotrons during 1.5 years in two naturally regenerated mixed forests in the French Alps. These forests are composed of trees growing in groups (tree islands) with large gaps between the islands. Three categories of driving variables were measured: (i) spatial factors: altitude (1,400 m, 1,700 m), ecological patch (gap, tree island), soil depth (0.0–1.0 m divided into five layers of 0.2 m); (ii) temporal factors: month (12 months from March 2010 to February 2011), winter (winter of 2009–2010 and 2010–2011); (iii) biological factors: root diameter classes (]0, 1] mm, ]1, 2] mm, ]2, 5] mm (according to the international standard ISO 31–11, ]x, y] denotes a left half-open interval from x (excluded) to y (included)). Two types of two-part models, a Hurdle model (H) and a Zero-inflated model (ZI) were used to fit root data with a high zero population, i.e. if root initiation or mortality was zero during a given time period, or if roots were not present at all points throughout a soil profile.

Results

Root initiation quantity decreased with increasing soil depth, as well as being lower in tree islands. Both soil depth and ecological patch interacted strongly with altitude. Root dynamics were significantly less active with a lower net production and c _r increment in winter and spring than in summer and autumn. Roots which were ]1, 2] mm in diameter contributed the most to c _r compared to other diameter classes, as they had a high production but a low mortality. With regard to model selection, both H and ZI demonstrated similar outcomes and underestimated extreme values of root demography data.

Conclusion

All factors contributed towards explaining the variability of root demography and c _r . We suggest taking into consideration the seasonality of root dynamics when studying root reinforcement.     

Methionine and homocysteine modulate the rate of ROS generation of isolated mitochondria in vitro

Dietary methionine restriction and supplementation in mammals have beneficial (antiaging) and detrimental effects respectively, which have been related to chronic modifications in the rate of mitochondrial ROS generation. However it is not known if methionine or its metabolites can have, in addition, direct effects on the rate of mitochondrial ROS production. This is studied here for the methionine cycle metabolites S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), homocysteine and methionine itself in isolated rat liver, kidney, heart, and brain mitochondria. The results show that methionine increases ROS production in liver and kidney mitochondria, homocysteine increases it in kidney and decreases it in the other three organs, and SAM and SAH have no effects. The variations in ROS production are localized at complexes I or III. These changes add to previously described chronic effects of methionine restriction and supplementation in vivo.     

Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase

Lysyl oxidase (LOX), a matrix cross-linking protein, is known to be selectively expressed and to enhance a fibrotic phenotype. A recent study of ours showed that LOX oxidizes the PDGF receptor-β (PDGFR-β), leading to amplified downstream signaling. Here, we examined the expression and functions of LOX in megakaryocytes (MKs), the platelet precursors. Cells committed to the MK lineage undergo mitotic proliferation to yield diploid cells, followed by endomitosis and acquisition of polyploidy. Intriguingly, LOX expression is detected in diploid-tetraploid MKs, but scarce in polyploid MKs. PDGFR-BB is an inducer of mitotic proliferation in MKs. LOX inhibition with β-aminopropionitrile reduces PDGFR-BB binding to cells and downstream signaling, as well as its proliferative effect on the MK lineage. Inhibition of LOX activity has no influence on MK polyploidy. We next rationalized that, in a system with an abundance of low ploidy MKs, LOX could be highly expressed and with functional significance. Thus, we resorted to GATA-1(low) mice, where there is an increase in low ploidy MKs, augmented levels of PDGF-BB, and an extensive matrix of fibers. MKs from these mice display high expression of LOX, compared with control mice. Importantly, treatment of GATA-1(low) mice with β-aminopropionitrile significantly improves the bone marrow fibrotic phenotype, and MK number in the spleen. Thus, our in vitro and in vivo data support a novel role for LOX in regulating MK expansion by PDGF-BB and suggest LOX as a new potential therapeutic target for myelofibrosis.     

Mediational Effects of Self-Efficacy Dimensions in the Relationship between Knowledge of Dengue and Dengue Preventive Behaviour with Respect to Control of Dengue Outbreaks: A Structural Equation Model of a Cross-Sectional Survey

Background

Dengue fever is endemic in Malaysia, with frequent major outbreaks in urban areas. The major control strategy relies on health promotional campaigns aimed at encouraging people to reduce mosquito breeding sites close to people''s homes. However, such campaigns have not always been 100% effective. The concept of self-efficacy is an area of increasing research interest in understanding how health promotion can be most effective. This paper reports on a study of the impact of self-efficacy on dengue knowledge and dengue preventive behaviour.

Methods and Findings

We recruited 280 adults from 27 post-outbreak villages in the state of Terengganu, east coast of Malaysia. Measures of health promotion and educational intervention activities and types of communication during outbreak, level of dengue knowledge, level and strength of self-efficacy and dengue preventive behaviour were obtained via face-to-face interviews and questionnaires. A structural equation model was tested and fitted the data well (χ² = 71.659, df = 40, p = 0.002, RMSEA = 0.053, CFI = 0.973, TLI = 0.963). Mass media, local contact and direct information-giving sessions significantly predicted level of knowledge of dengue. Level and strength of self-efficacy fully mediated the relationship between knowledge of dengue and dengue preventive behaviours. Strength of self-efficacy acted as partial mediator in the relationship between knowledge of dengue and dengue preventive behaviours.

Conclusions

To control and prevent dengue outbreaks by behavioural measures, health promotion and educational interventions during outbreaks should now focus on those approaches that are most likely to increase the level and strength of self-efficacy.     

Rifampicin exposure reveals within-host Mycobacterium tuberculosis diversity in patients with delayed culture conversion

Mycobacterium tuberculosis (Mtb) genetic micro-diversity in clinical isolates may underline mycobacterial adaptation to tuberculosis (TB) infection and provide insights to anti-TB treatment response and emergence of resistance. Herein we followed within-host evolution of Mtb clinical isolates in two cohorts of TB patients, either with delayed Mtb culture conversion (> 2 months), or with fast culture conversion (< 2 months). We captured the genetic diversity of Mtb isolates obtained in each patient, by focusing on minor variants detected as unfixed single nucleotide polymorphisms (SNPs). To unmask antibiotic tolerant sub-populations, we exposed these isolates to rifampicin (RIF) prior to whole genome sequencing (WGS) analysis. Thanks to WGS, we detected at least 1 unfixed SNP within the Mtb isolates for 9/15 patients with delayed culture conversion, and non-synonymous (ns) SNPs for 8/15 patients. Furthermore, RIF exposure revealed 9 additional unfixed nsSNP from 6/15 isolates unlinked to drug resistance. By contrast, in the fast culture conversion cohort, RIF exposure only revealed 2 unfixed nsSNP from 2/20 patients. To better understand the dynamics of Mtb micro-diversity, we investigated the variant composition of a persistent Mtb clinical isolate before and after controlled stress experiments mimicking the course of TB disease. A minor variant, featuring a particular mycocerosates profile, became enriched during both RIF exposure and macrophage infection. The variant was associated with drug tolerance and intracellular persistence, consistent with the pharmacological modeling predicting increased risk of treatment failure. A thorough study of such variants not necessarily linked to canonical drug-resistance, but which are prone to promote anti-TB drug tolerance, may be crucial to prevent the subsequent emergence of resistance. Taken together, the present findings support the further exploration of Mtb micro-diversity as a promising tool to detect patients at risk of poorly responding to anti-TB treatment, ultimately allowing improved and personalized TB management.