Rituximab‐induced interleukin‐15 reduction associated with clinical improvement in rheumatoid arthritis

Rituximab therapy alters all aspects of B‐cell participation in the disturbed immune response of rheumatoid arthritis patients. To determine the impact of B‐cell depletion on other immune compartments, we analysed levels of soluble and surface interleukin‐15 (IL‐15) along with the frequency of IL‐15‐related subsets after rituximab treatment. We then studied the correlation of observed changes with clinical activity. Heparinized blood samples from 33 rheumatoid arthritis patients were collected on days 0, 30, 90 and 180 after each of three rituximab cycles. Serum cytokine levels were determined by ELISA. Interleukin‐15 trans‐presentation was analysed by cytometry. Flow cytometry with monoclonal antibodies was performed to analyse circulating cell subsets. Interleukin‐15 was detected in the serum of 25 patients before initiating the treatment. Rituximab then progressively reduced serum IL‐15 (138 ± 21 pg/ml at baseline, 48 ± 18 pg/ml after third cycle, P = 0·03) along with IL‐17 (1197 ± 203 pg/ml at baseline, 623 ± 213 pg/ml after third cycle, P = 0·03) and tended to increase the frequency of circulating regulatory T cells (3·1 ± 1 cells/μl at baseline, 7·7 ± 2 cells/μl after third cycle). Rituximab also significantly decreased IL‐15 trans‐presentation on surface monocytes of patients negative for IL‐15 serum (mean fluorescence intensity: 4·82 ± 1·30 at baseline, 1·42 ± 0·69 after third cycle P = 0·05). Reduction of serum IL‐15 was associated with decrease in CD8⁺ CD45RO⁺/RA⁺ ratio (1·17 ± 0·21 at baseline, 0·36 ± 0·06 at third cycle, P = 0·02). DAS28, erythrocyte sedimentation rate and C‐reactive protein correlated significantly with CD8⁺ CD45RO⁺/RA⁺ ratio (R = 0·323, R = 0·357, R = 0·369 respectively, P < 0·001). Our results suggest that sustained clinical improvement after rituximab treatment is associated with IL‐15/memory T‐cell‐related mechanisms beyond circulating B cells.     

Genetic and Epigenetic Determinants of Low Dysferlin Expression in Monocytes

Dysferlinopathies are autosomal recessive inherited muscular dystrophies caused by mutations in the gene DYSF. Dysferlin is primarily expressed in skeletal muscle, cardiac muscle, and peripheral blood monocytes. Expression in skeletal muscle and monocytes strongly correlates in healthy and disease states. We evaluated the efficiency of the monocyte assay to detect carriers and to determine the carrier frequency of dysferlinopathies in the general population. We enrolled 149 healthy volunteers and collected peripheral blood samples for protein analysis. While 18 of these individuals with protein levels in the range of 40%–64% were predicted to be carriers by the monocyte assay, subsequent DYSF sequencing analysis in 14 of 18 detected missense variants in only four. Analysis of DNA methylation patterns at the DYSF locus showed no changes in methylation levels at CpG islands and shores between samples. Our results suggest that: (1) dysferlin expression can also be regulated by factors outside of the dysferlin gene, but not related to DNA methylation; (2) carrier frequency and therefore the number of affected individuals could be higher than previously estimated; and (3) although reliable for evaluating dysferlinopathies, the monocyte assay cannot be used to determine the carrier status; for this, a molecular analysis of DYSF must be performed.     

Timescales of developmental toxicity impacting on research and needs for intervention

Much progress has happened in understanding developmental vulnerability to preventable environmental hazards. Along with the improved insight, the perspective has widened, and developmental toxicity now involves latent effects that can result in delayed adverse effects in adults or at old age and additional effects that can be transgenerationally transferred to future generations. Although epidemiology and toxicology to an increasing degree are exploring the adverse effects from developmental exposures in human beings, the improved documentation has resulted in little progress in protection, and few environmental chemicals are currently regulated to protect against developmental toxicity, whether it be neurotoxicity, endocrine disruption or other adverse outcome. The desire to obtain a high degree of certainty and verification of the evidence used for decision‐making must be weighed against the costs and necessary duration of research, as well as the long‐term costs to human health because of delayed protection of vulnerable early‐life stages of human development and, possibly, future generations. Although two‐generation toxicology tests may be useful for initial test purposes, other rapidly emerging tools need to be seriously considered from computational chemistry and metabolomics to CLARITY‐BPA‐type designs, big data and population record linkage approaches that will allow efficient generation of new insight; epigenetic mechanisms may necessitate a set of additional regulatory tests to reveal such effects. As reflected by the Prenatal Programming and Toxicity (PPTOX) VI conference, the current scientific understanding and the timescales involved require an intensified approach to protect against preventable adverse health effects that can harm the next generation and generations to come. While further research is needed, the main emphasis should be on research translation and timely public health intervention to avoid serious, irreversible and perhaps transgenerational harm.     

Pre‐natal brain development as a target for urban air pollution

Air pollution is the main urban‐related environmental hazard and one of the major contributors to the global burden of disease based on its cardiovascular‐respiratory impacts. In children, exposure to urban air pollution is associated, among others, with decelerated neurodevelopment early in life and increased risk of neurodevelopmental problems such as attention‐deficit hyperactivity disorder, autism spectrum disorders, academic failure and the start of Alzheimer's pathogenesis. However, the evidence of the effects of air pollution on brain development is still inadequate, mainly due to the limitations in (a) characterizing brain development (most studies were based on subjective tools such as questionnaires or neuropsychological tests) and (b) air pollution exposure (most studies only used residential levels based on geographical modelling and also overlooking the variation in the mixture of air pollutants as well as the composition and hence toxicity of particulate pollutants in different settings), (c) the lack of studies during the most vulnerable stages of brain development (foetal and early life (first two years post‐natally)) and (d) the lack of structural and functional imaging data underlying these effects. In mice, in utero exposure to fine particles was linked to structural brain changes and there is a need to establish the generalizability of these findings in human beings. Though scarce, current evidence in children supports the importance of the pre‐natal period as a susceptible window of exposure. Two studies in schoolchildren found that pre‐natal air pollution exposure might damage brain structure while exposure during childhood was not linked to any structural alteration. Another study showed that children with higher traffic‐related air pollution at school had lower functional integration in key brain networks, but no changes in brain structure, possibly partly because of the time window of air pollution exposure (in utero versus childhood exposure). A key development is to discover the windows of greatest sensitivity of structural brain changes to air pollution exposure by incorporating the recent advances in non‐invasive imaging to characterize natal and post‐natal brain development and exploring whether and to what extend placental dysfunction could mediate such an association. Studying pre‐natal life is important because effects at this time are of a potentially irreversible nature and because the largest preventive opportunities occur during these periods.     

I.31, a new combination of probiotics,improves irritable bowel syndrome-related quality of life

AIM: To determine the dose-related effects of a novel probiotic combination, I.31, on irritable bowel syndrome (IBS)-related quality of life (IBS-QoL).METHODS: A multicenter, randomized, double-blind, placebo-controlled intervention clinical trial with three parallel arms was designed. A total of 84 patients (53 female, 31 male; age range 20-70 years) with IBS and diarrhea according to Rome-III criteria were randomly allocated to receive one capsule a day for 6 wk containing: (1) I.31 high dose (n = 28); (2) I.31 low dose (n = 27); and (3) placebo (n = 29). At baseline, and 3 and 6 wk of treatment, patients filled the IBSQoL, Visceral Sensitivity Index (VSI), and global symptom relief questionnaires.RESULTS: During treatment, IBS-QoL increased in all groups, but this increment was significantly larger in patients treated with I.31 than in those receiving placebo (P = 0.008). After 6 wk of treatment, IBS-QoL increased by 18 ± 3 and 22 ± 4 points in the high and the low dose groups, respectively (P = 0.041 and P = 0.023 vs placebo), but only 9 ± 3 in the placebo group. Gut-specific anxiety, as measured with VSI, also showed a significantly greater improvement after 6 wk of treatment in patients treated with probiotics (by 10 ± 2 and 14 ± 2 points, high and low dose respectively, P < 0.05 for both vs 7 ± 1 score increment in placebo). Symptom relief showed no significant changes between groups. No adverse drug reactions were reported following the consumption of probiotic or placebo capsules.CONCLUSION: A new combination of three different probiotic bacteria was superior to placebo in improving IBS-related quality of life in patients with IBS and diarrhea.     

Impact of heterogeneity and socioeconomic factors on individual behavior in decentralized sharing ecosystems

Tens of millions of individuals around the world use decentralized content distribution systems, a fact of growing social, economic, and technological importance. These sharing systems are poorly understood because, unlike in other technosocial systems, it is difficult to gather large-scale data about user behavior. Here, we investigate user activity patterns and the socioeconomic factors that could explain the behavior. Our analysis reveals that (i) the ecosystem is heterogeneous at several levels: content types are heterogeneous, users specialize in a few content types, and countries are heterogeneous in user profiles; and (ii) there is a strong correlation between socioeconomic indicators of a country and users behavior. Our findings open a research area on the dynamics of decentralized sharing ecosystems and the socioeconomic factors affecting them, and may have implications for the design of algorithms and for policymaking.Every month, ∼150 million users worldwide share files over the Internet using BitTorrent (1), the most widely used decentralized peer-to-peer (P2P) communication protocol. Eleven years after its inception, file sharing through BitTorrent is one of the top three major contributors to the overall Internet traffic, accounting for 9–27% of the total traffic, depending on the continent (2, 3).The expansion in scale and breadth of decentralized file-sharing has highlighted the conflicts between the interests of creators (musicians and writers, e.g.) and those of P2P users. Creators and creative industries argue that they are being deprived of fair compensation for their work (4), which is being widely distributed for free in violation of copyright laws. Users, however, argue that P2P can be (and is) used for sharing nonproprietary contents, and warn that widespread monitoring of online activity by corporations and law enforcement violates P2P users’ right to privacy. Proof of the complexity of the situation includes the rejection of the Anti-Counterfeiting Trade Agreement by the European Parliament and the controversy with the Stop Online Piracy Act in the United States.Despite the growing social, economic, and technological importance of BitTorrent (4), there is currently little understanding of how users behave in this complex technosocial (5, 6) ecosystem. Due to the decentralized structure of P2P ecosystems, it is very difficult to gather large-scale data about interactions and behavioral patterns of the users without their explicit consent; this is in contrast to other forms of online exchange where all of the information is stored in a central system, be it publicly accessible as in Wikipedia (7), partially accessible through a public interface as in Twitter (8, 9) or Google [through its search logs (10) or its public services (11, 12)], or restricted as in Facebook (13, 14) or in email communications within organizations (15–18).Because of the difficulty to collect complete user-level data of large and representative samples of users (3), studies of user behavior in P2P networks have so far been based on (i) small datasets; (ii) aggregate data collected from “trackers” or from individual Internet service providers (ISPs); and (iii) incomplete user data collected using a single crawler client connected to the network (19–23).Here, we investigate the complete activity patterns of a large and representative pool of BitTorrent users. Our analysis reveals that P2P sharing is highly heterogeneous, that users are specialized, giving rise to well-defined user profiles, and that the abundance of certain user profiles in a country is highly correlated with socioeconomic factors. Our findings open a research area on the dynamics of decentralized sharing ecosystems, and may have implications for the understanding and design of algorithms and for policymaking.