Environmental flow limits to global groundwater pumping.

Groundwater is the world's largest freshwater resource and is critically important for irrigation, and hence for global food security1-3. Already, unsustainable groundwater pumping exceeds recharge from precipitation and rivers4, leading to substantial drops in the levels of groundwater and losses of groundwater from its storage, especially in intensively irrigated regions5-7. When groundwater levels drop, discharges from groundwater to streams decline, reverse in direction or even stop completely, thereby decreasing streamflow, with potentially devastating effects on aquatic ecosystems. Here we link declines in the levels of groundwater that result from groundwater pumping to decreases in streamflow globally, and estimate where and when environmentally critical streamflows-which are required to maintain healthy ecosystems-will no longer be sustained. We estimate that, by 2050, environmental flow limits will be reached for approximately 42 to 79 per cent of the watersheds in which there is groundwater pumping worldwide, and that this will generally occur before substantial losses in groundwater storage are experienced. Only a small decline in groundwater level is needed to affect streamflow, making our estimates uncertain for streams near a transition to reversed groundwater discharge. However, for many areas, groundwater pumping rates are high and environmental flow limits are known to be severely exceeded. Compared to surface-water use, the effects of groundwater pumping are markedly delayed. Our results thus reveal the current and future environmental legacy of groundwater use.

DOCK2-deficiency causes defects in anti-viral T cell responses and impaired control of herpes simplex virus infection.

The expanding number of rare immunodeficiency syndromes offers an opportunity to understand key genes that support immune defence against infectious diseases. However, analysis of these in patients is complicated by their treatments and co-morbid infections requiring the use of mouse models for detailed investigations. Here we develop a mouse model of DOCK2 immunodeficiency and demonstrate that these mice have delayed clearance of herpes simplex virus type 1 (HSV-1) infections. We also uncovered a critical, cell intrinsic role of DOCK2 in the priming of anti-viral CD8+ T cells and in particular their initial expansion, despite apparently normal early activation of these cells. When this defect was overcome by priming in vitro, DOCK2-deficient CD8+ T cells were surprisingly protective against HSV-1-disease, albeit not as effectively as wild type cells. These results shed light on a cellular deficiency that is likely to impact anti-viral immunity in DOCK2-deficient patients.

Adolescents' belonging in post-divorce families: Examining residential and digital contact with mothers and fathers.

Using data of 166 adolescents from divorced families, this study examined longitudinal associations between the quantity and quality of adolescents' residential contact and digital contact with parents, and their sense of family belonging. Cross-lagged panel models showed concurrent associations among adolescents' residential and digital contact with each parent, yet positively for fathers and negatively for mothers. Some cross-lagged paths revealed that higher-quality interactions may contribute to positive changes in contact. Although there were effects of parent-adolescent contact on family belongingness, over time belongingness was mostly predicted by the general quality of contact. The results suggest that post-divorce relationships require frequent and meaningful time together, the effects of which, however, do hardly transfer over time in terms of adolescents' belongingness.

Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors.

PURPOSE: The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors. METHODS: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans. RESULTS: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-É£ and CXCL10 were downregulated. CONCLUSIONS: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.

Unplanned hospital admissions due to secondary health conditions after spinal cord injury: a population-based description of determinants of length of stay.

STUDY DESIGN: Population-based prospective study. OBJECTIVES: To provide a population-based description of length of stay (LOS) and person-related risk factors following unplanned hospital admission due to a secondary health condition (SHC) in persons with spinal cord injury (SCI). SETTING: Specialized SCI hospital and rehabilitation center in Switzerland. METHODS: Descriptive analysis of LOS using routine clinical data of persons with SCI, who were acutely hospitalized between 01.01.2017-30.06.2018. Multivariable regression analysis was used to derive marginal predictions of LOS by acute SHCs and person characteristics. RESULTS: The study included 183 persons, 83% were male, and the median age was 57 years (interquartile range, IQR, 49-67 years). SCI cause was traumatic in 160 (88.4%) cases, 92 (50.3%) were persons with tetraplegia, 147 (80.3%) were classified as motor complete lesions (American Spinal Injury Association Impairment Scale (AIS) A or B) and median time since injury (TSI) was 24 (IQR 13-34) years. Median LOS was 19 (IQR 9-39) days, varying from 74 (IQR 39-92) days for pressure ulcers, 13 (IQR 8-24) days for urinary tract infections (UTI), to 27 (IQR 18-47) days for fractures. LOS was prolonged in persons with multiple co-morbidities or those developing complications during hospitalization. Sex, SCI etiology and lesion level were not associated with LOS. CONCLUSIONS: This population-based description identified substantial variation in LOS between acute SHCs and clinical complications as the main, potentially modifiable, person-related risk factors for extended hospital stay.

Most viral peptides displayed by class I MHC on infected cells are immunogenic.

CD8+ T cells are essential effectors in antiviral immunity, recognizing short virus-derived peptides presented by MHC class I (pMHCI) on the surface of infected cells. However, the fraction of viral pMHCI on infected cells that are immunogenic has not been shown for any virus. To approach this fundamental question, we used peptide sequencing by high-resolution mass spectrometry to identify more than 170 vaccinia virus pMHCI presented on infected mouse cells. Next, we screened each peptide for immunogenicity in multiple virus-infected mice, revealing a wide range of immunogenicities. A surprisingly high fraction (>80%) of pMHCI were immunogenic in at least one infected mouse, and nearly 40% were immunogenic across more than half of the mice screened. The high number of peptides found to be immunogenic and the distribution of responses across mice give us insight into the specificity of antiviral CD8+ T cell responses.

The Role of Sense of Belonging and Family Structure in Adolescent Adjustment.

The present study adopted an ecological perspective, and examined effects of sense of belonging to multiple contexts in relation to adolescent adjustment, as well as possible differences between adolescents from intact and divorced families. Self-report questionnaires were used to investigate perceptions of family, school, peer, and neighborhood belonging among 969 adolescents. Results showed that mean level differences in belonging exist based on family structure, and that levels of family and neighborhood belonging vary between post-divorce maternal and paternal households. For all adolescents, sense of belonging predicted self-reported well-being, internalizing, and externalizing problems. Belonging was found to partly explain the relation between divorce and adjustment. Improving adolescents' belonging could therefore be an important step in ensuring a better adjustment post-divorce.

Surprisingly Effective Priming of CD8+ T Cells by Heat-Inactivated Vaccinia Virus Virions.

Robust priming of CD8+ T cells by viruses is considered to require infection and de novo expression of viral antigens. A corollary of this is that inactivated viruses are thought of as being inevitably poor vaccines for eliciting these responses. In contrast to this dogma, we found that some antigens present in vaccinia virus (VACV) virions prime strong CD8+ T cell responses when the virus was rendered noninfectious by heat. More surprisingly, in some cases these responses were similar in magnitude to those primed by infectious virus administered at an equivalent dose. Next, we tested whether this was a special property of particular antigens and their epitopes and found that foreign epitopes tagged onto three different VACV virion proteins were able to elicit CD8+ T cell responses irrespective of whether the virus was viable or heat killed. Further, the polyfunctionality and cytotoxic ability of the CD8+ T cells primed by these VACVs was equivalent irrespective of whether they were administered to mice as inactivated or live viruses. Finally, we used these VACVs in prime-boost combinations of inactivated and live virus and found that priming with dead virus before a live booster was the most immunogenic regime. We conclude that VACV virions can be efficient vectors for targeting antigens to dendritic cells for effective priming of CD8+ T cells, even when rendered noninfectious and speculate that this might also be the case for other viruses.IMPORTANCE The design of viral vectored vaccines is often considered to require a trade-off between efficacy and safety. This is especially the case for vaccines that aim to induce killer (CD8+) T cells, where there is a well-established dogma that links infection in vaccinated individuals with effective induction of immunity. However, we found that some proteins of vaccinia virus generate strong CD8+ T cell responses even when the virus preparation was inactivated by heat prior to administration as a vaccine. We took advantage of this finding by engineering a new vaccine vector virus that could be used as an inactivated vaccine. These results suggest that vaccinia virus may be a more versatile vaccine vector than previously appreciated and that in some instances safety can be prioritized by the complete elimination of viral replication without a proportional loss of immunogenicity.

Three-Dimensional Upper Airway Assessment in Treacher Collins Syndrome.

OBJECTIVES: The purpose of this investigation was to assess the pharyngeal dimensions and the craniofacial morphology of individuals with Treacher Collins syndrome (TCS) when compared to vertical skeletal class II individuals. It is our hypothesis that the upper airways of individuals with TCS are reduced in view of the skeletal pattern and the maxillomandibular dysmorphologies. MATERIALS AND METHODS: Cone-beam computed tomography scans of 26 individuals had the pharyngeal volume (V) and minimal cross-sectional area (mCSA) evaluated. Study group (TCS) was formed by 13 scans of patients with TCS (7 males and 6 females; 20.2 ± 4.7 years). Control group (CG) assembled 13 scans of nonaffected individuals with the same type of skeletal pattern (2 males and 11 females; 26.6 ± 5.4 years). Cephalometric data of maxillomandibular position, maxillomandibular dimensions, and growth pattern were assessed. Statistical analysis (P ≤ .05) included Student t test and Pearson correlation coefficient. RESULTS: Although reduced, pharyngeal V and mCSA of TCS were not statistically different from the CG. On both groups, mCSA was mostly at the oropharyngeal level. Individuals with TCS presented retrognathic chin, reduced maxillomandibular dimensions, and increased clockwise rotation of the palatal plane. Maxillary and mandibular lengths were correlated with pharyngeal V and mCSA. CONCLUSIONS: The pharyngeal dimensions of individuals with TCS are impacted by the micrognathia and retrognathia. In association with the skeletal pattern, the reduction of the airways, although not statistically significant, may explain the increased prevalence of airways disorder in this syndrome.

Linking Parent-Child and Peer Relationship Quality to Empathy in Adolescence: A Multilevel Meta-Analysis.

Empathy, which is the ability to feel concern for and to understand others' feelings, is thought to develop in high quality relationships with parent and peers, but also to facilitate the quality of these relationships. While a wide literature has addressed this aspect, the heterogeneity of primary studies, in which different indicators of relationship quality (e.g., support, conflict) and empathy (i.e., affective and cognitive) have been examined, makes it difficult to draw conclusive answers. Therefore, it remained ambiguous how parent-child and peer relationship quality are associated with adolescents' empathy. In order to increase the understanding of these associations, a multilevel meta-analysis was performed, which allowed for including multiple effect sizes from each study. By a systematic literate search, 70 eligible studies were found that provided 390 effect sizes from 75 independent samples. The results showed a small positive correlation between parent-child relationship quality and empathy, and a small-to-moderate positive correlation between peer relationship quality and empathy, which was significantly stronger than the correlation with parent-child relationship quality. Hence, the meta-analytic results indicate that adolescents with higher quality relationships, especially with peers, indeed tend to show more concern for and understanding of others' emotions than adolescents with lower quality relationships. Moreover, the moderation analyses showed stronger correlations for the positive dimension of relationship quality than for the negative dimension, and stronger correlations for composite scores of affective and cognitive empathy than for separate scores of the empathy dimensions. However, no differences in correlations were found between the affective and cognitive empathy dimension, and no moderation effects were found for gender and age. Thus, this meta-analysis demonstrates robust positive associations between parent-child and peer relationship quality and empathy in adolescence, implying that good empathic abilities may be a protective factor for experiencing poor relationships.

Longitudinal Transmission of Conflict Management Styles Across Inter-Parental and Adolescent Relationships.

This study longitudinally investigated transmission of conflict management styles across inter-parental, adolescent-parent, adolescent-friend, and adolescent-partner relationships. During four waves, 799 middle-to-late adolescents (Mage-t1  = 15.80; 54% boys) and their parents completed the Conflict Resolution Style Inventory. Cross-lagged path analyses indicated transmission of adolescent conflict management styles in relationships with parents to relationships with friends and romantic partners: Positive problem solving and conflict engagement utilized by adolescents in conflicts with parents were significantly, positively related to, respectively, adolescent positive problem solving and conflict engagement in relationships with friends 1 year later and relationships with partners 2 years later. Thus, the study showed that the way adolescents manage conflicts with parents predicts how they handle conflicts later in relationships outside the family.

Short-Term and Long-Term Outcomes of a Vocational Rehabilitation Program for Patients with Acquired Brain Injury in The Netherlands.

Purpose To describe short-term and long-term work status after a vocational rehabilitation (VR) program in patients with acquired brain injury (ABI) in the Netherlands. Methods Patients with ABI who participated in a VR program between 2007 and 2010 were included in this study. The 4-month VR program included a multidisciplinary assessment, three meetings with all stakeholders and reintegration with coaching on the job. Short-term results at the end of the VR program were based on data extracted from medical records. Long-term results were determined at 3-6 years (mean 4.4 years) after the program based on patient-reported data. Outcome measures included return to work, hours at work and task adjustments. Results Fifty-eight patients were included [mean age 48 (SD 9.4) years; n = 33 male; all working before ABI]. After the intervention, 50 patients (86%) had returned to work, working on average 60% of their former hours. Working tasks were adjusted in 48 patients. At long-term follow-up 28 patients had paid work, working on average 5.3 h more than immediately after the VR program. Conclusions Directly after the intervention 86% of the patients had returned to work. After 3-6 years, 64% of these patients were still working in a paid job.

Reducing falls in Parkinson's disease: interactions between donepezil and the 5-HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements.

Falls are a leading cause of death in the elderly and, in a majority of patients with Parkinson's disease (PD), the leading levodopa-insensitive cause of hospitalization and long-term care. Falling in PD has been attributed to degeneration of forebrain cholinergic neurons that, in interaction with striatal dopamine losses, impairs the cognitive control of balance, gait, and movement. We previously established an animal model of these dual cholinergic-dopaminergic losses ("DL rats") and a behavioral test system (Michigan Complex Motor Control Task, MCMCT) to measure falls associated with traversing dynamic surfaces and distractors. Because the combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer's disease, here we assessed the effects of this treatment on MCMCT performance and attention in DL rats. Compared with the vehicle-treated group, the combined treatment greatly reduced (Cohen's d = 0.96) falls in DL rats when traversing dynamic surfaces and when exposed to a passive distractor. However, falls associated with a dual task distractor and sustained attentional performance did not benefit from this treatment. Analyses of the behavior in fall-prone moments suggested that this treatment improved the efficacy and speed of re-instating forward movement after relatively short stoppages. This treatment may reduce fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait.

Inflammatory bowel disease is associated with hidradenitis suppurativa: Results from a multicenter cross-sectional study.

BACKGROUND: Hidradenitis suppurativa (HS) is often associated with inflammatory bowel disease (IBD; Crohn's disease or ulcerative colitis). However, the prevalence of IBD in HS patients is unknown. OBJECTIVE: To determine the prevalence of IBD in HS patients, and determine if patients with HS and IBD have a distinct HS phenotype. METHODS: For this multicenter, cross-sectional study, HS patients were asked during their first consultation if they had IBD. The diagnosis of IBD was checked in the medical files, and clinical characteristics were collected. RESULTS: IBD had a prevalence of 3.3% (95% CI 2.3-4.4) in 1076 HS patients. The prevalence of Crohn's disease was 2.5% (95% CI 1.6-3.4) and the prevalence of ulcerative colitis was 0.8% (95% CI 0.3-1.4). HS-IBD patients were less frequently obese (13.9% vs 31.2%, P = .04) than HS-only patients, but there were no differences in gender, family history of HS, disease severity, body areas affected by HS, or smoking status. LIMITATIONS: The prevalence might be underestimated since HS patients might still develop IBD. CONCLUSION: The prevalence of IBD in HS patients (3.3%) is 4-8 times higher than the prevalence in the general northern European population (0.41%-0.74%), however HS-IBD patients do not have a distinct HS phenotype.

Extent of Systemic Spread Determines CD8+ T Cell Immunodominance for Laboratory Strains, Smallpox Vaccines, and Zoonotic Isolates of Vaccinia Virus.

CD8(+) T cells that recognize virus-derived peptides presented on MHC class I are vital antiviral effectors. Such peptides presented by any given virus vary greatly in immunogenicity, allowing them to be ranked in an immunodominance hierarchy. However, the full range of parameters that determine immunodominance and the underlying mechanisms remain unknown. In this study, we show across a range of vaccinia virus strains, including the current clonal smallpox vaccine, that the ability of a strain to spread systemically correlated with reduced immunodominance. Reduction in immunodominance was observed both in the lymphoid system and at the primary site of infection. Mechanistically, reduced immunodominance was associated with more robust priming and especially priming in the spleen. Finally, we show this is not just a property of vaccine and laboratory strains of virus, because an association between virulence and immunodominance was also observed in isolates from an outbreak of zoonotic vaccinia virus that occurred in Brazil.

Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression.

OBJECTIVES: Epigenetic modifications play an important role in the regulation of gene transcription and cellular function. Here, we examined if pro-inflammatory factors present in the inflamed joint of patients with rheumatoid arthritis (RA) could regulate histone deacetylase (HDAC) expression and function in fibroblast-like synoviocytes (FLS). METHODS: Protein acetylation in synovial tissue was assessed by immunohistochemistry. The mRNA levels of HDAC family members and inflammatory mediators in the synovial tissue and the changes in HDAC expression in RA FLS were measured by quantitative (q) PCR. FLS were either transfected with HDAC5 siRNA or transduced with adenoviral vector encoding wild-type HDAC5 and the effects of HDAC5 manipulation were examined by qPCR arrays, ELISA and ELISA-based assays. RESULTS: Synovial class I HDAC expression was associated with local expression of tumour necrosis factor (TNF) and matrix metalloproteinase-1, while class IIa HDAC5 expression was inversely associated with parameters of disease activity (erythrocyte sedimentation rate, C-reactive protein, Disease Activity Score in 28 Joints). Interleukin (IL)-1ß or TNF stimulation selectively suppressed HDAC5 expression in RA FLS, which was sufficient and required for optimal IFNB, CXCL9, CXCL10 and CXCL11 induction by IL-1ß, associated with increased nuclear accumulation of the transcription factor, interferon regulatory factor 1(IRF1). CONCLUSIONS: Inflammatory cytokines suppress RA FLS HDAC5 expression, promoting nuclear localisation of IRF1 and transcription of a subset of type I interferon response genes. Our results identify HDAC5 as a novel inflammatory mediator in RA, and suggest that strategies rescuing HDAC5 expression in vivo, or the development of HDAC inhibitors not affecting HDAC5 activity, may have therapeutic applications in RA treatment.

Hidradenitis suppurativa (HS) is associated with low socioeconomic status (SES): A cross-sectional reference study.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic debilitating disease, whereby school attendance and employment can be disturbed. OBJECTIVE: We sought to determine the socioeconomic status (SES) in patients with HS relative to other dermatologic patients, and whether specific clinical HS characteristics correlate with SES. METHODS: For this multicenter cross-sectional reference study, data were collected from patients with HS and sex- and age-matched dermatologic patients in a 1:2 ratio. SES was derived from the mean household income and real estate value on a neighborhood level. RESULTS: The SES distribution among 1018 patients with HS was significantly lower than among 2039 age- and sex-matched dermatologic control patients (P < .001). In patients with HS a low SES was associated with axillary involvement (odds ratio 1.42, P = .04), high body mass index (odds ratio 1.03, P = .003), and lower age at inclusion (odds ratio 0.98, P = .001), but not with disease severity or age of disease onset. LIMITATIONS: SES was based on postal code level and causality cannot be determined. CONCLUSION: In the general population, low SES is associated with an unhealthy lifestyle such as smoking and obesity. Therefore, low SES might be a risk factor for developing HS.

Intralesional triamcinolone for flares of hidradenitis suppurativa (HS): A case series.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease of the hair follicle. Standard practice of managing acute flares with corticosteroid injection lacks scientific evidence. OBJECTIVE: We sought to assess the outcomes of routine treatment using intralesional triamcinolone (triamcinolone acetonide 10 mg/mL) in the management of acute flares in HS. METHODS: This was a prospective case series evaluating the effect of intralesional corticosteroids for alleviation of acute flares in HS. Physician- and patient-reported outcomes were noted. RESULTS: Significant reductions in physician-assessed erythema (median score from 2-1, P < .0001), edema (median score from 2-1, P < .0001), suppuration (median score from 2-1, P < .0001), and size (median score from 3-1, P < .0001) was demonstrated at follow-up. A significant difference in patient-reported pain visual analog scale scores occurred after 1 day (from 5.5-2.3, P < .005) and from day 1 to day 2 (from 2.3-1.4, P < .002). LIMITATIONS: Small study size, open single-arm design, and short follow-up time are the limitations of this study. CONCLUSION: Intralesional injection of corticosteroids is perceived as beneficial by physicians and patients in the management of HS flares by reducing pain after 1 day and signs of inflammation approximately 7 days later.

Delayed control of herpes simplex virus infection and impaired CD4(+) T-cell migration to the skin in mouse models of DOCK8 deficiency.

DOCK8 deficiency in humans and mice leads to multiple defects in immune cell numbers and function. Patients with this immunodeficiency have a high morbidity and mortality, and are distinguished by chronic cutaneous viral infections, including those caused by herpes simplex virus (HSV). The underlying mechanism of the specific susceptibility to these chronic cutaneous viral infections is currently unknown, largely because the effect of DOCK8 deficiency has not been studied in suitable models. A better understanding of these mechanisms is required to underpin the development of more specific therapies. Here we show that DOCK8-deficient mice have poor control of primary cutaneous herpes simplex lesions and this is associated with increased virus loads. Furthermore, DOCK8-deficient mice showed a lack of CD4(+) T-cell infiltration into HSV-infected skin.

Btk inhibition suppresses agonist-induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants.

OBJECTIVES: Bruton's tyrosine kinase (Btk) is required for B lymphocyte and myeloid cell contributions to pathology in murine models of arthritis. Here, we examined the potential contributions of synovial Btk expression and activation to inflammation in rheumatoid arthritis (RA). MATERIALS AND METHODS: Btk was detected by immunohistochemistry and digital image analysis in synovial tissue from biologically naive RA (n=16) and psoriatic arthritis (PsA) (n=12) patients. Cell populations expressing Btk were identified by immunofluorescent double labelling confocal microscopy, quantitative (q-) PCR and immunoblotting. The effects of a Btk-specific inhibitor, RN486, on gene expression in human macrophages and RA synovial tissue explants (n=8) were assessed by qPCR, ELISA and single-plex assays. RESULTS: Btk was expressed at equivalent levels in RA and PsA synovial tissue, restricted to B lymphocytes, monocytes, macrophages and mast cells. RN486 significantly inhibited macrophage IL-6 production induced by Fc receptor and CD40 ligation. RN486 also reduced mRNA expression of overlapping gene sets induced by IgG, CD40 ligand (CD40L) and RA synovial fluid, and significantly suppressed macrophage production of CD40L-induced IL-8, TNF, MMP-1 and MMP-10, LPS-induced MMP-1, MMP-7 and MMP-10 production, and spontaneous production of IL-6, PDGF, CXCL-9 and MMP-1 by RA synovial explants. CONCLUSIONS: Btk is expressed equivalently in RA and PsA synovial tissue, primarily in macrophages. Btk activity is needed to drive macrophage activation in response to multiple agonists relevant to inflammatory arthritis, and promotes RA synovial tissue cytokine and MMP production. Pharmacological targeting of Btk may be of therapeutic benefit in the treatment of RA and other inflammatory diseases.