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Enthesophyte formation plays a crucial role in the development of spinal ankylosis in ankylosing spondylitis (AS). We aimed to investigate the role of platelet-derived growth factor B (PDGFB) in enthesophyte formation of AS using in vitro and in vivo models, and to determine the association between PDGFB and spinal progression in AS. Serum PDGFB levels were measured in AS patients and healthy controls (HC). Human entheseal tissues attached to facet joints or spinous processes were harvested at the time of surgery and investigated for bone-forming activity. The impact of a pharmacological agonist and antagonist of platelet-derived growth factor B receptor (PDGFRB) were investigated respectively in curdlan-treated SKG mice. PDGFB levels were elevated in AS sera and correlated with radiographic progression of AS in the spine. Mature osteoclasts secreting PDGFB proteins were increased in the AS group compared to HC and were observed in bony ankylosis tissues of AS. Expression of PDGFRB was significantly elevated in the spinous enthesis and facet joints of AS compared to controls. Moreover, recombinant PDGFB treatment accelerated bone mineralization of enthesis cells, which was pronounced in AS, whereas PDGFRB inhibition efficiently reduced the PDGFB-induced bone mineralization. Also, PDGFRB inhibition attenuated the severity of arthritis and enthesophyte formation at the joints of curdlan-treated SKG mice. This study suggests that regulating PDGFB/PDGFRB signaling could be a novel therapeutic strategy to block key pathophysiological processes of AS. This article is protected by copyright. All rights reserved.

To evaluate a stratified screening process for the early identification of axial spondyloarthritis (SpA) with consideration of the following: 1) wait times from primary care to rheumatology screen, 2) incremental precision and accuracy from primary care to rheumatology screening, and 3) diagnostic delay.Adults with low back pain attending primary care at low back pain clinics prospectively underwent a primary standardized clinical screening. Patients with low back pain of3 months who experienced symptom onset at age50 years were referred for a comprehensive secondary screening by a physical therapist with advanced rheumatology training. At secondary screening, patients with features of inflammation were classified as being at a low, medium, or high risk for axial SpA versus no risk for axial SpA. Precision and accuracy of this screening strata were measured against a rheumatologist with expertise in axial SpA.Overall, 405 patients underwent primary and secondary screening in the present study. The study cohort had a mean ± SD age of 36.9 ± 9.9 years, and 55% were women. HLA-B27 was present in 14.4% of patients. Median wait time from primary screening to secondary screening was 15 days. Axial SpA risk assignment by rheumatologist was 64.9% for no risk or low risk for axial SpA and 35.1% for medium risk or high risk for axial SpA. The best combination of sensitivity (68%), specificity (90%), positive predictive values (80%), and negative predictive values (84%) was evident in the secondary screening. In this cohort, 15.6% of patients received a final diagnosis of axial SpA. Median low back pain duration from symptom onset to diagnosis was 2 years for nonradiographic axial SpA and 7 years for ankylosing spondylitis.A stratified interprofessional screening process can facilitate rapid diagnosis of persistent low back pain with high precision and accuracy in patients who have axial SpA.

Objective Ankylosing spondylitis (AS) is an inflammatory arthritis in which men have a higher risk of developing progressive axial disease than women. Transcriptomic studies have shown reduced expression of cytotoxic cell genes in the blood of AS patients. HLA-B27 contributes the greatest risk for AS, suggesting a role for CD8+ T cells. This study was undertaken to profile AS patient cytotoxic cells with the hypothesis that an alteration in CD8+ T cells might explain the aberrant cytotoxic profile observed in patients. Methods Whole blood was examined for GZM and PRF1 gene expression by quantitative polymerase chain reaction. Serum and synovial fluid (SF) were examined for granzyme and perforin 1 expression by bead array, and blood and SF mononuclear cells were examined for granzyme and perforin 1 expression by fluorescence-activated cell sorting (FACS). Results GZM and PRF1 gene expression were both reduced in AS patients compared to healthy controls, especially in men. Perforin 1, but not granzyme, protein levels were reduced in AS patient serum. Granzymes were elevated in AS SF, but not in rheumatoid arthritis or osteoarthritis SF. FACS revealed a reduction in granzyme-positive and perforin 1-positive lymphocytes, but not an intrinsic defect in CD8+ T cell granzyme or perforin 1 production. CD8+ T cell frequency was reduced in the blood and increased in the SF of AS patients. Conclusion Our findings indicate that AS patients have an altered cytotoxic T cell profile. These data suggest that CD8+ T cells with a cytotoxic phenotype are recruited to the joints, where they exhibit an activated phenotype. Thus, a central role for CD8+ T cells in AS may have been overlooked and deserves further study.

The Akikiki (Oreomystis bairdi) and Akekee (Loxops caeruleirostris) are two honeycreepers endemic to Kauai, Hawaii, that were listed as federally endangered in 2010. Both species are rare, little‐studied, and occur in a remote, roadless area. We analyzed high‐resolution airborne lidar data to identify forest structure and topography metrics associated with Akikiki and Akekee nest locations (88 for Akikiki and 22 for Akekee) and occurrences (3706 for Akikiki and 1581 for Akekee) from 2012 to 2017 on the Alakai Plateau to predict their distribution in unsurveyed areas. Akikiki and Akekee nested in areas with similar forest structure at 10 m resolution, but different maximum tree heights. Akikiki and Akekee foraged in areas with significantly different forest structure (maximum tree height, mean canopy height, relative heights) and topography (slope) based on occurrences. Elevation was consistently one of the most important metrics for predicting both species nest locations and occurrences across scales (10, 100, 250 m) and it appears that both species are at the upper limits of their elevational range. We estimate that the area of suitable nesting habitat for Akikiki is 17.59 km2 while the area of suitable nesting habitat for Akekee is 11.10 km2 at 10 m resolution. The Akikiki has a potential range of 38 km2 while the Akekee has a range of 58 km2 at 100 m resolution. We produce predictive nest and occurrence maps at 10 m and 100 m resolutions to spatially target conservation actions. Results suggest that if avian malaria cannot be controlled and both species populations do not stabilize over the coming years, translocation may be needed to insure their viability.

Objective To describe the surgical approach and outcomes in the treatment of adult patients with complications of childhood hypospadias surgery, as such patients present a significant reconstructive challenge due to the combination of anatomical and cosmetic deformity, which often results in major functional and psychosexual sequelae. Patients and methods We analysed prospectively collected data on 79 adults with complications of childhood hypospadias surgery, who were operated on between 2004 and 2016. Of the 79 patients, 48 underwent a two-stage urethroplasty using a buccal mucosa graft, and 31 underwent a one-stage distal urethroplasty. Results Patients were followed up using flexible cystoscopy (every 6-9 months). The mean (range) follow-up was 48 (12-96) months. Of the 48 patients who underwent a two-stage repair, eight (16%) needed a revision of the first-stage graft. In total, nine of the 48 patients (16%) developed fistula requiring closure after the second stage; all but one was closed successfully on the first attempt, whilst one required two attempts before closure. Only two of the 48 patients that underwent a two-stage procedure required a re-do urethroplasty within 3 years. Of the 31 patients who underwent a one-stage repair, six (19%) needed fistula closure, all of which were successful. No patient required a further urethroplasty during follow-up. Conclusions Despite the significant surgical challenges found in this patient group, excellent long-term functional outcomes can be achieved. As expected there is a need for additional intervention, either for revision of the first stage or to close fistulae and less commonly for further reconstruction for stricture recurrence.

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have been associated with fibrotic lung disease, although exactly how they modulate this process remains unclear. Here we investigated the role of GRP78, the main UPR regulator, in an experimental model of lung injury and fibrosis. Grp78(+/-) , Chop(-/-) and wild type C57BL6/J mice were exposed to bleomycin by oropharyngeal intubation and lungs were examined at days 7 and 21. We demonstrate here that Grp78(+/-) mice were strongly protected from bleomycin-induced fibrosis, as shown by immunohistochemical analysis, collagen content and lung function measurements. In the inflammatory phase of this model, a reduced number of lung macrophages associated with an increased number of TUNEL-positive cells were observed in Grp78(+/-) mice. Dual immunohistochemical and in situ hybridization experiments showed that the macrophage population from the protected Grp78(+/-) mice was also strongly positive for cleaved caspase-3 and Chop mRNA, respectively. In contrast, the administration of bleomycin to Chop(-/-) mice resulted in increased quasi-static elastance and extracellular matrix deposition associated with an increased number of parenchymal arginase-1-positive macrophages that were negative for cleaved caspase-3. The data presented indicate that the UPR is activated in fibrotic lung tissue and strongly localized to macrophages. GRP78- and CHOP-mediated macrophage apoptosis was found to protect against bleomycin-induced fibrosis. Overall, we demonstrate here that the fibrotic response to bleomycin is dependent on GRP78-mediated events and provides evidence that macrophage polarization and apoptosis may play a role in this process. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Conservation planning and biodiversity management require information on landscape connectivity across a range of spatial scales from individual home ranges to large regions. Reduction in landscape connectivity due changes in land use or development is expected to act synergistically with alterations to habitat mosaic configuration arising from climate change. We illustrate a multiscale connectivity framework to aid habitat conservation prioritization in the context of changing land use and climate. Our approach, which builds upon the strengths of multiple landscape connectivity methods, including graph theory, circuit theory, and least-cost path analysis, is here applied to the conservation planning requirements of the Mohave ground squirrel. The distribution of this threatened Californian species, as for numerous other desert species, overlaps with the proposed placement of several utility-scale renewable energy developments in the American southwest. Our approach uses information derived at three spatial scales to forecast potential changes in habitat connectivity under various scenarios of energy development and climate change. By disentangling the potential effects of habitat loss and fragmentation across multiple scales, we identify priority conservation areas for both core habitat and critical corridor or stepping stone habitats. This approach is a first step toward applying graph theory to analyze habitat connectivity for species with continuously distributed habitat and should be applicable across a broad range of taxa.

Objective To identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS). Methods Cohorts of male and female patients with AS and age- and sex-matched healthy control subjects were selected, and the levels of serum cytokines (interferon-γ [IFNγ], tumor necrosis factor α, interleukin-17A [IL-17A], and IL-6) were examined by enzyme-linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches. Results The frequency of IL-17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS-associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex-related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS. Conclusion The results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex-related differences in the clinical features of AS and could provide a rationale for sex-specific treatment of AS.

Background/Purpose Because ankylosing spondylitis (AS) is uncommon, large medical record databases offer important opportunities for pharmacoepidemiologic research. However, the validity of AS diagnoses recorded by a general practitioner (GP) is unknown. We assessed the validity of algorithms for identifying AS in The Health Improvement Network (THIN). Methods THIN is a database of GP records for over 10 million persons in the UK. In 2014, we administered a questionnaire to GPs of 100 adults for whom an AS diagnosis had been recorded. As high positive predictive value (PPV) is critically important in AS research, we sought to determine the PPV of an AS diagnostic code relative to the GP's clinical impression as the gold standard. Other AS algorithms included: more than one AS diagnostic code, prescription of a nonsteroidal anti-inflammatory drug (NSAID), disease modifying anti-rheumatic drug (DMARD) or biologic. Results In 61 of 85 returned questionnaires, the GP's clinical impression confirmed AS yielding an overall PPV of 72%. PPV was 89% for two AS codes >7 days apart, and was 86% for an AS code plus a DMARD/biologic. Sensitivity was reduced with algorithms requiring two AS codes (64%) and a DMARD/biologic prescription (30%). Algorithms requiring prescription of an NSAID, or the absence of OA or RA had lower PPV (71–75%) and higher sensitivity (95–98%). Conclusion An AS identification algorithm of two AS diagnoses separated by >7 days provided the highest PPV. This algorithm should be used for pharmacoepidemiologic studies in THIN. Copyright © 2016 John Wiley & Sons, Ltd.

BACKGROUND: An unresolved issue in T regulatory (Treg) cell biology is the lack of consensus on phenotypic markers that accurately define the natural Treg (nTreg) population. OBJECTIVES: To examine nTreg frequency and functional capacity in healthy controls, and their frequency in asthmatic subjects using three different phenotypic strategies. We hypothesized that phenotypically different nTreg are quantitatively and functionally different. METHODS: 34 healthy, non-asthmatic and 17 asthmatic subjects were studied. Three nTreg phenotypes were defined: nTreg1 (CD4(+) CD25(+) Foxp3(+) ), nTreg2 (CD4(+) CD25(+) CD127(low) Foxp3(+) ), and nTreg3 (CD4(+) CD25(high) Foxp3(+) ). The flow cytometric determination of nTreg frequency in peripheral blood (PB) and bronchoalveolar lavage (BAL) was performed using fluorescently labelled antibodies. PB nTreg functional capacity was assessed using a CFSE-based suppression assay. RESULTS: There was a significantly lower frequency of peripheral blood nTreg3 compared to nTreg2 and nTreg1 (p

Protective immunity to the pathogen Chlamydia is dependent on a robust IFN-γ response generated by innate and adaptive lymphocytes. Here we assess the role of the macrophage in orchestrating a protective response in vivo to the murine pathogen, Chlamydia muridarum. During acute pulmonary and peritoneal infection, resident macrophages in both sites are infected with C. muridarum and adopt an inflammatory phenotype. In the lung, this activation is restricted to interstitial macrophages, which harbor higher levels of C. muridarum 16sRNA than alveolar macrophages. We examined innate and adaptive lymphocyte activation in the peritoneal cavity with macrophage depletion and with adoptive transfer of infected macrophages. These experiments demonstrate macrophage activation correlates with a protective IFN-γ response and effective control of C. muridarum. These studies suggest that a quantitative or qualitative alteration in macrophages may play a key role in the development of Chlamydia-associated diseases.

Objective To provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). Methods A core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946–2014), PubMed (1966–2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework. Results In patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS. Conclusion These recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

Free to read Objective To use high-density genotyping to investigate the genetic associations of acute anterior uveitis (AAU) in patients with and those without ankylosing spondylitis (AS). Methods We genotyped samples from 1,711 patients with AAU (either primary or combined with AS), 2,339 AS patients without AAU, and 10,000 control subjects on an Illumina Immunochip Infinium microarray. We also used data for AS patients from previous genome-wide association studies to investigate the AS risk locus ANTXR2 for its putative effect in AAU. ANTXR2 expression in mouse eyes was investigated by real-time quantitative reverse transcription–polymerase chain reaction. Results A comparison between all patients with AAU and healthy control subjects showed strong association over HLA–B, corresponding to the HLA–B27 tag single-nucleotide polymorphism rs116488202. The association of 3 non–major histocompatibility complex loci, IL23R, the intergenic region 2p15, and ERAP1, reached genome-wide significance (P < 5 × 10−8). Five loci harboring the immune-related genes IL10–IL19, IL18R1–IL1R1, IL6R, the chromosome 1q32 locus harboring KIF21B, as well as the eye-related gene EYS, were also associated, reaching a suggestive level of significance (P < 5 × 10−6). Several previously confirmed AS associations demonstrated significant differences in effect size between AS patients with AAU and AS patients without AAU. ANTXR2 expression varied across eye compartments. Conclusion These findings of both novel AAU-specific associations and associations shared with AS demonstrate overlapping but also distinct genetic susceptibility loci for AAU and AS. The associations in IL10 and IL18R1 are shared with inflammatory bowel disease, suggesting common etiologic pathways.

Objective Fatigue is one of the cardinal features of ankylosing spondylitis (AS) and contributes substantially to the disability associated with this disease. The mechanisms underlying fatigue in AS remain poorly understood, and this has hampered the development of targeted, effective treatment of this disabling feature of AS. The current study was undertaken, therefore, to investigate the brain networks underlying fatigue in AS. Methods Twenty patients with back pain secondary to AS (15 men and 5 women; mean ± SD age 34.8 ± 11.9 years) and 20 age- and sex-matched controls consented to participate in the study. Patients underwent clinical assessment of AS using the Fatigue Severity Scale, the Affect Intensity Measure, and the McGill Pain Questionnaire. Brain gray matter and white matter connectivity was assessed using 3T magnetic resonance imaging. Results The patients with AS had significant fatigue that correlated with measures of their emotional strength and spinal mobility. Individual fatigue scores were negatively correlated with the amount of gray matter in areas of the dorsal and ventral attention networks, the somatosensory cortices, and the caudate nucleus, but were positively correlated with gray matter within the executive control network and putamen. Moreover, in patients with high fatigue scores, white matter tracts connecting these brain structures (e.g., inferior fronto-occipital fasciculi, superior/inferior longitudinal fasciculi, and corticothalamic tracts) exhibited low fractional anisotropy (indicative of decreased white matter tract integrity). Conclusion These data indicate that fatigue in AS involves sensory salience and attention brain networks.

Objective To develop and validate a reference image module aimed at calibration of readers using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) to assess radiographic progression in spondyloarthritis. Methods Our working group comprised 6 rheumatologists and 3 musculoskeletal radiologists. The following developmental steps were conducted: 1) review of the literature to identify aspects of the mSASSS requiring methodologic clarity; 2) independent assessment of baseline and 2-year radiographs from 25 patients using the mSASSS (pilot exercise); 3) development of a training module (the Spondyloarthritis Radiography [SPAR] module) that clarifies definitions, rules, and scoring methodology and a set of reference radiographic images; 4) scoring exercise 1 by 6 readers on 39 patients, where baseline and 2-year radiographs were scored blinded to time point; and 5) revision of the SPAR module followed by scoring exercise 2 conducted by the same 6 readers on 35 patients. Reliability of status and 2-year change scores was assessed by the intraclass correlation coefficient (ICC) method. Results ICCs for change scores for the radiologist reader pair improved from 0.46 to 0.62 after minimal calibration with the SPAR module. Recalibration from exercise 1 to exercise 2 with the SPAR module led to substantial improvement in interreader reliability for change in mSASSS score from ICC 0.44 (range 0.31–0.62) to ICC 0.62 (range 0.34–0.84). Simultaneous assessment of anteroposterior and lateral lumbar radiographs did not enhance reliability or detection of progression. Conclusion Calibration according to the SPAR module led to improved reliability in the scoring of the mSASSS, even for expert readers.

It is recognized that host response following viral infection is characterized by immunodominance, but deciphering the different factors contributing to immunodominance has proved a challenge due to concurrent expression of multiple MHC class I alleles. To address this, we generated H2-K−/−/D−/− double-knockout transgenic mice expressing either one or two human MHC-I alleles. We hypothesized that co-expression of different allele combinations figures critically in immunodominance and examined this in influenza-infected, double Tg MHC-I mice. In A2/B7 or A2/B27 mice, using ELISpot assays with the A2-restricted matrix I.58–66, the B7-restricted NP418–426 or the B27-restricted NP383–391 influenza A (flu) epitopes, we observed the expected recognition of both peptides for both alleles. In contrast, in flu-infected B7/B27 mice, a significantly reduced level of B27/NP383-restricted CTL response was detected while there was no change in the B7/NP418-restricted CTL response. Flu-specific tetramer studies revealed a partial deletion of Vβ8.1+ NP383/B27-restricted CD8+ T cells, and a diminished Vβ12+ CD8+ T-cell expansion in B7/B27 Tg mice. Using HLA Tg chimeric mice, we confirmed these findings. These findings shed light on the immune consequences of co-dominant expression of MHC-I alleles for host immune response to pathogens.

Objective To determine whether there is a neuropathic component in ankylosing spondylitis (AS) back pain and to delineate gray matter brain abnormalities associated with AS. Methods Seventeen patients with back pain secondary to AS who were not receiving biologic agents and 17 age- and sex-matched healthy controls consented to participate in the study and were assessed using the painDETECT instrument (scores of ≤12 indicating low probability of neuropathic pain) and the McGill Pain Questionnaire. Mechanical and thermal thresholds were determined in all subjects, and brain gray matter was assessed by 3T magnetic resonance imaging. Results Eleven of the 17 AS patients had painDETECT scores of >12. The patients had decreased mechanical and cold sensitivity on the dorsum of their feet but did not have altered pain thresholds. Compared to controls, the AS patients exhibited cortical thinning in the primary somatosensory, insular, anterior cingulate, and anterior mid-cingulate cortices and the supplemental motor area, and increased gray matter volume in the thalamus and putamen. Scores on the painDETECT in AS patients were correlated with decreased gray matter in the primary somatosensory cortex and with increased gray matter in the motor cortex, anterior cingulate cortex, prefrontal cortex, thalamus, and striatum. Conclusion The present findings indicate that neuropathic pain occurs in AS. Furthermore, abnormal brain gray matter and neural correlates of neuropathic pain are concordant with the clinical picture of AS, which includes sensorimotor and mood deficits as well as neuropathic pain symptoms. These results suggest that back pain in AS is a mixed pain condition that includes a neuropathic pain component.

Aim We explored lineage diversification within desert-dwelling fauna. Our goals were (1) to determine whether phylogenetic lineages and population expansions were consistent with younger Pleistocene climate fluctuation hypotheses or much older events predicted by pre-Pleistocene vicariance hypotheses, (2) to assess concordance in spatial patterns of genetic divergence and diversity among species and (3) to identify regional evolutionary hotspots of divergence and diversity and assess their conservation status. Location Mojave, Colorado, and Sonoran Deserts, USA. Methods We analysed previously published gene sequence data for twelve species. We used Bayesian gene tree methods to estimate lineages and divergence times. Within each lineage, we tested for population expansion and age of expansion using coalescent approaches. We mapped interpopulation genetic divergence and intra-population genetic diversity in a GIS to identify hotspots of highest genetic divergence and diversity and to assess whether protected lands overlapped with evolutionary hotspots. Results In seven of the 12 species, lineage divergence substantially predated the Pleistocene. Historical population expansion was found in eight species, but expansion events postdated the Last Glacial Maximum (LGM) in only four. For all species assessed, six hotspots of high genetic divergence and diversity were concentrated in the Colorado Desert, along the Colorado River and in the Mojave/Sonoran ecotone. At least some proportion of the land within each recovered hotspot was categorized as protected, yet four of the six also overlapped with major areas of human development. Main conclusions Most of the species studied here diversified into distinct Mojave and Sonoran lineages prior to the LGM – supporting older diversification hypotheses. Several evolutionary hotspots were recovered but are not strategically paired with areas of protected land. Long-term preservation of species-level biodiversity would entail selecting areas for protection in Mojave and Sonoran Deserts to retain divergent genetic diversity and ensure connectedness across environmental gradients.

AIM We examined the electrophysiological properties of reverse-mode Na(+) /Ca(2+) exchange (NCX) in mouse airway smooth muscle (ASM), assessing its contributions to regulation of [Ca(2+) ], and its expression in acute and chronic airway hyperresponsiveness (AHR). METHODS Membrane currents were studied in single murine ASM cells under voltage clamp at -60 mV using ramp depolarizing commands to +80 mV. Confocal fluorimetric and RT-PCR techniques were used to monitor changes in cytosolic [Ca(2+) ] and NCX expression, respectively. RESULTS With standard KCl-containing electrode, 30 μm KB-R7943 (an inhibitor of reverse-mode NCX activity) exhibited variable effects on membrane current, indicating modulation of more than one conductance. KB-R7943 activated outwardly rectifying current that was inhibited by 100 μm iberiotoxin (blocker of large-conductance Ca(2+) -dependent K(+) channels), indicating a direct enhancing effect of KB-R7943 on those K(+) channels. After obviating K(+) currents, we found that a current sensitive to 4-4'-diisothiocyanostilbene-2,2'-disulfonic acid (blocker of Ca(2+) -dependent Cl- channels) was markedly increased by elevating [Na(+) ] in the electrode solution to 13, 15.5 and 18 mm and suppressed by KB-R7943, indicating Ca(2+) influx via reverse-mode NCX activity. With conditions preventing Ca(2+) influx through voltage-dependent Ca(2+) channels but promoting that through NCX, we found that introduction of Ca(2+) led to marked but transient KB-R7943-sensitive elevation of [Ca(2+) ]. Additionally, KB-R7943 suppressed cholinergically evoked Ca(2+) waves. Finally, NCX1 expression was not significantly changed in allergen-induced AHR acute model but increased approx. 2.5-fold in a chronic model. CONCLUSION Reverse-mode NCX activity leads to a physiologically relevant increase in [Ca(2+) ] even under control conditions, and this may be exaggerated in allergen-induced AHR and asthma.

Recently, a number of different structural health monitoring (SHM) techniques have been developed for the online inspection of air, land and sea engineering structures. Various smart materials are employed for detecting eminent damage in situ. Fatigue cracks in structural components are the most common cause of structural failure when exposed to fatigue loading. Fatigue design of structural components is typically accomplished either using a set of stress cycle (S-N) data obtained from prior fatigue tests or using the fracture mechanics approach. The fracture mechanics approach considers the fatigue life of structures as a summation of crack initiation life and crack propagation life. The stress intensity factor (SIF) is required for the estimation of fatigue crack propagation life from the linear elastic fracture mechanics (LEFM) perspective. However, the accurate prediction of the SIF is difficult especially when the geometry or the boundary conditions of a structure becomes complex. In this study, a SHM application of macrofibre composite (MFC) sensors is presented. A set of MFC sensors is used for the real-time measurement of the SIF. The measured values of the SIF are later used for the prediction of the crack propagation life. The impedance-based SHM technique using the same set of MFC sensors is employed for the detection of crack initiation life.

Summary Background The syndrome of allergic asthma features reversible bronchoconstriction, airway inflammation and hyperresponsiveness as well as airway remodelling, including goblet cell hyperplasia. Managing severe asthma is still a clinical challenge. Numerous studies report that furosemide, an inhibitor of Na+–K+–Cl− cotransporter (NKCC) reduces airway hyperresponsiveness (AHR) in asthmatic patients. However, the mechanism by which furosemide exerts anti-asthmatic action remains unclear. Objective This study sought to investigate the cellular profile of NKCC1 expression in the lung and examine the effects of furosemide on several outcome measurements in a mouse model of allergic asthma. Methods Mice were sensitized and challenged with ovalbumin (OVA). Before challenge, the OVA-sensitized mice were treated with furosemide (4.0 mg/kg/day, via daily intraperitoneal injection for 5 days). Outcome measurements in naive, OVA-exposure, furosemide-treated naive and furosemide-treated OVA-exposed mice included the slope of the relationship between inhaled methacholine (MCh) concentration and respiratory system resistance (Slope·RRS), bronchoalveolar lavage (BAL) cell counts and immunohistochemical and immunoblotting assays of lung tissues. Results NKCC1 immunoreactivity was observed in airway epithelial cells (AECs) and alveolar type II (ATII) cells of the control mice. OVA exposure enhanced the expression of NKCC1 in AECs and ATII cells, and increased the infiltration of NKCC1-expressing T lymphocytes in the lung. NKCC1 immunoreactivity was not detected in the airway smooth muscle (ASM) cells. Furosemide treatment reduced the Slope·RRS in both naive and OVA-exposed mice by about 50%. Furosemide treatment also increased T lymphocyte infiltration to the lung in OVA-exposed mice by approximately 53%, but had no effect on pulmonary goblet cell hyperplasia. Conclusions and Clinical Relevance Furosemide decreases basal airway responsiveness, thereby reducing the extent of allergen-induced AHR. However, the same treatment also increases T lymphocytes infiltration in the course of allergic asthma. Further studies are necessary to address the usefulness of furosemide in the clinical treatment of asthma. Cite this as: S. Wang, Y.-Y. Xiang, R. Ellis, J. Wattie, M. Feng, M. D. Inman and W.-Y. Lu, Clinical & Experimental Allergy, 2011 (41) 1456–1467.

To cite this article: Vahlkvist S, Inman MD, Pedersen S. Effect of asthma treatment on fitness, daily activity and body composition in children with asthma. Allergy 2010; 65: 1464–1471. Abstract Background: Although several cross-sectional studies have assessed the daily physical activity in children with asthma, the impact of the level of asthma control remains unknown. Aim: To assess the influence of asthma treatment–induced changes in asthma control on daily physical activity, cardiovascular fitness and body composition in children with asthma. Methods: Daily accelerometer-measured physical activity, cardiovascular fitness, body composition (percent fat, percent lean tissue and bone mineral density) and a variety of asthma outcomes (to assess the level of asthma control) were measured over 4 weeks in 55 children with newly diagnosed untreated asthma and 154 healthy, sex and age-matched controls. Treatment with inhaled corticosteroids was initiated after the baseline period. All outcome measurements were repeated after 1 year and some also during the year of treatment. Results: Asthma control improved markedly during the year of treatment. The improvement in control was associated with a significant increase in total daily activity of 2.8 h/week compared with the healthy controls (P

Objective To evaluate the effect of golimumab on sleep disturbance in patients with active ankylosing spondylitis (AS). Methods Golimumab was studied in a multicenter, randomized, placebo-controlled study (GO-RAISE). At baseline, 356 patients were randomly assigned in a 1.8:1.8:1 ratio to subcutaneous golimumab 50 mg, 100 mg, or placebo every 4 weeks. Sleep disturbance was assessed using the Jenkins Sleep Evaluation Questionnaire (JSEQ), which was administered at baseline, week 14, and week 24. Treatment effect was evaluated using analysis of variance on the van der Waerden normal scores. Results Median JSEQ scores at baseline were 9.0 in the placebo group, 10.0 in the 50-mg group, and 11.0 in the 100-mg group, indicating moderate to severe sleep disturbance. Patients who received golimumab showed significantly greater median improvement from baseline in JSEQ scores compared with placebo at week 14 (−3.0 versus 0.0; P < 0.001) and week 24 (−3.0 versus −1.0; P < 0.001). Changes from baseline in JSEQ scores significantly correlated with changes from baseline in Short Form 36 summary scores, Bath AS Functional Index scores, total back pain, night back pain, and Bath AS Disease Activity Index scores. Multiple regression analyses indicated that improvement in the night back pain score was the most consistent predictor of change in JSEQ score or reduction in sleep disturbance. Conclusion Patients with active AS showed significant sleep disturbance at baseline due to underlying pain associated with AS. Treatment with subcutaneous golimumab every 4 weeks significantly reduced sleep disturbance and improved health-related quality of life.

Objective The prevalence of sacroiliac (SI) joint abnormalities in a primary low back pain population remains unresolved. The aims of our study were to define the prevalence of SI joint disease in this cohort, and to identify clinical features that might accurately predict radiographic changes in the SI joint and spine. Methods Lumbar spine and anteroposterior pelvis radiographs taken over a 3-year period for the evaluation of back pain at a major chiropractic college were scored for the presence of inflammatory or degenerative features. Data were subsequently extracted by means of a predetermined template from the clinical notes. The outcomes were correlated using Spearman's correlation coefficients. Results We identified 315 patients (173 men, 142 women), ages 18–60 years. Of these, 100 patients (31.7%) demonstrated SI joint abnormalities: 75 (23.8%) degenerative, 25 (7.9%) inflammatory. Sex was strongly associated with type of SI joint pathology; degenerative disease was predominantly found in women (68%), whereas inflammatory disease was predominantly found in men (63%). In women there was no correlation between degenerative SI joint abnormalities and degenerative changes in the lumbar spine. Of the clinical descriptors evaluated, none were associated with the radiographic findings with the exception of buttock pain, which was associated with inflammatory sacroiliitis. Neither being overweight nor pregnancy history was associated with degenerative changes in the SI joint. Conclusion In a primary back pain cohort, degenerative SI joint disease may be an under-recognized clinical entity. It is strongly influenced by sex but is unrelated to degenerative changes in the lumbar spine. Currently proposed clinical discriminators performed poorly in correlating with radiographic changes in the SI joint.

Background Asthma is a disease characterized by airway inflammation, remodelling and dysfunction. Airway inflammation contributes to remodelling, a term that is used to describe structural changes including goblet cell metaplasia (GCM), matrix deposition, and smooth muscle hyperplasia/hypertrophy. GCM has been implicated in asthma mortality by contributing to mucus plugs and leading to asphyxiation. In animal models, this process is highly dependent on IL-13. Recently, we have described an IL-13-dependent up-regulation of a GABAergic signalling system in airway epithelium that contributes to GCM. The mechanism by which IL-13 up-regulates GABA signalling in airway epithelium is unknown. Objectives To test the hypothesis that IL-4Ralpha signalling is required for allergen induced up-regulation of GABAergic signalling and GCM. Methods BALB/c mice were exposed to an acute house dust mite (HDM) protocol and received vehicle, anti-IL-4Ralpha-monoclonal antibody, or control antibody. Outcomes included airway responses to inhaled methacholine (MCh), histology for eosinophilia and GCM, phosphorylated STAT6 levels using immunohistochemistry and immunoblot, and glutamic acid decarboxylase (GAD) 65/67 and GABA(A)beta(2/3) receptor subunit expression using confocal microscopy. Results Acute HDM exposure resulted in increased airway responses to MCh, lung eosinophilia, STAT6 phosphorylation, elevations in GAD65/67 and GABA(A)beta(2/3) receptor expression, and GCM that were inhibited with anti-IL-4Ralpha-monoclonal treatment. Control antibody had no effect. Conclusion The IL-4Ralpha is required for allergen-induced up-regulation of a GABAergic system in airway epithelium implicated in GCM following acute HDM exposure.

Objective. Anemia is a common complication in patients with inflammatory diseases such as ankylosing spondylitis (AS). This post hoc analysis of a large, randomized, placebo-controlled trial examined the effect of infliximab on hemoglobin levels, physical function, and fatigue in patients with AS.Methods. Patients received infliximab 5 mg/kg (n = 188) or placebo (n = 68) at weeks 0, 2, 6, 12, and 18. Hemoglobin, interleukin-6 (IL-6), and C-reactive protein (CRP) levels, fatigue (visual analog scale [VAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]) and disease activity were evaluated at baseline and week 24. Anemia was defined as a hemoglobin level

Objective Alterations in antigen processing have been proposed to play a significant role in the pathogenesis of ankylosing spondylitis (AS). A non–major histocompatibility complex gene encoding an endoplasmic reticulum aminopeptidase, ERAP1, has been implicated recently. This study assessed 13 coding single-nucleotide polymorphisms (SNPs) from 5 genes involved in antigen processing (ERAP1, TAP1, TAP2, LMP2, and LMP7) in 3 Canadian cohorts of patients with AS, to address the possibility of gene interactions in disease susceptibility. Methods The study involved 992 AS cases and 1,437 controls from 3 centers (472 cases and 451 controls from Alberta, 138 cases and 392 controls from Newfoundland, and 382 cases and 594 controls from Toronto). Most of the patients with AS and healthy, unrelated controls were Caucasians of northern European descent. Single-marker and haplotype associations were determined using an allelic likelihood ratio test in UNPHASED, version 3.0.12, and the WHAP program, respectively. P values for significance of haplotype associations were calculated using a permutation test. Results A specific ERAP1 haplotype, rs27044/10050860/30187-CCT, was strongly associated with increased risk of AS in all 3 case–control cohorts (pooled odds ratio [OR] 1.81, 95% confidence interval [95% CI] 1.46–2.24; P = 7 × 10−8), while a second specific ERAP1 haplotype, rs30187/26618/26653-CTG, reduced the disease risk (pooled OR 0.77, 95% CI 0.67–0.88; P = 9 × 10−5). Significant associations were also noted for 3 ERAP1 SNP variants (rs10050860, rs30187, and rs26653), although no significant haplotype interaction between ERAP1 and TAP/LMP loci was evident. Conclusion These data indicate that an AS disease locus may reside on a specific ERAP1 haplotype, and its effect is not multiplicative with contributions from TAP and LMP genes.

To evaluate the efficacy and safety of golimumab in patients with ankylosing spondylitis (AS) in the GO-RAISE study.Patients with active AS, a Bath AS Disease Activity Index (BASDAI) scoreor =4, and a back pain score ofor =4 were randomly assigned in a 1.8:1.8:1 ratio to receive subcutaneous injections of golimumab (50 mg or 100 mg) or placebo every 4 weeks. The primary end point was the proportion of patients with at least 20% improvement in the ASsessment in AS (ASAS20) criteria at week 14.At randomization, 138, 140, and 78 patients were assigned to the 50-mg, 100-mg, and placebo groups, respectively. After 14 weeks, 59.4%, 60.0%, and 21.8% of patients, respectively, were ASAS20 responders (P0.001). A 40% improvement in the ASAS criteria at week 24 occurred in 43.5%, 54.3%, and 15.4% of patients, respectively. Patients receiving golimumab also showed significant improvement in the physical and mental component summary scores of the Short Form 36 Health Survey, the Jenkins Sleep Evaluation Questionnaire score, the BASDAI score, and the Bath AS Functional Index score, but not the Bath AS Metrology Index score. Through week 24, 85.6% of golimumab-treated patients and 76.6% of patients in the placebo group hador =1 adverse event, and 5.4% and 6.5% of patients, respectively, hador =1 serious adverse event. Eight golimumab-treated patients and 1 placebo-treated patient had markedly abnormal liver enzyme values (or =100% increase from baseline and a value150 IU/liter), which were transient.Golimumab was effective and well tolerated in a large cohort of patients with AS during a 24-week study period.

Objective To determine whether macrophages, a type of cell implicated in the pathogenesis of ankylosing spondylitis (AS), exhibit a characteristic gene expression pattern. Methods Macrophages were derived from the peripheral blood of 8 AS patients (median disease duration 13 years [range

Objective To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS). Methods This was a randomized, multicenter, double-blind, placebo-controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24-week double-blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index. Results The spine SPARCC score in placebo-treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab-treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo-treated patients and by 52.9% in adalimumab-treated patients (P = 0.017). The response in adalimumab-treated patients was maintained at week 52. Placebo-treated patients were switched to open-label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab-treated patients, a reduced C-reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018). Conclusion Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

The technique of thermodynamic studies by means of galvanic cells and the processes occurring at working electrodes is described. Measurement of the dependence of the reversible, or stationary, electrode upon concentration, temperature, current density, and time are described for the systems U/UCl/sub 3/ ; Zr/ZrCl/sub 4/; Th/ThCl/sub 4/; and Ce/ CeCl/sub 3/. (W.L.H.)

Eosinophil recruitment to the airways, including involvement of haemopoietic eosinophil-basophil progenitors (Eo/B-CFU), is primarily regulated by interleukin-5 (IL-5) and eotaxin. In this study, we investigated the haemopoietic mechanisms in upper and lower airway eosinophilic inflammation. Ovalbumin (OVA) sensitized and challenged BALB/c mice were used to establish isolated upper (UAC), isolated lower (LAC), or combined upper and lower airway (ULAC) inflammation. Airway, blood and bone marrow responses were evaluated in each model. Numbers of airway eosinophils and CD4(+) cells were increased significantly in the nasal mucosa in UAC and ULAC mice, and in the lung tissue in LAC and ULAC groups. Levels of IL-5 and eotaxin were increased significantly in the nasal lavage fluid (NL) in UAC and ULAC mice, and in the bronchoalveolar lavage fluid (BAL) in LAC and ULAC groups. The proportion of IL-5-responsive bone marrow Eo/B-CFU was significantly higher than the control in all treatment groups, but peaked much earlier in the ULAC group. Kinetic studies revealed that IL-5 and eotaxin in NL, BAL and serum peaked between 2 and 12 hr after OVA challenge in ULAC mice, and at 24 hr in UAC mice, related to the timing of maximal progenitor responses. These data support the concept that the systemic mechanisms linking rhinitis to asthma depend on the location and extent of airway allergen exposure.

To develop a feasible magnetic resonance imaging (MRI)-based scoring system for spinal inflammation in patients with spondylarthropathy that requires minimal scan time, does not require contrast enhancement, evaluates the extent of lesions in 3 dimensional planes, and limits the number of vertebral levels that are scored because MRI demonstrates characteristic inflammatory lesions in the spine of patients with ankylosing spondylitis (AS) prior to the development of typical features on plain radiographic.Our scoring method was based entirely on the assessment of increased signal denoting bone marrow edema on T2-weighted STIR sequences. Blinded MRI films were assessed in random order at 2 sites by 3 blinded readers at each of the 2 sites (the Universities of Alberta and Toronto). Intra- and interreader reliability was assessed by intraclass correlation coefficient. The 24-week response of patients with AS randomized to infliximab:placebo (8:3) was assessed by effect size and standardized response mean.An initial analysis of all discovertebral units (DVUs) in the spine of 11 patients demonstrated a mean of 3.2 (95% confidence interval 3.2, 5.2) affected units, while limiting the scoring to a maximum of 6 units captured most of the affected units. We scanned 11 patients with AS with clinically active disease and 20 additional patients randomized to a 24-week trial of either infliximab or placebo. Intraobserver reproducibility for the 6-DVU STIR score ranged from 0.93 to 0.98 (P0.0001). Interobserver reproducibility of scores by readers from both sites was 0.79 (P0.0001) for status score and 0.82 (P0.0001) for change score. Analysis of pretreatment and posttreatment scores for all 20 patients randomized to infliximab/placebo showed a large degree of responsiveness (standardized response mean = 0.87). Reproducibility and responsiveness were only slightly improved by using contrast enhancement with gadolinium diethylenetriaminepentaacetic acid.The Spondyloarthritis Research Consortium of Canada MRI index is a feasible, reproducible, and responsive index for measuring spinal inflammation in AS.

Objective The role of innate immunity in Chlamydia-induced arthritis has not been defined. The purpose of this study was to examine the role of neutrophils in experimental arthritis in mice with targeted elimination of the small GTPases Rac1 and Rac2, as well as the role of Toll-like receptors (TLRs) in this model. Methods Arthritis was induced by intraarticular inoculation of synoviocyte-packaged Chlamydia trachomatis. The degree of arthritis was assessed according to joint swelling and pathology scores. The persistence of Chlamydia in joints was assessed by immunoassay. The expression of TLR-2 and TLR-4 in neutrophils was detected by semiquantitative reverse transcription–polymerase chain reaction. Results In the acute phase, wild-type mice developed more severe arthritis than did Rac-deficient mice, with abundant infiltration of neutrophils into the joint. In the chronic phase, the Rac-deficient mice developed more severe arthritis and demonstrated defective clearance of the pathogen from the joint. In vitro stimulation of neutrophils with Chlamydia up-regulated the expression of TLR-4, but not TLR-2, in wild-type mice. However, neutrophils from Rac-deficient mice did not show this up-regulation of TLR-4. Sustained TLR-4 expression in neutrophils was found to be dependent on the expression of Rac. Mice genetically deficient in TLR-4 demonstrated more severe arthritis than did the controls. Thus, Rac expression plays a profound role in infection-triggered arthritis and demonstrates a bimodal influence on the disease process, exacerbating acute joint inflammation but controlling chronic arthritis. Rac deficiency was associated with diminished TLR-4 expression, impaired host clearance of the pathogen, and more severe chronic arthritis. Conclusion In infection-triggered arthritis, innate immunity plays a critical role. Effective host clearance of an arthritogenic pathogen depends on intact expression of Rac and appropriate expression of TLR-4 by neutrophils.

Objective Ankylosing spondylitis (AS) is a progressive disease in which chronic inflammation can lead to extensive new bone formation throughout the spine. At present, few measures of the activity or extent of the disease are available. In this study, we sought to determine whether markers of cartilage synthesis and degradation could provide such quantitative measures. Methods Serum samples from 23 patients receiving infliximab treatment for AS were obtained at baseline and at weeks 2, 6, 14, and 22. Patients were stratified with respect to joint involvement and baseline levels of inflammatory markers, and responders were defined according to the Assessments in Ankylosing Spondylitis 20% criteria. Serial measurements of interferon-γ, tumor necrosis factor α, transforming growth factor β (TGFβ), interleukin-10 (IL-10), and IL-1 were done at each time point. The following biomarkers were measured by enzyme-linked immunosorbent assay: the proteoglycan aggrecan 846 epitope, a marker of cartilage turnover; C-propeptide of type II collagen (CPII), a biosynthesis marker; and the Col2-3/4long mono (C2C) and Col2-3/4short (C1–2C) neoepitopes, reflecting collagen cleavage of type II collagen and type I/type II collagen, respectively. Results At baseline, patients with AS demonstrated significant elevations in serum levels of CPII, the 846 epitope, and the CPII-to-C2C (CPII:C2C) ratio (but not C2C or C1–2C) compared with normal controls. Of the biomarkers examined, only CPII:C2C showed a correlation with the C-reactive protein (CRP) level. Among the biomarker–cytokine relationships, TGFβ demonstrated a trend toward a positive correlation with the 846 epitope. Conclusion In AS, elevated serum levels of CPII and the 846 epitope may be related to biosynthetic turnover of hyaline cartilage and the intervertebral discs but may also reflect progressive bone formation as a result of endochondral ossification. The correlation of the CPII:C2C ratio with CRP suggests that the CPII:C2C ratio might prove to be a useful marker of disease activity in AS.

Objective To compare functional outcome of patients with juvenile-onset ankylosing spondylitis (JoAS; defined as AS with symptom onset before 16 years of age) with that of patients with adult-onset AS (AoAS) and to identify variables associated with a poor functional outcome of JoAS. Methods A cross-sectional study was performed of 326 JoAS patients who participated in a postal survey conducted by the Spondylitis Association of America. This cohort was compared with 2,021 AoAS patients who participated in the same survey. Simple and multiple logistic regression analyses were performed to identify differences with respect to clinical features, demographic features, and functional outcome (defined by the Bath Ankylosing Spondylitis Functional Index [BASFI]) between the 2 groups. A validation cohort of 255 AS patients was also surveyed. Results The mean ± SD BASFI score (controlled for disease duration) for JoAS was 51.3 ± 1.5 compared with 46.4 ± 0.6 for AoAS (P < 0.0001). Multiple logistic regression identified only age (P < 0.0001) and income status (P < 0.0001) as factors associated with functional impairment. Conclusion It appears that JoAS is a progressive disease and is associated with significant delay in diagnosis and worse functional outcome compared with AoAS. Furthermore, women do worse than men with JoAS. This would argue for the importance of early diagnosis and treatment of AS, particularly in the subgroup of patients with JoAS.

Objectives To define what expert clinicians consider a dramatic response in ankylosing spondylitis (AS) patients treated with biologic therapies based on patient and physician assessments of global disease activity. To compare this expert clinician-derived criteria to the Ankylosing Spondylitis Assessment Study (ASAS) Group criteria for improvement. Methods Forty consecutive AS patients were treated in a 1-year open-label protocol with infliximab. Response to treatment at week 52 was defined using ASAS response criteria. For the purpose of this exercise, improvement using ASAS criteria was defined by consensus among experts as good with 50% improvement from baseline (ASAS50) and dramatic with 70% improvement from baseline (ASAS70). Experts established separate criteria for improvement in disease activity as good or dramatic based on patient and physician global assessment of disease activity. Results Twelve of 40 patients met the ASAS70 criteria, however, only 8 met the expert definition of a dramatic improvement based on physician global scores and 5 met the expert definition of a dramatic improvement based on patient global assessment of disease activity. Agreement was poor between ASAS50 or ASAS70 and expert definition of improvement based on physician global scores (κ < 0.3), but agreement was moderate to good between ASAS50 or ASAS70 and expert definition of improvement based on patient global scores, (κ = 0.6–0.7). Conclusions Differential response experienced by AS patients treated with infliximab was adequately captured by the ASAS composite improvement criteria. Overall, this study demonstrates the validity of the ASAS criteria for the detection of improvement in AS patients treated with biologics. However, the patient global assessment of disease activity may be sufficient to monitor changes in disease activity in these patients.

Objective To define the genetic basis of susceptibility to ankylosing spondylitis (AS), especially non–major histocompatibility complex (MHC) genes. Methods The study group comprised 244 affected sibling pairs from 180 pedigrees of primarily European ancestry. Sibling pairs were concordant for AS by the modified New York criteria and had available sacroiliac radiographs. The subjects were genotyped for 400 markers in ABI PRISM linkage map MD-10 and for 17 additional markers on chromosomes 6p, 6q, and 11q (including HLA–B, DRB1, DQA1, DQB1, and DPB1 alleles). Two-point and multipoint nonparametric linkage (NPL) analyses were conducted using the NPL statistic and 1-parameter allele-sharing model logarithm of odds (LOD) scores, calculated using the Allele-Sharing Model (ASM) computer program. Results Linkage of the MHC region was supported by both 2-point and multipoint analyses, with the strongest peak (45.90 cM) in the MHC at the HLA–DRB1 locus (NPL score 8.720, ASM LOD score 20.49; P = 6.8 × 10−20 for 2-point analysis). A second region was found to have positive linkage at the q arm of chromosome 6 (D6S441) in 2-point analysis; this was supported by a 39.13-cM region (135.58–174.71 cM) in multipoint analysis, with the smallest P value (4.2 × 10−3) at 166.39 cM. A third region was found on chromosome 11q, with the strongest evidence for linkage for D11S4094 at 123 cM (NPL score 2.235, ASM LOD score 1.939) and, on transmission disequilibrium test analysis, D11S4090 at 105.74 cM (P = 6.2 × 10−5). Linkage in this area was supported by multipoint analysis, spanning 22.19 cM continuously from 101.68 cM to 123.87 cM, with the strongest peak at 112.33 cM (P = 0.014); this was confirmed by subsequent fine mapping studies. Conclusion Thus, this genome-wide scan implicates, in addition to the MHC, regions outside the MHC in AS susceptibility, especially on chromosomes 6q and 11q.