bluuebunny/crossref_metadata_2025 huggingface dataset:
New Centromere Autoantigens Identified in Systemic Sclerosis Using Centromere Protein Microarrays
Authors: Song Guang , Hu Chaojun , Zhu Heng , Wang Li , Zhang Fengchun , Li Yongzhe , Wu Lin
Published: February 2013

Objective.

To identify novel centromere protein (CENP) targets of anticentromere antibodies (ACA), and to investigate their association with clinical manifestations of systemic sclerosis (SSc).

Methods.

A CENP-focused protein microarray was fabricated by spotting 14 purified CENP. These microarrays were individually incubated with 35 ACA-positive SSc sera and 20 ACA-negative healthy control samples. Newly identified CENP autoantigens with high sensitivities were selected for validation and characterization.

Results.

Statistical analysis revealed 11 CENP are potential target antigens of ACA in patients with SSc. Of them, 5 [CENP-P, CENP-Q, CENP-M (isoform I), CENP-J, and CENP-T] are novel, among which CENP-P and CENP-Q showed high sensitivities in ACA-positive SSc sera of 34.3% and 28.6%, respectively. Subsequently, 186 SSc sera (35 ACA-positives and 151 negatives), 69 ACA-positive sera from other various autoimmune diseases (primary Sjögren syndrome, systemic lupus erythematosus, rheumatoid arthritis, and primary biliary cirrhosis), and 31 healthy sera were assayed for the presence of anti-CENP-P and -Q autoantibodies by ELISA followed by Western blotting analysis. CENP-P and -Q autoantibodies were detected in ACA-positive sera of various disease groups; among them, SSc showed the highest detection rate. Anti-CENP-P was also found in 9 of the 151 ACA-negative sera. Analyses of the correlation with clinical information showed anti-CENP-P-positive patients had higher levels of IgG, IgA, and erythrocyte sedimentation rate among the ACA-positive cohort and were more vulnerable to renal disease in the ACA-negative patients with SSc. Regardless of ACA status, anti-CENP-P or Q-negative patients seem to be predominantly affected by interstitial lung disease.

Conclusion.

CENP-P and CENP-Q were identified as novel ACA autoantigens by CENP microarray assays followed by validation of ELISA and Western blotting. Both of them have prognostic utility for interstitial lung disease. CENP-P was associated with renal disease in an ACA-negative cohort.
Low Socioeconomic Status (Measured by Education) and Outcomes in Systemic Sclerosis: Data from the Canadian Scleroderma Research Group
Authors: Mansour Samah , Bonner Ashley , Muangchan Chayawee , Hudson Marie , Baron Murray , Pope Janet E. ,   The Canadian Scleroderma Research Group
Published: February 2013

Objective.

In systemic lupus erythematosus, socioeconomic status (SES) affects outcomes. SES can modify outcomes by altering timing of access to care and adherence. It is unknown whether SES affects systemic sclerosis (SSc) outcomes. Disease can affect income and cause work disability, thus education (completed long before SSc onset) may be a proxy for SES.

Methods.

The Canadian Scleroderma Research Group collects annual data on patients with SSc. Baseline data were used from a prevalent cohort. Education was stratified by whether participants completed high school. Regression models assessed effects of education on organ complications and survival.

Results.

In our study, 1145 patients with SSc had 11.0 ± 9.5 years' disease duration; 86% were women, with a mean age of 55.4 ± 12.1 years. About one-quarter did not complete high school; this was more common in older patients (p < 0.0001), men (p = 0.017), those with lower income (p < 0.0001), the unemployed (p < 0.054), smokers (p < 0.001), where DLCO was < 70% predicted (p = 0.009), in those with arthritis (p = 0.047), higher Health Assessment Questionnaire-Disability Index (p = 0.017), elevated erythrocyte sedimentation rate (p = 0.019), median C-reactive protein (p = 0.002), proteinuria (p = 0.016), steroid use ever (p = 0.039), and those more likely to have died in followup (12.7% vs 8.0%; p = 0.024). However, adjusting for confounders, there was no effect of education on mortality; whereas mortality was related to age, diffuse cutaneous SSc (dcSSc) subset, elevated pulmonary arterial (PA) pressure on echocardiography, low forced vital capacity expressed as percentage of predicted, and proteinuria (similar in the dcSSc subset and in limited cutaneous SSc), mortality was increased in older patients, those with elevated PA pressure, and those with low DLCO.

Conclusion.

Completing less education than high school was not associated with a worse prognosis in SSc after adjustment for confounding characteristics.
Disease Course, Outcome, and Predictors of Outcome in a Population-based Juvenile Chronic Arthritis Cohort Followed for 17 Years
Authors: Bertilsson Lennart , Andersson-Gäre Boel , Fasth Anders , Petersson Ingemar F. , Forsblad-D’elia Helena
Published: February 2013

Objective.

To investigate disease course, outcome, and predictors of outcome in an unselected population-based cohort of individuals diagnosed with juvenile chronic arthritis (JCA) followed for 17 years.

Methods.

The cohort consisted of 132 incidence JCA cases identified 1984–1986 according to EULAR criteria. At 5-year followup, 129 individuals underwent joint assessment, laboratory measurements, radiographic examination, and medication and functional assessment. At 17-year followup, 86 were examined with joint assessment, laboratory measurements, medication assessment, Health Assessment Questionnaire (HAQ), Keitel functional test (KFT), and Medical Outcomes Study Short Form-36 (SF-36).

Results.

At 17-year followup, 40% were in remission, 44% changed subgroups, median HAQ score was 0.0 (range 0.0–1.5), and median KFT was 100 (range 54–100). SF-36 scores were significantly lower compared to a reference group. Thirty-nine percent of those in remission at 5-year followup were not in remission at 17-year followup. In multivariate analyses of variables from the 17-year followup: remission was predicted by remission at 5-year followup (OR 4.8); HAQ > 0 by rheumatoid factor (RF)-positivity at 5-year followup (OR 3.6); KFT < 100 by nonremission (OR 11.3); and RF-positivity (OR 5.6) at 5-year followup; and the SF-36 physical component summary score above average of the reference group by remission at 5-year followup (OR 5.8).

Conclusion.

This longterm study of 86 individuals with JCA showed large variability of disease courses and of impaired health-related quality of life. Sixty percent were not in remission at 17-year followup. Longterm outcome was best predicted by and associated with characteristics at 5-year followup rather than those at onset.
Quantitative and Semiquantitative Bone Erosion Assessment on High-resolution Peripheral Quantitative Computed Tomography in Rheumatoid Arthritis
Authors: Srikhum Waraporn , Virayavanich Warapat , Burghardt Andrew J. , Yu Andrew , Link Thomas M. , Imboden John B. , Li Xiaojuan
Published: February 2013

Objective.

To develop novel quantitative and semiquantitative bone erosion measures at metacarpophalangeal (MCP) and wrist joints in patients with rheumatoid arthritis (RA) using high-resolution peripheral quantitative computed tomography (HR-pQCT), and to correlate these measurements with disease duration and bone marrow edema (BME) patterns derived from magnetic resonance imaging (MRI).

Methods.

Sixteen patients with RA and 7 healthy subjects underwent hand and wrist HR-pQCT and 3-Tesla MRI. Bone erosions of the MCP2, MCP3, and distal radius were evaluated by measuring maximal erosion dimension on axial slices, which is a simple and fast measurement, and then were graded (grades 0–3) based on the maximal dimension. Correlation coefficients were calculated between (1) sum maximal dimensions, highest grades, and sum grades of bone erosions; (2) erosion measures and the clinical evaluation; (3) erosion measures and BME volume in distal radius.

Results.

The inter- and intrareader agreements of maximal erosion dimensions were excellent (intraclass correlation coefficients 0.89, 0.99, and root mean square error 9.4%, 4.7%, respectively). Highest grades and sum grades were significantly correlated to sum maximal dimensions of all erosions. Number of erosions, sum maximal erosion dimensions, highest grades, and sum grades correlated significantly with disease duration. Number of erosions, sum maximal dimensions, and erosion grading of the distal radius correlated significantly with BME volume.

Conclusion.

HR-pQCT provides a sensitive method with high reader agreement in assessment of structural bone damage in RA. The good correlation of erosion measures with disease duration as well as BME volume suggests that they could become feasible measures of erosions in RA.
Coronary Artery Involvement in Takayasu Arteritis in 45 Chinese Patients
Authors: Sun Teng , Zhang Huimin , Ma Wenjun , Yang Lirui , Jiang Xiongjing , Wu Haiying , Hui Rutai , Zheng Deyu
Published: February 2013

Objective.

We investigated the clinical characteristics, potential difficulties in diagnosis, and therapy for coronary artery involvement in patients with Takayasu arteritis (TA).

Methods.

Of 587 consecutive patients hospitalized with TA from 1998 to 2011, those found to have > 50% reduction of diameter of coronary artery by angiography were recruited. We defined the first finding of coronary involvement as baseline. The clinical features, laboratory data, coronary angiographic findings, treatment, and followup outcomes were summarized retrospectively.

Results.

A total of 45 (7.7%, 45/587) patients with coronary involvement were identified, including 40 with typical angina, and 15 with myocardial infarction. Some had complications such as peripheral vascular murmur, pulseless disease, and hypertension. The average age at onset of cardiac symptoms was 40.3 ± 12.8 years (range 15–64) and 36 were female. At admission, erythrocyte sedimentation rates were elevated in 27 patients (60%) and C-reactive protein levels in 23 (51.1%). The ostia (37.4%) and proximal segments (33.3%) of coronary artery were most frequently involved. The treatment was stent implantation in 10 patients and coronary artery bypass grafting in 13. One female patient suffered sudden death during the angiography. During a mean followup of 5.8 ± 4.5 years, 8 patients died.

Conclusion.

Coronary artery involvement in TA that leads to cardiovascular events, especially to cardiovascular death, is not rare. Early diagnosis and therapy should be emphasized.
Longterm Outcomes and Treatment After Myocardial Infarction in Patients with Rheumatoid Arthritis
Authors: McCoy Sara S. , Crowson Cynthia S. , Maradit-Kremers Hilal , Therneau Terry M. , Roger Veronique L. , Matteson Eric L. , Gabriel Sherine E.
Published: February 2013

Objective.

To investigate the risk profiles, treatment, and outcomes of patients with rheumatoid arthritis (RA) with myocardial infarction (MI) and matched MI patients without RA.

Methods.

We used a population-based cohort of Olmsted County, Minnesota, residents with MI from the period 1979–2009. We identified 77 patients who fulfilled the American College of Rheumatology 1987 criteria for RA and 154 MI patients without RA matched for age, sex, and calendar year. Data collection from medical records included RA and MI characteristics, antirheumatic and cardioprotective medications, reperfusion therapy, and outcomes (mortality, heart failure, and recurrent ischemia).

Results.

The mean age at MI was 72.4 years and 55% of patients were female in both cohorts. Cardiovascular risk factor profiles, MI characteristics, and treatment with reperfusion therapy or cardioprotective medications were similar in MI patients with and those without RA. Patients with RA experienced poorer longterm outcomes compared to patients without RA — for mortality: hazard ratio (HR) 1.47; 95% CI 1.04, 2.08; and for recurrent ischemia: HR 1.51; 95% CI 1.04, 2.18.

Conclusion.

MI patients with RA received similar treatment with reperfusion therapy and cardioprotective medications and had similar short-term outcomes compared to patients without RA. Patients with RA had poorer longterm outcomes. Despite similar treatment, MI patients with RA had worse longterm outcomes than MI patients without RA.
Radiological Peripheral Involvement in a Cohort of Patients with Polyarticular Juvenile Idiopathic Arthritis at Adulthood
Authors: Elhai Muriel , Bazeli Ramin , Freire Véronique , Feydy Antoine , Drapé Jean-Luc , Quartier Pierre , Kahan André , Deslandre Chantal , Wipff Julien
Published: February 2013

Objective.

Radiographic damage was recently identified as a feature of poor prognosis in polyarticular juvenile idiopathic arthritis (pJIA). However, most radiographic studies did not differentiate pJIA from other subtypes of JIA and little is known about pJIA persisting into adulthood. We describe radiological peripheral involvement in young adults with pJIA compared to patients with rheumatoid arthritis (RA).

Methods.

All consecutive patients with pJIA followed in a transition program were included. Age, sex, disease duration, and medical or surgical treatment information was collected. Laboratory tests and standard radiographs of the hands and wrists, feet, and hips were analyzed by 2 independent radiologists blinded to the diagnosis. One RA control group (age < 55 yrs), matched for sex and disease duration, was recruited.

Results.

Forty-three patients with pJIA and 59 with RA were included. Radiographs showed hand lesions in 79% of pJIA and 86% of patients with RA, feet lesions in 74% of pJIA and 80% of patients with RA, and hip damage in 35% of pJIA and 17% of patients with RA (p = nonsignificant). Specific to the juvenile forms were lower frequency of proximal interphalangeal joint involvement (51% vs 76%; p = 0.03) and higher risk of bilateral hip damage (86% vs 25%; p < 0.01) than in adult RA.

Conclusion.

Structural peripheral damage is as common and as severe in young adults with pJIA as in adults with RA. The main specific feature of pJIA seems to be a high risk of bilateral hip damage. This requires a particular monitoring of pJIA patients with unilateral hip involvement to detect bilateralization.
Cyclosporine in Anti-Jo1-positive Patients with Corticosteroid-refractory Interstitial Lung Disease
Authors: Cavagna Lorenzo , Caporali Roberto , Abdì-Alì Lul , Dore Roberto , Meloni Federica , Montecucco Carlomaurizio
Published: February 2013

Objective.

To describe the longterm effectiveness and safety of cyclosporine (CYC) in patients with anti-Jo1-positive antisynthetase syndrome with corticosteroid-refractory interstitial lung disease (ILD).

Methods.

All patients with anti-Jo1 antisynthetase syndrome referred to our division between June 1991 and February 2010 were retrospectively evaluated for ILD. ILD was assessed using pulmonary function tests (PFT) and/or high-resolution computed tomography (HRCT). Kazerooni score was used to evaluate the HRCT extent of ILD. Prednisone was the first-line treatment in all cases (1 mg/kg/day orally, then tapering). Patients with corticosteroid-refractory or relapsing ILD were then included in this retrospective study. All patients started CYC (3 mg/kg/day) without increasing prednisone dosage. Both PFT and chest HRCT were regularly reassessed during followup.

Results.

Over the period of study we evaluated 18 patients with antisynthetase syndrome; 17 had ILD (13 women; median age at ILD onset 57 yrs); all patients failed prednisone within 12 months of ILD onset and subsequently started CYC. The median followup on CYC was 96 months [interquartile range (IQR) 57–120 mo]. Upon starting CYC, median forced vital capacity (FVC) was 60% (IQR 56%–70%), median DLCO 60% (IQR 50%–62.75%), and median Kazerooni score 16 (IQR 7–18). After 1 year of CYC, FVC (p = 0.0006), DLCO (p = 0.0010), and total Kazerooni score (p = 0.0002) improved and prednisone was tapered (median reduced from 25 mg/day to 2.5 mg/day; p < 0.0001). The results were substantially maintained including at last available followup. CYC side effects were hypertension (5 patients) and creatinine increase (6 patients). CYC was reduced in 3 cases and withdrawn in 4. Three out of 4 patients who interrupted CYC experienced ILD relapse; 2 patients recommenced low-dose CYC with subsequent ILD control. One patient refused re-treatment and subsequently died.

Conclusion.

CYC is effective and substantially safe in patients with anti-Jo1 antisynthetase syndrome with corticosteroid-refractory ILD. CYC withdrawal may be associated with ILD relapse, and low-dose CYC was effective in ILD control.
A Delphi Exercise to Identify Characteristic Features of Gout — Opinions from Patients and Physicians, the First Stage in Developing New Classification Criteria
Authors: Prowse Rebecca L. , Dalbeth Nicola , Kavanaugh Arthur , Adebajo Adewale O. , Gaffo Angelo L. , Terkeltaub Robert , Mandell Brian F. , Suryana Bagus P.P. , Goldenstein-Schainberg Claudia , Diaz-Torne Cèsar , Khanna Dinesh , Lioté Frederic , Mccarthy Geraldine , Kerr Gail S. , Yamanaka Hisashi , Janssens Hein , Baraf Herbert F. , Chen Jiunn-Horng , Vazquez-Mellado Janitzia , Harrold Leslie R. , Stamp Lisa K. , Van De Laar Mart A. , Janssen Matthijs , Doherty Michael , Boers Maarten , Edwards N. Lawrence , Gow Peter , Chapman Peter , Khanna Puja , Helliwell Philip S. , Grainger Rebecca , Schumacher H. Ralph , Neogi Tuhina , Jansen Tim L. , Louthrenoo Worawit , Sivera Francisca , Taylor William J.
Published: February 2013

Objective.

To identify a comprehensive list of features that might discriminate between gout and other rheumatic musculoskeletal conditions, to be used subsequently for a case-control study to develop and test new classification criteria for gout.

Methods.

Two Delphi exercises were conducted using Web-based questionnaires: one with physicians from several countries who had an interest in gout and one with patients from New Zealand who had gout. Physicians rated a list of potentially discriminating features that were identified by literature review and expert opinion, and patients rated a list of features that they generated themselves. Agreement was defined by the RAND/UCLA disagreement index.

Results.

Forty-four experienced physicians and 9 patients responded to all iterations. For physicians, 71 items were identified by literature review and 15 more were suggested by physicians. The physician survey showed agreement for 26 discriminatory features and 15 as not discriminatory. The patients identified 46 features of gout, for which there was agreement on 25 items as being discriminatory and 7 items as not discriminatory.

Conclusion.

Patients and physicians agreed upon several key features of gout. Physicians emphasized objective findings, imaging, and patterns of symptoms, whereas patients emphasized severity, functional results, and idiographic perception of symptoms.
Influence of Environmental Factors on Disease Activity in Spondyloarthritis: A Prospective Cohort Study
Authors: Zeboulon-Ktorza Nadine , Boelle Pierre Yves , Nahal Roula Said , D'agostino Maria Antonietta , Vibert Jean François , Turbelin Clément , Madrakian Homa , Durand Emmanuelle , Launay Odile , Mahr Alfred , Flahault Antoine , Breban Maxime , Hanslik Thomas
Published: February 2013

Objective.

Spondyloarthritis (SpA) is a complex inflammatory disorder. We investigated the influence of environmental factors on SpA disease activity.

Methods.

A prospective cohort of adults with SpA was followed for 3 years. Patients logged on to a secured Website every 3 months to complete a questionnaire. They reported whether they had been exposed to environmental factors such as stressful or traumatic life events, infections, or vaccinations. Outcome variables included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), and pain and patient global assessment (PGA) on visual numerical scales (each rated 0–10). Analyses were performed using a generalized estimating equation for repeated measures, adjusted for the outcome variable collected by the previous questionnaire.

Results.

In total, 272 patients were included in the analysis, completing the questionnaire on 2240 occasions. The average time (mean ± SD) between 2 connections to the Website was 4.0 ± 2.0 months. Occurrence of life events was followed by an increase of 0.5 (95% CI 0.4–0.7) in the BASDAI, 0.5 (95% CI 0.3–0.6) in the BASFI, 0.7 (95% CI 0.5–0.9) in the PGA, and 0.8 (95% CI 0.6–1.0) for pain (p < 0.0001 for all variations). A moderately statistically significant link was found between vaccination and an elevation of the BASDAI of 0.3 (95% CI 0.0–0.5; p = 0.032). No influence of other factors was detected.

Conclusion.

This prospective study in a dedicated SpA cohort shows for the first time a link between stressful events and disease activity. Although this link was statistically highly significant, its clinical meaning remains to be determined because the average magnitude of variation of the different variables studied was rather mild.
Gastric Antral Vascular Ectasia and Its Clinical Correlates in Patients with Early Diffuse Systemic Sclerosis in the SCOT Trial
Authors: Hung Emily W. , Mayes Maureen D. , Sharif Roozbeh , Assassi Shervin , Machicao Victor I. , Hosing Chitra , St. Clair E. William , Furst Daniel E. , Khanna Dinesh , Forman Stephen , Mineishi Shin , Phillips Kristine , Seibold James R. , Bredeson Christopher , Csuka Mary Ellen , Nash Richard A. , Wener Mark H. , Simms Robert , Ballen Karen , Leclercq Sharon , Storek Jan , Goldmuntz Ellen , Welch Beverly , Keyes-Elstein Lynette , Castina Sharon , Crofford Leslie J. , Mcsweeney Peter , Sullivan Keith M.
Published: February 2013

Objective.

To describe the prevalence and clinical correlates of endoscopic gastric antral vascular ectasia (GAVE; “watermelon stomach”) in early diffuse systemic sclerosis (SSc).

Methods.

Subjects with early, diffuse SSc and evidence of specific internal organ involvement were considered for the Scleroderma: Cyclophosphamide Or Transplant (SCOT) trial. In the screening procedures, all patients underwent upper gastrointestinal endoscopy. Patients were then categorized into those with or without endoscopic evidence of GAVE. Demographic data, clinical disease characteristics, and autoantibody data were compared using Pearson chi-square or Student t tests.

Results.

Twenty-three of 103 (22.3%) individuals were found to have GAVE on endoscopy. Although not statistically significant, anti-topoisomerase I (anti-Scl70) was detected less frequently among those with GAVE (18.8% vs 44.7%; p = 0.071). Similarly, anti-RNP antibodies (anti-U1 RNP) showed a trend to a negative association with GAVE (0 vs 18.4%; p = 0.066). There was no association between anti-RNA polymerase III and GAVE. Patients with GAVE had significantly more erythema or vascular ectasias in other parts of the stomach (26.1% vs 5.0%; p = 0.003).

Conclusion.

Endoscopic GAVE was present on screening in almost one-fourth of these highly selected patients with early and severe diffuse SSc. While anti-Scl70 and anti-U1 RNP trended toward a negative association with GAVE, there was no correlation between anti-RNA Pol III and GAVE. Patients with GAVE had a higher frequency of other gastric vascular ectasias outside the antrum, suggesting that GAVE may represent part of the spectrum of the vasculopathy in SSc.
Pivotal Role of the ISO 14001 Standard in the Carbon Economy
Authors: Pradhan Alok
Published: February 2013

The ISO 14000 and ISO 9000 standards have a positive impact on achieving sustainable and efficient business. The ISO 14001, in particular, is credited with a crucial role of assisting businesses with managing their environmental credentials which are vital in the upcoming carbon economy. This paper explores the significance of ISO 14001 and expands on the possibilities of the use of this standard in a creative way by organizations. Furthermore, with regards to ISO 14001, adjustments could be made to improve its effectiveness in implementing an Environmental Management System (EMS). The areas of this standard that could be upgraded are also outlined, including measuring compliance, specified, strict environmental targets for business, and a stronger sustainability component.
Reduced CD18 Levels Drive Regulatory T Cell Conversion into Th17 Cells in the CD18hypo PL/J Mouse Model of Psoriasis
Authors: Singh Kamayani , Gatzka Martina , Peters Thorsten , Borkner Lisa , Hainzl Adelheid , Wang Honglin , Sindrilaru Anca , Scharffetter-Kochanek Karin
Published: February 2013

Defective development and function of CD4+CD25high+Foxp3+ regulatory T cells (Tregs) contribute to the pathogenesis of psoriasis and other autoimmune diseases. Little is known about the influence of adhesions molecules on the differentiation of Foxp3+ Tregs into proinflammatory Th17 cells occurring in lesional skin and blood of psoriasis patients. In the CD18hypo PL/J mouse model of psoriasis, reduced expression of CD18/β2 integrin to 2–16% of wild-type levels is associated with progressive loss of Tregs, impaired cell–cell contact between Tregs and dendritic cells (DCs), as well as Treg dysfunction as reported earlier. In the present investigation, Tregs derived from CD18hypo PL/J mice were analyzed for their propensity to differentiate into IL-17–producing Th17 cells in vivo and in in vitro Treg–DC cocultures. Adoptively transferred CD18hypo PL/J Tregs were more inclined toward conversion into IL-17–producing Th17 cells in vivo in an inflammatory as well as noninflammatory environment compared with CD18wt PL/J Tregs. Addition of neutralizing Ab against CD18 to Treg–DC cocultures in vitro promoted conversion of CD18wt PL/J Tregs to Th17 cells in a dose-dependent manner similar to conversion rates of CD18hypo PL/J Tregs. Reduced thymic output of naturally occurring Tregs and peripheral conversion of Tregs into Th17 cells therefore both contribute to the loss of Tregs and the psoriasiform dermatitis observed in CD18hypo PL/J mice. Our data overall indicate that CD18 expression levels impact Treg development as well as Treg plasticity and that differentiation of Tregs into IL-17–producing Th17 cells is distinctly facilitated by a subtotal deficiency of CD18.
Comparative Assessment of Clinically Utilized CD20-Directed Antibodies in Chronic Lymphocytic Leukemia Cells Reveals Divergent NK Cell, Monocyte, and Macrophage Properties
Authors: Rafiq Sarwish , Butchar Jonathan P. , Cheney Carolyn , Mo Xiaokui , Trotta Rossana , Caligiuri Michael , Jarjoura David , Tridandapani Susheela , Muthusamy Natarajan , Byrd John C.
Published: February 2013

CD20 is a widely validated, B cell–specific target for therapy in B cell malignancies. Rituximab is an anti-CD20 Ab that prolongs survival of chronic lymphocytic leukemia (CLL) patients when combined with chemotherapy. Ofatumumab and GA101 (obinutuzumab) are CD20-directed Abs currently being developed as alternative agents to rituximab in CLL based upon different properties of enhanced direct cell death, NK cell-mediated Ab-dependent cellular cytotoxicity, or complement-dependent cytotoxicity. Despite widespread study, ofatumumab and GA101 have not been compared with each other, nor studied for their interactions with monocytes and macrophages which are critical for the efficacy of anti-CD20 Abs in murine models. In CLL cells, we show that direct cell death and complement-dependent cytotoxicity are greatest with GA101 and ofatumumab, respectively. GA101 promotes enhanced NK cell activation and Ab-dependent cellular cytotoxicity at high Ab concentrations. Ofatumumab elicits superior Ab-dependent cellular phagocytosis with monocyte-derived macrophages. GA101 demonstrated reduced activation of monocytes with diminished pERK, TNF-α release, and FcγRIIa recruitment to lipid rafts. These data demonstrate that GA101 and ofatumumab are both superior to rituximab against CLL cells via different mechanisms of potential tumor elimination. These findings bear relevance to potential combination strategies with each of these anti-CD20 Abs in the treatment of CLL.
The NF-κB Inhibitory Proteins IκBα and IκBβ Mediate Disparate Responses to Inflammation in Fetal Pulmonary Endothelial Cells
Authors: Tang Jen-Ruey , Michaelis Katherine A. , Nozik-Grayck Eva , Seedorf Gregory J. , Hartman-Filson Marlena , Abman Steven H. , Wright Clyde J.
Published: February 2013

Exposure to intrauterine inflammation impairs lung growth but paradoxically protects the neonatal pulmonary vasculature from hyperoxic injury. The mechanisms mediating these contradictory effects are unknown. The objective is to identify the role of NF-κB in mediating cytoprotective and proinflammatory responses to inflammation in the fetal pulmonary endothelium. In newborn rats exposed to intra-amniotic LPS, we found increased expression of the NF-κB target gene manganese superoxide dismutase (MnSOD) in the pulmonary endothelium. Supporting these in vivo findings, LPS induced NF-κB activation and MnSOD expression in isolated fetal pulmonary arterial endothelial cells. In addition, LPS exposure caused apoptosis and suppressed cellular growth and induced P-selectin expression. LPS-induced NF-κB activation that proceeded through specific isoforms of the inhibitory protein IκB mediated these diverse responses; NF-κB signaling through IκBα degradation resulted in MnSOD upregulation and preserved cell growth, whereas NF-κB signaling through IκBβ degradation mediated apoptosis and P-selectin expression. These findings suggest that selective inhibition of NF-κB activation that results from IκBβ degradation preserves the enhanced antioxidant defense and protects the developing pulmonary vascular endothelium from ongoing inflammatory injury.
Amphisomal Route of MHC Class I Cross-Presentation in Bacteria-Infected Dendritic Cells
Authors: Fiegl Dorothee , Kägebein Danny , Liebler-Tenorio Elisabeth M. , Weisser Tanja , Sens Mareen , Gutjahr Melanie , Knittler Michael R.
Published: February 2013

Dendritic cells (DCs) are among the first professional APCs encountered by the obligate intracellular bacterium Chlamydia during infection. Using an established mouse bone marrow–derived DC line, we show that DCs control chlamydial infection in multiple small inclusions characterized by restricted bacterial growth, impaired cytosolic export of the virulence factor chlamydial protease–like activity factor, and interaction with guanylate-binding protein 1, a host cell factor involved in the initiation of autophagy. During maturation of infected DCs, chlamydial inclusions disintegrate, likely because they lack chlamydial protease–like activity factor–mediated protection. Released cytosolic Chlamydia are taken up by autophagosomes and colocalize with cathepsin-positive amphisomal vacuoles, to which peptide transporter TAP and upregulated MHC class I (MHC I) are recruited. Chlamydial Ags are subsequently generated through routes involving preprocessing in amphisomes via cathepsins and entry into the cytosol for further processing by the proteasome. Finally, bacterial peptides are reimported into the endosomal pathway for loading onto recycling MHC I. Thus, we unravel a novel pathway of MHC I–mediated cross-presentation that is initiated with a host cellular attack physically disrupting the parasitophorous vacuole, involves autophagy to collect cytosolic organisms into autophagosomes, and concludes with complex multistep antigenic processing in separate cellular compartments.
Postthymic Expansion in Human CD4 Naive T Cells Defined by Expression of Functional High-Affinity IL-2 Receptors
Authors: Pekalski Marcin L. , Ferreira Ricardo C. , Coulson Richard M. R. , Cutler Antony J. , Guo Hui , Smyth Deborah J. , Downes Kate , Dendrou Calliope A. , Castro Dopico Xaquin , Esposito Laura , Coleman Gillian , Stevens Helen E. , Nutland Sarah , Walker Neil M. , Guy Catherine , Dunger David B. , Wallace Chris , Tree Timothy I. M. , Todd John A. , Wicker Linda S.
Published: February 2013

As the thymus involutes with age, the maintenance of peripheral naive T cells in humans becomes strongly dependent on peripheral cell division. However, mechanisms that orchestrate homeostatic division remain unclear. In this study we present evidence that the frequency of naive CD4 T cells that express CD25 (IL-2 receptor α-chain) increases with age on subsets of both CD31+ and CD31− naive CD4 T cells. Analyses of TCR excision circles from sorted subsets indicate that CD25+ naive CD4 T cells have undergone more rounds of homeostatic proliferation than their CD25− counterparts in both the CD31+ and CD31− subsets, indicating that CD25 is a marker of naive CD4 T cells that have preferentially responded to survival signals from self-Ags or cytokines. CD25 expression on CD25− naive CD4 T cells can be induced by IL-7 in vitro in the absence of TCR activation. Although CD25+ naive T cells respond to lower concentrations of IL-2 as compared with their CD25− counterparts, IL-2 responsiveness is further increased in CD31− naive T cells by their expression of the signaling IL-2 receptor β-chain CD122, forming with common γ-chain functional high-affinity IL-2 receptors. CD25 plays a role during activation: CD25+ naive T cells stimulated in an APC-dependent manner were shown to produce increased levels of IL-2 as compared with their CD25− counterparts. This study establishes CD25+ naive CD4 T cells, which are further delineated by CD31 expression, as a major functionally distinct immune cell subset in humans that warrants further characterization in health and disease.
Fasciola hepatica Tegumental Coat Impairs Mast Cells’ Ability To Drive Th1 Immune Responses
Authors: Vukman Krisztina V. , Adams Paul N. , Metz Martin , Maurer Marcus , O’Neill Sandra M.
Published: February 2013

The parasitic worm Fasciola hepatica induces strong Th2 and T-regulatory immune responses while simultaneously suppressing Th1-driven immune responses to bystander microbial infections. It also prevents the initiation of Th1-mediated autoimmune disorders in mice through the suppression of Th17 and Th1 immune responses, and this can be mimicked by parasite-derived molecules. We have isolated F. hepatica tegumental coat Ag (FhTeg) and demonstrated its suppressive effect in vivo by directly targeting dendritic cells, impairing their ability to drive Th1 responses. Mast cells are critical in promoting Th1 protective immunity during bacterial infection and in driving Th1-mediated pathological conditions in autoimmune diseases. In this article, we show that FhTeg inhibits the ability of mast cells to drive the Th1 immune response by suppressing cytokine secretion (TNF-α, IL-6, IFN-γ, and IL-10) and ICAM1 expression in mast cells stimulated with LPS or heat-inactivated Bordetella pertussis Ag. These heat-inactivated B. pertussis Ag/LPS–stimulated mast cells fail to promote Th1 immune responses in CD4+ T cells when pretreated with FhTeg, and a role for ICAM1 in this process was demonstrated. FhTeg suppresses the activation of transcription factors in the TLR signaling pathway, which explains the decrease in cytokine production and cell surface marker expression. We demonstrated that FhTeg suppresses MAPK and NF-κB activation and enhances SOCS3 expression, which could explain its negative effect on the TLR pathways. We conclude that FhTeg targets innate immune cells, inhibiting their ability to drive Th1 immune responses.
Dendritic Cell–Derived Exosomes Need To Activate Both T and B Cells To Induce Antitumor Immunity
Authors: Näslund Tanja I. , Gehrmann Ulf , Qazi Khaleda R. , Karlsson Mikael C. I. , Gabrielsson Susanne
Published: February 2013

Exosomes are secreted membrane nanovesicles of endosomal origin and are considered potential cancer vaccine vectors. Phase I clinical trials have been successfully conducted with tumor peptide–loaded exosomes derived from dendritic cells (dexosomes), and a phase II clinical trial is ongoing. However, much is still unknown regarding the in vivo role of dexosomes and whether their immunogenicity can be enhanced. We previously reported that dexosomes induce CD4+ T cell responses in a B cell–dependent manner, suggesting that immunization with dexosomes carrying only T cell peptides induce suboptimal immune responses. In this study, we show that CD8+ T cell responses were induced in vivo when mice were immunized with protein-loaded, but not peptide-loaded, dexosomes. We also show that the cytotoxic T cell response was totally dependent on CD4+ T cells and, interestingly, also on B cells. Mice deficient in complement activation and Ag shuttling by B cells have lower responses to protein-loaded dexosomes, showing involvement of these B cell–mediated mechanisms. Finally, protein-loaded dexosomes were superior in protecting against tumor growth. In conclusion, proper activation of CD4+ T and B cells needs to be considered when designing cancer vaccines to ensure full potential of the treatment.
Dynamic decision making for dam-break emergency management – Part 2: Application to Tangjiashan landslide dam failure
Authors: Peng M. , Zhang L. M.
Published: February 2013

Abstract. Tangjiashan landslide dam, which was triggered by the Ms = 8.0 Wenchuan earthquake in 2008 in China, threatened 1.2 million people downstream of the dam. All people in Beichuan Town 3.5 km downstream of the dam and 197 thousand people in Mianyang City 85 km downstream of the dam were evacuated 10 days before the breaching of the dam. Making such an important decision under uncertainty was difficult. This paper applied a dynamic decision-making framework for dam-break emergency management (DYDEM) to help rational decision in the emergency management of the Tangjiashan landslide dam. Three stages are identified with different levels of hydrological, geological and social-economic information along the timeline of the landslide dam failure event. The probability of dam failure is taken as a time series. The dam breaching parameters are predicted with a set of empirical models in stage 1 when no soil property information is known, and a physical model in stages 2 and 3 when knowledge of soil properties has been obtained. The flood routing downstream of the dam in these three stages is analyzed to evaluate the population at risk (PAR). The flood consequences, including evacuation costs, flood damage and monetized loss of life, are evaluated as functions of warning time using a human risk analysis model based on Bayesian networks. Finally, dynamic decision analysis is conducted to find the optimal time to evacuate the population at risk with minimum total loss in each of these three stages.
Personal and spousal decision making on the funding of medical care not covered by healthcare insurance
Authors: Kagan Maya
Published: February 2013

The purpose of this study was to investigate personal and spousal decisions to seek funding for spousal medical care, when such treatments are not covered by the National Package of Healthcare Services or by other types of healthcare insurance. Research data were collected in Israel during 2008-2010 by means of structured questionnaires. The questionnaires were administered to a nonrandom sample of 160 patients with a health condition requiring private funding of treatment. The study clearly reveals that the decision to forego fundraising results not only from financial considerations. Patients' illness-related factors and available personal, spousal, and social resources are significant as well.
A Mechanistic Study of Wetting Superhydrophobic Porous 3D Meshes
Authors: Yohe Stefan T. , Freedman Jonathan D. , Falde Eric J. , Colson Yolonda L. , Grinstaff Mark W.
Published: February 2013

Superhydrophobic, porous, 3D materials composed of poly(ϵ‐caprolactone) (PCL) and the hydrophobic polymer dopant poly(glycerol monostearate‐co‐ϵ‐caprolactone) (PGC‐C18) are fabricated using the electrospinning technique. These 3D materials are distinct from 2D superhydrophobic surfaces, with maintenance of air at the surface as well as within the bulk of the material. These superhydrophobic materials float in water, and when held underwater and pressed, an air bubble is released and will rise to the surface. By changing the PGC‐C18 doping concentration in the meshes and/or the fiber size from the micro‐ to nanoscale, the long‐term stability of the entrapped air layer is controlled. The rate of water infiltration into the meshes, and the resulting displacement of the entrapped air, is quantitatively measured using X‐ray computed tomography. The properties of the meshes are further probed using surfactants and solvents of different surface tensions. Finally, the application of hydraulic pressure is used to quantify the breakthrough pressure to wet the meshes. The tools for fabrication and analysis of these superhydrophobic materials as well as the ability to control the robustness of the entrapped air layer are highly desirable for a number of existing and emerging applications.
Properties of electrospun poly(vinyl alcohol) hydrogel nanofibers crosslinked with 1,2,3,4‐butanetetracarboxylic acid
Authors: Çay Ahmet , Mohsen Miraftab
Published: February 2013

ABSTRACT: Electrospun nanofibrous hydrogel membranes have been gaining significant importance due to the combination of unique physical properties of nanofibers and biocompatibility of hydrogels. Thus, they are considered as potential candidates for medical textile applications. This study deals with electrospinning of poly(vinyl alcohol) (PVA) hydrogel nanofibrous membranes. The chemical crosslinking of PVA with proportionate quantities of 1,2,3,4 butanetetracarboxylic acid (BTCA) was undertaken to form hydrogel structures. Cross‐linked membranes were characterized by scanning electron microscopy, FT‐IR and thermogravimetric analysis, water swelling, and durability tests. FT‐IR analysis demonstrated the formation of ester linkages between PVA and BTCA and thermogravimetric analysis showed that crosslinking improved the thermal stability of the nanofibrous structure. Furthermore, the results indicated that crosslinking with BTCA improved water stability of PVA membranes and the nanofibrous structure was preserved after water treatment. It is envisaged that use of BTCA as a cross‐linker to form hydrogel nanofibers could be a practical and a promising method for medical textile applications, especially for wound dressings given its nontoxicity and immiscibility with polymer solutions. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Solvent‐resistant nanofiltration membranes based on multilayered polyelectrolytes deposited on silicon composite
Authors: Chen Dongju
Published: February 2013

Alternating deposition of oppositely charged polyelectrolyte complexes (PECs) on inorganic–organic composite membranes can efficiently overcome the drawback of microcracks induced by inorganic particles. Different bilayers of Poly (diallyldimethylammonium, chloride)/sulfonated poly(ether ether ketone) (PDDA/SPEEK) were first deposited on the charged silicon composite with hydrolyzed polyacrylonitrile (PAN‐H) support and evaluated for solvent resistant nanofiltration membranes (SRNF) application. The morphology of the membranes was studied in detail via SEM and AFM. Because of Donnan exclusion, the multilayered PEC silicon composite membranes showed very high retentions up to 99% for negatively charged solutes (Rose Bengal (RB), 1017 Da) in the pressure driven filtration of isopropanol (IPA) solutions. For the first time, PEC‐based silicon composite membranes were also applied in the filtration of organic solvents, where they were found to combine a remarkable stability in polar solvents with high fluxes and retentions. Compared with silicon composite membranes, the introduction of multilayered PDDA/SPEEK can efficiently improve the membrane performance and overcome the drawback induced by inorganic fillers. PEC‐based silicon composite membranes thus show excellent prospective use in SRNF. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Copper(II) Triflate Promoted Multicomponent Catalytic Clubbing of Piperazinyl‐Thiazoloquinolines and Thiazolocoumarins as Antimicrobials
Authors: Patel Rahul V. , Patel Jigar K. , Nile Shivraj H. , Park Se Won
Published: February 2013

Step economical, multicomponent construction of two series based on quinoline and coumarin ring systems was carried out. Annulation towards the 2‐piperazinylthiazole system was established in satisfactory yields, using copper(II) triflate. These multicomponent reaction products were examined for their potential inhibitory effect against two Gram‐positive bacteria (Staphylococcus aureus and Bacillus cereus), three Gram‐negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae) and two fungal species (Aspergillus niger and Candida albicans). In vitro pharmacological screening data demonstrated that the majority of the compounds were found to possess a significant broad‐spectrum antimicrobial (25–50 µg/mL of MIC) potential and the results were comparable to control drugs. The structural assignments of final products were done on the basis of IR, 1H NMR, 13C NMR spectroscopy, and elemental analysis. The structure–activity relationship (SAR) was explored to facilitate further development of this class of compounds.
Investigation on the co‐luminescence effect of europium (III)–lanthanum(III)–dopamine–sodium dodecylbenzene sulfonate system and its application
Authors: Si Hailin , Zhao Fang , Cai Huan
Published: February 2013

A novel luminescence, enhancement phenomenon in the europium(III)–dopamine–sodium dodecylbenzene sulfonate system was observed when lanthanum(III) was added. Based on this, a sensitive co‐luminescence method was established for the determination of dopamine. The luminescence signal for the europium (III)–lanthanum(III)–dopamine–sodium dodecylbenzene sulfonate system was monitored at λex = 300 nm, λem =618 nm and pH 8.3. Under optimized conditions, the enhanced luminescence signal responded linearly to the concentration of dopamine in the range 1.0 × 10–10–5.0 × 10–7 mol/L with a correlation coefficient of 0.9993 (n = 11). The detection limit (3σ) was 2.7 × 10–11 mol/L and the relative standard deviation for 11 parallel measurements of 3.0 × 10–8 mol/L dopamine was 1.9%. The presented method was successfully applied for the estimation of dopamine in samples of pharmaceutical preparations, human serum and urine. The possible luminescence enhancement mechanism of the system is discussed briefly. Copyright © 2013 John Wiley & Sons, Ltd.
Sonochemical synthesis of Ag nanoclusters: electrogenerated chemiluminescence determination of dopamine
Authors: Liu Tao , Zhang Lichun , Song Hongjie , Wang Zhonghui , Lv Yi
Published: February 2013

We report a facile one‐pot sonochemical approach to preparing highly water‐soluble Ag nanoclusters (NCs) using bovine serum albumin as a stabilizing agent and reducing agent in aqueous solution. Intensive electrogenerated chemiluminescence (ECL) was observed from the as‐prepared Ag (NCs) and successfully applied for the ECL detection of dopamine with high sensitivity and a wide detection range. A possible ECL mechanism is proposed for the preparation of Ag NCs. With this method, the dopamine concentration was determined in the range of 8.3 × 10–9 to 8.3 × 10–7 mol/L without the obvious interference of uric acid, ascorbic acid and some other neurotransmitters, such as serotonin, epinephrine and norepinephrine, and the detection limit was 9.2 × 10–10 mol/L at a signal/noise ratio of 3. Copyright © 2013 John Wiley & Sons, Ltd.