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Rheumatoid arthritis, anti-CCP positivity, and cardiovascular disease risk in the Women's Health Initiative. - Arthritis & rheumatology (Hoboken, N.J.)
This report evaluates incidence of cardiovascular disease (CVD) morbidity and mortality over 10 years among the >160,000 postmenopausal women in the Women's Health Initiative (WHI) in relation to self-reported RA, disease modifying anti-rheumatic drugs (DMARD) use, anti-CCP+, RF+, CVD risk factors, joint pain, and inflammation (white blood cell (WBC) count and IL-6.) Methods: Anti-CCP and RF were measured on a sample (n=9,988) of WHI participants with self-reported RA. RA was classified as self-reported RA plus anti-CCP+ positivity and/or use of DMARDs. Self-reported RA that was both anti-CCP- and DMARD- was classified as "unverified RA."Age-adjusted rates of coronary heart disease (CHD), stroke, CVD, fatal CVD and total mortality were higher for women with RA vs. no RA, with multivariable-adjusted HR(95%CI) of 1.46(1.17, 1.83) for CHD, and 2.55(1.86, 3.51) for fatal CVD. Within RA, anti-CCP+ and RF+ were not significantly associated with higher risk of any outcomes, despite slightly higher risk of fatal CVD and death for anti-CCP+ vs. anti-CCP- RA. Joint pain severity and CVD risk factors were strongly associated with CVD risk, even for women with no RA. CVD incidence was increased for RA vs. no RA at almost all risk factor levels, except low levels of joint pain or inflammation. Within RA, inflammation was more strongly associated with fatal CVD and total mortality than CHD or CVD.Among postmenopausal women, RA was associated with 1.5-2.5 higher CVD risk, strongly associated with CV risk factors, joint pain severity, and inflammation, but similar for anti-CCP+ and RF+. This article is protected by copyright. All rights reserved.Â© 2015, American College of Rheumatology.
CD11c-mediated deletion of Flip promotes autoreactivity and inflammatory arthritis. - Nature communications
Dendritic cells (DCs) are critical for immune homeostasis. To target DCs, we generated a mouse line with Flip deficiency in cells that express cre under the CD11c promoter (CD11c-Flip-KO). CD11c-Flip-KO mice spontaneously develop erosive, inflammatory arthritis, resembling rheumatoid arthritis, which is dramatically reduced when these mice are crossed with Rag(-/-) mice. The CD8Î±(+) DC subset is significantly reduced, along with alterations in NK cells and macrophages. Autoreactive CD4(+) T cells and autoantibodies specific for joint tissue are present, and arthritis severity correlates with the number of autoreactive CD4(+) T cells and plasmablasts in the joint-draining lymph nodes. Reduced T regulatory cells (Tregs) inversely correlate with arthritis severity, and the transfer of Tregs ameliorates arthritis. This KO line identifies a model that will permit in depth interrogation of the pathogenesis of rheumatoid arthritis, including the role of CD8Î±(+) DCs and other cells of the immune system.
Pelvic pleomorphic rhabdomyosarcoma presenting as oliguria in a 61-year-old woman. - The Journal of community and supportive oncology
Rhabdomyosarcomas (RMSs) are malignant soft-tissue tumors arising from skeletal muscle progenitor cells. They are most commonly diagnosed in children and adolescents and are rare in adults. These tumors arise from a variety of anatomical sites, including the head and neck, urogenital tract, and extremities. Classification of RMSs depends on histopathologic and immunohistochemical features. Embryonal and alveolar subtypes are more common in children and adolescents, whereas the pleomorphic subtype is seen almost exclusively in adults. Adult RMS is associated with poor outcomes and high recurrence rate. Because of the low incidence of adult RMS, most published reports of RMS in adults are either case series or retrospective analyses, and most treatment protocols are extrapolated from clinical trials performed in children. The present report describes a 61-year-old woman with RMS whose presentation included atypical symptoms.Â©2015 Frontline Medical Communications.
Vascular calcifications on hand radiographs in rheumatoid arthritis and associations with autoantibodies, cardiovascular risk factors and mortality. - Rheumatology (Oxford, England)
To examine whether vascular calcifications on hand films in RA might aid in determining mortality risk.Hand radiographs from 906 RA patients were scored as positive or negative for vascular calcifications. Patient characteristics associated with vascular calcifications were assessed using multivariable logistic regression, and associations with mortality were examined using Cox proportional hazards regression. Cytokines and multiplex ACPA were measured in both groups.A total of 99 patients (11%) demonstrated radiographic vascular calcifications. Factors independently associated with vascular calcifications included diabetes [odds ratio (OR) 2.85; 95% CI 1.43, 5.66], cardiovascular disease at enrolment (OR 2.48; 95% CI 1.01, 6.09), prednisone use (OR 1.90; 95% CI 1.25, 2.91), current smoking (OR 0.06; 95% CI 0.01, 0.23) and former smoking (OR 0.36; 95% CI 0.27, 0.48) vs never smoking. In cytokine and ACPA subtype analysis, IL-4 and anti-citrullinated apolipoprotein E were significantly increased in patients with vascular calcifications in fully adjusted multivariable models. After multivariable adjustment, vascular calcifications were associated with an increase in all-cause mortality (hazard ratio 1.41; 95% CI 1.12, 1.78; P = 0.004).Vascular calcifications on hand radiographs were independently associated with increased all-cause mortality in RA. Mechanisms underpinning the associations of IL-4 and select ACPA with vascular calcifications and their utility as biomarkers predictive of cardiovascular disease risk in RA merit further study.Published by Oxford University Press on behalf of the British Society for Rheumatology 2015. This work is written by US Government employees and is in the public domain in the US.
Narrow Band Ultraviolet B Treatment for Human Vitiligo Is Associated with Proliferation, Migration, and Differentiation of Melanocyte Precursors. - The Journal of investigative dermatology
In vitiligo, the autoimmune destruction of epidermal melanocytes produces white spots that can be repigmented by melanocyte precursors from the hair follicles, following stimulation with UV light. We examined by immunofluorescence the distribution of melanocyte markers (C-KIT, DCT, PAX3, and TYR) coupled with markers of proliferation (KI-67) and migration (MCAM) in precursors and mature melanocytes from the hair follicle and the epidermis of untreated and narrow band UVB (NBUVB)-treated human vitiligo skin. NBUVB was associated with a significant increase in the number of melanocytes in the infundibulum and with restoration of the normal melanocyte population in the epidermis, which was lacking in the untreated vitiligo. We identified several precursor populations (melanocyte stem cells, melanoblasts, and other immature phenotypes), and progressively differentiating melanocytes, some with putative migratory and/or proliferative abilities. The primary melanocyte germ was present in the untreated and treated hair follicle bulge, whereas a possible secondary melanocyte germ composed of C-KIT+ melanocytes was found in the infundibulum and interfollicular epidermis of UV-treated vitiligo. This is an exceptional model for studying the mobilization of melanocyte stem cells in human skin. Improved understanding of this process is essential for designing better treatments for vitiligo, ultimately based on melanocyte stem cell activation and mobilization.Journal of Investigative Dermatology advance online publication, 14 May 2015; doi:10.1038/jid.2015.126.
In patients stratified by preoperative risk, endovascular repair of ruptured abdominal aortic aneurysms has a lower in-hospital mortality and morbidity than open repair. - Journal of vascular surgery
Previous studies have reported that endovascular repair (EVAR) of ruptured abdominal aortic aneurysms (RAAAs) has lower postoperative mortality than open repair (OR). However, comparisons involved heterogeneous populations that lacked adjustment for preoperative risk. We hypothesize that for RAAA patients stratified by a validated measure of preoperative mortality risk, EVAR has a lower in-hospital mortality and morbidity than does OR.In-hospital mortality and morbidity after EVAR and OR of RAAA were compared in patients from the Vascular Quality Initiative (2003-2013) stratified by the validated Vascular Study Group of New England RAAA risk score into low-risk (score 0-1), medium-risk (score 2-3), and high-risk (score 4-6) groups.Among 514 patients who underwent EVAR and 651 patients who underwent OR of RAAA, EVAR had lower in-hospital mortality (25% vs 33%, PÂ = .001). In risk-stratified patients, EVAR trended toward a lower mortality in the low-risk group (nÂ = 626; EVAR, 10% vs OR, 15%; PÂ = .07), had a significantly lower mortality in the medium-risk group (nÂ = 457; EVAR, 37% vs OR, 48%; PÂ = .02), and no advantage in the high-risk group (nÂ = 82; EVAR, 95% vs OR, 79%; PÂ = .17). Across all risk groups, cardiac complications (EVAR, 29% vs OR, 38%; PÂ = .001), respiratory complications (EVAR, 28% vs OR, 46%; PÂ < .0001), renal insufficiency (EVAR, 24% vs OR, 38%; PÂ < .0001), lower extremity ischemia (EVAR, 2.7% vs OR, 8.1%; PÂ < .0001), and bowel ischemia (EVAR, 3.9% vs OR, 10%; PÂ < .0001) were significantly lower after EVAR than after OR. Across all risk groups, median (interquartile range) intensive care unit length of stay (EVAR, 2 [1-5] days vs OR, 6 [3-13] days; PÂ < .0001) and hospital length of stay (EVAR, 6 [4-12] days vs OR, 13 [8-22] days; PÂ < .0001) were lower after EVAR.This novel risk-stratified comparison using a national clinical database showed that EVAR of RAAA has a lower mortality and morbidity compared with OR in low-risk and medium-risk patients and that EVAR should be used to treat these patients when anatomically feasible. For RAAA patients at the highest preoperative risk, there is no benefit to using EVAR compared with OR.Copyright Â© 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Mass Cytometry Analysis Shows That a Novel Memory Phenotype B Cell Is Expanded in Multiple Myeloma. - Cancer immunology research
It would be very beneficial if the status of cancers could be determined from a blood specimen. However, peripheral blood leukocytes are very heterogeneous between individuals, and thus high-resolution technologies are likely required. We used cytometry by time-of-flight and next-generation sequencing to ask whether a plasma cell cancer (multiple myeloma) and related precancerous states had any consistent effect on the peripheral blood mononuclear cell phenotypes of patients. Analysis of peripheral blood samples from 13 cancer patients, 9 precancer patients, and 9 healthy individuals revealed significant differences in the frequencies of the T-cell, B-cell, and natural killer-cell compartments. Most strikingly, we identified a novel B-cell population that normally accounts for 4.0% Â± 0.7% (mean Â± SD) of total B cells and is up to 13-fold expanded in multiple myeloma patients with active disease. This population expressed markers previously associated with both memory (CD27(+)) and naÃ¯ve (CD24(lo)CD38(+)) phenotypes. Single-cell immunoglobulin gene sequencing showed polyclonality, indicating that these cells are not precursors to the myeloma, and somatic mutations, a characteristic of memory cells. SYK, ERK, and p38 phosphorylation responses, and the fact that most of these cells expressed isotypes other than IgM or IgD, confirmed the memory character of this population, defining it as a novel type of memory B cells. Cancer Immunol Res; 3(6); 1-11. Â©2015 AACR.Â©2015 American Association for Cancer Research.
Developing a complex endovascular fenestrated and branched aortic program. - Journal of vascular surgery
In 2008, the top priority in our division's 5-year strategic plan was "to become an internationally recognized center of excellence for the endovascular treatment of complex aortic pathology extending from the aortic valve to the external iliac artery." Five components were identified as "most critical" to achieve this strategic priority: (1) training at centers of excellence in complex endovascular repair; (2) industry partnership to improve access to developing technologies; (3) a fully integrated team approach with one leader involved in all steps of all cases; (4) prospective data collection; and (5) development and implementation of a physician-sponsored investigational device exemption for juxtarenal, pararenal, and thoracoabdominal aneurysms. We have now performed 49 repairs (16 commercially manufactured devices, 33 physician-modified devices) for 3 common iliac, 20 juxtarenal, 9 pararenal, and 17 thoracoabdominal aneurysms, using 142 fenestrations, branches, and scallops. All patients had complete 30-day follow-up for calculation of 30-day events. Kaplan-Meier analysis was used to calculate 1-year events. In 5 years, we developed a successful complex endovascular aortic program that uses fenestrated/branched repair techniques. A focused team strategic planning approach to program development is an effective way for vascular surgery divisions to gain experience and expertise with new complex technologies while ensuring acceptable patient outcomes.Copyright Â© 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
Associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms and rheumatoid arthritis disease progression: an observational cohort study. - International immunopharmacology
To examine the associations of toll-like receptor (TLR)-4 single nucleotide polymorphisms (SNPs) with disease progression in rheumatoid arthritis (RA).A total of 1188 RA patients were genotyped for TLR4 SNPs (rs1927911, rs11536878, and rs4986790). Measures of disease activity were examined, including Disease Activity Score-28 (DAS28), Multidimensional Health Assessment Questionnaire (MD-HAQ), Clinical Disease Activity Index (CDAI), and Simplified Disease Activity Index (SDAI). Genetic associations with these longitudinal measures were examined using generalized estimating equations in both univariate and multivariate analyses. Analyses were then stratified by antigen specific anti-citrullinated peptide antibody (ACPA) status including antibody to citrullinated fibrinogen and citrullinated histone H2B.Disease activity measures progressed less over time in the homozygous minor allele group of rs1927911 including DAS28 (p<0.001), CDAI (p=0.008), and MD-HAQ (p=0.015) in univariate analysis and DAS28, CDAI and SDAI in multivariate analysis. Disease activity progression among those homozygous for the minor allele tended to be lower in the groups with positive ACPA though major differences by autoantibody status were not identified. There were no associations of TLR4 rs11536878 and rs4986790 SNPs with RA disease activity progression.In this population, TLR4 rs1927911 genotypes are associated with disease activity independent of other covariates.Published by Elsevier B.V.
Evaluating a community-partnered cancer clinical trials pilot intervention with African American communities. - Journal of cancer education : the official journal of the American Association for Cancer Education
Cancer clinical trial (CCT) accrual and retention rates remain disproportionately low among African Americans. Awarenesss and access to trials are crucial facilitators of trial participation. Strategies developed within a community-based participatory framework (CBPR) are potential solutions to increase awareness and access to CCTs. In this study, we describe the pilot phase of three innovative community-centered modules to improve basic CCT knowledge, awareness of locations to access CCT information, and opportunities to participate in CCTs. Four community organizations completed Community Bridges to CCT training-of-the-trainer and recruited adult African American volunteers to participate in one of three CCT education modules: a workshop about CCTs, a role play describing one person's experience with CCTs, or a call and response session reviewing myths and facts about CCTs. Pre- and post-test surveys were collected and analyzed using McNemar agreement statistic to evaluate changes in knowledge and attitudes regarding trials. Trainers enrolled 125 participants in the call and response (nâ€‰=â€‰22), role play (nâ€‰=â€‰60), and workshop (nâ€‰=â€‰43) modules. Module participants were mostly African American, female, and with a mean age of 53Â years. Comparison of pre- and post-test responses demonstrates favorable changes in awareness of CCTs and where to access CCTs across the sample. Analysis by module type indicates significant increases for participants in the call and response (pâ€‰<â€‰0.01) and role play modules (pâ€‰<â€‰0.001), but not the workshop module. Despite measures taken to increase the participation and retention rate of African Americans in clinical trials, little advancement has been made. Developing tailored community education modules on CCTs within the CBPR framework is a promising innovation to increase knowledge about CCTs and favorable attitudes about participation that are known precursors to trial enrollment.
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