bluuebunny/crossref_metadata_2025 huggingface dataset:
Are tall people at higher risk of low back pain surgery? A discussion on the results of a multipurpose cohort
Authors: Coeuret‐Pellicer Mireille , Descatha Alexis , Leclerc Annette , Zins Marie
Published: December 2009

Objective

To investigate whether height is associated with low back pain (LBP) and surgery, taking into account personal and socioeconomic risk factors in a general population.

Methods

In 2001, 13,680 participants of the Gazel cohort completed a self‐reported questionnaire on LBP and surgery interventions. Three groups were compared according to their body height: no LBP (reference group, participants who declared they never had LBP), LBP without surgery (participants who ever had LBP but without surgery), and back surgery (participants who ever had surgery for LBP). Adjusted variables were sex, age, educational level, marital status, height, and body mass index.

Results

Mean height was significantly higher in men in the back surgery group than in the reference group and the LBP group. The proportion of surgically‐treated LBP was higher for people whose height was ≥4th quartile (P < 0.0001). Being in the highest quartile for height was a stronger risk factor for surgery (adjusted odds ratio [ORadj] = 2.01, 95% confidence interval [95% CI] 1.61–2.51) than for LBP without surgery (ORadj = 1.29, 95% CI 1.18–1.40).

Conclusion

The results suggest that being tall is a predictor for back surgery.
Fault detection for a class of nonlinear networked control systems
Authors: Mao Zehui , Jiang Bin , Shi Peng
Published: December 2009

In this paper, an observer‐based fault detection (FD) method is presented for a class of nonlinear networked control systems (NCSs) with Markov transfer delays. Firstly, based on Euler approximate method, a nonlinear NCS model with uncertainty is proposed using the Takagi‐Sugeno (T‐S) fuzzy model. Some geometric conditions are given to transfer the NCS model into an output‐feedback form. Then, the H∞ FD observer is designed such that the estimation error (residual) converges to zero, if there exist no fault and uncertainty in the system, or the residual is minimized in the sense of H∞ norm, when system contains fault and uncertainties. Furthermore, to simplify the model, the approximate model without uncertainty is considered. Then, sufficient conditions for the existence of FD observer gain and the sampling time of NCSs are given to achieve the semiglobal practical property. An inverted pendulum example is used to illustrate the efficiency of the developed techniques. Copyright © 2009 John Wiley & Sons, Ltd.
Reactive Imprint Lithography: Combined Topographical Patterning and Chemical Surface Functionalization of Polystyrene‐block‐poly(tert‐butyl acrylate) Films
Authors: Duvigneau Joost , Cornelissen Stijn , Bardají Valls Núria , Schönherr Holger , Vancso G. Julius
Published: December 2009

Here, reactive imprint lithography (RIL) is introduced as a new, one‐step lithographic tool for the fabrication of large‐area topographically patterned, chemically activated polymer platforms. Films of polystyrene‐block‐poly(tert‐butyl acrylate) (PS‐b‐PtBA) are imprinted with PDMS master stamps at temperatures above the corresponding glass transition and chemical deprotection temperatures to yield structured films with exposed carboxylic acid and anhydride groups. Faithful pattern transfer is confirmed by AFM analyses. Transmission‐mode FTIR spectra shows a conversion of over 95% of the tert‐butyl ester groups after RIL at 230 °C for 5 minutes and a significantly reduced conversion to anhydride compared to thermolysis of neat films with free surfaces in air or nitrogen. An enrichment of the surface layer in PS is detected by angle‐resolved X‐ray photoelectron spectroscopy (XPS). In order to demonstrate application potentials of the activated platforms, a 7 nm ± 1 nm thick NH2‐terminated PEG layer (grafting density of 0.9 chains nm−2) is covalently grafted to RIL‐activated substrates. This layer reduces the non‐specific adsorption (NSA) of bovine serum albumin by 95% to a residual mass coverage of 9.1 ± 2.9 ng cm−2. As shown by these examples, RIL comprises an attractive complementary approach to produce bio‐reactive polymer surfaces with topographic patterns in a one‐step process.
Compact and Light Supercapacitor Electrodes from a Surface‐Only Solid by Opened Carbon Nanotubes with 2 200 m2 g−1 Surface Area
Authors: Hiraoka Tatsuki , Izadi‐Najafabadi Ali , Yamada Takeo , Futaba Don N. , Yasuda Satoshi , Tanaike Osamu , Hatori Hiroaki , Yumura Motoo , Iijima Sumio , Hata Kenji
Published: December 2009

An approach is presented to make a “surface‐only solid” with a surface area of 2 240 m2 g−1 (1 310 m2 cm−3), corresponding to 85% of the atoms constituting a surface, by opening single‐walled carbon nanotube forests and solids via controlled oxidation. The controllability of the approach is demonstrated by tailoring the hole size to match the guest molecule, for example, nitrogen, fullerene, or solvated ions. These features make the surface‐only solid an ideal vessel for material and energy storage, as demonstrated by its use for electrodes to realize a light and compact supercapacitor with high energy (24.7 W h kg−1) and power (98.9 kW kg−1) densities, exceeding those of activated carbon (16.9 W h kg−1 and 35.7 kW kg−1).
Nonspherical Noble Metal Nanoparticles: Colloid‐Chemical Synthesis and Morphology Control
Authors: Sau Tapan K. , Rogach Andrey L.
Published: December 2009

Metal nanoparticles have been the subject of widespread research over the past two decades. In recent years, noble metals have been the focus of numerous studies involving synthesis, characterization, and applications. Synthesis of an impressive range of noble metal nanoparticles with varied morphologies has been reported. Researchers have made a great progress in learning how to engineer materials on a nanometer length scale that has led to the understanding of the fundamental size‐ and shape‐dependent properties of matter and to devising of new applications. In this article, we review the recent progress in the colloid‐chemical synthesis of nonspherical nanoparticles of a few important noble metals (mainly Ag, Au, Pd, and Pt), highlighting the factors that influence the particle morphology and discussing the mechanisms behind the nonspherical shape evolution. The article attempts to present a thorough discussion of the basic principles as well as state‐of‐the‐art morphology control in noble metal nanoparticles.
One‐Pot Thioetherification of Aryl Halides Using Thiourea and Alkyl Bromides Catalyzed by Copper(I) Iodide Free from Foul‐Smelling Thiols in Wet Polyethylene Glycol (PEG 200)
Authors: Firouzabadi Habib , Iranpoor Nasser , Gholinejad Mohammad
Published: December 2009

In this article, we have developed a new protocol for the thioarylation of structurally diverse alkyl bromides such as benzyl, cinnamyl, n‐octyl, cyclohexyl, cyclopentyl, and tert‐butyl bromides with aryl iodides, bromides and an activated chloride using thiourea catalyzed by copper(I) iodide in wet polyethylene glycol (PEG 200) as an eco‐friendly medium in the presence of potassium carbonate at 80 and 100 °C under an inert atmosphere. The process is free from foul‐smelling thiols which makes this method more practical for the thioetherification of aryl halides. Another important feature of this method is the variety of alkyl bromides which are commercially available for the in situ generation of thiolate ions with respect to the existing protocols in which the less commercially available thiols are directly used for the preparation of arylthio ethers.
On the continuum approximation of large reaction mixtures
Authors: Ho Teh C. , White Benjamin S.
Published: December 2009

In analyzing a reaction mixture of very many components, treating the mixture as a continuum can produce results of generality. In many practical situations (e.g., hydrodesulfurization), it is highly desirable to predict the overall behavior of the mixture at large times (high conversions) with minimum information on the mixture property. For irreversible first‐order reactions in a plug‐flow reactor, it was previously shown that the continuum approximation cannot be valid at arbitrarily large times. This work is an investigation of the validity of the approximation for mixtures with complex kinetics. It is found that the approximation can be conditionally or universally valid, depending on kinetics, reactor type, pore diffusion, and mixture properties. The validity conditions for a variety of situations, nontrivial as they may seem, take a power‐law form. Backmixing and pore diffusion widen the range of validity. The underlying physics and some dichotomies/subtleties are discussed. The results are applied to catalytic hydroprocessing in petroleum refining. © 2009 American Institute of Chemical Engineers AIChE J, 2010
Modeling multisystem biological risk in young adults: The Coronary Artery Risk Development in Young Adults Study
Authors: Seeman Teresa , Gruenewald Tara , Karlamangla Arun , Sidney Steve , Liu Kiang , Mcewen Bruce , Schwartz Joseph
Published: December 2009

Although much prior research has focused on identifying the roles of major regulatory systems in health risks, the concept of allostatic load (AL) focuses on the importance of a more multisystems view of health risks. How best to operationalize allostatic load, however, remains the subject of some debate. We sought to test a hypothesized metafactor model of allostatic load composed of a number of biological system factors, and to investigate model invariance across sex and ethnicity. Biological data from 782 men and women, aged 32–47, from the Oakland, CA and Chicago, IL sites of the Coronary Artery Risk Development in Young Adults Study (CARDIA) were collected as part of the Year 15exam in 2000. These include measures of blood pressure, metabolic parameters (glucose, insulin, lipid profiles, and waist circumference), markers of inflammation (interleukin‐6, C‐reactive protein, and fibrinogen), heart rate variability, sympathetic nervous system activity (12‐hr urinary norepinephrine and epinephrine) and hypothalamic‐pituitary‐adrenal axis activity (diurnal salivary free cortisol). A “metafactor” model of AL as an aggregate measure of six underlying latent biological subfactors was found to fit the data, with the metafactor structure capturing 84% of variance of all pairwise associations among biological subsystems. There was little evidence of model variance across sex and/or ethnicity. These analyses extend work operationalizing AL as a multisystems index of biological dysregulation, providing initial support for a model of AL as a metaconstruct of inter‐relationships among multiple biological regulatory systems, that varies little across sex or ethnicity. Am. J. Hum. Biol. 2010. © 2009 Wiley‐Liss, Inc.
Conservation education in Madagascar: three case studies in the biologically diverse island‐continent
Authors: Dolins Francine L. , Jolly Alison , Rasamimanana Hantanirina , Ratsimbazafy Jonah , Feistner Anna T.C. , Ravoavy Florent
Published: December 2009

Few Malagasy children and adults are aware of the rare and unique fauna and flora indigenous to their island‐continent, including flagship lemur species. Even the Malagasy ancestral proverbs never mentioned lemurs, but these same proverbs talked about the now extinct hippopotamus. Madagascar's geography, history, and economic constraints contribute to severe biodiversity loss. Deforestation on Madagascar is reported to be over 100,000 ha/year, with only 10–15% of the island retaining natural forest [Green & Sussman, 1990]. Educating children, teacher‐training, and community projects about environmental and conservation efforts to protect the remaining natural habitats of endangered lemur species provide a basis for long‐term changes in attitudes and practices. Case studies of three conservation education projects located in different geographical regions of Madagascar, Centre ValBio, Madagacar Wildlife Conservation Alaotra Comic Book Project, and The Ako Book Project, are presented together with their ongoing stages of development, assessment, and outcomes. We argue that while nongovernmental organizational efforts are and will be very important, the Ministry of Education urgently needs to incorporate biodiversity education in the curriculum at all levels, from primary school to university. Am. J. Primatol. 72:391–406, 2010. © 2009 Wiley‐Liss, Inc.
The species–area relationship and confounding variables in a threatened monkey community
Authors: Marshall Andrew R. , Jørgensbye Helle I.O. , Rovero Francesco , Platts Philip J. , White Piran C.L. , Lovett Jon C.
Published: December 2009

This study investigates the species–area relationship (SAR) for forest monkeys in a biodiversity hotspot. The Udzungwa Mountains of Tanzania are well‐suited to investigate the SAR, with seven monkey species in a range of fragment sizes (0.06–526 km2). We test the relationship between species richness and forest fragment size, relative to human and environmental factors. We distinguish resident and transitory species because the latter have an “effective patch size” beyond the area of forest. Forest area was the strongest (log‐linear) predictor of species richness. However, forest area, elevation range and annual moisture index were intercorrelated. Previous knowledge of the relationship between elevation and tree communities suggests that the SAR is largely a result of habitat heterogeneity. Isolation by farmland (matrix habitat) also had a significant negative effect on species richness, probably exacerbated by hunting in small forests. The effect of area and isolation was less for transitory species. The human influence on species' presence/absence was negatively related to the extent of occurrence. Weaker relationships with temperature and precipitation suggest underlying climatic influences, and give some support for the influence of productivity. A reduced area relationship for smaller forests suggests that fragment sizes below 12–40 km2 may not be reliable for determining SAR in forest monkeys. Further practical implications are for management to encourage connectivity, and for future SAR research to consider residency, matrix classification and moisture besides precipitation. Am. J. Primatol. 72:325–336, 2010. © 2009 Wiley‐Liss, Inc.
Conservation Education and primates: twenty‐first century challenges and opportunities
Authors: Sherrow Hogan M.
Published: December 2009

Conservation Education has gone through a transformation since it was originally introduced. Numerous primatologists, working in all regions of the world where primates are endemic, have been extremely proactive in the application of Conservation Education (CE) and CE principles in their work. Here, I discuss the ongoing threats to primate populations around the world. Finally, I introduce a framework that can guide primatologists, as we move forward and face the challenges of the twenty‐first century. Am. J. Primatol. 72:420–424, 2010. © 2009 Wiley‐Liss, Inc.
Effective primate conservation education: gaps and opportunities
Authors: Jacobson Susan K.
Published: December 2009

Conservation education goals generally include influencing people's conservation awareness, attitudes, and behaviors. Effective programs can help foster sustainable behavior, improve public support for conservation, reduce vandalism and poaching in protected areas, improve compliance with conservation regulations, increase recreation carrying capacities, and influence policies and decisions that affect the environment. Primate conservation problems cut across many disciplines, and primate conservation education must likewise address crossdisciplinary issues. Conservation educators must incorporate both theoretical and practical knowledge and skills to develop effective programs, and the skill set must stretch beyond pedagogy. Expertize needed comes from the areas of planning, collaboration, psychology, entertainment, and evaluation. Integration of these elements can lead to greater program success. Am. J. Primatol. 72:414–419, 2010. © 2009 Wiley‐Liss, Inc.
Effects of reproductive condition and dominance rank on cortisol responsiveness to stress in free‐ranging female rhesus macaques
Authors: Hoffman Christy L. , Ayala James E. , Mas‐Rivera Adaris , Maestripieri Dario
Published: December 2009

The hypothalamic–pituitary–adrenal (HPA) axis modulates individuals' physiological responses to social stress, which is an inevitable aspect of the daily lives of group‐living animals. Previous nonhuman primate studies have reported that sex, age, rank, and reproductive condition influence cortisol levels under stressful conditions. In this study we investigated cortisol responses to stress among 70 multiparous, free‐ranging female rhesus macaques (Macaca mulatta) on the island of Cayo Santiago, PR. Plasma cortisol samples were collected in two consecutive years under similar conditions. Twenty‐two females were sampled both years, and most of those females were lactating in only one of the years. Individual differences in cortisol levels were stable across years, even though reproductive condition changed for most individuals. No relationship was found between age or social rank and cortisol levels. Of the females that changed reproductive conditions, cortisol levels were higher when they were lactating than when they were cycling, and the amount of change in cortisol from cycling to lactating was greatest for low‐ranking individuals. Heightened reactivity to stress during lactation may be the result of concerns about infant safety, and such concerns may be higher among low‐ranking mothers than among higher ranking mothers. Psychosocial stress and hyperactivation of the HPA axis during lactation can suppress immune function and increase vulnerability to infectious diseases, thus explaining why adult females in the free‐ranging rhesus macaque population on Cayo Santiago have a higher probability of mortality during the birth season than during the mating season. Am. J. Primatol. 72:559–565, 2010. © 2009 Wiley‐Liss, Inc.
Usefulness of species range polygons for predicting local primate occurrences in southeastern Peru
Authors: Palminteri Suzanne , Powell George , Endo Whaldener , Kirkby Chris , Yu Douglas , Peres Carlos A.
Published: December 2009

Species distribution maps are widely used in predicting areas of conservation concern, particularly where species distributions are poorly known. However, the accuracy of range maps for regional/local planning is questionable. We compared published putative geographic range polygons of ten primate species to their actual occupancy at 23 survey sites in southeastern Peru to assess the fine‐scale accuracy of these polygons for regional conservation planning. We analyzed the proportion of sites at which each species was detected, both inside and outside of its published NatureServe [Patterson et al., Digital distribution maps of the mammals of the western hemisphere. Version 1.0. Arlington, VA, 2003] and IUCN [2008; Red List, 2008] range polygons. There were mismatches between our line‐transect survey data and range polygon boundaries for nine of the ten species (from 15 to 80% cases), including both false presences and false absences. Each published dataset overestimated the presence of seven primate species and the absence of four species, though errors varied among species. Occupancy patterns of species with larger geographic ranges were no more accurately predicted than those of more narrow‐range species. Regional barriers to dispersal, such as rivers, and finer‐scale ecological specialization may limit the applicability of range map polygons to regional‐scale conservation priority setting, even for relatively well‐studied taxa. Despite the risk of errors, range polygons are still used as baseline data in conservation planning. We suggest some measures that could reduce the error risk. Am. J. Primatol. 73:53–61, 2011. © 2009 Wiley‐Liss, Inc.
Die klinische Chemie – Herausforderung der Medizin für die analytische Chemie und die Nanowissenschaften
Authors: Durner Jürgen
Published: December 2009

Die klinische Chemie und Laboratoriumsmedizin blickt auf eine über 150jährige, ereignisreiche Geschichte zurück. Das Fach repräsentiert einen Querschnitt zu allen medizinischen Disziplinen und den übrigen Naturwissenschaften. Die klinische Chemie zeigt, wie neue Erkenntnisse aus der biochemischen, biologischen, chemisch‐analytischen, technischen und informationstechnologischen Grundlagenforschung zum Nutzen einer verbesserten Diagnostik, Therapiekontrolle und Prävention in den medizinischen Alltag transferiert werden können. Im vorliegenden Aufsatz wird zunächst die Entwicklung der klinischen Chemie dargelegt. Anschließend werden die einzelnen Schritte von der Blutabnahme bis zum interpretierten Laborwert vorgestellt; hierbei werden sowohl Fallstricke als auch das Qualitätsmanagementsystem beschrieben. Der Einzug neuer Methoden und Trends in die medizinische Analytik wird ebenso erörtert wie Chancen und Probleme der personalisierten Medizin.
Clinical Chemistry: Challenges for Analytical Chemistry and the Nanosciences from Medicine
Authors: Durner Jürgen
Published: December 2009

Clinical chemistry and laboratory medicine can look back over more than 150 years of eventful history. The subject encompasses all the medicinal disciplines as well as the remaining natural sciences. Clinical chemistry demonstrates how new insights from basic research in biochemical, biological, analytical chemical, engineering, and information technology can be transferred into the daily routine of medicine to improve diagnosis, therapeutic monitoring, and prevention. This Review begins with a presentation of the development of clinical chemistry. Individual steps between the drawing of blood and interpretation of laboratory data are then illustrated; here not only are pitfalls described, but so are quality control systems. The introduction of new methods and trends into medicinal analysis is explored, along with opportunities and problems associated with personalized medicine.
The Developmental Remodeling of Eye‐Specific Afferents in the Ferret Dorsal Lateral Geniculate Nucleus
Authors: Speer Colenso M. , Mikula Shawn , Huberman Andrew D. , Chapman Barbara
Published: December 2009

Eye‐specific projections to the dorsal lateral geniculate nucleus (dLGN) serve as a model for exploring how precise patterns of circuitry form during development in the mammalian central nervous system. Using a combination of dual‐label anterograde retinogeniculate tracing and Nissl‐staining, we studied the patterns of eye‐specific afferents and cellular laminae in the dLGN of the pigmented sable ferret at eight developmental timepoints between birth and adulthood. Each time point was investigated in the three standard orthogonal planes of section, allowing us to generate a complete anatomical map of eye‐specific development in this species. We find that eye‐specific retinal ganglion cell axon segregation varies according to location in the dLGN, with the principle contralateral (A) and ipsilateral layers (A1) maturing first, followed by the contralateral and ipsilateral C laminae. Cytoarchitectural lamination lags behind eye‐specific segregation, except in the C laminae where underlying cellular layers never develop to accompany eye‐specific afferent domains. The emergence of On/Off sublaminae occurs following eye‐specific segregation in this species. On the basis of these findings, we constructed a three‐dimensional map of eye‐specific channels in the developing and mature ferret dLGN. Anat Rec, 293:1–24, 2010. © 2010 Wiley‐Liss, Inc.
The Developmental Remodeling of Eye‐Specific Afferents in the Ferret Dorsal Lateral Geniculate Nucleus
Authors: Speer Colenso M. , Mikula Shawn , Huberman Andrew D. , Chapman Barbara
Published: December 2009

Ferret vision mandala. This photo was created by overlapping multiple images of a horizontal section through the central portion of the adult ferret lateral geniculate nucleus and superior colliculus. The retinofugal projections from one eye were labeled with a green fluorescent tracer and those from the other eye with a red fluorescent tracer. See Speer, et al., on page 1, in this issue.
Decorrugation, edge detection, and modelling of total field magnetic observations from a historic town site, Yellowstone National Park, USA
Authors: Sheriff Steven D. , Macdonald Douglas , Dick David
Published: December 2009

Cinnabar, Montana is a historic town site and railroad depot near the northern edge of Yellowstone National Park and was inhabited between 1883 and 1903. Remains of foundations and old photographs help determine the area of the town, but the south and east limits are unknown. We acquired total field magnetic intensity data to help determine the full extent of the town. Randomly distributed ferrous magnetic sources on the surface and typical noise associated with acquisition complicate the signal. To separate signal and noise we applied filtering and edge detection techniques common in the aeromagnetic industry to our data. Regional removal, decorrugation, upward continuation, and edge detection successfully separated signal and noise. Following filtering, we extracted two larger anomalies from the data set. For those two anomalies, we estimated the edges of their causative sources by calculating the maxima in the horizontal gradient of their anomalies and by inverse modelling those sources; both methods yield similar results. An archaeological test unit excavation within one of the anomalies clearly indicates the remains of buried domestic features, the foundation to a house or other building associated with the late nineteenth to early twentieth century use of Cinnabar. Thus the southeast extent of Cinnabar is greater than previously thought. The lack of surface indicators or adequate historic photography precluded the identification of this buried feature without the aid of the magnetic study. Copyright © 2009 John Wiley & Sons, Ltd.
Inhibition of synovial hyperplasia, rheumatoid T cell activation, and experimental arthritis in mice by sulforaphane, a naturally occurring isothiocyanate
Authors: Kong Jin‐Sun , Yoo Seung‐Ah , Kim Hyun‐Sook , Kim Hyun Ah , Yea Kyungmoo , Ryu Sung‐Ho , Chung Yeun‐Jun , Cho Chul‐Soo , Kim Wan‐Uk
Published: December 2009

Objective

To investigate whether sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables such as broccoli, regulates synoviocyte hyperplasia and T cell activation in rheumatoid arthritis (RA).

Methods

Synoviocyte survival was assessed by MTT assay. The levels of Bcl‐2, Bax, p53, and pAkt were determined by Western blot analysis. Cytokine concentrations in culture supernatants from mononuclear cells were analyzed by enzyme‐linked immunosorbent assay. The in vivo effects of SFN were examined in mice with experimentally induced arthritis.

Results

SFN induced synoviocyte apoptosis by modulating the expression of Bcl‐2/Bax, p53, and pAkt. In addition, nonapoptotic doses of SFN inhibited T cell proliferation and the production of interleukin‐17 (IL‐17) and tumor necrosis factor α (TNFα) by RA CD4+ T cells stimulated with anti‐CD3 antibody. Anti‐CD3 antibody–induced increases in the expression of retinoic acid–related orphan receptor γt and T‐bet were also repressed by SFN. Moreover, the intraperitoneal administration of SFN to mice suppressed the clinical severity of arthritis induced by injection of type II collagen (CII), the anti‐CII antibody levels, and the T cell responses to CII. The production of IL‐17, TNFα, IL‐6, and interferon‐γ by lymph node cells and spleen cells from these mice was markedly reduced by treatment with SFN. Anti‐CII antibody–induced arthritis in mice was also alleviated by SFN injection.

Conclusion

SFN was found to inhibit synovial hyperplasia, activated T cell proliferation, and the production of IL‐17 and TNFα by rheumatoid T cells in vitro. The antiarthritic and immune regulatory effects of SFN, which were confirmed in vivo, suggest that SFN may offer a possible treatment option for RA.
Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus
Authors: Simpson Nicholas , Gatenby Paul A. , Wilson Anastasia , Malik Shreya , Fulcher David A. , Tangye Stuart G. , Manku Harinder , Vyse Timothy J. , Roncador Giovanna , Huttley Gavin A. , Goodnow Christopher C. , Vinuesa Carola G. , Cook Matthew C.
Published: December 2009

Objective

In the sanroque mouse model of lupus, pathologic germinal centers (GCs) arise due to increased numbers of follicular helper T (Tfh) cells, resulting in high‐affinity anti–double‐stranded DNA antibodies that cause end‐organ inflammation, such as glomerulonephritis. The purpose of this study was to examine the hypothesis that this pathway could account for a subset of patients with systemic lupus erythematosus (SLE).

Methods

An expansion of Tfh cells is a causal, and therefore consistent, component of the sanroque mouse phenotype. We validated the enumeration of circulating T cells resembling Tfh cells as a biomarker of this expansion in sanroque mice, and we performed a comprehensive comparison of the surface phenotype of circulating and tonsillar Tfh cells in humans. This circulating biomarker was enumerated in SLE patients (n = 46), Sjögren's syndrome patients (n = 17), and healthy controls (n = 48) and was correlated with disease activity and end‐organ involvement.

Results

In sanroque mice, circulating Tfh cells increased in proportion to their GC counterparts, making circulating Tfh cells a feasible human biomarker of this novel mechanism of breakdown in GC tolerance. In a subset of SLE patients (14 of 46), but in none of the controls, the levels of circulating Tfh cells (defined as circulating CXCR5+CD4+ cells with high expression of Tfh‐associated molecules, such as inducible T cell costimulator or programmed death 1) were increased. This cellular phenotype did not vary with time, disease activity, or treatment, but it did correlate with the diversity and titers of autoantibodies and with the severity of end‐organ involvement.

Conclusion

These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.
Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab
Authors: van Assen Sander , Holvast Albert , Benne Cornelis A. , Posthumus Marcel D. , van Leeuwen Miek A. , Voskuyl Alexandre E. , Blom Marlies , Risselada Anke P. , de Haan Aalzen , Westra Johanna , Kallenberg Cees G. M. , Bijl Marc
Published: December 2009

Objective

For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination.

Methods

Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4–8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6–10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity.

Results

Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX‐treated group and in healthy controls, but for no strains in the rituximab‐treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab‐treated group than in the MTX‐treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab‐treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab‐treated group, previously vaccinated patients in the rituximab‐treated group had higher pre‐ and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination.

Conclusion

Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6–10 months after rituximab administration. Previous influenza vaccination in rituximab‐treated patients increases pre‐ and postvaccination titers. RA activity was not influenced.
Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial
Authors: Bingham Clifton O. , Looney R. John , Deodhar Atul , Halsey Neal , Greenwald Maria , Codding Christine , Trzaskoma Benjamin , Martin Flavius , Agarwal Sunil , Kelman Ariella
Published: December 2009

Objective

To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab‐induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell–dependent antigen), pneumococcal polysaccharide (T cell–independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed‐type hypersensitivity (DTH).

Methods

In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab‐treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a ≥4‐fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti‐KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2–3 days following placement.

Results

Responses to tetanus toxoid vaccine (≥4‐fold rise) were similar in both groups (39.1% of rituximab‐treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab‐treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab‐treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2‐fold rise in titer in response to ≥1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti‐KLH IgG, compared with 93% of patients treated with MTX alone).

Conclusion

Recall responses to the T cell–dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab‐treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell–independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.
Thalidomide dramatically improves the symptoms of early‐onset Sarcoidosis/Blau syndrome: Its possible action and mechanism
Authors: Yasui Kozo , Yashiro Masato , Tsuge Mitsuru , Manki Akira , Takemoto Kei , Yamamoto Michiko , Morishima Tsuneo
Published: December 2009

Objective

Early‐onset sarcoidosis (EOS), which occurs in children younger than 5 years of age, is associated with granulomatous lesions and a sporadic genetic mutation of the nucleotide‐binding oligomerization domain 2 that causes constitutive NF‐κB activation. The symptoms of EOS can be uncontrollable, progressive, and associated with profound complications. However, appropriate therapy is still under investigation. The aim of this study was to assess the efficacy of thalidomide in patients with severe EOS, based on etiology supporting an initial role of NF‐κB in activation of this disease.

Methods

Thalidomide was given to 2 patients with EOS (a 16‐year‐old girl and an 8‐year‐old boy) at an initial dosage of 2 mg/kg/day, and the dosage was increased if necessary. To elucidate the mechanism of the drug, peripheral blood monocytes were isolated from the patients and stimulated with cytokines (macrophage colony‐stimulating factor, tumor necrosis factor α, and interleukin‐4), and their ability to form multinucleated giant cells (MGCs) and osteoclasts was measured.

Results

Both patients showed dramatic improvement of their clinical symptoms (alleviation of fever and optic nerve papillitis, achievement of a response according to the American College of Rheumatology Pediatric 50 and Pediatric 70 criteria) and laboratory findings. Monocytes from patients with EOS had a greater ability to survive and induce MGCs and osteoclasts than those from healthy control subjects. The formation of MGCs and osteoclasts was inhibited by the presence of thalidomide.

Conclusion

The ability of thalidomide to improve clinical symptoms and laboratory findings in patients with EOS indicates a central role for NF‐κB activity in this disorder. Inhibition of IKK might be a pharmacologic action by which thalidomide down‐regulates NF‐κB signaling. Thalidomide may be an effective medication in patients with severe complications of EOS, including ocular involvement.
Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients
Authors: Snir Omri , Widhe Mona , Hermansson Monika , von Spee Caroline , Lindberg Johan , Hensen Sanne , Lundberg Karin , Engström Åke , Venables Patrick J. W. , Toes René E. M. , Holmdahl Rikard , Klareskog Lars , Malmström Vivianne
Published: December 2009

Objective

High titers of specific anti–citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well‐defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA‐specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well‐defined HLA–DR groups.

Methods

Paired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age‐ and sex‐matched healthy controls were analyzed for the presence of anti‐MCV and anti‐CCP antibodies and for reactivity to citrullinated fibrinogen, α‐enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA–DR shared epitope alleles.

Results

Significantly higher proportions of antibodies against all RA‐associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non–RA‐associated anti–tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA–DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients.

Conclusion

MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti‐CCP+/anti‐MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA‐predisposing genes.
Novel role of plasmacytoid dendritic cells in humans: Induction of interleukin‐10–producing treg cells by plasmacytoid dendritic cells in patients with rheumatoid arthritis responding to therapy
Authors: Kavousanaki Melina , Makrigiannakis Antonis , Boumpas Dimitrios , Verginis Panayotis
Published: December 2009

Objective

Reestablishing immune tolerance and long‐term suppression of disease represent major therapeutic goals in rheumatoid arthritis (RA). Dendritic cells (DCs) likely play a central role in such regulation via the expansion and/or induction of Treg cells. The present study was undertaken to explore the contribution of DCs to the development of Treg cells in a human autoimmune disease setting.

Methods

DC subsets were characterized by flow cytometry in the peripheral blood and synovial fluid of patients with RA. Proliferation of and cytokine release by naive CD4+CD25− T cells were measured in cocultures of these cells with DCs from patients with RA and healthy controls. The suppressive capacity of DC‐polarized T cells was explored in vitro by a standard suppression assay.

Results

Only very low numbers of both plasmacytoid DCs (CD303+) and myeloid DCs (CD1c+) were present in the peripheral blood of patients with active RA. In contrast, patients with therapy‐induced remission of RA exhibited higher numbers of circulating plasmacytoid DCs. Mature plasmacytoid DCs from RA patients with low disease activity, but not those from healthy controls, expressed high levels of indoleamine 2,3‐dioxygenase and promoted the differentiation of allogeneic naive CD4+CD25− T cells into interleukin‐10–secreting Treg cells, or Tr1 cells, that showed poor proliferation in vitro. Importantly, these plasmacytoid DC–primed Treg cells potently suppressed the proliferation of autologous naive CD4+ T cells, in a dose‐dependent manner.

Conclusion

These results demonstrate, for the first time, that human plasmacytoid DCs may be educated within the rheumatoid microenvironment to acquire a tolerogenic phenotype. Modulation of the immune response by plasmacytoid DCs might provide novel immune‐based therapies in autoimmunity and transplantation.
1,25‐dihydroxyvitamin D3 modulates Th17 polarization and interleukin‐22 expression by memory T cells from patients with early rheumatoid arthritis
Authors: Colin E. M. , Asmawidjaja P. S. , van Hamburg J. P. , Mus A. M. C. , van Driel M. , Hazes J. M. W. , van Leeuwen J. P. T. M. , Lubberts E.
Published: December 2009

Objective

To examine the immunologic mechanism by which 1,25‐dihydroxyvitamin D3 (1,25[OH]2D3) may prevent corticosteroid‐induced osteoporosis in patients with early rheumatoid arthritis (RA), with a focus on T cell biology.

Methods

Peripheral blood mononuclear cells (PBMCs) and CD4+CD45RO+ (memory) and CD4+CD45RO− (non‐memory) T cells separated by fluorescence‐activated cell sorting (FACS) from treatment‐naive patients with early RA were stimulated with anti‐CD3/anti‐CD28 in the absence or presence of various concentrations of 1,25(OH)2D3, dexamethasone (DEX), and 1,25(OH)2D3 and DEX combined. Levels of T cell cytokines were determined by enzyme‐linked immunosorbent assay and flow cytometry.

Results

The presence of 1,25(OH)2D3 reduced interleukin‐17A (IL‐17A) and interferon‐γ levels and increased IL‐4 levels in stimulated PBMCs from treatment‐naive patients with early RA. In addition, 1,25(OH)2D3 had favorable effects on tumor necrosis factor α (TNFα):IL‐4 and IL‐17A:IL‐4 ratios and prevented the unfavorable effects of DEX on these ratios. Enhanced percentages of IL‐17A– and IL‐22–expressing CD4+ T cells and IL‐17A–expressing memory T cells were observed in PBMCs from treatment‐naive patients with early RA as compared with healthy controls. Of note, we found no difference in the percentage of CD45RO+ and CD45RO− cells between these 2 groups. Interestingly, 1,25(OH)2D3, in contrast to DEX, directly modulated human Th17 polarization, accompanied by suppression of IL‐17A, IL‐17F, TNFα, and IL‐22 production by memory T cells sorted by FACS from patients with early RA.

Conclusion

These data indicate that 1,25(OH)2D3 may contribute its bone‐sparing effects in RA patients taking corticosteroids by the modulation of Th17 polarization, inhibition of Th17 cytokines, and stimulation of IL‐4.
Rho kinase–dependent activation of SOX9 in chondrocytes
Authors: Haudenschild Dominik R. , Chen Jianfen , Pang Nina , Lotz Martin K. , D'Lima Darryl D.
Published: December 2009

Objective

The transcription factor SOX9 directly regulates the expression of the major proteoglycans and collagens comprising the cartilage extracellular matrix. The DNA binding activity and cellular localization of SOX9 is controlled through posttranslational modifications, including phosphorylation. The activity of Rho kinase (ROCK) has profound effects on the actin cytoskeleton, and these effects are instrumental in determining the phenotype and differentiation of chondrocytes. However, the mechanisms linking ROCK to altered chondrocyte gene expression remain unknown. The purpose of the present study was to test for a direct interaction between ROCK and SOX9.

Methods

Human SW1353 chondrosarcoma cells were transfected with constructs coding for RhoA, ROCK, Lim kinase, and SOX9. The interaction between ROCK and SOX9 was tested on purified proteins, and was verified within a cellular context using induced overexpression and activation of the Rho pathway. The effects of SOX9 transcriptional activation were quantified with a luciferase reporter plasmid containing SOX9 binding sites from the COL2A1 enhancer element.

Results

SOX9 was found to contain a consensus phosphorylation site for ROCK. In vitro, ROCK directly phosphorylated SOX9 at Ser181, and the overexpression of ROCK or the activation of the RhoA pathway in SW1353 chondrosarcoma cells increased SOX9Ser181 phosphorylation. ROCK caused a dose‐dependent increase in the transcription of a SOX9‐luciferase reporter construct, and increased phosphorylation and nuclear accumulation of SOX9 protein in response to transforming growth factor β treatment and mechanical compression.

Conclusion

These results demonstrate a new interaction that directly links ROCK to increased cartilage matrix production via activation of SOX9 in response to mechanical and growth factor stimulation.