bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical Chemistry: Challenges for Analytical Chemistry and the Nanosciences from Medicine
Authors: Durner Jürgen 
Published: December 2009

AbstractClinical 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

AbstractEye‐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

AbstractFerret 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

AbstractCinnabar, 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

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

AbstractObjectiveIn 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).MethodsAn 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.ResultsIn 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.ConclusionThese 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

AbstractObjectiveFor 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.MethodsTrivalent 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.ResultsFollowing 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.ConclusionRituximab 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

AbstractObjectiveTo 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).MethodsIn 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.ResultsResponses 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).ConclusionRecall 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

AbstractObjectiveEarly‐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.MethodsThalidomide 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.ResultsBoth 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.ConclusionThe 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

AbstractObjectiveHigh 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.MethodsPaired 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.ResultsSignificantly 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.ConclusionMCV 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

AbstractObjectiveReestablishing 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.MethodsDC 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.ResultsOnly 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.ConclusionThese 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

AbstractObjectiveTo 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.MethodsPeripheral 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.ResultsThe 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.ConclusionThese 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.