bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutrophils Sequestered in the Liver Suppress the Proinflammatory Response of Kupffer Cells to Systemic Bacterial Infection
Authors: Holub Martin , Cheng Chao-Wen , Mott Stephanie , Wintermeyer Philip , van Rooijen Nico , Gregory Stephen H.
Published: July 2009

The liver plays a major role in clearing bacteria from the bloodstream. Rapid clearance is primarily the function of fixed tissue macrophages (Kupffer cells) that line the hepatic sinusoids. Although Kupffer cells play a critical role in blood clearance, the actual elimination of the bulk of bacteria taken up by the liver depends upon the accumulation of bactericidal neutrophils. Subsequent experiments demonstrating neutrophils inside Kupffer cells derived from infected animals prompted our speculation that neutrophils modulate the proinflammatory response of Kupffer cells to bacteria cleared from the bloodstream. Indeed, we report here that neutrophils accumulated in the liver sinusoids suppress cytokine and chemokine mRNA expression and protein production by Kupffer cells. Using listeriosis in mice as an experimental model, we found that IL-1β, IL-6, IL-10, IL-12, TNF-α, MIP-1α, keratinocyte-derived chemokine, and MCP-1 mRNA levels were ≥10-fold more in the livers of Listeria-infected, relative to noninfected control, mice at 0.5–2 h after i.v. infection. Most message levels were sharply diminished thereafter, correlating inversely with increased neutrophil sequestration. Relative to intact animals, mice rendered neutrophil deficient exhibited marked increases in cytokine/chemokine mRNA expression and protein production in the liver subsequent to infection. Moreover, purified Kupffer cells derived from infected, neutrophil-depleted mice produced significantly more IL-6, IL-10, IL-12, TNF-α, keratinocyte-derived chemokine, and MCP-1 in culture. These findings document the critical role of neutrophils in moderating the proinflammatory response of Kupffer cells to bacteria taken up by the liver.
Membrane-Bound Fas Ligand Requires RIP1 for Efficient Activation of Caspase-8 within the Death-Inducing Signaling Complex
Authors: Morgan Michael J. , Kim You-Sun , Liu Zheng-gang
Published: July 2009

The serine-threonine kinase RIP1 was originally identified through its ability to bind to the death domain of Fas (CD95). RIP1 has been shown to be recruited to the Fas death-inducing signaling complex (DISC) and is required for the induction of necrotic cell death. In this study, we show that in Jurkat T lymphocytes, RIP1 is also necessary for the most efficient activation of downstream caspases by Fas when treated with membrane-bound Fas ligand, but not with agonistic Abs or cross-linked soluble Fas ligand. RIP1 participates in the Fas-associated death domain protein-mediated recruitment of caspase-8 to the Fas receptor complex in a manner that promotes caspase-8 activation. Cross-linking Abs, such as CH11, bypass the requirement for RIP1 in caspase activation by initiating larger, though less efficient, DISC complexes, while membrane-bound Fas ligand initiates a smaller but more efficient DISC that functions, in part, by effectively incorporating more RIP1 into the complex. Consequently, RIP1 is likely a more integral part of physiological signaling through the Fas/CD95 receptor complex than previously recognized; at least when the signal is mediated by full-length membrane-bound FasL. Cross-linked soluble FasL, which also occurs physiologically, behaves similarly to the CH11 Ab, and may therefore be more likely to initiate nonapoptotic Fas signaling due to less RIP1 in the receptor complex. Thus, agonists that bind the same Fas receptor initiate mechanistically distinct pathways resulting in differential cytotoxicity.
Lymphocytes in the Development of Lung Inflammation: A Role for Regulatory CD4+ T Cells in Indirect Pulmonary Lung Injury
Authors: Venet Fabienne , Chung Chun-Shiang , Huang Xin , Lomas-Neira Joanne , Chen Yaping , Ayala Alfred
Published: July 2009

Although roles for myelocytes have been suggested in the pathophysiology of indirect acute lung injury (ALI not due to a direct insult to the lung), the contribution of various regulatory lymphoid subsets is unknown. We hypothesized a role for lymphocytes in this process. Using a sequential model of indirect ALI induced in mice by hemorrhagic shock followed 24 h later by polymicrobial sepsis; we observed a specific and nonredundant role for each lymphocyte subpopulation in indirect ALI pathophysiology. In particular, we showed that CD4+ T cells are specifically recruited to the lung in a dendritic cell-independent but IL-16-dependent process and diminish neutrophil recruitment through increased IL-10 production. Most importantly, this appears to be mediated by the specific subpopulation of CD4+CD25+Foxp3+ regulatory T cells. Although indirect ALI has constantly been described as a proinflammatory pathology mediated by cells of the innate immune system, we now demonstrate that cells of the adaptive immune response play a major role in its pathophysiology as well. Most importantly, we also describe for the first time the nature of the regulatory mechanisms activated in the lung during indirect ALI, with CD4+ regulatory T cells being central to the control of neutrophil recruitment via increased IL-10 production.
GM-CSF Regulates Fusion of Mononuclear Osteoclasts into Bone-Resorbing Osteoclasts by Activating the Ras/ERK Pathway
Authors: Lee Myeung Su , Kim Hun Soo , Yeon Jeong-Tae , Choi Sik-Won , Chun Churl Hong , Kwak Han Bok , Oh Jaemin
Published: July 2009

Osteoclasts are multinucleated cells that are formed by the fusion of mononuclear osteoclasts, which is an essential process in bone resorption leading to bone remodeling. Herein we show that GM-CSF promoted the fusion of prefusion osteoclasts (pOCs). The expression of GM-CSF receptor-α was significantly up-regulated at the fusion stage of pOCs induced by RANKL. GM-CSF induced the expression of dendritic cell-specific transmembrane protein (DC-STAMP), which was mediated by inducing NFATc1 via induction of c-Fos. The expression of c-Fos and NFATc1 was regulated by the ERK signaling pathway. Inhibition of ERK and NFATc1 suppressed the expression of DC-STAMP and led to the fusion inhibition of pOC. However, retrovirus-mediated expression of NFATc1 in pOCs rescued the defect in pOC fusion, despite the presence of U0126 and cyclosporin A. GM-CSF-stimulated pOCs had an intact actin ring and could resorb bone. Importantly, pOCs infected with constitutively active MEK adenovirus expressed c-Fos and NFATc1, followed by the binding of NFATc1 to the DC-STAMP promoter, which enables its transcription and expression. Constitutively active MEK-infected pOCs are able to resorb bone by undergoing cell-cell fusion. Taken together, our results demonstrated that GM-CSF induced fusion of pOCs to form multinucleated osteoclasts, making the osteoclast capable of bone resorption.
Elucidation of CXCR7-Mediated Signaling Events and Inhibition of CXCR4-Mediated Tumor Cell Transendothelial Migration by CXCR7 Ligands
Authors: Zabel Brian A. , Wang Yu , Lewén Susanna , Berahovich Robert D. , Penfold Mark E. T. , Zhang Penglie , Powers Jay , Summers Bretton C. , Miao Zhenhua , Zhao Bin , Jalili Ali , Janowska-Wieczorek Anna , Jaen Juan C. , Schall Thomas J.
Published: July 2009

CXCR7 binds chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1) but does not act as a classical chemoattractant receptor. Using CCX771, a novel small molecule with high affinity and selectivity for CXCR7, we found that, although CXCR7 is dispensable for “bare filter” in vitro chemotaxis, CXCR7 plays an essential role in the CXCL12/CXCR4-mediated transendothelial migration (TEM) of CXCR4+CXCR7+ human tumor cells. Importantly, although CXCL11 is unable to stimulate directly the migration of these cells, it acts as a potent antagonist of their CXCL12-induced TEM. Furthermore, even though this TEM is driven by CXCR4, the CXCR7 ligand CCX771 is substantially more potent at inhibiting it than the CXCR4 antagonist AMD3100, which is more than 100 times weaker at inhibiting TEM when compared with its ability to block bare filter chemotaxis. Far from being a “silent” receptor, we show that CXCR7 displays early hallmark events associated with intracellular signaling. Upon cognate chemokine binding, CXCR7 associates with β-arrestin2, an interaction that can be blocked by CXCR7-specific mAbs. Remarkably, the synthetic CXCR7 ligand CCX771 also potently stimulates β-arrestin2 recruitment to CXCR7, with greater potency and efficacy than the endogenous chemokine ligands. These results indicate that CXCR7 can regulate CXCL12-mediated migratory cues, and thus may play a critical role in driving CXCR4+CXCR7+ tumor cell metastasis and tissue invasion. CXCR7 ligands, such as the chemokine CXCL11 and the newly described synthetic molecule CCX771, may represent novel therapeutic opportunities for the control of such cells.
T Cell Activation by Heat Shock Protein 70 Vaccine Requires TLR Signaling and Scavenger Receptor Expressed by Endothelial Cells-1
Authors: Gong Jianlin , Zhu Bangmin , Murshid Ayesha , Adachi Hideki , Song Baizheng , Lee Allegra , Liu Chunlei , Calderwood Stuart K.
Published: July 2009

Heat shock protein (HSP) 70 isolated from tumor-dendritic cell (DC) fusions (HSP70.PC-F) induces potent antitumor immunity and prevents growth of such tumors. In the present study, we have examined mechanisms underlying such antitumor activity of the HSP70.PC-F vaccine. The degree of antitumor immunity induced by HSP70.PC-F depended on intact TLR signaling in immunized animals, and mice in which the tlr2 and tlr4 genes were both inactivated did not respond to the vaccine. The reduced responses to HSP70.PC-F vaccine in such tlr knockout mice were restored by immunization of animals with HSP70.PC-F-pulsed wild-type DC, indicating a key role for this cell type in HSP70.PC-F-mediated immunity. Our studies also indicate a role for the scavenger receptor expressed by endothelial cells-1 (SREC-1) in antitumor immunity induced by HSP70.PC-F. These two receptor types appeared functionally interdependent, as indicated by the finding that tlr2 and tlr4 knockout decreases HSP70 binding in double-knockout DC and reduces SREC-1 expression. In addition, TLR-dependent, tumor cell killing was suppressed by SREC-1 knockdown in DC, suggesting a significant role for this receptor in HSP70.PC-F-mediated tumor immunity.
Psychological career resources as predictors of working adults’ career anchors: An exploratory study
Authors: Coetzee Melinde , Schreuder Dries
Published: July 2009

This study explored the relationship between the psychological career resources and career anchors of a sample of 2 997 working adults at predominantly managerial and supervisory levels in the service industry. The Psychological Career Resources Inventory and the Career Orientations Inventory were applied. Stepwise regression analyses indicated dimensions of psychological career resources as significant predictors of  participants’ career anchors. The findings add valuable new knowledge that can be used to inform organisational career development support practices as well as career counselling and guidance services concerned with promoting individuals’ employability and experiences of intrinsic career success.
IgA Plasma Cell Leukemia
Authors: Singh Tejinder , Premalata C S , Sajeevan K V , Jain Ankit , Batra Ullas , Saini K S , Satheesh C T , Babu K Govind , Lokanatha D
Published: July 2009

Plasma cell leukemia (PCL) is a rare entity. There are two presentations of PCL, primary or secondary. The primary or de novo form of PCL presents with an acute and rapidly progressive leukemic phase. This form occurs when the patient has no pre-existing multiple myeloma (MM). The secondary form is the most advanced form of MM. The PCL is a rare disorder representing 1‒2% of the diagnosed cases of MM. Median age at presentation is usually above 50 years. The monoclonal protein in patients with PCL may be IgG (50%), IgA (15%), or in rare cases IgD or IgE (6%). We report a case of IgA primary PCL that is very rare. Patient was started on combination therapy with vincristine, adriamycin, and dexamethasone. There was poor response and patient died three months after diagnosis.
Hunt for the Hidden Trait
Authors: Alwar Vanamala , Kavdia Reeti , Singh Nandini , Rameshkumar Karuna
Published: July 2009

Objective: To assess the efficacy of a peripheral smear examination as a screening tool for β-thalassemia trait.

Materials and Methods: 17 623 Leishman-stained peripheral smears were evaluated during the period from July 2006 to September 2007. The following parameters were studied: hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration and red cell distribution width. All the cases that showed microcytosis, hypochromia, erythrocytosis and absence of anisopoikilocytosis were suspected of having the thalassemia trait (TT), and all these cases were further evaluated with Alkaline Hemoglobin Electrophoresis for confirmation.

Results: Of the 17 623 smears examined, 60 cases were considered suspicious of having TT. Alkaline hemoglobin electrophoresis carried out on all these cases revealed an elevated HbA 2 (Mean = 7.5%). Five cases evaluated were found to have other hemoglobinopathies (1 Sickle cell trait, 3 Hb-E, 1 thalassemia intermedia).

Conclusion: Careful screening of peripheral smear is an invaluable screening tool for thalassemia trait (PPV - 95%). There must be awareness among the peripheral centers about the importance of peripheral smear screening and the affected persons should be counseled.
An Interesting Case of Lung Mass
Authors: Attili Venkata Satya Suresh , Reddy C Obula
Published: July 2009

A 46-year-male smoker presented with cough and fever to a chest physician, who on the basis of chest X-ray started him on antitubercular treatment. However, further evaluation suggested that the patient was suffering from a rare disease, i.e. Anaplastic large cell lymphoma of lung. Although lung involvement in cases of lymphoma is observed in as high as 40% of cases, in autopsy series, the exact clinical incidence is not known. One of the largest lymphoma groups reported it to be around 25%. However, primary pulmonary lymphomas have been extremely rare (0.4%), and whenever present they are of (Mucosa Associate Lymphoid tissue) MALT type, with occasional diffuse large cell lymphomas. The anaplastic variant is extremely uncommon. Usually the treatment results are satisfactory with more than 80% of the cases surviving even after 3 years. Here we report the case of anaplastic primary nonHodgkin′s lymphoma of lung and review the literature.
Perovskite oxide absorbents for oxygen separation
Authors: He Yufeng , Zhu Xuefeng , Li Qiming , Yang Weishen
Published: July 2009

The fixed‐bed oxygen absorption processes of the series of Ba1−xSrxCo0.8Fe0.2O3−δ oxides were studied by oxygen partial pressure swing absorption in the temperature range of 300–850°C. The results show that SrCo0.8Fe0.2O3−δ, with the smallest A‐site ion radius, has the largest oxygen absorption capacity (0.402 mmol/g) at 500°C. The oxygen absorption and desorption kinetics fit well with the pseudo‐second‐order kinetics model. Comparing the modeling absorption rate coefficient k2 with the desorption rate coefficient k2′, all the oxides studied had higher oxygen absorption rates than oxygen desorption ones. In addition, the combined results of X‐ray diffraction analysis, O2‐TPD, room temperature iodometric titration, and thermogravimetric analysis explained the relationship between the oxygen absorption capacities and the average radii of the A‐site ions for this series of Ba1−xSrxCo0.8Fe0.2O3−δ in the temperature range of 300–600°C. © 2009 American Institute of Chemical Engineers AIChE J, 2009
The course and correlates of high hospital utilization in sickle cell disease: Evidence from a large, urban Medicaid managed care organization
Authors: Carroll C. Patrick , Haywood Carlton , Fagan Peter , Lanzkron Sophie
Published: July 2009

Although most patients with sickle cell disease (SCD) are hospitalized infrequently and manage painful crises at home, a small subpopulation is frequently admitted to emergency departments and inpatient units. This small group accounts for the majority of health care expenses for patients with SCD. Using inpatient claims data from a large, urban Medicaid MCO for 5 consecutive years, this study sought to describe the course of high inpatient utilization (averaging four or more admissions enrolled per year for at least 1 year) in members with a diagnosis of SCD and a history of hospitalizations for vaso‐occlusive crisis. High utilizers were compared with the other members with SCD on demographics, medical and psychiatric comorbidity, and use of other health care resources. Members who were high utilizers had more diagnostic mentions of sickle cell complications than low utilizers. However, the pattern of high inpatient utilization was likely to moderate over successive years, and return to the pattern after moderation was uncommon. Despite this, a small subpopulation engaged in exceptional levels of inpatient utilization over multiple years. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.
Hydrogen Peroxide Induces G2 Cell Cycle Arrest and Inhibits Cell Proliferation in Osteoblasts
Authors: Li Ming , Zhao Li , Liu Jun , Liu An‐Ling , Zeng Wei‐Sen , Luo Shen‐Qiu , Bai Xiao‐Chun
Published: July 2009

Reactive oxygen species (ROSs) are involved in osteoporosis by inhibiting osteoblastic differentiation and stimulating osteoclastgenesis. Little is known about the role and how ROS controls proliferation of osteoblasts. Mammalian target of rapamycin, mTOR, is a central regulator of cell growth and proliferation. Here, we report for the first time that 5–200 μM hydrogen peroxide (H2O2) dose‐ and time‐dependently suppressed cell proliferation without affecting cell viability in mouse osteoblast cell line, MC3T3‐E1, and in human osteoblast‐like cell line, MG63. Further study revealed that protein level of cyclin B1 decreased markedly and the percentage of the cells in G2/M phase increased about 2‐4 fold by 200 μM H2O2 treatment for 24–72 hr. A total of 0.5–5 mM of H2O2 but not lower concentrations (5–200 μM) of H2O2 inhibited mTOR signaling, as manifested by dephosphorylation of S6K (T389), 4E‐BP1 (T37/46), and S6(S235/236) in MC3T3‐E1 and MG63 cells. Rapamycin, which could inhibit mTOR signaling and cell proliferation, however, did not reduce the protein level of cyclin B1. In a summary, H2O2 prevents cell proliferation of osteoblasts by down‐regulating cyclin B1 and inducing G2 cell cycle arrest. Inhibition of mTOR signaling by H2O2 may not be involved in this process. Anat Rec, 292:1107–1113, 2009. © 2009 Wiley‐Liss, Inc.
Gefitinib Inhibits the Proliferation of Pancreatic Cancer Cells via Cell Cycle Arrest
Authors: Zhou Xiaohua , Zheng Maqing , Chen Fang , Zhu Yunxia , Yong Wei , Lin Haiyan , Sun Yujie , Han Xiao
Published: July 2009

High expression of the epidermal growth factor receptor (EGFR) has been implicated in the development of pancreatic cancer. Gefitinib is an orally active and selective EGFR‐TKI (EGFR‐tyrosine kinase inhibitor) that blocks signal transduction pathways responsible for the proliferation and survival of cancer cells, and other host‐dependent processes promoting cancer growth. This study investigated the anticancer effect of gefitinib on human pancreatic cancer cells and the molecular mechanism involved. We first evaluated the effect of gefitinib on cell proliferation with MTT assay and the results demonstrated that gefitinib significantly inhibited the proliferation of pancreatic cancer cells. Flow cytometric analysis showed that gefitinib induced a delay in cell cycle progression and a G0/G1 arrest together with a G2/M block; these were associated with increased expression of p27Kip1 cyclin‐dependent kinase inhibitor combined with decreased expression of aurora B. Besides, luciferase reporter assay revealed that transcriptional mechanism was responsible for the down‐regulation of aurora B protein by gefitinib. Overall, the results suggest a mechanistic connection among these events to provide new insights into the mechanism underlying the antiproliferative effect of gefitinib on pancreatic cancer and supplement a theory basis of gefitinib in clinical treatment of pancreatic cancer. Anat Rec, 292:1122–1127, 2009. © 2009 Wiley‐Liss, Inc.
The Microanatomy of the Palatine Tonsils of the One‐Humped Camel (Camelus dromedarius)
Authors: Zidan Mohamed , Pabst Reinhard
Published: July 2009

Tonsils form a first line of defense against foreign antigens and are also a route of entry and a replication site for some pathogens. The palatine tonsils are the largest of all the tonsils. Despite their general importance, little is known about the microanatomy of the palatine tonsils of the one‐humped camel. Palatine tonsils of 10 clinically healthy male camels were obtained directly after slaughtering for human consumption. The tonsils were examined macroscopically and by light, scanning, and transmission electron microscopy. Palatine tonsils had the unique form of several spherical macroscopic nodules protruding into the pharyngeal lumen. These spherical masses were numerous and close together in the lateral oropharyngeal wall, with a few solitary nodules in the dorsal wall. Each nodule had one or two apical openings to crypts, and was enclosed by an incomplete connective tissue capsule and covered apically with stratified squamous keratinized epithelium. The tonsillar crypt was lined with stratified squamous non keratinized epithelium. Several lymphocytes infiltrated the epithelial layer, forming patches of reticular epithelium. Lymphoid follicles with obvious germinal centers extended under the epithelial surface. Diffusely localized lymphocytes were seen in the interfollicular region. High endothelial venules, dendritic cells, macrophages, and plasma cells were observed among these lymphocytes. The unique arrangement of palatine tonsils in separate units with individual crypts results in a very large surface exposed to antigen and indicates a significant immunological role of palatine tonsils in the camel. Anat Rec, 292:1192–1197, 2009. © 2009 Wiley‐Liss, Inc.
Expression of KiSS‐1 Gene and its Role in Invasion and Metastasis of Human Hepatocellular Carcinoma
Authors: Shengbing Zang , Jing Feng Liu , Bin Wang , Lingyun Gao , Aimin Huang
Published: July 2009

KiSS‐1 has been identified as a putative metastasis‐suppressor gene in human melanomas and breast cancer cell lines. Although loss of KiSS‐1 expression has been associated with progression and poor prognosis of various cancers, the exact role of KiSS‐1 expression in HCC is not well‐defined. Our study investigated KiSS‐1 expression levels in HCC and its role in invasion and metastasis of human HCC. The expression levels of KiSS‐1 and MMP‐9 protein were determined by tissue microarray (TMA) serial sections, immunohistochemistry and semi‐quantitative image analysis. All clinical and histological data obtained were subjected to statistical analysis. The expression of KiSS‐1 protein in HCC and intrahepatic metastasis lesions was significantly lower (P < 0.01) when compared with non‐tumor liver tissue and normal liver tissue. Multivariate analysis revealed a significant inverse correlation between KiSS‐1 expression and ○1
TNM stage, (F = 7.113, P < 0.01) and
○2intrahepatic metastasis (t = 2.898, P < 0.01). Loss of KiSS‐1 in intrahepatic metastasis versus primary carcinomas was statistically significant (P<0.01). We also found a negative correlation between KiSS‐1 and MMP‐9 expression in HCC (r = ‐0.506, P < 0.01). We conclude that loss of KiSS‐1 during HCC metastasis, along with a concomitant upregulation of MMP‐9 suggests a possible mechanism for cell motility and invasion during HCC metastasis, with KiSS‐1 emerging as a possible therapeutic target during HCC metastasis. Anat Rec, 292:1128–1134, 2009. © 2009 Wiley‐Liss, Inc.
Blood Flow Patterns Spatially Associated with Platelet Aggregates in Murine Colitis
Authors: Miele Lino F. , Turhan Aslihan , Lee Grace S. , Lin Miao , Ravnic Dino , Tsuda Akira , Konerding Moritz A. , Mentzer Steven J.
Published: July 2009

In the normal murine mucosal plexus, blood flow is generally smooth and continuous. In inflammatory conditions, such as chemically‐induced murine colitis, the mucosal plexus demonstrates markedly abnormal flow patterns. The inflamed mucosal plexus is associated with widely variable blood flow velocity as well as discontinuous and even bidirectional flow. To investigate the mechanisms responsible for these blood flow patterns, we used intravital microscopic examination of blood flow within the murine mucosal plexus during dextran sodium sulphate‐and trinitrobenzenesulfonic acid‐induced colitis. The blood flow patterns within the mucosal plexus demonstrated flow exclusion in 18% of the vessel segments (P < 0.01). Associated with these segmental exclusions was significant variation in neighboring flow velocities. Intravascular injection of fluorescent platelets demonstrated platelet incorporation into both fixed and rolling platelet aggregates. Rolling platelet aggregates (mean velocity 113 μm/sec; range, 14–186 μm/sec) were associated with reversible occlusions and flow variations within the mucosal plexus. Gene expression profiles of microdissected mucosal plexus demonstrated enhanced expression of genes for CCL3, CXCL1, CCL2, CXCL5, CCL7, CCL8, and Il‐1b (P < 0.01), and decreased expression of CCL6 (P < 0.01). These results suggest that platelet aggregation, activated by the inflammatory mileau, contributes to the complex flow dynamics observed in acute murine colitis. Anat Rec, 292:1143–1153, 2009. © 2009 Wiley‐Liss, Inc.
Predictors of early inactive disease in a juvenile idiopathic arthritis cohort: Results of a Canadian multicenter, prospective inception cohort study
Authors: Oen Kiem , Tucker Lori , Huber Adam M. , Miettunen Paivi , Scuccimarri Rosie , Campillo Sarah , Cabral David A. , Feldman Brian M. , Tse Shirley , Chédeville Gaëlle , Spiegel Lynn , Schneider Rayfel , Lang Bianca , Ellsworth Janet , Ramsey Suzanne , Dancey Paul , Silverman Earl , Chetaille Anne‐Laure , Cameron Bonnie , Johnson Nicole , Dorval Jean , Petty Ross E. , Duffy Karen Watanabe , Boire Gilles , Haddad Elie , Houghton Kristin , Saint‐Cyr Claire , Turvey Stuart E. , Benseler Susanne , Cheang Mary , Yeung Rae S. M. , Duffy Ciarán M.
Published: July 2009

Objective

To determine early predictors of 6‐month outcomes in a prospective cohort of patients with juvenile idiopathic arthritis (JIA).

Methods

Patients selected were those enrolled in an inception cohort study of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study, within 6 months after diagnosis. The juvenile rheumatoid arthritis core criteria set and quality of life measures were collected at enrollment and 6 months later. Outcomes evaluated included inactive disease, Juvenile Arthritis Quality of Life Questionnaire (JAQQ) scores, and Childhood Health Assessment Questionnaire (C‐HAQ) scores at 6 months.

Results

Thirty‐three percent of patients had inactive disease at 6 months. Onset subtype and most baseline core criteria set measures correlated with all 3 outcomes. Relative to oligoarticular JIA, the risks of inactive disease were lower for enthesitis‐related arthritis, polyarthritis rheumatoid factor (RF)–negative JIA, and polyarthritis RF‐positive JIA, and were similar for psoriatic arthritis. In multiple regression analyses, the baseline JAQQ score was an independent predictor of all 3 outcomes. Other independent baseline predictors included polyarthritis RF‐negative and systemic JIA for inactive disease; C‐HAQ score and polyarthritis RF‐positive JIA for the 6‐month C‐HAQ score; and active joint count, pain, and time to diagnosis for the 6‐month JAQQ score.

Conclusion

Clinical measures soon after diagnosis predict short‐term outcomes for patients with JIA. The JAQQ is a predictor of multiple outcomes. Time to diagnosis affects quality of life in the short term.
The effects of impaired joint position sense on the development and progression of pain and structural damage in knee osteoarthritis
Authors: Felson David T. , Gross K. Douglas , Nevitt Michael C. , Yang Mei , Lane Nancy E. , Torner James C. , Lewis Cora E. , Hurley Michael V.
Published: July 2009

Objective

Although cross‐sectional studies have reported impaired proprioceptive acuity in people with osteoarthritis (OA), there have been no longitudinal studies to evaluate whether those with such impairments increase the risk of OA or its worsening.

Methods

We studied subjects from the Multicenter Osteoarthritis Study study, a longitudinal study of people with or at high risk of knee OA. At baseline, we quantified acuity as the amount of a subject's error when attempting to reproduce a test knee flexion angle (a measure of joint position sense). We tested proprioception 10 times in the right leg and used a person's worst score as their proprioceptive acuity. At baseline and the 30‐month followup, we assessed the presence of frequent pain, obtained Western Ontario and McMasters Universities OA Index (WOMAC) scores, and acquired posteroanterior and lateral weight‐bearing knee radiographs read for Kellgren/Lawrence grade and individual radiographic features. We examined the relation of baseline proprioceptive acuity in quartiles with baseline knee pain (frequent pain yes/no), WOMAC pain score, self‐reported physical function, and radiographic OA, and with changes from baseline in pain, physical function, and radiographic OA adjusted for age, sex, body mass index, and quadriceps strength.

Results

At baseline, proprioceptive acuity was associated with the presence and severity of knee pain but not with the presence of radiographic OA. However, among the 2,243 subjects with baseline acuity assessments and 30‐month followup, there were no strong associations between proprioceptive acuity and development of adverse OA outcomes. Acuity was not significantly associated with the new onset of frequent knee pain. Those with the worst acuity at baseline had slightly greater worsening of WOMAC pain scores (0.47 on a 20‐point scale) and physical function scores (by 1.5 points on a 0–68‐point scale) compared with those with the best proprioceptive acuity, whose pain and physical function score deteriorated less (for pain P = 0.05; for physical function P = 0.02). Radiographic worsening was not significantly associated with proprioceptive acuity.

Conclusion

Proprioceptive acuity as assessed by the accuracy of reproduction of the angle of knee flexion had modest effects on the trajectory of pain and physical functional limitation in knee OA.
Noninvasive imaging techniques in the assessment of scleroderma spectrum disorders
Authors: Murray Andrea K. , Moore Tonia L. , Manning Joanne B. , Taylor Christopher , Griffiths Christopher E. M. , Herrick Ariane L.
Published: July 2009

Objective

Systemic sclerosis (SSc) affects both microvascular structure and function. Laser Doppler imaging (LDI) and thermal imaging can be used to measure cutaneous blood vessel function. Nailfold capillaroscopy (NC) measures capillary morphology. The aim of this study was to investigate the relationship between capillary morphology and blood flow, and to determine which combination of techniques allows the best discrimination between patients with SSc, primary Raynaud's phenomenon (RP), and healthy controls.

Methods

NC was performed in 16 patients with SSc, 14 patients with primary RP, and 16 healthy controls. In addition, participants underwent cold stimulus with cold water. Hands were imaged to monitor rewarming and reperfusion. Nailfold morphologic features were measured and baseline images and rewarming curves were analyzed.

Results

Significant differences were found between groups (analysis of variance) for capillary morphologic features and rewarming curve characteristics. A correlation (P < 0.001) was found between LDI and thermal imaging at baseline (0.667) and maximum (0.729) blood flow and skin temperature, and for the areas under the rewarming curves (0.684). Receiver operating characteristic curves indicated that NC, thermal imaging, and LDI allowed 89%, 74%, and 72%, respectively, of SSc patient data to be correctly classified versus primary RP patients and controls.

Conclusion

NC, LDI, and thermal imaging each independently provide good discrimination between patients with SSc and those with primary RP and healthy controls (NC being the most suitable technique for classifying patient groups). However, a combination of all 3 techniques improves classification. LDI and thermal imaging give equivalent information on dynamic changes in the cutaneous microcirculation; however, these only weakly correspond to capillary morphology.
Depression, inflammation, and pain in patients with rheumatoid arthritis
Authors: Kojima Masayo , Kojima Toshihisa , Suzuki Sadao , Oguchi Takeshi , Oba Michinari , Tsuchiya Hiroki , Sugiura Fumiaki , Kanayama Yasuhide , Furukawa Toshiaki A. , Tokudome Shinkan , Ishiguro Naoki
Published: July 2009

Objective

An association between depression and inflammation has been suggested. In patients with rheumatoid arthritis (RA), pain is a major symptom associated with depression and inflammation. We examined the independent associations between depression, the inflammation marker C‐reactive protein (CRP) level, and pain in patients with RA.

Methods

In total, 218 RA outpatients completed self‐administered questionnaires, using the Beck Depression Inventory II to measure depressive symptoms and a visual analog scale to quantify their perceived pain. Functional disability and CRP level were also measured.

Results

Depression scores were mildly and positively correlated with the CRP level (r = 0.46, P < 0.001). Both the depression score (standardized β = 0.35, P < 0.001) and the CRP level (standardized β = 0.35, P < 0.001) were significantly associated with pain, even after adjustment for clinical covariates in regression analysis. In logistic analysis, the combined effects on the risk of severe pain (pain score in the upper tertile) increased with depression scores and CRP levels linearly.

Conclusion

Depression severity and inflammation were associated with each other and appeared to have independent effects on perceived pain. Therefore, a clinical approach that takes into account both the body and the mind could have benefits and could enable optimal pain control.
Hypoxia and glucocorticoid signaling converge to regulate macrophage migration inhibitory factor gene expression
Authors: Elsby Laura M. , Donn Rachelle , Alourfi Zaynab , Green Laura M. , Beaulieu Elaine , Ray David W.
Published: July 2009

Objective

Macrophage migration inhibitory factor (MIF) is a proinflammatory mediator involved in the pathogenesis of rheumatoid arthritis. This study was undertaken to identify the MIF promoter elements responsible for regulating gene expression.

Methods

Luciferase reporter gene assays were used to identify the MIF promoter sequence responsible for basal activity. Bioinformatic analysis was used to predict transcription factor binding sites, and electrophoretic mobility shift assay (EMSA) was used to demonstrate transcription factor binding. Chromatin immunoprecipitation (ChIP) was used to demonstrate transcription factor loading on the MIF promoter.

Results

We identified the minimal promoter sequence required for basal MIF promoter activity that was also capable of conferring glucocorticoid‐dependent inhibition in a T lymphocyte model cell line. Deletion studies and EMSA revealed 2 elements in the MIF promoter that were responsible for basal promoter activity. The 5′ element binds CREB/activating transcription factor 1, and the 3′ element is a functional hypoxia‐responsive element binding hypoxia‐inducible factor 1α. Further studies demonstrated that the cis elements are both required for glucocorticoid‐dependent inhibition. ChIP demonstrated glucocorticoid‐dependent recruitment of glucocorticoid receptor α to the MIF promoter in lymphocytes within 1 hour of treatment and a concomitant decrease in acetylated histone H3.

Conclusion

Our findings indicate that hypoxia and glucocorticoid signaling converge on a single element regulating MIF; this regulatory unit is a potential interacting node for microenvironment sensing of oxygen tension and glucocorticoid action in foci of inflammation.
Prevalence of and predictive factors for sustained disease‐modifying antirheumatic drug–free remission in rheumatoid arthritis: Results from two large early arthritis cohorts
Authors: van der Woude Diane , Young Adam , Jayakumar Keeranur , Mertens Bart J. , Toes René E. M. , van der Heijde Désirée , Huizinga Tom W. J. , van der Helm‐van Mil Annette H. M.
Published: July 2009

Objective

Remission has become an attainable goal of rheumatoid arthritis (RA) treatment, especially since the advent of biologic antirheumatic therapy. Because little is known about patients who achieve disease remission with conventional treatment, we used 2 large independent inception cohorts to study the prevalence of and predictive factors for disease‐modifying antirheumatic drug (DMARD)–free sustained remission after treatment with conventional therapy.

Methods

Remission of disease was assessed in 454 patients from the Leiden Early Arthritis Clinic (EAC) and in 895 patients from the British Early Rheumatoid Arthritis Study (ERAS) who fulfilled the American College of Rheumatology 1987 revised criteria for the classification of RA and were treated with conventional therapy. Sustained DMARD‐free remission was defined as fulfilling the following criteria for at least 1 year: 1) no current DMARD use, 2) no swollen joints, and 3) classification as DMARD‐free remission by the patient's rheumatologist. Predictive factors were identified by Cox regression analysis.

Results

Sustained DMARD‐free remission was achieved by 68 of 454 patients (15.0%) in the Leiden EAC and by 84 of 895 patients (9.4%) in the ERAS. Six factors were associated with sustained DMARD‐free remission in both cohorts: acute onset, short symptom duration before inclusion, not smoking, little radiographic damage at baseline, absence of IgM rheumatoid factor (IgM‐RF), and absence of HLA shared epitope alleles. In the ERAS, low disease activity at baseline was also predictive of remission. Multivariate analyses revealed symptom duration and the absence of autoantibodies (anti–cyclic citrullinated peptide 2 and IgM‐RF) as independent predictors.

Conclusion

Sustained DMARD‐free remission in RA patients treated with conventional therapy is not uncommon. Symptom duration at presentation and the absence of autoantibodies are associated with sustained DMARD‐free remission.
Dysfunctional proinflammatory high‐density lipoproteins confer increased risk of atherosclerosis in women with systemic lupus erythematosus
Authors: McMahon Maureen , Grossman Jennifer , Skaggs Brian , FitzGerald John , Sahakian Lori , Ragavendra Nagesh , Charles‐Schoeman Christina , Watson Karol , Wong Weng Kee , Volkmann Elizabeth , Chen Weiling , Gorn Alan , Karpouzas George , Weisman Michael , Wallace Daniel J. , Hahn Bevra H.
Published: July 2009

Objective

Women with systemic lupus erythematosus (SLE) have an increased risk of atherosclerosis. Identification of at‐risk patients and the etiology underlying atherosclerosis in SLE remain elusive. The antioxidant capacity of normal high‐density lipoproteins (HDLs) is lost during inflammation, and these dysfunctional HDLs might predispose individuals to atherosclerosis. The aim of this study was to determine whether dysfunctional proinflammatory HDL (piHDL) is associated with subclinical atherosclerosis in SLE.

Methods

Carotid artery ultrasound was performed in 276 women with SLE to identify carotid plaques and measure intima‐media thickness (IMT). The antioxidant function of HDL was measured as the change in oxidation of low‐density lipoprotein after the addition of HDL cholesterol. Two antiinflammatory HDL components, paraoxonase 1 and apolipoprotein A‐I, were also measured.

Results

Among the SLE patients, 48.2% were determined to have piHDL on carotid ultrasound, while 86.7% of patients with plaque had piHDL compared with 40.7% of those without plaque (P < 0.001). Patients with piHDL also had a higher IMT (P < 0.001). After multivariate analysis, the only factors found to be significantly associated with plaque were the presence of piHDL (odds ratio [OR] 16.1, P < 0.001), older age (OR 1.2, P < 0.001), hypertension (OR 3.0, P = 0.04), dyslipidemia (OR 3.4, P = 0.04), and mixed racial background (OR 8.3, P = 0.04). Factors associated with IMT measurements in the highest quartile were the presence of piHDL (OR 2.5, P = 0.02), older age (OR 1.1, P < 0.001), a higher body mass index (OR 1.07, P = 0.04), a cumulative lifetime prednisone dose ≥20 gm (OR 2.9, P = 0.04), and African American race (OR 8.3, P = 0.001).

Conclusion

Dysfunctional piHDL greatly increases the risk of developing subclinical atherosclerosis in SLE. The presence of piHDL was associated with an increased prevalence of carotid plaque and with a higher IMT. Therefore, determination of piHDL may help identify patients at risk for atherosclerosis.
Studies of cell‐mediated immune responses to influenza vaccination in systemic lupus erythematosus
Authors: Holvast Albert , van Assen Sander , de Haan Aalzen , Huckriede Anke , Benne Cornelis A. , Westra Johanna , Palache Abraham , Wilschut Jan , Kallenberg Cees G. M. , Bijl Marc
Published: July 2009

Objective

Both antibody and cell‐mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell‐mediated responses have not yet been assessed. This study was therefore undertaken to assess cell‐mediated responses to influenza vaccination in patients with SLE.

Methods

Fifty‐four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell‐mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon‐γ (IFNγ) enzyme‐linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test.

Results

Prior to vaccination, patients with SLE had fewer IFNγ spot‐forming cells against A/H1N1 compared with control subjects and a lower frequency of IFNγ‐positive CD8+ T cells. After vaccination, the number of IFNγ spot‐forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin‐2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2‐specific responses, results were comparable. Diminished cell‐mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1‐specific and A/H3N2‐specific antibody titers after vaccination was lower in patients compared with control subjects.

Conclusion

In addition to a decreased antibody response, cell‐mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.
Course of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: Analysis of three large multicenter, double‐blind, randomized controlled trials
Authors: Amjadi Sogol , Maranian Paul , Furst Daniel E. , Clements Philip J. , Wong Weng Kee , Postlethwaite Arnold E. , Khanna Puja P. , Khanna Dinesh
Published: July 2009

Objective

To assess the course of the modified Rodnan skin thickness score (MRSS) in 3 large, multicenter, double‐blind, randomized controlled trials (RCTs) of patients with diffuse cutaneous systemic sclerosis (dcSSc) with different baseline disease durations, as defined from the date of onset of the first dcSSc symptom (excluding Raynaud's phenomenon) or from the date of onset of the first dcSSc‐related symptom (including Raynaud's phenomenon).

Methods

Data from 3 RCTs examining high‐dose versus low‐dose D‐penicillamine (D‐Pen Trial), recombinant human relaxin versus placebo (Relaxin Trial), and oral bovine type I collagen versus placebo (Collagen Trial) treatment in patients with dcSSc were pooled and analyzed. Patients were divided into 5 groups according to their disease duration at baseline. The linear mixed model for correlated data was used to model the 2 predictors of MRSS: time in study (expressed in months after baseline) and baseline disease duration (expressed in months, calculated from the date of onset of the first symptom characteristic of dcSSc with and without Raynaud's phenomenon).

Results

At study entry, the mean MRSS value was 21.0 in the D‐Pen Trial cohort, 27.3 in the Relaxin Trial cohort, and 26.1 in the Collagen Trial cohort. Time in study was a significant predictor of improvement in MRSS regardless of the disease duration at baseline (P < 0.0001). Patients with a disease duration of ≥24 months showed a greater rate of decline as compared with patients with a disease duration of <24 months (P < 0.05). Similar results were obtained when disease duration was reclassified by including the time of the first Raynaud's phenomenon symptom in the definition.

Conclusion

Our study confirms recent findings that in patients entered into these 3 RCTs, skin thickening did not follow the same trend in natural history as that seen in the dcSSc populations entered into early, open longitudinal studies previously reported. These findings have important implications for study design, in which “prevention of worsening” is the main objective.
Independent association of anti–β2‐glycoprotein I antibodies with macrovascular disease and mortality in scleroderma patients
Authors: Boin Francesco , Franchini Stefano , Colantuoni Elizabeth , Rosen Antony , Wigley Fredrick M. , Casciola‐Rosen Livia
Published: July 2009

Objective

Systemic sclerosis (SSc; scleroderma) is characterized by a unique widespread vascular involvement that can lead to severe digital ischemia, pulmonary arterial hypertension (PAH), or other organ dysfunction. Microthrombotic events and procoagulation factors such as anti–β2‐glycoprotein I (anti‐β2GPI) or anticardiolipin antibodies (aCL) may be implicated in the development of these manifestations. This study was undertaken to investigate whether anti‐β2GPI and aCL are correlated with macrovascular disease, including ischemic digital loss and PAH, in SSc patients.

Methods

Seventy‐five SSc patients with a history of ischemic digital loss and 75 matched SSc controls were evaluated. Anticentromere antibodies (ACAs), anti‐β2GPI, and aCL were measured, and clinical associations were determined using conditional and simple logistic regression models.

Results

Positivity for anti‐β2GPI was significantly more frequent in SSc patients with digital loss than in patients without digital loss (P = 0.017), with the IgA isotype of anti‐β2GPI showing the strongest association (odds ratio [OR] 4.0). There was no significant difference in aCL frequency between patients with digital loss and control patients. After adjustment for demographic characteristics, disease type, smoking, and ACA, anti‐β2GPI positivity was significantly associated with active digital ischemia (OR 9.4), echocardiographically evident PAH (OR 4.8), and mortality (OR 2.9). ACA positivity was associated with history of digital loss (OR 3.28), but not with PAH or mortality. History of digital loss was strongly associated with increased mortality (OR 12.5).

Conclusion

Anti‐β2GPI is significantly associated with macrovascular disease in SSc and independently predicts mortality. It is unclear whether it has a pathogenetic role or simply reveals the presence of underlying endothelial injury. The use of anti‐β2GPI as a biomarker of vascular disease in SSc should be further explored.