bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intrauterine Exposure to Maternal Diabetes Is Associated With Higher Adiposity and Insulin Resistance and Clustering of Cardiovascular Risk Markers in Indian Children
Authors: Krishnaveni Ghattu V. , Veena Sargoor R. , Hill Jacqueline C. , Kehoe Sarah , Karat Samuel C. , Fall Caroline H.D. 
Published: November 2009

OBJECTIVE
To test the hypothesis that maternal gestational diabetes increases cardiovascular risk markers in Indian children.

RESEARCH DESIGN AND METHODS
Anthropometry, blood pressure, and glucose/insulin concentrations were measured in 514 children at 5 and 9.5 years of age (35 offspring of diabetic mothers [ODMs], 39 offspring of diabetic fathers [ODFs]). Children of nondiabetic parents were control subjects.

RESULTS
At age 9.5 years, female ODMs had larger skinfolds (P &lt; 0.001), higher glucose (30 min) and insulin concentrations, and higher homeostasis model assessment (HOMA) of insulin resistance and systolic blood pressure (P &lt; 0.05) than control subjects. Male ODMs had higher HOMA (P &lt; 0.01). Associations were stronger than at age 5 years. Female ODFs had larger skinfolds and male ODFs had higher HOMA (P &lt; 0.05) than control subjects; associations were weaker than for ODMs. Associations between outcomes in control subjects and parental BMI, glucose, and insulin concentrations were similar for mothers and fathers.

CONCLUSIONS
The intrauterine environment experienced by ODMs increases diabetes and cardiovascular risk over genetic factors; the effects strengthen during childhood.
Decaffeinated Coffee and Glucose Metabolism in Young Men
Authors: Greenberg James A. , Owen David R. , Geliebter Allan 
Published: November 2009

OBJECTIVE
The epidemiological association between coffee drinking and decreased risk of type 2 diabetes is strong. However, caffeinated coffee acutely impairs glucose metabolism. We assessed acute effects of decaffeinated coffee on glucose and insulin levels.

RESEARCH DESIGN AND METHODS
This was a randomized, cross-over, placebo-controlled trial of the effects of decaffeinated coffee, caffeinated coffee, and caffeine on glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) levels during a 2-h oral glucose tolerance test (OGTT) in 11 young men.

RESULTS
Within the first hour of the OGTT, glucose and insulin were higher for decaffeinated coffee than for placebo (P &lt; 0.05). During the whole OGTT, decaffeinated coffee yielded higher insulin than placebo and lower glucose and a higher insulin sensitivity index than caffeine. Changes in GIP could not explain any beverage effects on glucose and insulin.

CONCLUSIONS
Some types of decaffeinated coffee may acutely impair glucose metabolism but less than caffeine.
Aspirin Is Associated With Reduced Cardiovascular and All-Cause Mortality in Type 2 Diabetes in a Primary Prevention Setting
Authors: Ong Greg , Davis Timothy M.E. , Davis Wendy A. 
Published: November 2009

OBJECTIVE
To determine whether regular aspirin use (≥75 mg/day) is independently associated with cardiovascular disease (CVD) and all-cause mortality in community-based patients with type 2 diabetes and no history of CVD.

RESEARCH DESIGN AND METHODS
Of the type 2 diabetic patients recruited to the longitudinal observational Fremantle Diabetes Study, 651 (50.3%) with no prior CVD history at entry between 1993 and 1996 were followed until death or the end of June 2007, representing a total of 7,537 patient-years (mean ± SD 11.6 ± 2.9 years). Cox proportional hazards modeling was used to determine independent baseline predictors of CVD and all-cause mortality including regular aspirin use.

RESULTS
There were 160 deaths (24.6%) during follow-up, with 70 (43.8%) due to CVD. In Kaplan-Meier survival analysis, there was no difference in either CVD or all-cause mortality in aspirin users versus nonusers (P = 0.52 and 0.94, respectively, by log-rank test). After adjustment for significant variables in the most parsimonious Cox models, regular aspirin use at baseline independently predicted reduced CVD and all-cause mortality (hazard ratio [HR] 0.30 [95% CI 0.09–0.95] and 0.53 [0.28–0.98[, respectively; P ≤ 0.044). In subgroup analyses, aspirin use was independently associated with reduced all-cause mortality in those aged ≥65 years and men.

CONCLUSIONS
Regular low-dose aspirin may reduce all-cause and CVD mortality in a primary prevention setting in type 2 diabetes. All-cause mortality reductions are greatest in men and in those aged ≥65 years. The present observational data support recommendations that aspirin should be used in primary CVD prevention in all but the lowest risk patients.
Initial evaluation of the Roche COBAS TaqMan HIV-1 v2.0 assay for determining viral load in HIV-infected individuals
Authors: Taylor Ninon , Schmid Ilse , Egle Alexander , Greil Richard , Patsch Wolfgang , Oberkofer Hannes 
Published: November 2009

Background HIV type-1 (HIV-1) genetic diversity poses a challenge for the development of diagnostic tests based on nucleic acid amplification, which can be overcome, at least in part, by targeting multiple genomic regions. The new Roche Diagnostics COBAS TaqMan (CTM) HIV-1 v2.0 assay uses multiplex real-time PCR detection of sequences in the long terminal repeat and gag regions within the HIV-1 genome. Methods We conducted initial comparative testing of HIV-1 viral load values in plasma samples from HIV-1-infected individuals using the Abbott RealTime HIV-1 (Abbott RT HIV-1), and the Roche CTM v1.0 and CTM v2.0 real-time PCR amplification systems, with a particular focus on patients previously undetectable or underestimated with the CTM v1.0 assay. Results The new Roche CTM v2.0 assay showed excellent agreement with the other two assays over a wide dynamic range ( r=0.9685). The assay also allowed accurate determination of viral load levels in individuals infected with HIV-1 isolates that were found falsely negative or underestimated with the Roche CTM v1.0 assay because of mutations within the gag region. Conclusions The reliability and accuracy of the CTM v2.0 assay is similar to the Abbott RT HIV-1 assay. The implementation of a multiplex real-time PCR approach in the CTM v2.0 is a significant improvement in viral load testing in comparison with the CTM v1.0 assay.
Agreement Between Quantiferon-TB Gold Test and Tuberculin Skin Test in the Identification of Latent Tuberculosis Infection in Patients with Rheumatoid Arthritis and Ankylosing Spondylitis
Authors: INANC NEVSUN , AYDIN SIBEL ZEHRA , KARAKURT SAIT , ATAGUNDUZ PAMIR , YAVUZ SULE , DIRESKENELI HANER 
Published: November 2009

Objective.To compare the Quantiferon-TB Gold test (QTF-G) with the tuberculin skin test (TST) for the detection of latent tuberculosis infection (LTBI) among patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS), with reevaluation of the patients treated with tumor necrosis factor-α (TNF-α) antagonists in the followup.Methods.The study involved 140 consecutive patients, 82 with RA and 58 with AS. Thirty patients were evaluated with QTF-G for detection of LTBI before and after 6 months of TNF-α antagonist treatment. QTF-G was also performed on 49 healthy controls. QTF-G results were recorded as positive, negative, or indeterminate. A positive TST was defined as ≥ 5 mm for RA and AS.Results.The percentages of positive QTF-G were comparable in RA and AS (37% vs 32%). The rate of positive QTF-G in healthy controls (29%) was also similar to RA and AS. In contrast to QTF-G results, a high rate of TST positivity was observed in AS compared to RA (82% vs 55%; p = 0.02). The total agreement between QTF-G and TST was observed to be 61% (κ = 0.29) in the whole group, 70% (κ = 0.42) in RA, and 49% (κ = 0.14) in AS. After 6 months of treatment with TNF-α antagonists, a high rate of QTF-G change was observed in patients with indeterminate results (23% vs 3%; p = 0.03).Conclusion.The comparable prevalence of LTBI among the study groups according to QTF-G supports the view that QTF-G is less susceptible to external factors than TST. Sequential testing for QTF-G in patients with indeterminate or negative results may also be helpful in discriminating LTBI better.
Association of Interleukin 23 Receptor Polymorphisms with Anti-Topoisomerase-I Positivity and Pulmonary Hypertension in Systemic Sclerosis
Authors: AGARWAL SANDEEP K. , GOURH PRAVITT , SHETE SANJAY , PAZ GENE , DIVECHA DIPAL , REVEILLE JOHN D. , ASSASSI SHERVIN , TAN FILEMON K. , MAYES MAUREEN D. , ARNETT FRANK C. 
Published: November 2009

Objective.IL23Rhas been identified as a susceptibility gene for development of multiple autoimmune diseases. We investigated the possible association ofIL23Rwith systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis.Methods.We tested 9 single-nucleotide polymorphisms (SNP) inIL23Rfor association with SSc in a cohort of 1402 SSc cases and 1038 controls.IL23RSNP tested were previously identified as SNP showing associations with inflammatory bowel disease.Results.Case-control comparisons revealed no statistically significant differences between patients and healthy controls with any of theIL23Rpolymorphisms. Analyses of subsets of SSc patients showed that rs11209026 (Arg381Gln variant) was associated with anti-topoisomerase I antibody (ATA)-positive SSc (p = 0.001)) and rs11465804 SNP was associated with diffuse and ATA-positive SSc (p = 0.0001, p = 0.0026, respectively). These associations remained significant after accounting for multiple comparisons using the false discovery rate method. Wild-type genotype at both rs11209026 and rs11465804 showed significant protection against the presence of pulmonary hypertension (PHT). (p = 3×10−5, p = 1×10−5, respectively).Conclusion.Polymorphisms inIL23Rare associated with susceptibility to ATA-positive SSc and protective against development of PHT in patients with SSc.
G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation
Authors: Sina Christian , Gavrilova Olga , Förster Matti , Till Andreas , Derer Stefanie , Hildebrand Friederike , Raabe Björn , Chalaris Athena , Scheller Jürgen , Rehmann Ateequr , Franke Andre , Ott Stephan , Häsler Robert , Nikolaus Susanna , Fölsch Ulrich R. , Rose-John Stefan , Jiang Hui-Ping , Li Jun , Schreiber Stefan , Rosenstiel Philip 
Published: November 2009

Abstract
Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43−/− animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38α, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43−/− mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.
Tc17 CD8 T Cells: Functional Plasticity and Subset Diversity
Authors: Yen Hung-Rong , Harris Timothy J. , Wada Satoshi , Grosso Joseph F. , Getnet Derese , Goldberg Monica V. , Liang Kai-Li , Bruno Tullia C. , Pyle Kristin J. , Chan Siaw-Li , Anders Robert A. , Trimble Cornelia L. , Adler Adam J. , Lin Tzou-Yien , Pardoll Drew M. , Huang Ching-Tai , Drake Charles G. 
Published: November 2009

Abstract
IL-17-secreting CD8 T cells (Tc17) have been described in several settings, but little is known regarding their functional characteristics. While Tc1 cells produced IFN-γ and efficiently killed targets, Tc17 cells lacked lytic function in vitro. Interestingly, the small numbers of IFN-γ-positive or IL-17/IFN-γ-double-positive cells generated under Tc17 conditions also lacked lytic activity and expressed a similar pattern of cell surface proteins to IL-17-producing cells. As is the case for Th17 (CD4) cells, STAT3 is important for Tc17 polarization, both in vitro and in vivo. Adoptive transfer of highly purified, Ag-specific IL-17-secreting Tc17 cells into Ag-bearing hosts resulted in near complete conversion to an IFN-γ-secreting phenotype and substantial pulmonary pathology, demonstrating functional plasticity. Tc17 also accumulated to a greater extent than did Tc1 cells, suggesting that adoptive transfer of CD8 T cells cultured in Tc17 conditions may have therapeutic potential for diseases in which IFN-γ-producing cells are desired.
Early Response of Mucosal Epithelial Cells duringToxoplasma gondiiInfection
Authors: Ju Chia-Hsin , Chockalingam Annapoorani , Leifer Cynthia A. 
Published: November 2009

AbstractThe innate immune response of mucosal epithelial cells during pathogen invasion plays a central role in immune regulation in the gut. Toxoplasma gondii is a protozoan intracellular parasite that is usually transmitted through oral infection. Although much of the information on immunity to T. gondii has come from i.p. infection models, more recent studies have revealed the importance of studying immunity following infection through the natural peroral route. Oral infection studies have identified many of the key players in the intestinal response; however, they have relied on responses detected days to weeks following infection. Much less is known about how the gut epithelial layer senses and reacts during initial contact with the pathogen. Given the importance of epithelial cells during pathogen invasion, this study uses an in vitro approach to isolate the key players and examine the early response of intestinal epithelial cells during infection by T. gondii. We show that human intestinal epithelial cells infected with T. gondii elicit rapid MAPK phosphorylation, NF-κB nuclear translocation, and secretion of IL-8. Both ERK1/2 activation and IL-8 secretion responses were shown to be MyD88 dependent and TLR2 was identified to be involved in the recognition of the parasite regardless of the parasite genotype. Furthermore, we were able to identify additional T. gondii-regulated genes in the infected cells using a pathway-focused array. Together, our findings suggest that intestinal epithelial cells were able to recognize T. gondii during infection, and the outcome is important for modulating intestinal immune responses.
Hematopoietic Lineage Cell-Specific Protein 1 Is Recruited to the Immunological Synapse by IL-2-Inducible T Cell Kinase and Regulates Phospholipase Cγ1 Microcluster Dynamics during T Cell Spreading
Authors: Carrizosa Esteban , Gomez Timothy S. , Labno Christine M. , Klos Dehring Deborah A. , Liu Xiaohong , Freedman Bruce D. , Billadeau Daniel D. , Burkhardt Janis K. 
Published: November 2009

Abstract
Productive T cell activation requires efficient reorganization of the actin cytoskeleton. We showed previously that the actin-regulatory protein, hematopoietic lineage cell-specific protein 1 (HS1), is required for the stabilization of F-actin and Vav1 at the immunological synapse and for efficient calcium responses. The Tec family kinase IL-2-inducible T cell kinase (Itk) regulates similar aspects of T cell activation, suggesting that these proteins act in the same pathway. Using video microscopy, we show that T cells lacking Itk or HS1 exhibited similar defects in actin responses, extending unstable lamellipodial protrusions upon TCR stimulation. HS1 and Itk could be coimmunoprecipitated from T cell lysates, and GST-pulldown studies showed that Itk’s Src homology 2 domain binds directly to two phosphotyrosines in HS1. In the absence of Itk, or in T cells overexpressing an Itk Src homology 2 domain mutant, HS1 failed to localize to the immunological synapse, indicating that Itk serves to recruit HS1 to sites of TCR engagement. Because Itk is required for phospholipase C (PLC)γ1 phosphorylation and calcium store release, we examined the calcium signaling pathway in HS1−/− T cells in greater detail. In response to TCR engagement, T cells lacking HS1 exhibited diminished calcium store release, but TCR-dependent PLCγ1 phosphorylation was intact, indicating that HS1’s role in calcium signaling is distinct from that of Itk. HS1-deficient T cells exhibited defective cytoskeletal association of PLCγ1 and altered formation of PLCγ1 microclusters. We conclude that HS1 functions as an effector of Itk in the T cell actin-regulatory pathway, and directs the spatial organization of PLCγ1 signaling complexes.
Dominant Expression of the Inhibitory FcγRIIB Prevents Antigen Presentation by Murine Plasmacytoid Dendritic Cells
Authors: Flores Marcella , Desai Dharmesh D. , Downie Matthew , Liang Bitao , Reilly Michael P. , McKenzie Steven E. , Clynes Raphael 
Published: November 2009

Abstract
Plasmacytoid dendritic cells (pDCs) are key regulators of the innate immune response, yet their direct role as APCs in the adaptive immune response is unclear. We found that unlike conventional DCs, immune complex (IC) exposed murine pDCs neither up-regulated costimulatory molecules nor activated Ag-specific CD4+ and CD8+ T cells. The inability of murine pDCs to promote T cell activation was due to inefficient proteolytic processing of internalized ICs. This defect in the IC processing capacity of pDCs results from a lack of activating FcγR expression (FcγRI, III, IV) and the dominant expression of the inhibitory receptor FcγRIIB. Consistent with this idea, transgenic expression of the activating human FcγRIIA gene, not present in the mouse genome, recapitulated the human situation and rescued IC antigenic presentation capacity by murine pDCs. The selective expression of FcγRIIB by murine pDCs was not strain dependent and was maintained even following stimulation with TLR ligands and inflammatory cytokines. The unexpected difference between the mouse and human in the expression of activating/inhibitory FcγRs has implications for the role of pDCs in Ab-modulated autoimmunity and anti-viral immunity.
β Cell-Specific CD4+ T Cell Clonotypes in Peripheral Blood and the Pancreatic Islets Are Distinct
Authors: Li Li , He Qiuming , Garland Alaina , Yi Zuoan , Aybar Lydia T. , Kepler Thomas B. , Frelinger Jeffrey A. , Wang Bo , Tisch Roland 
Published: November 2009

AbstractType 1 diabetes is an autoimmune disease mediated by β cell-specific CD4+ and CD8+ T cells. Tracking β cell-specific T cells is one approach to monitor the diabetogenic response in at risk or diabetic individuals. Such analyses, however, are limited to PBL because T cells infiltrating the pancreatic islets are normally inaccessible. A key issue is whether peripheral β cell-specific T cells accurately reflect those cells infiltrating the target tissue. We investigated the properties of CD4+ T cells specific for a mimetic epitope recognized by the BDC2.5 clonotypic TCR in NOD mice. Soluble IAg7-Ig (sIAg7-Ig) multimer complexes covalently linked to a mimetic BDC peptide (sIAg7-mBDC) were used to identify or isolate CD4+ T cells from PBL and the islets of NOD mice. A temporal increase in sIAg7-mBDC binding (g7-mBDC+) T cells corresponding with the progression of β cell autoimmunity was detected in both PBL and islets in NOD female mice. In contrast to T cells in PBL, however, the majority of islet g7-mBDC+ T cells exhibited a type 1 phenotype, and mediated diabetes upon transfer into NOD.scid recipients. TCR-β and CDR-β gene usage of single islet-infiltrating g7-mBDC+ CD4+ T cells from individual NOD mice showed a restricted repertoire dominated by one or two clones typically expressing TCR β-chain variable TRBV-15. In contrast, a distinct and diverse TCR repertoire was detected for PBL-derived g7-mBDC+ T cells. These results demonstrate that PBL and islet CD4+ T cells specific for a given β cell epitope can differ regarding pathogenicity and TCR repertoire.
Role of T Cell TGFβ Signaling and IL-17 in Allograft Acceptance and Fibrosis Associated with Chronic Rejection
Authors: Faust Susan M. , Lu Guanyi , Marini Bernard L. , Zou Weiping , Gordon David , Iwakura Yoichiro , Laouar Yasmina , Bishop D. Keith 
Published: November 2009

Abstract
Chronic allograft rejection (CR) is the main barrier to long-term transplant survival. CR is a progressive disease defined by interstitial fibrosis, vascular neointimal development, and graft dysfunction. The underlying mechanisms responsible for CR remain poorly defined. TGFβ has been implicated in promoting fibrotic diseases including CR, but is beneficial in the transplant setting due to its immunosuppressive activity. To assess the requirement for T cell TGFβ signaling in allograft acceptance and the progression of CR, we used mice with abrogated T cell TGFβ signaling as allograft recipients. We compared responses from recipients that were transiently depleted of CD4+ cells (that develop CR and express intragraft TGFβ) with responses from mice that received anti-CD40L mAb therapy (that do not develop CR and do not express intragraft TGFβ). Allograft acceptance and suppression of graft-reactive T and B cells were independent of T cell TGFβ signaling in mice treated with anti-CD40L mAb. In recipients transiently depleted of CD4+ T cells, T cell TGFβ signaling was required for the development of fibrosis associated with CR, long-term graft acceptance, and suppression of graft-reactive T and B cell responses. Furthermore, IL-17 was identified as a critical element in TGFβ-driven allograft fibrosis. Thus, IL-17 may provide a therapeutic target for preventing graft fibrosis, a measure of CR, while sparing the immunosuppressive activity of TGFβ.
Taking Advantage: High-Affinity B Cells in the Germinal Center Have Lower Death Rates, but Similar Rates of Division, Compared to Low-Affinity Cells
Authors: Anderson Shannon M. , Khalil Ashraf , Uduman Mohamed , Hershberg Uri , Louzoun Yoram , Haberman Ann M. , Kleinstein Steven H. , Shlomchik Mark J. 
Published: November 2009

Abstract
B lymphocytes producing high-affinity Abs are critical for protection from extracellular pathogens, such as bacteria and parasites. The process by which high-affinity B cells are selected during the immune response has never been elucidated. Although it has been shown that high-affinity cells directly outcompete low-affinity cells in the germinal center (GC), whether there are also intrinsic differences between these cells has not been addressed. It could be that higher affinity cells proliferate more rapidly or are more likely to enter cell cycle, thereby outgrowing lower affinity cells. Alternatively, higher affinity cells could be relatively more resistant to cell death in the GC. By comparing high- and low-affinity B cells for the same Ag, we show here that low-affinity cells have an intrinsically higher death rate than do cells of higher affinity, even in the absence of competition. This suggests that selection in the GC reaction is due at least in part to the control of survival of higher affinity B cells and not by a proliferative advantage conferred upon these cells compared with lower affinity B cells. Control over survival rather than proliferation of low- and high-affinity B cells in the GC allows greater diversity not only in the primary response but also in the memory response.