bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD44 Participates in IP-10 Induction in Cells in Which Hepatitis C Virus RNA Is Replicating, through an Interaction with Toll-Like Receptor 2 and Hyaluronan
Authors: Abe Takayuki , Fukuhara Takasuke , Wen Xiauyu , Ninomiya Akinori , Moriishi Kohji , Maehara Yoshihiko , Takeuchi Osamu , Kawai Taro , Akira Shizuo , Matsuura Yoshiharu 
Published: April 2012

ABSTRACTThe mechanisms of induction of liver injury during chronic infection with hepatitis C virus (HCV) are not well understood. Gamma interferon (IFN-γ)-inducible protein 10 (IP-10), a member of the CXC chemokine family, is expressed in the liver of chronic hepatitis C (CHC) patients and selectively recruits activated T cells to the sites of inflammation. Recently, it was shown that a low plasma concentration of IP-10 in CHC patients was closely associated with the outcome of antiviral therapy. In this study, we examined the role of the Toll-like receptor (TLR) pathway on IP-10 production in cells replicating HCV. Among the CXC chemokines, the expression of IP-10 was specifically increased in cells replicating HCV upon stimulation with conventional TLR2 ligands. The enhancement of IP-10 production upon stimulation with TLR2 ligands in cells replicating HCV induced CD44 expression. CD44 is a broadly distributed type I transmembrane glycoprotein and a receptor for the glycosaminoglycan hyaluronan (HA). In CHC patients, the expression of HA in serum has been shown to increase in accord with the progression of liver fibrosis, and HA also works as a ligand for TLR2. In the present study, IP-10 production upon HA stimulation was dependent on the expression of TLR2 and CD44, and a direct association between TLR2 and CD44 was observed. These results suggest that endogenous expression of HA in hepatocytes in CHC patients participates in IP-10 production through an engagement of TLR2 and CD44.
Association of Major Histocompatibility Complex Class I Haplotypes with Disease Progression after Simian Immunodeficiency Virus Challenge in Burmese Rhesus Macaques
Authors: Nomura Takushi , Yamamoto Hiroyuki , Shiino Teiichiro , Takahashi Naofumi , Nakane Taku , Iwamoto Nami , Ishii Hiroshi , Tsukamoto Tetsuo , Kawada Miki , Matsuoka Saori , Takeda Akiko , Terahara Kazutaka , Tsunetsugu-Yokota Yasuko , Iwata-Yoshikawa Naoko , Hasegawa Hideki , Sata Tetsutaro , Naruse Taeko K. , Kimura Akinori , Matano Tetsuro 
Published: April 2012

ABSTRACTNonhuman primate AIDS models are essential for the analysis of AIDS pathogenesis and the evaluation of vaccine efficacy. Multiple studies on human immunodeficiency virus and simian immunodeficiency virus (SIV) infection have indicated the association of major histocompatibility complex class I (MHC-I) genotypes with rapid or slow AIDS progression. The accumulation of macaque groups that share not only a single MHC-I allele but also an MHC-I haplotype consisting of multiple polymorphic MHC-I loci would greatly contribute to the progress of AIDS research. Here, we investigated SIVmac239 infections in four groups of Burmese rhesus macaques sharing individual MHC-I haplotypes, referred to as A, E, B, and J. Out of 20 macaques belonging to A+(n= 6), E+(n= 6), B+(n= 4), and J+(n= 4) groups, 18 showed persistent viremia. Fifteen of them developed AIDS in 0.5 to 4 years, with the remaining three at 1 or 2 years under observation. A+animals, including two controllers, showed slower disease progression, whereas J+animals exhibited rapid progression. E+and B+animals showed intermediate plasma viral loads and survival periods. Gag-specific CD8+T-cell responses were efficiently induced in A+animals, while Nef-specific CD8+T-cell responses were in A+, E+, and B+animals. Multiple comparisons among these groups revealed significant differences in survival periods, peripheral CD4+T-cell decline, and SIV-specific CD4+T-cell polyfunctionality in the chronic phase. This study indicates the association of MHC-I haplotypes with AIDS progression and presents an AIDS model facilitating the analysis of virus-host immune interaction.
Suppression of Antigen-Specific T Cell Responses by the Kaposi's Sarcoma-Associated Herpesvirus Viral OX2 Protein and Its Cellular Orthologue, CD200
Authors: Misstear Karen , Chanas Simon A. , Rezaee S. A. Rahim , Colman Rachel , Quinn Laura L. , Long Heather M. , Goodyear Oliver , Lord Janet M. , Hislop Andrew D. , Blackbourn David J. 
Published: April 2012

ABSTRACTRegulating appropriate activation of the immune response in the healthy host despite continual immune surveillance dictates that immune responses must be either self-limiting and therefore negatively regulated following their activation or prevented from developing inappropriately. In the case of antigen-specific T cells, their response is attenuated by several mechanisms, including ligation of CTLA-4 and PD-1. Through the study of the viral OX2 (vOX2) immunoregulator encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), we have identified a T cell-attenuating role both for this protein and for CD200, a cellular orthologue of the viral vOX2 protein.In vitro, antigen-presenting cells (APC) expressing either native vOX2 or CD200 suppressed two functions of cognate antigen-specific T cell clones: gamma interferon (IFN-γ) production and mobilization of CD107a, a cytolytic granule component and measure of target cell killing ability. Mechanistically, vOX2 and CD200 expression on APC suppressed the phosphorylation of ERK1/2 mitogen-activated protein kinase in responding T cells. These data provide the first evidence for a role of both KSHV vOX2 and cellular CD200 in the negative regulation of antigen-specific T cell responses. They suggest that KSHV has evolved to harness the host CD200-based mechanism of attenuation of T cell responses to facilitate virus persistence and dissemination within the infected individual. Moreover, our studies define a new paradigm in immune modulation by viruses: the provision of a negative costimulatory signal to T cells by a virus-encoded orthologue of CD200.
Thirty-day mortality after elective and emergency total colectomy in Danish patients with inflammatory bowel disease: a population-based nationwide cohort study
Authors: Tøttrup Anders , Erichsen Rune , Sværke Claus , Laurberg Søren , Srensen Henrik Toft 
Published: April 2012

ObjectivesThe purpose of this investigation was to assess 30-day mortality among Danish inflammatory bowel diseases (IBD) patients and to examine the prognostic impact of hospital total colectomy volume, age, gender and comorbidity.DesignCohort study.SettingThe authors compared 30-day survival over the period 1996–2010 among 2889 IBD patients with total colectomy identified in the Danish National Registry of Patients. This registry covers all hospitals in Denmark. Postoperative survival patterns for patients with ulcerative colitis and Crohn's disease were compared, using proportional hazard regression. The regression model accounted for the timing of surgery, hospital total colectomy volume, age, gender and comorbidity.ParticipantsPatients were enrolled in the study if they had a hospital registry diagnosis of IBD, with accompanying procedure codes for total colectomy (see codes in online appendix table 1). Hospitalisations were described as elective or emergency, and patients were categorised as having Crohn's disease, ulcerative colitis or as a mixed group.Outcome measuresPrimary outcome measure was 30-day mortality.ResultsAmong 2889 IBD patients with total colectomy, 1439 (50%) underwent surgery during an emergency hospitalisation. Thirty-day mortality was 5.3% (76/1439) among emergency cases compared with 1% (14/1450) among elective cases. The highest mortality (8.1%; 11 of 136) was observed among Crohn's patients undergoing emergency surgery. The mortality of patients with ulcerative colitis undergoing emergency surgery was 5.2% (55/1056). After elective surgery, the 30-day mortality was 0.9% (8/938) among patients with ulcerative colitis and 1.5% (3/201) among Crohn's disease patients. Low hospital total colectomy volume, comorbidity and high age were associated with increased 30-day mortality in ulcerative colitis patients undergoing emergency surgery.ConclusionEmergency total colectomy among patients with ulcerative colitis and particularly Crohn's disease is associated with substantial 30-day mortality.
How does a history of psychiatric hospital care influence access to coronary care: a cohort study
Authors: Manderbacka Kristiina , Arffman Martti , Sund Reijo , Haukka Jari , Keskimäki Ilmo , Wahlbeck Kristian 
Published: April 2012

ObjectivesEquity in physical health of patients with severe mental disorders is a major public health concern. The aim of this cohort study was to examine equity in access to coronary care among persons with a history of severe mental disorder in 1998–2009.DesignNationwide register linkage cohort study.SettingHospital care in the Finnish healthcare system.PopulationThe study population consisted of all residents in Finland aged 40 years or older. All hospital discharges in 1998–2009 with a diagnosis of coronary heart disease or severe mental disorder were obtained from the Care Register.Primary outcome measuresData on deaths, hospitalisations and coronary revascularisations were linked to the data set using unique personal identifiers.ResultsPatients with severe mental disorders had increased likelihood of hospital care due to coronary heart disease (RR between 1.22, 95% CI 1.18 to 1.25 and 1.93, 1.84 to 2.03 in different age groups) and in 40–49-year-olds also increased likelihood of revascularisation (1.26, 1.16 to 1.38) compared with persons without mental disorders. Access to revascularisation was poorer among older persons with severe mental disorders in relation to need suggested by increased coronary mortality. In spite of excess coronary mortality (ranging from 0.95, 0.89 to 1.01 to 3.16, 2.82 to 3.54), worst off were people with a history of psychosis, who did not have increased use of hospital care and had lower likelihood of receiving revascularisations (ranging from 0.44, 0.37 to 0.51 to 0.74, 0.59 to 0.93) compared with persons without mental disorders.ConclusionsSelective mechanisms seem to be at work in access to care and revascularisations among people with severe mental disorders. Healthcare professionals need to be aware of the need for targeted measures to address challenges in provision of somatic care among people with severe mental health problems, especially among people with psychoses and old people.
The apparent breastfeeding paradox in very preterm infants: relationship between breast feeding, early weight gain and neurodevelopment based on results from two cohorts, EPIPAGE and LIFT
Authors: Rozé Jean-Christophe , Darmaun Dominique , Boquien Clair-Yves , Flamant Cyril , Picaud Jean-Charles , Savagner Christophe , Claris Olivier , Lapillonne Alexandre , Mitanchez Delphine , Branger Bernard , Simeoni Umberto , Kaminski Monique , Ancel Pierre-Yves 
Published: April 2012

ContextSupplementation of breast milk is difficult once infants suckle the breast and is often discontinued at end of hospitalisation and after discharge. Thus, breastfed preterm infants are exposed to an increased risk of nutritional deficit with a possible consequence on neurodevelopmental outcome.ObjectiveTo assess the relationship between breast feeding at time of discharge, weight gain during hospitalisation and neurodevelopmental outcome.DesignObservational cohort study.SettingTwo large, independent population-based cohorts of very preterm infants: the Loire Infant Follow-up Team (LIFT) and the EPIPAGE cohorts.Patients2925 very preterm infants alive at discharge.Main outcome measureSuboptimal neurodevelopmental outcome, defined as a score in the lower tercile, using Age and Stages Questionnaire at 2 years in LIFT and Kaufman Assessment Battery for Children Test at 5 years in EPIPAGE. Two propensity scores for breast feeding at discharge, one for each cohort, were used to reduce bias.ResultsBreast feeding at time of discharge concerned only 278/1733 (16%) infants in LIFT and 409/2163 (19%) infants in EPIPAGE cohort. Breast feeding is significantly associated with an increased risk of losing one weight Z-score during hospitalisation (LIFT: n=1463, adjusted odd ratio (aOR)=2.51 (95% CI 1.87 to 3.36); EPIPAGE: n=1417, aOR=1.55 (95% CI 1.14 to 2.12)) and with a decreased risk for a suboptimal neurodevelopmental assessment (LIFT: n=1463, aOR=0.63 (95% CI 0.45 to 0.87); EPIPAGE: n=1441, aOR=0.65 (95% CI 0.47 to 0.89) and an increased chance of having a head circumference Z-score higher than 0.5 at 2 years in LIFT cohort (n=1276, aOR=1.43 (95% CI 1.02 to 2.02)) and at 5 years in EPIPAGE cohort (n=1412, aOR=1.47 (95% CI 1.10 to 1.95)).ConclusionsThe observed better neurodevelopment in spite of suboptimal initial weight gain could be termed the ‘apparent breastfeeding paradox’ in very preterm infants. Regardless of the mechanisms involved, the current data provide encouragement for the use of breast feeding in preterm infants.
In Vivo Diagnosis of Melanoma and Nonmelanoma Skin Cancer Using Oblique Incidence Diffuse Reflectance Spectrometry
Authors: Garcia-Uribe Alejandro , Zou Jun , Duvic Madeleine , Cho-Vega Jeong Hee , Prieto Victor G. , Wang Lihong V. 
Published: April 2012

Abstract
Early detection and treatment of skin cancer can significantly improve patient outcome. However, present standards for diagnosis require biopsy and histopathologic examinations that are relatively invasive, expensive, and difficult for patients with many early-stage lesions. Here, we show an oblique incidence diffuse reflectance spectroscopic (OIDRS) system that can be used for rapid skin cancer detection in vivo. This system was tested under clinical conditions by obtaining spectra from pigmented and nonpigmented skin lesions, including melanomas, differently staged dysplastic nevi, and common nevi that were validated by standard pathohistologic criteria. For diagnosis of pigmented melanoma, the data obtained achieved 90% sensitivity and specificity for a blinded test set. In a second analysis, we showed that this spectroscopy system can also differentiate nonpigmented basal cell or squamous cell carcinomas from noncancerous skin abnormalities, such as actinic keratoses and seborrheic keratoses, achieving 92% sensitivity and specificity. Taken together, our findings establish how OIDRS can be used to more rapidly and easily diagnose skin cancer in an accurate and automated manner in the clinic. Cancer Res; 72(11); 2738–45. ©2012 AACR.
Exenatide, a Glucagon-like Peptide-1 Receptor Agonist, Acutely Inhibits Intestinal Lipoprotein Production in Healthy Humans
Authors: Xiao Changting , Bandsma Robert H. J. , Dash Satya , Szeto Linda , Lewis Gary F. 
Published: April 2012

Objectives—
Incretin-based therapies for the treatment of type 2 diabetes mellitus improve plasma lipid profiles and postprandial lipemia, but their exact mechanism of action remains unclear. Here, we examined the acute effect of the glucagon-like peptide-1 receptor agonist, exenatide, on intestinal and hepatic triglyceride-rich lipoprotein production and clearance in healthy humans.

Methods and Results—
Fifteen normolipidemic, normoglycemic men underwent 2 studies each (SC 10 μg exenatide versus placebo), 4 to 6 weeks apart, in random order, in which triglyceride-rich lipoprotein particle kinetics were examined with a primed, constant infusion of deuterated leucine and analyzed by multicompartmental modeling under pancreatic clamp conditions. A fed state was maintained during each study by infusing a high-fat, mixed macronutrient, liquid formula at a constant rate directly into the duodenum via a nasoduodenal tube. Exenatide significantly suppressed the plasma concentration and production rate of triglyceride-rich lipoprotein-apolipoprotein B-48, but not of triglyceride-rich lipoprotein-apolipoprotein B-100.

Conclusions—
These results suggest a possible direct effect of exenatide on intestinal lipoprotein particle production, independent of changes in weight gain and satiety as seen in long-term studies and independent of changes in gastric emptying. This finding expands our understanding of the effects of exenatide in metabolic regulation beyond its primary therapeutic role in regulation of glucose homeostasis.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
, NCT01056549.
Synergistic Effect of Thrombin and CD40 Ligand on Endothelial Matrix Metalloproteinase-10 Expression and Microparticle Generation In Vitro and In Vivo
Authors: de Lizarrondo Sara Martínez , Roncal Carmen , Calvayrac Olivier , Rodríguez Cristina , Varo Nerea , Purroy Ana , Lorente Leonardo , Rodríguez José A. , Doeuvre Loïc , Hervás-Stubbs Sandra , Angles-Cano Eduardo , Páramo José A. , Martínez-González José , Orbe Josune 
Published: April 2012

Objective—
Thrombin induces CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) under inflammatory/prothrombotic conditions. Thrombin and CD40L could modulate endothelial MMP-10 expression in vitro and in vivo.

Methods and Results—

Human endothelial cells were stimulated with thrombin (0.1–10 U/mL), CD40L (0.25–1 μg/mL), or their combination (thrombin/CD40L) to assess MMP-10 expression and microparticle generation. Thrombin/CD40L elicited higher MMP-10 mRNA (5-fold;
P
<0.001) and protein levels (4.5-fold;
P
<0.001) than either stimulus alone. This effect was mimicked by a protease-activated receptor-1 agonist and antagonized by hirudin, a-protease-activated receptor-1, α-CD40L, and α-CD40 antibodies. The synergistic effect was dependent on p38 mitogen-activated protein kinase and c-Jun
N
-terminal kinase-1 pathways. Thrombin also upregulated the expression of CD40 in endothelial cell surface increasing its availability, thereby favoring its synergistic effects with CD40L. In mice, thrombin/CD40L further increased the aortic MMP-10 expression. Septic patients with systemic inflammation and enhanced thrombin generation (n=60) exhibited increased MMP-10 and soluble CD40L levels associated with adverse clinical outcome. Endothelial and systemic activation by thrombin/CD40L and lipopolysaccharide also increased microparticles harboring MMP-10 and CD40L.

Conclusion—
Thrombin/CD40L elicited a strong synergistic effect on endothelial MMP-10 expression and microparticles containing MMP-10 in vitro and in vivo, which may represent a new link between inflammation/thrombosis with prognostic implications.
Increasing Plasma Free Fatty Acids in Healthy Subjects Induces Aortic Distensibility Changes Seen in Obesity
Authors: Rider Oliver J. , Holloway Cameron J. , Emmanuel Yaso , Bloch Edward , Clarke Kieran , Neubauer Stefan 
Published: April 2012

Background—
Elevated free fatty acid (FFA) levels are known to impair aortic elastic function. In obesity, FFA levels are elevated and aortic distensibility (AD) reduced in a pattern that predominantly affects the distal aorta. Despite this, the role of FFAs in obesity-related aortic stiffness remains unclear.

Methods and Results—

Using vascular MRI, we aimed to determine if (1) FFA level correlated with AD in obesity; and (2) whether elevating FFA acutely and subacutely in normal-weight subjects reproduced the distal pattern of AD change in obesity. To do this, regional AD was recorded in 35 normal-weight and 70 obese subjects and then correlated with FFA levels. When compared with normal weight, obesity was associated with reduced AD in a pattern predominantly affecting the distal aorta (ascending aorta by −22%, proximal descending aorta by −25%, and abdominal aorta by −35%;
P
<0.001). After controlling for age, blood pressure, and body mass index, FFA levels remained negatively correlated with abdominal AD (
r
=−0.43,
P
<0.01). In 2 further normal-weight groups, AD was recorded before and after elevation of FFA levels with intralipid infusion (by +535%, n=9) and a 5-day high-fat, low-carbohydrate diet (by +48%, n=14).

Conclusions—

Both intralipid infusion and a low-carbohydrate diet resulted in reduced abdominal AD (infusion −22%, diet −28%; both
P
<0.05), reproducing the distal pattern AD reduction seen in obesity. These findings suggest that elevated FFA impair AD in obesity and provide a potential therapeutic target to improve aortic elastic function in obesity.
Vascular Klotho Deficiency Potentiates the Development of Human Artery Calcification and Mediates Resistance to Fibroblast Growth Factor 23
Authors: Lim Kenneth , Lu Tzong-Shi , Molostvov Guerman , Lee Christina , Lam F.T. , Zehnder Daniel , Hsiao Li-Li 
Published: April 2012

Background—
Klotho is known to function as a cofactor for the phosphatonin, fibroblast growth factor (FGF)-23 at the kidney. FGF-23 levels rise in chronic kidney disease (CKD) despite progression of accelerated vascular calcification. There are currently conflicting data on whether FGF-23 may exhibit direct vasculoprotective effects in CKD.

Methods and Results—
In this study, we describe for the first time endogenous Klotho expression in human arteries and human aortic smooth muscle cells. We show that CKD is a state of vascular Klotho deficiency promoted by chronic circulating stress factors, including proinflammatory, uremic, and disordered metabolic conditions. Mechanistic studies demonstrated that Klotho knockdown potentiated the development of accelerated calcification through a Runx2 and myocardin-serum response factor–dependent pathway. Klotho knockdown studies further revealed that vascular cells are a Klotho-dependent target tissue for FGF-23. FGF-23 mediated cellular activation of p-ERK, p-AKT, and cellular proliferative effects, which were abrogated following Klotho knockdown. We next showed that vascular Klotho deficiency driven by procalcific stressors could be restored by vitamin D receptor activators, in vitro and further confirmed using human arterial organ cultures from CKD patients, in vivo. Furthermore, restoration of suppressed Klotho expression by vitamin D receptor activators conferred human aortic smooth muscle cells responsive to FGF-23 signaling and unmasked potential anticalcific effects.

Conclusions—
Chronic metabolic stress factors found in CKD promote vascular Klotho deficiency. Mechanistic studies revealed a bifunctional role for local vascular Klotho, first, as an endogenous inhibitor of vascular calcification and, second, as a cofactor required for vascular FGF-23 signaling. Furthermore, vitamin D receptor activators can restore Klotho expression and unmask FGF-23 anticalcific effects.