bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variation at the FTO Locus Influences RBL2 Gene Expression
Authors: Jowett Jeremy B.M. , Curran Joanne E. , Johnson Matthew P. , Carless Melanie A. , Göring Harald H.H. , Dyer Thomas D. , Cole Shelley A. , Comuzzie Anthony G. , MacCluer Jean W. , Moses Eric K. , Blangero John 
Published: December 2009

OBJECTIVE
Genome-wide association studies that compare the statistical association between thousands of DNA variations and a human trait have detected 958 loci across 127 different diseases and traits. However, these statistical associations only provide evidence for genomic regions likely to harbor a causal gene(s) and do not directly identify such genes. We combined gene variation and expression data in a human cohort to identify causal genes.

RESEARCH DESIGN AND METHODS
Global gene transcription activity was obtained for each individual in a large human cohort (n = 1,240). These quantitative transcript data were tested for correlation with genotype data generated from the same individuals to identify gene expression patterns influenced by the variants.

RESULTS
Variant rs8050136 lies within intron 1 of the FTO gene on chromosome 16 and marks a locus strongly associated with type 2 diabetes and obesity and widely replicated across many populations. We report that genetic variation at this locus does not influence FTO gene expression levels (P = 0.38), but is strongly correlated with expression of RBL2 (P = 2.7 × 10−5), ∼270,000 base pairs distant to FTO.

CONCLUSIONS
These data suggest that variants at FTO influence RBL2 gene expression at large genetic distances. This observation underscores the complexity of human transcriptional regulation and highlights the utility of large human cohorts in which both genetic variation and global gene expression data are available to identify disease genes. Expedient identification of genes mediating the effects of genome-wide association study–identified loci will enable mechanism-of-action studies and accelerate understanding of human disease processes under genetic influence.
Lipotoxicity and Decreased Islet Graft Survival
Authors: Leitão Cristiane B. , Bernetti Karina , Tharavanij Thipaporn , Cure Pablo , Lauriola Vincenzo , Berggren Per-Olof , Ricordi Camillo , Alejandro Rodolfo 
Published: December 2009

OBJECTIVE
To evaluate if baseline serum lipids are associated with islet graft survival in type 1 diabetes islet transplant (ITx) recipients.

RESEARCH DESIGN AND METHODS
Baseline fasting lipid profile was collected from 44 ITx recipients. Comparisons were performed between subjects below and above the median values of each lipid fraction. Differences in outcomes were compared by Kaplan-Meier curves and Cox regression analysis.

RESULTS
Subjects with baseline fasting plasma triglycerides and VLDL cholesterol above the median had shorter islet graft survival (triglycerides: 39.7 ± 6.1 vs. 61.3 ± 6.6 months, P = 0.029, and VLDL: 41.5 ± 5.7 vs. 62.8 ± 7.3 months, P = 0.032). Total, LDL, and HDL cholesterol did not influence islet function. Triglycerides (odds ratio 2.97 [95% CI 1.03–8.52], P = 0.044) maintained its association with graft failure after adjustments for confounders.

CONCLUSIONS
Higher baseline triglycerides are associated with earlier decline in islet graft function. Prospective clinical trials should address whether it is directly caused by lipotoxicity and if strategies focusing on lowering serum lipids may prolong islet graft survival.
Antioxidant activities of dithiol alpha-lipoic acid
Authors: Islam Mohammad Toowhidul 
Published: December 2009

Alpha-lipoic acid, a dithiol compound derived from octanoic acid, which acts as a coenzyme for several redox reactions in almost all the tissue of the body. It retains its protective functions in both oxidized and reduced forms. Alpha-lipoic acid reduces oxidative stress by redox generation of other antioxidants such as vitamin C, E and increasing the intracellular glutathione. Exogenous alpha-lipoic acid has been shown to increase ATP production due to its role in the oxidation of pyruvate and alpha-ketoglutarate in the mitochondria. Alpha-lipoic acid administration has been shown to be effective in preventing pathology in various experimental models in which reactive oxygen species have been implicated. Key words: Antioxidant, free radical, alpha-lipoic acid DOI: 10.3329/bjms.v8i3.3982 Bangladesh Journal of Medical Sciences Vol.8(3) 2009 p46-51
Unresponsiveness to Colchicine Therapy in Patients with Familial Mediterranean Fever Homozygous for the M694V Mutation
Authors: SOYLEMEZOGLU OGUZ , ARGA MUSTAFA , FIDAN KIBRIYA , GONEN SEVIM , EMEKSIZ HAMDI CIHAN , HASANOGLU ENVER , BUYAN NECLA 
Published: December 2009

Objective.More than 50 disease-associated mutations of the Mediterranean fever gene (MEFV) have been identified in familial Mediterranean fever (FMF), some of which were shown to have different clinical, diagnostic, prognostic, and therapeutic implications. The aim of our study was to define the frequency of mutation type, genotype-phenotype correlation, and response to colchicine treatment in patients with FMF.Methods.This study included 222 pediatric FMF patients. All patients were investigated for 6 MEFV mutations. Then patients were divided into 3 groups according to the presence of M694V mutation on both of the alleles (homozygotes), on only 1 allele (heterozygotes), and on none of the alleles, and compared according to their phenotypic characteristics and response to treatment. M694V/M694V was denoted Group A, M694V/Other Group B, and Other/Other, Group C.Results.Complete colchicine response was significantly lower while the rate of unresponsiveness was significantly higher in Group A compared to Groups B and C (p = 0.031, p < 0.001 and p = 0.005, p = 0.029, respectively). No differences except proteinuria were found between the phenotypic features of 3 groups. Group C had the lowest rate of proteinuria development (p = 0.024). All the amyloidosis patients were in Group A.Conclusion.Our results indicate that the M694V/M694V mutation is associated with lower response to colchicine treatment. Therefore, patients homozygous for M694V/M694V may be carrying an increased risk for development of amyloidosis.
Can Tumor Necrosis Factor Inhibitors Be Safely Used in Pregnancy?
Authors: ALI YASER M. , KURIYA BINDEE , OROZCO CATALINA , CUSH JOHN J. , KEYSTONE EDWARD C. 
Published: December 2009

Objective.We review available safety data for use of currently approved tumor necrosis factor (TNF) inhibitors during pregnancy and lactation and suggest guidelines for use of these agents among women of reproductive age.Method.Although regulatory agencies encourage the inclusion of pregnant women and those of child-bearing age in randomized controlled trials, pregnant and lactating women have universally been excluded from studies because of unknown or potential risks to the fetus. Thus, strong evidence-based treatment recommendations during pregnancy are usually lacking and safety information is derived from voluntary reports of adverse events during postmarketing surveillance or via uncontrolled, observational studies, reviewed here.Results.Uncommon adverse pregnancy outcomes observed with TNF inhibitor therapy appear to approximate those seen in women not receiving such therapy and may include premature birth, miscarriage, low birthweight, hypertension, and preeclampsia. There are rare reports of fetal malformations or congenital anomalies in patients exposed to TNF inhibitors during conception or pregnancy. However, the incidence of these events appears to be far below the 3% rate of congenital anomalies in the general population.Conclusion.If the activity or disease severity precludes the cessation of a TNF inhibitor and/or DMARD, uncontrolled observations suggest that conception and early pregnancy are not adversely affected by use of TNF inhibitors. Nearly 70% of pregnant patients can discontinue their TNF inhibitor early in the pregnancy (or with determination of pregnancy) without augmenting maternal or fetal risks.
Trp64Arg Polymorphism of the ADRB3 Gene Predicts Hyperuricemia Risk in a Population from Southern Spain
Authors: MORCILLO SONSOLES , ROJO-MARTÍNEZ GEMMA , MARTÍN-NÚÑEZ GRACIA MARÍA , GÓMEZ-ZUMAQUERO JUAN MIGUEL , GARCÍA-FUENTES EDUARDO , de ADANA MARISOL RUIZ , de la CRUZ ALMARAZ MARÍA , SORIGUER FEDERICO 
Published: December 2009

Objective. To study the role of Trp64Arg polymorphism of the ADRB3 gene in the risk of developing hyperuricemia in 1051 subjects from southern Spain, with a followup of 6 years. The inclusion of plasma levels of uric acid as a diagnostic criterion to define the metabolic syndrome is under discussion. Genes responsible for insulin resistance could contribute to the development of hyperuricemia. Previous cross-sectional studies have suggested ADRB3 as a possible candidate gene in the development of hyperuricemia and insulin resistance.Methods. A prospective, population-based, cohort study of 1051 persons examined in 1997–98 and reassessed at a second examination 6 years later. The metabolic phenotype was assessed at baseline and again at the followup. Insulin resistance was measured by homeostasis model assessment. The Trp64Arg polymorphism of ADRB3 was detected by real-time polymerase chain reaction. Subjects were considered normouricemic if their serum uric acid levels were ≤7 mg/dl for men or ≤ 6 mg/dl for women.Results. Carriers of the Arg64 allele who were normouricemic at baseline had a higher risk of developing hyperuricemia 6 years later (p = 0.017, OR 2.3, 95% CI 1.1–4.6). Multivariate logistic regression analysis showed that the OR of having hyperuricemia at the 6-year followup was significantly associated with the Arg64 allele, after adjusting for age, weight gain, baseline levels of triglycerides, serum uric acid, and insulin resistance (OR 3.1, 95% CI 1.3–7.1).Conclusion. Trp64Arg polymorphism of the ADRB3 gene predicted the risk of developing hyperuricemia in this adult population.
A rapid and simple chemiluminescence method for screening levels of inosine and hypoxanthine in non‐traumatic chest pain patients
Authors: Farthing Don E. , Sica Domenic , Hindle Michael , Edinboro Les , Xi Lei , Gehr Todd W.B. , Gehr Lynne , Farthing Christine A. , Larus Terri L. , Fakhry Itaf , Karnes H. Thomas 
Published: December 2009

AbstractA rapid and simple chemiluminescence method was developed for detection of inosine and hypoxanthine in human plasma. The method utilized a microplate luminometer with direct injectors to automatically dispense reagents during sample analysis. Enzymatic conversions of inosine to hypoxanthine, followed by hypoxanthine to xanthine to uric acid, generated superoxide anion radicals as a useful metabolic by‐product. The free radicals react with Pholasin®, a sensitive photoprotein used for chemiluminescence detection, to produce measurable blue‐green light. The use of Pholasin® and a chemiluminescence signal enhancer, Adjuvant‐K™, eliminated the need for plasma clean‐up steps prior to analysis. The method used 20 μL of heparinized plasma, with complete analysis of total hypoxanthine levels (inosine is metabolized to hypoxanthine using purine nucleoside phosphorylase) in approximately 3.7 min. The rapid chemiluminescence method demonstrated the capability of differentiating total hypoxanthine levels between healthy individuals, and patients presenting with non‐traumatic chest pain and potential acute cardiac ischemia. The results support the potential use of chemiluminescence methodology as a diagnostic tool to rapidly screen for elevated levels of inosine and hypoxanthine in human plasma, potential biomarkers of acute cardiac ischemia.Copyright ©2009 John Wiley & Sons, Ltd.
Dried blood spot sampling in combination with LC‐MS/MS for quantitative analysis of small molecules
Authors: Li Wenkui , Tse Francis L. S. 
Published: December 2009

AbstractThe collection of whole blood samples on paper, known as dried blood spot (DBS), dates back to the early 1960s in newborn screening for inherited metabolic disorders. DBS offers a number of advantages over conventional blood collection. As a less invasive sampling method, DBS offers simpler sample collection and storage and easier transfer, with reduced infection risk of various pathogens, and requires a smaller blood volume. To date, DBS‐LC‐MS/MS has emerged as an important method for quantitative analysis of small molecules. Despite the increasing popularity of DBS‐LC‐MS/MS, the method has its limitations in assay sensitivity due to the small sample size. Sample quality is often a concern. Systematic assessment on the potential impact of various blood sample properties on accurate quantification of analyte of interest is necessary. Whereas most analytes may be stable on DBS, unstable compounds present another challenge for DBS as enzyme inhibitors cannot be conveniently mixed during sample collection. Improvements on the chemistry of DBS card are desirable. In addition to capturing many representative DBS‐LS‐MS/MS applications, this review highlights some important aspects of developing and validating a rugged DBS‐LC‐MS/MS method for quantitative analysis of small molecules along with DBS sample collection, processing and storage. Copyright © 2009 John Wiley & Sons, Ltd.
Systematic LC‐MS/MS bioanalytical method development that incorporates plasma phospholipids risk avoidance, usage of incurred sample and well thought‐out chromatography
Authors: Jemal Mohammed , Ouyang Zheng , Xia Yuan‐Qing 
Published: December 2009

AbstractThis treatise summarizes the underlying principle and the road map for systematic LC‐MS/MS bioanalytical method development. The three themes that have recently emerged as central to building quality during method development—phospholipids, incurred sample and sound chromatographic considerations—are the main focus of this article. In order to reduce the bioanalytical risk associated with plasma phospholipids, a dual approach involving extraction and chromatography is recommended. The use of incurred sample during method development is essential to avoid interference arising from drug‐related components. This is different from the current practice of incurred sample reanalysis, which tests reproducibility during method application. LC column/mobile phase optimization is needed to achieve appropriate peak shape, sensitivity and the separation of the analyte from interfering metabolites and phospholipids. Related to sound chromatographic considerations, we lay out facts and myths related to UPLC, vis‐à‐vis HPLC. Incorporation of quality during method development avoids the costly experience of finding out by chance about the invalidity of a method after it has been used in support of a number of pivotal clinical and non‐clinical studies. To this end, we put forth an outline of a protocol for a systematic LC‐MS/MS bioanalytical method development. Copyright © 2009 John Wiley & Sons, Ltd.
Endothelial IQGAP1 regulates efficient lymphocyte transendothelial migration
Authors: Nakhaei‐Nejad Maryam , Zhang Qiu‐Xia , Murray Allan G. 
Published: December 2009

AbstractLeukocyte movement from the blood to the tissues is a fundamental process in acute and chronic inflammatory diseases. While the role of endothelial cells (EC) to recruit leukocytes to sites of inflammation is well known, the mechanisms that control remodeling of EC shape and adhesive contacts during leukocyte transendothelial migration (TEM) are not completely understood. We studied the role of IQGAP1, an adaptor protein that binds to filamentous‐actin and microtubules (MT) at interendothelial junctions, during lymphocyte TEM. EC IQGAP1 knockdown decreases MT tethered to the adherens junction, and decreases lymphocyte TEM to ∼70% (p<0.05) versus control. Similarly, loss of adherens junction‐associated MT induced by brief nocodazole (ND) treatment decreases lymphocyte TEM to ∼65% of control (p<0.01). Confocal microscopy imaging indicates that EC IQGAP1 knockdown and MT depolymerization both result in lymphocyte accumulation above the vascular endothelial cadherin (VE‐cadherin) junctions and reduces the fraction of adherent lymphocytes that complete diapedesis across interendothelial cell junctions. However, we observe no change in VE‐cadherin gap formation underlying adherent lymphocytes among control, IQGAP1 knockdown, or MT depolymerised EC monolayers. These data indicate that IQGAP1 contributes to MT stability at endothelial junctions. Further, IQGAP1 is involved in junction remodeling required for efficient lymphocyte diapedesis, independent of VE‐cadherin gap formation.
C5a receptor‐deficient dendritic cells promote induction of Treg and Th17 cells
Authors: Weaver Donald J. , Reis Edimara S. , Pandey Manoj K. , Köhl Gabriele , Harris Nathaniel , Gerard Craig , Köhl Jörg 
Published: December 2009

AbstractC5a is a proinflammatory mediator that has recently been shown to regulate adaptive immune responses. Here we demonstrate that C5a receptor (C5aR) signaling in DC affects the development of Treg and Th17 cells. Genetic ablation or pharmacological targeting of the C5aR in spleen‐derived DC results in increased production of TGF‐β leading to de novo differentiation of Foxp3+ Treg within 12 h after co‐incubation with CD4+ T cells from DO11.10/RAG2−/− mice. Stimulation of C5aR−/− DC with OVA and TLR2 ligand Pam3CSK4 increased TGF‐β production and induced high levels of IL‐6 and IL‐23 but only minor amounts of IL‐12 leading to differentiation of Th cells producing IL‐17A and IL‐21. Th17 differentiation was also found in vivo after adoptive transfer of CD4+ Th cell into C5aR−/− mice immunized with OVA and Pam3CSK4. The altered cytokine production of C5aR−/− DC was associated with low steady state MHC class II expression and an impaired ability to upregulate CD86 and CD40 in response to TLR2. Our data suggest critical roles for C5aR in Treg and Th17‐cell differentiation through regulation of DC function.
Intrathecal immune responses to EBV in early MS
Authors: Jaquiéry Emilie , Jilek Samantha , Schluep Myriam , Meylan Pascal , Lysandropoulos Andreas , Pantaleo Giuseppe , Du Pasquier Renaud A. 
Published: December 2009

AbstractEBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV‐specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non‐inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus‐specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus‐specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8+ CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE‐based CTL assay. We found that viral capsid antigen and EBV‐encoded nuclear antigen‐1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV‐, but not CMV‐specific, CD8+ CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV‐ nor CMV‐specific CD8+ CTL in the CSF. Our data, showing a high EBV‐, but not CMV‐specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.
Synthesis and GC–MS analysis of angelates and tiglates as an aid to identification of these components in essential oils
Authors: Adams Robert P. , Dev Vasu 
Published: December 2009

AbstractOne‐hundred‐and‐forty‐one angelates and tiglates were synthesized and their Kováts retention indices and mass spectra are presented. It is anticipated that the publication of these data will aid in the identification of angelates and tiglates from natural sources. Copyright © 2009 John Wiley & Sons, Ltd.
Nanoscale Transport Dynamics inside a Hydrated Nafion Membrane with Electric Field Effects
Authors: Chen P. Y. , Hong C. W. 
Published: December 2009

AbstractAtomistic simulations were performed to investigate the effects of electric field on the transport dynamics inside a hydrated Nafion membrane. An electric field, varied from 2.5 × 103 to 7.5 × 103 V m–1 simulating the operating voltage from 0.25 to 0.75 V and the membrane thickness of 100 μm was applied along the proton transport direction in the simulation cell. A significant change in the membrane morphology can be observed when the electric field was considered. With increase in the electric field strength, mobilities of hydronium ions and water molecules are enhanced. The difference in the transport phenomena, with and without the electric field, can be visualised from the molecular trajectory diagrams. The distribution of water clusters and their sizes under the influence of the electric field can also be investigated using this molecular analysis technique.
Microsurgical free flap in head and neck reconstruction
Authors: Wong Chin‐Ho , Wei Fu‐Chan 
Published: December 2009

AbstractMicrosurgical free flaps are today considered state of the art in head and neck reconstruction after composite tumor resections. Free flaps provide superior functional and aesthetic restoration with less donor‐site morbidity. This article details our approach to this challenging and complex procedure. Free tissue transfer can be viewed as consisting of 4 essential stages: (1) defect assessment, (2) preparation of recipient vessels, (3) flap selection and harvest, and (4) flap inset and microsurgical anastomoses. The essential details of each step are highlighted. Meticulous attention to each step is important because each plays a crucial role in the overall success of the procedure. Workhorse flaps in our practice are the anterolateral thigh, radial forearm, fibula, and jejunum flaps. Unique issues related to postoperative care and monitoring of head and neck free flaps are discussed. The management of complications, in particular those threatening flap survival, are reviewed in detail. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Core 2 N‐acetylglucosaminyltransferase‐1 expression induces aggressive potential of testicular germ cell tumor
Authors: Hatakeyama Shingo , Kyan Atsushi , Yamamoto Hayato , Okamoto Akiko , Sugiyama Naoki , Suzuki Yuichiro , Yoneyama Takahiro , Hashimoto Yasuhiro , Koie Takuya , Yamada Shigeyuki , Saito Hideo , Arai Yoichi , Fukuda Minoru , Ohyama Chikara 
Published: December 2009

AbstractWe studied orchiectomy specimens from 130 patients immuhistochemically with testicular germ cell tumor (TGCT) using anti‐core 2 N‐acetylglucosaminyltransferase‐1 (C2GnT‐1) antibody. The incidence of C2GnT‐1 positivity in stage I disease (29.5%, 21/71) was significantly lower than that in higher stages (84.7%, 50/59) (P < 0.001, χ2 test). This significant difference was also found when the cases were divided into seminoma and NSGCT according to histopathological classification. Kaplan‐Meier plots and the log rank test showed that in the patients with stage I seminoma, C2GnT‐1‐positive cases had a higher risk for recurrence (P < 0.001). This was also the case with the patients with stage I NSGCT (P < 0.001). To determine whether C2GnT‐1 promotes aggressive behavior of cancer cells, a C2GnT‐1‐negative human TGCT cell line, JKT‐1, was stably transfected with a mammalian expression vector containing C2GnT‐1 cDNA. In vitro assays revealed that JKT‐1‐C2 cells are more invasive than mock transfectants, although there are no differences in proliferation activity. When orthotopically inoculated into athymic nude mice, JKT‐1‐C2 cells produced larger testicular tumors extending to the retroperitoneum with mesenteric metastasis, while mock transfectants produced small tumors without metastasis (P < 0.01, Mann‐Whitney's U‐test). When injected via the tail vein, JKT‐1‐C2 cells produced a number of metastatic lung foci. In contrast, mock transfectants produced a small number of nodules (p < 0.01, Mann‐Whitney's U‐test). These results strongly suggest that C2GnT‐1 enhances the metastatic potential of TGCT and may be a reliable biomarker for aggressive potential of TGCT.