bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large chromosome deletions, duplications, and gene conversion events accumulate with age in normal human colon crypts
Authors: Hsieh John C. F. , Van Den Berg David , Kang Haeyoun , Hsieh Chih‐Lin , Lieber Michael R. 
Published: February 2013

SummaryLittle is known about the types and numbers of mutations that may accumulate in normal human cells with age. Such information would require obtaining enough DNA from a single cell to accurately carry out reliable analysis despite extensive amplification; and complete genomic coverage under these circumstances is difficult. We have compared colon crypts, which are putatively clonal and contain ~2000 cells each, to determine how much somatic genetic variation occurs in vivo (without ex vivo cell culturing). Using high‐density SNP microarrays, we find that chromosome deletions, duplications, and gene conversions were significantly more frequent in colons from the older individuals. These changes affected lengths ranging from 73 kb to 46 Mb. Although detection requires progeny of a single mutant stem cell to reach niche dominance over neighboring stem cells, none of the deletions appear likely to confer a selective advantage. Mutations can become fixed randomly during stem cell evolution through neutral drift in normal human crypts. The fact that chromosomal changes are detected in individual crypts with increasing age suggests that either such changes accumulate with age or single stem cell dominance increases with age, and the former is more likely. This progressive genome‐wide divergence of human somatic cells with age has implications for aging and disease in multicellular organisms.
Self‐reported alcohol abuse in HIV–HCV co‐infected patients: a better predictor of HIV virological rebound than physician's perceptions (HEPAVIH ARNS CO13 cohort)
Authors: Marcellin Fabienne , Lions Caroline , Winnock Maria , Salmon Dominique , Durant Jacques , Spire Bruno , Mora Marion , Loko Marc‐Arthur , Dabis François , Dominguez Stéphanie , Roux Perrine , Carrieri Maria Patrizia ,   ANRS CO13 HEPAVIH Study Group
Published: February 2013

AbstractAimsStudying alcohol abuse impact, as measured by physicians' perceptions and patients' self‐reports, on HIV virological rebound among patients chronically co‐infected with HIV and hepatitis C virus (HCV).DesignCohort study.SettingSeventeen French hospitals.ParticipantsFive hundred and twelve patients receiving antiretroviral therapy (ART) with an undetectable initial HIV viral load and at least two viral load measures during follow‐up.MeasurementsMedical records and self‐administered questionnaires. HIV virological rebound defined as HIV viral load above the limit of detection of the given hospital's laboratory test. Alcohol abuse defined as reporting to have drunk regularly at least 4 (for men) or 3 (for women) alcohol units per day during the previous 6 months. Correlates of time to HIV virological rebound identified using Cox proportional hazards models.FindingsAt enrolment, 9% of patients reported alcohol abuse. Physicians considered 14.8% of all participants as alcohol abusers. Self‐reported alcohol abuse was associated independently with HIV virological rebound [hazard ratio (95% confidence interval): 2.04 (1.13–3.67); P = 0.02], after adjustment for CD4 count, time since ART initiation and hospital HIV caseload. No significant relationship was observed between physician‐reported alcohol abuse and virological rebound (P = 0.87).ConclusionsIn France, the assessment of alcohol abuse in patients co‐infected with HIV and hepatitis C virus should be based on patients' self‐reports, rather than physicians' perceptions. Baseline screening of self‐reported alcohol abuse may help identify co‐infected patients at risk of subsequent HIV virological rebound.
Clinical usefulness of portal venous stent in hepatobiliary pancreatic cancers
Authors: Zhou Zun Qiang , Lee Jae Hoon , Song Ki Byung , Hwang Ji Woong , Kim Song Cheol , Lee Young‐Joo , Park Kwang‐Min 
Published: February 2013

AbstractBackgroundTreatment options for patients with portal vein (PV) stenosis or occlusion after surgery are limited. The purpose of this study was to investigate the efficacy and safety of PV stent placement in patients with portal vein occlusion or stenosis after radical operation for hepatobiliary pancreatic malignant tumour.MethodsWe retrospectively reviewed the records of 59 patients who underwent portal venous stent placement at the Asan Medical Center, Seoul, Korea, for PV stenosis or occlusion between February 2008 and February 2012.ResultsStents were placed in the portal venous system across stenotic (n = 47) and occlusive (n = 12) lesions after percutaneous transhepatic portography. Reasons for stent placement were tumour recurrence (n = 30), portal vein resection and anastomosis (n = 18) and post‐operative inflammatory changes (n = 11). Pressure gradients (superior mesenteric vein, main PV) decreased immediately after stent placement, from 10.5 mm Hg ± 4.4 (standard deviation) to 2.5 mm Hg ± 2.6 (P < 0.0001). Liver function was improved post‐stenting (P < 0.05). The median time between the original surgery and stent placement was 16 (1–137) days in the vascular‐orientated group and 306 (13–3703) days in the tumour recurrence group (P < 0.0001). Transient fever developed in 11 patients, but resolved in 2–5 days. Stents were occluded in 15 of the 59 patients (25.4%).ConclusionPV stent placement is a safe choice, has an acceptable success rate and provides marked relief from portal hypertension due to portal vein occlusion or stenosis after hepatobiliary pancreatic surgery. Liver function data are also improved after portal venous stent placement.
Economics of childbirth
Authors: Fahy Michael , Doyle Orla , Denny Kevin , Mcauliffe Fionnuala M. , Robson Michael 
Published: February 2013

AbstractBackgroundIncreasing birth rates have raised questions for policy makers and hospital management about the economic costs of childbirth.ObjectiveThe purpose of this article is to identify and review all existing scientific studies in relation to the economic costs of alternative modes of childbirth delivery and to highlight deficiencies in the existing scientific research.MethodWe searched Cochrane, Centre for Reviews and Dissemination, EconLit, the Excerpta Medica Database, the Health Economic Evaluations Database, MEDLINE and PubMed.ResultsThirty articles are included in this review. The main findings suggest that there is no internationally acceptable childbirth cost and clinical outcome classification system that allows for comparisons across different delivery modes.ConclusionThis review demonstrates that a better understanding and classification of the costs and associated clinical outcomes of childbirth is required to allow for valid comparisons between maternity units, and to inform policy makers and hospital management.
Meta‐analysis: oral or enteral nutritional supplementation in cirrhosis
Authors: Ney M. , Vandermeer B. , van Zanten S. J. V. , Ma M. M. , Gramlich L. , Tandon P. 
Published: February 2013

SummaryBackgroundMalnutrition is a common and clinically significant problem in patients with cirrhosis. The impact of nutritional therapy remains unclear.AimTo provide an up‐to‐date systematic review and meta‐analysis of RCTs of oral or enteral nutritional supplementation (ONS or ENS) on nutritional and clinical outcomes in adult patients with cirrhosis.MethodsThe primary outcome measure was survival. Included: full‐text English language RCTs investigating ONS or ENS vs. a standard nonsupplemented diet in patients with cirrhosis. Excluded: parenteral or branched chain amino acids intervention; treatment duration ≤7 days, exclusive evaluation of posttransplant, postsurgical or quality of life outcomes.ResultsSix trials (4 ONS/2 ENS) and 470 patients were included with 71% males and median age 53 years. When all studies were combined, there was no reduction in mortality [Relative risk (RR): 0.75 (0.42, 1.32), P = 0.31]. Subgroup analysis of 3 of the 4 ONS studies did demonstrate a mortality reduction [RR: 0.40 (0.18, 0.90), P = 0.03]. Of the 2 ENS studies, one included the sickest patients in the meta‐analysis (82% Child Pugh C) and the other had the shortest mean intervention duration (8.6 days), possibly impacting the potential for benefit. Study quality was suboptimal (median Jadad = 2).ConclusionsAlthough there is insufficient evidence to definitively state that oro‐enteral nutritional supplementation impacts clinical outcomes, on the basis of this analysis, one can be cautiously optimistic that there is the potential for benefit without an increase in adverse events. Adequately powered, Child Pugh stratified studies of at least 1 month in duration are needed to clarify the impact on relevant clinical outcomes.
CGRP in the trigeminovascular system: a role for CGRP, adrenomedullin and amylin receptors?
Authors: Walker C S , Hay D L 
Published: February 2013

The neuropeptide calcitonin gene‐related peptide (CGRP) is reported to play an important role in migraine. It is expressed throughout the trigeminovascular system. Antagonists targeting the CGRP receptor have been developed and have shown efficacy in clinical trials for migraine. However, no CGRP antagonist is yet approved for treating this condition. The molecular composition of the CGRP receptor is unusual because it comprises two subunits; one is a GPCR, the calcitonin receptor‐like receptor (CLR). This associates with receptor activity‐modifying protein (RAMP) 1 to yield a functional receptor for CGRP. However, RAMP1 also associates with the calcitonin receptor, creating a receptor for the related peptide amylin but this also has high affinity for CGRP. Other combinations of CLR or the calcitonin receptor with RAMPs can also generate receptors that are responsive to CGRP. CGRP potentially modulates an array of signal transduction pathways downstream of activation of these receptors, in a cell type‐dependent manner. The physiological significance of these signalling processes remains unclear but may be a potential avenue for refining drug design. This complexity has prompted us to review the signalling and expression of CGRP and related receptors in the trigeminovascular system. This reveals that more than one CGRP responsive receptor may be expressed in key parts of this system and that further work is required to determine their contribution to CGRP physiology and pathophysiology.Linked ArticlesThis article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue‐7
Molecular mechanisms underlying the anti‐proliferative and anti‐migratory effects of folate on homocysteine‐challenged rat aortic smooth muscle cells
Authors: Chou Ying , Lin Hui‐Chen , Chen Kuan‐Chou , Chang Chi‐Cheng , Lee Wen‐Sen , Juan Shu‐Hui 
Published: February 2013

Background and PurposeHomocysteine is an intermediate product formed during the metabolism of methionine, and is increased in cells with folate deficiency. Patients with hyperhomocysteinemia tend to develop cardiovascular disease. Here, we have examined the molecular mechanisms underlying the anti‐proliferative and anti‐migratory effects of folate on homocysteine‐challenged rat aortic smooth muscle cells (RASMCs).Experimental ApproachCultures of RASMC were challenged with homocysteine and then incubated with folate added. Changes in p21/p27, AKT and RhoA were followed by RT‐PCR, Western blotting and immunocytochemistry. Transfection and anti‐sense techniques were also used. Cell viability, growth and migration were measured.Key ResultsFolate up‐regulated p21/p27 through a Src/ERK‐dependent mechanism that accounted for its anti‐proliferative effects on RASMC. Folate protected RASMC from the effects of homocysteine by reducing AKT1, focal adhesion kinase (FAK), paxillin, and p190RhoGAP activation/phosphorylation, along with cytosolic levels of p21 and p27, and increasing RhoA activation. Overexpression of AKT1, but not of AKT2, induced p21/p27 phosphorylation and increased cytosolic p21/p27 levels, as did homocysteine treatment. By contrast, and similarly to folate treatment, transfection with dominant negative (DN) AKT1 counteracted these effects. Additionally, AKT was shown to be an upstream target of FAK activation. In RASMC overexpressing constitutively active RhoA, activation of RhoA mediated the anti‐migratory effects of folate. Addition of Y27632 (a RhoA inhibitor) and DNRhoA counteracted the anti‐migratory effects, confirming RhoA involvement.Conclusion and implicationsFolate was anti‐proliferative and anti‐migratory in homocysteine‐challenged RASMC. Mechanisms underlying folate‐mediated protection against the proatherosclerotic effects of homocysteine have been delineated.
The macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 produces short‐acting κ opioid receptor antagonism in the CNS after oral administration
Authors: Eans Shainnel O , Ganno Michelle L , Reilley Kate J , Patkar Kshitij A , Senadheera Sanjeewa N , Aldrich Jane V , McLaughlin Jay P 
Published: February 2013

Background and PurposeCyclic peptides are resistant to proteolytic cleavage, therefore potentially exhibiting activity after systemic administration. We hypothesized that the macrocyclic κ opioid receptor (KOR)‐selective antagonist [D‐Trp]CJ‐15,208 would demonstrate antagonist activity after systemic, that is, s.c. and oral (per os, p. o.), administration.Experimental ApproachC57BL/6J mice were pretreated with [D‐Trp]CJ‐15,208 s.c. or p.o. before administration of the KOR‐selective agonist U50,488 and the determination of antinociception in the warm‐water tail‐withdrawal assay. The locomotor activity of mice treated with [D‐Trp]CJ‐15,208 was determined by rotorod testing. Additional mice demonstrating cocaine conditioned place preference and subsequent extinction were pretreated daily with vehicle or [D‐Trp]CJ‐15,208 and then exposed to repeated forced swim stress or a single additional session of cocaine place conditioning before redetermining place preference.Key ResultsPretreatment with [D‐Trp]CJ‐15,208 administered s.c. or p.o. dose‐dependently antagonized the antinociception induced by i.p. administration of U50,488 in mice tested in the warm‐water tail‐withdrawal assay for less than 12 and 6 h respectively. [D‐Trp]CJ‐15,208 also produced limited (<25%), short‐duration antinociception mediated through KOR agonism. Orally administered [D‐Trp]CJ‐15,208 dose‐dependently antagonized centrally administered U50,488‐induced antinociception, and prevented stress‐, but not cocaine‐induced, reinstatement of extinguished cocaine‐seeking behaviour, consistent with its KOR antagonist activity, without affecting locomotor activity.Conclusions and ImplicationsThe macrocyclic tetrapeptide [D‐Trp]CJ‐15,208 is a short‐duration KOR antagonist with weak KOR agonist activity that is active after oral administration and demonstrates blood–brain barrier permeability. These data validate the use of systemically active peptides such as [D‐Trp]CJ‐15,208 as potentially useful therapeutics.
Thymus transplantation restores the repertoires of forkhead box protein 3 (FoxP3)+ and FoxP3− T cells in complete DiGeorge anomaly
Authors: Chinn I K , Milner J D , Scheinberg P , Douek D C , Markert M L 
Published: February 2013

Summary
The development of T cells with a regulatory phenotype after thymus transplantation has not been examined previously in complete DiGeorge anomaly (cDGA). Seven athymic infants with cDGA and non-maternal pretransplantation T cell clones were assessed. Pretransplantation forkhead box protein 3 (Foxp3)+ T cells were detected in five of the subjects. Two subjects were studied in greater depth. T cell receptor variable β chain (TCR-Vβ) expression was assessed by flow cytometry. In both subjects, pretransplantation FoxP3+ and total CD4+ T cells showed restricted TCR-Vβ expression. The development of naive T cells and diverse CD4+ TCR-Vβ repertoires following thymic transplantation indicated successful thymopoiesis from the thymic tissue grafts. Infants with atypical cDGA develop rashes and autoimmune phenomena before transplantation, requiring treatment with immunosuppression, which was discontinued successfully subsequent to the observed thymopoiesis. Post-transplantation, diverse TCR-Vβ family expression was also observed in FoxP3+ CD4+ T cells. Interestingly, the percentages of each of the TCR-Vβ families expressed on FoxP3+ and total CD4+ T cells differed significantly between these T lymphocyte subpopulations before transplantation. By 16 months post-transplantation, however, the percentages of expression of each TCR-Vβ family became significantly similar between FoxP3+ and total CD4+ T cells. Sequencing of TCRBV DNA confirmed the presence of clonally amplified pretransplantation FoxP3+ and FoxP3− T cells. After thymus transplantation, increased polyclonality was observed for both FoxP3+ and FoxP3− cells, and pretransplantation FoxP3+ and FoxP3− clonotypes essentially disappeared. Thus, post-transplantation thymic function was associated with the development of a diverse repertoire of FoxP3+ T cells in cDGA, corresponding with immunological and clinical recovery.
Exposure to anthrax toxin alters human leucocyte expression of anthrax toxin receptor 1
Authors: Ingram R J , Harris A , Ascough S , Metan G , Doganay M , Ballie L , Williamson E D , Dyson H , Robinson J H , Sriskandan S , Altmann D M 
Published: February 2013

Summary
Anthrax is a toxin-mediated disease, the lethal effects of which are initiated by the binding of protective antigen (PA) with one of three reported cell surface toxin receptors (ANTXR). Receptor binding has been shown to influence host susceptibility to the toxins. Despite this crucial role for ANTXR in the outcome of disease, and the reported immunomodulatory consequence of the anthrax toxins during infection, little is known about ANTXR expression on human leucocytes. We characterized the expression levels of ANTXR1 (TEM8) on human leucocytes using flow cytometry. In order to assess the effect of prior toxin exposure on ANTXR1 expression levels, leucocytes from individuals with no known exposure, those exposed to toxin through vaccination and convalescent individuals were analysed. Donors could be defined as either ‘low’ or ‘high’ expressers based on the percentage of ANTXR1-positive monocytes detected. Previous exposure to toxins appears to modulate ANTXR1 expression, exposure through active infection being associated with lower receptor expression. A significant correlation between low receptor expression and high anthrax toxin-specific interferon (IFN)-γ responses was observed in previously infected individuals. We propose that there is an attenuation of ANTXR1 expression post-infection which may be a protective mechanism that has evolved to prevent reinfection.
Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia
Authors: Dahal L N , Hall L S , Barker R N , Ward F J 
Published: February 2013

Summary
Autoimmune haemolytic anaemia (AIHA) is caused by autoantibodies against red blood cell (RBC) surface antigens that render RBC susceptible to Fc-mediated phagocytosis and complement-mediated lysis. Experimental AIHA can be induced by injection of rat RBC to naive mice, but a lymphocyte-mediated regulatory mechanism eventually suppresses the production of autoantibodies specific for mouse RBC. Critically, this tolerogenic response can be transferred to naive mice by splenocytes from the rat RBC-immunized mouse. Here we investigate whether indoleamine 2,3 dioxygenase (IDO) or the initiators of IDO cascade, including the cytotoxic T lymphocyte antigen (CTLA)-4 receptor and its soluble isoform, contribute to this tolerogenic mechanism. Splenocytes from experimental AIHA mice were transferred adoptively to naive mice under the cover of anti-CTLA-4, anti-soluble CTLA-4 antibodies or IDO inhibitor 1-methyl tryptophan (1-MT). Recipient mice were immunized with rat RBC and levels of antibody against self-RBC and rat-RBC were monitored. Our results indicate that transfer of tolerance to naive recipients is dependent upon IDO-mediated immunosuppression, as mice receiving previously tolerized splenocytes under the cover of 1-MT were refractory to tolerance and developed haemolytic disease upon further challenge with rat RBC. Initiators of IDO activity, CTLA-4 or soluble CTLA-4 did not mediate this tolerogenic process but, on their blockade, boosted antigen-specific effector immune responses.
Polymorphism −116C/Gof HumanX‐box‐Binding Protein 1 Promoter is Associated with Risk ofAlzheimer's Disease
Authors: Liu Sheng‐Yuan , Wang Wei , Cai Zhi‐You , Yao Li‐Fen , Chen Zhong‐Wei , Wang Chang‐Yi , Zhao Bin , Li Ke‐Shen 
Published: February 2013

SummaryAimAlzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with endoplasmic reticulum (ER) stress response. In the response, the regulator factor humanX‐box‐binding protein 1 (XBP1) has been shown to facilitate the refolding and degradation of misfolded proteins, prevent neurotoxicity of amyloid‐beta (Aβ) and tau, and play an important role in the survival of neurons. The aim in the study was to analyze the potential association between the −116C/Gpolymorphism ofXBP1and the risk ofAD.MethodsThe association between −116C/Gpolymorphism ofXBP1promoter and possible risk ofADwas assessed among 276 patients withADand 254 matched healthy individuals in a case–control study.ResultsOverall, there was a significantly statistical difference in genotype (P = 0.0354) and allele frequencies (P = 0.0150,OR = 1.3642, 95%CI = 1.0618–1.7528) between theADsubjects and control subjects, showing that the −116C/Gpolymorphism ofXBP1might lead to increased susceptibility forADin aChineseHan population. In addition, the −116CGand −116GGgenotypes were significantly associated with increasedADrisk in female (P = 0.0217) and in subjects withAPOEє4 (−) (P = 0.0070) in stratified analyses, and the −116CCgenotype was significantly associated with fast cognitive deterioration in theADpatients (P = 0.0270).ConclusionThe study supports a role for the −116C/G polymorphism ofXBP1gene in the pathogenesis ofAD, and further studies with a larger sample size and detailed data should be performed in other populations.
Once weekly exenatide: efficacy, tolerability and place in therapy
Authors: Wysham C. , Grimm M. , Chen S. 
Published: February 2013

AbstractExenatide once weekly is the first glucose‐lowering agent available to patients with type 2 diabetes mellitus (T2DM) which is administered once per week. This long‐acting formulation contains the same active ingredient as exenatide twice daily, except that the exenatide is encapsulated in dissolvable microspheres. Following subcutaneous injection, exenatide once weekly microspheres remain in place under the skin and slowly degrade, releasing active exenatide continuously into circulation. In randomized clinical trials, exenatide once weekly was associated with significant glycaemic improvement and moderate weight loss in patients with T2DM when administered as monotherapy or in combination with a variety of oral antidiabetic agents. Exenatide once weekly also lowered blood glucose more effectively than titrated basal insulin in patients on metformin or metformin plus sulphonylurea background therapy. Gastrointestinal side effects (nausea, vomiting and diarrhoea) were the most common tolerability issues associated with exenatide once weekly administration, but they occurred at lower rates than in patients on other glucagon‐like peptide receptor agonists (i.e., exenatide twice daily or liraglutide). Issues regarding the place of exenatide once weekly in T2DM pharmacotherapy are discussed.