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2461. Can encapsulated glutamine increase GLP-1 secretion, improve glucose tolerance, and reduce meal size in healthy volunteers? A randomised, placebo-controlled, cross-over trial.
Obesity is a global concern and can be effectively treated with bariatric surgery, which is expensive and invasive. Weight loss after surgery has been attributed to increased nutrient delivery to the lower small intestine with release of satiety-promoting gut hormones such as glucagon-like peptide 1 (GLP-1). We aimed to assess whether glutamine, a potent secretagogue of GLP-1 in vivo, increases GLP-1 release, improves glucose tolerance, or reduces meal size in volunteers.
2462. Assessment of glycogen phosphorylase isoenzyme BB as a biomarker for pre-eclampsia and small for gestational age.
Glycogen phosphorylase is a key enzyme in the regulation of glycogen metabolism and consists of three isoenzymes, including glycogen phosphorylase isoenzyme BB (GPBB). Pre-eclampsia, gestational hypertension, and small-for-gestational-age (SGA) infants are complications in about 15% of all nulliparous pregnancies. Biomarkers for these adverse pregnancy outcomes remain elusive. GPBB has been proposed as a potential biomarker for the detection of these adverse outcomes. We aimed to investigate this hypothesis.
2463. Antagonism of aminoacid transport in primary CD4 T cells by HIV-1 Vpu.
作者: Nicholas Matheson.;Kim Wals.;Michael Weekes.;Radu Rapiteanu.;Raphael Vigan.;Robin Antrobus.;Duncan Smith.;Stuart Neil.;Paul Lehner.
来源: Lancet. 2015年385 Suppl 1卷S66页
Less than 100 years since it was first transmitted to the human population HIV-1 infects more than 30 million people worldwide and causes almost 2 million AIDS-related deaths every year. Viruses manipulate cellular genes and pathways to benefit their survival, and the study of cell surface proteins downregulated by viruses has provided insights into both viral pathogenesis and crucial aspects of cell biology. We aimed to identify novel cell surface proteins targeted for downregulation by HIV-1.
2464. Effect of a GRIN2A de novo mutation associated with epilepsy and intellectual disability on NMDA receptor currents and Mg(2+) block in cultured primary cortical neurons.
Background GRIN2A encodes the GluN2A subunit of the NMDA receptor (NMDAR), an ionotropic glutamate receptor that has important roles in synaptogenesis and synaptic plasticity. Some individuals with early onset epilepsies and intellectual disability carry heterozygous missense mutations in this gene, including a de-novo mutation in the receptor pore region (GluN2A(N615K)). We hypothesised that this mutation underlies the carrier's brain disorder and sought to explore its functional consequences.
2465. Comparative effectiveness and safety of image guidance systems in surgery: a preclinical randomised study.
作者: Hani J Marcus.;Philip Pratt.;Archie Hughes-Hallett.;Thomas P Cundy.;Adam P Marcus.;Guang-Zhong Yang.;Ara Darzi.;Dipankar Nandi.
来源: Lancet. 2015年385 Suppl 1卷S64页
Over the past decade image guidance systems have been widely adopted in specialties such as neurosurgery and otorhinolaryngology. Nonetheless, the evidence supporting the use of image guidance systems in surgery remains limited. New augmented reality systems offer the possibility of enhanced operating room workflow compared with existing triplanar image displays, but recent studies have highlighted several concerns, particularly the risk of inattentional blindness and impaired depth perception. The aim of this study was to compare simultaneously the effectiveness and safety of various image guidance systems against standard surgery.
2466. Association between hypercortisolaemia and adipose tissue blood flow in vivo.
作者: Konstantinos Manolopoulos.;Hafwen Thornhill.;Jennifer Thomas.;Wiebke Arlt.;Jeremy Tomlinson.
来源: Lancet. 2015年385 Suppl 1卷S63页
An apple-shaped fat distribution is associated with an adverse cardiometabolic phenotype. Hypercortisolaemia (Cushing's syndrome) is characterised by abdominal fat accumulation and gluteofemoral fat loss. The mechanisms underpinning this redistribution of fat mass are unknown. Since adipose tissue blood flow (ATBF) is an important determinant of lipolytic rate in vivo, we hypothesised that hypercortisolaemia might lead to differential abdominal and femoral ATBF.
2467. Role of ANO4 in regulation of aldosterone secretion in the zona glomerulosa of the human adrenal gland.
作者: Carmela Maniero.;Junhua Zhou.;Lalarukh H Shaikh.;Elena A B Azizan.;Ian McFarlane.;Sudeshna Neogi.;Paolo Scudieri.;Louis J Galietta.;Morris J Brown.
来源: Lancet. 2015年385 Suppl 1卷S62页
Cell origin of aldosterone-producing adenomas, a major cause of hypertension, is unknown. A less common subtype of these adenomas, composed of cells resembling zona glomerulosa, have mutations in genes ATP1A1 and CACNA1D. To understand whether the adenomas originate from zona glomerulosa, we carried out a microarray analysis comparing transcriptomes of zona glomerulosa, zona fasciculata, and tumour in human adrenal tissue, and investigated the functional role of genes upregulated in the zona glomerulosa.
2468. Physical health indicators in major mental illness: data from the Quality and Outcome Framework in the UK.
作者: Julie Langan Martin.;Richard Lowrie.;Alex McConnachie.;Gary McLean.;Frances Mair.;Stewart Mercer.;Daniel Smith.
来源: Lancet. 2015年385 Suppl 1卷S61页
In the UK, the Quality and Outcome Framework (QOF) has specific targets for general practictioners to record body-mass index (BMI) and blood pressure (BP) in major mental illness, diabetes, and chronic kidney disease. Although incentives are given for aspects of major mental illness (schizophrenia, bipolar disorder, and related psychoses), barriers to care can occur. Our aim was to compare recording of specific targets for BP and BMI in individuals with major mental illness relative to diabetes and chronic kidney disease across the UK.
2469. The effect of trauma on invasive group A streptococcal disease.
作者: Lucy Lamb.;Warren McDonald.;Cheryl Scudamore.;Lionel Tan.;Nicola Lynskey.;Shiranee Sriskandan.
来源: Lancet. 2015年385 Suppl 1卷S60页
Necrotising fasciitis due to invasive group A streptococcus (iGAS) is frequently associated with type emm1 isolates, with an attendant mortality of 40%. Some cases occur in previously healthy individuals with a history of upper respiratory tract infection, soft tissue contusion, and no obvious portal of entry. Using a new model of mild contusion injury, we set out to determine the effect of contusion on iGAS bacterial burden, phenotype, and host cytokine response.
2470. Characteristics of immunosuppressive regulatory T cells in cutaneous squamous cell carcinomas and role in metastasis.
作者: Chester Lai.;Suzannah August.;Ramnik Behar.;Marta Polak.;Mike Ardern-Jones.;Jeff Theaker.;Aymen Al-Shamkhani.;Eugene Healy.
来源: Lancet. 2015年385 Suppl 1卷S59页
Non-melanoma skin cancer is the most common cancer worldwide, and cutaneous squamous cell carcinomas (SCCs) account for substantial morbidity and mortality because of their potential for metastasis. SCCs are surrounded by an immune cell infiltrate containing regulatory T cells (Tregs). The aim of this study was to characterise Tregs in SCCs and investigate whether increased Treg numbers in primary skin SCCs are associated with subsequent metastasis.
2471. Synthetic lethality in chronic lymphocytic leukaemia with DNA damage response defects by targeting the ATR pathway.
作者: Marwan Kwok.;Nicholas Davies.;Angelo Agathanggelou.;Edward Smith.;Eva Petermann.;Eliot Yates.;Jeffrey Brown.;Alan Lau.;Tatjana Stankovic.
来源: Lancet. 2015年385 Suppl 1卷S58页
DNA damage response (DDR) defects, particularly TP53 and biallelic ataxia telangiectasia mutated (ATM) aberrations, are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukaemia (CLL). Therapies capable of providing long-term disease control in CLL patients with DDR defects are lacking. Using AZD6738, a novel ATR inhibitor, we investigated ATR pathway inhibition as a synthetically lethal strategy for targeting CLL cells with these defects.
2472. Inhibition of complement C3 and fibrinogen interaction: a potential novel therapeutic target to reduce cardiovascular disease in diabetes.
作者: Rhodri King.;Christian Tiede.;Katie Simmons.;Colin Fishwick.;Darren Tomlinson.;Ramzi Ajjan.
来源: Lancet. 2015年385 Suppl 1卷S57页
Enhanced complement C3 incorporation into the fibrin network in diabetes is one mechanism for impaired fibrinolysis and increased thrombosis risk in this condition. Our aim was to develop new strategies to modulate fibrinolysis in diabetes by interfering with fibrin-C3 interaction.
2473. Anti-cancer effects of oncolytic viral therapy combined with photodynamic therapy in human pancreatic cancer cell lines.
Oncolytic viral therapy and photodynamic therapy are potential therapies for inoperable or advanced pancreatic cancer. Our aim was to investigate the anti-cancer killing effects of reovirus therapy combined with protoporphyrin IX (PpIX)-mediated photodynamic therapy on a variety of human pancreatic cancer cell lines.
2474. Genome-wide transcription profiling in neutrophils in acute respiratory distress syndrome.
作者: JatinderK Juss.;Jurgen Herre.;Malcolm Begg.;Glyn Bradley.;Mark Lennon.;Augustin Amour.;David House.;Edith M Hessel.;Charlotte Summers.;Alison M Condliffe.;Edwin R Chilvers.
来源: Lancet. 2015年385 Suppl 1卷S55页
Acute respiratory distress syndrome (ARDS) is characterised by diffuse neutrophil-mediated alveolar inflammation. Recently, we demonstrated that blood polymorphonuclear leucocytes (PMNs) in ARDS are basally activated, and exhibit aberrant oxidative burst and survival responses. The molecular mechanisms governing ARDS PMN function and longevity are incompletely understood. We aimed to use genome-wide transcriptional profiling of ARDS blood PMNs to explore underlying disease mechanisms and identify therapeutic targets aimed at manipulating PMN function and longevity.
2475. Divergent transcriptional activation by glucocorticoids in mouse and human macrophages.
Innate immune cells are major targets of glucocorticoids as anti-inflammatory therapies. Glucocorticoids are metabolic hormones that provide natural feedback regulation of immune function. They are widely prescribed, but use is restricted by side-effects. Much of our knowledge about how glucocorticoids work comes from studies in mice. However, since mice are imperfect models of human macrophage biology, for example in inflammation, whether this knowledge can be directly translated to man is uncertain. We aimed to address this uncertainty.
2476. Potential for monocyte recruitment by IgE immunotherapy for cancer in a rat model of tumour metastasis.
作者: Debra H Josephs.;Heather J Bax.;Heike Lentfer.;Chris Selkirk.;James F Spicer.;Sophia N Karagiannis.
来源: Lancet. 2015年385 Suppl 1卷S53页
Nearly all anti-tumour antibodies are of a single class-namely, IgG. Efficacy might be improved by development of tumour-specific IgE antibodies, which have higher affinities for effector cell receptors and perform potent immune functions. MOv18IgE, which targets folate receptor α (FRα), is a novel system to model this hypothesis. Human chimeric MOv18 IgE has shown superior efficacy in two murine xenograft models compared with MOv18 IgG1. Our aim was to examine the potential of this antibody class to activate monocytes.
2477. Regulation of neutrophilic inflammation in lung injury induced by community-acquired pneumonia.
作者: Ricardo José.;Andrew Williams.;Michal Sulikowski.;David Brealey.;Jeremy Brown.;Rachel Chambers.
来源: Lancet. 2015年385 Suppl 1卷S52页
Community-acquired pneumonia is commonly caused by Streptococcus pneumoniae, which is associated with excessive neutrophilic inflammation. The high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR1), has been implicated in mediating the interplay between coagulation and inflammation. However, its role during S pneumoniae-induced neutrophilic inflammation, and the mechanisms for neutrophil recruitment in this context are poorly understood. We aimed to investigate the role of neutrophilic inflammation and PAR1 in S pneumoniae-induced pneumonia.
2478. Neural respiratory drive and symptoms that limit exercise in chronic obstructive pulmonary disease.
作者: Caroline Jolley.;Yuanming Luo.;Joerg Steier.;Karl Sylvester.;William Man.;Gerrard Rafferty.;Michael Polkey.;John Moxham.
来源: Lancet. 2015年385 Suppl 1卷S51页
Exercise capacity in chronic obstructive pulmonary disease (COPD) is limited by both breathlessness and leg muscle fatigue. Neural respiratory drive, measured as diaphragm electromyogram (EMGdi) activity expressed as a proportion of maximum (EMGdi%max), quantifies the mechanical load on the respiratory muscles and relates closely to breathlessness. We tested the hypothesis that end-exercise EMGdi%max would be higher in patients stopping because of breathlessness than in those limited by leg fatigue.
2479. A role for helminth parasites in achieving immunological tolerance in transplantation.
作者: Chris Johnston.;Henry McSorley.;Danielle Smyth.;Stephen Anderton.;Stephen Wigmore.;Rick Maizels.
来源: Lancet. 2015年385 Suppl 1卷S50页
Helminths infect more than a quarter of the world's population. Their success as parasites is the result of active immunomodulation of the host immune response, which can have benefits for the host, particularly in suppressing harmful allergic and autoimmune responses. Accordingly, we tested the hypothesis that helminth infection reduces the immune response to allograft transplantation.
2480. Molecular mechanisms of myocardial nitroso-redox imbalance during on-pump cardiac surgery.
作者: Raja Jayaram.;Nicky Goodfellow.;Mei Hua Zhang.;Svetlana Reilly.;Mark Crabtree.;Ravi De Silva.;Rana Sayeed.;Barbara Casadei.
来源: Lancet. 2015年385 Suppl 1卷S49页
The mechanism responsible for left ventricular dysfunction after cardiac surgery is only partly understood. In isolated rat hearts subjected to an ischaemia-reperfusion protocol, left ventricular dysfunction was associated with uncoupling of endothelial nitric oxide synthase (NOS) activity secondary to oxidation of the NOS cofactor, tetrahydrobiopterin (BH4). Here we investigated the effect of cardiopulmonary bypass and reperfusion on myocardial nitroso-redox balance in patients undergoing cardiac surgery.
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