tbuckley/cabot-search huggingface dataset:
Creating new β cells: cellular transmutation by genomic alchemy
Authors: Larry G. Moss
Journal: Journal of Clinical Investigation (2013)

To address insulin insufficiency, diabetes research has long focused on techniques for replacing insulin-producing β cells. Studies in mice have suggested that, under some conditions, α cells possess the capacity to transdifferentiate into β cells, although the mechanisms that drive this conversion are unclear. In this issue, Bramswig et al. analyzed the methylation states of purified human α, β, and acinar cells and found α cells exhibit intrinsic phenotypic plasticity associated with specific histone methylation profiles. In addition to expanding our understanding of this potential source of β cells, this compendium of carefully generated human gene expression and epigenomic data in islet cell subtypes constitutes a truly valuable resource for the field.
The early management of muscle strains in the elite athlete: best practice in a world with a limited evidence basis
Authors: John W Orchard, Thomas M Best, Hans-Wilhelm Mueller-Wohlfahrt, Glenn Hunter, Bruce H Hamilton, Nick Webborn, Rod Jaques, Dean Kenneally, Richard Budgett, Nicola Phillips, Caryl Becker, Philip Glasgow
Journal: British Journal of Sports Medicine (2008)

From 12 to 14 December 2007 UK Sport held a think tank on “muscle strains” in London.

This brought together many of UK Sport’s top sports medicine clinicians along with three invited international experts. Many issues of muscle strains were discussed over the three days, but the aspect that attracted the most attention was the early management of strains in the elite athlete. A consensus summary of conclusions on this specific topic from the think tank is presented here.

The international experts were chosen by request of the UK clinicians for different reasons. Drs Best (basic science) and Orchard (epidemiology) are recognised internationally by the peer-review system as experts in their fields. Dr Mueller-Wohlfahrt is also recognised internationally as Europe’s premier clinician in the early management of muscle strains. This recognition was initially bestowed on him by his patients, most notably from the thousands of professional football players he has managed over the past 30 years from every country in Europe. Increasingly this recognition has been accorded by the “mainstream” clinicians in the United Kingdom, hence his invitation to the think tank.

With the reserve typical of both the British and the scientific community, a common assessment of Dr Mueller-Wohlfahrt’s methods by delegates was “initially I had to be sceptical, but I have seen and heard of so many good results that I am now curious to know why these good outcomes are occurring”.

One session of the think tank involved an assessment of our “expert recommendations” for the early management of muscle strains in the elite athlete and a judgement of the evidence base for making the recommendations. The evidence base part was generally easy: almost all of our so-called knowledge has a basis …
Bacteraemia after open-heart surgery
Authors: E. Lockey, L. Gonzalez-Lavin, I. Ray, R. Chen
Journal: Thorax (1973)

We have analysed the bacteraemias occurring before discharge from hospital in patients subjected to open-heart surgery. The overall incidence was 2·7%. The predominant organisms at first were staphylococci and streptococci, but in the later years of the study almost all positive blood cultures were due to Gram-negative bacilli. Short-term prophylactic antibiotics were used throughout. Eleven of the 12 Gram-positive bacteraemias occurred after the period of antibiotic prophylaxis; eight of the patients had endocarditis and a further three had serious wound infections. Most of the 32 Gram-negative bacillaemias occurred while antibiotics were being given. Some were transient phenomena in well patients; others were associated with terminal states. Infection was a major cause of death in four patients, however, and two patients had endocarditis. Serratia, providence, hafnia, and citrobacter were all identified as well as the more usual escherichia, klebsiella, and pseudomonas. We discuss the possible origins and management of these bacteraemias.
Circulating Histones Are Mediators of Trauma-associated Lung Injury
Authors: Simon T. Abrams, Nan Zhang, Joanna Manson, Tingting Liu, Caroline Dart, Florence Baluwa, Susan Siyu Wang, Karim Brohi, Anja Kipar, Weiping Yu, Guozheng Wang, Cheng-Hock Toh
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Acute lung injury is a common complication after severe trauma, which predisposes patients to multiple organ failure. This syndrome largely accounts for the late mortality that arises and despite many theories, the pathological mechanism is not fully understood. Discovery of histone-induced toxicity in mice presents a new dimension for elucidating the underlying pathophysiology.To investigate the pathological roles of circulating histones in trauma-induced lung injury.Circulating histone levels in patients with severe trauma were determined and correlated with respiratory failure and Sequential Organ Failure Assessment (SOFA) scores. Their cause-effect relationship was studied using cells and mouse models.In a cohort of 52 patients with severe nonthoracic blunt trauma, circulating histones surged immediately after trauma to levels that were toxic to cultured endothelial cells. The high levels were significantly associated with the incidence of acute lung injury and SOFA scores, as well as markers of endothelial damage and coagulation activation. In in vitro systems, histones damaged endothelial cells, stimulated cytokine release, and induced neutrophil extracellular trap formation and myeloperoxidase release. Cellular toxicity resulted from their direct membrane interaction and resultant calcium influx. In mouse models, cytokines and markers for endothelial damage and coagulation activation significantly increased immediately after trauma or histone infusion. Pathological examinations showed that lungs were the predominantly affected organ with edema, hemorrhage, microvascular thrombosis, and neutrophil congestion. An anti-histone antibody could reduce these changes and protect mice from histone-induced lethality.This study elucidates a new mechanism for acute lung injury after severe trauma and proposes that circulating histones are viable therapeutic targets for improving survival outcomes in patients.
PTU-037 Double Balloon Enteroscopy – A Single Australian Tertiary Centre Experience
Authors: P Sattianayagam, P Desmond, A Taylor
Journal: Gut (2014)

<h3>Introduction</h3> Double balloon enteroscopy (DBE) has revolutionised the diagnosis and therapies available in the management of small bowel diseases. There are currently no large series of its diagnostic and therapeutic capability from Australia. <h3>Methods</h3> We evaluated the baseline demographics, diagnostic findings and therapeutic interventions of all patients undergoing DBE between 2004 and 2012 at St. Vincent’s Hospital, Melbourne. <h3>Results</h3> There were 357 procedures (218 antegrade) performed in 294 patients (152 female and 142 male). Intubation distances were greater via an antegrade route than retrograde and were even lower in those retrograde cases who had undergone prior abdominal surgery. Thirty-five patients had bidirectional DBE with complete enteroscopy in one of these cases. Indications for DBE included obscure gastrointestinal bleeding (76%), abdominal pain (13%) and diarrhoea (3%). Obscure gastrointestinal bleeding was the main indication contributing to the diagnostic yield of 46% in the entire series. This was especially prevalent in those &gt;75 years, who typically had more cardiorespiratory co-morbidities and were also more likely to be on anti-platelet therapy or anticoagulation. An antegrade approach had a higher diagnostic yield in the series than a retrograde one (54% vs. 34%). Angioectasias were the commonest diagnosis (21% cases) and occurred more frequently in those presenting with overt haemorrhage or requiring transfusion. Polyps/mass lesions (several of which were discovered on screening of patients with polyposis syndromes) and ulcers/strictures (which were typically associated with Crohn’s disease) were the other major diagnostic groups (12 and 4% cases respectively). Both were more prevalent in younger patients. A retrograde approach was better for diagnosis of ulcers/strictures. The therapeutic yield in the entire series of 23% was noticeably better via an antegrade approach and in the elderly. Haemostasis of angioectasias was the commonest therapy (19% cases in the whole series) followed by polypectomy and stricture dilatation (4 and 2% cases in the series respectively), which potentially obviated the need for surgery. <h3>Conclusion</h3> DBE is a major contributor to the management of small bowel disease in an Australian population. Obscure gastrointestinal bleeding is the main indication with better diagnostic and therapeutic yields in the elderly and when there is overt haemorrhage or transfusion requirement. An antegrade approach is more useful in these patients unlike in those with ulcers and strictures, who typically had Crohn’s disease and were younger and in whom a retrograde approach was more beneficial. With its diagnostic and therapeutic capability DBE should be contemplated in small bowel disease in the setting of a multidisciplinary approach. <h3>Disclosure of Interest</h3> None Declared.
Early measures of cognitive function predict survival in patients with newly diagnosed glioblastoma
Authors: D. R. Johnson, A. M. Sawyer, C. A. Meyers, B. P. O'Neill, J. S. Wefel
Journal: Neuro-Oncology (2012)

Cognitive dysfunction is a common manifestation of primary brain tumors. We evaluated the association between early cognitive dysfunction and prognosis in a cohort of patients with newly diagnosed glioblastoma. Ninety-one patients who completed neuropsychological assessment after tumor resection but before further treatment were identified in the MD Anderson Neuropsychology database. The relationship between performance on cognitive testing and survival was evaluated using not only Cox proportional hazards models that included clinical factors such as age and KPS but also the Kaplan-Meier method. Median survival time from surgery was 20.7 months. Rates of impairment on cognitive testing ranged from 7.1% for Similarities, to 60.0% for Hopkins Verbal Learning Test-Revised Total Recall. As continuous variables, the Clinical Trial Battery Composite, Trail Making Test Part B, and Controlled Oral Word Association test were associated with survival. Impairment on the Trail Making Test Part B, Controlled Oral Word Association, Similarities, and Digit Span were associated with mortality. Kaplan-Meier analysis demonstrated the survival impact of these tests on the group as a whole and in select patient subgroups defined by classification by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA). Cognitive impairment as measured by specific neuropsychological tests is independently associated with poor prognosis in patients with newly diagnosed glioblastoma, and this effect remains significant even within patient subgroups defined by RTOG RPA class. Executive function and attention are the cognitive domains most closely associated with prognosis in this analysis.
Prospective evaluation of 2 acute graft-versus-host (GVHD) grading systems: a joint Societe Francaise de Greffe de Moelle et Therapie Cellulaire (SFGM-TC), Dana Farber Cancer Institute (DFCI), and International Bone Marrow Transplant Registry (IBMTR) prospective study
Authors: Jean-Yves Cahn, John P. Klein, Stephanie J. Lee, Noël Milpied, Didier Blaise, Joseph H. Antin, Véronique Leblond, Norbert Ifrah, Jean-Pierre Jouet, Fausto Loberiza, Olle Ringden, A. John Barrett, Mary M. Horowitz, Gérard Socié
Journal: Blood (2005)
Regulatory T Cells Selectively Express Toll-like Receptors and Are Activated by Lipopolysaccharide
Authors: Iris Caramalho, Thiago Lopes-Carvalho, Dominique Ostler, Santiago Zelenay, Matthias Haury, Jocelyne Demengeot
Journal: The Journal of Experimental Medicine (2003)

Regulatory CD4 T cells (Treg) control inflammatory reactions to commensal bacteria and opportunist pathogens. Activation of Treg functions during these processes might be mediated by host-derived proinflammatory molecules or directly by bacterial products. We tested the hypothesis that engagement of germline-encoded receptors expressed by Treg participate in the triggering of their function. We report that the subset of CD4 cells known to exert regulatory functions in vivo (CD45RBlow CD25+) selectively express Toll-like receptors (TLR)-4, -5, -7, and -8. Exposure of CD4+ CD25+ cells to the TLR-4 ligand lipopolysaccharide (LPS) induces up-regulation of several activation markers and enhances their survival/proliferation. This proliferative response does not require antigen-presenting cells and is augmented by T cell receptor triggering and interleukin 2 stimulation. Most importantly, LPS treatment increases CD4+ CD25+ cell suppressor efficiency by 10-fold and reveals suppressive activity in the CD4+ CD45RBlow CD25− subset that when tested ex-vivo, scores negative. Moreover, LPS-activated Treg efficiently control naive CD4 T cell–dependent wasting disease. These findings provide the first evidence that Treg respond directly to proinflammatory bacterial products, a mechanism that likely contributes to the control of inflammatory responses.
Attention-Induced Variance and Noise Correlation Reduction in Macaque V1 Is Mediated by NMDA Receptors
Authors: Jose L. Herrero, Marc A. Gieselmann, Mehdi Sanayei, Alexander Thiele
Journal: Neuron (2013)

Attention improves perception by affecting different aspects of the neuronal code. It enhances firing rates, it reduces firing rate variability and noise correlations of neurons, and it alters the strength of oscillatory activity. Attention-induced rate enhancement in striate cortex requires cholinergic mechanisms. The neuropharmacological mechanisms responsible for attention-induced variance and noise correlation reduction or those supporting changes in oscillatory activity are unknown. We show that ionotropic glutamatergic receptor activation is required for attention-induced rate variance, noise correlation, and LFP gamma power reduction in macaque V1, but not for attention-induced rate modulations. NMDA receptors mediate attention-induced variance reduction and attention-induced noise correlation reduction. Our results demonstrate that attention improves sensory processing by a variety of mechanisms that are dissociable at the receptor level.
Mixed Chimerism and Growth Factors Augment β Cell Regeneration and Reverse Late-Stage Type 1 Diabetes
Authors: Miao Wang, Jeremy J. Racine, Xiaoping Song, Xiaofan Li, Indu Nair, Hongjun Liu, Alina Avakian-Mansoorian, Heather F. Johnston, Can Liu, Christine Shen, Mark Atkinson, Ivan Todorov, Fouad Kandeel, Stephen Forman, Brian Wilson, Defu Zeng
Journal: Science Translational Medicine (2012)

Combination therapy that induces mixed chimerism and augments both β cell neogenesis and replication reverses late-stage type 1 diabetes in NOD mice.
Management of Glomerular Proteinuria
Authors: William A. Wilmer, Brad H. Rovin, Christopher J. Hebert, Sunil V. Rao, Karen Kumor, Lee A. Hebert
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. It is widely accepted that proteinuria reduction is an appropriate therapeutic goal in chronic proteinuric kidney disease. Based on large randomized controlled clinical trials (RCT), ACE inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy have emerged as the most important antiproteinuric and renal protective interventions. However, there are numerous other interventions that have been shown to be antiproteinuric and, therefore, likely to be renoprotective. Unfortunately testing each of these antiproteinuric therapies in RCT is not feasible. The nephrologist has two choices: restrict antiproteinuric therapies to those shown to be effective in RCT or expand the use of antiproteinuric therapies to include those that, although unproven, are plausibly effective and prudent to use. The goal of this work is to provide the documentation needed for the nephrologist to choose between these strategies. This work describes 25 separate interventions that are either antiproteinuric or may block injurious mechanisms of proteinuria. Each intervention is assigned a level of recommendation (Level 1 is the highest; Level 3 is the lowest) according to the strength of the evidence supporting its antiproteinuric and renoprotective efficacy. Pathophysiologic mechanisms possibly involved are also discussed. The number of interventions at each level of recommendation are: Level 1, n = 7; Level 2, n = 9; Level 3, n = 9. Our experience indicates that we can achieve in most patients the majority of Level 1 and many of the Level 2 and 3 recommendations. We suggest that, until better information becomes available, a broad-based, multiple-risk factor intervention to reduce proteinuria can be justified in those with progressive nephropathies. This work is intended primarily for clinical nephrologists; therefore, each antiproteinuria intervention is described in practical detail.
Constitutive STAT3-activation in Sezary syndrome: tyrphostin AG490 inhibits STAT3-activation, interleukin-2 receptor expression and growth of leukemic Sezary cells
Authors: KW Eriksen, K Kaltoft, G Mikkelsen, M Nielsen, Q Zhang, C Geisler, MH Nissen, C Röpke, MA Wasik, N Ødum
Journal: Leukemia (2001)
Apixaban Compared With Warfarin for Stroke Prevention in Atrial Fibrillation
Authors: Pilar Gallego, Juan Antonio Vilchez, Deirdre A. Lane
Journal: Circulation (2013)

C linical guidelines 1,2 advocate the use of oral anticoagu- lation, whether a vitamin K antagonist (VKA) or 1 of the novel agents, for stroke prevention in patients with atrial fibrillation who have ≥1 risk factors for stroke.The benefits of traditional oral anticoagulants (VKAs), in terms of a reduction in stroke and major bleeding events, are experienced only over a narrow therapeutic window (international normalized ratio [INR] of 2.0-3.0).Their intricate pharmacokinetic profile with a slow onset and offset of action and numerous drug, food, and alcohol interactions, as well as genetic, ethnicity, and age-related differences in dose response, necessitates regular INR monitoring.
S84 Cigarette Smoke Promotes Exaggerated Inflammatory Response in the Presence of Z-AT
Authors: S Alam, S Janciauskiene, R Mahadeva
Journal: Thorax (2012)

Severe deficiency <i>of</i> the major anti-elastase α<sub>1</sub>-antitrypsin (AT) due to the Z (Glu342Lys) variant is the commonest genetic reason for the development of COPD. Cigarette smoke (CS) accelerates decline in lung function in Z-AT homozygotes. We investigated whether Z-AT is associated with an exaggerated inflammatory response compared to normal AT (M-AT). Lung epithelial (A549 and NHBE) cells transfected with human M-AT or Z-AT (M-AT/Z-AT cells) were exposed to 12.5% CSE generated from 1R3F cigarettes. Supernatants, lysates and inclusion bodies were assessed for total AT to confirm a successful cell-model system. Supernatant was assessed for TNF-α, IL-6, IL-8 and MCP-1, oxidised pZ-AT (Ox-pZ-AT), NF-kB and AP-1 by ELISA, immunoblot or RT-PCR. N-acetylcysteine (NAC,10<sup>–3</sup>M) was used to probe the effect of oxidants. At 24h CSE in Z-AT (CSE-Z-AT) compared to CSE-M-AT (unless stated) significantly induced TNF-α (212±20.71pg/ml vs. 37.1±2.7), IL-6 (421.4±20.8pg/ml vs. 159.3±12.1), IL-8 (8763±497pg/ml vs. 2593±450) and MCP-1 (23564±1852pg/ml vs. 5329±706), p&lt;0.001 for all. CSE-Z-AT had significantly induced mRNA for TNF-α, IL-6, IL-8 and MCP-1 at 0.5h (p&lt;0.001 for all). Development of Ox-pZ-AT were exclusively detected in CSE-Z-AT inclusion (3246±433ng/ml vs. undetectable, p&lt;0.001). CSE-Z-AT had significantly activated NF-κB (p&lt;0.001) and AP-1 (p=0.001) at 0.5h. In CSE-Z-AT treatment with NAC significantly inhibited TNF-α, IL-6, IL-8, MCP-1, NF-κB, AP-1 and Ox-pZ-AT formation (p&lt;0.001 for all). These findings were confirmed on NHBE cells. In conclusion, following CS exposure Z-AT cells had significantly elevated inflammatory mediators compared to M-AT cells, which was inhibited by NAC. We propose that during CS exposed lung inflammation Z-AT monomer undergoes oxidation to form oxidised polymers thereby further reducing the level of protective monomeric AT, which predisposes to increased lung inflammation.
IMMUNITY AND TOLERANCE TO A HAPTEN (NIP) COUPLED TO AN ISOLOGOUS CARRIER (MOUSE GAMMA GLOBULIN)
Authors: Curla S. Walters, John W. Moorhead, Henry N. Claman
Journal: The Journal of Experimental Medicine (1972)

A hapten, 4-hydroxy-3-iodo-5-nitrophenylacetic acid (NIP) when coupled to isologous mouse gamma globulin (MgammaG) elicits a hapten-specific immune response in mice if administered in Freund's complete adjuvant. This response is measurable by the capacity of the sera to bind N(125)IP, by detection of NIP-specific plaque-forming cells (B cells), and by in vitro secondary type antigen-driven DNA synthesis (T cells and probably B cells). The in vitro response requires both the hapten and carrier since neither by itself is capable of stimulating the spleen cells. This same antigen gives rise to hapten-specific tolerance when given in the soluble form. Mice pretreated with soluble NIP-MgammaG and challenged with NIP coupled to a heterologous carrier give a normal antibody response to the carrier but have barely detectable levels of antibody to NIP. Spleen cells from mice made tolerant to NIP-MgammaG do not respond in vitro with increased DNA synthesis. This implies that thymus-derived cells as well as bone marrow-derived cells are involved in hapten-specific tolerance.
Long‐term clinical outcomes after fatty liver screening in patients undergoing coronary angiogram: A prospective cohort study
Authors: Vincent Wai‐Sun Wong, Grace Lai‐Hung Wong, Judy Ching‐Lam Yeung, Chloe Yuk‐Kiu Fung, Jasmine Ka‐Lei Chan, Zoe Hoi‐Yi Chang, Chelsia Tsz‐Yan Kwan, Hiu‐Wan Lam, Jenny Limquiaco, Angel Mei‐Ling Chim, Cheuk‐Man Yu, Henry Lik‐Yuen Chan
Journal: Hepatology (2015)

There is ongoing debate on whether screening for nonalcoholic fatty liver disease (NAFLD) is worthwhile in high‐risk groups. Because of shared risk factors, NAFLD is highly prevalent in patients with coronary artery disease. We aimed to test the hypothesis that NAFLD screening in patients requiring coronary angiogram would identify high‐risk patients and predict long‐term clinical outcomes. This was a prospective cohort study. NAFLD screening was performed by abdominal ultrasonography before coronary angiogram in 612 consecutive patients. At baseline, 356 (58.2%) patients had NAFLD. NAFLD patients, compared with those without, were more likely to have &gt;50% stenosis in one or more coronary arteries (84.6% vs. 64.1%; P &lt; 0.001) and therefore require percutaneous coronary intervention (68.3% vs. 43.4%; P &lt; 0.001). During 3,679 patient‐years of follow‐up, 47 (13.2%) NAFLD patients and 59 (23.0%) patients without NAFLD died (age‐ and sex‐adjusted hazard ratio [aHR]: 0.36; 95% confidence interval [CI]: 0.18‐0.70; P = 0.003). Composite cardiovascular outcomes (cardiovascular deaths, nonfatal myocardial infarction, heart failure, or secondary interventions) were similar between groups (36.5% vs. 37.1%; aHR, 0.90; 95% CI: 0.69‐1.18). Older age and diabetes were the only independent factors associated with cardiovascular events. Only 2 patients, both in the NAFLD group, died of primary liver cancer. No other patients developed liver‐related complications. Conclusion : In patients with clinical indications for coronary angiogram, the presence of NAFLD is associated with coronary artery stenosis and need for coronary intervention, but not increased mortality or cardiovascular complications. Liver cancer and cirrhotic complications are rare. Our data do not support NAFLD screening in this patient group at present, but studies with a longer duration of follow‐up are needed. (H epatology 2016;63:754–763)