tbuckley/cabot-search huggingface dataset:
Do helmets worn for hurling fail to protect the ear? Identification of an emerging injury pattern
Authors: James D Martin-Smith, Jeffery C Y Chan, Kieran T Power, Paddy J Crowley, Anthony James P Clover
Journal: British Journal of Sports Medicine (2012)

Hurling is an Irish national game of stick and ball known for its ferocity, played by 190 000 players. Facial injuries were common but have been significantly reduced by legislation enforcing compulsory helmet wearing. Current standard helmets worn by hurlers do not offer protection to the external ear. Here we describe an emerging pattern of ear injuries and demonstrate the risk of external ear injuries in hurlers complying with current helmet safety standards. A 6-month retrospective analysis was carried out of patients attending Cork University Hospital (CUH) with ear lacerations sustained while hurling. Patient notes were reviewed and helmet manufacturers were interviewed. Seven patients were identified, all of whom sustained complex through ear lacerations while wearing helmets complying with current safety standards. Current helmet design fails to protect the external ear placing it at an increased risk of injury, a potential solution is to include ear protection in the helmet design.
What do European community oncologists expect from the European Society for Medical Oncology? Results from a survey among community oncologists in Germany, Greece, Hungary, Italy, Luxembourg, Romania, and Spain
Authors: R. Eckert, R. Curca, G. D'Addario, G. Lanzetta, P.M. Martorell, D. Mauri, S. Rauh, S. Schmitz, K. Tamas, M.V. Karamouzis
Journal: Annals of Oncology (2013)
A mutation in <i>Irak2c</i> identifies IRAK-2 as a central component of the TLR regulatory network of wild-derived mice
Authors: James R. Conner, Irina I. Smirnova, Alexander Poltorak
Journal: The Journal of Experimental Medicine (2009)

In a phenotypic screen of the wild-derived mouse strain MOLF/Ei, we describe an earlier and more potent toll-like receptor (TLR)–mediated induction of IL-6 transcription compared with the classical inbred strain C57BL/6J. The phenotype correlated with increased activity of the IκB kinase axis as well as p38, but not extracellular signal-regulated kinase or c-Jun N-terminal kinase, mitogen-activated protein kinase (MAPK) phosphorylation. The trait was mapped to the Why1 locus, which contains Irak2, a gene previously implicated as sustaining the late phase of TLR responses. In the MOLF/Ei TLR signaling network, IRAK-2 promotes early nuclear factor κB (NF-κB) activity and is essential for the activation of p38 MAPK. We identify a deletion in the MOLF/Ei promoter of the inhibitory Irak2c gene, leading to an increased ratio of pro- to antiinflammatory IRAK-2 isoforms. These findings demonstrate that IRAK-2 is an essential component of the early TLR response in MOLF/Ei mice and show a distinct pathway of p38 and NF-κB activation in this model organism. In addition, they demonstrate that studies in evolutionarily divergent model organisms are essential to complete dissection of signal transduction pathways.
Patients' own assessments of quality of primary care compared with objective records based measures of technical quality of care: cross sectional study
Authors: Mala Rao, Aileen Clarke, Colin Sanderson, Richard Hammersley
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To investigate the relation between older patients9 assessments of the quality of their primary care and measures of good clinical practice on the basis of data from administrative and clinical records. <b>Design</b> Cross sectional population based study using the general practice assessment survey. <b>Setting</b> 18 general practices in the Basildon primary care trust area, south east England. <b>Participants</b> 3487 people aged 65 or more. <b>Main outcome measures</b> Correlations between mean practice scores on the general practice assessment survey and three evidence based measures on survey of case records (monitoring for, and control of, hypertension, and vaccination against influenza). <b>Results</b> 76% of people (3487/4563) responded to the general practice assessment survey. Correlations between patient assessed survey scores for technical quality and the objective records based measures of good clinical practice were 0.22 (95% confidence interval −0.28 to 0.62) for hypertension monitored, 0.30 (−0.19 to 0.67) for hypertension controlled, and −0.05 (−0.50 to 0.43) for influenza vaccination. <b>Conclusions</b> Older patients9 assessments are not a sufficient basis for assessing the technical quality of their primary care. For an overall assessment both patient based and records based measures are required.
Inotropic response to norepinephrine is augmented early and maintained late in conscious dogs with perinephritic hypertension.
Authors: R P Shannon, R J Gelpi, L Hittinger, D E Vatner, C J Homcy, R M Graham, S F Vatner
Journal: Circulation Research (1991)

We studied the inotropic responses to intravenous infusions of norepinephrine in nine conscious chronically instrumented dogs before and early (2-4 weeks) in the development of perinephritic hypertension; seven conscious dogs were studied later (approximately 14 weeks), during a more stable phase of hypertension. perinephritic hypertension was associated with a 24% increase in left ventricular (LV) mass during developing hypertension; no further increase was seen during the stable hypertension phase. LV end-systolic stress was increased early (p less than 0.01) but was normalized later. The LV end-systolic stress-volume relation demonstrated an enhanced contractile response to norepinephrine during developing hypertension, which returned toward control later in the course of stable hypertension. The LV dP/dt responses to norepinephrine (0.4 microgram/kg/min) were significantly greater during developing hypertension (7,509 +/- 337 mm Hg/sec, p less than 0.05) compared with the control period (4,737 +/- 286 mm Hg/sec) and returned toward the control value during stable hypertension (5,168 +/- 465 mm Hg/sec). The enhanced inotropic responses to norepinephrine in developing hypertension were preserved in the presence of ganglionic blockade, suggesting that the augmentation was not mediated via reflex mechanisms. These physiological responses were associated with an increase in beta-adrenergic receptor density, but no significant change in basal or maximal adenylate cyclase stimulation occurred during developing hypertension. Thus, in contrast to prior studies in anesthetized animals, the inotropic response to beta-adrenergic stimulation is not depressed in conscious dogs but is enhanced selectively during the development of hypertension and maintained during stable hypertension.
A synthetic tumor necrosis factor-alpha agonist peptide enhances human polymorphonuclear leukocyte-mediated killing of Plasmodium falciparum in vitro and suppresses Plasmodium chabaudi infection in mice.
Authors: L M Kumaratilake, D A Rathjen, P Mack, F Widmer, V Prasertsiriroj, A Ferrante
Journal: Journal of Clinical Investigation (1995)

A peptide corresponding to residues 70-80 of the TNF-alpha polypeptide was synthesized and shown to enhance human PMN-mediated killing of Plasmodium falciparum in vitro and reduced the Plasmodium chabaudi parasitemia in mice. Studies of the mechanism of action showed that the peptide, TNF(70-80), stimulated and primed PMN for an increased respiratory burst and release of granule constituents in response to a second agonist. The PMN-stimulatory activity of the peptide was inhibited by mAbs against the p55 and p75 TNF receptors and a TNF-neutralizing mAb. Analysis of PMN receptor expression showed that CR3 (CD18/CD11b) and Fc gamma RIII were upregulated by TNF(70-80), which was consistent with the peptide's ability to enhance parasite killing by PMN. The peptide, unlike TNF, did not increase the expression of adhesion molecules on endothelial cells and failed to promote binding of P. falciparum-infected erythrocytes to endothelial cells. TNF(70-80) also inhibited the TNF-induced increase in adhesion of P. falciparum-infected erythrocytes to endothelial cells. The results demonstrate that the host-protective effects of TNF can be retained while toxic effects are eliminated using a selected, characterized subunit of the cytokine.
Field tests in pulmonary disease
Authors: N AMBROSINO
Journal: Thorax (1999)

Proper evaluation of potential patients is the keystone to a successful pulmonary rehabilitation programme.1 The so-called functional approach which relates to impairment (the physiological deficit), disability (total effect of impairment on the patient’s life), and handicap (the social disadvantages) as part of the comprehensive programme of care is one approach. It is useful not only for monitoring the patient’s functional status, but it enables the rehabilitation team to set and to achieve goals to improve the quality of the patient’s life.

Although an exercise test may help to uncover other coexisting diseases, it is generally necessary to assess the patient’s exercise tolerance and to evaluate possible blood gas changes which cannot be predicted from baseline lung function tests.2 The exercise test is also used to establish a safe and appropriate prescription for subsequent training. Cardiopulmonary exercise testing has been found to be useful in the evaluation of exercise tolerance in patients with dyspnoea and cardiopulmonary diseases. Compared with a clinical laboratory approach, it allows the detection of an underestimated circulatory component causing exercise limitation.3 Graded exercise testing has been shown to be useful in diagnosing patients with chronic unexplained dyspnoea although it was not sensitive in distinguishing a cardiac disease from deconditioning.4Variables measured and/or monitored during testing should include workload, heart rate, electrocardiogram, arterial oxygenation, and symptoms. Blood gas sampling during exercise adds a significant degree of complexity to testing. Non-invasive techniques such as cutaneous oximetry of arterial oxygen saturation are useful for continuous monitoring but should not be relied on for precise assessment of arterial oxygenation because of their limited accuracy.5Other measurements such as analysis of expired gas to calculate variables such as oxygen consumption (V˙o 2) may be performed, depending on the interest and expertise of the referring physician, laboratory …
DIFFERENTIAL SIGNALING BY LYMPHOCYTE ANTIGEN RECEPTORS
Authors: Jose Alberola-Ila, Satoshi Takaki, James D. Kerner, Roger M. Perlmutter
Journal: Annual Review of Immunology (1997)

▪ Abstract Studies performed during the past several years make plain that ligand occupancy of antigen receptors need not necessarily provoke identical responses in all instances. For example, ligation of antigen receptors may stimulate a proliferative response, induce a state of unresponsiveness to subsequent stimulation (anergy), or induce apoptosis. How does a single type of transmembrane receptor induce these very heterogeneous cellular responses? In the following pages, we outline evidence supporting the view that the nature of the ligand/receptor interaction directs the physical recruitment of signaling pathways differentially inside the lymphocyte and hence defines the nature of the subsequent immune response. We begin by providing a functional categorization of antigen receptor components, considering the ways in which these components interact with the known set of signal transduction pathways, and then review the evidence suggesting that differential signaling through the TCR is achieved by qualitative differences in the effector pathways recruited by TCR, perhaps reflecting the time required to bring complicated signal transduction elements into proximity within the cell. The time-constant of the interaction between antigen and receptor in this way determines, at least in part, the nature of the resulting response. Finally, although our review focuses substantially on T cell receptor signaling, we have included a less detailed description of B cell receptor signaling as well, simply to emphasize the parallels that exist in these two closely related systems.
Chronic thromboembolic pulmonary hypertension: role of medical therapy
Authors: Joanna Pepke-Zaba, Pavel Jansa, Nick H. Kim, Robert Naeije, Gerald Simonneau
Journal: European Respiratory Journal (2013)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease with poor prognosis if not treated. The treatment of choice is surgery with pulmonary endarterectomy. However, a significant percentage of patients are deemed non-operable due to distal distribution of the disease and arteriopathy in the non-occluded areas that is indistinguishable from pulmonary arterial hypertension (PAH). The overlap in clinical presentation, pathological features and pathogenesis between PAH and CTEPH provides a compelling rationale for exploring the efficacy of PAH-targeted therapies in CTEPH. These therapies are often considered for non-operable patients and are also used in operable patients as a bridge to surgery or as post-pulmonary endarterectomy therapy for persistent pulmonary hypertension, despite the fact they are not licensed for CTEPH. Two randomised clinical trials have been performed in non-operable CTEPH patients. The BENEFiT study, with the endothelin receptor antagonist bosentan, did not show improvement in walking distance. Recently, the CHEST-1 trial, with the soluble guanylate cyclase stimulator riociguat, met study end-point and demonstrated significant improvement in walking distance in patients with non-operable CTEPH. There is an urgent need for more randomised clinical trials designed to clarify whether administration of PAH-targeted therapies improves clinically meaningful end-points in various CTEPH populations.
Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study. Groupe d'Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif (GETAID).
Authors: J Y Mary, R Modigliani
Journal: Gut (1989)

The aim of this study was to develop and validate an endoscopic index for assessing the severity of Crohn's disease. Endoscopic findings were prospectively collected by a multicentre group in 75 patients with Crohn's colitis according to a previously validated procedure. The presence of nine preselected lesions was recorded in the following segments (1) rectum, (2) sigmoid and left colon, (3) transverse colon, (4) right colon, and (5) ileum. In addition the extent of the diseased and ulcerated areas were estimated in each segment. These segmental data were recorded on a standard form, together with the endoscopist's global estimate of lesion severity. A stepwise multiple regression was used to derive an index which was correlated with the endoscopist's global evaluation of lesion severity. Four mucosal lesions: deep and superficial ulcerations, ulcerated and non-ulcerated stenosis, and both estimates of extent involved were selected and weighted to obtain a Crohn's Disease Endoscopic Index of Severity which correlated with the endoscopist's global appraisal of lesion severity (r = 0.83). This index was then prospectively shown to be valid in a further series of 113 colonoscopies (r = 0.81). The index was calculated in 54 patients with active Crohn's disease, before and at the end of a course of corticosteroids: index variations correctly reflected changes in colitis severity as evaluated by the endoscopists (r = 0.72). For endoscopists familiar with the data collection procedure, this Crohn's Disease Endoscopic Index of Severity should be of value in the follow up of patients, especially in clinical trials.
The effects of Provent on moderate to severe obstructive sleep apnoea during continuous positive airway pressure therapy withdrawal: a randomised controlled trial
Authors: Valentina A Rossi, Barbara Winter, Najib M Rahman, Ly-Mee Yu, Janet Fallon, Christian F Clarenbach, Konrad E Bloch, John R Stradling, Malcolm Kohler
Journal: Thorax (2013)

<h3>Objectives</h3> The aim of this study was to test the effectiveness of Provent, an expiratory nasal resistance valve, to prevent the recurrence of OSA following CPAP withdrawal. <h3>Design</h3> Randomised, partially blinded, parallel, placebo-controlled trial. <h3>Setting</h3> Outpatient sleep clinics in the UK (Oxford) and Switzerland (Zurich). <h3>Participants</h3> 67 patients with OSA receiving CPAP were randomised to one of three groups for 2 weeks: continuing CPAP, Provent or placebo Provent. <h3>Main outcome measures</h3> Primary outcomes included for Provent versus placebo Provent, OSA severity (oxygen desaturation index (ODI), apnoea–hypopnoea index (AHI)) and Epworth Sleepiness Scale (ESS) score. Secondary outcomes for Provent versus placebo Provent included ODI from ambulatory pulse oximetry and blood pressure (BP). For CPAP versus Provent, or CPAP versus placebo Provent, secondary outcomes included ODI/AHI, ESS and BP. <h3>Results</h3> 63 patients were included in the per protocol analysis. OSA recurred in the Provent (ODI 35.8, SD 17.4) and placebo Provent (ODI 28.2, SD 18.3) groups, and there was no significant difference in ODI, AHI and ESS between Provent and placebo Provent at 2 weeks (mean difference ODI −1.0, 95% CI −10.0 to +12.0, p=0.85; AHI +3.2, 95% CI −7.7 to +14.1, p=0.52; and ESS −1.4, 95% CI −4.1 to +1.4, p=0.33). ODI from ambulatory pulse-oximetry and BP at 2 weeks were not different in the Provent versus placebo Provent groups. ODI, AHI and BP, but not ESS, were significantly higher in the Provent and placebo Provent groups compared with CPAP. <h3>Conclusions</h3> Provent cannot be recommended as an alternative short-term therapy for patients with moderate to severe OSA already on CPAP. <h3>TrialRegNo</h3> NCT01332175.
Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia
Authors: Farhad Ravandi, Jorge E. Cortes, Daniel Jones, Stefan Faderl, Guillermo Garcia-Manero, Marina Y. Konopleva, Susan O'Brien, Zeev Estrov, Gautam Borthakur, Deborah Thomas, Sherry R. Pierce, Mark Brandt, Anna Byrd, B. Nebiyou Bekele, Keith Pratz, Rajyalakshmi Luthra, Mark Levis, Michael Andreeff, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2010)

PURPOSE To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. PATIENTS AND METHODS In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. RESULTS Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.
FATS is a transcriptional target of p53 and associated with antitumor activity
Authors: Xifeng Zhang, Qian Zhang, Jun Zhang, Li Qiu, Shuang-shuang Yan, Juling Feng, Yan Sun, Xingxu Huang, Karen H Lu, Zheng Li
Journal: Molecular Cancer (2010)

Abstract Frequent mutations of p53 in human cancers exemplify its crucial role as a tumor suppressor transcription factor, and p21, a transcriptional target of p53, plays a central role in surveillance of cell-cycle checkpoints. Our previous study has shown that FATS stabilize p21 to preserve genome integrity. In this study we identified a novel transcript variant of FATS (GenBank: GQ499374) through screening a cDNA library from mouse testis, which uncovered the promoter region of mouse FATS. Mouse FATS was highly expressed in testis. The p53-responsive elements existed in proximal region of both mouse and human FATS promoters. Functional study indicated that the transcription of FATS gene was activated by p53, whereas such effect was abolished by site-directed mutagenesis in the p53-RE of FATS promoter. Furthermore, the expression of FATS increased upon DNA damage in a p53-dependent manner. FATS expression was silent or downregulated in human cancers, and overexpression of FATS suppressed tumorigenicity in vivo independently of p53. Our results reveal FATS as a p53-regulated gene to monitor genomic stability.
Spike-Driven Glutamate Electrodiffusion Triggers Synaptic Potentiation via a Homer-Dependent mGluR-NMDAR Link
Authors: Sergiy Sylantyev, Leonid P. Savtchenko, Yaroslav Ermolyuk, Piotr Michaluk, Dmitri A. Rusakov
Journal: Neuron (2013)

Electric fields of synaptic currents can influence diffusion of charged neurotransmitters, such as glutamate, in the synaptic cleft. However, this phenomenon has hitherto been detected only through sustained depolarization of large principal neurons, and its adaptive significance remains unknown. Here, we find that in cerebellar synapses formed on electrically compact granule cells, a single postsynaptic action potential can retard escape of glutamate released into the cleft. This retardation boosts activation of perisynaptic group I metabotropic glutamate receptors (mGluRs), which in turn rapidly facilitates local NMDA receptor currents. The underlying mechanism relies on a Homer-containing protein scaffold, but not GPCR- or Ca(2+)-dependent signaling. Through the mGluR-NMDAR interaction, the coincidence between a postsynaptic spike and glutamate release triggers a lasting enhancement of synaptic transmission that alters the basic integrate-and-spike rule in the circuitry. Our results thus reveal an electrodiffusion-driven synaptic memory mechanism that requires high-precision coincidence detection suitable for high-fidelity circuitries.
Reforming research in the NHS
Authors: D J Sheridan
Journal: BMJ (2005)

EDITOR—Cole highlights some of the challenges to the proposals to reform research support from the Department of Health,1–3 but the need to restore academic medicine does not reflect an intrinsic failure. Rather, it has been a victim of financial constraints, and clinical research has been marginalised in an increasingly citation and commercial focused academic environment.

The proposed creation of a virtual National Institute of Health Research could provide a powerful national voice for academic medicine at a …