bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ethyl pyruvate modulates acute inflammatory reactions in human endothelial cells in relation to the NF‐κB pathway
Authors: Johansson A‐S , Johansson‐Haque K , Okret S , Palmblad J 
Published: May 2008

Background and purpose:Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Ethanol (EtOH) reduces host defence systems, including cell adhesion. However, well‐known side effects of EtOH limit its clinical use as an anti‐inflammatory drug. Instead, ethyl pyruvate (EtP) may represent a better alternative. Here, we compared effects of EtP and EtOH on neutrophil recruitment and activation of human umbilical vein endothelial cells (HUVECs).Experimental approach:Adhesion of neutrophils to HUVEC monolayers, surface expression of intercellular cell adhesion molecule, E‐selectin, vascular cell adhesion molecule, release of interleukin (IL)‐8 and granulocyte colony‐stimulating factor (G‐CSF) from HUVECs were assessed as well as translocation of interleukin‐1 receptor‐associated kinase (IRAK‐1), the nuclear factor‐kappa B (NF‐κB) subunits p50, p65 and IκB‐α. NF‐κB activation was analysed with a luciferase reporter plasmid. Cells were stimulated with IL‐1β, lipopolysaccharide (LPS) or tumour necrosis factor‐α.Key results:EtP was several‐fold more potent than EtOH in reducing adhesion of neutrophils to activated HUVECs, generation of IL‐8 or G‐CSF and surface expression of the adhesion molecules. This last reaction was decreased by EtP even when added after cytokines or LPS. Translocation of IRAK‐1, IκBα and the NF‐κB p65 subunit to the HUVEC nucleus was inhibited by EtP for all stimuli, whereas the diminished p50 translocation was stimulus specific. When p65 was constitutively expressed in Cos7 cells, stimulation of an NF‐κB‐dependent reporter gene was not affected by EtP, suggesting that EtP acted upstream of gene activation.Conclusions and implications:EtP impedes adhesive, secretory and signalling events typical of the early inflammatory response in endothelial cells, suggesting EtP as a possible treatment for acute inflammatory conditions.British Journal of Pharmacology (2008) 154, 1318–1326; doi:10.1038/bjp.2008.201; published online 26 May 2008
Anti‐inflammatory effects of dimemorfan on inflammatory cells and LPS‐induced endotoxin shock in mice
Authors: Wang Y‐H , Shen Y‐C , Liao J‐F , Li C‐H , Chou C‐Y , Liou K‐T , Chou Y‐C 
Published: May 2008

Background and purpose:Dimemorfan (a σ1 receptor agonist) showed neuroprotective properties in animal models of inflammation‐mediated neurodegenerative conditions, but its effects on inflammatory cells and systemic inflammation remain unclear.Experimental approach:The effects of dimemorfan on phorbol‐12‐myristate‐13‐acetate (PMA)‐ and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP)‐ induced neutrophils and lipopolysaccharide (LPS)‐activated microglial cells, as well as LPS‐induced endotoxin shock in mice were elucidated.Key results:Dimemorfan decreased PMA‐ and fMLP‐induced production of reactive oxygen species (ROS) and CD11b expression in neutrophils, through mechanisms independent of σ1 receptors, possibly by blocking ROS production and G‐protein‐mediated intracellular calcium increase. Dimemorfan also inhibited LPS‐induced ROS and nitric oxide (NO) production, as well as that of monocyte chemoattractant protein‐1 and tumour necrosis factor‐alpha (TNF‐α), by inhibition of NADPH oxidase (NOX) activity and suppression of iNOS up‐regulation through interfering with nuclear factor kappa‐B (NF‐κB) signalling in microglial cells. Treatment in vivo with dimemorfan (1 and 5 mg kg−1, i.p., at three successive times after LPS) decreased plasma TNF‐α, and neutrophil infiltration and oxidative stress in the lung and liver.Conclusions and implications:Our results suggest that dimemorfan acts via σ1 receptor‐independent mechanisms to modulate intracellular calcium increase, NOX activity, and NF‐κB signalling, resulting in inhibition of iNOS expression and NO production, and production of pro‐inflammatory cytokines. These effects may contribute its anti‐inflammatory action and protective effects against endotoxin shock in mice.British Journal of Pharmacology (2008) 154, 1327–1338; doi:10.1038/bjp.2008.202; published online 26 May 2008
Strategies to reduce the risk of drug‐induced QT interval prolongation: a pharmaceutical company perspective
Authors: Pollard C E , Valentin J‐P , Hammond T G 
Published: May 2008

Drug‐induced prolongation of the QT interval is having a significant impact on the ability of the pharmaceutical industry to develop new drugs. The development implications for a compound causing a significant effect in the ‘Thorough QT/QTc Study’—as defined in the clinical regulatory guidance (ICH E14)—are substantial. In view of this, and the fact that QT interval prolongation is linked to direct inhibition of the hERG channel, in the early stages of drug discovery the focus is on testing for and screening out hERG activity. This has led to understanding of how to produce low potency hERG blockers whilst retaining desirable properties. Despite this, a number of factors mean that when an integrated risk assessment is generated towards the end of the discovery phase (by conducting at least anin vivoQT assessment) a QT interval prolongation risk is still often apparent; inhibition of hERG channel trafficking and partitioning into cardiac tissue are just two confounding factors. However, emerging information suggests that hERG safety margins have high predictive value and that when hERG andin vivonon‐clinical data are combined, their predictive value to man, whilst not perfect, is >80%. Although understanding the anomalies is important and is being addressed, of greater importance is developing a better understanding of TdP, with the aim of being able to predict TdP rather than using an imperfect surrogate marker (QT interval prolongation). Without an understanding of how to predict TdP risk, high‐benefit drugs for serious indications may never be marketed.British Journal of Pharmacology(2008)154, 1538–1543; doi:fn1; published online 26 May 2008
Pharmacological targeting of the KIT growth factor receptor: a therapeutic consideration for mast cell disorders
Authors: Jensen B M , Akin C , Gilfillan A M 
Published: May 2008

KIT is a member of the tyrosine kinase family of growth factor receptors which is expressed on a variety of haematopoietic cells including mast cells. Stem cell factor (SCF)‐dependent activation of KIT is critical for mast cell homeostasis and function. However, when KIT is inappropriately activated, accumulation of mast cells in tissues results in mastocytosis. Such dysregulated KIT activation is a manifestation of specific activating point mutations within KIT, with the human D816V mutation considered as a hallmark of human systemic mastocytosis. A number of other activating mutations in KIT have recently been identified and these mutations may also contribute to aberrant mast cell growth. In addition to its role in mast cell growth, differentiation and survival, localized concentration gradients of SCF may control the targeting of mast cells to specific tissues and, once resident within these tissues, mast cell activation by antigen may also be amplified by SCF. Thus, KIT inhibitors may have potential application in multiple conditions linked to mast cells including systemic mastocytosis, anaphylaxis, and asthma. In this review, we discuss the role of KIT in the context of mast cells in these disease states and how recent advances in the development of inhibitors of KIT activity and function may offer novel therapies for the treatment of these disorders.British Journal of Pharmacology (2008) 154, 1572–1582; doi:10.1038/bjp.2008.204; published online 26 May 2008
Regional haemodynamic responses to adenosine receptor activation vary across time following lipopolysaccharide treatment in conscious rats
Authors: Jolly L , March J E , Kemp P A , Bennett T , Gardiner S M 
Published: May 2008

Background and purpose:Studies using adenosine receptor antagonists have shown that adenosine‐mediated vasodilatations play an important role in the maintenance of regional perfusion during sepsis, but it is unclear whether vascular sensitivity to adenosine is affected. Here, we assessed regional haemodynamic responses to adenosine agonists and antagonists in normal and lipopolysaccharide (LPS)‐treated rats to investigate a possible role for adenosine in the haemodynamic sequelae.Experimental approach:Male Sprague–Dawley rats were chronically instrumented with pulsed Doppler flow probes to measure regional haemodynamic responses to adenosine‐receptor agonists (adenosine, 2‐choloro‐N6‐cyclopentyladenosine (CCPA)) and antagonists (8‐phenyltheophylline (8‐PT), 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX)), at selected time points in control and LPS‐treated rats.Key results:The responses to 8‐PT were consistent with endogenous adenosine causing bradycardia, and renal and hindquarters vasodilatation in control rats, whereas in LPS‐treated rats, there was evidence for endogenous adenosine causing renal (at 1.5 h) and hindquarters (at 6 h) vasoconstriction. In control animals, exogenous adenosine caused hypotension, tachycardia and widespread vasodilatation, whereas in LPS‐treated rats, the adenosine‐induced renal (at 1.5 h) and hindquarters (at 6 h) vasodilatations were abolished. As enhanced A1receptor‐mediated vasoconstriction could explain the results in LPS‐treated rats, vascular responsiveness to a selective A1‐receptor agonist (CCPA) or antagonist (DPCPX) was assessed. There was no evidence for enhanced vasoconstrictor responsiveness to CCPA in LPS‐treated rats, but DPCPX caused renal vasodilatation, consistent with endogenous adenosine mediating renal vasoconstriction under these conditions.Conclusions and implications:The results show changes in adenosine receptor‐mediated cardiovascular effects in endotoxaemia that may have implications for the use of adenosine‐based therapies in sepsis.British Journal of Pharmacology(2008)154, 1600–1610; doi:10.1038/bjp.2008.205; published online 26 May 2008
Development of a Guideline for the Management of Ventilator-Associated Pneumonia Based on Local Microbiologic Findings and Impact of the Guideline on Antimicrobial Use Practices
Authors: Dellit Timothy H. , Chan Jeannie D. , Skerrett Shawn J. , Nathens Avery B. 
Published: May 2008

Objective.To describe the development of a guideline for the management of ventilator-associated pneumonia (VAP) based on local microbiologic findings and to evaluate the impact of the guideline on antimicrobial use practices.Design.Retrospective comparison of antimicrobial use practices before and after implementation of the guideline.Setting.Intensive care units at Harborview Medical Center, Seattle, Washington, a university-affiliated urban teaching hospital.Patients.A total of 819 patients who received mechanical ventilation and who underwent quantitative bronchoscopy between July 1, 2003, and June 30, 2005, for suspected VAP.Interventions.Implementation of an evidence-based VAP guideline that focused on the use of quantitative bronchoscopy for diagnosis, administration of empirical antimicrobial therapy based on local microbiologic findings and resistance patterns, tailoring definitive antimicrobial therapy on the basis of culture results, and appropriate duration of therapy.Results.During the baseline period, 168 (46.7%) of 360 patients had quantitative cultures that met the diagnostic criteria for VAP, compared with 216 (47.1%) of 459 patients in the period after the guideline was implemented. The pathogens responsible for VAP remained similar between the 2 periods, except that the prevalence of VAP due to carbapenem-resistant Acinetobacter species increased from 1.8% to 15.3% (P < .001), particularly in late-onset VAP. Compared with the baseline period, there was an improvement in antimicrobial use practices after implementation of the guideline: antimicrobial therapy was more frequently tailored on the basis of quantitative culture results (103 [61.3%] of 168 vs 150 [69.4%] of 216 patients; P = .034), there was an increase in the use of appropriate definitive therapy (135 [80.4%] of 168 vs 193 [89.4%] of 216 patients; P = .001), and there wasadecrease in the mean duration oftherapy (12.0vs 10.7days; P = .0014). The all-cause mortality rate was similar in the periods before and after the guideline was implemented (38 [22.6%] of 168 vs 46 [21.3%] of 216 patients; P = .756).Conclusions.Implementation of a guideline for the management of VAP that incorporated the use of quantitative bronchoscopy, the use of empirical therapy based on local microbiologic findings, tailoring of therapy on the basis of culture results, and use of shortened durations of therapy led to significant improvements in antimicrobial use practices without adversely affecting the all-cause mortality rate.
Hypogonadism is Common in Men With Myopathies
Authors: Al-Harbi Talal M , Bainbridge Laura J , McQueen Matthew J , Tarnopolsky Mark A 
Published: May 2008

Abstract

Background:
Hypogonadism has been described in patients with myotonic muscular dystrophy type 1 but has not been evaluated in other myopathies.

Methods:
We measured total and free serum testosterone levels in 59 men with myotonic muscular dystrophy type 1 (N = 12), facioscapulohumeral muscular dystrophy (N = 11), dystrophinopathy (N = 12), metabolic myopathy (N = 7), and inclusion body myositis (N = 17) and compared these with the normal reference interval.

Results:
Thirty-two of the 59 (54%) participants had low total testosterone, 23 (39%) had low total and free values, and 5 (8%) had low free with normal total levels. There were no significant differences in the prevalence of hypogonadism between those with myotonic muscular dystrophy type 1 and the other groups even after considering age as a confounder.

Conclusions:
Hypogonadism is common in men with myopathies, and with the importance of testosterone in the maintenance of muscle mass, treatment of hypogonadism should be considered.
The structure of an archaeal homodimeric ligase which has RNA circularization activity
Authors: Brooks Mark Adrian , Meslet‐Cladiére Laurence , Graille Marc , Kuhn Joëlle , Blondeau Karine , Myllykallio Hannu , van Tilbeurgh Herman 
Published: May 2008

AbstractThe genome of Pyrococcus abyssi contains two open reading frames encoding proteins which had been previously predicted to be DNA ligases, Pab2002 and Pab1020. We show that while the former is indeed a DNA ligase, Pab1020 had no effect on the substrate deoxyoligo‐ribonucleotides tested. Instead, Pab1020 catalyzes the nucleotidylation of oligo‐ribonucleotides in an ATP‐dependent reaction, suggesting that it is an RNA ligase. We have solved the structure of Pab1020 in complex with the ATP analog AMPPNP by single‐wavelength anomalous dispersion (SAD), elucidating a structure with high structural similarity to the catalytic domains of two RNA ligases from the bacteriophage T4. Additional carboxy‐terminal domains are also present, and one of these mediates contacts with a second protomer, which is related by noncrystallographic symmetry, generating a homodimeric structure. These C‐terminal domains are terminated by short domain swaps which themselves end within 5 Å of the active sites of the partner molecules. Additionally, we show that the protein is indeed capable of circularizing RNA molecules in an ATP‐dependent reaction. These structural and biochemical results provide an insight into the potential physiological roles of Pab1020.
Wheat leaf rust caused by Puccinia triticina
Authors: BOLTON MELVIN D. , KOLMER JAMES A. , GARVIN DAVID F. 
Published: May 2008

SUMMARYLeaf rust, caused by Puccinia triticina, is the most common rust disease of wheat. The fungus is an obligate parasite capable of producing infectious urediniospores as long as infected leaf tissue remains alive. Urediniospores can be wind‐disseminated and infect host plants hundreds of kilometres from their source plant, which can result in wheat leaf rust epidemics on a continental scale. This review summarizes current knowledge of the P. triticina/wheat interaction with emphasis on the infection process, molecular aspects of pathogenicity, rust resistance genes in wheat, genetics of the host parasite interaction, and the population biology of P. triticina.Taxonomy:   Puccinia triticina Eriks.: kingdom Fungi, phylum Basidiomycota, class Urediniomycetes, order Uredinales, family Pucciniaceae, genus Puccinia.Host range:   Telial/uredinial (primary) hosts: common wheat (Triticum aestivum L.), durum wheat (T. turgidum L. var. durum), cultivated emmer wheat (T. dicoccon) and wild emmer wheat (T. dicoccoides), Aegilops speltoides, goatgrass (Ae. cylindrica), and triticale (X Triticosecale). Pycnial/aecial (alternative) hosts: Thalictrum speciosissimum (= T. flavum glaucum) and Isopyrum fumaroides.Identification:   Leaf rust is characterized by the uredinial stage. Uredinia are up to 1.5 mm in diameter, erumpent, round to ovoid, with orange to brown uredinia that are scattered on both the upper and the lower leaf surfaces of the primary host. Uredinia produce urediniospores that are sub‐globoid, average 20 µm in diameter and are orange–brown, with up to eight germ pores scattered in thick, echinulate walls.Disease symptoms:   Wheat varieties that are fully susceptible have large uredinia without causing chlorosis or necrosis in the host tissues. Resistant wheat varieties are characterized by various responses from small hypersensitive flecks to small to moderate size uredinia that may be surrounded by chlorotic and/or necrotic zones.Useful website:   USDA Cereal Disease Laboratory: http://www.ars.usda.gov/mwa/cdl
Learning how we learn: an ethnographic study in a neonatal intensive care unit
Authors: Hunter Cynthia Louise , Spence Kaye , McKenna Kate , Iedema Rick 
Published: May 2008

AbstractTitle.  Learning how we learn: an ethnographic study in a neonatal intensive care unit. Aim.  This paper is a report of a study to identify how nurse clinicians learn with and from each other in the workplace.Background.  Clinicians’ everyday practices and interactions with each other have recently been targeted as areas of research, because it is there that quality of care and patient safety are achieved. Orientation of new nurses and doctors into a specialty unit often results in stress.Method.  An ethnographic approach was used, including a 12‐month period of fieldwork observations involving participation and in‐depth interviews with nurse, doctor and allied health clinicians in their workplace. The data were collected in 2005–2006 in a paediatric teaching hospital in Australia.Findings.  The findings were grouped into four dimensions: orientation of nurses, orientation of medical registrars, preceptoring and decision‐making. The orientation of new staff (nursing and medical) is a complex and multi‐layered process which accommodates multiple kinds of learning, in addition to formal learning. Workplace learning also can be informal, incidental, interpersonal and interactive. Interactive and interpersonal learning and the transfer of knowledge include codified and tacit knowledge as well as intuitive understandings of ‘how we do things here’.Conclusion.  Research into how nurses learn is crucial for illuminating learning that is non‐formal and less recognized than more formal kinds. To provide a safe practice environment built on a foundation of knowledge and best practice, there needs to be an allocation of time in the busy workday for learning and reflection.
‘Do no harm’? Professional regulation of disabled nursing students and nurses in Great Britain
Authors: Sin Chih Hoong , Fong Janice 
Published: May 2008

AbstractTitle.  ‘Do no harm’? Professional regulation of disabled nursing students and nurses in Great Britain. Aim. This paper is a report of the findings of a General Formal Investigation launched by the Disability Rights Commission, Great Britain into the impact of regulatory fitness standards on disabled people, and on nursing students and nurses in particular.Background. The potential for systemic discrimination against disabled nursing professionals lies in the existence and nature of regulatory fitness standards, as well as in how these are interpreted and implemented in practice.Methods. A review of relevant legislation, regulation and guidance was conducted to explore the interaction of the regulatory framework with the Disability Discrimination Act. A formal call to key national stakeholder organizations solicited information on perceptions of the regulatory framework and the adequacy of guidance issued. Independent research was commissioned on disabled people’s disclosure of disability, informal and formal decision‐making around fitness within the educational, and employment contexts. An Inquiry Panel examined all evidence sources, solicited further oral evidence from key organizations, and developed recommendations.Findings. No mention was found of the Disability Discrimination Act in any regulation and guidance governing nursing prior to 2006. There are particular requirements for ‘good health and good character’. Respondents from key national stakeholder organizations, higher educational institutions and employers struggle to interpret the fitness requirements consistently. Implementation is variable, with reliance on ad hoc self‐initiated strategies. The variability of interpretation and implementation can lead to discrimination against disabled people.Conclusion. The imprecision of fitness requirements and variability of implementation raise serious doubts about their utility in managing risk.
Striving for independence: experiences and needs of service users with life limiting conditions
Authors: Cotterell Phil 
Published: May 2008

AbstractTitle.  Striving for independence: experiences and needs of service users with lifelimiting conditions. Aim.  This paper is a report of a study to explore what service users with a range of life‐limiting conditions identify as their key experiences and needs generally and, specifically, from health and social care services.Background.  Whilst internationally palliative care has a primary focus on service users who have cancer, there is growing evidence that those with non‐cancer life‐limiting conditions have similar palliative care needs. The literature has mainly been focused on independence, choice and control at an individual level, with wider influences on the maintenance or attainment of independence ignored.Method.  A participatory approach was used in 2003–2004, with both the researcher and a group of service users working together in all stages of the study. Twenty‐five participants in receipt of support from an acute hospital, primary care, social services and a hospice took part. Face‐to‐face individual interviews and small discussion groups were conducted and data were analysed thematically.Findings.  Eight different but interconnected themes were identified. Independence/dependence was an overarching theme, with negotiation between independence and dependence being evident across all themes. This theme and the influence of health and social care services on the experience of living with life‐limiting conditions are the focus of this paper.Conclusion.  Palliative care and practitioners should focus on maximizing independence at both the individual and structural levels. How services for those with life‐limiting conditions are provided and relationships with health and social care staff can directly impact on an individual’s experience of independence, choice and control.