Genome-wide profiling of methylation identifies novel targets with aberrant hyper-methylation and reduced expression in low-risk myelodysplastic syndromes

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.

Deep vein thrombosis and caesarean section

Deep vein thrombosis (DVT) presents a significant risk for women requiring Caesarean section.
Venous thromboembolism (VTE) remains the leading direct cause of maternal death in the
UK and is the second most common cause of maternal death worldwide, accounting for 11%
of maternal deaths (RCOG 2009). This article uses a reflective cycle to explore the role of the
preoperative practitioner in the prevention of DVT for women undergoing elective Caesarean
section.

'Securing' the past: Policing and the contest over truth in Northern Ireland

The question of whether Northern Ireland should have a formal truth recovery process has been amplified by the recent Report of the Consultative Group on the Past. Compared to the volume at which the truth recovery debate has been played out, relatively little is known about policing attitudes to this form of dealing with the past. This paper analyses the ways in which the history and context of policing in Northern Ireland have shaped attitudes towards truth recovery. It will be argued that differing opinions on the need for truth recovery are part of a debate over 'ownership of the past' between the ardent supporters of the Royal Ulster Constabulary and the new post-Patten managers and modernizers.

Clinical management and outcome of refractory asthma in the UK from the British Thoracic Society Difficult Asthma Registry

Refractory asthma represents a significant unmet clinical need. Data from a national online registry audited clinical outcome in 349 adults with refractory asthma from four UK specialist centres in the British Thoracic Society Difficult Asthma Network. At follow-up, lung function improved, with a reduction in important healthcare outcomes, specifically hospital admission, unscheduled healthcare visits and rescue courses of oral steroids. The most frequent therapeutic intervention was maintenance oral corticosteroids and most steroid sparing agents (apart from omalizumab) demonstrated minimal steroid sparing benefit. A significant unmet clinical need remains in this group, specifically a requirement for therapies which reduce systemic steroid exposure.

Pre-hospital body surface potential mapping improves early diagnosis of acute coronary artery occlusion in patients with ventricular fibrillation and cardiac arrest

Aims: To determine whether 80-lead body surface potential mapping (BSPM) improves detection of acute coronary artery occlusion in patients presenting with out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) and who survived to reach hospital. Methods and results: Of 645 consecutive patients with OHCA who were attended by the mobile coronary care unit, VF was the initial rhythm in 168 patients. Eighty patients survived initial resuscitation, 59 of these having had BSPM and 12-lead ECG post-return of spontaneous circulation (ROSC) and in 35 patients (age 69±13 yrs; 60% male) coronary angiography performed within 24. h post-ROSC. Of these, 26 (74%) patients had an acutely occluded coronary artery (TIMI flow grade [TFG] 0/1) at angiography. Twelve-lead ECG criteria showed ST-segment elevation (STE) myocardial infarction (STEMI) using Minnesota 9-2 criteria - sensitivity 19%, specificity 100%; ST-segment depression (STD) =0.05. mV in =2 contiguous leads - sensitivity 23%, specificity 89%; and, combination of STEMI or STD criteria - sensitivity 46%, specificity 100%. BSPM STE occurred in 23 (66%) patients. For the diagnosis of TFG 0/1 in a main coronary artery, BSPM STE had sensitivity 88% and specificity 100% (c-statistic 0.94), with STE occurring most commonly in either the posterior, right ventricular or high right anterior territories. Conclusion: Among OHCA patients presenting with VF and who survived resuscitation to reach hospital, post-resuscitation BSPM STE identifies acute coronary occlusion with sensitivity 88% and specificity 100% (c-statistic 0.94). © 2012 Elsevier Ireland Ltd.

International Association for Hospice and Palliative Care (IAHPC) List of Essential Practices in Palliative Care

The objective of this study was to identify, through a consensus process, the essential practices in primary palliative care. A three-phase study was designed. Phase 1 methods included development of a working group; a literature review; development of a baseline list of practices; and identification of levels of intervention. In Phase 2, physicians, nurses, and nurse aides (n = 425) from 63 countries were asked in three Delphi rounds to rate the baseline practices as essential or nonessential and select the appropriate levels of intervention for each. In Phase 3, representatives of 45 palliative care organizations were asked to select and rank the 10 most important practices resulting from Phase 2. Scores (1-10) were assigned to each, based on the selected level of importance. Results of Phase 1 were a baseline list of 140 practices. Three levels of intervention were identified: Identification/Evaluation; Diagnosis; and Treatment/Solution measures. In Phase 2, the response rates (RR) for the Delphi rounds were 96.5%, 73.6%, and 71.8%, respectively. A consensus point (=80% agreement) was applied, resulting in 62 practices. In Phase 3, RR was 100%. Forty-nine practices were selected and ranked. "Evaluation, Diagnosis and Treatment of Pain" scored the highest (352 points). The working group (WG) arranged the resulting practices in four categories: Physical care needs, Psychological/Emotional/Spiritual care needs, Care Planning and Coordination, and Communication. The IAHPC List of Essential Practices in Palliative care may help define appropriate primary palliative care and improve the quality of care delivered globally. Further studies are needed to evaluate their uptake and impact.

Guidelines for the psychosocial and bereavement support of family caregivers of palliative care patients

Support for family caregivers, including bereavement follow-up, is a core function of palliative care. Many caregivers acknowledge positive aspects associated with the role; however a considerable proportion will experience poor psychological, social, financial, spiritual, and physical well-being and some will suffer from complicated grief. Many family caregivers have unmet needs and would like more information, preparation, and support to assist them in the caregiving role. There is a shortage of evidence-based strategies to guide health professionals in providing optimal support while the caregiver is providing care and after the patient's death.

Treatment of lung infection in patients with cystic fibrosis:Current and future strategies

In patients with cystic fibrosis (CF) lung damage secondary to chronic infection is the main cause of death. Treatment of lung disease to reduce the impact of infection, inflammation and subsequent lung injury is therefore of major importance. Here we discuss the present status of antibiotic therapy for the major pathogens in CF airways, including prophylaxis against infection, eradication of early infection, suppression of chronic infection, and the treatment of infective exacerbations. We outline measures to optimize maintenance treatment for infection in the light of novel antibiotic drug formulations. We discuss new developments in culture-independent microbiological diagnostic techniques and the use of tools for monitoring the success of antibiotic treatment courses. Finally, cost-effectiveness analyses for antibiotic treatment in CF patients are discussed.

Efficacy, safety and effect on biomarkers of AZD9668 in cystic fibrosis

The aim of this study was to evaluate the safety and effect on clinical outcomes and biomarkers of inflammation and tissue damage of the neutrophil elastase inhibitor AZD9668 (60 mg twice daily orally for 4 weeks) in cystic fibrosis. This was a randomised, double-blind, placebo-controlled study. Primary outcome measures were sputum neutrophil count, lung function, 24-h sputum weight, BronkoTest® diary card data and health-related quality-of-life (revised cystic fibrosis quality-of-life questionnaire). Secondary end-points included sputum neutrophil elastase activity, inflammatory biomarkers in sputum and blood, urine and plasma desmosine (an elastin degradation marker), AZD9668 levels and safety parameters (adverse events, routine haematology, biochemistry, electrocardiogram and sputum bacteriology). 56 patients were randomised, of which 27 received AZD9668. There was no effect for AZD9668 on sputum neutrophil counts, neutrophil elastase activity, lung function or clinical outcomes, including quality of life. In the AZD9668 group, there was a trend towards reduction in sputum inflammatory biomarkers with statistically significant changes in interleukin-6, RANTES and urinary desmosine. The pattern of adverse events was similar between groups. Consistent reductions in sputum inflammatory biomarkers were seen in the AZD9668 group, and reduction in urinary desmosine suggests that AZD9668 impacts elastin cleavage by neutrophil elastase.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia

ABSTRACT BACKGROUND: Acute exposure to high-altitude stimulates free radical formation in lowlanders yet whether this persists during chronic exposure in healthy well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress [ascorbate radical (A•-), electron paramagnetic resonance spectroscopy and nitrite (NO2-), ozone-based chemiluminescence] was assessed in venous blood of 25 male highlanders living at 3,600 m with (n = 13, CMS+) and without (n = 12, CMS-) CMS. Twelve age and activity-matched healthy male lowlanders were examined at sea-level and during acute hypoxia. We also measured flow-mediated dilatation (FMD), arterial stiffness (AIx-75) and carotid intima-media thickness (IMT). RESULTS: Compared to normoxic lowlanders, oxidative-nitrosative stress was moderately increased in CMS- (P < 0.05) as indicated by elevated A•- (3,191 ± 457 vs. 2,640 ± 445 arbitrary units (AU)] and lower NO2- (206 ± 55 vs. 420 ± 128 nmol/L) whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS+ (A•-: 3,765 ± 429 AU and NO2- : 148 ± 50 nmol/L) compared to both CMS- and lowlanders (P < 0.05). This was associated with systemic vascular dysfunction as indicated by lower (P < 0.05 vs. CMS-) FMD (4.2 ± 0.7 vs. 7.6 ± 1.7 %) and increased AIx-75 (23 ± 8 vs. 12 ± 7 %) and carotid IMT (714 ± 127 vs. 588 ± 94 µM). CONCLUSIONS: Healthy highlanders display a moderate sustained elevation in oxidative-nitrosative stress that unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.Clinical Trials Gov Registration # NCT011827921Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, Wales, UK;2Sondes Moléculaires en Biologie et Stress Oxydant, Institut de Chimie Radicalaire, CNRS UMR 7273, Aix-Marseille University, France;3Department of Cardiology, University Hospital of Bern, Bern, Switzerland;4Institute of Clinical Physiology, CNR, Pisa, Italy;5Instituto Bolivano de Biologia de Altura, La Paz, Bolivia;6Centre for Clinical and Population Sciences, Queen's University Belfast, Belfast, Northern Ireland,7Botnar Center for Clinical Research, Hirslanden Group, Lausanne, Switzerland;8Facultad de Ciencias, Departamento de Biología, Universidad de Tarapacá, Arica, Chile and9Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland*Drs Bailey, Rimoldi, Scherrer and Sartori contributed equally to this workCorrespondence: Damian Miles Bailey, Neurovascular Research Laboratory, Faculty of Health, Science and Sport, University of Glamorgan, UK CF37 4AT email: dbailey1@glam.ac.uk.

Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland

Elevated plasma homocysteine level has been associated with increased risk for cardiovascular and cerebrovascular disease. Variation in the levels of this amino acid has been shown to be due to nutritional status and methylenetetrahydrofolate reductase (MTHFR) genotype.

Apolipoprotein E polymorphism and serum concentration in Alzheimer's disease in nine European centres:the ApoEurope study. ApoEurope group

As part of the ApoEurope Project, apolipoprotein E (apo E) common polymorphism and serum concentration were determined in 489 Alzheimer's disease patients and 429 controls. Patients and controls were recruited through nine centres in eight European countries. Age, sex ratios and education levels of both case and control populations were similar, although discrete differences appeared between centres. The prevalence of the epsilon4 allele was higher in Alzheimer's disease than in controls (increased by 140%), while serum apo E concentration was lower by 11.2% (p

Elderly patients with hypercholesterolaemia:a double-blind study of the efficacy, safety and tolerability of fluvastatin

Coronary heart disease is a major cause of morbidity and mortality in the elderly, a rapidly growing section of the population. Elderly patients have been excluded from most preventative risk factor trials.