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1.  EXCESS PRESSURE INTEGRAL PREDICTS CARDIOVASCULAR EVENTS INDEPENDENT OF OTHER RISK FACTORS IN THE CONDUIT ARTERY FUNCTIONAL EVALUATION (CAFE) SUB-STUDY OF ANGLO-SCANDINAVIAN CARDIAC OUTCOMES TRIAL (ASCOT) 
Hypertension  2014;64(1):60-68.
Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure (BP) waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular (CV) events and target organ damage in treated hypertensive individuals.
Radial BP waveforms were acquired by tonometry in 2069 individuals (63±8y) in the Conduit Artery Functional Evaluation sub-study of the Anglo-Scandinavian Cardiac Outcomes trial. Measurements of left ventricular mass index (LVMI; n = 862) and common carotid artery intima media thickness (cIMT; n = 923) were also performed. XSPI and the integral of reservoir pressure (PRI) were lower in people treated with amlodipine ± perindopril than atenolol ± bendroflumethiazide, although brachial systolic BP was similar. A total of 134 CV events accrued over a median 3.4 years of follow-up; XSPI was a significant predictor of CV events after adjustment for age and sex and this relationship was unaffected by adjustment for conventional CV risk factors or Framingham risk score. XSPI, central systolic BP, central augmentation pressure (AP), central pulse pressure (cPP) and PRI were correlated with LVMI, but only XSPI, AP and cPP were positively associated with cIMT. Associations between LVMI and XSPI and PRI, and cIMT and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of CV dysfunction and independently predicts CV events and target organ damage in a prospective clinical trial.
doi:10.1161/HYPERTENSIONAHA.113.02838
PMCID: PMC4067534  PMID: 24821941
Blood Pressure; Cardiovascular events; Antihypertensive therapy
2.  Development of a Pseudomonas aeruginosa Agmatine Biosensor 
Biosensors  2014;4(4):387-402.
Agmatine, decarboxylated arginine, is an important intermediary in polyamine production for many prokaryotes, but serves higher functions in eukaryotes such as nitric oxide inhibition and roles in neurotransmission. Pseudomonas aeruginosa relies on the arginine decarboxylase and agmatine deiminase pathways to convert arginine into putrescine. One of the two known agmatine deiminase operons, aguBA, contains an agmatine sensitive TetR promoter controlled by AguR. We have discovered that this promoter element can produce a titratable induction of its gene products in response to agmatine, and utilized this discovery to make a luminescent agmatine biosensor in P. aeruginosa. The genome of the P. aeruginosa lab strain UCBPP-PA14 was altered to remove both its ability to synthesize or destroy agmatine, and insertion of the luminescent reporter construct allows it to produce light in proportion to the amount of exogenous agmatine applied from ~100 nM to 1mM. Furthermore it does not respond to related compounds including arginine or putrescine. To demonstrate potential applications the biosensor was used to detect agmatine in spent supernatants, to monitor the development of arginine decarboxylase over time, and to detect agmatine in the spinal cords of live mice.
doi:10.3390/bios4040387
PMCID: PMC4287709  PMID: 25587430
agmatine; Pseudomonas; arginine decarboxylase; bioluminescence; polyamines
3.  Discovery of an operon that participates in agmatine metabolism and regulates biofilm formation in Pseudomonas aeruginosa 
Molecular microbiology  2010;76(1):104-119.
Summary
Agmatine is the decarboxylation product of arginine and a number of bacteria have devoted enzymatic pathways for its metabolism. Pseudomonas aeruginosa harbours the aguBA operon that metabolizes agmatine to putrescine, which can be subsequently converted into other polyamines or shunted into the TCA cycle for energy production. We discovered an alternate agmatine operon in the P. aeruginosa strain PA14 named agu2ABCA′ that contains two genes for agmatine deiminases (agu2A and agu2A′). This operon was found to be present in 25% of clinical P. aeruginosa isolates. Agu2A′ contains a twin-arginine translocation signal at its N-terminus and site-directed mutagenesis and cell fractionation experiments confirmed this protein is secreted to the periplasm. Analysis of the agu2ABCA′ promoter demonstrates that agmatine induces expression of the operon during the stationary phase of growth and during biofilm growth and agu2ABCA′ provides only weak complementation of aguBA, which is induced during log phase. Biofilm assays of mutants of all three agmatine deiminase genes in PA14 revealed that deletion of agu2ABCA′, specifically its secreted product Agu2A′, reduces biofilm production of PA14 following addition of exogenous agmatine. Together, these findings reveal a novel role for the agu2ABCA′ operon in the biofilm development of P. aeruginosa.
doi:10.1111/j.1365-2958.2010.07083.x
PMCID: PMC4227303  PMID: 20149107
4.  The Arginine Decarboxylase Pathways of Host and Pathogen Interact to Impact Inflammatory Pathways in the Lung 
PLoS ONE  2014;9(10):e111441.
The arginine decarboxylase pathway, which converts arginine to agmatine, is present in both humans and most bacterial pathogens. In humans agmatine is a neurotransmitter with affinities towards α2-adrenoreceptors, serotonin receptors, and may inhibit nitric oxide synthase. In bacteria agmatine serves as a precursor to polyamine synthesis and was recently shown to enhance biofilm development in some strains of the respiratory pathogen Pseudomonas aeruginosa. We determined agmatine is at the center of a competing metabolism in the human lung during airways infections and is influenced by the metabolic phenotypes of the infecting pathogens. Ultra performance liquid chromatography with mass spectrometry detection was used to measure agmatine in human sputum samples from patients with cystic fibrosis, spent supernatant from clinical sputum isolates, and from bronchoalvelolar lavage fluid from mice infected with P. aeruginosa agmatine mutants. Agmatine in human sputum peaks during illness, decreased with treatment and is positively correlated with inflammatory cytokines. Analysis of the agmatine metabolic phenotype in clinical sputum isolates revealed most deplete agmatine when grown in its presence; however a minority appeared to generate large amounts of agmatine presumably driving sputum agmatine to high levels. Agmatine exposure to inflammatory cells and in mice demonstrated its role as a direct immune activator with effects on TNF-α production, likely through NF-κB activation. P. aeruginosa mutants for agmatine detection and metabolism were constructed and show the real-time evolution of host-derived agmatine in the airways during acute lung infection. These experiments also demonstrated pathogen agmatine production can upregulate the inflammatory response. As some clinical isolates have adapted to hypersecrete agmatine, these combined data would suggest agmatine is a novel target for immune modulation in the host-pathogen dynamic.
doi:10.1371/journal.pone.0111441
PMCID: PMC4211729  PMID: 25350753
5.  Updated National and International Hypertension Guidelines: A Review of Current Recommendations 
Drugs  2014;74(17):2033-2051.
Despite the availability of effective pharmacological treatments to aid the control of blood pressure, the global rate of uncontrolled blood pressure remains high. As such, further measures are required to improve blood pressure control. Recently, several national and international guidelines for the management of hypertension have been published. These aim to provide easily accessible information for healthcare professionals and patients to aid the diagnosis and treatment of hypertension. In this review, we have compared new and current guidelines from the American and International Societies of Hypertension; the American Heart Association, American College of Cardiology and the US Center for Disease Control and Prevention; the panel appointed to the Eighth Joint National Committee; the European Societies of Hypertension and Cardiology; the French Society of Hypertension; the Canadian Hypertension Education Program; the National Institute for Health and Clinical Excellence (UK); the Taiwan Society of Cardiology and the Chinese Hypertension League. We have identified consensus opinion regarding best practises for the management of hypertension and have highlighted any discrepancies between the recommendations. In general there is good agreement between the guidelines, however, in some areas, such as target blood pressure ranges for the elderly, further trials are required to provide sufficient high-quality evidence to form the basis of recommendations.
doi:10.1007/s40265-014-0306-5
PMCID: PMC4224739  PMID: 25315030
6.  Oregon Indigenous Farmworkers: Results of Promotor Intervention on Pesticide Knowledge and Organophosphate Metabolite Levels 
Objectives
Examine changes in health beliefs, pesticide safety knowledge, and biomarkers of pesticide exposure in indigenous farmworker who received enhanced pesticide safety training compared to those receiving the standard training.
Methods
Farmworkers in Oregon were randomly assigned to either a promotores pesticide safety training program or a standard video-based training. Spot urine samples were analyzed for dialkylphosphate (DAP) urinary metabolites. Pre/post intervention questionnaires were used to measure pesticide safety knowledge, health beliefs and work practices.
Results
Baseline to follow-up improvements in total pesticide knowledge scores were higher in the promotor group compared to the video. Pairwise differences in mean concentrations of DAP metabolite levels showed declines from baseline to follow-up for both intervention groups.
Conclusions
Results showed reductions in pesticide exposure in indigenous-language speaking farmworkers who receive enhanced pesticide safety training.
doi:10.1097/JOM.0b013e31829b28e4
PMCID: PMC3795976  PMID: 24064776
7.  High density lipoprotein mediates anti-inflammatory transcriptional reprogramming of macrophages via the transcriptional repressor ATF3 
Nature immunology  2013;15(2):152-160.
High Density Lipoprotein (HDL) mediates reverse cholesterol transport and it is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood. Here we identify the transcriptional repressor ATF3, as an HDL-inducible target gene in macrophages that down-regulates the expression of Toll-like receptor (TLR)-induced pro-inflammatory cytokines. The protective effects of HDL against TLR-induced inflammation were fully dependent on ATF3 in vitro and in vivo. Our findings may explain the broad anti-inflammatory and metabolic actions of HDL and provide the basis for predicting the success of novel HDL-based therapies.
doi:10.1038/ni.2784
PMCID: PMC4009731  PMID: 24317040
8.  Inosine-Mediated Modulation of RNA Sensing by Toll-Like Receptor 7 (TLR7) and TLR8 
Journal of Virology  2014;88(2):799-810.
RNA-specific adenosine deaminase (ADAR)-mediated adenosine-to-inosine (A-to-I) editing is a critical arm of the antiviral response. However, mechanistic insights into how A-to-I RNA editing affects viral infection are lacking. We posited that inosine incorporation into RNA facilitates sensing of nonself RNA by innate immune sensors and accordingly investigated the impact of inosine-modified RNA on Toll-like receptor 7 and 8 (TLR7/8) sensing. Inosine incorporation into synthetic single-stranded RNA (ssRNA) potentiated tumor necrosis factor alpha (TNF-α) or alpha interferon (IFN-α) production in human peripheral blood mononuclear cells (PBMCs) in a sequence-dependent manner, indicative of TLR7/8 recruitment. The effect of inosine incorporation on TLR7/8 sensing was restricted to immunostimulatory ssRNAs and was not seen with inosine-containing short double-stranded RNAs or with a deoxy-inosine-modified ssRNA. Inosine-mediated increase of self-secondary structure of an ssRNA resulted in potentiated IFN-α production in human PBMCs through TLR7 recruitment, as established through the use of a TLR7 antagonist and Tlr7-deficient cells. There was a correlation between hyperediting of influenza A viral ssRNA and its ability to stimulate TNF-α, independent of 5′-triphosphate residues, and involving Adar-1. Furthermore, A-to-I editing of viral ssRNA directly enhanced mouse Tlr7 sensing, when present in proportions reproducing biologically relevant levels of RNA editing. Thus, we demonstrate for the first time that inosine incorporation into immunostimulatory ssRNA can potentiate TLR7/8 activation. Our results suggest a novel function of A-to-I RNA editing, which is to facilitate TLR7/8 sensing of phagocytosed viral RNA.
doi:10.1128/JVI.01571-13
PMCID: PMC3911656  PMID: 24227841
9.  Distinctive Roles for OAS and PKR in the in Vivo Anti-Viral Effect of an Adenoviral Vector Expressing Murine IFN-β1 
To evaluate the anti-herpes simplex virus type 1 (HSV-1) mechanisms of murine IFN-β in ocular infection mice were transduced with an adenoviral vector expressing murine IFN-β (Ad:IFN-β). Ocular transduction with Ad:IFN-β resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in (i) viral titer, (ii) viral gene expression, (iii) IFN-γ levels, and (iv) the percentage of CD8+ T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-β resulted in an elevation of the IFN-induced anti-viral gene 2′ 5′-oligoadenylate synthetase (OAS1a) but not double-stranded RNA-dependent protein kinase (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared to wild type controls in the TG measuring viral titer. However, the efficacy of Ad:IFN-β was transiently lost in the eyes of RNase L mice. By comparison, PKR deficient mice were more susceptible to ocular HSV-1 infection and the anti-viral efficacy following transduction with Ad:IFN-β was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN whereas the OAS pathway appears to respond to exogenous IFN contributing to the establishment of an anti-viral environment in a tissue-restricted manner.
PMCID: PMC4060620  PMID: 15100308
HSV-1; keratitis; adenoviral vector; IFN-β; OAS; OKR
10.  Patient self-monitoring of blood pressure and self-titration of medication in primary care: the TASMINH2 trial qualitative study of health professionals’ experiences 
The British Journal of General Practice  2013;63(611):e378-e385.
Background
Self-monitoring with self-titration of antihypertensives leads to reduced blood pressure. Patients are keen on self-monitoring but little is known about healthcare professional views.
Aim
To explore health professionals‘ views and experiences of patient self-management, particularly with respect to future implementation into routine care.
Design and setting
Qualitative study embedded within a randomised controlled trial of healthcare professionals participating in the TASMINH2 trial of patient self-monitoring with self-titration of antihypertensives from 24 West Midlands general practices.
Method
Taped and transcribed semi-structured interviews with 13 GPs, two practice nurses and one healthcare assistant. Constant comparative method of analysis.
Results
Primary care professionals were positive about self-monitoring, but procedures for ensuring patients measured blood pressure correctly were haphazard. GPs interpreted home readings variably, with many not making adjustment for lower home blood pressure. Interviewees were satisfied with patient training and arrangements for blood pressure monitoring and self-titration of medication during the trial, but less sure about future implementation into routine care. There was evidence of a need for training of both patients and professionals for successful integration of self-management.
Conclusion
Health professionals wanted more patient involvement in hypertension care but needed a framework to work within. Consideration of how to train patients to measure blood pressure and how home readings become part of their care is required before self-monitoring and self-titration can be implemented widely. As home monitoring becomes more widespread, the development of patient self-management, including self-titration of medication, should follow but this may take time to achieve.
doi:10.3399/bjgp13X668168
PMCID: PMC3662454  PMID: 23735408
general practice; hypertension, primary care; qualitative research, self-monitoring
11.  Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy life-years lost, and age-specific associations in 1·25 million people 
Lancet  2014;383(9932):1899-1911.
Summary
Background
The associations of blood pressure with the different manifestations of incident cardiovascular disease in a contemporary population have not been compared. In this study, we aimed to analyse the associations of blood pressure with 12 different presentations of cardiovascular disease.
Methods
We used linked electronic health records from 1997 to 2010 in the CALIBER (CArdiovascular research using LInked Bespoke studies and Electronic health Records) programme to assemble a cohort of 1·25 million patients, 30 years of age or older and initially free from cardiovascular disease, a fifth of whom received blood pressure-lowering treatments. We studied the heterogeneity in the age-specific associations of clinically measured blood pressure with 12 acute and chronic cardiovascular diseases, and estimated the lifetime risks (up to 95 years of age) and cardiovascular disease-free life-years lost adjusted for other risk factors at index ages 30, 60, and 80 years. This study is registered at ClinicalTrials.gov, number NCT01164371.
Findings
During 5·2 years median follow-up, we recorded 83 098 initial cardiovascular disease presentations. In each age group, the lowest risk for cardiovascular disease was in people with systolic blood pressure of 90–114 mm Hg and diastolic blood pressure of 60–74 mm Hg, with no evidence of a J-shaped increased risk at lower blood pressures. The effect of high blood pressure varied by cardiovascular disease endpoint, from strongly positive to no effect. Associations with high systolic blood pressure were strongest for intracerebral haemorrhage (hazard ratio 1·44 [95% CI 1·32–1·58]), subarachnoid haemorrhage (1·43 [1·25–1·63]), and stable angina (1·41 [1·36–1·46]), and weakest for abdominal aortic aneurysm (1·08 [1·00–1·17]). Compared with diastolic blood pressure, raised systolic blood pressure had a greater effect on angina, myocardial infarction, and peripheral arterial disease, whereas raised diastolic blood pressure had a greater effect on abdominal aortic aneurysm than did raised systolic pressure. Pulse pressure associations were inverse for abdominal aortic aneurysm (HR per 10 mm Hg 0·91 [95% CI 0·86–0·98]) and strongest for peripheral arterial disease (1·23 [1·20–1·27]). People with hypertension (blood pressure ≥140/90 mm Hg or those receiving blood pressure-lowering drugs) had a lifetime risk of overall cardiovascular disease at 30 years of age of 63·3% (95% CI 62·9–63·8) compared with 46·1% (45·5–46·8) for those with normal blood pressure, and developed cardiovascular disease 5·0 years earlier (95% CI 4·8–5·2). Stable and unstable angina accounted for most (43%) of the cardiovascular disease-free years of life lost associated with hypertension from index age 30 years, whereas heart failure and stable angina accounted for the largest proportion (19% each) of years of life lost from index age 80 years.
Interpretation
The widely held assumptions that blood pressure has strong associations with the occurrence of all cardiovascular diseases across a wide age range, and that diastolic and systolic associations are concordant, are not supported by the findings of this high-resolution study. Despite modern treatments, the lifetime burden of hypertension is substantial. These findings emphasise the need for new blood pressure-lowering strategies, and will help to inform the design of randomised trials to assess them.
Funding
Medical Research Council, National Institute for Health Research, and Wellcome Trust.
doi:10.1016/S0140-6736(14)60685-1
PMCID: PMC4042017  PMID: 24881994
12.  Parental Human Papillomavirus Vaccine Survey (PHPVS): Nurse-Led Instrument Development and Psychometric Testing for Use in Research and Primary Care Screening 
Journal of nursing measurement  2013;21(1):96-109.
Background and Purpose
Human papillomavirus (HPV) vaccine was approved for girls aged 9–24 years in 2006 to prevent HPV infection and cervical cancer. The Parental Human Papillomavirus Survey (PHPVS) was framed on theoretical constructs of the health belief model (HBM) and developed to survey parents regarding their HPV knowledge, attitudes, and intent to vaccinate.
Methods
We evaluated the psychometric properties of the PHPVS using classical item analysis and exploratory factor analysis (EFA) among a sample of 200 parents/caregivers.
Results
The EFA yielded a 4-factor unidimensional model that explained between 62% and 68% of the total variance depending on the extraction method used. The estimated Cronbach’s alpha for the PHPVS was .96.
Conclusions
The PHPVS is a reliable measure of HPV knowledge, attitudes, and intent to vaccinate.
PMCID: PMC3952023  PMID: 23786137
HPV vaccines; health surveys; health care disparities; pediatrics; adolescents; Parents
13.  Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study 
BMJ Open  2014;4(2):e004254.
Introduction
Hypertension in elderly people is characterised by elevated systolic blood pressure (SBP) and increased pulse pressure (PP), which indicate large artery ageing and stiffness. LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor (ARNI), is being developed to treat hypertension and heart failure. The Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study will assess the efficacy of LCZ696 versus olmesartan on aortic stiffness and central aortic haemodynamics.
Methods and analysis
In this 52-week multicentre study, patients with hypertension aged ≥60 years with a mean sitting (ms) SBP ≥150 to <180 and a PP>60 mm Hg will be randomised to once daily LCZ696 200 mg or olmesartan 20 mg for 4 weeks, followed by a forced-titration to double the initial doses for the next 8 weeks. At 12–24 weeks, if the BP target has not been attained (msSBP <140  and ms diastolic BP <90 mm Hg), amlodipine (2.5–5 mg) and subsequently hydrochlorothiazide (6.25–25 mg) can be added. The primary and secondary endpoints are changes from baseline in central aortic systolic pressure (CASP) and central aortic PP (CAPP) at week 12, respectively. Other secondary endpoints are the changes in CASP and CAPP at week 52. A sample size of 432 randomised patients is estimated to ensure a power of 90% to assess the superiority of LCZ696 over olmesartan at week 12 in the change from baseline of mean CASP, assuming an SD of 19 mm Hg, the difference of 6.5 mm Hg and a 15% dropout rate. The primary variable will be analysed using a two-way analysis of covariance.
Ethics and dissemination
The study was initiated in December 2012 and final results are expected in 2015. The results of this study will impact the design of future phase III studies assessing cardiovascular protection.
Clinical trials identifier
EUDract number 2012-002899-14 and ClinicalTrials.gov NCT01692301.
doi:10.1136/bmjopen-2013-004254
PMCID: PMC3918996  PMID: 24496699
14.  Rationale and design of the PRognostic Importance of MIcrovascular Dysfunction in asymptomatic patients with Aortic Stenosis (PRIMID-AS): a multicentre observational study with blinded investigations 
BMJ Open  2013;3(12):e004348.
Introduction
Aortic stenosis (AS) is the commonest valve disorder in the developed world requiring surgery. Surgery in patients with severe asymptomatic AS remains controversial. Exercise testing can identify asymptomatic patients at increased risk of death and symptom development, but with limited specificity, especially in older adults. Cardiac MRI (CMR), including myocardial perfusion reserve (MPR) may be a novel imaging biomarker in AS.
Aims
(1) To improve risk stratification in asymptomatic patients with AS and (2) to determine whether MPR is a better predictor of outcome than exercise testing and brain natriuretic peptide (BNP).
Method/design
Multicentre, prospective observational study in the UK, comparing MPR with exercise testing and BNP (with blinded CMR analysis) for predicting outcome.
Population
170 asymptomatic patients with moderate-to-severe AS, who would be considered for aortic valve replacement (AVR).
Primary outcome
Composite of: typical symptoms necessitating referral for AVR and major adverse cardiovascular events. Follow-up: 12–30 months (minimum 12 months).
Primary hypothesis
MPR will be a better predictor of outcome than exercise testing and BNP.
Ethics/dissemination
The study has full ethical approval and is actively recruiting patients. Data collection will be completed in November 2014 and the study results will be submitted for publication within 6 months of completion.
ClinicalTrials.gov identifier
NCT01658345.
doi:10.1136/bmjopen-2013-004348
PMCID: PMC3884636  PMID: 24353258
15.  Structure and function of OprD protein in Pseudomonas aeruginosa: From antibiotic resistance to novel therapies 
International journal of medical microbiology : IJMM  2012;302(2):10.1016/j.ijmm.2011.10.001.
Pseudomonas aeruginosa (P. aeruginosa) is a common pathogen isolated from patients with nosocomial infections. Due to its intrinsic and acquired antimicrobial resistance, limited classes of antibiotics can be used for the treatment of infection with P. aeruginosa. Of these, the carbapenems are very important; however, the occurrence of carbapenem-resistant strains is gradually increasing over time. Deficiency of the outer membrane protein OprD confers P. aeruginosa a basal level of resistance to carbapenems, especially to imipenem. Functional studies have revealed that loops 2 and 3 in the OprD protein contain the entrance and/or binding sites for imipenem. Therefore, any mutation in loop 2 and/or loop 3 that causes conformational changes could result in carbapenem resistance. OprD is also a common channel for some amino acids and peptides, and competition with carbapenems through the channel may also occur. Furthermore, OprD is a highly regulated protein at transcriptional and post-transcriptional levels by some metals, small bioactive molecules, amino acids, and efflux pump regulators. Because of its hypermutability and highly regulated properties, OprD is thought to be the most prevalent mechanism for carbapenem resistance in P. aeruginosa. Developing new strategies to combat infection with carbapenem-resistant P. aeruginosa lacking OprD is an ongoing challenge.
doi:10.1016/j.ijmm.2011.10.001
PMCID: PMC3831278  PMID: 22226846
Pseudomonas aeruginosa; OprD; Carbapenem
16.  24-hour central aortic systolic pressure and 24-hour central pulse pressure are related to diabetic complications in type 1 diabetes – a cross-sectional study 
Background
Non-invasive measurements of 24 hour ambulatory central aortic systolic pressure (24 h-CASP) and central pulse pressure (24 h-CPP) are now feasible. We evaluate the relationship between 24 h central blood pressure and diabetes-related complications in patients with type 1 diabetes.
Methods
The study was cross-sectional, including 715 subjects: 86 controls (C), 69 patients with short diabetes duration (< 10 years), normoalbuminuria (< 30 mg/24 h) without receiving antihypertensive treatment (SN), 211 with longstanding diabetes (≥ 10 years) and normoalbuminuria (LN), 163 with microalbuminuria (30-299 mg/24 h) (Mi) and 186 with macroalbuminuria (> 300 mg/24 h) (Ma).
24 h-CASP and 24 h-CPP was measured using a tonometric wrist-watch-like device (BPro, HealthStats, Singapore) and derived using N-point moving average.
Results
In C, SN, LN, Mi and Ma mean ± SD 24 h-CASP was: 114 ± 17, 115 ± 13, 121 ± 13, 119 ± 16 and 121 ± 13 mmHg (p < 0.001); and 24 h-CPP: 38 ± 8, 38 ± 7, 44 ± 10, 46 ± 11 and 46 ± 11 mmHg, (p < 0.001).
Following rigorous adjustment (24 h mean arterial pressure and conventional risk factors), 24 h-CASP and 24 h-CPP increased with diabetes, albuminuria degree, previous cardiovascular disease (CVD), retinopathy and autonomic dysfunction (p ≤ 0.031).
Odds ratios per 1 standard deviation increase in 24 h-CASP, 24 h-CPP and 24 h systolic blood pressure (24 h-SBP) were for CVD: 3.19 (1.68-6.05), 1.43 (1.01-2.02) and 2.39 (1.32-4.33), retinopathy: 4.41 (2.03-9.57), 1.77 (1.17-2.68) and 3.72 (1.85-7.47) and autonomic dysfunction: 3.25 (1.65-6.41), 1.64 (1.12-2.39) and 2.89 (1.54-5.42).
Conclusions
24 h-CASP and 24 h-CPP was higher in patients vs. controls and increased with diabetic complications independently of covariates. Furthermore, 24 h-CASP was stronger associated to complications than 24 h-SBP.
The prognostic significance of 24 h-CASP and 24 h-CPP needs to be determined in follow-up studies.
Trial registration
ClinicalTrials.gov ID NCT01171248.
doi:10.1186/1475-2840-12-122
PMCID: PMC3765827  PMID: 23978271
Ambulatory blood pressure; Brachial systolic blood pressure; Central aortic systolic pressure; Central pulse pressure; Diabetic complications; Type 1 diabetes
17.  A role for mitochondrial oxidants in stress-induced premature senescence of human vascular smooth muscle cells☆ 
Redox Biology  2013;1(1):411-417.
Mitochondria are a major source of cellular oxidants and have been implicated in aging and associated pathologies, notably cardiovascular diseases. Vascular cell senescence is observed in experimental and human cardiovascular pathologies. Our previous data highlighted a role for angiotensin II in the induction of telomere-dependent and -independent premature senescence of human vascular smooth muscle cells and suggested this was due to production of superoxide by NADPH oxidase. However, since a role for mitochondrial oxidants was not ruled out we hypothesise that angiotensin II mediates senescence by mitochondrial superoxide generation and suggest that inhibition of superoxide may prevent vascular smooth muscle cell aging in vitro. Cellular senescence was induced using a stress-induced premature senescence protocol consisting of three successive once-daily exposure of cells to 1×10−8 mol/L angiotensin II and was dependent upon the type-1 angiotensin II receptor. Angiotensin stimulated NADPH-dependent superoxide production as estimated using lucigenin chemiluminescence in cell lysates and this was attenuated by the mitochondrial electron transport chain inhibitor, rotenone. Angiotensin also resulted in an increase in mitoSOX fluorescence indicating stimulation of mitochondrial superoxide. Significantly, the induction of senescence by angiotensin II was abrogated by rotenone and by the mitochondria-targeted superoxide dismutase mimetic, mitoTEMPO. These data suggest that mitochondrial superoxide is necessary for the induction of stress-induced premature senescence by angiotensin II and taken together with other data suggest that mitochondrial cross-talk with NADPH oxidases, via as yet unidentified signalling pathways, is likely to play a key role.
Graphical abstract
Highlights
•Angiotensin II causes stress-induced premature senescence in hVSMC.•Mitochondrial superoxide is necessary for premature senescence.•Mitochondrial cross-talk with NADPH oxidases is implicated in this mechanism.
doi:10.1016/j.redox.2013.08.004
PMCID: PMC3814954  PMID: 24191234
Vascular smooth muscle cell; Angiotensin II; Mitochondria; Superoxide; Cell senescence; Stress-induced premature senescence
18.  Targets and self-management for the control of blood pressure in stroke and at risk groups (TASMIN-SR): protocol for a randomised controlled trial 
Background
Self-monitoring of hypertension with self-titration of antihypertensives (self-management) results in lower systolic blood pressure for at least one year. However, few people in high risk groups have been evaluated to date and previous work suggests a smaller effect size in these groups. This trial therefore aims to assess the added value of self-management in high risk groups over and above usual care.
Methods/Design
The targets and self-management for the control of blood pressure in stroke and at risk groups (TASMIN-SR) trial will be a pragmatic primary care based, unblinded, randomised controlled trial of self-management of blood pressure (BP) compared to usual care. Eligible patients will have a history of stroke, coronary heart disease, diabetes or chronic kidney disease and will be recruited from primary care. Participants will be individually randomised to either usual care or self-management. The primary outcome of the trial will be difference in office SBP between intervention and control groups at 12 months adjusted for baseline SBP and covariates. 540 patients will be sufficient to detect a difference in SBP between self-management and usual care of 5 mmHg with 90% power. Secondary outcomes will include self-efficacy, lifestyle behaviours, health-related quality of life and adverse events. An economic analysis will consider both within trial costs and a model extrapolating the results thereafter. A qualitative analysis will gain insights into patients’ views, experiences and decision making processes.
Discussion
The results of the trial will be directly applicable to primary care in the UK. If successful, self-management of blood pressure in people with stroke and other high risk conditions would be applicable to many hundreds of thousands of individuals in the UK and beyond.
Trial Registration
ISRCTN87171227
doi:10.1186/1471-2261-13-21
PMCID: PMC3623796  PMID: 23522245
Hypertension; Self-management; Stroke, Diabetes; Coronary heart disease; Chronic kidney disease; Primary care
19.  Patients’ experiences of self-monitoring blood pressure and self-titration of medication: the TASMINH2 trial qualitative study 
The British Journal of General Practice  2011;62(595):e135-e142.
Background
Self-management of hypertension, comprising self-monitoring of blood pressure with self-titration of medication, improves blood pressure control, but little is known regarding the views of patients undertaking it.
Aim
To explore patients’ views of self-monitoring blood pressure and self-titration of antihypertensive medication.
Design and setting
Qualitative study embedded within the randomised controlled trial TASMINH2 (Telemonitoirng and Self Management in the Control of Hypertension) trial of patient self-management of hypertension from 24 general practices in the West Midlands.
Method
Taped and transcribed semi-structured interviews with 23 intervention patients were used. Six family members were also interviewed. Analysis was by a constant comparative method.
Results
Patients were confident about self-monitoring and many felt their multiple home readings were more valid than single office readings taken by their GP. Although many patients self-titrated medication when required, others lacked the confidence to increase medication without reconsulting with their GP. Patients were more comfortable with titrating medication if their blood pressure readings were substantially above target, but were reluctant to implement such a change if readings were borderline. Many planned to continue self-monitoring after the study finished and report home readings to their GP, but few wished to continue with a self-management plan.
Conclusion
Participants valued the additional information and many felt confident in both self-monitoring blood pressure and self-titrating medication. The reluctance to change medication for borderline readings suggests behaviour similar to the clinical inertia seen for physicians in analogous circumstances. Additional support for those lacking in confidence to implement prearranged medication changes may allow more patients to undertake self-management.
doi:10.3399/bjgp12X625201
PMCID: PMC3268493  PMID: 22520791
family practice; hypertension; qualitative research; self blood pressure monitoring
20.  Conformational rearrangements of RIG-I receptor on formation of a multiprotein:dsRNA assembly 
Nucleic Acids Research  2013;41(5):3436-3445.
The retinoic acid inducible gene-I (RIG-I)-like family of receptors is positioned at the front line of our innate cellular defence system. RIG-I detects and binds to foreign duplex RNA in the cytoplasm of both immune and non-immune cells, and initiates the induction of type I interferons and pro-inflammatory cytokines. The mechanism of RIG-I activation by double-stranded RNA (dsRNA) involves a molecular rearrangement proposed to expose the N-terminal pair of caspase activation recruitment domains, enabling an interaction with interferon-beta promoter stimulator 1 (IPS-1) and thereby initiating downstream signalling. dsRNA is particularly stimulatory when longer than 20 bp, potentially through allowing binding of more than one RIG-I molecule. Here, we characterize full-length RIG-I and RIG-I subdomains combined with a stimulatory 29mer dsRNA using multi-angle light scattering and size-exclusion chromatography–coupled small-angle X-ray scattering, to build up a molecular model of RIG-I before and after the formation of a 2:1 protein:dsRNA assembly. We report the small-angle X-ray scattering–derived solution structure of the human apo-RIG-I and observe that on binding of RIG-I to dsRNA in a 2:1 ratio, the complex becomes highly extended and flexible. Hence, here we present the first model of the fully activated oligomeric RIG-I.
doi:10.1093/nar/gks1477
PMCID: PMC3597671  PMID: 23325848
21.  Resting Heart Rate and the Risk of Microvascular Complications in Patients With Type 2 Diabetes Mellitus 
Background
A higher resting heart rate is associated with an increased probability of cardiovascular complications and premature death in patients with type 2 diabetes mellitus. The impact of heart rate on the risk of developing microvascular complications, such as diabetic retinopathy and nephropathy, is, however, unknown. The present study tests the hypothesis that a higher resting heart rate is associated with an increased incidence and a greater progression of microvascular complications in patients with type 2 diabetes mellitus.
Methods and Results
The relation between baseline resting heart rate and the development of a major microvascular event was examined in 11 140 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. Major microvascular events were defined as a composite of new or worsening nephropathy or new or worsening retinopathy. Patients with a higher baseline heart rate were at increased risk of a new major microvascular complication during follow-up (adjusted hazard ratio: 1.13 per 10 beats per minute; 95% confidence interval: 1.07–1.20; P<0.001). The excess hazard was evident for both nephropathy (adjusted hazard ratio: 1.16 per 10 beats per minute; 95% confidence interval: 1.08–1.25) and retinopathy (adjusted hazard ratio: 1.11 per 10 beats per minute; 95% confidence interval: 1.02–1.21).
Conclusion
Patients with type 2 diabetes mellitus who have a higher resting heart rate experience a greater incidence of new-onset or progressive nephropathy and retinopathy.
Clinical Trial Registration
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00145925. http://www.advance-trial.com/static/html/prehome/prehome.asp
doi:10.1161/JAHA.112.002832
PMCID: PMC3541618  PMID: 23316296
diabetes mellitus, type 2; heart rate; microcirculation
22.  A miR-19 regulon that controls NF-κB signaling 
Nucleic Acids Research  2012;40(16):8048-8058.
Fine-tuning of inflammatory responses by microRNAs (miRNAs) is complex, as they can both enhance and repress expression of pro-inflammatory mediators. In this study, we investigate inflammatory responses following global miRNA depletion, to better define the overall contribution of miRNAs to inflammation. We demonstrate that miRNAs positively regulate Toll-like receptor signaling using inducible Dicer1 deletion and global miRNA depletion. We establish an important contribution of miR-19b in this effect, which potentiates nuclear factor-κB (NF-κB) activity in human and mouse cells. Positive regulation of NF-κB signaling by miR-19b involves the coordinated suppression of a regulon of negative regulators of NF-κB signaling (including A20/Tnfaip3, Rnf11, Fbxl11/Kdm2a and Zbtb16). Transfection of miR-19b mimics exacerbated the inflammatory activation of rheumatoid arthritis primary fibroblast-like synoviocytes, demonstrating its physiological importance in the pathology of this disease. This study constitutes, to our knowledge, the first description of a miR-19 regulon that controls NF-κB signaling, and suggests that targeting this miRNA and linked family members could regulate the activity of NF-κB signaling in inflammation.
doi:10.1093/nar/gks521
PMCID: PMC3439911  PMID: 22684508
23.  A mechanical diagnosis and treatment (MDT) approach for a patient with discogenic low back pain and a relevant lateral component: a case report 
Patients with a lateral lumbar shift are often managed with a frontal plane, manual correction first described by McKenzie. However, there is a subset of patients that require a frontal plane correction who do not demonstrate a lateral shift. Both of these patient groups have what is termed a relevant lateral component (RLC). The subset of patients who have an RLC, without a shift, has received very little attention in the literature to date. This case report describes a patient with no shift who had a remarkable disc extrusion identified by magnetic resonance imaging (MRI). The patient responded nicely to a combination of frontal and transverse plane loading strategies in six treatments using the mechanical diagnosis and treatment (MDT) evaluation and treatment system. The case report is unique in the literature in that it describes a patient with no apparent frontal plane, lumbar deformity that had documented evidence of a large disc extrusion and who responded to a variation of McKenzie’s flexion–rotation mobilization. The centralization phenomenon was demonstrated immediately when a non-weight bearing, multiplanar, loading strategy was administered.
doi:10.1179/2042618610Y.0000000008
PMCID: PMC3172947  PMID: 22547922
Back pain; McKenzie; Mechanical diagnosis and treatment; Physical therapy; Relevant lateral component
24.  The Promyelocytic Leukemia Zinc Finger Protein: Two Decades of Molecular Oncology 
The promyelocytic leukemia zinc finger (PLZF) protein, also known as Zbtb16 or Zfp145, was first identified in a patient with acute promyelocytic leukemia, where a reciprocal chromosomal translocation t(11;17)(q23;q21) resulted in a fusion with the RARA gene encoding retinoic acid receptor alpha. The wild-type Zbtb16 gene encodes a transcription factor that belongs to the POK (POZ and Krüppel) family of transcriptional repressors. In addition to nine Krüppel-type sequence-specific zinc fingers, which make it a member of the Krüppel-like zinc finger protein family, the PLZF protein contains an N-terminal BTB/POZ domain and RD2 domain. PLZF has been shown to be involved in major developmental and biological processes, such as spermatogenesis, hind limb formation, hematopoiesis, and immune regulation. PLZF is localized mainly in the nucleus where it exerts its transcriptional repression function, and many post-translational modifications affect this ability and also have an impact on its cytoplasmic/nuclear dissociation. PLZF achieves its transcriptional regulation by binding to many secondary molecules to form large multi-protein complexes that bind to the regulatory elements in the promoter region of the target genes. These complexes are also capable of physically interacting with its target proteins. Recently, PLZF has become implicated in carcinogenesis as a tumor suppressor gene, since it regulates the cell cycle and apoptosis in many cell types. This review will examine the major advances in our knowledge of PLZF biological activities that augment its value as a therapeutic target, particularly in cancer and immunological diseases.
doi:10.3389/fonc.2012.00074
PMCID: PMC3398472  PMID: 22822476
PLZF; cancer; leukemia; cell cycle; stem cells; apoptosis; cytokines
25.  Urinary Concentrations of Dialkylphosphate Metabolites of Organophosphorus Pesticides: National Health and Nutrition Examination Survey 1999–2004 
Organophosphorus (OP) insecticides were among the first pesticides that EPA reevaluated as part of the Food Quality Protection Act of 1996. Our goal was to assess exposure to OP insecticides in the U.S. general population over a six-year period. We analyzed 7,456 urine samples collected as part of three two-year cycles of the National Health and Nutrition Examination Survey (NHANES) from 1999–2004. We measured six dialkylphosphate metabolites of OP pesticides to assess OP pesticide exposure. In NHANES 2003–2004, dimethylthiophosphate was detected most frequently with median and 95th percentile concentrations of 2.03 and 35.3 μg/L, respectively. Adolescents were two to three times more likely to have diethylphosphate concentrations above the 95th percentile estimate of 15.5 μg/L than adults and senior adults. Conversely, for dimethyldithiophosphate, senior adults were 3.8 times and 1.8 times more likely to be above the 95th percentile than adults and adolescents, respectively, while adults were 2.1 times more likely to be above the 95th percentile than the adolescents. Our data indicate that the most vulnerable segments of our population—children and older adults—have higher exposures to OP pesticides than other population segments. However, according to DAP urinary metabolite data, exposures to OP pesticides have declined during the last six years at both the median and 95th percentile levels.
doi:10.3390/ijerph8083063
PMCID: PMC3166728  PMID: 21909292
NHANES; urine; organophosphorus; pesticide; dialkylphosphate

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