An echocardiographic survey of a random sample of the population of North Glasgow aged 55 to 74 years

The syndrome of chronic heart failure resulting from left ventricular dysfunction, either systolic or diastolic, is a public health problem for the Western world. The study presented in this thesis looked at 1009 individuals aged between 55 and 74 years of age randomly selected from the population of north Glasgow - response rate 59.8%. Within the study cohort there was a significant prevalence of both hypertension (44.1%) and ischaemic heart disease (43.9%). Left ventricular (L.V.) systolic function was measured by calculating an echocardiographic left ventricular ejection fraction (L.V.E.F.) in 75% of participants. The median L.V.E.F. was 50.7% and significant left ventricular systolic dysftinction (L.V.D.) was shown to be represented by an L.V.E.F. of < 35%; being present in 6.7% of the cohort with a measured L.V.E.F. The prevalence of L.V.D. rose with age and was higher in men than in women (9.4% v 4.0% P=0.004). The proportion which was considered symptomatic was 45.0% with no age or gender effect. The principle aetiological associate of L.V.D. was ischaemic heart disease with it accompanying 78% of all cases. Isolated hypertension was no more prevalent in individuals with L.V.D. than in the whole population. The L.V.D. was undertreated with only 16% of cases currently receiving treatment with an angiotensin converting enzyme inhibitor. The presence of L.V.D., even when apparently asymptomatic, was associated with a reduced effort capacity on treadmill testing. Similarly it was associated with impaired quality of life scores in affected individuals, being true for both symptomatic and for treated L.V.D. (using loop diuretics), and there was possibly a small effect seen in asymptomatic L.V.D. Transmitral Doppler indices were used to examine L.V. diastolic filling in participants and showed diastolic filling to be affected by several biological variables including gender, age, body mass index, blood pressure and relative L.V. wall thickness. Disease states such as hypertension, ischaemic heart disease and L.V.D. were all shown to be associated with abnormal L.V. diastolic filling. Looking at a group of individuals who reported breathlessness in the absence of either airways disease or L.V.D. showed that they had a higher prevalence of ischaemic heart disease but without any evidence of abnormal diastolic filling. Removing the individuals with ischaemic heart disease from this group revealed some abnormalities of diastolic filling but also removed any objective impairment of effort capacity. Circulating plasma concentrations of the natriuretic peptides N-terminal atrial natriuretic (N-ANP) and brain natriuretic (BNP) peptides were shown to be elevated in the presence of L.V.D.. Individuals with increased measurements of L.V. mass also had higher levels of both peptides; as did individuals with evidence, by transmitral Doppler indices, of elevated L.V. operating pressures. Examining their potential as screening blood tests for the presence of L.V.D. in the population showed that BNP fared better than N-ANP with a sensitivity of 82.0% and a specificity of 57.6% at a concentration of 15.20 pg./ml. BNP also performed better in a high risk group with ischaemic heart disease (sensitivity - 97.4%, specificity - 20.5%, concentration - 8.30 pg./ml) and had an excellent negative predictive value of 98.2% in this group. It also had a high negative predictive value in a group of breathless individuals for the presence of L.V. systolic dysfunction (97.1%). Natriuretic peptides were shown to lack some discriminatory power with reduced specificities and positive predictive values owing to the presence of confounding factors in the population. Their future role may therefore be to exclude the presence of L.V.D. in individuals. BNP concentrations measured in unextracted plasma using the relatively simpler, and recently commercially available, Shionoria immunoradiometric assay kit also performed well as screening blood tests but not as well those obtained using a standard radioimmunoassay from extracted plasma

Perspectives On The Sources And Eventual Outcome Of The 2008 Economic And Financial Crisis: A Panel Discussion

In October 2008 the Southern Utah University School of Business held a panel discussion on the current economic crisis. This discussion was part of the School’s Business Convocation series and was open to the public. The panel was designed with two components in mind. First, a pair of academics with expertise in financial institutions and business cycles offered historical and theoretical perspectives on the crisis. Second, a pair of professionals – a local banking official and a fund manager – offered perspectives on the current financial situation and practical experience based on the policy responses to past crises. As moderator, Joe Baker asked each panelist to make a short presentation on a question of general interest that was related to their area of expertise; this was followed by an open question and answer session. The participating panelists and opening questions follow. 1. Stephen Evans, Professor of Finance: Dr. Evans teaches courses on financial institutions and was asked to provide background of how the crisis occurred and what the proposed government bailout plan is expected to accomplish. 2. David Tufte, Associate Professor of Economics: Dr. Tufte is a macroeconomist and was asked to discuss the macroeconomic implications of the crisis in such areas as inflation, interest rates, economic growth and unemployment. 3. Mr. Robb Kerry, Chief Credit Officer of ADB Bank: Mr. Kerry has an extensive background in banking as a bank regulator and banker. Mr. Kerry was asked to discuss the implications of the crisis on banking credit and lending. Mr. Steve Harrop, Finance Professional in Residence: Mr. Harrop was a mutual fund manager for several decades before joining the School of Business faculty where he teaches investments and manages (pro bono) an investment fund. Mr. Harrop will discuss the implications of the crisis on the stock and bond markets

Inhibition of cyclin-dependent kinase 9 downregulates cytokine production without detrimentally affecting human monocyte-derived macrophage viability

Cyclin-dependent kinase (CDK) inhibitor drugs (CDKi), such as R-roscovitine and AT7519, induce neutrophil apoptosis in vitro and enhance the resolution of inflammation in a number of in vivo models. This class of compounds are potential novel therapeutic agents that could promote the resolution of acute and chronic inflammatory conditions where neutrophil activation contributes to tissue damage and aberrant tissue repair. In this study we investigated CDKi effects on macrophage pro-inflammatory mediator production and viability. Treatment of human monocyte-derived macrophages (MDMs) with the CDKi AT7519 and R-roscovitine at concentrations that induce neutrophil apoptosis had no significant effect on control or LPS-activated MDM apoptosis and viability, and did not detrimentally affect MDM efferocytosis of apoptotic cells. In addition, enhanced efferocytosis, induced by the glucocorticoid dexamethasone, was also unaffected after a short time treatment with R-roscovitine. Macrophage cytokine responses to inflammatory stimuli are also of importance during inflammation and resolution. As a key target of CDKi, CDK9, is involved in protein transcription via the RNA polymerase II complex, we investigated the effect of CDKi drugs on cytokine production. Our data show that treatment with AT7519 significantly downregulated expression and release of key MDM cytokines IL-6, TNF, IL-10 and IL-1β, as well as markers of pro-inflammatory macrophage polarisation. R-Roscovitine was also able to downregulate inflammatory cytokine protein secretion from MDMs. Using siRNA transfection, we demonstrate that genetic knock-down of CDK9 replicates these findings, reducing expression and release of pro-inflammatory cytokines. Furthermore, overexpression of CDK9 in THP-1 cells can promote a pro-inflammatory phenotype in these cells, suggesting that CDK9 plays an important role in the inflammatory phenotype of macrophages. Overall, this study demonstrates that pharmacological and genetic targeting of CDK9 inhibits an inflammatory phenotype in human MDMs. As such these data indicate that CDK9 may be key to therapeutically targeting pro-inflammatory macrophage functions during chronic inflammation

Decontamination Strategies Used for AFB Culture Significantly Reduce the Viability of Mycobacterium abscessus Complex in Sputum Samples from Patients with Cystic Fibrosis

Nontuberculous mycobacteria are important respiratory pathogens in patients with cystic fibrosis (CF). For diagnosis, international guidelines recommend culture of sputum that has been decontaminated via chemical treatment. Fifty-six sputum samples from 32 patients known to be previously colonized or infected with NTM were subdivided, and the aliquots were subjected to six different decontamination strategies, followed by quantitative culture for NTM. Thirty sputum samples contained Mycobacterium abscessus complex (MABSC) and 11 contained Mycobacterium avium complex (MAC). Decontamination strategies included treatment with N-acetyl L-cysteine with 2 sodium hydroxide (NALC-NaOH), 4 NaOH, 1 chlorhexidine, 0.5 N sulfuric acid, 5 oxalic acid, double decontamination with NALC-NaOH, followed by 5 oxalic acid, and saline (0.85) as a control. The samples were also cultured directly with no treatment. Treatment with NALC-NaOH resulted in an average reduction in colony count of 87 for MABSC when compared with direct culture. NaOH at 4 caused a 98.3 average reduction in colony count. All treatments that included NaOH resulted in colony counts that were statistically lower than those obtained from direct culture or the saline-treated control (p &lt; 0.05). Standard treatments using sulfuric or oxalic acids were less deleterious, but still resulted in an average reduction in colony count of at least 30. The viability of MAC was much less affected by most decontamination treatments. In conclusion, the viability of MABSC was severely compromised by standard decontamination regimens. This supports recent evidence showing that optimal recovery of MABSC is achieved by culture on an appropriate selective agar without decontamination of sputum samples

Using Grizzly Bears to Assess Harvest-Ecosystem Tradeoffs in Salmon Fisheries

Using grizzly bears as surrogates for “salmon ecosystem” function, the authors develop a generalizable ecosystem-based management framework that enables decision-makers to quantify ecosystem-harvest tradeoffs between wild and human recipients of natural resources like fish

COMPASS identifies T-cell subsets correlated with clinical outcomes.

Advances in flow cytometry and other single-cell technologies have enabled high-dimensional, high-throughput measurements of individual cells as well as the interrogation of cell population heterogeneity. However, in many instances, computational tools to analyze the wealth of data generated by these technologies are lacking. Here, we present a computational framework for unbiased combinatorial polyfunctionality analysis of antigen-specific T-cell subsets (COMPASS). COMPASS uses a Bayesian hierarchical framework to model all observed cell subsets and select those most likely to have antigen-specific responses. Cell-subset responses are quantified by posterior probabilities, and human subject-level responses are quantified by two summary statistics that describe the quality of an individual's polyfunctional response and can be correlated directly with clinical outcome. Using three clinical data sets of cytokine production, we demonstrate how COMPASS improves characterization of antigen-specific T cells and reveals cellular 'correlates of protection/immunity' in the RV144 HIV vaccine efficacy trial that are missed by other methods. COMPASS is available as open-source software

Discovery of a series of 2-(pyridinyl) pyrimidines as potent antagonists of GPR40

A series of 2-(pyridinyl)pyrimidines were identified as potent GPR40 antagonists. Despite significant challenges related to improving the combination of potency and lipophilicity within the series, the compounds were optimised to identify a suitable in vivo probe compound, which was confirmed to exhibit pharmacology consistent with GPR40 antagonism

Sequencing of the Sea Lamprey (Petromyzon marinus) Genome Provides Insights into Vertebrate Evolution

Lampreys are representatives of an ancient vertebrate lineage that diverged from our own ∼500 million years ago. By virtue of this deeply shared ancestry, the sea lamprey (P. marinus) genome is uniquely poised to provide insight into the ancestry of vertebrate genomes and the underlying principles of vertebrate biology. Here, we present the first lamprey whole-genome sequence and assembly. We note challenges faced owing to its high content of repetitive elements and GC bases, as well as the absence of broad-scale sequence information from closely related species. Analyses of the assembly indicate that two whole-genome duplications likely occurred before the divergence of ancestral lamprey and gnathostome lineages. Moreover, the results help define key evolutionary events within vertebrate lineages, including the origin of myelin-associated proteins and the development of appendages. The lamprey genome provides an important resource for reconstructing vertebrate origins and the evolutionary events that have shaped the genomes of extant organisms

An Outer Arm Dynein Conformational Switch Is Required for Metachronal Synchrony of Motile Cilia in Planaria

Here we use the motile ventral cilia of the planarian S. mediterranea to examine the role of outer arm dynein in the generation and maintenance of metachronal synchrony. We demonstrate that a single dynein light chain plays a mechanosensory role necessary to entrain and maintain the metachronal synchrony of motile cilia