Hypertensive Encephalopathy and Renal Failure in a Young Man

No abstract available

Predictive response-relevant clustering of expression data provides insights into disease processes

This article describes and illustrates a novel method of microarray data analysis that couples model-based clustering and binary classification to form clusters of ;response-relevant' genes; that is, genes that are informative when discriminating between the different values of the response. Predictions are subsequently made using an appropriate statistical summary of each gene cluster, which we call the ;meta-covariate' representation of the cluster, in a probit regression model. We first illustrate this method by analysing a leukaemia expression dataset, before focusing closely on the meta-covariate analysis of a renal gene expression dataset in a rat model of salt-sensitive hypertension. We explore the biological insights provided by our analysis of these data. In particular, we identify a highly influential cluster of 13 genes-including three transcription factors (Arntl, Bhlhe41 and Npas2)-that is implicated as being protective against hypertension in response to increased dietary sodium. Functional and canonical pathway analysis of this cluster using Ingenuity Pathway Analysis implicated transcriptional activation and circadian rhythm signalling, respectively. Although we illustrate our method using only expression data, the method is applicable to any high-dimensional datasets

Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background&lt;p&gt;&lt;/p&gt; Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.&lt;p&gt;&lt;/p&gt; Methods&lt;p&gt;&lt;/p&gt; We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.&lt;p&gt;&lt;/p&gt; Results&lt;p&gt;&lt;/p&gt; Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.&lt;p&gt;&lt;/p&gt; Conclusions&lt;p&gt;&lt;/p&gt; We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

Condensational symbols in British press coverage of Boko Haram

This study of British press coverage of Boko Haram, a militant group in Nigeria, concentrates on condensational symbols in news reports of one of its major acts of terrorism, the bombing of the United Nations House in Abuja, the country’s capital city, in August 2011. The study examines the visibility of Boko Haram in British newspapers before and after the attack. It identifies the condensational symbols that dominated the coverage and how these provided a particular trajectory that could have shaped newspaper readers’ understanding of the event. The study argues that the symbolic terms that journalists used in their reports were not only easily identifiable but were specifically chosen to simplify a complex story for audiences that were perhaps uninformed about the group and its activities. The terms also reflect the repertoire of news frames that journalists mine to reconstruct reality for their audiences

Genome-wide association scan meta-analysis identifies three Loci influencing adiposity and fat distribution.

To identify genetic loci influencing central obesity and fat distribution, we performed a meta-analysis of 16 genome-wide association studies (GWAS, N = 38,580) informative for adult waist circumference (WC) and waist-hip ratio (WHR). We selected 26 SNPs for follow-up, for which the evidence of association with measures of central adiposity (WC and/or WHR) was strong and disproportionate to that for overall adiposity or height. Follow-up studies in a maximum of 70,689 individuals identified two loci strongly associated with measures of central adiposity; these map near TFAP2B (WC, P = 1.9x10(-11)) and MSRA (WC, P = 8.9x10(-9)). A third locus, near LYPLAL1, was associated with WHR in women only (P = 2.6x10(-8)). The variants near TFAP2B appear to influence central adiposity through an effect on overall obesity/fat-mass, whereas LYPLAL1 displays a strong female-only association with fat distribution. By focusing on anthropometric measures of central obesity and fat distribution, we have identified three loci implicated in the regulation of human adiposity

Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology

Background: The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D). Methodology/Principal Findings: Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92-95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81-94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81-88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed. Conclusions/Significance: These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling

Mechanisms of Vasorelaxation

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72633/1/j.1527-3466.1992.tb00249.x.pd