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Evans M.I.,Columbia University | Wright D.A.,University of Plymouth | Pergament E.,Genetics | Cuckle H.S.,Columbia University | Nicolaides K.H.,Foundation Medicine
Fetal Diagnosis and Therapy | Year: 2012

Objective: To determine the feasibility of digital PCR analysis for noninvasive prenatal diagnosis of trisomy 21. Methods: Through power equations, we modeled the number of wells necessary to determine the feasibility of digital PCR as a practical method for trisomy 21 risk assessment. Results: The number of wells needed is a direct correlate of the ability to isolate free fetal DNA. If a 20% fetal DNA enhancement can be achieved, then 2,609 counts would be sufficient to achieve a 99% detection rate for a 1% false-positive rate and potentially feasible with readily available plates. However, if only a 2% increase is seen, then 220,816 counts will be necessary, and over 110,000 would be needed just to achieve 95% for a 5% false-positive rate - both far beyond current commercially available technology. Conclusion: There are several noninvasive prenatal diagnostic methods which may reach commercialization; all have differing potential advantages and disadvantages. Digital PCR is potentially a cheaper methodology for trisomy 21, but it is too early to determine the optimal method. Copyright © 2012 S. Karger AG.

Al-Bulushi B.,Prince Sultan Military Medical City | Al-Hashem A.,Genetics | Tabarki B.,Prince Sultan Military Medical City
Journal of Child Neurology | Year: 2014

The clinical spectrum associated with ATP1A2 mutations is expanding and includes familial hemiplegic migraine, alternating hemiplegia of childhood, and epilepsy. We have identified a novel c.1766T>C. (Ile589Thr) heterozygous mutation in the ATP1A2 gene in a Saudi kindred with hemiplegic attacks and seizures. Our findings broaden the phenotypic spectrum of patients with ATP1A2 mutations. © The Author(s) 2013.

Riisgard H.U.,University of Southern Denmark | Funch P.,Genetics | Larsen P.S.,Technical University of Denmark
Acta Zoologica | Year: 2015

Filter feeding in mussels is a secondary adaptation where the gills have become W-shaped and greatly enlarged, acting as the mussel filter-pump. Water pumping and particle capture in the blue mussel, Mytilus edulis, have been studied over many years. Here, we give a short status of the present understanding of ciliary structure and function of the mussel filter-pump, supplemented with new photo-microscope and scanning electron microscopy (SEM) pictures of gill preparations. Pumping rate (filtration) and pressure to maintain flow have been extensively studied so the power delivered by the mussel pump to the water flow is known (1.1% of total respiratory power), but the actual cost based on gill respiration is much higher (19%), implying that the cost of maintaining of the large gill pump is considerable and that only relatively little energy can be saved by stopping or reducing the activity of the water-pumping cilia so that continuous feeding with a 'minimal scaled' pump is cheaper than discontinuous feeding with a correspondingly larger pump. According to the present view, the pump proper is the beating lateral cilia (lc) on the gill filaments and particle capture is accomplished by the action of laterofrontal cirri (lfc) transferring particles from the main water current to the frontal gill filament currents driven by frontal cilia (fc). Unexplained aspects include retention efficiency according to particle size and the role of pro-laterofrontal cilia (p-lfc) placed between the lfc and fc. The structure of cilia and the mode of ciliary beating have been re-examined in this study by new high-resolution light and scanning electron microscopy of isolated gill preparations exposed to serotonin (5-HT) stimulation which can activate the lc and lfc at low concentrations (10-6 M), but removes the lfc from the interfilament canals at higher concentrations (10-5 M). © 2014 The Royal Swedish Academy of Sciences.

Williams F.M.,Kings College London | MOnica Risk,Genetics
Annals of neurology | Year: 2013

End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype. Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3). Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811). ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype. Copyright © 2012 American Neurological Association.

Dadd T.,Colworth Science Park | Lewis C.M.,Genetics | Lewis C.M.,Kings College London | Weale M.E.,Genetics
Human Heredity | Year: 2010

Objective: To investigate the validity of simulations and assumptions used to underpin the delta-centralization (DC) method for correcting for population stratification in genetic association studies; to assess the effectiveness of DC compared to genomic control (GC) under valid simulation conditions; and to highlight other studies employing similarly flawed simulations. Methods: DC and GC use data from unlinked null loci to correct the test statistic at the target locus, but differ in the way the correction is performed. We compare DC and GC under two simulation approaches: an invalid approach adopted by the originators of DC, which permits subpopulation allele frequency matching of null markers to the target locus; and a valid approach, based on the Balding-Nichols model, which does not allow subpopulation matching. Results: DC works under invalid simulation conditions (subpopulation allele frequency matching), but not under our valid ones. We use theoretical arguments to assert that there are no valid conditions under which DC might work. We identify several studies which have adopted similarly invalid simulation approaches in this field. Conclusion: DC fails to control for population stratification and should not be used. Other results from studies which have used the same invalid simulation approach should be treated cautiously. © 2010 S. Karger AG, Basel.

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