Genetic Etiologies for Phenotypic Diversity in Sickle Cell Anemia

The clinical course of patients with sickle cell anemia, a Mendelian trait, is characteristically highly variable. HbF concentration and the presence of a thalassemia are established modulators of the disease, but cannot account for all of its clinical heterogeneity. To find additional genetic modulators of disease, genotype-phenotype association studies, where single nucleotide polymorphisms (SNPs) in candidate genes are linked with a particular phenotype, have been informative. SNPs in several genes of the TGF-ß/MP superfamily, and some other genes linked to the endothelial function, and nitric oxide biology are associated with the subphenotypes of stroke, osteonecrosis, priapism, leg ulcers, pulmonary hypertension, and a more general measure of overall disease severity. Genome-wide association studies should help to confirm these observations and also to find hitherto unsuspected genetic modulators. Genetic association studies can have immediate prognostic value; they might also help to identify new pathophysiological pathways that could be susceptible to modulation

Hydroxyurea Treatment for Sickle Cell Disease

High fetal hemoglobin (HbF) levels inhibit the polymerization of sickle hemoglobin (HbS) and reduce the complications of sickle cell disease. Pharmacologic agents that can reverse the switch from γ- to β-chain synthesis — γ-globin chains characterize HbF, and sickle β-globin chains are present in HbS — or selectively increase the proportion of adult erythroid precursors that maintain the ability to produce HbF are therapeutically useful. Hydroxyurea promotes HbF production by perturbing the maturation of erythroid precursors. This treatment increases the total hemoglobin concentration, reduces the vaso-occlusive complications of pain and acute chest syndrome, and attenuates mortality in adults. It is a promising beginning for pharmacologic therapy of sickle cell disease. Still, its effects are inconsistent, trials in infants and children are ongoing, and its ultimate value — and peril — when started early in life are still unknown

Genetic Etiologies for Phenotypic Diversity in Sickle Cell Anemia TheScientificWorldJOURNAL

The clinical course of patients with sickle cell anemia, a Mendelian trait, is characteristically highly variable. HbF concentration and the presence of α thalassemia are established modulators of the disease, but cannot account for all of its clinical heterogeneity. To find additional genetic modulators of disease, genotype-phenotype association studies, where single nucleotide polymorphisms (SNPs) in candidate genes are linked with a particular phenotype, have been informative. SNPs in several genes of the TGF-β/BMP superfamily, and some other genes linked to the endothelial function, and nitric oxide biology are associated with the subphenotypes of stroke, osteonecrosis, priapism, leg ulcers, pulmonary hypertension, and a more general measure of overall disease severity. Genome-wide association studies should help to confirm these observations and also to find hitherto unsuspected genetic modulators. Genetic association studies can have immediate prognostic value; they might also help to identify new pathophysiological pathways that could be susceptible to modulation

Ultrasonic in-situ determination of the regression rate of the melting interface in burning metal rods

Results of tests in which metallic rods are burned in oxygen enriched atmospheres often include the determination of the regression rate of the melting interface for the burning test specimen. This regression rate is used as an indication of a metallic material's relative flammability and its general ability to sustain burning under the test conditions. This paper reports on the development and first application of an ultrasonic measurement system that enables in situ measurement of the regression rate of the melting interface in burning metal rods. All other methods currently used for determining this parameter are based on posttest, visual interrogation, which is costly and often inaccurate. The transducer and associated equipment used to drive and record the transducer's output signal are described and typical results for iron rods burning in pure oxygen at different gauge pressures are given along with a comparison of these results with regression gates obtained from visual interrogation. The excellent sensitivity, accuracy and reliability of the new ultrasonic transducer are demonstrated, thus indicating the transducer's great potential. (C) 1999 Acoustical Society of America. [S0001-4966(99)00702-X]

Leg ulcers in sickle cell disease.

Sickle cell disease is a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. The manifestations of this disease are protean.Among them, leg ulcers represent a particularly disabling and chronic complication, often associated with a more severe clinical course.Despite the fact that this complication has been recognized since the early times of SCD, there has been little improvement in the efficacy of its management and clinical outcome over the past 100 years. Recently, vasculopathic abnormalities involving abnormal vascular tone and activated, adhesive endothelium have been recognized as another pathway to end organ damage in sickle cell disease. Vasculopathy of sickle cell disease has been implicated in the development of pulmonary hypertension, stroke, leg ulceration and priapism, particularly associated with hemolytic severity, and reported in other severe hemolytic disorders. The authors present the proceedings from the Educational Session on Chronic leg ulcers in Sickle cell disease, held during the 4th Annual Sickle Cell Disease Research and Educational Symposium, on February 17, 2010 in Fort Lauderdale, Fla

Conditional probabilities in quantum theory, and the tunneling time controversy

It is argued that there is a sensible way to define conditional probabilities in quantum mechanics, assuming only Bayes's theorem and standard quantum theory. These probabilities are equivalent to the ``weak measurement'' predictions due to Aharonov {\it et al.}, and hence describe the outcomes of real measurements made on subensembles. In particular, this approach is used to address the question of the history of a particle which has tunnelled across a barrier. A {\it gedankenexperiment} is presented to demonstrate the physically testable implications of the results of these calculations, along with graphs of the time-evolution of the conditional probability distribution for a tunneling particle and for one undergoing allowed transmission. Numerical results are also presented for the effects of loss in a bandgap medium on transmission and on reflection, as a function of the position of the lossy region; such loss should provide a feasible, though indirect, test of the present conclusions. It is argued that the effects of loss on the pulse {\it delay time} are related to the imaginary value of the momentum of a tunneling particle, and it is suggested that this might help explain a small discrepancy in an earlier experiment.Comment: 11 pages, latex, 4 postscript figures separate (one w/ 3 parts

Sub-femtosecond determination of transmission delay times for a dielectric mirror (photonic bandgap) as a function of angle of incidence

Using a two-photon interference technique, we measure the delay for single-photon wavepackets to be transmitted through a multilayer dielectric mirror, which functions as a ``photonic bandgap'' medium. By varying the angle of incidence, we are able to confirm the behavior predicted by the group delay (stationary phase approximation), including a variation of the delay time from superluminal to subluminal as the band edge is tuned towards to the wavelength of our photons. The agreement with theory is better than 0.5 femtoseconds (less than one quarter of an optical period) except at large angles of incidence. The source of the remaining discrepancy is not yet fully understood.Comment: 5 pages and 5 figure

Clustering by genetic ancestry using genome-wide SNP data

<p>Abstract</p> <p>Background</p> <p>Population stratification can cause spurious associations in a genome-wide association study (GWAS), and occurs when differences in allele frequencies of single nucleotide polymorphisms (SNPs) are due to ancestral differences between cases and controls rather than the trait of interest. Principal components analysis (PCA) is the established approach to detect population substructure using genome-wide data and to adjust the genetic association for stratification by including the top principal components in the analysis. An alternative solution is genetic matching of cases and controls that requires, however, well defined population strata for appropriate selection of cases and controls.</p> <p>Results</p> <p>We developed a novel algorithm to cluster individuals into groups with similar ancestral backgrounds based on the principal components computed by PCA. We demonstrate the effectiveness of our algorithm in real and simulated data, and show that matching cases and controls using the clusters assigned by the algorithm substantially reduces population stratification bias. Through simulation we show that the power of our method is higher than adjustment for PCs in certain situations.</p> <p>Conclusions</p> <p>In addition to reducing population stratification bias and improving power, matching creates a clean dataset free of population stratification which can then be used to build prediction models without including variables to adjust for ancestry. The cluster assignments also allow for the estimation of genetic heterogeneity by examining cluster specific effects.</p

The responses of brown macroalgae to environmental change from local to global scales: direct versus ecologically mediated effects

In many temperate regions, brown macroalgae fulfil essential ecosystem services such as the provision of structure, the fixation of nutrients and carbon, and the production of biomass and oxygen. Their populations in many regions around the globe have declined and/or spatially shifted in recent decades. In this review we highlight the potential global and regional drives of these changes, describe the status of regionally particularly important brown macroalgal species, and describe the capacity of interactions among abiotic and biotic factors to amplify or buffer environmental pressure on brown macroalgae. We conclude with a consideration of possible management and restoration measures

Negative group delay for Dirac particles traveling through a potential well

The properties of group delay for Dirac particles traveling through a potential well are investigated. A necessary condition is put forward for the group delay to be negative. It is shown that this negative group delay is closely related to its anomalous dependence on the width of the potential well. In order to demonstrate the validity of stationary-phase approach, numerical simulations are made for Gaussian-shaped temporal wave packets. A restriction to the potential-well's width is obtained that is necessary for the wave packet to remain distortionless in the travelling. Numerical comparison shows that the relativistic group delay is larger than its corresponding non-relativistic one.Comment: 10 pages, 5 figure