Reconstruction from free‐breathing cardiac MRI data using reproducing kernel Hilbert spaces

This paper describes a rigorous framework for reconstructing MR images of the heart, acquired continuously over the cardiac and respiratory cycle. The framework generalizes existing techniques, commonly referred to as retrospective gating, and is based on the properties of reproducing kernel Hilbert spaces. The reconstruction problem is formulated as a moment problem in a multidimensional reproducing kernel Hilbert spaces (a two‐dimensional space for cardiac and respiratory resolved imaging). Several reproducing kernel Hilbert spaces were tested and compared, including those corresponding to commonly used interpolation techniques (sinc‐based and splines kernels) and a more specific kernel allowed by the framework (based on a first‐order Sobolev RKHS). The Sobolev reproducing kernel Hilbert spaces was shown to allow improved reconstructions in both simulated and real data from healthy volunteers, acquired in free breathing. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.     

Two-dimensional flow index mapping for hemodynamic imaging: a feasibility study

The resistive index (RI) is a functional hemodynamic index used to measure flow resistance within an organ, such as the kidney, to assess if there is any vascular disease associated with that organ. Currently, the measurement of RI values using spectral Doppler ultrasound (US) is performed in one location at a time. As a result, RI values are typically obtained only from a few locations. To visualize the entire two-dimensional distribution of RI values, we developed a method called two-dimensional flow index mapping (2D-FIM). To evaluate this method, we performed a feasibility study using 16 kidney data sets, with eight from healthy volunteers with normal native kidneys and eight from kidney transplant recipients. Quadrature-demodulated baseband Doppler data were used to calculate the spatial distribution of RI values using 2D-FIM. For comparison, the intrarenal RI values at different levels of renal arterial branches were measured with conventional spectral Doppler US. The RI values determined from 2D-FIM were compared with those from spectral Doppler US, which led to a Pearson correlation coefficient of 0.84. There was no significant difference between 2D-FIM- and spectral Doppler US-produced RI values. With the ability to visualize RI in more than one dimension, 2D-FIM could help guide placement of the spectral Doppler range gate to regions of abnormal RI, thus potentially reducing exam times.     

Modeling and Characterization of Complex Concentrated Alloys with Reduced Content of Critical Raw Materials

The continuous development of society has increased the demand for critical raw materials (CRMs) by using them in different industrial applications. Since 2010, the European Commission has compiled a list of CRMs and potential consumption scenarios with significant economic and environmental impacts. Various efforts were made to reduce or replace the CRM content used in the obtaining process of high-performance materials. Complex concentrated alloys (CCAs) are an innovative solution due to their multitude of attractive characteristics, which make them suitable to be used in a wide range of industrial applications. In order to demonstrate their efficiency in use, materials should have improved recyclability, good mechanical or biocompatible properties, and/or oxidation resistance, according to their destination. In order to predict the formation of solid solutions in CCAs and provide the optimal compositions, thermodynamic and kinetic simulations were performed. The selected compositions were formed in an induction furnace and then structurally characterized with different techniques. The empirical results indicate that the obtained CCAs are suitable to be used in advanced applications, providing original contributions, both in terms of scientific and technological fields, which can open new perspectives for the selection, design, and development of new materials with reduced CRM contents.     

ROCK inhibitor (Y-27632) disrupts somitogenesis in chick embryos

Aim

In chick embryos, administration of cadmium (Cd) induces ventral body wall defects (VBWD) similar to human omphalocele. It has been shown that failure of proper VBW formation may be due to disruption of somite development during early embryogenesis. In the VBWD chick model, Cd causes abnormal cell death in the somitic region resulting in improperly developed somites and tortuosity of the neural tube. However, the exact molecular mechanisms leading to VBWD still remain unclear. Wnt signaling is crucial during embryogenesis and plays a key role in normal somite formation. The Rho-associated coiled-coil containing protein kinase (ROCK) is involved in the non-canonical Wnt pathway which controls actin cytoskeleton assembly and cell contractility, and contributes to several developmental processes including somitogenesis. ROCK gene expression levels have recently been reported to be significantly decreased in the Cd-induced VBWD chick model. We designed this study to investigate the hypothesis that administration of ROCK inhibitor (Y-27632) in the absence of Cd disrupts somitogenesis and could contribute to the development of VBWD during early embryogenesis.

Methods

After 60 h of incubation chick embryos were transferred from eggs to culture dishes containing 20 μM of Y-27632 for experimental group (Y-27, n = 22) or chick saline for controls (n = 14). Following 24 h in the incubator they were assessed for stage development and gross abnormalities in morphology using the dissecting microscope. Western blot was performed to confirm Y-27632 inhibition of ROCK downstream signaling using an antibody against phosphorylated cofilin-2.

Results

20 (90.9 %) embryos from Y-27 group and all controls were alive at examination. Morphological abnormalities were detected in 14 (70 %) Y-27 embryos. Somites appeared improperly developed, flattened in the cranio-caudal direction, and elongated in transverse direction in relation to controls. Chick embryos in Y-27 also presented with tortuosity of the neural tube in the lumbosacral region. Western blot analysis showed inhibition of cofilin-2 phosphorylation in affected embryos in comparison to controls.

Conclusion

Our study provides evidence that ROCK inhibitor results in the disruption of normal somitogenesis in chick embryos which may contribute to the failure of fusion of the anterior abdominal wall causing VBWD.     

First evaluation of an improved assay for molecular genetic detection of tuberculosis as well as rifampin and isoniazid resistances

The commercially available line probe assay MTBDRplus 2.0 (Hain Lifescience, Nehren, Germany) was evaluated for its ability to detect Mycobacterium tuberculosis complex (MTBC) and mutations conferring resistance to rifampin (RMP) and isoniazid (INH) directly in smear-negative and smear-positive pulmonary clinical specimens under routine laboratory conditions. A total of 348 samples originating from Moldova, a high-incidence country for tuberculosis (TB), were investigated. Two hundred fifty-seven (73.9%) were smear negative, 12 samples were excluded, and 81 (23.3%) were smear positive. Two DNA extraction methods were applied. Compared to culture and clinical data as the reference standard (adapted from Vadwai V et al., J. Clin. Microbiol. 49:2540-2545, 2011), overall sensitivity and specificity were 87.6 and 99.2%, respectively. One hundred four of the 257 smear-negative samples turned out to be culture positive, and 20 were MTBC culture negative but were positive based on clinical symptoms. The combined sensitivity and specificity in the subgroup of smear-negative samples were calculated to be 79.8 and 99.2%, respectively. MTBDRplus 2.0 detected RMP and INH resistance with sensitivity and specificity of 94.3 and 96.0%, respectively. In conclusion, the MTBDRplus 2.0 assay is a rapid and highly sensitive test for the detection of M. tuberculosis strains from smear-positive and -negative clinical specimens and provides additional information on RMP and INH resistance status, which can easily be included in routine laboratory work flow.     

Genome-wide meta-analysis for severe diabetic retinopathy

Diabetic retinopathy is a leading cause of blindness. The purpose of this study is to identify novel genetic loci associated with the sight threatening complications of diabetic retinopathy. We performed a meta-analysis of genome-wide association data for severe diabetic retinopathy as defined by diabetic macular edema or proliferative diabetic retinopathy in unrelated cases ascertained from two large, type I diabetic cohorts: the Genetics of Kidney in Diabetes (GoKinD) and the Epidemiology of Diabetes Intervention and Control Trial (EDIC) studies. Controls were other diabetic subjects in the cohort. A combined total of 2829 subjects (973 cases, 1856 controls) were studied on 2 543 887 single nucleotide polymorphisms (SNPs). Subjects with nephropathy were excluded in a sub-analysis of 281 severe retinopathy cases. We also performed an association analysis of 1390 copy number variations (CNVs) using tag SNPs. No associations were significant at a genome-wide level after correcting for multiple measures. The meta-analysis did identify several associations that can be pursued in future replication studies, including an intergenic SNP, rs476141, on chromosome 1 (P-value 1.2 × 10(-7)). The most interesting signal from the CNV analysis came from the sub-group analysis without nephropathy subjects and is rs10521145 (P-value 3.4 × 10(-6)) in the intron of CCDC101, a histone acetyltransferase. This SNP tags the copy number region CNVR6685.1 on chromosome 16 at 28.5 Mb, a gain/loss site. In summary, this study nominates several novel genetic loci associated with the sight-threatening complications of diabetic retinopathy and anticipates future large-scale consortium-based validation studies.     

Effects of dog ownership and genotype on immune development and atopy in infancy

BACKGROUND: Exposure to furred pets might confer protection against the development of allergic sensitization through a mechanism that is incompletely understood. OBJECTIVE: The objective of this study was to determine the effects of pet exposure and genotype on immunologic development and the incidence of atopic markers and diseases in the first year of life. METHODS: Pet exposure in the home was compared with cytokine secretion patterns (mitogen-stimulated mononuclear cells at birth and age 1 year) and indicators of atopy (allergen-specific and total IgE, eosinophilia, food allergy, atopic dermatitis) in 285 infants. Interactions with genotype at the CD14 locus were also evaluated in the data analyses. RESULTS: Exposure to dogs was associated with reduced allergen sensitization (19% vs 33%, P =.020) and atopic dermatitis (30% vs 51%, P <.001). The risk for atopic dermatitis was further influenced by genotype at the CD14 locus (P =.006), even after adjusting for exposure to dogs (P =.003). Furthermore, infants with the genotype -159TT were less likely to develop atopic dermatitis if they were exposed to a dog (5% vs 43%, P =.04). Last, dog exposure was associated with increased IL-10 (117 vs 79 pg/mL, P =.002) and IL-13 (280 vs 226 pg/mL, P =.013) responses at age 1 year. CONCLUSIONS: Having a dog in infancy is associated with higher IL-10 and IL-13 cytokine secretion profiles and reduced allergic sensitization and atopic dermatitis. These findings suggest that postnatal exposure to dogs can influence immune development in a genotype-specific fashion and thereby attenuate the development of atopy in at-risk children.     

Are common disease susceptibility alleles the same in outbred and founder populations?

Founder populations have been the subjects of complex disease studies because of their decreased genetic heterogeneity, increased linkage disequilibrium and more homogeneous environmental exposures. However, it is possible that disease alleles identified in founder populations may not contribute significantly to susceptibility in outbred populations. In this study we examine the Hutterites, a founder population of European descent, for 103 polymorphisms in 66 genes that are candidates for cardiovascular or inflammatory diseases. We compare the frequencies of alleles at these loci in the Hutterites to their frequencies in outbred European-American populations and test for associations with cardiovascular disease-associated phenotypes in the Hutterites. We show that alleles at these loci are found at similar frequencies in the Hutterites and in outbred populations. In addition, we report associations between 39 alleles or haplotypes and cardiovascular disease phenotypes (P<0.05), with five loci remaining significant after adjusting for multiple comparisons. These data indicate that this founder population is informative and offers considerable advantages for genetic studies of common complex diseases.     

RECON syndrome is a genome instability disorder caused by mutations in the DNA helicase RECQL1

Despite being the first homolog of the bacterial RecQ helicase to be identified in humans, the function of RECQL1 remains poorly characterized. Furthermore, unlike other members of the human RECQ family of helicases, mutations in RECQL1 have not been associated with a genetic disease. Here, we identify 2 families with a genome instability disorder that we have named RECON (RECql ONe) syndrome, caused by biallelic mutations in the RECQL gene. The affected individuals had short stature, progeroid facial features, a hypoplastic nose, xeroderma, and skin photosensitivity and were homozygous for the same missense mutation in RECQL1 (p.Ala459Ser), located within its zinc binding domain. Biochemical analysis of the mutant RECQL1 protein revealed that the p.A459S missense mutation compromised its ATPase, helicase, and fork restoration activity, while its capacity to promote single-strand DNA annealing was largely unaffected. At the cellular level, this mutation in RECQL1 gave rise to a defect in the ability to repair DNA damage induced by exposure to topoisomerase poisons and a failure of DNA replication to progress efficiently in the presence of abortive topoisomerase lesions. Taken together, RECQL1 is the fourth member of the RecQ family of helicases to be associated with a human genome instability disorder.