Diagnostic, Prognostic, and Therapeutic Implications of Genetic Testing for Hypertrophic Cardiomyopathy

Over the last 2 decades, the pathogenic basis for the most common heritable cardiovascular disease, hypertrophic cardiomyopathy (HCM), has been investigated extensively. Affecting approximately 1 in 500 individuals, HCM is the most common cause of sudden death in young athletes. In recent years, genomic medicine has been moving from the bench to the bedside throughout all medical disciplines including cardiology. Now, genomic medicine has entered clinical practice as it pertains to the evaluation and management of patients with HCM. The continuous research and discoveries of new HCM susceptibility genes, the growing amount of data from genotype-phenotype correlation studies, and the introduction of commercially available genetic tests for HCM make it essential that the modern-day cardiologist understand the diagnostic, prognostic, and therapeutic implications of HCM genetic testing

Calibration of a semi-distributed hydrological model using discharge and remote sensing data

The objective of this study is to present an approach to calibrate a semi-distributed hydrological model using observed streamflow data and actual evapotranspiration time series estimates based on remote sensing data. First, daily actual evapotranspiration is estimated using available MODIS satellite data, routinely collected meteorological data, and applying the SEBS algorithm. Second, the semi-distributed hydrological model HBV is calibrated and validated using the estimated evapotranspiration and observed discharge. This is done for multiple sub-basins of the Karkheh River basin in Iran. The Nash-Sutcliffe coefficient (NS) is calculated for each sub-basin. Maximum and minimum NS values for the calibration using observed discharge are 0.81 and 0.23, respectively, and using estimated evapotranspiration 0.61 and 0.46, respectively. The comparison of model simulations with multiple observed variables increases the probability of selecting a parameter set that represents the actual hydrological situation of the basin. The new calibration approach can be useful for further applications, especially in data-sparse river basin

Screening for germline DND1 mutations in testicular cancer patients

Although several observations suggest that a strong genetic predisposition to developing testicular germ cell tumors (TGCT) exists, no associated, highly penetrant germline mutations have been identified so far. In the 129/Sv mouse strain, a germline mutation in the DND1 gene has been shown to strongly increase the TGCT risk. We screened 272 men with TGCT (89% sporadic cases, 11% familial) for germline mutations in the human homologue of DND1. A single nucleotide substitution c.657C > G (p.Asp219Glu) was observed in a non-familial case of testicular embryonal carcinoma. The variant was also present in the patient’s asymptomatic father and two brothers, but not observed in 210 control chromosomes. The wild type DND1 allele was not lost in the patient’s tumor. In silico analysis of the variant predicts it to be non-pathogenic. We conclude that germline DND1 mutations are unlikely to contribute significantly to human testicular germ cell tumor susceptibility. The role of human DND1 in normal physiology and disease, however, is still virtually unknown and it therefore warrants further research

Carbonized blood deposited on fibres during 810, 940 and 1,470 nm endovenous laser ablation: thickness and absorption by optical coherence tomography

Endovenous laser ablation (EVLA) is commonly used to treat saphenous varicosities. Very high temperatures at the laser fibre tip have been reported during EVLA. We hypothesized that the laser irradiation deposits a layer of strongly absorbing carbonized blood of very high temperature on the fibre tip. We sought to prove the existence of these layers and study their properties by optical transmission, optical coherence tomography (OCT) and microscopy. We analysed 23 EVLA fibres, 8 used at 810 nm, 7 at 940 nm and 8 at 1,470 nm. We measured the transmission of these fibres in two wavelength bands (450–950 nm; 950–1,650 nm). We used 1,310 nm OCT to assess the thickness of the layers and the attenuation as a function of depth to determine the absorption coefficient. Microscopy was used to view the tip surface. All fibres showed a slightly increasing transmission with wavelength in the 450–950 nm band, and a virtually wavelength-independent transmission in the 950–1,650 nm band. OCT scans showed a thin layer deposited on all 13 fibres investigated, 6 used at 810 nm, 4 at 940 nm and 3 at 1,470 nm, some with inhomogeneities over the tip area. The average absorption coefficient of the 13 layers was 72 ± 16 mm−1. The average layer thickness estimated from the transmission and absorption measurements was 8.0 ± 2.7 µm. From the OCT data, the average maximal thickness was 26 ± 6 µm. Microscopy of three fibre tips, one for each EVLA wavelength, showed rough, cracked and sometimes seriously damaged tip surfaces. There was no clear correlation between the properties of the layers and the EVLA parameters such as wavelength, except for a positive correlation between layer thickness and total delivered energy. In conclusion, we found strong evidence that all EVLA procedures in blood filled veins deposit a heavily absorbing hot layer of carbonized blood on the fibre tip, with concomitant tip damage. This major EVLA mechanism is unlikely to have much wavelength dependence at similar delivered energies per centimetre of vein. Optical–thermal interaction between the vein wall and the transmitted laser light depends on wavelength

Source Coding Optimization for Distributed Average Consensus

Consensus is a common method for computing a function of the data distributed among the nodes of a network. Of particular interest is distributed average consensus, whereby the nodes iteratively compute the sample average of the data stored at all the nodes of the network using only near-neighbor communications. In real-world scenarios, these communications must undergo quantization, which introduces distortion to the internode messages. In this thesis, a model for the evolution of the network state statistics at each iteration is developed under the assumptions of Gaussian data and additive quantization error. It is shown that minimization of the communication load in terms of aggregate source coding rate can be posed as a generalized geometric program, for which an equivalent convex optimization can efficiently solve for the global minimum. Optimization procedures are developed for rate-distortion-optimal vector quantization, uniform entropy-coded scalar quantization, and fixed-rate uniform quantization. Numerical results demonstrate the performance of these approaches. For small numbers of iterations, the fixed-rate optimizations are verified using exhaustive search. Comparison to the prior art suggests competitive performance under certain circumstances but strongly motivates the incorporation of more sophisticated coding strategies, such as differential, predictive, or Wyner-Ziv coding.Comment: Master's Thesis, Electrical Engineering, North Carolina State Universit

Modeling Phenotypic Heterogeneity of Glycogen Storage Disease Type 1a Liver Disease in Mice by Somatic CRISPR/CRISPR-associated protein 9-Mediated Gene Editing

BACKGROUND AND AIMS: Patients with glycogen storage disease type 1a (GSD‐1a) primarily present with life‐threatening hypoglycemia and display severe liver disease characterized by hepatomegaly. Despite strict dietary management, long‐term complications still occur, such as liver tumor development. Variations in residual glucose‐6‐phosphatase (G6PC1) activity likely contribute to phenotypic heterogeneity in biochemical symptoms and complications between patients. However, lack of insight into the relationship between G6PC1 activity and symptoms/complications and poor understanding of the underlying disease mechanisms pose major challenges to provide optimal health care and quality of life for GSD‐1a patients. Currently available GSD‐1a animal models are not suitable to systematically investigate the relationship between hepatic G6PC activity and phenotypic heterogeneity or the contribution of gene‐gene interactions (GGIs) in the liver. APPROACH AND RESULTS: To meet these needs, we generated and characterized a hepatocyte‐specific GSD‐1a mouse model using somatic CRISPR/CRISPR‐associated protein 9 (Cas9)–mediated gene editing. Hepatic G6pc editing reduced hepatic G6PC activity up to 98% and resulted in failure to thrive, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly, hepatic steatosis (HS), and increased liver tumor incidence. This approach was furthermore successful in simultaneously modulating hepatic G6PC and carbohydrate response element‐binding protein, a transcription factor that is activated in GSD‐1a and protects against HS under these conditions. Importantly, it also allowed for the modeling of a spectrum of GSD‐1a phenotypes in terms of hepatic G6PC activity, fasting hypoglycemia, hypertriglyceridemia, hepatomegaly and HS. CONCLUSIONS: In conclusion, we show that somatic CRISPR/Cas9‐mediated gene editing allows for the modeling of a spectrum of hepatocyte‐borne GSD‐1a disease symptoms in mice and to efficiently study GGIs in the liver. This approach opens perspectives for translational research and will likely contribute to personalized treatments for GSD‐1a and other genetic liver diseases

Heritability in genetic heart disease : the role of genetic background

Background Mutations in genes encoding ion channels or sarcomeric proteins are an important cause of hereditary cardiac disease. However, the severity of the resultant disease varies considerably even among those with an identical mutation. Such clinical variation is often thought to be explained largely by differences in genetic background or ` modifier genes'. We aimed to test the prediction that identical genetic backgrounds result in largely similar clinical expression of a cardiac disease causing mutation, by studying the clinical expression of mutations causing cardiac disease in monozygotic twins. Methods We compared first available clinical information on 46 monozygotic twin pairs and 59 control pairs that had either a hereditary cardiomyopathy or channelopathy. Results Despite limited power of this study, we found significant heritability for corrected QT interval (QTc) in long QT syndrome (LQTS). We could not detect significant heritability for structural traits, but found a significant environmental effect on thickness of the interventricular septum in hypertrophic cardiomyopathy. Conclusions Our study confirms previously found robust heritability for electrical traits like QTc in LQTS, and adds information on low or lacking heritability for structural traits in heritable cardiomyopathies. This may steer the search for genetic modifiers in heritable cardiac disease.Peer reviewe

The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity

Direct interaction between the catalytic domain of Epac1 and the nuclear pore component RanBP2 blocks Epac1 catalytic activity and downstream cAMP signaling

Interprofessional Consensus Regarding Design Requirements for Liquid-Based Perinatal Life Support (PLS) Technology

Liquid-based perinatal life support (PLS) technology will probably be applied in a first-in-human study within the next decade. Research and development of PLS technology should not only address technical issues, but also consider socio-ethical and legal aspects, its application area, and the corresponding design implications. This paper represents the consensus opinion of a group of healthcare professionals, designers, ethicists, researchers and patient representatives, who have expertise in tertiary obstetric and neonatal care, bio-ethics, experimental perinatal animal models for physiologic research, biomedical modeling, monitoring, and design. The aim of this paper is to provide a framework for research and development of PLS technology. These requirements are considering the possible respective user perspectives, with the aim to co-create a PLS system that facilitates physiological growth and development for extremely preterm born infants