Evaluation of Genetic Causes of Cardiomyopathy in Childhood

Cardiomyopathy frequently has a genetic basis. In adults, mutations in genes encoding components of the sarcomere, cytoskeleton, or desmosome are frequent genetic causes of cardiomyopathy. Although children share these causes, ~30% of children have an underlying metabolic, syndromic, or neuromuscular condition causing their cardiomyopathy, making the aetiologies more diverse in children as compared with adults. Although some children present with obvious signs or symptoms of metabolic, syndromic, or neuromuscular disease, other cases may be quite subtle, requiring a high level of suspicion in order to diagnose them. In general, the younger the child, the more extensive the differential. Advantages of identifying the underlying genetic cause of cardiomyopathy in the paediatric population include confirming the diagnosis in ambiguous cases, facilitating appropriate surveillance and management of cardiac and extra-cardiac diseases, providing prognostic information, and establishing the genetic basis in the family, thereby allowing the identification of at-risk relatives and institution of appropriate family screening as indicated. For these reasons, genetic testing is increasingly recognised as standard of care, and guidelines for genetic counselling, testing, and incorporation of family-based risk assessment have been established. Therapies aimed at treating specific genetic aetiologies of cardiomyopathy are emerging and are exciting new developments that require increasingly sophisticated approaches to diagnosis. As genetic testing capabilities continue to expand technically, careful interpretation, knowledgeable clinical utilisation, and appropriate dissemination of genetic information are important and challenging components of clinical care

Interactions between the endocrine and immune systems in locusts

The prophenoloxidase cascade in the haemolymph of mature adult Locusta migratoria migratorioides (R & F) is activated in response to injection of laminarin, a -1,3 glucan. Co-injection of adipokinetic hormone-I (Lom-AKH-I) and laminarin prolongs the activation of the enzyme in a dose-dependent manner. However, injections of bacterial lipopolysaccharide (LPS) do not activate prophenoloxidase unless AKH is co-injected, when there is a dose-dependent increase in the level of phenoloxidase that persists in the haemolymph for several hours. Even when AKH is co-injected, the highest levels of phenoloxidase activity are always greater after injection of laminarin than after LPS, and these two immunogens must activate the prophenoloxidase cascade by quite distinct pathways. In the present study, interactions between the endocrine and immune systems were examined with respect to activation of prophenoloxidase and the formation of nodules: injection of LPS induces nodule formation in adult locusts. With LPS from Pseudomonas aeruginosa, nodules form exclusively in dense accumulations in the anterior portion of the abdomen on either side of the dorsal blood vessel associated with the dorsal diaphragm. However, with LPS from Escherichia coli, fewer nodules are formed but with a similar distribution, except that occasionally some nodules are aligned additionally on either side of the ventral nerve cord. Co-injection of Lom-AKH-I with LPS from either bacteria stimulates greater numbers of nodules to be formed. This effect of coinjection of AKH on nodule formation is seen at low doses of hormone with only 0.3 or 0.4 pmol of Lom-AKH-1, respectively, increasing the number of nodules by 50%. Injections of octopamine or 5-hydroxytryptamine do not mimic either of the actions of Lom-AKH-I described here. Co-injection of an angiotensin-converting enzyme inhibitor, captopril, reduces nodule formation in response to injections of LPS but has no effect on the activation of phenoloxidase. Co-injection of an inhibitor of eicosanoid synthesis, dexamethasone, with LPS influences nodule formation (with or without AKH) in different ways according to the dose of dexamethasone used, but does not affect activation of prophenoloxidase. Eicosanoid synthesis is important for nodule formation, but not for the activation of the prophenoloxidase cascade in locust haemolymph

Exploring Causal Influences

Recent data mining techniques exploit patterns of statistical independence in multivariate data to make conjectures about cause/effect relationships. These relationships can be used to construct causal graphs, which are sometimes represented by weighted node-link diagrams, with nodes representing variables and combinations of weighted links and/or nodes showing the strength of causal relationships. We present an interactive visualization for causal graphs (ICGs), inspired in part by the Influence Explorer. The key principles of this visualization are as follows: Variables are represented with vertical bars attached to nodes in a graph. Direct manipulation of variables is achieved by sliding a variable value up and down, which reveals causality by producing instantaneous change in causally and/or probabilistically linked variables. This direct manipulation technique gives users the impression they are causally influencing the variables linked to the one they are manipulating. In this context, we demonstrate the subtle distinction between seeing and setting of variable values, and in an extended example, show how this visualization can help a user understand the relationships in a large variable set, and with some intuitions about the domain and a few basic concepts, quickly detect bugs in causal models constructed from these data mining techniques

Subunit interactions influence the biochemical and biological properties of Hsp104

Point mutations in either of the two nucleotide-binding domains (NBD) of Hsp104 (NBD1 and NBD2) eliminate its thermotolerance function in vivo. In vitro, NBD1 mutations virtually eliminate ATP hydrolysis with little effect on hexamerization; analogous NBD2 mutations reduce ATPase activity and severely impair hexamerization. We report that high protein concentrations overcome the assembly defects of NBD2 mutants and increase ATP hydrolysis severalfold, changing V(max) with little effect on K(m). In a complementary fashion, the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate inhibits hexamerization of wild-type (WT) Hsp104, lowering V(max) with little effect on K(m). ATP hydrolysis exhibits a Hill coefficient between 1.5 and 2, indicating that it is influenced by cooperative subunit interactions. To further analyze the effects of subunit interactions on Hsp104, we assessed the effects of mutant Hsp104 proteins on WT Hsp104 activities. An NBD1 mutant that hexamerizes but does not hydrolyze ATP reduces the ATPase activity of WT Hsp104 in vitro. In vivo, this mutant is not toxic but specifically inhibits the thermotolerance function of WT Hsp104. Thus, interactions between subunits influence the ATPase activity of Hsp104, play a vital role in its biological functions, and provide a mechanism for conditionally inactivating Hsp104 function in vivo

Subsonic aerodynamic characteristics of a proposed advanced manned launch system orbiter configuration

The Advanced Manned Launch System is a proposed near-term technology, two-stage, fully reusable launch system that consists of an unmanned glide-back booster and a manned orbiter. An orbiter model that featured a large fuselage and an aft delta wing with tip fins was tested in the Langley 7- by 10-Foot High-Speed Tunnel. A crew cabin, large payload fairing, and crew access tunnel were mounted on the upper body. The results of the investigation indicated that the configuration was longitudinally stable to an angle of attack of about 6 deg about a center-of-gravity position of 0.7 body length. The model had an untrimmed lift-drag ratio of 6.6, but could not be trimmed at positive lift. The orbiter model was also directionally unstable. The payload fairing was responsible for about half the instability. The tip-fin controllers, which are designed as active controls to produce artificial directional stability, were effective in producing yawing moment, but sizable adverse rolling moment occurred at angles of attack above 6 deg. Differential deflection of the elevon surfaces was effective in producing rolling moment with only small values of adverse yawing moment

A study of local and non-local spatial densities in quantum field theory

We use a one-dimensional model system to compare the predictions of two different 'yardsticks' to compute the position of a particle from its quantum field theoretical state. Based on the first yardstick (defined by the Newton-Wigner position operator), the spatial density can be arbitrarily narrow and its time-evolution is superluminal for short time intervals. Furthermore, two spatially distant particles might be able to interact with each other outside the light cone, which is manifested by an asymmetric spreading of the spatial density. The second yardstick (defined by the quantum field operator) does not permit localized states and the time evolution is subluminal.Comment: 29 pages, 3 figure

Toward Personalized Medicine: Does Genetic Diagnosis of Pediatric Cardiomyopathy Influence Patient Management?

A goal of personalized medicine is to provide increasingly sophisticated, individualized approaches to management and therapy for disease. Genetics is the engine that drives personalized medicine, holding the promise of therapeutics directed toward the unique needs of each patient. The 3(rd) International Conference on Cardiomyopathy in Children provided a forum to discuss the current status of personalized approaches to diagnosis, management, and therapy in the pediatric cardiomyopathy population. This review will focus on the importance of genetic diagnosis in this population as a necessary first step toward understanding the best approach to management and influencing disease outcome. The genetic heterogeneity of cardiomyopathy in children, the implications of specific genotypes, the ability to risk stratify based on genotype, and the impact on cascade screening in family members will be discussed

Genetic and Developmental Basis of Cardiovascular Malformations

Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1% to 5% of all live births. Genetic, epigenetic, and environmental factors all influence the development of CVMs, and an improved understanding of the causation of CVMs is a prerequisite for prevention. Cardiac development is a complex, multistep process of morphogenesis that is under genetic regulation. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are still identified infrequently. This article discusses the key genetic concepts characterizing human CVMs, their developmental basis, and the critical developmental and genetic concepts underlying their pathogenesis