Cardiac Catheterization in Congenital Heart Disease

Interventional pediatric cardiology is a specialty of pediatric cardiology that deals specifically with the catheter-based treatment of congenital heart diseases. Cardiac catheterization involves the evaluation and manipulation of the heart and surrounding vessels through catheters place in peripheral vessels. In this chapter we begin by discussing the significant difference between adult and pediatric interventional cardiology. We will discuss basic hemodynamic measurements performed in cardiac catheterization and its application to congenital heart disease. Stent and balloon catheters are briefly discussed. Finally, specific catheter based interventional techniques, indications, and complications for various pediatric congenital heart disease is described

Systems Analysis of Chaperone Networks in the Malarial Parasite Plasmodium falciparum

Molecular chaperones participate in the maintenance of cellular protein homeostasis, cell growth and differentiation, signal transduction, and development. Although a vast body of information is available regarding individual chaperones, few studies have attempted a systems level analysis of chaperone function. In this paper, we have constructed a chaperone interaction network for the malarial parasite, Plasmodium falciparum. P. falciparum is responsible for several million deaths every year, and understanding the biology of the parasite is a top priority. The parasite regularly experiences heat shock as part of its life cycle, and chaperones have often been implicated in parasite survival and growth. To better understand the participation of chaperones in cellular processes, we created a parasite chaperone network by combining experimental interactome data with in silico analysis. We used interolog mapping to predict protein–protein interactions for parasite chaperones based on the interactions of corresponding human chaperones. This data was then combined with information derived from existing high-throughput yeast two-hybrid assays. Analysis of the network reveals the broad range of functions regulated by chaperones. The network predicts involvement of chaperones in chromatin remodeling, protein trafficking, and cytoadherence. Importantly, it allows us to make predictions regarding the functions of hypothetical proteins based on their interactions. It allows us to make specific predictions about Hsp70–Hsp40 interactions in the parasite and assign functions to members of the Hsp90 and Hsp100 families. Analysis of the network provides a rational basis for the anti-malarial activity of geldanamycin, a well-known Hsp90 inhibitor. Finally, analysis of the network provides a theoretical basis for further experiments designed toward understanding the involvement of this important class of molecules in parasite biology

Factors associated with safe early discharge after transcatheter aortic valve implantation

  Background: As transcatheter aortic valve implantation (TAVI) becomes more straightforward, a larger proportion of patients will be well enough to be discharged early. This study sought to charac­terise the clinical features that allowed patients to be discharged early after TAVI and to evaluate the safety of an early discharge policy. Methods: All patients undergoing TAVI at the above cited center from August 2007 to March 2015 were included in this study. Baseline characteristics, in-hospital outcomes, re-admissions and mortality were compared. Results: Three hundred thirty-seven TAVIs were performed during the study period, and 18 died in-hospital (18/337, 5.3%). Of the remaining patients, 56 were discharged within 3 days of the index procedure (‘early discharge group’ 56/319, 17.5%). There was no difference between the early discharge and late discharge group in terms of Valve Academic Research Consortium-2 (VARC-2) criteria out­comes, all-cause re-admission rates and the need for permanent pacemaker implantation. Mortality at 1 year was better among the early discharge group (3.6% vs. 15.6%, p = 0.014); a reflection of baseline clinical differences. Conclusion: Early discharge of clinically selected TAVI patients is safe and appropriate. Lower logistic EuroSCORE, smaller delta creatinine and not developing any complications are factors associated with early discharge. (Cardiol J 2018; 25, 1: 14–23

Hospital admission with non-alcoholic fatty liver disease is associated with increased all-cause mortality independent of cardiovascular risk factors

Non-alcoholic fatty liver disease (NAFLD) is common and strongly associated with the metabolic syndrome. Though NAFLD may progress to end-stage liver disease, the top cause of mortality in NAFLD is cardiovascular disease (CVD). Most of the data on liver-related mortality in NAFLD derives from specialist liver centres. It is not clear if the higher reported mortality rates in individuals with non-cirrhotic NAFLD are entirely accounted for by complications of atherosclerosis and diabetes. Therefore, we aimed to describe the CVD burden and mortality in NAFLD when adjusting for metabolic risk factors using a ‘real world’ cohort. We performed a retrospective study of patients followed-up after an admission to non-specialist hospitals with a NAFLD-spectrum diagnosis. Non-cirrhotic NAFLD and NAFLD-cirrhosis patients were defined by ICD-10 codes. Cases were age-/sex-matched with non-NAFLD hospitalised patients. All-cause mortality over 14-years follow-up after discharge was compared between groups using Cox proportional hazard models adjusted for demographics, CVD, and metabolic syndrome components. We identified 1,802 patients with NAFLD-diagnoses: 1,091 with non-cirrhotic NAFLD and 711 with NAFLD-cirrhosis, matched to 24,737 controls. There was an increasing burden of CVD with progression of NAFLD: for congestive heart failure 3.5% control, 4.2% non-cirrhotic NAFLD, 6.6% NAFLD-cirrhosis; and for atrial fibrillation 4.7% control, 5.9% non-cirrhotic NAFLD, 12.1% NAFLD-cirrhosis. Over 14-years follow-up, crude mortality rates were 14.7% control, 13.7% non-cirrhotic NAFLD, and 40.5% NAFLD-cirrhosis. However, after adjusting for demographics, non-cirrhotic NAFLD (HR 1.3 (95% CI 1.1–1.5)) as well as NAFLD-cirrhosis (HR 3.7 (95% CI 3.0–4.5)) patients had higher mortality compared to controls. These differences remained after adjusting for CVD and metabolic syndrome components: non-cirrhotic NAFLD (HR 1.2 (95% CI 1.0–1.4)) and NAFLD-cirrhosis (HR 3.4 (95% CI 2.8–4.2)). In conclusion, from a large non-specialist registry of hospitalised patients, those with non-cirrhotic NAFLD had increased overall mortality compared to controls even after adjusting for CVD

Complete genome sequence of Vibrio gazogenes PB1: an estuarine bacterium capable of producing prodigiosin from starch or cellulose

Vibrio is a genus of gram-negative, rod-shaped, motile bacteria commonly found in saltwater. One species in particular, Vibrio gazogenes PB1, sourced from an estuarine environment, is known to produce the secondary metabolite, prodigiosin. This high-value compound has potential uses as an antibiotic, a fungicide, and an anti-cancer agent. To further explore its metabolic and genetic features for biotechnological purposes, the complete genome sequence of V. gazogenes PB1 was determined by Illumina and Pacbio sequencing. Two chromosomes were assembled with a mean coverage of 293x. Chromosome 1 is 3.5 Mbp in size with 45.3% GC content and chromosome 2 is 1.2 Mbp in size with 45.1% GC content. The entire genome harbours 4178 genes, of which 3988 are protein-coding and 114 are RNA-coding. A total of 55 virulence-related genes, 38 antimicrobial resistance genes, 48 transposase sequences, 2 intact prophage regions, and 10 genomic islands were present within the genome. Six genes associated with the degradation of cellulose and starch were also identified within the genome. Four of them were strongly up-regulated, as confirmed by RT-qPCR, thus providing strong evidence for their involvement in starch and cellulose degradation. Quite importantly, we demonstrate for the first time that starch and cellulose is associated with the synthesis of prodigiosin in a native prodigiosin-producing bacterium. The prodigiosin titres obtained in the presence of cellulose were on par with glucose as the carbon source which lends further support in the use of V. gazogenes PB1 as a biotechnological host for prodigiosin production

Reconfiguration of the proteasome during chaperone-mediated assembly

The proteasomal ATPase ring, comprising Rpt1-Rpt6, associates with the heptameric α ring of the proteasome core particle (CP) in the mature proteasome, with the Rpt C-terminal tails inserting into pockets of the α ring1–4. Rpt ring assembly is mediated by four chaperones, each binding a distinct Rpt subunit5–10. We report that the base subassembly of the proteasome, which includes the Rpt ring, forms a high affinity complex with the CP. This complex is subject to active dissociation by the chaperones Hsm3, Nas6, and Rpn14. Chaperone-mediated dissociation was abrogated by a nonhydrolyzable ATP analog, indicating that chaperone action is coupled to nucleotide hydrolysis by the Rpt ring. Unexpectedly, synthetic Rpt tail peptides bound α pockets with poor specificity, except for Rpt6, which uniquely bound the α2/α3 pocket. Although the Rpt6 tail is not visualized within an α pocket in mature proteasomes2–4, it inserts into the α2/α3 pocket in the base-CP complex and is important for complex formation. Thus, the Rpt-CP interface is reconfigured when the lid complex joins the nascent proteasome to form the mature holoenzyme

Refinement Reflection:Complete Verification with SMT

We introduce Refinement Reflection, a new framework for building SMT-based deductive verifiers. The key idea is to reflect the code implementing a user-defined function into the function's (output) refinement type. As a consequence, at uses of the function, the function definition is instantiated in the SMT logic in a precise fashion that permits decidable verification. Reflection allows the user to write equational proofs of programs just by writing other programs using pattern-matching and recursion to perform case-splitting and induction. Thus, via the propositions-as-types principle, we show that reflection permits the specification of arbitrary functional correctness properties. Finally, we introduce a proof-search algorithm called Proof by Logical Evaluation that uses techniques from model checking and abstract interpretation, to completely automate equational reasoning. We have implemented reflection in Liquid Haskell and used it to verify that the widely used instances of the Monoid, Applicative, Functor, and Monad typeclasses actually satisfy key algebraic laws required to make the clients safe, and have used reflection to build the first library that actually verifies assumptions about associativity and ordering that are crucial for safe deterministic parallelism.Comment: 29 pages plus appendices, to appear in POPL 2018. arXiv admin note: text overlap with arXiv:1610.0464

Molecular landscape of the ribosome pre-initiation complex during mRNA scanning: structural role for eIF3c and its control by eIF5

During eukaryotic translation initiation, eIF3 binds the solvent-accessible side of the 40S ribosome and recruits the gate-keeper protein eIF1 and eIF5 to the decoding center. This is largely mediated by the N-terminal domain (NTD) of eIF3c, which can be divided into three parts: 3c0, 3c1 and 3c2. The N-terminal part, 3c0, binds eIF5 strongly, but only weakly to the ribosome-binding surface of eIF1, whereas 3c1 and 3c2 form a stoichiometric complex with eIF1. 3c1 contacts eIF1 through Arg-53 and Leu-96, while 3c2 faces 40S protein uS15/S13, to anchor eIF1 to the scanning pre-initiation complex (PIC). We propose that the 3c0:eIF1 interaction diminishes eIF1 binding to the 40S, whereas 3c0:eIF5 interaction stabilizes the scanning PIC by precluding this inhibitory interaction. Upon start codon recognition, interactions involving eIF5, and ultimately 3c0:eIF1 association facilitate eIF1 release. Our results reveal intricate molecular interactions within the PIC, programmed for rapid scanning-arrest at the start codon

Study of water supply & sanitation practices in India using geographic information systems: some design & other considerations in a village setting

Background & objectives: Availability of clean water and adequate sanitation facilities are of prime importance for limiting diarrhoeal diseases. We examined the water and sanitation facilities of a village in southern India using geographic information system (GIS) tools. Methods: Places of residence, water storage and distribution, sewage and places where people in the village defaecated were mapped and drinking water sources were tested for microbial contamination in Nelvoy village, Vellore district, Tamil Nadu. Results: Water in the village was found to be microbiologically unfit for consumption. Analysis using direct observations supplemented by GIS maps revealed poor planning, poor engineering design and lack of policing of the water distribution system causing possible contamination of drinking water from sewage at multiple sites. Interpretation & conclusions: Until appropriate engineering designs for water supply and sewage disposal to suit individual village needs are made available, point-of-use water disinfection methods could serve as an interim solution