Niemann-Pick type C (NP-C) disease is a fatal lysosomal lipid storage disorder for which no effective therapy exists. A genome-wide, conditional synthetic lethality screen was performed using the yeast model of NP-C disease during anaerobiosis, an auxotrophic condition that requires yeast to utilize exogenous sterol. We identified 12 pathways and 13 genes as modifiers of the absence of the yeast NPC1 ortholog (NCR1) and quantified the impact of loss of these genes on sterol metabolism in ncr1⌬ strains grown under viable aerobic conditions. Deletion of components of the yeast NuA4 histone acetyltransferase complex in ncr1⌬ strains conferred anaerobic inviability and accumulation of multiple sterol intermediates. Thus, we hypothesize an imbalance in histone acetylation in human NP-C disease. Accordingly, we show that the majority of the 11 histone deacetylase (HDAC) genes are transcriptionally up-regulated in three genetically distinct fibroblast lines derived from patients with NP-C disease. A clinically approved HDAC inhibitor (suberoylanilide hydroxamic acid) reverses the dysregulation of the majority of the HDAC genes. Consequently, three key cellular diagnostic criteria of NP-C disease are dramatically ameliorated as follows: lysosomal accumulation of both cholesterol and sphingolipids and defective esterification of LDL-derived cholesterol. These data suggest HDAC inhibition as a candidate therapy for NP-C disease. We conclude that pathways that exacerbate lethality in a model organism can be reversed in human cells as a novel therapeutic strategy. This "exacerbatereverse" approach can potentially be utilized in any model organism for any disease.

Retrospective clinical and dosimetric data from diagnostic catheterisations (DXC) and CTO-PCI procedures performed on one of three variants of interventional fluoroscopic equipment were collected. Fluoroscopic time, air kerma, kerma area product and contrast utilisation were stratified by procedure type and compared among equipment types. To standardise comparisons among equipment configurations, an efficiency index (EI) was calculated. In total, 2,947 DXC and 276 CTO-PCI procedures were studied. For DXC, radiation dose (AK) decreased by 45% (despite modest increases in fluoroscopic time [FT]) between the reference (REF) and moderately dose-optimised (ECO) machines. A further 20% decrease in AK was observed on the highly dose-optimised machine (CLA). For CTO-PCI, AK declined by almost half (48%), despite a 76% increase in FT and higher procedural success rates (69.8% versus 83.0%) between REF and CLA. • Conclusions: Novel dose-optimised fluoroscopic equipment allows longer FT with a decrease in radiation dose to both patient and operator. This should allow operators to undertake increasingly longer and more complex procedures and reduce operators' lifetime irradiation.

Introduction of the PC reduced both hyperaemic FFR and resting Pd/Pa compared with the PW alone, leading to re-classifying physiological significance to below the clinical threshold in one out of five assessments.

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