Hepatic steatosis does not cause insulin resistance in people with familial hypobetalipoproteinaemia

Item does not contain fulltextAIMS/HYPOTHESIS: Hepatic steatosis is strongly associated with hepatic and whole-body insulin resistance. It has proved difficult to determine whether hepatic steatosis itself is a direct cause of insulin resistance. In patients with familial hypobetalipoproteinaemia (FHBL), hepatic steatosis is a direct consequence of impaired hepatic VLDL excretion, independently of metabolic derangements. Thus, patients with FHBL provide a unique opportunity to investigate the relation between increased liver fat and insulin sensitivity. METHODS: We included seven male participants with FHBL and seven healthy matched controls. Intrahepatic triacylglycerol content and intramyocellular lipid content were measured using localised proton magnetic resonance spectroscopy ((1)H-MRS). A two-step hyperinsulinaemic-euglycaemic clamp, using stable isotopes, was assessed to determine hepatic and peripheral insulin sensitivity. RESULTS: (1)H-MRS showed moderate to severe hepatic steatosis in patients with FHBL. Basal endogenous glucose production (EGP) and glucose levels did not differ between the two groups, whereas insulin levels tended to be higher in patients compared with controls. Insulin-mediated suppression of EGP during lower dose insulin infusion and insulin-mediated peripheral glucose uptake during higher dose insulin infusion were comparable between FHBL participants and controls. Baseline fatty acids and lipolysis (glycerol turnover) at baseline and during the clamp did not differ between groups. CONCLUSIONS/INTERPRETATION: In spite of moderate to severe hepatic steatosis, people with FHBL do not display a reduction in hepatic or peripheral insulin sensitivity compared with healthy matched controls. These results indicate that hepatic steatosis per se is not a causal factor leading to insulin resistance. TRIAL REGISTRATION: ISRCTN35161775

Biomarkers of angiogenesis and their role in the development of VEGF inhibitors

Vascular endothelial growth factor (VEGF) has been confirmed as an important therapeutic target in randomised clinical trials in multiple disease settings. However, the extent to which individual patients benefit from VEGF inhibitors is unclear. If we are to optimise the use of these drugs or develop combination regimens that build on this efficacy, it is critical to identify those patients who are likely to benefit, particularly as these agents can be toxic and are expensive. To this end, biomarkers have been evaluated in tissue, in circulation and by imaging. Consistent drug-induced increases in plasma VEGF-A and blood pressure, as well as reductions in soluble VEGF-R2 and dynamic contrast-enhanced MRI parameters have been reported. In some clinical trials, biomarker changes were statistically significant and associated with clinical end points, but there is considerable heterogeneity between studies that are to some extent attributable to methodological issues. On the basis of observations with these biomarkers, it is now appropriate to conduct detailed prospective studies to define a suite of predictive, pharmacodynamic and surrogate response biomarkers that identify those patients most likely to benefit from and monitor their response to this novel class of drugs

Optimization of dual-saturation single bolus acquisition for quantitative cardiac perfusion and myocardial blood flow maps

BACKGROUND: In-vivo quantification of cardiac perfusion is of great research and clinical value. The dual-bolus strategy is universally used in clinical protocols but has known limitations. The dual-saturation acquisition strategy has been proposed as a more accurate alternative, but has not been validated across the wide range of perfusion rates encountered clinically. Dual-saturation acquisition also lacks a clinically-applicable procedure for optimizing parameter selection. Here we present a comprehensive validation study of dual-saturation strategy in vitro and in vivo. METHODS: The impact of saturation time and profile ordering in acquisitions was systematically analyzed in a phantom consisting of 15 tubes containing different concentrations of contrast agent. In-vivo experiments in healthy pigs were conducted to evaluate the effect of R2* on the definition of the arterial input function (AIF) and to evaluate the relationship between R2* and R1 variations during first-pass of the contrast agent. Quantification by dual-saturation perfusion was compared with the reference-standard dual-bolus strategy in 11 pigs with different grades of myocardial perfusion. RESULTS: Adequate flow estimation by the dual-saturation strategy is achieved with myocardial tissue saturation times around 100 ms (always <30 ms of AIF), with the lowest echo time, and following a signal model for contrast conversion that takes into account the residual R2* effect and profile ordering. There was a good correlation and agreement between myocardial perfusion quantitation by dual-saturation and dual-bolus techniques (R(2) = 0.92, mean difference of 0.1 ml/min/g; myocardial perfusion ranges between 0.18 and 3.93 ml/min/g). CONCLUSIONS: The dual-saturation acquisition strategy produces accurate estimates of absolute myocardial perfusion in vivo. The procedure presented here can be applied with minimal interference in standard clinical procedures

Incorporating radiomics into clinical trials: expert consensus on considerations for data-driven compared to biologically-driven quantitative biomarkers

Existing Quantitative Imaging Biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials

Analysis of the beam decomposition problem in Signal Based Ray Tracing

In the context of an airship development programme, inviscid flow behavior and its coupling with structure flexibility are investigated. For this purpose, we have chosen a nonlinear analysis tool relying on the unsteady Euler model for the flow part and the classical elastodynamic equations for the structure. The numerical model for the flow is based on a Mixed Element Volume discretization derived in an Arbitrary-Lagrangian- Eulerian framework in order to cope with the structural deformations. The case of low- Mach flows (natural flight regime for an airship) can be handled by a special dissipation preconditioner which improves the accuracy of the flow simulation. The structural model, coupled to the flow solver, is discretized by the finite element method in a Lagrangian formulation. In this work we have performed a series of inviscid flow calculations with the goal to evaluate accurately the global aerodynamical coefficients. We first compare the influence of different stiffeners in the airship structural model for flows with zero and nonzero (20º) angle of attack. Then, we study the influence of the numerical dissipation and of the low-Mach preconditioning. We observe -as expected- the stabilizing effect of the stiffeners, specially longitudinal ones. The positive impact of low Mach preconditioning and numerical dissipation on the results is also evaluated

Continuous Flow-Driven Inversion for Arterial Spin Labeling Using Pulsed Radio Frequency and Gradient Fields

Continuous labeling by flow driven adiabatic inversion is advantageous for arterial spin labeling (ASL) perfusion studies, but details of the implementation, including inefficiency, magnetization transfer, and limited support for continuous-mode operation on clinical scanners has restricted the benefits of this approach. Here a new approach to continuous labeling that employs rapidly repeated gradient and RF pulses to achieve continuous labeling with high efficiency is characterized. The theoretical underpinnings, numerical simulations, and in-vivo implementation of this pulsed continuous ASL (PCASL) are described. In-vivo PCASL labeling efficiency of 96% relative to continuous labeling with comparable labeling parameters far exceeded the 33% duty cycle of the PCASL RF pulses. Imaging at 3 Tesla with body coil transmission was readily achieved. This technique should help to realize the benefits of continuous labeling in clinical imagers

Reducing Radiation Dose at Chest CT: Comparison Among Model-based Type Iterative Reconstruction, Hybrid Iterative Reconstruction, and Filtered Back Projection.

The study aimed to evaluate the performances of two iterative reconstruction (IR) algorithms and of filtered back projection (FBP) when using reduced-dose chest computed tomography (RDCT) compared to standard-of-care CT. An institutional review board approval was obtained. Thirty-six patients with hematologic malignancies referred for a control chest CT of a known lung disease were prospectively enrolled. Patients underwent standard-of-care scan reconstructed with hybrid IR, followed by an RDCT reconstructed with FBP, hybrid IR, and iterative model reconstruction. Objective and subjective quality measurements, lesion detectability, and evolution assessment on RDCT were recorded. For RDCT, the CTDIvol (volumetric computed tomography dose index) was 0.43 mGy⋅cm for all patients, and the median [interquartile range] effective dose was 0.22 mSv [0.22-0.24]; corresponding measurements for standard-of-care scan were 3.4 mGy [3.1-3.9] and 1.8 mSv [1.6-2.0]. Noise significantly decreased from FBP to hybrid IR and from hybrid IR to iterative model reconstruction on RDCT, whereas lesion conspicuity and diagnostic confidence increased. Accurate evolution assessment was obtained in all cases with IR. Emphysema identification was higher with iterative model reconstruction. Although iterative model reconstruction offered better diagnostic confidence and emphysema detection, both IR algorithms allowed an accurate evolution assessment with an effective dose of 0.22 mSv