Simultaneous Quantification of Bone Edema/Adiposity and Structure in Inflamed Bone Using Chemical Shift-Encoded MRI in Spondyloarthritis

PURPOSE: To evaluate proton density fat fraction (PDFF) and R2* as markers of bone marrow composition and structure in inflamed bone in patients with spondyloarthritis. METHODS: Phantoms containing fat, water, and trabecular bone were constructed with proton density fat fraction (PDFF) and bone mineral density (BMD) values matching those expected in healthy bone marrow and disease states, and scanned using chemical shift-encoded MRI (CSE-MRI) at 3T. Measured PDFF and R2* values in phantoms were compared with reference FF and BMD values. Eight spondyloarthritis patients and 10 controls underwent CSE-MRI of the sacroiliac joints. PDFF and R2* in areas of inflamed bone and fat metaplasia in patients were compared with normal bone marrow in controls. RESULTS: In phantoms, PDFF measurements were accurate over the full range of PDFF and BMD values. R2* measurements were positively associated with BMD but also were influenced by variations in PDFF. In patients, PDFF was reduced in areas of inflammation and increased in fat metaplasia compared to normal marrow. R2* measurements were significantly reduced in areas of fat metaplasia. CONCLUSION: PDFF measurements reflect changes in marrow composition in areas of active inflammation and structural damage and could be used for disease monitoring in spondyloarthritis. R2* measurements may provide additional information bone mineral density but also are influenced by fat content

Whole Body MRI in Multiple Myeloma: Optimising Image Acquisition and Read Times

Objective: To identify the whole-body MRI (WB-MRI) image type(s) with the highest value for assessment of multiple myeloma, in order to optimise acquisition protocols and read times. Methods: Thirty patients with clinically-suspected MM underwent WB-MRI at 3 Tesla. Unenhanced Dixon images [fat-only (FO) and water-only (WO)], post contrast Dixon [fat-only plus contrast (FOC) and water-only plus contrast (WOC)] and diffusion weighted images (DWI) of the pelvis from all 30 patients were randomised and read by three experienced readers. For each image type, each reader identified and labelled all visible myeloma lesions. Each identified lesion was compared with a composite reference standard achieved by review of a complete imaging dataset by a further experienced consultant radiologist to determine truly positive lesions. Lesion count, true positives, sensitivity, and positive predictive value were determined. Time to read each scan set was recorded. Confidence for a diagnosis of myeloma was scored using a Likert scale. Conspicuity of focal lesions was assessed in terms of percent contrast and contrast to noise ratio (CNR). Results: Lesion count, true positives, sensitivity and confidence scores were significantly higher when compared to other image types for DWI (P<0.0001 to 0.003), followed by WOC (significant for sensitivity (P<0.0001 to 0.004), true positives (P = 0.003 to 0.049) and positive predictive value (P< 0.0001 to 0.006)). There was no statistically significant difference in these metrics between FO and FOC. Percent contrast was highest for WOC (P = 0.001 to 0.005) and contrast to noise ratio (CNR) was highest for DWI (P = 0.03 to 0.05). Reading times were fastest for DWI across all observers (P< 0.0001 to 0.014). Discussion: Observers detected more myeloma lesions on DWI images and WOC images when compared to other image types. We suggest that these image types should be read preferentially by radiologists to improve diagnostic accuracy and reporting efficiency

Quantifying bone structure, micro-architecture, and pathophysiology with MRI

The radiology of bone has been transformed by magnetic resonance imaging, which has the ability to interrogate bone's complex architecture and physiology. New techniques provide information about both the macrostructure and microstructure of bone ranging from micrometre detail to the whole skeleton. Furthermore functional information about bone physiology can be used to detect disease early before structural changes occur. The future of bone imaging is in quantifying the anatomical and functional information to diagnose and monitor disease more precisely. This review explores the state of the art in quantitative MRI bone imaging

A diffusion-based quantification technique for assessment of sacroiliitis in adolescents with enthesitis-related arthritis

OBJECTIVE: To investigate the use of a quantitative diffusion-weighted imaging (DWI) tool for measuring inflammation of the sacroiliac joints (SIJs) in enthesitis-related arthritis (ERA). METHODS: A retrospective study was performed with institutional review board approval. Subjects were adolescents who had undergone MRI of the SIJs since January 2010. 10 patients with a clinical diagnosis of ERA and 10 controls with a clinical diagnosis of mechanical back pain were assessed. Axial T1 weighted, short tau inversion recovery (STIR) and DWI (b-values 0, 50, 100, 300 and 600 mm(2) s(-1)) images were acquired. Apparent diffusion coefficient (ADC) maps were generated using a monoexponential fit. On each of four slices, two to three linear regions-of-interest were placed on each joint. Normalized ADC (nADC) values were defined as joint ADC divided by a reference ADC derived from normal sacral bone. STIR images were scored using a modification of an established technique. The correlation between nADC values and STIR scores was evaluated using Spearman's rank correlation. RESULTS: Mean nADC values were significantly higher in cases than in controls (p = 0.0015). There was a strong correlation between STIR scores and nADC values (R = 0.85). CONCLUSION: ADC values are significantly increased in inflamed SIJs compared with controls. There is a good correlation between this diffusion-based method and STIR scores of inflammation. ADVANCES IN KNOWLEDGE: We have described and provisionally validated a method for quantifying the severity of inflammation in the SIJs in ERA using ADC measurements. This method is quick, is reproducible and could potentially be automated

White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)

Background; Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. Methods; We used post‐mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro‐caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. Results; The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (P < 0.01) with the WM underlying the primary motor cortex exhibiting the most severe change. SMI32 immunoreactive axons in CADASIL were invariably increased compared with controls (P < 0.01), with most prominent axonal abnormalities observed in the frontal WM (P < 0.05). The SIs of arterioles in CADASIL were increased by 25–45% throughout the regions assessed, with the highest change in the mid‐frontal region (P = 0.000). Conclusions; Our results suggest disruption of either cortico‐cortical or subcortical‐cortical networks in the WM of the frontal lobe that may explain motor deficits and executive dysfunction in CADASIL. Widespread WM axonal changes arise from differential stenosis and sclerosis of arterioles in the WM of CADASIL subjects, possibly affecting some axons of projection neurones connecting to targets in the subcortical structures

DNA replication initiation in Bacillus subtilis: Structural and functional characterization of the essential DnaA-DnaD interaction

© 2018 The Author(s). The homotetrameric DnaD protein is essential in low G+C content gram positive bacteria and is involved in replication initiation at oriC and re-start of collapsed replication forks. It interacts with the ubiquitously conserved bacterial master replication initiation protein DnaA at the oriC but structural and functional details of this interaction are lacking, thus contributing to our incomplete understanding of the molecular details that underpin replication initiation in bacteria. DnaD comprises N-terminal (DDBH1) and C-terminal (DDBH2) domains, with contradicting bacterial two-hybrid and yeast two-hybrid studies suggesting that either the former or the latter interact with DnaA, respectively. Using Nuclear Magnetic Resonance (NMR) we showed that both DDBH1 and DDBH2 interact with the N-terminal domain I of DnaA and studied the DDBH2 interaction in structural detail. We revealed two families of conformations for the DDBH2-DnaA domain I complex and showed that the DnaA-interaction patch of DnaD is distinct from the DNA-interaction patch, suggesting that DnaD can bind simultaneously DNA and DnaA. Using sensitive single-molecule FRET techniques we revealed that DnaD remodels DnaA-DNA filaments consistent with stretching and/or untwisting. Furthermore, the DNA binding activity of DnaD is redundant for this filament remodelling. This in turn suggests that DnaA and DnaD are working collaboratively in the oriC to locally melt the DNA duplex during replication initiation

The tyrosine phosphatase DEP-1 induces cytoskeletal rearrangements, aberrant cell-substratum interactions and a reduction in cell proliferation

The receptor protein tyrosine phosphatase density-enhanced phosphatase-1 (DEP-1) has been implicated in aberrant cancer cell growth and immune cell function, however, its function within cells has yet to be properly elucidated. To investigate the cellular function of DEP-1, stable cell lines inducibly expressing DEP-1 were generated. Induction of DEP-1 expression was found to decrease PDGF-stimulated tyrosine phosphorylation of a number of cellular proteins including the PDGF receptor, and to inhibit growth factor-stimulated phosphorylation of components of the MAPK pathway, indicating that DEP-1 antagonised PDGF receptor signalling. This was supported by data showing that DEP-1 expression resulted in a reduction in cell proliferation. DEP-1-expressing cells had fewer actin-containing microfilament bundles, reduced vinculin and paxillin-containing adhesion plaques, and were defective in interactions with fibronectin. Defective cell-substratum adhesion correlated with lack of activation of FAK in DEP-1-expressing cells. Time-lapse interference reflection microscopy of live cells revealed that although small focal contacts at the leading edge were generated in DEP-1-expressing cells, they failed to mature into stable focal adhesions, as found in control cells. Further motility analysis revealed that DEP-1-expressing cells retained limited random motility, but showed no chemotaxis towards a gradient of PDGF. In addition, cell-cell contacts were disrupted, with a change in the localisation of cadherin from discrete areas of cell-cell contact to large areas of membrane interaction, and there was a parallel redistribution of beta-catenin. These results demonstrate that DEP-1 is a negative regulator of cell proliferation, cell-substratum contacts, motility and chemotaxis in fibroblasts

Fast synthesis of platinum nanopetals and nanospheres for highly-sensitive non-enzymatic detection of glucose and selective sensing of ions

Novel methods to obtain Pt nanostructured electrodes have raised particular interest due to their high performance in electrochemistry. Several nanostructuration methods proposed in the literature use costly and bulky equipment or are time-consuming due to the numerous steps they involve. Here, Pt nanostructures were produced for the first time by one-step template-free electrodeposition on Pt bare electrodes. The change in size and shape of the nanostructures is proven to be dependent on the deposition parameters and on the ratio between sulphuric acid and chloride-complexes (i.e., hexachloroplatinate or tetrachloroplatinate). To further improve the electrochemical properties of electrodes, depositions of Pt nanostructures on previously synthesised Pt nanostructures are also performed. The electroactive surface areas exhibit a two order of magnitude improvement when Pt nanostructures with the smallest size are used. All the biosensors based on Pt nanostructures and immobilised glucose oxidase display higher sensitivity as compared to bare Pt electrodes. Pt nanostructures retained an excellent electrocatalytic activity towards the direct oxidation of glucose. Finally, the nanodeposits were proven to be an excellent solid contact for ion measurements, significantly improving the time-stability of the potential. The use of these new nanostructured coatings in electrochemical sensors opens new perspectives for multipanel monitoring of human metabolism

Fat fraction mapping using magnetic resonance imaging: insight into pathophysiology

Adipose cells have traditionally been viewed as a simple, passive energy storage depot for triglycerides. However, in recent years it has become clear that adipose cells are highly physiologically active and have a multitude of endocrine, metabolic, haematological and immune functions. Changes in the number or size of adipose cells may be directly implicated in disease (for example, in the metabolic syndrome), but may also be linked to other pathological processes such as inflammation, malignant infiltration or infarction. Magnetic resonance imaging (MRI) is ideally suited to the quantification of fat, since most of the acquired signal comes from water and fat protons. Fat fraction (FF, the proportion of the acquired signal derived from fat protons) has therefore emerged as an objective, image-based biomarker of disease. Methods for fat fraction quantification are becoming increasingly available in both research and clinical settings, but these methods vary depending on the scanner, manufacturer, imaging sequence and reconstruction software being used. Careful selection of the imaging method - and correct interpretation - can improve the accuracy of FF measurements, minimize potential confounding factors and maximize clinical utility. Here, we review methods for fat quantification and their strengths and weaknesses, before considering how they can be tailored to specific applications, particularly in the gastrointestinal and musculoskeletal systems. FF quantification is becoming established as a clinical and research tool, and understanding the underlying principles will be helpful to both imaging scientists and clinicians