Ultra-short echo time cardiovascular magnetic resonance of atherosclerotic carotid plaque.

BACKGROUND: Multi-contrast weighted cardiovascular magnetic resonance (CMR) allows detailed plaque characterisation and assessment of plaque vulnerability. The aim of this preliminary study was to show the potential of Ultra-short Echo Time (UTE) subtraction MR in detecting calcification. METHODS: 14 ex-vivo human carotid arteries were scanned using CMR and CT, prior to histological slide preparation. Two images were acquired using a double-echo 3D UTE pulse, one with a long TE and the second with an ultra-short TE, with the same TR. An UTE subtraction (DeltaUTE) image containing only ultra-short T2 (and T2*) signals was obtained by post-processing subtraction of the 2 UTE images. The DeltaUTE image was compared to the conventional 3D T1-weighted sequence and CT scan of the carotid arteries. RESULTS: In atheromatous carotid arteries, there was a 71% agreement between the high signal intensity areas on DeltaUTE images and CT scan. The same areas were represented as low signal intensity on T1W and areas of void on histology, indicating focal calcification. However, in 15% of all the scans there were some incongruent regions of high intensity on DeltaUTE that did not correspond with a high intensity signal on CT, and histology confirmed the absence of calcification. CONCLUSIONS: We have demonstrated that the UTE sequence has potential to identify calcified plaque. Further work is needed to fully understand the UTE findings

Fusion to snowdrop lectin magnifies the oral activity of insecticidal omega-Hexatoxin-Hv1a peptide by enabling its delivery to the central nervous system

Background: The spider-venom peptide v-hexatoxin-Hv1a (Hv1a) targets insect voltage-gated calcium channels, acting directly at sites within the central nervous system. It is potently insecticidal when injected into a wide variety of insect pests, but it has limited oral toxicity. We examined the ability of snowdrop lectin (GNA), which is capable of traversing the insect gut epithelium, to act as a ‘‘carrier’’ in order to enhance the oral activity of Hv1a. Methodology/Principal Findings: A synthetic Hv1a/GNA fusion protein was produced by recombinant expression in the yeast Pichia pastoris. When injected into Mamestra brassicae larvae, the insecticidal activity of the Hv1a/GNA fusion protein was similar to that of recombinant Hv1a. However, when proteins were delivered orally via droplet feeding assays, Hv1a/ GNA, but not Hv1a alone, caused a significant reduction in growth and survival of fifth stadium Mamestra brassicae (cabbage moth) larvae. Feeding second stadium larvae on leaf discs coated with Hv1a/GNA (0.1–0.2% w/v) caused $80% larval mortality within 10 days, whereas leaf discs coated with GNA (0.2% w/v) showed no acute effects. Intact Hv1a/GNA fusion protein was delivered to insect haemolymph following ingestion, as shown by Western blotting. Immunoblotting of nerve chords dissected from larvae following injection of GNA or Hv1a/GNA showed high levels of bound proteins. When insects were injected with, or fed on, fluorescently labelled GNA or HV1a/GNA, fluorescence was detected specifically associated with the central nerve chord. Conclusions/Significance: In addition to mediating transport of Hv1a across the gut epithelium in lepidopteran larvae, GNA is also capable of delivering Hv1a to sites of action within the insect central nervous system. We propose that fusion to GNA provides a general mechanism for dramatically enhancing the oral activity of insecticidal peptides and proteins

Effect of insecticidal fusion proteins containing spider toxins targeting sodium and calcium ion channels on pyrethroid-resistant strains of peach-potato aphid (Myzus persicae)

BACKGROUND: The recombinant fusion proteins Pl1a/GNA and Hv1a/GNA contain the spider venom peptides δ-amaurobitoxin-PI1a or ω-hexatoxin-Hv1a respectively, linked to snowdrop lectin (GNA). Pl1a targets receptor site 4 of insect voltage-gated sodium channels (NaCh), while Hv1a targets voltage-gated calcium channels. Insecticide-resistant strains of peach-potato aphid (Myzus persicae) contain mutations in NaCh. The pyrethroid-resistant kdr (794J) and super-kdr (UKO) strains contain mutations at residues L1014 and M918 in the channel α-subunit respectively, while the kdr + super-kdr strain (4824J), insensitive to pyrethroids, contains mutations at both L1014 and M918. RESULTS: Pl1a/GNA and Hv1a/GNA fusion proteins have estimated LC50 values of 0.35 and 0.19 mg mL−1 when fed to wild-type M. persicae. For insecticide-resistant aphids, LC50 for the Pl1a/GNA fusion protein increased by 2–6-fold, correlating with pyrethroid resistance (wild type < kdr < super-kdr < kdr + super-kdr strains). In contrast, LC50 for the Hv1a/GNA fusion protein showed limited correlation with pyrethroid resistance. CONCLUSION: Mutations in the sodium channel in pyrethroid-resistant aphids also protect against a fusion protein containing a sodium-channel-specific toxin, in spite of differences in ligand–channel interactions, but do not confer resistance to a fusion protein targeting calcium channels. The use of fusion proteins with differing targets could play a role in managing pesticide resistance

Synthetic velocity mapping cardiac MRI coupled with automated left ventricle segmentation

Temporal patterns of cardiac motion provide important information for cardiac disease diagnosis. This pattern could be obtained by three-directional CINE multi-slice left ventricular myocardial velocity mapping (3Dir MVM), which is a cardiac MR technique providing magnitude and phase information of the myocardial motion simultaneously. However, long acquisition time limits the usage of this technique by causing breathing artifacts, while shortening the time causes low temporal resolution and may provide an inaccurate assessment of cardiac motion. In this study, we proposed a frame synthesis algorithm to increase the temporal resolution of 3Dir MVM data. Our algorithm is featured by 1) three attention-based encoders which accept magnitude images, phase images, and myocardium segmentation masks respectively as inputs; 2) three decoders that output the interpolated frames and corresponding myocardium segmentation results; and 3) loss functions highlighting myocardium pixels. Our algorithm can not only increase the temporal resolution 3Dir MVMs, but can also generates the myocardium segmentation results at the same time

A developmentally regulated chaperone complex for the endoplasmic reticulum of male haploid germ cells

Glycoprotein folding is mediated by lectin-like chaperones and protein disulfide isomerases (PDIs) in the endoplasmic reticulum (ER). Calnexin and the PDI homologue ERp57 work together to help fold nascent polypeptides with glycans located toward the N-terminus of a protein, whereas PDI and BiP may engage proteins that lack glycans or have sugars toward the C-terminus. In this study, we show that the PDI homologue PDILT is expressed exclusively in post-meiotic male germ cells, in contrast to the ubiquitous expression of many other PDI family members in the testis. PDILT is induced during puberty and represents the first example of a PDI family member under developmental control. We find that PDILT is not active as an oxido-reductase, but interacts with the model peptide -somatostatin and nonnative BPTI in vitro, indicative of chaperone activity. In vivo, PDILT forms a tissue-specific chaperone complex with the calnexin homologue calmegin. The identification of a redox-inactive chaperone partnership defines a new system of testis-specific protein folding with implications for male fertility

Coronary microvascular ischemia in hypertrophic cardiomyopathy - a pixel-wise quantitative cardiovascular magnetic resonance perfusion study.

BACKGROUND: Microvascular dysfunction in HCM has been associated with adverse clinical outcomes. Advances in quantitative cardiovascular magnetic resonance (CMR) perfusion imaging now allow myocardial blood flow to be quantified at the pixel level. We applied these techniques to investigate the spectrum of microvascular dysfunction in hypertrophic cardiomyopathy (HCM) and to explore its relationship with fibrosis and wall thickness. METHODS: CMR perfusion imaging was undertaken during adenosine-induced hyperemia and again at rest in 35 patients together with late gadolinium enhancement (LGE) imaging. Myocardial blood flow (MBF) was quantified on a pixel-by-pixel basis from CMR perfusion images using a Fermi-constrained deconvolution algorithm. Regions-of-interest (ROI) in hypoperfused and hyperemic myocardium were identified from the MBF pixel maps. The myocardium was also divided into 16 AHA segments. RESULTS: Resting MBF was significantly higher in the endocardium than in the epicardium (mean ± SD: 1.25 ± 0.35 ml/g/min versus 1.20 ± 0.35 ml/g/min, P < 0.001), a pattern that reversed with stress (2.00 ± 0.76 ml/g/min versus 2.36 ± 0.83 ml/g/min, P < 0.001). ROI analysis revealed 11 (31%) patients with stress MBF lower than resting values (1.05 ± 0.39 ml/g/min versus 1.22 ± 0.36 ml/g/min, P = 0.021). There was a significant negative association between hyperemic MBF and wall thickness (β = −0.047 ml/g/min per mm, 95% CI: −0.057 to −0.038, P < 0.001) and a significantly lower probability of fibrosis in a segment with increasing hyperemic MBF (odds ratio per ml/g/min: 0.086, 95% CI: 0.078 to 0.095, P = 0.003). CONCLUSIONS: Pixel-wise quantitative CMR perfusion imaging identifies a subgroup of patients with HCM that have localised severe microvascular dysfunction which may give rise to myocardial ischemia

HDL: hybrid deep learning for the synthesis of myocardial velocity maps in digital twins for cardiac analysis

Synthetic digital twins based on medical data accelerate the acquisition, labelling and decision making procedure in digital healthcare. A core part of digital healthcare twins is model based data synthesis, which permits the generation of realistic medical signals without requiring to cope with the modelling complexity of anatomical and biochemical phenomena producing them in reality. Unfortunately, algorithms for cardiac data synthesis have been so far scarcely studied in the literature. An important imaging modality in the cardiac examination is three-directional CINE multi-slice myocardial velocity mapping (3Dir MVM), which provides a quantitative assessment of cardiac motion in three orthogonal directions of the left ventricle. The long acquisition time and complex acquisition produce make it more urgent to produce synthetic digital twins of this imaging modality. In this study, we propose a hybrid deep learning (HDL) network, especially for synthetic 3Dir MVM data. Our algorithm is featured by a hybrid UNet and a Generative Adversarial Network with a foreground-background generation scheme. The experimental results show that from temporally down-sampled magnitude CINE images (six times), our proposed algorithm can still successfully synthesise high temporal resolution 3Dir MVM CMR data (PSNR=42.32) with precise left ventricle segmentation (DICE=0.92). These performance scores indicate that our proposed HDL algorithm can be implemented in real-world digital twins for myocardial velocity mapping data simulation. To the best of our knowledge, this work is the first one in the literature investigating digital twins of the 3Dir MVM CMR, which has shown great potential for improving the efficiency of clinical studies via synthesised cardiac data

A multi-center inter-manufacturer study of the temporal stability of phase-contrast velocity mapping background offset errors.

BACKGROUND: Phase-contrast velocity images often contain a background or baseline offset error, which adds an unknown offset to the measured velocities. For accurate flow measurements, this offset must be shown negligible or corrected. Some correction techniques depend on replicating the clinical flow acquisition using a uniform stationary phantom, in order to measure the baseline offset at the region of interest and subtract it from the clinical study. Such techniques assume that the background offset is stable over the time of a patient scan, or even longer if the phantom scans are acquired later, or derived from pre-stored background correction images. There is no published evidence regarding temporal stability of the background offset. METHODS: This study assessed the temporal stability of the background offset on 3 different manufacturers' scanners over 8 weeks, using a retrospectively-gated phase-contrast cine acquisition with fixed parameters and at a fixed location, repeated 5 times in rapid succession each week. A significant offset was defined as 0.6 cm/s within 50 mm of isocenter, based upon an accuracy of 10% in a typical cardiac shunt measurement. RESULTS: Over the 5 repeated cine acquisitions, temporal drift in the baseline offset was insignificant on two machines (0.3 cm/s, 0.2 cm/s), and marginally insignificant on the third machine (0.5 cm/s) due to an apparent heating effect. Over a longer timescale of 8 weeks, insignificant drift (0.4 cm/s) occurred on one, with larger drifts (0.9 cm/s, 0.6 cm/s) on the other machines. CONCLUSIONS: During a typical patient study, background drift was insignificant. Extended high gradient power scanning with work requires care to avoid drift on some machines. Over the longer term of 8 weeks, significant drift is likely, preventing accurate correction by delayed phantom corrections or derivation from pre-stored background offset data.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomised controlled trial

Aims To determine the clinical impact of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a) > 500 mg/L on the primary end point of quantitative myocardial perfusion, as well as secondary end points including atheroma burden, exercise capacity, symptoms, and quality of life. Methods We conducted a single-blinded randomized controlled trial in 20 patients with refractory angina and raised lipoprotein(a) > 500 mg/L, with 3 months of blinded weekly lipoprotein apheresis or sham, followed by crossover. The primary endpoint was change in quantitative myocardial perfusion reserve (MPR) assessed by cardiovascular magnetic resonance. Secondary endpoints included measures of atheroma burden, exercise capacity, symptoms and quality of life. Results The primary endpoint, namely MPR, increased following apheresis (0.47; 95% CI 0.31–0.63) compared with sham (−0.16; 95% CI − 0.33–0.02) yielding a net treatment increase of 0.63 (95% CI 0.37–0.89; P < 0.001 between groups). Improvements with apheresis compared with sham also occurred in atherosclerotic burden as assessed by total carotid wall volume (P < 0.001), exercise capacity by the 6 min walk test (P = 0.001), 4 of 5 domains of the Seattle angina questionnaire (all P < 0.02) and quality of life physical component summary by the short form 36 survey (P = 0.001). Conclusion Lipoprotein apheresis may represent an effective novel treatment for patients with refractory angina and raised lipoprotein(a) improving myocardial perfusion, atheroma burden, exercise capacity and symptoms