Optically Generated Ultrasound for Intracoronary Imaging

Conventional intravascular ultrasound (IVUS) devices use piezoelectric transducers to electrically generate and receive US. With this paradigm, there are numerous challenges that restrict improvements in image quality. First, with miniaturization of the transducers to reduce device size, it can be challenging to achieve the sensitivities and bandwidths required for large tissue penetration depths and high spatial resolution. Second, complexities associated with manufacturing miniaturized electronic transducers can have significant cost implications. Third, with increasing interest in molecular characterization of tissue in-vivo, it has been challenging to incorporate optical elements for multimodality imaging with photoacoustics (PA) or near-infrared spectroscopy (NIRS) whilst maintaining the lateral dimensions suitable for intracoronary imaging. Optical Ultrasound (OpUS) is a new paradigm for intracoronary imaging. US is generated at the surface of a fiber optic transducer via the photoacoustic effect. Pulsed or modulated light is absorbed in an engineered coating on the fiber surface and converted to thermal energy. The subsequent temperature rise leads to a pressure rise within the coating, which results in a propagating ultrasound wave. US reflections from imaged structures are received with optical interferometry. With OpUS, high bandwidths (31.5 MHz) and pressures (21.5 MPa) have enabled imaging with axial resolutions better than 50 μm and at depths >20 mm. These values challenge those of conventional 40 MHz IVUS technology and show great potential for future clinical application. Recently developed nanocomposite coating materials, that are highly transmissive at light wavelengths used for PA and NIRS light, can facilitate multimodality imaging, thereby enabling molecular characterization

Deciphering interplay between Salmonella invasion effectors

Bacterial pathogens have evolved a specialized type III secretion system (T3SS) to translocate virulence effector proteins directly into eukaryotic target cells. Salmonellae deploy effectors that trigger localized actin reorganization to force their own entry into non-phagocytic host cells. Six effectors (SipC, SipA, SopE/2, SopB, SptP) can individually manipulate actin dynamics at the plasma membrane, which acts as a ‘signaling hub’ during Salmonella invasion. The extent of crosstalk between these spatially coincident effectors remains unknown. Here we describe trans and cis binary entry effector interplay (BENEFIT) screens that systematically examine functional associations between effectors following their delivery into the host cell. The results reveal extensive ordered synergistic and antagonistic relationships and their relative potency, and illuminate an unexpectedly sophisticated signaling network evolved through longstanding pathogen–host interaction

Development of outcome measures for autoimmune dermatoses

Validated outcome measures are essential in monitoring disease severity. Specifically in dermatology, which relies heavily on the clinical evaluation of the patient and not on laboratory values and radiographic tests, outcome measures help standardize patient care. Validated cutaneous scoring systems, much like standardized laboratory values, facilitate disease management and follow therapeutic response. Several cutaneous autoimmune dermatoses, specifically cutaneous lupus erythematosus (CLE), dermatomyositis (DM), and pemphigus vulgaris (PV), lack such outcome measures. As a result, evaluation of disease severity and patients’ response to therapy over time is less reliable. Ultimately, patient care is compromised. These diseases, which are often chronic and relapsing and remitting, are also often refractory to treatment. Without outcome measures, new therapies cannot be systematically assessed in these diseases. Clinical trials that are completed without standardized outcome measures produce less reliable results. Therefore, the development of validated outcome measures in these autoimmune dermatoses is critical. However, the process of developing these tools is as important, if not more so, than their availability. This review examines the steps that should be considered when developing outcome measures, while further examining their importance in clinical practice and trials. Finally, this review more closely looks at CLE, DM, and PV and addresses the recent and ongoing progress that has been made in the development of their outcome measures

Adenosine-mono-phosphate-activated protein kinase-independent effects of metformin in T cells

The anti-diabetic drug metformin regulates T-cell responses to immune activation and is proposed to function by regulating the energy-stress-sensing adenosine-monophosphate-activated protein kinase (AMPK). However, the molecular details of how metformin controls T cell immune responses have not been studied nor is there any direct evidence that metformin acts on T cells via AMPK. Here, we report that metformin regulates cell growth and proliferation of antigen-activated T cells by modulating the metabolic reprogramming that is required for effector T cell differentiation. Metformin thus inhibits the mammalian target of rapamycin complex I signalling pathway and prevents the expression of the transcription factors c-Myc and hypoxia-inducible factor 1 alpha. However, the inhibitory effects of metformin on T cells did not depend on the expression of AMPK in T cells. Accordingly, experiments with metformin inform about the importance of metabolic reprogramming for T cell immune responses but do not inform about the importance of AMPK

Extremely high He isotope ratios in MORB-source mantle from the proto-Iceland plume

The high <sup>3</sup>He/<sup>4</sup>He ratio of volcanic rocks thought to be derived from mantle plumes is taken as evidence for the existence of a mantle reservoir that has remained largely undegassed since the Earth's accretion. The helium isotope composition of this reservoir places constraints on the origin of volatiles within the Earth and on the evolution and structure of the Earth's mantle. Here we show that olivine phenocrysts in picritic basalts presumably derived from the proto-Iceland plume at Baffin Island, Canada, have the highest magmatic <sup>3</sup>He/<sup>4</sup>He ratios yet recorded. A strong correlation between <sup>3</sup>He/<sup>4</sup>He and <sup>87</sup>Sr/<sup>86</sup>Sr, <sup>143</sup>Nd/<sup>144</sup>Nd and trace element ratios demonstrate that the <sup>3</sup>He-rich end-member is present in basalts that are derived from large-volume melts of depleted upper-mantle rocks. This reservoir is consistent with the recharging of depleted upper-mantle rocks by small volumes of primordial volatile-rich lower-mantle material at a thermal boundary layer between convectively isolated reservoirs. The highest <sup>3</sup>He/<sup>4</sup>He basalts from Hawaii and Iceland plot on the observed mixing trend. This indicates that a <sup>3</sup>He-recharged depleted mantle (HRDM) reservoir may be the principal source of high <sup>3</sup>He/<sup>4</sup>He in mantle plumes, and may explain why the helium concentration of the 'plume' component in ocean island basalts is lower than that predicted for a two-layer, steady-state model of mantle structure

Wall-less vascular poly(vinyl) alcohol gel ultrasound imaging phantoms using 3D printed vessels

Vascular phantoms are crucial tools for clinical training and for calibration and validation of medical imaging systems. With current methods, it can be challenging to replicate anatomically-realistic vasculature. Here, we present a novel method that enables the fabrication of complex vascular phantoms. Poly(vinyl alcohol) (PVA) in two forms was used to create wall-less vessels and the surrounding tissue mimicking material (TMM). For the latter, PVA cryogel (PVA-c) was used as the TMM, which was made from a solution of PVA (10% by weight), distilled water, and glass spheres for ultrasonic scattering (0.5% by weight). PVA-c is not water soluble, and after a freeze-thaw cycle it is mechanically robust. To form the wall-less vessels, vessel structures were 3D printed in water-soluble PVA and submerged in the aqueous solution of PVA-c. Once the PVA-c had solidified, the 3D printed PVA vessel structures were dissolved in water. Three phantoms were created, as initial demonstrations of the capabilities of this method: a straight vessel, a stenosed (narrowed), and a bifurcated (branched) vessel. Ultrasound images of the phantoms had realistic appearances. We conclude that this method is promising for creating wall-less, anatomically realistic, vascular phantoms

Dynamic physiological temperature and pressure sensing with phase-resolved low-coherence interferometry

We report the development and characterisation of highly miniaturised fibre-optic sensors for simultaneous pressure and temperature measurement, and a compact interrogation system with a high sampling rate. The sensors, which have a maximum diameter of 250 µm, are based on multiple low-finesse optical cavities formed from polydimethylsiloxane (PDMS), positioned at the distal ends of optical fibres, and interrogated using phase-resolved low-coherence interferometry. At acquisition rates of 250 Hz, temperature and pressure changes of 0.0021 °C and 0.22 mmHg are detectable. An in vivo experiment demonstrated that the sensors had sufficient speed and sensitivity for monitoring dynamic physiological pressure waveforms. These sensors are ideally suited to various applications in minimally invasive surgery, where diminutive lateral dimensions, high sensitivity and low manufacturing complexities are particularly valuable

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al

Factor H autoantibody is associated with atypical hemolytic uremic syndrome in children in the United Kingdom and Ireland

Factor H autoantibodies can impair complement regulation, resulting in atypical hemolytic uremic syndrome, predominantly in childhood. There are no trials investigating treatment, and clinical practice is only informed by retrospective cohort analysis. Here we examined 175 children presenting with atypical hemolytic uremic syndrome in the United Kingdom and Ireland for factor H autoantibodies that included 17 children with titers above the international standard. Of the 17, seven had a concomitant rare genetic variant in a gene encoding a complement pathway component or regulator. Two children received supportive treatment; both developed established renal failure. Plasma exchange was associated with a poor rate of renal recovery in seven of 11 treated. Six patients treated with eculizumab recovered renal function. Contrary to global practice, immunosuppressive therapy to prevent relapse in plasma exchange–treated patients was not adopted due to concerns over treatment-associated complications. Without immunosuppression, the relapse rate was high (five of seven). However, reintroduction of treatment resulted in recovery of renal function. All patients treated with eculizumab achieved sustained remission. Five patients received renal transplants without specific factor H autoantibody–targeted treatment with recurrence in one who also had a functionally significant CFI mutation. Thus, our current practice is to initiate eculizumab therapy for treatment of factor H autoantibody–mediated atypical hemolytic uremic syndrome rather than plasma exchange with or without immunosuppression. Based on this retrospective analysis we see no suggestion of inferior treatment, albeit the strength of our conclusions is limited by the small sample siz

Lactate Regulates Metabolic and Proinflammatory Circuits in Control of T Cell Migration and Effector Functions

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