Development of a novel magnetic resonance imaging contrast agent for pressure measurements using lipid-coated microbubbles

The aim of this study was to prepare gas-filled lipid-coated microbubbles as potential MRI contrast agents for imaging of fluid pressure. Air-filled microbubbles were produced with phospholipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) in the presence or absence of cholesterol and/or polyethylene-glycol distearate (PEG-distearate). Microbubbles were also prepared containing a fluorinated phospholipid, perfluoroalkylated glycerol-phosphatidylcholine, F-GPC shells encompassing perfluorohexane-saturated nitrogen gas. These microbubbles were evaluated in terms of physico-chemical characteristics such as size and stability. In parallel to these studies, DSPC microbubbles were also formulated containing nitrogen (N2) gas and compared to air-filled microbubbles. By preventing advection, signal drifts were used to assess their stability. DSPC microbubbles were found to have a drift of 20% signal change per bar of applied pressure in contrast to the F-GPC microbubbles which are considerably more stable with a lower drift of 5% signal change per bar of applied pressure. By increasing the pressure of the system and monitoring the MR signal intensity, the point at which the majority of the microbubbles have been damaged was determined. For the DSPC microbubbles this occurs at 1.3 bar whilst the F-GPC microbubbles withstand pressures up to 2.6 bar. For the comparison between air-filled and N2-filled microbubbles, the MRI sensitivity is assessed by cycling the pressure of the system and monitoring the MR signal intensity. It was found that the sensitivity exhibited by the N2-filled microbubbles remained constant, whilst the air-filled microbubbles demonstrated a continuous drop in sensitivity due to continuous bubble damage.

Robust spatially resolved pressure measurements using MRI with novel buoyant advection-free preparations of stable microbubbles in polysaccharide gels

MRI of fluids containing lipid coated microbubbles has been shown to be an effective toot for measuring the local fluid pressure. However, the intrinsically buoyant nature of these microbubbles precludes lengthy measurements due to their vertical migration under gravity and pressure-induced coalescence. A novel preparation is presented which is shown to minimize both these effects for at least 25 min. By using a 2% polysaccharide gel base with a small concentration of glycerol and 1,2-distearoyl-sn-glycero-3-phosphocholine coated gas microbubbles, MR measurements are made for pressures between 0.95 and 1.44 bar. The signal drifts due to migration and amalgamation are shown to be minimized for such an experiment whilst yielding very high NMR sensitivities up to 38% signal change per bar.

Does rebound tonometry probe misalignment modify intraocular pressure measurements in human eyes?

Purpose. To examine the influence of positional misalignments on intraocular pressure (IOP) measurement with a rebound tonometer. Methods. Using the iCare rebound tonometer, IOP readings were taken from the right eye of 36 healthy subjects at the central corneal apex (CC) and compared to IOP measures using the Goldmann applanation tonometer (GAT). Using a bespoke rig, iCare IOP readings were also taken 2 mm laterally from CC, both nasally and temporally, along with angular deviations of 5 and 10 degrees, both nasally and temporally to the visual axis. Results. Mean IOP ± SD, as measured by GAT, was 14.7±2.5 mmHg versus iCare tonometer readings of 17.4±3.6 mmHg at CC, representing an iCare IOP overestimation of 2.7±2.8 mmHg (P<0.001), which increased at higher average IOPs. IOP at CC using the iCare tonometer was not significantly different to values at lateral displacements. IOP was marginally underestimated with angular deviation of the probe but only reaching significance at 10 degrees nasally. Conclusions. As shown previously, the iCare tonometer overestimates IOP compared to GAT. However, IOP measurement in normal, healthy subjects using the iCare rebound tonometer appears insensitive to misalignments. An IOP underestimation of <1 mmHg with the probe deviated 10 degrees nasally reached statistical but not clinical significance levels. © 2013 Ian G. Beasley et al.

The influence of simulated cataract on retinal vessel oximetry measurements

PURPOSE: To assess the impact of human crystalline lens opacification and yellowing, similar to that observed in patients with cataracts, on retinal vessel blood oxygen saturation measurements using custom manufactured soft contact lenses. METHODS: Ten healthy, non-smoking individuals were enrolled for this study. All subjects underwent digital blood pressure measurements, assessment of non-contact intra-ocular pressure, pupil dilation and retinal vessel oximetry using dual-wavelength photography (Oximetry Module, Imedos Systems). To simulate lens changes, three different contact lenses were inserted, one to simulate opacities followed by two more lenses to simulate different levels of lens yellowing (Cantor & Nissel). RESULTS: The measurements obtained showed an opposite change in arterial and venous oxygen saturation and optical density ratio across conditions, resulting in a statistically significant difference in arterial minus venous oxygen saturation value (p = 0.003). However, this difference was only significant for the 'opacity' condition but not for the 'yellowing' conditions. CONCLUSION: Lenticular changes such as cataracts can impact on spectrophotometric analysis in particular dual-wavelength retinal vessel oximetry. Hence, lenticular assessment and cataract grading should be considered when assessing elderly individuals and patient groups developing cataract earlier in life such as those suffering from diabetes mellitus.

Clinical evaluation of rebound tonometer

Purpose: To evaluate the reliability and repeatability of intraocular pressure (IOP) measurements using a new rebound tonometer. Methods: Intraocular pressure was measured in 42 healthy human eyes of subjects aged 18-30 years (mean ± standard deviation [SD] 21.5 ± 3.2 years) using the ICare Rebound and Goldmann tonometers in two separate sessions. Results: Intraocular pressure measurements were found to read slightly, but not significantly, higher with the ICare tonometer compared with the Goldmann instrument in both sessions (first session: mean bias ± SD + 0.50 ± 2.33 mmHg; second session: mean bias ± SD + 0.52 ± 1.92 mmHg). Limits of agreement between repeated readings were ± 5.11 mmHg for measurements taken with the ICare tonometer, compared with ± 3.15 mmHg for measurements taken with the Goldmann method. Conclusion: Measurement of IOP in normal, healthy subjects using the ICare rebound tonometer produced a small, statistically insignificant, positive bias when compared with the Goldmann tonometer. Intersessional repeatability of IOP taken with the ICare is poorer than that of IOP taken with the Goldmann tonometer, but is comparable with that of other non-Goldman-type tonometers currently available. Copyright © Acta Ophthalmol Scand, 2006.

Local shell-side coefficients in shell and tube exchanges the use of a mass transfer technique

A diffusion-controlled electrochemical mass transfer technique has been employed in making local measurements of shell-side coefficients in segmentally baffled shell and tube heat exchangers. Corresponding heat transfer data are predicted through the Chilton and Colburn heat and mass transfer analogy. Mass transfer coefficients were measured for baffle spacing lengths of individual tubes in an internal baffle compartment. Shell-side pressure measurements were also made. Baffle compartment average coefficients derived from individual tube coefficients are shown to be in good agreement with reported experimental bundle average heat transfer data for a heat exchanger model of similar geometry. Mass transfer coefficients of individual tubes compare favourably with those obtained previously by another mass transfer technique. Experimental data are reported for a variety of segmental baffle configurations over the shell-side Reynolds number range 100 to 42 000. Baffles with zero clearances were studied at three baffle cuts and two baffle spacings. Baffle geometry is shown to have a large effect on the distribution of tube coefficients within the baffle compartment. Fluid "jetting" is identified with some baffle configurations. No simple characteristic velocity is found to correlate zonal or baffle compartment average mass transfer data for the effect of both baffle cut and baffle spacing. Experiments with baffle clearances typical of commercial heat exchangers are also reported. The effect of leakage streams associated with these baffles is identified. Investigations were extended to double segmental baffles for which no data had previously been published. The similarity in the shell-side characteristics of this baffle arrangement and two parallel single segmental baffle arrangements is demonstrated. A general relationship between the shell-side mass transfer performance and pressure drop was indicated by the data for all the baffle configurations examined.

The effect of simulated cataract light scatter on retinal vessel oximetry

To assess the impact of light scatter, similar to that introduced by cataract on retinal vessel blood oxygen saturation measurements using poly-bead solutions of varying concentrations. Eight healthy, young, non-smoking individuals were enrolled for this study. All subjects underwent digital blood pressure measurements, assessment of non-contact intraocular pressure, pupil dilation and retinal vessel oximetry using dual wavelength photography (Oximetry Module, Imedos Systems, Germany). To simulate light scatter, cells comprising a plastic collar and two plano lenses were filled with solutions of differing concentrations (0.001, 0.002 and 0.004%) of polystyrene microspheres (Polysciences Inc., USA). The adopted light scatter model showed an artifactual increase in venous optical density ratio (p=0.036), with the 0.004% condition producing significantly higher venous optical density ratio values when compared to images without a cell in place. Spectrophotometric analysis, and thus retinal vessel oximetry of the retinal vessels, is altered by artificial light scatter. © 2013 Elsevier Ltd.

Comparison of subjective and objective methods to determine the retinal arterio-venous ratio using fundus photography

Purpose: To assess the inter and intra observer variability of subjective grading of the retinal arterio-venous ratio (AVR) using a visual grading and to compare the subjectively derived grades to an objective method using a semi-automated computer program. Methods: Following intraocular pressure and blood pressure measurements all subjects underwent dilated fundus photography. 86 monochromatic retinal images with the optic nerve head centred (52 healthy volunteers) were obtained using a Zeiss FF450+ fundus camera. Arterio-venous ratios (AVR), central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) were calculated on three separate occasions by one single observer semi-automatically using the software VesselMap (ImedosSystems, Jena, Germany). Following the automated grading, three examiners graded the AVR visually on three separate occasions in order to assess their agreement. Results: Reproducibility of the semi-automatic parameters was excellent (ICCs: 0.97 (CRAE); 0.985 (CRVE) and 0.952 (AVR)). However, visual grading of AVR showed inter grader differences as well as discrepancies between subjectively derived and objectively calculated AVR (all p < 0.000001). Conclusion: Grader education and experience leads to inter-grader differences but more importantly, subjective grading is not capable to pick up subtle differences across healthy individuals and does not represent true AVR when compared with an objective assessment method. Technology advancements mean we no longer rely on opthalmoscopic evaluation but can capture and store fundus images with retinal cameras, enabling us to measure vessel calibre more accurately compared to visual estimation; hence it should be integrated in optometric practise for improved accuracy and reliability of clinical assessments of retinal vessel calibres. © 2014 Spanish General Council of Optometry.

The hypotensive effect of acute and chronic AMP-activated protein kinase activation in normal and hyperlipidemic mice

AMP-activated protein kinase (AMPK) is present in the arterial wall and is activated in response to cellular stressors that raise AMP relative to ADP/ATP. Activation of AMPK in vivo lowers blood pressure but the influence of hyperlipidemia on this response has not been studied. ApoE-/- mice on high fat diet for 6 weeks and age-matched controls were treated with the AMPK activator, AICAR daily for two weeks. Under anesthesia, the carotid artery was cannulated for blood pressure measurements. Aortic tissue was removed for in vitro functional experiments and AMPK activity was measured in artery homogenates by Western blotting. ApoE-/- mice had significantly raised mean arterial pressure; chronic AICAR treatment normalized this but had no effect in normolipidemic mice, whereas acute administration of AICAR lowered mean arterial pressure in both groups. Chronic AICAR treatment increased phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase in normolipidemic but not ApoE-/- mice. In aortic rings, AMPK activation induced vasodilation and an anticontractile effect, which was attenuated in ApoE-/- mice. This study demonstrates that hyperlipidemia dysregulates the AMPK pathway in the arterial wall but this effect can be reversed by AMPK activation, possibly through improving vessel compliance.

The time course of changes in retinal vessel diameter in response to differing durations of flicker light provocation

Purpose: To determine the response of retinal vessels to differing durations of flicker light (FL) sitmulation. Methods: We recorded retinal arterial and venous vessel dilation to 12.5 Hz flicker light provocation (Retinal Vessel Analyzer, Imedos Systems) of varying duration (5, 7, 10 and 20 seconds) in twelve healthy young individuals (age range 26-45 yrs). All participants underwent a full ocular examination including intraocular pressure and blood pressure measurements. Results: Maximum dilation (MD) did not show a significant dependence on flicker duration in arteries whereas maximum constriction (MC) did. However, in veins MD significantly increased with flicker duration. Approximately 80-90% of MD in arteries is reached within 10 seconds of flicker light stimulation. Conclusions: The vast majority of arterial dilatory capacity is reached within 10 seconds of flicker light stimulation even though venous dilation continues strongly. Since the MC of arteries shows a significant dependence on flicker duration measurements at two different durations can provide more information about the retinal vascular system than at a single flicker duration alone.

Measurements of polarimetric sensitivity to hydrostatic pressure, strain and temperature in birefringent dual-core microstructured polymer fiber

We experimentally characterized a birefringent microstructured polymer fiber of specific construction, which allows for single mode propagation in two cores separated by a pair of large holes. The fiber exhibits high birefringence in each of the cores as well as relatively weak coupling between the cores. Spectral dependence of the group and the phase modal birefringence was measured using an interferometric method. We have also measured the sensing characteristics of the fiber such as polarimetric sensitivity to hydrostatic pressure, strain and temperature. Moreover, we have studied the effect of hydrostatic pressure and strain on coupling between the cores.