Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.
  • Optimization-based wavefront sensorless adaptive optics for multiphoton microscopy.

    2 July 2018

    Optical aberrations have detrimental effects in multiphoton microscopy. These effects can be curtailed by implementing model-based wavefront sensorless adaptive optics, which only requires the addition of a wavefront shaping device, such as a deformable mirror (DM) to an existing microscope. The aberration correction is achieved by maximizing a suitable image quality metric. We implement a model-based aberration correction algorithm in a second-harmonic microscope. The tip, tilt, and defocus aberrations are removed from the basis functions used for the control of the DM, as these aberrations induce distortions in the acquired images. We compute the parameters of a quadratic polynomial that is used to model the image quality metric directly from experimental input-output measurements. Finally, we apply the aberration correction by maximizing the image quality metric using the least-squares estimate of the unknown aberration.

  • Supplementation of iron in pulmonary hypertension: Rationale and design of a phase II clinical trial in idiopathic pulmonary arterial hypertension.

    3 July 2018

    Our aim is to assess the safety and potential clinical benefit of intravenous iron (Ferinject) infusion in iron deficient patients with idiopathic pulmonary arterial hypertension (IPAH). Iron deficiency in the absence of anemia (1) is common in patients with IPAH; (2) is associated with inappropriately raised levels of hepcidin, the key regulator of iron homeostasis; and (3) correlates with disease severity and worse clinical outcomes. Oral iron absorption may be impeded by reduced absorption due to elevated hepcidin levels. The safety and benefits of parenteral iron replacement in IPAH are unknown. Supplementation of Iron in Pulmonary Hypertension (SIPHON) is a Phase II, multicenter, double-blind, randomized, placebo-controlled, crossover clinical trial of iron in IPAH. At least 60 patients will be randomized to intravenous ferric carboxymaltose (Ferinject) or saline placebo with a crossover point after 12 weeks of treatment. The primary outcome will be the change in resting pulmonary vascular resistance from baseline at 12 weeks, measured by cardiac catheterization. Secondary measures include resting and exercise hemodynamics and exercise performance from serial bicycle incremental and endurance cardiopulmonary exercise tests. Other secondary measurements include serum iron indices, 6-Minute Walk Distance, WHO functional class, quality of life score, N-terminal pro-brain natriuretic peptide (NT-proBNP), and cardiac anatomy and function from cardiac magnetic resonance. We propose that intravenous iron replacement will improve hemodynamics and clinical outcomes in IPAH. If the data supports a potentially useful therapeutic effect and suggest this drug is safe, the study will be used to power a Phase III study to address efficacy.

  • Cardiac troponins: from myocardial infarction to chronic disease.

    2 July 2018

    Elucidation of the physiologically distinct subunits of troponin in 1973 greatly facilitated our understanding of cardiac contraction. Although troponins are expressed in both skeletal and cardiac muscle, there are isoforms of troponin I/T expressed selectively in the heart. By exploiting cardiac-restricted epitopes within these proteins, one of the most successful diagnostic tests to date has been developed: cardiac troponin (cTn) assays. For the past decade, cTn has been regarded as the gold-standard marker for acute myocardial necrosis: the pathological hallmark of acute myocardial infarction (AMI). Whilst cTn is the cornerstone for ruling-out AMI in patients presenting with a suspected acute coronary syndrome (ACS), elevated cTn is frequently observed in those without clinical signs indicative of AMI, often reflecting myocardial injury of 'unknown origin'. cTn is commonly elevated in acute non-ACS conditions, as well as in chronic diseases. It is unclear why these elevations occur; yet they cannot be ignored as cTn levels in chronically unwell patients are directly correlated to prognosis. Paradoxically, improvements in assay sensitivity have meant more differential diagnoses have to be considered due to decreased specificity, since cTn is now more easily detected in these non-ACS conditions. It is important to be aware cTn is highly specific for myocardial injury, which could be attributable to a myriad of underlying causes, emphasizing the notion that cTn is an organ-specific, not disease-specific biomarker. Furthermore, the ability to detect increased cTn using high-sensitivity assays following extreme exercise is disconcerting. It has been suggested troponin release can occur without cardiomyocyte necrosis, contradicting conventional dogma, emphasizing a need to understand the mechanisms of such release. This review discusses basic troponin biology, the physiology behind its detection in serum, its use in the diagnosis of AMI, and some key concepts and experimental evidence as to why cTn can be elevated in chronic diseases.

  • Endoscopic transsphenoidal drainage of an aggressive petrous apex cholesterol granuloma: unusual complications and lessons learnt.

    2 July 2018

    OBJECTIVES: This case report describes the endoscopic transsphenoidal management of a cholesterol granuloma situated in a technically challenging part of the petrous apex, and the associated peri- and post-operative complications that arose. The literature on diagnosis and management of petrous apex cholesterol granulomas is reviewed. METHOD AND RESULTS: Surgical intervention was attempted on three occasions, each time via an endoscopic, transsphenoidal approach with image guidance. The procedure was abandoned on the first occasion as there was a significant risk to the carotid artery; only a small drainage ostium was created because of the proximity of the carotid artery. The second attempt, complicated by copious bleeding from the clival venous plexus, was arrested prematurely. Successful drainage was achieved at the third attempt, but recovery was complicated by tension pneumocephalus. CONCLUSION: The transnasal route is less invasive than a lateral labyrinthine or cochlear approach, and spares cochlear and vestibular function. However, this approach is not without risk. It is important to consider the natural anatomical variance of vasculature when planning surgical intervention for a lesion situated in a technically challenging part of the petrous apex. Additional magnetic resonance venography is recommended to circumnavigate the venous plexus, thereby avoiding an unexpected breach.

  • Restitution slope is principally determined by steady-state action potential duration.

    3 July 2018

    Aims: The steepness of the action potential duration (APD) restitution curve and local tissue refractoriness are both thought to play important roles in arrhythmogenesis. Despite this, there has been little recognition of the apparent association between steady-state APD and the slope of the restitution curve. The objective of this study was to test the hypothesis that restitution slope is determined by APD and to examine the relationship between restitution slope, refractoriness and susceptibility to VF. Methods and results: Experiments were conducted in isolated hearts and ventricular myocytes from adult guinea pigs and rabbits. Restitution curves were measured under control conditions and following intervention to prolong (clofilium, veratridine, bretylium, low [Ca]e, chronic transverse aortic constriction) or shorten (catecholamines, rapid pacing) ventricular APD. Despite markedly differing mechanisms of action, all interventions that prolonged the action potential led to a steepening of the restitution curve (and vice versa). Normalizing the restitution curve as a % of steady-state APD abolished the difference in restitution curves with all interventions. Effects on restitution were preserved when APD was modulated by current injection in myocytes pre-treated with the calcium chelator BAPTA-AM - to abolish the intracellular calcium transient. The non-linear relation between APD and the rate of repolarization of the action potential is shown to underpin the common influence of APD on the slope of the restitution curve. Susceptibility to VF was found to parallel changes in APD/refractoriness, rather than restitution slope. Conclusion(s): Steady-state APD is the principal determinant of the slope of the ventricular electrical restitution curve. In the absence of post-repolarization refractoriness, factors that prolong the action potential would be expected to steepen the restitution curve. However, concomitant changes in tissue refractoriness act to reduce susceptibility to sustained VF. Dependence on steady-state APD may contribute to the failure of restitution slope to predict sudden cardiac death.

  • Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths.

    3 July 2018

    ATP fuels the removal of metabolic end-products, including H+ ions that profoundly modulate biological activities. Energetic resources in hypoxic tumor regions are constrained by low-yielding glycolysis, and any means of reducing the cost of acid extrusion, without compromising pH homeostasis, would therefore be advantageous for cancer cells. Some cancers express connexin channels that allow solute exchange between cells, and we propose that, via this route, normoxic cells supply hypoxic neighbors with acid-neutralizing HCO3- ions. This hypothesis was tested by imaging cytoplasmic pH in spheroidal tissue growths of connexin43-positive pancreatic cancer Colo357 cells during light-controlled H+ uncaging at the hypoxic core. Cytoplasmic acid retention at the core was halved in the presence of CO2/HCO3-, but this process requires a restorative HCO3- flux. The effect of CO2/HCO3- was ablated by connexin43 inhibition or knockdown. In connexin-decoupled spheroids, 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), an inhibitor of HCO3- uptake, had no effect on cytoplasmic [H+] in the H+-uncaging region, indicating that DIDS-sensitive transport is not an adequate pH-regulatory strategy therein. With intact connexin-coupling, acid retention at the core increased upon DIDS treatment, indicating that HCO3- ions are taken up actively by peripheral cells and then transmitted passively to cells at the hypoxic core. Thus, the energetic burden of pH regulation is offloaded from hypoxic cells onto metabolically altruistic normoxic neighbors.-Dovmark, T. H., Hulikova, A., Niederer, S. A., Vaughan-Jones, R. D., Swietach, P. Normoxic cells remotely regulate the acid-base balance of cells at the hypoxic core of connexin-coupled tumor growths.

  • Phospholemman

    2 July 2018

  • High-frequency stimulation of the subthalamic nucleus selectively decreases central variance of rhythmic finger tapping in Parkinson's disease.

    3 July 2018

    Timing is central to all motor behavior, especially repetitive or rhythmic movements. Such complex programs are underpinned by a network of motor structures, including the cerebellum, motor cortex, and basal ganglia. Patients with Parkinson's disease (PD) are impaired in some aspects of timing behavior, presumably as a result of the disruption to basal ganglia function. However, direct evidence that this deficit is specifically due to basal ganglia dysfunction is limited. Here, we sought to further understand the role of the basal ganglia in motor timing by studying PD patients with implanted subthalamic nucleus (STN) electrodes. Patients performed a synchronization-continuation tapping task at 500 ms and 2000 ms intervals both off and on therapeutic high frequency stimulation of the STN. Our results show that the mean tap interval was not affected by STN stimulation. However, in the un-stimulated state variability of tapping was abnormally high relative to controls, and this deficit was significantly improved, even normalized, with stimulation. Moreover, when partitioning the variance into central and peripheral motor components according to the Wing and Kristofferson model (1973), a selective reduction of central, but not motor, variance was revealed. The effect of stimulation on central variance was dependent on off-stimulation performance. These results demonstrate that STN stimulation can improve rhythmic movement performance in PD through an effect on central timing. Our experimental approach strongly implicates the STN, and more generally the basal ganglia, in the control of timing stability.

  • de Wet Group

    16 December 2013

    Role of ABC transporters in gut endocrine K-and L-cells

  • Bajo Lorenzana Group

    26 May 2015

    Hearing Loss and Tinnitus

  • Kohl Group

    10 July 2016

    Information encoding in the brain

  • Booth Group

    14 March 2014

    Optical engineering and microscopy for neuroscience and biomedical imaging

  • Ashcroft Group

    10 July 2016

    ATP-sensitive potassium (K-ATP) channels, insulin secretion and diabetes

  • Wade-Martins Group

    10 July 2016

    Understanding molecular mechanisms of age-related neurodegenerative diseases to generate novel molecular therapies

  • Walker Group

    16 September 2013

    We investigate how the activity of neurons in the brain give rise to our perception of sound.

  • Webber Group

    10 July 2016

    Computational Disease Genomics and Networks

  • Wilkins Group

    10 July 2016

    Membrane transport in cartilage and cancer cells

  • Wilson Group

    10 July 2016

    Cell Biology of Exosome Signalling, Secretion and Growth in Normal and Cancer Cells at Super-Resolution