Alex Smith - Academia.edu (original) (raw)
Papers by Alex Smith
Advances in Therapy, 2021
Magnetic Resonance in Medicine, 2020
Blood, 2010
2917 Background: The European LeukemiaNet MDS (EUMDS) registry is designed to collect information... more 2917 Background: The European LeukemiaNet MDS (EUMDS) registry is designed to collect information about the demographics and disease-management of newly diagnosed low-risk and intermediate-1 risk MDS patients. From April 2008 until July 2010, 828 patients have been registered in eleven participating countries through a web-based reporting system. Objectives: This report describes the disease-management of the first 800 registered patients, including transfusion-related issues like secondary iron overload and its treatment. Results: 159 of 800 patients (20%) started MDS specific treatment within three months before registration; this percentage increased to 50% at 18 months of follow-up. Most patients received erythroid-stimulating agents (ESA), like erythropoietin (Table 1). In patients with a clinical indication for ESA, the percentage of transfusion-independency was similar to the transfusion-independent group without indication for ESA at 18 months of follow-up (Table 1). Overall...
Journal of Pediatric Gastroenterology & Nutrition, 2019
The Journal of Physiology, 2019
Acta Neuropathologica Communications, 2019
Open Forum Infectious Diseases, 2018
Journal of neuroinflammation, Jan 22, 2018
Aquaporin-4-immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (here... more Aquaporin-4-immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune disease of the central nervous system in which AQP4-IgG binding to AQP4 on astrocytes results in complement-dependent astrocyte injury and secondary inflammation, demyelination, and neuron loss. We previously reported evidence for a complement bystander mechanism for early oligodendrocyte injury in NMO. Herein, we tested the hypothesis that complement bystander injury, which involves diffusion to nearby cells of activated soluble complement components from complement-injured astrocytes, is a general phenomenon that may contribute to neuronal injury in NMO. Primary cocultures of rat astrocytes and cortical neurons were established to study complement-dependent cell death after exposure to AQP4-IgG and complement. In animal experiments, AQP4-IgG was delivered to adult rats by intracerebral injection. Cell cultures and rat brain were studied by immunofluoresc...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Feb 1, 2018
How solutes and macromolecules are removed from brain tissue is of central importance in normal b... more How solutes and macromolecules are removed from brain tissue is of central importance in normal brain physiology and in how toxic protein aggregates are cleared in neurodegenerative conditions, including Alzheimer's disease (AD). Conventionally, solute transport in the narrow and tortuous extracellular space in brain parenchyma has been thought to be primarily diffusive and nondirectional. The recently proposed "glymphatic" (glial-lymphatic) hypothesis posits that solute clearance is convective and driven by active fluid transport from para-arterial to paravenous spaces though aquaporin-4 water channels in astrocyte endfeet. Glymphatic, convective solute clearance has received much attention because of its broad implications for AD and other brain pathologies and even the function of sleep. However, the theoretical plausibility of glymphatic transport has been questioned, and recent data have challenged its experimental underpinnings. A substantiated mechanism of solut...
Journal of cellular and molecular medicine, Jan 24, 2018
Expert opinion on therapeutic targets, Dec 1, 2017
Aquaporin-4 (AQP4) is a water transporting protein expressed at the plasma membrane of astrocytes... more Aquaporin-4 (AQP4) is a water transporting protein expressed at the plasma membrane of astrocytes throughout the central nervous system (CNS). Analysis of AQP4 knockout mice has suggested its broad involvement in brain water balance, neuroexcitation, glial scarring, neuroinflammation, and even neurodegenerative and neuropsychiatric disorders. Broad clinical utility of AQP4 modulators has been speculated. Area covered: This review covers the biology of AQP4, evidence for its roles in normal CNS function and neurological disorders, and progress in AQP4 drug discovery. Expert opinion: Critical examination of available data reduces the lengthy potential applications list to AQP4 inhibitors for early therapy of ischemic stroke and perhaps for reduction of glial scarring following CNS injury. Major challenges in identification and clinical development of AQP4 inhibitors include the apparent poor druggability of AQPs, the many homologous AQP isoforms with broad tissue distribution and func...
The Astronomical Journal, 1966
Physics of the Earth and Planetary Interiors, 2004
Recent studies of intra-plate seismicity have focused on detailed earthquake locations and potent... more Recent studies of intra-plate seismicity have focused on detailed earthquake locations and potential hypotheses for intermediate depth events. Three main competing hypotheses for intra-plate events are: (1) transformational faulting; (2) shear melt instabilities; and (3) dehydration reactions. Recent work, using precise hypocenters and thermal-petrological models, indicates that the spatial distribution of intra-plate events coincides with dehydration reactions. These studies have
eLife, Aug 21, 2017
Transport of solutes through brain involves diffusion and convection. The importance of convectiv... more Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-...
Scientific reports, Jan 11, 2017
We utilise spray-coating under ambient conditions to sequentially deposit compact-TiO2, mesoporou... more We utilise spray-coating under ambient conditions to sequentially deposit compact-TiO2, mesoporous-TiO2, CH3NH3PbI(3-x)Clx perovskite and doped spiro-OMeTAD layers, creating a mesoporous standard architecture perovskite solar cell (PSC). The devices created had an average power conversion efficiency (PCE) of 9.2% and a peak PCE of 10.2%; values that compare favourably with control-devices fabricated by spin-casting that had an average efficiency of 11.4%. We show that our process can be used to create devices having an active-area of 1.5 cm(2) having an independently verified efficiency of 6.6%. This work demonstrates the versatility of spray-coating as well as its potential as a method of manufacturing low-cost, large-area, efficient perovskite devices.
Annals of hematology, Jan 20, 2017
The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS... more The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3-9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fi...
Acta neuropathologica, Jul 31, 2017
Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease ... more Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement 'bystander mechanism' to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to astrocyte AQP4 result in deposition of the complement membrane attack complex (MAC) on nearby oligodendrocytes. Primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4-IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures, in cocultures exposed to AQP4-IgG and C6-dep...
The Journal of general physiology, Dec 1, 2016
A "glymphatic system," which involves convective fluid transport from para-arterial to ... more A "glymphatic system," which involves convective fluid transport from para-arterial to paravenous cerebrospinal fluid through brain extracellular space (ECS), has been proposed to account for solute clearance in brain, and aquaporin-4 water channels in astrocyte endfeet may have a role in this process. Here, we investigate the major predictions of the glymphatic mechanism by modeling diffusive and convective transport in brain ECS and by solving the Navier-Stokes and convection-diffusion equations, using realistic ECS geometry for short-range transport between para-arterial and paravenous spaces. Major model parameters include para-arterial and paravenous pressures, ECS volume fraction, solute diffusion coefficient, and astrocyte foot-process water permeability. The model predicts solute accumulation and clearance from the ECS after a step change in solute concentration in para-arterial fluid. The principal and robust conclusions of the model are as follows: (a) significan...
PloS one, 2016
The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imagi... more The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imaging (DTI) protocols, implemented at multiple sites (using scanners from two different manufacturers), one available on any clinical scanner, and one using more advanced options currently available in the research setting, and to use an automated processing method for unbiased quantification. DTI parameters are sensitive to changes in the diseased SC. However, imaging the cord can be technically challenging due to various factors including its small size, patient-related and physiological motion, and field inhomogeneities. Rapid acquisition sequences such as Echo Planar Imaging (EPI) are desirable but may suffer from image distortions. We present a multi-centre comparison of two acquisition protocols implemented on scanners from two different vendors (Siemens and Philips), one using a reduced field-of-view (rFOV) EPI sequence, and one only using options available on standard clinical scann...
Advances in Therapy, 2021
Magnetic Resonance in Medicine, 2020
Blood, 2010
2917 Background: The European LeukemiaNet MDS (EUMDS) registry is designed to collect information... more 2917 Background: The European LeukemiaNet MDS (EUMDS) registry is designed to collect information about the demographics and disease-management of newly diagnosed low-risk and intermediate-1 risk MDS patients. From April 2008 until July 2010, 828 patients have been registered in eleven participating countries through a web-based reporting system. Objectives: This report describes the disease-management of the first 800 registered patients, including transfusion-related issues like secondary iron overload and its treatment. Results: 159 of 800 patients (20%) started MDS specific treatment within three months before registration; this percentage increased to 50% at 18 months of follow-up. Most patients received erythroid-stimulating agents (ESA), like erythropoietin (Table 1). In patients with a clinical indication for ESA, the percentage of transfusion-independency was similar to the transfusion-independent group without indication for ESA at 18 months of follow-up (Table 1). Overall...
Journal of Pediatric Gastroenterology & Nutrition, 2019
The Journal of Physiology, 2019
Acta Neuropathologica Communications, 2019
Open Forum Infectious Diseases, 2018
Journal of neuroinflammation, Jan 22, 2018
Aquaporin-4-immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (here... more Aquaporin-4-immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune disease of the central nervous system in which AQP4-IgG binding to AQP4 on astrocytes results in complement-dependent astrocyte injury and secondary inflammation, demyelination, and neuron loss. We previously reported evidence for a complement bystander mechanism for early oligodendrocyte injury in NMO. Herein, we tested the hypothesis that complement bystander injury, which involves diffusion to nearby cells of activated soluble complement components from complement-injured astrocytes, is a general phenomenon that may contribute to neuronal injury in NMO. Primary cocultures of rat astrocytes and cortical neurons were established to study complement-dependent cell death after exposure to AQP4-IgG and complement. In animal experiments, AQP4-IgG was delivered to adult rats by intracerebral injection. Cell cultures and rat brain were studied by immunofluoresc...
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Feb 1, 2018
How solutes and macromolecules are removed from brain tissue is of central importance in normal b... more How solutes and macromolecules are removed from brain tissue is of central importance in normal brain physiology and in how toxic protein aggregates are cleared in neurodegenerative conditions, including Alzheimer's disease (AD). Conventionally, solute transport in the narrow and tortuous extracellular space in brain parenchyma has been thought to be primarily diffusive and nondirectional. The recently proposed "glymphatic" (glial-lymphatic) hypothesis posits that solute clearance is convective and driven by active fluid transport from para-arterial to paravenous spaces though aquaporin-4 water channels in astrocyte endfeet. Glymphatic, convective solute clearance has received much attention because of its broad implications for AD and other brain pathologies and even the function of sleep. However, the theoretical plausibility of glymphatic transport has been questioned, and recent data have challenged its experimental underpinnings. A substantiated mechanism of solut...
Journal of cellular and molecular medicine, Jan 24, 2018
Expert opinion on therapeutic targets, Dec 1, 2017
Aquaporin-4 (AQP4) is a water transporting protein expressed at the plasma membrane of astrocytes... more Aquaporin-4 (AQP4) is a water transporting protein expressed at the plasma membrane of astrocytes throughout the central nervous system (CNS). Analysis of AQP4 knockout mice has suggested its broad involvement in brain water balance, neuroexcitation, glial scarring, neuroinflammation, and even neurodegenerative and neuropsychiatric disorders. Broad clinical utility of AQP4 modulators has been speculated. Area covered: This review covers the biology of AQP4, evidence for its roles in normal CNS function and neurological disorders, and progress in AQP4 drug discovery. Expert opinion: Critical examination of available data reduces the lengthy potential applications list to AQP4 inhibitors for early therapy of ischemic stroke and perhaps for reduction of glial scarring following CNS injury. Major challenges in identification and clinical development of AQP4 inhibitors include the apparent poor druggability of AQPs, the many homologous AQP isoforms with broad tissue distribution and func...
The Astronomical Journal, 1966
Physics of the Earth and Planetary Interiors, 2004
Recent studies of intra-plate seismicity have focused on detailed earthquake locations and potent... more Recent studies of intra-plate seismicity have focused on detailed earthquake locations and potential hypotheses for intermediate depth events. Three main competing hypotheses for intra-plate events are: (1) transformational faulting; (2) shear melt instabilities; and (3) dehydration reactions. Recent work, using precise hypocenters and thermal-petrological models, indicates that the spatial distribution of intra-plate events coincides with dehydration reactions. These studies have
eLife, Aug 21, 2017
Transport of solutes through brain involves diffusion and convection. The importance of convectiv... more Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-...
Scientific reports, Jan 11, 2017
We utilise spray-coating under ambient conditions to sequentially deposit compact-TiO2, mesoporou... more We utilise spray-coating under ambient conditions to sequentially deposit compact-TiO2, mesoporous-TiO2, CH3NH3PbI(3-x)Clx perovskite and doped spiro-OMeTAD layers, creating a mesoporous standard architecture perovskite solar cell (PSC). The devices created had an average power conversion efficiency (PCE) of 9.2% and a peak PCE of 10.2%; values that compare favourably with control-devices fabricated by spin-casting that had an average efficiency of 11.4%. We show that our process can be used to create devices having an active-area of 1.5 cm(2) having an independently verified efficiency of 6.6%. This work demonstrates the versatility of spray-coating as well as its potential as a method of manufacturing low-cost, large-area, efficient perovskite devices.
Annals of hematology, Jan 20, 2017
The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS... more The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3-9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fi...
Acta neuropathologica, Jul 31, 2017
Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease ... more Neuromyelitis optica spectrum disorder (herein called NMO) is an autoimmune inflammatory disease of the central nervous system in which immunoglobulin G antibodies against astrocyte water channel aquaporin-4 (AQP4-IgG) cause demyelination and neurological deficit. Injury to oligodendrocytes, which do not express AQP4, links the initiating pathogenic event of AQP4-IgG binding to astrocyte AQP4 to demyelination. Here, we report evidence for a complement 'bystander mechanism' to account for early oligodendrocyte injury in NMO in which activated, soluble complement proteins following AQP4-IgG binding to astrocyte AQP4 result in deposition of the complement membrane attack complex (MAC) on nearby oligodendrocytes. Primary cocultures of rat astrocytes and mature oligodendrocytes exposed to AQP4-IgG and complement showed early death of oligodendrocytes in close contact with astrocytes, which was not seen in pure oligodendrocyte cultures, in cocultures exposed to AQP4-IgG and C6-dep...
The Journal of general physiology, Dec 1, 2016
A "glymphatic system," which involves convective fluid transport from para-arterial to ... more A "glymphatic system," which involves convective fluid transport from para-arterial to paravenous cerebrospinal fluid through brain extracellular space (ECS), has been proposed to account for solute clearance in brain, and aquaporin-4 water channels in astrocyte endfeet may have a role in this process. Here, we investigate the major predictions of the glymphatic mechanism by modeling diffusive and convective transport in brain ECS and by solving the Navier-Stokes and convection-diffusion equations, using realistic ECS geometry for short-range transport between para-arterial and paravenous spaces. Major model parameters include para-arterial and paravenous pressures, ECS volume fraction, solute diffusion coefficient, and astrocyte foot-process water permeability. The model predicts solute accumulation and clearance from the ECS after a step change in solute concentration in para-arterial fluid. The principal and robust conclusions of the model are as follows: (a) significan...
PloS one, 2016
The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imagi... more The purpose of this study was to develop and evaluate two spinal cord (SC) diffusion tensor imaging (DTI) protocols, implemented at multiple sites (using scanners from two different manufacturers), one available on any clinical scanner, and one using more advanced options currently available in the research setting, and to use an automated processing method for unbiased quantification. DTI parameters are sensitive to changes in the diseased SC. However, imaging the cord can be technically challenging due to various factors including its small size, patient-related and physiological motion, and field inhomogeneities. Rapid acquisition sequences such as Echo Planar Imaging (EPI) are desirable but may suffer from image distortions. We present a multi-centre comparison of two acquisition protocols implemented on scanners from two different vendors (Siemens and Philips), one using a reduced field-of-view (rFOV) EPI sequence, and one only using options available on standard clinical scann...