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Search Results: 1 - 10 of 274043 matches for " David R. Brown "
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Role of Microglia in Age-Related Changes to the Nervous System
David R. Brown
The Scientific World Journal , 2009, DOI: 10.1100/tsw.2009.111
The Treatment of Breast Cancer Using Liposome Technology
Sarah Brown,David R. Khan
Journal of Drug Delivery , 2012, DOI: 10.1155/2012/212965
Abstract: Liposome-based chemotherapeutics used in the treatment of breast cancer can in principle enhance the therapeutic index of otherwise unencapsulated anticancer drugs. This is partially attributed to the fact that encapsulation of cytotoxic agents within liposomes allows for increased concentrations of the drug to be delivered to the tumor site. In addition, the presence of the phospholipid bilayer prevents the encapsulated active form of the drug from being broken down in the body prior to reaching tumor tissue and also serves to minimize exposure of the drug to healthy sensitive tissue. While clinically approved liposome-based chemotherapeutics such as Doxil have proven to be quite effective in the treatment of breast cancer, significant challenges remain involving poor drug transfer between the liposome and cancerous cells. In this review, we discuss the recent advancements made in the development of liposome-based chemotherapeutics with respect to improved drug transfer for use in breast cancer therapy.
Manganese Enhances Prion Protein Survival in Model Soils and Increases Prion Infectivity to Cells
Paul Davies,David R. Brown
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007518
Abstract: Prion diseases are considered to be transmissible. The existence of sporadic forms of prion diseases such as scrapie implies an environmental source for the infectious agent. This would suggest that under certain conditions the prion protein, the accepted agent of transmission, can survive in the environment. We have developed a novel technique to extract the prion protein from soil matrices. Previous studies have suggested that environmental manganese is a possible risk factor for prion diseases. We have shown that exposure to manganese is a soil matrix causes a dramatic increase in prion protein survival (~10 fold) over a two year period. We have also shown that manganese increases infectivity of mouse passaged scrapie to culture cells by 2 logs. These results clearly verify that manganese is a risk factor for both the survival of the infectious agent in the environment and its transmissibility.
Solving the measurement problem: de Broglie-Bohm loses out to Everett
Harvey R. Brown,David Wallace
Physics , 2004, DOI: 10.1007/s10701-004-2009-3
Abstract: The quantum theory of de Broglie and Bohm solves the measurement problem, but the hypothetical corpuscles play no role in the argument. The solution finds a more natural home in the Everett interpretation.
Longitudinal Analysis of Arterial Blood Pressure and Heart Rate Response to Acute Behavioral Stress in Rats with Type 1 Diabetes Mellitus and in Age-Matched Controls
David C. Randall,David R. Brown
Frontiers in Physiology , 2011, DOI: 10.3389/fphys.2011.00053
Abstract: We recorded via telemetry the arterial blood pressure (BP) and heart rate (HR) response to classical conditioning following the spontaneous onset of autoimmune diabetes in BBDP/Wor rats vs. age-matched, diabetes-resistant control (BBDR/Wor) rats. Our purpose was to evaluate the autonomic regulatory responses to an acute stress in a diabetic state of up to 12 months duration. The stress was a 15-s pulsed tone (CS+) followed by a 0.5-s tail shock. The initial, transient increase in BP (i.e., the “first component,” or C1), known to be derived from an orienting response and produced by a sympathetic increase in peripheral resistance, was similar in diabetic and control rats through ~9 months of diabetes; it was smaller in diabetic rats 10 months after diabetes onset. Weakening of the C1 BP increase in rats that were diabetic for >10 months is consistent with the effects of sympathetic neuropathy. A longer-latency, smaller, but sustained “second component” (C2) conditional increase in BP, that is acquired as a rat learns the association between CS+ and the shock, and which results from an increase in cardiac output, was smaller in the diabetic vs. control rats starting from the first month of diabetes. A concomitant HR slowing was also smaller in diabetic rats. The difference in the C2 BP increase, as observed already during the first month of diabetes, is probably secondary to the effects of hyperglycemia upon myocardial metabolism and contractile function, but it may also result from effects on cognition. The small HR slowing concomitant with the C2 pressor event is probably secondary to differences in baroreflex activation or function, though parasympathetic dysfunction may contribute later in the duration of diabetes. The nearly immediate deficit after disease onset in the C2 response indicates that diabetes alters BP and HR responses to external challenges prior to the development of structural changes in the vasculature or autonomic nerves.
Using Intradermal Rabies Vaccine to Boost Immunity in People with Low Rabies Antibody Levels
David Brown,Anthony R. Fooks,Martin Schweiger
Advances in Preventive Medicine , 2011, DOI: 10.4061/2011/601789
Abstract: Intradermal rabies vaccine is recommended by the World Health Organisation, but not all countries, including England, follow this recommendation. A group of 12 adults in England previously given pre-exposure intradermal rabies vaccine were considered to be non-immune to rabies because their rabies antibody titres were known to be less than 0.5?IU/mL. A cohort study examined the immunizing effect of increasing the participants' cumulative dose of intradermal rabies to 2.0?IU. All patients subsequently demonstrated rabies antibody levels >0.5?IU·mL supporting evidence of adequate sero-conversion. No adverse effects of intradermal rabies vaccine boosting were noted. Within the limits of a small study the findings support the hypothesis that adequate levels of rabies antibody can be achieved by a schedule of intradermal injections delivered on at least three occasions with a cumulative rabies vaccine dose of 2.0?IU. 1. Introduction A study undertaken in 2007 on the duration of the immunogenicity of intradermal rabies vaccine demonstrated titres of rabies antibodies consistent with a protective response a decade or more after immunization with human diploid cell vaccine [1]. Twenty one of the 89 participants in that study failed to demonstrate titres of rabies antibodies greater than 0.5?IU/mL and were considered not to be adequately protected against rabies. Of the twenty one, none had received a cumulative dose of intradermal rabies vaccine greater than 1?IU nor had they received rabies intradermal vaccination on more than two occasions. Based on this observation, we hypothesised that the production of levels of rabies antibodies that can be correlated with protective efficacy requires a minimum cumulative dose of 2.0?IU of rabies vaccine administered intradermally over not less than three separate occasions. An antibody titre of greater than or equal to 0.5?IU/mL was considered indicative of seroconversion, providing an adequate titre, in line with the World Health Organization (WHO) recommendations [2]. The study reported in this paper was undertaken in order to examine that hypothesis. 2. Method This study was based on inviting the 21 nonresponding participants of the first study to provide 4?mL blood samples to confirm the previously determined antibody titres. Twelve of the 21 were both willing and able to participate. They were given booster doses by the intradermal route to bring them up to a life time cumulative dose of 2.0?IU of rabies vaccine. In all cases this proved to require 1.0?IU of rabies vaccine. After an interval of approximately 6 weeks
Alpha-Synuclein Is a Cellular Ferrireductase
Paul Davies,Dima Moualla,David R. Brown
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015814
Abstract: α-synuclein (αS) is a cellular protein mostly known for the association of its aggregated forms with a variety of diseases that include Parkinson's disease and Dementia with Lewy Bodies. While the role of αS in disease is well documented there is currently no agreement on the physiological function of the normal isoform of the protein. Here we provide strong evidence that αS is a cellular ferrireductase, responsible for reducing iron (III) to bio available iron (II). The recombinant form of the protein has a VMax of 2.72 nmols/min/mg and Km 23 μM. This activity is also evident in lysates from neuronal cell lines overexpressing αS. This activity is dependent on copper bound to αS as a cofactor and NADH as an electron donor. Overexpression of α-synuclein by cells significantly increases the percentage of iron (II) in cells. The common disease mutations associated with increased susceptibility to PD show differences in activity or iron (II) levels. This discovery may well provide new therapeutic targets for PD and Lewy body dementias.
An Analysis of Interactions between Fluorescently-Tagged Mutant and Wild-Type SOD1 in Intracellular Inclusions
David A. Qualls, Keith Crosby, Hilda Brown, David R. Borchelt
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083981
Abstract: Background By mechanisms yet to be discerned, the co-expression of high levels of wild-type human superoxide dismutase 1 (hSOD1) with variants of hSOD1 encoding mutations linked familial amyotrophic lateral sclerosis (fALS) hastens the onset of motor neuron degeneration in transgenic mice. Although it is known that spinal cords of paralyzed mice accumulate detergent insoluble forms of WT hSOD1 along with mutant hSOD1, it has been difficult to determine whether there is co-deposition of the proteins in inclusion structures. Methodology/Principal Findings In the present study, we use cell culture models of mutant SOD1 aggregation, focusing on the A4V, G37R, and G85R variants, to examine interactions between WT-hSOD1 and misfolded mutant SOD1. In these studies, we fuse WT and mutant proteins to either yellow or red fluorescent protein so that the two proteins can be distinguished within inclusions structures. Conclusions/Significance Although the interpretation of the data is not entirely straightforward because we have strong evidence that the nature of the fused fluorophores affects the organization of the inclusions that form, our data are most consistent with the idea that normal dimeric WT-hSOD1 does not readily interact with misfolded forms of mutant hSOD1. We also demonstrate the monomerization of WT-hSOD1 by experimental mutation does induce the protein to aggregate, although such monomerization may enable interactions with misfolded mutant SOD1. Our data suggest that WT-hSOD1 is not prone to become intimately associated with misfolded mutant hSOD1 within intracellular inclusions that can be generated in cultured cells.
Accuracy of 3-Dimensional Transoesophageal Echocardiography in Assessment of Prosthetic Mitral Valve Dehiscence with Comparison to Anatomical Specimens
Martin R. Brown,George Javorsky,David G. Platts
Cardiology Research and Practice , 2010, DOI: 10.4061/2010/750874
Abstract: The evolution of echocardiography from 2-Dimensional Transthoracic Echo through to real time 3-Dimensional Transoesophageal Echo has enabled more accurate visualisation and quantification of valvular disorders especially prosthetic mitral valve paravalvular regurgitation. However, validation of accuracy is rarely confirmed by surgical or post-mortem specimens. We present a case directly comparing different echocardiographic modality images to post mortem specimens in a patient with prosthetic mitral valve paravalvular regurgitation. 1. Case An 80-year-old male was admitted with recurrent prosthetic mitral valve endocarditis. He had a myocardial infarction in 1997 complicated by acute posterior mitral valve papillary muscle rupture requiring urgent mitral valve replacement (MVR) with a 31?mm St. Jude and coronary artery bypass grafting. Six years later he developed Staphylococcus aureus prosthetic valve endocarditis along the sewing ring with a small posterior sewing ring abscess. He required repeat MVR with a 31?mm Mosaic valve. Recurrent mitral valve and aortic valve endocarditis occurred three weeks later with infection extending from noncoronary cusp down to mitral curtain and sewing ring requiring another 31?mm Mosaic MVR and a 27?mm Mosaic aortic valve replacement. He was admitted five years later with recurrent prosthetic mitral valve endocarditis and severe paravalvular mitral regurgitation. Due to comorbidities he was deemed unsuitable for further surgery. He was treated unsuccessfully with intravenous antibiotics, finally succumbing to his cardiac disease. Serial Figures 1(a)–1(f) and supplementary movies 1–6 (see supplementary movies in Supplementary Material available online at http://dx.doi.org/10.4061/2010/750874) demonstrate the increasing accuracy of diagnosis using 2-dimensional transthoracic echocardiography (2D TTE), 2D transoesophageal echocardiography (TOE), and real-time 3-dimensional (RT 3D) TOE. Figure 1: Comparison of prosthetic mitral valve dehiscence by differing echo modalities and direct comparison to postmortem specimens. (a) demonstrates the prosthetic mitral valve paravalvular dehiscence using 2D TTE (Online Video 1). The 3mm defect is shown in more detail using 2D TOE (b) (Online Videos 2 and 3). Real-time 3D TOE clearly shows the crescent-shaped posteromedial paravalvular dehiscence from the atrial aspect (c) (Online Video 4) compared to the postmortem specimen (d) and the ventricular aspects (e) and (f) (Online Video 5). Also, note the two 4mm echo densities on the atrial surface of the prosthetic mitral valve on the 2D
Transcriptional Regulation of the Beta-Synuclein 5′-Promoter Metal Response Element by Metal Transcription Factor-1
Patrick C. McHugh,Josephine A. Wright,David R. Brown
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017354
Abstract: The progression of many human neurodegenerative disorders is associated with an accumulation of alpha-synuclein. Alpha-synuclein belongs to the homologous synuclein family, which includes beta-synuclein. It has been proposed that beta-synuclein may be a natural regulator of alpha-synuclein. Therefore controlling beta-synuclein expression may control the accumulation of alpha-synuclein and ultimately prevent disease progression. The regulation of synucleins is poorly understood. We investigated the transcriptional regulation of beta-synuclein, with the aim of identifying molecules that differentially control beta-synuclein expression levels. To investigate transcriptional regulation of beta-synuclein, we used reporter gene assays and bioinformatics. We identified a region ?1.1/?0.6 kb upstream of the beta-synuclein translational start site to be a key regulatory region of beta-synuclein 5′-promoter activity in human dopaminergic cells (SH-SY5Y). Within this key promoter region we identified a metal response element pertaining to a putative Metal Transcription Factor-1 (MTF-1) binding site. We demonstrated that MTF-1 binds to this 5′-promoter region using EMSA analysis. Moreover, we showed that MTF-1 differentially regulates beta-synuclein promoter binding site, as well as beta-synuclein mRNA and protein expression. This effect of MTF-1 on expression was found to be specific to beta-synuclein when compared to alpha-synuclein. Understanding the regulation of synucleins and how they interact may point to molecular targets that could be manipulated for therapeutic benefit. In this study we showed that MTF-1 differentially controls the expression of beta-synuclein when compared to its homolog alpha-synuclein. This could potentially provide a novel targets or pathways for therapeutic intervention and/or treatment of synucleinopathies.
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