91 research outputs found
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Computational Methods and Epidemiologic Approaches for Revealing the Etiology of Autoimmune Diseases
No full textAutoimmune diseases, in which normal tissues are inappropriately attacked by the immune system, are complex diseases driven by a combination of genetic and environmental factors. Most are chronic inflammatory diseases with some treatments available but no known cures, and the disease mechanisms are not completely understood. Epigenetic factors, such as DNA methylation and microRNAs, are affected by genetic and environmental exposures and in turn affect gene expression and thus may play a role in autoimmune disease pathogenesis. In this dissertation, I employ a combination of computational, bioinformatic, statistical, and epidemiologic methods to study the role of epigenetics in autoimmune diseases in humans, and to characterize inflammatory changes in human cell lines.Chapter one introduces some complexities of studying autoimmune diseases in humans and introduces concepts of epigenetics. Chapter two shows that naïve T cells from rheumatoid arthritis patients share DNA methylation sites with fibroblast-like synoviocytes, cells that line joints and are involved in joint inflammation. Chapter three shows that there are differences in DNA methylation in CD4+ and CD8+ T cells from multiple sclerosis patients compared to cells from healthy controls. Chapter four uses genome-wide association study results to implicate specific microRNAs and tissues in pediatric-onset multiple sclerosis. Chapter five shows that the inflammatory cytokine tumor necrosis factor alpha drives DNA methylation and transcriptional changes and activates autoimmune disease genes in endothelial cells. Chapter six is a summary of conclusions and key findings
A Role for the Vacuolating Cytotoxin, VacA, in Colonization and Helicobacter pylori-Induced Metaplasia in the Stomach
No full textCarriage of Helicobacter pylori strains producing more active (s1/i1) forms of VacA is strongly associated with gas-tric adenocarcinoma. To our knowledge, we are the
first to determine effects of different polymorphic forms of VacA on inflammation and metaplasia in the mouse stomach. Bacteria producing the less active s2/i2 form of VacA colonized mice more efficiently than mutants null for VacA or producing more active forms of it, providing the
first evidence of a positive role for the minimally active s2/i2 toxin. Strains producing more active toxin forms induced more severe and extensive metaplasia and in flammation in the mouse stomach than strains producing weakly active (s2/i2) toxin. We also examined the association in humans, controlling for cag PAI status. In human gastric biopsy specimens, the vacA i1 allele was strongly associated with precancerous intestinal metaplasia, with almost complete absence of intestinal metaplasia in subjects infected with i2-type strains, even in a vacA s1, cagA+ background
American trout-stream insects; a guide to angling flies and other aquatic insects alluring to trout, selected and painted for each month of the trout season from nearly one hundred living specimens native to the rivers and lakes of the temperate zone of North America, with notes on and reproductions of artificial imitation flies tied by the author, and a chapter on the mode of tying artificial flies, with assisting charts and illustrations in the text, together with descriptions and illustrations of a complete set of new artificial nature-lures copied exactly from carefully colored life-pictures of all creatures that bass and other game fishes consume as food
No full textPost-Reperfusion Syndrome in Kidney Transplant Case Study
No full textBackground: Kidney transplants happen everyday, one of the most serious risks associated with this procedure is Post-Reperfusion Syndrome (PRS). PRS is a phenomenon of a more than 15% drop in mean arterial pressure (MAP) in the first 5 minutes post reperfusion. This hemodynamic instability usually lasts for at least 1 minute. The exact cause of PRS is unknown, but there may be ways to pretreat a patient, which would limit the effects experienced long term. Case Information: This case review investigates the procedures performed by the anesthesiologist on a 45-year-old female to manage severe hypotension that occurred during a kidney transplant. It also looks to educate others on the steps necessary to take when caring for a kidney transplant patient and how to lower the risk of severe hypotension. Our patient was intubated with an endotracheal tube at time 1007. Normotensive pressures for the patient, with a MAP around 100 mmHg, were initially achieved through the use of a dual anesthesia method using both a propofol drip and inhaled sevoflurane along with multimodal pain control. The sevoflurane inhalation was constant while the propofol drip was adjusted to control blood pressure. Vasopressors were avoided in the management of hypotension, thus limiting the vasoconstrictive effects on the new kidney to allow max reperfusion. The new kidney was placed in the right lower abdomen, and the renal artery was attached to the external iliac artery, and the renal vein was attached to the external iliac vein with the ureter being connected to the bladder. Reperfusion occurred at approximately 1300 after which at 1304 the patient went severely hypotensive with a MAP of nearly 40 mmHg. A dopamine infusion was initiated at this time at a rate of 5 mcg/kg/min. 1 gram of calcium carbonate was then given. The patient began to recover to a MAP of 80 over the course of 15 minutes. Another 1 gram of calcium carbonate was given and the dopamine infusion was adjusted to 7.5 mcg/kg/min when the MAP began to drop again. After which the patient’s pressures remained relatively normotensive until extubation and transfer to recovery. Discussion: PRS has been shown to increase transplant failure within 6 months and increased hospital stays. The exact cause of PRS is unknown, but resources suggest that it may be produced by hypothermia plus the sudden increase in cardiac preload, hyperkalemia, and possibly other vasoactive substances present. These factors may trigger a reflex response by the vagus nerve. Some suggest preemptively addressing PRS by treating with atropine to increase HR and thus hope to minimize the decreased MAP. As anesthesia providers, we need to be aware of this potential complication of kidney reperfusion. Pretreatment and anticipatory medicine will facilitate better outcomes for patients and a better overall surgical experience
Working towards an international ANPR Standard — An initial investigation into the UK standard
No full textThis paper examines the use of the UK National ACPO ANPR Standard (NAAS) as the “de facto” technical standard applied in many international countries. It considers the requirement for a standard and examines the effectiveness of the current NAAS and questions its fitness for purpose. The need for accuracy is discussed in terms of both tackling terrorism, serious crime and other law enforcement investigations alongside the need to protect citizens from unwarranted infringement of their privacy as a result of ANPR misreads. The causes of inaccurate ANPR read data are examined in more detail and recommendations made as to how improvements could be introduced to minimise the risk of misreads and “missed” reads. This paper recommends future parameters of measurement and provides examples of gaps between the current standards and existing legislation. Laboratory and field testing was carried out to gain a better understanding of the factors that affect the performance of ANPR systems. These tests were carried out under a variety of weather and lighting conditions. The results of this work have led to further testing to better understand the optimum conditions for number plate capture by a variety of ANPR systems. Additional testing has been carried out using "hard to read" number plates with a number of differing characteristics such as illegally spaced characters, illegal fonts, screw caps that interfere with infrared imaging and defects in the construction of the number plate itself (whether created inadvertently at the point of manufacture or subsequently caused by damage / wear and tear / weather conditions). The first author is a UK police officer and, like his senior analyst colleague who is the second author, has wide experience in testing and developing ANPR systems. The authors have been commissioned by the UK Home Office to carry out post graduate ANPR research at the University of Hertfordshire
My Dear Horace Kephart: Letters from George Mac Reynolds and Louise Rhead
No full textHorace Kephart was a renaissance man of his day. A librarian, author, and impassioned outdoorsman, he maintained a career at the St. Louis Mercantile Library before moving to North Carolina in 1904. Kephart wrote extensively on camping, woodcraft, and wildlife. He also worked to establish the smoky mountain national park. To offer a sense of his personality and appreciation for both the human-made and the natural world, he wrote the following in a letter dated Oct. 2, 1888 to friend Harry Koopman: “Imagine Boston or Florence set in the midst of the Yellowstone Park with no suburbs or even a farm within 200 miles – that’s my idea of paradise! When a fellow wanted to he could go to the public library or the opera, when he wanted to, he could walk right out into the primeval truth of things and cuss the universe of shams – be Samuel Jonson and Daniel Boone by turns!”(26). The ensuing letters from 1916 reflect Kephart’s foothold in both the professional and natural worlds
Ordering of organic molecules on templated surfaces
No full textThis thesis describes the controlled growth of molecular nanostructures using modified metallic and semiconductor surfaces. The Ag/Si(lll)-(root3 x root3),the Sn/Cu(100) surface alloy system and the Bi/Si(100) nanolines and (2xn) surfaces were all investigated as suitable substrates for the controlled growth of pentacene, (C22H14) or trimesic acid, (C6H3(COOH)3) organic molecules. The following techniques were used in this study; Scanning Tunnelling Microscopy (STM), Low Energy Electron Diffraction (LEED), Normal Incident X-Ray Standing Waves (NIXSW) and Temperature Programmed Desorption (TPD).
The room temperature growth and ordering of trimesic acid on the AgfSi(ll1)-(root3 x root3) surface was investigated. An oblique unit cell was determined and a model proposed for the highly ordered close-packed domains.
The discovery of a new submonolayer phase on Sn/Cu(100) and the re-examined known phase are discussed. New models for these reconstructions are proposed. Adsorption of trimesic acid at room temperature on the clean substrate the lowest Sn coverage phase were studied. Two new Sn coverage dependent structures were discovered and bonding schemes in upright and flat orientations are discussed.
BifSi(100)-(2xn) surface was exploited as a template for the ordered growth of pentacene, which exhibited orientation specific adsorption. The Bi/Si(100)-(2xn) single domain surface created on vicinal silicon was used to test the suitable of Daresbury 4.2 beamline for NIXSW Imaging experiments and the quality of the results are discussed
Global expression and CpG methylation analysis of primary endothelial cells before and after TNFa stimulation reveals gene modules enriched in inflammatory and infectious diseases and associated DMRs
No full textEndothelial cells are a primary site of leukocyte recruitment during inflammation. An increase in tumor necrosis factor-alpha (TNFa) levels as a result of infection or some autoimmune diseases can trigger this process. Several autoimmune diseases are now treated with TNFa inhibitors. However, genomic alterations that occur as a result of TNF-mediated inflammation are not well understood. To investigate molecular targets and networks resulting from increased TNFa, we measured DNA methylation and gene expression in 40 human umbilical vein endothelial cell primary cell lines before and 24 hours after stimulation with TNFa via microarray. Weighted gene co-expression network analysis identified 15 gene groups (modules) with similar expression correlation patterns; four modules showed a strong association with TNFa treatment. Genes in the top TNFa-associated module were all up-regulated, had the highest proportion of hypomethylated regions, and were associated with 136 Disease Ontology terms, including autoimmune/inflammatory, infectious and cardiovascular diseases, and cancers. They included chemokines CXCL1, CXCL10 and CXCL8, and genes associated with autoimmune diseases including HLA-C, DDX58, IL4, NFKBIA and TNFAIP3. Cardiovascular and metabolic disease genes, including APOC1, ACLY, ELOVL6, FASN and SCD, were overrepresented in a module that was not associated with TNFa treatment. Of 223 hypomethylated regions identified, several were in promoters of autoimmune disease GWAS loci (ARID5B, CD69, HDAC9, IL7R, TNIP1 and TRAF1). Results reveal specific gene groups acting in concert in endothelial cells, delineate those driven by TNFa, and establish their relationship to DNA methylation changes, which has strong implications for understanding disease etiology and precision medicine approaches.</div
Author Correction: A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
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Author Correction: A phenotypic and genomics approach in a multi-ethnic cohort to subtype systemic lupus erythematosus
No full textAn amendment to this paper has been published and can be accessed via a link at the top of the paper
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