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Search Results: 1 - 10 of 300314 matches for " Ryan J. Uitti "
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Evaluation of the Role of SNCA Variants in Survival without Neurological Disease
Michael G. Heckman, Alexandra I. Soto-Ortolaza, Nancy N. Diehl, Minerva M. Carrasquillo, Ryan J. Uitti, Zbigniew K. Wszolek, Neill R. Graff-Radford, Owen A. Ross
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042877
Abstract: Background A variety of definitions of successful aging have been proposed, many of which relate to longevity, freedom from disease and disability, or preservation of high physical and cognitive function. Many behavioral, biomedical, and psychological factors have been linked with these various measures of successful aging, however genetic predictors are less understood. Parkinson's disease (PD) is an age-related neurodegenerative disorder, and variants in the α-synuclein gene (SNCA) affect susceptibility to PD. This exploratory study examined whether SNCA variants may also promote successful aging as defined by survival without neurological disease. Methods We utilized 769 controls without neurological disease (Mean age: 79 years, Range: 33–99 years) and examined the frequency of 20 different SNCA variants across age groups using logistic regression models. We also included 426 PD cases to assess the effect of these variants on PD risk. Results There was a significant decline in the proportion of carriers of the minor allele of rs10014396 as age increased (P = 0.021), from 30% in controls younger than 60 to 14% in controls 90 years of age or older. Findings were similar for rs3775439, where the proportion of carriers of the minor allele declined from 32% in controls less than 60 years old to 19% in those 90 or older (P = 0.025). A number of SNCA variants, not including rs10014396 or rs3775439, were significantly associated with susceptibility to PD. Conclusions In addition to its documented roles in PD and α-synucleinopathies, our results suggest that SNCA has a role in survival free of neurological disease. Acknowledging that our findings would not have withstood correction for multiple testing, validation in an independent series of aged neurologically normal controls is needed.
Polymorphic genes of detoxification and mitochondrial enzymes and risk for progressive supranuclear palsy: a case control study
Lisa F Potts, Alex C Cambon, Owen A Ross, Rosa Rademakers, Dennis W Dickson, Ryan J Uitti, Zbigniew K Wszolek, Shesh N Rai, Matthew J Farrer, David W Hein, Irene Litvan
BMC Medical Genetics , 2012, DOI: 10.1186/1471-2350-13-16
Abstract: DNA from 553 autopsy-confirmed Caucasian PSP cases (266 females, 279 males; age at onset 68 ± 8 years; age at death 75 ± 8) from the Society for PSP Brain Bank and 425 clinical control samples (197 females, 226 males; age at draw 72 ± 11 years) from healthy volunteers were genotyped using Taqman PCR and the SequenomiPLEX Gold assay.The proportion of NAT2 rapid acetylators compared to intermediate and slow acetylators was larger in cases than in controls (OR = 1.82, p < 0.05). There were no allelic or genotypic associations with PSP for any other SNPs tested with the exception of MAPT (p < 0.001).Our results show that NAT2 rapid acetylator phenotype is associated with PSP, suggesting that NAT2 may be responsible for activation of a xenobiotic whose metabolite is neurotoxic. Although our results need to be further confirmed in an independent sample, NAT2 acetylation status should be considered in future genetic and epidemiological studies of PSP.Progressive supranuclear palsy (PSP) is the most common atypical parkinsonian disorder. Classically, patients present with progressive postural instability and falls followed by slow and hypometric vertical saccades and eventually vertical supranuclear gaze palsy.Neuropathologically, PSP is characterized by deposits of four-repeat microtubule associated protein tau (encoded by the MAPT gene) aggregates in neurons and glia of the basal ganglia and brain-stem [1]. Additionally, there is mitochondrial dysfunction, decreased ATP levels and inflammation in the brains of PSP patients [2-4]. The MAPT H1 haplotype has been consistently reported to be associated with PSP; however, it is also common in the general population, suggesting that gene-gene or gene-environment interactions are likely required for the development of this disease [5,6]. Recently, MAPT H1 was also associated with risk of Parkinson's disease (PD) suggesting shared pathways of disease [7]. Early-onset PD and PSP can present with a similar phenotype and be misdiagn
High-throughput mutational analysis of TOR1A in primary dystonia
Jianfeng Xiao, Robert W Bastian, Joel S Perlmutter, Brad A Racette, Samer D Tabbal, Morvarid Karimi, Randal C Paniello, Andrew Blitzer, Sat Batish, Zbigniew K Wszolek, Ryan J Uitti, Peter Hedera, David K Simon, Daniel Tarsy, Daniel D Truong, Karen P Frei, Ronald F Pfeiffer, Suzhen Gong, Yu Zhao, Mark S LeDoux
BMC Medical Genetics , 2009, DOI: 10.1186/1471-2350-10-24
Abstract: High resolution melting (HRM) was used to examine the entire TOR1A Exon 5 coding sequence in 1014 subjects with primary dystonia (422 spasmodic dysphonia, 285 cervical dystonia, 67 blepharospasm, 41 writer's cramp, 16 oromandibular dystonia, 38 other primary focal dystonia, 112 segmental dystonia, 16 multifocal dystonia, and 17 generalized dystonia) and 250 controls (150 neurologically normal and 100 with other movement disorders). Diagnostic sensitivity and specificity were evaluated in an additional 8 subjects with known ΔGAG DYT1 dystonia and 88 subjects with ΔGAG-negative dystonia.HRM of TOR1A Exon 5 showed high (100%) diagnostic sensitivity and specificity. HRM was rapid and economical. HRM reliably differentiated the TOR1A ΔGAG and c.863G>A mutations. Melting curves were normal in 250/250 controls and 1012/1014 subjects with primary dystonia. The two subjects with shifted melting curves were found to harbor the classic ΔGAG deletion: 1) a non-Jewish Caucasian female with childhood-onset multifocal dystonia and 2) an Ashkenazi Jewish female with adolescent-onset spasmodic dysphonia.First, HRM is an inexpensive, diagnostically sensitive and specific, high-throughput method for mutation discovery. Second, Exon 5 mutations in TOR1A are rarely associated with non-generalized primary dystonia.Dystonia is a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures [1]. Dystonia can be classified by etiology (primary or secondary), age of onset (childhood-onset [0–12 yrs], adolescent-onset [13–20 yrs], or late-onset [>20 yrs]), and anatomical distribution (focal, segmental, multifocal, hemidystonia, or generalized) [1-4]. Primary generalized dystonias usually begin in childhood or adolescence, whereas focal dystonias typically present during adult life. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation, with the exception that tremor may be present as well.In most neur
Glutathione S-transferase omega genes in Alzheimer and Parkinson disease risk, age-at-diagnosis and brain gene expression: an association study with mechanistic implications
Mariet Allen, Fanggeng Zou, High Chai, Curtis S Younkin, Richard Miles, Asha A Nair, Julia E Crook, V Pankratz, Minerva M Carrasquillo, Christopher N Rowley, Thuy Nguyen, Li Ma, Kimberly G Malphrus, Gina Bisceglio, Alexandra I Ortolaza, Ryan Palusak, Sumit Middha, Sooraj Maharjan, Constantin Georgescu, Debra Schultz, Fariborz Rakhshan, Christopher P Kolbert, Jin Jen, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Ryan J Uitti, Zbigniew K Wszolek, Owen A Ross, Ronald C Petersen, Neill R Graff-Radford, Dennis W Dickson, Steven G Younkin, Nilüfer Ertekin-Taner
Molecular Neurodegeneration , 2012, DOI: 10.1186/1750-1326-7-13
Abstract: We found that rs156697 minor allele associates with significantly increased risk (odds ratio = 1.14, p = 0.038) in the older ADs with age-at-diagnosis > 80 years. The minor allele of GSTO1 rs4925 associates with decreased risk in familial PD (odds ratio = 0.78, p = 0.034). There was no other association with disease risk or age-at-diagnosis. The minor alleles of both GSTO SNPs associate with lower brain levels of GSTO2 (p = 4.7 × 10-11-1.9 × 10-27), but not GSTO1. Pathway analysis of significant genes in our brain expression GWAS, identified significant enrichment for glutathione metabolism genes (p = 0.003).These results suggest that GSTO locus variants may lower brain GSTO2 levels and consequently confer AD risk in older age. Other glutathione metabolism genes should be assessed for their effects on AD and other chronic, neurologic diseases.Glutathione S-Transferase (GST) family of genes have been implicated in multiple neuropsychiatric [1-4] and neurodegenerative diseases [5-11]; where altered levels or function of these enzymes is thought to impact levels of oxidative stress and/or inflammation in a way that contributes to disease susceptibility. A linkage locus on chromosome 10q that has been implicated in both Alzheimer's (AD)[11-13] and Parkinson's disease (PD)[13] harbors two GST genes of the omega class: GSTO1 and GSTO2, which are approximately 75 kb apart.GSTOs have enzymatic activities as thioltransferases and dehydroascorbate reductases that promote antioxidant activity and can also function in metabolism of drugs and toxins[14]. Additionally, GSTO1 was shown to promote activation of the pro-inflammatory cytokine, interleukin-1β (IL-1β) by post-translational processing[15]. Given their location and function, they have been studied as candidate genes in AD and PD[5,6,9,11,14,16-18]. Li et al. compared hippocampal gene expression levels in 6 AD vs. 2 control brains and identified significantly lower GSTO1 levels in the AD hippocampi[5]. This group studied
Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research
Selina Wray, Matthew Self, NINDS Parkinson's Disease iPSC Consortium , NINDS Huntington's Disease iPSC Consortium , NINDS ALS iPSC Consortium , Patrick A. Lewis, Jan-Willem Taanman, Natalie S. Ryan, Colin J. Mahoney, Yuying Liang, Michael J. Devine, Una-Marie Sheerin, Henry Houlden, Huw R. Morris, Daniel Healy, Jose-Felix Marti-Masso, Elisavet Preza, Suzanne Barker, Margaret Sutherland, Roderick A. Corriveau, Michael D'Andrea, Anthony H. V. Schapira, Ryan J. Uitti, Mark Guttman, Grzegorz Opala, Barbara Jasinska-Myga, Andreas Puschmann, Christer Nilsson, Alberto J. Espay, Jaroslaw Slawek, Ludwig Gutmann, Bradley F. Boeve, Kevin Boylan, A. Jon Stoessl, Owen A. Ross, Nicholas J. Maragakis, Jay Van Gerpen, Melissa Gerstenhaber, Katrina Gwinn, Ted M. Dawson, Ole Isacson, Karen S. Marder, Lorraine N. Clark, Serge E. Przedborski, Steven Finkbeiner, Jeffrey D. Rothstein, Zbigniew K. Wszolek, Martin N. Rossor, John Hardy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0043099
Abstract: Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community.
Minimal Bratteli diagrams and the dimension groups of AF -algebras
Ryan J. Zerr
International Journal of Mathematics and Mathematical Sciences , 2006, DOI: 10.1155/ijmms/2006/65737
Abstract: A method is described which identifies a wide variety of AF algebra dimension groups with groups of continuous functions. The results here generalize the well-known fact that commutative AF algebras have dimension groups which can be identified with groups of integer-valued continuous functions.
A topological isomorphism invariant for certain AF algebras
Ryan J. Zerr
International Journal of Mathematics and Mathematical Sciences , 2005, DOI: 10.1155/ijmms.2005.1665
Abstract: For certain AF algebras, a topological space is described which provides an isomorphism invariant for the algebras in this class. These AF algebras can be described in graphical terms by virtue of the existence of a certain type of Bratteli diagram, and the order-preserving automorphisms of the corresponding AF algebra's dimension group are then studied by utilizing this graph. This will also provide information about the automorphism groups of the corresponding AF algebras.
A.J. Ryan
Akroterion , 2012, DOI: 10.7445/52-0-57
Abstract: With the help of a generous donation from Miss Joan Law, the Museum of Classical Archaeology has recently acquired a small Roman bronze ithyphallic herm of Pan holding a pedum or shepherd’s crook (Figs. 1 & 2) from the 1st or 2nd century CE. 1 The bottom-most part of the base has broken off, but the object is otherwise in excellent condition with slight patination. The base is rectangular up to the waist. The buttocks are not sculpted but simply indicated by a single incised line. From the waist up the details, such as the musculature, face and hair, are very finely rendered. The figure arches his back and raises his right hand to his forehead while his left hand supports a pedum. He is bearded with short unkempt hair and visible horns.
A.j. Ryan
Akroterion , 2012, DOI: 10.7445/49-0-92
Abstract: Two Egyptian artefacts from the first millennium BC have recently been acquired by the Museum of Classical Archaeology at the University of KwaZulu-Natal, courtesy of a kind donation by Miss Joan Law. At a time when academia in South Africa is placing considerable emphasis on African-oriented scholarship, it is appropriate that the museum has on display a large selection of small Egyptian artefacts dating from as early as the 4th millennium BC. These items are of particular interest for teaching as they reflect a variety of different aspects of Egyptian life.
A.J. Ryan
Akroterion , 2012, DOI: 10.7445/47-0-112
Abstract: The Museum of Classical Archaeology has on loan from Dr. David Spurrett four arrowheads of varying antiquity, ranging from the late Neolithic to the Hellenistic period. Although small, these artefacts are of significant pedagogical value to a museum whose primary function is teaching. In particular, the Classics Programme at the University of Natal allows senior students, in lieu of a research essay, to submit web projects based on the artefacts in the museum.1 Ancient weaponry and warfare has always been a popular topic for students and these items offer considerable scope for new projects.
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