245 results on '"Finn, Patrick"'
Search Results
202. An evaluation of the effects of supplemental “fluency” training during maintenance
- Author
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Shenker, Rosalee C., primary and Finn, Patrick, additional
- Published
- 1985
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203. Bowling for Columbine (Film).
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Finn, Patrick
- Subjects
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VIOLENCE in motion pictures , *FRAME-stories (Motion pictures) - Abstract
This article reviews the motion picture Bowling for Columbine, directed by Michael Moore, which concerned the prevalence of violence in the U.S. The movie, which allegedly is the most commercially successful documentary of all time, looks at the U.S. gun debate through the lens of a number of tragedies involving gun deaths. The double frame story examines the April 20, 1999 shootings at Columbine High School by Eric Harris and Dylan Klebold, and the continuing saga of socioeconomic strife in and around Flint, Michigan. Bowling for Columbine is allegedly an engaging film that provides a lot of interesting information. Viewer reactions to the film seem to fall into two categories, wherein one sees more left wing claptrap from the filmmaker that brought the audience the other witnesses a scathing indictment of a gun-loving, fear ridden society that is a menace to itself and its neighbors. Such distinctions neatly divide across lines already established in the gun debate between conservative, pro-gun lobbyists and liberal anti-gun protestors. The film begins with a black and white NRA promo-clip. Using a mixture of stock footage, cartoons, montages, and inter-views, Moore creates a film that allegedly is both frightening and entertaining.
- Published
- 2003
204. Book review: A Handbook on Stuttering
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Finn, Patrick
- Published
- 2009
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205. ADVANCE PRAISE FOR Hungry Minds in Hard Times.
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Finn, Patrick J.
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EDUCATION policy ,DRAWING - Abstract
A drawing depicting a student's situation is presented.
- Published
- 2002
206. MAILBOX.
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Triffo, Linda K., Cagle, Bunny, Carpenter, Steven, Finn, Patrick, and Griffiths, Allen D.
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LETTERS to the editor ,DWELLINGS ,DOMESTIC architecture ,WINE cellars ,WINE storage - Abstract
Several letters to the editor are presented in response to articles in previous issues including an article about an ancestral home in the April 2009 issue, article about the Heritage House Museum in San Bernardino, California, in the March 2009 issue and "Wine and Dine" article in the April 2009 issue.
- Published
- 2009
207. Amnio acid substitution at position 298 of human glucose-6 phosphatase-α significantly impacts its stability in mammalian cells.
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Cao, Jingsong, Markel, Arianna, Hanahoe, Erin, Ketova, Tatiana, Mihai, Cosmin, Zalinger, Zach, Marquardt, David, Amato, Nicholas J., Cheng, Yi Min, Reid, David W., Dousis, Athanasios, Giangrande, Paloma H., Schultz, Joshua R., Martini, Paolo G. V., and Finn, Patrick F.
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GLYCOGEN storage disease , *MOLECULAR genetics , *PROTEIN genetics , *SITE-specific mutagenesis , *PROTEIN expression , *CYSTEINE , *AMINO acids - Abstract
Glucose-6-phosphatase-α (G6Pase-α) catalyzes the hydrolysis of glucose-6-phosphate to glucose and functions as a key regulator in maintaining blood glucose homeostasis. Deficiency in G6Pase-α causes glycogen storage disease 1a (GSD1a), an inherited disorder characterized by life-threatening hypoglycemia and other long-term complications. We have developed a potential mRNA-based therapy for GSD1a and demonstrated that a human G6Pase-α (hG6Pase-α) variant harboring a single serine (S) to cysteine (C) substitution at the amino acid site 298 (S298C) had > twofold increase in protein expression, resulting in improved in vivo efficacy. Here, we sought to investigate the mechanisms contributing to the increased expression of the S298C variant. Mutagenesis of hG6Pase-α identified distinct protein variants at the 298 amino acid position with substantial reduction in protein expression in cultured cells. Kinetic analysis of expression and subcellular localization in mammalian cells, combined with cell-free in vitro translation assays, revealed that altered protein expression stemmed from differences in cellular protein stability rather than biosynthetic rates. Site-specific mutagenesis studies targeting other cysteines of the hG6Pase-α S298C variant suggest the observed improvements in stability are not due to additional disulfide bond formation. The glycosylation at Asparagine (N)-96 is critical in maintaining enzymatic activity and mutations at position 298 mainly affected glycosylated forms of hG6Pase-α. Finally, proteasome inhibition by lactacystin improved expression levels of unstable hG6Pase-α variants. Taken together, these data uncover a critical role for a single amino acid substitution impacting the stability of G6Pase-α and provide insights into the molecular genetics of GSD1a and protein engineering for therapeutic development. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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208. LETTERS.
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SCHINDLER, DAVID, FINN, PATRICK, EDWARDS, MALCOLM V., and SWANN, DAVID
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CHEMICALS ,CANADIAN politics & government - Abstract
Several letters to the editor are presented in response to articles in previous issues including "Gender-bending Water" in the October 2014 issue, "Reeling in Alberta" by Mari Sasano in the October 2014 issue, and "One Party State" in the September 2014 issue.
- Published
- 2014
209. Large amplitude nonlinear seakeeping using a desingularized method.
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Finn, Patrick Janssen
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- Desingularized, Large-amplitude, Method, Nonlinear Seakeeping, Ship Slamming, Using
- Abstract
Large amplitude ship motion problems are addressed using a non-linear blended time-domain strip theory. The strip theory utilizes body-exact Froude-Krylov and hydrostatic forces with linear diffraction forces. The radiation forces over the bow region are determined via a fully non-linear two-dimensional potential flow solver, while linear added mass and damping terms are used over the remainder of the hull. The two-dimensional potential flow solver uses a desingularized technique to discretize the domain. A new damping mechanism is introduced that modifies the dynamic free surface boundary condition. The new technique allows the solver to remain stable in large amplitude motions as well as free-surface impacting situations. Results are presented for a ship section oscillating in heave, sway, and roll in two dimensions. Additional results are presented for various two dimensional wedges impacting on a free surface. Finally, motions of a high-speed containership in large seas are presented.
- Published
- 2003
210. The synthesis and physical properties of backbone modified nucleic acids
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Finn, Patrick John
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- 547, Peptide nucleic acid
- Abstract
The chemical synthesis of thymine, cytosine and adenine Peptide Nucleic Acid (PNA) monomers, incorporating a protecting group strategy compatible with solid phase DNA synthesis has been achieved. PNA oligomer synthesis using novel reagents and subsequent PNA/DNA chimeric oligomer synthesis, purification and analysis are described. Ultraviolet melting studies have indicated that PNA/DNA chimeric oligomers form stable hybrids with complementary DNA. The complexes are more stable than the native DNA.DNA duplexes and mismatches involving the PNA segment are extremely destabilising compared to the native DNA.DNA mismatch. Only minor destabilisation of the complex is observed when the mismatch involved the DNA moiety of the chimeric oligomer. The chemical synthesis of 3-deoxyguanosine and 3'-deoxycytidine DNA phosphoramidites and synthesis by solid phase methodology of the corresponding 5'-2' Oligodeoxynucleotides has been successfully achieved. The oligonucleotide was analysed by Capillary Zone Electrophoresis and characterised by electrospray mass spectrometry. U.V. melting analysis indicated that the 5'-2' oligomer hybridised to complementary RNA but not DNA. The 5'-2' DNA/RNA hybrid was found to be thermally and thermodynamically less stable than the native 5'-3' DNA/RNA and RNA/RNA hybrid which could in part explain the preference for the 5'-3' linked isomer in nature.
- Published
- 1998
211. An estimate of the ultralow waste heat available in the European Union.
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Luberti, Mauro, Gowans, Robert, Finn, Patrick, and Santori, Giulio
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WASTE heat , *ENERGY industries , *PAPER pulp , *HEAT recovery , *POWER resources , *EXERGY - Abstract
A large amount of low grade heat is wasted at temperatures below 100 °C but its quantity remains mostly unknown. Therefore, the identification and quantitation of low grade heat availability enables further assessments on whether or not the recovery of this fraction of heat is convenient. By considering the countries composing the European Union (EU), this work quantifies the low grade heat from power generation and industrial sectors (mining, minerals, metals, chemicals, pulp and paper, food) with a particular focus on the faction of heat below 100 °C. The analysis shows that, in the year 2018, 8774.4∙106 GJ (2437.3 TWh) of heat was available in the EU below 100 °C, with the power generation sector accounting for 95% of the total low grade heat emitted. In addition, around 96% of the waste heat was in the temperature range from 25 °C to 80 °C, being of ultralow grade. Similar conclusions were obtained in terms of exergy loss, which was essentially from the power generation sector, especially in the range of temperatures between 40 °C and 60 °C. These results suggest that ultralow waste heat is an untapped source of energy which can be conveniently exploited by the same point-source emitters, primarily in the power generation sector or in wider industrial areas where infrastructure is present. • 8774.4∙106 GJ of heat below 100 °C in EU are from power generation and industrial sectors. • Largest fraction (7847.2⋅106 GJ) of ultralow heat in EU is between 40 °C and 60 °C. • The greatest contributor to ultralow grade waste heat is the power generation sector. • An exergy amount of 733.5∙106 GJ is available from ultralow grade waste heat. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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212. Characterization of an ornithine transcarbamylase conditional knockout mouse model: A novel model for understanding the effect of MRNA therapies for treatment of ornithine transcarbamylase deficiency.
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Zimmer, Mike, Zhou, Jenny, Liang, Shi, Yin, Ling, Frassetto, Andrea, Graham, Anne-Renee, White, Rebecca, Principe, Maria, Palmer, Tiffany, Naidu, Shan, Jacquinet, Eric, Finn, Patrick, and Martini, Paolo
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KNOCKOUT mice , *LABORATORY mice , *ORNITHINE , *ANIMAL disease models - Published
- 2024
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213. Extracellular matrix remodeling—Methods to quantify cell–matrix interactions
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Abraham, Leah C., Dice, J. Fred, Finn, Patrick F., Mesires, Nicholas T., Lee, Kyongbum, and Kaplan, David L.
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CONNECTIVE tissues , *EXTRACELLULAR matrix proteins , *ANTIGEN-antibody reactions , *BIOMEDICAL materials - Abstract
Abstract: Tissue turnover during wound healing, regeneration or integration of biomedical materials depends on the rate and extent of materials trafficking into and out of cells involved in extracellular matrix (ECM) remodeling. To exploit these processes, we report the first model for matrix trafficking in which these issues are quantitatively assessed for cells grown on both native collagen (normal tissue) and denatured collagen (wound state) substrates. Human fibroblasts more rapidly remodeled denatured versus normal collagen type I to form new ECM. Fluxes to and from the cells from the collagen substrates and the formation of new ECM were quantified using radioactively labeled substrates. The model can be employed for the systematic and quantitative study of the impact of a broad range of physiological factors and disease states on tissue remodeling, integrating extracellular matrix structures and cell biology. [Copyright &y& Elsevier]
- Published
- 2007
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214. Towards a functional neural systems model of developmental stuttering
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Ingham, Roger J., Ingham, Janis C., Finn, Patrick, and Fox, Peter T.
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STUTTERING , *BRAIN , *SPEECH disorders , *BIOLOGICAL neural networks , *NEUROLOGY , *POSITRON emission tomography - Abstract
This paper overviews recent developments in an ongoing program of brain imaging research on developmental stuttering that is being conducted at the University of Texas Health Science Center, San Antonio. This program has primarily used
H215O PET imaging of different speaking tasks by right-handed adult male and female persistent stutterers, recovered stutterers and controls in order to isolate the neural regions that are functionally associated with stuttered speech. The principal findings have emerged from studies using condition contrasts and performance correlation techniques. The emerging findings from these studies are reviewed and referenced to a neural model of normal speech production recently proposed by Ju¨rgens [Neurosci. Biobehav. Rev. 26 (2002) 235]. This paper will report (1) the reconfiguration of previous findings within the Ju¨rgens Model; (2) preliminary findings of an investigation with late recovered stutterers; (3) an investigation of neural activations during a treatment procedure designed to produce a sustained improvement in fluency; and (4) an across-studies comparison that seeks to isolate neural regions within the Ju¨rgens Model that are consistently associated with stuttering. Two regions appear to meet this criterion: right anterior insula (activated) and anterior middle and superior temporal gyri (deactivated) mainly in right hemisphere. The implications of these findings and the direction of future imaging investigations are discussed.Educational objectives: The reader will learn about (1) recent uses ofH215O PET imaging in stuttering research; (2) the use of a new neurological model of speech production in imaging research on stuttering; and (3) initial findings from PET imaging investigations of treated and recovered stutterers. [Copyright &y& Elsevier]- Published
- 2003
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215. Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4-/- mouse model of PFIC3.
- Author
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Wei, Guangyan, Cao, Jingsong, Huang, Pinzhu, An, Ping, Badlani, Disha, Vaid, Kahini A., Zhao, Shuangshuang, Wang, David Q-H., Zhuo, Jenny, Yin, Ling, Frassetto, Andrea, Markel, Arianna, Presnyak, Vladimir, Gandham, Srujan, Hua, Serenus, Lukacs, Christine, Finn, Patrick F., Giangrande, Paloma H., Martini, Paolo G.V., and Popov, Yury V.
- Subjects
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LIVER diseases , *MESSENGER RNA , *FIBROSIS , *ANIMAL disease models , *LIVER regeneration , *LIVER enzymes - Abstract
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare lethal autosomal recessive liver disorder caused by loss-of-function variations of the ABCB4 gene, encoding a phosphatidylcholine transporter (ABCB4/MDR3). Currently, no effective treatment exists for PFIC3 outside of liver transplantation. We have produced and screened chemically and genetically modified mRNA variants encoding human ABCB4 (h ABCB4 mRNA) encapsulated in lipid nanoparticles (LNPs). We examined their pharmacological effects in a cell-based model and in a new in vivo mouse model resembling human PFIC3 as a result of homozygous disruption of the Abcb4 gene in fibrosis-susceptible BALB/c. Abcb4 -/- mice. We show that treatment with liver-targeted h ABCB4 mRNA resulted in de novo expression of functional hABCB4 protein and restored phospholipid transport in cultured cells and in PFIC3 mouse livers. Importantly, repeated injections of the h ABCB4 mRNA effectively rescued the severe disease phenotype in young Abcb4 -/- mice, with rapid and dramatic normalisation of all clinically relevant parameters such as inflammation, ductular reaction, and liver fibrosis. Synthetic mRNA therapy also promoted favourable hepatocyte-driven liver regeneration to restore normal homeostasis, including liver weight, body weight, liver enzymes, and portal vein blood pressure. Our data provide strong preclinical proof-of-concept for h ABCB4 mRNA therapy as a potential treatment option for patients with PFIC3. This report describes the development of an innovative mRNA therapy as a potential treatment for PFIC3, a devastating rare paediatric liver disease with no treatment options except liver transplantation. We show that administration of our mRNA construct completely rescues severe liver disease in a genetic model of PFIC3 in mice. [Display omitted] • Synthetic liver-targeted h ABCB4 mRNA therapy was designed for PFIC3, a devastating rare paediatric liver disease. • Single injection restores hepatocyte ABCB4 expression and biliary phosphatidylcholine secretion in a genetic model of PFIC3. • Repeated administration rapidly and completely rescues PFIC3 disease in young Abcb4 -/- mice. • Treatment ameliorated liver injury, inflammation, ductular reaction, fibrosis, portal hypertension and 'failure to thrive'. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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216. Science, She Loves Me.
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Finn, Patrick
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SCIENCE & society ,NONFICTION - Abstract
The article reviews the book "Science, She Loves Me," edited by Mary Anne Moser.
- Published
- 2013
217. Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates.
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Zhu, Xuling, Yin, Ling, Theisen, Matt, Zhuo, Jenny, Siddiqui, Summar, Levy, Becca, Presnyak, Vladimir, Frassetto, Andrea, Milton, Jaclyn, Salerno, Timothy, Benenato, Kerry E., Milano, Joe, Lynn, Andy, Sabnis, Staci, Burke, Kristine, Besin, Gilles, Lukacs, Christine M., Guey, Lin T., Finn, Patrick F., and Martini, Paolo G.V.
- Subjects
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GALACTOSIDASES , *ANGIOKERATOMA corporis diffusum , *LYSOSOMAL storage diseases , *THERAPEUTICS , *PRIMATES , *MESSENGER RNA - Abstract
Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-α-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of α-Gal A in tissues and plasma. Single intravenous administration of h-α-Gal A mRNA to Gla -deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6 weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-α-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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218. Leaving Dublin.
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Finn, Patrick
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AUTOBIOGRAPHY ,NONFICTION - Abstract
The article reviews the book "Leaving Dublin: Writing My Way From Ireland to Canada," by Brian Brennan.
- Published
- 2011
219. Early experience of a virtual journal club.
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Oliphant, Raymond, Blackhall, Vivienne, Moug, Susan, Finn, Patrick, Vella, Mark, and Renwick, Andrew
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ASSOCIATIONS, institutions, etc. , *PERIODICAL articles , *SOCIAL media , *DISTANCE education , *MEDICAL education - Abstract
Background: Traditional journal club models based on didactic presentation sessions followed by group discussion have many limitations. To overcome some of these shortcomings, a virtual journal club (VJC) using social media and e-mail was developed. The aim of this study was to report the initial experience of this novel multimodal e-learning platform to facilitate journal club discussion and promote the development of critical appraisal skills. Methods: Journal articles were discussed monthly via e-mail and social media. After a 3-week period of discussion, all comments were collated and groupgenerated critical appraisal summaries were fed back to participants. In addition, letters to the journal editors based on the group appraisal were submitted. A questionnaire survey to evaluate the VJC concept was also conducted. Findings: After eight cycles of the VJC, the mean trainee participation rate was 29.6 per cent (range 21.1-42.1%). Senior trainees (≥4 years of postgraduate experience) were more likely to participate than more junior trainees (75.0 versus 21.1%; p = 0.005). The majority of participants thought that the VJC was educationally valuable, easy to participate in, helpful in keeping up to date with recent papers and useful in developing critical appraisal skills. Barriers to participation were lack of time, motivation and lack of experience in critical appraisal. In addition, the group- generated critical appraisal summaries derived from VJC discussions led to eight published 'letters to the editor'. Conclusion: This novel VJC model is a feasible and popular method of delivering a journal club in the postgraduate setting. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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220. Muscle Regeneration and Repair in the Pompe Mouse
- Author
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D'Angona, Alida, LaCasse, Emily, Finn, Patrick, Phillips, Lucy, Ziegler, Robin, Matthews, Doug, Andrews, Laura, and McVie-Wylie, Alison
- Published
- 2011
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221. "Spontaneous" late recovery from stuttering: Dimensions of reported techniques and causal attributions.
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Neumann, Katrin, Euler, Harald A., Zens, Rebekka, Piskernik, Bernhard, Packman, Ann, St. Louis, Kenneth O., Kell, Christian A., Amir, Ofer, Blomgren, Michael, Boucand, Véronique Aumont, Eggers, Kurt, Fibiger, Steen, Fourches, Audrey, Franken, Marie-Christine J.P., and Finn, Patrick
- Subjects
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STUTTERING , *AGE distribution , *ATTRIBUTION (Social psychology) , *CONTENT analysis , *CONVALESCENCE , *QUESTIONNAIRES , *SELF-evaluation , *SEX distribution , *T-test (Statistics) , *PATIENTS' attitudes , *DESCRIPTIVE statistics , *MANN Whitney U Test , *THERAPEUTICS - Abstract
• Techniques for late spontaneous recovery from stuttering clustered into six strategies. • The strategies reflect components of established treatments and naïve explanations. • Causal attributions of recovery clustered into three implicit theories about recovery. • Knowledge about strategies and implicit theories may help to improve treatment. (1) To survey the employed techniques and the reasons/occasions which adults who had recovered from stuttering after age 11 without previous treatment reported as causal to overcome stuttering, (2) to investigate whether the techniques and causal attributions can be reduced to coherent (inherently consistent) dimensions, and (3) whether these dimensions reflect common therapy components. 124 recovered persons from 8 countries responded by SurveyMonkey or paper-and-pencil to rating scale questions about 49 possible techniques and 15 causal attributions. A Principal Component Analysis of 110 questionnaires identified 6 components (dimensions) for self-assisted techniques (Speech Restructuring; Relaxed/Monitored Speech; Elocution; Stage Performance; Sought Speech Demands; Reassurance; 63.7% variance explained), and 3 components of perceived causal attributions of recovery (Life Change, Attitude Change, Social Support; 58.0% variance explained). Two components for self-assisted techniques (Speech Restructuring; Elocution) reflect treatment methods. Another component (Relaxed/Monitored Speech) consists mainly of items that reflect a common, non-professional understanding of effective management of stuttering. The components of the various perceived reasons for recovery reflect differing implicit theories of causes for recovery from stuttering. These theories are considered susceptible to various biases. This identification of components of reported techniques and of causal attributions is novel compared to previous studies who just list techniques and attributions. The identified dimensions of self-assisted techniques and causal attributions to reduce stuttering as extracted from self-reports of a large, international sample of recovered formerly stuttering adults may guide the application of behavioral stuttering therapies. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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222. Perforation of the sigmoid colon secondary to segmental absence of the intestinal musculature (SAIM) in an adult.
- Author
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Rewhorn, Matthew, Oliphant, Raymond, Jackson, Andrew, Keltie, Rachel, Going, James, and Finn, Patrick
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INTESTINAL physiology , *MUSCLES , *HOLES , *COMPUTED tomography , *DISEASES in older women - Abstract
The article presents a case study of a 68-year-old woman suffering from idiopathic peripheral neuropathy and hypertension as well as diarrhoea, abdominal pain and nausea. The patient underwent abdominal computed tomography (CT) scan before laparotomy which showed perforation at her distal signoid. An overview of pathological analysis and its uncovering of a segmental absence of the intestinal musculature (SAIM) is also presented.
- Published
- 2015
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223. Characterizing the mechanism of action for mRNA therapeutics for the treatment of propionic acidemia, methylmalonic acidemia, and phenylketonuria.
- Author
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Baek R, Coughlan K, Jiang L, Liang M, Ci L, Singh H, Zhang H, Kaushal N, Rajlic IL, Van L, Dimen R, Cavedon A, Yin L, Rice L, Frassetto A, Guey L, Finn P, and Martini PGV
- Subjects
- Animals, Mice, Humans, Male, Female, Nanoparticles chemistry, Mice, Inbred C57BL, Liposomes, Propionic Acidemia genetics, Propionic Acidemia therapy, Propionic Acidemia drug therapy, Phenylketonurias genetics, Phenylketonurias drug therapy, Phenylketonurias therapy, RNA, Messenger genetics, RNA, Messenger metabolism, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors therapy, Amino Acid Metabolism, Inborn Errors drug therapy, Disease Models, Animal
- Abstract
Messenger RNA (mRNA) therapeutics delivered via lipid nanoparticles hold the potential to treat metabolic diseases caused by protein deficiency, including propionic acidemia (PA), methylmalonic acidemia (MMA), and phenylketonuria (PKU). Herein we report results from multiple independent preclinical studies of mRNA-3927 (an investigational treatment for PA), mRNA-3705 (an investigational treatment for MMA), and mRNA-3210 (an investigational treatment for PKU) in murine models of each disease. All 3 mRNA therapeutics exhibited pharmacokinetic/pharmacodynamic (PK/PD) responses in their respective murine model by driving mRNA, protein, and/or protein activity responses, as well as by decreasing levels of the relevant biomarker(s) when compared to control-treated animals. These preclinical data were then used to develop translational PK/PD models, which were scaled allometrically to humans to predict starting doses for first-in-human clinical studies for each disease. The predicted first-in-human doses for mRNA-3927, mRNA-3705, and mRNA-3210 were determined to be 0.3, 0.1, and 0.4 mg/kg, respectively., (© 2024. The Author(s).)
- Published
- 2024
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224. Ex vivo precision-cut liver slices model disease phenotype and monitor therapeutic response for liver monogenic diseases.
- Author
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Perocheau D, Gurung S, Touramanidou L, Duff C, Sharma G, Sebire N, Finn PF, Cavedon A, Siddiqui S, Rice L, Martini PGV, Frassetto A, and Baruteau J
- Subjects
- Animals, Mice, Reproducibility of Results, Phenotype, Liver Diseases genetics, Liver Diseases therapy, Metabolic Diseases
- Abstract
Background: In academic research and the pharmaceutical industry, in vitro cell lines and in vivo animal models are considered as gold standards in modelling diseases and assessing therapeutic efficacy. However, both models have intrinsic limitations, whilst the use of precision-cut tissue slices can bridge the gap between these mainstream models. Precision-cut tissue slices combine the advantage of high reproducibility, studying all cell sub-types whilst preserving the tissue matrix and extracellular architecture, thereby closely mimicking a mini-organ. This approach can be used to replicate the biological phenotype of liver monogenic diseases using mouse models., Methods: Here, we describe an optimised and easy-to-implement protocol for the culture of sections from mouse livers, enabling its use as a reliable ex-vivo model to assess the therapeutic screening of inherited metabolic diseases., Results: We show that precision-cut liver sections can be a reliable model for recapitulating the biological phenotype of inherited metabolic diseases, exemplified by common urea cycle defects such as citrullinemia type 1 and argininosuccinic aciduria, caused by argininosuccinic synthase (ASS1) and argininosuccinic lyase (ASL) deficiencies respectively., Conclusions: Therapeutic response to gene therapy such as messenger RNA replacement delivered via lipid nanoparticles can be monitored, demonstrating that precision-cut liver sections can be used as a preclinical screening tool to assess therapeutic response and toxicity in monogenic liver diseases., Competing Interests: Competing interests: The mRNA lipid nanoparticles were provided by Moderna. JB is receiving research funding from Moderna Therapeutics, (Copyright: © 2024 Perocheau D et al.)
- Published
- 2024
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225. Development of a measure for assessing malingered incompetency in criminal proceedings: Denney competency related test (D-CRT).
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Denney RL, Thinda S, Finn PM, Fazio RL, Chen MJ, and Walsh MR
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- Humans, Male, Female, Adult, Adolescent, Reproducibility of Results, Young Adult, Middle Aged, Criminals, Psychometrics standards, Psychometrics instrumentation, Aged, Malingering diagnosis, Mental Competency, Neuropsychological Tests standards
- Abstract
Introduction: Experts frequently assess competency in criminal settings where the rate of feigning cognitive deficit is demonstrably elevated. We describe the construction and validation of the Denney Competency Related Test (D-CRT) to assess feigned incompetency of defendants in the criminal adjudicative setting. It was expected the D-CRT would prove effective at identifying feigned incompetence based on its two alternative, forced-choice and performance curve characteristics., Method: Development and validation of the D-CRT occurred in described phases. Items were developed to measure competency based upon expert review. Item analysis and adjustments were completed with 304 young teenage volunteers to obtain a proper spread of item difficulty in preparation for eventual performance curve analysis (PCA). Test-retest reliability was assessed with 44 adult community volunteers. Validation included an analog simulation design with 101 jail detainees using MacArthur Competency Assessment Test-Criminal Adjudication and Word Memory Test as criterion measures. Effects of racial/ethnic demographic differences were examined in a separate study of 208 undergraduate volunteers. D-CRT specificity was identified with 46 elderly clinic referrals diagnosed with mild cognitive impairment and dementia., Results: Item development, adjustment, and repeat analysis resulted in item probabilities evenly spread from .28 to 1.0. Test-retest correlation was good (.83). Internal consistency of items was excellent (KR-20 > .91). D-CRT demonstrated convergent validity in regard to measuring competency related information and as well as malingering. The test successfully differentiated between jail inmates asked to perforfm their best and inmates asked to simulate incompetency (AUC = .945). There were no statistically significant differences found in performance across racial/ethnic backgrounds. D-CRT specificity remained excellent among elderly clinic referrals with significant cognitive compromise at the recommended total score cutoff., Conclusions: D-CRT is an effective measure of feigned criminal incompetency in the context of potential cognitive deficiency, and PCA is assistive in the determination. Additional validation using knowns groups designs with various mental health-related conditions are needed.
- Published
- 2024
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226. Whole-body galactose oxidation as a robust functional assay to assess the efficacy of gene-based therapies in a mouse model of Galactosemia.
- Author
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Balakrishnan B, Yan X, McCue MD, Bellagamba O, Guo A, Winkler F, Thall J, Crawford L, Dimen R, Chen S, McEnaney S, Wu Y, Zimmer M, Sarkis J, Martini PGV, Finn PF, and Lai K
- Abstract
Despite the implementation of lifesaving newborn screening programs and a galactose-restricted diet, many patients with classic galactosemia develop long-term debilitating neurological deficits and primary ovarian insufficiency. Previously, we showed that the administration of human GALT mRNA predominantly expressed in the GalT gene-trapped mouse liver augmented the expression of hepatic GALT activity, which decreased not only galactose-1 phosphate (gal-1P) in the liver but also peripheral tissues. Since each peripheral tissue requires distinct methods to examine the biomarker and/or GALT effect, this highlights the necessity for alternative strategies to evaluate the overall impact of therapies. In this study, we established that whole-body galactose oxidation (WBGO) as a robust, noninvasive, and specific method to assess the in vivo pharmacokinetic and pharmacodynamic parameters of two experimental gene-based therapies that aimed to restore GALT activity in a mouse model of galactosemia. Although our results illustrated the long-lasting efficacy of AAVrh10-mediated GALT gene transfer, we found that GALT mRNA therapy that targets the liver predominantly is sufficient to sustain WBGO. The latter could have important implications in the design of novel targeted therapy to ensure optimal efficacy and safety., Competing Interests: The authors declare the following competing interests: X.Y., F.W., J.T., L.C., R.D., S.C., S.M., Y.W., M.Z., J.S., P.G.V.M., and P.F.F. are employees of Moderna and hold equities from the company., (© 2024 The Author(s).)
- Published
- 2024
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227. mRNA therapy corrects defective glutathione metabolism and restores ureagenesis in preclinical argininosuccinic aciduria.
- Author
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Gurung S, Timmermand OV, Perocheau D, Gil-Martinez AL, Minnion M, Touramanidou L, Fang S, Messina M, Khalil Y, Spiewak J, Barber AR, Edwards RS, Pinto PL, Finn PF, Cavedon A, Siddiqui S, Rice L, Martini PGV, Ridout D, Heywood W, Hargreaves I, Heales S, Mills PB, Waddington SN, Gissen P, Eaton S, Ryten M, Feelisch M, Frassetto A, Witney TH, and Baruteau J
- Subjects
- Adult, Humans, Animals, Mice, Cysteine, Glutathione, Metabolomics, Argininosuccinic Aciduria genetics, Argininosuccinic Aciduria therapy, Liver Diseases
- Abstract
The urea cycle enzyme argininosuccinate lyase (ASL) enables the clearance of neurotoxic ammonia and the biosynthesis of arginine. Patients with ASL deficiency present with argininosuccinic aciduria, an inherited metabolic disease with hyperammonemia and a systemic phenotype coinciding with neurocognitive impairment and chronic liver disease. Here, we describe the dysregulation of glutathione biosynthesis and upstream cysteine utilization in ASL-deficient patients and mice using targeted metabolomics and in vivo positron emission tomography (PET) imaging using ( S )-4-(3-
18 F-fluoropropyl)-l-glutamate ([18 F]FSPG). Up-regulation of cysteine metabolism contrasted with glutathione depletion and down-regulated antioxidant pathways. To assess hepatic glutathione dysregulation and liver disease, we present [18 F]FSPG PET as a noninvasive diagnostic tool to monitor therapeutic response in argininosuccinic aciduria. Human hASL mRNA encapsulated in lipid nanoparticles improved glutathione metabolism and chronic liver disease. In addition, hASL mRNA therapy corrected and rescued the neonatal and adult Asl-deficient mouse phenotypes, respectively, enhancing ureagenesis. These findings provide mechanistic insights in liver glutathione metabolism and support clinical translation of mRNA therapy for argininosuccinic aciduria.- Published
- 2024
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228. The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.
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Gurung S, Karamched S, Perocheau D, Seunarine KK, Baldwin T, Alrashidi H, Touramanidou L, Duff C, Elkhateeb N, Stepien KM, Sharma R, Morris A, Hartley T, Crowther L, Grunewald S, Cleary M, Mundy H, Chakrapani A, Batzios S, Davison J, Footitt E, Tuschl K, Lachmann R, Murphy E, Santra S, Uudelepp ML, Yeo M, Finn PF, Cavedon A, Siddiqui S, Rice L, Martini PGV, Frassetto A, Heales S, Mills PB, Gissen P, Clayden JD, Clark CA, Eaton S, Kalber TL, and Baruteau J
- Abstract
Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide
123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)- Published
- 2023
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229. Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice.
- Author
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Anding A, Kinton S, Baranowski K, Brezzani A, De Busser H, Dufault MR, Finn P, Keefe K, Tetrault T, Li Y, Qiu W, Raes K, Vitse O, Zhang M, Ziegler R, Sardi SP, Hunter B, and George K
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Male, Receptor, IGF Type 2 metabolism, Muscle, Skeletal metabolism, Muscle, Skeletal drug effects, Glycogen Storage Disease Type II drug therapy, Mannosephosphates metabolism, alpha-Glucosidases metabolism, 1-Deoxynojirimycin analogs & derivatives, 1-Deoxynojirimycin administration & dosage, 1-Deoxynojirimycin therapeutic use, 1-Deoxynojirimycin pharmacokinetics, 1-Deoxynojirimycin pharmacology, Enzyme Replacement Therapy methods
- Abstract
Pompe disease is a rare glycogen storage disorder caused by a deficiency in the lysosomal enzyme acid α -glucosidase, which leads to muscle weakness, cardiac and respiratory failure, and early mortality. Alglucosidase alfa, a recombinant human acid α -glucosidase, was the first approved treatment of Pompe disease, but its uptake into skeletal muscle via the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) is limited. Avalglucosidase alfa has received marketing authorization in several countries for infantile-onset and/or late-onset Pompe disease. This recently approved enzyme replacement therapy (ERT) was glycoengineered to maximize CIMPR binding through high-affinity interactions with ∼7 bis-M6P moieties. Recently, small molecules like the glucosylceramide synthase inhibitor miglustat were reported to increase the stability of recombinant human acid α -glucosidase, and it was suggested that an increased serum half-life would result in better glycogen clearance. Here, the effects of miglustat on alglucosidase alfa and avalglucosidase alfa stability, activity, and efficacy in Pompe mice were evaluated. Although miglustat increased the stability of both enzymes in fluorescent protein thermal shift assays and when incubated in neutral pH buffer over time, it reduced their enzymatic activity by ∼50%. Improvement in tissue glycogen clearance and transcriptional dysregulation in Pompe mice correlated with M6P levels but not with miglustat coadministration. These results further substantiate the crucial role of CIMPR binding in lysosomal targeting of ERTs. SIGNIFICANCE STATEMENT: This work describes important new insights into the treatment of Pompe disease using currently approved enzyme replacement therapies (ERTs) coadministered with miglustat. Although miglustat increased the stability of ERTs in vitro, there was no positive impact to glycogen clearance and transcriptional correction in Pompe mice. However, increasing mannose-6-phosphate levels resulted in increased cell uptake in vitro and increased glycogen clearance and transcriptional correction in Pompe mice, further underscoring the crucial role of cation-independent mannose-6-phosphate receptor-mediated lysosomal targeting for ERTs., (Copyright © 2023 by The Author(s).)
- Published
- 2023
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230. GLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals.
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Ter Huurne M, Parker BL, Liu NQ, Qian EL, Vivien C, Karavendzas K, Mills RJ, Saville JT, Abu-Bonsrah D, Wise AF, Hudson JE, Talbot AS, Finn PF, Martini PGV, Fuller M, Ricardo SD, Watt KI, Nicholls KM, Porrello ER, and Elliott DA
- Subjects
- Humans, Myocytes, Cardiac, RNA, RNA, Messenger, Induced Pluripotent Stem Cells, Fabry Disease genetics, Fabry Disease therapy
- Abstract
Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart., Competing Interests: Declaration of interests R.J.M., J.E.H., and E.R.P. are co-founders, scientific advisors, and hold equity in Dynomics, a biotechnology company focused on the development of heart failure therapeutics. P.F. and P.G.V.M. are employees of and hold equity in Moderna., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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231. Systematic literature review of the epidemiology of glycogen storage disease type 1a.
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Zelei T, Kovács S, Finn P, Nagy D, Sikirica V, Carlson KB, and Vokó Z
- Subjects
- Infant, Newborn, Humans, Pregnancy, Female, Glucose-6-Phosphatase, Parents, Parturition, Glycogen Storage Disease Type I epidemiology
- Abstract
Glycogen storage disease (GSD) type 1a is an inherited autosomal recessive metabolic disease caused by a deficiency in glucose-6-phosphatase activity. The objectives of this research were to systematically review the published literature on the epidemiology of GSD 1a and to assess the performance of reported epidemiology measures in a simulation model. In this systematic literature review 2,539 record titles and abstracts were screened. Of these, only 11 studies contained relevant data on GSD 1a disease epidemiology. Reported disease frequency ranged from 0.085/100,000 to 10.3/100,000 newborns when considering all the GSD literature. When this was narrowed to GSD 1 and GSD 1a, the range was tightened to 0.25-3.02/100,000 and 0.085-4.9/100,000 newborns, respectively. Most of the identified studies counted the number of diagnoses in a defined period and related to the number of births in the same (Dx method) or different time period (DoB method). The simulation model results indicate that in most of the situations, the Dx method provides a closer estimate to the true disease incidence than the DoB method. Despite the scarcity of epidemiology data, the results of this systematic review strongly support that GSD 1a and its parent disease groups (GSD and GSD 1) are rare diseases., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)
- Published
- 2023
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232. The relationship between health-related quality of life, perceived social support, and social network size in African Americans with aphasia: a cross-sectional study.
- Author
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Gadson DS, Wallace G, Young HN, Vail C, and Finn P
- Subjects
- Adult, Black or African American, Case-Control Studies, Cross-Sectional Studies, Humans, Quality of Life psychology, Social Networking, Social Support, Aphasia etiology, Aphasia psychology, Stroke complications
- Abstract
Stroke significantly impairs health-related quality of life (HRQL). Stroke survivors with aphasia (SWA) experience lower HRQL than stroke survivors without aphasia (SSA) as a result of poorer communication and social functioning. The extent to which aphasia influences HRQL in African-Americans and the components of social functioning that are most important to HRQL warrants further exploration.There were two main objectives of this paper. The first was to survey HRQL domains of communication, physical, mental/emotional, role, and social functioning in African American SWA and SSA. The second was to examine if social support and social network predicted HRQL in SWA.A total of 39 African American adults (62.4 ± 11.10) participated in this descriptive cross-sectional case control study. Patient-reported outcome measures were used to assess HRQL, perceived social support, and social network in SWA, SSA, and normal-aging healthy controls (NAH). Data analysis included an ANOVA and moderator regression to determine if social support or social network predicted HRQL in SWA.SWA reported a significantly lower overall HRQL (p = <.000) than NAH adults. Communication HRQL was the hallmark difference found between SWA and SSA (p = <.000). Social support and social network were relatively similar among all three groups. However, social support and social network did not predict HRQL in SWA.Findings from this study suggest that social HRQL continues to be significantly lower in SWA; however, social support and social network factors do not drive differences among African-Americans. Moreover, communication HRQL remains the hallmark difference between SWA and SSA.
- Published
- 2022
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233. mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease.
- Author
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Cao J, Choi M, Guadagnin E, Soty M, Silva M, Verzieux V, Weisser E, Markel A, Zhuo J, Liang S, Yin L, Frassetto A, Graham AR, Burke K, Ketova T, Mihai C, Zalinger Z, Levy B, Besin G, Wolfrom M, Tran B, Tunkey C, Owen E, Sarkis J, Dousis A, Presnyak V, Pepin C, Zheng W, Ci L, Hard M, Miracco E, Rice L, Nguyen V, Zimmer M, Rajarajacholan U, Finn PF, Mithieux G, Rajas F, Martini PGV, and Giangrande PH
- Subjects
- Animals, Cell Line, Tumor, Cytokines blood, Cytokines metabolism, Glucose-6-Phosphatase metabolism, Glycogen metabolism, Glycogen Storage Disease genetics, Glycogen Storage Disease pathology, HeLa Cells, Humans, Liver metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Nanoparticles administration & dosage, Nanoparticles chemistry, RNA, Messenger administration & dosage, RNA, Messenger chemistry, Treatment Outcome, Triglycerides metabolism, Mice, Disease Models, Animal, Genetic Therapy methods, Glucose-6-Phosphatase genetics, Glycogen Storage Disease therapy, RNA, Messenger genetics
- Abstract
Glycogen Storage Disease 1a (GSD1a) is a rare, inherited metabolic disorder caused by deficiency of glucose 6-phosphatase (G6Pase-α). G6Pase-α is critical for maintaining interprandial euglycemia. GSD1a patients exhibit life-threatening hypoglycemia and long-term liver complications including hepatocellular adenomas (HCAs) and carcinomas (HCCs). There is no treatment for GSD1a and the current standard-of-care for managing hypoglycemia (Glycosade
® /modified cornstarch) fails to prevent HCA/HCC risk. Therapeutic modalities such as enzyme replacement therapy and gene therapy are not ideal options for patients due to challenges in drug-delivery, efficacy, and safety. To develop a new treatment for GSD1a capable of addressing both the life-threatening hypoglycemia and HCA/HCC risk, we encapsulated engineered mRNAs encoding human G6Pase-α in lipid nanoparticles. We demonstrate the efficacy and safety of our approach in a preclinical murine model that phenotypically resembles the human condition, thus presenting a potential therapy that could have a significant therapeutic impact on the treatment of GSD1a.- Published
- 2021
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234. mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency.
- Author
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Cao J, An D, Galduroz M, Zhuo J, Liang S, Eybye M, Frassetto A, Kuroda E, Funahashi A, Santana J, Mihai C, Benenato KE, Kumarasinghe ES, Sabnis S, Salerno T, Coughlan K, Miracco EJ, Levy B, Besin G, Schultz J, Lukacs C, Guey L, Finn P, Furukawa T, Giangrande PH, Saheki T, and Martini PGV
- Subjects
- Animals, Behavior, Animal drug effects, Disease Models, Animal, Gene Knockout Techniques, Glucosephosphate Dehydrogenase genetics, HeLa Cells, Hep G2 Cells, Humans, Lipids chemistry, Loss of Function Mutation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria metabolism, Nanoparticles chemistry, Open Reading Frames genetics, RNA, Messenger chemical synthesis, RNA, Messenger chemistry, RNA, Messenger genetics, Transfection, Treatment Outcome, Citrullinemia drug therapy, Citrullinemia metabolism, Drug Delivery Systems methods, Genetic Therapy methods, Mitochondrial Membrane Transport Proteins genetics, Mitochondrial Membrane Transport Proteins metabolism, RNA, Messenger therapeutic use
- Abstract
Citrin deficiency is an autosomal recessive disorder caused by loss-of-function mutations in SLC25A13, encoding the liver-specific mitochondrial aspartate/glutamate transporter. It has a broad spectrum of clinical phenotypes, including life-threatening neurological complications. Conventional protein replacement therapy is not an option for these patients because of drug delivery hurdles, and current gene therapy approaches (e.g., AAV) have been hampered by immunogenicity and genotoxicity. Although dietary approaches have shown some benefits in managing citrin deficiency, the only curative treatment option for these patients is liver transplantation, which is high-risk and associated with long-term complications because of chronic immunosuppression. To develop a new class of therapy for citrin deficiency, codon-optimized mRNA encoding human citrin (hCitrin) was encapsulated in lipid nanoparticles (LNPs). We demonstrate the efficacy of hCitrin-mRNA-LNP therapy in cultured human cells and in a murine model of citrin deficiency that resembles the human condition. Of note, intravenous (i.v.) administration of the hCitrin-mRNA resulted in a significant reduction in (1) hepatic citrulline and blood ammonia levels following oral sucrose challenge and (2) sucrose aversion, hallmarks of hCitrin deficiency. In conclusion, mRNA-LNP therapy could have a significant therapeutic effect on the treatment of citrin deficiency and other mitochondrial enzymopathies with limited treatment options., (Copyright © 2019 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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235. Critical Thinking Is a Noble Endeavor-A Response to Paul's Question: An Invited Essay.
- Author
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Finn P
- Subjects
- Humans, Empathy physiology, Self Concept, Thinking
- Abstract
Paul (2018a, 2018b) discussed the concept of critical thinking in a series of American Annals of the Deaf editorials examining how critical thinking might serve as a "springboard" to deep knowledge or wisdom and wondering if critical thinking should be viewed as a noble endeavor or hopeless cause. Paul explored three questions in which he considered (a) types of critical thinkers, (b) teaching and evaluating critical thinking, and (c) empathy's role in critical thinking. Responding to Paul, the author focuses on the same questions by summarizing Paul's view, then following with his own. He also explores the question What is critical thinking? Mostly, the author's views resemble Paul's, but he elaborates on places where he thinks gaps or possible misunderstandings exist. The author concludes that critical thinking is indeed a noble endeavor because it is not just what you think that matters, but how you think.
- Published
- 2019
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236. Proteolytic and lipolytic responses to starvation.
- Author
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Finn PF and Dice JF
- Subjects
- Acyl Coenzyme A metabolism, Autophagy, Enzyme Activation, Fatty Acids, Nonesterified metabolism, Humans, Ketone Bodies metabolism, Lysosomes metabolism, Molecular Chaperones physiology, Muscle Proteins metabolism, Muscle, Skeletal chemistry, Proteasome Endopeptidase Complex metabolism, Triglycerides metabolism, Ubiquitin metabolism, Lipolysis, Peptide Hydrolases metabolism, Starvation metabolism
- Abstract
Mammals survive starvation by activating proteolysis and lipolysis in many different tissues. These responses are triggered, at least in part, by changing hormonal and neural statuses during starvation. Pathways of proteolysis that are activated during starvation are surprisingly diverse, depending on tissue type and duration of starvation. The ubiquitin-proteasome system is primarily responsible for increased skeletal muscle protein breakdown during starvation. However, in most other tissues, lysosomal pathways of proteolysis are stimulated during fasting. Short-term starvation activates macroautophagy, whereas long-term starvation activates chaperone-mediated autophagy. Lipolysis also increases in response to starvation, and the breakdown of triacylglycerols provides free fatty acids to be used as an energy source by skeletal muscle and other tissues. In addition, glycerol released from triacylglycerols can be converted to glucose by hepatic gluconeogenesis. During long-term starvation, oxidation of free fatty acids by the liver leads to the production of ketone bodies that can be used for energy by skeletal muscle and brain. Tissues that cannot use ketone bodies for energy respond to these small molecules by activating chaperone-mediated autophagy. This is one form of interaction between proteolytic and lipolytic responses to starvation.
- Published
- 2006
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237. "Roadblocks" revisited: neural change, stuttering treatment, and recovery from stuttering.
- Author
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Ingham RJ, Finn P, and Bothe AK
- Subjects
- Adolescent, Adult, Child, Humans, Mental Recall, Psycholinguistics, Recovery of Function, Research Design, Speech Therapy, Treatment Outcome, Verbal Behavior, Cognition physiology, Neuronal Plasticity physiology, Stuttering physiopathology, Stuttering therapy
- Abstract
Unlabelled: In light of emerging findings concerning untreated recovery and neural plasticity, this paper re-examines the viability of an NIH conference recommendation [Cooper, J. A. (1990). Research directions in stuttering: Consensus and conflict. In Cooper, J. A. (Ed.), Research needs in stuttering: Roadblocks and future directions (pp. 98-100). Rockville, MD: American Speech-Language-Hearing Association.] that adults who have recovered from stuttering might inform our understanding of the nature and treatment of persistent stuttering. It is suggested that those who have recovered could constitute a behavioral, cognitive, and neurophysiologic benchmark for evaluating stuttering treatment for adolescents and adults, while helping to identify the limits of recovery from a persistent disorder. This possibility seems especially promising because of findings from recent studies investigating untreated recovery during childhood and adulthood, the emerging evidence concerning neural plasticity and reorganization, and reports of neural system changes during stuttering treatment. Potential obstacles to applying findings from unassisted recovery to treatment do exist, but the benefits of attempts to fully understand stuttering certainly outweigh the difficulties., Educational Objectives: After completing this activity, the learner will be able to: (1) describe two complexities involved in determining whether recovery from stuttering was assisted or unassisted; (2) discuss the implications for stuttering research of two neural plasticity research findings from areas other than stuttering; and (3) evaluate the possible implications for stuttering treatment of a coordinated research program that addresses behavioral, cognitive, and neurological characteristics of assisted and unassisted recovery from stuttering.
- Published
- 2005
- Full Text
- View/download PDF
238. Unassisted recovery from stuttering: self-perceptions of current speech behavior, attitudes, and feelings.
- Author
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Finn P, Howard R, and Kubala R
- Subjects
- Adult, Aged, Attitude, Cognition, Emotions, Female, Humans, Interviews as Topic, Male, Middle Aged, Reproducibility of Results, Speech Intelligibility, Verbal Behavior, Convalescence psychology, Self-Assessment, Stuttering psychology
- Abstract
Unlabelled: The purpose of this study was to investigate the nature of recovery from stuttering based on the experiences of adults who recovered without treatment. Using a semi-structured, open-ended interview format, 15 speakers verified as persons who recovered without treatment were asked to describe their status as everyday speakers. Seven speakers reported that they no longer stuttered and eight reported that they still stuttered on occasion. Interview material was coded and analyzed by the investigators and checked by independent judges. Results suggested that complete recovery was possible for speakers who reported that they no longer stuttered; whereas, those who still stuttered occasionally appeared to no longer be handicapped by stuttering, but required some vigilance to maintain their relatively fluent speech., Educational Objectives: After completing this activity, the learner will be able to: (1) describe the relevance of self-report data for evaluating the nature of recovery from stuttering without treatment; (2) describe the differences in self-perception concerning the nature of recovery for those who no longer have any tendency to stutter compared to those who still have an occasional tendency to stutter; and (3) suggest the possible implications for understanding the nature of recovery from persistent stuttering based on investigations of late recovery without treatment.
- Published
- 2005
- Full Text
- View/download PDF
239. Evidence-based treatment of stuttering: II. Clinical significance of behavioral stuttering treatments.
- Author
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Finn P
- Subjects
- Biomedical Research trends, Decision Making, Endpoint Determination, Humans, Stuttering psychology, Treatment Outcome, Evidence-Based Medicine, Speech Therapy, Stuttering therapy
- Abstract
Unlabelled: An evidence-based framework can be described as an empirically-driven, measurement-based, client-sensitive approach for selecting treatments. It is believed that using such a framework is more likely to result in a clinically significant outcome. For this paper, a clinically significant outcome was defined as a meaningful treatment change. It was suggested that there are at least three groups for whom a treatment's outcome is meaningful. These groups include clinicians/clinical researchers, the clients, and relevant others who have some interest in the outcome (e.g., parents of a child who stutters). The meaning and measurement of clinical significance was discussed for each of these three groups, based on research from the behavioral stuttering treatment literature., Educational Objectives: The reader will learn about and be able to (1) broadly define a clinically significant outcome and identify some of the groups who are interested in such an outcome and (2) describe how clinical significance has been evaluated in stuttering treatment within an evidence-based framework.
- Published
- 2003
- Full Text
- View/download PDF
240. Efficient incorporation of positively charged 2', 3'-dideoxynucleoside-5'-triphosphates by DNA polymerases and their application in 'direct-load' DNA sequencing.
- Author
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Finn PJ, Bull MG, Xiao H, Phillips PD, Nelson JR, Grossmann G, Nampalli S, McArdle BF, Mamone JA, Flick PK, Fuller CW, and Kumar S
- Subjects
- Base Sequence, Chromatography, High Pressure Liquid methods, Coloring Agents chemistry, DNA chemistry, DNA genetics, Lysine chemistry, Molecular Sequence Data, Molecular Structure, Nucleotides chemistry, Nucleotides genetics, Reproducibility of Results, Sensitivity and Specificity, DNA-Directed DNA Polymerase metabolism, Dideoxynucleosides chemistry, Lysine analogs & derivatives, Nucleotides metabolism, Sequence Analysis, DNA methods
- Abstract
A series of charge-modified, dye-labeled 2', 3'-dideoxynucleoside-5'-triphosphates have been synthesized and evaluated as reagents for dye-terminator DNA sequencing. Unlike the commonly used dye-labeled terminators, these terminators possess a net positive charge and migrate in the opposite direction to dye-labeled Sanger fragments during electrophoresis. Post-sequencing reaction purification is not required to remove unreacted nucleotide or associated breakdown products prior to electrophoresis. Thus, DNA sequencing reaction mixtures can be loaded directly onto a separating medium such as a sequencing gel. The charge-modified nucleotides have also been shown to be more efficiently incorporated by a number of DNA polymerases than regular dye-labeled dideoxynucleotide terminators or indeed normal dideoxynucleoside-5'-triphosphates.
- Published
- 2003
- Full Text
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241. Addressing generalization and maintenance of stuttering treatment in the schools: a critical look.
- Author
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Finn P
- Subjects
- Adolescent, Child, Child, Preschool, Humans, Self Efficacy, Social Control, Informal, Generalization, Psychological, School Health Services, Speech Therapy methods, Stuttering therapy
- Abstract
Unlabelled: Generalization and maintenance are a widely recognized challenge for stuttering treatment. There are many reasons why this is the case. First, there is no accepted model of recovery, though self-efficacy may be a helpful construct and, secondly, the client's age, stuttering severity, and negative attitudes may be complicating factors. Three strategies for promoting generalization and maintenance in school settings are suggested based on current research evidence. They include probing and training for generalization, incorporating real-life elements into therapy, and training clients to self-regulate their behavior. These strategies appear to be viable and practical, but further research is needed to fully evaluate their effectiveness for school settings., Learning Outcomes: Readers will learn about (1) typical approaches to managing stuttering in the school setting, (2) barriers to generalization and maintenance of stuttering treatment gains, and (3) three strategies for promoting generalization and maintenance.
- Published
- 2003
- Full Text
- View/download PDF
242. Synthesis and application of charge-modified dye-labeled dideoxynucleoside-5'-triphosphates to 'direct-load' DNA sequencing.
- Author
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Finn PJ, Sun L, Nampalli S, Xiao H, Nelson JR, Mamone JA, Grossmann G, Flick PK, Fuller CW, and Kumar S
- Subjects
- Coloring Agents chemistry, DNA genetics, DNA metabolism, Electrophoresis methods, Mutation, Reproducibility of Results, Taq Polymerase genetics, Taq Polymerase metabolism, DNA chemistry, Deoxyribonucleotides chemistry, Sequence Analysis, DNA methods
- Abstract
A novel series of charge-modified, dye-labeled 2',3'-dideoxynucleoside-triphosphate terminators were synthesized and evaluated as reagents for DNA sequencing. These terminators possess an advantage over existing reagents in that no purification is required to remove unreacted nucleotide or associated breakdown products prior to electrophoretic separation of the sequencing fragments. This obviates the need for a time consuming post-reaction work up, allowing direct loading of DNA sequencing reaction mixtures onto a slab gel. Thermo Sequenase II DNA polymerase poorly incorporates the charge-modified terminators compared with regular dye-labeled terminators. However, extending the linker arm between dye and nucleotide and using a mutant form of a related DNA polymerase can in part mitigate the decrease in substrate efficiency. We also present evidence that these charge-modified terminators can relieve gel compression artefacts when used with dGTP in sequencing reactions.
- Published
- 2002
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243. Thomas Lodge.
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Finn, Patrick
- Subjects
Lodge, Thomas, ca. 1558-1625 - Abstract
English novelist, poet, and translator. Thomas Lodge was possibly born in London in 1558, the same year that Henry VIII took the throne. Lodge was educated at Oxford University. A prolific writer, he published extensively in a number of genres. His father, Sir Thomas Lodge, had an auspicious political career, serving as an alderman and, for a time, as the lord mayor of London. His income, however, was not sufficient to offer his son a lavish education.
- Published
- 2022
244. John Heywood.
- Author
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Finn, Patrick
- Subjects
Heywood, John, ca. 1497-ca. 1580 - Abstract
English playwright and poet. John Heywood, an English dramatist and poet, was possibly born in London. A staunch, but by no means pedantic Catholic, the events of his life would largely be determined by his commitment to that faith. He was friends with Sir Thomas More, and was familiar at court with Henry VIII, Edward VI, and Mary I. Once Elizabeth I came to power in 1558, he fell out of favor. The Protestantism advocated during that reign left little room for Heywood’s outspoken theological position. His beliefs were clearly illustrated in his long poem The Spider and the Fly, where he cast Roman Catholics as flies and Protestants as the spiders with Queen Mary as the heroine destroying the spiders under the direction of a benevolent God. As a result of this change in the state of religion in England, Heywood moved to Belgium where he spent the rest of his life. This move, while not legislated, allowed him to continue to practice his faith more freely.
- Published
- 2022
245. Robert Sidney.
- Author
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Finn, Patrick
- Subjects
Sidney, Robert - Abstract
English poet. Sir Robert Sidney was the fifth of six children born to Sir Henry Sidney, of whom only three survived. The children’s father was lord deputy of Ireland, and their uncle was Robert Dudley, earl of Leicester, who may have given his name to his nephew. His older brother, Sir Philip (1554-1586), and sister, Mary, countess of Pembroke (1561-1621), both distinguished themselves in letters and politics. The fertile ground that led to this productive mix was the family home at Penshurst Place.
- Published
- 2022
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