The Paradigm Of Huntington Disease

I recall it as vividly as though it had occurred but yesterday. It made a most enduring impression upon my boyish mind which was my very first impulse to choosing chorea as my virgin contribution to medical lore. Driving with my father through a wooded road leading from East Hampton to Amagansett we suddenly came upon two women, mother and daughter, both tall and thin, almost cadaverous, both bowing, twisting, grimacing. I stared in wonderment, almost in fear. What could it mean? My father paused to speak with them and we passed on. Then my Gamaliel-like instruction began; my medical education had its inception. From this point on, my interest in the disease has never wholly ceased. [George Huntington, at 59, recalling how at the age of 8 years he first saw Huntington disease while traveling with his physician father on his professional rounds in 1858]

Thomas Davis's education policies: theory and practice

This thesis explores the education policies of Thomas Davis. On the eve of the Great Famine Ireland was economically impoverished and politically dependent. The Irish people had a subservient mentality, were mainly uneducated and were unaware of their potential. He believed that education would develop a self-reliant, self-sufficient people; it would create a new generation of leaders and citizens necessary to transform Ireland into a prosperous, independent nation. This thesis explores his education philosophy which was political in orientation; he called for reform of university education so that it would educate leaders who were knowledgeable, patriotic and responsible. He formulated a curriculum which consisted of knowledge that would have direct use and application in public life; his curriculum included moral philosophy, oratory, philological studies and history. His contribution to the debate on the Queens Colleges bill, 1845, is explored including his public disagreement with Daniel O’Connell on the principle of multi-denominational education. This work also examines his policies on learning methodologies and teaching methods. It provides details of his thoughts on learning by experience, by observation, book learning and learning in the home. It focuses on the deficiencies evident in the system of teaching and learning that operated in Trinity College Dublin and it provides an analysis of his preferred method of instruction: Lyceum teaching. This thesis also explores his national curriculum in history and Irish culture which was designed to forge a sense of national identity, to win support for repeal and to develop the principle of nationality. He formulated a national curriculum to counteract the absence of national knowledge in the state schools, to provide the people with a positive self-image and ultimately to empower them to reclaim Ireland and to develop it. Davis knew the power of education and he used it as an instrument of political and social change

Variability in the three-dimensional geometry of segmented normal fault surfaces

Normal faults are often complex three-dimensional structures comprising multiple sub-parallel segments separated by intact or breached relay zones. Relay zones are classified according to whether they step in the strike or dip direction and whether the relay zone-bounding fault segments are unconnected in 3D or bifurcate from a single surface. Complex fault surface geometry is described in terms of the relative numbers of different types of relay zones to allow comparison of fault geometry between different faults and different geological settings. A large database of fault surfaces compiled primarily from mapping 3D seismic reflection surveys and classified according to this scheme, reveals the diversity of 3D fault geometry. Analysis demonstrates that mapped fault geometries depend on geological controls, primarily the heterogeneity of the faulted sequence and the presence of a pre-existing structure, as well as on resolution limits and biases in fault mapping from seismic data. Where a significant number of relay zones are mapped on a single fault, a wide variety of relay zone geometries occurs, demonstrating that individual faults can comprise segments that are both bifurcating and unconnected in three dimensions.Variability in the three-dimensional geometry of segmented normal fault surfacespublishedVersio

Defining alcohol-related phenotypes in humans. The Collaborative Study on the Genetics of Alcoholism.

Alcoholism is a disease that runs in families and results at least in part from genetic risk factors. The Collaborative Study on the Genetics of Alcoholism (COGA) is a Federally funded effort to identify and characterize those genetic factors. The study involves more than 1,000 alcoholic subjects and their families, with researchers conducting comprehensive psychological, physiological, electrophysiological, and genetic analyses of the participants. These analyses have identified several traits, or phenotypes, that appear to be genetically determined, such as the presence of alcohol dependence, the level of response to alcohol, the presence of coexisting depression, or the maximum number of drinks a person consumes per occasion. Genetic analyses have identified regions on several chromosomes that are associated with these phenotypes and need to be studied further

Variability in the three-dimensional geometry of segmented normal fault surfaces

Normal faults are often complex three-dimensional structures comprising multiple sub-parallel segments separated by intact or breached relay zones. Relay zones are classified according to whether they step in the strike or dip direction and whether the relay zone-bounding fault segments are unconnected in 3D or bifurcate from a single surface. Complex fault surface geometry is described in terms of the relative numbers of different types of relay zones to allow comparison of fault geometry between different faults and different geological settings. A large database of fault surfaces compiled primarily from mapping 3D seismic reflection surveys and classified according to this scheme, reveals the diversity of 3D fault geometry. Analysis demonstrates that mapped fault geometries depend on geological controls, primarily the heterogeneity of the faulted sequence and the presence of a pre-existing structure, as well as on resolution limits and biases in fault mapping from seismic data. Where a significant number of relay zones are mapped on a single fault, a wide variety of relay zone geometries occurs, demonstrating that individual faults can comprise segments that are both bifurcating and unconnected in three dimensions.Science Foundation IrelandEuropean Commission - European Regional Development FundAnadarkoConocoPhillips (UK)EniExxonMobilEquinorShellTotal E&P UKWoodside EnergyPIPCO RS

Influence of cytogenetic abnormalities on outcome after allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission

AbstractCytogenetic abnormalities detected at diagnosis are recognized as important in predicting response to chemotherapy in acute myeloid leukemia (AML). However, there is controversy concerning the prognostic significance of karyotype for outcome after allogeneic bone marrow transplantation (allo-BMT) performed in first complete remission (CR1). This single-institution report describes allo-BMT for AML in CR1 and the effect of diagnostic cytogenetic findings on the results of that treatment. Between August 1981 and December 1999, 93 patients underwent related donor (n = 82) or unrelated donor (n = 11) BMT. Conditioning and GVHD prophylaxis were achieved predominantly with busulfan and cyclophosphamide and with cyclosporine and methotrexate, respectively. Seventy-nine (85%) of 93 patients had successful marrow karyotyping at diagnosis, and the patients were categorized into 3 prognostic groups based on the British Medical Research Council AML 10 trial classification: 15 patients(19%) were classified as having favorable risk [inv(16), t(8;2 1), t(15;17)]; 55 (70%) as having intermediate risk [no abnormality, +8, +21, +22, del(7q), del(9q), 11q23 rearrangement, and other numerical or structural abnormalities]; and 9 (11%) as having adverse risk [-5, del(5q), -7, 3q rearrangements, > or = 5 abnormalities, t(6;9), t(9;22)]. The median follow-up was 93 months (range, 16-241 months). The overall survival (OS) rate, event-free survival (EFS) rate, relapse rate, and treatment-related mortality (TRM) were not statistically different between the groups. The 5-year actuarial EFS rates for favorable, intermediate, and adverse risk groups were 58% (95% confidence interval [CI], 29%-79%), 58% (95% CI, 43%-70%), and 67% (95% CI 28%-88%), respectively. Reclassification of patients into cytogenetic prognostic subgroups according to Southwest Oncology Group criteria did not change these results. In univariate analysis, the only variable found to have a prognostic influence on OS (P = .04) and TRM (P = .03) was the type of donor (unrelated donor was linked to a worse prognosis), which was confirmed in multivariate analysis. Our study suggests that presentation karyotype has less prognostic significance for outcome following allo-BMT than for outcome following conventional chemotherapy. In particular, AML patients with poor prognostic cytogenetic changes in CR1 who are unlikely to be cured with chemotherapy alone may benefit from allo-BMT.Biol Blood Marrow Transplant 2002;8(8):435-43

Breakpoint mapping of 13 large parkin deletions/duplications reveals an exon 4 deletion and an exon 7 duplication as founder mutations

Early-onset Parkinson’s disease (EOPD) has been associated with recessive mutations in parkin (PARK2). About half of the mutations found in parkin are genomic rearrangements, i.e., large deletions or duplications. Although many different rearrangements have been found in parkin before, the exact breakpoints involving these rearrangements are rarely mapped. In the present study, the exact breakpoints of 13 different parkin deletions/duplications, detected in 13 patients out of a total screened sample of 116 EOPD patients using Multiple Ligation Probe Amplification (MLPA) analysis, were mapped using real time quantitative polymerase chain reaction (PCR), long-range PCR and sequence analysis. Deletion/duplication-specific PCR tests were developed as a rapid and low cost tool to confirm MLPA results and to test family members or patients with similar parkin deletions/duplications. Besides several different deletions, an exon 3 deletion, an exon 4 deletion and an exon 7 duplication were found in multiple families. Haplotype analysis in four families showed that a common haplotype of 1.2 Mb could be distinguished for the exon 7 duplication and a common haplotype of 6.3 Mb for the deletion of exon 4. These findings suggest common founder effects for distinct large rearrangements in parkin

Behavioral genetics and taste

This review focuses on behavioral genetic studies of sweet, umami, bitter and salt taste responses in mammals. Studies involving mouse inbred strain comparisons and genetic analyses, and their impact on elucidation of taste receptors and transduction mechanisms are discussed. Finally, the effect of genetic variation in taste responsiveness on complex traits such as drug intake is considered. Recent advances in development of genomic resources make behavioral genetics a powerful approach for understanding mechanisms of taste

Thomas Davis\u27s education policies: theory and practice

This thesis explores the education policies of Thomas Davis. On the eve of the Great Famine Ireland was economically impoverished and politically dependent. The Irish people had a subservient mentality, were mainly uneducated and were unaware of their potential. He believed that education would develop a self-reliant, self-sufficient people; it would create a new generation of leaders and citizens necessary to transform Ireland into a prosperous, independent nation. This thesis explores his education philosophy which was political in orientation; he called for reform of university education so that it would educate leaders who were knowledgeable, patriotic and responsible. He formulated a curriculum which consisted of knowledge that would have direct use and application in public life; his curriculum included moral philosophy, oratory, philological studies and history. His contribution to the debate on the Queens Colleges bill, 1845, is explored including his public disagreement with Daniel O’Connell on the principle of multi-denominational education. This work also examines his policies on learning methodologies and teaching methods. It provides details of his thoughts on learning by experience, by observation, book learning and learning in the home. It focuses on the deficiencies evident in the system of teaching and learning that operated in Trinity College Dublin and it provides an analysis of his preferred method of instruction: Lyceum teaching. This thesis also explores his national curriculum in history and Irish culture which was designed to forge a sense of national identity, to win support for repeal and to develop the principle of nationality. He formulated a national curriculum to counteract the absence of national knowledge in the state schools, to provide the people with a positive self-image and ultimately to empower them to reclaim Ireland and to develop it. Davis knew the power of education and he used it as an instrument of political and social change

The kinematics and geometry of segment boundaries on normal faults

Normal faults, when observed in detail, are commonly seen to consist of arrays of segments. The geometry of the boundaries between these segments has been extensively studied in outcrop and in subsurface geophysical datasets. Existing models generally consider that at low displacements the segments interact by deformation of the intervening rock volume, and become progressively linked as the displacement increases. The interaction and linkage of these segments is important in the formation and development of fault zones. The recent increase in availability of high quality 3-D seismic reflection data has allowed the detailed geometry of faults to be better imaged. While there are some studies focused on the geometry of segment boundaries, few have focused on the detailed small scale features of these structures and very few studies have focused on the kinematics of these structures. In this project a highly detailed analysis of the geometry and kinematics of segmented normal faults imaged in high quality 3-D seismic reflection data has been carried out. This analysis has revealed substantial departures from the relatively simple geometries and evolutionary models which are generally inferred from 2-D or lower resolution 3-D mapping. These departures include:- the formation of an array of parallel faults which become an array of interacting segments by the localisation of displacement onto shorter lengths of the established fault surfaces; the formation of a segment boundary by the propagation of a splay from a preexisting through going fault; the removal of large scale asperities and also stepping during lateral propagation of a fault giving rise to a segmented geometry. Adjustments to the existing models and a classification scheme for segment boundaries based on their 3-D geometry are proposed. Despite the observed variability in the nature of segment boundaries, all of the structures examined in this thesis formed in a way which was geometrically and kinematically coherent throughout their development and evidence for the development of segment boundaries by the coalescence of initially isolated faults has not been found. In each case, combining displacements accommodated by discontinuous (faulting) and continuous (folding) deformation yielded simple overall displacement distributions associated with a single structure. Kinematic analysis demonstrates that faulting and folding show, not only spatially complementary variations, but also, that these components are complementary in time. During the development of a segmented fault array segment boundaries are the areas where continuous deformation is most prevalent