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]

Linkage analysis in a large kindred with autosomal dominant transmission of polyglandular autoimmune disease type II (Schmidt syndrome)

Schmidt syndrome (PGA syndrome type II) is a rare condition characterized by polyglandular failure. It is an autosomal dominant trait with variable expressivity that was inherited over four generations in an Indiana kindred. Association of HLA-B8 has been reported with Schmidt syndrome. Our proband is a 12-year-old boy with Addison disease, insulin dependent diabetes mellitus (IDDM), and vitiligo. Two of his eight sibs had either IDDM (sister) or vitiligo and hyperthyroidism (brother). His mother had hypothyroidism. Seven members of earlier generations apparently were also affected. We obtained peripheral blood for HLA and genetic analysis from 21 relatives in a family with 8 Schmidt syndrome individuals in three generations. HLA studies on 15 affected and unaffected relatives showed only 2 of 7 persons with B8-containing haplotypes. Therefore, no association exists between the B8-containing haplotype and the syndrome. We identified informative marker loci. No evidence for linkage of the Schmidt locus to any of the 14 markers was found and close linkage to esterase D and adenylate kinase and possibly properdin factor B was excluded

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

The global prevalence of Huntington’s disease: a systematic review and discussion

The ascertained prevalence of Huntington's disease (HD) increased significantly following the provision of diagnostic testing. A systematic review was conducted to estimate the prevalence of HD in the post-diagnostic testing era. Twenty-two studies with original data pertaining to the prevalence of HD (1993–2015) were included and analyzed. A global meta-analysis was not performed due to heterogeneity in study methods and geographical variation. The prevalence of HD is significantly lower in Asian populations compared with western Europe, North America and Australia. The global variation in HD prevalence is partly explained by the average CAG repeat lengths and frequency of different HTT gene haplotypes in the general population. Understanding the prevalence of HD has significant implications for healthcare resource planning

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

Chronic Myeloid Leukemia with an e6a2 BCR-ABL1

A minority of chronic myeloid leukemia patients (CML) express a variety of atypical BCR-ABL1 fusion variants and, of these, the e6a2 BCR-ABL1 fusion is generally associated with an aggressive disease course. Progression of CML to blast crisis is associated with acquisition of additional somatic mutations yet these events have not been elucidated in patients with the e6a2 BCR-ABL1 genotype. Moreover, molecular monitoring is only sporadically performed in CML patients with atypical BCR-ABL1 fusion transcripts due to lack of consensus approaches or standardization. A case of CML is described in which comprehensive molecular analysis, including targeted next-generation sequencing, revealed a single ASXL1 mutation cooperating with an e6a2 BCR-ABL1 fusion transcript at blast crisis. A quantitative molecular monitoring approach was devised and adopted that reflected the disease response from initial treatment through allogeneic stem cell transplantation which resulted in undetectable e6a2 BCR-ABL1 transcripts. This case emphasizes the requirement for molecular monitoring in CML patients with atypical BCR-ABL1 fusion transcripts and emphasizes that comprehensive sequencing has the potential to identify targets for novel therapies in CML patients with advanced disease

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

Genetic aspects of dental disorders

The document attached has been archived with permission from the Australian Dental Association. An external link to the publisher’s copy is included.This paper reviews past and present applications of quantitative and molecular genetics to dental disorders. Examples are given relating to craniofacial development (including malocclusion), oral supporting tissues (including periodontal diseases) and dental hard tissues (including defects of enamel and dentine as well as dental caries). Future developments and applications to clinical dentistry are discussed. Early investigations confirmed genetic bases to dental caries, periodontal diseases and malocclusion, but research findings have had little impact on clinical practice. The complex multifactorial aetiologies of these conditions, together with methodological problems, have limited progress until recently. Present studies are clarifying previously unrecognized genetic and phenotypic heterogeneities and attempting to unravel the complex interactions between genes and environment by applying new statistical modelling approaches to twin and family data. linkage studies using highly polymorphic DNA markers are providing a means of locating candidate genes, including quantitative trait loci (QTL). In future, as knowledge increases: it should be possible to implement preventive strategies for those genetically-predisposed individuals who are identified-predisposed individuals who are identified to be at risk.Grant C. Townsend, Michael J. Aldred and P. Mark Bartol