Heart disease remains the leading cause of death globally, and prevalence has nearly doubled over the past three decades. It is estimated that up to 90% of cardiovascular events are preventable, but early detection and treatment is crucial. In this dissertation, we report on the optimization of the ultrasound-based cardiac strain imaging technique known as Myocardial Elastography (ME), a method for the detection of the most common and most lethal forms of heart disease: Coronary Artery Disease (CAD) which affects the major coronary arteries, and Coronary Microvascular Disease (CMD) which affects smaller coronary vessels. CAD has historically been the primary focus of clinical cardiac imaging, whereas CMD has been under-diagnosed due to a lack of awareness and challenges associated with imaging at the microvascular level. Ultrasound-based cardiac strain imaging has been shown capable of detecting functional changes due to CAD and may be effective in CMD detection, although the latter has not yet been sufficiently investigated. However, the diagnostic accuracy of strain imaging is reduced by noise from transcostal imaging, known as clutter, and by the limited lateral resolution of high framerate ultrasound. These factors preclude accurate strain imaging in up to 30% of patients. Myocardial elastography is a precise high framerate strain imaging technique that analyzes radiofrequency (RF) signals to quantify myocardial deformation. We hypothesize that ME can effectively image and diagnose the functional effects of CMD and CAD, and that novel beamforming and clutter-filtering techniques can improve ME imaging and strain estimation quality, thereby increasing diagnostic accuracy. To improve disease detection, Stress ME (S-ME) was proposed as a method to compare strain measurements at rest to strain during induced cardiac stress. A novel strain difference (Δ𝜺) metric was presented and investigated in a canine model of induced acute ischemia, as well as in a human CAD patient study with validation by myocardial perfusion imaging. In the canine model, flow-limiting stenosis was induced by partial ligation in N=2 canines, and stenosis was found to significantly reduce Δ𝜺 in the affected myocardial regions. In the clinical study, radial and circumferential ME strain and radial Δ𝜺 was measured in N=49 myocardial segments from 8 patients suspected to have ischemia or infarction due to CAD. The median Δ?, radial strain, and circumferential strain magnitudes were lowest in infarcted regions and highest in regions with normal perfusion, while measurements in ischemic regions fell in between. ROC analysis of radial strain metrics revealed that Δ𝜺 had the highest AUC for detecting ischemia (AUC=0.788 p<0.01) and infarction (AUC=0.792, p<0.05), followed by radial strain during stress (ischemia AUC=0.774 p<0.05, infarct AUC=0.758 p<0.05) while the AUC was lowest when considering only the radial strain at rest (ischemia AUC=0.52 p>0.05, infarct AUC=0.58 p>0.05). The results thus indicate that S-ME may improve detection of mild CAD cases that are functionally asymptomatic at rest. Despite these promising findings, accurate strain imaging remains hindered by clutter noise and poor image quality. Two complementary techniques were thus developed to improve image quality and strain estimation in high frame rate cardiac strain imaging; a novel Sliding Window implementation of the Minimum Variance beamformer (SWMV) was proposed to enhance speckle quality, while a spatiotemporal singular value decomposition filter (SVD) was developed to increase tissue visibility and contrast by suppressing static clutter signals using automated cutoff selection. SWMV and SVD were shown to effectively improve image quality in simulation studies and phantom imaging experiments. In vivo performance evaluation consisted of applying SWMV beamforming and SVD filtering techniques to a dataset of N=70 strain images from 13 patients suspected to have CAD. CCTA imaging was used for validation of strain estimation. Tracking was improved in 92% of cases with a median improvement of 15% in displacement estimation accuracy as evaluated by an intersection-over-union (IoU) metric. The proposed techniques also improve agreement with CCTA results; ROC analysis shows improved AUC with SWMV+SVD compared to DAS when comparing healthy regions to those with any degree of stenosis (AUC 0.64 vs 0.56) as well as when comparing healthy to severely stenosed regions (AUC 0.69 vs 0.60). The observed results point to significant improvement in strain estimation reliability due to SWMV beamforming combined with SVD processing. The final aim and the overarching goal of this work is a culmination of the previous sections for a clinical evaluation of ME as a diagnostic tool for CAD and CMD. In this clinical study, the enhanced ME technique utilizing SWMV and SVD filtering was applied to a cohort of N=201 patients with suspected coronary disease. All patients underwent invasive angiography or noninvasive cardiac imaging in the form of coronary computed tomography or nuclear stress testing. In addition, demographic information and patient clinical history were collected and accounted for in a multivariate statistical analysis. A K-nearest-neighbor (KNN) classifier was trained to distinguish between healthy and stenosed myocardial regions, and achieved an AUC of 0.91, with sensitivity of 86% and a specificity of 85% after training with 10-fold cross validation. CMD was also shown to significantly reduce regional strain measurements. This retrospective study identified the clinical factors which impact strain, and assessed the potential advantages of incorporating ME imaging to the existing clinical imaging pipeline for CAD and CMD diagnosis.

Alzheimer's disease~(AD) is the most frequent neurodegenerative dementia and a growing health problem. Early and accurate diagnosis and prediction of AD is crucial because treatment may be most efficacious if introduced as early as possible. Neuropsychological testing, which is clinically used, sometimes fails to recognize probable dementia, especially to recognize the disease at an early time point such as the mild cognitive impairment~(MCI), which is the prodromal stage of AD. Recently, there has been a realization that magnetic resonance imaging~(MRI) may help diagnoses of AD and MCI. In this dissertation, we introduce an MRI-analysis based algorithm to help diagnose the illness before irreversible neuronal loss has set in, and to help detect brain changes between MCI patients who may convert and may not convert to AD. Given a set of brain MR images, the algorithm first calculates the distance between each pair of images via a registration process. Then images are projected from a high dimensional Euclidean space to a low dimensional Euclidean subspace based on the calculated distances, with a dimension reduction method. Finally classical supervised classification approaches are employed to assign images to appropriate groups in the low dimensional space. The classification accuracy rates we obtained in our experiments are higher than, or at least comparable to, those reported in recently published papers. Moreover, this algorithm can be extended to explore the pathology distribution of AD. Exploring the distribution of AD pathology is of great importance to reveal AD related regional atrophy at specific stages of the disease and provide insight into longitudinal sequence of disease progression. Calculating distances between different brain structures produces different classification accuracy. Those structures yielding higher classification accuracy are considered as pathological regions. Our experimental results on pathology localization are also compared with the reproduced results using other existing popular algorithms; the observations are consistent. / Ph. D.

In conclusion, gene expression profiling in blood may have potential to be an adjuvant marker for early detection of AD. Expression marker panel is more informative than single gene expression signature. Further validation in prospective studies will substantiate its clinical application and explore its potential to differentiate AD from other dementias and to predict the progression from MCI to AD. (Abstract shortened by UMI.) / In the study, the profile of 12 target gene expression levels in peripheral blood cells were determined in 96 AD, 145 MCI and 167 normal controls (NC) by quantitative real-time RT-PCR. The genes were identified with (i) high expression in blood and brain; (ii) differential expression between AD and control; (iii) AD related candidate genes. Then, a list of genes were selected including CTSB, CTSD, DDT, ITPKB, NDUFA6, NRD1, PIN1, SNX2, TSC1, UQCRC1, CNR2, GSTM3. Seven genes were found to be differentially expressed between AD and NC group, with upregulation of CTSB, CTSD, DDT, TSC1 and UQCRC1, and downregulation of ITPKB and PIN1 in AD patients. Expression levels of two genes were increased in the MCI compared with NC group, including CTSB and CTSD. In addition, an upregulation of CTSD, UQCRC1, NRD1 and downregulation of ITPKB were observed in AD subjects in comparison to the MCI group (Mann-Whitney U test, p&lt;0.05). After adjusting for confounding factors of age, gender, education level, ApoE4 status and the total CIRS score, expression level of any single gene was not associated with the classfication of AD or MCI (Logistic regression, p>0.05). A five gene biomarker panel, including DDT, ITPKB, PIN1, TSC1 and UQCRC1 was identified with logistic regression analysis. The function of Logit(P)= ln(P/(1-P))= b0+b1RatioDDT+ b2RatioITPKB + b3Ratio PIN1 +b4 RatioTSC1+b5Ratio UQCRC1 were defined as the probability of a subject to be diagnosed as "AD" or "MCI' by using 5-gene biomarker panel. ROC analysis showed that the AUC for the 5-gene biomarkers panel in differentiating between AD and NC, between MCI and NC, between AD and MCI were 0.79 (95% CI, 0.72-0.86; p&lt;0.001), 0.61 (95% CI, 0.53-0.69; p=0.007) and 0.68 (95% CI, 0.60-0.76; p&lt;0.001) respectively. The 5-gene combination was found to discriminate AD subjects from normal controls with good sensitivity and specificity of 70.7% and 86.7% respectively at an optimal cut-off point of 0.486. Low sensitivity (42.4%) and acceptable specificity (76.2%) were observed at a cut-off threshold of 0.505 when differentiating MCI from NC subjects. Between AD and MCI subjects, gene combination showed a sensitivity of 61% and specificity of 73.7% at a cut-off value of 0.496. / Several genes including CTSD, DDT, NDUFA6, TSC1 and UQCRC1 were found in association with the cognitive and psychiatric symptoms, indicating the role of genetic factors in moderating the presence of cognitive and NP profiles in demented individuals. / The aim of the present study is to evaluate the gene expression profiling of peripheral leukocytes in Chinese subjects with Alzheimer's disease (AD) and explored its potential of clinical application. Behavioral phenotypes of cognitive performance and neuropsychiatric assessment were also investigated in association with gene expression in AD. Persons with mild cognitive impairment (MCI), as an at-risk state between normal aging and clinical dementia, was also assessed in consideration that the information may provide a better understanding of the mechanisms involved in clinical progression of AD. / The genes identified in this study were involved in processes implicated in neurodegneration, including protein isomerization (PIN1), calcium disequilibrium and mitochondria insufficiency (ITPKB and UQCRC1), increased inflammatory response (DDT), apoptosis (CTSB and CTSD) and neurogeneration (NRD1 and TSC1). / Fu, Yan. / Adviser: Chiu Wa Lam. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 132-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

A prospective study of patients with pneumonia admitted to Groote Schuur Hospital took place over a one-year period in an attempt to assess the incidence of legionella pneumonia. Acute and convalescent serum samples were obtained from 113 patients. Eight patients (7,1%) showed a fourfold rise in antibody titre against Legionella pneumophila group 1 antigen by indirect immunofluorescent test (IFAT). The findings suggest that legionella pneumonia, although not common, should be considered in the aetiology of pneumonia at Groote Schuur Hospital. The results are presented and a review of the literature is undertaken.

Thesis (MScMedSc (Biomedical Sciences. Molecular Biology and Human Genetics))--Stellenbosch University, 2008. / A South African family of Mixed Ancestry presented with a rapidly progressive dementia and a movement disorder which affected a number of individuals across three generations. The initial symptoms included personality changes and tremors that escalated to severe dementia and eventually a completely bedridden state. It was determined that the mean age at onset was in the third decade of life and affected individuals died within 10-15 years after the onset of symptoms. The aim of the present study was to elucidate the genetic cause of the disorder in this family and to further investigate the patho-biology of the disease. Mutations that could possibly cause the observed phenotype in this family were screened for. These included loci implicated in Huntington’s disease, Parkinson’s disease, Dentatorubral-Pallidoluysian Atrophy, Spinocerebellar ataxias (types 1, 2, 3, 6, and 7), Huntington’s disease-like 2 (HDL2) and several mitochondrial disorders. Single-strand Conformation Polymorphism (SSCP) analysis and direct sequencing were used to detect possible mutations while genotyping on an ABI genetic analyser was used to detect disorders caused by repeat expansions. Haplogroup and Short Tandem Repeats (STRs) analyses of the Y-chromosome and mitochondrial DNA of one affected family member was used to determine the family’s genetic ancestry. Reverse transcriptase polymerase chain reaction (RT- PCR) and complementary DNA (cDNA) analyses of the Junctophlin-3 (JPH3) gene was performed to provide information on the expression profile of this gene. After the exclusion of several genetic loci it was shown that this family had HDL2. This is a rare disease caused by a CAG/CTG repeat expansion in an alternatively spliced version of the JPH3 gene. HDL2 occurs almost exclusively in individuals of Black African ancestry. The genetic ancestry data suggested that the family member was most likely of South African Mixed Ancestry making this the first reported family of South African Mixed Ancestry with HDL2. A pilot study investigated the repeat distribution amongst three South African sub-populations in order to determine whether there was a bias in the repeat distribution that possibly predisposes Black Africans to develop the disease. The results showed a statistically significant difference (P= 0.0014) in the distribution of the repeats between the Black African and Caucasian cohorts. However, no conclusions could be drawn as to whether Black Africans harboured larger repeats that predisposes them to developing HDL2. The expanded repeat is located in an alternatively spliced version of the JPH3 mRNA. Interestingly, this repeat is not present in the mouse homologue of the gene although the rest of the genomic sequence is highly conserved across the human, mouse and chimpanzee genomes. Using foetal brain cDNA and PCR primers designed to be specific for different JPH3 isoforms, independent confirmation of the presence of two JPH3 mRNA transcripts (the full length and a shorter alternatively spliced version) was provided. In the absence of brain tissue from an HDL2-affected individual, it was investigated whether both JPH3 mRNA transcripts could be detected in lymphocytes. Using RNA isolated from the transformed lymphocytes of two HDL2-affected family members, real-time PCR was attempted. These experiments produced inconclusive results and required further optimisation. Further RT-PCR experiments for JHP3 expression in different tissues (brain and other) obtained from HDL2-affected individuals would be of interest. The present study identified the first Mixed Ancestry family with HDL2. This family will now be able to request genetic counselling and pre-symptomatic testing for all at-risk family members. Aspects of this study provided independent confirmation of characteristics of the mutated gene. More research on HDL2 will be crucial in understanding the pathogenesis of this disease.

Coronary heart disease is the leading cause of premature death in the UK. Chest pain, the most common symptoms associated with this disease, accounts for 1% of all primary care consultations, 5% of visits to emergency departments, and up to 40% of emergency admissions to hospital. When people experience acute coronary symptoms such as chest pain, or other symptoms such as pain in the arms, back or shoulder pain and pain in the jaw and neck, we know that prompt diagnosis and treatment of heart disease can significantly reduce mortality. However, we also know that when people experience these symptoms they can wait sometime before seeking medical help. Part of the problem may be that people do not attribute their symptoms a serious problem such as heart disease. Whilst several campaigns have been aimed at the general population there is no information resource targeted at people who may be at risk of heart disease to help them understand and evaluate their symptoms and take prompt action. The overall aim of this thesis is to fill this gap by producing a piloted draft information resource which aims to help people to respond effectively to symptoms that might be attributable to heart disease for people at high risk of heart disease. Using focus group discussions and individual interviews with people who had experienced symptoms that might be attributable to heart disease or might be at high risk of heart disease experiential data about their response to symptoms were gathered. Participants were also asked their views on what an information resource should be like and their experiences and views formed the basis of the content of the first draft of the information resource. In making sense of their symptom the participants drew upon a range of past experiences and the experiences of others to help them; participants who experienced severe symptoms sought help quickly; those whose symptoms were mild or transient waited, in some cases a considerable time, before seeking help. Previous personal experience may be the factor that helped those who acted quickly. Whereas the experience of others, evident in many of the accounts of those who waited, may not be sufficient to help people interpret and make sense of their own symptom experiences. The information resource incorporated the experiences of people with symptoms that ended up being attributable to heart disease and included examples of the range of symptoms that can be encountered to illustrate the different ways in which heart disease can be manifested as well as information drawn from best practice resources in the management of heart disease. Participants in the original focus group discussions and interviews were asked to be involved in the development of the resource and seventeen agreed. The information resource went through three drafts; at each stage changes were made to incorporate respondent views; at the penultimate draft health professionals’ views were also sought and used to inform the final draft which is now ready for further evaluation.

Os objetivos desse estudo foram: 1) Padronizar a pesquisa do anti-tTg, comparando-o com o anticorpo antiendomísio (AAE) e 2) Avaliar as interações da tTg com a fibronectina. 49 celíacos e 124 controles com AAE negativo foram avaliados. O AAE foi pesquisado por imunofluorescência indireta e a reatividade contra a tTg e a fibronectina por ELISA in house e com kits comerciais. O antitTg foi positivo em 46,9% e 100% dos celíacos com o ELISA in house e com kits comerciais, respectivamente. A adição de fibronectina não melhorou a sensibilidade do ELISA. Em conclusão: a detecção do antitTg por ELISA apresenta percentual elevado de falso-positivos, não podendo substituir a pesquisa do AAE / The aims of the current study were: to standardize the detection of anti-tTg antibodies, comparing them with antiendomysial antibodies (EMA) and to assess the interaction of tTg with fibronectin. 49 celiac patients and 124 controls were enrolled. EMA was detected by indirect immunofluorescence reaction and tTg and fibronectin reactivity by in house ELISA and with commercially available kits. Seropositivity to anti-tTG was found in 46.9% and 100% of patients by the in house technique and by commercial kits, respectively. Fibronectin addition did not improve the ELISA sensibility. In conclusion, ELISA for anti-tTG detection has a high rate of false positive results and does not replace EMA

Two skills necessary for the execution of proficient calculation, retrieving arithmetic facts from memory and accessing number magnitude information, were studied in a group of patients diagnosed with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy controls to try to elucidate the locus of impairment in AD-related calculation deficits. This was achieved through the use of an arithmetic production task and a number-matching task as measures of explicit and implicit retrieval of arithmetic facts, and a numerical Stroop task that assesses automatic access to number magnitude representation. AD patients, but not MCI patients, showed high response latencies and a high number of errors when performing multiplications in the production task, and reduced automatic retrieval of arithmetic task in the number-matching task. All participants showed the classic problem-size effect often reported in the mathematical cognition literature. Performance on the numerical Stroop task suggests that access to number magnitude information is relatively resistant to cognitive impairment. ... Results for the AD group are consistent with a pattern of preserved and impaired cognitive processes that might mediate the reported calculation deficits in AD. / by Marâia Beatriz Jurado Noboa. / Thesis (Ph.D.)--Florida Atlantic University, 2013. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

A doença arterial coronária (DAC) avançada caracteriza-se pela presença de vasos calcificados e difusamente estenosados, o que reduz a acurácia da angiografia coronária não-invasiva por meio dos atuais aparelhos de tomografia computadorizada (CT) com 16 colunas de detectores (16-MDCTA). O principal objetivo deste estudo foi tentar demonstrar uma acurácia diagnóstica global de pelo menos 90% para a detecção de estenoses coronárias >= 50% em pacientes com DAC avançada e alta probabilidade de possuírem escores de cálcio coronário elevados, mediante a utilização de um sistema de CT com 32 colunas de detectores, todas capazes de adquirir simultaneamente cortes com 0,5 mm de espessura (32x0,5-MDCTA). Angiografias coronárias sincronizadas ao traçado de ECG foram obtidas por meio da 32x0,5-MDCTA (32 cortes de 0,5 mm, voxels isotrópicos de 0,35x0,35x0,35 mm³, rotação do gantry a 400 ms) em 30 pacientes consecutivos (25 do sexo masculino, com idade média igual a 59±13 anos e índice de massa corpórea médio de 26,2±4,9 Kg/m²) e portadores de DAC avançada. As principais artérias nativas, incluindo seus ramos de primeira ordem com diâmetro >= 1,5 mm bem como os enxertos coronários existentes, foram avaliados de forma independente quanto à presença de estenoses >= 50%. Os stents foram excluídos. As angiografias coronarianas convencionais (realizadas em média 18±12 dias antes das respectivas 32x0,5-MDCTAs) foram analisadas de maneira quantitativa (angiografia coronária quantitativa). A mediana do escore de cálcio de Agatston foi igual a 510 (variação entre 3 e 5066). A sensibilidade, a especificidade e os valores preditivos positivo e negativo para a detecção de estenoses >= 50% nas artérias coronárias nativas foram seguintes: 76% (29/38), 94% (190/202), 71% (29/41), e 96% (190/199), respectivamente. A acurácia diagnóstica global foi de 91% (219/240). Do total de vasos analisados, 20% (69/352) foram excluídos devido à existência de um dos seguintes artefatos: movimento, ruído e baixo realce do contraste radiológico isoladamente ou em conjunto (45/69 ou 65%), distorção da imagem secundária à presença de eletrodo de desfibrilador ou marcapasso (18/69 ou26%), e calcificação arterial excessiva (6/69 ou 9%). Conclui-se que a 32x0,5-MDCTA exclui com precisão as estenoses coronarianas >= 50% em pacientes com DAC avançada e escore de cálcio coronário elevado, com acurácia diagnóstica global de 91% / Advanced coronary artery disease (CAD) is characterized by calcified and diffusely stenotic vessels, hampering accuracy of noninvasive coronary angiography with current 16-detector computed tomography (CT) scanners. The main purpose of this study was to try to demonstrate an overall diagnostic accuracy of at least 90% for detection of coronary stenoses >= 50% by half-millimeter 32-detector CT angiography (32x0.5-MDCTA) in patients with advanced CAD and a high likelihood of having elevated coronary calcium scores. ECG-gated coronary 32x0.5-MDCTA (32x0.5 mm cross-sections, 0.35x0.35x0.35 mm³ isotropic voxels, 400 ms gantry rotation) was performed in 30 consecutive patients (25 male, 59±13 years-old, 26.2±4.9 Kg/m²) with advanced CAD. Major coronary arteries, including >=1.5-mm first order branches, and bypass grafts were independently evaluated for >= 50% stenoses. Stents were excluded. Conventional coronary angiography (performed on average 18±12 days before their corresponding 32x0.5-MDCTAs) was analyzed by quantitative coronary angiography. Median Agatston calcium score was 510 (3-5066 range). Sensitivity, specificity, positive and negative predictive values for detection of >= 50% stenoses in the native coronary arteries were: 76% (29/38), 94% (190/202), 71% (29/41), and 96% (190/199), respectively. Overall diagnostic accuracy was 91% (219/240). Twenty percent (69/352) of the vessels were excluded from the analysis due to one of the following artifacts: motion, noise, and low contrast enhancement isolated or in combination (45/69 or 65%), image distortion secondary to an ICD or pacemaker lead (18/69 or 26%), and severe arterial calcification (6/69 or 9%). We concluded that 32x0.5-MDCTA accurately excludes >= 50% coronary stenoses in patients with advanced CAD and high calcium scores, showing an overall diagnostic accuracy of 91%

by Tam Shuk Yin, Jeanny. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 26-29). / Abstract and appendix in English and Chinese. / ABSTRACT --- p.ii / ACKNOWLEDGEMENTS --- p.iii / TABLE OF CONTENTS --- p.iv / LIST OF TABLES --- p.v / LIST OF FIGURES --- p.vi / Chapter CHAPTER I - --- INTRODUCTION --- p.1 / Chapter CHAPTER II - --- METHOD --- p.5 / Chapter CHAPTER III - --- RESULTS --- p.12 / Chapter CHAPTER IV - --- DISCUSSION --- p.22 / REFERENCES --- p.26 / APPENDICES --- p.30