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OBERTI, LUCA. "EXPLORING THE MOLECULAR AND BIOPHYSICAL MECHANISMS OF PROTEOTOXIC IMMUNOGLOBULIN LIGHT CHAINS IN AL AMYLOIDOSIS." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/630665.
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Herein, immunoglobulin light chains (LCs) native state was studied in the context of the pathology known as light chain amyloidosis (AL). This pathology is characterized by LCs overexpression, which leads to toxicity and aggregation into amyloid fibrils in target organs, with heart being the most affected one. Due to genetic rearrangement and somatic hypermutation, virtually, each AL patient presents a different amyloidogenic LC (Merlini, 2017). Because of such complexity, the fine molecular determinants of LC aggregation propensity and proteotoxicity are, to date, unclear; significantly, their decoding requires investigating large sets of cases. This project is aimed to unravel the molecular determinants linked with LCs toxicity. First, we screened several independent biophysical and structural properties of the LCs native state. In particular, we considered hydrophobicity, fold stability, flexibility and 3D structure.
Our experimental approach considered two LCs sets called ‘H’ and ‘M’. The H set is composed of eight LCs from AL patients while the M set by LCs from multiple myeloma (MM) patients. M LCs were chosen as control since they are overexpressed as the toxic H LCs but they do not lead to toxicity or aggregation. To date, the molecular bases leading to LC proteotoxicity remain to be elucidated. Our data show that low fold stability and high protein flexibility correlate with amyloidogenic LCs, while hydrophobicity, structural rearrangements and nature of the LC dimeric association interface (as observed in seven crystal structures here presented) do not appear to play a significant role in protein aggregation.
Additionally, it has been demonstrated that the LCs toxicity in vivo is linked to copper (Cu2+) (Diomede et al., 2017a) by increasing the radical oxygen species (ROS) production. We aimed our studied to clarify Cu2+ LCs interaction. Moreover, we wanted to assess whether Cu2+ is able to alter the biophysical properties of the native state to more aggregation prone states. Our findings reveal that H LCs interacts with Cu2+ with a higher affinity than M LCs and that His residues may be involved in Cu2+ binding. Indeed the affinity decreases in presence of protonated His residues. Moreover, data suggest that the interaction with Cu2+ increases the molecular flexibility and decreases the fold stability.
These observations suggests that protein aggregation cannot be evaluated through one single parameters but by the co-action of several biophysical traits. Moreover, our results suggest that the presence of Cu2+ can alter the native LCs properties leading to a higher toxicity in vivo.
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Bartlam, Mark Gerrard. "Structural studies of amyloid proteins." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342536.
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BROGGINI, LUCA. "MOLECULAR DETERMINANTS UNDERLYING PROTEIN MISFOLDING AND AGGREGATION." Doctoral thesis, Università degli Studi di Milano, 2021. http://hdl.handle.net/2434/831967.
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Proteins have evolved to adopt distinctive and well-defined functional states under physiological conditions, either as monomers or complexes. The achievement of a three-dimensional structure allows proteins to exert their physiological functions. Nevertheless, when proteins lose – or fail to acquire – their spatial organization, they can convert into aggregated species that can be harmful to the organism.
Conformational diseases gather all those pathologies characterized by the misfolding and aggregation of proteins. Indeed, while the formation and deposition of proteinaceous aggregates can be toxic to cells, the lack of active folded protein disrupts normal physiological pathways.
Although considerable progresses have been made in the recent years, to date conformational diseases are still incurable. Indeed, the incomplete understanding of the causes guiding protein misfolding and aggregation prevents the development of efficient treatments. At the same time, the complexity and the diversity of the processes leading to the formation of aggregated species make the task extremely challenging.
This PhD project was developed to provide a more comprehensive overview of the molecular bases underlying the conversion of soluble and functional states into aggregated and potentially toxic species.
To reach such aims, we applied an integrative approach on two model systems, neuroserpin (NS) and beta-2 microglobulin (2m). In particular, we combined a series of biophysical, biochemical and structural techniques to study these two proteins which have been largely used as model systems for serpin polymerization and amyloid formation, respectively.
We found that protein misfolding and aggregation processes depend on several molecular properties, including primary sequence, denatured state compactness, thermal stability, ability to form oligomers under physiological conditions, and the presence of post-translation modifications.
The data presented in this PhD thesis add valuable information to depict the complex framework of protein misfolding and aggregation.
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RELLA, VALERIA. "AMILOIDOSI CARDIACA ANALISI DI PREVALENZA IN DUE STUDI MULTICENTRICI ITALIANI." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2022. http://hdl.handle.net/10281/366496.
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Tra i pazienti con diagnosi iniziale di cardiomiopatia ipertrofica afferiti a Centri di Riferimento per le Cardiomiopatie, l’AC è la malattia non riconosciuta più comune con una prevalenza complessiva del 9%, e che aumenta con l'età (dall'1% nella fascia di età tra i 40-49 anni al 26% sopra gli 80 anni). Nella popolazione generale ≥55 anni più del 7% ha almeno un reperto ecocardiografico suggestivo di AC e l’ispessimento del setto interatriale è quello più frequente. I pazienti con elevato sospetto di AC (≥3 reperti) rappresentano l’1% della popolazione generale e il 4,9% di quelli con cuore non dilatato, ipertrofico e con FE normale.Among patients with initial diagnosis of HCM, cardiac amiloidosis has a prevalence of 9% and it increases with age. In the general population > 55 yo more than 7% has echocardiographic suspicion of the disease and echocardiography has an important role in the early diagnosis of the disease
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Moreira, Carolina Lavigne. "Epidemiologia mutacional da polineuropatia amiloidótica familiar transtiretina em um serviço brasileiro terciário de neuropatias periféricas." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17140/tde-30032017-142719/.
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Introdução: A amiloidose transtiretina é uma doença autossômica dominante decorrente de uma proteína transtiretina (TTR) variante, que sofre uma mudança conformacional e origina um tetrâmero de TTR instável, passo que é decisivo para o início da formação dos depósitos amilóides em diferentes órgãos e tecidos. Na maioria dos pacientes, o sistema nervoso periférico é o alvo principal, resultando na polineuropatia amiloidótica familiar transtiretina (TTR-FAP), classicamente uma neuropatia sensitivo-motora e autonômica progressiva, evoluindo para o óbito em aproximadamente 10 anos. A mutação de ponto mais frequente no mundo, incluindo o Brasil, é a TTRVal30Met, entretanto mais de 100 mutações de ponto diferentes já foram descritas. Objetivos: descrever a epidemiologia mutacional do gene TTR na polineuropatia amiloidótica familiar e correlacionar estas mutações com seus achados clínicos e eletroneuromiográficos. Métodos: estudo de coorte, descritivo e retrospectivo de um grupo de pacientes brasileiros encaminhados para o serviço de neurogenética do HC da FMRP-USP para investigação de neuropatia periférica, cujo estudo genético identificou uma mutação no gene TTR, com posterior análise transversal dos resultados obtidos entre os subgrupos com as diferentes mutações. Resultados: um total de 128 pacientes tiveram uma mutação de ponto no gene TTR identificada, dos quais 12 (9,4%) pacientes apresentaram uma mutação não TTRVal30Met, incluindo 4 patogênicas (6 pacientes, 4,7%) e 2 não patogênicas (6 pacientes, 4,7%). A mutações não TTRVal30Met patogênicas foram TTRAsp38Tyr (2 pacientes), TTRIle107Val (2 pacientes), TTRVal71Ala (1 paciente) e TTRVal122Ile (1 paciente). Dentre as mutações não patogênicas, foram encontradas TTRGly6Ser (5 pacientes) e TTRThr119Thr (1 paciente). A mutação TTRVal30Met estava presente em 116 (90,6%) pacientes, dos quais 52 possuíam dados clínicos e eletroneuromiográficos completos: 39 (75%) tiveram início precoce e 13 (25%), início tardio. O grupo de início precoce apresentou-se como a forma clássica da PAF-TTR, sem predileção de gênero (homens: 53,8%), manifestação inicial como neuropatia de fibras finas e autonômica (82,1%) e história familiar positiva (90,3%). A ENMG estava normal em 36,7% destes pacientes. O envolvimento cardiovascular foi caracterizado mais frequentemente por alterações da condução cardíaca (84,2%), sendo menos prevalente a cardiomiopatia (11,1%). Por outro lado, o grupo de início tardio mostrou uma predominância do sexo masculino (92,3%), presença de sintomas motores na primeira consulta (38,5%), resultando numa neuropatia sensitivo-motora com acometimento de fibras grossas e história familiar negativa (69,2%). Todos apresentaram neuropatia sensitivo-motora na ENMG. Neste grupo, a cardiomiopatia estava presente em 71,4% dos pacientes. Todos os pacientes, em ambos os grupos, tiveram disautonomia em algum momento do seu seguimento clínico. Conclusões: no nosso estudo aproximadamente 5% dos pacientes com FAP-TTR tinham uma mutação não TTRVal30Met, demonstrando a importância do sequenciamento do gene TTR em pacientes com história clínica sugestiva e screening negativo para a mutação TTR Val30Met. Além disso, os pacientes brasileiros com FAP-TTRVal30Met apresentaram achados clínicos e eletroneuromiográficos similares as populações descritas com esta mutação em outros países.Background: Transthyretin amyloidosis is an autossomal dominant disease caused by variant transthyretin, that is misfolded, originating a unstable transthyretin tetramer, a rate-limiting step in the formation of the amyloid deposits in different organs and tissues. In most patients, the peripheral nervous system is the main target, leading to transtyretin familial amyloid neuropathy (TTR-FAP), classically characterized as a progressive sensory-motor and autonomic neuropathy, that leads to death in about 10 years. TTRVal30Met is the most frequent point mutation worldwide, including Brazil, but more than 100 different point mutations has been described. Objectives: describe the mutational epidemiology of TTR gene in TTR-FAP and characterize its clinical and electrophysiological findings. Methods: a descriptive and retrospective study of a group of Brazilian patients forwarded to the Neurogenetics or Peripheral Nerve Clinics from FMRP-USP whose etiological investigation identified a mutation in the TTR gene. A cross-sectional analysis evaluating the subgroups with different mutations was also carried on. Results: we identified one hundred and twenty eight patients carrying a TTR point mutation, of whom 12 (9,4%) harbored a non-Val30Met mutation, including 4 pathogenic (6 patients, 4,7%) and 2 non-pathogenic abnormalities (6 patients, 4,7%). The non Val30Met pathogenic mutations were TTRAsp38Tyr (2 patients), TTRIle107Val (2 patients), TTRVal71Ala (1 patient) and TTRVal122Ile (1 patient). Among the non-pathogenic mutations, we found the TTRGly6Ser (5 patients) and the TTRThr119Thr (1 patient). The TTRVal30Met mutation was present in 116 (90,6%) patients, of whom 52 had a complete clinical and neurophysiological data: 39 (75%) with early-onset and 13(25%) with late-onset neuropathies. The early-onset group presented as the classic TTRFAP, with no gender predominance (male: 53,8%), the first manifestations were those of a small fiber sensory and autonomic neuropathy (82,1%) and a highly positive family history (90,3%). EMG was normal in 36,7% of these patients. The cardiovascular involvement was characterized by frequent ECG abnormalities (84,2%), less often associated with cardiomayopathy (11,1%). On the other hand, the late-onset TTRVal30Met showed a male predominance (92,3%), presence of motor complaints in the first evaluation (38,5%) resulting in a sensory-motor polyneuropathy with large fiber involvement and a negative family history (69,2%). All patients presented a sensory and motor neuropathy on EMG examination. In this group, cardiomiopathy was frequently associated with the neuropathy (71,4%). All patients, in both groups, had autonomic symptoms at some point in clinical follow up. Conclusions: In our study almost 5% of the patients with TTR-FAP have a non Val30Met pathogenic mutation, highlighting the importance of sequecing the whole TTR gene in patients with a sugestive clinical history and negative screening for TTRVal30Met mutation. In adition, the Brazilian patients we studied with early and late onset TTR-FAP, present similar findings to TTRVal30Met populations from other countries submitted to similar studies.
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Herranz-Trillo, Fatima. "Disentangling structural complexity in proteins by decomposing SAXS data with chemometric approaches." Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT044/document.
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De nombreux systèmes biologiques sont intrinsèquement polydispersés, présentant de multiples espèces coexistantes, de taille, de forme ou de conformation différentes (c'est-à-dire, mélanges oligomèriques, des complexes faiblement liés se dissociant en composantes individuelles ou des espèces apparaissant lors de processus amyloïdogéniques). L'étude de tels systèmes complexes est une tâche difficile en raison de l'instabilité des espèces concernées, de leurs concentrations relatives faibles et interdépendantes et des difficultés rencontrées pour l'isolation des composantes pures. Dans cette thèse, j'ai développé des approches méthodologiques pour appliquer la diffusion des rayons X aux petits angles (SAXS), une technique de biologie structurale, à l'étude de systèmes polydispersés. SAXS est une technique additive et par conséquent, le diagramme de diffusion mesuré pour un échantillon polydispersé correspond à la somme pondérée en concentration des contributions de chacune des composantes individuelles du mélange. Cependant, la décomposition des données de SAXS en des spectres spécifiques des espèces et de leurs concentrations relatives est extrêmement laborieuse et ambigue. Dans cette thèse, je présente d'abord une approche objective pour solidement décomposer les jeux de données de SAXS en composantes individuelles. Cette approche adapte la méthode chimiométrique « Multivariable Curve Resolution Alternate Least Squares » (MCR-ALS) aux spécificités des données de SAXS. Notre méthode permet une décomposition rigoureuse et robuste des données de SAXS en introduisant simultanément différentes représentations de ces données et par conséquent, en mettant l'accent sur des changements moléculaires à différentes plages de temps et de résolution structurale. Nous avons appliqué cette approche, que nous appelons COSMiCS (Analyse structurelle objective complexe des systèmes multi-composants) pour étudier deux systèmes polydispersés: la fibrillation des protéines, et les fluctuations conformationnelles de protéines grâce à l'analyse de données obtenues à l'aide d’une technique de couplage de chromatographie d'exclusion de taille (SEC) avec le ligne de SAXS (SEC-SAXS). L'importance d'étudier les processus de fibrillation réside dans leur implication dans des pathologies amyloïdogéniques telles que les maladies de Parkinson ou d'Alzheimer. Il existe de fortes indications que les espèces oligomériques solubles, et non les fibrilles matures, sont la cause principale de la cytotoxicité et des dommages neuronaux. Cette observation souligne l'importance de caractériser les premiers stades des processus de fibrillation. Notre approche COSMiCS a permis d'étudier les processus amyloïdogéniques de l'insuline et du mutant familial E46K de l'α-synucléine, une protéine associée à la maladie de Parkinson. Cette analyse permet la caractérisation structurale des espèces présentes (y compris les espèces oligomériques) et la caractérisation cinétique de leurs transformations.La deuxième partie de la thèse est consacrée à l'utilisation de COSMiCS pour analyser des données de SEC-SAXS. Le SEC-SAXS est extrêmement populaire et a été implémenté sur plusieurs lignes de SAXS à travers le monde. En utilisant des données synthétiques, je démontre la capacité des approches chimiométriques à décomposer des profils chromatographiques complexes. À l'aide de cette approche, j'ai décomposé l’ensemble des données SEC-SAXS mesurés pour la Prolyl OligoPeptidase (POP).En résumé, cette thèse présente une nouvelle approche chimiométrique qui peut être généralement appliquée à tout mélange macromoléculaire pouvant subir une modifacation de son équilibre et pouvant être abordé par SAXS. Les complexes biomoleculaires transitoires, les processus de repliement, les réarrangements structuraux dépendants d’un ligand ou la formation de grands ensembles supramoleculaires peuvent être sondés de façon structurale en utilisant l'approche COSMiCSMany biological systems are inherently polydisperse, presenting multiple coexisting species differing in size, shape or conformation (i.e. oligomeric mixtures, weakly bound complexes, and species appearing along amyloidogenic processes). The study of such complex systems is challenging due to the instability of the species involved, their low and interdependent relative concentrations, and the difficulties to isolate the pure components. In this thesis, I have developed methodological approaches to apply Small-Angle X-ray Scattering (SAXS), a low-resolution structural biology technique, to the study of polydisperse systems. As an additive technique, the SAXS pattern measured for a polydisperse sample corresponds to the concentration-weighted sum of the contributions from each of the individual components. However, decomposition of SAXS data into species-specific spectra and relative concentrations is laborious and burdened by ambiguity. In this thesis, I present an approach to decompose SAXS datasets into the individual components. This approach adapts the chemometrics Multivariate Curve Resolution Alternating Least Squares (MCR-ALS) method to the specificities of SAXS data. Our method enables the rigorous and robust decomposition of SAXS data by simultaneously introducing different representations of these data and, consequently, emphasizing molecular changes at different time and structural resolution ranges. We have applied this approach, which we name COSMiCS (Complex Objective Structural analysis of Multi-Component Systems), to study two polydisperse systems: amyloid fibrillation by analysing time-dependent SAXSdata, and conformational fluctuations through the analysis of data obtained using on-line size-exclusion chromatography coupled to SAXS (SEC-SAXS). The importance of studying fibrillation processes lies in their implication in amyloidogenic pathologies such as Parkinson’s or Alzheimer’s diseases. There exist strong indications that soluble oligomeric species, and not mature fibrils, are the main cause of cytotoxicity and neuronal damage emphasizing the importance of characterizing early stages of fibrillation. The first application of our COSMiCS approach has allowed the study of the amyloidogenic mechanisms of insulin and the familial mutant E46K of ↵-synuclein, a Parkinson’s disease related protein. The analysis enables the structural characterization of all the species present as well as their kinetic transformations. The second part of the thesis is dedicated to the use of COSMiCS to analyze on-line SEC-SAXS experiments. Using synthetic data, I demonstrate the capacity of chemometric approaches to decompose complex chromatographic profiles. Using this approach, I have studied the conformational fluctuations in prolyl oligopeptidase (POP), a protein related to synaptic functions and neuronal development. In summary, this thesis presents a novel chemometrics approach that can be generally applied to any macromolecular mixture with a tuneable equilibrium that is amenableto SAXS. Transient biomolecular complexes, folding processes, or ligand-dependent structural rearrangements can be probed structurally using COSMiCS
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Hazenberg, Bouke Pier Cornelis. "Diagnostic studies in amyloidosis." [S.l. : Groningen : s.n. ; University Library of Groningen] [Host], 2007. http://irs.ub.rug.nl/ppn/30519349X.
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Slamova, I. "Modelling amyloidosis in mice." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1534595/.
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Amyloidosis is a group of disorders in which specific soluble proteins convert into insoluble extracellular fibrillar deposits. Certain mutations in amyloid prone proteins result in aggressive forms of the disease. β2-microglobulin (β2m), a cell surface protein and transthyretin (TTR), a normal plasma protein, are inherently amyloidogenic. In patients undergoing long-term dialysis, ineffective clearance of β2m from the plasma results in sustained increase of its concentration and its deposition as amyloid. Wild type TTR is the amyloid precursor in senile systemic amyloidosis, a cause of heart failure in the elderly, and various different mutations in the human TTR gene cause the autosomal dominant conditions familial amyloid polyneuropathy and familial amyloid cardiomyopathy. The D76N β2m variant causes highly penetrant hereditary systemic amyloidosis. Similarly, the S52P TTR variant also causes aggressive amyloidosis which is characterised by prominent cardiac ATTR deposits. Animal models for Aβ2m amyloidosis and ATTR amyloidosis have long been sought to enable a better understanding of disease mechanisms and for validation of diagnostic methods and treatments, but previous attempts to model these diseases in vivo have met with limited or no success. The aims of this project were to generate mouse models of: (1) Aβ2m amyloidosis and (2) cardiac ATTR amyloidosis by transgenic expression of these highly amyloidogenic variants. In the work presented here, hβ2mD76N transgenic mice and hTTRS52P transgenic mice were generated. Despite expressing high plasma concentrations of the amyloidogenic proteins, the mice did not spontaneously develop amyloidosis. After priming amyloid deposition with pre formed amyloid fibrils, the hβ2mD76N transgenic mice failed to develop amyloid deposits. It is notable that most of the β2m circulates bound in a complex, potentially limiting the availability of free β2m monomers for conversion into fibrils. In the hTTRS52P transgenic mice, priming of amyloid deposition with amyloid fibrils led to consistent and reproducible development of cardiac ATTR amyloidosis.
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Richon, Jacques. "Amyloidose pulmonaire nodulaire multiple /." [S.l : s.n.], 1985. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Getmans’ka, V. "Amyloidosis in the cardiovascular system." Thesis, Sumy State University, 2016. http://essuir.sumdu.edu.ua/handle/123456789/45034.
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In the most industrialized countries with a high degree of urbanization (including Ukraine), the leading cause of morbidity and mortality is occupied by diseases of the cardiovascular system. Detection of amyloidosis is prognostically the most serious complication for patients with various diseases of the cardiovascular system, causes the development of functional organ failure and patient's death.
The aim of the work is a detailed study of amyloidosis problems, especially its etiology and pathogenesis.
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Noborn, Fredrik. "Heparan Sulfate Dependent Mechanisms of Amyloidosis." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-168309.
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A common theme in amyloid disorders is the deposition of disease-specific protein aggregates in tissues. Amyloid proteins bind to heparan sulfate (HS), a sulfated glycosaminoglycan, and HS has been found to promote the aggregation process. The present work relates to HS mediated mechanisms of amyloidosis, particularly transthyretin (TTR) amyloidosis, AA-amyloidosis and Alzheimer’s disease (AD). TTR is a transport protein present in the blood and cerebrospinal fluid, which under unclear circumstances can deposit as amyloid in the myocardium of elderly individuals. Examination of cardiac tissue from a 70 year old patient with reported cardiomyopathy reveald co-deposition of TTR amyloid and HS. Studies revealed that HS promotes TTR fibrillization through interaction with a basic motif in the protein. Empolyment of a cell model demonstrated that cell surface HS mediates internalization of TTR, an effect likely facilitated by HS-binding to the basic motif on TTR. Collectively, HS-TTR interactions at the cell surface may have dual outcomes, resulting in either fibrillization or internalization, respectively. During inflammatory conditions, serum amyloid A (SAA), an acute-phase protein associated with the high-density lipoprotein (HDL), can assemble into insoluble amyloid fibrils, causing AA-amyloidosis. We found that HS structures exceeding 12-14 sugar units in length separates SAA from HDL and induces subsequent aggregation of the polypeptide. Our result proposes a novel role for HS in AA-amyloidosis in which a critical length of HS is required for separation of SAA from HDL. Late-onset AD patients show reduced ability to clear cerebral amyloid-β (Aβ) aggregates, a pathological hallmark of the disease. Althought the pathway of Aβ clearance is still unclear, several cell-surface receptors are implicated in Aβ internalization. We found that ApoE facilitated Aβ uptake through interactions with HS-proteoglycans and low-density lipoprotein receptor-related protein 1. The ApoE interaction with Aβ likely promotes Aβ clearance in the brain, but, if unbalanced, may contribute to the pathology of AD. These findings are in accord with the concept of HS as a promoter of amyloid protein aggregation, but also point to more complex relationship.
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Wixner, Jonas. "Gastrointestinal disturbances in hereditary transthyretin amyloidosis." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-88745.
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Background Transthyretin amyloid (ATTR) amyloidosis is a systemic disorder caused by amyloid deposits formed by misfolded transthyretin (TTR) monomers. Two main forms exist – wild-type and hereditary ATTR amyloidosis, the latter associated with TTR gene mutations. Wild-type ATTR amyloidosis has a late onset and primarily cardiac manifestations, whereas hereditary ATTR amyloidosis is a rare autosomal dominant condition with a considerable phenotypic diversity. Both disorders are present all over the world, but endemic areas of the hereditary form are found in Sweden, Portugal, Brazil and Japan. Gastrointestinal (GI) complications are common in hereditary ATTR amyloidosis and play an important role in the patients’ morbidity and mortality. Malfunction of the autonomic and enteric nervous systems has been proposed to contribute to the GI disturbances, but the underlying mechanisms have not been fully elucidated. The aims of this thesis were to assess the prevalence of GI disturbances for different subtypes of ATTR amyloidosis, to further explore the mechanisms behind these disturbances, and to evaluate the outcome of the patients’ GI function after liver transplantation, which currently is the standard treatment for hereditary ATTR amyloidosis. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is the first global, multicenter, longitudinal, observational survey that collects data on patients with ATTR amyloidosis. THAOS enrollment data were used to assess the prevalence of GI symptoms and to evaluate their impact on nutritional status (mBMI) and health-related quality of life (EQ-5D Index Score). Data from routine investigations of heart-rate variability and cardio-vascular response to tilt tests were utilized to evaluate the impact of autonomic neuropathy on the scintigraphically measured gastric emptying half-times in Swedish patients with hereditary ATTR amyloidosis. Gastric wall autopsy specimens from Japanese patients with hereditary ATTR amyloidosis and Japanese non-amyloidosis controls were analyzed with immunohistochemistry and computerized image analysis to assess the densities of interstitial cells of Cajal (ICC) and nervous tissue. Data from gastric emptying scintigraphies and validated questionnaires were used to evaluate the outcome of Swedish patients’ GI function after liver transplantation for hereditary ATTR amyloidosis. Results Sixty-three percent of the patients with TTR mutations and 15 % of those with wild-type ATTR amyloidosis reported GI symptoms at enrollment into THAOS. Subsequent analyses focused on patients with TTR mutations and, among them, unintentional weight loss was the most frequent symptom (32 %) followed by early satiety (26 %). Early-onset patients (<50 years of age) reported GI symptoms more frequently than late-onset cases (70 % vs. 50 %, p <0.01), and GI symptoms were more common in patients with the V30M mutation than in those with non-V30M mutations (69 % vs. 56 %, p <0.01). Both upper and lower GI symptoms were significant negative predictors of nutritional status and health-related quality of life (p <0.01 for both). Weak but significant correlations were found between gastric emptying half-times and the function of both the sympathetic (rs = -0.4, p <0.01) and parasympathetic (rs = -0.3, p <0.01) nervous systems. The densities of c-Kit-immunoreactive ICC were significantly lower in the circular (median density 0.0 vs. 2.6, p <0.01) and longitudinal (median density 0.0 vs. 1.8, p <0.01) muscle layers of the gastric wall in patients compared to controls. Yet, no significant differences in protein gene product 9.5-immunoreactive nervous cells were found between patients and controls either in the circular (median density 3.0 vs. 6.8, p = 0.17) or longitudinal (median density 1.4 vs. 2.5, p = 0.10) muscle layers. Lastly, the patients’ GI symptoms scores had increased slightly from before liver transplantation to the follow-ups performed in median two and nine years after transplantation (median score 7 vs. 10 vs. 13, p <0.01). However, their gastric emptying half-times (median half-time 137 vs. 132 vs. 125 min, p = 0.52) and nutritional statuses (median mBMI 975 vs. 991 vs. 973, p = 0.75) were maintained at follow-ups in median two and five years after transplantation. Conclusion GI disturbances are common in hereditary ATTR amyloidosis and have a negative impact on the patients’ nutritional status and health-related quality of life. Fortunately, a liver transplantation appears to halt the progressive GI involvement of the disease, although the patients’ GI symptoms tend to increase after transplantation. An autonomic neuropathy and a depletion of gastrointestinal ICC seem to contribute to the GI disturbances, but additional factors must be involved.
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Pinney, J. H. "Amyloidosis : incidence, prognosis, investigation and management." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1420494/.
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Background: Amyloidosis is a rare disorder of protein folding in which a variety of proteins deposit as fibrils in the extracellular space. The two most commonly affected organs are the kidneys and heart. Deposition of amyloid in these two critical organs is of major prognostic importance. Aims: To identify the burden of systemic amyloidosis in the English population. To characterise the phenotype and diagnostic features of wild type transthyretin amyloidosis and identify the type and frequency of arrhythmic activity in cardiac amyloidosis. To evaluate outcome in renal amyloidosis, and assess the role of renal replacement therapy. Results and Conclusions: Amyloidosis was mentioned in 0.58/1000 deaths in England between 2000 and 2008. Sensitivity of death certificates in identifying patients with amyloidosis was 79%. The estimated true incidence of the disease is ~1/100000 population in England. Wild type transthyretin amyloidosis (ATTRwt) is increasingly diagnosed in the UK. Age of the patient at diagnosis and N T-proB N P level can aid in distinguishing ATTRwt from cardiac AL amyloidosis. Median survival is significantly better in ATTRwt than in cardiac AL amyloidosis. A positive troponin T, a pacemaker and NYHA class IV symptoms are all associated with worse outcome. Complex ventricular arrhythmias are seen more frequently on Holter monitoring in patients with transthyretin cardiac amyloidosis compared to cardiac AL which are in turn more frequent than patients without myocardial amyloid infiltration. There does not appear to be an association between the frequency of complex ventricular arrhythmi as and disease severity in cardiac amyl oi dosi s. Renal and overall outcome in AL amyl oi dosi s are both strongly associated with FLC response and are best among patients who achieve >90% suppression of the monoclonal component of the FLC. Survival on dialysis is improving. Outcome following renal transplantation is dependent on the amyloid fibril type and suppression of the precursor protein.
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Santos, Sofia Alexandra Duque. "The Stress response in transthyretin amyloidosis." Doctoral thesis, Universidade do Porto. Reitoria, 2005. http://hdl.handle.net/10216/10615.
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Lachira-Yparraguirre, Lizbeth, Ali Al-kassab-Córdova, Edgar Quispe-Silvestre, and Daniel Enriquez-Vera. "Cardiac amyloidosis secondary to waldenström macroglobulinemia." Editorial Ciencias Medicas, 2020. http://hdl.handle.net/10757/655705.
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Introduction: Waldenström's macroglobulinemia is a hematological neoplasm belonging to the group of monoclonal gammopathies, which includes systemic symptoms and those related to an increase in M paraprotein. Objective: To describe a case of cardiac amyloidosis associated with macroglobulinemia. Clinical case: Male patient who was admitted for asthenia, dysphonia, and who, during his evolution, developed progressive dyspnea, heart failure and pleural effusion. Additionally, echocardiography showed myocardial granular pattern, while pleural biopsy was positive for Congo red staining. Subsequently, he received treatment with bortezomib, dexamethasone and rituximab, with favorable evolution. Conclusions: In this disease, early diagnosis is an important advantage for survival. Therefore, its management is palliative of cardiac manifestations. The present case shows a diagnostic challenge, in which the less frequent etiologies of heart failure must be taken into account.Revisión por pares
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Fontana, M. "Systemic amyloidosis by Cardiovascular Magnetic Resonance." Thesis, University College London (University of London), 2016. http://discovery.ucl.ac.uk/1497122/.
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Systemic amyloidosis is an infiltrative disorder caused by amyloid deposition in the extracellular space. Two main types of systemic amyloidosis affect the ventricular myocardium, immunoglobulin light chain (AL) and transthyretin (ATTR). These have different natural histories and prognosis but in both, cardiac involvement is the main driver of outcome. For cardiac amyloidosis, Cardiovascular Magnetic Resonance (CMR) with the late gadolinium enhancement (LGE) technique provides sensitivity for early detection but is highly dependent on operator skills and not quantitative - there is no current method of measuring cardiac amyloid burden. A new technique, T1 mapping permits tissue abnormalities to be directly visualised in a simple scan – the colour changes being instantly recognisable, either before contrast (native T1 mapping) or after, when the myocardial extracellular volume (ECV) can be measured. Furthermore, a widely available LGE approach, phase sensitive inversion recovery (PSIR) LGE, being less operator dependent, had potential for improved performance.
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Santos, Sofia Alexandra Duque. "The Stress response in transthyretin amyloidosis." Tese, Universidade do Porto. Reitoria, 2005. http://hdl.handle.net/10216/10615.
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Wigenstam, Veronica. "Behandling av familjär amyloidos med polyneuropati." Thesis, Umeå universitet, Farmakologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-119817.
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Inledning Familjär amyloidos med polyneuropati (FAP) är en genetisk sjukdom som påverkar deperifera nerverna i kroppen. FAP utbryter pga. en mutation i TTR-genen som kodar förtransthyretin (TTR). Den vanligaste TTR-mutationen heter Val30Met. TTR har entetrametrisk struktur, men när TTR-genen är muterad kommer denna tetramer att brytas upp. Till följd av att tetrameren faller sönder, bildas en onormal substans som heter amyloid. Amyloid lagras i kroppens perifera nerver och orsakar skada. Idag finns två etableradebehandlingar: Levertransplantation och behandling med substansen tafamidis. Idag forskasdet på en ny behandling med substansen diflunisal. Diflunisal är ett NSAID och finns inte på marknaden i Sverige. Syfte Syftet med denna litteratur studie är att undersöka hur familjär amyloidos medpolyneuropati behandlas idag. Frågeställningarna är följande: Hur effektiv är levertransplantation vid familjär amyloidos med polyneuropati? Hur effektiv är tafamidis vid familjär amyloidos med polyneuropati? Har behandling med diflunisal någon effekt motFAP? Vilken verkningsmekanism har diflunisal mot FAP? Metod En litteraturstudie gjordes för att få svar på frågeställningarna. Åtta originalartiklar hittades i databasen PubMed. Filter “Clinical trial” , “human” och “5 years” användes för att begränsa antalet träffar. Sökningar gjordes också i web of science där en originalartikel hittades. Tre hemsidor hittades med hjälp av sökord på Google.se, som användes till inledningen. Resultat Kaplan-Meiers analys användes i tre av studierna för att mäta överlevnadsgraden hos patienter med FAP som genomgått en levertransplantation (LTx). Kontrollgrupper togs medför att jämföra med LTx grupperna. En betydligt högre överlevnadsgrad kunde ses i en LTxgrupp jämfört med en kontrollgrupp. Patienter som genomgått en levertransplantation i sendebut (≥50år) har en lägre överlevnadsgrad än patienter som fått sjukdomen tidigt. Studierna som mätt tafamidis effekt vid FAP visade på en minskad neurologisk försämring, bevarande av funktionen hos små- och stora fibrer samt bevarad quality of life (QOL). Behandling med tafamidis hos patienter som har en sen debut av sjukdomen och en mer avancerad sjukdomsbild gav ej någon effekt. Patienter som fick diflunisal jämfört med placebo i 2 år, visade en minskad progression av neurologisk försämring. De hade även en bevarad livskvalitet. Diflunisal binder till T4 på TTR tetramern. Uppbundit TTR stabiliserasoch kommer inte att brytas upp och starta amyloidgenesen. Diskussion/slutsats Levertransplantation är en bra behandlingsmetod då stora skillnader kan ses mellan LTxgrupper och kontrollgrupper. Tafamidis ger bättre effekt vid FAP än diflunisal och tafamidishar färre biverkningar. Både tafamidis och diflunisal kan stabilisera TTR tetramerer, men iolika grad. Tafamidis kunde stabilisera en högre grad (%) tetramerer. Slutsatsen avresultaten från de beskrivna studierna i detta arbete blir att det är tveksamt att ta in diflunisalsom behandling mot FAP eftersom andra behandlingsmetoder är bättre.
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Bergström, Joakim. "Apolipoprotein A-IV and Transthyretin in Swedish Forms of Systemic Amyloidosis." Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4535.
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Over 20 different plasma proteins have been shown to have the capacity to undergo conformational changes and self-assemble into highly stable and insoluble amyloid fibrils.
One, transthyretin (TTR), consists of 127 amino acid residues arranged in eight β-strands (named A to H) and is involved in two different clinical forms of amyloidosis. In familial amyloidotic polyneuropathy (FAP), mutated TTR is found in the amyloid deposits while in senile systemic amyloidosis (SSA) only wild type TTR is present in the amyloid deposits.
In this study, we have identified a novel form of amyloidosis that is caused by the deposition of an N-terminal fragment of apolipoprotein A-IV (apoA-IV). Interestingly, apoA-IV amyloid was found deposited in a patient that also suffered from SSA. Thus, this patient had two biochemically distinct and concurrent forms of amyloidosis that were derived from apoA-IV and TTR.
We have also discovered that two different morphological deposition patterns (identified as patterns A and B) exist in TTR-derived amyloidosis. Pattern A, observed in all SSA patients studied and in half of the FAP patients examined contained large homogenous deposits that were composed of short randomly oriented fibrils. In contrast, pattern B was observed in the remaining FAP patients and was represented by smaller-sized deposits that consisted of longer fibrils that were arranged in parallel bundles. The predominant TTR component deposited also differed between the two amyloid patterns. Amyloid pattern A contained mainly C-terminal TTR fragments while pattern B amyloid consisted of full-length TTR. Our findings suggest that two different mechanisms of fibril formation may exist in TTR-derived amyloidosis.
We have found two epitopes, corresponding to strand C and H that are surface-exposed in TTR-derived amyloid fibrils but hidden and part of the hydrophobic core in the native molecular structure. This indicates that TTR undergoes partial unfolding during fibril formation.
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Blasi, Pérez Daniel. "Drug Discovery Targeted to Transthyretin Related Amyloidosis." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/108283.
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Several drug discovery approaches has been performed to find new compounds able to interact with high affinity with the hormone binding site of the homotetrameric protein transthyretin (TTR), and stabilize this tetramer, becoming drug candidates to treat several rare amyloid diseases associated with TTR.
With this aim, several computational workflows and chemico-biological databases have been developed, and in collaboration with two experimental research laboratories of our TTR Consortium (one contributing with the chemical synthesis or acquisition of the designed compounds, and the other contributing with the biological activity assay results for the synthesized or acquired compounds).
The specific objectives of this thesis are:
a) The generation of a chemico-biological database containing the historical and newly generated results of the TTR Consortium, containing the chemical structures and biological activities of the TTR ligands.
b) Explore the possibility of using repurposing techniques applied to the discovery of new TTR inhibitors among the existing drugs, with particular focus on anti-inflammatory drugs, which are known to be good TTR ligands.
c) Design of new flavonoid compounds as TTR ligands by means of structure-based drug design.
d) Incorporate the Ligand Efficiency Indices analysis (both retrospective and prospective) as a new tool for designing new compounds with increased efficiency as TTR ligands.
e) The computational development of a combined predictive/experimental workflow for the analysis of the metabolic stability of TTR ligands, as a tool for improving the prioritized compounds in our in-house database to obtain new compounds with better metabolic and pharmacokinetic properties.
Among this thesis those workflows have been developed in order to obtain possible new amyloidogenic inhibitors:
a) A computational workflow to obtain TTR ligand fingerprints has been developed, and the application of this workflow to the repurposing of marketed antiinflammatory drugs has delivered 3 compounds as new TTR stabilizers.
b) A computational workflow to obtain a TTR-protein structure based pharmacophore has been developed, and the application of this workflow to a database of flavonoid compounds has delivered one compound as a new TTR stabilizer.
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Dadgar, Ashraf. "Methods for identification and diagnosis of amyloidosis." Thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7175.
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The amyloidoses are biochemically heterogeneous diseases with patholophysiologic deposits of various proteins. Amyloid deposits can occur either localized to one organ or tissue or as part of a systemic disease with deposits in many different tissue. The clinical course, prognosis and therapy are different for each type of amyloidosis and therefore a type specific diagnosis is demanded as early as possible. We describe a method for typing of the most common systemic amyloidoses based on Western blot analysis combined with specific
in- house antibodies, using subcutaneous fat biopsies. We found that the method is reliable and easy to perform and the tissue sample needed is obtained by minor surgery.
In the aortic intima amyloid deposits are often associated with atherosclerosis plaques. In our study we also investigated the prevalence of intimal amyloid from 10 patients age 58-94, amyloid deposits were present in 50% of the cases.
Amyloidos är ett sjukdomstillstånd där proteiner som normalt är lösliga i kroppen felveckas och formar långa olösliga fibriller som ansamlas i vävnader och organ såsom t.ex. hjärta, hjärna och lever. Det finns cirka 25 proteiner som kan ge upphov till amyloidos. Man kan skilja på två huvudgrupper av amyloidos, systemisk och lokaliserad. Vid lokal amyloidos kan inlagringar förekomma i specifika vävnader vid framför allt vissa åldersberoende sjukdomar som t.ex. Alzheimers sjukdom. Vid systemisk amyloidos förekommer inlagringar i praktiskt taget alla vävnader. Symtomatologin vid systemisk amyloidos är variabel och sjukdomsbilden kan vara svårtolkad men tidig och specifik diagnostik ger möjlighet till riktad terapi mot den bakomliggande sjukdomen. Syftet med denna studie var att utvärdera en Western blot metod som använts för typning av vanligaste formerna av systemisk amyloidos. De slutsatser som nåtts är att denna metod är snabbt, pålitligt och enkel att utföra. Diagnos erhölls med finnålsbiopsi av bukfettvävnad som är enkel, snabb och billig metod med liten risk för patienternas hälsa. Vi lyckades också med hjälp av immunhistokemisk infärgning titta på prevalens av amyloid i aortas intima.
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Lovat, Laurence Bruce. "Molecular, therapeutic and clinical aspects of amyloidosis." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400220.
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Banypersad, S. M. "Systemic amyloidosis : insights by cardiovascular magnetic resonance." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1466263/.
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Systemic amyloidosis is the exemplar infiltrative, extracellular disease. Although it is a multi-organ disorder, cardiac involvement drives prognosis. Survival is worst in the AL amyloidosis subtype. It can affect any age and any race. There is no direct test for amyloid burden and there is no treatment for amyloidosis, there is only treatment for the underlying condition. Earlier diagnosis permits prompt treatment and improves survival. A number of imaging modalities exist to non-invasively detect cardiac disease but all have limitations. Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) imaging provides the highest sensitivity for early detection. However, this also has its shortcomings. There is currently no non-invasive method of directly measuring amyloid burden in the extracellular space. New therapies are pending – but their development needs new surrogate endpoints and new tests are therefore desperately needed. T1 mapping permits tissue abnormalities to be directly visualised in a simple scan – the colour changes being instantly recognisable, either before contrast (pre contrast or native T1 mapping) or after, when the myocardial extracellular volume (ECV) can be measured. In a collaboration between the National Amyloidosis Centre and the Heart Hospital, I explored the possibility and potential that T1 mapping might measure cardiac (and other organ) involvement in systemic amyloidosis using EQ-MRI. In early clinical exploration in systemic AL amyloid, I showed that native myocardial T1 was elevated in cardiac amyloidosis and tracked disease, particularly early disease. Mean pre contrast myocardial T1 as measured by ShMOLLI was higher in patients at 1086 ± 90msec, compared to healthy volunteers of 958 ± 20msec (P<0.001). Myocardial T1 times showed a stepwise elevation as the probability for cardiac involvement increased: 1009 ± 31msec without cardiac involvement, 1048 ± 48msec with possible cardiac involvement, 1140 ± 61msec with definite cardiac involvement (P<0.001). Using contrast to measure the ECV, I was able to non-invasively and directly measure the amyloid burden in the heart for the first time. Mean cardiac ECV was greater in patients compared to healthy volunteers with a wider range (0.44 ± 0.12 vs 0.25 ± 0.02, P<0.001) and tracked pre-test probability of cardiac involvement by conventional parameters (P<0.001). ECV also tracked conventional measures of disease severity and correlated with survival with a median ECV of 0.45 being the best model for assessing survival: HR 3.84 (1.53 – 9.61), P=0.004. I demonstrated good reproducibility of the technique with an ICC of > 0.9 for both the FLASH IR and ShMOLLI techniques of T1 mapping and good agreement of ECV derived from both techniques. In pilot studies, I also demonstrated by serial scanning that changes (including regression) over time could be measured. In other organs, I showed that the amyloid burden could be measured and was higher in amyloidosis compared to healthy volunteer: ECV 0.32 vs 0.29 (P<0.001) for liver, 0.39 vs 0.34 (P<0.001) for spleen and 0.16 vs 0.09 (P<0.001) for skeletal muscle. These ECVs also tracked current conventional measures of disease severity by nuclear scintigraphy. These results demonstrate that the interstitial volume in patients with systemic AL amyloidosis can be measured non invasively in the heart, liver, spleen and skeletal muscle and that this correlates with existing markers of disease and survival. Pre contrast myocardial T1 was a good alternative measure for the heart. In conclusion, the work in this thesis has enabled a deeper understanding of cardiac amyloidosis, disease processes and stages. It has pioneered a new prognostic marker that is also able to identify some patients with cardiac involvement that were previously unrecognised. Novel subtypes are now recognised (e.g. cardiac amyloidosis with no LVH) and it has also allowed direct quantification of the liver and spleen. ECV is a new and powerful biomarker that has already been adopted by industry allowing development of new therapies and providing hope that an end to the scourge of this disease is near.
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Susen, Kathrin. "Untersuchungen zur Signaltransduktion des ss-Amyloids [Beta-Amyloids] über den p75LNTR." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=965229599.
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Nordeman, Patrik. "Development of Palladium-Promoted 11C/12C-Carbonylations and Radiosynthesis of Amyloid PET Ligands." Doctoral thesis, Uppsala universitet, Plattformen för preklinisk PET, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-213863.
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In the first part of this thesis, palladium(0)-catalyzed and -mediated carbonylations are discussed. Paper I describes a new method for the safe, efficient use of a solid carbon monoxide source in the synthesis of primary and secondary benzamides. In total, 35 benzamides were synthesized from aryl iodides (20 examples, 69-97% yield) and aryl bromides (15 examples, 32-93% yield). Reduction-prone groups were used successfully in the reactions. In paper II, the same protocol was adopted for the palladium(0)-catalyzed synthesis of N-cyanobenzamides from aryl iodides/bromides, carbon monoxide and cyanamide. In total, 22 N-cyanobenzamides were synthesized (42-88% yield). The radiosynthesis of [11C]N-cyanobenzamides is discussed in paper III. In total, 22 compounds were synthesized from various aryl halides in 28-79% decay corrected radiochemical yield. The protocol was then applied to the radiosynthesis of [11C]N-cyanobenzamide analogs of flufenamic acid and dazoxibene. In the second part of this thesis, compounds of interest in relation to amyloid diseases are discussed. Paper IV describes the solid-phase synthesis of BACE-1 enzyme inhibitors containing secondary and tertiary hydroxyl as the transition state isostere. In total, 22 inhibitors were synthesized. The most potent compound (IC50= 0.19 µM) was co-crystallized at the active site of the enzyme to reveal a new binding mode. In paper V, the evaluation of a potent BACE-1 inhibitor as a potential radiotracer for use in PET is described. The radiolabeled [11C]BSI-IV was obtained in 29±12% decay corrected radiochemical yield by a three-component palladium(0)-mediated aminocarbonylation. Its properties as a potential PET tracer were investigated in vitro by autoradiography and in vivo in rats using small animal PET-CT. A new class of amyloid-binding PET ligands is described in paper VI. Three polythiophenes were labeled with carbon-11 or fluorine-18 (26-43% decay-corrected radiochemical yield). The in vitro studies showed that these ligands bind specifically to amyloid deposits. In vivo PET showed low uptake in the organs of interest in healthy rats and a monkey. These results suggest the labeled thiophenes derivatives could be useful as PET tracers for the study of amyloid diseases.
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Pokrzywa, Malgorzata. "A Drosophila Disease-Model for Transthyretin-associated Amyloidosis." Doctoral thesis, Umeå : Umeå University, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1677.
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Wechalekar, Ashutosh Dilip. "Prognosis, characterisation and treatment of systemic AL amyloidosis." Thesis, University of Southampton, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.543387.
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Coker, Rebecca. "The role of serum amyloid P in amyloidosis." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10055802/.
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Amyloid is a term used to describe a set of diseases caused by protein misfolding. There are 36 proteins known to undergo amyloidosis to date. They each unfold from their unique native states and refold into a specific cross β- sheet motif to which various macromolecules can bind. These protein deposits invade tissues and organs disrupting tissue structure and function. The protein serum amyloid P (SAP) is a universal component to all amyloid deposits regardless of the protein involved. It is a disc shaped protein which is known to protect amyloid fibres against degradation. The role of SAP in amyloidosis has been a subject of discussion for many years. Some have found SAP to enhance fibre formation whereas others have found SAP to prevent it. This thesis can be divided into two parts. The first half focuses on the molecular analysis of SAP in relation to amyloid fibre growth whereas the second half focuses solely on the structural aspects of SAP. Chapters 2 and 3 demonstrate that SAP actually exhibits a dual role in relation to fibrillogenesis. It is capable of acting as both a chaperone and a fibrillogenic enhancer depending on its conformation at the time. As a monomer SAP is responsible for the enhancement and stabilisation of fibres whereas in its dimerised form it demonstrates characteristics similar to that of a molecular chaperone. Recent developments in amyloid treatment involve the removal of SAP from deposits using anti-SAP antibodies. As of yet, structural analysis has not been carried out on the SAP:antibody complex. Chapters 4 and 5 conclude this thesis by using crystallographic techniques to demonstrate that a single antibody binds to an SAP molecule during dissociation from amyloid deposits.
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Sattianayagam, P. T. "The pathogenesis, investigation and management of systemic amyloidosis." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1348208/.
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Background: Amyloidosis is a multisystem disorder characterised by abnormal protein folding, in which proteins adopt an abnormal conformation and deposit as insoluble fibrils that disrupt tissue structure and function. Aims and Methods: To characterise the phenotype of the heredo-familial forms of systemic amyloidosis, the role of solid organ transplantation in the different systemic amyloidosis syndromes and to evaluate the gastroenterological and hepatological causes and sequaelae of systemic amyloidosis. These features were sought in patients followed at the UK National Amyloidosis Centre between 1984 and 2011. Results and Conclusions: Familial amyloid polyneuropathy associated with the T60A transthyretin variant has a prominent cardiac phenotype, which negatively impacts upon prognosis. Furthermore this cardiac phenotype has a negative impact upon survival in those who undergo liver transplantation to eliminate variant transthyretin, which is synthesised in the liver, not only by increasing operative risk but also as there is likely ongoing cardiac amyloid deposition associated with wild-type transthyretin from the liver graft. In the face of failing organ function, liver and renal transplantation in hereditary lysozyme amyloidosis (ALys) appears feasible, despite ongoing amyloidogenesis and the risk of recurrent graft amyloid, due to slow turnover of amyloid. Similarly, renal and cardiac transplantation in AL amyloidosis and renal transplantation in AA amyloidosis appear favourable when strategies to suppress amyloidogenic precursor protein production are employed in tandem. Gastrointestinal and hepatic amyloid are recognised in systemic amyloidosis. In ALys both are prevalent; the former is associated with endoscopic abnormalities and the latter may be asymptomatic or present as hepatic rupture. In patients diagnosed with amyloid by liver biopsy after presenting with deranged liver biochemistry, AL amyloidosis is the commonest cause and although this presentation has been historically associated with a poor prognosis as there is frequently concomitant extra-hepatic amyloid, in those who achieve a good clonal response to chemotherapeutic regimes in the modern era of treatment a survival advantage is conferred. Primary gastrointestinal disease, such as inflammatory bowel disease, can cause systemic AA amyloidosis. Tight inflammatory control, guided by serial serum amyloid A protein levels, benefits amyloidotic kidneys, as does aggressive treatment of physiological renal stresses, such as sepsis. Systemic AL amyloidosis is commonly associated with malnutrition, especially when there is multisystem amyloid. Malnutrition in this group is associated with a poor quality of life and worse survival and it would appear therefore to be a potential target for intervention studies.
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Geenty, Paul. "Echocardiography in Infiltrative Cardiomyopathy: Amyloidosis and Fabry Disease." Thesis, The University of Sydney, 2021. https://hdl.handle.net/2123/29152.
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The infiltrative cardiomyopathies are a heterogeneous group of disorders classically characterised by increased wall thickness and progressive diastolic dysfunction. While considered relatively rare, they are likely underdiagnosed, and are increasingly recognized as a significant cause of heart failure with preserved ejection fraction, particularly in the case of amyloidosis. Despite varying markedly in their natural histories and treatments available, they are often difficult to distinguish using conventional echocardiographic techniques. For this reason, novel imaging techniques, and multi-modality imaging are playing an increasing role in the diagnosis, prognostication and monitoring of infiltrative cardiomyopathies.
This thesis aims to investigate the role of both conventional and novel echocardiographic techniques in the diagnosis and management of amyloidosis and Fabry disease, two of the more common forms of infiltrative cardiomyopathy.
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Johnson, R. J. K. "Insight into amyloidosis from structural studies of human lysozymes." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.605639.
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Reported here is the X-ray crystal structure and the solution dynamics of T70N lysozyme, as monitored by hydrogen/deuterium exchange and NMR relaxation experiments. The X-ray crystal structure shows that a substantial structural rearrangement results from the amino acid substitution, involving residues 45-51 and 68-75 in particular, and gives rise to a concomitant separation of these two loops of up to 6.5 Angstroms. A marked decrease in the magnitudes of the generalised order parameter (S2) values of the amide nitrogen, for residues 70-74, shows that the T70N substitution increased the flexibility of the peptide backbone around the site of mutation. In hydrogen/deuterium exchange experiments monitored by mass spectrometry, a transient but locally cooperative unfolding event was observed for the T70N variant (at 47°C) and the wild type protein (57°C), but at higher temperatures than for the amyloidogenic variants I56T and D67H (37°C). These findings reveal that such partial unfolding is an intrinsic property of the lysozyme structure, and suggest that the readiness with which it occurs is a critical feature determining whether or not amyloid deposition occurs in vivo. At physiological temperature, the protection factors for many of backbone amides in the β-domain of the T70N variant are decreased relative to those in the wild type protein, whereas those in the α-domain display wild type-like values. At the higher temperature a dramatic decrease in protection was observed for the β-domain and C-helix for the T70N variant. This clearly demonstrated that partial unfolding event affects the β-domain and C-helix is similar to that observed previously for the I56T and D67H variants.
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Norgren, Nina. "Hereditary transthyretin amyloidosis (ATTR V30M) : from genes to genealogy." Doctoral thesis, Umeå universitet, Medicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-84494.
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Background: Hereditary transthyretin amyloidosis is an autosomal dominant disease with a reduced penetrance. The most common mutation in Sweden is the V30M mutation in the transthyretin gene. Clustering areas of the disease can be found in Northern Sweden, Portugal, Brazil and Japan, although sporadic cases exist worldwide. Despite being caused by the same mutation, there are large differences in onset, penetrance and symptoms of the disease. Swedish V30M patients typically have a later onset with a lower penetrance compared to those from the clustering Portuguese V30M areas. The reasons for these differences have not been fully understood. The aim of this thesis is to study mechanisms that may influence onset and symptoms and investigate why patients carrying the same mutation have different phenotypes. Methods: Genealogy studies were performed on all known V30M carriers in Sweden using standard genealogy methods. DNA samples from patients, asymptomatic carriers and controls from different countries were collected and the transthyretin gene was sequenced. Liver biopsies from patients were used for allele specific expression analysis and a cell assay was used for miRNA analysis with the mutated allele. Gene expression analysis was performed on biopsies from liver and fat from patients and controls. Results and conclusions: Genealogic analysis of all known Swedish V30M carriers managed to link together 73% of the Swedish ATTR V30M population to six different ancestors from the 17th and 18th century, thus dating the Swedish V30M mutation to be more than 400 years old. A founder effect was also visible in descendants to one of the ancestors, producing a later age at onset. Sequencing of the transthyretin gene revealed a SNP in the 3’ UTR of all Swedish V30M carriers that was not found in any of the Japanese or French V30M carriers. The SNP was present on the Swedish transthyretin haplotype and defined the Swedish V30M population as separate from others. However, the SNP itself had no effect upon phenotype or onset of disease. Gene expression analysis of liver and fat tissue revealed a change in genetic profile of the patients’ livers, in contrast to the unchanged profile of the fat tissue. A changed genetic profile of the liver could explain why domino liver recipients develop the disease much earlier than expected.
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Morten, Isobel Jane. "The role of the lysosome in dialysis-related amyloidosis." Thesis, University of Leeds, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439564.
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Arvidsson, Sandra. "Cardiac function in hereditary transthyretin amyloidosis : an echocardiographic study." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-113891.
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Background: Hereditary transthyretin amyloidosis (ATTR) is a lethal disease in which misfolded transthyretin (TTR) proteins accumulate as insoluble aggregates in tissues throughout the body. A common mutation is the exchange of valine to methionine at place 30 (TTR V30M), a form endemically found in the northern parts of Sweden. The main treatment option for ATTR amyloidosis is liver transplantation as the procedure halts production of mutated transthyretin. The disease is associated with marked phenotypic diversity ranging from predominant cardiac complications to pure neuropathy. Two different types of fibril composition – one in which both fragmented and full-length TTR are present (type A) and one consisting of only full-length TTR (type B) have been suggested to account for some phenotypic differences. Cardiac amyloidosis is associated with increased myocardial thickness and the disease could easily be mistaken for other entities characterised by myocardial thickening, such as sarcomeric hypertrophic cardiomyopathy (HCM). The aims in this thesis were to investigate echocardiographic characteristics in Swedish ATTR amyloidosis patients, and to identify markers aiding in differentiating ATTR heart disease from HCM. Another objective was to examine the impact of fibril composition and sex on the phenotypic variation in amyloid heart disease. Methods: A total of 122 ATTR amyloidosis patients that had undergone thorough echocardiographic examinations were included in the studies. Analyses of ventricular geometry as well as assessment of systolic and diastolic function were performed, using both conventional echocardiographic methods and speckle tracking technique. ECG analysis was conducted in study I, allowing measurement of QRS voltage. In study I and study II ATTR patients were compared to patients with HCM. In addition, 30 healthy controls were added to study II. Results: When parameters from ECG and echocardiography were investigated, the results revealed that the combination of QRS voltage <30 mm (<3 mV) and an interventricular/posterior wall thickness quotient <1.6 could differentiate cardiac ATTR amyloidosis from HCM. Differences in degree of right ventricular involvement were also demonstrated between HCM and ATTR amyloidosis, where ATTR patients displayed a right ventricular apical sparing pattern whereas the inverse pattern was found in HCM. Analysis of fibril composition revealed increased LV wall thickness in type A patients compared to type B, but in addition type A women displayed both lower myocardial thickness and more preserved systolic function as compared to type A males. When cardiac geometry and function were evaluated pre and post liver transplantation in type A and B patients, significant deterioration was detected in type A but not in type B patients after liver transplantation. Conclusions: Increasing awareness of typical cardiac amyloidotic signs by echocardiography is important to reduce the risk of delayed diagnosis. Our classification model based on ECG and echocardiography could aid in differentiating ATTR amyloidosis from HCM. Furthermore, the apical sparing pattern found in the right ventricle may pose another clue for amyloid heart disease, although it requires to be studied further. Furthermore, we disclosed that type A fibrils, male sex and increasing age were important determinants of increased myocardial thickness. As type A fibril patients displayed rapid cardiac deterioration after liver transplantation other treatment options should probably be sought for this group of patients.
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GENOVA, FRANCESCA. "NEXT GENERATION GENOMIC AND PROTEOMIC ANALYSES IN FELINE AMYLOIDOSIS." Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/709439.
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The advent of genomics in human health-care management has led to the introduction of a new powerful tool for diagnosis, allowing for genetic variants potentially associated to a disease phenotype to be identified using the genome sequence of a single patient. The development of improved technologies together with the cost reduction, made the whole genome sequencing (WGS) feasible for domestic animals as well. Cats are among the most common pets and share different diseases with humans, representing therefore a valuable biomedical model for studies focused on human disorders. The 99 Lives Cat Genome Sequencing Initiative was launched in 2015, with the main aim of collecting 99 whole genome cat sequences through the collaboration of different researchers and institutes worldwide. Up to date, almost 200 cats of different breeds and random bred cats have joined the project and have their whole genome sequences as part of the database. Some disease-causing variants have already been identified thanks to the sequencing data available from the database, while many others are currently under investigation. The present PhD project shows how WGS is suitable for different kinds of research, including the detection of disease-associated variants and genomic breed descriptive studies.
The main part of the present PhD project has been focused on the investigation of the pathogenic pathways characterizing feline amyloidosis, a common disease in both the Abyssinian and Siamese breeds. The whole genome sequences of two affected Siamese and two affected Abyssinians were used to detect amyloidosis associated variants and were compared to the WGS data of the other cats present in the 99 Lives database for variants exclusion. Each breed was analyzed separately. At first, all the analyses were carried out referring to the version 6.2 of the cat genome assembly and using the WGS of 113 cats. Amyloidosis resulted to be a polygenic disease and variants underlying the affected phenotype were not shared between Abyssinian and Siamese cats, leading to the hypothesis of different mechanisms involved in the disease onset in the two breeds.
With the advent of the version 9.0 of the Felis catus genome in November 2017, and the increased number of cats that joined the 99 Lives Project, the analysis was repeated using the new genome assembly and 195 cats as controls for variants filtering. Moreover, as in the first part of the work feline amyloidosis turned out to be a multifactorial complex disorder, the new genomic analyses were further integrated with both proteomic and miRNAomic approach in the Abyssinians. When the variants detection with the version 9.0 of the cat genome was repeated, most of the variants related to the affected cats mapped into intronic or intergenic regions, and the variants mapping within exonic regions did not match those found with version 6.2. However, through the multi-omics approach conducted in the Abyssinian breed, different miRNAs resulted to be differentially expressed between healthy and affected Abyssinians. In particular, almost all the downregulated miRNAs were already reported in the Alzheimer Disease (AD) literature, a disorder having many features in common with amyloidosis. Additionally, these miRNAs targeted proteins expressed exclusively in the affected cats and one gene resulted mutated in the binding site of one of the most significantly downregulated miRNA.
Finally, the sequencing data of the 99 Lives Project were used to detect Copy Number Variants (CNVs) in 41 cats belonging to 14 different breeds. This genomic structure characterization, which represents the first study mapping CNVs in domestic cats, showed that individuals belonging to different breeds can cluster together based on their CNVs similarities.
Overall, the present PhD project demonstrated how WGS data available through the 99 Lives Initiative represent an important source for genomic analyses in cats, providing useful data for research and bridging the gap between the new frontiers of genomics and cats health-care.
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Bergström, Joakim. "Apolipoprotein A-IV and transthyretin in Swedish forms of systemic amyloidosis /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4535.
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O'Callaghan, Paul. "Heparan Sulfate in the Amyloidosis and Inflammation of Alzheimer’s Disease." Doctoral thesis, Uppsala universitet, Geriatrik, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-159927.
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Alzheimer’s disease (AD) is a neurodegenerative disorder, with extensive evidence implicating the misfolding, aggregation and deposition of the amyloid-β (Aβ) peptide as central to the pathogenesis. Heparan sulfate (HS) is an interactive glycosaminoglycan, attached to core proteins as HS proteoglycans (HSPGs). HSPGs are present on cell surfaces and in the extracellular matrix where they facilitate multiple signaling functions, but HS is also consistently present in all amyloid deposits, including those of AD. In amyloidosis HS has been studied as an aggregation template, promoting fibril formation and serving a scaffold function in the resulting deposits. The objective of this thesis was to assess how cell surface HS is potentially implicated in Aβ amyloidosis and the associated neuroinflammation of AD. In AD brain we determined that HS predominantly accumulated in Aβ deposits with dense cores and found glial-expressed HSPGs within these deposits. Aβ elevated HSPG levels in primary glial cultures, implicating activated glia as one source of the Aβ-associated HS. Next, we determined that microglial HSPGs are critical for the upregulation of interleukin-1β and tumor necrosis factor-α following exposure to lipopolysaccharide, an established inflammatory insult. Together these results raise the possibility that Aβ-induced expression of microglial HSPGs may promote neuroinflammation. Multiple mechanisms of Aβ toxicity have been proposed and different Aβ assemblies exert their toxicity through alternative routes. We found that three different preparations of Aβ aggregates all exhibited HS-dependent cytotoxicity, which in part correlated with Aβ internalization. Furthermore, heparin treatment attenuated Aβ cytotoxicity and uptake. In Aβ-positive AD microvasculature, HS deposited with Apolipoprotein E (ApoE) and its receptor, the low density lipoprotein receptor-related protein 1 (LRP1). In cell culture, HS and LRP1 co-operated in Aβ interactions and the addition of ApoE increased the levels of cell-associated Aβ in a HS- and LRP1-dependent manner. This ApoE-mediated increase in cell-associated Aβ may promote toxicity and vascular degeneration, but equally HS-mediated internalization of Aβ could represent a clearance route across the blood-brain-barrier. The findings presented here illustrate multiple roles for cell-surface HSPGs in interactions relevant to the pathogenesis of AD.
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Dungu, Jason N. "Cardiac transthyretin amyloidosis in the British African and Caribbean population." Thesis, St George's, University of London, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.676103.
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Cardiac amyloidosis is a condition characterised by infiltration of the myocardium with fibrillar proteins. Transthyretin (TTR) is a plasma protein that may form amyloid fibrils and the V122I mutant form of TTR is associated with isolated cardiac amyloidosis. Previous studies have estimated a 4% V122I allele frequency in African Americans. The prevalence of cardiac transthyretin amyloidosis (ATTR) V122I in the British population is not known. I was awarded a British Heart Foundation Clinical Research Fellowship to investigate the diagnosis and prevalence of ATTR V122I in the UK population. More than one million people of Afro-Caribbean ethnicity live in the Greater London area, and in the local ward of Wandsworth make up more than 10% of the population (2011 census data). The prevalence of ATTR V122I at St George's Hospital was high, affecting 12% of all Afro-Caribbean heart failure patients aged ~60 years. The estimated incidence of ATTR V122I in Afro-Caribbean subjects in the St George's Hospital catchment area was over twice the reported incidence of amyloidosis of all types in the general, predominantly Caucasian, UK population. The clinical phenotype is characterised by resistant heart failure, increased wall thickness and diastolic dysfunction on echocardiography and poor outcomes (median survival 29 months). The ECG had poor sensitivity to detect ATTR V122I because 25% of patients present with left ventricular hypertrophy criteria, contrary to the reported low voltage complexes widely reported in AL amyloidosis. Cardiovascular magnetic resonance (CMR) imaging demonstrated extensive late gadolinium enhancement (LGE) and I developed a novel LGE scoring system to differentiate ATTR from AL amyloidosis with high accuracy. A simple diagnostic algorithm to detect new cases of ATTR amyloidosis was retrospectively employed at a separate tertiary heart failure clinic and demonstrated that 5.2% of elderly black patients had ATTR amyloidosis, having previously been given a diagnosis of hypertensive heart failure. Improved detection of ATTR amyloidosis is increasingly important as novel treatments are now undergoing phase 3 clinical trial assessment and newly diagnosed patients now have the potential for disease modifying therapies. This will have implications for counselling and family screening of this inherited autosomal dominant condition in the future.
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Москаленко, Роман Андрійович, Роман Андреевич Москаленко, Roman Andriiovych Moskalenko, I. Iashlichyn, and E. Chernov. "Amyloidosis in aorta wall and heart valves afected by atherosclerosis." Thesis, Sumy State University, 2015. http://essuir.sumdu.edu.ua/handle/123456789/41234.
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Hornshaw, Martin P. "Peptide metal ion interactions in cerebral amyloidoses." Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260931.
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Östman, Johan. "Mechanisms involved in amyloid induced cytotoxicity /." Umeå : Dept. of Molecular Biology, Univ, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-541.
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Terry, Carolyn Jane. "Structural studies of plasma proteins of medical interest." Thesis, University of Oxford, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302858.
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Bunka, David Harry John. "Isolation and characterisation of RNA aptamers against DNA binding domains and amyloid." Thesis, University of Leeds, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275670.
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Griffiths, Martin Huw. "#beta#-Amyloidosis and the cholinergic system in ageing and Alzheimer's disease." Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263021.
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Sayed, Rabya Hussain. "Advances in the diagnosis and treatment of amyloidosis and related disorders." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10041023/.
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BACKGROUND: Amyloidosis is a disorder arising from the variable physiological effects of dysregulated, extracellular protein deposition. There are >30 different subtypes, all possessing the same histological characteristics and the two major organs affected are the kidneys and the heart. AIMS AND HYPOTHESIS: To evaluate current UK histological practices leading to a misdiagnosis of amyloidosis; To establish proteomics as a new diagnostic technique for identifying amyloid, in the UK; To investigate the usefulness of a relatively new biomarker i.e. Retinol Binding Protein (RBP), across amyloid subtypes and correlate values with biopsy findings, which has not previously been done; To identify the cause of death in patients with Stage III/ IV cardiac amyloidosis using, for the first time, Implantable Loop Recorders; To present the first comprehensive review of Light Chain Deposition Disease highlighting the relationship between haematological response and overall prognosis. RESULTS: In 65% of cases where renal amyloidosis was misdiagnosed as minimal change disease, Congo red staining was not undertaken and in 35% of cases neither Congo red staining, with cross-polarised light visualisation, nor electron microscopy was undertaken. Proteomics has now been established as a specific and sensitive technique by which to diagnose amyloid and the subtype, demonstrated by distinguishing Fibrinogen Aα-Chain (AFib) renal biopsies from other subtypes. Urinary RBP/Creatinine (RCR) correlated with the: degree of tubular atrophy, number of light chains, eGFR, presence of glycosuria and degree of tubular phosphate reabsorption. RCR values were especially high in AFib and AA amyloidosis. Pulseless Electrical Activity was identified as the terminal rhythm in patients with Stage III/IV cardiac amyloidosis and this was preceded by a high degree AV block. Deep clonal responses to chemotherapy are associated with improved renal and overall outcomes in LCDD and should be pursued even in advanced chronic kidney disease.
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Tan, S. Y. "Clinical and experimental studies of hereditary and acquired forms of amyloidosis." Thesis, University of Edinburgh, 1997. http://hdl.handle.net/1842/21563.
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In this thesis, I describe the development of a novel "mini-fibril" extraction technique, allowing the extraction of amyloid fibril proteins from tiny milligram quantities of biopsy tissue. This led directly to the identification of a novel amyloid fibril precursor protein in a case of primary localised orbital amyloidosis and enabled the identification and full characterisations of a novel apolipoprotein AI variant in an Australian family with hereditary renal amyloidosis (HRA). In a large Spanish family with HRA, a novel apolipoprotein AI deletion variant was identified as the precursor protein. In both these families, simple dsDNA sequencing using DNA extracted and amplified from the probands' white blood cells confirmed complete concordance between mutation and the presence of exclusively variant protein sequence in the fibril proteins. Two other families with previously described apolipoprotein AI and fibrinogen α-chain variants, together with an Italian family and a Colombian family with novel transthyretin variants associated with familial amyloid polyneuropathy were also studied. Clinical and scintigraphic studies using radio-labelled serum amyloid P (SAP) component, an in vivo technique for the diagnosis of systemic amyloidosis, was also performed in all these families. Dialysis-related amyloid (DRA) is an invariable complication of long term haemodialysis (HD). The long term outcome of successful renal transplantation and the prevalence of this disease in patients dialysed predominantly by peritoneal dialysis (PD) compared to long term HD populations were studied for the first time using radiolabelled SAP scintigraphy and radiology leading to unique observations demonstrating regression of DRA deposits following a successful renal transplant in contrast to relentless progression of DRA in patients maintained on HD. Although prevalence of the disease appears to be comparable in long term PD populations, clinical expression of the disease may be different, an interesting observation which suggests that dialysis modality may be important in modulating symptoms associated with the deposits.
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Bonifácio, Maria João Macedo da Silva. "Studies on amyloid formation in familial amyloidotic polyneuropathy." Doctoral thesis, Porto : Edição do Autor, 1996. http://hdl.handle.net/10216/64551.
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Hutten, Johanna von [Verfasser]. "Prävalenz und Herkunft renaler Amyloidosen / Johanna von Hutten." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2011. http://d-nb.info/102593900X/34.
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Bonifácio, Maria João Macedo da Silva. "Studies on amyloid formation in familial amyloidotic polyneuropathy." Tese, Porto : Edição do Autor, 1996. http://catalogo.up.pt/F?func=find-b&local_base=UPB01&find_code=SYS&request=000084315.
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Hörnberg, Andreas. "Transthyretin from a structural perspective /." Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-190.
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