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2.
Paediatr Respir Rev ; 31: 32-34, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31288987

RESUMO

As the life expectancy of patients with cystic fibrosis has increased, greater attention has been paid towards the diagnosis and management of the longer term consequences of the condition. A recognised but rare complication of the disease is the development of secondary amyloidosis. Whilst deposition of amyloid protein has been reported in a high proportion of patients with cystic fibrosis at post-mortem [1] and Serum Amyloid A protein has been shown to correlate with disease activity and response to antibiotics [2], the manifestation of clinical disease remains extremely uncommon. The prognosis for patients with amyloid secondary to cystic fibrosis in published reports has been historically bleak [3-6], however there may be novel approaches in the era of biological therapies. The theoretical potential for an increase in the incidence of secondary amyloid amongst the population of cystic fibrosis patients who are experiencing much longer lifespans means that it is worthwhile to consider the condition and its possible treatments in more detail. We report a case and a review of the literature.


Assuntos
Amiloidose/metabolismo , Fibrose Cística/metabolismo , Síndrome Nefrótica/metabolismo , Proteína Amiloide A Sérica/metabolismo , Amiloidose/etiologia , Amiloidose/fisiopatologia , Fibrose Cística/complicações , Fibrose Cística/fisiopatologia , Feminino , Humanos , Síndrome Nefrótica/etiologia , Adulto Jovem
7.
Amyloid ; 26(3): 139-147, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31210531

RESUMO

Objective: Amyloid A (AA) amyloidosis is found in humans and non-human primates, but quantifying disease risk prior to clinical symptoms is challenging. We applied machine learning to identify the best predictors of amyloidosis in rhesus macaques from available clinical and pathology records. To explore potential biomarkers, we also assessed whether changes in circulating serum amyloid A (SAA) or lipoprotein profiles accompany the disease. Methods: We conducted a retrospective study using 86 cases and 163 controls matched for age and sex. We performed data reduction on 62 clinical, pathological and demographic variables, and applied multivariate modelling and model selection with cross-validation. To test the performance of our final model, we applied it to a replication cohort of 2,775 macaques. Results: The strongest predictors of disease were colitis, gastrointestinal adenocarcinoma, endometriosis, arthritis, trauma, diarrhoea and number of pregnancies. Sensitivity and specificity of the risk model were predicted to be 82%, and were assessed at 79 and 72%, respectively. Total, low density lipoprotein and high density lipoprotein cholesterol levels were significantly lower, and SAA levels and triglyceride-to-HDL ratios were significantly higher in cases versus controls. Conclusion: Machine learning is a powerful approach to identifying macaques at risk of AA amyloidosis, which is accompanied by increased circulating SAA and altered lipoprotein profiles.


Assuntos
Amiloidose/diagnóstico , Aprendizado de Máquina/estatística & dados numéricos , Modelos Estatísticos , Proteína Amiloide A Sérica/metabolismo , Adenocarcinoma/diagnóstico , Adenocarcinoma/fisiopatologia , Amiloidose/sangue , Amiloidose/fisiopatologia , Animais , Artrite/diagnóstico , Artrite/fisiopatologia , Biomarcadores/sangue , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Colite/diagnóstico , Colite/fisiopatologia , Diarreia/diagnóstico , Diarreia/fisiopatologia , Modelos Animais de Doenças , Endometriose/diagnóstico , Endometriose/fisiopatologia , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/fisiopatologia , Humanos , Macaca mulatta , Masculino , Estudos Retrospectivos , Fatores de Risco , Triglicerídeos/sangue , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/fisiopatologia
8.
Sao Paulo Med J ; 137(1): 39-44, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31116269

RESUMO

BACKGROUND: Up to 5% of familial Mediterranean fever (FMF) cases are unresponsive to colchicine, through resistance, side effects and toxicity. Anakinra is an alternative treatment for FMF patients whose disease remains uncontrolled with colchicine. We aimed to evaluate anti-interleukin-1 treatment regarding clinical findings, laboratory parameters and quality of life (QoL) among FMF patients presenting resistance and toxicity towards colchicine. DESIGN AND SETTING: Descriptive observational study at the rheumatology clinic, Adnan Menderes University Medical School, Aydin, Turkey. METHODS: Among the patients included, age, sex, MEFV genotypes, acute-phase reactants, hepatic/renal function tests, average colchicine dose, disease duration, attack frequency, attack duration, disease severity, proteinuria, amyloidosis and QoL were evaluated. Colchicine resistance was defined as > 6 typical episodes/year or > 3 per 4-6 months. Kolmogorov-Smirnov, Friedman and two-way analysis of variance tests were used for statistical analyses. RESULTS: Between 2015 and 2017, 14 FMF patients receiving anakinra were enrolled. The mean colchicine dose was 1.7 ± 0.3 mg/day before use of anakinra. Ten patients were attack-free after treatment, while three showed reductions of at least 50% in attack frequency, attack duration and disease severity. Proteinuria levels in all patients with renal amyloidosis decreased after treatment. QoL among patients with renal amyloidosis differed significantly from QoL among non-amyloidosis patients. Mean visual analogue scale scores significantly improved in both groups after use of anakinra. CONCLUSIONS: Use of anakinra reduced attack frequency and proteinuria and acute-phase reactant levels, and improved QoL, with only a few uncomplicated side effects among colchicine-resistant or intolerant FMF patients. Injection-site reactions of severity insufficient to require discontinuation of treatment were seen.


Assuntos
Antirreumáticos/uso terapêutico , Colchicina/uso terapêutico , Resistência a Medicamentos/efeitos dos fármacos , Febre Familiar do Mediterrâneo/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1/antagonistas & inibidores , Qualidade de Vida , Adulto , Amiloidose/tratamento farmacológico , Amiloidose/fisiopatologia , Análise de Variância , Sedimentação Sanguínea , Febre Familiar do Mediterrâneo/fisiopatologia , Feminino , Humanos , Nefropatias/tratamento farmacológico , Nefropatias/fisiopatologia , Masculino , Pessoa de Meia-Idade , Proteinúria/urina , Valores de Referência , Reprodutibilidade dos Testes , Estudos Retrospectivos , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento , Turquia , Escala Visual Analógica
10.
Int J Cardiovasc Imaging ; 35(2): 351-358, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30848402

RESUMO

Gelsolin (AGel) amyloidosis is a hereditary condition with common neurological effects. Myocardial involvement, especially strain, T1, or extracellular volume (ECV), in this disease has not been investigated before. Local myocardial effects and possible amyloid accumulation were the targets of interest in this study. Fifty patients with AGel amyloidosis were enrolled in the study. All patients underwent cardiovascular magnetic resonance imaging, including cine imaging, T1 mapping, tagging, and late gadolinium enhancement (LGE) imaging at 1.5 T. Results for volumetry, myocardial feature-tracking strain, rotation, torsion, native T1, ECV, and LGE were investigated. The population mean native T1 values in different segments of the left ventricle (LV) varied between 1003 and 1080 ms. Myocardial mean T1 was 1031 ± 37 ms. T1 was highest in the basal plane of the LV (1055 ± 40 ms), similarly to ECV (30.0% ± 4.4%). ECV correlated with native T1 in all LV segments (p < 0.005). Basal LGE was detected in 76% of patients, and mid-ventricular LGE in 32%. LV longitudinal strain was impaired (- 17.4% ± 2.6%), significantly decreasing apical rotation (p = 0.018) and concurrently myocardial torsion (p = 0.005). LV longitudinal strain correlated with mean T1 and ECV of different LV planes (p < 0.04; basal p < 0.01). Myocardial involvement in AGel amyloidosis is significant, but the effects are local, focusing on the basal plane of the LV.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Distrofias Hereditárias da Córnea/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Contração Miocárdica , Função Ventricular Esquerda , Amiloidose/genética , Amiloidose/patologia , Amiloidose/fisiopatologia , Fenômenos Biomecânicos , Cardiomiopatias/genética , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Distrofias Hereditárias da Córnea/genética , Distrofias Hereditárias da Córnea/patologia , Distrofias Hereditárias da Córnea/fisiopatologia , Gelsolina/genética , Predisposição Genética para Doença , Humanos , Mutação , Miocárdio/patologia , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Volume Sistólico , Função Ventricular Direita
11.
BMJ Case Rep ; 12(2)2019 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-30796071

RESUMO

A 43-year-old woman who was diagnosed with the cryopyrine-associated periodic syndrome (CAPS) with severe renal failure and heart failure due to amyloid accumulation was examined by swept source optical cohernce tomography (OCT) (SS-OCT; DRI-OCT, Topcon, Tokyo, Japan) and optical coherence tomography angiography (OCTA) (RTVue XR Avanti, Optovue, Fremont, CA). Her best-corrected visual acuity was 20/40 OD and 20/25 OS. A hyporeflective band of about 100 µm thickness was seen just inferior to the retinal pigment epithelium in the cross-sectional SS-OCT images, but the deeper choroidal structures were clearly visible. In the OCTA images, the density of the retinal capillaries in the superficial and deep capillary plexus slabs were reduced, and no signals of the choroidal capillary slab was detected after removing the projection artefacts. The accumulation of amyloid can cause a reduction of both the retinal and choroidal capillary circulations although the circulation in the larger vessels are preserved.


Assuntos
Amiloidose/fisiopatologia , Corioide/irrigação sanguínea , Síndromes Periódicas Associadas à Criopirina/fisiopatologia , Vasos Retinianos/diagnóstico por imagem , Tomografia de Coerência Óptica , Adulto , Corioide/diagnóstico por imagem , Corioide/patologia , Síndromes Periódicas Associadas à Criopirina/complicações , Feminino , Angiofluoresceinografia , Insuficiência Cardíaca/fisiopatologia , Humanos , Insuficiência Renal/fisiopatologia , Vasos Retinianos/patologia , Resultado do Tratamento
12.
Eur Heart J Cardiovasc Imaging ; 20(4): 426-437, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085025

RESUMO

AIMS: We aimed at investigating the relationship between segmental morphology [wall thickness (WT) and WT location (LT: base-mid-apex)], loading conditions and underlying pathological substrate [histology (H), hypertrophy vs. infiltration] with segmental longitudinal (SLS) and circumferential (SCS) strain in a group of patients with hypertrophic cardiomyopathy (HCM) and cardiac amyloidosis (CA). METHODS AND RESULTS: We included 30 patients with biopsy-proven CA (65.4 ± 10.7 years, 66% male, 76.7% AL type) and 50 patients with HCM matched for maximum WT (60 ± 16 years, 80% male). SLS and SCS were assessed with speckle-tracking echocardiography in an 18-segment model of left ventricle, while morphological parameters were measured in short-axis cardiovascular magnetic resonance cine loops which corresponded with echo segments. In total, 1440 segments were evaluated of which 198 (36.7%) in CA and 252 (28%) in HCM had WT >12 mm (maximum WT 18.1 ± 3.7 mm in CA vs. 18.6 ± 4.1 in HCM, P = 0.59). SLS showed association with WT [beta 0.49, 95% confidence interval (CI) 0.37-0.6; P < 0.0005], LT and H (P < 0.0005 for both), with CA segments demonstrating 5.94% more impaired SLS compared with HCM segments with the same WT and LT. On the other hand, there was no linear association between SCS and WT, with SCS being dependent on LT, H (P < 0.0005) and preload (P < 0.002). CONCLUSION: Our study indicates that regional myocardial mechanics are differentially influenced by local morphological parameters. While SLS is dominated by WT, SCS is more determined by LT and H. These findings may have an important role in diagnosis and prognosis of patients with thickened hearts.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Ecocardiografia , Ventrículos do Coração/diagnóstico por imagem , Imagem por Ressonância Magnética , Idoso , Amiloidose/patologia , Amiloidose/fisiopatologia , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Cardiomiopatia Hipertrófica/patologia , Cardiomiopatia Hipertrófica/fisiopatologia , Feminino , Coração/diagnóstico por imagem , Coração/fisiopatologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Prognóstico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
13.
Trends Cardiovasc Med ; 29(2): 83-94, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29983337

RESUMO

Amyloidosis results from insoluble precursor proteins being deposited in the extracellular compartment. The prognosis of the disease is predominantly determined by cardiac involvement due to amyloid accumulation that contributes to cardiac dysfunction and disturbed conduction of cardiac electrical signals. The clinical and radiological manifestations of amyloidosis are often non-specific, making amyloidosis a diagnostic challenge both for clinicians and radiologists. Cardiovascular magnetic resonance imaging, including conventional sequences, late gadolinium enhancement, T1 mapping and determination of extracellular volume fraction is a multi-dimensional modality for the assessment and diagnosis of cardiac amyloidosis and, in addition, is an excellent tool for risk stratification and disease tracking.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Imagem Cinética por Ressonância Magnética , Amiloidose/patologia , Amiloidose/fisiopatologia , Cardiomiopatias/patologia , Cardiomiopatias/fisiopatologia , Meios de Contraste/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica , Miocárdio/patologia , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Função Ventricular
16.
Pan Afr Med J ; 34: 79, 2019.
Artigo em Francês | MEDLINE | ID: mdl-31934222

RESUMO

The purpose of this study was to investigate the epidemiological, evolutionary and clinical features of the renal amyloidosis and to identify poor prognostic factors. We conducted a retrospective study focusing on all patients hospitalized for renal amyloidosis between January 2013 and December 2014. The diagnosis was confirmed by renal puncture-biopsy or by biopsy of minor salivary glands. We collected data from 25 patients, 17 men and eight women, with an average age of 47.2 ± 18 years. Hospitalization rate and prevalence were 2.4% and 12.5 cases/year respectively. On admission, nephrotic syndrome was detected in 100% of cases and renal failure in 68% of cases. Proteinuria was ≥6g/24h in 60% of cases. Digestive symptoms (n=14), cardiac symptoms (n=10) and arterial hypotension (n=11) were the other manifestations. Infectious and inflammatory diseases were the main causes found (60%). Tuberculosis alone accounted for 20%. After a mean follow-up period of 219.5 days, chronic renal failure was found in 16 cases (64%), including 11 cases with end-stage disease (44%). Six patients died. Renal insufficiency at the time of diagnosis, the worsening of renal function and readmission were associated with a risk for chronic terminal renal failure (p: 0.03-0.04). Cardiac damage, the readmission and proteinuria ≥6g/24h were factors associated with the risk of mortality (p< 0.03). Renal failure, cardiac damage, proteinuria ≥6g/24h and readmission were the main factors for poor prognosis in this cohort.


Assuntos
Amiloidose/epidemiologia , Nefropatias/epidemiologia , Síndrome Nefrótica/epidemiologia , Proteinúria/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/diagnóstico , Amiloidose/fisiopatologia , Biópsia , Estudos de Coortes , Feminino , Seguimentos , Hospitalização/estatística & dados numéricos , Humanos , Nefropatias/diagnóstico , Nefropatias/fisiopatologia , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/estatística & dados numéricos , Prevalência , Prognóstico , Estudos Retrospectivos , Adulto Jovem
17.
J Am Heart Assoc ; 7(21): e009974, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30571379

RESUMO

Background This study evaluated myocardial oxygen consumption (MVO2) and myocardial external efficiency (MEE) in patients with cardiac amyloidosis (CA). Furthermore, we compared MEE and MVO2 in subjects with light chain amyloidosis versus transthyretin (ATTR) amyloidosis. Methods and Results The study population comprised 40 subjects: 25 patients with confirmed CA and 15 control subjects. All subjects underwent an 11C-acetate positron emission tomography. Furthermore, the CA patients underwent comprehensive echocardiography and right heart catheterization during a symptom-limited, semi-supine exercise test. MEE was calculated from 11C-acetate positron emission tomography as the ratio of left ventricular (LV) stroke work and the energy equivalent of MVO2. Myocardial work efficiency was calculated as echocardiography-derived work pressure product divided by three-dimensional LV mass. CA patients had significantly lower LV-ejection fraction (54±13% versus 63±4%, P<0.05) and LV-global longitudinal strain (LVGLS) (12±4% versus 19±2%, P<0.0001) and a more restrictive filling pattern (E/e'-ratio 18 [12-25] versus 8 [7-9], P<0.0001) than controls. MEE was severely reduced (13±5% versus 22±5%, P<0.0001) whereas total MVO2 was higher (18±6 mL/min versus 13±3 mL/min, P<0.01) in CA patients than controls. MEE decreased with increasing New York Heart Association symptom burden ( P<0.0001). We found a good relationship between MEE and peak exercise systolic performance (LVGLS: R2=0.60, P<0.0001; myocardial work efficiency: R2=0.48, P<0.0001; cardiac index: R2=0.52, P<0.0001) and between MEE and myocardial blood flow ( R2=0.44, P<0.0001). Conclusion Myocardial oxidative metabolism is disturbed in CA patients with increased total MVO2 and reduced MEE. MEE correlated significantly with echocardiographic derived systolic parameters such as myocardial work efficiency and LVGLS that might be used as surrogate MEE markers.


Assuntos
Amiloidose/metabolismo , Amiloidose/fisiopatologia , Cardiopatias/metabolismo , Cardiopatias/fisiopatologia , Coração/fisiopatologia , Miocárdio/metabolismo , Consumo de Oxigênio , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Medicina (B Aires) ; 78(6): 395-398, 2018.
Artigo em Espanhol | MEDLINE | ID: mdl-30504105

RESUMO

Transthyretin cardiac amyloidosis (ATTR) is a restrictive cardiomyopathy that leads to heart failure in considerable number of patients. Early diagnosis allows specific treatment options. However, ATTR diagnosis is complex and requires invasive procedures. The utility of 99mTc-phosphate tracers for non-invasive diagnosis is well-known but the experience in Argentina is insufficient. The aim of this work was to assess the utility of 99m Tc-phosphate tracers for the diagnosis of ATTR. A total of 46 scintigraphies for detection of cardiac amyloidosis performed between September 2016 and January 2018 were analyzed. Cardiac retention after one hour was assessed in relation to bone uptake using two methods: A semi-quantitative visual score (grade 0 = absent, I = low II = moderate-III = high) and a quantitative method (heart/lung ratio). The final diagnosis and the amyloidosis subtype were carried out by our institution cardiomyopathy team according to international guidelines. The positive and negative predictive values for Grade ≥ II were 96% and 100% respectively for diagnosis of ATTR. Using 1.38 as cut-off value for heart/lung ratio the sensitivity and the specificity were 96% and 100%, respectively for differentiating transthyretin cardiac amyloidosis from light-chain cardiac amyloidosis and other cardiopathies. Scintigraphy with 99m Tc-phosphate tracers enable noninvasive diagnosis and subtype classification of cardiac amyloidosis. The use of this non-invasive, inexpensive and widely available tool will result in better patient management.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Fosfatos , Cintilografia/métodos , Compostos de Tecnécio , Idoso , Idoso de 80 Anos ou mais , Amiloidose/fisiopatologia , Cardiomiopatias/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Estatísticas não Paramétricas
19.
Circulation ; 138(16): 1623-1635, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30354459

RESUMO

BACKGROUND: Automated cardiac image interpretation has the potential to transform clinical practice in multiple ways, including enabling serial assessment of cardiac function by nonexperts in primary care and rural settings. We hypothesized that advances in computer vision could enable building a fully automated, scalable analysis pipeline for echocardiogram interpretation, including (1) view identification, (2) image segmentation, (3) quantification of structure and function, and (4) disease detection. METHODS: Using 14 035 echocardiograms spanning a 10-year period, we trained and evaluated convolutional neural network models for multiple tasks, including automated identification of 23 viewpoints and segmentation of cardiac chambers across 5 common views. The segmentation output was used to quantify chamber volumes and left ventricular mass, determine ejection fraction, and facilitate automated determination of longitudinal strain through speckle tracking. Results were evaluated through comparison to manual segmentation and measurements from 8666 echocardiograms obtained during the routine clinical workflow. Finally, we developed models to detect 3 diseases: hypertrophic cardiomyopathy, cardiac amyloid, and pulmonary arterial hypertension. RESULTS: Convolutional neural networks accurately identified views (eg, 96% for parasternal long axis), including flagging partially obscured cardiac chambers, and enabled the segmentation of individual cardiac chambers. The resulting cardiac structure measurements agreed with study report values (eg, median absolute deviations of 15% to 17% of observed values for left ventricular mass, left ventricular diastolic volume, and left atrial volume). In terms of function, we computed automated ejection fraction and longitudinal strain measurements (within 2 cohorts), which agreed with commercial software-derived values (for ejection fraction, median absolute deviation=9.7% of observed, N=6407 studies; for strain, median absolute deviation=7.5%, n=419, and 9.0%, n=110) and demonstrated applicability to serial monitoring of patients with breast cancer for trastuzumab cardiotoxicity. Overall, we found automated measurements to be comparable or superior to manual measurements across 11 internal consistency metrics (eg, the correlation of left atrial and ventricular volumes). Finally, we trained convolutional neural networks to detect hypertrophic cardiomyopathy, cardiac amyloidosis, and pulmonary arterial hypertension with C statistics of 0.93, 0.87, and 0.85, respectively. CONCLUSIONS: Our pipeline lays the groundwork for using automated interpretation to support serial patient tracking and scalable analysis of millions of echocardiograms archived within healthcare systems.


Assuntos
Amiloidose/diagnóstico por imagem , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Aprendizado Profundo , Ecocardiografia/métodos , Hipertensão Pulmonar/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Amiloidose/fisiopatologia , Automação , Cardiomiopatia Hipertrófica/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Volume Sistólico , Função Ventricular Esquerda
20.
Nat Rev Mol Cell Biol ; 19(12): 755-773, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30237470

RESUMO

The aggregation of proteins into amyloid fibrils and their deposition into plaques and intracellular inclusions is the hallmark of amyloid disease. The accumulation and deposition of amyloid fibrils, collectively known as amyloidosis, is associated with many pathological conditions that can be associated with ageing, such as Alzheimer disease, Parkinson disease, type II diabetes and dialysis-related amyloidosis. However, elucidation of the atomic structure of amyloid fibrils formed from their intact protein precursors and how fibril formation relates to disease has remained elusive. Recent advances in structural biology techniques, including cryo-electron microscopy and solid-state NMR spectroscopy, have finally broken this impasse. The first near-atomic-resolution structures of amyloid fibrils formed in vitro, seeded from plaque material and analysed directly ex vivo are now available. The results reveal cross-ß structures that are far more intricate than anticipated. Here, we describe these structures, highlighting their similarities and differences, and the basis for their toxicity. We discuss how amyloid structure may affect the ability of fibrils to spread to different sites in the cell and between organisms in a prion-like manner, along with their roles in disease. These molecular insights will aid in understanding the development and spread of amyloid diseases and are inspiring new strategies for therapeutic intervention.


Assuntos
Amiloide/metabolismo , Amiloide/fisiologia , Amiloide/ultraestrutura , Doença de Alzheimer/fisiopatologia , Amiloidose/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Humanos , Doença de Parkinson/fisiopatologia , Placa Amiloide/metabolismo , Placa Amiloide/fisiopatologia
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