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1.
Biochemistry (Mosc) ; 84(11): 1256-1267, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760916

RESUMO

The review discusses the role of small heat shock proteins (sHsps) in human neurodegenerative disorders, such as Charcot-Marie-Tooth disease (CMT), Parkinson's and Alzheimer's diseases, and different forms of tauopathies. The effects of CMT-associated mutations in two small heat shock proteins (HspB1 and HspB8) on the protein stability, oligomeric structure, and chaperone-like activity are described. Mutations in HspB1 shift the equilibrium between different protein oligomeric forms, leading to the alterations in its chaperone-like activity and interaction with protein partners, which can induce damage of the cytoskeleton and neuronal death. Mutations in HspB8 affect its interaction with the adapter protein Bag3, as well as the process of autophagy, also resulting in neuronal death. The impact of sHsps on different forms of amyloidosis is discussed. Experimental studies have shown that sHsps interact with monomers or small oligomers of amyloidogenic proteins, stabilize their structure, prevent their aggregation, and/or promote their specific proteolytic degradation. This effect might be due to the interaction between the ß-strands of sHsps and ß-strands of target proteins, which prevents aggregation of the latter. In cooperation with the other heat shock proteins, sHsps can promote disassembly of oligomers formed by amyloidogenic proteins. Despite significant achievements, further investigations are required for understanding the role of sHsps in protection against various neurodegenerative diseases.


Assuntos
Proteínas de Choque Térmico Pequenas/metabolismo , Doenças Neurodegenerativas/patologia , Amiloidose/metabolismo , Amiloidose/patologia , Proteínas de Choque Térmico HSP27/química , Proteínas de Choque Térmico HSP27/genética , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico Pequenas/química , Proteínas de Choque Térmico Pequenas/genética , Humanos , Doenças Neurodegenerativas/metabolismo , Conformação Proteica em Folha beta , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo
2.
Medicine (Baltimore) ; 98(46): e17999, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725668

RESUMO

INTRODUCTION: Heavy and light chain amyloidosis is an extremely rare condition. There are few reports referring to the clinical impact of cardiac involvement in heavy and light chain amyloidosis, and the significance of myocardial impairment has not yet been completely explained. PATIENT CONCERNS: A 66-year-old Japanese man was admitted to our hospital presenting with nephrotic syndrome and congestive heart failure. DIAGNOSIS: Kidney and endoscopic gastric mucosal biopsy demonstrated congophilic hyalinization in most of the glomeruli and surrounding vessel walls, which were highly positive for immunoglobulin A and lambda. Finally, the patient was diagnosed as an atypical multiple myeloma with systemic heavy and light chain amyloidosis. INTERVENTIONS: The patient was referred to hematology for further treatment and was moved to another hospital for the administration of chemotherapy using melphalan and dexamethasone. OUTCOMES: The patient was still alive after 15-month follow-up from the initial diagnosis. CONCLUSION: Initial screening and follow-up for cardiac involvement are important for heavy and light chain amyloidosis. Further investigation for the prognosis of heavy and light chain amyloidosis is required to improve the strategies of diagnosis and treatment options for patients with this disease.


Assuntos
Amiloidose/complicações , Insuficiência Cardíaca/complicações , Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Síndrome Nefrótica/complicações , Idoso , Amiloidose/patologia , Insuficiência Cardíaca/patologia , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/complicações , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Masculino , Síndrome Nefrótica/patologia
3.
Arkh Patol ; 81(5): 74-79, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31626208

RESUMO

The paper describes 11 cases of local tumor-like amyloidosis (LTA) of the upper respiratory tract, among which laryngeal amyloidosis was most common. The clinical diagnosis of suspected local amyloidosis was made in only two cases. The diagnosis of local amyloidosis was established at a morphological examination of a distant neoplasm, by using special Congo red staining followed by polarizing microscopy. Attention is drawn to the localization and sequence of amyloid deposition and morphological changes related to the age of patients and the duration of the disease. The paper discusses the nature of local amyloidosis as stromal vascular proteinosis with the deposition of AL amyloid (immunoglobulin light chain amyloid) that are formed apparently by local immunocytes of the mucosa-associated lymphoid tissue (MALT) system. It emphasizes the need for the clinical monitoring of patients with LTA to rule out systemic amyloidosis.


Assuntos
Amiloidose/patologia , Sistema Respiratório/patologia , Amiloide , Humanos , Linfoma de Zona Marginal Tipo Células B
4.
Medicine (Baltimore) ; 98(38): e17256, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31567998

RESUMO

RATIONALE: Cardiac amyloidosis, considered for the last years to be a rare disease, is one of the determinants of HFpEF. The non-specific clinical presentation and the difficulties related to endomyocardial biopsy have made cardiac amyloidosis an underdiagnosed clinical entity. Improvement of non-invasive diagnostic techniques and the development of new therapies increased clinical awareness for this form of restrictive cardiomyopathy. We here summarize echocardiography and Tc-HDP scintigraphy findings in 6 cases of cardiac amyloidosis and review the literature data of this progressive and fatal cardiomyopathy. PATIENTS CONCERNS: The main clinical manifestations were fatigue, low exercise tolerance and edemas. The right heart failure symptoms usually dominated the clinical picture. DIAGNOSES: All cases were evaluated by echocardiography; 3 cases were further examined by bone scintigraphy and 4 cases a peripheral biopsy was performed. Electrocardiography showed low-voltage QRS complexes and "pseudo-infarct" pattern in the precordial leads, contrary to the echocardiographic aspect, which revealed thickening of ventricle walls. Biatrial dilation and diastolic disfunction were observed. Impaired systolic function was detected in advanced stages of the disease. Tc-HDP scintigraphy revealed cardiac uptake of radiopharmaceutical and managed to confirm the diagnosis in 1 case of cardiac amyloidosis in which salivary gland biopsy was negative. INTERVENTIONS: The treatment was based on managing fluid balance, with the mainstream therapy represented by diuretics. Neurohormonal agents, usually used in heart failure treatment were avoided, due to poor tolerance and worsening of disease course. The management of these 6 cases was challenging due to the refractory manifestation of congestive heart failure. OUTCOMES: During follow-up, 4 of the 6 patients from the current study died in the first year after the final diagnosis was established. LESSONS: Nuclear imaging of cardiac amyloidosis has a revolutionary development nowadays. Bone scintigraphy presents promising results for identifying patients at early stages of disease and to differentiate between cardiac amyloidosis types. Further studies are necessary for the standardization of imaging protocol and development of non-invasive diagnostic tools, especially in assessing the response to treatment and disease progression, for which little is known.


Assuntos
Amiloidose/diagnóstico por imagem , Ecocardiografia , Cardiopatias/diagnóstico por imagem , Cintilografia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/diagnóstico , Amiloidose/patologia , Difosfonatos , Feminino , Coração/diagnóstico por imagem , Cardiopatias/diagnóstico , Cardiopatias/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Compostos de Organotecnécio
13.
Amyloid ; 26(sup1): 1-3, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31343350
17.
BMJ Case Rep ; 12(6)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31256048

RESUMO

A previously healthy 54-year-old woman was admitted to the stroke unit with an acute ischaemic stroke attributed to atrial fibrillation newly diagnosed at the emergency room. Nevertheless, preliminary investigation on stroke aetiology revealed incidental hypoalbuminaemia in the context of nephrotic syndrome, while clinically, the patient developed progressive signs of cardiac failure raising the suspicion of an underlying disorder. Systemic amyloidosis was histologically confirmed a few weeks after hospital admission. The rare presentation and non-specific symptom constellation contributed to delayed institution of the appropriated treatment regimen at a point where multiorganic involvement was irreversible leading to death only 2 months after the first manifestation. The presented case reminds us of the importance of always keeping in mind this rarer cause of ischaemic stroke since an early diagnosis remains the key to a more hopeful prognosis.


Assuntos
Amiloidose/complicações , Amiloidose/diagnóstico , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/etiologia , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/etiologia , Amiloidose/patologia , Biópsia , Encéfalo/diagnóstico por imagem , Evolução Fatal , Feminino , Humanos , Rim/patologia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X
18.
Blood Rev ; 37: 100581, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31167719

RESUMO

Immunoglobulin light-chain (AL) amyloidosis is a rare life-threatening disease caused by light chains that are toxic to vital organs such as the heart, kidneys, liver and peripheral nervous system, and that misfold and assemble as amyloid fibrils and deposit both in affected organs and systemically in the vasculature and other tissues. Patients afflicted by this disease have B-cell disorders, almost always related to clonal plasma cells in the bone marrow, the burden of which can range from small clones involving 5% or less of marrow cells to frank multiple myeloma. The goal of therapy is to eliminate the clonal plasma cells producing these toxic light chains to halt and possibly reverse symptomatic organ damage. While autologous stem cell transplantation can be a very effective treatment modality in AL, it has a limited role due to the frailty of this particular population. Conservative treatment in the form of chemotherapy has become the backbone of therapy. Bortezomib combined with alkylators has proven quite successful in inducing hematologic responses. However, despite these advances, tolerability and resistance continue to be an ongoing issue. Novel anti-plasma cell therapies such as ixazomib, carfilzomib, lenalidomide and pomalidomide are actively being combined and evaluated in clinical trials for efficacy and toxicity in this challenging patient population. Other approaches, such as monoclonal antibodies targeting surface proteins and amyloid deposits, are being tested and combined with novel agents. In this review, we will provide an overview of the clinical trials that have led to current treatment algorithms and will also discuss monoclonal antibodies currently under investigation and in various stages of clinical development.


Assuntos
Amiloidose/terapia , Cadeias Leves de Imunoglobulina/metabolismo , Amiloidose/patologia , Humanos
19.
BMC Endocr Disord ; 19(1): 61, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196059

RESUMO

BACKGROUND: Insulin-derived amyloidosis is a skin-related complication of insulin therapy that interferes with insulin therapy. Although toxicities of in vitro-formed insulin amyloid fibrils have been well studied, the toxicity of insulin-derived amyloidosis remains to be clarified. CASE PRESENTATION: A 58-year-old man with type 2 diabetes mellitus underwent a lower limb amputation due to diabetic gangrene. Several antibiotics including minocycline were administered for infection and sepsis. A hard mass at the insulin injection sites in the lower abdomen was discovered by chance four months later. Although no abnormal findings in the surface skin of the mass were observed, necrotic tissue was seen around the mass when a biopsy was performed. Histological and toxicity studies were performed for this patient and four other patients with abdominal masses at insulin injection sites. Histological and immunohistochemical studies showed that the masses had typical characteristics of amyloid deposits in all cases, whereas necrotic findings were seen adjacent to the amyloid deposit only in the case presented. Toxicity studies indicated that the amyloid tissue from the present case had significant cell toxicity compared to the control skin tissue or the amyloid tissues from the other four cases. CONCLUSIONS: This report showed that toxic insulin-derived amyloidosis can occur. In addition, this report suggested that toxic insulin-derived amyloidosis may cause necrosis in the surrounding tissue. Although the toxic amyloid deposit of insulin-derived amyloidosis was found in only one patient, no structural differences between toxic and non-toxic deposits were seen on histological and immunohistochemical studies.


Assuntos
Amiloidose/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Amiloidose/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico
20.
Diagn Pathol ; 14(1): 57, 2019 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-31200733

RESUMO

Systemic amyloidosis is a devastating group of disorders for which there is no current cure. The treatment goal is to reduce the burden of amyloidogenic protein precursors. The treatment is only effective if applied early in the disease process before significant and irreversible end organ damage has taken place. Congo red is still the standard stain used in most histopathology laboratories to identify amyloid material in tissues. The identification of Congophilic amyloid material is challenging because of multiple interfering factors. Here we describe improved sensitivity of identifying Congophilic materials in histologic sections using a metallurgical polarized microscope specifically constructed for polarized microscopy. The microscope is equipped with strain-free optics, matching polarizers, dis-integrated compensators, and a circular mobile stage. Compared to a standard clinical microscope, this setup significantly improves sensitivity of identifying amyloid material in Congo red-stained slides. We also describe the deleterious effect of plastic coverslip which can interfere with the ability to examine the slides under polarized light. We present a series of 10 different patients who had cardiac, brain, and salivary gland biopsies that were either equivocal or deemed negative using a standard clinical microscope but were positive using the equipment described above. These samples were confirmed to be positive by other methods including electron microscopy. We conclude that use of the correct equipment is needed before ruling out amyloidosis in tissue sections.


Assuntos
Amiloide/metabolismo , Amiloidose/patologia , Vermelho Congo/metabolismo , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Proteínas Amiloidogênicas/metabolismo , Amiloidose/diagnóstico , Corantes , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Coloração e Rotulagem/métodos
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