Adjuvantes no tratamento da hiperglicemia do diabetes melito tipo 1: [revisão] / Adjunctive therapies to glycaemic control of type 1 diabetes mellitus: [review]

Desde o Diabetes Control and Complications Trial (DCCT), a terapia insulínica intensiva tem sido direcionada para alcançar valores de glicemia e hemoglobina glicada (HbA1c) tão próximos do normal quanto a segurança permita. Entretanto, a hiperglicemia (especialmente a hiperglicemia pós-prandial) e a hipoglicemia continuam a ser um problema no manejo do diabetes tipo 1. O objetivo de associar outras drogas à terapia insulínica é diminuir a glicemia pós-prandial. A terapia adjunta pode ser dividida em três grupos, conforme seu mecanismo de ação: 1. Aumento da ação da insulina (metformina e tiazolidinedionas); 2. Alteração da liberação de nutrientes no trato gastrintestinal (acarbose e amilina); 3. Outros modos de ação [pirenzepina, fator de crescimento insulina-símile (IGF-1) e peptídeo semelhante ao glucagon 1 (GLP-1). Muitos desses agentes mostraram, em estudos de curto prazo, diminuição de 0,5 por cento a 1 por cento na HbA1c, diminuir a hiperglicemia pós-prandial e as doses diárias de insulina.

Since Diabetes Control and Complications Trial (DCCT), intensive therapy has been directed at achieving glucose and glycosylated hemoglobin (HbA1c) values as close to normal as possible regarding safety issues. However, hyperglycemia (especially postprandial hyperglycemia) and hypoglicemia continue to be problematic in the management of type 1 diabetes. The objective of associating other drugs to insulin therapy is to achieve better metabolic control lowering postprandial blood glucose levels. Adjunctive therapies can be divided in four categories based on their mechanism of action: enhancement of insulin action (e.g. the biguanides and thiazolidinediones), alteration of gastrointestinal nutrient delivery (e.g. acarbose and amylin) and other targets of action (e.g. pirenzepine, insulin-like growth factor I and glucagon-like peptide-1). Many of these agents have been found to be effective in short-term studies with decreases in HbA1c of 0.5-1 percent, lowering postprandial blood glucose levels and decreasing daily insulin doses.

Activation of nicotinic acetylcholine receptor prevents the production of reactive oxygen species in fibrillar beta amyloid peptide (1-42)-stimulated microglia

Recent studies have reported that the "cholinergic anti-inflammatory pathway" regulates peripheral inflammatory responses via alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) and that acetylcholine and nicotine regulate the expression of proinflammatory mediators such as TNF-alpha and prostaglandin E2 in microglial cultures. In a previous study we showed that ATP released by beta-amyloid-stimulated microglia induced reactive oxygen species (ROS) production, in a process involving the P2X7 receptor (P2X7R), in an autocrine fashion. These observations led us to investigate whether stimulation by nicotine could regulate fibrillar beta amyloid peptide (1-42) (fA beta(1-42))-induced ROS production by modulating ATP efflux-mediated Ca2+ influx through P2X7R. Nicotine inhibited ROS generation in fA beta(1-42)-stimulated microglial cells, and this inhibition was blocked by mecamylamine, a non-selective nAChR antagonist, and a-bungarotoxin, a selective alpha7 nAChR antagonist. Nicotine inhibited NADPH oxidase activation and completely blocked Ca2+ influx in fA beta(1-42)-stimulated microglia. Moreover, ATP release from fA beta(1-42)-stimulated microglia was significantly suppressed by nicotine treatment. In contrast, nicotine did not inhibit 2',3'-O-(4-benzoyl)-benzoyl ATP (BzATP)-induced Ca2+ influx, but inhibited ROS generation in BzATP-stimulated microglia, indicating an inhibitory effect of nicotine on a signaling process downstream of P2X7R. Taken together, these results suggest that the inhibitory effect of nicotine on ROS production in fA beta(1-42)-stimulated microglia is mediated by indirect blockage of ATP release and by directly altering the signaling process downstream from P2X7R.

Primary amyloidosis presenting as intrahepatic cholestasis.

Hepatic involvement in primary amyloidosis is not rare but is often clinically silent. A mild elevation of the serum alkaline phosphatase level and hepatomegaly are the most common findings. We report a case of primary amyloidosis in an adult male presenting with intrahepatic cholestasis where viral, drug, alcohol, and autoimmune etiologies were all excluded and the definite diagnosis was established by liver biopsy with Congo red staining. Subsequently the patient was found to have monoclonal light chain disorder.

Cerebral and cardiac amyloidosis in autopsied elderly individuals

INTRODUÇÃO: A amiloidose em idosos pode ser uma alteração independente e própria do envelhecimento. Entretanto, as características clínicas, fisiopatológicas e bioquímicas da Amiloidose relacionada à idade ainda permanecem incertas. OBJETIVO: Verificar se o coração e o encéfalo de indivíduos acima de 60 anos apresentavam depósito amilóide. MATERIAL E MÉTODOS: Foram estudados laudos consecutivos de autópsias de indivíduos acima de 60 anos realizadas entre 1976 e 2000, que apresentavam corações sem cardiopatias, com sorologia negativa para Doença de Chagas e encéfalos sem alterações morfológicas de encefalopatias, chegando a um n de 10 casos. Lâminas de fragmentos do coração e de encéfalo foram processadas e analisadas em microscopia de luz comum e polarizada. RESULTADOS: Dos 10 casos, 3 apresentaram depósito amilóide no encéfalo e 1 no encéfalo e no coração. Em 50% dos casos, os indivíduos tinham entre 60 e 69 anos. A relação entre o peso encefálico e o peso corporal mostrou ter uma associação significativa com os casos positivos, sendo esta menor em relação aos negativos. CONCLUSÃO: A análise conjunta de depósitos amilóides em encéfalo e coração de indivíduos idosos talvez direcione para um acometimento sistêmico comum ao envelhecimento natural. Alguma alteração adicional do organismo poderia determinar a quebra de um equilíbrio natural sobre o acúmulo dessas proteínas, levando dessa forma aos contextos patológicos da amiloidose.

Pathophysiology of dementias and implications for therapy.

Dementia is characterized clinically by progressive cognitive decline, often with impairment of memory. The pathology of dementias is either focal as with infarcts in Vascular Dementia or diffuse as typified by Alzheimer's disease. In many cases of Alzheimer's disease there is a mixture of focal infarcts and diffuse changes. Diffuse pathology in dementias comprises mainly intracellular and extracellular protein deposits. Intracellular inclusions are of tau protein (Alzheimer's disease; and some frontotemporal dementias), alpha-synuclein (Dementia with Lewy bodies) and huntingtin (Huntington's disease). Soluble and insoluble peptides also accumulate in the extracellular spaces of brain parenchyma in dementias with diffuse pathology, mainly amyloid-beta (Abeta) in parenchymal plaques and in artery walls as cerebral amyloid angiopathy (Alzheimer's disease and Dementia with Lewy bodies). Insoluble prion protein (PrP) is deposited in brain parenchyma in Creutzfeldt-Jakob disease and other insoluble amyloid peptides accumulate in brain and vessel walls infamilial dementias. The pattern of extracellular deposits in brain and artery walls suggests that there is a failure of elimination of peptides, such as Abeta along perivascular interstitial fluid drainage pathways ("lymphatics") from the aged brain and in Alzheimer's disease. Such failure may be due to reduced pulsations as arteries stiffen with age and cerebrovascular disease. Immunization against Abeta removes insoluble deposits of Abeta from brain parenchyma and may allow improved clearance of soluble Abeta. Reducing cerebrovascular disease and facilitating elimination of Abeta along perivascular drainage routes may offer long-term preventative measuresfor both Vascular Dementia and for Alzheimer's disease.

Solitary amyloid tumour of breast--a case report.

45 years old woman with solitary amyloid tumor of breast is described. Clinically, the breast mass was hard and was suspicious of carcinoma. Microscopically there was no neoplasia. Instead there was extensive fibrosis with amyloid deposition in perivascular periductal areas and also in intervening stroma. The presence of amyloid was confirmed by Special stains and by Polarised microscope. Investigations revealed no evidence of systemic amyloidosis or amyloid related illness.

Amyloid (spheroid) deposits in pituitary adenoma presenting as Cushing disease--a case report.

A rare case of pituitary adenoma with spheroid amyloid deposits encountered in a 40 year old male is presented.

Amiloidose cutânea atípica (nodular primitiva) e doença de Rendu-Osler-Weber / Primary localized cutaneous amyloidosis and hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber's disease)

Os autores relatam um caso de amiloidose cutânea, localizada em uma paciente de 58 anos, associada a telangiectasia hemorrágica hereditária. Esta forma de amiloidose é rara, e apresenta as características histopatológicas e prognósticas diferentes das variantes liquenóide e maculosa. O aspecto peculiar deste caso é associaçäo das doenças, fato do nosso conhecimento näo foi referido na literatura

Molecular biology of the amyloid of Alzheimer's disease. An overview

Alzheimer's disease is a progressive neurodegenerative disorder that affects a significant percentage of elderly individuals. Degenerative nerve cells express atypical proteins, and amyloid is deposited. The hallmark event of Alzheimer's disease is the deposition of amyloid as insoluble fibrous masses in extracellular neuritic plaques and around the walls of cerebral blood vessels. This review will focus on the advances on the knowledge of Alzheimer's amyloid, because it is becoming increasingly clear that the deposition of amyloid on neuritic plaques in the brain represents the earliest and most characteristic pathological feature of Alzheimer's disease. The main component of amyloid is a 4.2-4.5 KDa hydrophobic peptide, named amyloid beta-peptide, that is codified in chromosome 21 as part of a much larger precursor protein. The study of the mechanism by which the amyloid beta-peptide arises from the amyloid precursor protein is very important in order to understand the biological basis of amyloid deposition and its role in Alzheimer's disease

Nefropatia amilóide e transplante renal

Insuficiência renal crônica secundária à amiloidose renal é rara, acometendo cerca de 0,5% dos urêmicos terminais. Säo muitas as doenças sistêmicas que podem produzir amiloidose renal. No Brasil a hanseníase é causa freqüente. Até há alguns anos tais pacientes eram recusados nos programas de diálise e transplante renal, como, em geral, todos aqueles portadores de doenças sistêmicas. Atualmente näo existem mais tais restriçöes e o sucesso de tais terapêuticas substitutivas tem sido relatado. A evoluçäo do paciente com amiloidose submetido a transplante renal é melhor do que quando mantido em diálise crônica, embora em ambos os casos seja inferior à populaçäo geral. A recidiva da amiloidose no rim transplantado é freqüente, pode ser precoce e ter evoluçäo longa. Näo foi descrita ainda perda do enxerto decorrente de recidiva. Nos pacientes portadores de hanseníase ela pode ocorrer precocemente, mesmo quando a doença esteja quiescente. A colchicina parece ser benéfica na profilaxia da recidiva em pacientes com febre familiar do Mediterrâneo. Nos demais casos seu papel ainda está para ser demonstrado. Complicaçöes infecciosas no paciente transplantado parecem ser mais freqüentes no paciente com amiloidose do que naqueles da populaçäo geral. A amiloidose sistêmica pode ser um risco adicional para o paciente. Em suma, apesar da possibilidade de recidiva, de uma possível maior predisposiçäo a infecçöes e dos riscos adicionais trazidos pela amiloidose sistêmcia, o transplante renal em portadores de amiloidose é uma modalidade terapêutica satisfatória e superior à diálise crônica. Sobrevidas superiores a dez anos têm sido descritas