Familial amyloid polyneuropathy (FAP): clinical features, pathophysiology and treatment

In the literature, concepts of “polyneuropathy”, “peripheral neuropathy” and “neuropathy” are often mistakenly used as synonyms. Polyneuropathy is a specific term that refers to a relatively homogenous process that affects multiple peripheral nerves. Most of these tend to present as symmetric polyneuropathies that first manifest in the distal portions of the affected nerves. Many of these distal symmetric polyneuropathies are due to toxic-metabolic causes such as alcohol abuse and diabetes mellitus. Other distal symmetric polyneuropathies may result from an overproduction of substances that result in nerve pathology such as is observed in anti-MAG neuropathy and monoclonal gammopathy of undetermined significance. Other “overproduction” disorders are hereditary such as noted in the Portuguese type of familial amyloid polyneuropathy (FAP). FAP is a manifestation of a group of hereditary amyloidoses; an autosomal dominant, multisystemic disorder wherein the mutant amyloid precursor, transthyretin, is produced in excess primarily by the liver. The liver accounts for approximately 98% of all transthyretin production. FAP is confirmed by detecting a transthyretin variant with a methionine for valine substitution at position 30 [TTR (Met30)]. Familial Amyloidotic Polyneuropathy (FAP) – Portuguese type was first described by a Portuguese neurologist, Corino de Andrade in 1939 and published in 1951. Most persons with this disorder are descended from Portuguese sailors who sired offspring in various locations, primarily in Sweden, Japan and Mallorca. Their descendants emigrated worldwide such that this disorder has been reported in other countries as well. More than 2000 symptomatic cases have been reported in Portugal. FAP progresses rapidly with an average time course from symptom onset to multi-organ involvement and death between ten and twenty years. Treatments directed at removing this aberrant protein such as plasmapheresis and immunoadsorption proved to be unsuccessful. Liver transplantation has been the only effective solution as evidenced by almost 2000 liver transplants performed worldwide. A therapy for FAP with a novel agent, “Tafamidis” has shown some promise in ongoing phase III clinical trials. It is well recognized that regular physical activity of moderate intensity has a positive effect on physical fitness as gauged by body composition, aerobic capacity, muscular strength and endurance and flexibility. Physical fitness has been reported to result in the reduction of symptoms and lesser impairment when performing activities of daily living. Exercise has been advocated as part of a comprehensive approach to the treatment of chronic diseases. Therefore, this chapter concludes with a discussion of the role of exercise training on FAP.

Dynamics and orchestral effects in late Eighteenth-Century portuguese organ music: the works of José Marques e Silva (1782-1837) and the organs of António Xavier Machado e Cerveira (1756-1828)

A maioria dos órgãos históricos portugueses data dos finais do século XVIII ou do princípio do século XIX. Durante este período foi construído um invulgar número de instrumentos em Lisboa e nas áreas circundantes por António Xavier Machado e Cerveira (1756-1828) e outros organeiros menos prolíficos. O estudo desses órgãos, muitos dos quais (restaurados ou não) se encontram próximos das condições originais, permite a identificação de um tipo de instrumento com uma morfologia específica, claramente emancipada do chamado «órgão ibérico». No entanto, até muito recentemente, não era conhecida música que se adaptasse às idiossincrasisas daqueles instrumentos. O recente estudo das obras para órgão de José Marques e Silva (1782-1837) permitiu clarificar esta situação. Bem conhecido durante a sua vida como organista e compositor, José Marques e Silva foi um dos ultimos mestres do Seminário Patriarcal. A importância da sua produção musical reside não só num substancial número de obras com autoria firmemente estabelecida – escritas, na maior parte, para coro misto com acompanhamento de órgão obbligato – mas também na íntima relação entre a sua escrita e a morfologia dos órgãos construídos em Portugal durante a sua vida. Este artigo enfatiza a importância de José Marques e Silva (indubitavelmente, o mais significativo compositor português para órgão do seu tempo) sublinhando a relevância das suas obras para órgão solo, cujo uso extensivo de escrita idiomática e indicações de registação fazem delas um dos mais importantes documentos só início do século XIX sobre a prática organística em Portugal.

The organ verses of Frei Jerónimo da Madre de Deus: Portuguese organ music in the time of D. João V

Contrastando com o importante legado dos mestres organistas portugueses dos séculos XVI e XVII, a música portuguesa para órgão pós-1700 parece quase inexistente (excluindo raros exemplos, como as quatro sonatas para órgão de Carlos Seixas). Seja devido à destruição causada pelo grande terramoto de Lisboa em 1755, ou a outras causas, a ausência de fontes é surpreendente, considerando os testemunhos de actividade musical durante aquele período. Este artigo lida com uma fonte até hoje relativamente ignorada: o manuscrito CLI/1-4 nº 7 da Biblioteca do Palácio Ducal de Vila Viçosa (Versos / Sobre o Canto Chão / Para Orgão / De Fr. Jeronimo da M.dre de DS.). Esta colecção de vinte versos para órgão de Jerónimo da Madre de Deus é, de longe, a maior obra portuguesa para órgão da primeira metade do século XVIII até hoje conhecida. Claramente pensadas para o órgão, estas curtas peças testemunham a transformação da escrita para tecla em Portugal durante o reinado de D. João V (nomeadamente através da absorção de influências italianas) e fornecem informações preciosas sobre o tipo de instrumento em que eram tocadas.

Living bacteria rheology: Population growth, aggregation patterns, and collective behaviour under diferente shear flows

The activity of growing living bacteria was investigated using real-time and in situ rheology-in stationary and oscillatory shear. Two different strains of the human pathogen Staphylococcus aureus-strain COL and its isogenic cell wall autolysis mutant, RUSAL9-were considered in this work. For low bacteria density, strain COL forms small clusters, while the mutant, presenting deficient cell separation, forms irregular larger aggregates. In the early stages of growth, when subjected to a stationary shear, the viscosity of the cultures of both strains increases with the population of cells. As the bacteria reach the exponential phase of growth, the viscosity of the cultures of the two strains follows different and rich behaviors, with no counterpart in the optical density or in the population's colony-forming units measurements. While the viscosity of strain COL culture keeps increasing during the exponential phase and returns close to its initial value for the late phase of growth, where the population stabilizes, the viscosity of the mutant strain culture decreases steeply, still in the exponential phase, remains constant for some time, and increases again, reaching a constant plateau at a maximum value for the late phase of growth. These complex viscoelastic behaviors, which were observed to be shear-stress-dependent, are a consequence of two coupled effects: the cell density continuous increase and its changing interacting properties. The viscous and elastic moduli of strain COL culture, obtained with oscillatory shear, exhibit power-law behaviors whose exponents are dependent on the bacteria growth stage. The viscous and elastic moduli of the mutant culture have complex behaviors, emerging from the different relaxation times that are associated with the large molecules of the medium and the self-organized structures of bacteria. Nevertheless, these behaviors reflect the bacteria growth stage.