Molecular pathology of human prion disease

Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria. Considerable experimental evidence suggests that phenotypic diversity in human prion disease relates in significant part to the existence of distinct human prion strains encoded by abnormal PrP isoforms with differing physicochemical properties. To date, however, the conformational repertoire of pathological isoforms of wild-type human PrP and the various forms of mutant human PrP has not been fully defined. Efforts to produce a unified international classification of human prion disease are still ongoing. The ability of genetic background to influence prion strain selection together with knowledge of numerous other factors that may influence clinical and neuropathological presentation strongly emphasises the requirement to identify distinct human prion strains in appropriate transgenic models, where host genetic variability and other modifiers of phenotype are removed. Defining how many human prion strains exist allied with transgenic modelling of potentially zoonotic prion strains will inform on how many human infections may have an animal origin. Understanding these relationships will have direct translation to protecting public health

Current and Future Drug Targets in Weight Management

Obesity will continue to be one of the leading causes of chronic disease unless the ongoing rise in the prevalence of this condition is reversed. Accumulating morbidity figures and a shortage of effective drugs have generated substantial research activity with several molecular targets being investigated. However, pharmacological modulation of body weight is extremely complex, since it is essentially a battle against one of the strongest human instincts and highly efficient mechanisms of energy uptake and storage. This review provides an overview of the different molecular strategies intended to lower body weight or adipose tissue mass. Weight-loss drugs in development include molecules intended to reduce the absorption of lipids from the GI tract, various ways to limit food intake, and compounds that increase energy expenditure or reduce adipose tissue size. A number of new preparations, including combinations of the existing drugs topiramate plus phentermine, bupropion plus naltrexone, and the selective 5-HT2C agonist lorcaserin have recently been filed for approval. Behind these leading candidates are several other potentially promising compounds and combinations currently undergoing phase II and III testing. Some interesting targets further on the horizon are also discussed

Methods for Molecular Diagnosis of Human Prion Disease.

Human prion diseases are associated with a range of clinical presentations, and they are classified by both clinicopathological syndrome and etiology, with subclassification according to molecular criteria. Here, we describe updated procedures that are currently used within the MRC Prion Unit at UCL to determine a molecular diagnosis of human prion disease. Sequencing of the PRNP open reading frame to establish the presence of pathogenic mutations is described, together with detailed methods for immunoblot or immunohistochemical determination of the presence of abnormal prion protein in the brain or peripheral tissues

Renal Failure

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Tumores do tronco cerebral: estudo anatomopatológico em 35 casos de necrópsia

Os tumores do tronco cerebral são raros e geralmente tratados sem diagnóstico histopatológico. Sua incidência varia na literatura entre 1,09% e 17,5% dos tumores cerebrais. O objetivo do trabalho foi relatar a casuísti desses tumores em 28500 necrópsias realizadas de 1952 a 1985 no Departamento de Anatomia Patológica da Santa Casa de São Paulo. Enfatizamos os aspectos neuropatológicos, comparamos nossos casos com os de outras séries e salientamos os tumores mais observados nessa região, com a finalidade de procurar contribuir para melhor abordagem terapêutica. Utilizamos alguns dados clínicos e, através do exame anatomopatológico, localizamos o tumor no tronco cerebral sendo o diagnóstico microscópico estabelecido segundo os critérios da Organização Mundial da Saúde. Dos 428 tumores intracranianos observados, 35 estavam localizados no tronco cerebral. Foram aqui incluídos os tumores próprios do tronco cerebral e as metástases e excluídos os tumores que infiltravam o tronco. A maior incidência ocorreu na primeira década e a causa de óbito predominante foi edema cerebral. A localização preferencial foi a ponte e o tumor mais freqüente foi o glioblas-tomia multiforme (19 casos). As metástases ficaram em segundo lugar na freqüência (9 casos), na maioria dos casos de origem pulmonar. Apesar de alguns autores se posicionarem contra a biópsia de tumor nessa região, baseando-se no alto risco cirúrgico, discordamos dessa opinião, pois acreditamos que, frente ao diagnóstico de glioma, será importante a caracterização ou não de malignidade. Ainda, não devemos deixar de considerar os diagnósticos diferenciais de processo expansivo no tronco. Enfim, com o diagnóstico anatomopatológico de glioma ou de uma das possibilidades aventadas, o procedimento terapêutico poderá ser mais adequado