Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson's disease and related disorders.

An abundance of genetic, histopathological, and biochemical evidence has implicated the neuronal protein, alpha-synuclein (alpha-syn) as a key player in the development of several neurodegenerative diseases, the so-called synucleinopathies, of which Parkinson's disease (PD) is the most prevalent. Development of disease appears to be linked to events that increase the intracellular concentration of alpha-syn or cause its chemical modification, either of which can accelerate the rate at which it forms aggregates. Examples of such events include increased copy number of genes, decreased rate of degradation via the proteasome or other proteases, or altered forms of alpha-syn, such as truncations, missense mutations, or chemical modifications by oxidative reactions. Aggregated forms of the protein, especially newly formed soluble aggregates, are toxic to cells, so that one therapeutic strategy would be to reduce the rate at which such oligomerization occurs. We have therefore designed several peptides and also identified small molecules that can inhibit alpha-syn oligomerization and toxicity in vitro. These compounds could serve as lead compounds for the design of new drugs for the treatment of PD and related disorders in the future.

The origins of the Irish hospitals' sweepstake

This article examines the two main reasons for the setting up of the Irish sweepstakes in 1930; the financial crisis facing voluntary hospitals and the tradition of using sweepstake gambling to raise funds for charitable purposes. Such gambling, although technically illegal, was prevalent and widely tolerated during the late 19th and early 20th centuries. The change of government that accompanied Irish independence in 1921 led to much confusion surrounding the law on gambling and large-scale sweepstakes proliferated during the early 1920s, many of them selling tickets illegally in Britain. At the same time the Irish voluntary hospitals faced a financial crisis that threatened their future, brought about by the adverse impact of war-time inflation on the value of their endowments, the emigration of supporters of the Protestant voluntary hospitals after independence, the political upheaval of the revolutionary period, the decline in fees from medical students and the increasing cost of and demand for hospital treatment. This article provides a detailed account of the enactment of the sweepstake legislation and of the first sweepstake on the 1930 Manchester November Handicap.