Substrate specificity of gamma-secretase and other intramembrane proteases.

Gamma-Secretase is a promiscuous protease that cleaves bitopic membrane proteins within the lipid bilayer. Elucidating both the mechanistic basis of gamma-secretase proteolysis and the precise factors regulating substrate identification is important because modulation of this biochemical degradative process can have important consequences in a physiological and pathophysiological context. Here, we briefly review such information for all major classes of intramembranously cleaving proteases (I-CLiPs), with an emphasis on gamma-secretase, an I-CLiP closely linked to the etiology of Alzheimer's disease. A large body of emerging data allows us to survey the substrates of gamma-secretase to ascertain the conformational features that predispose a peptide to cleavage by this enigmatic protease. Because substrate specificity in vivo is closely linked to the relative subcellular compartmentalization of gamma-secretase and its substrates, we also survey the voluminous body of literature concerning the traffic of gamma-secretase and its most prominent substrate, the amyloid precursor protein.

Beverage sales and drinking and driving: the role of on-premise drinking places.

OBJECTIVE: The relationships between on-premise drinking places, beverage specific alcohol sales and drinking and driving were examined in a time series cross-sectional study of place-of-last-drink data from Perth, Western Australia. METHOD: At arrest, 2,411 drinking drivers reported their last location of consumption. Tabulated by 57 premises over 4 years, the rates at which individual premises were referenced as the place-of-last-drink were taken to reflect the relative distributions of numbers of drinking drivers coming from different premise types (hotels, taverns and nightclubs). The data were then statistically related to measures of premise types and characteristics and beverage specific alcohol sales. RESULTS: Significant cross-sectional relationships were obtained between measures of premise types, alcohol sales and drinking and driving. Greatest numbers of drinking drivers came from taverns and from places selling greater amounts of beer and spirits. Significant longitudinal effects were obtained for sales of beer, proportions of high alcohol beer sold and sales of spirits. CONCLUSIONS: As a whole, the results suggest that, at least for Western Australia, outlets selling greater amounts of beer and spirits, and greater amounts of high alcohol beer, will produce larger numbers of drinking drivers.

Can training bar staff in responsible serving practices reduce alcohol-related harm?

A responsible service training programme aimed at reducing alcohol-related harm was implemented in a popular entertainment area over several months in 1992-93. Another popular entertainment area provided a control site. A number of evaluation measures were used: breath tests on 872 patrons from selected venues; drink driving data; risk assessments; the use of 'pseudo patrons'; and knowledge and attitude changes among trained bar staff (n = 88). Compared to control sites the intervention sites showed an immediate pre- to post-test reduction in patrons rated by researchers as extremely drunk and an eventual reduction from pre-test to follow-up in patrons with blood alcohol levels > = 0.08. There was also a small but significant increase in knowledge among bar staff. There was no significant reduction in patrons with blood alcohol levels > = 0.15 or in the number of drink driving offences from intervention sites during the study period. Pseudo drunk patrons were rarely refused service, identification was rarely checked and non-photographic identification was accepted on most occasions. The less than satisfactory outcome is attributed to poor implementation of the training and a lack of support among managers. The positive results from one venue, whose manager embraced the programme, served to highlight the importance of management support. It is suggested that mandatory training and routine enforcement of licensing laws are essential if the goals of responsible serving are to be met.

Current perspectives on anabolic steroids.

Steroids are used outside the realm of competitive athletics in Australia among a wide variety of groups with different motivations and goals. This paper provides an overview of the reasons for use; rates of usage; physical and psychological side effects; and sources of steroids. Issues associated with injecting steroids; their current legal status; and drug education and prevention programmes are reviewed briefly. Research involving identified sub-populations is needed to determine user profiles and prevalence rates of users and potential users. Studies of Australian users are also needed to obtain baseline information on areas of potential harm associated with steroids use, e.g. aggressive behaviour, needle-sharing behaviour, physical side effects and potential for dependency. It is concluded that future deterrence strategies should focus more on demand reduction, rather than supply.

Pseudo-drunk-patron evaluation of bar-staff compliance with Western Australian liquor law.

Compliance of bar staff with the Western Australian liquor law prohibiting service to drunk patrons was assessed through the deployment of actors trained to behave in a drunken manner. The serving practices of 23 licensed premises (19 hotels and four nightclubs) were examined. During 120 visits to hotel and nightclub bars, more than 350 drink orders were placed by pairs of pseudo-drunk actors who ordered up to three drinks each on each visit. On placing these drink orders, pseudo-drunks were refused service by bar staff on only 12 occasions. The rate of refusal of service across all premises was 10 per cent of visits. Partial interventions by servers, such as offering food or low-alcohol or nonalcoholic drinks, occurred in only four instances of the 120 visits. Qualitative observations and results obtained from a separate study examining a subsample of the servers who trained in responsible service of alcohol are discussed.

Use of pseudo-patrons to assess compliance with laws regarding under-age drinking.

The extent to which door and bar staff of licensed premises responded to possibly under-age patrons was assessed through the use of research assistants (young pseudo-patrons) selected for having the appearance of being under 18 years old. A total of 156 visits were made to 13 licensed premises: 1. before delivery of a server training program, 2. immediately after training, and 3. after three months. Staff rarely checked the age and/or identification (ID) of the young pseudo-patrons before or after training. However, a significant interaction was found between the sex of the pseudo-patron and the type of premises. Door staff, who were predominantly at nightclubs, were more likely to check the ID of female pseudo-patrons and hotel bar staff were more likely to check the ID of males. In most cases, however, nonphotographic ID was accepted. While some strategies are suggested, the strongest and most effective measure to prevent under-age drinking will be a more rigorous enforcement of existing liquor laws.

Alcohol consumption and harm in two Western Australian regional centres.

The application of national or state alcohol harm-prevention programs at a regional level can be inappropriate. The involvement of local communities is critical if harm-prevention responses are to be sensitive to local needs. Unfortunately, individuals and agencies usually have little idea of the impact of alcohol at the local level. Alcohol consumption and harm data have been gathered for Geraldton and Bunbury, two regional centres of comparable size in Western Australia. The indices of harm presented include the nature and cost of hospital morbidity attributable to alcohol, and drink-driving charges. In Geraldton, the impact of alcohol tends to be acute and affects young adults, particularly young males. In Bunbury, the consequences of alcohol use tend to be more chronic in nature and affect older adults. These findings have been used to inform local harm-prevention responses, but more than that, this study is a practical example of how available data can be aggregated at a community level to illustrate local alcohol use and harm. This method can be replicated in any community that wants to understand better the effects of alcohol in its own local context.