The discovery of adamantyl-derived, inhaled, long acting beta(2)-adrenoreceptor agonists

The design and profile of a series of adamantyl-containing long acting beta(2)-adrenoreceptor agonists are described. An optimal pharmacokinetic profile of low oral bioavailability was combined with a strong pharmacology profile when assessed using a guinea pig trachea tissue model. A focus was then placed on developing a robust synthetic route to ensure rapid delivery of material for clinical trials.     

Incidence and Characteristics of Total Stroke in the United States

Background and Purpose  

Stroke, increasingly referred to as a "brain attack", is one of the leading causes of death and the leading cause of adult disability in the United States. It has recently been estimated that there were three quarters of a million strokes in the United States in 1995. The aim of this study was to replicate the 1995 estimate and examine if there was an increase from 1995 to 1996 by using a large administrative claims database representative of all 1996 US inpatient discharges.     

Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells

Skin-draining lymph nodes contain a number of dendritic cell (DC) subsets of different origins. Some of these are migratory, such as the skin-derived epidermal Langerhans cells and a separate dermal DC subset, whereas others are lymphoid resident in nature, such as the CD8+ DCs found throughout the lymphoid tissues. In this study, we examine the DC subset presentation of skin-derived self-Ag by migratory and lymphoid-resident DCs, both in the steady state and under conditions of local skin infection. We show that presentation of self-Ag is confined to skin-derived migrating DCs in both settings. Steady state presentation resulted in deletional T cell tolerance despite these DCs expressing a relatively mature phenotype as measured by traditional markers such as the level of MHC class II and CD86 expression. Thus, self-Ag can be carried to the draining lymph nodes by skin-derived DCs and there presented by these same cells for tolerization of the circulating T cell pool.     

Rate of decline of the Oriental white-backed vulture population in India estimated from a survey of diclofenac residues in carcasses of ungulates

The non-steroidal anti-inflammatory drug diclofenac is a major cause of the rapid declines in the Indian subcontinent of three species of vultures endemic to South Asia. The drug causes kidney failure and death in vultures. Exposure probably arises through vultures feeding on carcasses of domesticated ungulates treated with the drug. However, before the study reported here, it had not been established from field surveys of ungulate carcasses that a sufficient proportion was contaminated to cause the observed declines. We surveyed diclofenac concentrations in samples of liver from carcasses of domesticated ungulates in India in 2004-2005. We estimated the concentration of diclofenac in tissues available to vultures, relative to that in liver, and the proportion of vultures killed after feeding on a carcass with a known level of contamination. We assessed the impact of this mortality on vulture population trend with a population model. We expected levels of diclofenac found in ungulate carcasses in 2004-2005 to cause oriental white-backed vulture population declines of 80-99% per year, depending upon the assumptions used in the model. This compares with an observed rate of decline, from road transect counts, of 48% per year in 2000-2003. The precision of the estimate based upon carcass surveys is low and the two types of estimate were not significantly different. Our analyses indicate that the level of diclofenac contamination found in carcasses of domesticated ungulates in 2004-2005 was sufficient to account for the observed rapid decline of the oriental white-backed vulture in India. The methods we describe could be used again to assess changes in the effect on vulture population trend of diclofenac and similar drugs. In this way, the effectiveness of the recent ban in India on the manufacture and importation of diclofenac for veterinary use could be monitored.     

Geographical variation in species' population responses to changes in temperature and precipitation

Despite increasing concerns about the vulnerability of species'' populations to climate change, there has been little overall synthesis of how individual population responses to variation in climate differ between taxa, with trophic level or geographically. To address this, we extracted data from 132 long-term (greater than or equal to 20 years) studies of population responses to temperature and precipitation covering 236 animal and plant species across terrestrial and freshwater habitats. Our results identify likely geographical differences in the effects of climate change on populations and communities in line with macroecological theory. Temperature tended to have a greater overall impact on populations than precipitation, although the effects of increased precipitation varied strongly with latitude, being most positive at low latitudes. Population responses to increased temperature were generally positive, but did not vary significantly with latitude. Studies reporting significant climatic trends through time tended to show more negative effects of temperature and more positive effects of precipitation upon populations than other studies, indicating climate change has already impacted many populations. Most studies of climate change impacts on biodiversity have focused on temperature and are from middle to high northern latitudes. Our results suggest their findings may be less applicable to low latitudes.     

Use of microsatellite‐based paternity assignment to establish where Corn Crake Crex crex chicks are at risk from mechanized mowing

We used microsatellite DNA to assign probable parentage of young Corn Crakes to adult males and females and used these assignments to estimate the distribution of distances between broods of chicks and juveniles and the night‐time singing place of the father at the time of initiation of the clutch. Estimated distances for broods of young chicks were in accord with those estimated previously by radiotracking, but distances were greater for older unfledged independent chicks not studied previously. Our results indicate that modifications of the timing and method of mowing to reduce losses of nests and chicks should be implemented inside an area within about 500 m of the singing places of male Corn Crakes, rather than the 250 m previously considered to be safe.