Species differences in the multiple-dose pharmacokinetics of the non-nucleoside reverse transcriptase inhibitor (NNRTI) UK-453,061 in animals and man: implications for safety considerations.

The requirements for safe testing of pharmaceuticals in humans places substantial emphasis on the translation of safety testing performed in animals to man. The comparison of systemic exposure in animals and man has taken on increasing importance in this assessment, with the underlying assumption that plasma concentrations will elicit the same response in different species. This assumption may be flawed for a number of different reasons, one of which is differences in drug disposition between species leading to high doses required in animal species to yield equivalent systemic exposure to humans and consequent higher exposure to organs such as the intestine and liver. Hepatic clearance can vary substantially, particularly between rodents and man, resulting in vast differences in the dose-exposure relationship. A specific example of a non-nucleoside reverse transcriptase inhibitor, which causes substantial auto-induction in rodents, is used to illustrate this situation and the impact this has on the interpretation of safety extrapolation from animals to man. In such circumstances, it is important to recognize the impact of species differences in drug clearance and disposition and consider broader input in the assessment of clinical safety.

Blood gene expression signatures predict exposure levels.

To respond to potential adverse exposures properly, health care providers need accurate indicators of exposure levels. The indicators are particularly important in the case of acetaminophen (APAP) intoxication, the leading cause of liver failure in the U.S. We hypothesized that gene expression patterns derived from blood cells would provide useful indicators of acute exposure levels. To test this hypothesis, we used a blood gene expression data set from rats exposed to APAP to train classifiers in two prediction algorithms and to extract patterns for prediction using a profiling algorithm. Prediction accuracy was tested on a blinded, independent rat blood test data set and ranged from 88.9% to 95.8%. Genomic markers outperformed predictions based on traditional clinical parameters. The expression profiles of the predictor genes from the patterns extracted from the blood exhibited remarkable (97% accuracy) transtissue APAP exposure prediction when liver gene expression data were used as a test set. Analysis of human samples revealed separation of APAP-intoxicated patients from control individuals based on blood expression levels of human orthologs of the rat discriminatory genes. The major biological signal in the discriminating genes was activation of an inflammatory response after exposure to toxic doses of APAP. These results support the hypothesis that gene expression data from peripheral blood cells can provide valuable information about exposure levels, well before liver damage is detected by classical parameters. It also supports the potential use of genomic markers in the blood as surrogates for clinical markers of potential acute liver damage.

Protective effect of pregnancy for development of uterine leiomyoma.

Many factors that can modulate the risk of developing uterine leiomyoma have been identified, including parity. Epidemiological data on decreased risk of developing this disease has been subject to different interpretations regarding whether pregnancy per se is protective or, as leiomyomas are a major cause of infertility, women that develop these tumors are less fertile and thus have lower pregnancy rates. We have utilized an animal model genetically predisposed to uterine leiomyoma to investigate the potential protective effect of pregnancy on the risk of developing this disease. Female Eker rats that carry a mutation in the tuberous sclerosis 2 (Tsc-2) tumor suppressor gene develop uterine leiomyoma with a frequency of 65% when nulliparous. These animals were bred with intact or vasectomized males and tumor incidence determined after a single pregnancy (to confirm fertility) or multiple pregnancies over the lifetime of the animals. Females with multiple litters displayed a dramatic shift in tumor incidence and presentation. Tumor incidence decreased from 71% in single litter females to 10% in females that had multiple litters (average: five litters/animal). Interestingly, females bred with vasectomized males also exhibited a reduced tumor incidence of 41%, suggesting that the hormonal changes associated with early stages of pregnancy that occur in pseudopregnant females may have contributed to the protective effect of pregnancy.

Restoration of reproductive potential following expiration or removal of melengestrol acetate contraceptive implants in golden lion tamarins (Leontopithecus rosalia).

Although reversible contraception is important to successful management of small populations, there are concerns about the reversibility of melengestrol acetate (MGA), the most commonly used implant in captive animals. Female golden lion tamarins (Leontopithecus rosalia) placed in potential breeding situations after surgical MGA implant removal showed a 75% return to reproduction within 2 yr, unlike golden-headed tamarins (Leontopithecus chrysomelas), which have had a 29% return to reproduction following implant removal. This rate was indistinguishable from the breeding probability for newly formed pairs involving nonimplanted females. Litter size, stillbirth rate, and infant survival rate were not significantly different between nonimplanted and implant-removed female golden lion tamarins. However, females with implants left in (and assumed to have expired) showed higher stillbirth and infant mortality rates than did females with implants removed. For seven female golden lion tamarins for which reproductive histories before and after MGA implantation were available, litter size was unaffected by MGA implantation and subsequent removal. Infant survival rate for these females appeared to be lower after removal but was indistinguishable from rates in the nonimplanted females. Prior reproductive experience, length of time with an implant, and age of the females did not affect the probability of breeding for females after removal of the implants. Overall, breeding probability of nonimplanted females declined with age. Although the results of this study confirm the reversibility of MGA implants in golden lion tamarins, there appear to be some effects on viability of offspring, particularly offspring born to females with implants left in and presumed expired.

Living at home or in an institution: what makes the difference for seniors?

OBJECTIVES: This article examines some of the health and socio-demographic factors associated with living in long-term health care facilities rather than in private households, for elderly people with various levels of disability. DATA SOURCE: The data are from the 1996/97 National Population Health Survey conducted by Statistics Canada. Data from a sample of 1,711 people aged 65 or older living in long-term health care facilities and 13,363 in private households were weighted to represent about 185,100 and 3.4 million seniors, respectively. ANALYTICAL TECHNIQUES: Descriptive data were produced using bivariate frequencies. Multiple logistic regression models were used to examine associations between living in long-term health care facilities and selected health and socio-demographic characteristics for seniors with self-reported severe, moderate or no disability. MAIN RESULTS: While health status was strongly associated with residence in a long-term health care facility, the absence of a spouse, low income, low education, and advanced age were also significant.

Vitamin E deficiency and pansteatitis in juvenile boat-billed herons (Cochlearius cochlearius).

Steatitis due to vitamin E deficiency occurred in three 10-wk-old boat-billed herons (Cochlearius cochlearius) despite daily placement of a powdered vitamin supplement on the fish that was subsequently washed off by the parents. Physical findings included emaciation, yellow-brown subcutaneous nodules, a firm distended coelom, stomatitis, and yellow-white, submucosal pharyngeal nodules. Clinical pathology revealed heterophilic leukocytosis, anemia, hypoproteinemia, and low plasma alpha (alpha)-tocopherol levels (1.94 microg/ml and 2.14 microg/ml). Two of the chicks died of severe, diffuse pansteatitis and respiratory aspergillosis.

A model for estimating the costs and burdens of breast cancer diagnosis and treatment in Canada.

As health care costs continue to rise in Canada, there is a need to evaluate the resources required for diagnosing and treating the major diseases having an impact on Canadian. In 1993, breast cancer was the most predominant female cancer in Canada, both in terms of incidence and mortality. It would be useful to identify the direct health care costs associated with this disease and to create an analytical framework within which diagnostic and therapeutic options can be assessed. This paper provides a description of the approach to be taken in developing a realistic conceptual model of the management of all stages of breast cancer, including diagnostic and treatment approaches, survival outcomes and costs. It includes an outline of our research objectives, a description of the kind of information required, a section on the methodology and sources to be used, and a brief explanation of the analytical framework into which it will be incorporated and used.

Choice behaviour of red-winged blackbirds (Agelaius phoeniceus ) searching for food: The role of certain variables in stay and shift strategies.

This experiment examined the extent to which the food searching strategies of Red-winged Blackbirds are influenced by the age of the birds and by information about the food supply gained from a previously visited location. Birds entered a maze and were given a choice between the three parallel, foraging locations. After making its choice, each bird was either allowed to consume all of the food present at the site (depletion condition) or only some of it (non-depletion condition). All birds were tested under both conditions. After its first choice, each bird was subsequently re-tested to determine if it returned to the previously visited site or whether it chose an alternate site. Subjects were more likely to choose an alternate location after experiencing the depletion condition. Under the non-depletion condition, adult birds showed a strong predisposition to return to the initially chosen sites while immature birds only returned to those sites randomly. The results were related to the current theory of staying/shifting dichotomy.