Abstract
Organ weights are an important quantitative endpoint in many toxicologic studies. However, comparison of organ weights among treatment groups is often complicated by differences in body weight. To determine the best format for evaluating target organ toxicity using organ weights, toxicologic pathologists examined data for control rats involved in 26 similarly conducted toxicity studies. All studies were 1-month toxicity studies using male and female Crl: CD[SD]BR rats. Three commonly used measures, organ weights, organ-to-body weight ratios, and organ-to-brain weight ratios, were compared for adrenals, heart, thyroids, kidneys, liver, pituitary, testes, ovaries, and brain. The linear relationships between organ weight and body weight and between organ weight and brain weight were evaluated using a simple linear regression model. The results clearly demonstrated that organ-to-body weight ratios are optimal for analysis of liver and thyroid weights, whereas organ-to-brain weight ratios are best for analysis of ovary and adrenal weights. None of the methods tested accurately modeled brain, heart, kidney, pituitary, or testis weights. For these organs, analysis of covariance, using body weight as the covariate, is recommended.
Bailey SA, Zidell RH, Perry RW: Relationships between organ weight and body/brain weight in the rat: what is the best analytic endpoint?. Toxicol Pathol 32:448–466, 2004
The multifactorial disease called shipping fever, a severe bronchofibrinous pneumonia, causes important economic losses to the beef industry. The coccobacillus Mannheimia hemolytica contributes significantly to the pathogenesis of shipping fever. M. hemolytica produces a variety of proinflammatory virulence factors, including lipopolysaccharide, leukotoxin, and O-sialoglycoprotease. Canadian investigators recently studied the relationship between these virulence factors and the activity of matrix metalloproteinases (MMPs), host-derived zinc-binding proteases implicated in inflammation-associated lung damage. They demonstrated markedly increased MMP activity in lung lesions caused by the bacterium. Moreover, MMPs were produced but not activated by monocytes exposed to M. hemolytica virulence factors, and exposure to these factors caused the release of activated MMPs from neutrophils. These findings indicate that M. hemolytica–stimulated production, release, and activation of MMPs are likely to play an important role in shipping fever pathogenesis.
Starr AE, Dan T, Minhas K, Shewen PE, Coomber BL: Potential involvement of gelatinases and their inhibitors in Mannheimia haemolytica pneumonia in cattle. Infect Immun 72:4393–4400, 2004
Neurotoxicosis has been reported in some Collies treated with the anthelminthic drug ivermectin. This susceptibility has been linked to a specific mutation in the multiple drug resistance gene MDR1. American scientists tested a variety of dogs that showed ivermectin sensitivity and found that, in all cases, sensitivity was due to the presence of the same mutation. This indicated that all ivermectin-sensitive dogs shared a common ancestor. When more than 4,000 purebred dogs were tested, the mutant allele was detected in at least nine breeds. These breeds included herding breeds of the collie lineage (Australian Shepherd, Miniature Australian Shepherd, Collie, English Shepherd, McNab, Old English Sheepdog, and Shetland Sheepdog), as expected. Unexpectedly, two sighthound breeds (Longhaired Whippet and Silken Windhound) also carried the mutation, suggesting an unsuspected contribution of the collie lineage to these breeds. These findings demonstrated unexpected relationships among dog breeds and confirmed the usefulness of this approach in tracing the origins of specific breeds.
Neff MW, Robertson KR, Wong AK, Safra N, Broman KW, Slatkin M, Mealey KL, Pedersen NC: Breed distribution and history of canine mdr1-1Delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci USA 101:11725–11730, 2004
Reactive gliosis is a hallmark of central nervous system disease due to prions. It is likely that microglia are activated by aggregated prion-derived peptides. In turn, activated microglia cells may mediate gliosis and neuronal death. European investigators evaluated the contribution of interleukin-1β (IL-1β), a well-characterized inflammatory cytokine, to the development of gliosis. Using a mouse model of scrapie, they determined that expression of the IL-1β–activating enzyme IL-1β ICE and IL-1 receptor type I were markedly increased in scrapie-infected mice. In addition, IL-1β–deficient mice demonstrated increased resistance to prion disease, as assessed by the onset of clinical signs and survival time. Microscopic examination of brains at the time of clinical disease onset in wild-type mice revealed reduced astrocytosis and prion protein accumulation in IL-1β knockout mice compared with wild-type mice. These results confirm a role for IL-1 in prion disease and suggest that anti-inflammatory therapy may be useful in delaying neurologic disease onset in established prion infections.
Schultz J, Schwarz A, Neidhold S, Burwinkel M, Riemer C, Simon D, Kopf M, Otto M, Baier M: Role of interleukin-1 in prion disease-associated astrocyte activation. Am J Pathol 165:671–678, 2004
Expression profiling of cultured human melanoma cells and normal melanocytes performed by an international team of scientists has revealed a wide variety of pathways involved in melanocyte transformation. Prominent changes included alterations in the expression of receptors (receptor tyrosine kinases), ligands (growth factors), cell surface, and adhesion molecules (integrins, cadherins) that play important roles in tumor cell proliferation, invasion, and motility. In addition, expression of genes involved in differentiation (cancertestis antigens), immune modulation (interferon-regulated genes, leukemia inhibitory factor), vesicular transport, the ubiquitin pathway, transcription regulation (Twist), and growth suppression was modulated to favor tumor cell proliferation and invasion, as well as avoidance of immunosurveillance. Two genes with prognostic significance were identified. Elevated expression of the Twist transcription factor and reduced expression of ubiquitin esterase were associated with worse disease outcome. In addition, some of the pathways identified may offer attractive targets for therapy.
Hoek K, Rimm DL, Williams KR, Zhao H, Ariyan S, Lin A, Kluger HM, Berger AJ, Cheng E, Trombetta ES, Wu T, Niinobe M, Yoshikawa K, Hannigan GE, Halaban R: Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res 64:5270–5282, 2004