Abstract
Cystic fibrosis (CF) is a caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which is carried by approximately 5% of Caucasians. The disease is inherited in an autosomal recessive manner and affects multiple organs, including the lungs, pancreas, sweat glands, intestines, liver, and gallbladder. Although mouse models of CF have been studied for years, they do not adequately recapitulate the human disease. Rogers and colleagues developed a porcine model of CF with homozygous disruption of the CFTR gene. Similar to what is seen in humans, the CFTR−/− piglets appeared normal at birth. However, they had loss of chloride channel activity that is characteristic of CF. They also had meconium ileus and degeneration and atrophy of intestinal villi. Pancreatic lesions consisted of small, degenerative lobules with increased adipose and myxomatous tissue, and scattered inflammation. The piglets eventually developed pancreatic exocrine insufficiency. The pigs lacked pulmonary lesions, as is usually the case in very young humans. The authors did not report on whether or not any piglets survived long enough to subsequently develop pulmonary disease. In summary, this porcine model appears to be potentially very useful for further investigation of cystic fibrosis.
Rogers CS, Stoltz DA, Meyeholz DK, et al. & Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science
Proventricular dilatation disease (PDD), otherwise known as Macaw Wasting Disease, is a fatal disease of psittacines. Birds present with signs of gastrointestinal and/or nervous system dysfunction due to lesions in the autonomic nerves. Histopathologic examination of the gastrointestinal tract shows lymphoplasmacytic inflammation in mesenteric ganglia and nerves. A viral etiology has long been speculated, but not proven. To more fully explore a potential viral cause, the authors of this paper analyzed tissues from PDD cases from two continents on a microarray that contains DNA representative of all viral taxonomy. Five of eight PDD cases gave a positive signal for a bornavirus signature. All 8 control samples from unaffected cases were negative for the bornavirus signature. PCR-based screening of a second set of PDD samples confirmed the association between the disease and presence of bornavirus. The sequence of the viral genome had a high degree of divergence from previously characterized bornavirus isolates. The proposed name of this newly identified virus is avian bornavirus (ABV). Although experiments to satisfy Koch's postulates were not performed, ABV appears to be a strong candidate for the etiologic agent of PDD.
Kistler AL, Gancz A, Clubb S, et al. & Recovery of divergent avian bornaviruses from cases of proventricular dilatation disease: identification of a candidate etiologic agent. Virol J
The normal symbiotic relationship between gut flora and host immune cells is disrupted in inflammatory bowel disease (IBD). Recent work suggests that host epithelial cells may also play a critical role in maintaining homeostasis in the gut lumen. Kaser and colleagues hypothesized that endoplasmic reticulum (ER) stress may be linked to IBD. To study this connection they created mice that lacked expression of a key regulator of ER stress, X-Box-Binding Protein 1 (Xbp1), in intestinal epithelial cells. The mice developed spontaneous inflammation in the ileum due to the inability of the epithelial cells to respond to normal inflammatory signals in the gut. Other intestinal lesions included an absence of Paneth cells and a reduction in the size and number of goblet cells. Genetic analysis of humans with IBD revealed single nucleotide polymorphisms in XBP1 that may confer susceptibility to the disease.
Kaser A, Lee A-H, Frank A. & XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell
Peroxisome proliferator-activated receptors (PPAR) are heavily investigated due to their role in the pathogenesis of type 2 diabetes and the metabolic syndrome. Rodent studies have shown that PPAR agonists have tumorigenic properties, but the exact mechanism of their tumorigenicity is unclear. In addition, there are changes in the urothelium in monkeys following exposure to PPAR agonists. This paper describes the findings of a Pathology Working Group (PWG) convened to establish consistent diagnostic criteria for morphologic changes in the urinary bladders of monkeys after treatment with PPAR agonists. Investigators determined that the normal urothelium could be up to ten to twelve cell layers thick. They also found a wide range of mononuclear infiltrates in the urothelium of all monkeys (treated and controls), including the presence of occasional submucosal lymphoid follicles. Eosinophilic cytoplasmic granules were present in the urothelium of all monkeys, with some variation in the size and number of granules per cell. Likewise, vacuolization of urothelial cells was seen in all monkeys, but the vacuoles were larger and more numerous in treated animals. Some of the larger vacuoles were determined to be intracellular within umbrella cells. The PWG members did not find urothelial hypertrophy, hyperplasia, or neoplasia during the review process. This manuscript provides a framework for detailed evaluation of the urinary bladder of cynomolgus monkeys, with guidelines for consistent diagnostic criteria and nomenclature.
Hardisty JF, Anderson DC, Brodie S, et al. Histopathology of the urinary bladders of cynomolgus monkeys treated with PPAR agonists. Toxicol Pathol