The Chlamydia trachomatis Plasmid and CT135 Virulence Factors Are Not Essential for Genital Tract Infection or Pathology in Female Pig-Tailed Macaques.

The Chlamydia trachomatis plasmid and inclusion membrane protein CT135 are virulence factors in the pathogenesis of murine female genital tract infection. To determine if these virulence factors play a similar role in female nonhuman primates, we infected pig-tailed macaques with the same C. trachomatis strains shown to be important in the murine model. Wild-type C. trachomatis and its isogenic mutant strain deficient in both plasmid and CT135 were used to infect macaques. Macaques were given primary and repeated cervicovaginal challenges with the wild-type and mutant strains. The infection rate, infection duration, and antibody response were similar among macaques infected with both strains. Unexpectedly, colposcopy, laparoscopy, and histologic analysis revealed no substantial genital tract pathology following either primary or repeated cervicovaginal challenges. Cytokine analysis of cervicovaginal secretions from both challenged groups revealed low concentrations of interleukin 1ß (IL-1ß) and elevated levels of the interleukin 1 receptor agonist (IL-1RA). We propose that an imbalance of IL-1ß and IL-1RA in macaques is the reason for the mild inflammatory responses observed in infected urogenital tissues. Thus, understanding the pathobiology of chlamydial infection requires a better understanding of host epigenetic and chlamydial genetic factors. Our findings also have implications for understanding the high frequency of asymptomatic infections in humans.

Uterine overdistention induces preterm labor mediated by inflammation: observations in pregnant women and nonhuman primates.

OBJECTIVE: Uterine overdistention is thought to induce preterm labor in women with twin and multiple pregnancies, but the pathophysiology remains unclear. We investigated for the first time the pathogenesis of preterm birth associated with rapid uterine distention in a pregnant nonhuman primate model. STUDY DESIGN: A nonhuman primate model of uterine overdistention was created using preterm chronically catheterized pregnant pigtail macaques (Macaca nemestrina) by inflation of intraamniotic balloons (N = 6), which were compared to saline controls (N = 5). Cesarean delivery was performed due to preterm labor or at experimental end. Microarray, quantitative reverse transcriptase polymerase chain reaction, Luminex (Austin, TX), and enzyme-linked immunosorbent assay were used to measure messenger RNA (mRNA) and/or protein levels from monkey (amniotic fluid, myometrium, maternal plasma) and human (amniocytes, amnion, myometrium) tissues. Statistical analysis employed analysis of covariance and Wilcoxon rank sum. Biomechanical forces were calculated using the law of Laplace. RESULTS: Preterm labor occurred in 3 of 6 animals after balloon inflation and correlated with greater balloon volume and uterine wall stress. Significant elevations of inflammatory cytokines and prostaglandins occurred following uterine overdistention in an "inflammatory pulse" that correlated with preterm labor (interleukin [IL]-1ß, tumor necrosis factor [TNF]-α, IL-6, IL-8, CCL2, prostaglandin E2, prostaglandin F2α, all P < .05). A similar inflammatory response was observed in amniocytes in vitro following mechanical stretch (IL1ß, IL6, and IL8 mRNA multiple time points, P < .05), in amnion of women with polyhydramnios (IL6 and TNF mRNA, P < .05) and in amnion (TNF-α) and myometrium of women with twins in early labor (IL6, IL8, CCL2, all P < .05). Genes differentially expressed in the nonhuman primate after balloon inflation and in women with polyhydramnios and twins are involved in tissue remodeling and muscle growth. CONCLUSION: Uterine overdistention by inflation of an intraamniotic balloon is associated with an inflammatory pulse that precedes and correlates with preterm labor. Our results indicate that inflammation is an early event after a mechanical stress on the uterus and leads to preterm labor when the stress is sufficiently great. Further, we find evidence of uterine tissue remodeling and muscle growth as a common, perhaps compensatory, response to uterine distension.

Intraepidermal adenocarcinoma in the perianal skin of two cats, a condition resembling human extramammary Paget's disease.

In humans, mammary and extramammary Paget's disease is an uncommon to rare manifestation of intraepidermal adenocarcinoma arising from simple epithelium, usually glandular in origin. This report describes two cats with lesions in perianal skin consisting of atypical intraepidermal neoplastic cells. Differential diagnoses included intraepidermal adenocarcinoma, in situ squamous or basal cell carcinoma, junctional amelanotic melanoma, and epitheliotropic tumours of histiocytic or lymphocytic origin. The atypical intraepidermal cells in the cats were immunohistochemically positive for cytokeratin 8/18 (CK8/18), which stains simple (glandular) epithelium. The keratinocytes and basal cells were negative for CK8/18. In addition, the atypical intraepidermal cells were immunohistochemically negative for melanocytic, lymphocytic, and histiocytic markers. The staining results confirmed the atypical intraepidermal cells to be of simple glandular origin, and ruled out other causes of intraepidermal malignancy. In one cat the clinical lesions consisted of a pruritic erythematous eruption surrounding the anus. Another cat presented clinically for an area of irregular anal thickening; this cat had well-regulated diabetes mellitus. The cats were otherwise clinically healthy. The clinical features, histological appearance, and immunohistochemical staining of the skin lesions were consistent with those described for human perianal extramammary Paget's disease. To the authors' knowledge, this is the first report of an intraepidermal adenocarcinoma in a cat or other animal species.

Genetic background modifies intestinal pseudo-obstruction and the expression of a reporter gene in Hox11L1-/- mice.

BACKGROUND & AIMS: The transcription factor Hox11L1 is expressed by enteric neurons. Two groups mutated murine Hox11L1, and reported lethal intestinal pseudo-obstruction and colonic hyperganglionosis in many, but not all, homozygous null mutants. We investigated the regulation of Hox11L1 and factors that influence the penetrance of pseudo-obstruction in Hox11L1-null mice. METHODS: Expression of beta-galactosidase (lacZ), under control of putative Hox11L1 regulatory sequences, was assessed in transgenic mice wild-type, heterozygous, and null for native Hox11L1. Transgene expression and signs of pseudo-obstruction were compared in null mice with different genetic backgrounds. RESULTS: In enteric neurons and other parts of the nervous system, the transgene was expressed in a pattern consistent with native Hox11L1. Enteric beta-galactosidase activity initiated in the proximal small intestine and spread cranially and caudally in a subset of postmitotic enteric neurons. Hox11L1-lacZ transgene expression persisted in Hox11L1-null animals, suggesting that Hox11L1 is not required cell autonomously for neuronal survival. Genetic background dramatically affected the phenotypes of Hox11L1-null animals, with complete penetrance of severe proximal colonic distention on a predominantly C57BL/6J (B6) background and very low penetrance of dysmotility on a 129SvJ (129) background. Coincidently, Hox11L1-lacZ expression by most enteric neurons, but not CNS neurons, was lost on a 129 background. CONCLUSIONS: Cis-acting, 5' regulatory elements are sufficient to regulate site-specific expression of Hox11L1 in vivo. Expression of the transgene by enteric neurons and penetrance of pseudo-obstruction in Hox11L1-null animals are influenced by one or more modifier genes, counterparts of which may play a similar role in human disease.