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Maternal cigarette smoking during pregnancy remains one of the most common and preventable causes of fetal growth restriction (FGR), a condition in which a fetus is unable to achieve its genetically determined potential size. Even though epidemiologic evidence clearly links maternal cigarette smoking with FGR, insight into the molecular mechanisms of cigarette smoke-induced FGR is lacking. Here, we performed transcriptional profiling of placentas obtained from smoking mothers who delivered growth-restricted infants and identified secreted frizzled-related protein 1 (sFRPI), an extracellular antagonist of endogenous WNT signaling, as a candidate molecule. sFRPI mRNA and protein levels were markedly upregulated (-10fold) in placentas from smoking mothers compared with those from nonsmokers. In pregnant mice, adenovirus-mediated overexpression of sFRP1 led to FGR, increased karyorrhexis in the junctional zone, and decreased proliferation of labyrinthine trophoblasts. Consistent with our hypothesis that placental WNT signaling is suppressed in maternal smokers, we found that exposure to carbon monoxide analogs led to reduced WNT signaling, increased SFRP1 mRNA expression, and decreased cellular proliferation in a trophoblast cell line. Moreover, administration of carbon monoxide analogs to pregnant mice in late gestation led to FGR. In summary, our results indicate that the increased placental expression of sFRP1 seen in smokers impairs fetal growth by inhibiting WNT signaling and trophoblast proliferation., Introduction Fetal growth restriction (FGR), a condition in which a fetus is unable to achieve its genetically determined potential size, results in substantial perinatal and neonatal morbidity and mortality (1). [...]

Context.--Endometrial carcinoma of endometrioid histology is frequently preceded by endometrial hyperplasia, from which localized, premalignant lesions called endometrial intraepithelial neoplasia (EIN) emerge. Diagnostic criteria for EIN have been developed by histopathologic correlation with clinical outcome, molecular changes, and objective computerized histomorphometry. However, several benign mimics of EIN continue to cause diagnostic confusion. Objective.--To better understand the diagnostic pitfalls of EIN. Design.--An online quiz of 18 endometrial biopsies considered difficult by a gynecologic pathologist was constructed. Each case contained clinical history and at least 2 microscopic images. Answer choices included the following: (1) EIN, (2) polyp, (3) benign endometrium (proliferative, secretory, disordered, tubal metaplasia, and lower uterine segment), and (4) adenocarcinoma. Online tutorials were offered at the start, and the authors' diagnosis and clinical follow-up were provided at the end. Results.--The quiz was completed by 78 participants from 13 countries. Agreement with the authors ranged from 17% to 100% (mean, 55%). For analysis, polyp and benign responses were grouped. The mean percentage of agreement was highest in cases of polyp with no special features (88%), tubal metaplasia (87%), and secretory change (75%). Poorer agreement was seen with cases containing mucinous metaplasia (38%), extensive morular metaplasia (28%), and EIN arising in a polyp (53%). The mean percentage of agreement for EIN without these features was 63%. Conclusions.--Although the reproducibility of EIN criteria was good, a subset of biopsies with morular metaplasia and EIN in polyps was problematic and likely required consensus review., It is well recognized that endometrial carcinoma of endometrioid histology is often preceded by estrogen-driven glandular alterations harboring premalignant lesions. Originally recognized as adenomatous hyperplasia, these changes were codified by [...]

A 61-year-old woman noted pruritic lesions on her back, proximal right thigh, and in her left supraclavicular area about 2 weeks after returning from a 10-day vacation in Belize, which [...]