Correction: Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn's colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease.

[This corrects the article DOI: 10.1371/journal.pone.0246393.].

Linking bacterial enterotoxins and alpha defensin 5 expansion in the Crohn's colitis: A new insight into the etiopathogenetic and differentiation triggers driving colonic inflammatory bowel disease.

Evidence link bacterial enterotoxins to apparent crypt-cell like cells (CCLCs), and Alpha Defensin 5 (DEFA5) expansion in the colonic mucosa of Crohn's colitis disease (CC) patients. These areas of ectopic ileal metaplasia, positive for Paneth cell (PC) markers are consistent with diagnosis of CC. Retrospectively, we: 1. Identified 21 patients with indeterminate colitis (IC) between 2000-2007 and were reevaluation their final clinical diagnosis in 2014 after a followed-up for mean 8.7±3.7 (range, 4-14) years. Their initial biopsies were analyzed by DEFA5 bioassay. 2. Differentiated ulcer-associated cell lineage (UACL) analysis by immunohistochemistry (IHC) of the CC patients, stained for Mucin 6 (MUC6) and DEFA5. 3. Treated human immortalized colonic epithelial cells (NCM460) and colonoids with pure DEFA5 on the secretion of signatures after 24hr. The control colonoids were not treated. 4. Treated colonoids with/without enterotoxins for 14 days and the spent medium were collected and determined by quantitative expression of DEFA5, CCLCs and other biologic signatures. The experiments were repeated twice. Three statistical methods were used: (i) Univariate analysis; (ii) LASSO; and (iii) Elastic net. DEFA5 bioassay discriminated CC and ulcerative colitis (UC) in a cohort of IC patients with accuracy. A fit logistic model with group CC and UC as the outcome and the DEFA5 as independent variable differentiator with a positive predictive value of 96 percent. IHC staining of CC for MUC6 and DEFA5 stained in different locations indicating that DEFA5 is not co-expressed in UACL and is therefore NOT the genesis of CC, rather a secretagogue for specific signature(s) that underlie the distinct crypt pathobiology of CC. Notably, we observed expansion of signatures after DEFA5 treatment on NCM460 and colonoids cells expressed at different times, intervals, and intensity. These factors are key stem cell niche regulators leading to DEFA5 secreting CCLCs differentiation 'the colonic ectopy ileal metaplasia formation' conspicuously of pathogenic importance in CC.

The interaction between IL-18 and IL-18 receptor limits the magnitude of protective immunity and enhances pathogenic responses following infection with intracellular bacteria.

The binding of IL-18 to IL-18Rα induces both proinflammatory and protective functions during infection, depending on the context in which it occurs. IL-18 is highly expressed in the liver of wild-type (WT) C57BL/6 mice following lethal infection with highly virulent Ixodes ovatus ehrlichia (IOE), an obligate intracellular bacterium that causes acute fatal toxic shock-like syndrome. In this study, we found that IOE infection of IL-18Rα(-/-) mice resulted in significantly less host cell apoptosis, decreased hepatic leukocyte recruitment, enhanced bacterial clearance, and prolonged survival compared with infected WT mice, suggesting a pathogenic role for IL-18/IL-18Rα in Ehrlichia-induced toxic shock. Although lack of IL-18R decreased the magnitude of IFN-γ producing type-1 immune response, enhanced resistance of IL-18Rα(-/-) mice against Ehrlichia correlated with increased proinflammatory cytokines at sites of infection, decreased systemic IL-10 production, increased frequency of protective NKT cells producing TNF-α and IFN-γ, and decreased frequency of pathogenic TNF-α-producing CD8(+) T cells. Adoptive transfer of immune WT CD8(+) T cells increased bacterial burden in IL-18Rα(-/-) mice following IOE infection. Furthermore, rIL-18 treatment of WT mice infected with mildly virulent Ehrlichia muris impaired bacterial clearance and enhanced liver injury. Finally, lack of IL-18R signal reduced dendritic cell maturation and their TNF-α production, suggesting that IL-18 might promote the adaptive pathogenic immune responses against Ehrlichia by influencing T cell priming functions of dendritic cells. Together, these results suggested that the presence or absence of IL-18R signals governs the pathogenic versus protective immunity in a model of Ehrlichia-induced immunopathology.

Use of electric bedding devices and risk of breast cancer in African-American women.

In this case-control study, the authors aimed to examine whether use of an electric bedding device increased breast cancer risk in African-American women. Cases were 304 African-American patients diagnosed with breast cancer during 1995-1998 who were aged 20-64 years and lived in one of three Tennessee counties. Controls were 305 African-American women without breast cancer who were selected through random digit dialing and frequency-matched to cases by age and county. Information on the use of an electric blanket or heated water bed and other risk factors was collected through telephone interviews. Breast cancer risk associated with use of an electric bedding device increased with the number of years of use, the number of seasons of use, and the length of time of use during sleep. When women who used an electric bedding device for more than 6 months per year (and therefore were more likely to have used a heated water bed, which generates lower magnetic fields) were excluded, the corresponding dose-response relations were more striking. Similar trends in dose response were shown in both premenopausal and postmenopausal women and for both estrogen receptor-positive and estrogen receptor-negative tumors. The use of electric bedding devices may increase breast cancer risk in African-American women aged 20-64 years. Such an association might not vary substantially by menopausal status or estrogen receptor status.

The relationship between menstrual factors and breast cancer according to estrogen receptor status of tumor: a case-control study in African-American women.

BACKGROUND: Exposure to estrogen is a risk factor for breast cancer. Since estrogen executes its effect through estrogen receptors (ERs), the relationship between menstrual factors, which are estrogen-related, and breast cancer may be different depending upon ER status of tumors. This case-control study aimed to examine such a relationship according to ER status of breast cancer in African-American women. METHODS: Cases were 304 African-American patients pathologically diagnosed with breast cancer during 1995-1998, who were 20-64 years old and lived in 3 Tennessee counties. Controls were 305 African-American women without breast cancer, selected through random-digit dialing and frequency matched to cases by age and county. Information on menstrual factors (age at menarche, age at menopause, time from menarche to menstrual regularity, cycle length, and length of flow) and other risk factors were collected through telephone interviews. Estrogen receptor status of tumor samples was defined based on immunohistochemical measurement. Logistic regression analysis was used to calculate odds ratios and 95% confidence interval (CI). RESULTS: Compared to women with an average cycle length less than 28 days, the risks of breast cancer for those with longer length were 0.62 (95% CI, 0.36-1.06) and 0.56 (95% CI, 0.32-1.00) for ER-positive and ER-negative tumors, respectively. The corresponding odds ratio (OR) estimates were 0.42 (95% CI, 0.20-0.86) and 0.38 (95% CI, 0.16-0.90) for postmenopausal women. Other menstrual factors were not significantly associated with breast cancer for either ER status. CONCLUSIONS: Our results did not show a different menstrual factor/breast cancer relationship in terms of ER status in African-American women, although there might be an association between menstrual cycle length and the disease.