Pancreatic glycoprotein 2 is a first line of defense for mucosal protection in intestinal inflammation.

Increases in adhesive and invasive commensal bacteria, such as Escherichia coli, and subsequent disruption of the epithelial barrier is implicated in the pathogenesis of inflammatory bowel disease (IBD). However, the protective systems against such barrier disruption are not fully understood. Here, we show that secretion of luminal glycoprotein 2 (GP2) from pancreatic acinar cells is induced in a TNF-dependent manner in mice with chemically induced colitis. Fecal GP2 concentration is also increased in Crohn's diease patients. Furthermore, pancreas-specific GP2-deficient colitis mice have more severe intestinal inflammation and a larger mucosal E. coli population than do intact mice, indicating that digestive-tract GP2 binds commensal E. coli, preventing epithelial attachment and penetration. Thus, the pancreas-intestinal barrier axis and pancreatic GP2 are important as a first line of defense against adhesive and invasive commensal bacteria during intestinal inflammation.

Orally desensitized mast cells form a regulatory network with Treg cells for the control of food allergy.

Oral immunotherapy (OIT) is an effective approach to controlling food allergy. Although the detailed molecular and cellular mechanisms of OIT are unknown currently, they must be understood to advance the treatment of allergic diseases in general. To elucidate the mechanisms of OIT, especially during the immunological transition from desensitization to allergy regulation, we generated a clinical OIT murine model and used it to examine immunological events of OIT. We found that in mice that completed OIT successfully, desensitized mast cells (MCs) showed functionally beneficial alterations, such as increased induction of regulatory cytokines and enhanced expansion of regulatory T cells. Importantly, these regulatory-T-cell-mediated inhibitions of allergic responses were dramatically decreased in mice lacking OIT-induced desensitized MC. Collectively, these findings show that the desensitization process modulates the activation of MCs, leading directly to enhanced induction of regulatory-T-cell expansion and promotion of clinical allergic unresponsiveness. Our results suggest that efficiently inducing regulatory MCs is a novel strategy for the treatment of allergic disease.

Stratified layer analysis reveals intrinsic leptin stimulates cryptal mesenchymal cells for controlling mucosal inflammation.

Mesenchymal cells in the crypt play indispensable roles in the maintenance of intestinal epithelial homeostasis through their contribution to the preservation of stem cells. However, the acquisition properties of the production of stem cell niche factors by the mesenchymal cells have not been well elucidated, due to technical limitations regarding the isolation and subsequent molecular and cellular analyses of cryptal mesenchymal cells. To evaluate the function of mesenchymal cells located at the large intestinal crypt, we established a novel method through which cells are harvested according to the histologic layers of mouse colon, and we compared cellular properties between microenvironmental niches, the luminal mucosa and crypts. The gene expression pattern in the cryptal mesenchymal cells showed that receptors of the hormone/cytokine leptin were highly expressed, and we found a decrease in Wnt2b expression under conditions of leptin receptor deficiency, which also induced a delay in cryptal epithelial proliferation. Our novel stratified layer isolation strategies thus revealed new microenvironmental characteristics of colonic mesenchymal cells, including the intrinsic involvement of leptin in the control of mucosal homeostasis.

Altered arterial stiffness in male-to-female transsexuals undergoing hormonal treatment.

AIM: Male-to-female (MTF) transsexuals are treated with estrogen with and without progestin through a variety of routes. The aim of this study is to evaluate the arterial stiffness in MTF transsexuals undergoing hormonal treatment. METHODS: We evaluated the arterial stiffness in 156 MTF transsexuals (22 untreated and 129 treated with estrogen only or plus progestin) using a volume-plethysmographic apparatus equipped with a multi-element applanation tonometry sensor. RESULTS: MTF transsexuals treated with parenteral estrogen were significantly older than untreated MTF transsexuals. Hematocrit, uric acid and activated partial thromboplastin time in treated MTF transsexuals were significantly lower than in untreated MTF transsexuals. The level of high-density lipoprotein cholesterol in MTF transsexuals treated with oral estrogen was significantly higher than in untreated MTF transsexuals or those treated with parenteral estrogen with and without progestin. The systolic blood pressure in MTF transsexuals treated with estrogen only is significantly lower than that in untreated MTF transsexuals. The brachial-ankle pulse wave velocity was significantly decreased in MTF transsexuals treated with estrogen compared to that in untreated MTF transsexuals or in those treated with estrogen plus progestin. The carotid augmentation index in MTF transsexuals treated with oral estrogen was significantly lower than that in MTF transsexuals treated with parenteral estrogen or oral estrogen plus progestin. CONCLUSIONS: Estrogen treatment is likely to have some beneficial effects on lipid metabolism and vascular function in MTF transsexuals; however, progestin administered with estrogen may have adverse effects on arterial stiffness.

Mirror syndrome associated with hydropic acardius in triplet pregnancy.

UNLABELLED: Mirror syndrome is the association of triple edema, i.e. fetal, placental and maternal edema, with maternal preeclampsia. We here report the first case of mirror syndrome resulting from hydropic acardius in triplet pregnancy. METHODS/RESULTS: A 26-year-old nulliparous woman spontaneously conceived two living fetuses and one acardius, and suffered preterm rupture of the membranes at 23 2/7 weeks of gestation. We observed triple edema, hydropic acardius, placental edema, and maternal edema, together with maternal high blood pressure, proteinuria and low hematocrit, and therefore suspected the presence of mirror syndrome. Due to the prematurity of the fetuses, we closely observed her, awaiting fetal maturity. Three days later (23 5/7 weeks), cord prolapse occurred, leading to emergent cesarean section. Female infants, weighing 492 and 554 g, respectively, were born alive; the former died on the 13th postnatal day and the latter was healthy with no sequelae. An acardius weighing 860 g had vascular communication with the 492-gram fetus. Histological examination confirmed a monochorionic, triamniotic single placenta. The mother suffered from pulmonary edema and was treated in the intensive care unit under respiratory support, but soon improved. CONCLUSIONS: When dealing with multifetal pregnancy, especially when complicated by an acardius, obstetricians must have the highest level of concern for the occurrence of mirror syndrome, a life-threatening condition both to the mother and the fetus.

Alterations in placental growth factor levels before and after the onset of preeclampsia are more pronounced in women with early onset severe preeclampsia.

It has been established that the serum placental growth factor (PlGF) decreases and the soluble fms-like tyrosine kinase-1 (sFlt-1) increases in women with preeclampsia. However, there have been no studies on the relation between preeclampsia onset time and the changes in PlGF and sFlt-1. Furthermore, the PlGF and sFlt-1 levels have not been evaluated using their reference values specific to each gestational age. In this study we reevaluated the serum PlGF and sFlt-1 levels before and after the clinical manifestation of early and late onset severe preeclampsia using the new reference values developed in our recent longitudinal study. Blood specimens were obtained immediately after the clinical manifestation of severe preeclampsia in 34 referred women, and both before and after the clinical manifestation in 8 women receiving a routine checkup at our institute. Both women with early and those with late preeclampsia showed decreased PlGF and increased sFlt-1 levels compared to normotensive controls at 28 and 37 weeks (n=68). However, those with early onset preeclampsia had a higher incidence of low PlGF (<5th percentile on the reference values) and high sFlt-1 (>or=95th percentile) than those with late onset (low PlGF: 93% vs. 55%; high sFlt-1: 100% vs. 60%). log10PlGF (r=0.574, p<0.001) and log10(sFlt-1/PlGF) (r=-0.556, p<0.001) were correlated with the week of onset of preeclampsia. Before the onset of preeclampsia, the incidence rate of low PlGF in the women with early onset preeclampsia was 100% (5/5), whereas that in the women with late onset preeclampsia was 0% (0/2) (p=0.048). Therefore, alterations in the PlGF levels both before and after the onset of preeclampsia may be more pronounced in women with early onset than those with late onset severe preeclampsia.

Establishing reference values for both total soluble Fms-like tyrosine kinase 1 and free placental growth factor in pregnant women.

It has been reported that the concentration of free placental growth factor (PIGF) is decreased and that of soluble fms-like tyrosine kinase 1 (sFlt-1) is increased before the onset of preeclampsia. However, no study has determined the reference values for sFlt-1 and free PIGF during pregnancy using a commercially available enzyme-linked immunosorbent assay (ELISA) kit. This longitudinal cohort study was undertaken to address this issue. Serum samples were collected from 148 women at 10, 18, 28, and 37 weeks of gestation. Preeclampsia occurred in 6 women: 4 women who delivered at <37 weeks of gestation, and 2 women who delivered at > or =37 weeks. The average and 90% confidence interval (90% CI) of the serum concentration of both sFIt-1 and free PIGF were determined in a total of 433 specimens from 148 subjects with 1 to 4 collections at 7 to 39 weeks of gestation, and were represented as quadric curves. The mean values (90% CI) of sFlt-1 (pg/ml) at 10, 18, 28, and 37 weeks of gestation were 413 (174-981), 296 (125-704), 413 (174-982), and 1,130 (477-2,690), respectively. The mean values (90% CI) of free PIGF (pg/ml) were 36 (14-89), 206 (83-515), 518 (207-1,290), and 354 (142-884), respectively. We also established the reference values for the ratio of sFlt-1/PIGF. These values may be useful for predicting the subsequent occurrence of preeclampsia.