Protein kinase A antagonist inhibits β-catenin nuclear translocation, c-Myc and COX-2 expression and tumor promotion in ApcMin/+ mice

<p>Abstract</p> <p>Background</p> <p>The adenomatous polyposis coli (APC) protein is part of the destruction complex controlling proteosomal degradation of β-catenin and limiting its nuclear translocation, which is thought to play a gate-keeping role in colorectal cancer. The destruction complex is inhibited by Wnt-Frz and prostaglandin E₂(PGE₂) - PI-3 kinase pathways. Recent reports show that PGE₂-induced phosphorylation of β-catenin by protein kinase A (PKA) increases nuclear translocation indicating two mechanisms of action of PGE₂on β-catenin homeostasis.</p> <p>Findings</p> <p>Treatment of <it>Apc</it>^Min/+mice that spontaneously develop intestinal adenomas with a PKA antagonist (Rp-8-Br-cAMPS) selectively targeting only the latter pathway reduced tumor load, but not the number of adenomas. Immunohistochemical characterization of intestines from treated and control animals revealed that expression of β-catenin, β-catenin nuclear translocation and expression of the β-catenin target genes c-Myc and COX-2 were significantly down-regulated upon Rp-8-Br-cAMPS treatment. Parallel experiments in a human colon cancer cell line (HCT116) revealed that Rp-8-Br-cAMPS blocked PGE₂-induced β-catenin phosphorylation and c-Myc upregulation.</p> <p>Conclusion</p> <p>Based on our findings we suggest that PGE₂act through PKA to promote β-catenin nuclear translocation and tumor development in <it>Apc</it>^Min/+mice <it>in vivo</it>, indicating that the direct regulatory effect of PKA on β-catenin nuclear translocation is operative in intestinal cancer.</p

A systematic review of handheld tools in lieu of colposcopy for cervical neoplasia and female genital schistosomiasis

publishedVersio

Increased Vascularity in Cervicovaginal Mucosa with Schistosoma haematobium Infection

Schistosomiasis is a fresh water parasite infection that affects millions of people, especially in Africa. Recent knowledge about the genital manifestations of schistosomiasis; especially its possible association with human immunodeficiency virus (HIV) infection, has led to increased focus on this neglected tropical disease. Millions of women remain undiagnosed for genital schistosomiasis, and may suffer from abnormal mucosal blood vessels, contact bleeding and lesions named sandy patches. This study analyses a unique selection of female genital biopsies containing parasite eggs. Protein detection and standard histopathological assessment are combined to quantify and study the characteristics of the mucosal blood vessels surrounding the eggs. Our results show that the genital mucosa with parasite eggs is more vascularised compared to healthy tissue, and that viable eggs tend to be surrounded by proliferating blood vessels. These findings have not yet been correlated directly to clinical manifestations. Further studies are needed in order to provide clinical advice on the risks and consequences of mucosal lesions particular to female genital schistosomiasis

Lack of Chemokine Signaling through CXCR5 Causes Increased Mortality, Ventricular Dilatation and Deranged Matrix during Cardiac Pressure Overload

RATIONALE: Inflammatory mechanisms have been suggested to play a role in the development of heart failure (HF), but a role for chemokines is largely unknown. Based on their role in inflammation and matrix remodeling in other tissues, we hypothesized that CXCL13 and CXCR5 could be involved in cardiac remodeling during HF. OBJECTIVE: We sought to analyze the role of the chemokine CXCL13 and its receptor CXCR5 in cardiac pathophysiology leading to HF. METHODS AND RESULTS: Mice harboring a systemic knockout of the CXCR5 (CXCR5(-/-)) displayed increased mortality during a follow-up of 80 days after aortic banding (AB). Following three weeks of AB, CXCR5(-/-) developed significant left ventricular (LV) dilatation compared to wild type (WT) mice. Microarray analysis revealed altered expression of several small leucine-rich proteoglycans (SLRPs) that bind to collagen and modulate fibril assembly. Protein levels of fibromodulin, decorin and lumican (all SLRPs) were significantly reduced in AB CXCR5(-/-) compared to AB WT mice. Electron microscopy revealed loosely packed extracellular matrix with individual collagen fibers and small networks of proteoglycans in AB CXCR5(-/-) mice. Addition of CXCL13 to cultured cardiac fibroblasts enhanced the expression of SLRPs. In patients with HF, we observed increased myocardial levels of CXCR5 and SLRPs, which was reversed following LV assist device treatment. CONCLUSIONS: Lack of CXCR5 leads to LV dilatation and increased mortality during pressure overload, possibly via lack of an increase in SLRPs. This study demonstrates a critical role of the chemokine CXCL13 and CXCR5 in survival and maintaining of cardiac structure upon pressure overload, by regulating proteoglycans essential for correct collagen assembly

Kvalitetshåndbok for biogassanlegg

Rapporten viser hvordan strømmen av biomasse av husdyrgjødsel går fra bonde til biogassanlegg og hvordan næringsstoffene ivaretas fram til ferdig hygienisert biorest. Selve biogassproduksjonen er bare i liten grad berørt i rapporten, mens innholdet av næringsstoffer er vist for de ulike fraksjonene. Rapporten viser grunnlaget for beregning av spredeareal som bøndene sparer ved å levere den faste delen av separert husdyrgjødsel til biogassanlegget. En gjødseldyrenhet tilsvarer 14 kg fosfor og krever minimum 4 dekar spredeareal. Levering av ett tonn separert tørrfraksjon av svinegjødsel vil kunne frigjøre 0,83 daa spredeareal. Ett tonn kugjødsel levert til biogassanlegget frigir tilsvarende 0,49 daa spredeareal hos bonden. Utgangspunktet er at separasjon av gjødsel øker tørrstoffinnholdet til 25 % ts og 31 % ts for henholdsvis ku og svinegjødsel. Beregningene for frigjort spredeareal for gårdsbruka som leverer gjødsel til biogassanlegget bør baseres på mengde levert tørrstoff med kjent innhold av forsfor. Forutsetningen for frigjort spredeareal er at mottakeren har ledig spredeareal eller har godkjent produksjon av gjødselvarer. Det fordrer at bioresten enten blir brukt i sektorer som ikke er definert som jord- eller hagebruk, omdannes til nye produkter, eller at bioresten blir brukt utenfor det gitte reguleringsområdet

Kvalitetshåndbok for biogassanlegg

Rapporten viser hvordan strømmen av biomasse av husdyrgjødsel går fra bonde til biogassanlegg og hvordan næringsstoffene ivaretas fram til ferdig hygienisert biorest. Selve biogassproduksjonen er bare i liten grad berørt i rapporten, mens innholdet av næringsstoffer er vist for de ulike fraksjonene. Rapporten viser grunnlaget for beregning av spredeareal som bøndene sparer ved å levere den faste delen av separert husdyrgjødsel til biogassanlegget. En gjødseldyrenhet tilsvarer 14 kg fosfor og krever minimum 4 dekar spredeareal. Levering av ett tonn separert tørrfraksjon av svinegjødsel vil kunne frigjøre 0,83 daa spredeareal. Ett tonn kugjødsel levert til biogassanlegget frigir tilsvarende 0,49 daa spredeareal hos bonden. Utgangspunktet er at separasjon av gjødsel øker tørrstoffinnholdet til 25 % ts og 31 % ts for henholdsvis ku og svinegjødsel. Beregningene for frigjort spredeareal for gårdsbruka som leverer gjødsel til biogassanlegget bør baseres på mengde levert tørrstoff med kjent innhold av forsfor. Forutsetningen for frigjort spredeareal er at mottakeren har ledig spredeareal eller har godkjent produksjon av gjødselvarer. Det fordrer at bioresten enten blir brukt i sektorer som ikke er definert som jord- eller hagebruk, omdannes til nye produkter, eller at bioresten blir brukt utenfor det gitte reguleringsområdet.publishedVersio

Uteroplacental acute atherosis in preeclamptic pregnancies: Rates and clinical outcomes differ by tissue collection methods

Objectives Acute atherosis (AA) is a uteroplacental spiral artery lesion, identified by intramural lipid-laden foam cells, with highest rates in preeclampsia (PE). We compared AA detection rates in preeclampsia (PE) across three different decidual spiral artery collection methods in same patients. We tested whether the rate and topographical distribution of AA associates with clinical parameters. Study design Three decidual tissue types were harvested from each of 107 preeclamptic women delivered by cesarean section. Routine sampled basal surface placenta (decidua basalis, DB) and fetal membrane roll (decidua parietalis, DP) biopsies were compared with decidual vacuum suction biopsies (DB), regarding spiral artery rate and AA presence. Spiral arteries and AA were identified using predefined, immunohistochemically based criteria on serial sections. Main outcome measures and results Detection of spiral arteries (87%) and AA (35%) was highest in DB samples collected by vacuum suction compared to the two other methods. Pregnancies with AA detected in vacuum suctioned DB had lower gestational age at delivery, lower birth weight percentile and more often fetal growth restriction. Basal plate DB samples demonstrating AA associated with pregnancies affected by pathological fetal Dopplers, whereas AA detected in DP membrane rolls, did not. Conclusions Placental bed vacuum suction provides more spiral arteries and higher AA rate, suggesting underestimation of AA in conventional pathology samples of basal plate DB biopsies and DP. The association of AA with PE-related clinical parameters varies according to tissue collection method. Longitudinal studies could elucidate whether AA also identifies women with future premature cardiovascular risk

Placental Pathology in Pregnancies with Maternally Perceived Decreased Fetal Movement - A Population-Based Nested Case-Cohort Study

<div><h3>Background</h3><p>Decreased fetal movements (DFM) are associated with fetal growth restriction and stillbirth, presumably linked through an underlying placental dysfunction. Yet, the role of placental pathology has received limited attention in DFM studies. Our main objective was to explore whether maternal perceptions of DFM were associated with placental pathology in pregnancies recruited from a low-risk total population.</p> <h3>Methods/Principal Findings</h3><p>Placentas from 129 DFM and 191 non-DFM pregnancies were examined according to standardized macro- and microscopic protocols. DFM was defined as any maternal complaint of DFM leading to a hospital examination. Morphological findings were timed and graded according to their estimated onset and clinical importance, and classified in line with a newly constructed Norwegian classification system for reporting placental pathology. With our population-based approach we were unable to link DFM to an overall measure of all forms of placental pathology (OR 1.3, 95% CI 0.8–2.2, p = 0.249). However, placental pathology leading to imminent delivery could be a competing risk for DFM, making separate subgroup analyses more appropriate. Our study suggests a link between DFM and macroscopic placental pathology related to maternal, uteroplacental vessels, i.e. infarctions, placental lesions (intraplacental hematomas) and abruptions. Although not statistically significant separately, a compound measure showed a significant association with DFM (OR 2.4, 95%CI 1.1–5.0, p = 0.023). This association was strengthened when we accounted for relevant temporal aspects. More subtle microscopic materno-placental ischemic changes outside the areas of localized pathology showed no association with DFM (OR 0.5, 95%CI 0.2–1.4, p = 0.203). There was a strong association between placental pathology and neonatal complications (OR 2.9, 95% CI 1.6–5.1, p<0.001).</p> <h3>Conclusions</h3><p>In our population-based study we were generally unable to link maternally perceived DFM to placental pathology. Some associations were seen for subgroups.</p> </div