Induction of plasminogen activator inhibitor I by the PPARalpha ligand, Wy-14,643, is dependent on ERK1/2 signaling pathway

Impairment of the fibrinolytic system, mostly due to elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1), is often associated with metabolic disorders such as diabetes mellitus and insulin-resistance syndrome. Moreover, insulin, as we have previously shown, directly stimulates PAI-1 production with a mechanism underlying a complex signaling network which ultimately leads to ERK activation. In this study we have analyzed the effects of agonists of the peroxisome proliferator-activated receptor (PPAR) alpha and gamma on PAI-1 biosynthesis in HepG2 cells in the presence or absence of insulin. The high affinity PPARalpha agonist, Wy-14,643, increased basal and insulin-stimulated PAI-1 antigen release with a mechanism involving gene transcription. We then investigated whether the MAP kinase pathway also plays a role in the stimulatory properties of Wy-L4,643. Wy-L4,643 increases phosphorylation of ERK and p38 in a time-dependent manner without affecting that of SAPK/JNK or ERK5. Moreover, the MEK (ERK kinase) inhibitors, PD98059 and UO126, completely prevented PAI-1 induction by Wy-14,643 without inhibiting the activation of a reporter gene carrying the PPRE element. Interestingly, the addition of p38 inhibitor followed by insulin and Wy-14,643 resulted in a greater than additive stimulation of PAI-1 secretion acting through ERK1/2 phosphorylation. In contrast, the synthetic PPARgamma agonist, rosiglitazone, did not change PAI-1 level, although this compound induced transcription from the PPRE-driven luciferase reporter construct. In conclusion, Wy-14,643 induces PAI-1 gene expression, in the presence or absence of insulin, with a mechanism which is independent on PPARalpha activation and requires signaling through the ERK1/2 signaling pathway

Differential Diagnosis of Malignant Pleural Mesothelioma on Cytology: A Gene Expression Panel Versus BRCA1-Associated Protein 1 and p16 Tests

Pleural effusions are among the first clinical manifestations of malignant pleural mesothelioma (MPM) and often constitute the only available material for diagnosis. Although an MPM diagnosis can be reliable on cytology, the reported sensitivity is low (30% to 75%). Particularly, it can be hard to discriminate epithelioid MPM, the most common histotype, from reactive mesothelial hyperplasia (MH). Currently, BRCA1-associated protein 1 (BAP1) and CDKN2A (p16), evaluated by immunohistochemistry and fluorescent in situ hybridization, respectively, are the most valuable markers to discriminate MPM and MH. Both markers have a high specificity, but their sensitivity is not always satisfying, even when used together. We have recently developed a 117-gene expression panel, based on Nanostring technology, able to differentiate epithelioid MPM from MH pleural tissues better than BAP1 and p16. Herein, we evaluated the efficacy of the same panel on an independent retrospective cohort of 23 MPM and 11 MH pleural effusions (cell blocks and smears). The overall sensitivity and specificity of the panel were equal to 0.9565 and 1, respectively. Moreover, the panel performance was compared with BAP1 and p16 on 25 cell blocks. Sensitivity levels of gene panel, BAP1 alone, p16 alone, and BAP1 plus p16 were 1, 0.5882, 0.4706, and 0.7647, respectively. Specificity was always 1. Although further validation is needed, this gene panel could really facilitate patients' management, allowing a definitive MPM diagnosis directly on pleural effusions

Outcomes of induced versus spontaneous labor

PURPOSE: Induced labor is associated with a higher request for analgesia than spontaneous labor. This study compared duration of labor, mode of delivery, quantity of blood loss, type of perineal outcome and neonatal outcomes between women in induced labor and women in spontaneous labor, both on epidural analgesia (administered at cervical dilation  ≤ 4 cm). METHODS: In a two-year longitudinal cohort study, data were gathered from nulliparous women with a single cephalic pregnancy of at least 37 weeks attending the labor and delivery ward in Policlinico San Matteo Fundation-Pavia. Data were compared for women with early labor analgesia in (1) spontaneous labor (Robson group 1) and (2) induced labor (dinoprostone - vaginal insert or gel, Robson group 2a). RESULTS: Of the 1104 women who underwent epidural analgesia in the study period, 531 were included: 326 in spontaneous labor and 205 in induced labor. The only significant difference found was duration of the first stage, which lasted 305 (200-390) min in spontaneous labor compared to 205 min (120-345) in induced labor (p  <0.001). CONCLUSIONS: In women on early epidural analgesia, induction is associated with a shorter duration of the first stage of labor and does not affect other outcomes

Cross-sectional study on intestinal parasite infections in different ecological zones of the Department of La Paz, Bolivia

We performed a cross-sectional parasitological survey to assess the prevalence of protozoa and helminth infection among 275 school-age children (SAC) living in rural and peri-urban areas located in different ecological zones of the Department of La Paz, Bolivia. Public health activities for the control of STH, based on the biannual administration of mebendazole to preschool and school children are implemented at national level since 1986.We found an overall prevalence of 82.2% for intestinal parasites, including protozoa (80%) and helminths (23.3%). Blastocystis and Entamoeba coli were the most prevalent protozoa (found in 44% and 20.7% of the SAC enrolled); as for helminths, Ascaris lumbricoides and Hymenolepis nana were diagnosed in 14.5% and 3.3% of the children, respectively, followed by Trichuris trichiura 1.4%, Enterobius vermicularis 1.4%, Strongyloides stercoralis 0.7% and hookworms 0.7%.Molecular characterization of Blastocystis positive samples evidenced three different subtypes (ST1, ST2, ST3) highlighting the risk of transmission also from animal reservoir. We found a significant difference in the distribution of intestinal parasitic infection (IPIs) by ecological zone (44/74. 59% in Andean highlands, 94/170, 88% in tropical lowlands and 88/94, 94% in the Yungas, p < 0.001). Access to potable water (OR 0.1 95%CI 0.02–0.5, p = 0.004) and the habit of boiling drinking water (OR 0.3, 95% CI 0.2–0.7, p = 0.004) showed an independent association with a lower risk of all IPIs and STHs, respectively. The very low prevalence of STH infections of moderate heavy intensity demonstrate that periodical deworming has been successful in reducing the morbidity due to these parasites, however the high prevalence of protozoa demonstrate that sanitation is still problematic and there is a relevant contamination of the environment with human faeces.Significant efforts are still needed to reduce IPIs transmission and to improve health and sanitation in this area