Role of apoptotic and anti-apoptotic mechanisms in erythroblast differentiation

The present study focuses on deciphering the differentiation mechanisms of erythroid cells. In particular, the involvement of apoptotic mechanisms in erythroblast differentiation and enucleation was examined. A model system of erythroid differentiation was established. The primary culture of human erythroid cells fully recapitulated in vivo erythropoiesis as shown by cell morphology and cell surface markers. In addition this culture system was amenable for manipulation. Using this culture system, caspase activation was found to be associated with and required for erythroblast differentiation. In vitro erythropoiesis was blocked by the pan-caspase inhibitor zVAD.fmk as indicated by the accumulation of early progenitors with concomitant drop in the number of late erythroblasts. We also found that caspase-3 and caspase-9 were specifically activated during erythroid differentiation. DNA fragmentation has emerged as a second apoptotic mechanism involved in erythropoesis. DNA degradation occurs at late stages of differentiation as assessed by the detection of TUNELpositive erythroblasts in cord blood, bone marrow and erythroid culture. The mechanism of DNA degradation was cell-autonomous and resulted in production of high molecular DNA fragments with approximate length of about 50 kb. During these studies we made the rather unexpected observation that late stage erythroblast did not undergo apoptosis when treated with apoptosis inducers. This observation suggested to us that mature erythroblasts were therefore protected from cell death. We next examined the mechanisms involved in erythroblast protection. The levels of cytochrome c, a potent inducer engaging the mitochondrial pathway in apoptosis, were shown to significantly decrease with the differentiation. In addition, the levels of anti-apoptotic protein Bcl-xL increased, reaching maxima just before enucleation. Altogether these mechanisms might contribute to the protection from apoptosis in mature erythroblasts, described here for the first time

Macrophage migration inhibition factor is elevated in pregnancy, but not to a greater extent in preeclampsia

Background: Maternal serum concentrations of macrophage migration inhibitory factor (MIF) have recently been reported to be elevated in cases with preeclampsia. These findings may be important in increasing our understanding of the underlying events leading to the development of preeclampsia, as this cytokine is also expressed in the placenta, where it has been shown to possess immunemodulatory activities. For this reason we attempted to independently verify this report. Methods: Plasma levels of MIF were assessed by ELISA in plasma samples collected from normal healthy male and female blood donors (n=20 per group), as well as healthy normal pregnant women in all three trimesters of pregnancy (n=60). In addition, MIF levels were examined from cases with mild and severe preeclampsia (n=20 per study cohort) and matched normotensive pregnancies (n=20). Results: MIF levels were found to be elevated in pregnancy (median=10.1ng/ml) when compared to non-pregnant controls (median=1.7ng/ml). A moderate, but not significant, elevation was found to occur from the first to the third trimester of pregnancy. No significant difference was found to occur between the two preeclampsia study groups when compared to the normotensive control group. Conclusions: Our data suggest that circulatory MIF concentrations are elevated throughout pregnancy, but are not further increased in preeclampsi

Online information discrepancies regarding safety of medicine use during pregnancy and lactation: a ConcePTION study

Abstract Introduction Inconsistencies in information concerning the safety of medicines during pregnancy and lactation might result in non-optimal treatment to pregnant and lactating women, subsequent risks to the fetus and to unnecessary weaning from breastfeeding. Objectives To analyze information discrepancies concerning medicines during pregnancy and lactation between different on-line sources for patients and health care professionals (HCPs) in four European languages. Methods The medicines analyzed were ibuprofen, ondansetron, olanzapine, fingolimod, methylphenidate and adalimumab. A standardized google search was performed in Swedish, Dutch, French and English. The identified recommendations were classified into data source categories, e.g regulatory sources, scientific sources and blogs/forums/social media for patients and for HCPs. The recommendations were compared between the data source categories for each medicine and language: 24 comparisons for pregnancy and 24 for lactation. Results For patients, 46% (11/24 comparisons) of the pregnancy recommendations were consistent between all information sources, while for lactation, 17% (4/24) were consistent. The corresponding figures for HCP data sources were 54% (13/24) and 21% (5/24). The regulatory sources were generally more conservative than other sources. Recommendations from five TIS centers (Teratology Information Services) were consistent in 93% (25/27) of the comparisons for pregnancy and 68% (15/22) for lactation. Conclusion Discrepancies in online information sources regarding medicines during pregnancy and lactation are common. These differences are more pronounced for lactation than for pregnancy. Recommendations from TIS centers showed better consistency, indicating more consensus on a scientific level. Additional work is needed to harmonize information within and between countries, to avoid conflicting messages

Efficacy and safety of the direct switch to indacaterol/glycopyrronium from salmeterol/fluticasone in non-frequently exacerbating COPD patients: The FLASH randomized controlled trial

WOS: 000450142800014PubMed ID: 30074294Background and objective Combination long-acting beta(2)-agonist/long-acting muscarinic antagonist (LABA/LAMA) has demonstrated superior clinical outcomes over LABA/inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) patients; however, data from blinded randomized controlled trials on direct switching from LABA/ICS to LABA/LAMA are lacking. FLASH (Assessment of switching salmeterol/Fluticasone to indacateroL/glycopyrronium in A Symptomatic COPD patient coHort) investigated if direct switch, without a washout period, from salmeterol/fluticasone (SFC) to indacaterol/glycopyrronium (IND/GLY) in COPD patients improves lung function and is well tolerated. Methods In this 12-week, multicentre, double-blind study, patients with moderate-to-severe COPD and up to one exacerbation in previous year, receiving SFC for >= 3 months, were randomized to continue SFC 50/500 mu g twice daily (bd) or switch to IND/GLY 110/50 mu g once daily (od). Primary endpoint was pre-dose trough forced expiratory volume in 1 s (FEV1) at Week 12. Results In total, 502 patients were randomized (1:1) to IND/GLY or SFC. Patients switched to IND/GLY demonstrated superior lung function (pre-dose trough FEV1) versus SFC at Week 12 (treatment difference (Delta) = 45 mL; P = 0.028). IND/GLY provided significant improvements in pre-dose trough forced vital capacity (FVC; Delta = 102 mL; P = 0.002) and numerical improvements in transition dyspnoea index (TDI; Delta = 0.46; P = 0.063). Rescue medication use and COPD assessment test (CAT) scores were comparable between groups. Both treatments had similar safety profiles. Conclusion FLASH demonstrated that a direct switch to IND/GLY from SFC improved pre-dose FEV1 and FVC in COPD patients with up to one exacerbation in the previous year. No new safety signals were identified.NovartisNovartis; Good Publication Practice (GPP3) guidelinesThe authors would like to thank the patients, investigators and staff at participating centres in this study (a full list of principal investigators and centres is provided in Appendix S3 (Supplementary Information)). Authors also thank Peggy Hours-Zesiger (Novartis) for contribution to the conduct of the study. The authors thank Geetika Kainthla (M. Sc) and M. Fahad Haroon (PhD), Novartis, Hyderabad, India, for providing medical writing support/editorial support, which was funded by Novartis, in accordance with Good Publication Practice (GPP3) guidelines