BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients

Azacitidine is the leading compound to treat patients suffering myelodysplastic syndrome (MDS) or AML with less than 30% of blasts, but a majority of patients is primary refractory or rapidly relapses under treatment. These patients have a drastically reduced life expectancy as compared to sensitive patients. Therefore identifying predictive factors for AZA resistance is of great interest to propose alternative therapeutic strategies for non-responsive patients. We generated AZA-resistant myeloid cell line (SKM1-R) that exhibited increased expression of BCL2L10 an anti-apoptotic Bcl-2 member. Importantly, BCL2L10 knockdown sensitized SKM1-R cells to AZA effect suggesting that increased BCL2L10 expression is linked to AZA resistance in SKM1-R. We next established in 77 MDS patients that resistance to AZA is significantly correlated with the percentage of MDS or AML cells expressing BCL2L10. In addition, we showed that the proportion of BCL2L10 positive bone marrow cells can predict overall survival in MDS or AML patients. We propose a convenient assay in which the percentage of BCL2L10 expressing cells as assessed by flow cytometry is predictive of whether or not a patient will become resistant to AZA. Therefore, systematic determination of BCL2L10 expression could be of great interest in newly diagnosed and AZA-treated MDS patients.     

Determinants of 6-month maternal satisfaction with breastfeeding experience in a multicenter prospective cohort study

Although a personally defined experience, successful breastfeeding is usually measured with regard to duration. This study investigated the determinants of maternal satisfaction with breastfeeding experience for 907 mothers enrolled in a prospective cohort study. Despite a median breastfeeding duration (18 weeks) that fell short of recommendations, 822 mothers (90.6%) rated their breastfeeding experience as very or fairly satisfactory. Anticipated breastfeeding duration was a determinant of satisfaction only for women who actually breastfeed < 2 months; in this subgroup of mothers, satisfaction rates ranged from 84.6% for those who anticipated breastfeeding < 2 months to 69.8% for those who anticipated breastfeeding > 4 months (P = .01). Smoking during pregnancy and experiencing breastfeeding difficulties after discharge were independently associated with decreased satisfaction. Eliciting the mother's expectations regarding breastfeeding duration may help the lactation consultant in providing appropriate guidance. Future studies should assess maternal satisfaction using validated instruments.     

Lessons from “real life experience” of rifaximin use in the management of recurrent hepatic encephalopathy

BACKGROUND Hepatic encephalopathy(HE) is a major complication of cirrhosis with independent prognostic significance. The current management of HE is mainly based on lactulose. Rifaximin has been shown to decrease the risk of HE recurrence in patients with episodic forms. HE can also be persistent. However,there is no drug support recommendation for rifaximin use in this setting.AIM To assess the effectiveness of rifaximin in the management of recurrent episodes of HE and recurrent acute exacerbations on persistent HE, in "real life conditions".METHODS In this retrospective study, using a within-subjects design, we collected data of patients treated with rifaximin for HE in two liver diseases centers, during the six-month period before and during the six-month period after the initiation of rifaximin. The primary effectiveness endpoint was the total number of HE events involving hospitalization.RESULTSRifaximin was introduced for prevention of recurrent HE episodes in 29 out of 62 patients with normal mental status between episodes and for prevention of recurrent acute exacerbations on persistent HE in 33 out of 62 patients. In the"prevention of recurrent HE episodes" group, fewer HE events(0.79 vs 1.78; P =0.013) were reported during the period of time when rifaximin was used. In the"prevention of recurrent acute exacerbations on persistent HE" group, there was no significant difference in the number of HE-events(1.48 vs 1.77; P = 0.582).CONCLUSION In this real-life experience, the effectiveness of rifaximin was confirmed in the prevention of HE episodes recurrence but was not proved in the prevention of acute exacerbations recurrence on persistent HE.     

Early Miocene hippopotamids (Cetartiodactyla) constrain the phylogenetic and spatiotemporal settings of hippopotamid origin

The affinities of the Hippopotamidae are at the core of the phylogeny of Cetartiodactyla (even-toed mammals: cetaceans, ruminants, camels, suoids, and hippos). Molecular phylogenies support Cetacea as sister group of the Hippopotamidae, implying a long ghost lineage between the earliest cetaceans (∼53 Ma) and the earliest hippopotamids (∼16 Ma). Morphological studies have proposed two different sister taxa for hippopotamids: suoids (notably palaeochoerids) or anthracotheriids. Evaluating these phylogenetic hypotheses requires substantiating the poorly known early history of the Hippopotamidae. Here, we undertake an original morphological phylogenetic analysis including several “suiform” families and previously unexamined early Miocene taxa to test previous conflicting hypotheses. According to our results, Morotochoerus ugandensis and Kulutherium rusingensis, until now regarded as the sole African palaeochoerid and the sole African bunodont anthracotheriid, respectively, are unambiguously included within the Hippopotamidae. They are the earliest known hippopotamids and set the family fossil record back to the early Miocene (∼21 Ma). The analysis reveals that hippopotamids displayed an unsuspected taxonomic and body size diversity and remained restricted to Africa during most of their history, until the latest Miocene. Our results also confirm the deep nesting of Hippopotamidae within the paraphyletic Anthracotheriidae; this finding allows us to reconstruct the sequence of dental innovations that links advanced selenodont anthracotheriids to hippopotamids, previously a source of major disagreements on hippopotamid origins. The analysis demonstrates a close relationship between Eocene choeropotamids and anthracotheriids, a relationship that potentially fills the evolutionary gap between earliest hippopotamids and cetaceans implied by molecular analyses.     

Dose-dependent biphasic leptin-induced proliferation is caused by non-specific IL-6/NF-κB pathway activation in human myometrial cells

Background and Purpose

Leptin, an adipokine synthesized by the placenta during pregnancy, has been proposed for the management of preterm labour (PTL), as it is able to prevent in vitro uterine contractility and remodelling associated with labour onset. Another common feature of labour onset is the phenotypic switch of myometrial smooth muscle cells from a proliferative to a hypertrophic state. As proliferative effects have been demonstrated for leptin in other tissues, we aimed to investigate its ability to induce myometrial proliferation and thus to maintain uterine quiescence.

Experimental Approach

We stimulated human primary myometrial smooth muscle cells with leptin in the presence or absence of receptor antagonists or signalling pathway inhibitors.

Key Results

Leptin induced myometrial cell proliferation in a biphasic manner. At 6.25 ng·mL⁻¹, leptin-induced proliferation was mediated by the leptin receptor and required the early activation of ERK1/2. At a concentration above 25 ng·mL⁻¹, leptin induced direct non-specific stimulation of the IL-6 receptor, leading to NF-κB activation, and exerted anti-proliferative effects. However, at 50 ng·mL⁻¹, leptin re-induces proliferation via IL-6 receptor stimulation that requires STAT3 and delayed ERK1/2 activation.

Conclusions and Implications

These data bring new insights into leptin signalling-induced myometrial proliferation and its interrelationship with the IL-6/IL-6 receptor axis. In the light of our previous work, the present study emphasizes the potential value of leptin in the pharmacological management of PTL and it also strengthens the hypothesis that leptin might be a contributory factor in the parturition-related disorders observed in obese women.     

Safety and Immunogenicity of a Yeast-Derived Recombinant Hepatitis B Vaccine in Bulgarian Newborns

Background: In 1998, Bulgaria adopted a recombinant DNA yeast-derived hepatitis B (HB) vaccine (Euvax B™) for universal vaccination of all Bulgarian newborns on a 0–1–6 month schedule, the first dose to be given within 24 h of birth. Materials and Methods: We evaluated the safety, immunogenicity and effectiveness of this vaccine in over 40,000 healthy infants from July 1998 to December 1999. Standard safety information was collected for all infants vaccinated, subsets being followed for solicited local and systemic adverse events (n = 200) and antibodies to HB surface antigen (anti-HBsAg) 1–3 months after the third dose (n = 140). Results: No serious adverse events were registered for any vaccinee, solicited local reactions were rare (lt; 1.5%), mild and transient. The overall geometric mean titer (GMT) was 1,012 mIU/ml (95% CI: 786; 1,302), the seroprotection rate being 98.6%. Conclusion: These surveillance data, obtained under the conditions of universal infant immunization show the novel recombinant HB vaccine, Euvax B™, is safe and well-tolerated with an immunogenicity similar to other recombinant HB vaccines. Received: October 9, 2000 · Revision accepted: September 22, 2001     

Encapsulation of BSA in hybrid PEG hydrogels: stability and controlled release

Hybrid hydrogels based on silylated polyethylene glycol, Si-PEG, were evaluated as hybrid matrices able to trap, stabilize and release bovine serum albumin (BSA) in a controlled manner. Parameters of the inorganic condensation reaction leading to a siloxane (Si–O–Si) three dimensional network were carefully investigated, in particular the temperature, the surrounding hygrometry and the Si-PEG concentration. The resulting hydrogel structural features affected the stability, swelling, and mechanical properties of the network, leading to different protein release profiles. Elongated polymer assemblies were observed, the length of which ranged from 150 nm to over 5 μm. The length could be correlated to the Si–O–Si condensation rate from 60% (hydrogels obtained at 24 °C) to about 90% (xerogels obtained at 24 °C), respectively. Consequently, the controlled release of BSA could be achieved from hours to several weeks, with respect to the fibers'' length and the condensation rate. The protein stability was evaluated by means of a thermal study. The main results gave insight into the biomolecule structure preservation during polymerisation, with ΔG < 0 for encapsulated BSA in any conditions, below the melting temperature (65 °C).

Silylated hybrid hydrogels of polyethylene glycol were designed to trap, stabilize and release a model protein (bovine serum albumin). Fine-tuning sol–gel reactions lead to sustained release of BSA over weeks, with good insight of protein stability.