Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV.

Tyrosine kinase inhibitors (TKI) have changed the natural course of chronic myeloid leukemia (CML). With the advent of second-generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM). 1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years, 965 patients (64%) still received IM. At 10 years, progression-free survival was 82%, overall survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% major molecular remission and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). Eight-year probabilities of adverse drug reactions (ADR) were 76%, of grades 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800 mg and IM 400 mg+IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.Leukemia advance online publication, 13 March 2015; doi:10.1038/leu.2015.36.

Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men

Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level. Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10. Compared to non-stress, acute stress induced significant and rapid increases in NF-κB-BA and delayed increases in plasma IL-6 and mRNA of IL-1ß, IL-6, and IκBα (p's<.045). In the stress group, significant increases over time were also observed for NF-κB mRNA and plasma IL-1ß and IL-10 (p's<.055). NF-κB-BA correlated significantly with mRNA of IL-1β (r=.52, p=.002), NF-κB (r=.48, p=.004), and IκBα (r=.42, p=.013), and marginally with IL-6 mRNA (r=.31, p=.11). Plasma cytokines did not relate to NF-κB-BA or mRNA levels of the respective cytokines. Our data suggest that stress induces increases in NF-κB-BA that relate to subsequent mRNA expression of pro-inflammatory, but not anti-inflammatory cytokines, and of regulatory-cytoplasmic-proteins. The stress-induced increases in plasma cytokines do not seem to derive from de novo synthesis in circulating blood cells.

Preconceptional use of folic acid in the region of the Kantonsspital Münsterlingen/Thurgau: has it changed over the past 10 years?

BACKGROUND  Numerous studies have shown that the preconceptional use of folic acid prevents neural tube defects. We created a study to find out whether the preconceptional use of folic acid has improved in the past 10 years, in the area of Münsterlingen, Switzerland. MATERIAL AND METHODS  We interviewed 2 groups of patients who delivered at our Institution, namely between 2000 and 2002 (period A) involving 287 women and from 2009 to 2010 (period B) involving 305 pregnant women. We asked them whether they used folic acid by means of a standardised questionnaire. RESULTS  In period B significantly more women have taken folic acid preconceptionally (period A: 27.5% vs. period B: 40.7%; p=0.001). A significant increase in folic acid intake was seen in the German speaking group from period A to B (30.3% vs. 52.7%; p=0.0005), while this was not the case in the non-German speaking group (21.4% in both periods). More multiparaé women were taking folic acid compared to nulliparae. A significant increase from period A to B was noted only in the German speaking group. Unexpectedly, in nulliparae non-German speaking women, folic acid supplementation decreased from 14% to 6.1%. DISCUSSION  We have found a significant increase in preconceptional folic acid supplementation from 2001 to 2010. The percentage of women taking folic acid is disappointingly low in all groups, particularly in nulliparae women of non-German ethnicity.

Map positions of third chromosomal female sterile and lethal mutations of Drosophila melanogaster

Chromosomal mutations induced by ethyl methanesulfonate (EMS) treatment can cause female sterility or maternal-effect lethality in Drosophila. EMS is particularly useful to researchers because it creates mutations independent of position effects. However, because researchers have little control over the chromosomal site of mutation, post-mutagenic genetic mapping is required to determine the cytological location of the mutation. To make a valuable set of mutants more useful to the research community, we have mapped the uncharacterized part of the female-sterile – maternal-effect lethal Tübingen collection. We mapped 49 female-sterile – maternal-effect lethal alleles and 72 lethal alleles to individual deficiency intervals on the third chromosome. In addition, we analyzed the phenotype of ovaries resulting from female sterile mutations. The observed phenotypes range from tumorous ovaries and early blocks in oogenesis, to later blocks, slow growth, blocks in stage 10, to apparently full development of the ovary. The mapping and phenotypic characterization of these 121 mutations provide the necessary information for the researcher to consider a specific mutant as a candidate for their gene of interest.Key words: Drosophila melanogaster, oogenesis, female sterile, maternal-effect lethal, EMS-induced mutations.

lets over eenige Joodsche Bezienswaardigheden te Frankfort A/Main

door J. S. Da Silva Rosa

Postnatal retention in HIV care: insight from the Swiss HIV Cohort Study over a 15-year observational period.

OBJECTIVES The aim of this study was to quantify loss to follow-up (LTFU) in HIV care after delivery and to identify risk factors for LTFU, and implications for HIV disease progression and subsequent pregnancies. METHODS We used data on pregnancies within the Swiss HIV Cohort Study from 1996 to 2011. A delayed clinical visit was defined as > 180 days and LTFU as no visit for > 365 days after delivery. Logistic regression analysis was used to identify risk factors for LTFU. RESULTS A total of 695 pregnancies in 580 women were included in the study, of which 115 (17%) were subsequent pregnancies. Median maternal age was 32 years (IQR 28-36 years) and 104 (15%) women reported any history of injecting drug use (IDU). Overall, 233 of 695 (34%) women had a delayed visit in the year after delivery and 84 (12%) women were lost to follow-up. Being lost to follow-up was significantly associated with a history of IDU [adjusted odds ratio (aOR) 2.79; 95% confidence interval (CI) 1.32-5.88; P = 0.007] and not achieving an undetectable HIV viral load (VL) at delivery (aOR 2.42; 95% CI 1.21-4.85; P = 0.017) after adjusting for maternal age, ethnicity and being on antiretroviral therapy (ART) at conception. Forty-three of 84 (55%) women returned to care after LTFU. Half of them (20 of 41) with available CD4 had a CD4 count < 350 cells/μL and 15% (six of 41) a CD4 count < 200 cells/μL at their return. CONCLUSIONS A history of IDU and detectable HIV VL at delivery were associated with LTFU. Effective strategies are warranted to retain women in care beyond pregnancy and to avoid CD4 cell count decline. ART continuation should be advised especially if a subsequent pregnancy is planned.

Mapping tree density at a global scale

The global extent and distribution of forest trees is central to our understanding of the terrestrial biosphere. We provide the first spatially continuous map of forest tree density at a global scale. This map reveals that the global number of trees is approximately 3.04 trillion, an order of magnitude higher than the previous estimate. Of these trees, approximately 1.39 trillion exist in tropical and subtropical forests, with 0.74 trillion in boreal regions and 0.61 trillion in temperate regions. Biome-level trends in tree density demonstrate the importance of climate and topography in controlling local tree densities at finer scales, as well as the overwhelming effect of humans across most of the world. Based on our projected tree densities, we estimate that over 15 billion trees are cut down each year, and the global number of trees has fallen by approximately 46% since the start of human civilization.

Chemical compositions of solid particles present in the Greenland NEEM ice core over the last 110,000 years

This study reports the chemical composition of particles present along Greenland’s North Greenland Eemian Ice Drilling (NEEM) ice core, back to 110,000 years before present. Insoluble and soluble particles larger than 0.45 μm were extracted from the ice core by ice sublimation, and their chemical composition was analyzed using scanning electron microscope and energy dispersive X-ray spectroscopy and micro-Raman spectroscopy. We show that the dominant insoluble components are silicates, whereas NaCl, Na₂SO₄, CaSO ₄, and CaCO₃ represent major soluble salts. For the first time, particles of CaMg(CO₃)₂ and Ca(NO₃)₂ 4H₂O are identified in a Greenland ice core. The chemical speciation of salts varies with past climatic conditions. Whereas the fraction of Na salts (NaCl + Na₂SO₄) exceeds that of Ca salts (CaSO₄+ CaCO₃) during the Holocene (0.6–11.7 kyr B.P.), the two fractions are similar during the Bølling-Allerød period (12.9–14.6 kyr B.P.). During cold climate such as over the Younger Dryas (12.0–12.6 kyr B.P.) and the Last Glacial Maximum (15.0–26.9 kyr B.P.), the fraction of Ca salts exceeds that of Na salts, showing that the most abundant ion generally controls the salt budget in each period. High-resolution analyses reveal changing particle compositions: those in Holocene ice show seasonal changes, and those in LGM ice show a difference between cloudy bands and clear layers, which again can be largely explained by the availability of ionic components in the atmospheric aerosol body of air masses reaching Greenland.

Effect of B-type Natriuretic Peptides on Long-Term Outcomes After Transcatheter Aortic Valve Implantation.

B-type natriuretic peptide (BNP) levels are elevated in patients with aortic stenosis (AS) and decrease acutely after replacement of the stenotic valve. The long-term prognostic value of BNP after transcatheter aortic valve implantation (TAVI) and the relative prognostic utility of single versus serial peri-interventional measurements of BNP and N-terminal prohormone BNP (NT-pro-BNP) are unknown. This study sought to determine the impact of BNP levels on long-term outcomes after TAVI and to compare the utility of BNP versus NT-pro-BNP measured before and after intervention. We analyzed 340 patients with severe AS and baseline pre-TAVI assessment of BNP. In 219 patients, BNP and NT-pro-BNP were measured serially before and after intervention. Clinical outcomes over 2 years were recorded. Patients with high baseline BNP (higher tertile ≥591 pg/ml) had increased risk of all-cause mortality (adjusted hazard ratio 3.16, 95% confidence interval 1.84 to 5.42; p <0.001) and cardiovascular death at 2 years (adjusted hazard ratio 3.37, 95% confidence interval 1.78 to 6.39; p <0.001). Outcomes were most unfavorable in patients with persistently high BNP before and after intervention. Comparing the 2 biomarkers, NT-pro-BNP levels measured after TAVI showed the highest prognostic discrimination for 2-year mortality (area under the curve 0.75; p <0.01). Baseline-to-discharge reduction, but not baseline levels of BNP, was related to New York Heart Association functional improvement. In conclusion, high preintervention BNP independently predicts 2-year outcomes after TAVI, particularly when elevated levels persist after the intervention. BNP and NT-pro-BNP and their serial periprocedural changes provide complementary prognostic information for symptomatic improvement and survival.

Understanding measured water rotational temperatures and column densities in the very innermost coma of Comet 73P/Schwassmann–Wachmann 3 B

Direct sublimation of a comet nucleus surface is usually considered to be the main source of gas in the coma of a comet. However, evidence from a number of comets including the recent spectacular images of Comet 103P/Hartley 2 by the EPOXI mission indicates that the nucleus alone may not be responsible for all, or possibly at times even most, of the total amount of gas seen in the coma. Indeed, the sublimation of icy grains, which have been injected into the coma, appears to constitute an important source. We use the fully-kinetic Direct Simulation Monte Carlo model of Tenishev et al. (Tenishev, V.M., Combi, M.R., Davidsson, B. [2008]. Astrophys. J., 685, 659−677; Tenishev, V.M., Combi, M.R., Rubin, M. [2011]. Astrophys. J., 732) to reproduce the measurements of column density and rotational temperature of water in Comet 73P-B/Schwassmann–Wachmann 3 obtained with a very high spatial resolution of ∼30 km using IRCS/Subaru in May 2006 (Bonev, B.P., Mumma, M.J., Kawakita, H., Kobayashi, H., Villanueva, G.L. [2008]. Icarus, 196, 241−248). For gas released solely from the cometary nucleus at a heliocentric distance of 1 AU, modeled rotational temperatures start at 110 K close to the surface and decrease to only several tens of degrees by 10–20 nucleus radii. However, the measured decay of both rotational temperature and column density with distance from the nucleus is much slower than predicted by this simple model. The addition of a substantial (distributed) source of gas from icy grains in the model slows the decay in rotational temperature and provides a more gradual drop in column density profiles. Together with a contribution of rotational heating of water molecules by electrons, the combined effects allow a much better match to the IRCS/Subaru observations. From the spatial distributions of water abundance and temperature measured in 73P/SW3-B, we have identified and quantified multiple mechanisms of release. The application of this tool to other comets may permit such studies over a range of heliocentric and geocentric distances.

Novel MesoPorous BioGlass/silk scaffold containing adPDGF-B and adBMP7 for the repair of periodontal defects in beagle dogs

AIM The local delivery of growth factors via gene therapy has gained tremendous awareness in recent years due to their sustained growth factor delivery to target tissues. The aim of this study was to fabricate and investigate a scaffold able to release growth factors via gene therapy for the repair of periodontal tissues. MATERIALS AND METHODS Novel mesoporous bioglass (MBG)/silk fibrin scaffold combined with BMP7 and/or PDGF-B adenovirus was fabricated and tested in vitro for cell migration, proliferation and differentiation. Furthermore, acute-type buccal dehiscence periodontal defects (mesiodistal width × depth: 5 × 5 mm) were created on the buccal portion of the maxillary premolars in five normal male beagle dogs (12 months old, 15.0 ± 2.0 kg) and histologically examined for periodontal regeneration following implantation of the following five groups: (1) no scaffold, (2) MBG/silk scaffold alone, (3) scaffold + adPDGF-B, (4) scaffold + adBMP7, (5) scaffold + adPDGF-b + adBMP7. RESULTS In vitro findings demonstrated that adPDGF-B was able to rapidly recruit periodontal ligament (PDL) cells over sixfold more effectively than adBMP7, whereas adBMP7 was more able to induce osteoblast differentiation of PDL cells. In vivo findings demonstrate that scaffolds loaded with adPDGF-B were able to partially regenerate the periodontal ligament while adBMP7 scaffolds primarily improved new bone formation. The combination of both adPDGF-B and adBMP7 synergistically promoted periodontal regeneration by allowing up to two times greater regeneration of the periodontal ligament, alveolar bone and cementum when compared to each adenovirus used alone. CONCLUSIONS Although both PDGF-B and BMP7 are individually capable of promoting periodontal regeneration to some degree, their combination synergistically promotes wound healing in acute-type buccal dehiscence periodontal defects when delivered simultaneously. This study demonstrates the promise for successful delivery of low-cost, effective growth factor delivery via gene therapy for the treatment of periodontal defects.

Morphologic predictors of aortic expansion in chronic type B aortic dissection.

AIM To identify morphologic factors affecting aortic expansion in patients with uncomplicated type B aortic dissections. METHODS Computed tomography data of 24 patients (18 male; median age: 61 years), diagnosed with acute uncomplicated type B aortic dissections between 2002 and 2013, were retrospectively reviewed. All patients had at least two computed tomography angiography scans and six months of uneventful follow-up. Computed tomography scans were assessed by two independent readers with regard to presence and number of entry tears. Thoracic and abdominal aortic diameters were derived using image processing software. RESULTS Twenty-two of 24 patients showed aortic expansion over a median computed tomography angiographic follow-up of 33.2 months. Annual rates showed an increase of 1.7 mm for total aortic diameter, 2.1 mm for the false and a decrease of -0.4 mm for the true lumen. In three patients (12.5%), aortic diameter exceeded 60 mm during follow-up, and all three patients underwent thoracic endovascular aortic repair. Patients with a maximum aortic diameter <4 cm at baseline showed a significantly higher expansion rate compared to cases with an initial maximum aortic diameter of ≥4 cm (p=0.0471). A median of two entries (range: 1-5) was recognized per patient. Presence of more than two entry tears (n = 13) was associated with faster overall diameter expansion (mean annual rates: 2.18 mm vs. 1.16 mm; p = 0.4556), and decrease of the cross-sectional surface of the true lumen over time (annual rate for > 2 entries vs. ≤2 entries: -7.8 mm(2) vs. +37.5 mm(2); p = 0.0369). Median size of entry tears was 12 mm (range: 2-53 mm). CONCLUSIONS The results presented herein suggest that uncomplicated type B aortic dissection patients with more than two entry tears and/or an initial maximum aortic diameter of<4 cm are at risk for aortic dilatation and, therefore, may require stricter follow-up including the possible need for early intervention.