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A series of 4-amino-tetrahydro-2-benzazepin-3-one derivatives (Ac–Aba–Xxx–NHMe) were prepared as tetrapeptide mimetics. Considering the structural resemblance with the so-called Freidinger lactams, their propensity to adopt a β-turn conformation was investigated by NMR spectroscopy (solvent and temperature dependence) and molecular modeling. Interestingly, most of these lactams adopt extended conformations, only the spiro-benzazepinone 9 has a strong preference for the formation of a β-turn. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A3 adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3‘:  amino, aminomethyl, azido, guanidino, ureido; and at 5‘:  uronamido, azidodeoxy. N6-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N6-3-iodobenzyl-3‘-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC50 = 0.18 μM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A3AR. The affinity enhancements for 10 and the corresponding 3‘-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A3AR (EC50 of 1.0 μM), but had no effect on the H272E mutant A3AR (100 μM). Compound 10 was inactive at human A1, A2A, and A3cARs. The orthogonal pair comprising an engineered receptor and a modified agonist should be useful for elucidating signaling pathways and could be therapeutically applied to diseases following organ-targeted delivery of the neoceptor gene.

To provide quantitative information on site effects in the northern part of Belgium, forty-seven H/V microtremor measurements were performed with 5 second seismometers over an area of about 15.000 km2. Most of the results show a northward regular increase of the fundamental period in agreement with the augmentation of the Mesozoic and Cainozoic soft sedimentsthickness from a few meters 40 km south of Brussels to 900 m at the Netherlands-Belgium border. The measured resonance frequency values wereconsistent with theoretical computations performed at different sites onthe basis of existing information and shallow seismic experiments. At oneparticular site (Uccle) where borehole data were available, microtremor measurements using an array of four seismological stations with differentapertures allowed to obtain the low frequency part of the Rayleigh wave dispersion curve, extending the range covered by the analysis of surfacewaves artificially generated. The Vs profile derived from the surface waveinversion corroborates the 1 Hz natural frequency of the site. Comparison of these results with the macroseismic information concerning the MS= 5.0 1938 earthquake which occurred 50 km west of Brussels,confirmed the hypothesis that the geological structure of the Brabant massifis likely to control damage distribution during such an earthquake. Comparisonbetween the intensity map of the 1938 earthquake and the resonance period ofsediments obtained by our microtremor study shows a clear relation betweenthe two parameters. During the 1938 earthquake, site effects played a prominent role due to the dimension of the source whose corner frequency wasabout 1 Hz.

Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has recently been introduced as a potential target for the structure-based design of anti-tuberculosis drugs. Based on the TMPKmt X-ray structure and previous S.A.R. studies, we synthesised the nucleoside analogues 3a−b, 6a−b, 7a−b, and 8a−b, modified in 2'- and 3'-position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. Ki between 118 and 1260 μM). This prompted us to investigate the conformational features of these nucleosides. We concluded that compounds of this series, especially 8a−b, are strongly biased towards the “Northern” furanose ring conformation, whereas X-ray crystallography reveals a preference of TMPKmt for the opposite “Southern” conformers. This paper covers the synthesis, biological evaluation and conformational features (i.e. preferred ring puckering) of the 2'- and 3'-modified dT analogues. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The combined thermodynamic‐micromechanical model of Fischer [1] is applied to a low‐alloyed TRIP steel with a volume fraction of 16% of retained austenite. The model is implemented in a finite element code. The mesh consists of 9 by 9 by 9 cubical elements, each representing a single grain with a random crystallographic orientation. The retained austenite grains are randomly dispersed through the entire mesh. The extent of the martensitic transformation in all austenite grains is calculated. A large spread in transformation rate is observed. The most favourably oriented grains reach a full martensitic structure, while the martensite volume fraction of less favourably oriented grains is less than 50%. When the chemical driving force is more negative, the onset of the transformation is delayed and the increase of the martensite volume fraction is slower. The calculated results are compared with experimentally obtained values. Although in general a reasonable agreement is found, Fischer's approach leads to some discrepancies with experimental observations. Das kombinierte thermodynamischmikromechanische Modell von Fischer [1] wird auf einen niedriglegierten TRIP‐Stahl mit einem Restaustenitgehalt von 16 Volumenprozent angewandt. Das Modell wird in einen FEM‐Code implementiert. Das Raster besteht aus 9×9×9 kubischen Elementen, wobei jedes Element ein einzelnes Korn mit einer zufälligen kristallographischen Orientierung darstellt. Die Restaustenitkörner sind nach dem Zufallsprinzip in dem Raster verteilt. Das Ausmaß der Umwandlung in Martensit in allen Austenitkörnern wird berechnet. Beobachtet wird eine breite Spanne bei den Umwandlungsgeschwindigkeiten. Die günstigest orientierten Körner erreichen eine vollständige Martensitstruktur, während der Martensitanteil der weniger günstig orientierten Körner unter 50 Volumenprozent liegt. Wenn die chemische Triebkraft stärker negativ wird, verzögert sich der Beginn der Umwandlung und das Martensitwachstum verlangsamt sich. Die berechneten Ergebnisse werden mit experimentell ermittelten Werten verglichen. Obwohl in großen Zügen eine annehmbare Übereinstimmung gefunden wird, führt Fischers Ansatz zu einigen Unstimmigkeiten mit den Versuchsergebnissen.

The major flavonoids present in the leaves and flowers of the cannabinoid-free cannabis (Cannabis sativasubsp. sativaL.) cultivars Felina and Futura are orientin (1), vitexin (2), luteolin-7-O-g-D-glucuronide (3), and apigenin-7-O-g-D-glucuronide (4), while prenylated flavonoids, to which the potent estrogenicity of hops (Humilus lupulusL.) is associated, are absent. The different composition of flavonoids has chemotaxonomic value.

The major flavonoids present in the leaves and flowers of the cannabinoid-free cannabis (Cannabis sativa subsp. sativa L.) cultivars Felina and Futura are orientin (1), vitexin (2), luteolin-7-O-g-D-glucuronide (3), and apigenin-7-O-g-D-glucuronide (4), while prenylated flavonoids, to which the potent estrogenicity of hops (Humilus lupulus L.) is associated, are absent. The different composition of flavonoids has chemotaxonomic value.

Thyroid hormones are pleiotropic factors important for many developmental and physiological functions in vertebrates. Their effects are mediated by two specific receptors (TRalpha and TRbeta) which are members of the nuclear hormone receptor superfamily. To clarify the function of these receptors, our laboratory has started a comparative study of their role in teleost fish. This type of approach has been hampered by the isolation of specific clones for each fish species studied. In this report, we describe an efficient reverse transcription/PCR procedure that allows the isolation of large fragments corresponding to TRalpha and TRbeta of a wide range of teleost fish. Phylogenetic analysis of these receptors revealed a placement consistent with their origin, sequences from teleost fish being clearly monophyletic for both TRalpha and TRbeta. Interestingly, this approach allowed us to isolate (from tilapia and salmon) several new TRalpha or TRbeta isoforms resulting from alternative splicing. These isoforms correspond to expressed transcripts and thus may have an important physiological function. In addition, we isolated a cDNA encoding TRbeta in the Atlantic salmon (Salmo salar) encoding a functional thyroid hormone receptor which binds specific thyroid hormone response elements and regulates transcription in response to thyroid hormones.

ABSTRACTThe Telgene (or ETV6) is the target of the translocation (12;22)(p13;q11) in myeloid leukemia. TEL is a member of the ETS family of transcription factors and contains the pointed protein interaction (PNT) domain and an ETS DNA binding domain (DBD). By contrast to other chimeric proteins that contain TEL's PNT domain, such as TEL–platelet-derived growth factor ß receptor in t(5;12)(q33;p13), MN1-TEL contains the DBD of TEL. The N-terminal MN1 moiety is rich in proline residues and contains two polyglutamine stretches, suggesting that MN1-TEL may act as a deregulated transcription factor. We now show that MN1-TEL type I, unlike TEL and MN1, transforms NIH 3T3 cells. The transforming potential depends on both N-terminal MN1 sequences and a functional TEL DBD. Furthermore, we demonstrate that MN1 has transcription activity and that MN1-TEL acts as a chimeric transcription factor on the Moloney sarcoma virus long terminal repeat and a synthetic promoter containing TEL binding sites. The transactivating capacity of MN1-TEL depended on both the DBD of TEL and sequences in MN1. MN1-TEL contributes to leukemogenesis by a mechanism distinct from that of other chimeric proteins containing TEL.

AbstractIn this study, a series of tillage experiments were set up to investigate the effect of variations in tillage depth and tillage speed on net soil displacement and the associated tillage erosion rates for up and downslope chisel tillage of a loamy soil under two different soil conditions: 1.) a consolidated soil under stubble vegetation (primary pass), and 2.) a freshly tilled, loosened soil (secondary pass). The experimental results show that the average displacement distance is not only a function of slope gradient, but also of soil condition, tillage depth, and speed. A model incorporating these additional effects was proposed and validated using data available in the literature: variations in displacement distance can be successfully predicted, but their absolute magnitude is probably also controlled by tillage implement geometry, which is at present not incorporated into the model. The fact that displacement distances are not affected by slope gradient only complicates the calculation of tillage erosivity. However, if only the controlled variations in tillage depth and speed are accounted for, the use of a single tillage transport coefficient k is still possible without an unacceptable loss of accuracy. Using the model, a series of nomograms have been developed that allow one to evaluate the effect of tillage depth and/or speed on soil erosivity of a given tillage operation. These nomograms are a valuable tool for evaluating possible strategies to remediate tillage erosion due to chisel tillage. Finally, experiment results show that chisel tillage in the Belgian Loam Belt is very erosive, leading to annual erosion rates exceeding 2 mm yr−1(0.08 in yr−1) locally.

The ETS family of proteins is a large group of transcription factors implicated in many aspects of normal hematopoietic development, as well as oncogenesis. For example, the TEL1/ETV6 (TEL1) gene is required for normal yolk sac angiogenesis, adult bone marrow hematopoiesis, and is rearranged or deleted in numerous leukemias. This report describes the cloning and characterization of a novelETS gene that is highly related to TEL1 and is therefore called TEL2. The TEL2 gene consists of 8 exons spanning approximately 21 kilobases (kb) in human chromosome 6p21. Unlike the ubiquitously expressed TEL1 gene, however,TEL2 appears to be expressed predominantly in hematopoietic tissues. Antibodies raised against the C-terminus of the TEL2 protein were used to show that TEL2 localizes to the nucleus. All ETS proteins can bind DNA via the highly conserved ETS domain, which recognizes a purine-rich DNA sequence with a GGAA core motif. DNA binding assays show that TEL2 can bind the same consensus DNA binding sequence recognized by TEL1/ETV6. Additionally, the TEL2 protein is capable of associating with itself and with TEL1 in doubly transfected Hela cells, and this interaction is mediated through the pointed (PNT) domain of TEL1. The striking similarities ofTEL2 to the oncogenic TEL1, its expression in hematopoietic tissues, and its ability to associate withTEL1 suggest that TEL2 may be an important hematopoietic regulatory protein.

Fasting and refeeding have considerable effects on thyroid hormone metabolism. In the present study, 8-day-old meat-type cockerels were subjected to a 2-day starvation period followed by 3 days' refeeding. Blood and tissue samples were collected at the start of the experiment, at 4, 24, and 48 h of starvation, and at 4, 8, 24, 48, and 72 h of refeeding. This study demonstrates that in chicken, fasting decreased plasma T3and TSH levels and increased plasma T4concentrations. This was accompanied by increased hepatic type III deiodinase (D3) and decreased renal D3 activity. There were no changes in hepatic or renal type I deiodinase (D1). Refeeding restored normal plasma T3, T4, and TSH levels, while hepatic D3 and renal D3 activities returned to prefasting levels. Again hepatic D1 was not affected, but renal D1 was lower than the ad libitumvalues during the entire refeeding period. These results confirm that liver D3 is involved in the regulation of plasma T3during fasting and refeeding in the chicken. Northern blot analysis demonstrated increased hepatic D3 mRNA levels during the first day of starvation that disappeared by the end of the second day; refeeding had no additional effects. These results suggest that in fasted chickens the rapid upregulation of hepatic D3 occurs predominantly at a pretranslational level, whereas the drop in hepatic D3 activity after refeeding is probably regulated at a posttranslational level. In addition, renal D3 may play a role in the regulation of local T3availability.

Translocations in hematologic disease of myeloid or lymphoid origin with breakpoints at chromosome band 12p13 frequently result in rearrangements of the Ets variant gene 6 (ETV6). As a consequence either the ETS DNA-binding domain or the Helix-Loop-Helix (HLH) oligomerization domain of ETV6 is fused to different partner genes. We show here that a t(9; 12)(p24; p13) in a case of early pre-B acute lymphoid leukemia and a t(9; 15; 12)(p24; q15; p13) in atypical chronic myelogenous leukemia in transformation involve the ETV6 gene at 12p13 and the JAK2 gene at 9p24. In each case different fusion mRNAs were found, with only one resulting in an open reading frame for a chimeric protein consisting of the HLH oligomerization domain of ETV6 and the protein tyrosine kinase (PTK) domain of JAK2. The cloning of the complete human JAK2 coding and genomic sequences and of the genomic junction fragments of the translocations allowed a characterization of the different splice events leading to the various mRNAs. JAK2 plays a central role in non–protein tyrosine kinase receptor signaling pathways, which could explain its involvement in malignancies of different hematologic lineages. Besides hop in Drosophila no member of the JAK family has yet been implicated in tumorigenesis.

The purpose of this commentary is to locate the symmetric scaling of intergenerational continuity (SSIC) within a detailed typology of vertical scales. In the course of doing so, we establish that SSIC cannot be seen as a "corrected" prestige or socioeconomic scale, nor is it a convincing proxy for the total assets and resources embedded in occupations. We argue that SSIC might be reinterpreted as the dominant dimension underlying patterns of intergenerational contact; however, some of the competing "network scales" tap a broader range of relational processes, and it would therefore be difficult to salvage a major role for SSIC within this tradition. We conclude by asking whether SSIC should be privileged relative to alternative scales that maximize other bivariate correlations.

SUMMARY. The thoracic outlet syndrome and shoulder instability provoke well known and partly similar sensations, often described by the patient as ''my arm feels dead...I have no strength in my arm...I feel pins and needles in my arm...''. In axillary surgery, there are sometimes reports of a fibromuscular band or string crossing the axilla. In the dissection room these bands are well known. Their reported incidence being about 10% at post mortem. Generally they are variations of the latissimus dorsi or the pectoralis major muscles, the most common form being known as the axillary arch or the arch of Langer. Simulations of abduction in combination with external rotation on dissected cadaveric material suggest a possible neurovascular compression at the transition from the axilla to the upper end of the brachial neurovascular bundle. Dissection confirms that the band is innervated by branches from the ansa pectoralis with a blood supply from the lateral thoracic artery. Following a case study, where the axillary arch negatively influenced the patients occupational skills, an extensive echographic study of 1321 subjects (1179 male, 142 female) was undertaken. A total of 188 arches was detected in 112 subjects (8.50%), mostly occurring bilaterally (incidence 5.80%). The incidence of the arch of Langer suggests that it should be considered in the differential diagnoses of thoracic outlet and shoulder instability syndromes.

Human alpha 2-macroglobulin (alpha 2M) inhibits a broad spectrum of proteases by changing its conformation and physically confining the enzyme. The inhibitory spectrum of alpha 2M is defined by a stretch of 39 amino acids, the bait region, located near the middle of the alpha 2M monomers. To investigate whether a new inhibitory specificity can be introduced by the manipulation of the bait region, recombinant alpha 2M (r alpha 2M) was produced in which the primary cleavage site was replaced by a heptapeptide containing the cleavage specificity of tobacco etch virus (TEV) protease. This protease is not inhibited by wild-type alpha 2M. The r alpha 2M, produced in an episomal expression system, was fully functional and able to inhibit the tobacco etch virus protease according to its normal ‘trap’ mechanism. The manipulation of the bait region of alpha 2M thus allows the design of new, specific protease inhibitors.

A full-length alpha 2-macroglobulin (alpha 2M) cDNA was cloned into the episomal expression vectors pREP7 and pMEP4. Electroporation of the cell lines WI-L2-729HF2, U-937, K-562 and an Epstein-Barr virus-transformed cell line resulted in stable transfectants only with K-562 cells. Stable expression was obtained exclusively with pMEP4-alpha 2M and was driven from the inducible human metallothionein IIA promoter. Expression of the wild-type alpha 2M cDNA resulted in a recombinant protein (r alpha 2M) that could not be distinguished from plasma alpha 2M (p-alpha 2M): the transfected K-562 cells secreted tetrameric alpha 2M with intact internal thiol esters, a functional bait domain and a latent receptor-binding domain. r alpha 2M inhibited trypsin and elastase from cleaving a high-molecular-mass substrate. When the Cys-949 involved in the formation of the internal thiol ester was mutated to tyrosine (C949Y-r alpha 2M), a tetrameric alpha 2M was secreted, with the electrophoretic mobility of methylamine-treated p-alpha 2M (p-alpha 2M/MA) and with a functional receptor-binding domain. The C949Y-r alpha 2M did not possess proteinase-inhibiting capacity. Heterozygosity was mimicked by co-transfecting the K-562 cells with wild-type and mutant expression vectors. In this case, r alpha 2M was secreted with zero, one, two, three or four internal thiol esters. A comparison of the interaction of interleukin 1 beta and basic fibroblast growth factor with native p-alpha 2M, p-alpha 2M/MA and the mutant C949Y-r alpha 2M revealed that when assayed under nondenaturing conditions, no binding occurred to ‘slow’ p-alpha 2M whereas quantitatively similar binding was observed to ‘fast’ p-alpha 2M/MA and C949Y-r alpha 2M. Covalent binding, however, was essentially limited to p-alpha 2M/MA, suggesting the involvement of Cys-949 in the process. Covalent binding of insulin, on the contrary, was only observed when it was present during hydrolysis of the internal thiol esters of p-alpha 2M by trypsin treatment, and thus involves the activated Glx residue.

Sub-Saharan Africa reported 550,000 new HIV infections among women in 2018. Pregnancy and the postpartum period are associated with an increased risk of HIV acquisition (adjusted risk ratio [RR]: 2.8 during pregnancy and 4.0 in postpartum period vs. non-pregnant or postpartum women, respectively). Acquisition of HIV during pregnancy and breastfeeding increases risk of mother to child transmission. We propose to test the impact of a peer-delivered oral storytelling intervention to increase retention in, and adherence to, pre-exposure prophylaxis (PrEP)/combination antiretroviral treatment (ART) among expectant couples.

ABSTRACTBackgroundPre-exposure prophylaxis (PrEP) has the potential to reduce HIV transmission and stem the HIV epidemic. Unfortunately, PrEP uptake in rural sub-Saharan Africa has been slow and medication adherence has been suboptimal.ObjectiveTo explore the perspectives, attitudes, and experiences of HIV serodiscordant partners taking PrEP and develop a messaging campaign to improve PrEP uptake in rural Mozambique to reduce HIV transmission among serodiscordant partners.MethodsIn this qualitative study, we interviewed 20 people in serodiscordant relationships using PrEP at a rural health center in Zambézia province, Mozambique and employed inductive and deductive coding to elicit their perspectives, attitudes, and experiences related to learning their partner’s HIV status, barriers to PrEP uptake, obstacles to PrEP adherence, and decisions to disclose their PrEP use with family and friends using thematic analysis.ResultsOur analysis generated nine themes across various levels of the socioecological model. Participants reported a strong desire to stay in the discordant relationship and highlighted the importance of working together to ensure PrEP and antiretroviral therapy adherence, with the majority skeptical that adherence could be achieved without both partners’ support (individual and interpersonal). Although most participants were reticent about sharing their serodiscordant status with family and friends (individual and interpersonal), those who did found their family and friends supportive (interpersonal). Participants suggested increasing community health agent availability to help people navigate HIV prevention and treatment (organizational). We then created three oral stories, using themes from the interviews, with examples from various levels of the socioecological model that will be used to generate support for PrEP use among community members.ConclusionsOur findings informed oral template stories that will be used to emphasize how couples can work together to improve PrEP uptake and reduce incident HIV infections in serodiscordant couples elsewhere in rural Mozambique.

There are 466 million people living with a disabling hearing loss and the challenges of managing this public health crisis cannot be underestimated. Yet, adult utilization of cochlear implants is poor with less than 10% of suitable candidates receiving one. The aim of this study was to investigate the awareness levels regarding cochlear implants in older adults after a digital campaign to raise awareness of cochlear implantation in this population. To address the lack of awareness of the cochlear implants in the general population, adverts were placed in online medical magazines and mainstream newspapers. Data were collected in 400 subjects via an online market research questionnaire, in Germany, Austria, Sweden, and the United Kingdom, and compared with baseline data collected in a previous study. Median click rates were in line with expectations for the medical industry and approximately 22 000 individuals clicked through to the cochlear implant Web site. However, there were few significant differences between the 2 sets of data. The Internet was consulted as much as the doctor for medical information in Germany, Austria, and Sweden. The study reinforces the importance of the Internet in accessing information about health, including hearing loss. The click through rates shows that there is interest in learning about cochlear implants. Further work is needed to assess the impact of this type of campaign on individuals who have already been identified as hearing impaired.

Van Rompaey: argenx: Employment, Equity Ownership, Patents & Royalties. Moshir:Argenx: Employment, Equity Ownership. Delahaye:argenx: Employment, Equity Ownership. Gandini:Argenx: Employment, Equity Ownership. Erzeel:argenx: Employment, Equity Ownership. Hultberg:Argenx: Employment. Fung:argenx: Consultancy, Equity Ownership. De Haard:Argenx: Employment, Equity Ownership, Patents & Royalties. Leupin:Argenx: Employment, Equity Ownership, Patents & Royalties.

Bagot: Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees; Actelion: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Maerevoet:Karyopharm: Membership on an entity's Board of Directors or advisory committees; takeda: Membership on an entity's Board of Directors or advisory committees, Other: travel grant; roche: Other: travel grant; abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grant. Zinzani:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Morschhauser:Janssen: Other: Scientific Lectures; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ribrag:Incyte Corporation: Consultancy; Amgen: Research Funding; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; epizyme: Consultancy, Honoraria; NanoString Technologies: Consultancy, Honoraria; Roche: Honoraria, Other: travel; Servier: Consultancy, Honoraria; pharmamar: Other: travel; argenX: Research Funding; BMS: Consultancy, Honoraria, Other: travel; MSD: Honoraria. Dalle:Kyowa Hakko Kirin Pharmaceutical: Research Funding. Cayuela:Cepheid: Other: financial sponsor to attend John Goldman Conference 2017. Hultberg:argenx: Employment. Gandini:argenx: Employment. Moshir:argenx: Employment. Delahaye:argenx: Employment. Zabrocki:argenx: Employment. Silence:argenx: Consultancy. Van Rompaey:argenx: Employment. De Haard:argenx: Employment. Leupin:argenx: Employment.

Outcomes in elderly patients with acute myeloid leukemia (AML) are still adverse, as the majority does not qualify for intensive therapy or allogenic stem cell transplantation (ASCT). DNA hypomethylating agents (HMAs) induce remissions and prolong survival in a fraction of these patients. However, overall prognosis remains dismal and all patients progress due to therapy-resistant leukemia stem cells (LSCs). We recently demonstrated that HMAs upregulate the expression of CD70 on primary human AML LSCs, potentially contributing to HMA resistance and that blocking the cell-autonomous CD70/CD27 signaling inhibits proliferation and myeloid differentiation of LSCs and contributes to HMA resistance. Consequently, combining HMA treatment with a blocking αCD70 monoclonal antibody potently reduced colony formation of AML LSCs in vitro and effectively eliminated human AML LCSs in xenograft experiments. Based on these results, we initiated an open-label, non-controlled, non-randomized Phase 1/2 trial combining the HMA azacitidine (AZA) with ARGX-110, a human monoclonal antibody targeting CD70, in newly diagnosed AML patients unfit for intensive chemotherapy (ARGX-110-1601, NCT03030612).

The objectives of this study were to assess the factors which contribute to individuals’ health motivation to address hearing loss and to gather baseline data that could then be used to measure the impact of an awareness campaign. An online questionnaire with 13 closed set questions was completed by 100 subjects in each country including Austria, Germany, France, Sweden, and the United Kingdom. The questionnaire was based around the Health Belief Model, which describes how, in order to take action to address a medical problem, the individual must perceive that the condition presents a threat to their well-being that exceeds any barriers to treatment. Good hearing was regarded as being important in all countries. There was agreement that the main sign of hearing loss was turning up the TV or radio. In most countries, hearing aids were thought to be not particularly visible, not require much maintenance, a hindrance while doing sport, and must be removed before bed. Perceptions of hearing implants were that they were permanently fitted, not externally visible, and do not need to be removed before bed. Medical issues were mostly researched through a doctor and then via the Internet. In this sample, there was a good understanding of the consequences and signs of hearing loss, but although hearing implants were viewed as being different to hearing aids, there was little understanding that the external speech processor was similar to a hearing aid in its physical characteristics. When actions were taken, the key professionals consulted about hearing problems were the general practitioner and ear, nose, and throat specialist.

Leukemia stem cells (LSCs) are the origin of acute myeloid leukemia (AML) and are resistant to standard therapeutic regimens resulting in frequent relapse of the disease and poor prognosis especially for AML patients not fit for intensive chemotherapy. Consequently, LSCs represent a major obstacle for AML therapy. We recently identified the interaction of the TNF ligand CD70 and its receptor CD27 on LSCs as a promising therapeutic strategy to target LSCs.

The article provides information on rhythms used in traditional belly dance music and how to play them on the drumset. A background on the origin of the art of belly dance is presented. Information on playing several belly dance rhythms on the drums is presented including maqsum, basic bambi and masmudi kabir.

Delirium is a common complication in the intensive care unit. The attention of researchers has shifted from the treatment to the prevention of the syndrome necessitating the study of associated risk factors.

Background Several reports indicate a high incidence of intensive care delirium. To develop strategies to prevent this complication, validated instruments are needed. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is widely used. A binary result diagnoses delirium. The Neelon and Champagne (NEECHAM) Confusion Scale recently has been validated for use in the ICU and has a numeric assessment. This scale allows the patients to be classified in four categories: non-delirious, at risk, confused, and delirious. In this study, we investigated the results of the NEECHAM scale in comparison with the CAM-ICU.Methods A consecutive sample of 172 non-intubated patients in a mixed ICU was assessed after a stay in the ICU for at least 24 hours. All adult patients with a Glasgow Coma Scale score of greater than 9 were included. A nurse researcher simultaneously assessed both scales once daily in the morning. A total of 599 paired observations were made.Results The CAM-ICU showed a 19.8% incidence of delirium. The NEECHAM scale detected incidence rates of 20.3% for delirious, 24.4% for confused, 29.7% for at risk, and 25.6% for normal patients. The majority of the positive CAM-ICU patients were detected by the NEECHAM scale. The sensitivity of the NEECHAM scale was 87% and the specificity was 95%. The positive predictive value and the negative predictive value were 79% and 97%, respectively. The diagnostic capability in cardiac surgery patients proved to be lower than in other patients.Conclusion In non-intubated patients, the NEECHAM scale identified most cases of delirium which were detected by the CAM-ICU. Additional confused patients were identified in the categorical approach of the scale. The NEECHAM scale proved to be a valuable screening tool compared with the CAM-ICU in the early detection of intensive care delirium by nurses.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.