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Meeting Abstract: 6043

AIM: To investigate persons with dementia and their informal caregivers' views of inter-sectoral information, communication and collaboration throughout the trajectory of dementia care, in eight European countries. BACKGROUND: Living with dementia and being next of kin to a person with dementia means having to live through stages that have different characteristics, needs, challenges and requirements. DESIGN: Qualitative research. Focus groups were conducted in England, Estonia, Finland, France, Germany, The Netherlands, Spain and Sweden. METHODS: Persons with dementia and their informal caregivers (N = 137) participated in focus group interviews during 2011. Content analysis generated a tentative model of information, communication and collaboration for people with dementia and their caregivers, which was then tested. RESULTS: The core finding was that information, communication and collaboration were to be focused on the persons with dementia and the informal caregivers. Entering into the trajectory of the disease and its consequences was addressed as an important point of departure. The relation to professional care required establishing a trusting relationship, tailor-made intervention and a single person or organization to contact. Professional knowledge and commitment, variation in service and care adapted to needs were important. CONCLUSION: As focus of care is on the person with dementia and their informal caregivers, a dyadic approach seems most suitable for dementia care. A trusting relationship and a specific person or organization to contact seem to be indicators of best practice, as does adaptation to the needs of the person with dementia and their informal caregiver.

Diamond-Blackfan anaemia (DBA) is a rare congenital disease causing severe anaemia and progressive bone marrow failure. The majority of patients carry mutations in ribosomal proteins, which leads to depletion of erythroid progenitors in the bone marrow. As many as 40% of all DBA patients receive glucocorticoids to alleviate their anaemia. However, despite their use in DBA treatment for more than half a century, the therapeutic mechanisms of glucocorticoids remain largely unknown. Therefore we sought to study disease specific effects of glucocorticoid treatment using a ribosomal protein s19 (Rps19) deficient mouse model of DBA. This study determines for the first time that a mouse model of DBA can respond to glucocorticoid treatment, similar to DBA patients. Our results demonstrate that glucocorticoid treatment reduces apoptosis, rescues erythroid progenitor depletion and premature differentiation of erythroid cells. Furthermore, glucocorticoids prevent Trp53 activation in Rps19-deficient cells- in a disease-specific manner. Dissecting the therapeutic mechanisms behind glucocorticoid treatment of DBA provides indispensible insight into DBA pathogenesis. Identifying mechanisms important for DBA treatment also enables development of more disease-specific treatments of DBA.

Members of the TALE (three-amino-acid loop extension) family of atypical homeodomain-containing transcription factors are important downstream effectors of oncogenic fusion proteins involving the mixed lineage leukemia (MLL) gene. A well-characterized member of this protein family is MEIS1, which orchestrates a transcriptional program required for the maintenance of MLL-rearranged acute myeloid leukemia (AML). TGIF1/TGIF2 are relatively uncharacterized TALE transcription factors, which, in contrast to the remaining family, have been shown to act as transcriptional repressors. Given the general importance of this family in malignant hematopoiesis, we therefore tested the potential function of TGIF1 in the maintenance of MLL-rearranged AML. Gene expression analysis of MLL-rearranged patient blasts demonstrated reduced TGIF1 levels, and, in accordance, we find that forced expression of TGIF1 in MLL-AF9-transformed cells promoted differentiation and cell cycle exit in vitro, and delayed leukemic onset in vivo. Mechanistically, we show that TGIF1 interferes with a MEIS1-dependent transcriptional program by associating with MEIS1-bound regions in a competitive manner and that the MEIS1:TGIF1 ratio influence the clinical outcome. Collectively, these findings demonstrate that TALE family members can act both positively and negatively on transcriptional programs responsible for leukemic maintenance and provide novel insights into the regulatory gene expression circuitries in MLL-rearranged AML.Leukemia advance online publication, 21 November 2014; doi:10.1038/leu.2014.307.

The aim of the present study was to examine the effect of beta2-adrenergic stimulation on skeletal muscle contractile properties, sarcoplasmic reticulum (SR) rates of Ca(2+) release and uptake, and Na(+)/K(+)-ATPase-activity before and after fatiguing exercise in trained men. The study consisted of two experiments (EXP1, n = 10 M, EXP2, n = 20 M), where beta2-adrenoceptor agonist (terbutaline) or placebo was randomly administered in double-blinded crossover designs. In EXP1, maximal voluntary isometric contraction of m.quadriceps (MVC) was measured, followed by exercise to fatigue at 120% of Vo2max. A muscle biopsy was taken after MVC (non-fatigue) and at time of fatigue. In EXP2, contractile properties of m.quadriceps were measured with electrical stimulations before (non-fatigue) and after two fatiguing 45-s sprints. Non-fatigued MVC was 6±3 and 6±2% higher (P < 0.05) for terbutaline than placebo in EXP1 and EXP2. Furthermore, peak twitch force was 11±7% higher (P < 0.01) for terbutaline than placebo at non-fatigue. After sprints, MVC declined (P < 0.05) to same levels for terbutaline as placebo, whereas peak twitch force was lower (P < 0.05) and half relaxation time prolonged (P < 0.05) with terbutaline. Rates of SR Ca(2+) release and uptake at 400 nM [Ca(2+)] were 15±5 and 14±5% (P < 0.05) higher for terbutaline than placebo at non-fatigue, but declined (P < 0.05) to similar levels at time of fatigue. Na(+)/K(+)-ATPase-activity was unaffected by terbutaline compared with placebo at non-fatigue, but terbutaline counteracted exercise-induced reductions in Vmax at time of fatigue. In conclusion, increased contractile force induced by beta2-adrenergic stimulation is associated with enhanced rate of Ca(2+) release in humans. While beta2-adrenergic stimulation elicits positive inotropic and lusitropic effects of non-fatigued m.quadriceps, these effects are blunted when muscles fatigue. This article is protected by copyright. All rights reserved

An accelerated hydrothermal degrading test was designed in order to analyse the synergic effect of water and temperature on PLA/sisal biocomposites with and without coupling agent. As well, the physicochemical properties of biocomposites were monitored along the hydrothermal test by means of Scanning Electron Microscopy, Size Exclusion Chromatography and Differential Scanning Calorimetry. The addition of fibre induced higher water absorption capability and promoted physical degradation, as observed in the surface topography. During the processing of biocomposites and throughout the hydrothermal ageing, a reduction of molecular weight due to chain scission was found. As a consequence, a faster formation of crystalline domains in the PIA matrix occurred the higher the amount of fibre was, which acted as a nucleating agent. Higher crystallinity was considered as a barrier against the advance of penetrant and a reduction in the diffusion coefficient was shown. The addition of coupling agent presented a different influence depending on the composition, showing an inflection point around 20% of sisal fibre. (C) 2014 Elsevier Ltd. All rights reserved.

Four river basins in southern Sweden, with catchment sizes from 0.3 to 127 km(2) (median 1.9), were sampled in October 2007. The 243 samples were analysed for 26 trace elements (Ag, As, Au, Ba, Be, Bi, Cd, Co, Cr, Cu, Ga, Ge, In, La, Li, Mo, Ni, Pb, Sb, Se, Sn, Tl, Ti, U, V and Zn) to identify spatial patterns within drainage networks. The range and median of each element were defined for different stream orders, and relationships to catchment characteristics, including deposition history, were explored. The sampling design made it possible to compare the differences along 40 stream reaches, above and below 53 stream junctions with 107 tributaries and between the 77 inlets and outlets of 36 lakes. The largest concentration differences (at reaches, junctions and lakes) were observed for lakes, with outlets usually having lower concentration compared to the inlets for As, Ba, Be, Bi, Cd, Co, Cr, Ga, Ge, Ni, Pb, Sn, Ti, Tl, U, V and Zn. Significantly lower concentrations were observed for Cd and Co when comparing headwaters with downstream sites in each catchment. Common factor analysis (FA) revealed that As, Bi, Cr, Ga, Ge, Tl and V co-vary positively with Al, Fe and total organic carbon (TOC) and negatively with La, Li and pH. The strong removal of a large number of trace elements when passing through lakes is evident though in the FA, where lake surface coverage plots opposite to many of those elements. Forest volume does not respond in a similar systematic fashion and, surprisingly, the amount of wetland does not relate strongly to either Fe or TOC at any of the rivers. A better understanding of the quantitative removal of organic carbon and iron will aid in understanding trace element fluxes from landscapes rich in organic matter and iron.

B-cell malignancies upregulate the B-cell lymphoma 2 (Bcl-2) family inhibitors of the intrinsic apoptosis pathway, making them therapy resistant. However, small-molecule inhibitors of Bcl-2 family members such as ABT-737 restore a functional apoptosis pathway in cancer cells, and its oral analog ABT-263 (Navitoclax) has entered clinical trials. Gene engineered chimeric antigen receptor (CAR) T cells also show promise in B-cell malignancy, and as they induce apoptosis via the extrinsic pathway, we hypothesized that small-molecule inhibitors of the Bcl-2 family may potentiate the efficacy of CAR T cells by engaging both apoptosis pathways. CAR T cells targeting CD19 were generated from healthy donors as well as from pre-B-ALL (precursor-B acute lymphoblastic leukemia) patients and tested together with ABT-737 to evaluate apoptosis induction in five B-cell tumor cell lines. The CAR T cells were effective even if the cell lines exhibited different apoptosis resistance profiles, as shown by analyzing the expression of apoptosis inhibitors by PCR and western blot. When combining T-cell and ABT-737 therapy simultaneously, or with ABT-737 as a presensitizer, tumor cell apoptosis was significantly increased. In conclusion, the apoptosis inducer ABT-737 enhanced the efficacy of CAR T cells and could be an interesting drug candidate to potentiate T-cell therapy.

QC 20170516

Contains fulltext : 117279.pdf (publisher's version ) (Open Access)

Background: Psychodynamic psychotherapy is a psychological treatment approach that has a growing empirical base. Research has indicated an association between therapist-facilitated affective experience and outcome in psychodynamic therapy. Affect-phobia therapy (APT), as outlined by McCullough et al., is a psychodynamic treatment that emphasizes a strong focus on expression and experience of affect. This model has neither been evaluated for depression nor anxiety disorders in a randomized controlled trial. While Internet-delivered psychodynamic treatments for depression and generalized anxiety disorder exist, they have not been based on APT. The aim of this randomized controlled trial was to investigate the efficacy of an Internet-based, psychodynamic, guided self-help treatment based on APT for depression and anxiety disorders. Methods: One hundred participants with diagnoses of mood and anxiety disorders participated in a randomized (1:1 ratio) controlled trial of an active group versus a control condition. The treatment group received a 10-week, psychodynamic, guided self-help treatment based on APT that was delivered through the Internet. The treatment consisted of eight text-based treatment modules and included therapist contact (9.5 min per client and week, on average) in a secure online environment. Participants in the control group also received online therapist support and clinical monitoring of symptoms, but received no treatment modules. Outcome measures were the 9-item Patient Health Questionnaire Depression Scale (PHQ-9) and the 7-item Generalized Anxiety Disorder Scale (GAD-7). Process measures were also included. All measures were administered weekly during the treatment period and at a 7-month follow-up. Results: Mixed models analyses using the full intention-to-treat sample revealed significant interaction effects of group and time on all outcome measures, when comparing treatment to the control group. A large between-group effect size of Cohen's d, Funding Agency:Linköping University

We have developed an ultra-fast photon-counting energy-resolved application specific integrated circuit (ASIC) for spectral computed tomography (CT). A comprehensive characterization has been carried out to investigate the performance of the ASIC in terms of energy resolution under different photon flux rates and the count rate linearity in photon-counting mode. An energy resolution of 4.7 % has been achieved for 59.5 keV low flux photons. The count rate performance of the ASIC was measured with 120 kVp polychromatic x-rays. The results indicate that the count rate linearity can be kept for a flux rate up to 150 Mphotons s-1 mm-2 with retained energy information, and this value is increased to be 250 Mphotons s-1 mm-2 in photon-counting mode

OBJECTIVE: To evaluate the incidence, treatment, and outcome of influenza A(H1N1) in Finnish intensive care units (ICUs) with special reference to corticosteroid treatment. METHODS: During the H1N1 outbreak in Finland between 11 October and 31 December 2009, we prospectively evaluated all consecutive ICU patients with high suspicion of or confirmed pandemic influenza A(H1N1) infection. We assessed severity of acute disease and daily organ dysfunction. Ventilatory support and other concomitant treatments were evaluated and recorded daily throughout the ICU stay. The primary outcome was hospital mortality. RESULTS: During the 3-month period altogether 132 ICU patients were tested polymerase chain reaction-positive for influenza A(H1N1). Of these patients, 78% needed non-invasive or invasive ventilatory support. The median (interquartile) length of ICU stay was 4 [2-12] days. Hospital mortality was 10 of 132 [8%, 95% confidence interval (CI) 3-12%]. Corticosteroids were administered to 72 (55%) patients, but rescue therapies except prone positioning were infrequently used. Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores in patients with and without corticosteroid treatment were 31 [24-36] and 6 [2-8] vs. 22 [5-30] and 3 [2-6], respectively. The crude hospital mortality was not different in patients with corticosteroid treatment compared to those without: 8 of 72 (11%, 95% CI 4-19%) vs. 2 of 60 (3%, 95% CI 0-8%) (P = 0.11). CONCLUSIONS: The majority of H1N1 patients in ICUs received ventilatory support. Corticosteroids were administered to more than half of the patients. Despite being more severely ill, patients given corticosteroids had comparable hospital outcome with patients not given corticosteroids.

Hydrolytic degradations of polyactic acid/rice hulls (PLA/RH) composites with various rice hulls contents due to water absorptions at 23, 51 and 69 degrees C were investigated by studying the thermal properties, chemical composition, molecular weight, and morphology of the degraded products. The results have attested that the stability of PLA/RH composites in water depends slightly on rice hulls contents but it is significantly influenced by water temperature. Water adsorption in 30 days at 23 degrees C was between 0.87 and 9.25% depending on rice hull contents. However, at thermophilic temperatures, the water adsorption and degradation of these products were increased significantly. Saturations were achieved in less than 25 and 9 days at 51 degrees C and 69 degrees C, respectively, while hydrolytic degradation was demonstrated by an increase in fragility and development of crystallinity. At 69 degrees C, there were significant reductions of the decomposition and glass transition temperatures of the polymer by 13 degrees C. These changes were associated with the reduction of the molecular weight of PLA from 153.1 kDa to similar to 10.7 kDa due to hydrolysis of its ester group., QC 20110301

Experiments were carried out using weathered shale samples containing about 30 ppm of U obtained from an open pit in Kumla, Sweden. Aspen wood shavings were used as an easily degradable carbon source for the naturally occurring heterotrophic microorganisms. Wood shavings of about 5 g and the crushed shale were stratified in test tubes to ensure good contact. The results showed that the addition of the wood shavings increased U mobilisation. The presence of organic acids in solution known to be produced by the microorganisms indicated that U mobilisation was related to microbial activity. The wood shavings may provide an alternative to expensive additives such as refined sugars., Experiments were carried out using weathered shale samples containing about 30 ppm of U obtained from an open pit in Kumla, Sweden. Aspen wood shavings were used as an easily degradable carbon source for the naturally occurring heterotrophic microorganisms. Wood shavings of about 5 g and the crushed shale were stratified in test tubes to ensure good contact. The results showed that the addition of the wood shavings increased U mobilisation. The presence of organic acids in solution known to be produced by the microorganisms indicated that U mobilisation was related to microbial activity. The wood shavings may provide an alternative to expensive additives such as refined sugars.

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Mining of a Cu deposit at Bersbo, Sweden, ceased in 1902 and the approximately 500 000 m3 of coarse sulphidic mine waste was covered with cement-stabilised fly ash on the East side and or compacted illitic clay on the west side during the period 1987-1989 to prevent weathering and the transport of metals. Sampling of surface waters was undertaken before and after emplacement of the covers. The results of chemical analyses of acid mine drainage as it entered into the stream are discussed, including pH, alkalinity, electrical conductivity and concentrations of chloride, sulphate, dissolved oxygen, organic matter and main and trace metals. The covers performed as expected, with the oxygen concentration decreasing from 21% to less than 0.1% within 6 months. Metal concentrations, in particular Zn, Cd, Pb and Cu, were reduced and the pH increased after one year. Large increases in sulphate and Fe concentrations were observed, particularly at the cement-stabilised fly ash site. Both covers were impermeable to rain water, but there was still a net outflow of groundwater that had been in contact with a fraction of the waste. Oxidation of pyrite would theoretically give a sulphate/Fe ratio in solution greater than 2 if oxygen is the electron acceptor and below 2 if Fe(III) is the oxidising agent. The effluents exhibited ratios of 35-50 and 2-0.8 before and after covering, indicating that weathering had continued. The changed hydrological regime contributes to changes in metal concentrations in the surrounding surface water., Mining of a Cu deposit at Bersbo, Sweden, ceased in 1902 and the approximately 500 000 m3 of coarse sulphidic mine waste was covered with cement-stabilised fly ash on the East side and or compacted illitic clay on the west side during the period 1987-1989 to prevent weathering and the transport of metals. Sampling of surface waters was undertaken before and after emplacement of the covers. The results of chemical analyses of acid mine drainage as it entered into the stream are discussed, including pH, alkalinity, electrical conductivity and concentrations of chloride, sulphate, dissolved oxygen, organic matter and main and trace metals. The covers performed as expected, with the oxygen concentration decreasing from 21% to less than 0.1% within 6 months. Metal concentrations, in particular Zn, Cd, Pb and Cu, were reduced and the pH increased after one year. Large increases in sulphate and Fe concentrations were observed, particularly at the cement-stabilised fly ash site. Both covers were impermeable to rain water, but there was still a net outflow of groundwater that had been in contact with a fraction of the waste. Oxidation of pyrite would theoretically give a sulphate/Fe ratio in solution greater than 2 if oxygen is the electron acceptor and below 2 if Fe(III) is the oxidising agent. The effluents exhibited ratios of 35-50 and 2-0.8 before and after covering, indicating that weathering had continued. The changed hydrological regime contributes to changes in metal concentrations in the surrounding surface water.

Transforming growth factor (TGF)-beta regulates vascular development through two type I receptors: activin receptor-like kinase (ALK) 1 and ALK5, each of which activates a different downstream Smad pathway. The endothelial cell (EC)-specific ALK1 increases EC proliferation and migration, whereas the ubiquitously expressed ALK5 inhibits both of these processes. As ALK1 requires the kinase activity of ALK5 for optimal activation, the lack of ALK5 in ECs results in defective phosphorylation of both Smad pathways on TGF-beta stimulation. To understand why TGF-beta signaling through ALK1 and ALK5 has opposing effects on ECs and whether this takes place in vivo, we carefully compared the phenotype of ALK5 knock-in (ALK5(KI/KI)) mice, in which the aspartic acid residue 266 in the L45 loop of ALK5 was replaced by an alanine residue, with the phenotypes of ALK5 knock-out (ALK5(-/-)) and wild-type mice. The ALK5(KI/KI) mice showed angiogenic defects with embryonic lethality at E10.5-11.5. Although the phenotype of the ALK5(KI/KI) mice was quite similar to that of the ALK5(-/-) mice, the hierarchical structure of blood vessels formed in the ALK5(KI/KI) embryos was more developed than that in the ALK5(-/-) mutants. Thus, the L45 loop mutation in ALK5 partially rescued the earliest vascular defects in the ALK5(-/-) embryos. This study supports our earlier observation that vascular maturation in vivo requires both TGF-beta/ALK1/BMP-Smad and TGF-beta/ALK5/activin-Smad pathways for normal vascular development., Transforming growth factor (TGF)-beta regulates vascular development through two type I receptors: activin receptor-like kinase (ALK) 1 and ALK5, each of which activates a different downstream Smad pathway. The endothelial cell (EC)-specific ALK1 increases EC proliferation and migration, whereas the ubiquitously expressed ALK5 inhibits both of these processes. As ALK1 requires the kinase activity of ALK5 for optimal activation, the lack of ALK5 in ECs results in defective phosphorylation of both Smad pathways on TGF-beta stimulation. To understand why TGF-beta signaling through ALK1 and ALK5 has opposing effects on ECs and whether this takes place in vivo, we carefully compared the phenotype of ALK5 knock-in (ALK5(KI/KI)) mice, in which the aspartic acid residue 266 in the L45 loop of ALK5 was replaced by an alanine residue, with the phenotypes of ALK5 knock-out (ALK5(-/-)) and wild-type mice. The ALK5(KI/KI) mice showed angiogenic defects with embryonic lethality at E10.5-11.5. Although the phenotype of the ALK5(KI/KI) mice was quite similar to that of the ALK5(-/-) mice, the hierarchical structure of blood vessels formed in the ALK5(KI/KI) embryos was more developed than that in the ALK5(-/-) mutants. Thus, the L45 loop mutation in ALK5 partially rescued the earliest vascular defects in the ALK5(-/-) embryos. This study supports our earlier observation that vascular maturation in vivo requires both TGF-beta/ALK1/BMP-Smad and TGF-beta/ALK5/activin-Smad pathways for normal vascular development.