The ACCESS trial examined the 12-month effectiveness of continuous therapeutic assertive community treatment (ACT) as part of integrated care compared to standard care in a catchment area comparison ...design in patients with schizophrenia spectrum disorders treated with quetiapine immediate release.
Two catchment areas in Hamburg, Germany, with similar population size and health care structures were assigned to offer 12-month ACT as part of integrated care (n = 64) or standard care (n = 56) to 120 patients with first- or multiple-episode schizophrenia spectrum disorders (Structured Clinical Interview for DSM-IV Axis I Disorders criteria); multiple-episode patients were restricted to those with a history of relapse due to medication nonadherence. The primary outcome was time to service disengagement. Secondary outcomes comprised medication nonadherence, improvements of symptoms, functioning, quality of life, satisfaction with care from patients' and relatives' perspectives, and service use data. The study was conducted from April 2005 to December 2008.
17 of 120 patients (14.2%) disengaged with service, 4 patients (6.3%) in the ACT and 13 patients (23.2%) in the standard care group. The mean Kaplan-Meier estimated time in service was 50.7 weeks in the ACT group (95% CI, 49.1-52.0) and 44.1 weeks in the standard care group (95% CI, 40.1-48.1). This difference was statistically significant (P = .0035). Mixed models repeated measures indicated larger improvements for ACT compared to standard care regarding symptoms (P < . 01), illness severity (P < . 001), global functioning (P < . 05), quality of life (P < . 05), and client satisfaction as perceived by patients and family (both P < . 05). Logistic regression analyses revealed that ACT was associated with a higher likelihood of being employed/occupied (P = .001), of living independently (P = .007), and of being adherent with medication (P < . 001) and a lower likelihood of persistent substance misuse (P = .027).
Compared to standard care, intensive therapeutic ACT as part of integrated care could improve 1-year outcome. Future studies need to address in which settings these improvements can be sustained.
clinicaltrials.gov Identifier: NCT01081418.
Time delays for atomic photoemission obtained in streaking or reconstruction of attosecond bursts by interference of two-photon transitions experiments originate from a combination of the quantum ...mechanical Wigner time and the Coulomb-laser coupling. While the former was investigated intensively theoretically as well as experimentally, the latter attracted less interest in experiments and has mostly been subject to calculations. Here, we present a measurement of the Coulomb-laser coupling-induced time shifts in photoionization of neon at 59.4 eV using a terahertz (THz) streaking field (λ=152 μm). Employing a reaction microscope at the THz beamline of the free-electron laser in Hamburg (FLASH), we have measured relative time shifts of up to 70 fs between the emission of 2p photoelectrons (∼38 eV) and low-energetic (<1 eV) photoelectrons. A comparison with theoretical predictions on Coulomb-laser coupling reveals reasonably good agreement.
The potential of the frequently encountered (βα)8-barrel fold to acquire new functions was tested by an approach combining random mutagenesis and selection in vivo. For this purpose, the genes ...encoding 52 different phosphate-binding (βα)8-barrel proteins were subjected to error-prone PCR and cloned into an expression plasmid. The resulting mixed repertoire was used to transform different auxotrophic Escherichia coli strains, each lacking an enzyme with a phosphate-containing substrate. After plating of the different transformants on minimal medium, growth was observed only for two strains, lacking either the gene for the serine phosphatase SerB or the phosphoserine aminotransferase SerC. The same mutants of the E. coli genes nanE (encoding a putative N-acetylmannosamine-6-phosphate 2-epimerase) and pdxJ (encoding the pyridoxine 5′-phosphate synthase) were responsible for rescuing both ΔserB and ΔserC. Unexpectedly, the complementing NanE and PdxJ variants did not catalyze the SerB or SerC reactions in vitro. Instead, RT-qPCR, RNAseq, and transcriptome analysis showed that they rescue the deletions by enlisting the help of endogenous E. coli enzymes HisB and HisC through exclusive up-regulation of histidine operon transcription. While the promiscuous SerB activity of HisB is well-established, our data indicate that HisC is promiscuous for the SerC reaction, as well. The successful rescue of ΔserB and ΔserC through point mutations and recruitment of additional amino acids in NanE and PdxJ provides another example for the adaptability of the (βα)8-barrel fold.
Objectives: Model-based hearing aid development considers the assessment of speech recognition using a master hearing aid (MHA). It is known that aided speech recognition in noise is related to ...cognitive factors such as working memory capacity (WMC). This relationship might be mediated by hearing aid experience (HAE). The aim of this study was to examine the relationship of WMC and speech recognition with a MHA for listeners with different HAE. Design: Using the MHA, unaided and aided 80% speech recognition thresholds in noise were determined. Individual WMC capacity was assed using the Verbal Learning and Memory Test (VLMT) and the Reading Span Test (RST). Study sample: Forty-nine hearing aid users with mild to moderate sensorineural hearing loss divided into three groups differing in HAE. Results: Whereas unaided speech recognition did not show a significant relationship with WMC, a significant correlation could be observed between WMC and aided speech recognition. However, this only applied to listeners with HAE of up to approximately three years, and a consistent weakening of the correlation could be observed with more experience. Conclusions: Speech recognition scores obtained in acute experiments with an MHA are less influenced by individual cognitive capacity when experienced HA users are taken into account.
Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in ...tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene. Instead, FOXO3 induced phosphorylation of its binding partner ATM and of the ATM downstream target cAMP-responsive element binding protein (CREB), which was critical for FOXO3-mediated caspase-8 expression. Caspase-8 levels above a critical threshold sensitized neuroblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced cell death. The DNA-demethylating drug 5-Aza-2-deoxycytidine (5-azadC) induced rapid nuclear accumulation of FOXO3, ATM-dependent CREB phosphorylation, and caspase-8 expression in a FOXO3-dependent manner. This indicates that 5-azadC activates the FOXO3-ATM-CREB signaling pathway, which contributes to caspase-8 expression. The combined data suggest that FOXO3 is activated by 5-azadC treatment and triggers expression of caspase-8 in caspase-8-negative neuroblastoma, which may have important implication for metastasis, therapy, and death resistance of this childhood malignancy.
Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to ...resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene BCR-ABL1
differ from BCR-ABL1 native (BCR-ABL1) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin β3, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1
tumor burden and significantly prolonged survival of mice with BCR-ABL1
CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin β3/ILK-mediated signaling pathway in BCR-ABL1
cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.
Double-stranded RNA-binding domains (dsRBDs) are commonly found in modular proteins that interact with RNA. Two varieties of dsRBD exist: canonical Type A dsRBDs interact with dsRNA, while ...non-canonical Type B dsRBDs lack RNA-binding residues and instead interact with other proteins. In higher eukaryotes, the microRNA biogenesis enzyme Dicer forms a 1:1 association with a dsRNA-binding protein (dsRBP). Human Dicer associates with HIV TAR RNA-binding protein (TRBP) or protein activator of PKR (PACT), while Drosophila Dicer-1 associates with Loquacious (Loqs). In each case, the interaction involves a region of the protein that contains a Type B dsRBD. All three dsRBPs are reported to homodimerize, with the Dicer-binding region implicated in self-association. We report that these dsRBD homodimers display structural asymmetry and that this unusual self-association mechanism is conserved from flies to humans. We show that the core dsRBD is sufficient for homodimerization and that mutation of a conserved leucine residue abolishes self-association. We attribute differences in the self-association properties of Loqs, TRBP and PACT to divergence of the composition of the homodimerization interface. Modifications that make TRBP more like PACT enhance self-association. These data are examined in the context of miRNA biogenesis and the protein/protein interaction properties of Type B dsRBDs.
Deletions of cryptococcal PIK1 , RUB1 , and ENA1 genes independently rendered defects in yeast survival in human CSF and within macrophages. We evaluated virulence potential of these genes by ...comparing wild-type Cryptococcus neoformans strain H99 with deletant and complement strains in a BALB/c mouse model of pulmonary infection. Survival of infected mice; pulmonary cryptococcal growth and pathology; immunological parameters; dissemination kinetics; and CNS pathology were examined. Deletion of each PIK1 , RUB1 , and ENA1 differentially reduced pulmonary growth and dissemination rates of C. neoformans and extended mice survival. Furthermore, pik1Δ induced similar pathologies to H99, however, with significantly delayed onset; rub1Δ was more efficiently contained within pulmonary macrophages and was further delayed in causing CNS dissemination/pathology; whereas ena1Δ was progressively eliminated from the lungs and did not induce pathological lesions or disseminate into the CNS. The diminished virulence of mutant strains was associated with differential modulation of pulmonary immune responses, including changes in leukocyte subsets, cytokine responses, and macrophage activation status. Compared to H99 infection, mutants induced more hallmarks of a protective Th1 immune response, rather than Th2, and more classical, rather than alternative, macrophage activation. The magnitude of immunological effects precisely corresponded to the level of virulence displayed by each strain. Thus, cryptococcal PIK1 , RUB1 , and ENA1 differentially contribute to cryptococcal virulence, in correlation with their differential capacity to modulate immune responses.
Some general comments about ionic liquids (ILs) and carbohydrates are given. The main scope of the review is to discuss the present state of the art of chemical modification of cellulose applying IL ...as reaction media considering own research results. ILs, namely 1‐butyl‐3‐methylimidazolium chloride (BMIMCl), 1‐ethyl‐ 3‐methylimidazolium chloride (EMIMCl), 1‐butyl‐2,3‐dimethylimidazolium chloride (BDMIMCl), 1‐allyl‐2,3‐dimethylimidazolium bromide (ADMIMBr) and 1‐ethyl‐3‐ methylimidazolium acetate (EMIMAc) are solvents for cellulose (even for high molecular bacterial synthesized cellulose) and can easily be applied as reaction media for cellulose modification. We investigated the homogeneous acylation, carbanilation and silylation of the biopolymer cellulose. Under mild conditions and within short reaction time at low temperature (65 °C to 80 °C) and low excess of reagent, various cellulose esters and carbanilates, dendronized cellulose and trimethylsilyl cellulose were obtained. The DS of the cellulose derivatives can be controlled by varying the reaction time, reaction temperature and the IL used as reaction medium.
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