[Incredible language! A qualitative investigation of conversations about delusions]. / Wahnsinns Sprache! Eine qualitative Untersuchung zur kommunikativen Darstellung von Wahn im Gespräch.

BACKGROUND: Communicating about delusions is generally considered a challenging task. MATERIAL AND METHODS: Assuming that there are nevertheless a variety of communicative resources competently employed to meet this challenge, the authors present a conversation analytic study of two narrative interviews in which people talk about their experience of delusions. RESULTS: It is shown that through pauses, breaks, reformulations, negotiations of the so-called common ground and the use of metaphoric speech, they succeed in conveying many aspects of the experience of delusions that cannot simply be described in terms of content. CONCLUSIONS: These examples of communicative strategies can be a resource for others and encourage mental health professionals and users alike to engage in conversations on delusions.

Development of an integrated model of care for allogeneic stem cell transplantation facilitated by eHealth-the SMILe study.

PURPOSE: Allogeneic stem cell transplantation would benefit from re-engineering care towards an integrated eHealth-facilitated care model. With this paper we aim to: (1) describe the development of an integrated care model (ICM) in allogeneic SteM-cell-transplantatIon faciLitated by eHealth (SMILe) by combining implementation, behavioral, and computer science methods (e.g., contextual analysis, Behavior Change Wheel, and user-centered design combined with agile software development); and (2) describe that model's characteristics and its application in clinical practice. METHODS: The SMILe intervention's development consisted of four steps, with implementation science methods informing each: (1) planning its set-up within a theoretical foundation; (2) using behavioral science methods to develop the content; (3) choosing and developing its delivery method (human/technology) using behavioral and computer science methods; and (4) describing its characteristics and application in clinical practice. RESULTS: The SMILe intervention is embedded within the eHealth enhanced Chronic Care Model, entailing four self-management intervention modules, targeting monitoring and follow-up of important medical and symptom-related parameters, infection prevention, medication adherence, and physical activity. Interventions are delivered partly face-to-face by a care coordinator embedded within the transplant team, and partly via the SMILeApp that connects patients to the transplant team, who can monitor and rapidly respond to any relevant changes within 1 year post-transplant. CONCLUSION: This paper provides stepwise guidance on how implementation, behavioral, and computer science methods can be used to develop interventions aiming to improve care for stem cell transplant patients in real-world clinical settings. This new care model is currently being tested in a hybrid I effectiveness-implementation trial.

Antibody-based targeted delivery of interleukin-4 synergizes with dexamethasone for the reduction of inflammation in arthritis.

Objectives: We have previously reported that F8-IL4, a fusion protein consisting of the F8 antibody specific to the alternatively-spliced extra domain A of fibronectin and of murine IL-4, cures mice with established arthritis, when used in combination with dexamethasone (DXM). The goal of this study was to assess whether other therapeutic agents, besides DXM, could induce cures in combination with F8-IL4 and to elucidate which leucocytes are most affected by the pharmacological treatment. Methods: We performed therapy experiments in mice with CIA, using intravenous administrations of F8-IL4 in combination with DXM, MTX, murine cytotoxic T-lymphocyte-associated protein 4 fused to the fragment crystallizable portion of murine IgG2a, as well as mAbs to murine IL17A or the p40 subunit of murine IL12/IL23. Histology and immunohistochemistry for the identification of the various leucocytes were performed on the paws of mice euthanized at different therapy time points. Results: Only the use of F8-IL4 in combination with DXM induced complete remissions, while all other combinations did not lead to cures. The light microscopical evaluation of paws with arthritis revealed a predominant infiltration of neutrophils, which substantially decreased 24 h after treatment with F8-IL4 and DXM. Conclusion: The combination of F8-IL4 with DXM promotes a rapid anti-arthritic action by potently inhibiting neutrophil activity. A fully human analogue of F8-IL4 may find clinical utility for the treatment of neutrophil-driven chronic inflammatory conditions.

Affinity Enhancement of Protein Ligands by Reversible Covalent Modification of Neighboring Lysine Residues.

The discovery of protein ligands, capable of forming a reversible covalent bond with amino acid residues on a protein target of interest, may represent a general strategy for the discovery of potent small-molecule inhibitors. We analyzed the ability of different aromatic aldehydes to form imines by reaction with lysine using 1 H NMR techniques. 2-Hydroxybenzaldehyde derivatives were found to efficiently form imines in the millimolar concentration range. These benzaldehyde derivatives could increase the binding affinity of protein ligands towards the cognate protein target. Affinity maturation was achieved not only by displaying ligand and aldehyde moieties on two complementary locked nucleic acid strands but also by incorporating the binding fragments in a single small-molecule ligand. The affinity gain was only observed when lysine residues were accessible in the immediate surroundings of the ligand-binding site and could be abrogated by quenching with a molar excess of hydroxylamine.

Investigating the use of digital health tools in physiotherapy: facilitators and barriers.

BACKGROUND: Digital tools are becoming more and more common in healthcare. Their potential to improve treatment, monitoring, and coaching in physiotherapy has been recognized. Yet studies report that the adoption of digital health tools in ambulatory physiotherapy is rather low and that their potential is underexploited. OBJECTIVE: This paper aims to investigate how digital health tools in general, and the mobile health tool physitrackTM (hereafter the app) more particularly, are used in outpatient physiotherapy clinics and also to identify what facilitates or hinders the app's use. METHODS: The paper is part of a larger study and adopts an ethnographic approach. It is based on observational and interview data collected at two outpatient clinics. RESULTS: We reveal how physiotherapists and patients use the app in physiotherapy and identify 16 interdependent factors, on the macro-, meso-, and micro-level, that either facilitate or hinder its use. CONCLUSIONS: We argue that a single factor's facilitating or hindering impact cannot be grasped in isolation but needs to be investigated as one piece of a dynamic interplay. Further qualitative research is required, especially to shed more light on the app's compatibility with physiotherapy practice and use in therapist-patient interactions.

Tumor lymphatics.

In this article we survey more than three centuries of observation and research into tumor-associated lymphatic vessels, and their role in the metastatic spread of cancer. This historical overview documents how questions regarding tumor lymphatics have been central to concepts about the process of metastasis, and how this has subsequently influenced the clinical treatment of cancer. In turn, we show how analysis of the efficacy of these treatments has challenged long-standing notions regarding the tumor lymphatics. Starting with the discovery of VEGFR-3 and its ligands VEGF-C and VEGF-D, we also review how the rapid developments over the last 15 years in the molecular analysis of the lymphatic system and in particular lymphangiogenesis have contributed to this debate. Finally we speculate on how apparently paradoxical bodies of evidence regarding the role of tumor lymphatics in determining patterns of metastatic spread might be reconciled.

Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor-induced lymphangiogenesis in vivo.

The phloroglucinol derivative hyperforin, a major bioactive constituent of St. John's wort, is increasingly recognized as being able to regulate a variety of pathobiological processes and, thus, to possess potential therapeutic properties. In the context of cancer, hyperforin induces the apoptosis of cancer cells, inhibits angiogenesis and suppresses metastasis formation. Here, we report a new pharmacological function of hyperforin and its stabilized derivative aristoforin, namely the suppression of lymphatic endothelial cell (LEC) growth and lymphangiogenesis. At concentrations less than 10 microM, we found that these compounds induce cell cycle arrest of LECs, and at higher concentrations induce apoptosis. The loss of mitochondrial membrane potential and the activation of caspase-9 during the induction of apoptosis indicate that the intrinsic pathway of apoptosis is stimulated by these compounds, similar to the situation in tumor cells. In thoracic duct ring outgrowth assays, hyperforin and aristoforin both inhibited lymphangiogenesis, as evidenced by the suppression of lymphatic capillary outgrowth. In an in vivo animal model, both compounds were able to inhibit tumor-induced lymphangiogenesis. Together these data substantiate a new role for hyperforin and its derivatives as suppressors of lymphangiogenesis, and support their further investigation as potential anticancer drugs that target tumor growth and metastasis at multiple levels.

Advances in antibody engineering for rheumatic diseases.

The advent of biologic therapies, particularly antibody therapeutics, has revolutionized the pharmacological treatment of many rheumatic diseases. Antibody discovery began with the immunization of mice for the production of rodent immunoglobulins, but advances in protein and genetic engineering have now made it possible to generate fully human antibodies, which are better tolerated by patients. For most clinical applications in rheumatology, antibodies have been used as blocking agents capable of neutralizing the function of pro-inflammatory proteins, such as TNF. The latest strategies involve antibody products armed with effector moieties, such as anti-inflammatory drugs or cytokines, or antibody products that are specific for multiple targets for the selective inhibition of inflammation at sites of disease. Antibodies are some of the best-selling drugs in the world, and with further advances in antibody development, engineering of armed antibodies and bispecific products will have an important role in the treatment of rheumatic diseases.

Design and characterisation of a novel interleukin-15 receptor alpha fusion protein and analysis of interleukin-15 complexation.

Interleukin-15 (IL15) is one of the most important cytokines currently being considered for cancer therapy applications. It is thought that by administering IL15 in complex with its cognate receptor alpha chain (IL15Rα) its biological activity could be increased manifold. We produced a fusion protein of mouse IL15Rα and the F8 antibody, that targets the alternatively-spliced extra-domain A (EDA) of fibronectin, which is overexpressed in many types of cancer. The fusion protein F8IL15Rα was cloned, expressed and characterized in vitro and its ability to bind to mouse IL15 was assessed with both size exclusion chromatography (SEC) and surface plasmon resonance (SPR) experiments. Furthermore, mouse and human IL15 and their corresponding Fc fused IL15Rα subunits were purchased, characterized and used to compare the capacity of F8IL15Rα to generate complexes. Surprisingly, none of the IL15Rα fusion proteins showed IL15 complexation on SEC. However, on SPR, F8IL15Rα displayed the ability to bind IL15. In a cell-based activity assay none of the IL15Rα fusions were able to increase cellular proliferation in combination with IL15 compared to IL15 alone. A better understanding of the molecular requirements for effective IL15 signalling are likely to be important for the development of IL15-based biopharmaceuticals.

Novel antibody-cytokine fusion proteins featuring granulocyte-colony stimulating factor, interleukin-3 and interleukin-4 as payloads.

Neutrophils can strongly influence disease activity in cancer and in chronic inflammation. Here, we report for the first time the construction and characterization of antibody-fusion proteins featuring granulocyte-colony stimulating factor and interleukin-3 as payloads capable of enhancing neutrophil activity and a novel antibody-interleukin-4 fusion protein with neutrophil inhibitory potential. We used the F8 antibody specific to the alternatively-spliced extra domain A (EDA) of fibronectin as a targeting agent, since the cognate antigen is strongly upregulated in diseases characterized by angiogenesis. The fusion proteins GCSF-F8, F8-IL3 and F8-IL4-F8, were cloned, expressed, and their targeting ability assessed, exhibiting preferential tumor uptake with tumor:blood ratios at 24 h after injection of 3.3, 18.2 and 27.3, respectively. In F9 tumor bearing-mice GCSF-F8 and F8-IL3 did not provide a therapeutic benefit, while F8-IL4-F8 showed a potent tumor growth retardation. In the collagen-induced model of arthritis, GCSF-F8 and F8-IL3 induced a worsening of the disease, while F8-IL4-F8 slowed arthritis progression but, surprisingly, exhibited substantial toxicity when used in combination with dexamethasone. Collectively, the results indicate that the novel fusion proteins could be expressed and efficiently delivered to the site of disease. However, they were not superior to other antibody-cytokine fusions previously described by our laboratory.

Results of a randomized controlled trial analyzing telemedically supported case management in the first year after living donor kidney transplantation - a budget impact analysis from the healthcare perspective.

ᅟ: We analyze one-year costs and savings of a telemedically supported case management program after kidney transplantation from the perspective of the German Healthcare System. Recipients of living donor kidney transplantation (N = 46) were randomly allocated to either (1) standard aftercare or (2) standard aftercare plus additional telemedically supported case management. A range of cost figures of each patient's medical service utilization were calculated at month 3, 6 and 12 and analyzed using two-part regression models. In comparison to standard aftercare, patients receiving telemedically supported case management are associated with substantial lower costs related to unscheduled hospitalizations (mean difference: €3,417.46 per patient for the entire one-year period, p = 0.003). Taking all cost figures into account, patients receiving standard aftercare are associated, on average, with one-year medical service utilization costs of €10,449.28, while patients receiving telemedically supported case management are associated with €5,504.21 of costs (mean difference: € 4,945.07 per patient, p < 0.001). With estimated expenditures of €3,001.5 for telemedically supported case management of a single patient, we determined a mean difference of €1,943.57, but this result is not statistically significant (p = 0.128). Sensitivity analyses show that the program becomes cost-neutral at around ten participating patients, and was beneficial starting at 15 patients. Routine implementation of telemedically supported case management in German medium and high-volume transplant centers would result in annual cost savings of €791,033 for the German healthcare system. Patients with telemedically supported case management showed a lower utilization of medical services as well as better medical outcomes. Therefore, such programs should be implemented in medium and high-volume transplant centers. TRIAL REGISTRATION: DRKS00007634 ( http://www.drks.de/DRKS00007634 ).

Alternatively Spliced EDA Domain of Fibronectin Is a Target for Pharmacodelivery Applications in Inflammatory Bowel Disease.

The antibody-based pharmacodelivery of cytokines to sites of disease has been extensively studied for various indications but not for the treatment of inflammatory bowel diseases. Here, we report that the alternatively spliced EDA domain of fibronectin, a marker of angiogenesis and of tissue remodeling, is expressed in the dextran sodium sulfate mouse model of colitis and in patients with inflammatory bowel conditions, while being virtually undetectable in most normal adult tissues. Radiolabeled preparations of the F8 antibody, specific to the EDA domain of fibronectin, were shown to selectively localize to sites of inflammation in mice with colitis, as revealed by autoradiographic analysis. Fusion proteins of the F8 antibody with various murine payloads (interleukin-4, the p40 subunit of interleukin-12, interleukin-13) were administered to mice with colitis. IL12p40-F8 mediated an anti-inflammatory activity, which was comparable with the one of cyclosporine, whereas F8-IL4 did not inhibit colitis and F8-IL13 worsened the inflammatory conditions.

Tetrahydrochromenoimidazoles as potassium-competitive acid blockers (P-CABs): structure-activity relationship of their antisecretory properties and their affinity toward the hERG channel.

Potassium-competitive acid blockers (P-CABs) constitute a new therapeutic option for the treatment of acid-related diseases that are widespread and constitute a significant economical burden. Enantiomerically pure tetrahydrochromenoimidazoles were prepared using the readily available candidate 4 (BYK 405879) as starting material or the Noyori asymmetric reduction of ketones as key reaction. A comprehensive SAR regarding the influence of the 5-carboxamide and the 8-aryl residue on in vitro activity, acid-suppression in the Ghosh Schild rat, and affinity toward the hERG channel was established. In addition, efficacy and duration of the antisecretory action was examined for the most promising target compounds by 24 h pH-metry in the fistula dog and a significantly different SAR was observed as compared to the Ghosh Schild rat. Several tetrahydrochromenoimidazoles were identified that possessed a comparable profile as the candidate 4.

Cell cycle quiescence can suppress transcription from an ecdysone receptor-based inducible promoter in mammalian cells.

Inducible gene expression is a powerful tool for basic research, gene therapy and biotechnology, whose utility depends in part on consistent levels of induction regardless of metabolic status or physiological context. Here we examined the inducibility of the ecdysone receptor-based RheoSwitch mammalian inducible expression system in proliferating cells and in cell cycle-arrested cells. We found that both contact inhibition and growth arrest subsequent to serum deprivation dramatically reduced the levels of induction of reporter genes that could be achieved in 3T3 fibroblasts but in not NMuMG mammary epithelial cells. These data have implications for the use of the RheoSwitch system in inducible gene expression applications.