Protocol for stage 1 of the GaP study (Genetic testing acceptability for Paget's disease of bone): an interview study about genetic testing and preventive treatment: would relatives of people with Paget's disease want testing and treatment if they were available?

BACKGROUND: Paget's disease of bone (PDB) is characterised by focal increases in bone turnover, affecting one or more bones throughout the skeleton. This disrupts normal bone architecture and causes pain, deformity, deafness, osteoarthritis, and fractures. Genetic factors are recognised to play a role in PDB and it is now possible to carry out genetic tests for research. In view of this, it is timely to investigate the clinical potential for a programme of genetic testing and preventative treatment for people who have a family history of PDB, to prevent or delay the development of PDB. Evidence from non-genetic conditions, that have effective treatments, demonstrates that patients' beliefs may affect the acceptability and uptake of treatment. Two groups of beliefs (illness and treatment representations) are likely to be influential. Illness representations describe how people see their illness, as outlined in Leventhal's Self-Regulation Model. Treatment representations describe how people perceive potential treatment for their disease. People offered a programme of genetic testing and treatment will develop their own treatment representations based on what is offered, but the beliefs rather than the objective programme of treatment are likely to determine their willingness to participate. The Theory of Planned Behaviour is a theoretical model that predicts behaviours from people's beliefs about the consequences, social pressures and perceived control over the behaviour, including uptake of treatment. METHODS/DESIGN: This study aims to examine the acceptability of genetic testing, followed by preventative treatment, to relatives of people with PDB. We aim to interview people with Paget's disease, and their families, from the UK. Our research questions are: 1. What do individuals with Paget's disease think would influence the involvement of their relatives in a programme of genetic testing and preventative treatment? 2. What do relatives of Paget's disease sufferers think would influence them in accepting an offer of a programme of genetic testing and preventative treatment? DISCUSSION: Our research will be informed by relevant psychological theory: primarily the Self-Regulation Model and the Theory of Planned Behaviour. The results of these interviews will inform the development of a separate questionnaire-based study to explore these research questions in greater detail

The evolution of Adele Wiseman's creative vision.

The Canadian literary canon contains few writers of such diversity as Adele Wiseman. Although she is chiefly remembered for her two novels, her canon extends well beyond the fiction for which she is chiefly remembered. In fact, Wiseman was a skilled practitioner of numerous genres including drama, the essay, the short story, and the memoir. To discern the creative vision underlying Wiseman's oeuvre, this thesis devotes one chapter to each of her major works: The Sacrifice (ch. 1); The Lovebound (ch. 2); Crackpot (ch. 3); Testimonial Dinner (ch. 4); Old Woman at Play (ch. 5); and Memoirs of a Book Molesting Childhood and Other Essays and "Goon of the Moon and the Expendables" (ch. 6). While existing criticism of Wiseman's writing generally concentrates on single dimensions of her personhood (i.e. faith, gender, nationality), this thesis suggests that a more valid analysis of Wiseman's oeuvre would acknowledge its hybridity. The diversity apparent in Wiseman's canon should be seen as a reflection of her triply marginalized subject position as a Jewish Canadian female writer. As such, the thesis draws on feminist theory, post-colonial theory and Jewish hermeneutics to elucidate Wiseman's creative vision. By combining these three theoretical perspectives, one can ascertain how Wiseman's faith, gender and nationality intersected to create the unique canon she left behind. Because Wiseman was such an astute critic of her own work, this thesis relies heavily upon her own statements about her craft. The Adele Wiseman Fonds at the W. B. Scott Library, York University was an invaluable source for such information. Of particular importance was Wiseman's thirty-year correspondence with Margaret Laurence, her best friend, and Malcolm Ross, her mentor. These letters provide readers with a rare opportunity to assess Wiseman's creative vision. They confirm that Wiseman's stylistic experimentation was an outgrowth of her peripheral status in mainstream society. Her need to question and reevaluate existing literary conventions reflected her belief that such conventions were restrictive and exclusionary. Despite the heterogeneity apparent in Wiseman's work, it is nonetheless united by a single underlying vision: Wiseman writes in order to teach people how to live--particularly in communion with others. All of her writing radiates immense compassion for human beings, but especially the dispossessed. Her writing is a plea to reject hierarchical structures in society--structures which divide people into "haves" and "have-nots." She presents readers with an alternative, salutary vision of a world where such divisions are obliterated in favour of heterogeneity and an accompanying awareness of each individual's unique contribution to the whole

MFG-E8 Released by Apoptotic Endothelial Cells Triggers Anti-Inflammatory Macrophage Reprogramming

Apoptotic endothelial cells are an important component of the ‘‘response to injury’ ’ process. Several atherosclerosis risk factors such as hyperglycemia and oxidized low-density lipoproteins, and immune injuries, such as antibodies and complement, induce endothelial cell apoptosis. While endothelial cell apoptosis is known to affect neighboring vascular wall cell biology, its consequences on macrophage reprogramming are ill defined. In this study, we report that apoptosis of human and mouse endothelial cells triggers the release of milk fat globule-epidermal growth factor 8 (MFG-E8) and reprograms macrophages into an anti-inflammatory cells. We demonstrated that MFG-E8 is released by apoptotic endothelial cells in a caspase-3-dependent manner. When macrophages were exposed to conditioned media from serumstarved apoptotic endothelial cells, they adopt a high anti-inflammatory, low pro-inflammatory cytokine/chemokine secreting phenotype that is lost if MFG-E8 is absent from the media. Macrophage treatment with recombinant MFG-E8 recapitulates the effect of conditioned media. Finally, we showed that MFG-E8-mediated reprogramming of macrophages occurs through increased phosphorylation of signal transducer and activator of transcription-3 (STAT-3). Taken together, our study suggests a key role of MFG-E8 release from apoptotic endothelial cells in macrophage reprogramming an

Dynamics of depressive and psychomotor symptoms during electroconvulsive therapy in older depressive patients: A case series

International audienceObjective. Electroconvulsive therapy (ECT) is an effective treatment for patients suffering from a major depressive episode, especially older ones. Identification of specific responses within early ECT sessions remains an issue of debate, however. Hence, this pilot study prospectively examined the outcome in terms of depressive signs, symptom by symptom, throughout a course of ECT, concentrating particularly on psychomotor retardation symptoms. Methods. Nine patients were clinically evaluated several times during the ECT course, before the first session and then weekly (over 3 to 6 weeks, according to their evolution), by completing the Montgomery–Asberg Depression Rating Scale (MADRS), the Mini-Mental State Examination test, and the French Retardation Rating Scale for Depression (ERD) for assessing the severity of psychomotor retardation. Results. Non-parametric Friedman tests showed significant positive changes in mood disorders during ECT in older depressive patients (mean: -27.3% of initial MADRS total score). Fast improvement in ERD score was observed at t1 (i.e., after 3–4 ECT sessions), whereas a slightly delayed improvement in the MADRS scores was found at t2 (i.e., after 5–6 ECT sessions). Moreover, the scores for items linked to the motor component of psychomotor retardation (e.g., Gait, Postural control, Fatigability) were the first to significantly decrease during the first two weeks of the ECT course compared with the cognitive component. Conclusions. Interestingly, participants' concentration on daily functional activities, their interest and fatigability, and their reported state of sadness were the first to progress, representing possible precursor signs of positive patient outcomes following ECT

Cost-Utility Analysis of Curative and Maintenance Repetitive Transcranial Magnetic Stimulation (rTMS) for Treatment-Resistant Unipolar Depression: A Randomized Controlled Trial Protocol

International audienceBACKGROUND: Depression is a debilitating and costly disease for our society, especially in the case of treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) is an effective adjuvant therapy in treatment-resistant unipolar and non-psychotic depression. It can be applied according to two therapeutic strategies after an initial rTMS cure: a further rTMS cure can be performed at the first sign of relapse or recurrence, or systematic maintenance rTMS (M-rTMS) can be proposed. TMS adjuvant to treatment as usual (TAU) could improve long-term prognosis. However, no controlled study has yet compared the cost-effectiveness of these two additional rTMS therapeutic strategies versus TAU alone. METHODS/DESIGN: This paper focuses on the design of a health-economic, prospective, randomized, double-blind, multicenter study with three parallel arms carried out in France. This study assesses the cost-effectiveness of the adjunctive and maintenance low frequency rTMS on the right dorsolateral prefrontal cortex versus TAU alone. A total of 318 patients suffering from a current TRD will be enrolled. The primary endpoint is to investigate the incremental cost-effectiveness ratio (ICER) (ratio costs / quality-adjusted life-years [QALY] measured by the Euroqol Five Dimension Questionnaire) over 12\,months in a population of patients assigned to one of three arms: systematic M-rTMS for responders (arm A); additional new rTMS cure in case of mood deterioration among responders (arm B); and a placebo arm (arm C) in which responders are allocated in two subgroups: sham systematic M-rTMS and supplementary rTMS course in case of mood deterioration. ICER and QALYs will be compared between arm A or B versus arm C. The secondary endpoints in each three arms will be: ICER at 24\,months; the cost-utility ratio analysis at 12 and 24\,months; 5-year budget impact analysis; and prognosis factors of rTMS. The following criteria will be compared between arm A or B and arm C: rates of responders; remission and disease-free survival; clinical evolution; tolerance; observance; treatment modifications; hospitalization; suicide attempts; work stoppage; marital / professional statues; and quality of life at 12 and 24\,months. DISCUSSION: The purpose of our study is to check the cost-effectiveness of rTMS and we will discuss its economic impact over time. In the case of significant decrease in the depression costs and expenditures associated with a good long-term prognosis (sustained response and remission) and tolerance, rTMS could be considered as an efficient treatment within the armamentarium for resistant unipolar depression. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03701724. Registered on 10 October 2018. Protocol Amendment Version 2.0 accepted on 29 June 2019

Intermittent theta burst stimulation (iTBS) versus 10-Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP)

International audienceBackground: Recently intermittent theta burst stimulation (iTBS) proved to be non-inferior to conventional repetitive transcranial magnetic stimulation (10 Hz rTMS) in unipolar depression after failure of one antidepressant trial, but to date no randomized control trial assessed the ability of iTBS to improve depression level and quality of life in more resistant features of depression with a long-term (6 month) follow-up in comparison to 10 Hz rTMS.Objectives/hypothesis: The aim of our study was to compare the efficacy of 10 Hz rTMS and iTBS in treatment-resistant unipolar depression on response rates (50% decrease of MADRS scores at one month from baseline) and change in quality of life during a 6-month follow-up. In addition, we investigated whether some clinical features at baseline were associated with the response in the different groups.Method: Sixty patients were randomized in a double-blind, controlled study at the University Hospital Center of Nantes, and received 20 sessions of either rTMS or iTBS applied to the left dorsolateral prefrontal cortex targeted by neuronavigation. Statistical analysis used Fischer's exact test and Chi-square test as appropriate, linear mixed model, and logistic regression (occurrence of depressive relapse and factors associated with the therapeutic response).Results: Included patients showed in mean more than 3 antidepressants trials. Response rates were 36.7% and 33.3%, and remission rates were 18.5% and 14.8%, in the iTBS and 10Hz-rTMS groups respectively. Both groups showed a similar significant reduction in depression scores and quality of life improvement at 6 months. We did not find any clinical predictive factor of therapeutic response in this sample.Conclusion: Our study suggests the clinical interest of iTBS stimulation (which is more time saving and cost-effective as conventional rTMS) to provide long-lasting improvement of depression and quality of life in highly resistant unipolar depression

SSC from MFG-E8 KO mice reduces the anti-inflammatory reprogramming of macrophages.

<p>Data are presented as value mean ± SD in pg/mL; SSC: apoptotic serum-starved conditioned medium; TGF: transforming growth factor; IL: interleukin; MIP: macrophage inflammatory protein; MCP: monocyte chemotactic protein.</p

Apoptotic EC-conditioned media contain MFG-E8 and reprogram macrophages.

<p><b>A</b> Percentage of cells with increased chromatin condensation and cell membrane permeabilization (as evaluated with HO and PI staining) in HUVEC exposed to normal medium with growth factors without serum (normal serum-starved, NSS) or serum starvation (SS) for 1 h to 4 h (*<i>p</i><0.001 versus Normal, <i>n</i> = 3). Example of HO/PI staining on serum starved HUVEC for 4 h showing chromatin condensation, right panel. <b>B</b> MEC and HUVEC were serum-starved for 1 h to 4 h. Supernatants (upper panels) and cells (lower panels) were harvested. Immunoblotting of MEC protein extracts showed that MFG-E8 levels decreased over time in parallel with increased active caspase-3 levels (lower left panel). HUVEC also exhibited reduced intracellular MFG-E8 levels over time (lower right panel). MFG-E8 levels increased over time in serum-starved conditioned medium (SSC) from EC (upper panels). β-Actin and Ponceau red staining were loading controls. Representative of 3 experiments. <b>C</b> Percentage of cells with increased chromatin condensation and cell membrane permeabilization (as evaluated with HO and PI staining) in HUVEC exposed to MMC 0.01 mg/mL or vehicle in normal medium and serum starvation (as positive control) for 15 h (left panel), *<i>p</i><0.0001 versus vehicle, <i>n</i> = 3. Immunoblot for hMFG-E8 in supernatant of EC treated with MMC (right panel). Ponceau red staining is shown as loading control. Representative of 2 experiments. <b>D</b> Immunoblot for hMFG-E8 in supernatants conditioned by necrotic HUVEC (3 freeze-thaw cycles) and serum-starved HUVEC as positive control. Ponceau red staining included as loading control. Representative of 2 experiments. <b>E</b> Immunoblot for mMFG-E8 from total medium conditioned by apoptotic EC (Total SSC), supernatant after removal of apoptotic blebs by centrifugation at 50 000 g (SSC without (W/O) blebs) and apoptotic blebs (Blebs) purified from total SSC by centrifugation, supernatant obtained from the supernatant after 50 000 g and 200 000 g centrifugation (SSC W/O exo.) and exosome-like nanovesicle fraction pelleted after the 200 000 g centrifugation (Exo.). Proteins from equal initial volumes were precipitated by TCA. Ponceau red staining is shown as loading control of samples. Representative of 2 experiments. <b>F</b> MEC were serum-starved for 4 h, the SSC were harvested, centrifuged to remove apoptotic cells. Murine macrophages were exposed to SSC or serum starvation (SS) for 24 h. ELISA were performed for TGF-β₁, VEGF, IL-10, (left panel) MCP-1 and MIP-2 (right panel), *<i>p</i><0.05, representative of <i>n</i> = 14, 12, 4, 7 and 9 separate experiments respectively.</p