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In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α7 n-AChRs (Ki of 22±4 and 14±1 nM, respectively). Ex vivo 3[H]α-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID50=8 mg/kg p.o.). In functional studies performed with human α7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC50=4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

People with severe mental illness (PSMI) have a shorter life expectancy and are more likely to have cardiovascular disease than the general population. Patients, carers, psychiatric professionals and primary care providers can all play a role in increasing PSMI physical health. The present qualitative exploratory study aimed to explore the views of these four populations as part of the multi-phase COPsyCAT project, whose objective is to build and test a cardiovascular risk prevention programme for PSMI. Overall, 107 people participated in the study’s 16 focus groups, which were transcribed and analysed in a thematic analysis. With a view to building the health promotion programme, major themes identified in the corpus were translated into a list of needs as follows: communication, information, training and support. Results show that it is essential to improve communication between all the different stakeholders in mental health. The greatest challenge facing this programme will be to adapt it to the needs and expectations of PSMI while facilitating work between the various mental health stakeholders. Simple and inexpensive actions could be taken to improve the cardiovascular health of PSMI and will be experimented with during the programme’s feasibility study which will start in September 2022.

Background Persons with a diagnosis of severe mental illness have a life expectancy that is 20 years lower than the general population, and they are disproportionately affected by cardiovascular disorders. Improving the management of cardiovascular risk is one of the main challenges for the public health system. In the care pathway of persons with a diagnosis of severe mental illness, a better understanding of limiting and facilitating factors is required. The objective was to include persons with a diagnosis of severe mental illness, carers, and primary and mental health professionals in the creation and evaluation (feasibility) of a health promotion program designed to improve cardiovascular risk management through empowerment. Methods This study combines a mixed methodology with qualitative and quantitative components. A multicenter prospective qualitative study was conducted in seven mental health units in France and was coordinated by a steering committee composed of persons with a diagnosis of severe mental illness, carers, and primary and mental health professionals. Results This health promotion program must enable persons with a diagnosis of severe mental illness to assert their right to self-determination and to exercise greater control over their lives, beyond their diagnosis and care. Following a preliminary feasibility study, the effectiveness of this new tool will be evaluated using a randomized controlled trial in a second study. Conclusions The findings can be used by health organizations as a starting point for developing new and improved services for persons with a diagnosis of severe mental illness. Trial registration Clinical Trials Gov NCT03689296. Date registered September 28, 2018

Gene therapy using the herpes simplex virus thymidine kinase (HSV-TK) gene in combination with the drug ganciclovir (GCV) is a promising approach for the treatment of cancer-inducing gliomas, a tumor with a poor prognosis. In an attempt to limit the toxic effects on normal tissues, we constructed a recombinant adenoviral vector, Adgfa2TK, in which the HSV-TK gene is driven by the promoter for the gene encoding glial fibrillary acidic protein, an intermediate filament protein expressed primarily in astrocytes. Infection by Adgfa2TK of a glial cell line (C6) and a non-glial cell line (MDA-MB-231) revealed markedly increased expression of HSV-TK in glial cells as determined by Western blot. In comparison, high HSV-TK protein levels were produced in both cell lines after infection with a control virus, AdCMVTK, in which the constitutive cytomegalovirus viral promoter was used to direct HSV-TK expression. Infection of two glial cell lines (C6, U251) and two non-glial cell lines (HepG2, MDA-MB-231) with Adgfa2TK followed by GCV treatment revealed high toxicity in glial cell lines (50% growth inhibitory concentration: <2 microg/mL of GCV) with little or no toxicity (50% growth inhibitory concentration: >75 microg/mL) in the non-glial cell lines. In vivo, injection of Adgfa2TK into C6 tumors grown in nude mice followed by intraperitoneal GCV treatment significantly repressed tumor growth compared with the controls. Adgfa2TK may be useful for directing expression of the HSV-TK gene to gliomas.

Interest in obtaining cell lines for use in studies on the development and biochemistry of the central nervous system has motivated efforts to establish cells from primary brain cultures by the use of oncogene-transfer techniques. In previous reports, cell lines derived from astrocytes in this way have had immature or abnormal phenotypes. We have explored the possibility of specifically \"targeting\" expression of exogenous oncogenes to differentiated astrocytes by using the promoter of the gene encoding glial fibrillary acidic protein, which is expressed almost exclusively in such cells. We report here that cell lines displaying the phenotypic characteristics of type 1 astrocytes can be established reproducibly in this manner. Given the heterogeneity of primary cultures, the availability of clonal cell lines displaying characteristics of type 1 astrocytes should greatly facilitate our understanding of the biology of these cells.

The maintenance cost is known to be an important part of the levelized cost of energy generated by wind parks. Operational costs can be significantly reduced by optimizing decisions for maintenance strategies, maintenance support organization and maintenance planning. This is especially important for offshore wind power systems to reduce the high economic risks related to the uncertainties in the accessibility and reliability of wind turbines.This thesis proposes decision models for cost efficient maintenance for offshore wind power systems. The economical benefits of condition based maintenance strategies are evaluated for drive train and for blades of wind turbines. A model is presented to optimize the inspection interval for the blades. Models are proposed to perform cost-benefit analysis of the maintenance support organization by evaluating the benefit of logistic and personnel planning on availability. The maintenance planning of service maintenance activities is optimized by taking advantage of opportunities arising at low wind or when corrective maintenance activities are necessary.The models are tested in case studies with real environmental, reliability and cost data when available, and sensitivity analyses are performed for the parameters of interests. The results show that the proposed models can be used to reduce the maintenance costs through optimizing the maintenance strategies, the support organization and the maintenance planning.

In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective α 7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human α 7 n-AChRs ( K i of 22±4 and 14±1 nM, respectively). Ex vivo 3 [H] α -bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 =8 mg/kg p.o.). In functional studies performed with human α 7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC 50 =4.4 and 0.9 μM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small α -bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic α 7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 μM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the α 7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3–10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse α 7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.