Using an adaptive autoregressive model for the early detection of action potential duration alternans

Cardiostim 2012, Nice, France

Do N-arachidonyl-glycine (NA-glycine) and 2-arachidonoyl glycerol (2-AG) share mode of action and the binding site on the β 2 subunit of GABA A receptors?

NA-glycine is an endogenous lipid molecule with analgesic properties, which is structurally similar to the endocannabinoids 2-AG and anandamide but does not interact with cannabinoid receptors. NA-glycine has been suggested to act at the G-protein coupled receptors GPR18 and GPR92. Recently, we have described that NA-glycine can also modulate recombinant α1β2γ2 GABAA receptors. Here we characterize in more detail this modulation and investigate the relationship of its binding site with that of the endocannabinoid 2-AG.

The Cytotoxic Mode of Action of the Venom of Cupiennius salei (Ctenidae)

The venom of the ctenid spider Cupiennius salei (Fig.16.1) is rich in components which belong to different functional groups. Besides low molecular mass compounds, the venom contains several disulphide-rich peptides, also called mini-proteins, which act as neurotoxins on ion channels or as enhancers of neurotoxins. Likewise, a variety of small cytolytic peptides, which destroy membranes very efficiently, and enzymes are present in the venom. Neurotoxins with cytolytic activity, cytolytic a-helical small cationic peptides and enzymes most probably attacking connective tissue and phospholipid membranes cause the overall cytotoxic effect of this venom. Synergistic and enhancing interactions between components enable the spider to achieve a maximum of toxicity with a minimum of venom quantity.

Characterization and mechanism of action of suppressor factors derived from human T cell hybridomas

This laboratory developed human T-cell hybridomas which constitutively secrete suppressor factors (SF) capable of inhibiting immune responses (Hybridoma 6:589 (1987). The mechanisms by which human T-cell hybridoma-derived SFs (designated 160 and 169) and Jurkat leukemic T-cell line derived SF inhibit the proliferative response to mitogen by human PBMC were investigated. The Jurkat SF had a pI of 5.2 whereas the 160 and 169 SF had pI of 5.7 and 4.7 (two peaks) and 4.7, respectively. The SF was not transforming growth factor-beta based upon neutralization and iummunoprecipitation experiments with anti-TGF-beta polyclonal antibody. Il-2 production by human PBMC cultured with Con A or OKT3 mAb in the presence of SF was found to be inhibited by greater than 80%. The proliferative responses of SF treated PBMC could not be restored by addition of exogeneous human IL-2. Inhibition of the proliferative responses could not be reversed by addition of exogenous rIL-1, rIL-2 or rIL-4 alone or in paired combinations. The expression of IL-2 receptors (TAC Ag) on Con A activated cultures time points was not affected by treatment with any SFs. Both the 160 and 169 hybridoma-derived SFs were found to arrest PHA induced cell cycle progression in G$\sb0$/G$\sb1$ phase, whereas SF from the Jurkat T-cell line arrested progression in the S phase. Pretreatment of PBMC with SF prior to the addition of mitogen, followed by washing, did not alter the proliferative response of these PBMC nor their cell cycle progression suggesting that cell activation is necessary for these SF to inhibit proliferative responses. Northern blot analysis of total mRNA from mitogen stimulated PBMC in the presence of SF, revealed a time dependent accumulation of an IL-2 specific mRNA of increased size (2.8 kB) in addition to the expected 1.0 kB mature IL-2 message. Interferon-gamma mRNA was of the appropriate size but its half-life was prolonged in SF treated cultures. IL-2 receptor and IL-1 beta mRNA expression was not altered in these cells. ^

International standards for programmes of training in intensive care medicine in Europe.

PURPOSE To develop internationally harmonised standards for programmes of training in intensive care medicine (ICM). METHODS Standards were developed by using consensus techniques. A nine-member nominal group of European intensive care experts developed a preliminary set of standards. These were revised and refined through a modified Delphi process involving 28 European national coordinators representing national training organisations using a combination of moderated discussion meetings, email, and a Web-based tool for determining the level of agreement with each proposed standard, and whether the standard could be achieved in the respondent's country. RESULTS The nominal group developed an initial set of 52 possible standards which underwent four iterations to achieve maximal consensus. All national coordinators approved a final set of 29 standards in four domains: training centres, training programmes, selection of trainees, and trainers' profiles. Only three standards were considered immediately achievable by all countries, demonstrating a willingness to aspire to quality rather than merely setting a minimum level. Nine proposed standards which did not achieve full consensus were identified as potential candidates for future review. CONCLUSIONS This preliminary set of clearly defined and agreed standards provides a transparent framework for assuring the quality of training programmes, and a foundation for international harmonisation and quality improvement of training in ICM.

Functionally Optimized Neuritogenic Farinosone C Analogs: SAR-Study and Investigations on Their Mode of Action

Several natural products derived from entomopathogenic fungi have been shown to initiate neuronal differentiation in the rat pheochromocytoma PC12 cell line. After the successful completion of the total synthesis program, the reduction of structural complexity while retaining biological activity was targeted. In this study, farinosone C served as a lead structure and inspired the preparation of small molecules with reduced complexity, of which several were able to induce neurite outgrowth. This allowed for the elaboration of a detailed structure-activity relationship. Investigations on the mode of action utilizing a computational similarity ensemble approach suggested the involvement of the endocannabinoid system as potential target for our analogs and also led to the discovery of four potent new endocannabinoid transport inhibitors.

Best practices and innovative capacity development approaches in ARD programmes of ERA-ARD consortium members: Draft compilation of National Contribution

In the framework of the European Research Area for Agricultural Research for Development (ERA-ARD) project, a survey of innovative approaches in capacity development (CD) was undertaken. All Consortium members were asked to describe innovative approaches and best practices of CD mechanisms within their ARD programmes. A tabular overview of all the programmes or mechanisms can be found on page 4. Abstracts of the programmes or mechanisms are compiled in alphabetic order of the consortium members in this document. The intention of this catalogue of mechanisms is to give an overview of different approaches and practices and not to provide a comprehensive mapping of all the ongoing CD activities of the Consortium members. Thus, the programmes described represent only a fraction of all the ongoing CD programmes on the national level.

Short- and long-term efficacy and mechanism of action of tumescent suction curettage for axillary hyperhidrosis

BACKGROUND Axillary hyperhidrosis is a common and distressing problem interfering with the life of affected individuals. Currently, local surgery is the treatment of choice once conservative treatment has failed. OBJECTIVES To evaluate the clinical efficacy and safety of tumescent suction curettage (TSC) in treating axillary hyperhidrosis and to correlate it with histological markers. METHODS Thirty patients (17 females and 13 males, average age 29.9 years) underwent TSC. After tumescent anaesthesia, a suction cannula was inserted in the axilla on each side through two tiny incisions and subcutaneous tissue was removed by suction. We evaluated the clinical efficacy and complications, and in a subset of patients performed biopsies before surgery, as well as 1 month and 1 year after the operation. RESULTS In comparison with preoperative values, the sweat rate was diminished by 85% after 1 month, 71% after 6 months, 77% after 12 months and 61% after 24 months. The reduced efficacy with time was histologically correlated with an increase in the innervation, whereas the number of sweat glands continued to diminish. The majority of patients were satisfied with the operation but the satisfaction diminished with time. Patients with the highest preoperative sweat rates were the most satisfied after the intervention. CONCLUSION TSC is an effective and safe treatment for axillary hyperhidrosis. The long-term recurrence may be due to reinnervation.