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.

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.

Reconsidering the logic of World Federation of Neurosurgical Societies grading in patients with severe subarachnoid hemorrhage.

OBJECT Current data show a favorable outcome in up to 50% of patients with World Federation of Neurosurgical Societies (WFNS) Grade V subarachnoid hemorrhage (SAH) and a rather poor prediction of worst cases. Thus, the usefulness of the current WFNS grading system for identifying the worst scenarios for clinical studies and for making treatment decisions is limited. One reason for this lack of differentiation is the use of "negative" or "silent" diagnostic signs as part of the WFNS Grade V definition. The authors therefore reevaluated the WFNS scale by using "positive" clinical signs and the logic of the Glasgow Coma Scale as a progressive herniation score. METHODS The authors performed a retrospective analysis of 182 patients with SAH who had poor grades on the WFNS scale. Patients were graded according to the original WFNS scale and additionally according to a modified classification, the WFNS herniation (hWFNS) scale (Grade IV, no clinical signs of herniation; Grade V, clinical signs of herniation). The prediction of poor outcome was compared between these two grading systems. RESULTS The positive predictive values of Grade V for poor outcome were 74.3% (OR 3.79, 95% CI 1.94-7.54) for WFNS Grade V and 85.7% (OR 8.27, 95% CI 3.78-19.47) for hWFNS Grade V. With respect to mortality, the positive predictive values were 68.3% (OR 3.9, 95% CI 2.01-7.69) for WFNS Grade V and 77.9% (OR 6.22, 95% CI 3.07-13.14) for hWFNS Grade V. CONCLUSIONS Limiting WFNS Grade V to the positive clinical signs of the Glasgow Coma Scale such as flexion, extension, and pupillary abnormalities instead of including "no motor response" increases the prediction of mortality and poor outcome in patients with severe SAH.

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.

Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers

In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 μM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze-fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association - drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin-5, which can be targeted to improve drug delivery.

Beyond a logic of effectiveness: Horizontal coordination, democratic legitimacy and accountability

Horizontal coordination, where actors join together to accomplish a common task, has been applauded for its output legitimacy. However, such processes often face challenges due to opposition from local actors who raise concerns about democratic legitimacy and accountability. Moving beyond a logic of effectiveness, we aim to show how and why other forms of legitimacy such as input and throughput dimensions also affect horizontal coordination, in addition to output criteria. Beyond the assumed positive relationship between coordination and effectiveness, we additionally expect horizontal coordination to be (a) impeded by local actors' fear of losing democratic legitimacy; and (b) fostered by accountability in terms of the steering capacity of the state. A comparative case study analysis of water supply structures at the regional level in Switzerland shows, in contrast to our expectation, that effectiveness has mixed impacts on horizontal coordination. Rather than being solely a positive factor for horizontal coordination, certain output criteria such as financial redistribution are found to be a key hindrance. We also find that democratic legitimacy may, indeed, impede horizontal coordination whereas increased accountability positively affects such coordination.

The use of mechanisms and modes of toxic action in integrated testing strategies: the report and recommendations of a workshop held as part of the European Union OSIRIS Integrated Project

This report on The Potential of Mode of Action (MoA) Information Derived from Non-testing and Screening Methodologies to Support Informed Hazard Assessment, resulted from a workshop organised within OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-test and Test Information), a project partly funded by the EU Commission within the Sixth Framework Programme. The workshop was held in Liverpool, UK, on 30 October 2008, with 35 attendees. The goal of the OSIRIS project is to develop integrated testing strategies (ITS) fit for use in the REACH system, that would enable a significant increase in the use of non-testing information for regulatory decision making, and thus minimise the need for animal testing. One way to improve the evaluation of chemicals may be through categorisation by way of mechanisms or modes of toxic action. Defining such groups can enhance read-across possibilities and priority settings for certain toxic modes or chemical structures responsible for these toxic modes. Overall, this may result in a reduction of in vivo testing on organisms, through combining available data on mode of action and a focus on the potentially most-toxic groups. In this report, the possibilities of a mechanistic approach to assist in and guide ITS are explored, and the differences between human health and environmental areas are summarised.

Action crisis and cost–benefit thinking: A cognitive analysis of a goal-disengagement phase

The present research is based on the notion that disengagement from goals is not a discrete event but a process (Klinger, 1975). A critical phase in this process is when difficulties and setbacks in striving for a goal accumulate. This critical phase is termed here as an action crisis. Given the profound effects that people's thoughts have on their self-regulatory efficiency, it is essential to understand the cognitive correlates of an action crisis. In two experimental lab and two correlational field studies, the hypothesis that goal-related costs and benefits become cognitively highly accessible during an action crisis was tested and supported. Participants who were experiencing an action crisis in such diverse goal areas as intimate relationships, sports, and university studies, thought about goal-related costs and benefits more intensively and frequently in comparison to participants who were not in an action crisis. In an incidental learning task they recognized more of cost–benefit-items and less of implementation-items than the control group. Results are interpreted in terms of action phase specific mindsets (Gollwitzer, 1990, 2012).