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.

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.

THE SITE AND MECHANISM OF ACTION OF BENZODIAZEPINE IN RABBIT HIPPOCAMPUS

The purpose of this study was to determine the effects of benzodiazepine in area CA1 of the hippocampus, and to explore possible mechanisms of action for these agents in this brain area. Two distinctly different benzodiazepine-induced changes in hippocampal physiology have been identified. First, benzodiazepine depresses the population spike recorded in stratum pyramidale, indicating a decrease in action potential generation. Second, benzodiazepine decreases the magnitude of post-tetanic potentiation of the population EPSP recorded in stratum radiatum, and shortens the duration. The effect of benzodiazepine on pyramidal cell excitation was reversed by the GABA antagonis bicuculline, and mimicked by GABA itself. Thus the available evidence is consistent with the hypothesis that benzodiazepine acts by enhancing the effect of GABA in this area. In stratum radiatum, on the other hand, the effect of benzodiazepine on post tetanic potentiation of the population EPSP was not altered by bicuculline although bicuculline did antagonize GABA in this area. In addition, application of GABA, while it caused profound changes in the population EPSP,p, did not cause the same changes that were induced by benzodiazepine. Thus the evidence does not support the hypothesis that benzodiazepine is acting in stratum radiatum by enhancing the effects of GABA. ^

Implementing the Global Plan of Action on workers' health: Components to protect health care workers

Health care workers are at risk for percutaneous injuries and infection with blood born pathogens due to needle stick injuries with contaminated needles. The most common pathogens transmitted are hepatitis B, and C and HIV/AIDS. According to the WHO Global Plan of Action (GPA) a large gap exist between and within countries with regards to the health status of workers and their exposure to occupational risk. Less than 15% of the world's work forces have access to occupational health services despite the availability of effective interventions that can prevent occupational hazards, or protect and promote health in the workplace. The 2006 World Health Report declared that there is a global crisis in the health care work force. 1 in 400 of the world's health care workers work in Sub-Saharan Africa. 1 in 3 work in the U.S or Canada. The shortage of health care workers is worst in Southeast Asia and Sub-Saharan Africa. These countries have the highest burden of exposure to contaminated sharps. They rarely, if ever monitor the exposure or health impact of occupational ailments and injuries on workers. Many injuries are unreported. Occupational health services in the developing world are virtually non existent. Many health care workers leave their home countries and go to work in other countries where the working conditions, occupational services included, are better. The inability of countries to provide the necessary numbers of health care workers to provide a high level of health coverage is a threat to national and international public health security. Immunizing health care workers against hepatitis B and providing them PEP, PPE, education and safety training is an essential part of increasing and maintaining the numbers of health care workers in the critical shortage areas. ^

Elevation lines of modelled ice sheet extension during last glacial maximum

A numerical ice-sheet model was used to reconstruct the Late Weichselian glaciation of the Eurasian High Arctic, between Franz Josef Land and Severnaya Zemlya. An ice sheet was developed over the entire Eurasian High Arctic so that ice flow from the central Barents and Kara seas toward the northern Russian Arctic could be accounted for. An inverse approach to modeling was utilized, where ice-sheet results were forced to be compatible with geological information indicating ice-free conditions over the Taymyr Peninsula during the Late Weichselian. The model indicates complete glaciation of the Barents and Kara seas and predicts a "maximum-sized" ice sheet for the Late Weichselian Russian High Arctic. In this scenario, full-glacial conditions are characterized by a 1500-m-thick ice mass over the Barents Sea, from which ice flowed to the north and west within several bathymetric troughs as large ice streams. In contrast to this reconstruction, a "minimum" model of glaciation involves restricted glaciation in the Kara Sea, where the ice thickness is only 300 m in the south and which is free of ice in the north across Severnaya Zemlya. Our maximum reconstruction is compatible with geological information that indicates complete glaciation of the Barents Sea. However, geological data from Severnaya Zemlya suggest our minimum model is more relevant further east. This, in turn, implies a strong paleoclimatic gradient to colder and drier conditions eastward across the Eurasian Arctic during the Late Weichselian.

14 ground-penetrating radar lines of Area 5 - Periglacial outwash plain from Potter Cove, King George Island, Antarctic Peninsula

During a field campaign in the Austral spring 2012 the sedimentary architecture of a periglacial flood plain at the northeastern coast of Potter Peninsula (Area 5) was revealed using ground-penetrating radar (GPR, Geophysical Survey Systems, Inc. SIR-3000). 14 profiles were collected using a mono-static 200 MHz antenna operated in common offset mode. Trace increment was set to 0.05 m. A differential global-positioning system (dGPS, Leica GS09) was used to obtain topographical information along the GPR lines. GPR data are provided in RADAN-Format, dGPS coordinates are provided in ascii format; projection is UTM (WGS 84, zone 21S).

31 ground-penetrating radar lines of Area 3 - Beach ridge plain (high wave energy) from Maxwell Bay, King George Island, Antarctic Peninsula

During a field campaign in the Austral spring 2012 the sedimentary architecture of a polar gravel-beach system at the southern coast of Potter Peninsula (Area 3) was revealed using ground-penetrating radar (GPR, Geophysical Survey Systems, Inc. SIR-3000). 31 profiles were collected using a mono-static 200 MHz antenna operated in common offset mode. Trace increment was set to 0.05 m. A differential global-positioning system (dGPS, Leica GS09) was used to obtain topographical information along the GPR lines. GPR data are provided in RADAN-Format, dGPS coordinates are provided in ascii format; projection is UTM (WGS 84, zone 21S).

47 ground-penetrating radar lines of Area 4 - Gravel spit system from Potter Cove, King George Island, Antarctic Peninsula

During two field campaigns (Austral springs 2011 and 2012) the sedimentary architecture of a polar gravel-spit system at the northern coast of Potter Peninsula (Area 4) was revealed using ground-penetrating radar (GPR, Geophysical Survey Systems, Inc. SIR-3000). 47 profiles were collected using a mono-static 200 MHz antenna operated in common offset mode. Trace increment was set to 0.05 m. A differential global-positioning system (dGPS, Leica GS09) was used to obtain topographical information along the GPR lines. GPR data are provided in RADAN-Format, dGPS coordinates are provided in ascii format; projection is UTM (WGS 84, zone 21S).