Bioactive mimetics of conotoxins and other venom peptides

© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/).Ziconotide (Prialt®), a synthetic version of the peptide ω-conotoxin MVIIA found in the venom of a fish-hunting marine cone snail Conus magnus, is one of very few drugs effective in the treatment of intractable chronic pain. However, its intrathecal mode of delivery and narrow therapeutic window cause complications for patients. This review will summarize progress in the development of small molecule, non-peptidic mimics of Conotoxins and a small number of other venom peptides. This will include a description of how some of the initially designed mimics have been modified to improve their drug-like properties

U.S. Navy Capstone Strategies and Concepts (2001-2010): Strategy, Policy, Concept, and Vision Documents

A report, in presentation form, of key Navy documents on topics of strategy, policy, concept and vision. The list includes references to several NPS-authored works such as the dissertation of Peter Haynes, “American Naval Thinking in the Post-Cold War Era: The U.S. Navy and the Emergence of Maritime Strategy, 1989- 2007” (2011). A full listing of substantive contributors can be found in Peter M. Swartz and Karin Duggan, U.S. Navy Capstone Strategies and Concepts: Introduction and Background: Volume I, (D0026421.A1, December 2011).This work was created in the performance of Federal Government Contract Number N00014-11-D-0323. Any copyright in this work is subject to the Government's Unlimited Rights license as defined in DFARS 252.227-7013 and/or DFARS 252.227-7014. TThis work was created in the performance of Federal Government Contract Number N00014-11-D-0323. Any copyright in this work is subject to the Government's Unlimited Rights license as defined in DFARS 252.227-7013 and/or DFARS 252.227-7014.

Low-dose stereotactic radiosurgery is inadequate for medically intractable mesial temporal lobe epilepsy: a case report

AbstractThe successful surgical treatment of medically refractory epilepsy is based on one of three different principles: (1) elimination of the epileptic focus, (2) interruption of the pathways of neural propagation, and (3) increasing the seizure threshold through cerebral lesions or electrical stimulation. Temporal lobe epilepsy, being the most common focal epilepsy, may ultimately require temporal lobectomy. This is a case report of a 36-year-old male with drug-resistant right mesial temporal lobe epilepsy who failed to obtain seizure control after stereotactic radiosurgery to the seizure focus. Complex-partial seizures occurred 6–7 times monthly, and consisted of a loss of awareness followed by involuntary movements of the right arm. EEG/CC TV monitoring indicated a right mesial temporal lobe focus, which was corroborated by decreased uptake in the right temporal lobe by FDG-PET and by MRI findings of right hippocampal sclerosis. Stereotactic radiosurgery was performed with a 4MV linac, utilizing three isocenters with collimator sizes of 10, 10, and 7 mm respectively. A dose of 1500 cGy (max dose 2535 cGy) was delivered in a single fraction to the patient’s right amygdala and hippocampus. There were no acute complications. Following radiosurgery the patient’s seizures were improved in both frequency and intensity for approximately 3 months. Antiepileptic medications were continued. Thereafter, seizures increased in both frequency and intensity, occurring 10–20 times monthly. At 1 year post radiosurgery, standard right temporal lobectomy including amygdalohippocampectomy was performed with subsequent resolution of complex-partial seizures. Histopathology of the resected temporal lobe revealed hippocampal cell loss and fibrillary astrocytosis, consistent with hippocampal sclerosis. No radiation-induced histopathologic changes were seen. We conclude that low-dose radiosurgery doses temporarily changed the intensity and character of seizure activity, but actually increased seizure activity long-term. If radiosurgery is to be an effective alternative to temporal lobectomy for medically intractable temporal lobe epilepsy, higher radiosurgery doses will be required. The toxicity and efficacy of higher-dose radiosurgery is currently under investigation

The geomorphic evolution of the Warrumbungle Volcanic Complex, New South Wales, Australia

Geomorphic analysis of the mid-Miocene Warrumbungle volcanic complex in north-central New South Wales revealed a highly dissected multi-vent ovoid shield, 55 km long and averaging 32 km wide. The volcanics rest unconformably on a pre-volcanic medium-relief sandstone landscape of broad valleys and flat interfluves. The degree of dissection, a function of the exceptionally large proportion of easily erodible pyroclastic material erupted during the volcano's 3.7 million year active life, varies considerably between the distal and proximal zones of extrusion. The proximal zone is preserved only in a skeletal state and is dominated by less erodible domes, plugs, and dykes. By contrast, the distal zone presents a characteristically gently sloping shield landscape with terraces where flow units are exposed. Remarkably, and probably as a result of the large number of explosive eruptions that were a dominant feature of Warrumbungle activity, four previously unrecorded crater remnants were recognised, as well as other previously unrecognised features. The preferential preservation of their lithology is perhaps a result of the partial/complete burial of these features by coeval activity and the development of dual scale radial drainage networks, with exhumation only occurring when local sub-drainage had been captured

ω-Conotoxin GVIA mimetics that bind and inhibit neuronal Cav2.2 ion channels

The neuronal voltage-gated N-type calcium channel (Cav2.2) is a validated target for the treatment of neuropathic pain. A small library of anthranilamide-derived ω-Conotoxin GVIA mimetics bearing the diphenylmethylpiperazine moiety were prepared and tested using three experimental measures of calcium channel blockade. These consisted of a 125I-ω-conotoxin GVIA displacement assay, a fluorescence-based calcium response assay with SH-SY5Y neuroblastoma cells, and a whole-cell patch clamp electrophysiology assay with HEK293 cells stably expressing human Cav2.2 channels. A subset of compounds were active in all three assays. This is the first time that compounds designed to be mimics of ω-conotoxin GVIA and found to be active in the 125I-ω-conotoxin GVIA displacement assay have also been shown to block functional ion channels in a dose-dependent manner

The face validity of an initial sub-typology of people with autism spectrum disorders detained in psychiatric hospitals

Autistic adults who have a history of committing crimes present a major problem for providers of services in terms of legal disposal options and possible interventions, and greater understanding of this group and their associated needs is required. For this reason, we aimed to investigate the face validity of a proposed sub-typology of autistic adults detained in secure psychiatric hospitals in the United Kingdom. Initially, a focus group was completed with psychiatrists, clinical psychologists, healthcare workers, family members, and autistic adults who had been detained in hospital, leading to revisions of the sub-typology. Following this, a consensus rating exercise of ten clinical vignettes based upon this subtypology with three rounds was completed with fifteen psychiatrists and clinical psychologists; revisions to the vignettes to improve clarity were made following each round. The findings indicated these subtypes possess face validity and raters were able to classify all ten clinical case vignettes into the sub-typology and percentage of agreement ranged from 96% to 100% for overall subtype classification. This study suggests that the further validity of the sub-typology should be investigated within a larger study, as these sub-types have the potential to directly inform the hospital care-pathway such that length of stay can be minimised

Results of search for magnetized quark-nugget dark matter from radial impacts on Earth

Magnetized Quark Nuggets (MQNs) are a recently proposed dark-matter candidate consistent with the Standard Model and with Tatsumi's theory of quark-nugget cores in magnetars. Previous publications have covered their formation in the early universe, aggregation into a broad mass distribution before they can decay by the weak force, interaction with normal matter through their magnetopause, and first observation consistent MQNs, i.e. a nearly tangential impact limiting their surface-magnetic-field parameter B_o from Tatsumi's values of 0.1 to 10.0 TT to new value of 1.65 TT +/- 21%. The MQN mass distribution and interaction cross section depend strongly on B_o. Their magnetopause is much larger than their geometric dimensions and can cause sufficient energy deposition to form non-meteorite craters, which are reported approximately annually. We report computer simulations of the MQN energy deposition in water-saturated peat, soft sediments, and granite and report results from excavating such a crater. Five points of agreement between observations and hydrodynamic simulations of an MQN impact support this second observation consistent with MQN dark matter and suggest a method for qualifying additional MQN events. The results also redundantly constrain B_o to greater than 0.4 TT.Comment: 30 pages, 13 figures, submitted to Univers