Brain Gene Expression Signatures From Cerebrospinal Fluid Exosome RNA Profiling

While the Visual Impairment and Intracranial Pressure (VIIP) syndrome observations have focused on ocular symptoms, spaceflight has been also associated with a number of other performance and neurologic signs, such as headaches, cognitive changes, vertigo, nausea, sleep/circadian disruption and mood alterations, which, albeit likely multifactorial, can also result from elevation of intracranial pressure (ICP). We therefore hypothesize that these various symptoms are caused by disturbances in the neurophysiology of the brain structures and are correlated with molecular markers in the cerebrospinal fluid (CSF) as indicators of neurophysiological changes. Exosomes are 30-200 nm microvesicles shed into all biofluids, including blood, urine, and CSF, carrying a highly rich source of intact protein and RNA cargo. Exosomes have been identified in human CSF, and their proteome and RNA pool is a potential new reservoir for biomarker discovery in neurological disorders. The purpose of this study is to investigate changes in brain gene expression via exosome analysis in patients suffering from ICP elevation of varied severity (idiopathic intracranial hypertension -IIH), a condition which shares some of the neuroophthalmological features of VIIP, as a first step toward obtaining evidence suggesting that cognitive function and ICP levels can be correlated with biomarkers in the CSF. Our preliminary work, reported last year, validated the exosomal technology applicable to CSF analysis and demonstrated that it was possible to obtain gene expression evidence of inflammation processes in traumatic brain injury patients. We are now recruiting patients with suspected IIH requiring lumbar puncture at Baylor College of Medicine. Both CSF (5 ml) and human plasma (10 ml) are being collected in order to compare the pattern of differentially expressed genes observed in CSF and in blood. Since blood is much more accessible than CSF, we would like to determine whether plasma biomarkers for elevated ICP can be identified. This may eventually lead to a blood test to diagnose intracranial hypertension

Intracranial Pressure Modulates Distortion Product Otoacoustic Emissions: A Proof-of-Principle Study

BACKGROUND: There is an important need to develop a noninvasive method for assessing intracranial pressure (ICP). We report a novel approach for monitoring ICP using cochlear-derived distortion product otoacoustic emissions (DPOAEs), which are affected by ICP. OBJECTIVE: We hypothesized that changes in ICP may be reflected by altered DPOAE responses via an associated change in perilymphatic pressure. METHODS: We measured the ICP and DPOAEs (magnitude and phase angle) during opening and closing in 20 patients undergoing lumbar puncture. RESULTS: We collected data on 18 patients and grouped them based on small (Hg), medium (5-11 mm Hg), or large (≥15 mm Hg) ICP changes. A permutation test was applied in each group to determine whether changes in DPOAEs differed from zero when ICP changed. We report significant changes in the DPOAE magnitudes and angles, respectively, for the group with the largest ICP changes and no changes for the group with the smallest changes; the group with medium changes had variable DPOAE changes. CONCLUSION: We report, for the first time, systematic changes in DPOAE magnitudes and phase in response to acute ICP changes. Future studies are warranted to further develop this new approach

Secure synthesis and activation of protocol translation agents

Protocol heterogeneity is pervasive and is a major obstacle to effective integration of services in large systems. However, standardization is not a complete answer. Standardized protocols must be general to prevent a proliferation of standards, and can therefore become complex and inefficient. Specialized protocols can be simple and efficient, since they can ignore situations that are precluded by application characteristics. One solution is to maintain agents for translating between protocols. However, n protocol types would require agents, since an agent must exist for a source - destination pair. A better solution is to create agents as needed. This paper examines the issues in the creation and management of protocol translation agents. We focus on the design of Nestor, an environment for synthesizing and managing RPC protocol translation agents. We provide rationale for the translation mechanism and the synthesis environment, with specific emphasis on the security issues arising in Nestor. Nestor has been implemented and manages heterogeneous RPC agents generated using the Cicero protocol construction language and the URPC toolkit.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/49229/2/ds7402.pd

Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances

New psychoactive substances (NPS) with amphetamine-, aminoindan-, and benzofuran basic chemical structures have recently emerged for recreational drug use. Detailed information about their psychotropic effects and health risks is often limited. At the same time, it emerged that the pharmacological profiles of these NPS resemble those of amphetamine or 3,4-methylenedioxymethamphetamine (MDMA). Amphetamine-like NPS induce psychostimulation and euphoria mediated predominantly by norepinephrine (NE) and dopamine (DA) transporter (NET and DAT) inhibition and transporter-mediated release of NE and DA, thus showing a more catecholamine-selective profile. MDMA-like NPS frequently induce well-being, empathy, and prosocial effects and have only moderate psychostimulant properties. These MDMA-like substances primarily act by inhibiting the serotonin (5-HT) transporter (SERT) and NET, also inducing 5-HT and NE release. Monoamine receptor interactions vary considerably among amphetamine- and MDMA-like NPS. Clinically, amphetamine- and MDMA-like NPS can induce sympathomimetic toxicity. The aim of this chapter is to review the state of knowledge regarding these substances with a focus on the description of the in vitro pharmacology of selected amphetamine- and MDMA-like NPS. In addition, it is aimed to provide links between pharmacological profiles and in vivo effects and toxicity, which leads to the conclusion that abuse liability for amphetamine-like NPS may be higher than for MDMA-like NPS, but that the risk for developing the life-threatening serotonin syndrome may be increased for MDMA-like NPS