Past, Present and Potential Future Prion Disease Treatment Strategies

The prion diseases are rare and invariably fatal neurodegenerative diseases characterized by a unique, protein‐only pathogenesis. Mechanistically, the prion diseases result from the coerced conversion of a protease‐sensitive form of the cellular prion protein (PrPC) into a protease‐resistant infectious form (PrPres). This chapter reviews the past, present, and potentially future prion disease treatment strategies. This chapter begins with an introduction to prion diseases, the misfolding of prion proteins and what is known about this process, and then proceeds to discuss approaches for treatments. Regarding approaches to treat prion diseases, we discuss (1) small molecule inhibitors, (2) antiprion protein antibodies, (3) prion gene disruption, (4) targeting of the unfolded protein response, and (5) heterologous prion proteins. We elaborate on using heterologous prion proteins to treat prion diseases, as this is an area that we are pursuing. The chapter ends with thoughts on the future direction of prion disease treatment strategies and how these strategies might be applicable to other neurodegenerative diseases involving protein misfolding. The increasing awareness of the role of protein misfolding in many neurodegenerative processes makes the development of an effective treatment strategy for prion diseases a high priority

Neurobehavioral Testing in Prion Disease Studies

The prion diseases are neurodegenerative diseases characterized by progressive neurocognitive decline and terminal dementia. In this review, we will discuss the role of neurobehavioral testing in mammalian prion disease model systems, including (1) a review of the clinical phenotype of the major prion diseases in natural disease, (2) an evidence-based summary of the benefits and shortcomings of commonly used behavioral assays, and (3) a review of the neurobehavioral testing in rodent prion models. Based upon this review, and in light of the established importance of model systems in studies of prion pathogenesis and the proven role of behavioral testing in nonprion disease neurodegenerative diseases, it is vital that prion researchers consider the clinical consequences of prion infection so as to maximize the impact of their work

A reassessment of Antarctic plateau reactive nitrogen based on ANTCI 2003 airborne and ground based measurements

The first airborne measurements of nitric oxide (NO) on the Antarctic plateau have demonstrated that the previously reported elevated levels of this species extend well beyond the immediate vicinity of South Pole. Although the current database is still relatively weak and critical laboratory experiments are still needed, the findings here suggest that the chemical uniqueness of the plateau may be substantially greater than first reported. For example, South Pole ground-based findings have provided new evidence showing that the dominant process driving the release of nitrogen from the snowpack during the spring/summer season (post-depositional loss) is photochemical in nature with evaporative processes playing a lesser role. There is also new evidence suggesting that nitrogen, in the form of nitrate, may undergo multiple recycling within a given photochemical season. Speculation here is that this may be a unique property of the plateau and much related to its having persistent cold temperatures even during summer. These conditions promote the efficient adsorption of molecules like HNO3 (and very likely HO2NO2) onto snow-pack surface ice where we have hypothesized enhanced photochemical processing can occur, leading to the efficient release of NOx to the atmosphere. In addition, to these process-oriented tentative conclusions, the findings from the airborne studies, in conjunction with modeling exercises suggest a new paradigm for the plateau atmosphere. The near-surface atmosphere over this massive region can be viewed as serving as much more than a temporary reservoir or holding tank for imported chemical species. It defines an immense atmospheric chemical reactor which is capable of modifying the chemical characteristics of select atmospheric constituents. This reactor has most likely been in place over geological time, and may have led to the chemical modulation of some trace species now found in ice cores. Reactive nitrogen has played a critical role in both establishing and in maintaining this reactor. © 2007 Elsevier Ltd. All rights reserved

Detection of CWD Prions in Urine and Saliva of Deer by Transgenic Mouse Bioassay

Chronic wasting disease (CWD) is a prion disease affecting captive and free-ranging cervids (e.g. deer, elk, and moose). The mechanisms of CWD transmission are poorly understood, though bodily fluids are thought to play an important role. Here we report the presence of infectious prions in the urine and saliva of deer with chronic wasting disease (CWD). Prion infectivity was detected by bioassay of concentrated, dialyzed urine and saliva in transgenic mice expressing the cervid PrP gene (Tg[CerPrP] mice). In addition, PrP(CWD) was detected in pooled and concentrated urine by protein misfolding cyclic amplification (PMCA). The concentration of abnormal prion protein in bodily fluids was very low, as indicated by: undetectable PrP(CWD) levels by traditional assays (western blot, ELISA) and prolonged incubation periods and incomplete TSE attack rates in inoculated Tg(CerPrP) mice (373(+/-)3 days in 2 of 9 urine-inoculated mice and 342(+/-)109 days in 8 of 9 saliva-inoculated mice). These findings help extend our understanding of CWD prion shedding and transmission and portend the detection of infectious prions in body fluids in other prion infections

Effectiveness of an evidence-based chiropractic continuing education workshop on participant knowledge of evidence-based health care

BACKGROUND: Chiropractors must continue to learn, develop themselves professionally throughout their careers, and become self-directed and lifelong learners. Using an evidence-based approach increases the probability of optimal patient outcomes. But most chiropractors lack knowledge and interest in evidence-based approaches. The purpose of this study was to develop and measure the effectiveness of evidence-based training for chiropractic practitioners in a continuing education setting. METHODS: We developed and evaluated a continuing education workshop on evidence-based principles and methods for chiropractic practitioners. Forty-seven chiropractors participated in the training and testing. The course consisted of 12.5 hours of training in which practitioners learned to develop focused questions, search electronic data bases, critically review articles and apply information from the literature to specific clinical questions. Following the workshop, we assessed the program performance through the use of knowledge testing and anonymous presentation quality surveys. RESULTS: Eighty-five percent of the participants completed all of the test, survey and data collection items. Pretest knowledge scores (15-item test) were low (47%). Post intervention scores (15-item test) improved with an effect size of 2.0. A 59-item knowledge posttest yielded very good results (mean score 88%). The quality of presentation was rated very good, and most participants (90%) would "definitely recommend" or "recommend" the workshop to a colleague. CONCLUSION: The results of the study suggest that the continuing education course was effective in enhancing knowledge in the evidence-based approach and that the presentation was well accepted

Key Role of Polyphosphoinositides in Dynamics of Fusogenic Nuclear Membrane Vesicles

The role of phosphoinositides has been thoroughly described in many signalling and membrane trafficking events but their function as modulators of membrane structure and dynamics in membrane fusion has not been investigated. We have reconstructed models that mimic the composition of nuclear envelope precursor membranes with naturally elevated amounts of phosphoinositides. These fusogenic membranes (membrane vesicle 1(MV1) and nuclear envelope remnants (NER) are critical for the assembly of the nuclear envelope. Phospholipids, cholesterol, and polyphosphoinositides, with polyunsaturated fatty acid chains that were identified in the natural nuclear membranes by lipid mass spectrometry, have been used to reconstruct complex model membranes mimicking nuclear envelope precursor membranes. Structural and dynamic events occurring in the membrane core and at the membrane surface were monitored by solid-state deuterium and phosphorus NMR. “MV1-like” (PC∶PI∶PIP∶PIP2, 30∶20∶18∶12, mol%) membranes that exhibited high levels of PtdIns, PtdInsP and PtdInsP2 had an unusually fluid membrane core (up to 20% increase, compared to membranes with low amounts of phosphoinositides to mimic the endoplasmic reticulum). “NER-like” (PC∶CH∶PI∶PIP∶PIP2, 28∶42∶16∶7∶7, mol%) membranes containing high amounts of both cholesterol and phosphoinositides exhibited liquid-ordered phase properties, but with markedly lower rigidity (10–15% decrease). Phosphoinositides are the first lipids reported to counterbalance the ordering effect of cholesterol. At the membrane surface, phosphoinositides control the orientation dynamics of other lipids in the model membranes, while remaining unchanged themselves. This is an important finding as it provides unprecedented mechanistic insight into the role of phosphoinositides in membrane dynamics. Biological implications of our findings and a model describing the roles of fusogenic membrane vesicles are proposed

Effect of intermonolayer coupling on the phase behavior of lipid bilayers

A statistical-mechanical lattice model is proposed to describe the acyl-chain main phase transition in a hydrated lipid bilayer. The model is built on a two-dimensional multistate lattice model to describe the intramonolayer interactions within the two separate lipid monolayers of the bilayer. The coupling between the two monolayers is modeled both indirectly by hydrophobic acyl-chain mismatch interactions that ensure compatibility between the two monolayers, and by a direct intermonolayer attractive dispersion force. The nature of the phase transition is studied by computer-simulation methods involving standard Monte Carlo simulation, as well as the extrapolation method of Ferrenberg and Swendsen [Phys. Rev. Lett. 61, 2635 (1988)] and the Lee-Kosterlitz technique [Phys. Rev. Lett. 65, 137 (1990); Phys. Rev. B 43, 3265 (1991)]. It is found that the absence of a phase transition in a set of uncoupled monolayers is restored by a weak intermonolayer interaction. The bilayer properties in the transition region are described with particular emphasis on the lateral density fluctuations and the resulting dynamic bilayer heterogeneity. The theoretical results are discussed in relation to experimental data