Iron deficiency in parkinsonism : region-specific iron dysregulation in Parkinson's disease and multiple system atrophy

Alpha synuclein pathology is widespread and found in diverse cell types in multiple system atrophy (MSA) as compared to Parkinson's disease (PD). The reason for this differential distribution is unknown. Regional differences in the distribution of iron are associated with neurodegenerative diseases, and here we characterize the relationship between iron homeostasis proteins and regional concentration, distribution and form of iron in MSA and PD. In PD substantia nigra, tissue iron and expression of the iron export protein ferroportin increased, while the iron storage protein ferritin expression was unchanged. In the basis pontis of MSA cases, increased total iron concentration coupled with a disproportionate increase in ferritin in dysmorphic microglia and a reduction in ferroportin expression. This is supported by isothermal remanent magnetisation evidence consistent with elevated concentrations of ferritin-bound iron in MSA basis pontis. Conventional opinion holds that excess iron is involved in neurodegeneration. Our data support that this may be the case in PD. While region-specific changes in iron are evident in both PD and MSA, the mechanisms of iron dysregulation appear quite distinct, with a failure to export iron from the MSA basis pontis coupling with significant intracellular accumulation of ferritin iron. This pattern also occurs, to a lesser extent, in the MSA putamen. Despite the excess tissue iron, the manner of iron dysregulation in MSA is reminiscent of changes in anemia of chronic disease, and our preliminary data, coupled with the widespread pathology and involvement of multiple cell types, may evidence a deficit in bioavailabile iron

On all possible static spherically symmetric EYM solitons and black holes

We prove local existence and uniqueness of static spherically symmetric solutions of the Einstein-Yang-Mills equations for any action of the rotation group (or SU(2)) by automorphisms of a principal bundle over space-time whose structure group is a compact semisimple Lie group G. These actions are characterized by a vector in the Cartan subalgebra of g and are called regular if the vector lies in the interior of a Weyl chamber. In the irregular cases (the majority for larger gauge groups) the boundary value problem that results for possible asymptotically flat soliton or black hole solutions is more complicated than in the previously discussed regular cases. In particular, there is no longer a gauge choice possible in general so that the Yang-Mills potential can be given by just real-valued functions. We prove the local existence of regular solutions near the singularities of the system at the center, the black hole horizon, and at infinity, establish the parameters that characterize these local solutions, and discuss the set of possible actions and the numerical methods necessary to search for global solutions. That some special global solutions exist is easily derived from the fact that su(2) is a subalgebra of any compact semisimple Lie algebra. But the set of less trivial global solutions remains to be explored.Comment: 26 pages, 2 figures, LaTeX, misprints corrected, 1 reference adde

Multi-black holes from nilpotent Lie algebra orbits

For N \ge 2 supergravities, BPS black hole solutions preserving four supersymmetries can be superposed linearly, leading to well defined solutions containing an arbitrary number of such BPS black holes at arbitrary positions. Being stationary, these solutions can be understood via associated non-linear sigma models over pseudo-Riemaniann spaces coupled to Euclidean gravity in three spatial dimensions. As the main result of this paper, we show that whenever this pseudo-Riemanniann space is an irreducible symmetric space G/H*, the most general solutions of this type can be entirely characterised and derived from the nilpotent orbits of the associated Lie algebra Lie(G). This technique also permits the explicit computation of non-supersymmetric extremal solutions which cannot be obtained by truncation to N=2 supergravity theories. For maximal supergravity, we not only recover the known BPS solutions depending on 32 independent harmonic functions, but in addition find a set of non-BPS solutions depending on 29 harmonic functions. While the BPS solutions can be understood within the appropriate N=2 truncation of N=8 supergravity, the general non-BPS solutions require the whole field content of the theory.Comment: Corrected version for publication, references adde

Multiple Hamiltonian structure of Bogoyavlensky-Toda lattices

This paper is mainly a review of the multi--Hamiltonian nature of Toda and generalized Toda lattices corresponding to the classical simple Lie groups but it includes also some new results. The areas investigated include master symmetries, recursion operators, higher Poisson brackets, invariants and group symmetries for the systems. In addition to the positive hierarchy we also consider the negative hierarchy which is crucial in establishing the bi--Hamiltonian structure for each particular simple Lie group. Finally, we include some results on point and Noether symmetries and an interesting connection with the exponents of simple Lie groups. The case of exceptional simple Lie groups is still an open problem.Comment: 65 pages, 67 reference

There are no magnetically charged particle-like solutions of the Einstein Yang-Mills equations for Abelian models

We prove that there are no magnetically charged particle-like solutions for Abelian models in Einstein Yang-Mills, but for non-Abelian models the possibility remains open. An analysis of the Lie algebraic structure of the Yang-Mills fields is essential to our results. In one key step of our analysis we use invariant polynomials to determine which orbits of the gauge group contain the possible asymptotic Yang-Mills field configurations. Together with a new horizontal/vertical space decomposition of the Yang-Mills fields this enables us to overcome some obstacles and complete a dynamical system existence theorem for asymptotic solutions with nonzero total magnetic charge. We then prove that these solutions cannot be extended globally for Abelian models and begin an investigation of the details for non-Abelian models.Comment: 48 pages, 1 figur

Mapping epilepsy-specific patient-reported outcome measures for children to a proposed core outcome set for childhood epilepsy

This is the final version. Available on open access from Elsevier via the DOI in this recordObjective: The objectives of the study were to (1) map questions in epilepsy-specific patient-reported outcome measures (PROMs) of children's health-related quality of life (HRQoL) to a proposed core outcome set (COS) for childhood epilepsy research and (2) gain insight into the acceptability of two leading candidate PROMs. Method: We identified 11 epilepsy-specific PROMs of children's HRQoL (17 questionnaire versions) in a previous systematic review. Each item from the PROMs was mapped to 38 discrete outcomes across 10 domains of the COS: seizures, sleep, social functioning, mental health, cognition, physical functioning, behavior, adverse events, family life, and global quality of life. We consulted with three children with epilepsy and six parents of children with epilepsy in Patient Public Involvement and Engagement (PPIE) work to gain an understanding of the acceptability of the two leading PROMs from our review of measurement properties: Quality of Life in Childhood Epilepsy (QOLCE-55) and Health-Related Quality of Life Measure for Children with Epilepsy (CHEQOL). Results: Social Functioning is covered by all PROMs except DISABKIDS and G-QOLCE and Mental Health is covered by all PROMs except G-QOLCE and Hague Restrictions in Childhood Epilepsy Scale (HARCES). Only two PROMs (Epilepsy and Learning Disability Quality of Life (ELDQOL) and Glasgow Epilepsy Outcome Scale (GEOS-YP)) have items that cover the Seizure domain. The QOLCE-55 includes items that cover the domains of Physical Functioning, Social Functioning, Behavior, Mental Health, and Cognition. The CHEQOL parent and child versions cover the same domains as QOLCE-55 except for Physical Functioning and Behavior, and the child version has one item that covers the discrete outcome of Overall Quality of Life and one item that covers the discrete outcome of Relationship with parents and siblings. The QOLCE-55 parent version was acceptable to the parents we consulted with, and CHEQOL parent and child versions were described as acceptable to our child and parent advisory panel members. Significance: Mapping items from existing epilepsy-specific PROMs for children is an important step in operationalizing our COS for childhood epilepsy research, alongside evaluation of their measurement properties. Two leading PROMS, QOLCE-55 and CHEQOL, cover a wide range of domains from our COS and would likely be used in conjunction with assessment tools selected for specific study objectives. The PPIE work provided practical insights into the administration and acceptability of candidate PROMs in appropriate context. We promote our COS as a framework for selecting outcomes and PROMs for future childhood epilepsy evaluative research.National Institute for Health Research (NIHR)Canadian Institutes of Health ResearchWaterloo FoundationCharles Sykes Epilepsy Research Trus

Feasibility and Informative Value of Environmental Sample Collection in the National Children\u27s Vanguard Study

Background: Birth cohort studies provide the opportunity to advance understanding of the impact of environmental factors on childhood health and development through prospective collection of environmental samples. Methods: We evaluated the feasibility and informative value of the environmental sample collection methodology in the initial pilot phase of the National Children\u27s Study, a planned U.S. environmental birth cohort study. Environmental samples were collected from January 2009–September 2010 at up to three home visits: pre-pregnancy (n¼306), pregnancy (n¼807), and 6-months postnatal (n¼117). Collections included air for particulate matter r2.5 mm (PM2.5), nitrogen dioxide, ozone, volatile organic compounds (VOCs), and carbonyls; vacuum dust for allergens/endotoxin; water for VOCs, trihalomethanes (THMs), and haloacetic acids (HAAs); and wipe samples for pesticides, semi-volatile organics, and metals. We characterized feasibility using sample collection rates and times and informative value using analyte detection frequencies (DF). Results: Among the 1230 home visits, environmental sample collection rates were high across all sample types (mean¼89%); all samples except the air PM2.5 samples had collection times o30 min. Informative value was low for water VOCs (median DF¼0%) and pesticide floor wipes (median DF¼5%). Informative value was moderate for air samples (median DF¼35%) and high for water THMs and HAAs (median DF¼91% and 75%, respectively). Conclusions: Though collection of environmental samples was feasible, some samples (e.g., wipe pesticides and water VOCs) yielded limited information. These results can be used in conjunction with other study design considerations, such as target population size and hypotheses of interest, to inform the method selection of future environmental health birth cohort studies

Metal ion binding to the amyloid beta monomer studied by native top-down FTICR mass spectrometry

Native top-down mass spectrometry is a fast, robust biophysical technique that can provide molecular-scale information on the interaction between proteins or peptides and ligands, including metal cations. Here we have analyzed complexes of the full-length amyloid β (1-42) monomer with a range of (patho)physiologically relevant metal cations using native Fourier transform ion cyclotron resonance mass spectrometry and three different fragmentation methods—collision-induced dissociation, electron capture dissociation, and infrared multiphoton dissociation—all yielding consistent results. Amyloid β is of particular interest as its oligomerization and aggregation are major events in the etiology of Alzheimer’s disease, and it is known that interactions between the peptide and bioavailable metal cations have the potential to significantly damage neurons. Those metals which exhibited the strongest binding to the peptide (Cu2+, Co2+, Ni2+) all shared a very similar binding region containing two of the histidine residues near the N-terminus (His6, His13). Notably, Fe3+ bound to the peptide only when stabilized toward hydrolysis, aggregation, and precipitation by a chelating ligand, binding in the region between Ser8 and Gly25. We also identified two additional binding regions near the flexible, hydrophobic C-terminus, where other metals (Mg2+, Ca2+, Mn2+, Na+, and K+) bound more weakly—one centered on Leu34, and one on Gly38. Unexpectedly, collisional activation of the complex formed between the peptide and [CoIII(NH3)6]3+ induced gas-phase reduction of the metal to CoII, allowing the peptide to fragment via radical-based dissociation pathways. This work demonstrates how native mass spectrometry can provide new insights into the interactions between amyloid β and metal cations