Antibody Concentrations to A Beta 1-42 Monomer and Soluble Oligomers in Untreated and Antibody-Antigen-Dissociated Intravenous Immunoglobulin Preparations

Cognitive improvement in Alzheimer\u27s disease (AD) patients treated with intravenous immunoglobulin (IvIg) has been attributed to its antibodies to amyloid beta (A beta) We compared the concentrations of specific antibodies to soluble A beta 1-42 conformations, namely A beta 1-42 monomer and A beta 1-42 soluble oligomers, between three IvIg preparations. Gamunex, Gammagard. and Flebogamma. To determine specific antibody Concentrations to these A beta 1-42 conformations. nonspecific binding of the IvIg preparations to the An reverse sequence, A beta 42-1. was subtracted These antibodies were measured in untreated IvIg preparations and also after they were treated to dissociate antibody-antigen complexes. because this procedure has been reported to increase the detectable levels of serum anti-A beta antibodies. Antibody levels to A beta 1-42 monomer were significantly higher in untreated Gamunex than in the other two IvIg preparations, and antibody-antigen dissociation increased the measured anti-A beta monomer concentrations in Gamunex and Gammagard Dissociated Gamunex and Gammagard had higher anti-A beta monomer levels than Flebogamma. Generally similar results were found for antibodies to soluble A beta 1-42 oligomers. with the exception that after antibody-antigen dissociation, only Gammagard had significantly higher antibody levels than Flebogamma. These differences in antibody concentrations to A beta 1-42 conformations (particularly to A beta 1-42 soluble oligomers, thought to be the most neurotoxic conformation of soluble A beta) and the increased availability of these antibodies after antibody-antigen complex dissociation have important implications for IvIg treatment of AD patients

ELISA Measurement of Specific Non-antigen-bound Antibodies to Ab1-42 Monomer and Soluble Oligomers in Sera from Alzheimer\u27s Disease, Mild Cognitively Impaired, and Noncognitively Impaired Subjects

The article presents a study for enzyme-linked immunosorbent assay (ELISA) measurement of specific non-antigen-bound antibodies to Aβ1-42 monomer and soluble oligomers in Alzheimer\u27s disease (AD), mild cognitively impaired (MCI), and noncognitively impaired (NCI) sera. In the study, serum samples were obtained from the Rush Alzheimer\u27s Disease Center, Chicago, Illinois

Effects of External Beam Radiation on \u3ci\u3eIn Vitro\u3c/i\u3e Formation of Abeta1-42 Fibrils and Preformed Fibrils

Plaques containing fibrillar amyloid-beta (Abeta) are a characteristic finding in Alzheimer\u27s disease. Although plaque counts correlate poorly with the extent of cognitive deficits in this disorder, fibrillar Abeta can promote neuronal damage through a variety of mechanisms. External beam radiotherapy has been reported to be an effective treatment for tracheobronchial amyloidosis, in which amyloid is deposited as submucosal plaques and tumor-like masses in the trachea and/or bronchi. Radiotherapy\u27s effectiveness in this disorder is thought to be due to its toxicity to plasma cells, but direct effects of radiotherapy on amyloid may also be involved. On this basis, whole-brain radiotherapy has been suggested as a treatment for Alzheimer\u27s disease. The objective of this study was to determine the effects of external beam radiation on preformed Abeta1-42 fibrils and on the formation of these fibrils. Using the Thioflavin-T assay, no effects of radiation were found on either of these parameters. Our results in this in vitro study suggest that whole-brain irradiation is unlikely to directly reduce plaque counts in the Alzheimer\u27s disease brain. This treatment might still lower plaque counts indirectly, but any potential benefits would need to be weighed against its possible neurotoxic effects, which could induce further cognitive deficits

Disease-associated Bias in T Helper Type 1 (Th1)/Th2 CD4+ T Cell Responses Against MAGE-6 in HLA-DRB1*0401+ Patients With Renal Cell Carcinoma or Melanoma

T helper type 1 (Th1)-type CD4+ antitumor T cell help appears critical to the induction and maintenance of antitumor cytotoxic T lymphocyte (CTL) responses in vivo. In contrast, Th2- or Th3/Tr-type CD4+ T cell responses may subvert Th1-type cell-mediated immunity, providing a microenvironment conducive to disease progression. We have recently identified helper T cell epitopes derived from the MAGE-6 gene product; a tumor-associated antigen expressed by most melanomas and renal cell carcinomas. In this study, we have assessed whether peripheral blood CD4+ T cells from human histocompatibility leukocyte antigens (HLA)-DRβ1*0401+ patients are Th1- or Th2-biased to MAGE-6 epitopes using interferon (IFN)-γ and interleukin (IL)-5 enzyme-linked immunospot assays, respectively. Strikingly, the vast majority of patients with active disease were highly-skewed toward Th2-type responses against MAGE-6–derived epitopes, regardless of their stage (stage I versus IV) of disease, but retained Th1-type responses against Epstein-Barr virus– or influenza-derived epitopes. In marked contrast, normal donors and cancer patients with no current evidence of disease tended to exhibit either mixed Th1/Th2 or strongly Th1-polarized responses to MAGE-6 peptides, respectively. CD4+ T cell secretion of IL-10 and transforming growth factor (TGF)-β1 against MAGE-6 peptides was not observed, suggesting that specific Th3/Tr-type CD4+ subsets were not common events in these patients. Our data suggest that immunotherapeutic approaches will likely have to overcome or complement systemic Th2-dominated, tumor-reactive CD4+ T cell responses to provide optimal clinical benefit

Key features of palliative care service delivery to Indigenous peoples in Australia, New Zealand, Canada and the United States: A comprehensive review

Background: Indigenous peoples in developed countries have reduced life expectancies, particularly from chronic diseases. The lack of access to and take up of palliative care services of Indigenous peoples is an ongoing concern. Objectives: To examine and learn from published studies on provision of culturally safe palliative care service delivery to Indigenous people in Australia, New Zealand (NZ), Canada and the United States of America (USA); and to compare Indigenous peoples’ preferences, needs, opportunities and barriers to palliative care. Methods: A comprehensive search of multiple databases was undertaken. Articles were included if they were published in English from 2000 onwards and related to palliative care service delivery for Indigenous populations; papers could use quantitative or qualitative approaches. Common themes were identified using thematic synthesis. Studies were evaluated using Daly’s hierarchy of evidence-for-practice in qualitative research. Results: Of 522 articles screened, 39 were eligible for inclusion. Despite diversity in Indigenous peoples’ experiences across countries, some commonalities were noted in the preferences for palliative care of Indigenous people: to die close to or at home; involvement of family; and the integration of cultural practices. Barriers identified included inaccessibility, affordability, lack of awareness of services, perceptions of palliative care, and inappropriate services. Identified models attempted to address these gaps by adopting the following strategies: community engagement and ownership; flexibility in approach; continuing education and training; a whole-of-service approach; and local partnerships among multiple agencies. Better engagement with Indigenous clients, an increase in number of palliative care patients, improved outcomes, and understanding about palliative care by patients and their families were identified as positive achievements. Conclusions: The results provide a comprehensive overview of identified effective practices with regards to palliative care delivered to Indigenous populations to guide future program developments in this field. Further research is required to explore the palliative care needs and experiences of Indigenous people living in urban areas

Constraining Very Heavy Dark Matter Using Diffuse Backgrounds of Neutrinos and Cascaded Gamma Rays

We consider multi-messenger constraints on very heavy dark matter (VHDM) from recent Fermi gamma-ray and IceCube neutrino observations of isotropic background radiation. Fermi data on the diffuse gamma-ray background (DGB) shows a possible unexplained feature at very high energies (VHE), which we have called the "VHE Excess" relative to expectations for an attenuated power law extrapolated from lower energies. We show that VHDM could explain this excess, and that neutrino observations will be an important tool for testing this scenario. More conservatively, we derive new constraints on the properties of VHDM for masses of 10^3-10^10 GeV. These generic bounds follow from cosmic energy budget constraints for gamma rays and neutrinos that we developed elsewhere, based on detailed calculations of cosmic electromagnetic cascades and also neutrino detection rates. We show that combining both gamma-ray and neutrino data is essential for making the constraints on VHDM properties both strong and robust. In the lower mass range, our constraints on VHDM annihilation and decay are comparable to other results; however, our constraints continue to much higher masses, where they become relatively stronger.Comment: 33 pages, 21 figures, accepted for publication in JCA

Rabies virus matrix protein interplay with eIF3, new insights into rabies virus pathogenesis

Viral proteins are frequently multifunctional to accommodate the high density of information encoded in viral genomes. Matrix (M) protein of negative-stranded RNA viruses such as Rhabdoviridae is one such example. Its primary function is virus assembly/budding but it is also involved in the switch from viral transcription to replication and the concomitant down regulation of host gene expression. In this study we undertook a search for potential rabies virus (RV) M protein's cellular partners. In a yeast two-hybrid screen the eIF3h subunit was identified as an M-interacting cellular factor, and the interaction was validated by co-immunoprecipitation and surface plasmon resonance assays. Upon expression in mammalian cell cultures, RV M protein was localized in early small ribosomal subunit fractions. Further, M protein added in trans inhibited in vitro translation on mRNA encompassing classical (Kozak-like) 5′-UTRs. Interestingly, translation of hepatitis C virus IRES-containing mRNA, which recruits eIF3 via a different noncanonical mechanism, was unaffected. Together, the data suggest that, as a complement to its functions in virus assembly/budding and regulation of viral transcription, RV M protein plays a role in inhibiting translation in virus-infected cells through a protein–protein interaction with the cellular translation machinery

Galaxy Clusters as Reservoirs of Heavy Dark Matter and High-Energy Cosmic Rays: Constraints from Neutrino Observations

Galaxy Clusters (GCs) are the largest reservoirs of both dark matter and cosmic rays (CRs). Dark matter self-annihilation can lead to a high luminosity in gamma rays and neutrinos, enhanced by a strong degree of clustering in dark matter substructures. Hadronic CR interactions can also lead to a high luminosity in gamma rays and neutrinos, enhanced by the confinement of CRs from cluster accretion/merger shocks and active galactic nuclei. We show that IceCube/KM3Net observations of high-energy neutrinos can probe the nature of GCs and the separate dark matter and CR emission processes, taking into account how the results depend on the still-substantial uncertainties. Neutrino observations are relevant at high energies, especially at >10 TeV. Our results should be useful for improving experimental searches for high-energy neutrino emission. Neutrino telescopes are sensitive to extended sources formed by dark matter substructures and CRs distributed over large scales. Recent observations by Fermi and imaging atmospheric Cherenkov telescopes have placed interesting constraints on the gamma-ray emission from GCs. We also provide calculations of the gamma-ray fluxes, taking into account electromagnetic cascades inside GCs, which can be important for injections at sufficiently high energies. This also allows us to extend previous gamma-ray constraints to very high dark matter masses and significant CR injections at very high energies. Using both neutrinos and gamma rays, which can lead to comparable constraints, will allow more complete understandings of GCs. Neutrinos are essential for some dark matter annihilation channels, and for hadronic instead of electronic CRs. Our results suggest that the multi-messenger observations of GCs will be able to give useful constraints on specific models of dark matter and CRs. [Abstract abridged.]Comment: 31 pages, 20 figures, 1 table, accepted for publication in JCAP, references and discussions adde

Energetic Particles of Cosmic Accelerators II: Active Galactic Nuclei and Gamma-ray Bursts

The high-energy universe has revealed that energetic particles are ubiquitous in the cosmos and play a vital role in the cultivation of cosmic environments on all scales. Though they play a key role in cultivating the cosmological environment and/or enabling our studies of it, there is still much we do not know about AGNs and GRBs, particularly the avenue in which and through which they supply radiation and energetic particles, namely their jets. This White Paper is the second of a two-part series highlighting the most well-known high-energy cosmic accelerators and contributions that MeV gamma-ray astronomy will bring to understanding their energetic particle phenomena. The focus of this white paper is active galactic nuclei and gamma-ray bursts.Comment: 11 pages (including references), 2 figures; Submitted to the Astro2020 call for science white paper