Neuroinvasion in Prion Diseases: The Roles of Ascending Neural Infection and Blood Dissemination

Prion disorders are infectious, neurodegenerative diseases that affect humans and animals. Susceptibility to some prion diseases such as kuru or the new variant of Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial Creutzfeldt-Jakob disease, or Gerstmann-Straussler-Scheinker disease in humans have an underlying inherited genetic basis. Several prion strains have been demonstrated experimentally in rodents and sheep. The progression and pathogenesis of disease is influenced by both genetic differences in the prion protein and prion strain. Some prion diseases only affect the central nervous system whereas others involve the peripheral organs prior to neuroinvasion. Many experiments undertaken in different species and using different prion strains have postulated common pathways of neuroinvasion. It is suggested that prions access the autonomic nerves innervating peripheral organs and tissues to finally reach the central nervous system. We review here published data supporting this view and additional data suggesting that neuroinvasion may concurrently or independently involve the blood vascular system

Pathogenesis of natural goat scrapie: modulation by host PRNP genotype and effect of co-existent conditions

After detection of a high prevalence of scrapie in a large dairy goat herd, 72 infected animals were examined by immunohistochemistry with prion protein (PrP) antibody Bar224 to study the pathogenesis of the infection. Tissues examined included the brain and thoracic spinal cord (TSC), a wide selection of lymphoreticular system (LRS) tissues, the distal ileum and its enteric nervous system (ENS), and other organs, including the mammary gland. The whole open reading frame of the PRNP gene was sequenced and antibodies to caprine arthritis-encephalitis virus (CAEV) infection were determined. Unexpectedly, accumulation of disease-associated PrP (PrPd) in the brain was more frequent in methionine carriers at codon 142 (24/32, 75.0%) than amongst isoleucine homozygotes (14/40, 35.0%). The latter, however, showed significantly greater amounts of brain PrPd than the former (average scores of 9.3 and 3.0, respectively). A significant proportion of the 38 goats that were positive in brain were negative in the ENS (44.7%) or in the TSC (39.5%). These results, together with the early and consistent involvement of the circumventricular organs and the hypothalamus, point towards a significant contribution of the haematogenous route in the process of neuroinvasion. Chronic enteritis was observed in 98 of the 200 goats examined, with no association with either scrapie infection or presence of PrPd in the gut. Lymphoproliferative interstitial mastitis was observed in 13/31 CAEV-positive and scrapie-infected goats; PrPd in the mammary gland was detected in five of those 13 goats, suggesting a possible contribution of CAEV infection in scrapie transmission via milk

Case Report : Neuroblastoma-Like Schwannoma in a Domestic Short-Haired Cat

An axillary mass was detected in a 6-year-old, neutered, male, domestic short-haired cat during a wellness exam. Gross examination following surgical removal revealed a discrete, deep subcutaneous, discoid mass that was between 0.5- and 0.7-cm-in-diameter and diffusely firm and white. Histologically, the mass was well-demarcated, partially encapsulated, and expanded the panniculus carnosus. It was composed of tightly packed, giant rosettes of radially arranged fusiform cells stacked in one to 10 layers with peripherally palisading nuclei and with centrally oriented, fibrillary, cytoplasmic processes, and collagenous fibers. Laminin immunoreactivity and ultrastructural examination highlighted a continuous basal lamina outside the plasma membrane of each neoplastic cell. Neoplastic cells were immunoreactive for GFAP, S100, periaxin, and Sox-10 and were immunonegative for synaptophysin, smooth muscle actin, and pancytokeratin. Collective findings were consistent with a diagnosis of neuroblastoma-like schwannoma. This is the first veterinary report of this rare variant of benign schwannoma

Experimental transmission of bovine spongiform encephalopathy to European red deer (Cervus elaphus elaphus)

<p>Abstract</p> <p>Background</p> <p>Bovine spongiform encephalopathy (BSE), a member of the transmissible spongiform encephalopathies (TSE), primarily affects cattle. Transmission is via concentrate feed rations contaminated with infected meat and bone meal (MBM). In addition to cattle, other food animal species are susceptible to BSE and also pose a potential threat to human health as consumption of infected meat products is the cause of variant Creutzfeldt-Jakob disease in humans, which is invariably fatal. In the UK, farmed and free ranging deer were almost certainly exposed to BSE infected MBM in proprietary feeds prior to legislation banning its inclusion. Therefore, although BSE has never been diagnosed in any deer species, a possible risk to human health remains via ingestion of cervine products. Chronic wasting disease (CWD), also a TSE, naturally infects several cervid species in North America and is spreading rapidly in both captive and free-ranging populations.</p> <p>Results</p> <p>Here we show that European red deer (<it>Cervus elaphus elaphus</it>) are susceptible to intra-cerebral (i/c) challenge with BSE positive cattle brain pool material resulting in clinical neurological disease and weight loss by 794–1290 days and the clinical signs are indistinguishable to those reported in deer with CWD. Spongiform changes typical of TSE infections were present in brain and accumulation of the disease-associated abnormal prion protein (PrP^d) was present in the central and peripheral nervous systems, but not in lymphoid or other tissues. Western immunoblot analysis of brain material showed a similar glycosylation pattern to that of BSE derived from infected cattle and experimentally infected sheep with respect to protease-resistant PrP isoforms. However, the di-, mono- and unglycosylated bands migrated significantly (p < 0.001) further in the samples from the clinically affected deer when compared to BSE infected brains of cattle and sheep.</p> <p>Conclusion</p> <p>This study shows that deer are susceptible to BSE by intra-cerebral inoculation and display clinical signs and vacuolar pathology that are similar to those of CWD. These findings highlight the importance of preventing the spread to Europe of CWD from North America as this may necessitate even more extensive testing of animal tissues destined for human consumption within the EU. Although the absence of PrP^din lymphoid and other non-neurological tissues potentially limits the risk of transmission to humans, the replication of TSE agents in peripheral tissues following intra-cerebral challenge is often limited. Thus the assessment of risk posed by cervine BSE as a human pathogen or for environmental contamination should await the outcome of ongoing oral challenge experiments.</p

Immunohistochemical and biochemical characteristics of BSE and CWD in experimentally infected European red deer (Cervus elaphus elaphus)

<p>Abstract</p> <p>Background</p> <p>The cause of the bovine spongiform encephalopathy (BSE) epidemic in the United Kingdom (UK) was the inclusion of contaminated meat and bone meal in the protein rations fed to cattle. Those rations were not restricted to cattle but were also fed to other livestock including farmed and free living deer. Although there are no reported cases to date of natural BSE in European deer, BSE has been shown to be naturally or experimentally transmissible to a wide range of different ungulate species. Moreover, several species of North America's cervids are highly susceptible to chronic wasting disease (CWD), a transmissible spongiform encephalopathy (TSE) that has become endemic. Should BSE infection have been introduced into the UK deer population, the CWD precedent could suggest that there is a danger for spread and maintenance of the disease in both free living and captive UK deer populations. This study compares the immunohistochemical and biochemical characteristics of BSE and CWD in experimentally-infected European red deer (<it>Cervus elpahus elaphus</it>).</p> <p>Results</p> <p>After intracerebral or alimentary challenge, BSE in red deer more closely resembled natural infection in cattle rather than experimental BSE in small ruminants, due to the lack of accumulation of abnormal PrP in lymphoid tissues. In this respect it was different from CWD, and although the neuropathological features of both diseases were similar, BSE could be clearly differentiated from CWD by immunohistochemical and Western blotting methods currently in routine use.</p> <p>Conclusion</p> <p>Red deer are susceptible to both BSE and CWD infection, but the resulting disease phenotypes are distinct and clearly distinguishable.</p

Cost-accuracy and patient experience assessment of blood pressure monitoring methods to diagnose hypertension: A comparative effectiveness study

Studies of the diagnosis of hypertension have emphasized long-term cost-effectiveness analysis, but the patient experience and costs of blood pressure monitoring methods at the diagnosis stage remain unclear. We studied four diagnostic methods: a new 1 h-automated office blood pressure (BP) monitoring, office BP measurement, home BP monitoring, and awake-ambulatory BP monitoring.We carried out a comparative effectiveness study of four methods of diagnosing hypertension in 500 participants with a clinical suspicion of hypertension from three primary healthcare (PHC) centers in Barcelona city (Spain). We evaluated the time required and the intrinsic and extrinsic costs of the four methods. The cost-accuracy ratio was calculated and differences between methods were assessed using ANOVA and Tukey's honestly significant difference (HSD) post-hoc test. Patient experience data were transformed using Rasch analysis and re-scaled from 0 to 10.Office BP measurement was the most expensive method (€156.82, 95% CI: 156.18-157.46) and 1 h-automated BP measurement the cheapest (€85.91, 95% CI: 85.59-86.23). 1 h-automated BP measurement had the best cost-accuracy ratio (€ 1.19) and office BP measurement the worst (€ 2.34). Home BP monitoring (8.01, 95% CI: 7.70-8.22), and 1 h-automated BP measurement (7.99, 95% CI: 7.80-8.18) had the greatest patient approval: 66.94% of participants would recommend 1 h-automated BP measurement as the first or second option.The relationship between the cost-accuracy ratio and the patient experience suggests physicians could use the new 1 h-automated BP measurement as the first option and awake-ambulatory BP monitoring in complicated cases and cease diagnosing hypertension using office BP measurement.Copyright © 2022 González-de Paz, Kostov, Freixa, Herranz, Lagarda, Ortega, Pérez, Porcar, Sánchez, Serrato, Vidiella and Sisó-Almirall

Cost-accuracy and patient experience assessment of blood pressure monitoring methods to diagnose hypertension: a comparative effectiveness study

Objectives: Studies of the diagnosis of hypertension have emphasized longterm cost-effectiveness analysis, but the patient experience and costs of blood pressure monitoring methods at the diagnosis stage remain unclear. We studied four diagnostic methods: a new 1 h-automated office blood pressure (BP) monitoring, office BP measurement, home BP monitoring, and awake-ambulatory BP monitoring. Methods: We carried out a comparative effectiveness study of four methods of diagnosing hypertension in 500 participants with a clinical suspicion of hypertension from three primary healthcare (PHC) centers in Barcelona city (Spain). We evaluated the time required and the intrinsic and extrinsic costs of the four methods. The cost-accuracy ratio was calculated and differences between methods were assessed using ANOVA and Tukey’s honestly significant difference (HSD) post-hoc test. Patient experience data were transformed using Rasch analysis and re-scaled from 0 to 10. Results: Office BP measurement was the most expensive method (€156.82, 95% CI: 156.18–157.46) and 1 h-automated BP measurement the cheapest (€85.91, 95% CI: 85.59–86.23). 1 h-automated BP measurement had the best cost-accuracy ratio (€ 1.19) and office BP measurement the worst (€ 2.34). Home BP monitoring (8.01, 95% CI: 7.70–8.22), and 1 h-automated BP measurement (7.99, 95% CI: 7.80–8.18) had the greatest patient approval: 66.94% of participants would recommend 1 h-automated BP measurement as the first or second option. Frontiers in Medicine 01 frontiersin.org González-de Paz et al. 10.3389/fmed.2022.827821 Conclusion: The relationship between the cost-accuracy ratio and the patient experience suggests physicians could use the new 1 h-automated BP measurement as the first option and awake-ambulatory BP monitoring in complicated cases and cease diagnosing hypertension using office BP measurement.This project received research grants from: The Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded on the 2016 call under the Health Strategy Action 2013–2016, within the National Research Program oriented to Societal Challenges, within the Technical, the Scientific and Innovation Research National Plan 2013–2016, with reference PI16/00660, co-funded with European Union ERDF funds (European Regional Development Fund). The Department of Health of the Generalitat de Catalunya, in the call corresponding to the year 2019 of the Strategic Plan of Research and Innovation in Health (PERIS) 2016–2020, with file code SLT008/18/00013.Peer ReviewedPostprint (published version

Susceptibility of European Red Deer (Cervus elaphus elaphus) to Alimentary Challenge with Bovine Spongiform Encephalopathy

European red deer (Cervus elaphus elaphus) are susceptible to the agent of bovine spongiform encephalopathy, one of the transmissible spongiform encephalopathies, when challenged intracerebrally but their susceptibility to alimentary challenge, the presumed natural route of transmission, is unknown. To determine this, eighteen deer were challenged via stomach tube with a large dose of the bovine spongiform encephalopathy agent and clinical signs, gross and histological lesions, presence and distribution of abnormal prion protein and the attack rate recorded. Only a single animal developed clinical disease, and this was acute with both neurological and respiratory signs, at 1726 days post challenge although there was significant (27.6%) weight loss in the preceding 141 days. The clinically affected animal had histological lesions of vacuolation in the neuronal perikaryon and neuropil, typical of transmissible spongiform encephalopathies. Abnormal prion protein, the diagnostic marker of transmissible encephalopathies, was primarily restricted to the central and peripheral nervous systems although a very small amount was present in tingible body macrophages in the lymphoid patches of the caecum and colon. Serial protein misfolding cyclical amplification, an in vitro ultra-sensitive diagnostic technique, was positive for neurological tissue from the single clinically diseased deer. All other alimentary challenged deer failed to develop clinical disease and were negative for all other investigations. These findings show that transmission of bovine spongiform encephalopathy to European red deer via the alimentary route is possible but the transmission rate is low. Additionally, when deer carcases are subjected to the same regulations that ruminants in Europe with respect to the removal of specified offal from the human food chain, the zoonotic risk of bovine spongiform encephalopathy, the cause of variant Creutzfeldt-Jakob disease, from consumption of venison is probably very low