Bovine spongiform encephalopathy (BSE) is caused by a novel contagion, known to as a prion. Prions are proteins capable of converting a normal cellular protein into a prion, thereby propagating an infection. BSE is the first known prion zoonotic. As such it has attracted broad scientific and, to a r...
Schreuder, B.E.C.; Somerville, R.A.
Bovine spongiform encephalopathy (BSE) in sheep has not been identified under natural conditions at the time of writing and remains a hypothetical issue. However, rumours about the possible finding of a BSE-like isolate in sheep have led to great unrest within the sheep industry, among the general p
... RIN 0579-AC68 Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products AGENCY... live bovines and products derived from bovines with regard to bovine spongiform encephalopathy. This... with regard to bovine spongiform encephalopathy. Comments on the proposed rule were required to......
Keulen, van L.J.M.; Vromans, M.E.W.; Dolstra, C.H.; Bossers, A.; Zijderveld, van F.G.
The pathogenesis of bovine spongiform encephalopathy (BSE) in sheep was studied by immunohistochemical detection of scrapie-associated prion protein (PrPSc) in the gastrointestinal, lymphoid and neural tissues following oral inoculation with BSE brain homogenate. First accumulation of PrPSc was dete
Jacobs, J.G.; Sauer, M.; Keulen, van L.J.M.; Tang, Y.; Bossers, A.; Langeveld, J.P.M.
With increased awareness of the diversity of transmissible spongiform encephalopathy (TSE) strains in the ruminant population, comes an appreciation of the need for improved methods of differential diagnosis. Exposure to bovine spongiform encephalopathy (BSE) has been associated with the human TSE,
G. K. Bruckner
Full Text Available Mad Cow Disease or BSE (Bovine Spongiform Encephalopathy became a household name internationally and also in South Africa. International hysteria resulted following reports of a possible link between a disease diagnosed in cattle in Britain and a variant of the disease diagnosed in humans after the presumed ingestion or contact with meat from infected cattle. The European Union instituted a ban on the importation of beef from the United Kingdom during March 1996 that had a severe effect on the beef industry in the UK and also resulted in a world wide consumer resistance against beef consumption.
Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy of cattle, first detected in 1986 in the United Kingdom and subsequently in other countries. It is the most likely cause of variant Creutzfeldt-Jakob disease (vCJD) in humans, but the origin of BSE has not been eluci...
Transmissible spongiform encephalopathies (TSEs) are fatal neurologic diseases that affect several mammalian species including human beings. Four animal TSE agents have been reported: scrapie of sheep and goats; chronic wasting disease (CWD) of deer, elk, and moose; transmissible mink encephalopath...
...; ] DEPARTMENT OF AGRICULTURE Animal and Plant Health Inspection Service 9 CFR Part 93 RIN 0579-AC68 Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products Correction In proposed rule...
... Health Inspection Service 9 CFR Parts 92, 93, 94, 95, 96, and 98 RIN 0579-AC68 Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products Corrections In rule document 2013-28228 appearing...
Tsutsui, Toshiyuki; Kasuga, Fumiko
Bovine spongiform encephalopathy (BSE) is a progressive neurological disease of cattle affecting the central nervous system and was first diagnosed in the United Kingdom (UK) in 1986 (Wells et al., 1987). This disease is one of the transmissible spongiform encephalopathy (TSE) which includes Creutzfeldt-Jakob disease (CJD) in humans and scrapie in sheep. The causative agent of TSE is considered to be an abnormal form of prion protein. However, the details of its pathogenic mechanism have not been fully identified. Scrapie, which causes neurological symptoms in sheep and goats, has existed in the UK for 200 years (Hoinville, 1996) and spread across the rest of the world in the 1900s (Detwiler & Baylis, 2003). There has been no report so far that scrapie can be transmitted to humans. Initially, BSE was also considered as a disease affecting only animals. However, a variant type of Creutzfeldt-Jakob disease (vCJD) was first reported in the UK, and exposure to a BSE agent was suspected (Collinge, Sidle, Meads, Ironside, & Hill, 1996). vCJD is clinically and pathologically different from the sporadic type of CJD, and age at clinical onset of vCJD is younger than sporadic type (Will et al., 1996). Since the UK government announced the possible association between BSE and vCJD in 1996, BSE has become a huge public health concern all over the world. Of particular concern about vCJD, the fatal disease in younger age, distorted consumer confidence in beef safety, and as a result reduced beef consumption has been seen in many BSE-affected countries.
van Keulen, L J M; Vromans, M E W; Dolstra, C H; Bossers, A; van Zijderveld, F G
The pathogenesis of bovine spongiform encephalopathy (BSE) in sheep was studied by immunohistochemical detection of scrapie-associated prion protein (PrP(Sc)) in the gastrointestinal, lymphoid and neural tissues following oral inoculation with BSE brain homogenate. First accumulation of PrP(Sc) was detected after 6 months in the tonsil and the ileal Peyer's patches. At 9 months postinfection, PrP(Sc) accumulation involved all gut-associated lymphoid tissues and lymph nodes as well as the spleen. At this time point, PrP(Sc) accumulation in the peripheral neural tissues was first seen in the enteric nervous system of the caudal jejunum and ileum and in the coeliac-mesenteric ganglion. In the central nervous system, PrP(Sc) was first detected in the dorsal motor nucleus of the nervus Vagus in the medulla oblongata and in the intermediolateral column in the spinal cord segments T7-L1. At subsequent time points, PrP(Sc) was seen to spread within the lymphoid system to also involve all non-gut-associated lymphoid tissues. In the enteric nervous system, further spread of PrP(Sc) involved the neural plexi along the entire gastrointestinal tract and in the CNS the complete neuraxis. These findings indicate a spread of the BSE agent in sheep from the enteric nervous system through parasympathetic and sympathetic nerves to the medulla oblongata and the spinal cord.
Bovine spongiform encephalopathy (BSE) had never been detected in Sweden until 2006, when the active surveillance identified a case in a 12-year-old cow. The case was an unusual form since several molecular features of the protease-resistant prion protein (PrP**res) were different from classical BSE...
Kadohira, M.; Stevenson, M.A.; Hogasen, H.R.; Koeijer, de A.A.
A predictive case-cohort model was applied to Japanese data to analyze the interaction between challenge and stability factors for bovine spongiform encephalopathy (BSE) for the period 1985–2020. BSE risk in cattle was estimated as the expected number of detectable cases per year. The model was comp
Bovine spongiform encephalopathy is a transmissible spongiform encephalopathy of domestic cattle. The disorder was reported in the United Kingdom in the late 1980s and was associated with recycling of ruminant byproducts in cattle feed. In 1996, the bovine disease was reported to be the cause of a...
Hörnlimann, B; Guidon, D; Griot, C
Since the occurrence of bovine spongiform encephalopathy (BSE) in Switzerland in 1990, extensive epidemiological investigations and risk factor analyses were carried out. In this study, statistical data on meat and bone meal traded from 1985 to 1989 were analysed addressing the following questions: i) what amount of meat and bone meal was exported from Great Britain (GB) and where to and ii) what amount of meat and bone meal was imported into Switzerland and where from? The findings led to the hypothesis that imported material potentially infected with scrapie-like agents was the cause for BSE in Switzerland.
Full Text Available To promote consumer confidence in the safety of beef and to ensure the proper implementation of eradication measures against bovine spongiform encephalopathy (BSE, the Cattle Traceability Law was approved by the Diet in June 2003 and a cattle traceability system has been in operation in Japan since December 2003. The system enables tracing the cohort and offspring animals of a BSE case within 24 h of its detection. The traceability database system also provides distributors, restaurants and consumers with information on the cattle from which the beef that they sell, serve and consume originate.
Lee, Y H; Kim, M J; Tark, D S; Sohn, H J; Yun, E I; Cho, I S; Choi, Y P; Kim, C L; Lee, J H; Kweon, C H; Joo, Y S; Chung, G S; Lee, J H
National surveillance for bovine spongiform encephalopathy (BSE) began in the Republic of Korea (ROK) in 1996. Surveillance programmes changed overtime to comply with the guidelines of the World Organisation for Animal Health (OIE). Bovine spongiform encephalopathy was designated as a notifiable disease in 1997. From July 2008, the BSE surveillance programme was intensified to test cattle in designated high-risk populations more effectively. New measures included the compulsory testing of all non-ambulatory cattle at abattoirs, and encouraging the testing of all dead cattle examined and recorded under the Mutual Aid Insurance Scheme (fallen stock). In addition, there was a vigorous search for animals suspected of being clinically infected. As a result, a total of 426,919 OIE points were achieved over a period of seven consecutive years to the end of October 2009. This enabled the submission of a successful application to the OIE in 2010 for recognition of the ROK's BSE disease status as being one of controlled risk, in accordance with Chapter 11.5. of the OIE Terrestrial Animal Health Code.
Until recently, transmissible spongiform encephalopathy (TSE) disease in cattle was thought to be caused by a single agent strain, bovine spongiform encephalopathy (BSE) (classical BSE or BSE-C). However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. These atypical BSE isolates have been previously transmitted to a range of tr...
Hedman, Carlos; Bolea, Rosa; Marín, Belén; Cobrière, Fabien; Filali, Hicham; Vazquez, Francisco; Pitarch, José Luis; Vargas, Antonia; Acín, Cristina; Moreno, Bernardino; Pumarola, Martí; Andreoletti, Olivier; Badiola, Juan José
Experimental transmission of the bovine spongiform encephalopathy (BSE) agent has been successfully reported in pigs inoculated via three simultaneous distinct routes (intracerebral, intraperitoneal and intravenous). Sheep derived BSE (Sh-BSE) is transmitted more efficiently than the original cattle-BSE isolate in a transgenic mouse model expressing porcine prion protein. However, the neuropathology and distribution of Sh-BSE in pigs as natural hosts, and susceptibility to this agent, is unknown. In the present study, seven pigs were intracerebrally inoculated with Sh-BSE prions. One pig was euthanized for analysis in the preclinical disease stage. The remaining six pigs developed neurological signs and histopathology revealed severe spongiform changes accompanied by astrogliosis and microgliosis throughout the central nervous system. Intracellular and neuropil-associated pathological prion protein (PrP(Sc)) deposition was consistently observed in different brain sections and corroborated by Western blot. PrP(Sc) was detected by immunohistochemistry and enzyme immunoassay in the following tissues in at least one animal: lymphoid tissues, peripheral nerves, gastrointestinal tract, skeletal muscle, adrenal gland and pancreas. PrP(Sc) deposition was revealed by immunohistochemistry alone in the retina, optic nerve and kidney. These results demonstrate the efficient transmission of Sh-BSE in pigs and show for the first time that in this species propagation of bovine PrP(Sc) in a wide range of peripheral tissues is possible. These results provide important insight into the distribution and detection of prions in non-ruminant animals.
Paul, Mathilde; Abrial, David; Jarrige, Nathalie; Rican, Stéphane; Garrido, Myriam; Calavas, Didier; Ducrot, Christian
In France, despite the ban of meat-and-bone meal (MBM) in cattle feed, bovine spongiform encephalopathy (BSE) was detected in hundreds of cattle born after the ban. To study the role of MBM, animal fat, and dicalcium phosphate on the risk for BSE after the feed ban, we conducted a spatial analysis of the feed industry. We used data from 629 BSE cases as well as data on use of each byproduct and market area of the feed factories. We mapped risk for BSE in 951 areas supplied by the same factories and connection with use of byproducts. A disease map of BSE with covariates was built with the hierarchical Bayesian modeling methods, based on Poisson distribution with spatial smoothing. Only use of MBM was spatially linked to risk for BSE, which highlights cross-contamination as the most probable source of infection after the feed ban.
Hamir, Amir N; Kehrli, Marcus E; Kunkle, Robert A; Greenlee, Justin J; Nicholson, Eric M; Richt, Jürgen A; Miller, Janice M; Cutlip, Randall C
Prion diseases or transmissible spongiform encephalopathies (TSEs) of animals include scrapie of sheep and goats; transmissible mink encephalopathy (TME); chronic wasting disease (CWD) of deer, elk and moose; and bovine spongiform encephalopathy (BSE) of cattle. The emergence of BSE and its spread to human beings in the form of variant Creutzfeldt-Jakob disease (vCJD) resulted in interest in susceptibility of cattle to CWD, TME and scrapie. Experimental cross-species transmission of TSE agents provides valuable information for potential host ranges of known TSEs. Some interspecies transmission studies have been conducted by inoculating disease-causing prions intracerebrally (IC) rather than orally; the latter is generally effective in intraspecies transmission studies and is considered a natural route by which animals acquire TSEs. The "species barrier" concept for TSEs resulted from unsuccessful interspecies oral transmission attempts. Oral inoculation of prions mimics the natural disease pathogenesis route whereas IC inoculation is rather artificial; however, it is very efficient since it requires smaller dosage of inoculum, and typically results in higher attack rates and reduces incubation time compared to oral transmission. A species resistant to a TSE by IC inoculation would have negligible potential for successful oral transmission. To date, results indicate that cattle are susceptible to IC inoculation of scrapie, TME, and CWD but it is only when inoculated with TME do they develop spongiform lesions or clinical disease similar to BSE. Importantly, cattle are resistant to oral transmission of scrapie or CWD; susceptibility of cattle to oral transmission of TME is not yet determined.
Holznagel, Edgar; Yutzy, Barbara; Schulz-Schaeffer, Walter; Kruip, Carina; Hahmann, Uwe; Bierke, Pär; Torres, Juan-Maria; Kim, Yong-Sun; Thomzig, Achim; Beekes, Michael; Hunsmann, Gerhard; Loewer, Johannes
Risk for human exposure to bovine spongiform encephalopathy (BSE)-inducing agent was estimated in a nonhuman primate model. To determine attack rates, incubation times, and molecular signatures, we orally exposed 18 macaques to 1 high dose of brain material from cattle with BSE. Several macaques were euthanized at regular intervals starting at 1 year postinoculation, and others were observed until clinical signs developed. Among those who received ≥5 g BSE-inducing agent, attack rates were 100% and prions could be detected in peripheral tissues from 1 year postinoculation onward. The overall median incubation time was 4.6 years (3.7-5.3). However, for 3 macaques orally exposed on multiple occasions, incubation periods were at least 7-10 years. Before clinical signs were noted, we detected a non-type 2B signature, indicating the existence of atypical prion protein during the incubation period. This finding could affect diagnosis of variant Creutzfeldt-Jakob disease in humans and might be relevant for retrospective studies of positive tonsillectomy or appendectomy specimens because time of infection is unknown.
Probst, C; Gethmann, J M; Heuser, R; Niemann, H; Conraths, F J
On 26 November 2000, the first autochthonous case of bovine spongiform encephalopathy (BSE) was detected in Germany. Since then, a total of 413 BSE cases have been confirmed, resulting in the culling and destruction of 17 313 heads of cattle. In view of the possible risks for human and animal health, Germany has adopted EU regulations along with some additional requirements concerning active surveillance and response measures after detecting a BSE-positive animal. In this study, we used a stochastic model to estimate the costs incurred by the ensuing legislative amendments responding to BSE between November 2000 and December 2010. The total costs were estimated to range between 1847 and 2094 million Euros. They peaked in 2001 (about 394 million Euros) and declined since. About 54% of the costs (approximately 1000 million Euros) were incurred by the extension of the feed ban for animal protein to all farmed livestock. Active surveillance accounted for 21% (405 million Euros), the incineration of animal protein for 13% (249 million Euros) and the removal of specified risk material for 11% (225 million Euros). Only 1% of the costs was related to response measures after detecting a BSE-positive animal, including indemnity payments for culled cattle and confiscated carcasses at the slaughterhouse.
Full Text Available Bovine spongiform encephalopathy (BSE is a fatal, transmissible, neurodegenerative disease of cattle. To date, the disease process is still poorly understood. In this study, brain tissue samples from animals naturally infected with BSE were analysed to identify differentially regulated genes using Affymetrix GeneChip Bovine Genome Arrays. A total of 230 genes were shown to be differentially regulated and many of these genes encode proteins involved in immune response, apoptosis, cell adhesion, stress response and transcription. Seventeen genes are associated with the endoplasmic reticulum (ER and 10 of these 17 genes are involved in stress related responses including ER chaperones, Grp94 and Grp170. Western blotting analysis showed that another ER chaperone, Grp78, was up-regulated in BSE. Up-regulation of these three chaperones strongly suggests the presence of ER stress and the activation of the unfolded protein response (UPR in BSE. The occurrence of ER stress was also supported by changes in gene expression for cytosolic proteins, such as the chaperone pair of Hsp70 and DnaJ. Many genes associated with the ubiquitin-proteasome pathway and the autophagy-lysosome system were differentially regulated, indicating that both pathways might be activated in response to ER stress. A model is presented to explain the mechanisms of prion neurotoxicity using these ER stress related responses. Clustering analysis showed that the differently regulated genes found from the naturally infected BSE cases could be used to predict the infectious status of the samples experimentally infected with BSE from the previous study and vice versa. Proof-of-principle gene expression biomarkers were found to represent BSE using 10 genes with 94% sensitivity and 87% specificity.
Moore, J.; Hawkins, S.A.C.; Austin, A.R.; Konold, T.; Green, R.B.; Blamire, I.W.; Dexter, I.; Stack, M.J.; Chaplin, M.J.; Langeveld, J.P.M.; Simmons, M.; Spencer, Y.I.; Webb, P.R.I.; Dawson, M.
Background: Transmission of the prion disease bovine spongiform encephalopathy (BSE) occurred accidentally to cattle and several other mammalian species via feed supplemented with meat and bone meal contaminated with infected bovine tissue. Prior to United Kingdom controls in 1996 on the feeding of
van Gelderen, C; Gimeno, E J; Schudel, A A
Bovine spongiform encephalopathy (BSE) is a neurodegenerative disease of cattle caused by prions that was first described in the United Kingdom (UK) in 1986. The BSE epizootic that commenced in the UK in the 1980s has since spread into other countries in Europe and Asia through exports of contaminated meat-and-bone meal or infected cattle. Over the past few years, other emerging or reemerging diseases have spread into previously free countries or regions through international trade. This negative effect of globalisation means that to implement successful preventive and strategic programmes to safeguard animal health, such programmes must, as a priority, take a regional approach. Global thinking, regional planning and local performance constitute the key factors for the successful control of animal diseases. In South America, initial preventive actions against BSE were adopted in 1989. Further measures adopted since then and based on new scientific and technical findings, have led to the demonstration that the region is free of BSE. These early preventive actions have reliably protected the region from importing BSE-infected material. An integral part of the project to determine the BSE status of South America was the training of personnel, the incorporation of technology and the provision of updated information through close relationships with international organisations and prominent international researcher workers. Regional activities aimed at harmonising BSE prevention programmes, producing objective and transparent data on the equivalence of regional BSE status and facilitating regional and international trade have recently been launched. Maintaining the BSE-free status of the region must be given high priority by the beef agro-industrial sectors.
Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal protein misfolding neurodegenerative diseases. TSEs have been described in several species including bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in cervids, tr...
Beck, Katy E; Sallis, Rosemary E; Lockey, Richard; Vickery, Christopher M; Béringue, Vincent; Laude, Hubert; Holder, Thomas M; Thorne, Leigh; Terry, Linda A; Tout, Anna C; Jayasena, Dhanushka; Griffiths, Peter C; Cawthraw, Saira; Ellis, Richard; Balkema-Buschmann, Anne; Groschup, Martin H; Simmons, Marion M; Spiropoulos, John
Two cases of unusual transmissible spongiform encephalopathy (TSE) were diagnosed on the same farm in ARQ/ARQ PrP sheep showing attributes of both bovine spongiform encephalopathy (BSE) and scrapie. These cases, UK-1 and UK-2, were investigated further by transmissions to wild-type and ovine transgenic mice. Lesion profiles (LP) on primary isolation and subpassage, incubation period (IP) of disease, PrP(Sc) immunohistochemical (IHC) deposition pattern and Western blot profiles were used to characterize the prions causing disease in these sheep. Results showed that both cases were compatible with scrapie. The presence of BSE was contraindicated by the following: LP on primary isolation in RIII and/or MR (modified RIII) mice; IP and LP after serial passage in wild-type mice; PrP(Sc) deposition pattern in wild-type mice; and IP and Western blot data in transgenic mice. Furthermore, immunohistochemistry (IHC) revealed that each case generated two distinct PrP(Sc) deposition patterns in both wild-type and transgenic mice, suggesting that two scrapie strains coexisted in the ovine hosts. Critically, these data confirmed the original differential IHC categorization that these UK-1 and UK-2 cases were not compatible with BSE.
Dagleish, Mark P; Martin, Stuart; Steele, Philip; Finlayson, Jeanie; Eaton, Samantha L; Sisó, Sílvia; Stewart, Paula; Fernández-Borges, Natalia; Hamilton, Scott; Pang, Yvonne; Chianini, Francesca; Reid, Hugh W; Goldmann, Wilfred; González, Lorenzo; Castilla, Joaquín; Jeffrey, Martin
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
Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle. Classical BSE is associated with ingestion of BSE-contaminated feedstuffs. H- and L-type BSE, collectively known as atypical BSE, differ from classical BSE by displaying a different disease phenoty...
Background: Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) of cattle. Classical BSE is associated with ingestion of BSE-contaminated feedstuffs. H- and L-type BSE, collectively known as atypical BSE, differ from classical BSE by displaying a different di...
Thuring, C.M.A.; Keulen, van L.J.M.; Langeveld, J.P.M.; Vromans, M.E.W.; Zijderveld, van F.G.; Sweeney, T.
Sheep are susceptible experimentally to bovine spongiform encephalopathy (BSE), the clinical signs being indistinguishable from those of scrapie. Because of the possibility of natural ovine BSE infection, laboratory tests are needed to distinguish between scrapie and BSE infection. The objectives of
The evolution of monitoring and surveillance for bovine spongiform encephalopathy (BSE) from the phase of passive surveillance that began in the United Kingdom in 1988 until the present is described. Currently, surveillance for BSE in Europe consists of mass testing of cattle slaughtered for human...
Bovine spongiform encephalopathy (BSE) can be subdivided into at least three groups: classical, H-type, and L-type. The latter 2 designations are based on higher or lower apparent molecular mass profiles of the unglycosylated PrP**Sc band in a western blot and are collectively referred to as atypica...
Gough, Kevin C; Bishop, Keith; Maddison, Ben C
It is assumed that sheep and goats consumed the same bovine spongiform encephalopathy (BSE)-contaminated meat and bone meal that was fed to cattle and precipitated the BSE epidemic in the United Kingdom that peaked more than 20 years ago. Despite intensive surveillance for cases of BSE within the small ruminant populations of the United Kingdom and European Union, no instances of BSE have been detected in sheep, and in only two instances has BSE been discovered in goats. If BSE is present within the small ruminant populations, it may be at subclinical levels, may manifest as scrapie, or may be masked by coinfection with scrapie. To determine whether BSE is potentially circulating at low levels within the European small ruminant populations, highly sensitive assays that can specifically detect BSE, even within the presence of scrapie prion protein, are required. Here, we present a novel assay based on the specific amplification of BSE PrP(Sc) using the serial protein misfolding cyclic amplification assay (sPMCA), which specifically amplified small amounts of ovine and caprine BSE agent which had been mixed into a range of scrapie-positive brain homogenates. We detected the BSE prion protein within a large excess of classical, atypical, and CH1641 scrapie isolates. In a blind trial, this sPMCA-based assay specifically amplified BSE PrP(Sc) within brain mixes with 100% specificity and 97% sensitivity when BSE agent was diluted into scrapie-infected brain homogenates at 1% (vol/vol).
Espinosa, J.C.; Andreoletti, O.; Castilla, J.; Herva, M.E.; Morales, M.; Alamillo, E.; San-Segundo, F.D.; Lacroux, C.; Lugan, S.; Salguero, F.J.; Langeveld, J.P.M.; Torres, J.M.
Sheep can be experimentally infected with bovine spongiform encephalopathy (BSE), and the ensuing disease is similar to scrapie in terms of pathogenesis and clinical signs. BSE infection in sheep is an animal and human health concern. In this study, the transmission in BoPrP-Tg110 mice of prions fro
Almeida, L M; Basu, U; Williams, J L; Moore, S S; Guan, L L
Bovine spongiform encephalopathy (BSE) is a fatal disorder in cattle characterized by progressive neurodegeneration of the central nervous system. We investigated the molecular mechanisms involved in neurodegeneration during prion infection through the identification of genes that are differentially expressed (DE) between experimentally infected and non-challenged cattle. Gene expression of caudal medulla from control and orally infected animals was compared by microarray analysis using 24,000 bovine oligonucleotides representing 16,846 different genes to identify DE genes associated with BSE disease. In total, 182 DE genes were identified between normal and BSE-infected tissues (>2.0-fold change, P bovine species.
Bhattacharjee, Ujjal; Graham, Catherine; Czub, Stefanie; Dudas, Sandor; Rasmussen, Mark A; Casey, Thomas A; Petrich, Jacob W
Transmissible spongiform encephalopathies (TSE) are progressive, neurodegenerative disorders, of which bovine spongiform encephalopathy (BSE) is of special concern because it is infectious and debilitating to humans. The possibility of using fluorescence spectroscopy to screen for BSE in cattle was explored. Fluorescence spectra from the retinas of experimentally infected BSE-positive cattle with clinical disease were compared with those from both sham-inoculated and non-inoculated BSE-negative cattle. The distinct intensity difference of about 4-10-fold between the spectra of the BSE-positive and the BSE-negative (sham-inoculated and non-inoculated) eyes suggests the basis for a means of developing a rapid, noninvasive examination of BSE in particular and TSEs in general.
The H-type of atypical bovine spongiform encephalopathy (H-BSE) was serially passaged in bovinized transgenic (TgBoPrP) mice. At the fourth passage, most challenged mice showed a typical H-BSE phenotype with incubation periods of 223 ± 7.8 days. However, a different phenotype of BSE prion with shorter incubation periods of 109 ± 4 days emerged in a minor subset of the inoculated mice. The latter showed distinct clinical signs, brain pathology, and abnormal prion protein profiles as compared t...
Full Text Available Bovine spongiform encephalopathy (BSE is a zoonotic transmissible spongiform encephalopathy (TSE thought to be caused by the same prion strain as variant Creutzfeldt-Jakob disease (vCJD. Unlike scrapie and chronic wasting disease there is no cell culture model allowing the replication of proteinase K resistant BSE (PrPBSE and the further in vitro study of this disease. We have generated a cell line based on the Madin-Darby Bovine Kidney (MDBK cell line over-expressing the bovine prion protein. After exposure to naturally BSE-infected bovine brain homogenate this cell line has shown to replicate and accumulate PrPBSE and maintain infection up to passage 83 after initial challenge. Collectively, we demonstrate, for the first time, that the BSE agent can infect cell lines over-expressing the bovine prion protein similar to other prion diseases. These BSE infected cells will provide a useful tool to facilitate the study of potential therapeutic agents and the diagnosis of BSE.
Tark, Dongseob; Kim, Hyojin; Neale, Michael H; Kim, Minjeong; Sohn, Hyunjoo; Lee, Yoonhee; Cho, Insoo; Joo, Yiseok; Windl, Otto
Bovine spongiform encephalopathy (BSE) is a zoonotic transmissible spongiform encephalopathy (TSE) thought to be caused by the same prion strain as variant Creutzfeldt-Jakob disease (vCJD). Unlike scrapie and chronic wasting disease there is no cell culture model allowing the replication of proteinase K resistant BSE (PrPBSE) and the further in vitro study of this disease. We have generated a cell line based on the Madin-Darby Bovine Kidney (MDBK) cell line over-expressing the bovine prion protein. After exposure to naturally BSE-infected bovine brain homogenate this cell line has shown to replicate and accumulate PrPBSE and maintain infection up to passage 83 after initial challenge. Collectively, we demonstrate, for the first time, that the BSE agent can infect cell lines over-expressing the bovine prion protein similar to other prion diseases. These BSE infected cells will provide a useful tool to facilitate the study of potential therapeutic agents and the diagnosis of BSE.
Wilson, Rona; Hart, Patricia; Piccardo, Pedro; Hunter, Nora; Casalone, Cristina; Baron, Thierry; Barron, Rona M
Until recently, transmissible spongiform encephalopathy (TSE) disease in cattle was thought to be caused by a single agent strain, bovine spongiform encephalopathy (BSE) (classical BSE or BSE-C). However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. These atypical BSE isolates have been previously transmitted to a range of transgenic mouse models overexpressing PrP from different species at different levels, on a variety of genetic backgrounds. To control for genetic background and expression level in the analysis of these isolates, we performed here a comprehensive comparison of the neuropathological and molecular properties of all three BSE agents (BASE, BSE-C and BSE-H) upon transmission into the same gene-targeted transgenic mouse line expressing the bovine prion protein (Bov6) and a wild-type control of the same genetic background. Significantly, upon challenge with these BSE agents, we found that BASE did not produce shorter survival times in these mice compared with BSE-C, contrary to previous studies using overexpressing bovine transgenic mice. Amyloid plaques were only present in mice challenged with atypical BSE and neuropathological features, including intensity of PrP deposition in the brain and severity of vacuolar degeneration were less pronounced in BASE compared with BSE-C-challenged mice.
Bovine spongiform encephalopathy (BSE) is a protein misfolding disease of cattle which belongs to the group of transmissible spongiform encephalopathies (TSEs) or prion diseases. This group also includes scrapie in sheep and goats, chronic wasting disease (CWD) of cervids and Creutzfeldt-Jakob disease (CJD) humans. The first case of BSE was recognised in England in 1986 as a progressive, neurological condition where affected animals behaved abnormally, exhibited anxiety, ataxia, hypersensitivity to touch and noise and poor body condition. Spongiform change was observed in the brain stem of cattle at post-mortem and its similarity to scrapie in sheep stimulated biochemical investigation and transmission studies which confirmed it as a novel prion disease of cattle. Epidemiological analysis of the initial cases of disease implicated a common extended source of infection, likely to be related to feed, and stimulated a series of control measures designed to restrict feeding of mammalian-derived protein to ruminants in various parts of the United Kingdom and to prevent the use of various bovine offals in feed or food production. This article outlines the rise and fall of the incidence of BSE in the UK and Europe, its classification as a zoonotic disease with the emergence of variant CJD, the implications of it as a prion disease and challenge its diagnosis and control continues to represent worldwide.
Baron, Thierry; Bencsik, Anna; Biacabe, Anne-Gaëlle; Morignat, Eric; Bessen, Richard A
Transmissible mink encepholapathy (TME) is a foodborne transmissible spongiform encephalopathy (TSE) of ranch-raised mink; infection with a ruminant TSE has been proposed as the cause, but the precise origin of TME is unknown. To compare the phenotypes of each TSE, bovine-passaged TME isolate and 3 distinct natural bovine spongiform encephalopathy (BSE) agents (typical BSE, H-type BSE, and L-type BSE) were inoculated into an ovine transgenic mouse line (TgOvPrP4). Transgenic mice were susceptible to infection with bovine-passaged TME, typical BSE, and L-type BSE but not to H-type BSE. Based on survival periods, brain lesions profiles, disease-associated prion protein brain distribution, and biochemical properties of protease-resistant prion protein, typical BSE had a distint phenotype in ovine transgenic mice compared to L-type BSE and bovine TME. The similar phenotypic properties of L-type BSE and bovine TME in TgOvPrP4 mice suggest that L-type BSE is a much more likely candidate for the origin of TME than is typical BSE.
... ENTRY INTO THE UNITED STATES § 96.2 Prohibition of casings due to African swine fever and bovine... processed in a region where African swine fever exists, as listed in § 94.8 of this subchapter, is... swine fever and bovine spongiform encephalopathy. 96.2 Section 96.2 Animals and Animal Products...
Torres, Juan-María; Andréoletti, Olivier; Lacroux, Caroline; Prieto, Irene; Lorenzo, Patricia; Larska, Magdalena; Baron, Thierry; Espinosa, Juan-Carlos
Bovine spongiform encephalopathy (BSE) and BSE-related disorders have been associated with a single major prion strain. Recently, 2 atypical, presumably sporadic forms of BSE have been associated with 2 distinct prion strains that are characterized mainly by distinct Western blot profiles of abnormal protease-resistant prion protein (PrPres), named high-type (BSE-H) and low-type (BSE-L), that also differed from classical BSE. We characterized 5 atypical BSE-H isolates by analyzing their molecular and neuropathologic properties during transmission in transgenic mice expressing homologous bovine prion protein. Unexpectedly, in several inoculated animals, strain features emerged that were highly similar to those of classical BSE agent. These findings demonstrate the capability of an atypical bovine prion to acquire classical BSE-like properties during propagation in a homologous bovine prion protein context and support the view that the epidemic BSE agent could have originated from such a cattle prion.
... Collection; Bovine Spongiform Encephalopathy; Importation of Animals and Animal Products AGENCY: Animal and... byproducts to protect against the introduction of bovine spongiform encephalopathy into the United States... animal products and byproducts to prevent the introduction of bovine spongiform encephalopathy into...
Bovine spongiform encephalopathy (BSE) and BSErelated disorders have been associated with a single major prion strain. Recently, 2 atypical, presumably sporadic forms of BSE have been associated with 2 distinct prion strains that are characterized mainly by distinct Western blot profi les of abnormal protease-resistant prion protein (PrPres), named high-type (BSE-H) and low-type (BSE-L), that also differed from classical BSE. We characterized 5 atypical BSE-H isolates by analyzing their molec...
Fukuda, Shigeo; Iwamaru, Yoshifumi; Imamura, Morikazu; Masujin, Kentarou; Shimizu, Yoshihisa; Matsuura, Yuichi; Shu, Yujing; Kurachi, Megumi; Kasai, Kazuo; Murayama, Yuichi; Onoe, Sadao; Hagiwara, Ken'ichi; Sata, Tetsutaro; Mohri, Shirou; Yokoyama, Takashi; Okada, Hiroyuki
It has been assumed that the agent causing BSE in cattle is a uniform strain (classical BSE); however, different neuropathological and molecular phenotypes of BSE (atypical BSE) have been recently reported. We demonstrated the successful transmission of L-type-like atypical BSE detected in Japan (BSE/JP24 isolate) to cattle. Based on the incubation period, neuropathological hallmarks, and molecular properties of the abnormal host prion protein, the characteristics of BSE/JP24 prion were apparently distinguishable from the classical BSE prion and closely resemble those of bovine amyloidotic spongiform encephalopathy prion detected in Italy.
Vickery, Christopher M; Lockey, Richard; Holder, Thomas M; Thorne, Leigh; Beck, Katy E; Wilson, Christina; Denyer, Margaret; Sheehan, John; Marsh, Sarah; Webb, Paul R; Dexter, Ian; Norman, Angela; Popescu, Emma; Schneider, Amanda; Holden, Paul; Griffiths, Peter C; Plater, Jane M; Dagleish, Mark P; Martin, Stuart; Telling, Glenn C; Simmons, Marion M; Spiropoulos, John
Several transgenic mouse models have been developed which facilitate the transmission of chronic wasting disease (CWD) of cervids and allow prion strain discrimination. The present study was designed to assess the susceptibility of the prototypic mouse line, Tg(CerPrP)1536(+/-), to bovine spongiform encephalopathy (BSE) prions, which have the ability to overcome species barriers. Tg(CerPrP)1536(+/-) mice challenged with red deer-adapted BSE resulted in 90% to 100% attack rates, and BSE from cattle failed to transmit, indicating agent adaptation in the deer.
Piccardo, P; Cervenak, J; Yakovleva, O; Gregori, L; Pomeroy, K; Cook, A; Muhammad, F S; Seuberlich, T; Cervenakova, L; Asher, D M
Squirrel monkeys (Saimiri sciureus) were infected experimentally with the agent of classical bovine spongiform encephalopathy (BSE). Two to four years later, six of the monkeys developed alterations in interactive behaviour and cognition and other neurological signs typical of transmissible spongiform encephalopathy (TSE). At necropsy examination, the brains from all of the monkeys showed pathological changes similar to those described in variant Creutzfeldt-Jakob disease (vCJD) of man, except that the squirrel monkey brains contained no PrP-amyloid plaques typical of that disease. Constant neuropathological features included spongiform degeneration, gliosis, deposition of abnormal prion protein (PrP(TSE)) and many deposits of abnormally phosphorylated tau protein (p-Tau) in several areas of the cerebrum and cerebellum. Western blots showed large amounts of proteinase K-resistant prion protein in the central nervous system. The striking absence of PrP plaques (prominent in brains of cynomolgus macaques [Macaca fascicularis] with experimentally-induced BSE and vCJD and in human patients with vCJD) reinforces the conclusion that the host plays a major role in determining the neuropathology of TSEs. Results of this study suggest that p-Tau, found in the brains of all BSE-infected monkeys, might play a role in the pathogenesis of TSEs. Whether p-Tau contributes to development of disease or appears as a secondary change late in the course of illness remains to be determined.
Full Text Available Abstract Gene expression analysis has proven to be a very useful tool to gain knowledge of the factors involved in the pathogenesis of diseases, particularly in the initial or preclinical stages. With the aim of finding new data on the events occurring in the Central Nervous System in animals affected with Bovine Spongiform Encephalopathy, a comprehensive genome wide gene expression study was conducted at different time points of the disease on mice genetically modified to model the bovine species brain in terms of cellular prion protein. An accurate analysis of the information generated by microarray technique was the key point to assess the biological relevance of the data obtained in terms of Transmissible Spongiform Encephalopathy pathogenesis. Validation of the microarray technique was achieved by RT-PCR confirming the RNA change and immunohistochemistry techniques that verified that expression changes were translated into variable levels of protein for selected genes. Our study reveals changes in the expression of genes, some of them not previously associated with prion diseases, at early stages of the disease previous to the detection of the pathological prion protein, that might have a role in neuronal degeneration and several transcriptional changes showing an important imbalance in the Central Nervous System homeostasis in advanced stages of the disease. Genes whose expression is altered at early stages of the disease should be considered as possible therapeutic targets and potential disease markers in preclinical diagnostic tool development. Genes non-previously related to prion diseases should be taken into consideration for further investigations.
Kong, Qingzhong; Zheng, Mengjie; Casalone, Cristina; Qing, Liuting; Huang, Shenghai; Chakraborty, Bikram; Wang, Ping; Chen, Fusong; Cali, Ignazio; Corona, Cristiano; Martucci, Francesca; Iulini, Barbara; Acutis, Pierluigi; Wang, Lan; Liang, Jingjing; Wang, Meiling; Li, Xinyi; Monaco, Salvatore; Zanusso, Gianluigi; Zou, Wen-Quan; Caramelli, Maria; Gambetti, Pierluigi
Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to be caused by only one strain, BSE-C. BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE strains by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE strain-infected cattle. Sixty percent of the inoculated Tg mice became infected after 20 to 22 months of incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE strain-infected Tg mice, but none of the Tg mice infected with prions causing a sporadic human prion disease, showed the presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE strain-infected humanized Tg mouse brains are different from those from the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation times are observed for the BASE strain-infected Tg mice. These results suggest that in humans, the BASE strain is a more virulent BSE strain and likely lymphotropic.
Tortosa, Raül; Castells, Xavier; Vidal, Enric; Costa, Carme; Ruiz de Villa, María del Carmen; Sánchez, Alex; Barceló, Anna; Torres, Juan María; Pumarola, Martí; Ariño, Joaquín
Gene expression analysis has proven to be a very useful tool to gain knowledge of the factors involved in the pathogenesis of diseases, particularly in the initial or preclinical stages. With the aim of finding new data on the events occurring in the Central Nervous System in animals affected with Bovine Spongiform Encephalopathy, a comprehensive genome wide gene expression study was conducted at different time points of the disease on mice genetically modified to model the bovine species brain in terms of cellular prion protein. An accurate analysis of the information generated by microarray technique was the key point to assess the biological relevance of the data obtained in terms of Transmissible Spongiform Encephalopathy pathogenesis. Validation of the microarray technique was achieved by RT-PCR confirming the RNA change and immunohistochemistry techniques that verified that expression changes were translated into variable levels of protein for selected genes. Our study reveals changes in the expression of genes, some of them not previously associated with prion diseases, at early stages of the disease previous to the detection of the pathological prion protein, that might have a role in neuronal degeneration and several transcriptional changes showing an important imbalance in the Central Nervous System homeostasis in advanced stages of the disease. Genes whose expression is altered at early stages of the disease should be considered as possible therapeutic targets and potential disease markers in preclinical diagnostic tool development. Genes non-previously related to prion diseases should be taken into consideration for further investigations.
Priem, J.; Langeveld, J.P.M.; Keulen, van L.J.M.; Zijderveld, van F.G.; Andreoletti, O.; Bossers, A.
Bovine spongiform encephalopathy (BSE) can be efficiently transmitted to small ruminants (sheep and goats) with certain prion protein (PrP) genotypes. Polymorphisms in PrP of both the host and donor influence the transmission efficiency of transmissible spongiform encephalopathies (TSEs) in general.
Biacabe, A.G.; Jacobs, J.G.; Bencsik, A.; Langeveld, J.P.M.; Baron, T.G.M.
We previously reported that some cattle affected by bovine spongiform encephalopathy (BSE) showed distinct molecular features of the protease-resistant prion protein (PrPres) in Western blot, with a 1-2 kDa higher apparent molecular mass of the unglycosylated PrPres associated with labelling by anti
Gizzi, G.; Raamsdonk, van L.W.D.; Baeten, V.; Murray, I.; Berben, G.; Brambilla, G.; Holst, von C.
Enforcing the ban on meat-and-bone meal in feed for farmed animals, and especially ruminants, is considered an important measure to prevent the spread of bovine spongiform encephalopathy. The authors describe current analytical methods for the detection and identification of animal tissues in feed.
Hogasen, H.R.; Koeijer, de A.A.
A predictive case-cohort model is applied to Norwegian data to analyze the interaction between challenge and stability factors for bovine spongiform encephalopathy (BSE) during the period 1980¿2010. For each year, the BSE risk in cattle is estimated as the expected number of cases. The age distribut
Thuring, C.M.A.; Erkens, J.H.F.; Jacobs, J.G.; Bossers, A.; Keulen, van L.J.M.; Garssen, G.J.; Zijderveld, van F.G.; Ryder, S.J.; Groschup, M.H.; Sweeney, T.; Langeveld, J.P.M.
A procedure for discrimination between scrapie and bovine spongiform encephalopathy (BSE) in sheep is of importance for establishing whether BSE has entered the sheep population. Since BSE has not yet been found in sheep at the farm level, such discrimination procedures can be developed only with ex
Crozet, Carole; Lehmann, Sylvain
Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) identified twenty years ago in the British cattle herds. Creutzfeldt-Jakob disease (CJD) is a TSE that occurs in humans. In 1996, scientists found a possible link between BSE and a new variant of CJD (vCJD). The fact that the non conventional infectious agent of TSE, named prions, could cross the species barrier from cattle to human through meat consumption, raised a tremendous concern for public safety in Europe. This led to the development in the following two decades of substantial and expensive measures to contain BSE and prevent its transmission to humans. In parallel, scientific programs have been funded to progress through the comprehension of the physiopathology of these fatal disorders. In Europe, the BSE epidemics is now ending and the number of cases is decreasing thanks to the strict control of animal foodstuff that was the main source of prion contamination. Only a small number of vCJD have been detected, however, additional concerns have been raised recently for public safety as secondary transmission of CJD through medical procedure and blood transfusion is possible. In addition, the possibility that the BSE was transmitted to other animals including small ruminants is also worrisome. Research efforts are now focussing on decontamination and ante mortem diagnosis of TSE to prevent animal and human transmission. However, needs for fundamental research are still important as many questions remain to be addressed to understand the mechanism of prion transmission, as well as its pathogenesis.
Bencsik, Anna; Leboidre, Mikael; Debeer, Sabine; Aufauvre, Claire; Baron, Thierry
In addition to classical bovine spongiform encephalopathy (C-BSE), which is recognized as being at the origin of the human variant form of Creutzfeldt-Jakob disease, 2 rare phenotypes of BSE (H-type BSE [H-BSE] and L-type BSE [L-BSE]) were identified in 2004. H-type BSE and L-BSE are considered to be sporadic forms of prion disease in cattle because they differ from C-BSE with respect to incubation period, vacuolar pathology in the brain, and biochemical properties of the protease-resistant prion protein (PrP) in natural hosts and in some mouse models that have been tested. Recently, we showed that H-BSE transmitted to C57Bl/6 mice resulted in a dissociation of the phenotypic features, that is, some mice showed an H-BSE phenotype, whereas others had a C-BSE phenotype. Here, these 2 phenotypes were further studied in VM mice and compared with cattle C-BSE, H-BSE, and L-BSE. Serial passages from the C-BSE-like phenotype on VM mice retained similarities with C-BSE. Moreover, our results indicate that strains 301V and 301C derived from C-BSE transmitted to VM and C57Bl/6 mice, respectively, are fundamentally the same strain. These VM transmission studies confirm the unique properties of the C-BSE strain and support the emergence of a strain that resembles C-BSE from H-BSE.
Doherr, Marcus G
In 1986, a new progressive neurological condition similar to scrapie of sheep and goats was recognised in cattle in the United Kingdom (UK), and was named bovine spongiform encephalopathy (BSE). There is an ongoing discussion whether BSE should be classified as infectious, contagious, or zoonotic, and if it fits the definition of a production disease. The objective of this work is to briefly describe the main characteristics of transmissible spongiform encephalopathies (TSE), to review the epidemiology of BSE, and to address the question of how to classify BSE. TSEs are characterised as chronic wasting diseases with spongiform vacuolation and the accumulation of infectious prion protein (PrP(Sc)) in the central nervous system. TSE infectivity is very difficult to inactivate. Cattle BSE most likely originated from sheep scrapie, although this will remain to be an issue for debate. The disease can be transmitted from cattle to a range of species, and has resulted in smaller TSE epidemics in domestic cats, zoo cats and zoo ruminants, and in humans. Transmission in the field occurred through feed containing ruminant-derived protein, and measures to prevent the recycling of infectivity have proven effective to reduce the number of new infections. Mandatory reporting of clinical suspects combined with targeted screening of risk populations is needed to assess the BSE status of a country. Infection studies and the transmissibility to other species classify BSE as infectious and zoonotic. Absence of excretion of the agent, and therefore of horizontal transmission, categorise BSE as non-contagious. However, BSE is a multifactorial infectious disease that is dependent on management factors (mainly feeding), and therefore fits into the broader definition of production diseases.
Doherr Marcus G
Full Text Available In 1986, a new progressive neurological condition similar to scrapie of sheep and goats was recognised in cattle in the United Kingdom (UK, and was named bovine spongiform encephalopathy (BSE. There is an ongoing discussion whether BSE should be classified as infectious, contagious, or zoonotic, and if it fits the definition of a production disease. The objective of this work is to briefly describe the main characteristics of transmissible spongiform encephalopathies (TSE, to review the epidemiology of BSE, and to address the question of how to classify BSE. TSEs are characterised as chronic wasting diseases with spongiform vacuolation and the accumulation of infectious prion protein (PrPSc in the central nervous system. TSE infectivity is very difficult to inactivate. Cattle BSE most likely originated from sheep scrapie, although this will remain to be an issue for debate. The disease can be transmitted from cattle to a range of species, and has resulted in smaller TSE epidemics in domestic cats, zoo cats and zoo ruminants, and in humans. Transmission in the field occurred through feed containing ruminant-derived protein, and measures to prevent the recycling of infectivity have proven effective to reduce the number of new infections. Mandatory reporting of clinical suspects combined with targeted screening of risk populations is needed to assess the BSE status of a country. Infection studies and the transmissibility to other species classify BSE as infectious and zoonotic. Absence of excretion of the agent, and therefor of horizontal transmission, categorise BSE as non-contagious. However, BSE is a multifactorial infectious disease that is dependent on management factors (mainly feeding, and therefore fits into the broader definition of production diseases.
Davidson, Debra J; Bogdan, Eva
The potential for reflexive modernization is defined by multiple factors, but the acknowledgment of risk is crucial, particularly among social groups that play a key role in risk minimization. This study offers an examination of the role of local media in response to the outbreak of bovine spongiform encephalopathy (BSE) in beef-producing communities in rural Alberta. BSE is one of several global risk issues that reflexive modernization theorists argue have the potential to trigger a transformation toward a critically reflexive society in which such risks are minimized. Content analysis of newspapers in beef-producing regions in Alberta, however, shows how local media framed BSE in a manner that maximized community cohesion and protection of local culture. This selective coverage of BSE in rural Alberta is quite likely to have contributed to, or at least reinforced, support for the current institutional structure of Canadian agriculture in beef-producing regions, through the constriction of discourse.
Gurgul, Artur; Czarnik, Urszula; Urszula, Czarnik; Larska, Magdalena; Polak, Mirosław P; Strychalski, Janusz; Słota, Ewa
Recent attempts to discover genetic factors affecting cattle resistance/susceptibility to bovine spongiform encephalopathy (BSE) have led to the identification of two insertion/deletion (indel) polymorphisms, located within the promoter and intron 1 of the prion protein gene PRNP, showing a significant association with the occurrence of classical form of the disease. Because the effect of the polymorphisms was studied only in few populations, in this study we investigated whether previously described association of PRNP indel polymorphisms with BSE susceptibility in cattle is also present in Polish cattle population. We found a significant relation between the investigated PRNP indel polymorphisms (23 and 12 bp indels), and susceptibility of Polish Holstein-Friesian cattle to classical BSE (P < 0.05). The deletion variants of both polymorphisms were related to increased susceptibility, whereas insertion variants were protective against BSE.
Full Text Available After the detection of the first case of bovine spongiform encephalopathy (BSE in Japan in September 2001, the Japanese government introduced a series of animal feed control measures to reduce the risk of the spread of the disease from a feed source. To ensure the proper implementation of these measures, the Food and Agricultural Materials Inspection Centre conducted audit inspections of feed importers, producers, distributors and end-users. The audit inspections include on-site inspection of the feed plants, warehouses, farms and other related premises and the laboratory analysis of feed samples taken from these premises to check for the presence of animal protein. The results of inspections conducted in recent years indicate good compliance with the feed control measures.
Full Text Available In the course of the last decades of the twentieth century, more than 30 new diseases were determined for the first time in history. Bovine spongiform encephalopathy (BSE, or "mad cow disease" is one of them. The disease implies the subacute neurodegenerative transmission of spongiform encephalopathy and it was diagnosed and described for the first time in Great Britain in 1986. A theory has been established that BSE is spread through feedstuffs, more precisely, meat-bone flour which contains infective proteins of ruminants, and legislature has been passed throughout the world with the objective of preventing the entry of meat-bone flour into the food chain. The complete ban of the use of meat-bone flour for all farm animals (with the exception of fish flour for non-ruminants and an adequate thermal treatment in the production of meat-bone flour (133ºC, 3 bar, 20 min are the elements on which the European Union (EU legislature is based. The regulations in our country include a ban on the use of meat-bone flour in cattle feedstuffs and a ban on imports of beef proteins. The implementation of this legislature throughout the world requires the corresponding analytical means. At the present time, there are several available possibilities: optic microscopy, PCR, immunoprobes, spectroscopic methods, and several others which are still being examined for use for this purpose. All the analytical methods are being applied with the objective of controlling the implementation of the current regulations, but also in order to discover possible cross contamination that could take place in factories of animal feedstuffs, during transportation, storage, or on farms, in particular when there are no separate lines for feedstuffs that contains meat-bone flour and others in which even its traces are banned. In order to secure the successful control and prevention of bovine spongiform encephalopathy in our country, as well as to secure the unhindered continuation of
Gurgul, Artur; Polak, Mirosław Paweł; Larska, Magdalena; Słota, Ewa
Polymorphisms in the coding region of the prion protein gene (PRNP) have been associated with the susceptibility and incubation period of prion diseases in humans and sheep. However, polymorphisms in this part of the bovine PRNP gene do not affect the classical bovine spongiform encephalopathy (BSE) susceptibility in cattle. Studies carried out in Germany have shown that insertion/deletion-type polymorphisms located in the promoter region of the bovine prion gene are possible genetic factors modulating BSE susceptibility by changing the level of PRNP expression. No such association was observed for atypical BSE cases; however, due to the rare nature of the disease, these results should be confirmed. Additionally, a single nonsynonymous mutation in PRNP codon 211 (E211K) was described in one H-type BSE case in the USA; however, it was not found in any other cases. Here, we performed genetic characterization of PRNP promoter indel variations and determined the polymorphism of open reading frames (ORFs) of PRNP and bovine prion-like Shadoo (SPRN) genes in six Polish atypical BSE cases and compared these results to the population of clinically healthy Polish Holstein cattle. No potentially pathogenic mutations were found in the PRNP ORF in atypical BSE-affected cattle, but our study showed a high frequency of deletions at the indel loci of PRNP promoter in these animals. Additionally, a rare sequence variation in the SPRN protein-coding sequence was found in one L-type atypical BSE-affected animal.
Ono, Fumiko; Terao, Keiji; Tase, Naomi; Hiyaoka, Akio; Ohyama, Atsushi; Tezuka, Yukio; Wada, Naomi; Kurosawa, Asuka; Sato, Yuko; Tobiume, Minoru; Hagiwara, Ken'ichi; Yamakawa, Yoshio; Sata, Tetsutaro
Bovine spongiform encephalopathy (BSE) was transmitted to three macaques by intracerebral inoculation of a brain homogenate from affected cattle detected in Japan. All monkeys developed abnormal behavioral signs, such as intermittent anorexia and hyperekplexia, around 24 months after inoculation. Neuronal symptoms, such as tremor, myoclonic jerking, and paralysis, appeared 27-44 months after inoculation. These symptoms worsened and total paralysis ensued within a year after onset. The disease duration was approximately 8-12 months. Both the incubation period and the duration of disease were shortened in the secondary transmission experiment to macaques. Heavy accumulation of disease-causing conformer(s) of prion protein (PrP(Sc)), with a similar glycoform profile to the PrP(Sc) contained in the inoculum, and severe spongiform changes in the histology of the brain, confirmed the successful transmission of BSE to monkeys. Florid plaques, a characteristic histological hallmark of variant Creutzfeldt-Jakob disease, were prominent in the cerebral cortex, in which a prion antigen was detected by immunohistochemistry (IHC). PrP(Sc) was mostly confined to the central nervous system, although small amounts of PrP(Sc) accumulated in the peripheral nerves of monkeys, as detected by Western blotting (WB). Neither IHC nor WB detected PrP(Sc) in the lymphatic organs/tissues, such as the tonsils, spleen, and appendix.
Furuoka, H; Horiuchi, M; Yamakawa, Y; Sata, T
This study reports the experimental transmission of bovine spongiform encephalopathy (BSE) to guinea pigs and describes the cerebellar lesions in these animals. Guinea pigs were inoculated intracerebrally with 10% brain homogenates from BSE-affected cattle. These animals were designated as the first passage. Second and third passages were subsequently performed. All guinea pigs developed infection at each passage. The mean incubation period of the first passage was 370 days post-infection (dpi) and this decreased to 307 dpi and 309 dpi for the second and third passages, respectively. Mild to severe spongiform degeneration and gliosis were observed in the cerebral cortex, thalamus and brainstem. In addition, the affected animals had marked pathological changes in the cerebellum characterized by severe cortical atrophy associated with Bergmann radial gliosis of the molecular layer and reduction in the width of the granular cell layer. Immunohistochemically, intense PrP(Sc) deposition and scattered plaque-like deposits were observed in the molecular and granular cell layers. Cerebellar lesions associated with severe atrophy of the cortex have not been reported in animal prion diseases, including in the experimental transmission of PrP(Sc) to small rodents. These lesions were similar to the lesions of human kuru or the VV2 variant of sporadic Creutzfeldt-Jakob disease, although typical kuru plaques or florid plaques were not observed in the affected animals.
Okada, H; Iwamaru, Y; Kakizaki, M; Masujin, K; Imamura, M; Fukuda, S; Matsuura, Y; Shimizu, Y; Kasai, K; Mohri, S; Yokoyama, T
The origin and transmission routes of atypical bovine spongiform encephalopathy (BSE) remain unclear. To assess whether the biological and biochemical characteristics of atypical L-type BSE detected in Japanese cattle (BSE/JP24) are conserved during serial passages within a single host, 3 calves were inoculated intracerebrally with a brain homogenate prepared from first-passaged BSE/JP24-affected cattle. Detailed immunohistochemical and neuropathologic analysis of the brains of second-passaged animals, which had developed the disease and survived for an average of 16 months after inoculation, revealed distribution of spongiform changes and disease-associated prion protein (PrP(Sc)) throughout the brain. Although immunolabeled PrP(Sc) obtained from brain tissue was characterized by the presence of PrP plaques and diffuse synaptic granular accumulations, no stellate-type deposits were detected. Western blot analysis suggested no obvious differences in PrP(Sc) molecular mass or glycoform pattern in the brains of first- and second-passaged cattle. These findings suggest failures to identify differences in mean incubation period and biochemical and neuropathologic properties of the BSE/JP24 prion between the first and second passages in cattle.
Masujin, Kentaro; Okada, Hiroyuki; Miyazawa, Kohtaro; Matsuura, Yuichi; Imamura, Morikazu; Iwamaru, Yoshifumi; Murayama, Yuichi; Yokoyama, Takashi
The H-type of atypical bovine spongiform encephalopathy (H-BSE) was serially passaged in bovinized transgenic (TgBoPrP) mice. At the fourth passage, most challenged mice showed a typical H-BSE phenotype with incubation periods of 223 ± 7.8 days. However, a different phenotype of BSE prion with shorter incubation periods of 109 ± 4 days emerged in a minor subset of the inoculated mice. The latter showed distinct clinical signs, brain pathology, and abnormal prion protein profiles as compared to H-BSE and other known BSE strains in mice. This novel prion was transmitted intracerebrally to cattle, with incubation periods of 14.8 ± 1.5 months, with phenotypes that differed from those of other bovine prion strains. These data suggest that intraspecies transmission of H-BSE in cattle allows the emergence of a novel BSE strain. Therefore, the continuation of feed ban programs may be necessary to exclude the recycling of H-BSE prions, which appear to arise spontaneously, in livestock. Such measures should help to reduce the risks from both novel and known strains of BSE.
Vickery, Christopher M; Beck, Katy E; Simmons, Marion M; Hawkins, Stephen A C; Spiropoulos, John
Mouse-adapted transmissible spongiform encephalopathy (TSE) strains are routinely distinguished based on reproducible disease characteristics in a given mouse line following inoculation via a consistent route. We investigated whether different administration routes (oral, intragastric (i.g.) and intracerebral (i.c.)) can alter the disease characteristics in IM mice after serial dilution of a stabilized mouse-adapted bovine spongiform encephalopathy (BSE) strain (301V). In addition, the infectivity of distal ileum and mesenteric lymph nodes (ln) sampled at three time points (35 days postinoculation (dpi), 70 dpi and terminal disease) after i.g. inoculation of 301V strain was assessed in mice by i.c. challenge. Strain characteristics were assessed according to standard methodology and PrP(Sc) immunohistochemistry deposition patterns. Mean incubation periods were prolonged following oral or i.g. inoculations compared to the i.c. route. Lesion profiles following i.c. challenges were elevated compared to i.g. and oral routes although vacuolation in the dorsal medulla was consistently high irrespective of the route of administration. Nevertheless, the same PrP(Sc) deposition pattern was associated with each route of administration. Distal and mesenteric ln infectivity was detected as early as 35 dpi and displayed consistent lesion profiles and PrP(Sc) deposition patterns. Our data suggest that although 301V retained its properties, some phenotypic parameters were affected by the route of inoculation. We conclude that bioassay data should be interpreted carefully and should be standardized for route of inoculation.
Rybner-Barnier, Catherine; Jacquemot, Catherine; Cuche, Céline; Doré, Grégory; Majlessi, Laleh; Gabellec, Marie-Madeleine; Moris, Arnaud; Schwartz, Olivier; Di Santo, James; Cumano, Ana; Leclerc, Claude; Lazarini, Françoise
Dendritic cells (DC) are suspected to be involved in transmissible spongiform encephalopathies, including bovine spongiform encephalopathy (BSE). We detected the disease-specific, protease-resistant prion protein (PrPbse) in splenic DC purified by magnetic cell sorting 45 days after intraperitoneal inoculation of BSE prions in immunocompetent mice. We showed that bone marrow-derived DC (BMDC) from wild-type or PrP-null mice acquired both PrPbse and prion infectivity within 2 h of in vitro culture with a BSE inoculum. BMDC cleared PrPbse within 2 to 3 days of culture, while BMDC infectivity was only 10-fold diminished between days 1 and 6 of culture, suggesting that the infectious unit in BMDC is not removed at the same rate as PrPbse is removed from these cells. Bone marrow-derived plasmacytoid DC and bone marrow-derived macrophages (BMM) also acquired and degraded PrPbse when incubated with a BSE inoculum, with kinetics very similar to those of BMDC. PrPbse capture is probably specific to antigen-presenting cells since no uptake of PrPbse was observed when splenic B or T lymphocytes were incubated with a BSE inoculum in vitro. Lipopolysaccharide activation of BMDC or BMM prior to BSE infection resulted in an accelerated breakdown of PrPbse. Injected by the intraperitoneal route, BMDC were not infectious for alymphoid recombination-activated gene 20/common cytokine γ chain-deficient mice, suggesting that these cells are not capable of directly propagating BSE infectivity to nerve endings. PMID:16641258
Rybner-Barnier, Catherine; Jacquemot, Catherine; Cuche, Céline; Doré, Grégory; Majlessi, Laleh; Gabellec, Marie-Madeleine; Moris, Arnaud; Schwartz, Olivier; Di Santo, James; Cumano, Ana; Leclerc, Claude; Lazarini, Françoise
Dendritic cells (DC) are suspected to be involved in transmissible spongiform encephalopathies, including bovine spongiform encephalopathy (BSE). We detected the disease-specific, protease-resistant prion protein (PrP(bse)) in splenic DC purified by magnetic cell sorting 45 days after intraperitoneal inoculation of BSE prions in immunocompetent mice. We showed that bone marrow-derived DC (BMDC) from wild-type or PrP-null mice acquired both PrP(bse) and prion infectivity within 2 h of in vitro culture with a BSE inoculum. BMDC cleared PrP(bse) within 2 to 3 days of culture, while BMDC infectivity was only 10-fold diminished between days 1 and 6 of culture, suggesting that the infectious unit in BMDC is not removed at the same rate as PrP(bse) is removed from these cells. Bone marrow-derived plasmacytoid DC and bone marrow-derived macrophages (BMM) also acquired and degraded PrP(bse) when incubated with a BSE inoculum, with kinetics very similar to those of BMDC. PrP(bse) capture is probably specific to antigen-presenting cells since no uptake of PrP(bse) was observed when splenic B or T lymphocytes were incubated with a BSE inoculum in vitro. Lipopolysaccharide activation of BMDC or BMM prior to BSE infection resulted in an accelerated breakdown of PrP(bse). Injected by the intraperitoneal route, BMDC were not infectious for alymphoid recombination-activated gene 2(0)/common cytokine gamma chain-deficient mice, suggesting that these cells are not capable of directly propagating BSE infectivity to nerve endings.
Wilson, Rona; Dobie, Karen; Hunter, Nora; Casalone, Cristina; Baron, Thierry; Barron, Rona M
The transmission of bovine spongiform encephalopathy (BSE) to humans, leading to variant Creutzfeldt-Jakob disease has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health. Until recently, TSE disease in cattle was thought to be caused by a single agent strain, BSE, also known as classical BSE, or BSE-C. However, due to the initiation of a large-scale surveillance programme throughout Europe, two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H have since been discovered. To model the risk to human health, we previously inoculated these two forms of atypical BSE (BASE and BSE-H) into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP) (HuTg) but were unable to detect any signs of TSE pathology in these mice. However, despite the absence of TSE pathology, upon subpassage of some BASE-challenged HuTg mice, a TSE was observed in recipient gene-targeted bovine PrP Tg (Bov6) mice but not in HuTg mice. Disease transmission from apparently healthy individuals indicates the presence of subclinical BASE infection in mice expressing human PrP that cannot be identified by current diagnostic methods. However, due to the lack of transmission to HuTg mice on subpassage, the efficiency of mouse-to-mouse transmission of BASE appears to be low when mice express human rather than bovine PrP.
Carson, C; McKay, J S; Brooks, H W; Kelly, D F; Stidworthy, M F; Wibbelt, G; Morgan, K L
This paper addresses the issues of tracing and compliance encountered in setting up and maintaining a UK-wide 5-year observational study of beef cattle. The 5-year prospective study was initiated in 1997 to investigate the occurrence of bovine spongiform encephalopathy (BSE) in a single herd of pedigree Aberdeen Angus cattle, in which BSE had been detected at low prevalence. The study was given the acronym ULiSES (University of Liverpool Spongiform Encephalopathy Scheme). All cattle present on the farm at the start of the scheme were registered as members of the study population (n=320), as were all calves subsequently born on the farm (n=350). Animals that were sold (n=291) were traced and monitored at destination farms. Farmers were requested to give advance notification of slaughter of any ULiSES animal and an attempt was made to collect post-mortem samples of nervous tissue, peripheral lymphoid tissue and striated muscle from all animals in the scheme at the time of slaughter, death or euthanasia. Sections of medulla were examined (by standard histopathological techniques) for the presence of spongiform change. Remaining samples were stored at -70 degrees C for future investigation by alternative tests. At the halfway point of the scheme in October 1999, 75.2% (506/673) of the study population was still alive; 42% (284) of the population was still alive on the study farm and 33% (222) was distributed on other farms throughout the UK. Complete sets of specimens had been recovered from 77% (129/167) of dead animals. All brainstem sections were negative by histopathological examination. No suspect cases of BSE were reported in ULiSES animals. Failure to recover specimens occurred principally in animals which had left the study farm. The main cause of specimen loss was a failure of compliance in a small number of individuals who had purchased large numbers of ULiSES animals, and subsequently slaughtered them without contacting the University. Despite this, farmer
Reid Hugh W
Full Text Available Abstract Background 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. Results Here we show that European red deer (Cervus elaphus elaphus 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 (PrPd 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 Conclusion 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
Suardi, Silvia; Vimercati, Chiara; Casalone, Cristina; Gelmetti, Daniela; Corona, Cristiano; Iulini, Barbara; Mazza, Maria; Lombardi, Guerino; Moda, Fabio; Ruggerone, Margherita; Campagnani, Ilaria; Piccoli, Elena; Catania, Marcella; Groschup, Martin H; Balkema-Buschmann, Anne; Caramelli, Maria; Monaco, Salvatore; Zanusso, Gianluigi; Tagliavini, Fabrizio
The amyloidotic form of bovine spongiform encephalopathy (BSE) termed BASE is caused by a prion strain whose biological properties differ from those of typical BSE, resulting in a clinically and pathologically distinct phenotype. Whether peripheral tissues of BASE-affected cattle contain infectivity is unknown. This is a critical issue since the BASE prion is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible. We carried out bioassays in transgenic mice overexpressing bovine PrP (Tgbov XV) and found infectivity in a variety of skeletal muscles from cattle with natural and experimental BASE. Noteworthy, all BASE muscles used for inoculation transmitted disease, although the attack rate differed between experimental and natural cases (∼70% versus ∼10%, respectively). This difference was likely related to different prion titers, possibly due to different stages of disease in the two conditions, i.e. terminal stage in experimental BASE and pre-symptomatic stage in natural BASE. The neuropathological phenotype and PrP(res) type were consistent in all affected mice and matched those of Tgbov XV mice infected with brain homogenate from natural BASE. The immunohistochemical analysis of skeletal muscles from cattle with natural and experimental BASE showed the presence of abnormal prion protein deposits within muscle fibers. Conversely, Tgbov XV mice challenged with lymphoid tissue and kidney from natural and experimental BASE did not develop disease. The novel information on the neuromuscular tropism of the BASE strain, efficiently overcoming species barriers, underlines the relevance of maintaining an active surveillance.
Full Text Available To date, bovine spongiform encephalopathy (BSE and its human counterpart, variant Creutzfeldt-Jakob disease, have been associated with a single prion strain. This strain is characterised by a unique and remarkably stable biochemical profile of abnormal protease-resistant prion protein (PrP(res isolated from brains of affected animals or humans. However, alternate PrP(res signatures in cattle have recently been discovered through large-scale screening. To test whether these also represent separate prion strains, we inoculated French cattle isolates characterised by a PrP(res of higher apparent molecular mass--called H-type--into transgenic mice expressing bovine or ovine PrP. All mice developed neurological symptoms and succumbed to these isolates, showing that these represent a novel strain of infectious prions. Importantly, this agent exhibited strain-specific features clearly distinct from that of BSE agent inoculated to the same mice, which were retained on further passage. Moreover, it also differed from all sheep scrapie isolates passaged so far in ovine PrP-expressing mice. Our findings therefore raise the possibility that either various prion strains may exist in cattle, or that the BSE agent has undergone divergent evolution in some animals.
Almeida, Luciane M; Basu, Urmila; Khaniya, Bina; Taniguchi, Masaaki; Williams, John L; Moore, Stephen S; Guan, Le Luo
The identification of variations in gene expression in response to bovine spongiform encephalopathy (BSE) may help to elucidate the mechanisms of neuropathology and prion replication and discover biomarkers for disease. In this study, genes that are differentially expressed in the caudal medulla tissues of animals infected with different doses of PrP(BSE) at 12 and 45 mo post infection were compared using array containing 24,000 oligonucleotide probes. Data analysis identified 966 differentially expressed (DE) genes between control and infected animals. Genes identified in at least two of four experiments (control versus 1-g infected animals at 12 and 45-mo; control versus 100-g infected animals at 12 and 45 mo) were considered to be the genes that may be associated with BSE disease. From the 176 DE genes associated with BSE, 84 had functions described in the Gene Ontology (GO) database. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of 14 genes revealed that prion infection may cause dysfunction of several different networks, including extracellular matrix (ECM), cell adhesion, neuroactive ligand-receptor interaction, complement and coagulation cascades, MAPK signaling, neurodegenerative disorder, SNARE interactions in vesicular transport, and the transforming growth factor (TGF) beta signaling pathways. The identification of DE genes will contribute to a better understanding of the molecular mechanisms of neuropathology in bovine species. Additional studies on larger number of animals are in progress in our laboratory to investigate the roles of these DE genes in pathogenesis of BSE.
Nomura, Sachiko; Miyasho, Taku; Maeda, Naoyuki; Doh-ura, Katsumi; Yokota, Hiroshi
It is desirable to make the diagnosis in live cattle with bovine spongiform encephalopathy (BSE), and thus surrogate markers for the disease have been eagerly sought. Serum proteins from BSE cattle were analyzed by 2-D Western blotting and TOF-MS. Autoantibodies against proteins in cytoskeletal fractions prepared from normal bovine brains were found in the sera of BSE cattle. The protein recognized was identified to be glial fibrillary acidic protein (GFAP), which is expressed mainly in astrocytes in the brain. The antigen protein, GFAP, was also found in the sera of BSE cattle. The percentages of both positive sera in the autoantibody and GFAP were 44.0% for the BSE cattle, 0% for the healthy cattle, and 5.0% for the clinically suspected BSE-negative cattle. A significant relationship between the presence of GFAP and the expression of its autoantibody in the serum was recognized in the BSE cattle. These findings suggest a leakage of GFAP into the peripheral blood during neurodegeneration associated with BSE, accompanied by the autoantibody production, and might be useful in understanding the pathogenesis and in developing a serological diagnosis of BSE in live cattle.
Wrathall, A E; Brown, K F D; Sayers, A R; Wells, G A H; Simmons, M M; Farrelly, S S J; Bellerby, P; Squirrell, J; Spencer, Y I; Wells, M; Stack, M J; Bastiman, B; Pullar, D; Scatcherd, J; Heasman, L; Parker, J; Hannam, D A R; Helliwell, D W; Chree, A; Fraser, H
Semen from 13 bulls, eight with clinical bovine spongiform encephalopathy (BSE), was used to artificially inseminate (AI) 167 cows with clinical BSE, and their resultant embryos were collected non-surgically seven days after AI. The viable and non-viable embryos with intact zonae pellucidae were washed 10 times (as recommended by the International Embryo Transfer Society) then frozen. Later, 587 of the viable embryos were transferred singly into 347 recipient heifers imported from New Zealand, and 266 live offspring were born of which 54.1 per cent had a BSE-positive sire and a BSE-positive dam. The recipients were monitored for clinical signs of BSE for seven years after the transfer, and the offspring were monitored for seven years after birth. Twenty-seven of the recipients and 20 offspring died while being monitored but none showed signs of BSE. Their brains, and the brains of the recipients and offspring killed after seven years, were examined for BSE by histopathology, PrP immunohistochemistry, and by electron microscopy for scrapie-associated fibrils. They were all negative. In addition, 1020 non-viable embryos were sonicated and injected intracerebrally into susceptible mice (20 embryos per mouse) which were monitored for up to 700 days, after which their brains were examined for spongiform lesions. They were all negative. It is concluded that embryos are unlikely to carry BSE infectivity even if they have been collected at the end-stage of the disease, when the risk of maternal transmission is believed to be highest.
... been fed ruminant protein, other than milk protein, during their lifetime; The bovines from which the... from animals that are not known to have been fed ruminant protein, other than milk protein, during... community is that the agent is an abnormal form of a normal protein known as cellular prion protein. The...
Thuring, C M A; van Keulen, L J M; Langeveld, J P M; Vromans, M E W; van Zijderveld, F G; Sweeney, T
Sheep are susceptible experimentally to bovine spongiform encephalopathy (BSE), the clinical signs being indistinguishable from those of scrapie. Because of the possibility of natural ovine BSE infection, laboratory tests are needed to distinguish between scrapie and BSE infection. The objectives of this study were to determine whether (1) PrPSc accumulates in biopsy samples of the tonsil or third eyelid, or both, of BSE-infected sheep before the appearance of clinical disease, and (2) such samples from BSE- and scrapie-infected sheep differ in respect of PrPSc accumulations. Homozygous ARQ sheep (n = 10) were dosed orally at 4-5 months of age with a brain homogenate from BSE-infected cattle. Third eyelid and tonsillar biopsy samples were taken at macrophages (TBMs) between BSE- and scrapie-infected sheep were detected with anti-peptide antibodies directed towards amino acids 93-106 of the ovine prion protein: thus, PrPSc appeared as single granules in TBMs of tonsillar sections from BSE-infected sheep, whereas clusters of PrPSc granules were observed within TBMs in the tonsils of scrapie-infected sheep. In contrast, antibodies against epitopes situated N- and C-terminally from the 93-106 region of the ovine prion protein revealed no differences between BSE- and scrapie-infected sheep in terms of PrPSc granules in TBMs.
Al-Zoughool, Mustafa; Cottrell, David; Elsaadany, Susie; Murray, Noel; Oraby, Tamer; Smith, Robert; Krewski, Daniel
When the bovine spongiform encephalopathy (BSE) epidemic first emerged in the United Kingdom in the mid 1980s, the etiology of animal prion diseases was largely unknown. Risk management efforts to control the disease were also subject to uncertainties regarding the extent of BSE infections and future course of the epidemic. As understanding of BSE increased, mathematical models were developed to estimate risk of BSE infection and to predict reductions in risk in response to BSE control measures. Risk models of BSE-transmission dynamics determined disease persistence in cattle herds and relative infectivity of cattle prior to onset of clinical disease. These BSE models helped in understanding key epidemiological features of BSE transmission and dynamics, such as incubation period distribution and age-dependent infection susceptibility to infection with the BSE agent. This review summarizes different mathematical models and methods that have been used to estimate risk of BSE, and discusses how such risk projection models have informed risk assessment and management of BSE. This review also provides some general insights on how mathematical models of the type discussed here may be used to estimate risks of emerging zoonotic diseases when biological data on transmission of the etiological agent are limited.
Balkema-Buschmann, A; Ziegler, U; McIntyre, L; Keller, M; Hoffmann, C; Rogers, R; Hills, B; Groschup, M H
For almost two decades after the discovery of the first bovine spongiform encephalopathy (BSE) case, it was generally accepted that only one BSE strain existed globally. However, in 2004, two novel BSE forms (L-type and H-type) were separately identified in two different European Member States, forms that differed from the classical (C-type) form by their biochemical properties and by the pattern of PrP(Sc) deposition as determined by immunohistochemistry (IHC). 60 atypical BSE cases have been identified worldwide as of November 2010, including one H- and one L-type BSE case each in Germany. However, it was not known whether the biological properties (pathogenesis and agent distribution, as well as transmissibility to other species) of these novel forms were the same as in classical BSE cases. Eleven calves were thus challenged intracranially, five with the German H-type and six with German L-type BSE cases. The experimental design and the clinical studies, followed by laboratory testing, are described in this manuscript.
Jianhong E Mu; Bruce A McCarl; Amy Hagerman; David Bessler
This paper examines the U.S. meat demand impacts of the announced outbreaks of bovine spongiform encephalopathy (BSE) and avian inlfuenza (AI). Findings indicate that beef and chicken demand was negatively affected by BSE and AI disease outbreaks. Speciifcal y, in the short run, U.S. consumers shift demand due to both outbreaks but more so due to domestic disease outbreaks than for outbreaks occurring overseas-the impact of U.S. AI outbreaks is about 0.5%for beef and the impact of U.S. BSE cases is around–0.42%for beef and 0.4%for pork, respectively. Regarding the BSE shock on meat demand, there is a high rate of beef demand adjusted from disturbance to the long-run equilibrium and a lower adjustment rate for chicken demand because of the repeated outbreaks of AI worldwide. In the long run, information related to severe, persistently recurring overseas animal disease outbreaks changes U.S. consumers’ meat consumption patterns. Although effects of animal diseases on U.S. meat demand were statistical y signiifcant, the magnitudes were smal-the impact of WHO reported human death numbers for AI is 0.005%for beef,–0.002%for pork, and–0.006%for chicken and the impact of U.S. BSE cases is 1.1%for pork and–0.7%for chicken.
Yang, Jun; Goddard, Ellen
In this study the dynamics of risk perceptions related to bovine spongiform encephalopathy (BSE) held by Canadian consumers and cow-calf producers were evaluated. Since the first domestic case of BSE in 2003, Canadian consumers and cow-calf producers have needed to make decisions on whether or not their purchasing/production behavior should change. Such changes in their behavior may relate to their levels of risk perceptions about BSE, risk perceptions that may be evolving over time and be affected by BSE media information available. An econometric analysis of the behavior of consumers and cow-calf producers might identify the impacts of evolving BSE risk perceptions. Risk perceptions related to BSE are evaluated through observed market behavior, an approach that differs from traditional stated preference approaches to eliciting risk perceptions at a particular point in time. BSE risk perceptions may be specified following a Social Amplification of Risk Framework (SARF) derived from sociology, psychology, and economics. Based on the SARF, various quality and quantity indices related to BSE media information are used as explanatory variables in risk perception equations. Risk perceptions are approximated using a predictive difference approach as defined by Liu et al. (1998). Results showed that Canadian consumer and cow-calf producer risk perceptions related to BSE have been amplified or attenuated by both quantity and quality of BSE media information. Government policies on risk communications need to address the different roles of BSE information in Canadian consumers' and cow-calf producers' behavior.
Fukuda, S; Okada, H; Arai, S; Yokoyama, T; Mohri, S
Bovine spongiform encephalopathy (BSE) is characterized by the appearance of spongy lesions in the brain, particularly in the brainstem nuclei. This study evaluated the degenerative changes observed in the central auditory brainstem of BSE-challenged cattle. The neuropathological changes in the auditory brainstem nuclei were assessed by determining the severity of vacuolation and the presence of disease-associated prion protein (PrP(Sc)). Sixteen female Holstein-Friesian calves, 2-4 months of age, were inoculated intracerebrally with BSE agent. BSE-challenged animals developed the characteristic clinical signs of BSE approximately 18 months post inoculation (mpi) and advanced neurological signs after 22 mpi. Before the appearance of clinical signs (i.e. at 3, 10, 12 and 16 mpi), vacuolar change was absent or mild and PrP(Sc) deposition was minimal in the auditory brainstem nuclei. The two cattle sacrificed at 18 and 19 mpi had no clinical signs and showed mild vacuolar degeneration and moderate amounts of PrP(Sc) accumulation in the auditory brainstem pathway. In the animals challenged with BSE agent that developed clinical sings (i.e. after 20 mpi), spongy changes were more prominent in the nucleus of the inferior colliculus compared with the other nuclei of the auditory brainstem and the medial geniculate body. Neuropathological changes characterized by spongy lesions accompanied by PrP(Sc) accumulation in the auditory brainstem nuclei of BSE-infected cattle may be associated with hyperacusia.
Matsuura, Y; Iwamaru, Y; Masujin, K; Imamura, M; Mohri, S; Yokoyama, T; Okada, H
To investigate the topographical distribution and patterns of deposition of immunolabelled abnormal prion protein (PrP(Sc)), interspecies transmission of atypical L-type bovine spongiform encephalopathy (BSE) to Cheviot ewes (ARQ/ARQ genotype) was performed. L-type BSE was successfully transmitted via the intracerebral route to a ewe, with an incubation period of 1,562 days. Minimal vacuolar change was detected in the basal ganglia, thalamus and brainstem, and PrP(Sc) accumulated throughout the brain. The L-type BSE-affected sheep was characterized by conspicuous fine particulate deposits in the neuropil, particulate and/or granular intraneuronal and intraglial deposits, and the absence of PrP(Sc) plaques or stellate deposits. In addition, immunohistochemical and western blot analyses revealed that PrP(Sc) accumulation was present in peripheral nervous tissues (including the trigeminal ganglia and dorsal root ganglion) and adrenal glands, but was absent in lymphoid tissues. These results suggest that L-type BSE has distinct and distinguishable characteristics as well as PrP(Sc) tissue tropism in sheep.
Quimby, Alexandra E; Shamy, Michel C F
On February 11, 2015, the Canadian Food Inspection Agency announced that a cow born and raised in Alberta had tested positive for bovine spongiform encephalopathy (BSE), commonly known as mad cow disease. BSE is a prion disease of cattle that, when transmitted to humans, produces a fatal neurodegenerative disease known as variant Creutzfeldt-Jakob disease. We believe that this latest case of BSE in Canadian cattle suggests the timeliness of a review of the management of BSE in Canada from a historically and scientifically informed perspective. In this article, we ask: how did the Canadian management of BSE between 1990 and 2014 engage with the contemporary understanding of BSE's human health implications? We propose that Canadian policies largely ignored the implicit medical nature of BSE, treating it as a purely agricultural and veterinary issue. In this way, policies to protect Canadians were often delayed and incomplete, in a manner disturbingly reminiscent of Britain's failed management of BSE. Despite assurances to the contrary, it is premature to conclude that BSE (and with it the risk of variant Creutzfeldt-Jakob disease) is a thing of Canada's past: BSE remains very much an issue in Canada's present.
Okada, H; Sato, Y; Sata, T; Sakurai, M; Endo, J; Yokoyama, T; Mohri, S
Formalin-fixed and paraffin wax-embedded (FFPE) tissue sections are usually used for histopathological and immunohistochemical analyses in prion diseases in animals and man. However, formalin fixation cross-links proteins, reducing disease-associated prion protein (PrP(Sc)) immunolabelling. To detect PrP(Sc) in animals naturally affected with bovine spongiform encephalopathy (BSE) and scrapie, we applied minimal pretreatment with sodium hydroxide (NaOH). This simple pretreatment, combined with enzymatic digestion using proteinase K (PK), was equally effective in the detection of PrP(Sc) in FFPE tissue, and superior in terms of speed, compared with the usual autoclaving method. The most effective results, without any section loss, were obtained with 10 μg/ml PK in phosphate buffered saline containing 0.1% Triton-X at room temperature for 10 min and 150 mM NaOH at 60 °C for 10 min. By this simple procedure, PrP(Sc) was visualized in the brain of animals with BSE and scrapie using a range of anti-PrP primary antibodies.
A case of L-type-like atypical bovine spongiform encephalopathy was detected in 14-year-old Japanese black beef cattle (BSE/JP24). To clarify the biological and biochemical properties of the prion in BSE/JP24, we performed a transmission study with wild-type mice and bovinized transgenic mice (TgBoPrP). The BSE/JP24 prion was transmitted to TgBoPrP mice with the incubation period of 199.7 ± 3.4 days, which was shorter than that of classical BSE (C-BSE) (223.5 ± 13.5 days). Further, C-BSE was ...
Agerholm, J.S.; Tegtmeier, C.L.; Nielsen, T.K.
A survey of the laboratory findings in suspected cases of bovine spongiform encephalopathy (BSE) in Denmark from I June 1990 to '31 December 2000 is presented. During this period BSE was a notifiable disease, and the heads of suspected cases were submitted according to the legislation on BSE....... A total of 176 submissions were made, mostly from bovines with neurological disorders and mainly during the last 3 years of this period. Lesions or other laboratory findings consistent with severe neurological disorders were found in 115 cases. The most frequent diagnosis was encephalic 41 p listeriosis...
Full Text Available Abstract Background After bovine spongiform encephalopathy (BSE emerged in European cattle livestock in 1986 a fundamental question was whether the agent established also in the small ruminants' population. In Switzerland transmissible spongiform encephalopathies (TSEs in small ruminants have been monitored since 1990. While in the most recent TSE cases a BSE infection could be excluded, for historical cases techniques to discriminate scrapie from BSE had not been available at the time of diagnosis and thus their status remained unclear. We herein applied state-of-the-art techniques to retrospectively classify these animals and to re-analyze the affected flocks for secondary cases. These results were the basis for models, simulating the course of TSEs over a period of 70 years. The aim was to come to a statistically based overall assessment of the TSE situation in the domestic small ruminant population in Switzerland. Results In sum 16 TSE cases were identified in small ruminants in Switzerland since 1981, of which eight were atypical and six were classical scrapie. In two animals retrospective analysis did not allow any further classification due to the lack of appropriate tissue samples. We found no evidence for an infection with the BSE agent in the cases under investigation. In none of the affected flocks, secondary cases were identified. A Bayesian prevalence calculation resulted in most likely estimates of one case of BSE, five cases of classical scrapie and 21 cases of atypical scrapie per 100'000 small ruminants. According to our models none of the TSEs is considered to cause a broader epidemic in Switzerland. In a closed population, they are rather expected to fade out in the next decades or, in case of a sporadic origin, may remain at a very low level. Conclusions In summary, these data indicate that despite a significant epidemic of BSE in cattle, there is no evidence that BSE established in the small ruminant population in
Full Text Available The amyloidotic form of bovine spongiform encephalopathy (BSE termed BASE is caused by a prion strain whose biological properties differ from those of typical BSE, resulting in a clinically and pathologically distinct phenotype. Whether peripheral tissues of BASE-affected cattle contain infectivity is unknown. This is a critical issue since the BASE prion is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible. We carried out bioassays in transgenic mice overexpressing bovine PrP (Tgbov XV and found infectivity in a variety of skeletal muscles from cattle with natural and experimental BASE. Noteworthy, all BASE muscles used for inoculation transmitted disease, although the attack rate differed between experimental and natural cases (∼70% versus ∼10%, respectively. This difference was likely related to different prion titers, possibly due to different stages of disease in the two conditions, i.e. terminal stage in experimental BASE and pre-symptomatic stage in natural BASE. The neuropathological phenotype and PrP(res type were consistent in all affected mice and matched those of Tgbov XV mice infected with brain homogenate from natural BASE. The immunohistochemical analysis of skeletal muscles from cattle with natural and experimental BASE showed the presence of abnormal prion protein deposits within muscle fibers. Conversely, Tgbov XV mice challenged with lymphoid tissue and kidney from natural and experimental BASE did not develop disease. The novel information on the neuromuscular tropism of the BASE strain, efficiently overcoming species barriers, underlines the relevance of maintaining an active surveillance.
Full Text Available Abstract Background Transmission of the prion disease bovine spongiform encephalopathy (BSE occurred accidentally to cattle and several other mammalian species via feed supplemented with meat and bone meal contaminated with infected bovine tissue. Prior to United Kingdom controls in 1996 on the feeding of mammalian meat and bone meal to farmed animals, the domestic chicken was potentially exposed to feed contaminated with the causal agent of BSE. Although confirmed prion diseases are unrecorded in avian species a study was undertaken to transmit BSE to the domestic chicken by parenteral and oral inoculations. Transmissibility was assessed by clinical monitoring, histopathological examinations, detection of a putative disease form of an avian prion protein (PrP in recipient tissues and by mouse bioassay of tissues. Occurrence of a progressive neurological syndrome in the primary transmission study was investigated by sub-passage experiments. Results No clinical, pathological or bioassay evidence of transmission of BSE to the chicken was obtained in the primary or sub-passage experiments. Survival data showed no significant differences between control and treatment groups. Neurological signs observed, not previously described in the domestic chicken, were not associated with significant pathology. The diagnostic techniques applied failed to detect a disease associated form of PrP. Conclusion Important from a risk assessment perspective, the present study has established that the domestic chicken does not develop a prion disease after large parenteral exposures to the BSE agent or after oral exposures equivalent to previous exposures via commercial diets. Future investigations into the potential susceptibility of avian species to mammalian prion diseases require species-specific immunochemical techniques and more refined experimental models.
Yokoyama, Takashi; Masujin, Kentaro; Yamakawa, Yoshio; Sata, Tetsutaro; Murayama, Yuichi; Shu, Yujing; Okada, Hiroyuki; Mohri, Shirou; Shinagawa, Morikazu
Bovine spongiform encephalopathy (BSE) is caused by a prion that primarily consists of an abnormal isoform of the prion protein (PrP(Sc)). Since PrP(Sc) is partially resistant to proteolytic digestion, the routine diagnosis of BSE is based on the immunological detection of the proteinase K (PK)-resistant moiety of PrP(Sc) (PrP(core)). However, transmission studies are indispensable in order to demonstrate prion infectivity and to analyze prion characteristics. Transmission experiments were accordingly performed on 2 young BSE cases (BSE/JP8, BSE/JP9) and 1 suspected BSE case (Suspended-1) that were detected by the BSE screening program in Japan. In this study, we attempted to transmit the prion from these 3 animals by using transgenic mice overexpressing bovine PrP (TgBoPrP). In spite of the use of BSE-sensitive transgenic mice, none of the mice developed neurological signs nor accumulated PrP(Sc) in their brains for more than 600 days post-inoculation, even with subsequent blind passages. The results of a dilution experiment using the classical BSE prion indicated that prion infectivity in these 3 cattle was below the detection limit of 10(3.0) LD(50)/g.
Jeffrey, Martin; Witz, Janey P; Martin, Stuart; Hawkins, Steve A C; Bellworthy, Sue J; Dexter, Glenda E; Thurston, Lisa; González, Lorenzo
Sheep are susceptible to the bovine spongiform encephalopathy (BSE) agent and in the UK they may have been exposed to BSE via contaminated meat and bone meal. An experimental sheep flock was established to determine whether ovine BSE could be naturally transmitted under conditions of intensive husbandry. The flock consisted of 113 sheep of different breeds and susceptible PRNP genotypes orally dosed with BSE, 159 sheep subsequently born to them and 125 unchallenged sentinel controls. BSE was confirmed in 104 (92%) orally dosed sheep and natural transmission was recorded for 14 of 79 (18%) lambs born to BSE infected dams, with rates varying according to PRNP genotype. The likelihood of natural BSE transmission was linked to stage of incubation period of the dam: the attack rate for lambs born within 100 days of the death of BSE infected dams was significantly higher (9/22, 41%) than for the rest (5/57, 9%). Within the group of ewes lambing close to death, those rearing infected progeny (n = 8, for 9/12 infected lambs) showed a significantly greater involvement of lymphoid tissues than those rearing non-infected offspring (n = 8, for 0/10 infected lambs). Horizontal transmission to the progeny of non-infected mothers was recorded only once (1/205, 0.5%). This low rate of lateral transmission was attributed, at least partly, to an almost complete absence of infected placentas. We conclude that, although BSE can be naturally transmitted through dam-lamb close contact, the infection in this study flock would not have persisted due to low-efficiency maternal and lateral transmissions.
Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano
Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions. PMID
Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano; Legname, Giuseppe
Prion diseases, such as bovine spongiform encephalopathies (BSE), are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD), a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE) is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE) have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic interventions.
Nwankiti, O O; Ikeh, E I; Asala, O; Seuberlich, T
Bovine spongiform encephalopathy (BSE), popularly known as 'mad cow disease', led to an epidemic in Europe that peaked in the mid-1990s. Its impact on developing countries, such as Nigeria, has not been fully established as information on livestock and surveillance has eluded those in charge of this task. The BSE risk to Nigeria's cattle population currently remains undetermined, which has resulted in international trade restrictions on commodities from the cattle population. This is mainly because of a lack of updated BSE risk assessments and disease surveillance data. To evaluate the feasibility of BSE surveillance in Nigeria, we carried out a pilot study targeting cattle that were presented for emergency or casualty slaughter. In total, 1551 cattle of local breeds, aged 24 months and above were clinically examined. Ataxia, recumbency and other neurological signs were topmost on our list of criteria. A total of 96 cattle, which correspond to 6.2%, presented clinical signs that supported a suspect of BSE. The caudal brainstem tissues of these animals were collected post-mortem and analysed for the disease-specific form of the prion protein using a rapid test approved by the International Animal Health Organization (OIE). None of the samples were positive for BSE. Although our findings do not exclude the presence of BSE in Nigeria, they do demonstrate that targeted sampling of clinically suspected cases of BSE is feasible in developing countries. In addition, these findings point to the possibility of implementing clinical monitoring schemes for BSE and potentially other diseases with grave economic and public health consequences.
Matsuura, Yuichi; Ishikawa, Yukiko; Bo, Xiao; Murayama, Yuichi; Yokoyama, Takashi [Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856 (Japan); Somerville, Robert A. [The Roslin Institute and Royal (Dick) School of Veterinary Studies, Roslin, Midlothian, EH25 9PS (United Kingdom); Kitamoto, Tetsuyuki [Division of CJD Science and Technology, Department of Prion Research, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba, Sendai 980-8575 (Japan); Mohri, Shirou, E-mail: email@example.com [Prion Disease Research Center, National Institute of Animal Health, 3-1-5 Kannondai, Tsukuba, Ibaraki 305-0856 (Japan)
Highlights: ► We quantitatively analyzed wet-heat inactivation of the BSE agent. ► Infectivity of the BSE macerate did not survive 155 °C wet-heat treatment. ► Once the sample was dehydrated, infectivity was observed even at 170 °C. ► A quantitative PMCA assay was used to evaluate the degree of BSE inactivation. - Abstract: The bovine spongiform encephalopathy (BSE) agent is resistant to conventional microbial inactivation procedures and thus threatens the safety of cattle products and by-products. To obtain information necessary to assess BSE inactivation, we performed quantitative analysis of wet-heat inactivation of infectivity in BSE-infected cattle spinal cords. Using a highly sensitive bioassay, we found that infectivity in BSE cattle macerates fell with increase in temperatures from 133 °C to 150 °C and was not detected in the samples subjected to temperatures above 155 °C. In dry cattle tissues, infectivity was detected even at 170 °C. Thus, BSE infectivity reduces with increase in wet-heat temperatures but is less affected when tissues are dehydrated prior to the wet-heat treatment. The results of the quantitative protein misfolding cyclic amplification assay also demonstrated that the level of the protease-resistant prion protein fell below the bioassay detection limit by wet-heat at 155 °C and higher and could help assess BSE inactivation. Our results show that BSE infectivity is strongly resistant to wet-heat inactivation and that it is necessary to pay attention to BSE decontamination in recycled cattle by-products.
Brown, Karen L; Mabbott, Neil A
The occurrence of variant Creutzfeldt-Jakob (vCJD) disease in humans was almost certainly the result of consumption of food contaminated with bovine spongiform encephalopathy (BSE) prions. Despite probable widespread exposure of the UK population to BSE-contaminated food in the 1980s, vCJD has been identified predominantly in young individuals, and there have been fewer cases of clinical disease than anticipated. The reasons for this are uncertain. Following peripheral exposure, many prions replicate within the lymphoid tissues before infecting the central nervous system. We have shown that the effects of host age on the microarchitecture of the spleen significantly impair susceptibility to mouse-adapted prions after peripheral exposure. The transmission of prions between different mammalian species is considered to be limited by the 'species barrier', which is dependent on several factors, including an intact immune system. Thus, cross-species prion transmission may be much less efficient in aged individuals. To test this hypothesis, we compared prion pathogenesis in groups of young (6-8 weeks old) and aged (600 days old) mice injected with primary BSE brain homogenate. We showed that prion pathogenesis was impaired dramatically in aged mice when compared with young animals. Whereas most young mice succumbed to clinical prion disease, all aged mice failed to develop clinical disease during their lifespans. However, the demonstration that prion accumulation was detected in the lymphoid tissues of some aged mice after injection with primary BSE brain homogenate, in the absence of clinical signs of prion disease, has important implications for human health.
Atypical forms of bovine spongiform encephalopathy (BSE) may be caused by different prions from classical BSE (C-BSE). In this study, we examined the susceptibility of mice overexpressing mouse and hamster chimeric prion protein (PrP) to L-type atypical BSE (L-BSE). None of the transgenic mice showed susceptibility to L-BSE, except mice overexpressing hamster PrP. We also examined the transmission properties of L-BSE in hamsters. The incubation period of hamsters intracerebrally inoculated wi...
Full Text Available Abstract Background Cattle with L-type (L-BSE and H-type (H-BSE atypical Bovine Spongiform encephalopathy (BSE were identified in 2003 in Italy and France respectively before being identified in other countries worldwide. As of December 2011, around 60 atypical BSE cases have currently been reported in 13 countries, with over one third in France. While the epidemiology of classical BSE (C-BSE has been widely described, atypical BSEs are still poorly documented, but appear to differ from C-BSE. We analysed the epidemiological characteristics of the 12 cases of L-BSE and 11 cases of H-BSE detected in France from January 2001 to late 2009 and looked for individual risk factors. As L-BSE cases did not appear to be homogeneously distributed throughout the country, two complementary methods were used: spatial analysis and regression modelling. L-BSE and H-BSE were studied separately as both the biochemical properties of their pathological prion protein and their features differ in animal models. Results The median age at detection for L-BSE and H-BSE cases was 12.4 (range 8.4-18.7 and 12.5 (8.3-18.2 years respectively, with no significant difference between the two distributions. However, this median age differed significantly from that of classical BSE (7.0 (range 3.5-15.4 years. A significant geographical cluster was detected for L-BSE. Among animals over eight years of age, we showed that the risk of being detected as a L-BSE case increased with age at death. This was not the case for H-BSE. Conclusion To the best of our knowledge this is the first study to describe the epidemiology of the two types of atypical BSE. The geographical cluster detected for L-BSE could be partly due to the age structure of the background-tested bovine population. Our regression analyses, which adjusted for the effect of age and birth cohort showed an age effect for L-BSE and the descriptive analysis showed a particular age structure in the area where the cluster was
Full Text Available Two distinct forms of atypical bovine spongiform encephalopathies (H-BSE and L-BSE can be distinguished from classical (C- BSE found in cattle based on biochemical signatures of disease-associated prion protein (PrPSc. H-BSE is transmissible to wild-type mice-with infected mice showing a long survival period that is close to their normal lifespan-but not to hamsters. Therefore, rodent-adapted H-BSE with a short survival period would be useful for analyzing H-BSE characteristics. In this study, we investigated the transmissibility of H-BSE to hamster prion protein transgenic (TgHaNSE mice with long survival periods. Although none of the TgHaNSE mice manifested the disease during their lifespan, PrPSc accumulation was observed in some areas of the brain after the first passage. With subsequent passages, TgHaNSE mice developed the disease with a mean survival period of 220 days. The molecular characteristics of proteinase K-resistant PrPSc (PrPres in the brain were identical to those observed in first-passage mice. The distribution of immunolabeled PrPSc in the brains of TgHaNSE mice differed between those infected with H-BSE as compared to C-BSE or L-BSE, and the molecular properties of PrPres in TgHaNSE mice infected with H-BSE differed from those of the original isolate. The strain-specific electromobility, glycoform profiles, and proteolytic cleavage sites of H-BSE in TgHaNSE mice were indistinguishable from those of C-BSE, in which the diglycosylated form was predominant. These findings indicate that strain-specific pathogenic characteristics and molecular features of PrPres in the brain are altered during cross-species transmission. Typical H-BSE features were restored after back passage from TgHaNSE to bovinized transgenic mice, indicating that the H-BSE strain was propagated in TgHaNSE mice. This could result from the overexpression of the hamster prion protein.
Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Yokoyama, Takashi
Two distinct forms of atypical bovine spongiform encephalopathies (H-BSE and L-BSE) can be distinguished from classical (C-) BSE found in cattle based on biochemical signatures of disease-associated prion protein (PrPSc). H-BSE is transmissible to wild-type mice-with infected mice showing a long survival period that is close to their normal lifespan-but not to hamsters. Therefore, rodent-adapted H-BSE with a short survival period would be useful for analyzing H-BSE characteristics. In this study, we investigated the transmissibility of H-BSE to hamster prion protein transgenic (TgHaNSE) mice with long survival periods. Although none of the TgHaNSE mice manifested the disease during their lifespan, PrPSc accumulation was observed in some areas of the brain after the first passage. With subsequent passages, TgHaNSE mice developed the disease with a mean survival period of 220 days. The molecular characteristics of proteinase K-resistant PrPSc (PrPres) in the brain were identical to those observed in first-passage mice. The distribution of immunolabeled PrPSc in the brains of TgHaNSE mice differed between those infected with H-BSE as compared to C-BSE or L-BSE, and the molecular properties of PrPres in TgHaNSE mice infected with H-BSE differed from those of the original isolate. The strain-specific electromobility, glycoform profiles, and proteolytic cleavage sites of H-BSE in TgHaNSE mice were indistinguishable from those of C-BSE, in which the diglycosylated form was predominant. These findings indicate that strain-specific pathogenic characteristics and molecular features of PrPres in the brain are altered during cross-species transmission. Typical H-BSE features were restored after back passage from TgHaNSE to bovinized transgenic mice, indicating that the H-BSE strain was propagated in TgHaNSE mice. This could result from the overexpression of the hamster prion protein.
Costa, Carme; Tortosa, Raül; Rodríguez, Agustín; Ferrer, Isidre; Torres, Juan Maria; Bassols, Anna; Pumarola, Martí
Aquaporins (AQP) are a family of transmembrane proteins that act as water selective channels. AQP1 and AQP4 are widely expressed in the central nervous system where they play several roles. Overexpression of AQP has been reported in some human and animal transmissible spongiform encephalopathies, but information is scanty about their distribution in the central nervous system in bovine spongiform encephalopathy (BSE). Double immunohistochemistry for AQP1, AQP4 and GFAP was developed in a transgenic mouse line overexpressing the bovine cellular prion protein (BoTg110), intracerebrally infected with cattle BSE. Western blot for AQP1 and AQP4, and immunohistochemistry for both AQP and GFAP were carried out in cases of BSE-diagnosed cattle as part of surveillance plan in Catalonia (Spain). A marked increase in AQP1 and AQP4 was observed in mice at the terminal stage of the disease, when they had a wide range of clinical signs, whereas no increase could be observed in the early stage before the onset of the clinical signs. In cattle which did not show evidence of clinical signs, both AQP already showed a great increase. The AQP overexpression correlated with GFAP-immunoreactive astrocytes and PrPres deposition in both cases. The results of this study suggest that AQP overexpression in glial cells could lead to an imbalance in water and ion homeostasis which could contribute to triggering the typical histopathological changes of BSE.
Full Text Available Abstract Background Heart rate variability (HRV analysis is a method to assess the function of the autonomic nervous system. Brainstem nuclei that influence HRV are affected by vacuolar changes and accumulation of disease-associated prion protein (PrPd in bovine spongiform encephalopathy (BSE resulting in clinical signs suggestive of an increased parasympathetic tone. It was hypothesised that BSE in cattle causes changes in the autonomic nervous system; this was tested by comparing HRV indices derived from 1048 electrocardiograms, which were recorded from 51 naturally or experimentally infected cattle with BSE confirmed by postmortem tests, 321 clinical suspect cases or cattle inoculated with potentially infectious tissue without disease confirmation and 78 BSE-free control cattle. Findings Statistically significant differences were found for low or high frequency power, their normalised values and ratio when the last recording prior to cull or repeated recordings were compared but only between male and female cattle of the three groups and not between groups of the same gender, even though BSE cases of each gender appeared to be more nervous during the recording. The same findings were made for heart rate, deviation from the mean RR interval and vasovagal tonus index when repeated recordings were compared. BSE cases with severe vacuolar changes in the parasympathetic nucleus of the vagus nerve had a significantly lower low:high frequency power ratio but not a lower heart rate than BSE cases with mild vacuolation, whereas severity of vacuolar changes in the solitary tract nucleus or intensity of PrPd accumulation in both nuclei did not appear to have any affect on either index. Abnormalities in the electrocardiogram were detected in 3% of the recordings irrespective of the BSE status; sinus arrhythmia was present in 93% of the remaining recordings. Conclusions HRV analysis was not useful to distinguish BSE-positive from BSE-negative cattle
Sisó, S; Martin, S; Konold, T; Hawkins, S A C; Thurston, L; Simmons, M M; Stack, M J; Jeffrey, M; González, L
In sheep infected experimentally with the bovine spongiform encephalopathy (BSE) agent, amplification of infectivity in peripheral organs during early preclinical stages is thought to contribute to high titres of the agent being detected in blood, with subsequent haematogenous neuroinvasion through the circumventricular organs (CVOs). In contrast, little disease-associated prion protein (PrP(d)) or infectivity is detected in the peripheral tissues of cattle during the preclinical and clinical stages of BSE. The aim of this study was to investigate immunohistochemically the role of haematogenous neuroinvasion in cattle with spontaneously arising and experimentally induced BSE. There was almost complete absence of PrP(d) in the peripheral organs of BSE infected cattle. Additionally, there was minimal involvement of the CVOs during preclinical disease and there was progressive caudorostral accumulation of PrP(d) in the brain. These findings do not support haematogenous neuroinvasion in the bovine disease.
Schwermer, H.; Brülisauer, F.; Koeijer, de A.A.; Heim, D.
The effectiveness of two measures against Bovine Spongiform Encephalopathy (BSE), the compulsory processing of animal by products to meat and bone mea (MBM) at 133 °C under 3 bars of pressure for 20 minutes in February 1993 and the exclusion offallen stock, heads with eyes and spinal cord of cattle
Sharpe, A.; McElroy, M.; Langeveld, J.P.M.; Bassett, H.; O'Donoghue, A.M.; Sweeney, T.
Since scrapie and bovine spongiform encephalopathy (BSE) in sheep are clinicopathologically indistinguishable, BSE in sheep may have been misdiagnosed as scrapie. Disease-specific prion protein (PrPd) patterns in archival tissues of 38 Irish ARQ/ARQ sheep diagnosed as scrapie-affected were compared
Guldimann, Claudia; Gsponer, Michaela; Drögemüller, Cord; Oevermann, Anna; Seuberlich, Torsten
The significance of atypical bovine spongiform encephalopathies (BSE) in cattle for controlling the BSE epidemic is poorly understood. Here we report a case of atypical H-type BSE in a cow born after the implementation of the reinforced feed ban in Europe. This supports an etiology of H-type BSE unrelated to that of classical BSE.
M Heather West Greenlee
Full Text Available Bovine spongiform encephalopathy (BSE belongs to a group of fatal, transmissible protein misfolding diseases known as transmissible spongiform encephalopathies (TSEs. All TSEs are caused by accumulation of misfolded prion protein (PrPSc throughout the central nervous system (CNS, which results in neuronal loss and ultimately death. Like other protein misfolding diseases including Parkinson's disease and Alzheimer's disease, TSEs are generally not diagnosed until the onset of disease after the appearance of unequivocal clinical signs. As such, identification of the earliest clinical signs of disease may facilitate diagnosis. The retina is the most accessible part of the central nervous system, and retinal pathology in TSE affected animals has been previously reported. Here we describe antemortem changes in retinal function and morphology that are detectable in BSE inoculated animals several months (up to 11 months prior to the appearance of any other signs of clinical disease. We also demonstrate that differences in the severity of these clinical signs reflect the amount of PrPSc accumulation in the retina and the resulting inflammatory response of the tissue. These results are the earliest reported clinical signs associated with TSE infection and provide a basis for understanding the pathology and evaluating therapeutic interventions.
Greenlee, M Heather West; Smith, Jodi D; Platt, Ekundayo M; Juarez, Jessica R; Timms, Leo L; Greenlee, Justin J
Bovine spongiform encephalopathy (BSE) belongs to a group of fatal, transmissible protein misfolding diseases known as transmissible spongiform encephalopathies (TSEs). All TSEs are caused by accumulation of misfolded prion protein (PrPSc) throughout the central nervous system (CNS), which results in neuronal loss and ultimately death. Like other protein misfolding diseases including Parkinson's disease and Alzheimer's disease, TSEs are generally not diagnosed until the onset of disease after the appearance of unequivocal clinical signs. As such, identification of the earliest clinical signs of disease may facilitate diagnosis. The retina is the most accessible part of the central nervous system, and retinal pathology in TSE affected animals has been previously reported. Here we describe antemortem changes in retinal function and morphology that are detectable in BSE inoculated animals several months (up to 11 months) prior to the appearance of any other signs of clinical disease. We also demonstrate that differences in the severity of these clinical signs reflect the amount of PrPSc accumulation in the retina and the resulting inflammatory response of the tissue. These results are the earliest reported clinical signs associated with TSE infection and provide a basis for understanding the pathology and evaluating therapeutic interventions.
Eric M Nicholson
Full Text Available BACKGROUND: Bovine spongiform encephalopathy (BSE is a transmissible spongiform encephalopathy (TSE of cattle. Classical BSE is associated with ingestion of BSE-contaminated feedstuffs. H- and L-type BSE, collectively known as atypical BSE, differ from classical BSE by displaying a different disease phenotype and they have not been linked to the consumption of contaminated feed. Interestingly, the 2006 US H-type atypical BSE animal had a polymorphism at codon 211 of the bovine prion gene resulting in a glutamic acid to lysine substitution (E211K. This substitution is analogous a human polymorphism associated with the most prevalent form of heritable TSE in humans, and it is considered to have caused BSE in the 2006 US atypical BSE animal. In order to determine if this amino acid change is a heritable trait in cattle, we sequenced the prion alleles of the only known offspring of this animal, a 2-year-old heifer. PRINCIPAL FINDINGS: Sequence analysis revealed that both the 2006 US atypical BSE animal and its 2-year-old heifer were heterozygous at bovine prion gene nucleotides 631 through 633 for GAA (glutamic acid and AAA (lysine. Both animals carry the E211K polymorphism, indicating that the allele is heritable and may persist within the cattle population. CONCLUSIONS: This is the first evidence that the E211K polymorphism is a germline polymorphism, not a somatic mutation, suggesting BSE may be transmitted genetically in cattle. In the event that E211K proves to result in a genetic form of BSE, this would be the first indication that all 3 etiologic forms of TSEs (spontaneous, hereditary, and infectious are present in a non-human species. Atypical BSE arising as both genetic and spontaneous disease, in the context of reports that at least some forms of atypical BSE can convert to classical BSE in mice, suggests a cattle origin for classical BSE.
Bradley, Ray; Liberski, Paweł P
Bovine spongiform encephalopathy (BSE) is a zoonosis being the origin of variant Creutzfeldt-Jakob disease and an important cattle disease in its own right. This association has driven both the research into the disease and extensive epidemiological investigations of practical value. Not only has the occurrence of BSE has a serious effect on animal health and public health, it has also seriously interrupted trade in cattle and cattle products from affected countries. Since 2001, several additional European countries, Japan, Israel and Canada have reported BSE in native-born stock and this has led to a concern about the BSE status of countries that have imported cattle and cattle products from any affected country. A single case recently reported in the USA was in a cow imported from Canada, thus extending the risk of BSE occurrence into the North American continent as a whole. Extensive feed and offal bans have protected the food and feed chains in all countries with BSE, even though initially they tended to be leaky. Application of newly-developed, approved 'Rapid' tests for misfolded PrP in central nervous tissue of targeted, high-risk animals and slaughter cattle now provides the tools whereby the real incidence of the disease (and to a degree, infection) can be determined in an active surveillance programme. 'Rapid' testing also enables the progress of epidemics to be monitored in response to applied measures. In the EU, over 10 million cattle are tested annually. Analysis of the extensive data shows that it is the beginning of the end of the BSE epidemic in the UK; most European countries, Israel and Japan are close behind. The epidemic in North America (two cases to date) is at the beginning. Significant measures had already been adopted there to reduce the risk from recycling of infection via feed but it remains to be seen if they are watertight. Advice has been given to ensure that public health is protected and to monitor the epidemic by strategic use of
Okada, Hiroyuki; Miyazawa, Kohtaro; Fukuda, Shigeo; Iwamaru, Yoshifumi; Imamura, Morikazu; Masujin, Kentaro; Matsuura, Yuichi; Fujii, Takashi; Fujii, Kei; Kageyama, Soichi; Yoshioka, Miyako; Murayama, Yuichi; Yokoyama, Takashi
The aim of this study was to investigate the presence of disease-associated prion protein (PrP(Sc)) in the skeletal muscle of cattle infected with classical bovine spongiform encephalopathy (C-BSE). The study was carried out systematically in 12 different muscle samples from 43 (3 field and 40 experimental) cases of C-BSE; however, muscle spindles were not available in many of these cases. Therefore, analysis became restricted to a total of 31 muscles in 23 cattle. Even after this restriction, low levels of PrP(Sc) were detected in the muscle spindles of the masseter, intercostal, triceps brachii, psoas major, quadriceps femoris and semitendinosus muscles from 3 field and 6 experimental clinical-stage cases. The present data indicate that small amounts of PrP(Sc) are detectable by immunohistochemistry in the skeletal muscles of animals terminally affected with C-BSE.
Fast, Christine; Keller, Markus; Balkema-Buschmann, Anne; Hills, Bob; Groschup, Martin H
Recently we have described the distribution of bovine spongiform encephalopathy (BSE) infectivity and/or PrPSc in Peyer's patches (PP) of the small intestine of orally BSE infected cattle. In this follow-up study additional jejunal and ileal PP's and ileocaecal-junction tissue samples from 1, 4, and 24 months post infection (mpi) were examined by mouse (Tgbov XV) bioassay. Infectivity was demonstrated in ileal PP's 4 mpi and the distribution/extent of infectivity at 24 mpi was comparable to those seen at earlier time points, revealing no indication for a decline/clearance. These data are relevant for the definition of Specified Risk Materials in the context of the TSE legislation worldwide.
Basu, Urmila; Almeida, Luciane; Olson, N Eric; Meng, Yan; Williams, John L; Moore, Stephen S; Guan, Le Luo
Bovine spongiform encephalopathy (BSE) is a transmissible, fatal neurodegenerative disorder of cattle produced by prions. The use of excessive parallel sequencing for comparison of gene expression in bovine control and infected tissues may help to elucidate the molecular mechanisms associated with this disease. In this study, tag profiling Solexa sequencing was used for transcriptome analysis of bovine brain tissues. Replicate libraries were prepared from mRNA isolated from control and infected (challenged with 100 g of BSE-infected brain) medulla tissues 45 mo after infection. For each library, 5-6 million sequence reads were generated and approximately 67-70% of the reads were mapped against the Bovine Genome database to approximately 13,700-14,120 transcripts (each having at least one read). About 42-47% of the total reads mapped uniquely. Using the GeneSifter software package, 190 differentially expressed (DE) genes were identified (>2.0-fold change, p < .01): 73 upregulated and 117 downregulated. Seventy-nine DE genes had functions described in the Gene Ontology (GO) database and 16 DE genes were involved in 38 different pathways described in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Digital analysis expression by tag profiling may be a powerful approach to comprehensive transcriptome analysis to identify changes associated with disease progression, leading to a better understanding of the underlying mechanism of pathogenesis of BSE.
Okada, Hiroyuki; Iwamaru, Yoshifumi; Imamura, Morikazu; Masujin, Kentaro; Matsuura, Yuichi; Shimizu, Yoshihisa; Kasai, Kazuo; Mohri, Shirou; Yokoyama, Takashi; Czub, Stefanie
Atypical bovine spongiform encephalopathy (BSE) has recently been identified in Europe, North America, and Japan. It is classified as H-type and L-type BSE according to the molecular mass of the disease-associated prion protein (Pr(PSc)). To investigate the topographical distribution and deposition patterns of immunolabeled Pr(PSc), H-type BSE isolate was inoculated intracerebrally into cattle. H-type BSE was successfully transmitted to 3 calves, with incubation periods between 500 and 600 days. Moderate to severe spongiform changes were detected in the cerebral and cerebellar cortices, basal ganglia, thalamus, and brainstem. H-type BSE was characterized by the presence of PrP-immunopositive amyloid plaques in the white matter of the cerebrum, basal ganglia, and thalamus. Moreover, intraglial-type immunolabeled Pr(PSc) was prominent throughout the brain. Stellate-type immunolabeled Pr(PSc) was conspicuous in the gray matter of the cerebral cortex, basal ganglia, and thalamus, but not in the brainstem. In addition, Pr(PSc) accumulation was detected in the peripheral nervous tissues, such as trigeminal ganglia, dorsal root ganglia, optic nerve, retina, and neurohypophysis. Cattle are susceptible to H-type BSE with a shorter incubation period, showing distinct and distinguishable phenotypes of Pr(PSc) accumulation.
Zhao, Hui; Du, Yanli; Chen, Shunmei; Qing, Lili; Wang, Xiaoyan; Huang, Jingfei; Wu, Dongdong; Zhang, Yaping
Prion protein, encoded by the prion protein gene (PRNP), plays a crucial role in the pathogenesis of transmissible spongiform encephalopathies (TSEs). Several polymorphisms within the PRNP are known to be associated with influencing bovine spongiform encephalopathy (BSE) susceptibility in cattle, namely two insertion/deletion (indel) polymorphisms (a 23-bp indel in the putative promoter and a 12-bp indel in intron 1), the number of octapeptide repeats (octarepeats) present in coding sequence (CDS) and amino acid polymorphisms. The domestic buffaloes, Bubalus bubalis, are a ruminant involved in various aspects of agriculture. It is of interest to ask whether the PRNP polymorphisms differ between cattle and buffalo. In this study, we analyzed the previously reported polymorphisms associated with BSE susceptibility in Chinese buffalo breeds, and compared these polymorphisms in cattle with BSE, healthy cattle and buffalo by pooling data from the literature. Our analysis revealed three significant findings in buffalo: 1) extraordinarily low deletion allele frequencies of the 23- and 12-bp indel polymorphisms; 2) significantly low allelic frequencies of six octarepeats in CDS and 3) the presence of S4R, A16V, P54S, G108S, V123M, S154N and F257L substitutions in buffalo CDSs. Sequence alignments comparing the buffalo coding sequence to other species were analyzed using the McDonald-Kreitman test to reveal five groups (Bison bonasus, Bos indicus, Bos gaurus, Boselaphus tragocamelus, Syncerus caffer caffer) with significantly divergent non-synonymous substitutions from buffalo, suggesting potential divergence of buffalo PRNP and others. To the best of our knowledge this is the first study of PRNP polymorphisms associated with BSE susceptibility in Chinese buffalo. Our findings have provided evidence that buffaloes have a unique genetic background in the PRNP gene in comparison with cattle.
González, Lorenzo; Thorne, Leigh; Jeffrey, Martin; Martin, Stuart; Spiropoulos, John; Beck, Katy E; Lockey, Richard W; Vickery, Christopher M; Holder, Thomas; Terry, Linda
It is widely accepted that abnormal forms of the prion protein (PrP) are the best surrogate marker for the infectious agent of prion diseases and, in practice, the detection of such disease-associated (PrP(d)) and/or protease-resistant (PrP(res)) forms of PrP is the cornerstone of diagnosis and surveillance of the transmissible spongiform encephalopathies (TSEs). Nevertheless, some studies question the consistent association between infectivity and abnormal PrP detection. To address this discrepancy, 11 brain samples of sheep affected with natural scrapie or experimental bovine spongiform encephalopathy were selected on the basis of the magnitude and predominant types of PrP(d) accumulation, as shown by immunohistochemical (IHC) examination; contra-lateral hemi-brain samples were inoculated at three different dilutions into transgenic mice overexpressing ovine PrP and were also subjected to quantitative analysis by three biochemical tests (BCTs). Six samples gave 'low' infectious titres (10⁶·⁵ to 10⁶·⁷ LD₅₀ g⁻¹) and five gave 'high titres' (10⁸·¹ to ≥ 10⁸·⁷ LD₅₀ g⁻¹) and, with the exception of the Western blot analysis, those two groups tended to correspond with samples with lower PrP(d)/PrP(res) results by IHC/BCTs. However, no statistical association could be confirmed due to high individual sample variability. It is concluded that although detection of abnormal forms of PrP by laboratory methods remains useful to confirm TSE infection, infectivity titres cannot be predicted from quantitative test results, at least for the TSE sources and host PRNP genotypes used in this study. Furthermore, the near inverse correlation between infectious titres and Western blot results (high protease pre-treatment) argues for a dissociation between infectivity and PrP(res).
Panelli, Simona; Strozzi, Francesco; Capoferri, Rossana; Barbieri, Ilaria; Martinelli, Nicola; Capucci, Lorenzo; Lombardi, Guerino; Williams, John L
Bovine amyloidotic spongiform encephalopathy (BASE) is one of the recently discovered atypical forms of BSE, which is transmissible to primates, and may be the bovine equivalent of sporadic Creutzfeldt-Jacob disease (CJD) in humans. Although it is transmissible, it is unknown whether BASE is acquired through infection or arises spontaneously. In the present study, the gene expression of white blood cells (WBCs) from 5 cattle at 1 yr after oral BASE challenge was compared with negative controls using a custom microarray containing 43,768 unique gene probes. In total, 56 genes were found to be differentially expressed between BASE and control animals with a log fold change of 2 or greater. Of these, 39 were upregulated in BASE animals, while 17 were downregulated. The majority of these genes are related to immune function. In particular, BASE animals appeared to have significantly modified expression of genes linked to T- and B-cell development and activation, and to inflammatory responses. The potential impacts of these gene expression changes are described.
Vidal, Enric; Fernández-Borges, Natalia; Pintado, Belén; Ordóñez, Montserrat; Márquez, Mercedes; Fondevila, Dolors; Torres, Juan María; Pumarola, Martí; Castilla, Joaquín
Bovine spongiform encephalopathy (BSE) prions were responsible for an unforeseen epizootic in cattle which had a vast social, economic, and public health impact. This was primarily because BSE prions were found to be transmissible to humans. Other species were also susceptible to BSE either by natural infection (e.g., felids, caprids) or in experimental settings (e.g., sheep, mice). However, certain species closely related to humans, such as canids and leporids, were apparently resistant to BSE. In vitro prion amplification techniques (saPMCA) were used to successfully misfold the cellular prion protein (PrP(c)) of these allegedly resistant species into a BSE-type prion protein. The biochemical and biological properties of the new prions generated in vitro after seeding rabbit and dog brain homogenates with classical BSE were studied. Pathobiological features of the resultant prion strains were determined after their inoculation into transgenic mice expressing bovine and human PrP(C). Strain characteristics of the in vitro-adapted rabbit and dog BSE agent remained invariable with respect to the original cattle BSE prion, suggesting that the naturally low susceptibility of rabbits and dogs to prion infections should not alter their zoonotic potential if these animals became infected with BSE. This study provides a sound basis for risk assessment regarding prion diseases in purportedly resistant species.
Franz, Martin; Eiden, Martin; Balkema-Buschmann, Anne; Greenlee, Justin; Schatzl, Hermann; Fast, Christine; Richt, Jürgen; Hildebrandt, Jan-Peter; Groschup, Martin H
Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that mainly affects cattle. Transmission of BSE to humans caused a variant form of Creutzfeldt-Jakob disease. Following infection, the protease-resistant, disease-associated isoform of prion protein (PrP(Sc)) accumulates in the central nervous system and in other tissues. Many countries have defined bovine tissues that may contain prions as specified risk materials, which must not enter the human or animal food chains and therefore must be discarded. Ultrasensitive techniques such as protein misfolding cyclic amplification (PMCA) have been developed to detect PrP(Sc) when present in minuscule amounts that are not readily detected by other diagnostic methods such as immunohistochemistry or Western blotting. This study was conducted to determine when and where PrP(Sc) can be found by PMCA in cattle orally challenged with BSE. A total of 48 different tissue samples from four cattle infected orally with BSE at various clinical stages of disease were examined using a standardized PMCA protocol. The protocol used brain homogenate from bovine PrP transgenic mice (Tgbov XV) as substrate and three consecutive rounds of PMCA. Using this protocol, PrP(Sc) was found in the brain, spinal cord, nerve ganglia, optic nerve and Peyer's patches. The presence of PrP(Sc) was confirmed in adrenal glands, as well as in mesenteric lymph nodes - a finding that was reported recently by another group. Interestingly, additional positive results were obtained for the first time in the oesophagus, abomasum, rumen and rectum of clinically affected cattle.
Wilson, Rona; Plinston, Chris; Hunter, Nora; Casalone, Cristina; Corona, Cristiano; Tagliavini, Fabrizio; Suardi, Silvia; Ruggerone, Margherita; Moda, Fabio; Graziano, Silvia; Sbriccoli, Marco; Cardone, Franco; Pocchiari, Maurizio; Ingrosso, Loredana; Baron, Thierry; Richt, Juergen; Andreoletti, Olivier; Simmons, Marion; Lockey, Richard; Manson, Jean C; Barron, Rona M
The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle transmissible spongiform encephalopathies (TSEs) can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several novel TSEs in sheep, cattle and deer have been described and the risk posed to humans by these agents is currently unknown. In this study, we inoculated two forms of atypical BSE (BASE and H-type BSE), a chronic wasting disease (CWD) isolate and seven isolates of atypical scrapie into gene-targeted transgenic (Tg) mice expressing the human prion protein (PrP). Upon challenge with these ruminant TSEs, gene-targeted Tg mice expressing human PrP did not show any signs of disease pathology. These data strongly suggest the presence of a substantial transmission barrier between these recently identified ruminant TSEs and humans.
Plinston, Chris; Hart, Patricia; Hunter, Nora; Manson, Jean C; Barron, Rona M
Bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt-Jakob disease in humans have previously been shown to be caused by the same strain of transmissible spongiform encephalopathy agent. It is hypothesized that the agent spread to humans following consumption of food products prepared from infected cattle. Despite evidence supporting zoonotic transmission, mouse models expressing human prion protein (HuTg) have consistently shown poor transmission rates when inoculated with cattle BSE. Higher rates of transmission have however been observed when these mice are exposed to BSE that has been experimentally transmitted through sheep or goats, indicating that humans may potentially be more susceptible to BSE from small ruminants. Here we demonstrate that increased transmissibility of small ruminant BSE to HuTg mice was not due to replication of higher levels of infectivity in sheep brain tissue, and is instead due to other specific changes in the infectious agent.
Full Text Available Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE-infected female cynomolgus monkeys (Macaca fascicularis. The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c. infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001 which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity.
Ono, Fumiko; Tase, Naomi; Kurosawa, Asuka; Hiyaoka, Akio; Ohyama, Atsushi; Tezuka, Yukio; Wada, Naomi; Sato, Yuko; Tobiume, Minoru; Hagiwara, Ken'ichi; Yamakawa, Yoshio; Terao, Keiji; Sata, Tetsutaro
A low molecular weight type of atypical bovine spongiform encephalopathy (L-BSE) was transmitted to two cynomolgus macaques by intracerebral inoculation of a brain homogenate of cattle with atypical BSE detected in Japan. They developed neurological signs and symptoms at 19 or 20 months post-inoculation and were euthanized 6 months after the onset of total paralysis. Both the incubation period and duration of the disease were shorter than those for experimental transmission of classical BSE (C-BSE) into macaques. Although the clinical manifestations, such as tremor, myoclonic jerking, and paralysis, were similar to those induced upon C-BSE transmission, no premonitory symptoms, such as hyperekplexia and depression, were evident. Most of the abnormal prion protein (PrP(Sc)) was confined to the tissues of the central nervous system, as determined by immunohistochemistry and Western blotting. The PrP(Sc) glycoform that accumulated in the monkey brain showed a similar profile to that of L-BSE and consistent with that in the cattle brain used as the inoculant. PrP(Sc) staining in the cerebral cortex showed a diffuse synaptic pattern by immunohistochemistry, whereas it accumulated as fine and coarse granules and/or small plaques in the cerebellar cortex and brain stem. Severe spongiosis spread widely in the cerebral cortex, whereas florid plaques, a hallmark of variant Creutzfeldt-Jakob disease in humans, were observed in macaques inoculated with C-BSE but not in those inoculated with L-BSE.
Krejciova, Zuzana; Barria, Marcelo A; Jones, Michael; Ironside, James W; Jeffrey, Martin; González, Lorenzo; Head, Mark W
Prion diseases are rare fatal neurological conditions of humans and animals, one of which (variant Creutzfeldt-Jakob disease) is known to be a zoonotic form of the cattle disease bovine spongiform encephalopathy (BSE). What makes one animal prion disease zoonotic and others not is poorly understood, but it appears to involve compatibility between the prion strain and the host prion protein sequence. Concerns have been raised that the United Kingdom sheep flock may have been exposed to BSE early in the cattle BSE epidemic and that serial BSE transmission in sheep might have resulted in adaptation of the agent, which may have come to phenotypically resemble scrapie while maintaining its pathogenicity for humans. We have modeled this scenario in vitro. Extrapolation from our results suggests that if BSE were to infect sheep in the field it may, with time and in some sheep genotypes, become scrapie-like at the molecular level. However, the results also suggest that if BSE in sheep were to come to resemble scrapie it would lose its ability to affect humans.
Fukuda, Shigeo; Onoe, Sadao; Nikaido, Satoshi; Fujii, Kei; Kageyama, Soichi; Iwamaru, Yoshifumi; Imamura, Morikazu; Masujin, Kentaro; Matsuura, Yuichi; Shimizu, Yoshihisa; Kasai, Kazuo; Yoshioka, Miyako; Murayama, Yuichi; Mohri, Shirou; Yokoyama, Takashi; Okada, Hiroyuki
The pathologic disease-associated prion protein (PrP(Sc)) has been shown to be expressed in the central nervous system of Holstein cattle inoculated intracerebrally with 3 sources of classical bovine spongiform encephalopathy (BSE) isolates. Several regions of the brain and spinal cord were analyzed for PrP(Sc) expression by immunohistochemical and Western blotting analyses. Animals euthanized at 10 months post-inoculation (mpi) showed PrP(Sc) deposits in the brainstem and thalamus, but no vacuolation; this suggested that the BSE agent might exhibit area-dependent tropism in the brain. At 16 and 18 mpi, a small amount of vacuolation was detected in the brainstem and thalamus, but not in the cerebral cortices. At 20 to 24 mpi, when clinical symptoms were apparent, heavy PrP(Sc) deposits were evident throughout the brain and spinal cord. The mean time to the appearance of clinical symptoms was 19.7 mpi, and the mean survival time was 22.7 mpi. These findings show that PrP(Sc) accumulation was detected approximately 10 months before the clinical symptoms of BSE became apparent. In addition, the 3 sources of BSE prion induced no detectable differences in the clinical signs, incubation periods, neuroanatomical location of vacuoles, or distribution and pattern of PrP(Sc) depositions in the brain.
Strom, Alexander; Yutzy, Barbara; Kruip, Carina; Ooms, Mark; Schloot, Nanette C; Roden, Michael; Scott, Fraser W; Loewer, Johannes; Holznagel, Edgar
Obesity has become one of the largest public health challenges worldwide. Recently, certain bacterial and viral pathogens have been implicated in the pathogenesis of obesity. In the present study, we retrospectively analyzed clinical data, plasma samples and post-mortem tissue specimens derived from a risk assessment study in bovine spongiform encephalopathy (BSE)-infected female cynomolgus monkeys (Macaca fascicularis). The original study design aimed to determine minimal infectious doses after oral or intracerebral (i.c.) infection of macaques to assess the risk for humans. High-dose exposures resulted in 100% attack rates and a median incubation time of 4.7 years as described previously. Retrospective analyses of clinical data from high-dosed macaques revealed that foodborne BSE transmission caused rapid weight gain within 1.5 years post infection (β = 0.915; P<0.0001) which was not seen in age- and sex-matched control animals or i.c. infected animals. The rapid-onset obesity was not associated with impaired pancreatic islet function or glucose metabolism. In the early preclinical phase of oral transmission associated with body weight gain, prion accumulation was confined to the gastrointestinal tract. Intriguingly, immunohistochemical findings suggest that foodborne BSE transmission has a pathophysiological impact on gut endocrine cells which may explain rapid weight gain. To our knowledge, this is the first experimental model which clearly demonstrates that foodborne pathogens can induce obesity.
Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Yokoyama, Takashi
L-type bovine spongiform encephalopathy (L-BSE) is an atypical form of BSE that is transmissible to cattle and several lines of prion protein (PrP) transgenic mice, but not to wild-type mice. In this study, we examined the transmissibility of sheep-passaged L-BSE prions to wild-type mice. Disease-associated prion protein (PrP(Sc)) was detected in the brain and/or lymphoid tissues during the lifespan of mice that were asymptomatic subclinical carriers, indicating that wild-type mice were susceptible to sheep-passaged L-BSE. The morphological characteristics of the PrP(Sc) of sheep-passaged L-BSE included florid plaques that were distributed mainly in the cerebral cortex and hippocampus of subsequent passaged mice. The PrP(Sc) glycoform profiles of wild-type mice infected with sheep-passaged L-BSE were similar to those of the original isolate. The data indicate that sheep-passaged L-BSE has an altered host range and acquired transmissibility to wild-type mice.
Full Text Available Abstract Background The definite diagnosis of prion diseases such as Creutzfeldt-Jakob disease (CJD in humans or bovine spongiform encephalopathy (BSE in cattle currently relies on the post mortem detection of the pathological form of the prion protein (PrPSc in brain tissue. Infectivity studies indicate that PrPSc may also be present in body fluids, even at presymptomatic stages of the disease, albeit at concentrations well below the detection limits of currently available analytical methods. Results We developed a highly sensitive method for detecting prion protein aggregates that takes advantage of kinetic differences between seeded and unseeded polymerization of prion protein monomers. Detection of the aggregates was carried out by flow cytometry. In the presence of prion seeds, the association of labelled recombinant PrP monomers in plasma and serum proceeds much more efficiently than in the absence of seeds. In a diagnostic model system, synthetic PrP aggregates were detected down to a concentration of approximately 10-8 nM [0.24 fg/ml]. A specific signal was detected in six out of six available serum samples from BSE-positive cattle. Conclusion We have developed a method based on seed-dependent PrP fibril formation that shows promising results in differentiating a small number of BSE-positive serum samples from healthy controls. This method may provide the basis for an ante mortem diagnostic test for prion diseases.
Wells, G A H; Konold, T; Arnold, M E; Austin, A R; Hawkins, S A C; Stack, M; Simmons, M M; Lee, Y H; Gavier-Widén, D; Dawson, M; Wilesmith, J W
The dose-response of cattle exposed to the bovine spongiform encephalopathy (BSE) agent is an important component of modelling exposure risks for animals and humans and thereby, the modulation of surveillance and control strategies for BSE. In two experiments calves were dosed orally with a range of amounts of a pool of brainstems from BSE-affected cattle. Infectivity in the pool was determined by end-point titration in mice. Recipient cattle were monitored for clinical disease and, from the incidence of pathologically confirmed cases and their incubation periods (IPs), the attack rate and IP distribution according to dose were estimated. The dose at which 50 % of cattle would be clinically affected was estimated at 0.20 g brain material used in the experiment, with 95 % confidence intervals of 0.04-1.00 g. The IP was highly variable across all dose groups and followed a log-normal distribution, with decreasing mean as dose increased. There was no evidence of a threshold dose at which the probability of infection became vanishingly small, with 1/15 (7 %) of animals affected at the lowest dose (1 mg).
Tang, Yue; Xiang, Wei; Hawkins, Steve A C; Kretzschmar, Hans A; Windl, Otto
Bovine spongiform encephalopathy (BSE) is a fatal, transmissible, neurodegenerative disease of cattle. BSE can be transmitted experimentally between cattle through the oral route, and in this study, brain tissue samples from animals at different time points postinoculation were analyzed for changes in gene expression. The aims of this study were to identify differentially regulated genes during the progression of BSE using microarray-based gene expression profiling and to understand the effect of prion pathogenesis on gene expression. A total of 114 genes were found to be differentially regulated over the time course of the infection, and many of these 114 genes encode proteins involved in immune response, apoptosis, cell adhesion, stress response, and transcription. This study also revealed a broad correlation between gene expression profiles and the progression of BSE in cattle. At 21 months postinoculation, the largest number of differentially regulated genes was detected, suggesting that there are many pathogenic processes in the animal brain even prior to the detection of infectivity in the central nervous systems of these orally infected cattle. Moreover, evidence is presented to suggest that it is possible to predict the infectious status of animals using the expression profiles from this study.
Sugiura, Katsuaki; Murray, Noel; Shinoda, Naoki; Onodera, Takashi
Cattle slaughtered in Japan for human consumption, regardless of their age, have been tested for bovine spongiform encephalopathy (BSE) since October 2001. Beginning in April 2004, all fallen stock from 24 months of age also have been tested. We evaluated the impact of potential changes to the current BSE surveillance programs for both slaughter cattle and fallen stock using a simple stochastic model. We calculated the probability that a BSE-infected dairy cow, Wagyu beef animal, Wagyu-Holstein cross steer or heifer, or Holstein steer slaughtered for human consumption or arising as fallen stock would be tested and detected. Four surveillance strategies were explored for cattle slaughtered for human consumption, with the minimum age at testing set at 0, 21, 31, or 41 months. Three surveillance strategies were explored for fallen stock, with the minimum age at testing set at 24, 31, or 41 months. Increasing the minimum age of testing from 0 to 21 months for both dairy cattle and Wagyu beef cattle had very little impact on the probability that a BSE-infected animal slaughtered for human consumption would be detected. Although increasing the minimum age at testing from 21 to 31 or 41 months would lead to fewer slaughtered animals being tested, the impact on the probability of detecting infected animals would be insignificant. The probability of infected Wagyu-Holstein crosses and Holstein steers being detected at slaughter or as fallen stock would be very low under all surveillance strategies.
Hesketh, S; Sassoon, J; Knight, R; Hopkins, J; Brown, D R
Prion diseases, or transmissible spongiform encephalopathies, are neurodegenerative diseases that can only be accurately diagnosed by analysis of central nervous system tissue for the presence of an abnormal isoform of the prion protein known as PrP(Sc). Furthermore, these diseases have long incubation periods during which there are no clear symptoms but where the infectious agent could still be present in the tissues. Therefore, the development of diagnostic assays to detect a surrogate marker for the presence of prion disease is essential. Previous studies on mice experimentally infected with scrapie, an ovine spongiform encephalopathy, suggested that changes in the levels of Mn occur in the blood and brain before the onset of symptoms of the disease. To assess whether these findings have relevance to the animal diseases scrapie and bovine spongiform encephalopathy, tissues from bovine spongiform encephalopathy- and scrapie-infected cattle and sheep were analyzed for their metal content and compared with values for noninfected animals. In field cases and experimentally infected animals, elevated Mn was associated with prion infection. Although some central nervous system regions showed elevated Mn, other regions did not. The most consistent finding was an elevation of Mn in blood. This change was present in experimentally infected animals before the onset of symptoms. In scrapie-infected sheep, elevated Mn levels occurred regardless of the genotype of the sheep and were even detected in scrapie-resistant sheep in which no symptoms of disease were detected. These findings suggest that elevated blood Mn could be a potential diagnostic marker for prion infection even in the absence of apparent clinical disease.
Masujin, Kentaro; Shu, Yujing; Yamakawa, Yoshio; Hagiwara, Ken'ichi; Sata, Tetsutaro; Matsuura, Yuichi; Iwamaru, Yoshifumi; Imamura, Morikazu; Okada, Hiroyuki; Mohri, Shirou; Yokoyama, Takashi
A case of L-type-like atypical bovine spongiform encephalopathy was detected in 14-year-old Japanese black beef cattle (BSE/JP24). To clarify the biological and biochemical properties of the prion in BSE/JP24, we performed a transmission study with wild-type mice and bovinized transgenic mice (TgBoPrP). The BSE/JP24 prion was transmitted to TgBoPrP mice with the incubation period of 199.7 +/- 3.4 days, which was shorter than that of classical BSE (C-BSE) (223.5 +/- 13.5 days). Further, C-BSE was transmitted to wild-type mice with the incubation period of about 409 days, whereas BSE/JP24 prion inoculated mice showed no clinical signs up to 649 days. Severe vacuolation and a widespread and uniform distribution of PrP(Sc) were pathologically observed in the brain of BSE/JP24 prion affected TgBoPrP mice. The molecular weight and glycoform ratio of PrP(Sc) in BSE/JP24 were different from those in C-BSE, and PrP(Sc) in BSE/JP24 exhibited weaker proteinase K resistance than that in C-BSE. These findings revealed that the BSE/JP24 prion has distinct biological and biochemical properties reported for that of C-BSE. Interestingly, a shorter incubation period was observed at the subsequent passage of the BSE/JP24 prion to TgBoPrP mice (152.2 +/- 3.1 days). This result implies that BSE/JP24 prion has newly emerged and showed the possibility that L-type BSE prion might be classified into multiple strains.
In 2006, a case of H-type bovine spongiform encephalopathy (BSE-H) was diagnosed in a cow that was associated with a heritable polymorphism in the bovine prion protein gene (PRNP) resulting in a lysine for glutamine amino acid substitution at codon 211 (called E211K) of the prion protein. Although t...
Justin J Greenlee
Full Text Available The majority of bovine spongiform encephalopathy (BSE cases have been ascribed to the classical form of the disease. H-type and L-type BSE cases have atypical molecular profiles compared to classical BSE and are thought to arise spontaneously. However, one case of H-type BSE was associated with a heritable E211K mutation in the prion protein gene. The purpose of this study was to describe transmission of this unique isolate of H-type BSE when inoculated into a calf of the same genotype by the intracranial route. Electroretinograms were used to demonstrate preclinical deficits in retinal function, and optical coherence tomography was used to demonstrate an antemortem decrease in retinal thickness. The calf rapidly progressed to clinical disease (9.4 months and was necropsied. Widespread distribution of abnormal prion protein was demonstrated within neural tissues by western blot and immunohistochemistry. While this isolate is categorized as BSE-H due to a higher molecular mass of the unglycosylated PrP(Sc isoform, a strong labeling of all 3 PrP(Sc bands with monoclonal antibodies 6H4 and P4, and a second unglycosylated band at approximately 14 kDa when developed with antibodies that bind in the C-terminal region, it is unique from other described cases of BSE-H because of an additional band 23 kDa demonstrated on western blots of the cerebellum. This work demonstrates that this isolate is transmissible, has a BSE-H phenotype when transmitted to cattle with the K211 polymorphism, and has molecular features that distinguish it from other cases of BSE-H described in the literature.
Full Text Available Sheep are natural hosts of the prion disease, scrapie. They are also susceptible to experimental challenge with various scrapie strains and with bovine spongiform encephalopathy (BSE, which affects cattle and has been accidentally transmitted to a range of other species, including man. Incidence and incubation period of clinical disease in sheep following inoculation is controlled by the PRNP gene, which has different alleles defined on the basis of polymorphisms, particularly at codons 136, 154 and 171, although other codons are associated with survival time, and the exact responses of the sheep may be influenced by other breed-related differences. Here we report the results of a long term single study of experimental scrapie and BSE susceptibility of sheep of Cheviot, Poll Dorset and Suffolk breeds, originating from New Zealand and of a wide range of susceptible and resistant PRNP genotypes. Responses were compared with those of sheep from a closed Cheviot flock of UK origin (Roslin Cheviot flock. The unusually long observation period (6-8 years for most, but up to 12 years for others allows us to draw robust conclusions about rates of survival of animals previously regarded as resistant to infection, particularly PRNP heterozygotes, and is the most comprehensive such study reported to date. BSE inoculation by an intracerebral route produced disease in all genotype groups with differing incubation periods, although M112T and L141F polymorphisms seemed to give some protection. Scrapie isolate SSBP/1, which has the shortest incubation period in sheep with at least one VRQ PRNP allele, also produced disease following sub-cutaneous inoculation in ARQ/ARQ animals of New Zealand origin, but ARQ/ARQ sheep from the Roslin flock survived the challenge. Our results demonstrate that the links between PRNP genotype and clinical prion disease in sheep are much less secure than previously thought, and may break down when, for example, a different breed of
Houston, Fiona; Goldmann, Wilfred; Foster, James; González, Lorenzo; Jeffrey, Martin; Hunter, Nora
Sheep are natural hosts of the prion disease, scrapie. They are also susceptible to experimental challenge with various scrapie strains and with bovine spongiform encephalopathy (BSE), which affects cattle and has been accidentally transmitted to a range of other species, including man. Incidence and incubation period of clinical disease in sheep following inoculation is controlled by the PRNP gene, which has different alleles defined on the basis of polymorphisms, particularly at codons 136, 154 and 171, although other codons are associated with survival time, and the exact responses of the sheep may be influenced by other breed-related differences. Here we report the results of a long term single study of experimental scrapie and BSE susceptibility of sheep of Cheviot, Poll Dorset and Suffolk breeds, originating from New Zealand and of a wide range of susceptible and resistant PRNP genotypes. Responses were compared with those of sheep from a closed Cheviot flock of UK origin (Roslin Cheviot flock). The unusually long observation period (6-8 years for most, but up to 12 years for others) allows us to draw robust conclusions about rates of survival of animals previously regarded as resistant to infection, particularly PRNP heterozygotes, and is the most comprehensive such study reported to date. BSE inoculation by an intracerebral route produced disease in all genotype groups with differing incubation periods, although M112T and L141F polymorphisms seemed to give some protection. Scrapie isolate SSBP/1, which has the shortest incubation period in sheep with at least one VRQ PRNP allele, also produced disease following sub-cutaneous inoculation in ARQ/ARQ animals of New Zealand origin, but ARQ/ARQ sheep from the Roslin flock survived the challenge. Our results demonstrate that the links between PRNP genotype and clinical prion disease in sheep are much less secure than previously thought, and may break down when, for example, a different breed of sheep is moved
Chen, Chu-Chih; Wang, Yin-Han; Wu, Kuen-Yuh
To date, the variant Creutzfeldt-Jakob disease (vCJD) risk assessments that have been performed have primarily focused on predicting future vCJD cases in the United Kingdom, which underwent a bovine spongiform encephalopathy (BSE) epidemic between 1980 and 1996. Surveillance of potential BSE cases was also used to assess vCJD risk, especially in other BSE-prevalent EU countries. However, little is known about the vCJD risk for uninfected individuals who accidentally consume BSE-contaminated meat products in or imported from a country with prevalent BSE. In this article, taking into account the biological mechanism of abnormal prion PrP(res) aggregation in the brain, the probability of exposure, and the expected amount of ingested infectivity, we establish a stochastic mean exponential growth model of lifetime exposure through dietary intake. Given the findings that BSE agents behave similarly in humans and macaques, we obtained parameter estimates from experimental macaque data. We then estimated the accumulation of abnormal prions to assess lifetime risk of developing clinical signs of vCJD. Based on the observed number of vCJD cases and the estimated number of exposed individuals during the BSE epidemic period from 1980 to 1996 in the United Kingdom, an exposure threshold hypothesis is proposed. Given the age-specific risk of infection, the hypothesis explains the observations very well from an extreme-value distribution fitting of the estimated BSE infectivity exposure. The current BSE statistics in the United Kingdom are provided as an example.
Ahmet Hulusi DİNÇOĞLU
Full Text Available Abstract Bovine Spongiform Encephalopathy (BSE is a virulent disease which may infect by affecting the central nervous system (CNS tissues in cattle and causes degeneration in nerves. Central nervous system tissues such as brain and spinal cord which are classified as specified risk materials (SRMs are regarded to be main source of infection. The contamination of the meat with the specific risk materials (SRMs can occur in phases of slaughter, fragmentation of carcass and processing. This study was conducted in order to investigate the existence of CNS tissues in raw meat ball (cig kofte which is commonly consumed in the Southeastern Region of Turkey, particularly in Şanlıurfa. For this purpose, 145 samples of raw meat ball were tested. The enzyme-linked immunosorbent assay (ELISA kits (Ridascreen risk material 10/5, R-biofarm GmbH which determine glial fibrillary acidic protein (GFAP as determinant were used. As a result of the analyses, positivity was detected in 21 of totally 145 samples of raw meat ball (14.48%. 6 (4.14% of the samples gave low level of positivity (≥ 0.1 standard absorbance, 10 (6.90% gave medium level of positivity (>0.2 standard absorbance and 5 (3.45% gave high level of positivity (≥0.5 standard absorbance. As a consequence, meats are contaminated in any phase of both slaughter and meat production even if accidentally. Regarding this matter, necessary measures should be taken and hygiene rules should be applied.
Full Text Available Abstract Background Prion diseases such as bovine spongiform encephalopathies (BSE are transmissible neurodegenerative diseases which are presumably caused by an infectious conformational isoform of the cellular prion protein. Previous work has provided evidence that in murine prion disease the endogenous retrovirus (ERV expression is altered in the brain. To determine if prion-induced changes in ERV expression are a general phenomenon we used a non-human primate model for prion disease. Results Cynomolgus macaques (Macaca fasicularis were infected intracerebrally with BSE-positive brain stem material from cattle and allowed to develop prion disease. Brain tissue from the basis pontis and vermis cerebelli of the six animals and the same regions from four healthy controls were subjected to ERV expression profiling using a retrovirus-specific microarray and quantitative real-time PCR. We could show that Class I gammaretroviruses HERV-E4-1, ERV-9, and MacERV-4 increase expression in BSE-infected macaques. In a second approach, we analysed ERV-K-(HML-2 RNA and protein expression in extracts from the same cynomolgus macaques. Here we found a significant downregulation of both, the macaque ERV-K-(HML-2 Gag protein and RNA in the frontal/parietal cortex of BSE-infected macaques. Conclusions We provide evidence that dysregulation of ERVs in response to BSE-infection can be detected on both, the RNA and the protein level. To our knowledge, this is the first report on the differential expression of ERV-derived structural proteins in prion disorders. Our findings suggest that endogenous retroviruses may induce or exacerbate the pathological consequences of prion-associated neurodegeneration.
Stack Michael J
Full Text Available Abstract Background Various clinical protocols have been developed to aid in the clinical diagnosis of classical bovine spongiform encephalopathy (BSE, which is confirmed by postmortem examinations based on vacuolation and accumulation of disease-associated prion protein (PrPd in the brain. The present study investigated the occurrence and progression of sixty selected clinical signs and behaviour combinations in 513 experimentally exposed cattle subsequently categorised postmortem as confirmed or unconfirmed BSE cases. Appropriate undosed or saline inoculated controls were examined similarly and the data analysed to explore the possible occurrence of BSE-specific clinical expression in animals unconfirmed by postmortem examinations. Results Based on the display of selected behavioural, sensory and locomotor changes, 20 (67% orally dosed and 17 (77% intracerebrally inoculated pathologically confirmed BSE cases and 21 (13% orally dosed and 18 (6% intracerebrally inoculated but unconfirmed cases were considered clinical BSE suspects. None of 103 controls showed significant signs and were all negative on diagnostic postmortem examinations. Signs indicative of BSE suspects, particularly over-reactivity and ataxia, were more frequently displayed in confirmed cases with vacuolar changes in the brain. The display of several BSE-associated signs over time, including repeated startle responses and nervousness, was significantly more frequent in confirmed BSE cases compared to controls, but these two signs were also significantly more frequent in orally dosed cattle unconfirmed by postmortem examinations. Conclusions The findings confirm that in experimentally infected cattle clinical abnormalities indicative of BSE are accompanied by vacuolar changes and PrPd accumulation in the brainstem. The presence of more frequently expressed signs in cases with vacuolar changes is consistent with this pathology representing a more advanced stage of disease. That
Greenlee, Justin J; Smith, Jodi D; West Greenlee, M Heather; Nicholson, Eric M
The majority of bovine spongiform encephalopathy (BSE) cases have been ascribed to the classical form of the disease. H-type and L-type BSE cases have atypical molecular profiles compared to classical BSE and are thought to arise spontaneously. However, one case of H-type BSE was associated with a heritable E211K mutation in the prion protein gene. The purpose of this study was to describe transmission of this unique isolate of H-type BSE when inoculated into a calf of the same genotype by the intracranial route. Electroretinograms were used to demonstrate preclinical deficits in retinal function, and optical coherence tomography was used to demonstrate an antemortem decrease in retinal thickness. The calf rapidly progressed to clinical disease (9.4 months) and was necropsied. Widespread distribution of abnormal prion protein was demonstrated within neural tissues by western blot and immunohistochemistry. While this isolate is categorized as BSE-H due to a higher molecular mass of the unglycosylated PrP(Sc) isoform, a strong labeling of all 3 PrP(Sc) bands with monoclonal antibodies 6H4 and P4, and a second unglycosylated band at approximately 14 kDa when developed with antibodies that bind in the C-terminal region, it is unique from other described cases of BSE-H because of an additional band 23 kDa demonstrated on western blots of the cerebellum. This work demonstrates that this isolate is transmissible, has a BSE-H phenotype when transmitted to cattle with the K211 polymorphism, and has molecular features that distinguish it from other cases of BSE-H described in the literature.
Full Text Available The complex nature of prions has intrigued the scientific community during the last 70 years. Since the first indication of scrapie infectivity and the experimental transmission of the scrapie agent in 1937, prions and their associated transmissible spongiform encephalopathies (TSEs have been under constant investigation. TSEs are neurodegenerative and fatal diseases with no early diagnosis, treatment or cure. Despite their diverse presentations, all TSEs stem from the infectious, spontaneous or hereditary conversion of the host-encoded cellular prion protein PrP C into the pathogenic isoform PrP Sc. Based on the prion hypothesis, PrP C has the autocatalytic or induced capacity to change its secondary configuration from a mainly α-helix structure into predominant β-sheet configuration. Another enigmatic aspect of the prion biology is the potential physiological function of PrP C, a protein that is widely distributed in mammalian tissues and intensely expressed in the nervous system. PrP C has been associated to several biological roles including cellular adhesion, protection and differentiation. The unpredictable properties of the PrP Sc and the complex presentation of TSEs have opened many questions yet to be answered. The potential zoonotic transmission of the bovine spongiform encephalopathy (BSE has generated intense concern in the international community over animal product biosecurity. During the last years, research in prion biology has mainly focused on determination of the pathogenesis of TSEs and the development of diagnostic and therapeutic methods. However, further research in prion biology is required in order to understand the complex nature of TSEs and how these diseases can be controlled.La compleja naturaleza de los priones ha intrigado a la comunidad científica durante los últimos 70 años. Desde el primer hallazgo de la infectividad del scrapie y la primera transmisión experimental de este agente en 1937, los priones y
Masujin, Kentaro; Orrú, Christina D; Miyazawa, Kohtaro; Groveman, Bradley R; Raymond, Lynne D; Hughson, Andrew G; Caughey, Byron
Prion diseases of cattle include the classical bovine spongiform encephalopathy (C-BSE) and the atypical H-type BSE (H-BSE) and L-type BSE (L-BSE) strains. Although the C- and L-BSE strains can be detected and discriminated by ultrasensitive real-time quaking-induced conversion (RT-QuIC) assays, no such test has yet been described for the detection of H-BSE or the discrimination of each of the major bovine prion strains. Here, we demonstrate an RT-QuIC assay for H-BSE that can detect as little as 10(-9) dilutions of brain tissue and neat cerebrospinal fluid samples from clinically affected cattle. Moreover, comparisons of the reactivities with different recombinant prion protein substrates and/or immunoblot band profiles of proteinase K-treated RT-QuIC reaction products indicated that H-, L-, and C-BSE have distinctive prion seeding activities and can be discriminated by RT-QuIC on this basis.
Jensen, Tim Kåre
, Chapter 2.4.6 and Chapter 2.7.13) regarding diagnostic examinations. The DTU-VET is the national reference laboratory of bovine spongiform encephalopathy (BSE) and TSE/Scrapie, and therefore the results of all neuropathological examinations on BSE and Scrapie in Denmark are given in the present report...
Jensen, Tim Kåre
, Chapter 2.4.6 and Chapter 2.7.13) regarding diagnostic examinations. The DTU-VET is the national reference laboratory of bovine spongiform encephalopathy (BSE) and TSE/Scrapie, and therefore the results of all neuropathological examinations on BSE and Scrapie in Denmark are given in the present report...
Jensen, Tim Kåre
, Chapter 2.4.6 and Chapter 2.7.13) regarding diagnostic examinations. The DTU-VET is the national reference laboratory of bovine spongiform encephalopathy (BSE) and TSE/Scrapie, and therefore the results of all neuropathological examinations on BSE and Scrapie in Denmark are given in the present report...
Transmissible Spongiform Encephalopathies (TSEs), including scrapie in sheep, chronic wasting disease (CWD) in cervids, and bovine spongiform encephalopathy (BSE), are fatal diseases of the nervous system associated with accumulation of misfolded prion protein (PrPSc). Different strains of BSE exist...
Orrú, Christina D; Favole, Alessandra; Corona, Cristiano; Mazza, Maria; Manca, Matteo; Groveman, Bradley R; Hughson, Andrew G; Acutis, Pier Luigi; Caramelli, Maria; Zanusso, Gianluigi; Casalone, Cristina; Caughey, Byron
Statutory surveillance of bovine spongiform encephalopathy (BSE) indicates that cattle are susceptible to both classical BSE (C-BSE) and atypical forms of BSE. Atypical forms of BSE appear to be sporadic and thus may never be eradicated. A major challenge for prion surveillance is the lack of sufficiently practical and sensitive tests for routine BSE detection and strain discrimination. The real-time quaking-induced conversion (RT-QuIC) test, which is based on prion-seeded fibrillization of recombinant prion protein (rPrPSen), is known to be highly specific and sensitive for the detection of multiple human and animal prion diseases but not BSE. Here, we tested brain tissue from cattle affected by C-BSE and atypical L-type bovine spongiform encephalopathy (L-type BSE or L-BSE) with the RT-QuIC assay and found that both BSE forms can be detected and distinguished using particular rPrPSen substrates. Specifically, L-BSE was detected using multiple rPrPSen substrates, while C-BSE was much more selective. This substrate-based approach suggests a diagnostic strategy for specific, sensitive, and rapid detection and discrimination of at least some BSE forms.
刘雨田; 孙成友; 迟田英; 肖卫华; 王志亮
自2001年欧盟实施疯牛病主动监测以后，人们发现一种新的与典型疯牛病不一样的疯牛病，即非典型疯牛病。后来，在日本、加拿大、美国、巴西等也发现非典型疯牛病。目前普遍认为，该类疯牛病多发于老年牛，临床上有的表现症状，有的无症状，具有自发性和散发性特征，发病率低，约为百万份之一至百万份之三。研究发现，非典型疯牛病可以分为 H型和L型，两者在PK酶抗性、糖基化、传染性、机体内分布等存在差异，同时与典型疯牛病也存在明显差异。比较来看，L型疯牛病的传染性最强，H型疯牛病的较弱。论文从非典型疯牛病的临床症状、病理变化、病原分布及分子特性、传染性等方面做了详细介绍。%Since the active surveillance of bovine spongiform encephalopathy (BSE) was implemented in EU in 2001 ,a new kind of BSE ,namely atypical BSE ,which was different from classical BSE was emerged . Subsequently ,atypical BSEs were also found in Japan ,Canada ,America ,Brazil ,and so on .It is widely accepted that this kind of BSE was often observed within old cattle with or without clinical signs .The ap‐parent incidence of atypical BSE was low ,approximately 1‐3 cases per million cattle .It was characterized by spontaneity and sporadicness .Experimental evidence showed that atypical BSE included H‐type and L‐type cases which were distinct from protease K resistant ,glycosylation ,transmission ,agent distribution in vivo ,and so on .Meanwhile ,there was obvious difference between atypical and classical BSE .L‐BSE had stronger transmissibility by comparison with H‐BSE .This paper introduced clinic symptoms ,patho‐logical lesions ,agent distribution ,molecular feature ,transmissibility of atypical BSE in detail .
Ryan, Eoin; McGrath, Guy; Sheridan, Hazel; More, Simon J; Aznar, Inma
Bovine spongiform encephalopathy (BSE) is a prion disease spread by the inclusion in cattle feed of meat and bone meal made from cattle infected with the BSE agent. In the Republic of Ireland, a reinforced feed ban on mammalian meat and bone meal (MMBM) was introduced on 17th October 1996 to stop further infection of cattle. Between then and July 2010, 44 cases of BSE from 40 herds have been born, termed "born after the reinforced ban" or "BARB" cases. The objectives of this project were: (a) to describe the epidemiology of these BARB cases, (b) to determine area-level risk factors for BSE herds and how they related to the stage of the BSE epidemic, and (c) to evaluate whether the spatial pattern of BSE cases was non-random and had changed over time. The BSE epidemic was divided into three phases: cases born prior to 1991, born 1991-October 1996 and BARB cases. To determine the area level risk factors for BSE herds, a case-control study was conducted for each phase of the epidemic. We selected four control herds for each herd with one or more BSE cases. A grid of hexagons of 10 km diameter was created covering the territory of the Republic of Ireland and BSE herds and control herds were assigned to a hexagon. The numbers of cattle herds, dairy herds, piggeries and poultry holdings within the hexagons containing these case and control herds were enumerated. To evaluate the spatial pattern of BSE cases, standardised mortality ratios were calculated for each hexagon, and Oden's Ipop was used to investigate clustering. The descriptive analysis showed "feeding of concentrates" as the only common factor to all BARB cases for which information existed. The case-control study identified being a dairy herd as a risk factor during the pre-1991 phase of the BSE epidemic. Dairy herd type, a large proportion of local herds which were dairy and large numbers of piggeries and poultry holdings locally were also risk factors during the 1991-1996 phase. For the post-October 1996
In 2006 an H-type bovine spongiform encephalopathy (BSE) case was reported in an animal with an unusual polymorphism (E211K) in the prion protein gene. Although the prevalence of this polymorphism is low, cattle carrying the K211 allele are predisposed to rapid onset of H-type BSE when exposed. The ...
Full Text Available BACKGROUND: Prions, infectious agents associated with prion diseases such as Creutzfeldt-Jakob disease in humans, bovine spongiform encephalopathy (BSE in cattle, and scrapie in sheep and goats, are primarily comprised of PrP(Sc, a protease-resistant misfolded isoform of the cellular prion protein PrP(C. Protein misfolding cyclic amplification (PMCA is a highly sensitive technique used to detect minute amounts of scrapie PrP(Sc. However, the current PMCA technique has been unsuccessful in achieving good amplification in cattle. The detailed distribution of PrP(Sc in BSE-affected cattle therefore remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We report here that PrP(Sc derived from BSE-affected cattle can be amplified ultra-efficiently by PMCA in the presence of sulfated dextran compounds. This method is capable of amplifying very small amounts of PrP(Sc from the saliva, palatine tonsils, lymph nodes, ileocecal region, and muscular tissues of BSE-affected cattle. Individual differences in the distribution of PrP(Sc in spleen and cerebrospinal fluid samples were observed in terminal-stage animals. However, the presence of PrP(Sc in blood was not substantiated in the BSE-affected cattle examined. CONCLUSIONS/SIGNIFICANCE: The distribution of PrP(Sc is not restricted to the nervous system and can spread to peripheral tissues in the terminal disease stage. The finding that PrP(Sc could be amplified in the saliva of an asymptomatic animal suggests a potential usefulness of this technique for BSE diagnosis. This highly sensitive method also has other practical applications, including safety evaluation or safety assurance of products and byproducts manufactured from bovine source materials.
Piccardo, Pedro; Cervenak, Juraj; Bu, Ming; Miller, Lindsay; Asher, David M
Proteins aggregate in several slowly progressive neurodegenerative diseases called 'proteinopathies'. Studies with cell cultures and transgenic mice overexpressing mutated proteins suggested that aggregates of one protein induced misfolding and aggregation of other proteins as well - a possible common mechanism for some neurodegenerative diseases. However, most proteinopathies are 'sporadic', without gene mutation or overexpression. Thus, proteinopathies in WT animals genetically close to humans might be informative. Squirrel monkeys infected with the classical bovine spongiform encephalopathy agent developed an encephalopathy resembling variant Creutzfeldt-Jakob disease with accumulations not only of abnormal prion protein (PrP(TSE)), but also three other proteins: hyperphosphorylated tau (p-tau), α-synuclein and ubiquitin; β-amyloid protein (Aβ) did not accumulate. Severity of brain lesions correlated with spongiform degeneration. No amyloid was detected. These results suggested that PrP(TSE) enhanced formation of p-tau and aggregation of α-synuclein and ubiquitin, but not Aβ, providing a new experimental model for neurodegenerative diseases associated with complex proteinopathies.
Full Text Available Spongiform encephalopathies, categorized as a subclass of neuro-degenerative diseases and commonly known as prion diseases, are a group of progressive conditions that affect the brain and nervous system of many animals, including humans. Prion diseases are common among cannibalistic communities; further research has revealed that the infected or malformed prion protein (named PrPsc spreads its virulence to the normal, healthy prion protein (named PrPc when people consume infected tissues. Knowing that a small interaction between normal and infected prion protein creates virulence, this relationship can be studied as a simple antigen-antibody interaction to understand the series of events that transform a normal prion protein into a virulent misfolded protein. Thoroughly modeled and validated structures of both PrPsc and PrPc can be effectively used to map the epitopes and thereby screen the antigen-antibody interaction using docking studies for a particular organism of concern. This simple immunological approach is used to understand the vital interaction between the normal and malformed proteins that is involved in the disease-spreading mechanism. Clarification of this mechanism could be used in various immune- and bioinformatics algorithms to map the interaction epitopes, furthering an understanding of these pathologies.
Okada, Hiroyuki; Miyazawa, Kohtaro; Masujin, Kentaro; Yokoyama, Takashi
H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in aged cattle. H-BSE is characterized by the presence of two proteinase K-resistant forms of disease-associated prion protein (PrP(Sc)), identified as PrP(Sc) #1 and PrP(Sc) #2, in the brain. To investigate the coexistence of different PrP(Sc) forms in the extracerebral tissues of cattle experimentally infected with H-BSE, immunohistochemical and molecular analyses were performed by using N-terminal-, core-region- and C-terminal-specific anti-prion protein antibodies. Our results demonstrated that two distinct forms of PrP(Sc) coexisted in the various extracerebral tissues.
Brown, D A; Bruce, M E; Fraser, J R
Bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) belong to a group of diseases called the transmissible spongiform encephalopathies (TSEs). Transmission studies in inbred mice (strain typing) provided overwhelming evidence that vCJD arose from BSE. In this study, we compare the patterns of neuropathology in a panel of three inbred mouse strains (RIII, C57BL and VM) and one cross (C57BL x VM) infected with either vCJD or BSE. For each mouse strain, patterns of abnormal prion protein (PrPres) deposition, astrocytosis and vacuolation were similar in the vCJD- and BSE-challenged mice. Prion protein (PrP)-positive plaques were prominent in the VM and C57BL x VM mice in addition to diffuse PrPres accumulation, whereas only diffuse PrPres labelling was observed in the RIII and C57BL mice. The hippocampus was targeted in all mouse strains, as was the cochlear nucleus in the medulla, both showing consistent severe vacuolation and heavy PrPres deposition. Although the targeting of PrPres was similar in the BSE- and vCJD-infected brains, the amount and intensity of PrPres observed in the brains treated with formic acid during fixation was reduced considerably. The distribution of astrocytosis was similar to the targeting of PrPres deposition in the brain, although some differences were observed in the hippocampi of mice challenged with vCJD. We conclude that there are no significant differences in the targeting of neuropathological changes observed in the BSE- and vCJD-infected mice, consistent with the previous evidence of a link between BSE and vCJD.
Simmons, M M; Chaplin, M J; Vickery, C M; Simon, S; Davis, L; Denyer, M; Lockey, R; Stack, M J; O'Connor, M J; Bishop, K; Gough, K C; Maddison, B C; Thorne, L; Spiropoulos, J
Current European Commission (EC) surveillance regulations require discriminatory testing of all transmissible spongiform encephalopathy (TSE)-positive small ruminant (SR) samples in order to classify them as bovine spongiform encephalopathy (BSE) or non-BSE. This requires a range of tests, including characterization by bioassay in mouse models. Since 2005, naturally occurring BSE has been identified in two goats. It has also been demonstrated that more than one distinct TSE strain can coinfect a single animal in natural field situations. This study assesses the ability of the statutory methods as listed in the regulation to identify BSE in a blinded series of brain samples, in which ovine BSE and distinct isolates of scrapie are mixed at various ratios ranging from 99% to 1%. Additionally, these current statutory tests were compared with a new in vitro discriminatory method, which uses serial protein misfolding cyclic amplification (sPMCA). Western blotting consistently detected 50% BSE within a mixture, but at higher dilutions it had variable success. The enzyme-linked immunosorbent assay (ELISA) method consistently detected BSE only when it was present as 99% of the mixture, with variable success at higher dilutions. Bioassay and sPMCA reported BSE in all samples where it was present, down to 1%. sPMCA also consistently detected the presence of BSE in mixtures at 0.1%. While bioassay is the only validated method that allows comprehensive phenotypic characterization of an unknown TSE isolate, the sPMCA assay appears to offer a fast and cost-effective alternative for the screening of unknown isolates when the purpose of the investigation was solely to determine the presence or absence of BSE.
Marco-Salazar, P; Márquez, M; Fondevila, D; Rabanal, R M; Torres, J M; Pumarola, M; Vidal, E
Neurotrophins are a family of growth factors that act on neuronal cells. The neurotrophins include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3, -4 and -5. The action of neurotrophins depends on two transmembrane-receptor signalling systems: (1) the tropomyosin-related kinase (Trk) family of tyrosine kinase receptors (Trk A, Trk B and Trk C) and (2) the p75 neurotrophin receptor (p75(NTR)). The interaction between neurotrophic factors and their receptors may be involved in the mechanisms that regulate the differential susceptibility of neuronal populations in neurodegenerative diseases. The aim of the present study was to evaluate the role of neurotrophins in the pathogenesis of bovine spongiform encephalopathy (BSE) using a transgenic mouse overexpressing bovine prnp (BoTg 110). Histochemistry for Lycopersicum esculentum agglutinin, haematoxylin and eosin staining and immunohistochemistry for the abnormal isoform of the prion protein (PrP(d)), glial fibrillary acidic protein (GFAP), NGF, BDNF, NT-3 and the receptors Trk A, Trk B, Trk C and p75(NTR) was performed. The lesions and the immunolabelling patterns were assessed semiquantitatively in different areas of the brain. No significant differences in the immunolabelling of neurotrophins and their receptors were observed between BSE-inoculated and control animals, except for p75(NTR), which showed increased expression correlating with the distribution of lesions, PrP(d) deposition and gliosis in the BSE-inoculated mice.
Sugiura, K; Ito, K; Yokoyama, R; Kumagai, S; Onodera, T
The authors developed a mathematical model to assess the release risk of the bovine spongiform encephalopathy (BSE) agent into a country through the importation of live cattle, bone-in bovine meat and meat-and-bone meal (MBM) from the United Kingdom and other countries with BSE. Monte Carlo simulation was attempted using this model and input variables. The release risk in Japan, expressed as the weight of infected MBM released in Japan between 1993 and 2000, was estimated to be 23.4 kg to 53.8 kg. The simulation also indicated that imported MBM represented the most important risk factor for releasing the BSE agent into Japan. This paper also provides details of the first five cases of BSE detected in Japan between September 2001 and the end of 2002. In addition, the results of the investigation conducted to determine the source of infection and the measures taken by the Government of Japan to prevent the BSE agent from entering the food and feed chains are also outlined.
Schwermer, Heinzpeter; Brülisauer, Franz; De Koeijer, Aline; Heim, Dagmar
The effectiveness of two measures against Bovine Spongiform Encephalopathy (BSE), the compulsory processing of animal by products to meat and bone meal (MBM) at 133 degrees C under 3 bars of pressure for 20 minutes in February 1993 and the exclusion of fallen stock, heads with eyes and spinal cord of cattle older than 30 month from MBM production in April 1996, was evaluated in a process model. The transmission of BSE by calculation of the basic reproduction ratio R0 was modelled. The results were verified by use of a cohort model, based on observed surveillance data. Prior to 1990, before the ban of feeding MBM to ruminants, R0, as calculated in the process model, was above 1, coherent with a slowly progressing BSE epidemic. Since 1991, values of R0 were low at 0.06. The corresponding R0 values derived from the cohort model were higher, the lowest value 0.13 calculated for 1996. Given such low R0 values, the epidemic should have died out. Additionally, no influence of the two measures was obvious at that time given the low level of R0. The discrepancy between the results of the two models is evidence for a dependency of the BSE epidemic from an infection source not considered in the process model. This infection source is most likely importation of feed ingredients and MBM.
李炎鑫; 马贵平; 刘全国; 史喜菊; 李冰玲; 徐立伟
非典型牛海绵状脑病为新发现的一种朊病毒病，通常发生于老牛，与典型牛海绵状脑病在病理表型、分子表型和生物表型方面不同。本文结合已发表的文献，对非典型牛海绵状脑病的发现、病原特性、流行病学、检测、发病机理、动物模型研究和实验感染等方面的最新研究进展进行了概述，以期增强人们对该病的认识，并为我国防控该病提供借鉴。%Atypical bovine spongiform encephalopathy(BSE)is a prion disease of usually older cattle that is distinct from classical BSE by its pathological,molecular and biological phenotype. In order to raise awareness of the disease and to provide the related authorities of our country with scientific bases for the prevention and control of this disease,the latest research progress in the aspects of etiology,epidemiology,detection of infection,pathogenesis, transmission studies in animal models of the disease were summrized in this review.
本文在概述人朊病毒的基础上,重点阐述新型克-雅氏病与早先已知的各种人朊病毒病的区别和它是由牛海绵状脑病朊病毒引起的证据,并对牛海绵状脑病并非源于痒病而是原于牛散发性朊病毒病、影响新型克-雅氏病流行规模的主要因素和该病的主要预防措施等问题进行了讨论。%Variant Creutzfeldt-Jakob disease (vCJD) is a new disease firstly described in April, 1996 in the United Kingdom. On the basis of a brief account of human prion diseases, this paper elucidates the differences between vCJD and bovine spongiform encephalopathy (BSE) and presents the evidence conforming that vCJD is caused by the BSE agent. In addition, the origin of BSE (it was not derived from scrapie), some important factors determining epidemic scale of vCJD and key preventive measures of vCJD are discussed.
Hoffmann, Christine; Ziegler, Ute; Buschmann, Anne; Weber, Artur; Kupfer, Leila; Oelschlegel, Anja; Hammerschmidt, Baerbel; Groschup, Martin H
To elucidate the still-unknown pathogenesis of bovine spongiform encephalopathy (BSE), an oral BSE challenge and sequential kill study was carried out on 56 calves. Relevant tissues belonging to the peripheral and central nervous system, as well as to the lymphoreticular tract, from necropsied animals were analysed by highly sensitive immunohistochemistry and immunoblotting techniques to reveal the presence of BSE-associated pathological prion protein (PrPSc) depositions. Our results demonstrate two routes involving the autonomic nervous system through which BSE prions spread by anterograde pathways from the gastrointestinal tract (GIT) to the central nervous system (CNS): (i) via the coeliac and mesenteric ganglion complex, splanchnic nerves and the lumbal/caudal thoracic spinal cord (representing the sympathetic GIT innervation); and (ii) via the Nervus vagus (parasympathetic GIT innervation). The dorsal root ganglia seem to be subsequently affected, so it is likely that BSE prion invasion of the non-autonomic peripheral nervous system (e.g. sciatic nerve) is a secondary retrograde event following prion replication in the CNS. Moreover, BSE-associated PrPSc was already detected in the brainstem of an animal 24 months post-infection, which is 8 months earlier than reported previously. These findings are important for the understanding of BSE pathogenesis and for the development of new diagnostic strategies for this infectious disease.
Strom, A; Yutzy, B; Kruip, C; Völker, I; Schloot, N C; Roden, M; Scott, F W; Löwer, J; Holznagel, E
A 9-year-old cynomolgus monkey (Macaca fascicularis) infected orally with bovine spongiform encephalopathy (BSE) was presented for necropsy following euthanasia 4 years post infection (p.i.). This macaque R984 was exposed to a BSE dose that causes a simian form of variant Creutzfeldt-Jakob disease (vCJD) within 5 years p.i. in other macaques. All orally BSE-infected macaques developed a significant weight gain within the first 2 years p.i. compared with non-BSE-infected age- and sex-matched control animals, suggesting increased risk of type 2 diabetes (T2D). In contrast, macaque R984 developed rapid weight loss, hyperglycemia, and glucosuria and had to be euthanatized 4 years p.i. before clinical signs of vCJD. Pancreas histopathological evaluation revealed severe islet degeneration but, remarkably, no islet amyloid deposits were present. Immunostaining of pancreas sections for insulin and glucagon confirmed the loss of endocrine cells. In addition, prions were present in the adenohypophysis but not in other areas of the brain, indicating centripetal prion spread from the gut during the preclinical phase of BSE infection. Plasma glucose and insulin concentrations of macaque R984 became abnormal with age and resembled T2D. This unusual case of spontaneous T2D in the absence of islet amyloid deposits could have been due to early prion spread from the periphery to the endocrine system or could have occurred spontaneously.
Okada, H; Iwamaru, Y; Yokoyama, T; Mohri, S
H-type bovine spongiform encephalopathy (BSE) has been identified in aged cattle in Europe and North America. To determine the localization of disease-associated prion protein (PrP(Sc)) in the peripheral nerve tissues of cattle affected with H-type BSE, we employed highly sensitive immunohistochemical and immunofluorescence techniques with the tyramide signal amplification (TSA) system. PrP(Sc) deposition was detected in the inferior ganglia, sympathetic nerve trunk, vagus nerve, spinal nerves, cauda equina, and adrenal medulla, using this system. Notably, granular PrP(Sc) deposits were present mainly in the Schwann cells and fibroblast-like cells and occasionally along certain nerve fibers at the surface of the axons. In the adrenal gland, PrP(Sc) immunolabeling was observed within the sympathetic nerve fibers and nerve endings in the adrenal medulla. Although our results were limited to only 3 experimental cases, these results suggest that the TSA system, a highly sensitive immunohistochemical procedure, may help in elucidating the peripheral pathogenesis of H-type BSE.
Zhu, Xiang-Yuan; Feng, Fu-Ying; Xue, Su-Yuan; Hou, Ting; Liu, Hui-Rong
Two insertion/deletion (indel) polymorphisms of the prion protein gene (PRNP), a 23-bp indel in the putative promoter region and a 12-bp indel within intron I, are associated with the susceptibility to bovine spongiform encephalopathy (BSE) in cattle. In the present study, the polymorphism frequencies of the two indels in four main beef cattle breeds (Hereford, Simmental, Black Angus, and Mongolian) from North China were studied. The results showed that the frequencies of deletion genotypes and alleles of 23- and 12-bp indels were lower, whereas the frequencies of insertion genotypes and alleles of the two indels were higher in Mongolian cattle than in the other three cattle breeds. In Mongolian cattle, the 23-bp insertion / 12-bp insertion was the major haplotype, whereas in Hereford, Simmental, and Black Angus cattle, the 23-bp deletion / 12-bp deletion was the major haplotype. These results demonstrated that Mongolian cattle could be more resistant to BSE, compared with the other three cattle breeds, because of its relatively low frequencies of deletion genotypes and alleles of 23- and 12-bp indel polymorphisms. Thus, this race could be important for selective breeding to improve resistance against BSE in this area.
Okada, Hiroyuki; Iwamaru, Yoshifumi; Fukuda, Shigeo; Yokoyama, Takashi; Mohri, Shirou
A sensitive immunohistochemical procedure, the tyramide signal amplification (TSA) system, was applied to detect the localization of immunolabeled disease-associated prion protein (PrP(Sc)) in cattle affected with bovine spongiform encephalopathy (BSE). In this procedure, immunolabeling could be visualized in the optic nerve and the adrenal medulla. In the optic nerve, the dual immunofluorescent technique showed that the granular PrP(Sc) was occasionally detected in the astrocytes, microglia, and myelin sheath adjacent to the axon. Clustered PrP(Sc) was also scattered in association with microglial cells and astrocytes of the optic nerve. In the adrenal gland, PrP(Sc) immunolabeling was confined within the sympathetic nerve fibers and endings. The results suggest that (1) PrP(Sc) might centrifugally spread within and between glial cells and/or the non-axonal (also known as ad-axonal) region of nerve fibers, rather than the axonal and/or extracellular space pathway in the optic nerve, and (2) the sympathetic innervations might be important for the trafficking of BSE agent in the adrenal glands of cattle. This study also suggests that tyramide-based immunochemical analysis should be performed to detect immunolabeled PrP(Sc) in the extracerebral tissues of BSE-affected cattle.
Tan, Boon Chin; Blanco, Anthony R Alejo; Houston, E Fiona; Stewart, Paula; Goldmann, Wilfred; Gill, Andrew C; de Wolf, Christopher; Manson, Jean C; McCutcheon, Sandra
The susceptibility of sheep to prion infection is linked to variation in the PRNP gene, which encodes the prion protein. Common polymorphisms occur at codons 136, 154 and 171. Sheep which are homozygous for the A(136)R(154)Q(171) allele are the most susceptible to bovine spongiform encephalopathy (BSE). The effect of other polymorphisms on BSE susceptibility is unknown. We orally infected ARQ/ARQ Cheviot sheep with equal amounts of BSE brain homogenate and a range of incubation periods was observed. When we segregated sheep according to the amino acid (L or F) encoded at codon 141 of the PRNP gene, the shortest incubation period was observed in LL(141) sheep, whilst incubation periods in FF(141) and LF(141) sheep were significantly longer. No statistically significant differences existed in the expression of total prion protein or the disease-associated isoform in BSE-infected sheep within each genotype subgroup. This suggested that the amino acid encoded at codon 141 probably affects incubation times through direct effects on protein misfolding rates.
Full Text Available Since 2004 it become clear that atypical bovine spongiform encephalopthies (BSEs exist in cattle. Whenever their detection has relied on active surveillance plans implemented in Europe since 2001 by rapid tests, the overall and inter-laboratory performance of these diagnostic systems in the detection of the atypical strains has not been studied thoroughly to date. To fill this gap, the present study reports on the analytical sensitivity of the EU-approved rapid tests for atypical L- and H-type and classical BSE in parallel. Each test was challenged with two dilution series, one created from a positive pool of the three BSE forms according to the EURL standard method of homogenate preparation (50% w/v and the other as per the test kit manufacturer's instructions. Multilevel logistic models and simple logistic models with the rapid test as the only covariate were fitted for each BSE form analyzed as directed by the test manufacturer's dilution protocol. The same schemes, but excluding the BSE type, were then applied to compare test performance under the manufacturer's versus the water protocol. The IDEXX HerdChek ® BSE-scrapie short protocol test showed the highest sensitivity for all BSE forms. The IDEXX® HerdChek BSE-scrapie ultra short protocol, the Prionics®--Check WESTERN and the AJ Roboscreen® BetaPrion tests showed similar sensitivities, followed by the Roche® PrionScreen, the Bio-Rad® TeSeE™ SAP and the Prionics®--Check PrioSTRIP in descending order of analytical sensitivity. Despite these differences, the limit of detection of all seven rapid tests against the different classes of material set within a 2 log(10 range of the best-performing test, thus meeting the European Food Safety Authority requirement for BSE surveillance purposes. These findings indicate that not many atypical cases would have been missed surveillance since 2001 which is important for further epidemiological interpretations of the sporadic character of
Full Text Available Transmissible spongiform encephalopathies (TSE encompass subacute neurological degenerative diseases for which the prototypes are scrapie in sheep and some forms of Creutzfeldt-Jakob disease in man. The emergence of a new form of TSE in cattle in United Kingdom (UK since 1986, namely bovine spongiform encephalopathy (BSE, sharply increased the interest for these diseases, especially because of the epidemic nature of BSE in UK, its subsequent spread in continental Europe and the later discovery of its zoonotic character. The number of measures of veterinary public health taken to control the disease and to prevent its spread to animals and human beings increased in time and culminated by the total feed ban. Indeed, since the beginning of 2001, feed containing proteins of animal origin is prohibited for the feeding of production animals, including ruminants and monogastric species. The effect of this total ban of mammalian meat and bone meal needs to be evaluated. The incidence of BSE has a trend to decrease in UK and in most of the other European member states. However, as BSE is a rare event distributed in a large bovine population, it is difficult to state unambiguously whether this trend is significant. Furthermore, the evaluation of this measure will be only effective at least five years after its introduction, since this period is the mean incubation time of BSE. The main concern is currently the eradication of BSE in the infected countries. Additionally, the control of scrapie is also carried out due to the possible contamination of sheep with the BSE agent. These actions must take into account several new facts: the recent discovery of BSE cases in countries with a low geographical BSE risk level as Japan, Canada and the United States of America (USA; the growing incidence of chronic wasting disease, a spongiform encephalopathy observed in deer in USA; the characterization of a new pattern of bovine amyloidotic spongiform encephalopathy in
Murayama, Yuichi; Masujin, Kentaro; Imamura, Morikazu; Ono, Fumiko; Shibata, Hiroaki; Tobiume, Minoru; Yamamura, Tomoaki; Shimozaki, Noriko; Terao, Keiji; Yamakawa, Yoshio; Sata, Tetsutaro
Prion diseases are characterized by the prominent accumulation of the misfolded form of a normal cellular protein (PrP(Sc)) in the central nervous system. The pathological features and biochemical properties of PrP(Sc) in macaque monkeys infected with the bovine spongiform encephalopathy (BSE) prion have been found to be similar to those of human subjects with variant Creutzfeldt-Jakob disease (vCJD). Non-human primate models are thus ideally suited for performing valid diagnostic tests and determining the efficacy of potential therapeutic agents. In the current study, we developed a highly efficient method for in vitro amplification of cynomolgus macaque BSE PrP(Sc). This method involves amplifying PrP(Sc) by protein misfolding cyclic amplification (PMCA) using mouse brain homogenate as a PrP(C) substrate in the presence of sulfated dextran compounds. This method is capable of amplifying very small amounts of PrP(Sc) contained in the cerebrospinal fluid (CSF) and white blood cells (WBCs), as well as in the peripheral tissues of macaques that have been intracerebrally inoculated with the BSE prion. After clinical signs of the disease appeared in three macaques, we detected PrP(Sc) in the CSF by serial PMCA, and the CSF levels of PrP(Sc) tended to increase with disease progression. In addition, PrP(Sc) was detectable in WBCs at the clinical phases of the disease in two of the three macaques. Thus, our highly sensitive, novel method may be useful for furthering the understanding of the tissue distribution of PrP(Sc) in non-human primate models of CJD.
Full Text Available Abstract Background The majority of atypical bovine spongiform encephalopathy (BSE cases so far identified worldwide have been detected by active surveillance. Consequently the volume and quality of material available for detailed characterisation is very limiting. Here we report on a small transmission study of both atypical forms, H- and L-type BSE, in cattle to provide tissue for test evaluation and research, and to generate clinical, molecular and pathological data in a standardised way to enable more robust comparison of the two variants with particular reference to those aspects most relevant to case ascertainment and confirmatory diagnosis within existing regulated surveillance programmes. Results Two groups of four cattle, intracerebrally inoculated with L-type or H-type BSE, all presented with a nervous disease form with some similarities to classical BSE, which progressed to a more dull form in one animal from each group. Difficulty rising was a consistent feature of both disease forms and not seen in two BSE-free, non-inoculated cattle that served as controls. The pathology and molecular characteristics were distinct from classical BSE, and broadly consistent with published data, but with some variation in the pathological characteristics. Both atypical BSE types were readily detectable as BSE by current confirmatory methods using the medulla brain region at the obex, but making a clear diagnostic distinction between the forms was not consistently straightforward in this brain region. Cerebellum proved a more reliable sample for discrimination when using immunohistochemistry. Conclusions The prominent feature of difficulty rising in atypical BSE cases may explain the detection of naturally occurring cases in emergency slaughter cattle and fallen stock. Current confirmatory diagnostic methods are effective for the detection of such atypical cases, but consistently and correctly identifying the variant forms may require modifications to
Van Muylem Patrick
Full Text Available Abstract Background The bovine spongiform encephalopathy (BSE epidemic presented homogeneity of the phenotype. This classical BSE (called C-type was probably due to the contamination of the food chain by a single prion strain. However, due to the active surveillance and better techniques, two rare variants of BSE have been recently reported in different continents without a clear correlation to the BSE epidemic. These emerging types behave as different strains of BSE and were named H-type and L-type according to the high and low molecular mass of the unglycosylated fragment of their proteinase K resistant prion protein (PrPres. In these types, the proportion of the un-, mono- and di-glycosylated fragments of PrP (glycoprofile is also atypical and represents an effective diagnostic parameter. This study evaluated the presence of such types in bovine of 7 years and older in Belgium. Results The Belgian BSE archive contained 41 bovines of at least 7 years of age. The biochemical features of their PrPres were analyzed by Western blot with five antibodies recognising different regions of PrPres, from N- to C-terminus: 12B2, 9A2, Sha31, SAF84 and 94B4. All antibodies clearly detected PrPres except 12B2 antibody, which is specific for N-terminal region 101-105, a PrP region that is only retained in H-types. The glycoprofiles did correspond to that of C-type (with more than 55% of diglycosylated PrPres using antibody 94B4. Therefore, all cases have the features of C-type BSE. Conclusions This study supports that, among the BSE cases of 7 years and older identified in Belgium, none was apparently of the H- or L- type. This is consistent with the very rare occurrence of atypical BSE and the restricted dimension of Belgium. These results shed some light on the worldwide prevalence of atypical BSE.
Full Text Available Although the incidence of variant Creutzfeldt-Jakob disease (vCJD has declined to 1 since 2012 in the UK, uncertainty remains regarding possible future cases and the size of the subclinical population that may cause secondary transmission of the disease through blood transfusion. Estimating the number of individuals who were exposed to the bovine spongiform encephalopathy (BSE infectious agent and may be susceptible to vCJD will help to clarify related public health concerns and plan strategies. In this paper, we explore this estimate by describing the probability of potential exposure due to dietary intake throughout the BSE epidemic period from 1980 to 1996 as a stochastic Poisson process. We estimate the age- and gender-specific exposure intensities in food categories of beef and beef-containing dishes, burgers and kebabs, pies, and sausages, separating the two periods of 1980-1989 and 1990-1996 due to the specified bovine offal legislation of 1989. The estimated total number of (living exposed individuals during each period is 5,089,027 (95% confidence interval [CI] 4,514,963-6,410,317, which was obtained by multiplying the population size of different birth cohorts by the probability of exposure via dietary intake and the probability of survival until the end of 2013. The estimated number is approximately doubled, assuming a contamination rate of [Formula: see text]. Among those individuals estimated, 31,855 (95% CI 26,849-42,541 are susceptible to infection. We also examined the threshold hypothesis by fitting an extreme-value distribution to the estimated infectious dose of the exposed individuals and obtained a threshold estimate of 13.7 bID50 (95% CI 6.6-26.2 bID50 (Weibull. The results provide useful information on potential carriers of prion disease who may pose a threat of infection via blood transfusion and thus provide insight into the likelihood of new incidents of vCJD occurring in the future.
Chou, Ming Li; Bailey, Andy; Avory, Tiffany; Tanimoto, Junji; Burnouf, Thierry
Cases of variant Creutzfeldt-Jakob disease in people who had consumed contaminated meat products from cattle with bovine spongiform encephalopathy emphasize the need for measures aimed at preventing the transmission of the pathogenic prion protein (PrPSc) from materials derived from cattle. Highly stringent scrutiny is required for fetal bovine serum (FBS), a growth-medium supplement used in the production of parenteral vaccines and therapeutic recombinant proteins and in the ex vivo expansion of stem cells for transplantation. One such approach is the implementation of manufacturing steps dedicated to removing PrPSc from materials containing FBS. We evaluated the use of the QyuSpeed D (QSD) adsorbent hollow-fiber anion-exchange chromatographic column (Asahi Kasei Medical, Tokyo, Japan) for the removal of PrPSc from cell culture media supplemented with FBS. We first established that QSD filtration had no adverse effect on the chemical composition of various types of culture media supplemented with 10% FBS or the growth and viability characteristics of human embryonic kidney (HEK293) cells, baby hamster kidney (BHK-21) cells, African green monkey kidney (Vero) cells, and Chinese hamster ovary (CHO-k1) cells propagated in the various culture-medium filtrates. We used a 0.6-mL QSD column for removing PrPSc from up to 1000 mL of Dulbecco's modified Eagle's medium containing 10% FBS previously spiked with the 263K strain of hamster-adapted scrapie. The Western blot analysis, validated alongside an infectivity assay, revealed that the level of PrPSc in the initial 200mL flow-through was reduced by 2.5 to > 3 log10, compared with that of the starting material. These results indicate that QSD filtration removes PrPSc from cell culture media containing 10% FBS, and demonstrate the ease with which QSD filtration can be implemented in at industrial-scale to improve the safety of vaccines, therapeutic recombinant proteins, and ex vivo expanded stem cells produced using growth
Murayama, Yuichi; Yoshioka, Miyako; Okada, Hiroyuki; Takata, Eri; Masujin, Kentaro; Iwamaru, Yoshifumi; Shimozaki, Noriko; Yamamura, Tomoaki; Yokoyama, Takashi; Mohri, Shirou; Tsutsumi, Yuji
The global outbreak of bovine spongiform encephalopathy (BSE) has been attributed to the recycling of contaminated meat and bone meals (MBMs) as feed supplements. The use of MBMs has been prohibited in many countries; however, the development of a method for inactivating BSE prions could enable the efficient and safe use of these products as an organic resource. Subcritical water (SCW), which is water heated under pressure to maintain a liquid state at temperatures below the critical temperature (374°C), exhibits strong hydrolytic activity against organic compounds. In this study, we examined the residual in vitro seeding activity of protease-resistant prion protein (PrPSc) and the infectivity of BSE prions after SCW treatments. Spinal cord homogenates prepared from BSE-infected cows were treated with SCW at 230-280°C for 5-7.5 min and used to intracerebrally inoculate transgenic mice overexpressing bovine prion protein. Serial protein misfolding cyclic amplification (sPMCA) analysis detected no PrPSc in the SCW-treated homogenates, and the mice treated with these samples survived for more than 700 days without any signs of disease. However, sPMCA analyses detected PrPSc accumulation in the brains of all inoculated mice. Furthermore, secondary passage mice, which inoculated with brain homogenates derived from a western blotting (WB)-positive primary passage mouse, died after an average of 240 days, similar to mice inoculated with untreated BSE-infected spinal cord homogenates. The PrPSc accumulation and vacuolation typically observed in the brains of BSE-infected mice were confirmed in these secondary passage mice, suggesting that the BSE prions maintained their infectivity after SCW treatment. One late-onset case, as well as asymptomatic but sPMCA-positive cases, were also recognized in secondary passage mice inoculated with brain homogenates from WB-negative but sPMCA-positive primary passage mice. These results indicated that SCW-mediated hydrolysis was
Ming Li Chou
Full Text Available Cases of variant Creutzfeldt-Jakob disease in people who had consumed contaminated meat products from cattle with bovine spongiform encephalopathy emphasize the need for measures aimed at preventing the transmission of the pathogenic prion protein (PrPSc from materials derived from cattle. Highly stringent scrutiny is required for fetal bovine serum (FBS, a growth-medium supplement used in the production of parenteral vaccines and therapeutic recombinant proteins and in the ex vivo expansion of stem cells for transplantation. One such approach is the implementation of manufacturing steps dedicated to removing PrPSc from materials containing FBS. We evaluated the use of the QyuSpeed D (QSD adsorbent hollow-fiber anion-exchange chromatographic column (Asahi Kasei Medical, Tokyo, Japan for the removal of PrPSc from cell culture media supplemented with FBS. We first established that QSD filtration had no adverse effect on the chemical composition of various types of culture media supplemented with 10% FBS or the growth and viability characteristics of human embryonic kidney (HEK293 cells, baby hamster kidney (BHK-21 cells, African green monkey kidney (Vero cells, and Chinese hamster ovary (CHO-k1 cells propagated in the various culture-medium filtrates. We used a 0.6-mL QSD column for removing PrPSc from up to 1000 mL of Dulbecco's modified Eagle's medium containing 10% FBS previously spiked with the 263K strain of hamster-adapted scrapie. The Western blot analysis, validated alongside an infectivity assay, revealed that the level of PrPSc in the initial 200mL flow-through was reduced by 2.5 to > 3 log10, compared with that of the starting material. These results indicate that QSD filtration removes PrPSc from cell culture media containing 10% FBS, and demonstrate the ease with which QSD filtration can be implemented in at industrial-scale to improve the safety of vaccines, therapeutic recombinant proteins, and ex vivo expanded stem cells produced
Simmons, Marion Mathieson; Spiropoulos, John; Hawkins, Stephen Anthony Charles; Bellworthy, Susan Jane; Tongue, Susan Carol
Bovine spongiform encephalopathy was a novel spongiform encephalopathy, in an hitherto unaffected species, that had characteristics of a point source epidemic, with an agent that could have been incorporated into a wide variety of feedstuffs and iatrogenically administered to naïve populations, and there was early evidence that it was not restricted to bovines. It was vital to establish, albeit experimentally, which other species might be affected, and whether the epidemic could be maintained by natural transmission, if the source was removed. In contrast, scrapie has been endemic throughout Great Britain for centuries, is maintained naturally (even if we don't know exactly how) and has a known host range. The principles, process and integration of evidence from different types of studies, however, are similar for both of these transmissible spongiform encephalopathies (TSE) and can be applied to any emerging or suspected spongiform encephalopathy. This review discusses the experimental approaches used to determine TSE transmissibility and infectivity and how they relate to natural disease and control measures.
Immunohistochemical detection of disease-associated prion protein in the intestine of cattle naturally affected with bovine spongiform encephalopathy by using an alkaline-based chemical antigen retrieval method.
Okada, Hiroyuki; Iwamaru, Yoshihumi; Imamura, Morikazu; Masujin, Kentaro; Yokoyama, Takashi; Mohri, Shirou
An alkaline-based chemical antigen retrieval pretreatment step was used to enhance immunolabeling of disease-associated prion protein (PrP(Sc)) in formalin-fixed and paraffin-embedded tissue sections from cattle naturally affected with bovine spongiform encephalopathy (BSE). The modified chemical method used in this study amplified the PrP(Sc) signal by unmasking PrP(Sc) compared with the normal cellular prion protein. In addition, this method reduced nonspecific background immunolabeling that resulted from the destruction of the residual normal cellular form of prion protein, and reduced the treatment time compared with the usual autoclave pretreatment step. Immunolabeled PrP(Sc) was thereby clearly detected in the myenteric plexus of the ileum in naturally occurring BSE cattle.
Jorge E Delgado-Hachmeister
Full Text Available Las encefalopatías espongiformes transmisibles (EET han cobrado gran importancia en los últimos años. Principalmente por el surgimiento de la encefalopatía espongiforme del bovino (EEB y la nueva variante de la ermedad de Creutzfeldt-Jakob (nvECJ, esta última probablemente adquirida por la ingesta de carne de bovino contaminada. Hasta la fecha se ha informado de 109 casos de la nvECJ en el humano y la gran mayoría de los casos ha ocurrido en el Reino Unido. No se sabe la magnitud real que podrán tener las EET en el humano, sin embargo algunos piensan que nos encontramos en el principio de una pandemia de la nvECJ. En el presente artículo se discuten varios aspectos de las EET y métodos para la prevención de la transmisión de estas enfermedades, tanto en rumiantes como en el humano.Transmissible spongiform encephalopathies (TSE are a group of diseases which have received a lot of attention in recent years. The interest on these diseases has been stimulated by the appearance of bovine spongiform encephalopathy (BSE and the new variant of Creutzfeldt-Jakob disease (nvCJD; the latter is likely to be acquired by ingesting contaminated beef. Until now 109 cases of nvCJD have been reported, most of them occurring in the United Kingdom. Some experts think that this is the beginning of a nvCJD pandemic. Deep knowledge of the mechanisms of transmission of TSE is needed to prevent the emergence of a TSE pandemic in humans.We address various aspects of TSE and discuss prevention methods of TSE in ruminants and humans.
Bett, Cyrus; Grgac, Ksenija; Long, Dianna; Karfunkle, Michael; Keire, David A; Asher, David M; Gregori, Luisa
In 2000, bovine heparin was withdrawn from the US market for fear of contamination with bovine spongiform encephalopathy (BSE) agent, the cause of variant Creutzfeldt-Jakob disease in humans. Thus, US heparin is currently sourced only from pig intestines. Availability of alternative sources of crude heparin, a life-saving drug, would benefit public health. Bovine heparin is an obvious option, but BSE clearance by the bovine heparin manufacturing process should be evaluated. To this end, using hamster 263K scrapie as a surrogate for BSE agent, we applied a four-step bench-scale heparin purification protocol resembling a typical heparin manufacturing process to investigate removal of the spiked scrapie agent. We removed aliquots from each step and analyzed them for residual abnormal prion protein (PrP(TSE)) using a sensitive in vitro method, real-time quaking-induced conversion (RT-QuIC) assay, and for infectivity using animal bioassays. The purification process reduced infectivity by 3.6 log10 and removed PrP(TSE), measured as seeding activity, by 3.4 log10. NaOH treatment was the most effective removal step tested. We also investigated NaOH at different concentrations and pH: the results showed that as much as 5.2 log10 of PrP(TSE) seeding activity was removed at pH 12.5. Thus, changes to the concentration, treatment time, and temperature of alkaline extraction might further improve removal. Our results, using a basic heparin manufacturing process, inform efforts to reintroduce safe bovine heparin in the USA.
牛海绵状脑病(Bovine spongiform encephalopathy，BSE)又称疯牛病，是成年牛的一种由非常规致病因子引起的进行性、神经性、致死性疾病。该病的主要特征是牛脑发生海绵状病变，并伴随大脑功能退化。临床表现为神经质、运动失调、痴呆和死。能够表现这种症状的疾病还有羊的痒病(Scrapie)、人的库鲁氏病和克雅氏病(CJD)等。自
L-Arginine ethylester enhances in vitro amplification of PrP(Sc) in macaques with atypical L-type bovine spongiform encephalopathy and enables presymptomatic detection of PrP(Sc) in the bodily fluids.
Murayama, Y; Ono, F; Shimozaki, N; Shibata, H
Protease-resistant, misfolded isoforms (PrP(Sc)) of a normal cellular prion protein (PrP(C)) in the bodily fluids, including blood, urine, and saliva, are expected to be useful diagnostic markers of prion diseases, and nonhuman primate models are suited for performing valid diagnostic tests for human Creutzfeldt-Jakob disease (CJD). We developed an effective amplification method for PrP(Sc) derived from macaques infected with the atypical L-type bovine spongiform encephalopathy (L-BSE) prion by using mouse brain homogenate as a substrate in the presence of polyanions and L-arginine ethylester. This method was highly sensitive and detected PrP(Sc) in infected brain homogenate diluted up to 10(10) by sequential amplification. This method in combination with PrP(Sc) precipitation by sodium phosphotungstic acid is capable of amplifying very small amounts of PrP(Sc) contained in the cerebrospinal fluid (CSF), saliva, urine, and plasma of macaques that have been intracerebrally inoculated with the L-BSE prion. Furthermore, PrP(Sc) was detectable in the saliva or urine samples as well as CSF samples obtained at the preclinical phases of the disease. Thus, our novel method may be useful for furthering the understanding of bodily fluid leakage of PrP(Sc) in nonhuman primate models.
Dressel, K; Perazzini, A; Ru, G; Van Wassenhove, W
The so-called "TSE roadmap" was published by the European Commission on July 15, 2005. The transmissible spongiform encephalopathy (TSE) roadmap suggests relaxation of bovine spongiform encephalopathy (BSE) in cattle and other animal transmissible spongiform encephalopathies measures in the short, medium, and long term. According to the TSE roadmap, "Any relaxation of BSE measures following the scientific assessment should be initiated by an open discussion with all stakeholders and supported by a strong communication strategy" ( European Commission 2005 , 5). Bearing this in mind, a social scientific project was designed to (1) involve different stakeholder groups, governmental risk managers, and their scientific advisors and (2) obtain their perception of the TSE roadmap and of its implications for precautionary consumer protection in five European Union (EU) Member States. This study describes the risk perception and risk management of TSE in Europe as exemplified by the TSE roadmap. The following query guided the international comparative study: How is TSE risk perceived by four interviewed stakeholder groups in five studied countries? The risk perceptions of TSE of risk managers from the ministries in charge in Belgium, France, Germany, Italy, and the United Kingdom, as well as their scientific advisors and stakeholder groups, were determined. The stakeholder groups were from three different areas involved with TSE, including farmers, consumers, and the meat/food industry. The issue to be addressed is roadmapping an adequate instrument for stakeholder involvement and for risk decision making.
Transmissible spongiform encephalopathies (TSE) as well as the properties of the major component of the infectious agent-prion, and the most important human and animal prion diseases are characterized. Considering the recent biochemical and molecular biological data, possible explanations of natural resistance, species barrier and lack of the immune response to the unconventional infectious particles are presented. Finally the importance of immunoblotting and immunostaining as the most specific confirmation of TSE diagnosis is underlined. (Ref. 11.)
Duque Velásquez, Camilo
Full Text Available We report the case of a 64 year-old woman with motor and cognitive deterioration that progressed rapidly during eight months. She was unsuccessfully treated with quinacrine, and died in a terminal status, by septic shock secondary to bronchopneumonia by broncho-aspiration. The brain was donated for research and the histopathological analysis showed spongiform changes, astrogliosis and prion protein (PrPRes deposits, confirmed by Western blot (WB. These features are considered characteristic of prion diseases, which are uncommon in Colombia. We highlight that its diagnosis was made for the first time in this country by the simultaneous use of immunohistochemistry and Western blot.
This book chapter is an invited, scholarly review of the mechanism(s) of TSEs for the 2nd edition of Metabolic Encephalopathies. Each chapter in the book assumes a professional knowledge of neuroscience and biochemistry, and the focus of the book is on the metabolic basis of dise...
Moore, S. Jo; West Greenlee, M. Heather; Smith, Jodi D.; Vrentas, Catherine E.; Nicholson, Eric M.; Greenlee, Justin J.
In 2006, a case of H-type bovine spongiform encephalopathy (BSE-H) was diagnosed in a cow that was associated with a heritable polymorphism in the bovine prion protein gene (PRNP) resulting in a lysine for glutamate amino acid substitution at codon 211 (called E211K) of the prion protein. Although the prevalence of this polymorphism is low, cattle carrying the K211 allele may be predisposed to rapid onset of BSE-H when exposed or to the potential development of a genetic BSE. This study was conducted to better understand the relationship between the K211 polymorphism and its effect on BSE phenotype. BSE-H from the US 2006 case was inoculated intracranially (IC) in one PRNP wild-type (EE211) calf and one EK211 calf. In addition, one wild-type calf and one EK211 calf were inoculated IC with brain homogenate from a US 2003 classical BSE case. All cattle developed clinical disease. The survival time of the E211K BSE-H inoculated EK211 calf (10 months) was shorter than the wild-type calf (18 months). This genotype effect was not observed in classical BSE inoculated cattle (both 26 months). Significant changes in retinal function were observed in H-type BSE challenged cattle only. Cattle challenged with the same inoculum showed similar severity and neuroanatomical distribution of vacuolation and disease-associated prion protein deposition in the brain, though differences in neuropathology were observed between E211K BSE-H and classical BSE inoculated animals. Western blot results for brain tissue from challenged animals were consistent with the inoculum strains. This study demonstrates that the phenotype of E211K BSE-H remains stable when transmitted to cattle without the K211 polymorphism, and exhibits a number of features that differ from classical BSE in both wild-type and heterozygous EK211 animals. PMID:27695695
Full Text Available In 2006, a case of H-type bovine spongiform encephalopathy (BSE-H was diagnosed in a cow that was associated with a heritable polymorphism in the bovine prion protein gene (PRNP resulting in a lysine for glutamine amino acid substitution at codon 211 (called E211K of the prion protein. Although the prevalence of this polymorphism is low, cattle carrying the K211 allele may be predisposed to rapid onset of BSE-H when exposed or to the potential development of a genetic BSE. This study was conducted to better understand the relationship between the K211 polymorphism and its effect on BSE phenotype. BSE-H from the US 2006 case was inoculated intracranially (IC in one PRNP wild type (EE211 calf and one EK211 calf. In addition, one wild type calf and one EK211 calf were inoculated IC with brain homogenate from a US 2003 classical BSE case. All cattle developed clinical disease. The survival times of the E211K BSE-H inoculated EK211 calf (10 months was shorter than the wild type calf (18 months. This genotype effect was not observed in classical BSE inoculated cattle (both 26 months. Significant changes in retinal function were observed in H-type BSE challenged cattle only. Cattle challenged with the same inoculum showed similar severity and neuroanatomical distribution of vacuolation and disease-associated prion protein deposition in the brain, though differences in neuropathology were observed between E211K BSE-H and classical BSE inoculated animals. Western blot results for brain tissue from challenged animals were consistent with the inoculum strains. This study demonstrates that the phenotype of E211K BSE-H remains stable when transmitted to cattle without the K211 polymorphism, and exhibits a number of features that differ from classical BSE in both wild type and heterozygous EK211 animals.
Full Text Available Feline spongiform encephalopathy (FSE is considered to be related to bovine spongiform encephalopathy (BSE and has been reported in domestic cats as well as in captive wild cats including cheetahs, first in the United Kingdom (UK and then in other European countries. In France, several cases were described in cheetahs either imported from UK or born in France. Here we report details of two other FSE cases in captive cheetah including a 2(nd case of FSE in a cheetah born in France, most likely due to maternal transmission. Complete prion protein immunohistochemical study on both brains and peripheral organs showed the close likeness between the two cases. In addition, transmission studies to the TgOvPrP4 mouse line were also performed, for comparison with the transmission of cattle BSE. The TgOvPrP4 mouse brains infected with cattle BSE and cheetah FSE revealed similar vacuolar lesion profiles, PrP(d brain mapping with occurrence of typical florid plaques. Collectively, these data indicate that they harbor the same strain of agent as the cattle BSE agent. This new observation may have some impact on our knowledge of vertical transmission of BSE agent-linked TSEs such as in housecat FSE, or vCJD.
Full Text Available Abstract Background The function of the autonomic nervous system can be assessed by determining heart rate variability (HRV, which is impaired in some brainstem diseases in humans. Transmissible spongiform encephalopathies (TSEs in sheep are diseases characterised by accumulation of disease-associated prion protein in the brainstem, including nuclei of the parasympathetic nervous system. This study was undertaken to assess whether analysis of HRV can be used as an aid in the diagnosis of TSEs in clinically affected, naturally or experimentally infected sheep. Findings When HRV indices were compared between 41 clinical TSE cases (18 sheep infected with scrapie and 23 sheep infected with bovine spongiform encephalopathy, 11 control sheep and six sheep reported as scrapie suspects or dosed with BSE brain homogenate, which were not confirmed as TSE cases by postmortem tests, no significant differences were found between the groups. Median heart rate was significantly different but only when sheep were grouped by gender: it was higher in female TSE cases than in control sheep and higher in female than castrated male ovine classical BSE cases. Conclusions HRV analysis was not useful as a diagnostic aid for TSEs of sheep.
McGovern, G; Martin, S; Jeffrey, M; Bellworthy, S J; Spiropoulos, J; Green, R; Lockey, R; Vickery, C M; Thurston, L; Dexter, G; Hawkins, S A C; González, L
The onset and distribution of infectivity and disease-specific prion protein (PrP(d)) accumulation was studied in Romney and Suffolk sheep of the ARQ/ARQ, ARQ/ARR and ARR/ARR prion protein gene (Prnp) genotypes (where A stands for alanine, R for arginine and Q for glutamine at codons 136, 154 and 171 of PrP), following experimental oral infection with cattle-derived bovine spongiform encephalopathy (BSE) agent. Groups of sheep were killed at regular intervals and a wide range of tissues taken for mouse bioassay or immunohistochemistry (IHC), or both. Bioassay results for infectivity were mostly coincident with those of PrP(d) detection by IHC both in terms of tissues and time post infection. Neither PrP(d) nor infectivity was detected in any tissues of BSE-dosed ARQ/ARR or ARR/ARR sheep or of undosed controls. Moreover, four ARQ/ARQ Suffolk sheep, which were methionine (M)/threonine heterozygous at codon 112 of the Prnp gene, did not show any biological or immunohistochemical evidence of infection, while those homozygous for methionine (MARQ/MARQ) did. In MARQ/MARQ sheep of both breeds, initial PrP(d) accumulation was identified in lymphoreticular system (LRS) tissues followed by the central nervous system (CNS) and enteric nervous system (ENS) and finally by the autonomic nervous system and peripheral nervous system and other organs. Detection of infectivity closely mimicked this sequence. No PrP(d) was observed in the ENS prior to its accumulation in the CNS, suggesting that ENS involvement occurred simultaneously to that of, or followed centrifugal spread from, the CNS. The distribution of PrP(d) within the ENS further suggested a progressive spread from the ileal plexus to other ENS segments via neuronal connections of the gut wall. Differences between the two breeds were noted in terms of involvement of LRS and ENS tissues, with Romney sheep showing a more delayed and less consistent PrP(d) accumulation than Suffolk sheep in such tissues. Whether this
To characterise in sheep the bovine spongiform encephalopathy agent (BSE) responsible for variant Creutzfeldt-Jakob disease in human beings, three ewes, presenting either a susceptible (2-ARQ/ARQ) or a resistant (1-ARR/ARR) genotype toward scrapie, were infected with a French BSE case. The research of abnormal prion protein (PrPsc) accumulating sites revealed traces of PrPsc in ARR/ARR sheep but did not distinguish BSE agent in ARQ/ARQ sheep from natural scrapie cases. The BSE agent was final...
陈婷; 刘万洪; 杨春玲; 李强飞; 郝甜甜; 席冬梅
朊蛋白(prion protein,PRNP)是近年来已证明的人和部分哺乳动物传染性海绵状脑病(transmissible spongiform encephalopathy,TSE)的主要根源,该蛋白编码基因的多态性显著影响了人和动物对TSE的易感性或抗病性.牛传染性海绵状脑病俗称“疯牛病”.作者分析了疯牛病的起源、监测和预防措施；简要介绍了牛PRNP基因的结构与功能；系统分析了牛科动物PRNP基因非编码区多态性与抗病性作用；总结了牛科动物PRNP基因启动子区域内23 bp插入/缺失和第1内含子区域内12 bp插入/缺失对疯牛病易感性的影响,为牛的抗病分子育种提供指导.
... deferral for time spent in Saudi Arabia to reduce the risk of variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products and human cells, tissues and cellular and tissue-based products. FDA intends to... HUMAN SERVICES Food and Drug Administration Transmissible Spongiform Encephalopathies Advisory...
Full Text Available Abstract Background The pathological hallmarks of transmissible spongiform encephalopathy (TSE diseases are the deposition of a misfolded form of a host-encoded protein (PrPres, marked astrocytosis, microglial activation and spongiosis. The development of powerful gene based technologies has permitted increased levels of pro-inflammatory cytokines to be demonstrated. However, due to the use of assays of differing sensitivities and typically the analysis of a single model system it remained unclear whether this was a general feature of these diseases or to what extent different model systems and routes of infection influenced the relative levels of expression. Similarly, it was not clear whether the elevated levels of cytokines observed in the brain were accompanied by similar increases in other tissues that accumulate PrPres, such as the spleen. Results The level of expression of the three interferon responsive genes, Eif2ak2, 2'5'-OAS, and Mx2, was measured in the brains of Syrian hamsters infected with scrapie 263K, VM mice infected with bovine spongiform encephalopathy and C57BL/6 mice infected with the scrapie strain ME7. Glial fibrillary acidic expression confirmed the occurrence of astrocytosis in all models. When infected intracranially all three models showed a similar pattern of increased expression of the interferon responsive genes at the onset of clinical symptoms. At the terminal stage of the disease the level and pattern of expression of the three genes was mostly unchanged in the mouse models. In contrast, in hamsters infected by either the intracranial or intraperitoneal routes, both the level of expression and the expression of the three genes relative to one another was altered. Increased interferon responsive gene expression was not observed in a transgenic mouse model of Alzheimer's disease or the spleens of C57BL/6 mice infected with ME7. Concurrent increases in TNFα, TNFR1, Fas/ApoI receptor, and caspase 8 expression in ME
Eiden, Martin; Hoffmann, Christine; Balkema-Buschmann, Anne; Müller, Matthias; Baumgartner, Katrin; Groschup, Martin H
Feline spongiform encephalopathy (FSE) is a transmissible spongiform encephalopathy that affects domestic cats (Felis catus) and captive wild members of the family Felidae. In this report we describe a case of FSE in a captive cheetah from the zoological garden of Nuremberg. The biochemical examination revealed a BSE-like pattern. Disease-associated scrapie prion protein (PrP(Sc)) was widely distributed in the central and peripheral nervous system, as well as in the lymphoreticular system and in other tissues of the affected animal, as demonstrated by immunohistochemistry and/or immunoblotting. Moreover, we report for the first time the use of the protein misfolding cyclic amplification technique for highly sensitive detection of PrP(Sc) in the family Felidae. The widespread PrP(Sc) deposition suggests a simultaneous lymphatic and neural spread of the FSE agent. The detection of PrP(Sc) in the spleen indicates a potential for prion infectivity of cheetah blood.
Zhiqi Song; Deming Zhao; Lifeng Yang
Transmissible spongiform encephalopathies refer to a group of infectious neurodegenerative diseases with an entirely novel mechanism of transmission and pathophysiology including synaptic damage,dendritic atrophy,vacuolization,and microglial activation.Extensive neuronal loss is the main cause of chronic brain deterioration and fatal outcome of prion diseases.As the final outcome of pathological alterations,neuronal death is a prominent feature of all prion diseases.The mechanisms responsible for prion diseases are not well understood.A more comprehensive understanding of the molecular basis of neuronal damage is essential for the development of an effective therapy for transmissible spongiform encephalopathies and other neurodegenerative diseases sharing similar features.Here,we review the molecular mechanisms of mitochondrial dysfunction and endoplasmic reticulum stress-mediated neuronal death,which play crucial roles in the pathogenisis of prion diseases.
Transmissible spongiform encephalopathies (TSEs), also know as prion diseases, represent a group of fatal neurodegenerative disorders in humans and several free-ranging and captive mammalian species. A report of scrapie in mouflon from England and the fact that Germany’s free-ranging mouflon population is the second largest in the world raised the question if mouflon in Germany are affected by TSEs. Therefore, the aim of this survey was (1) to examine the prevalence of prion diseases in moufl...
Full Text Available Abstract Background The purpose of this study is to analyse the trends in scientific research on transmissible spongiform encephalopathies by applying bibliometric tools to the scientific literature published between 1973 and 2002. Methods The data for the study were obtained from Medline database, in order to determine the volume of scientific output in the above period, the countries involved, the type of document and the trends in the subject matters addressed. The period 1973–2002 was divided in three sub-periods. Results We observed a significant growth in scientific production. The percentage of increase is 871.7 from 1973 to 2002. This is more evident since 1991 and particularly in the 1996–2001 period. The countries found to have the highest output were the United States, the United Kingdom, Japan, France and Germany. The evolution in the subject matters was almost constant in the three sub-periods in which the study was divided. In the first and second sub-periods, the subject matters of greatest interest were more general, i.e Nervous system or Nervous system diseases, Creutzfeldt-Jakob disease, Scrapie, and Chemicals and Drugs, but in the last sub-period, some changes were observed because the Prion-related matters had the greatest presence. Collaboration among authors is small from 1973 to 1992, but increases notably in the third sub-period, and also the number of authors and clusters formed. Some of the authors, like Gajdusek or Prusiner, appear in the whole period. Conclusion The study reveals a very high increase in scientific production. It is related also with the beginnings of research on bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease, with the establishment of progressive collaboration relationships and a reflection of public health concerns about this problem.
Paisley, Larry; de Koeijer, Aline; Hagenaars, Thomas J.
of the legislation regarding the control and eradication of BSE. Much uncertainty regarding important input parameters remains a major constraint in risk assessment. Uncertainty is one of the most critical and most difficult aspects of communication of risks about Transmissible Spongiform Encephalopathies (TSEs......). Nevertheless, the decline in the BSE epidemic in the UK and most European countries demonstrates that management has been, for the most part, sucessful. Literature pertaining to the three inter-related facets of risk analysis: risk assessment, risk management and risk communication of TSE's of animal origin...
Full Text Available Scrapie is a transmissible spongiform encephalopathy (TSE, which causes neurological signs in sheep but confirmatory diagnosis is usually made postmortem on examination of the brain for TSE-associated markers like vacuolar changes and disease-associated prion protein (PrPSc. The objective of this study was to evaluate whether testing of brainstem auditory evoked potentials (BAEPs at two different sound levels could aid in the clinical diagnosis of TSEs in sheep naturally or experimentally infected with different TSE strains [classical and atypical scrapie and bovine spongiform encephalopathy (BSE] and whether any BAEP abnormalities were associated with TSE-associated markers in the auditory pathways.BAEPs were recorded from 141 clinically healthy sheep of different breeds and ages that tested negative for TSEs on postmortem tests to establish a reference range and to allow comparison with 30 sheep clinically affected or exposed to classical scrapie without disease confirmation (test group 1 and 182 clinically affected sheep with disease confirmation (test group 2. Abnormal BAEPs were found in seven sheep (23% of group 1 and 42 sheep (23% of group 2. The proportion of sheep with abnormalities did not appear to be influenced by TSE strain or prion protein gene polymorphisms. When the magnitude of TSE-associated markers in the auditory pathways was compared between a subset of 12 sheep with and 12 sheep without BAEP abnormalities in group 2, no significant differences in the total PrPSc or vacuolation scores in the auditory pathways could be found. However, the data suggested that there was a difference in the PrPSc scores depending on the TSE strain because PrPSc scores were significantly higher in sheep with BAEP abnormalities infected with classical and L-type BSE but not with classical scrapie.The results indicated that BAEPs may be abnormal in sheep infected with TSEs but the test is not specific for TSEs, and that neither vacuolation nor Pr
Konold, Timm; Phelan, Laura J.; Cawthraw, Saira; Simmons, Marion M.; Chaplin, Melanie J.; González, Lorenzo
Scrapie is transmissible spongiform encephalopathy (TSE), which causes neurological signs in sheep, but confirmatory diagnosis is usually made postmortem on examination of the brain for TSE-associated markers like vacuolar changes and disease-associated prion protein (PrPSc). The objective of this study was to evaluate whether testing of brainstem auditory evoked potentials (BAEPs) at two different sound levels could aid in the clinical diagnosis of TSEs in sheep naturally or experimentally infected with different TSE strains [classical and atypical scrapie and bovine spongiform encephalopathy (BSE)] and whether any BAEP abnormalities were associated with TSE-associated markers in the auditory pathways. BAEPs were recorded from 141 clinically healthy sheep of different breeds and ages that tested negative for TSEs on postmortem tests to establish a reference range and to allow comparison with 30 sheep clinically affected or exposed to classical scrapie (CS) without disease confirmation (test group 1) and 182 clinically affected sheep with disease confirmation (test group 2). Abnormal BAEPs were found in 7 sheep (23%) of group 1 and 42 sheep (23%) of group 2. The proportion of sheep with abnormalities did not appear to be influenced by TSE strain or PrPSc gene polymorphisms. When the magnitude of TSE-associated markers in the auditory pathways was compared between a subset of 12 sheep with and 12 sheep without BAEP abnormalities in group 2, no significant differences in the total PrPSc or vacuolation scores in the auditory pathways could be found. However, the data suggested that there was a difference in the PrPSc scores depending on the TSE strain because PrPSc scores were significantly higher in sheep with BAEP abnormalities infected with classical and L-type BSE, but not with CS. The results indicated that BAEPs may be abnormal in sheep infected with TSEs but the test is not specific for TSEs and that neither vacuolation nor PrPSc accumulation appears to be
Full Text Available Distinct prion strains often exhibit different incubation periods and patterns of neuropathological lesions. Strain characteristics are generally retained upon intraspecies transmission, but may change on transmission to another species. We investigated the inactivation of two related prions strains: BSE prions from cattle and mouse-passaged BSE prions, termed 301V. Inactivation was manipulated by exposure to sodium dodecyl sulfate (SDS, variations in pH, and different temperatures. Infectivity was measured using transgenic mouse lines that are highly susceptible to either BSE or 301V prions. Bioassays demonstrated that BSE prions are up to 1,000-fold more resistant to inactivation than 301V prions while Western immunoblotting showed that short acidic SDS treatments reduced protease-resistant PrP(Sc from BSE prions and 301V prions at similar rates. Our findings argue that despite being derived from BSE prions, mouse 301V prions are not necessarily a reliable model for cattle BSE prions. Extending these comparisons to human sporadic Creutzfeldt-Jakob disease and hamster Sc237 prions, we found that BSE prions were 10- and 10(6-fold more resistant to inactivation, respectively. Our studies contend that any prion inactivation procedures must be validated by bioassay against the prion strain for which they are intended to be used.
Giles, Kurt; Glidden, David V; Beckwith, Robyn; Seoanes, Rose; Peretz, David; DeArmond, Stephen J; Prusiner, Stanley B
Distinct prion strains often exhibit different incubation periods and patterns of neuropathological lesions. Strain characteristics are generally retained upon intraspecies transmission, but may change on transmission to another species. We investigated the inactivation of two related prions strains: BSE prions from cattle and mouse-passaged BSE prions, termed 301V. Inactivation was manipulated by exposure to sodium dodecyl sulfate (SDS), variations in pH, and different temperatures. Infectivity was measured using transgenic mouse lines that are highly susceptible to either BSE or 301V prions. Bioassays demonstrated that BSE prions are up to 1,000-fold more resistant to inactivation than 301V prions while Western immunoblotting showed that short acidic SDS treatments reduced protease-resistant PrP(Sc) from BSE prions and 301V prions at similar rates. Our findings argue that despite being derived from BSE prions, mouse 301V prions are not necessarily a reliable model for cattle BSE prions. Extending these comparisons to human sporadic Creutzfeldt-Jakob disease and hamster Sc237 prions, we found that BSE prions were 10- and 10(6)-fold more resistant to inactivation, respectively. Our studies contend that any prion inactivation procedures must be validated by bioassay against the prion strain for which they are intended to be used.
Wilson, Rona; King, Declan; Hunter, Nora; Goldmann, Wilfred; Barron, Rona M
Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disorder of cattle, and its transmission to humans through contaminated food is thought to be the cause of the variant form of Creutzfeldt-Jakob disease. BSE is believed to have spread from the recycling in cattle of ruminant tissue in meat and bone meal (MBM). However, during this time, sheep and goats were also exposed to BSE-contaminated MBM. Both sheep and goats are experimentally susceptible to BSE, and while there have been no reported natural BSE cases in sheep, two goat BSE field cases have been documented. While cases of BSE are rare in small ruminants, the existence of scrapie in both sheep and goats is well established. In the UK, during 2006-2007, a serious outbreak of clinical scrapie was detected in a large dairy goat herd. Subsequently, 200 goats were selected for post-mortem examination, one of which showed biochemical and immunohistochemical features of the disease-associated prion protein (PrP(TSE)) which differed from all other infected goats. In the present study, we investigated this unusual case by performing transmission bioassays into a panel of mouse lines. Following characterization, we found that strain properties such as the ability to transmit to different mouse lines, lesion profile pattern, degree of PrP deposition in the brain and biochemical features of this unusual goat case were neither consistent with goat BSE nor with a goat scrapie herdmate control. However, our results suggest that this unusual case has BSE-like properties and highlights the need for continued surveillance.
Rainov, N G; Tsuboi, Y; Krolak-Salmon, P; Vighetto, A; Doh-Ura, K
Human transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are caused by the accumulation of an abnormal isoform of the prion protein in the CNS. Creutzfeldt-Jakob disease in its sporadic form is the most frequent type of human TSE. At present, there is no proven specific or effective treatment available for any form of TSE. Pentosan polysulfate (PPS) has been shown to prolong the incubation period when administered to the cerebral ventricles in a rodent TSE model. Cerebroventricular administration of PPS has been carried out in 26 patients with TSEs and has been shown to be well tolerated in doses < or = 220 microg/kg/day. Proof of efficacy has been difficult because the specific and objective criteria for measurement of response have not been established yet. Preliminary clinical experience confirms extended survival in patients with variant Creutzfeldt-Jakob disease receiving intraventricular PPS; however, it is still not clear if this is due to PPS itself. Further prospective investigations of long-term intraventricular PPS administration are essential for the assessment of its effects.
Johnson, Christopher J.; Carlson, Christina M.; Morawski, Aaron R.; Manthei, Alyson; Cashman, Neil R.
Studies to understanding interspecies transmission of transmissible spongiform encephalopathies (TSEs, prion diseases) are challenging in that they typically rely upon lengthy and costly in vivo animal challenge studies. A number of in vitro assays have been developed to aid in measuring prion species barriers, thereby reducing animal use and providing quicker results than animal bioassays. Here, we present the protocol for a rapid in vitroprion conversion assay called the conversion efficiency ratio (CER) assay. In this assay cellular prion protein (PrPC) from an uninfected host brain is denatured at both pH 7.4 and 3.5 to produce two substrates. When the pH 7.4 substrate is incubated with TSE agent, the amount of PrPC that converts to a proteinase K (PK)-resistant state is modulated by the original host’s species barrier to the TSE agent. In contrast, PrPC in the pH 3.5 substrate is misfolded by any TSE agent. By comparing the amount of PK-resistant prion protein in the two substrates, an assessment of the host’s species barrier can be made. We show that the CER assay correctly predicts known prion species barriers of laboratory mice and, as an example, show some preliminary results suggesting that bobcats (Lynx rufus) may be susceptible to white-tailed deer (Odocoileus virginianus) chronic wasting disease agent.
Owing to the high oxygen-respiration in the brain of mammals, oxidative damage to prion protein hasbeen suggested to be an additional factor. A large body of intriguing features of scrapie and prion diseases haveprovided multiple lines of indirect chemistry evidence, suggesting that the infectious agents may be putative forms ofsequence-specific prion radicals (SSPR) and/or their immediate precursors in the transmissible spongiform encepha-lopathies (TSE). Here a molecular mechanism corresponding to the self-replication of scrapie protein mediated byprion free-radical processes, consonant with "protein-only" hypotheses is proposed. This new theory may not onlyaid our understanding of the occurrence of prions, but also provides new insight into the possible chemistry principlesunderlying the neurodegenerative disorders. It is anticipated that future studies based on this suggestion and chem-istry principles of genetic diseases may allow us to determine an effective approach to stop mad cow disease and itshuman version, new variant of Creutzfeldt-Jakob disease (v CJD).
Johnson, Christopher J.; Morawski, A.R.; Carlson, C.M.; Chang, H.
Background: Transmissible spongiform encephalopathies (TSEs) affect both domestic sheep (scrapie) and captive and free-ranging cervids (chronic wasting disease; CWD). The geographical range of bighorn sheep (Ovis canadensis; BHS) overlaps with states or provinces that have contained scrapie-positive sheep or goats and areas with present epizootics of CWD in cervids. No TSEs have been documented in BHS, but the susceptibility of this species to TSEs remains unknown. Results: We acquired a library of BHS tissues and found no evidence of preexisting TSEs in these animals. The prion protein gene (Prnp) in all BHS in our library was identical to scrapie-susceptible domestic sheep (A136R 154Q171). Using an in vitro prion protein conversion assay, which has been previously used to assess TSE species barriers and, in our study appears to recollect known species barriers in mice, we assessed the potential transmissibility of TSEs to BHS. As expected based upon Prnp genotype, we observed BHS prion protein conversion by classical scrapie agent and evidence for a species barrier between transmissible mink encephalopathy (TME) and BHS. Interestingly, our data suggest that the species barrier of BHS to white-tailed deer or wapiti CWD agents is likely low. We also used protein misfolding cyclic amplification to confirm that CWD, but not TME, can template prion protein misfolding in A136R 154Q171genotype sheep. Conclusions: Our results indicate the in vitro conversion assay used in our study does mimic the species barrier of mice to the TSE agents that we tested. Based on Prnp genotype and results from conversion assays, BHS are likely to be susceptible to infection by classical scrapie. Despite mismatches in amino acids thought to modulate prion protein conversion, our data indicate that A136R154Q171 genotype sheep prion protein is misfolded by CWD agent, suggesting that these animals could be susceptible to CWD. Further investigation of TSE transmissibility to BHS, including
... title 9 of the Code of Federal Regulations, subchapter D, govern the exportation and importation of... that those countries where cattle are primarily raised on grass, such as Argentina and Brazil,...
Après avoir brossé un tableau des connaissances actuelles sur les sources de contamination et les voies de transmission des Encéphalopathies Spongiformes Transmissibles (EST), l’article présente l’éventail des travaux réalisés à l’INRA sur la résistance de l’agent pathogène dans le milieu extérieur, les sources d’infection, les voies de transmission et la dynamique de la maladie dans les populations animales, en matière de tremblante et d’Encéphalopathie Spongiforme Bovine (ESB). Ces travaux ...
Wunderlin Sabina S
Full Text Available Abstract Background Two domestic shorthair cats presenting with progressive hind-limb ataxia and increased aggressiveness were necropsied and a post mortem diagnosis of Feline Spongiform Encephalopathy (FSE was made. A wide spectrum of tissue samples was collected and evaluated histologically and immunohistologically for the presence of PrPSc. Results Histopathological examination revealed a diffuse vacuolation of the grey matter neuropil with the following areas being most severely affected: corpus geniculatum medialis, thalamus, gyrus dentatus of the hippocampus, corpus striatum, and deep layers of the cerebral and cerebellar cortex as well as in the brain stem. In addition, a diffuse glial reaction involving astrocytes and microglia and intraneuronal vacuolation in a few neurons in the brain stem was present. Heavy PrPSc immunostaining was detected in brain, retina, optic nerve, pars nervosa of the pituitary gland, trigeminal ganglia and small amounts in the myenteric plexus of the small intestine (duodenum, jejunum and slightly in the medulla of the adrenal gland. Conclusion The PrPSc distribution within the brain was consistent with that described in other FSE-affected cats. The pattern of abnormal PrP in the retina corresponded to that found in a captive cheetah with FSE, in sheep with scrapie and was similar to nvCJD in humans.
Baxter, H C; Campbell, G A; Whittaker, A G; Jones, A C; Aitken, A; Simpson, A H; Casey, M; Bountiff, L; Gibbard, L; Baxter, R L
It has now been established that transmissible spongiform encephalopathy (TSE) infectivity, which is highly resistant to conventional methods of deactivation, can be transmitted iatrogenically by contaminated stainless steel. It is important that new methods are evaluated for effective removal of protein residues from surgical instruments. Here, radio-frequency (RF) gas-plasma treatment was investigated as a method of removing both the protein debris and TSE infectivity. Stainless-steel spheres contaminated with the 263K strain of scrapie and a variety of used surgical instruments, which had been cleaned by a hospital sterile-services department, were examined both before and after treatment by RF gas plasma, using scanning electron microscopy and energy-dispersive X-ray spectroscopic analysis. Transmission of scrapie from the contaminated spheres was examined in hamsters by the peripheral route of infection. RF gas-plasma treatment effectively removed residual organic residues on reprocessed surgical instruments and gross contamination both from orthopaedic blades and from the experimentally contaminated spheres. In vivo testing showed that RF gas-plasma treatment of scrapie-infected spheres eliminated transmission of infectivity. The infectivity of the TSE agent adsorbed on metal spheres could be removed effectively by gas-plasma cleaning with argon/oxygen mixtures. This treatment can effectively remove 'stubborn' residual contamination on surgical instruments.
Experimental transmission of transmissible spongiform encephalopathies (scrapie, chronic wasting disease, transmissible mink encephalopathy) to cattle and their differentiation from bovine spongiform encephalopathy
Experimental cross-species transmission of TSE agents provides valuable information for identification of potential host ranges of known TSEs. This report provides a synopsis of TSE (scrapie, CWD, TME) transmission studies that have been conducted in cattle and compares these findings to those seen ...
Baron, T.G.M.; Biacabe, A.G.; Bencsik, A.; Langeveld, J.P.M.
We previously reported that cattle were affected by a prion disorder that differed from bovine spongiform encephalopathy (BSE) by showing distinct molecular features of disease-associated protease-resistant prion protein (PrPres). We show that intracerebral injection of such isolates into C57BL/6 mi
... Research Food and Agriculture Research OPEDA Scholarship Program MARKETING AND TRADE Exporting Goods Importing Goods Newsroom Agency ... This is directly attributable to the impact and effectiveness of feed bans as a primary control measure ...
...: Dr. Silvia Kreindel, Senior Staff Veterinarian, Regionalization Evaluation Services, National Center... Washington, DC, this 20th day of November 2013. Kevin Shea, Administrator, Animal and Plant Health...
Polak, M.P.; Zmudzinski, J.F.; Jacobs, J.G.; Langeveld, J.P.M.
The aim of this study was to analyze molecular features of protease-resistant prion protein (PrPres) in Western blots of BSE cases diagnosed in Poland with respect to a possible atypical status. Confirmed cases were analyzed by Western blotting with several monoclonal antibodies directed at N-termin
This contribution examines what animal meal is, how it is produced in rendering plants, and means of investigating feedstuff constituents. In addition to animal meal, numerous other products of animal origin are also on the market (e.g., blood meal, bone meal, feather meal, gelatin). Constituents of animal origin can be detected in feedstuffs by microscopy, but determining the animal species from which the constituents are derived, as required by law in Germany, requires methods such as enzyme-linked immunosorbent assay and polymerase chain reaction. We consider the problem of trace contamination being introduced accidentally during the production of ruminants' feedstuffs containing constituents of animal origin. The future of animal meal is discussed together with alternatives for disposing of animal carcasses and slaughtery offal, i.e., composting and incineration.
Meloni, D.; Davidse, A.; Langeveld, J.P.M.; varello, K.; Casalone, C.; Corona, C.; Balkema-Buschmann, A.; Groschup, M.; Ingravalle, F.; Bozzetta, E.
Since 2004 it become clear that atypical bovine spongiform encephalopthies (BSEs) exist in cattle. Whenever their detection has relied on active surveillance plans implemented in Europe since 2001 by rapid tests, the overall and inter-laboratory performance of these diagnostic systems in the detecti
Jennelle, C.S.; Samuel, M.D.; Nolden, C.A.; Keane, D.P.; Barr, D.J.; Johnson, Chad; Vanderloo, J.P.; Aiken, Judd M.; Hamir, A.N.; Hoover, E.A.
Chronic wasting disease (CWD), a class of neurodegenerative transmissible spongiform encephalopathies (TSE) occurring in cervids, is found in a number of states and provinces across North America. Misfolded prions, the infectious agents of CWD, are deposited in the environment via carcass remains and excreta, and pose a threat of cross-species transmission. In this study tissues were tested from 812 representative mammalian scavengers, collected in the CWD-affected area of Wisconsin, for TSE infection using the IDEXX HerdChek enzyme-linked immunosorbent assay (ELISA). Only four of the collected mammals tested positive using the ELISA, but these were negative when tested by Western blot. While our sample sizes permitted high probabilities of detecting TSE assuming 1% population prevalence in several common scavengers (93%, 87%, and 87% for raccoons, opossums, and coyotes, respectively), insufficient sample sizes for other species precluded similar conclusions. One cannot rule out successful cross-species TSE transmission to scavengers, but the results suggest that such transmission is not frequent in the CWD-affected area of Wisconsin. The need for further surveillance of scavenger species, especially those known to be susceptible to TSE (e.g., cat, American mink, raccoon), is highlighted in both a field and laboratory setting.
Kneipp, Janina; Lasch, Peter; Beekes, Michael; Naumann, Dieter
Transmissible spongiform encephalopathies (TSE), such as BSE in cattle, scrapie in sheep and goats, and Creutzfeldt-Jakob disease in man are a group of fatal infectious diseases of the central nervous system that are far from being fully understood. Presuming the pathological changes to originate from small disease-specific compositional and structural modifications at the molecular level, Fourier-transform infrared (FTIR) spectroscopy can be used to achieve insight into biochemical parameters underlying pathogenesis. We have developed an FTIR microspectroscopy-based strategy which, as a combination of image reconstruction and multivariate pattern recognition methods, permitted the comparison of identical substructures in the cerebellum of healthy and TSE-infected Syrian hamsters in the terminal stage of the disease. Here we present FTIR data about the pathological changes of scrapie-infected and normal tissue of the gray matter structures stratum granulosum and stratum moleculare. IR spectroscopy was also applied to tissue pieces of the medulla oblongata of infected and control Syrian hamsters. Mapping data were analyzed with cluster analysis and imaging methods. We found variations in the spectra of the infected tissue, which are due to changes in carbohydrates, nucleic acids, phospholipids, and proteins.
Jennelle, Christopher S; Samuel, Michael D; Nolden, Cherrie A; Keane, Delwyn P; Barr, Daniel J; Johnson, Chad; Vanderloo, Joshua P; Aiken, Judd M; Hamir, Amir N; Hoover, Edward A
Chronic wasting disease (CWD), a class of neurodegenerative transmissible spongiform encephalopathies (TSE) occurring in cervids, is found in a number of states and provinces across North America. Misfolded prions, the infectious agents of CWD, are deposited in the environment via carcass remains and excreta, and pose a threat of cross-species transmission. In this study tissues were tested from 812 representative mammalian scavengers, collected in the CWD-affected area of Wisconsin, for TSE infection using the IDEXX HerdChek enzyme-linked immunosorbent assay (ELISA). Only four of the collected mammals tested positive using the ELISA, but these were negative when tested by Western blot. While our sample sizes permitted high probabilities of detecting TSE assuming 1% population prevalence in several common scavengers (93%, 87%, and 87% for raccoons, opossums, and coyotes, respectively), insufficient sample sizes for other species precluded similar conclusions. One cannot rule out successful cross-species TSE transmission to scavengers, but the results suggest that such transmission is not frequent in the CWD-affected area of Wisconsin. The need for further surveillance of scavenger species, especially those known to be susceptible to TSE (e.g., cat, American mink, raccoon), is highlighted in both a field and laboratory setting.
Dobie, Karen; Barron, Rona
Most current diagnostic tests for transmissible spongiform encephalopathies (TSE) rely on the presence of proteinase K (PK)-resistant PrP(Sc) (PrP-res) in postmortem tissues as an indication of TSE disease. However, a number of studies have highlighted a discrepancy between TSE infectivity and PrP-res levels in both natural and experimental cases of TSE disease. Previously, we have shown high TSE infectivity levels in the brain tissue of mice that have a clinical TSE disease with associated vacuolar pathology but little or no detectable PrP-res. Here, the levels of TSE infectivity and PrP-res within a peripheral tissue of this mouse model were investigated. Biochemical analysis showed that low levels of PrP-res were present in the spleen tissue in comparison to the levels observed in the spleen of mice infected with ME7 or 79A. However, upon subpassage of brain and spleen tissue from clinically ill mice with little or no PrP-res detectable, similar short incubation periods to disease were observed, indicating that infectivity levels were similarly high in both tissues. Thus, the discrepancy between PrP-res and TSE infectivity was also present in the peripheral tissues of this disease model. This result indicates that peripheral tissues can contain higher levels of infectivity given the correct combination of host species, PrP genotype, and TSE agent. Therefore, the assumption that the levels of peripheral infectivity are lower than those in the central nervous system is not always correct, and this could have implications for current food safety regulations.
We recently reported the intraspecies transmission of L-type atypical bovine spongiform encephalopathy (BSE). To clarify the peripheral pathogenesis of L-type BSE, we studied prion distribution in nerve and lymphoid tissues obtained from experimentally challenged cattle. As with classical BSE prions, L-type BSE prions accumulated in central and peripheral nerve tissues.
Zentek, J; Oberthür, R C; Kamphues, J; Kreienbrock, L; Flachowsky, G; Coenen, M
Specific conditions and practices of cattle feeding in Germany have to be taken into account for assessing the risk of feed born transmission of bovine spongiform encephalopathy, especially regarding the situation before the year 2000 when specific directives were introduced for feed production. The present retrospective epidemiological study includes data on feed production and the estimated amount of animal derived feedstuffs for the production of compounded feed for cattle. Risk assessment was performed based on the 'reproduction rate' (R0), that is defined as the estimated number of infections resulting from the processing of brain and spinal cord of BSE affected cattle that is recycled to bovines via feed. Under the conditions as given in Germany until the year 2000 the reproduction rate of BSE via the inclusion of animal derived feedstuffs in compounded feed production for cattle was estimated to be 1.1. Thus, it can be expected that BSE could be reproduced in the system, but with comparatively low efficiency. The expected incidence of BSE should be considerably lower compared to the situation during the 90th in the UK, due to the markedly lower recycling rate of animal protein in cattle feeding. Animal fat could have been a significant factor for BSE transmission due to contamination by proteinaceous brain and spinal cord material during the production process. The relative significance of fat containing feedstuffs for BSE transmission could have been higher in Germany compared to the situation in the UK where meat and bone meal was produced under different conditions and frequently used in higher proportions as an ingredient for compounded feed for ruminants.
Aarts, H.J.M.; Bouw, E.M.; Buntjer, J.B.; Lenstra, J.A.; Raamsdonk, van L.W.D.
For the control of the transmission of bovine spongiform encephalopathy in cattle via feedstuff, a real-time polymerase chain reaction assay was developed with ruminant-specific Bov-B SINE primers, SYBR® Green fluorescence detection, and melting curve analysis. In formulated cattle and chicken feed
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Aarts, Henk J M; Bouw, El M; Buntjer, Jaap B; Lenstra, Johannes A; Van Raamsdonk, Leo W D
For the control of the transmission of bovine spongiform encephalopathy in cattle via feedstuff, a real-time polymerase chain reaction assay was developed with ruminant-specific Bov-B SINE primers, SYBR Green fluorescence detection, and melting curve analysis. In formulated cattle and chicken feed samples spiked with pure bovine and sheep meat and bone meal heated at 133 degrees C for 20 min, a contamination level of 0.1% was detected.
Paisley, Larry G; Hostrup-Pedersen, Julie
A Monte Carlo simulation model was constructed to assess the risk of BSE transmission to calves by calf milk-replacer (CMR). We assumed that any BSE infectivity in the CMR would be associated with the allowable levels of impurities in tallow used to manufacture the milk-replacer. Simulations used three different levels of impurities, six different distributions of the BSE infectivity titers of CNS tissues and with and without inclusion of specified risk material (SRM). Our results suggest that tallow-based CMR could have been responsible for some BSE infections in nearly all simulations. The reduction in the allowable impurities in tallow and the exclusion of SRM have greatly reduced--but have not eliminated--the risk of BSE transmission by CMR The results of the simulations are associated with much uncertainty.
Paisley, Larry; Hostrup-Pedersen, J.
A Monte Carlo simulation model was constructed to assess the risk of BSE transmission to calves by calf milk-replacer (CMR). We assumed that any BSE infectivity in the CMR would be associated with the allowable levels of impurities in tallow used to manufacture the milk-replacer. Simulations used...... three different levels of impurities, six different distributions of the BSE infectivity titers of CNS tissues and with and without inclusion of specified risk material (SRM). Our results suggest that tallow-based CMR could have been responsible for some BSE infections in nearly all simulations....... The reduction in the allowable impurities in tallow and the exclusion of SRM have greatly reduced-but have not eliminated-the risk of BSE transmission by CMR The results of the simulations are associated with much uncertainty....
Auvergnon, Nathalie; Reibel, Sophie; Touret, Monique; Honnorat, Jérôme; Baron, Thierry; Giraudon, Pascale; Bencsik, Anna
While recent studies suggest that synaptic alterations are first events in the mechanisms of prion-mediated neurodegeneration, little is known on the identity of the neuronal plasticity-related genes potentially concerned. Here the expression of 4 Collapsin Response Mediator Proteins (CRMPs), a family of signal transduction proteins involved in brain development and altered in Alzheimer's disease, was studied in the brain of C57Bl/6 mice infected with the BSE strain of prion agent, using RT-PCR and Western-blot methods. At the terminal stage of the disease, gene expression of each CRMP had decreased, while at the mid-stage of the disease only CRMP4 (mRNA and protein) expression had increased, concomitant to the start of PrP(Sc) accumulation in the brainstem. Altogether our findings picked out originally CRMPs, and especially CRMP4, as potential contributors to prion pathogenesis.
王辉暖; 赵德明; 杨建民; 王秀菊
传染性海绵状脑病(TSE)是人和动物共患的一类慢性、进行性、致死性、传染性和神经系统退行性脑病，在人类主要包括库鲁病(kuru)、克雅氏病(Creutzfeldt—Jakob Disease，CJD)、格施谢三氏症(Gerstmann Straussier Scheinker Disease，GSSD)、致死性家族失眠症(Fatal Familiar Insomnia．FFL)和变异性克雅氏病(Viriant Creutzfeldt—Jakob Disease，vCJD)；动物上主要有羊痒病(Scrapie)，牛海绵状脑病(Bovine Spongiform Encephalopathy．
...: Bovine Spongiform Encephalopathy; Importation of Animals and Animal Products. OMB Control Number: 0579... prevent the introduction of diseases, such as bovine spongiform encephalopathy (BSE), a...
To obtain high titer monoclonal antibodies(McAbs) which can react with mammalian prion protein(PrP),Balb/C mice were immunized with bovine(Bo) PrP peptide(BoPrP 209-228 aa) coupled to keyhole limpet hemocyanin(KLH).The hybridoma cell lines secreting monoclonal antibodies against the peptide were established by cell fusion and cloning.The obtained McAbs were applied to detect recombinant human,bovine and hamster PrP,cellular prion protein(PrPc) in normal bovine brain and pathogenic scrapie prion protein(PrPSc) accumulated in the medulla oblongata of bovine spongiform encephalopathy(BSE)specimen with Western blot and immunohistochemical detection,respectively.The current procedure might offer a simple,feasible method to raise high titer antibodies for studying biological features of PrP in mammals,as well as detection of transmissible spongiform encephalopathy(TSE) and diagnosis of BSE,in particular.
Xiong, Nalee; Brewer, Matt T; Anderson, Kristi L; Watrous, Gwyneth K; Weeks, Katherine E; Barnhill, Alison E; Day, Tim A; Kimber, Michael J; Carlson, Steve A
This study assessed the capacity of β-lactam antibiotics to prevent salmonella-mediated encephalopathy in calves given the putative neuroprotective effects of these drugs of increasing glutamate export from the brain. Both ampicillin and ceftiofur prevented the development of encephalopathy despite resistance of the inoculated Salmonella enterica serovar Saint-Paul isolate to both drugs. A glutamate receptor antagonist also prevented this salmonella-mediated encephalopathy. Glutamate exporters were hyper-expressed in the presence of β-lactam antibiotics while a glutamate export inhibitor obviated the effects of these antibiotics, demonstrating a neuroprotective effect through glutamate export from the brain. The findings indicate that β-lactam antibiotics remain an important treatment option for this atypical form of bovine salmonellosis.
Full Text Available Successful transmission of Transmissible Mink Encephalopathy (TME to cattle supports the bovine hypothesis for the still controversial origin of TME outbreaks. Human and primate susceptibility to classical Bovine Spongiform Encephalopathy (c-BSE and the transmissibility of L-type BSE to macaques indicate a low cattle-to-primate species barrier. We therefore evaluated the zoonotic potential of cattle-adapted TME. In less than two years, this strain induced in cynomolgus macaques a neurological disease similar to L-BSE but distinct from c-BSE. TME derived from another donor species (raccoon induced a similar disease with even shorter incubation periods. L-BSE and cattle-adapted TME were also transmissible to transgenic mice expressing human prion protein (PrP. Secondary transmissions to transgenic mice expressing bovine PrP maintained the features of the three tested bovine strains (cattle TME, c-BSE and L-BSE regardless of intermediate host. Thus, TME is the third animal prion strain transmissible to both macaques and humanized transgenic mice, suggesting zoonotic potentials that should be considered in the risk analysis of animal prion diseases for human health. Moreover, the similarities between TME and L-BSE are highly suggestive of a link between these strains, and therefore the possible presence of L-BSE for many decades prior to its identification in USA and Europe.
...; National Veterinary Services Laboratories; Bovine Spongiform Encephalopathy Surveillance Program Documents... associated with National Veterinary Services Laboratories diagnostic support for the bovine spongiform... Veterinary Services Laboratories; Bovine Spongiform Encephalopathy Surveillance Program Documents. OMB...
Full Text Available Abstract Background The Age-Period-Cohort (APC analysis is routinely used for time trend analysis of cancer incidence or mortality rates, but in veterinary epidemiology, there are still only a few examples of this application. APC models were recently used to model the French epidemic assuming that the time trend for BSE was mainly due to a cohort effect in relation to the control measures that may have modified the BSE exposure of cohorts over time. We used a categorical APC analysis which did not require any functional form for the effect of the variables, and examined second differences to estimate the variation of the BSE trend. We also reanalysed the French epidemic and performed a simultaneous analysis of Italian data using more appropriate birth cohort categories for comparison. Results We used data from the exhaustive surveillance carried out in France and Italy between 2001 and 2007, and comparatively described the trend of the epidemic in both countries. At the end, the shape and irregularities of the trends were discussed in light of the main control measures adopted to control the disease. In Italy a decrease in the epidemic became apparent from 1996, following the application of rendering standards for the processing of specific risk material (SRM. For the French epidemic, the pattern of second differences in the birth cohorts confirmed the beginning of the decrease from 1995, just after the implementation of the meat and bone meal (MBM ban for all ruminants (1994. Conclusion The APC analysis proved to be highly suitable for the study of the trend in BSE epidemics and was helpful in understanding the effects of management and control of the disease. Additionally, such an approach may help in the implementation of changes in BSE regulations.
Hald, Tine; Baggesen, Dorte Lau
Bovine intestines and mesenteries in the European Union (EU) have to be removed from the food and feed chain. The opinion provides a quantitative assessment of the Bovine Spongiform Encephalopathy (BSE) infectious load that might enter the food and feed chain yearly if bovine intestine...... indicated that the removal of the last four metres of the small intestine and of the caecum from the food and feed chain would result in a major reduction of the BSE exposure risk associated with intestine and mesentery in cattle....... infected cattle entering undetected in the food and feed chain yearly. A model named TSEi was developed to estimates the BSE infectious load in tissues from infected animals at different ages and the total yearly infectious load that could enter the food and feed chain in the EU27. In BSE infected cattle...
... vesicular disease, African swine fever, bovine fever, bovine spongiform encephalopathy, and contagious bovine pleuropneuomia. APHIS will collect the exporter's name, address, the name and address of...
Muñoz, Rosario; García, José L.; Carrascosa, Alfonso V.; Gonzalez, Ramon
Bovine pepsin is the second major proteolytic activity of rennet obtained from young calves and is the main protease when it is extracted from adult animals, and it is well recognized that the proteolytic specificity of this enzyme improves the sensory properties of cheese during maturation. Pepsin is synthesized as an inactive precursor, pepsinogen, which is autocatalytically activated at the pH of calf abomasum. A cDNA coding for bovine pepsin was assembled by fusing the cDNA fragments from two different bovine expressed sequence tag libraries to synthetic DNA sequences based on the previously described N-terminal sequence of pepsinogen. The sequence of this cDNA clearly differs from the previously described partial bovine pepsinogen sequences, which actually are rabbit pepsinogen sequences. By cloning this cDNA in different vectors we produced functional bovine pepsinogen in Escherichia coli and Saccharomyces cerevisiae. The recombinant pepsinogen is activated by low pH, and the resulting mature pepsin has milk-clotting activity. Moreover, the mature enzyme generates digestion profiles with α-, β-, or κ-casein indistinguishable from those obtained with a natural pepsin preparation. The potential applications of this recombinant enzyme include cheese making and bioactive peptide production. One remarkable advantage of the recombinant enzyme for food applications is that there is no risk of transmission of bovine spongiform encephalopathy. PMID:15128507
Alyahya, Ghassan Ayish Jabur; Heegaard, Steffen; Prause, J.U.
ophthalmology, melanoma associated spongiform scleropathy (MASS), MASS, malignant uveal melanoma, sclera, ciliary body, choroid, histopathology......ophthalmology, melanoma associated spongiform scleropathy (MASS), MASS, malignant uveal melanoma, sclera, ciliary body, choroid, histopathology...
Angel, Michael J; Young, G Bryan
Kinnier Wilson coined the term metabolic encephalopathy to describe a clinical state of global cerebral dysfunction induced by systemic stress that can vary in clinical presentation from mild executive dysfunction to deep coma with decerebrate posturing; the causes are numerous. Some mechanisms by which cerebral dysfunction occurs in metabolic encephalopathies include focal or global cerebral edema, alterations in transmitter function, the accumulation of uncleared toxic metabolites, postcapillary venule vasogenic edema, and energy failure. This article focuses on common causes of metabolic encephalopathy, and reviews common causes, clinical presentations and, where relevant, management.
Chronic wasting disease (CWD) is a fatal neurodegenerative disease, classified as a prion disease or transmissible spongiform encephalopathy (TSE) similar to bovine spongiform encephalopathy (BSE). Cervids affected by CWD accumulate an abnormal protease resistant prion protein throughout the central...
Full Text Available Abstract Background As there is limited information about the clinical signs of BSE and scrapie in goats, studies were conducted to describe the clinical progression of scrapie and BSE in goats and to evaluate a short clinical protocol for its use in detecting scrapie-affected goats in two herds with previously confirmed scrapie cases. Clinical assessments were carried out in five goats intracerebrally infected with the BSE agent as well as five reported scrapie suspects and 346 goats subject to cull from the two herds, 24 of which were retained for further monitoring. The brain and selected lymphoid tissue were examined by postmortem tests for disease confirmation. Results The sensitivity and specificity of the short clinical protocol in detecting a scrapie case in the scrapie-affected herds was 3.9% and 99.6%, respectively, based on the presence of tremor, positive scratch test, extensive hair loss, ataxia and absent menace response. All BSE- and scrapie-affected goats displayed abnormalities in sensation (over-reactivity to external stimuli, startle responses, pruritus, absent menace response and movement (ataxia, tremor, postural deficits at an advanced clinical stage but the first detectable sign associated with scrapie or BSE could vary between animals. Signs of pruritus were not always present despite similar prion protein genotypes. Clinical signs of scrapie were also displayed by two scrapie cases that presented with detectable disease-associated prion protein only in lymphoid tissues. Conclusions BSE and scrapie may present as pruritic and non-pruritic forms in goats. Signs assessed for the clinical diagnosis of scrapie or BSE in goats should include postural and gait abnormalities, pruritus and visual impairment. However, many scrapie cases will be missed if detection is solely based on the display of clinical signs. PrPd accumulation in the brain appeared to be related to the severity of clinical disease but not to the display of individual neurological signs.
Full Text Available ... Get Worse? How is HE Diagnosed? Prior to Treatment Who treats HE? Preparing for your Medical Appointment Hepatic Encephalopathy Treatment Options Treatment Basics Treatment Medications Importance of Adhering ...
Ranganathan, Yamini; Patel, Shifa; Pasupuleti, Vijai K.; Meganathan, R.
Tryptone (pancreatic digest of casein) is a common ingredient in laboratory and fermentation media for growing wild-type and genetically modified microorganisms. Many of the commercially manufactured products such as human growth hormone, antibiotics, insulin, etc. are produced by recombinant strains grown on materials derived from bovine sources. With the emergence of Bovine Spongiform Encephalopathy (BSE) and the consequent increase in Food and Drug Administration (FDA) regulations, elimination of materials of bovine origin from fermentation media is of paramount importance. To achieve this objective, a number of protein hydrolysates derived from non-bovine animal and plant sources were evaluated. Tryptone in Luria-Bertani (LB) broth was replaced with an equal quantity of alternate protein hydrolysates. Four of the six hydrolysates (one animal and three from plants) were found to efficiently replace the tryptone present in LB-medium as measured by growth rate and growth yield of a recombinant Escherichia coli strain. In addition, we have determined plasmid stability, inducibility and activity of the plasmid encoded β-galactosidase in the recombinant strain grown in the presence of various protein hydrolysates.
刘雨田; 吴晓东; 邹艳丽; 王志亮
Ramalho, Joana; Castillo, Mauricio
We report a case of Hashimoto's encephalopathy with atypical and partially reversible MRI findings. T2-weighted MRI images revealed bilaterally symmetric areas of increased signal in the mesial temporal lobes and basal ganglia. Despite clinical and imaging improvement after steroid therapy, some memory deficits and MRI abnormalities persisted.
A change in handedness (chirality) in some amino acids appears to be the basic physical change in degradation-resistant proteins (prions) found in conditions such as Creutzfeldt-Jacob disease (CJD), Alzheimer's disease (AD), bovine spongiform encephalopathy (BSE) and ovine scrapie. The affected structures are primarily innervated by cholinergic nerves. Much evidence suggests that these so-called prions (here named chirons) are harmless, non-infectious products. The importance of the cholinergic system allows a new simplified interpretation of these conditions. The main steps are the acetylcholine-cholinesterase splitting of body water with release of free protons in solution, followed by electron dissipation, dioxygen activation and Ca-fluxes. Abiotic physics conserves parity and symmetry by equal amounts of L- and D-forms of molecules. In contrast, the asymmetric pattern of life must be homochiral. Such biomolecules dissolve in water and are thus able to interact in cholinergic hydrodynamics. It is supposed that the instability of the composite weak force by beta-decay causes changes in chirality. These extremely rare events are not frequent enough to explain disease pathology. Experimental, accidental, surgical and abusive inoculations will propagate chirons according to the physical law of self-replication, which also occurs in test tubes without added biological products. Chirons will not be degraded into amino acids in the alimentary canal and will, because they are indigestible, leave the body with the faeces. Chirons are inert also to the immune system and will be engulfed without reaction by phagocytosing cells. They are then stored away in tissues, where they do no harm (if not detected and suspected to be deleterious, thereby causing pathogenic anxiety). The cholinergic system reacts to all kinds of integrity threats and it is this reaction which I propose causes the so-called prion diseases. This pathology seems generally valid, and is here exemplified
Montagna, Giacomo; Imperiali, Mauro; Agazzi, Pamela
Hashimoto's encephalopathy (HE) is a rare not well understood, progressive and relapsing multiform disease, characterized by seizures, movement disorders, subacute cognitive dysfunction, psychiatric symptoms and responsiveness to steroid therapy. The disorder is generally associated with thyroid...... diseases and the most common feature is the presence of anti-thyroperoxidase antibodies (TPOAb). Patients are usually euthyroid or mildly hypothyroid at presentation. All age groups can be affected. The pathophysiology is still unclear, especially the link between elevated serum TPOAb...
史新立; 谭芳奕; 王召旭; 奚廷斐; 解慧琪; 杨志明; 戴建武
目的 介绍关于疯牛病的基本知识,并对哺乳动物源性医疗器械的安全性评价作简要介绍.方法 查阅近年来对疯牛病、新克雅氏病、朊病毒的研究概况、检测方法、灭活方法,欧美等国对牛羊源性相关材料的控制措施以及国内对相关产品的管理方法相关的文献,综合分析. 结果 疯牛病,又称牛海绵状脑病(bovine spongiform encephacitis,BSE).该病与羊瘙痒病具有同源性,它们与人类克-雅氏病(Creutzfeldt-Jakob disease,CJD)均是海绵状脑组织病变,由Prion蛋白引起.疯牛病主要以缓慢破坏哺乳动物中枢神经系统为特征.结论 由于动物源性医疗器械产品在原材料方面存在疯牛病等人畜共患疾病的风险,同时Prion蛋白对传统的杀灭方法有较强抵抗性,因此,加强对这类产品的源头控制及灭活工艺等生产质量体系的管理是非常重要的,从而保证动物源性医疗器械产品的使用安全有效.
Moon, Suk-Ho; Lee, Yoon-Jae; Rhie, Jong-Won; Suh, Dong-Sam; Oh, Deuk-Young; Lee, Joong-Ho; Kim, Young-Jin; Kim, Sue-Min; Jun, Young-Joon
Bovine-derived collagen has been used for soft-tissue augmentation since 1977. However, there are issues regarding the possibility of bovine spongiform encephalopathy (BSE). Researchers discovered that the histologic structure of porcine-derived collagen is similar to that of human dermal collagen and that it is free from the risk of BSE. This study was conducted to establish the effectiveness and safety of porcine-derived collagen compared to bovine-derived collagen. The 73 patients included in this study were healthy volunteers who responded to an advertisement approved by the Institutional Review Board (IRB). They had visited the authors' hospital complaining of wrinkles on their nasolabial fold. Either porcine (TheraFill®) or bovine atelocollagen was randomly injected into each side of their nasolabial folds, and the five-grade Wrinkle Severity Rating Scale (WSRS) was used to evaluate the wrinkles before and after the injection. The average age of the 73 study patients was 46.18 years. The WSRS scores of the porcine and bovine atelocollagen-injected patients were 2.90 ± 0.71 and 2.85 ± 0.72 at the baseline and 2.15 ± 0.70 and 2.21 ± 0.67 after 6 months. There were no statistically significant differences between the two groups. Adverse effects of the porcine atelocollagen injection were seen in 12 patients, with the most common symptom being redness. This study showed that porcine atelocollagen can be used easily and without the need for the skin testing which is necessary before bovine atelocollagen injection. The efficacy of porcine atelocollagen is also similar to that of bovine atelocollagen.
EFSA Panel on Biological Hazards (BIOHAZ
Full Text Available Bovine intestines and mesenteries in the European Union (EU have to be removed from the food and feed chain. The opinion provides a quantitative assessment of the Bovine Spongiform Encephalopathy (BSE infectious load that might enter the food and feed chain yearly if bovine intestine and mesentery from animals born and raised in the EU would be re-allowed for consumption. Data on the evolution of the BSE infectious titre; and of the weight of histological structures accumulating BSE infectivity, were collected. The Cattle TSE Monitoring Model (C-TSEMM was used to estimate the number of BSE infected cattle entering undetected in the food and feed chain yearly. A model named TSEi was developed to estimates the BSE infectious load in tissues from infected animals at different ages and the total yearly infectious load that could enter the food and feed chain in the EU27. In BSE infected cattle, the infectivity associated with intestine and mesentery reaches its maximum in animals younger than 18 months and then progressively declines to a minimum value in animals older than 60 months. Due to the decline of the BSE prevalence in the EU, between 2007 and 2012, the yearly amount of BSE infectivity associated with intestine and mesentery (sent to destruction from animals entering the food and feed chain was reduced by a factor of 10. However, over this period, the maximum level of exposure to the BSE agent for individuals that would have consumed these tissues remained stable. Finally, the TSEi model indicated that the removal of the last four metres of the small intestine and of the caecum from the food and feed chain would result in a major reduction of the BSE exposure risk associated with intestine and mesentery in cattle.
Julien, Olivier; Chatterjee, Subhrangsu; Thiessen, Angela; Graether, Steffen P; Sykes, Brian D
Prion diseases, or transmissible spongiform encephalopathies, are a group of infectious neurological diseases associated with the structural conversion of an endogenous protein (PrP) in the central nervous system. There are two major forms of this protein: the native and noninfectious cellular form, PrPC; and the misfolded, infectious, and proteinase K-resistant form, PrPSc. The C-terminal domain of PrPC is mainly α-helical in structure, whereas PrPSc in known to aggregate into an assembly of β-sheets, forming amyloid fibrils. To identify the regions of PrPC potentially involved in the initial steps of the conversion to the infectious conformation, we have used high-resolution NMR spectroscopy to characterize the stability and structure of bovine recombinant PrPC (residues 121 to 230) during unfolding with the denaturant urea. Analysis of the 800 MHz 1H NMR spectra reveals region-specific information about the structural changes occurring upon unfolding. Our data suggest that the dissociation of the native β-sheet of PrPC is a primary step in the urea-induced unfolding process, while strong hydrophobic interactions between helices α1 and α3, and between α2 and α3, stabilize these regions even at very high concentrations of urea. PMID:19693935
Chin Jung Cheng
Full Text Available Bovine spongiform encephalopathy (BSE, or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP, which adopts two conformers; PrPC is the native innocuous form, which is α-helix rich; and PrPSc is the β-sheet rich misfolded form, which is infectious and forms neurotoxic species. Acidic pH induces the conversion of PrPC to PrPSc. We have performed molecular dynamics simulations of bovine PrP at various pH regimes. An acidic pH environment induced conformational changes that were not observed in neutral pH simulations. Putative misfolded structures, with nonnative β-strands formed in the flexible N-terminal domain, were found in acidic pH simulations. Two distinct pathways were observed for the formation of nonnative β-strands: at low pH, hydrophobic contacts with M129 nucleated the nonnative β-strand; at mid-pH, polar contacts involving Q168 and D178 facilitated the formation of a hairpin at the flexible N-terminus. These mid- and low pH simulations capture the process of nonnative β-strand formation, thereby improving our understanding of how PrPC misfolds into the β-sheet rich PrPSc and how pH factors into the process.
Full Text Available How to cite this article: Sharifian M. Hypertensive Encephalopathy. Iran J Child Neurol 2012; 6(3:1-7.Hypertension is called the silent killer and vital organs such as the brain, eyes,kidneys and the heart are the targets. Seizure, central nervous system (CNShemorrhage, and cerebrovascular accident (CVA, blindness and heart attacksare the end points.The prevalence of hypertension in children is much less than adults, but evidencereveals that the source of hypertension in adulthood goes back to childhood. In70-80% of cases hypertension is due to renal diseases. In children, hypertensiveencephalopathy (HE may be the first manifestation of renal diseases. Seizure isone of the most common manifestations of HE.In this article, definitions, etiology, pathophysiology and finally the acute andchronic managements of HE will be discussed.ReferencesSawicka K, Szczyrek M, Jastrzębska I, Prasal M, ZwolakA, Jadwiga D. Hypertension – The silent killer. J Pre-Clin Clin Res 2011;5(2:43-6.Croix B, Feig DI. Childhood hypertension is not a silent disease. Pediatr Nephrol 2006 Apr;21(4:527-32.Wong TY, Mitchell P. Hypertensive retinopathy. N Engl J Med 2004 Nov;351(22:2310-7.Krzesinski JM, Cohen EP.Hypertension and the kidney.Acta Clin Belg 2007 Jan-Feb;62(1:5-14.Report of the Second Task Force on Blood Pressure Control in Children – 1987. Task Force on Blood Pressure Control in Children. National Heart, Lung, and Blood Institute, Bethesda, Maryland. Pediatrics 1987Jan;79(1:1-25.Update on the 1987 Task Force Report on High Blood Pressure in Children and Adolescents: a working group report from the National High Blood Pressure Education Program. National High Blood Pressure Education Program Working Group on Hypertension Control in Children and Adolescents. Pediatrics 1996 Oct;98(4 Pt1:649-58.Ataei N, Aghamohammadi A, Yousefi E, Hosseini M, Nourijelyani K, Tayebi M, et al. Blood pressure nomograms for school children in Iran. Pediatr Nephrol 2004 Feb;19
Whatley, Brandi R; Li, Lian; Chin, Lih-Shen
Spongiform degeneration is characterized by vacuolation in nervous tissue accompanied by neuronal death and gliosis. Although spongiform degeneration is a hallmark of prion diseases, this pathology is also present in the brains of patients suffering from Alzheimer's disease, diffuse Lewy body disease, human immunodeficiency virus (HIV) infection, and Canavan's spongiform leukodystrophy. The shared outcome of spongiform degeneration in these diverse diseases suggests that common cellular mechanisms must underlie the processes of spongiform change and neurodegeneration in the central nervous system. Immunohistochemical analysis of brain tissues reveals increased ubiquitin immunoreactivity in and around areas of spongiform change, suggesting the involvement of ubiquitin-proteasome system dysfunction in the pathogenesis of spongiform neurodegeneration. The link between aberrant ubiquitination and spongiform neurodegeneration has been strengthened by the discovery that a null mutation in the E3 ubiquitin-protein ligase mahogunin ring finger-1 (Mgrn1) causes an autosomal recessively inherited form of spongiform neurodegeneration in animals. Recent studies have begun to suggest that abnormal ubiquitination may alter intracellular signaling and cell functions via proteasome-dependent and proteasome-independent mechanisms, leading to spongiform degeneration and neuronal cell death. Further elucidation of the pathogenic pathways involved in spongiform neurodegeneration should facilitate the development of novel rational therapies for treating prion diseases, HIV infection, and other spongiform degenerative disorders.
Full Text Available Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy.
Les encéphalopathies spongiformes transmissibles (EST) sont des maladies neurodégénératives affectant de nombreuses espèces de mammifères dont l’Homme (maladie de Creutzfeldt-Jakob – MCJ), la vache (encéphalopathie spongiforme bovine – ESB) et le mouton (tremblante). Au cours de ces maladies, une protéine, PrPSc, isoforme anormale de la protéine cellulaire PrP C, s’accumule dans le système nerveux central des individus atteints. Selon le concept du prion, la PrPSc elle-même serait l’agent ...
Weber, W.; Henkes, H.; Kuehne, D. [Klinik fuer Allgemeine Roentgendiagnostik und Neuroradiologie, Alfried-Krupp-Krankenhaus, Alfried Krupp Strasse 21, D-45117, Essen (Germany); Moeller, P.; Bade, K. [Neurologische Klinik, Knappschafts-Krankenhaus, D-45657 Recklinghausen (Germany)
This is a report of clinical, CT and MRI findings in a patient with toxic spongiform leucoencephalopathy after heroin ingestion. The disease is observed in drug addicts who inhale pre-heated heroin. The clinical onset, which usually occurs some days or even longer after the last heroin consumption, is characterized by a cerebellar syndrome. The cerebellar hemispheres, the cerebellar and cerebral peduncles and the pyramidal tract may be affected. Spongiform demyelination is the morphological substrate of the lesions, which are not contrast enhancing, hypodense on CT and hyperintense on T2-weighted MRI. The frequently perfect symmetry of the affection of functional systems points to a toxic and/or metabolic pathophysiological mechanism. (orig.) With 2 figs., 2 tabs., 26 refs.
Krasemann, Susanne; Mearini, Giulia; Krämer, Elisabeth; Wagenführ, Katja; Schulz-Schaeffer, Walter; Neumann, Melanie; Bodemer, Walter; Kaup, Franz-Josef; Beekes, Michael; Carrier, Lucie; Aguzzi, Adriano; Glatzel, Markus
Prion amyloidosis occurred in the heart of 1 of 3 macaques intraperitoneally inoculated with bovine spongiform encephalopathy prions. This macaque had a remarkably long duration of disease and signs of cardiac distress. Variant Creutzfeldt-Jakob disease, caused by transmission of bovine spongiform encephalopathy to humans, may manifest with cardiac symptoms from prion-amyloid cardiomyopathy.
Full Text Available Due to the widely supported theory of bovine spongiform encephalopathy (BSE spread in cattle by contaminated animal feeds, screening of feed products has become essential. For many years, manufacturers have used blood and plasma proteins as high quality ingredients of foods for both pets and farm animals. However, in Europe, the Commission Regulation 1234/2003/EC temporally bans the use of processed animal proteins, including blood-derivative products, in feedstuffs for all farm animals which are fattened or bred for the production of food. This regulation has some exceptions, such as the use of non ruminant blood products into the feed of farm fish. Authorization of the re-introduction of these proteins into animal feed formulations, especially non ruminant proteins into the feed for non ruminant farm animals, is expected when adequate control methods to discriminate ruminant proteins exist. Currently, the number of validated methods to differentiate the species of origin for most of the animal by-products is limited. Here we report the development of a rapid and sensitive polymerase chain reaction (PCR-based assay, which allows detection of bovine or porcine specific mitochondrial DNAfrom spray-dried blood derivate products (plasma, whole blood and red cells, as a marker for bovine contamination in porcine products. Sample extracts, suitable for PCR, were easily and quickly obtained with the commercial PrepManTM Ultra reagent (Applied Biosystems. To confirm the porcine origin of the samples, primers targeting a specific region of 134 bp of the porcine cytochrome b coding sequence were designed (cytbporc1-F and cytbporc2-R. Previously published PCR primers (L8129 and H8357, specific for a 271 bp fragment of the bovine mitochondrial ATPase 8-ATPase 6 genes, were chosen to accomplish amplification of bovine DNA. The limit of detection (LOD of the bovine PCR assay was at least of 0.05% (v/v of bovine inclusion in spray-dried porcine plasma or red
Full Text Available An important outcome of intensive worldwide Bovine spongiform encephalopathy (BSE obtained with the surveillance by The National Creutzfeldt-Jakob Disease Surveillance Unit (http://www.cjd.ed.ac.uk/figures. htm, has been the detection of atypical BSE in cattle. The discovery of a prion protein gene (PRNP E211K variant in an atypical BSE case is particularly remarkable because it is analogous to the most common pathogenic mutation in humans (E200K, which causes hereditary Creutzfeldt-Jakob disease (CJD. Knowledge of the distribution and frequency of PRNP E211K variants in cattle populations is critical for understanding and managing atypical BSE. This study was carried out to investigate the prevalence of the E211K variant in the South-East Asia bovine populations and in the Japanese cattle breeds. It was discovered that E211K variant was monomorphic for a G allele and the GG genotype in the 745 animals analyzed in this study. Therefore, neither the Bos indicus nor the Bos taurus animals analyzed are presently known to harbor the 211K variant predicting that the number of carriers for this variant will also be vanishingly low.
Münk, C; Löhler, J; Prassolov, V; Just, U; Stockschläder, M; Stocking, C
Recombinants of amphotropic murine leukemia virus (A-MuLV) have found widespread use in retroviral vector systems due to their ability to efficiently and stably infect cells of several different species, including human. Previous work has shown that replication-competent recombinants containing the amphotropic env gene, encoding the major SU envelope glycoprotein that determines host tropism, induce lymphomas in vivo. We show here that these viruses also induce a spongiform encephalomyelopathy in mice inoculated perinatally. This fatal central nervous system disease is characterized by noninflammatory spongiform lesions of nerve and glial cells and their processes, and is associated with moderate astro- and microgliosis. The first clinical symptoms are ataxia, tremor, and spasticity, progressing to complete tetraparesis and incontinence, and finally death of the animal. Sequences within the amphotropic env gene are necessary for disease induction. Coinfection of A-MuLV recombinants with nonneuropathogenic ecotropic or polytropic MuLV drastically increases the incidence, degree, and distribution of the neurodegenerative disorder. The consequence of these results in view of the use of A-MuLV recombinants in the clinic is discussed.
Cichoż-Lach, Halina; Michalak, Agata
Hepatic encephalopathy is a medical phenomenon that is described as a neuropsychiatric manifestation of chronic or acute liver disease that is characterized by psychomotor, intellectual and cognitive abnormalities with emotional/affective and behavioral disturbances. This article focuses on the underlying mechanisms of the condition and the differences between hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy. Hepatic encephalopathy is a serious condition that can cause neurological death with brain edema and intracranial hypertension. It is assumed that approximately 60%-80% of patients with liver cirrhosis develop hepatic encephalopathy. This review explores the complex mechanisms that lead to hepatic encephalopathy. However, noncirrhotic hyperammonemic encephalopathy is not associated with hepatic diseases and has a completely different etiology. Noncirrhotic hyperammonemic encephalopathy is a severe occurrence that is connected with multiple pathogeneses.
Kaczmarczyk, Aleksandra; Patalong-Ogiewa, M; Krzystanek, E
Hashimoto's encephalopathy (HE) is a rare neuropsychiatric syndrome associated with increased level of antithyroid antibodies. Two types of clinical manifestation can be described: a vasculitic type with stroke like episodes and diffuse progressive type with deterioration of mental function. Neurologic symptoms are present in euthyreosis as well as in thyroid dysfunction. Because of good response to immunosuppressive therapy, the prompt diagnosis and management of HE are crucial. In this study we present the review of current literature and discuss two representative cases.
Jackson, A C; Gilbert, J J; Young, G B; Bolton, C F
Twelve fatal cases of encephalopathy associated with sepsis were examined in a ten-year retrospective study. The sources of infection and organisms isolated were variable. Six of the patients had focal neurologic signs; five had seizures. The level of consciousness varied from drowsiness to deep coma, and electroencephalograms revealed diffuse or multifocal abnormalities. Computed tomographic head scans and cerebrospinal fluid examinations were usually unremarkable. Eight patients had disseminated microabscesses in the brain at autopsy. Four patients had proliferation of astrocytes and microglia in the cerebral cortex, a feature associated with metabolic encephalopathies. Additional findings included cerebral infarcts, brain purpura, multiple small white matter hemorrhages, and central pontine myelinolysis. Although sepsis may cause encephalopathy by producing disturbances in cerebral synaptic transmission and cerebral energy production through a toxic mechanism, bacterial invasion of the brain with the formation of disseminated microabscesses is also an important cause.
Zamora Nava, Luis Eduardo; Torre Delgadillo, Aldo
The term minimal hepatic encephalopathy (MHE) refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy; the prevalence is as high as 84% in patients with hepatic cirrhosis. Physician does generally not perceive cirrhosis complications, and neuropsychological tests and another especial measurement like evoked potentials and image studies like positron emission tomography can only make diagnosis. Diagnosis of minimal hepatic encephalopathy may have prognostic and therapeutic implications in cirrhotic patients. The present review pretends to explore the clinic, therapeutic, diagnosis and prognostic aspects of this complication.
Encephalopathy occasionally occurs in association with thyroid disorders, but most of these are treatable. These encephalopathies include a neuropsychiatric disorder associated with hypothyroidism, called myxedema encephalopathy. Moreover, Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease based on an autoimmune mechanism associated with Hashimoto's thyroiditis. Steroid treatment was successfully administered to these patients. Recently, we discovered that the serum autoantibodies against the NH2-terminal of α-enolase (NAE) are highly specific diagnostic biomarkers for HE. Further, we analyzed serum anti-NAE autoantibodies and the clinical features in many cases of HE from institutions throughout Japan and other countries. Approximately half of assessed HE patients carry anti-NAE antibodies. The age was widely distributed with 2 peaks (20-30 years and 50-70 years). Most HE patients were in euthyroid states, and all patients had anti-thyroid (TG) antibodies and anti-thyroid peroxidase (TPO) antibodies. Anti-TSH receptor (TSH-R) antibodies were observed in some cases. The common neuropsychiatry features are consciousness disturbance and psychosis, followed by cognitive dysfunction, involuntary movements, seizures, and ataxia. Abnormalities on electroencephalography (EEG) and decreased cerebral blood flow on brain SPECT were common findings, whereas abnormal findings on brain magnetic resonance imaging (MRI) were rare. HE patients have various clinical phenotypes such as the acute encephalopathy form, the chronic psychiatric form, and other particular clinical forms, including limbic encephalitis, progressive cerebellar ataxia, and Creutzfeldt-Jakob disease (CJD)-like form. The cerebellar ataxic form of HE clinically mimics spinocerebellar degeneration (SCD) and is characterized by the absence of nystagmus, absent or mild cerebellar atrophy, and lazy background activities on EEG. Taken together, these data suggest that the possibility of
Waghray, Abhijeet; Waghray, Nisheet; Mullen, Kevin
Hepatic encephalopathy is a reversible progressive neuropsychiatric disorder that encompasses a wide clinical spectrum. Covert hepatic encephalopathy is defined as patients with minimal hepatic encephalopathy and Grade I encephalopathy by West-Haven Criteria. Terminology such as "sub-clinical", "latent", and "minimal" appear to trivialize the disease and have been replaced by the term covert. The lack of clinical signs means that covert hepatic encephalopathy is rarely recognized or treated outside of clinical trials with options for therapy based on patients with episodic hepatic encephalopathy. This review discusses the current available options for therapy in covert hepatic encephalopathy and focuses on non-absorbable disacharides (lactulose or lactitol), antibiotics (rifaximin), probiotics/synbiotics and l-ornithine-l-aspartate.
Rigter, A.; Langeveld, J.P.M.; Zijderveld, van F.G.; Bossers, A.
Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative disorders and include among others Creutzfeldt–Jakob disease in humans, bovine spongiform encephalopathy (BSE) in cattle, and scrapie in sheep. The central event in disease development in TSEs is the refol
Tang, Y.; Thorne, J.; Whatling, K.L.; Jacobs, J.G.; Langeveld, J.P.M.; Sauer, M.
Although there is no evidence that the European sheep population has been infected with bovine spongiform encephalopathy (BSE), distinguishing this from scrapie is paramount, given the association between BSE exposure and the human transmissible spongiform encephalopathy (TSE), variant Creutzfeldt–J
Tang, Y.; gielbert, A.; Jacobs, J.G.; Baron, T.; Andreoletti, O.; Langeveld, J.P.M.; Sauer, M.J.
Prion diseases or transmissible spongiform encephalopathies (TSEs) in small ruminants are presented in many forms: classical scrapie, Nor98/atypical scrapie, CH1641 scrapie and bovine spongiform encephalopathy (BSE). We previously described a multiplex immunofluorometric assay (mIFMA), based on a be
Breyer, Johanna; Wemheuer, Wiebke M; Wrede, Arne; Graham, Catherine; Benestad, Sylvie L; Brenig, Bertram; Richt, Jürgen A; Schulz-Schaeffer, Walter J
Prion diseases are diagnosed by the detection of their proteinase K-resistant prion protein fragment (PrP(Sc)). Various biochemical protocols use different detergents for the tissue preparation. We found that the resistance of PrP(Sc) against proteinase K may vary strongly with the detergent used. In our study, we investigated the influence of the most commonly used detergents on eight different TSE agents derived from different species and distinct prion disease forms. For a high throughput we used a membrane adsorption assay to detect small amounts of prion aggregates, as well as Western blotting. Tissue lysates were prepared using DOC, SLS, SDS or Triton X-100 in different concentrations and these were digested with various amounts of proteinase K. Detergents are able to enhance or diminish the detectability of PrP(Sc) after proteinase K digestion. Depending on the kind of detergent, its concentration - but also on the host species that developed the TSE and the disease form or prion type - the detectability of PrP(Sc) can be very different. The results obtained here may be helpful during the development or improvement of a PrP(Sc) detection method and they point towards a detergent effect that can be additionally used for decontamination purposes. A plausible explanation for the detergent effects described in this article could be an interaction with the lipids associated with PrP(Sc) that may stabilize the aggregates.
Full Text Available Hepatic encephalopathy (HE, the neuropsychiatric presentation of liver disease, is associated with high morbidity and mortality. Reduction of plasma ammonia remains the central therapeutic strategy, but there is a need for newer novel therapies. We discuss current evidence supporting the use of interventions for both the general management of chronic HE and that necessary for more acute and advanced disease.
Full Text Available Differentiation of beef meat by quality. The necessary strategy of innovation. The beef meat supply chain faces with a very delicate situation: on the long term, red meat consumption in the Western countries is declining to benefit of meats of monogastrics (poultry and pork. Moreover, since the middle of the 1990s in France, a major sanitary crisis, the bovine spongiform encephalopathy, leads many consumers to stop or reduce their consumption of beef. Vis-a-vis this situation, the stakeholders have to react strongly. The purpose of this contribution is to show how the innovation, in all its forms, constitutes one of the means to restore the lost confidence. First of all, the author specially focuses on the various possible strategies while insisting on the innovations about products (technical and marketing and organisation. A historical analysis of the development of the bovine meat processing industry makes it possible to highlight its current forces and weaknesses. It leads to the acknowledgement of the recent development of pre-packaged units of sale made by the industry and of a larger range of processed products that allow communication on private marks. On the organisational level, these changes are accompanied by deep evolutions on the definition of the processes and by the emergence of standardisation (in order to ensure a complete traceability for example by tracing and tracking. In a second time, the author shows how the recent changes in the processing sector of the bovine meat lead to an acceleration of industrialisation: the implementation of standards, the diffusion of schedules coming from quality insurance systems (like guide of good practices for example as well as the requirements of the purchasers of supermarkets strongly boost the rationalisation of the production.
L’épidémie d’encéphalopathie spongiforme bovine (ESB) résulte de la consommation par les bovins de farines de viandes et d’os contaminées. En recyclant l’agent infectieux, ces farines ont permis d’amplifier la dissémination d’une maladie dont l’origine et l’agent responsable demeurent inconnus. Les hypothèses sur la nature protéique ou/et virale de l’agent sont évoquées, ainsi que l’éventualité d’une transmission à l’homme. Une grande partie de nos connaissances des encéphalopathies spongifor...
For approximately two decades, bovine spongiform encephalopathy (BSE), now termed classical BSE (BSE-C), has been regarded as the only and exclusive prion disorder affecting cattle. However, over the last 4 years, two additional bovine prion strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered and characterized in Canada, the United States, Japan, and nine European countries, which applied an active surveillance program on slaughtered ...
Silver, B E; Bean, C S
Cat scratch disease is usually benign, self-limited and without sequelae. Margileth has established four clinical criteria, three of which must be satisfied to make the diagnosis: 1) a history of animal exposure, usually kitten, with primary skin or ocular lesions; 2) regional chronic adenopathy without other apparent cause; 3) a positive cat scratch disease antigen skin test; and 4) lymph node biopsy demonstrating noncaseating granulomas and germinal center hyperplasia. Central nervous system involvement in cat scratch disease has been previously reported, although it is extremely uncommon. In a several-month period, we encountered two cases of cat scratch disease complicated by encephalopathy. The intents of this paper are twofold: 1) to briefly review the current literature on cat scratch disease, 2) to demonstrate that cat scratch disease complicated by encephalopathy presents acutely with seizures, posturing and coma and resolves rapidly with supportive care.
Niemann, B; Rochlitz, C; Herrmann, R; Pless, M
Toxic encephalopathy is a rarely described side effect of 5-fluorouracil which usually presents with cerebellar, neuropsychiatric, and focal neurological symptoms. Magnetic resonance imaging findings are described as patchy white matter alterations. We report the 1st case of capecitabine-induced toxic encephalopathy with epilepsy-like symptoms and diffuse white matter alterations on magnetic resonance imaging.
Groeneweg, M; Moerland, W; Quero, J C; Hop, W C; Krabbe, P F; Schalm, S W
BACKGROUND/AIMS: Subclinical hepatic encephalopathy adversely affects daily functioning. The aim of this study was to determine which elements of daily life have predictive value for subclinical hepatic encephalopathy. METHODS: The study was performed in 179 outpatients with liver cirrhosis. Subclin
Howell, Katherine B.; McMahon, Jacinta M.; Carvill, Gemma L.; Tambunan, Dimira; Mackay, Mark T.; Rodriguez-Casero, Victoria; Webster, Richard; Clark, Damian; Freeman, Jeremy L.; Calvert, Sophie; Olson, Heather E.; Mandelstam, Simone; Poduri, Annapurna; Mefford, Heather C.; Harvey, A. Simon
Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy. Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping. Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1–4 in 8, week 2–6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one. Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile–onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control. PMID:26291284
Price, Raymond S; Kasner, Scott E
The definition of hypertension has continuously evolved over the last 50 years. Hypertension is currently defined as a blood pressure greater than 140/90mmHg. One in every four people in the US has been diagnosed with hypertension. The prevalence of hypertension increases further with age, affecting 75% of people over the age of 70. Hypertension is by far the most common risk factor identified in stroke patients. Hypertension causes pathologic changes in the walls of small (diameter<300 microns) arteries and arterioles usually at short branches of major arteries, which may result in either ischemic stroke or intracerebral hemorrhage. Reduction of blood pressure with diuretics, β-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors have all been shown to markedly reduce the incidence of stroke. Hypertensive emergency is defined as a blood pressure greater than 180/120mmHg with end organ dysfunction, such as chest pain, shortness of breath, encephalopathy, or focal neurologic deficits. Hypertensive encephalopathy is believed to be caused by acute failure of cerebrovascular autoregulation. Hypertensive emergency is treated with intravenous antihypertensive agents to reduce blood pressure by 25% within the first hour. Selective inhibition of cerebrovascular blood vessel permeability for the treatment of hypertensive emergency is beginning early clinical trials.
... Information Collection; National Veterinary Services Laboratories; Bovine Spongiform Encephalopathy... information collection associated with National Veterinary Services Laboratories diagnostic support for the... Staff Veterinarian, Veterinary Services, APHIS, 4700 River Road Unit 43, Riverdale, MD 20737; (301)...
... found in specific kinds of animals. These include bovine spongiform encephalopathy (BSE), which is found in cows ... including amantadine, steroids, interferon, acyclovir, antiviral agents, and antibiotics. Studies of a variety of other drugs are ...
... regulations enacted in 2004 to protect consumers against Bovine Spongiform Encephalopathy, mechanically separated beef is considered inedible ... in raising the animals. [ Top of Page ] NO ANTIBIOTICS (red meat and poultry): The terms "no antibiotics ...
Junker, Anders Ellekær; Als-Nielsen, Bodil; Gluud, Christian
BACKGROUND: Patients with hepatic encephalopathy may present with extrapyramidal symptoms and changes in basal ganglia. These changes are similar to those seen in patients with Parkinson's disease. Dopamine agents (such as bromocriptine and levodopa, used for patients with Parkinson's disease) have...... therefore been assessed as a potential treatment for patients with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of dopamine agents versus placebo or no intervention for patients with hepatic encephalopathy. SEARCH METHODS: Trials were identified through the Cochrane...... of the trials followed participants after the end of treatment. Only one trial reported adequate bias control; the remaining four trials were considered to have high risk of bias. Random-effects model meta-analyses showed that dopamine agents had no beneficial or detrimental effect on hepatic encephalopathy...
Animal study: The aim was to investigate the role of vascular disturbances in the development of experimental diabetic encephalopathy. We describe the effects of treatment with the Angiotensin Converting Enzyme(ACE)-inhibitor enalapril (treatment aimed at the vasculature)
Kim, Jin Yong; Lee, Shi Kyung; Han, Chun Hwan; Rho, Eun Jin [Kangnam General Hospital Public Corporation, Seoul (Korea, Republic of)
Ethylmalonic encephalopathy is a rare syndrom characterized by developmental delay, acrocyanosis, petechiae, chronic diarrhea, and ethylmalonic, lactic, and methylsuccinic aciduria. We report the MRI finding of ethylmalonic encephalopathy including previously unreported intracranial hematoma.
Sanjeev Kumar Sharma; Dharma Choudhary; Anil Handoo; Gaurav Dhamija; Gaurav Kharya; Vipin Khandelwal; Mayank Dhamija; Sweta Kothari
The authors present here an interesting case of recent onset anemia that was associated with an encephalopathy of the unusual cause.Although severe anemia can theoretically result in anemic hypoxia and can then lead to hypoxic encephalopathy, it is not a primary cause of encephalopathy. More frequently anemia can contribute together with other multiple causes of encephalopathy, such as infections, metabolic abnormalities, trauma, hepatic dysfunction, hypertension, toxins.
Als-Nielsen, B; Gluud, L L; Gluud, C
Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....
Green, Rebecca; Scott, L Keith; Minagar, Alireza; Conrad, Steven
Sepsis associated encephalopathy (SAE) is a poorly understood condition that is associated with severe sepsis and appears to have a negative influence on survival. The incidence of encephalopathy secondary to sepsis is unknown. Amino acid derangements, blood-brain barrier disruption, abnormal neurotransmitters, and direct CNS effect are possible causes of septic encephalopathy. Research has not defined the pathogenesis of SAE.
João Gama Marques
Full Text Available Since Hippocrates that neuropsychiatric illness secondary to liver disease fascinates physicians, but only in the XIX century Marcel Nencki and Ivan Pavlov suggested the relation between high concentrations of ammonia and Hepatic Encephalopathy (HE. The reaction of ammonia and glutamate (origins glutamine, “the Trojan Horse of neurotoxicity of ammonia continues to be the main responsible for the neurologic lesions, recently confirmed by neurochemistry and neuroimagiology studies. Glutamine starts the inflammatory reaction at the central nervous sys- tem but other important actors seem to be manganese and the neurotransmitters systems of GABA and endocanabinoids. Nowadays there are three different etiologic big groups for HE: type A associated with acute liver failure; type B associated with portosystemic bypass; and type C associated with cirrhosis of the liver. The staging of HE is still based on classic West Haven system, but a latent Grade 0 was introduced (the so called minimal HE; remaining the aggra- vating HE from Grade 1 (subtle changes at clinical examination to Grade 4 (coma. In this work a bibliographic review was made on 30 of the most pertinent and recent papers, focusing in psychopathology, physiopathology, etiology and staging of this clinical entity transversal to Psychiatry and Gastroenterology. Alterations are described in vigility and conscience like temporal, spatial and personal disorientation. Attention, concentration and memory are impaired very early, on latent phase and can be accessed through neuropsychological tests. Mood oscillates between euphoric and depressive. Personality changes begin obviously and abruptly or in a subtle and insidious way. There can be changes in perception like visual hallucinations or even of acoustic-verbal. The thought disorders can be of delusional type, paranoid, systematized or not, but also monothematic ala Capgras Syndrome. Speech can be accelerated, slowed down or completely in
Juling, K; Schwarzenbacher, H; Frankenberg, U; Ziegler, U; Groschup, M; Williams, J L; Fries, R
Bovine spongiform encephalopathy (BSE) belongs to a group of neurodegenerative diseases known as transmissible prion diseases. Recently, variants in the promoter region of the prion protein (PRNP) gene have been shown to have a considerable effect on the susceptibility to BSE. However, a previous genome scan revealed other putative BSE-susceptibility loci. Here, we analysed such a region on BTA10, which contains the functional candidate gene HEXA. Three hundred and twenty kilobases that, besides HEXA, also contain ARIH1, BRUNOL6 and PARP6 were characterized and screened for polymorphisms. Genotyping of 38 SNPs in Holstein-Friesian animals from the UK (350 diseased and 270 controls) revealed two intronic SNPs that were associated with BSE incidence, with experiment-wise P-values of 3.5 x 10(-3) and 7.7 x 10(-3) respectively. Both SNPs were in strong linkage disequilibrium and the rare alleles had a protective effect. These alleles were contained in a haplotype dubbed 'UK-protective' that was significantly overrepresented in the controls with a permuted P-value of 2 x 10(-3). An association study in German Holstein animals (73 diseased and 627 controls) revealed an opposite effect of the 'UK-protective' haplotype in this population, i.e. it was overrepresented in the diseased animals, although not significant after correction for multiple testing. These findings indicate a causal variant for BSE susceptibility on BTA10 in linkage disequilibrium with the markers studied. Candidate gene analyses of the surrounding region and additional association studies will help to clarify the origin of the protective effects and to identify causal variants for BSE susceptibility on BTA10.
Sigurdson, C B; Polymenidou, M; Aguzzi, A
With the epizootics of bovine spongiform encephalopathy (BSE) in North American cattle, BSE infections in goats, new forms of human Creutzfeldt-Jakob disease (CJD) and the spread of chronic wasting disease in North American deer and elk, one wonders whether we are gaining control over the transmissible spongiform encephalopathies (TSEs). Although many basic scientific questions in the prion field remain hotly debated and unresolved , including the function of the cellular prion protein (Pr...
Soós, Zsuzsanna; Salamon, Mónika; Oláh, Roland; Czégeni, Anna; Salamon, Ferenc; Folyovich, András; Winkler, Gábor
Wernicke encephalopathy (or Wernicke-Korsakoff encephalopathy) is a rarely diagnosed neurological disorder, which is caused by vitamin B1 deficiency. In the classical form it is characterized by a typical triad (confusion, oculomotor disturbance and ataxia), however, in the majority of the cases only confusion is present. It can be frequently observed in subjects with chronic alcohol consumption, but it may accompany different pathological states of which end stage malignant diseases are the most importants, where confusion may have different backgrounds. The authors present the case of an old male patient with advanced gastric cancer recognised and treated vitamin B1 deficiency, and they draw attention to difficulties of the diagnosis of Wernicke's disease.
The term "hepatic encephalopathy" (HE) covers the neuropsychiatric syndrome associated with acute, chronic and acute-on-chronic liver disease (CLD). This paper deals with clinical features and diagnosis of HE in patients with liver cirrhosis and portal hypertension or porto-systemic shunts. The possible impact of concomitant disorders and the cirrhosis underlying liver disease upon brain function is described emphasizing the need of a detailed diagnostic work up of every individual case before diagnosing HE. Currently used methods for diagnosing minimal or covert hepatic encephalopathy are compared with regard to their sensitivity and specificity for diagnosing HE against the background of a multitude of concomitant disorders and diseases that could contribute to brain dysfunction.
Suvasini Sharma; Manjari Tripathi
The ketogenic diet is a medically supervised high-fat, low-carbohydrate diet that has been found useful in patients with refractory epilepsy. It has been shown to be effective in treating multiple seizure types and epilepsy syndromes. In this paper, we review the use of the ketogenic diet in epileptic encephalopathies such as Ohtahara syndrome, West syndrome, Dravet syndrome, epilepsy with myoclonic atonic seizures, and Lennox-Gastaut syndrome.
Full Text Available The ketogenic diet is a medically supervised high-fat, low-carbohydrate diet that has been found useful in patients with refractory epilepsy. It has been shown to be effective in treating multiple seizure types and epilepsy syndromes. In this paper, we review the use of the ketogenic diet in epileptic encephalopathies such as Ohtahara syndrome, West syndrome, Dravet syndrome, epilepsy with myoclonic atonic seizures, and Lennox-Gastaut syndrome.
Joe Yuezhou Yu
Full Text Available Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondria and large molecule disorders (including lysosomal storage disorders, peroxisomal disorders, glycosylation disorders, and leukodystrophies. Details including key clinical features, salient electrophysiological and neuroradiological findings, biochemical findings, and treatment options are summarized for prominent disorders in each category.
Hu, Baiyang; Fugetsu, Bunshi; Yu, Hongwen; Abe, Yoshiteru
We developed a spongiform adsorbent that contains Prussian blue, which showed a high capacity for eliminating cesium. An in situ synthesizing approach was used to synthesize Prussian blue inside diatomite cavities. Highly dispersed carbon nanotubes (CNTs) were used to form CNT networks that coated the diatomite to seal in the Prussian blue particles. These ternary (CNT/diatomite/Prussian-blue) composites were mixed with polyurethane (PU) prepolymers to produce a quaternary (PU/CNT/diatomite/Prussian-blue), spongiform adsorbent with an in situ foaming procedure. Prussian blue was permanently immobilized in the cell walls of the spongiform matrix and preferentially adsorbed cesium with a theoretical capacity of 167 mg/g cesium. Cesium was absorbed primarily by an ion-exchange mechanism, and the absorption was accomplished by self-uptake of radioactive water by the quaternary spongiform adsorbent.
Ce numéro hors-série est consacré aux travaux sur les maladies à prions des animaux de ferme, menés à l’Inra en collaboration avec de nombreux organismes nationaux et internationaux. Il aborde de nombreuses facettes de la recherche sur ces agents et les maladies qu’ils occasionnent, tant sur le modèle tremblante que sur l’Encéphalopathie Spongiforme Bovine (ESB) : biologie de l’agent pathogène et notion de souche de prion, pathogénie de la maladie et résistance génétique, voies de transmissio...
Felix, JF; Badawi, N; Kurinczuk, JJ; Bower, C; Keogh, JM; Pemberton, PJ
This study was designed to investigate birth defects found in association with newborn encephalopathy. All possible birth defects were ascertained in a population-based study of 276 term infants with moderate or severe encephalopathy and 564 unmatched term control infants. A strong association betwe
Allen, Andrew S.; Berkovic, Samuel F.; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E.; Epstein, Michael P.; Glauser, Tracy; Goldstein, David B.; Han, Yujun; Heinzen, Erin L.; Hitomi, Yuki; Howell, Katherine B.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Lu, Yi-Fan; Madou, Maura R. Z.; Marson, Anthony G.; Mefford, Heather C.; Nieh, Sahar Esmaeeli; O'Brien, Terence J.; Ottman, Ruth; Petrovski, Slave; Poduri, Annapurna; Ruzzo, Elizabeth K.; Scheffer, Ingrid E.; Sherr, Elliott H.; Yuskaitis, Christopher J.; Abou-Khalil, Bassel; Alldredge, Brian K.; Bautista, Jocelyn F.; Berkovic, Samuel F.; Boro, Alex; Cascino, Gregory D.; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Dlugos, Dennis; Epstein, Michael P.; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Geller, Eric B.; Glauser, Tracy; Glynn, Simon; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Erich; Kuperman, Rachel; Kuzniecky, Ruben; Lowenstein, Daniel H.; McGuire, Shannon M.; Motika, Paul V.; Novotny, Edward J.; Ottman, Ruth; Paolicchi, Juliann M.; Parent, Jack M.; Park, Kristen; Poduri, Annapurna; Scheffer, Ingrid E.; Shellhaas, Renee A.; Sherr, Elliott H.; Shih, Jerry J.; Singh, Rani; Sirven, Joseph; Smith, Michael C.; Sullivan, Joseph; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P. G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown(1). Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115)
Erol, Ilknur; Saygi, Semra; Alehan, Füsun
Hashimoto's encephalopathy is an underdiagnosed, steroid-responsive, progressive or relapsing encephalopathy associated with high titers of serum antithyroid antibodies. Although Hashimoto's encephalopathy is well documented in adults, it is rarely observed or studied in children and adolescents. We describe the clinical and laboratory findings of four children (aged 9-15 years) with Hashimoto's encephalopathy. The clinical features of two patients at presentation included epileptic seizures and confusion. The other presenting signs included breath-holding spells, behavioral problems, psychosis, and ataxia (one patient each). During their presentation, three patients were euthyroid, and one was hyperthyroid. All patients manifested increased antithyroid antibodies, and all improved with steroid treatment. Hashimoto's encephalopathy is rarely suspected at presentation. Therefore, greater awareness of its signs by clinicians is necessary for proper diagnoses.
Salazar, R; Mehta, C; Zaher, N; Miller, D
We present a 59-year-old male with early manifestation of opsoclonus associated with gait ataxia as a rare clinical presentation of Hashimoto's encephalopathy. Empiric use of intravenous immunoglobulin followed by intravenous high dose methylprednisolone was initiated with subsequent remittance of opsoclonus, encephalopathy, ataxia, and tremor. Extensive workup for infectious, autoimmune, and paraneoplastic etiologies were undertaken and all studies were negative. Thyroglobulin antibodies (312 U/mL) and thyroid peroxidase antibodies (457 U/mL) were elevated (normal antibodies were retested and found to have decreased considerably. Thus, with steroid therapy, the patient's opsoclonus and encephalopathy improved. We have presented a patient with a rare case of opsoclonus as the principal presenting feature of Hashimoto's encephalopathy that was incompletely responsive to intravenous immunoglobulin and resolved with corticosteroids. This report underscores the importance for clinical practitioners to maintain a high index of suspicion for Hashimoto's encephalopathy in cases of opsoclonus, especially when accompanied by an atypical presentation.
@@ 传染性海绵状脑病(Transmissible spongiform encephalopathies TSE)是一类人畜共患的慢性、亚急性中枢神经退行性疾病.包括羊搔痒病(Scrapie)、牛海绵状脑病(疯牛病)、人克雅氏病(CJD)等.共同的病理改变为中枢神经系统神经元退行性变性、脑实质中淀粉样变性形成斑块和空洞、呈海绵状,胶质细胞增生.因该病可能跨种属传染,故受到特别重视.
spongiform encephalopathy Sheep and goat diseases Equine diseases • Ovine epididymitis (Brucella ovis) • Caprine and ovine brucellosis (excluding B...Vesicular Stomatitis • Bluetongue • Sheep Pox and Goat Pox 9 • Swine Vesicular Disease • Rinderpest • Peste des Petits Ruminants • Contagious Bovine...Cochliomyia hominivorax) • Old World screwworm (Chrysomya bezziana) • Bovine anaplasmosis • Bovine babesiosis • Bovine brucellosis • Bovine genital
Kang, Woo-Hyuk; Na, Ju-Young; Kim, Meyung-Kug; Yoo, Bong-Goo
Hashimoto's encephalopathy is an immune-mediated disorder characterized by acute or subacute encephalopathy related to increased anti-thyroid antibodies. Clinical manifestations of Hashimoto's encephalopathy may include stroke-like episodes, altered consciousness, psychosis, myoclonus, abnormal movements, seizures, and cognitive dysfunction. Acute cognitive dysfunction with convulsion as initial clinical manifestations of Hashimoto's encephalopathy is very rare. We report a 65-year-old man who developed acute onset of cognitive decline and convulsion due to Hashimoto's encephalopathy.
Nardone, Raffaele; Taylor, Alexandra C; Höller, Yvonne; Brigo, Francesco; Lochner, Piergiorgio; Trinka, Eugen
Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy and can affect up to 80% of patients with liver cirrhosis. By definition, MHE is characterized by cognitive function impairment in the domains of attention, vigilance and integrative function, but obvious clinical manifestation are lacking. MHE has been shown to affect daily functioning, quality of life, driving and overall mortality. The diagnosis can be achieved through neuropsychological testing, recently developed computerized psychometric tests, such as the critical flicker frequency and the inhibitory control tests, as well as neurophysiological procedures. Event related potentials can reveal subtle changes in patients with normal neuropsychological performances. Spectral analysis of electroencephalography (EEG) and quantitative analysis of sleep EEG provide early markers of cerebral dysfunction in cirrhotic patients with MHE. Neuroimaging, in particular MRI, also increasingly reveals diffuse abnormalities in intrinsic brain activity and altered organization of functional connectivity networks. Medical treatment for MHE to date has been focused on reducing serum ammonia levels and includes non-absorbable disaccharides, probiotics or rifaximin. Liver transplantation may not reverse the cognitive deficits associated with MHE. We performed here an updated review on epidemiology, burden and quality of life, neuropsychological testing, neuroimaging, neurophysiology and therapy in subjects with MHE.
Full Text Available The protease-resistant prion protein (PrP(res of a few natural scrapie isolates identified in sheep, reminiscent of the experimental isolate CH1641 derived from a British natural scrapie case, showed partial molecular similarities to ovine bovine spongiform encephalopathy (BSE. Recent discovery of an atypical form of BSE in cattle, L-type BSE or BASE, suggests that also this form of BSE might have been transmitted to sheep. We studied by Western blot the molecular features of PrP(res in four "CH1641-like" natural scrapie isolates after transmission in an ovine transgenic model (TgOvPrP4, to see if "CH1641-like" isolates might be linked to L-type BSE. We found less diglycosylated PrP(res than in classical BSE, but similar glycoform proportions and apparent molecular masses of the usual PrP(res form (PrP(res #1 to L-type BSE. However, the "CH1641-like" isolates differed from both L-type and classical BSE by an abundant, C-terminally cleaved PrP(res product (PrP(res #2 specifically recognised by a C-terminal antibody (SAF84. Differential immunoprecipitation of PrP(res #1 and PrP(res #2 resulted in enrichment in PrP(res #2, and demonstrated the presence of mono- and diglycosylated PrP(res products. PrP(res #2 could not be obtained from several experimental scrapie sources (SSBP1, 79A, Chandler, C506M3 in TgOvPrP4 mice, but was identified in the 87V scrapie strain and, in lower and variable proportions, in 5 of 5 natural scrapie isolates with different molecular features to CH1641. PrP(res #2 identification provides an additional method for the molecular discrimination of prion strains, and demonstrates differences between "CH1641-like" ovine scrapie and bovine L-type BSE transmitted in an ovine transgenic mouse model.
Baron, Thierry; Bencsik, Anna; Vulin, Johann; Biacabe, Anne-Gaëlle; Morignat, Eric; Verchere, Jérémy; Betemps, Dominique
The protease-resistant prion protein (PrP(res)) of a few natural scrapie isolates identified in sheep, reminiscent of the experimental isolate CH1641 derived from a British natural scrapie case, showed partial molecular similarities to ovine bovine spongiform encephalopathy (BSE). Recent discovery of an atypical form of BSE in cattle, L-type BSE or BASE, suggests that also this form of BSE might have been transmitted to sheep. We studied by Western blot the molecular features of PrP(res) in four "CH1641-like" natural scrapie isolates after transmission in an ovine transgenic model (TgOvPrP4), to see if "CH1641-like" isolates might be linked to L-type BSE. We found less diglycosylated PrP(res) than in classical BSE, but similar glycoform proportions and apparent molecular masses of the usual PrP(res) form (PrP(res) #1) to L-type BSE. However, the "CH1641-like" isolates differed from both L-type and classical BSE by an abundant, C-terminally cleaved PrP(res) product (PrP(res) #2) specifically recognised by a C-terminal antibody (SAF84). Differential immunoprecipitation of PrP(res) #1 and PrP(res) #2 resulted in enrichment in PrP(res) #2, and demonstrated the presence of mono- and diglycosylated PrP(res) products. PrP(res) #2 could not be obtained from several experimental scrapie sources (SSBP1, 79A, Chandler, C506M3) in TgOvPrP4 mice, but was identified in the 87V scrapie strain and, in lower and variable proportions, in 5 of 5 natural scrapie isolates with different molecular features to CH1641. PrP(res) #2 identification provides an additional method for the molecular discrimination of prion strains, and demonstrates differences between "CH1641-like" ovine scrapie and bovine L-type BSE transmitted in an ovine transgenic mouse model.
Hu, Baiyang [Graduate School of Environmental Science, Hokkaido University, Sapporo 060-0810 (Japan); Fugetsu, Bunshi, E-mail: firstname.lastname@example.org [Graduate School of Environmental Science, Hokkaido University, Sapporo 060-0810 (Japan); Yu, Hongwen [Graduate School of Environmental Science, Hokkaido University, Sapporo 060-0810 (Japan); Abe, Yoshiteru [Kyoei Engineering Corporation, Niigata 959-1961 (Japan)
Highlights: Black-Right-Pointing-Pointer Prussian blue was sealed in cavities of diatomite using carbon nanotubes. Black-Right-Pointing-Pointer The caged Prussian blue after being permanently immobilized in polyurethane spongy showed a 167 mg/g capability for absorbing cesium. Black-Right-Pointing-Pointer Cesium elimination was accomplished by simply adding the Prussian-blue based spongiform adsorbent to radioactive water. - Abstract: We developed a spongiform adsorbent that contains Prussian blue, which showed a high capacity for eliminating cesium. An in situ synthesizing approach was used to synthesize Prussian blue inside diatomite cavities. Highly dispersed carbon nanotubes (CNTs) were used to form CNT networks that coated the diatomite to seal in the Prussian blue particles. These ternary (CNT/diatomite/Prussian-blue) composites were mixed with polyurethane (PU) prepolymers to produce a quaternary (PU/CNT/diatomite/Prussian-blue), spongiform adsorbent with an in situ foaming procedure. Prussian blue was permanently immobilized in the cell walls of the spongiform matrix and preferentially adsorbed cesium with a theoretical capacity of 167 mg/g cesium. Cesium was absorbed primarily by an ion-exchange mechanism, and the absorption was accomplished by self-uptake of radioactive water by the quaternary spongiform adsorbent.
Chang, Jan-Shun; Chang, Tien-Chun
Both severe thyrotoxicosis and hypothyroidism may affect brain function and cause a change in consciousness, as seen with a thyroid storm or myxedema coma. However, encephalopathy may also develop in patients with autoimmune thyroid diseases independent of actual thyroid function level, and this is known as Hashimoto's encephalopathy. Although most patients are found to have Hashimoto's thyroiditis, less frequently they have Graves' disease. Clinical manifestations include epilepsy, disturbance of consciousness, cognitive impairment, memory loss, myoclonus, hallucinations, stroke-like episodes, tremor, involuntary movements, language impairment, and gait impairment. Hashimoto's encephalopathy is a relatively rare disease. As a good response can be obtained with corticosteroid therapy, early diagnosis and treatment is very beneficial for patients. Here we report three patients with Hashimoto's encephalopathy with typical manifestations of hallucinations that were associated with hypothyroidism, hyperthyroidism, and euthyroid status, respectively. They all showed a dramatic response to methylprednisolone pulse therapy.
Hindawy, A; Gouda, A; El-Ayyadi, A; Megahed, H; Bazaraa, H
Fatty Acid Oxidation disorders represent an expanding group of inborn errors of metabolism. Clinical manifestations include episodic encephalopathy, hypoketotic hypoglycemia, Reye like episodes, hepatic, muscular, cardiac affection and sudden death. Analysis of urinary organic acids and plasma fatty acids of 44 clinically suspected patients by Gas Chromatography Mass spectrometry revealed 4 cases of Medium chain acyl-CoA dehydrogenase deficiency (MCADD), 3 cases of Very long chain acyl-CoA dehydrogenase deficiency, 9 cases of multiple defects of acyl-CoA dehydrogenation in addition to 3 patients with other metabolic disorders. Timely detection of these disorders including screening for MCADD can have a favorable impact on the outcome of these patients (Tab. 11, Fig. 3, Ref. 24) Full Text (Free, PDF).
... provide specific instructions for proper care and treatment. Anticonvulsants may be prescribed to reduce or halt any ... provide specific instructions for proper care and treatment. Anticonvulsants may be prescribed to reduce or halt any ...
Arnold, S.M.; Spreer, J.; Schumacher, M. [Section of Neuroradiology, Univ. of Freiburg (Germany); Els, T. [Dept. of Neurology, University of Freiburg (Germany)
Acute hepatic encephalopathy is a poorly defined syndrome of heterogeneous aetiology. We report a 49-year-old woman with alcoholic cirrhosis and hereditary haemorrhagic telangiectasia who developed acute hepatic coma induced by severe gastrointestinal bleeding. Laboratory analysis revealed excessively elevated blood ammonia. MRI showed lesions compatible with chronic hepatic encephalopathy and widespread cortical signal change sparing the perirolandic and occipital cortex. The cortical lesions resembled those of hypoxic brain damage and were interpreted as acute toxic cortical laminar necrosis. (orig.)
Heegaard, Peter M. H.; Bergström, Ann-Louise; Andersen, Heidi Gertz;
method for production of mouse monoclonal antibodies (MAbs) against peptides representing two sites of interest in the bovine prion protein (boPrP), the causative agent of bovine spongiform encephalopathy ("mad cow disease") and new variant Creutzfeldt-Jakob's disease (CJD) in humans, as well...
Xuhong Li; Liming Deng; Bin Ye
A 22-year-old man with a 2-year history of heroin vapor inhalation developed spongiform leukoencephalopathy and underwent clinical and home-based rehabilitative treatments.Activities of daily living were measured using the Functional Independence Measure at discharge and at 6, 12, and 24 months after discharge.His neurological symptoms gradually disappeared with rehabilitative treatment, and the functional scale scores increased from 55 on admission to 105 at 24 months after discharge.These results suggest that home-based rehabilitation was effective in ameliorating the pathology and improving activities of daily living in this patient with heroin-induced spongiform leukoencephalopathy.
Capobianco, Raffaella; Casalone, Cristina; Suardi, Silvia; Mangieri, Michela; Miccolo, Claudia; Limido, Lucia; Catania, Marcella; Rossi, Giacomina; Di Fede, Giuseppe; Giaccone, Giorgio; Bruzzone, Maria Grazia; Minati, Ludovico; Corona, Cristiano; Acutis, Pierluigi; Gelmetti, Daniela; Lombardi, Guerino; Groschup, Martin H; Buschmann, Anne; Zanusso, Gianluigi; Monaco, Salvatore; Caramelli, Maria; Tagliavini, Fabrizio
Atypical neuropathological and molecular phenotypes of bovine spongiform encephalopathy (BSE) have recently been identified in different countries. One of these phenotypes, named bovine "amyloidotic" spongiform encephalopathy (BASE), differs from classical BSE for the occurrence of a distinct type of the disease-associated prion protein (PrP), termed PrP(Sc), and the presence of PrP amyloid plaques. Here, we show that the agents responsible for BSE and BASE possess different biological properties upon transmission to transgenic mice expressing bovine PrP and inbred lines of nontransgenic mice. Strikingly, serial passages of the BASE strain to nontransgenic mice induced a neuropathological and molecular disease phenotype indistinguishable from that of BSE-infected mice. The existence of more than one agent associated with prion disease in cattle and the ability of the BASE strain to convert into the BSE strain may have important implications with respect to the origin of BSE and spongiform encephalopathies in other species, including humans.
Mocellin, Ramon; Walterfang, Mark; Velakoulis, Dennis
Hashimoto's encephalopathy is a term used to describe an encephalopathy of presumed autoimmune origin characterised by high titres of antithyroid peroxidase antibodies. In a similar fashion to autoimmune thyroid disease, Hashimoto's encephalopathy is more common in women than in men. It has been reported in paediatric, adult and elderly populations throughout the world. The clinical presentation may involve a relapsing and remitting course and include seizures, stroke-like episodes, cognitive decline, neuropsychiatric symptoms and myoclonus. Thyroid function is usually clinically and biochemically normal.Hashimoto's encephalopathy appears to be a rare disorder, but, as it is responsive to treatment with corticosteroids, it must be considered in cases of 'investigation negative encephalopathies'. Diagnosis is made in the first instance by excluding other toxic, metabolic and infectious causes of encephalopathy with neuroimaging and CSF examination. Neuroimaging findings are often not helpful in clarifying the diagnosis. Common differential diagnoses when these conditions are excluded are Creutzfeldt-Jakob disease, rapidly progressive dementias, and paraneoplastic and nonparaneoplastic limbic encephalitis. In the context of the typical clinical picture, high titres of antithyroid antibodies, in particular antithyroid peroxidase antibodies, are diagnostic. These antibodies, however, can be detected in elevated titres in the healthy general population. Treatment with corticosteroids is almost always successful, although relapse may occur if this treatment is ceased abruptly. Other forms of immunomodulation, such as intravenous immune-globulin and plasma exchange, may also be effective. Despite the link to autoimmune thyroid disease, the aetiology of Hashimoto's encephalopathy is unknown. It is likely that antithyroid antibodies are not pathogenic, but titres can be a marker of treatment response. Pathological findings can suggest an inflammatory process, but features
Dhiman, Radha K
There is a strong relationship between liver and gut; while the portal venous system receives blood from the gut, and its contents may affect liver functions, liver in turn, affects intestinal functions through bile secretion. There is robust evidence that the pathogenesis of hepatic encephalopathy (HE) is linked to alterations in gut microbiota and their by-products such as ammonia, indoles, oxindoles, endotoxins, etc. In the setting of intestinal barrier and immune dysfunction, these by-products are involved in the pathogenesis of complications of liver cirrhosis including HE and systemic inflammation plays an important role. Prebiotics, probiotics and synbiotics may exhibit efficacy in the treatment of HE by modulating the gut flora. They improve derangement in flora by decreasing the counts of pathogenic bacteria and thus improving the endotoxemia, HE and the liver disease. Current evidence suggest that the trials evaluating the role of probiotics in the treatment of HE are of not high quality and all trials had high risk of bias and high risk of random errors. Therefore, the use of probiotics for patients with HE cannot be currently recommended. Further RCTs are required. This review summarizes the main literature findings about the relationships between gut flora and HE, both in terms of the pathogenesis and the treatment of HE.
Fraile, Pilar; Cacharro, Luis Maria; Garcia-Cosmes, Pedro; Rosado, Consolacion; Tabernero, Jose Matias
Lanthanum carbonate is a nonaluminum, noncalcium phosphate-binding agent, which is widely used in patients with end-stage chronic kidney disease. Until now, no significant side-effects have been described for the clinical use of lanthanum carbonate, and there are no available clinical data regarding its tissue stores. Here we report the case of a 59-year-old patient who was admitted with confusional syndrome. The patient received 3750 mg of lanthanum carbonate daily. Examinations were carried out, and the etiology of the encephalopathy of the patient could not be singled out. The lanthanum carbonate levels in serum and cerebrospinal fluid were high, and the syndrome eased after the drug was removed. The results of our study confirm that, in our case, the lanthanum carbonate did cross the blood-brain barrier (BBB). Although lanthanum carbonate seems a safe drug with minimal absorption, this work reveals the problem derived from the increase of serum levels of lanthanum carbonate, and the possibility that it may cross the BBB. Further research is required on the possible pathologies that increase serum levels of lanthanum carbonate, as well as the risks and side-effects derived from its absorption.
Vigevano, Federico; Arzimanoglou, Alexis; Plouin, Perrine; Specchio, Nicola
Epileptic encephalopathies (EEs) are electroclinical entities with a peculiar course of disease; seizures and electroencephalographic (EEG) epileptiform abnormalities, ictal and interictal, contribute to progressive disturbance of cerebral functions. Frequently EEs are drug resistant, and consequences may be catastrophic. The main goal of treatment is to stop the peculiar course of epilepsy, operating on three parameters: seizure control, reduction of EEG abnormalities, and developmental outcome. For a correct therapeutic approach it is mandatory to have an as accurate as possible syndromic and etiologic diagnosis. Given the poor efficacy of conventional antiepileptic drugs (AEDs), the use of specific drugs for EEs, such as adrenocorticotropic hormone (ACTH) and corticosteroids or stiripentol is suggested. In some cases the choice of treatment is strictly related to the etiology: vigabatrin in tuberous sclerosis, ketogenic diet in glucose transporter type 1 (GLUT-1) deficiency, and pyridoxine in pyridoxine deficiency. Some AEDs combinations, such as sodium valproate with lamotrigine, have also provided interesting results, for example, in Lennox-Gastaut syndrome, although controlled studies are lacking. Finally, early surgery can be an option in children with focal structural abnormalities responsible for EEs preferably before irreversible damage on developmental outcome. Multispecialist support is recommended in EE. Management should be global from the onset, integrating not only seizure control but also all issues related to comorbidities, particularly neuropsychological and psychiatric.
Full Text Available Chronic traumatic encephalopathy (CTE is a progressive neurodegenerative disease that is a long-term consequence of single or repetitive closed head injuries for which there is no treatment and no definitive pre-mortem diagnosis. It has been closely tied to athletes who participate in contact sports like boxing, American football, soccer, professional wrestling and hockey. Risk factors include head trauma, presence of ApoE3 or ApoE4 allele, military service, and old age. It is histologically identified by the presence of tau-immunoreactive NFTs and NTs with some cases having a TDP-43 proteinopathy or beta-amyloid plaques. It has an insidious clinical presentation that begins with cognitive and emotional disturbances and can progress to Parkinsonian symptoms. The exact mechanism for CTE has not been precisely defined however, research suggest it is due to an ongoing metabolic and immunologic cascade called immunoexcitiotoxicity. Prevention and education are currently the most compelling way to combat CTE and will be an emphasis of both physicians and athletes. Further research is needed to aid in pre-mortem diagnosis, therapies, and support for individuals and their families living with CTE.
Weidauer, S.; Gaa, J.; Lanfermann, H.; Zanella, F.E. [Institute of Neuroradiology, University of Frankfurt, Schleusenweg 2-16, 60528, Frankfurt (Germany); Sitzer, M.; Hefner, R. [Department of Neurology, University of Frankfurt, Schleusenweg 2-16, 60528, Frankfurt (Germany)
Posterior encephalopathy is characterised by headache, impairment of consciousness, seizures and progressive visual loss. MRI shows bilateral, predominantly posterior, cortical and subcortical lesions with a distribution. Our aim was to analyse the MRI lesion pattern and angiographic findings because the pathophysiology of posterior encephalopathy is incompletely understood. We report three patients with clinical and imaging findings consistent with posterior encephalopathy who underwent serial MRI including diffusion-weighted imaging (DWI) and construction of apparent diffusion coefficient (ADC) maps, and four-vessel digital subtraction angiography (DSA). DWI revealed symmetrical subcortical and cortical parieto-occipital high signal. High and also low ADCs indicated probable vasogenic and cytotoxic oedema. On follow-up there was focal cortical laminar necrosis, while the white-matter lesions resolved almost completely, except in the arterial border zones. DSA revealed diffuse arterial narrowing, slightly more marked in the posterior circulation. These findings suggest that posterior encephalopathy may in some cases be due to diffuse, severe vasospasm affecting especially in the parieto-occipital grey matter, with its higher vulnerability to ischemia. Cerebral vasospasm due to digitoxin intoxication, resulting in posterior encephalopathy, has not yet been described previously. (orig.)
Gjedde, Albert; Keiding, Susanne; Vilstrup, Hendrik
declined in all gray matter regions of the brain in patients with HE but not significantly in patients with CL. Analysis of flow-metabolism coupling indicated that blood flow declined in HE as a consequence of reduced brain energy metabolism implied by the calculation of increased mitochondrial oxygen......Hepatic encephalopathy is a condition of reduced brain functioning in which both blood flow and brain energy metabolism declined. It is not known whether blood flow or metabolism is the primary limiting factor of brain function in this condition. We used calculations of mitochondrial oxygen tension...... to choose between cause and effect in three groups of volunteers, including healthy control subjects (HC), patients with cirrhosis of the liver without hepatic encephalopathy (CL), and patients with cirrhosis with acute hepatic encephalopathy. Compared to HC subjects, blood flow and energy metabolism had...
Morgan, Marsha Y; Amodio, Piero; Cook, Nicola A
, the Inhibitory Control Test, the Stroop test, the Scan package and the Continuous Reaction Time; each has its pros and cons; strengths and weaknesses; protagonists and detractors. Recent AASLD/EASL Practice Guidelines suggest that the diagnosis of minimal hepatic encephalopathy should be based on the PHES test...... hepatic encephalopathy since the 1950s but, once popular, the technology is not as accessible now as it once was. The performance characteristics of the EEG are critically dependent on the type of analysis undertaken; spectral analysis has better performance characteristics than visual analysis; evolving...
Full Text Available Epileptic encephalopathies are motor-mental retardations or cognitive disorders secondary to epileptic seizures or epileptiform activities. Encephalopaties due to brain damage, medications, or systemic diseases are generally not in the scope of this definition, but they may rarely accompany the condition. Appropriate differential diagnosis of epileptic seizures as well as subclinical electroencephalographic discharges are crucial for management of seizures and epileptiform discharges and relative regression of cognitive deterioration in long-term followup. Proper antiepileptic drug, hormonal treatment, or i.v. immunoglobulin choice play major role in prognosis. In this paper, we evaluated the current treatment approaches by reviewing clinical electrophysiological characteristics of epileptic encephalopathies.
Stamberger, Hannah; Nikanorova, Marina; Willemsen, Marjolein H
OBJECTIVE: To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients. METHODS: We recruited newly diagnosed patients with STXBP1 mutations through an international networ...
Matt Lallas; Jay Desai
Background: Wernicke encephalopathy is caused by thiamine (vitamin B1) defi ciency. It is generally considered to be a disease of adult alcoholics. However, it is known to occur in the pediatric population and in non-alcoholic conditions. Data sources: We searched PubMed with the key words Wernicke, thiamine, pediatric, children and adolescents and selected publications that were deemed appropriate. Results: The global prevalence rates of hunger, poverty and resultant nutrient deprivation have decreased in the 21st century. However, several scenarios which may predispose to Wernicke encephalopathy may be increasingly prevalent in children and adolescents such as malignancies, intensive care unit stays and surgical procedures for the treatment of obesity. Other predisposing conditions include magnesium defi ciency and defects in the SLC19A3 gene causing thiamine transporter-2 deficiency. The classic triad consists of encephalopathy, oculomotor dysfunction and gait ataxia but is not seen in a majority of patients. Treatment should be instituted immediately when the diagnosis is suspected clinically without waiting for laboratory confi rmation. Common magnetic resonance findings include symmetric T2 hyperintensities in dorsal medial thalamus, mammillary bodies, periaqueductal gray matter, and tectal plate. Conclusions: Wernicke encephalopathy is a medical emergency. Delay in its recognition and treatment may lead to significant morbidity, irreversible neurological damage or even death. This article aims to raise the awareness of this condition among pediatricians.
C.C.D. van der Rijt (Carin)
textabstractThe pathogenesis of hepatic encephalopathy is still unsolved. Therapy, therefore, is often insufficient. For the development of effective, new therapies insight into the disease-inducing substrates and the mechanisms of its toxic actions in the central nervous system ·are required. For b
Full Text Available Background: ″Wernicke’s Korsakoff″ syndrome is the most important complication of severe thiamine deficiency. The term refers to two different syndromes, each representing a different stage of the disease. Wernicke’s encephalopathy (WE is an acute syndrome requiring emergent treatment to prevent death and neurologic morbidity. Korsakoff syndrome (KS refers to a chronic neurologic condition that usually occurs as a consequence of WE. It is a rare complication of hyperemesis gravidarum that confusion, ocular signs, and gait ataxia are the most prevalent symptoms, respectively. Typical brain lesions of wernicke’s encephalopathy (WE are observed at autopsy in 0.4 to 2.8 percent of the general population in the western world and the majority of affected patients are alcoholic. The prevalence of wernicke’s encephalopathy lesions seen on autopsy was 12.5% of alcohol abusers in one report. Among those who with alcohol-related death, it has been reported to be even higher, 29 to 59%. The aim of this study was to report a case of wernicke’s encephalopathy following hyperemesis gravidarum. Case Presentation: A 28-year-old-pregnant woman in 19th weeks of gestation referred to the hospital with hyperemesis, gait ataxia, and dysarthria before that she had hyperemesis gravidarum with weight loss and unresponsive to outpatient and inpatient medical therapy. MRI showed hyperdense lesion around thalamus which was characteristic of wernicke’s encephalopathy. Rapid improvement in patient’s condition occurred after high dose thiamine infusion. Conclusion: In hyperemesis gravidarum, presence of either symptoms of ocular or mental disorder or ataxia must be considered to rule out and appropriate treatment of Wernicke’s syndrome which can cause maternal and fetal death.
Morgan, Marsha Y; Amodio, Piero; Cook, Nicola A; Jackson, Clive D; Kircheis, Gerald; Lauridsen, Mette M; Montagnese, Sara; Schiff, Sami; Weissenborn, Karin
Minimal hepatic encephalopathy is the term applied to the neuropsychiatric status of patients with cirrhosis who are unimpaired on clinical examination but show alterations in neuropsychological tests exploring psychomotor speed/executive function and/or in neurophysiological variables. There is no gold standard for the diagnosis of this syndrome. As these patients have, by definition, no recognizable clinical features of brain dysfunction, the primary prerequisite for the diagnosis is careful exclusion of clinical symptoms and signs. A large number of psychometric tests/test systems have been evaluated in this patient group. Of these the best known and validated is the Portal Systemic Hepatic Encephalopathy Score (PHES) derived from a test battery of five paper and pencil tests; normative reference data are available in several countries. The electroencephalogram (EEG) has been used to diagnose hepatic encephalopathy since the 1950s but, once popular, the technology is not as accessible now as it once was. The performance characteristics of the EEG are critically dependent on the type of analysis undertaken; spectral analysis has better performance characteristics than visual analysis; evolving analytical techniques may provide better diagnostic information while the advent of portable wireless headsets may facilitate more widespread use. A large number of other diagnostic tools have been validated for the diagnosis of minimal hepatic encephalopathy including Critical Flicker Frequency, the Inhibitory Control Test, the Stroop test, the Scan package and the Continuous Reaction Time; each has its pros and cons; strengths and weaknesses; protagonists and detractors. Recent AASLD/EASL Practice Guidelines suggest that the diagnosis of minimal hepatic encephalopathy should be based on the PHES test together with one of the validated alternative techniques or the EEG. Minimal hepatic encephalopathy has a detrimental effect on the well-being of patients and their care
Mcintyre, Sarah; Badawi, Nadia; Blair, Eve; Nelson, Karin B
Neonatal encephalopathy, a clinical syndrome affecting term-born and late preterm newborn infants, increases the risk of perinatal death and long-term neurological morbidity, especially cerebral palsy. With the advent of therapeutic hypothermia, a treatment designed for hypoxic or ischaemic injury, associated mortality and morbidity rates have decreased. Unfortunately, only about one in eight neonates (95% confidence interval) who meet eligibility criteria for therapeutic cooling apparently benefit from the treatment. Studies of infants in representative populations indicate that neonatal encephalopathy is a potential result of a variety of antecedents and that asphyxial complications at birth account for only a small percentage of neonatal encephalopathy. In contrast, clinical case series suggest that a large proportion of neonatal encephalopathy is hypoxic or ischaemic, and trials of therapeutic hypothermia are specifically designed to include only infants exposed to hypoxia or ischaemia. This review addresses the differences, definitional and methodological, between infants studied and investigations undertaken, in population studies compared with cooling trials. It raises the question if there may be subgroups of infants with a clinical diagnosis of hypoxic-ischaemic encephalopathy (HIE) in whom the pathobiology of neonatal neurological depression is not fundamentally hypoxic or ischaemic and, therefore, for whom cooling may not be beneficial. In addition, it suggests approaches to future trials of cooling plus adjuvant therapy that may contribute to further improvement of care for these vulnerable neonates.
m Hinblick auf die Problematik der bovinen spongiformen Enzephalopathie (BSE) und der daraus erwachsenden Sensibilisierung des Verbrauchers bezüglich der Zusammensetzung der Fleischerzeugnisse ist es notwendig, der Lebensmittelüberwachung ein geeignetes Kontrollverfahren der Roh- und Endprodukte an die Hand zu geben. Vorrangig ist die Einhaltung des Verarbeitungsverbots von Gewebe des zentralen Nervensystems (ZNS) in Lebensmitteln, da dies als Hauptinfektionsquelle der BSE angesehen ...
... DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE..., Finland, France, Germany, Greece, the Republic of Ireland, Israel, Italy, Japan, Liechtenstein,...
Goldbecker, Annemarie; Tryc, Anita Blanka; Raab, Peter; Worthmann, Hans; Herrmann, Julian; Weissenborn, Karin
Temozolomide in combination with radiation has been in use for more than 5 years for the therapy of glioblastoma. Known adverse effects concerning the gastrointestinal system are elevation of liver enzymes. We present the case of a patient treated with temozolomide who developed severe cholestatic liver damage and consecutive hepatic encephalopathy. Neurological symptoms were mistaken as being caused by focal brain damage for more than 9 months. After the correct diagnosis had been made and the treatment had been started, the patient's condition ameliorated. In conclusion, neurological deficits in patients with known brain lesion should not be attributed automatically to the pre-existing damage even if it is progressive but should be examined carefully, also including toxic and metabolic encephalopathies into the differential diagnosis. Furthermore, new side effects of drugs have to be considered. At least this case might lead to a closer monitoring of liver enzymes during temozolomide therapy.
Montagna, Giacomo; Imperiali, Mauro; Agazzi, Pamela; D'Aurizio, Federica; Tozzoli, Renato; Feldt-Rasmussen, Ulla; Giovanella, Luca
Hashimoto's encephalopathy (HE) is a rare not well understood, progressive and relapsing multiform disease, characterized by seizures, movement disorders, subacute cognitive dysfunction, psychiatric symptoms and responsiveness to steroid therapy. The disorder is generally associated with thyroid diseases and the most common feature is the presence of anti-thyroperoxidase antibodies (TPOAb). Patients are usually euthyroid or mildly hypothyroid at presentation. All age groups can be affected. The pathophysiology is still unclear, especially the link between elevated serum TPOAb and the encephalopathy. Most reported cases occurred in women and girls. Unspecific symptoms, non-pathognomonic laboratory neurophysiology and neuroimaging features make its diagnosis a real challenge for clinicians. The case of a 16 year old boy, with a clinical picture of HE associated with hypothyroidism, demonstrating an excellent response to high dose steroids is presented together with a systematic review of the literature.
Full Text Available We discuss a case of a 64-year-old male with a history of liver failure presenting with altered mental status, initially diagnosed with hepatic encephalopathy but ultimately diagnosed with nonconvulsive status epilepticus (NCSE by electroencephalogram (EEG. NCSE is a difficult diagnosis to make, given no clear consensus on diagnostic criteria. Especially in the intensive care unit setting of persistent altered mental status with no clear etiology, NCSE must be considered in the differential diagnosis, as the consequences of delayed diagnosis and treatment can be substantial. EEG can be useful in the evaluation of patients with hepatic encephalopathy who have persistently altered levels of consciousness despite optimal medical management. [West J Emerg Med. 2011;12(4:372–374.
Riviello, J J; Halligan, G E; Dunn, S P; Widzer, S J; Foley, C M; Breningstall, G N; Grover, W D
Plasmapheresis is used for treating the complications of liver failure. We performed plasmapheresis on 6 children with hepatic encephalopathy resulting from acute hepatic failure and prospectively assessed its effects on neurologic and electrophysiologic (electroencephalography and evoked potentials) function. Clinical improvement was observed in 3 of 6 patients; changes in the serum ammonia value or the results of initial electrophysiologic tests did not predict the patient response. Two patients underwent transplantation after neurologic improvement was produced by plasmapheresis; however, despite plasmapheresis, 4 patients progressed to brain death. Our data demonstrate that plasmapheresis may transiently improve the encephalopathy of acute hepatic failure but is not curative alone. Therefore, plasmapheresis may be a useful adjunct in the treatment of liver failure, potentially improving the pretransplantation status of the patient.
Jat, Kana Ram; Marwaha, R K; Panigrahi, Inusha; Gupta, Kunal
Infestation with Ascaris lumbricoides in children has a varied manifestation, but encephalopathy is a very rare presentation. This report describes a case of ascariasis-associated encephalopathy in a child. An 18-month-old boy was admitted with altered sensorium. He had a history of vomiting and was passing Ascaris worms in the vomitus. The cerebrospinal fluid analysis did not reveal any abnormality. The patient was treated with an antihelminthic drug and he recovered completely. Worm encephalopathy should be considered as a differential diagnosis for unexplained encephalopathy in tropical areas.
Full Text Available Baking soda is a readily available household product composed of sodium bicarbonate. It can be used as a home remedy to treat dyspepsia. If used in excessive amounts, baking soda has the potential to cause a variety of serious metabolic abnormalities. We believe this is the first reported case of hemorrhagic encephalopathy induced by baking soda ingestion. Healthcare providers should be aware of the dangers of baking soda misuse and the associated adverse effects.
Hughes, Adrienne; Brown, Alisha; Valento, Matthew
Baking soda is a readily available household product composed of sodium bicarbonate. It can be used as a home remedy to treat dyspepsia. If used in excessive amounts, baking soda has the potential to cause a variety of serious metabolic abnormalities. We believe this is the first reported case of hemorrhagic encephalopathy induced by baking soda ingestion. Healthcare providers should be aware of the dangers of baking soda misuse and the associated adverse effects.
Full Text Available Wernicke′s encephalopathy (WE is a potentially reversible yet serious neurological manifestation caused by vitamin B 1 (thiamine deficiency. It is commonly associated with heavy alcohol consumption. Other clinical associations are with hyperemesis gravidarum (HG, starvation, and prolonged intravenous feeding. Most patients present with the triad of ocular signs, ataxia, and confusion. It can be associated with life-threatening complication like central pontine myelinolysis (CPM. We report two cases of WE following HG, with two different outcomes.
Bagci, S; Zschocke, J; Hoffmann, G F; Bast, T; Klepper, J; Müller, A; Heep, A; Bartmann, P; Franz, A R
Pyridox(am)ine-5'-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5'-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unresponsive to pyridoxine.
Pyridox(am)ine-5′-phosphate oxidase converts pyridoxine phosphate and pyridoxamine phosphate to pyridoxal phosphate, a cofactor in many metabolic reactions, including neurotransmitter synthesis. A family with a mutation in the pyridox(am)ine-5′-phosphate oxidase gene presenting with neonatal seizures unresponsive to pyridoxine and anticonvulsant treatment but responsive to pyridoxal phosphate is described. Pyridoxal phosphate should be considered in neonatal epileptic encephalopathy unrespons...
Xiao-jun Cai; Hui-qin Xu; Yi Lu
With the changes of life style, diabetes and its complications have become a major cause of morbidity and mortality. It is reasonable to anticipate a continued rise in the incidence of diabetes and its complications along with the aging of the population, increase in adult obesity rate, and other risk factors. Diabetic encephalopathy is one of the severe microvascular complications of diabetes, characterized by impaired cognitive functions, and electrophysiological, neurochemical, and structural abnormalities. It may involve direct neuronal damage caused by intracellular glucose. However, the pathogenesis of this disease is complex and its diagnosis is not very clear. Previous researches have suggested that chronic metabolic alterations, vascular changes, and neuronal apoptosis may play important roles in neuronal loss and damaged cognitive fimctions.Multiple factors are responsible for neuronal apoptosis, such as disturbed insulin growth factor (IGF) system,hyperglycemia, and the aging process. Recent data suggest that insulin/C-peptide defidency may exert a primary and key effect in diabetic encephalopathy. Administration of C-peptide partially improves the condition of the IGF system in the brain and prevents neuronal apoptosis in the hippocampus of diabetic patients.Those Findings provide a basis for application of C-peptide as a potentially effective therapy for diabetes and diabetic encephalopathy.
Jasmohan S Bajaj
Minimal hepatic encephalopathy is a neuro-cognitive dysfunction which occurs in an epidemic proportion of cirrhotic patients, estimated as high as 80% of the population tested. It is characterized by a specific, complex cognitive dysfunction which is independent of sleep dysfunction or problems with overall intelligence. Although named "minimal", minimal hepatic encephalopathy (MHE) can have a far-reaching impact on quality of life, ability to function in daily life and progression to overt hepatic encephalopathy. Importantly, MHE has a profound negative impact on the ability to drive a car and may be a significant factor behind motor vehicle accidents. A crucial aspect of the clinical care of MHE patients is their driving history, which is often ignored in routine care and can add a vital dimension to the overall disease assessment. Driving history should be an integral part of care in patients with MHE. The lack of specific signs and symptoms, the preserved communication skills and lack of insight make MHE a difficult condition to diagnose. Diagnostic strategies for MHE abound, but are usually limited by financial, normative or time constraints. Recent studies into the inhibitory control and critical flicker frequency tests are encouraging since these tests can increase the rates of MHE diagnosis without requiring a psychologist. Although testing for MHE and subsequent therapy is not standard of care at this time, it is important to consider this in cirrhotics in order to improve their ability to live their life to the fullest.
Ernest Marshall Graham
Full Text Available Recent research in identification of brain injury after trauma shows many possible blood biomarkers that may help identify the fetus and neonate with encephalopathy. Traumatic brain injury shares many common features with perinatal hypoxic-ischemic encephalopathy. Trauma has a hypoxic component, and one of the 1st physiologic consequences of moderate-severe traumatic brain injury is apnea. Trauma and hypoxia-ischemia initiate an excitotoxic cascade and free radical injury followed by the inflammatory cascade, producing injury in neurons, glial cells and white matter. Increased excitatory amino acids, lipid peroxidation products and alteration in microRNAs and inflammatory markers are common to both traumatic brain injury and perinatal encephalopathy. The blood-brain barrier is disrupted in both leading to egress of substances normally only found in the central nervous system. Brain exosomes may represent ideal biomarker containers, as RNA and protein transported within the vesicles are protected from enzymatic degradation. Evaluation of fetal or neonatal brain derived exosomes that cross the blood-brain barrier and circulate peripherally has been referred to as the liquid brain biopsy. A multiplex of serum biomarkers could improve upon the current imprecise methods of identifying fetal and neonatal brain injury such as fetal heart rate abnormalities, meconium, cord gases at delivery, and Apgar scores. Quantitative biomarker measurements of perinatal brain injury and recovery could lead to operative delivery only in the presence of significant fetal risk, triage to appropriate therapy after birth and measure the effectiveness of treatment.
John, Elizabeth S; Sedhom, Ramy; Dalal, Ishita; Sharma, Ranita
Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiologic diagnosis that has become more widely recognized and reported over the past few decades. As such, there are a number of known risk factors that contribute to the development of this syndrome, including volatile blood pressures, renal failure, cytotoxic drugs, autoimmune disorders, pre-eclampsia, and eclampsia. This report documents the first reported case of PRES in a patient with severe alcoholic hepatitis with hepatic encephalopathy and delves into a molecular pathophysiology of the syndrome. PMID:28127211
Hvass, Henriette Cordes; Bergström, Ann-Louise; Ohm, Jakob
spongiform encephalopathy (bovine brain), scrapie (ovine brain) and experimental scrapie in hamster and in mice. The antibodies were also used for PET-blotting in which PrPSc blotted from brain tissue sections onto a nitrocellulose membrane is visualized with antibodies after protease and denaturant...
... products, including dry whole milk, nonfat dry milk, dried whey, dried buttermilk, and formulations which... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Milk and milk products. 94.16 Section... VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY: PROHIBITED AND RESTRICTED IMPORTATIONS § 94.16...
... packaged. FSIS requires that official establishments that slaughter cattle and or process carcasses or parts of cattle develop written procedures for the removal, segregation, and disposition of specified... meat products produced by the use of AMR systems is free from Bovine Spongiform Encephalopathy...
Krom, de M.P.M.M.
During the 1990s, many European countries faced one or more food crises, such as bovine spongiform encephalopathy (BSE), E. coli, dioxin residues, and foot-and-mouth disease. These crises were marked by a growing public recognition of food-related risks and the changing nature of these risks, and te
melitensis ) C Camel pox Brucellosis of swine ( Brucella suis) S Classical swine fever S Glanders (Burkholderia mallei) E Contagious caprine...highly pathogenic) A Bluetongue (exotic) MBrucellosis of cattle ( Brucella abortus) B Bovine spongiform encephalopathy B Brucellosis of sheep ( Brucella ...M(Valley fever) Coccidioides immitis Goat pox C Q fever (Coxiella burnetii) M Heartwater (Cowdria ruminantium) MEastern equine encephalitis E Japanese
Raamsdonk, van L.W.D.; Holst, von C.; Baeten, V.; Berben, G.; Boix, A.; Jong, de J.
It is generally accepted that the most likely route of infection of cattle with bovine spongiform encephalopathy (BSE) is by consumption of feeds containing low levels of processed animal proteins (PAPs). This likely route of infection resulted in feed bans, which were primarily aimed at ruminant fe
... ANIMAL PRODUCTS RINDERPEST, FOOT-AND-MOUTH DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY: PROHIBITED AND..., originating in any region where rinderpest or foot-and-mouth disease exists, as designated in § 94.1,...
... (INCLUDING POULTRY) AND ANIMAL PRODUCTS RINDERPEST, FOOT-AND-MOUTH DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY... vesicular disease exists; importations prohibited. 94.14 Section 94.14 Animals and Animal Products...
... (INCLUDING POULTRY) AND ANIMAL PRODUCTS RINDERPEST, FOOT-AND-MOUTH DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY... where rinderpest or foot-and-mouth disease exists. 94.4 Section 94.4 Animals and Animal Products...
Dorp, van C.A.
Prior to the Bovine Spongiform Encephalopathy (BSE) crisis, detailed information on beef products seemed no real necessity. However, following the outbreak of BSE, the Government felt obliged to protect consumer interest with legislation. Obligatory product information became required for beef trace
Scholtens-Toma, Ingrid; Prins, Theo W.; Raamsdonk, Van Leo W.D.
After the Bovine Spongiform Encephalopathy (BSE) crisis emerged in 1985/1986, all processed animal proteins (PAPs) were finally banned for use in animal feed in the European Union. To partially lift this feed ban, paths for re-introduction of PAPs from species other than ruminants e.g. pig and poult
Classical bovine spongiform encephalopathy (c-BSE) is an animal prion disease that also causes variant Creutzfeldt-Jakob disease in humans. Over the past decades, c-BSE's zoonotic potential has been the driving force in establishing extensive protective measures for animal and human health. In compl...
... (Ref. 12) and guidance on measures to address the risk for contamination by Salmonella spp. in raw meat... resulting from feeding of medicated animal food, Bovine Spongiform Encephalopathy (BSE), and Salmonella, but... regarding Salmonella contamination in all food for animals (Ref. 14), and a CPG that sets forth the...
Ducrot, C.; Calavas, D.; Arnold, M.; Koeijer, de A.A.; Heim, D.
The paper describes how the comprehensive surveillance of bovine spongiform encephalopathy (BSE) and studies carried out on these data has enhanced our knowledge of the epidemiology of BSE. Around 7 000 BSE cases were detected through the screening of about 50 million cattle with rapid tests in Euro
... RINDERPEST, FOOT-AND-MOUTH DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY: PROHIBITED AND RESTRICTED IMPORTATIONS... national government of the region of origin. The official certificate must state the species of animal...
... National Government of a region of origin listed in § 94.12 as a region considered free of the disease. (3... POULTRY) AND ANIMAL PRODUCTS RINDERPEST, FOOT-AND-MOUTH DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY:...
Montag, Judith; Schulz-Schaeffer, Walter; Schrod, Annette; Hunsmann, Gerhard; Motzkus, Dirk
To estimate the effect of the variability of prion disease onset on primary bovine spongiform encephalopathy transmission to humans, we studied 6 cynomolgus macaques. The preclinical incubation period was significantly prolonged in 2 animals, implying that onset of variant Creutzfeldt-Jacob disease in humans could be more diverse than previously expected.
Heres, L.; Elbers, A.R.W.; Schreuder, B.E.C.; Zijderveld, van F.G.
It is generally accepted that the bovine spongiform encephalopathy (BSE) epidemic is transmitted by feed contamination with meat and bone meal (MBM). Whether in some cases substances other than MBM have caused the spread of this disease cannot be excluded at present. Detailed knowledge about country
Grobben, A.H.; Steele, P.J.; Somerville, R.A.; Taylor, D.; Schreuder, B.E.C.
Dietary exposure to the bovine spongiform encephalopathy (BSE) agent is the probable cause of variant Creutzfeldt-Jakob disease in people. The industrial manufacturing process for the production of gelatine and colloidal protein by the heat and pressure process was downscaled accurately and its capa
Heres, L.; Brus, D.J.; Hagenaars, T.H.J.
Background: In many of the European countries affected by Bovine Spongiform Encephalopathy (BSE), case clustering patterns have been observed. Most of these patterns have been interpreted in terms of heterogeneities in exposure of cattle to the BSE agent. Here we investigate whether spatial clusteri
Nicot, Simon; Bencsik, Anna; Morignat, Eric; Mestre-Francés, Nadine; Perret-Liaudet, Armand; Baron, Thierry
We compared transmission characteristics for prions from L-type bovine spongiform encephalopathy and MM2-cortical sporadic Creutzfeldt-Jakob disease in the Syrian golden hamster and an ovine prion protein-transgenic mouse line and isolated distinct prion strains. Our findings suggest the absence of a causal relationship between these diseases, but further investigation is warranted.
... factors, measures to prevent the introduction and transmission of BSE, and other information relevant to... bovine spongiform encephalopathy (BSE)-related restrictions applicable to FDA-regulated human food and... efficient enforcement of section 801 of the FD&C Act. To address the potential risk of BSE in human food...
Raamsdonk, van L.W.D.; Pinotti, L.; Veys, P.; Bremer, M.G.E.G.; Hekman, W.E.; Kemmers-Voncken, A.E.M.; Campagnoli, A.; Paltanin, C.; Crespo, C.; Vliege, J.J.M.; Pinckaers, V.G.Z.; Jorgensen, J.S.
The official control of animal proteins in feed is focused on the prevention of Bovine Spongiform Encephalopathy (mad cow disease). The current legislation of the European Union is planned to avoid the feeding of animal by-products to the same species as its origin (ban of cannibalism, or species-to
Brandel, J.P.; Heath, C.A.; Head, M.W.; Levavasseur, E.; Knight, R.; Laplanche, J.L.; Langeveld, J.P.M.; Ironside, J.W.; Hauw, J.J.; Mackenzie, J.; Alperovitch, A.; Will, R.G.; Haik, S.
Objective: Variant Creutzfeldt-Jakob disease (vCJD) was first reported in the United Kingdom in 1996. Since then, the majority of cases have been observed in the United Kingdom where there was a major epidemic of bovine spongiform encephalopathy. France was the second country affected. To address th
A naturally occurring prion disease has not been recognized in swine, but the agent of bovine spongiform encephalopathy does transmit to swine by experimental routes. Swine are thought to have a robust species barrier when exposed to the naturally occurring prion diseases of other species, but the s...
Bouzalas, I.; Lörtscher, F.; Dovas, C.; Oevermann, A.; Langeveld, J.P.M.; Papanastassopoulou, M.; Papadopoulos, O.; Zurbriggen, A.; Seuberlich, T.
Considerable efforts have been directed toward the identification of small-ruminant prion diseases, i.e., classical and atypical scrapie as well as bovine spongiform encephalopathy (BSE). Here we report the in-depth molecular analysis of the proteinase K-resistant prion protein core fragment (PrPres
The association between bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) has demonstrated that cattle TSEs can pose a risk to human health and raises the possibility that other ruminant TSEs may be transmissible to humans. In recent years, several new TSEs in shee...
Langeveld, J.P.M.; Jacobs, J.G.; Erkens, J.H.F.; Baron, T.; Andreoletti, O.; Yokoyama, T.; Keulen, van L.J.M.; Zijderveld, van F.G.; Davidse, A.; Hope, J.; Tang, Y.; Bossers, A.
Efforts to differentiate bovine spongiform encephalopathy (BSE) from scrapie in prion infected sheep have resulted
in effective methods to decide about the absence of BSE. In rare instances uncertainties remain due to assumptions
that BSE, classical scrapie and CH1641–a rare scrapie variant–
Langeveld, J.P.M.; Jacobs, J.G.; Erkens, J.H.F.; Bossers, A.; Zijderveld, van F.G.; Keulen, van L.J.M.
Background Diagnosis based on prion detection in lymph nodes of sheep and goats can improve active surveillance for scrapie and, if it were circulating, for bovine spongiform encephalopathy (BSE). With sizes that allow repetitive testing and a location that is easily accessible at slaughter, retroph
... where classical swine fever exists. 94.9 Section 94.9 Animals and Animal Products ANIMAL AND PLANT... FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY: PROHIBITED AND RESTRICTED IMPORTATIONS § 94.9 Pork and pork products from regions where classical swine...
... swine fever exists. 94.10 Section 94.10 Animals and Animal Products ANIMAL AND PLANT HEALTH INSPECTION... PRODUCTS RINDERPEST, FOOT-AND-MOUTH DISEASE, EXOTIC NEWCASTLE DISEASE, AFRICAN SWINE FEVER, CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY: PROHIBITED AND...
... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Disposal of animals, meats, and other..., CLASSICAL SWINE FEVER, SWINE VESICULAR DISEASE, AND BOVINE SPONGIFORM ENCEPHALOPATHY: PROHIBITED AND RESTRICTED IMPORTATIONS § 94.7 Disposal of animals, meats, and other articles ineligible for importation....
E.A. Croes (Esther); C.M. van Duijn (Cock)
textabstractA variant form of Creutzfeldt-Jakob disease (vCJD) has had major impact in Europe during the last decade. In this article, we review the aetiology of vCJD and its relation with bovine spongiform encephalopathy. Further, treatment of the disease, the strategies focusing on prevention of t
Kramer, G.N.; Pauwels, J.; Le Guern, L.; Schimmel, H.; Trapmann, S. [Commission of the European Communities, Geel (Belgium). Joint Research Centre
In the execution of its mission to promote a common European measurement system in support of EU policies, IRMM's Reference Materials Unit is currently involved in preparation of proficiency-testing samples and candidate reference materials. Recent work related to bovine spongiform encephalopathy in cows, genetically modified organisms, and a variety of environmental materials is described. (orig.)
Böhning, Dankmar; Greiner, Matthias
Substantial resources are used for surveillance of bovine spongiform encephalopathy (BSE) despite an extremely low detection rate, especially in healthy slaughtered cattle. We have developed a method based on the geometric waiting time distribution to establish and update the statistical evidence...
Gerischer, C.N. [E.ON Kraftwerke GmbH, Kraftwerksgruppe Ingolstadt/Irsching, Grossmehring (Germany)
In 2001 the market was overflowing with animal fat due to the discussion about the bovine spongiform encephalopathy disease. One solution was the use as additional fuel in power plants. The fundamental technical requirements existed in Ingolstadt power station. Economical considerations led to the decision to test animal fat as added fuel. The main experiences are presented and discussed. (orig.)
Animal feed with meat and bone meal (MBM) has been the source of bovine spongiform encephalopathy (BSE) in cattle and other livestock animals. Many countries have banned the use MBM as an animal feed ingredient. Spectral imaging techniques have shown potential for rapid assessment and authentication...
Meat & bone meal (MBM) is a high-protein commodity produced by the rendering of fat from unmarketable animal tissue. Concerns related to bovine spongiform encephalopathy have progressively restricted MBM’s conventional use as a feed ingredient. Consequently, significant attention has focused on th...
Vos, de C.J.; Heres, L.
The total ban on use of meat and bone meal (MBM) in livestock feed has been very successful in reducing bovine spongiform encephalopathy (BSE) spread, but also implies a waste of high-quality proteins resulting in economic and ecological loss. Now that the BSE epidemic is fading out, a partial lifti
Chiappini, B.; Brambilla, G.; Agrimi, U.; Vaccari, G.; Aarts, H.J.M.; Berben, G.; Frezza, D.; Giambra, V.
The use of ruminant-derived proteins in ruminant feeds has been banned in both the European Union and the United States to prevent further spread of bovine spongiform encephalopathy. Enforcement of these regulations relies on the ability to identify the presence of prohibited proteins in feed. We de
Mendoza - Romero, L.; Verkaar, E.L.C.; Savelkoul, P.H.; Catsburg, A.; Aarts, H.J.M.; Buntjer, J.B.; Lenstra, J.A.
To control the spread of bovine spongiform encephalopathy, several DNA methods have been described for the detection of the species origin of meat and bone meal. Most of these methods are based on the amplification of a mitochondrial DNA segment. We have developed a semiquantitative method based on
Prado, M.; Berben, G.; Fumière, O.; Duijn, G. van; Mensinga-Kruize, J.; Reaney, S.; Boix, A.; Holst, C. von
The commercialization of animal feeds infected by prions proved to be the main cause of transmission of bovine spongiform encephalopathy (BSE). Therefore, feed bans were enforced, initially for ruminant feeds, and later for all feeds for farmed animals. The development and validation of analytical m
Worley Kim C
Full Text Available Abstract The draft genome sequence of cattle (Bos taurus has now been analyzed by the Bovine Genome Sequencing and Analysis Consortium and the Bovine HapMap Consortium, which together represent an extensive collaboration involving more than 300 scientists from 25 different countries.
Full Text Available Os príons são proteínas que se mostram capazes de auto-replicação apesar de, para isso, alterar o metabolismo celular. São responsáveis por inúmeras doenças em animais e no ser humano (doenças priônicas, todas elas fatais. Essas moléstias apresentam enorme variabilidade quanto ao período de incubação, de alguns meses a 40 anos. Os príons acumulam-se e destroem os neurônios, provocando quadros conhecidos como encefalopatias espongiosiformes. Discute-se a apresentação clínica, epidemiológica e histórica das doenças priônicas. O foco maior de discussão recai, no entanto, na possibilidade teórica da transmissão iatrogênica dos príons por meio das formulações tópicas que utilizam ceramidas (cerebrosídeos ou placenta de origem bovina, assim como pelo risco representado por alguns procedimentos dermatológicos, como transplantes da pele e implantes de colágeno.A prion is a protein that is capable of self replication, thereby altering a cell's metabolism. It is responsible for a number of human and animal diseases (prionic diseases, all of which are always lethal. These diseases have enormous variability in their incubation periods, ranging from a few months to forty years. Prions accumulate and destroy nerve cells, causing spongiform encephalopathy. We discuss the clinical picture, epidemiology, and historical background of prionic diseases. The major focus of the discussion lies, however, on the theoretical possibility of iatrogenic transmission of prion infection due to topical formulations using ceramides (cerebrosides or placenta of bovine origin, as well as the risk represented by some dermatological procedures such as skin grafts and collagen implants.
Gluud, Lise Lotte; Dam, Gitte; Les, Iñigo;
-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through...
McKee, Ann C.; Stein, Thor D.; Nowinski, Christopher J.; Stern, Robert A.; Daneshvar, Daniel H.; Alvarez, Victor E.; Lee, Hyo-Soon; Hall, Garth; Wojtowicz, Sydney M.; Baugh, Christine M.; Riley, David O.; Kubilus, Caroline A.; Cormier, Kerry A.; Jacobs, Matthew A.; Martin, Brett R.; Abraham, Carmela R.; Ikezu, Tsuneya; Reichard, Robert Ross; Wolozin, Benjamin L.; Budson, Andrew E.; Goldstein, Lee E.; Kowall, Neil W.; Cantu, Robert C.
Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging…
Le diagnostic des Encéphalopathies Spongiformes Transmissibles (EST) des ruminants est aujourd’hui basé sur la mise en évidence de l’isoforme pathologique, résistante à la protéinase K, de la protéine PrP, la PrPres. La PrPres peut être mise en évidence in situ, à l’aide de techniques immunohistochimiques ou, bien après extraction et traitement à la protéinase K, par des techniques immunochimiques (western blot, Enzyme Linked ImmunoSorbent Assay). Si le diagnostic de routine des encéphalopath...
Langholm Jensen, Jesper; Mølgaard, Anne; Navarro Poulsen, Jens Christian;
Bovine and camel chymosin are aspartic peptidases that are used industrially in cheese production. They cleave the Phe105-Met106 bond of the milk protein κ-casein, releasing its predominantly negatively charged C-terminus, which leads to the separation of the milk into curds and whey. Despite...... having 85% sequence identity, camel chymosin shows a 70% higher milk-clotting activity than bovine chymosin towards bovine milk. The activities, structures, thermal stabilities and glycosylation patterns of bovine and camel chymosin obtained by fermentation in Aspergillus niger have been examined...... interactions arising from variation in the surface charges and the greater malleability both in domain movements and substrate binding contribute to the better milk-clotting activity of camel chymosin towards bovine milk....
Amlan Kanti Biswas
Full Text Available Hepatic encephalopathy is a frequent and often fatal manifestation of chronic liver disease. The pathogenesis of hepatic encephalopathy is believed to be multifactorial including impaired blood-brain barrier function, imbalance between the excitatory and inhibitory neurotransmitters in cortex, accumulation of various toxic and false neurotransmitters, and lack of nutrients like oxygen and glucose. Signs and symptoms of hepatic encephalopathy varies and commonly ranges from personality changes, disturbed consciousness, sleep pattern alternation, intellectual deterioration, speech disturbances, asterixis to frank coma and even death. Reversible or transient cortical blindness is rare manifestation of hepatic encephalopathy. It may even precede the phase of altered consciousness in such patients. Very few similar cases have been reported worldwide. Hence, we would like to report a case of transient cortical blindness in a patient of hepatic encephalopathy.
Hiroto Tanaka; Hiroki Ueda; Yohei Kida; Hiroko Hamagami; Tomikimi Tsuji; Masakazu Ichinose
A 62-year-old male with decompensated liver cirrhosis due to hepatitis C virus developed severe hepatic encephalopathy with status epileptic us. The blood ammonia level on admission was more than twice the normal level. Brain computed tomography and magnetic resonance imaging were normal. In addition, electroencephalogram showed diffuse sharp waves, consistent with hepatic encephalopathy. The status epilepticus was resolved after antiepileptic therapy (phenytoin sodium) and treatment for hepatic encephalopathy (Branched chain amino acids). The blood ammonia level normalized with the clinical improvement and the patient did not have a recurrence of status epilepticus after the end of the antiepileptic treatment. Additionally, the electroencephalogram showed normal findings. Thus, we diagnosed the patient as hepatic encephalopathy with status epilepticus. We consider the status epilepticus of this patient to a rare and interesting finding in hepatic encephalopathy.
Metabolic encephalopathy is a clinical syndrome which describes a state of global cerebral dysfunction induced by many different metabolic disturbances.Organic acids disorders,hepatic encephalopathy,uremic encephalopathy and its dialysis disequilibrium posterior,reversible leukoencephalopathy syndrome,Hashimoto encephalopathy,acute adrenal failure and encephalopathy due to electrolyte disturbances were reviewed.%代谢性脑病是由不同代谢障碍引起全脑功能紊乱的一种临床综合征.本文就有机酸代谢障碍、肝性脑病、尿毒症性脑病及其血透后脑病、可逆性大脑后部白质脑病、Hashimoto脑病和电介质失衡脑病的临床表现和神经影像学进行讨论.
Garten, Lars; Hueseman, Dieter; Stoltenburg-Didinger, Gisela; Felderhoff-Mueser, Ursula; Weizsaecker, Katharina; Scheer, Ianina; Boltshauser, Eugen; Obladen, Michael
Progressive multicystic encephalopathy following prenatal or perinatal hypoxia-ischemia is a well-described phenomenon in the literature. The authors report on a term infant with a devastating encephalopathy and severe neuronal dysfunction immediately after delivery without a known antecedent of prenatal or perinatal hypoxia or distress. Clinical and paraclinical findings in the patient are compared with those described in the literature. The authors focus on the specific results guiding to the final diagnosis of progressive multicystic encephalopathy and the timing of morphologic changes. As in this case, if the criteria of an acute hypoxic event sufficient to cause neonatal encephalopathy are not met, then factors other than hypoxia-ischemia may be leading to progressive multicystic encephalopathy.
V. A. Tumanskiy
Full Text Available On the basis of the literary data and conducted large-scale research it was ascertained that diabetes mellitus raises the risk of cerebral stroke in 2-6 times, the risk of transitional ischemic attacks in 3 times in comparison with the same risk in the general population . Diabetic encephalopathy in its pure form can be found in 80.7% of patients with diabetes mellitus of the 1st type, its development is caused mainly by ineffective metabolic control of autoregulation of cerebral blood flow . Mixed encephalopathy is prevailed among patients with diabetes mellitus of the 2nd type; lacunar heart attack is more often developed among this category of patients , multiple focus of ischemic affection of white substance – leukoaraiosis regarded as the areas of increased level of water, gliosis, and demyelination of white substance is often registered . Pathogeny of diabetic encephalopathy hasn’t been studied properly. It is known that it is a multifactor effect in the development of which the main role is led by the vascular dysfunction with the reduction of blood supply and ischemia of brain tissue, as well as direct toxic influence of hyperglycemia and disorder of trophism of nerve tissue . Microangiopathy and macroangiopathy acquire the special meaning in encephalopathy development among patients with diabetes mellitus. The evidence of microangiopathy and macroangiopathy is identified by the disease course and prognosis. On the ultrastructural level the changes of vessel microcircular movement are registered on the 1st month of the experimental alloxan diabetes. During electronic microscopy the thickening of basal membrane of capillaries as well as their dissection is observed. In micro vessels such phenomena as precipitation of lipoproteids, raising of the synthesis of collagen (the second type, dystrophic changes of endotheliocytes, and lowering of micropinocytosis can be found [11,12,13,14]. As the severity of diabetes mellitus
Guo-Hui Sun; Yun-Sheng Yang; Qing-Sen Liu; Liu-Fang Cheng; Xu-Sheng Huang
AIM: To investigate clinical characteristics and therapy of pancreatic encephalopathy (PE) and Wernicke encephalopathy (WE).METHODS: In a retrospective study of 596 patients with acute pancreatitis (AP), patients with PE were compared to those with WE in regards to history, clinical manifestation, diagnosis, treatment and outcome.RESULTS: There were 93 patients with severe acute pancreatitis (SAP). Encephalopathies were discovered in 10 patients (1.7%). Six patients with PE all developed in SAP (6.5%), and three of them died (3% of SAP, 50% of PE). Four patients with WE developed in AP (0.7%),and two of them died (0.3% of AP, 50% of WE). Two patients with WE were treated with parenteral thiamine and survived. Global confusions were seen in all patients with encephalopathy. Ocular abnormalities were found.Conjugate gaze palsies were seen in 1 of 6 (16.7%)patients with PE. Of 4 patients with WE, one (25%)had conjugate gaze palsies, two (50%) had horizontal nystagmus, three (75%) had diplopia, and one (25%)had myosis. Ataxia was not seen in all patients. None of patients with WE presented with the classic clinical triad.CSF examinations for 2 patients with WE showed lightlyincreased proteins and glucose. CT and MRI of the brain had no evidence of characteristic abnormalities.CONCLUSION: PE occurs in early or reiteration stage of SAP, and WE in restoration stage of SAP/AR Ocular abnormalities are the hallmarks of WE, and horizontal nystagmus is common. It is difficult to diagnose earlier an encephalopathy as PE or WE, as well as differentiate one from the other. Long fasting, hyperemesis and total parenteral nutrition (TPN) without thiamine are main causes of thiamine deficiency in the course of pancreatitis.
al. Immunization with amyloid-β attenuates Alzheimer -disease-like pathology in the PDAPP mouse. Nature 400, 173–177 (1999). 83. Orgogozo, J. M. et al...pathways using the most powerful genetic tools available to biology. By reconstructing essential steps in Alzheimer ’’s pathology, such as amyloid (3...anti-TSE activity. Notably, aluminum (III) phthalocyanine tetrasulfonate was both the poorest anti-TSE compound and the least prone to oligomerization in
Salgado, Melissa; Cortes, Yonaira
Hepatic encephalopathy (HE) is a manifestation of clinical signs that may result from a variety of liver diseases. In small animals, HE is most commonly a result of portosystemic shunting. The pathogenesis is not completely understood, although it is likely multifactorial. Theories of pathogenesis include altered ammonia metabolism and glutamine and glutamate transmission, an increase in gamma-aminobutyric acid agonists and benzodiazepine-like substances, alterations of the serotonergic system and amino acid metabolism, elevated taurine levels, contributions from inflammatory mediators, and toxic effects of manganese. An understanding of the underlying mechanisms that result in HE may lead to new treatments in the future.
Severe perinatal asphyxia with hypoxic ischaemic encephalopathy occurs in approximately 1-2\\/1000 live births and is an important cause of cerebral palsy and associated neurological disabilities in children. Multiorgan dysfunction commonly occurs as part of the asphyxial episode, with cardiovascular dysfunction occurring in up to a third of infants. This narrative paper attempts to review the literature on the importance of early recognition of cardiac dysfunction using echocardiography and biomarkers such as troponin and brain type natriuretic peptide. These tools may allow accurate assessment of cardiac dysfunction and guide therapy to improve outcome.
Gauthier, Angela C; Baehring, Joachim M
Hashimoto's encephalopathy is a rare, imprecisely defined autoimmune neurologic syndrome associated with Hashimoto's thyroiditis that normally responds to corticosteroids. Here, we describe the case of a 55-year-old woman who presented with subacute cognitive decline and ataxia. Neoplastic, paraneoplastic, infectious, and metabolic etiologies were ruled out. Anti-TPO antibody level was markedly elevated at 966U/mL. After one month of 60mg/day of oral prednisone, she felt back to baseline and her Montreal Cognitive Assessment dramatically improved. Physicians should strongly consider this uncommon diagnosis in patients with rapid cognitive decline and no other clear etiology.
Bandyopadhyay, Sabyasachi; Mondal, Kanchan Kumar; Das, Somnath; Gupta, Anindya; Biswas, Jaya; Bhattacharyya, Subir Kumar; Biswas, Gautam
Cortical blindness is defined as visual failure with preserved pupillary reflexes in structurally intact eyes due to bilateral lesions affecting occipital cortex. Bilateral oedema and infarction of the posterior and middle cerebral arterial territory, trauma, glioma and meningioma of the occipital cortex are the main causes of cortical blindness. Posterior reversible encephalopathy syndrome (PRES) refers to the reversible subtype of cortical blindness and is usually associated with hypertension, diabetes, immunosuppression, puerperium with or without eclampsia. Here, 3 cases of PRES with complete or partial visual recovery following treatment in 6-month follow-up are reported.
Wellenberg, Gerardus Johannus
Mastitis is an often occurring disease in dairy cattle with an enormous economic impact for milk producers worldwide. Despite intensive research, which is historically based on the detection of bacterial udder pathogens, still around 20-35% of clinical cases of bovine mastitis have an unknown aetiol
Spiropoulos, John; Lockey, Richard; Sallis, Rosemary E; Terry, Linda A; Thorne, Leigh; Holder, Thomas M; Beck, Katy E; Simmons, Marion M
Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that include variant Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform encephalopathy (BSE) in cattle. Scrapie is not considered a public health risk, but BSE has been linked to variant Creutzfeldt-Jakob disease. Small ruminants are susceptible to BSE, and in 2005 BSE was identified in a farmed goat in France. We confirm another BSE case in a goat in which scrapie was originally diagnosed and retrospectively identified as suspected BSE. The prion strain in this case was further characterized by mouse bioassay after extraction from formaldehyde-fixed brain tissue embedded in paraffin blocks. Our data show that BSE can infect small ruminants under natural conditions and could be misdiagnosed as scrapie. Surveillance should continue so that another outbreak of this zoonotic transmissible spongiform encephalopathy can be prevented and public health safeguarded.
Full Text Available DEFINITION Ohtahara syndrome (early infantile epileptic encephalopathy with suppression bursts, is the earliest developing form of epileptic encephalopathy. ETHIOLOGY It considered to be a result of static structural developing brain damage. CLINICAL PICTURE Variable seizures develop mostly within the first 10 days of life, but may occur during the first hour after delivery. The most frequently observed seizure type are epileptic spasms, which may be either generalized and symmetrical or lateralized. The tonic spasms may occur in clusters or singly, while awake and during sleep alike. The duration of spasms is up to 10 seconds, and the interval between spasms within cluster ranges from 9 to 15 seconds. In one third of cases, other seizure types include partial motor seizures or hemiconvulsions The disorder takes a progressively deteriorating course with increasing frequency of seizures and severe retardation of psychomotor development. DIAGNOSTIC WORKUP In the initial stage of Ohtahara syndrome, interictal EEG shows a pattern of suppression-burst with high-voltage paroxysmal discharges separated by prolonged periods of nearly flat tracing that last for up to 18 seconds. PROGNOSIS AND THREATMENT Half of the reported children having Ohtahara syndrome die in infancy. Anticonvulsant helps little in controlling the seizures and halting the deterioration of psychomotor development. Severe psychomotor retardation is the rule. With time, the disorder may evolve into West syndrome or partial epilepsy. Psychomotor development may be slightly better if the infants do not develop West and later Lennox-Gastaut syndrome.
Full Text Available Vijay PB Grover, Joshua M Tognarelli, Nicolas Massie, Mary ME Crossey, Nicola A Cook, Simon D Taylor-Robinson Liver Unit, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK Abstract: Hepatic encephalopathy is a common neuropsychiatric abnormality, which complicates the course of patients with liver disease. It was probably first described by Hippocrates over 2000 years ago, who said that "those whose madness arises from phlegm are quiet and neither shout nor make a disturbance, while those whose madness arises from bile shout, play tricks and will not keep still, but are always up to some mischief". He was presumably describing the differences between patients with pneumonia and acute liver failure. Despite the fact that the syndrome was probably first recognized thousands of years ago, the exact pathogenesis still remains unclear. Furthermore, a precise definition of the syndrome is lacking, as are definitive methods of diagnosing this condition. It is important as both patients with cirrhosis and the general population with whom they interact may be affected as a consequence. At a minimum, the individual may be affected by impaired quality of life, impaired ability to work, and slowed reaction times, which are relevant to the population at large if affected individuals operate heavy machinery or drive a car. Pathogenic mechanisms, diagnostic tools, and treatment options are discussed. Keywords: hepatic encephalopathy, cirrhosis, ammonia, pathology, treatment, rifaximin, lactulose
Bigatello, L M; Broitman, S A; Fattori, L; Di Paoli, M; Pontello, M; Bevilacqua, G; Nespoli, A
Endotoxemia without sepsis was detected with a chromogenic Limulus assay in 36 of 39 (92.3%) cirrhotic patients and was absent in seven healthy volunteers. In 11 patients who underwent elective portasystemic shunt, portal vein endotoxemia was higher than inferior vena caval: p less than 0.05, systemic endotoxin levels did not change, compared to preoperative levels, on the 1st, 2nd, and 3rd postoperative days, attendant to an uneventful recovery. In 21 patients in hepatic encephalopathy after esophagogastric hemorrhage, systemic endotoxemia was higher than in well-compensated cirrhotics: p less than 0.001; it was higher in deep than in light coma: p less than 0.05; it was higher in those who died than in those who survived: p less than 0.001. Endotoxin levels showed a positive correlation with serum bilirubin: r = 0.59, p less than 0.001, and a negative correlation with prothrombin activity: r = -0.59, p less than 0.001. These data show endotoxemia without sepsis is a constant finding in cirrhosis and increasing levels of endotoxemia are associated with hepatic failure, encephalopathy, and death.
Gospe, Sidney M
The treatment of neonatal seizures generally relies on the use of one or more anticonvulsant medications along with evaluation and management of any underlying etiology. In some circumstances, neonatal seizures are refractory to therapy and result in poor outcomes, including death. Certain rare vitamin- responsive inborn errors of metabolism may present as neonatal encephalopathy with anticonvulsant-resistant seizures. Therefore, it is vital for the clinicians of caring for seizing encephalopathic newborns to consider these particular disorders early in the hospital course. Pyridoxine-dependent seizures are due to deficiency of alpha-aminoadipic semialdehyde dehydrogenase (antiquitin) which is encoded by ALDH7A1. Seizures in infants who are pyridoxine-dependent must be treated using pharmacologic doses of pyridoxine (vitamin B(6)), and life-long therapy is required. Despite medical therapy, developmental handicaps, particularly in expressive language, are common. Folinic acidresponsive seizures are treated with supplements of folinic acid (5-formyltetrahydrofolate). Recently, patients with this condition were also demonstrated to be antiquitin deficient. Pyridoxal phosphate-dependent seizures result from a deficiency of pyridox(am)ine 5'-phosphate oxidase which is encoded by PNPO. Patients with this cause of seizures respond to pyridoxal phosphate but not to pyridoxine. This review discusses our current understanding of these three neonatal vitamin-responsive epileptic encephalopathies and a diagnostic and treatment protocol is proposed.
Stawicka, Agnieszka; Zbrzeźniak, Justyna; Świderska, Aleksandra; Kilisińska, Natalia; Świderska, Magdalena; Jaroszewicz, Jerzy; Flisiak, Robert
Minimal hepatic encephalopathy (MHE) encompasses a number of neuropsychological and neurophysiological disorders in patients suffering from liver cirrhosis, who do not display abnormalities during a medical interview or physical examination. A negative influence of MHE on the quality of life of patients suffering from liver cirrhosis was confirmed, which include retardation of ability of operating motor vehicles and disruption of multiple health-related areas, as well as functioning in the society. The data on frequency of traffic offences and accidents amongst patients diagnosed with MHE in comparison to patients diagnosed with liver cirrhosis without MHE, as well as healthy persons is alarming. Those patients are unaware of their disorder and retardation of their ability to operate vehicles, therefore it is of utmost importance to define this group. The term minimal hepatic encephalopathy (formerly "subclinical" encephalopathy) erroneously suggested the unnecessity of diagnostic and therapeutic procedures in patients with liver cirrhosis. Diagnosing MHE is an important predictive factor for occurrence of overt encephalopathy - more than 50% of patients with this diagnosis develop overt encephalopathy during a period of 30 months after. Early diagnosing MHE gives a chance to implement proper treatment which can be a prevention of overt encephalopathy. Due to continuing lack of clinical research there exist no commonly agreed-upon standards for definition, diagnostics, classification and treatment of hepatic encephalopathy. This article introduces the newest findings regarding the importance of MHE, scientific recommendations and provides detailed descriptions of the most valuable diagnostic methods.
Vidal, E; Tortosa, R; Marco, P; Fondevila, D; Rabanal, R M; Torres, J M; Pumarola, M
A DNA microarray-based gene expression analysis study was performed with bovine spongiform encephalopathy (BSE) transgenic mice. Several genes were found to be overexpressed including the lysosomal enzyme cathepsin C, the chemokine CXCL13 and a number of genes related to cellular proliferation. The brains from terminal stage, BSE inoculated, 'bovinized', transgenic mice were subjected to immunohistochemistry with antibodies against these two proteins and Ki-67, a cell proliferation marker, to assess the biological relevance of the gene expression changes. Differential expression of cathepsin C and CXCL13 proteins and increased expression of Ki-67 was observed. These changes were localized to areas of deposition of PrP(res) and spongiform change and to areas showing an astroglial and microglial response. These findings suggest that these proteins are involved in the mechanisms leading to the establishment of transmissible spongiform encephalopathy.
Full Text Available The aim of this study was to determine the clinical characteristics and poor prognostic factors associated with high mortality in dengue encephalopathy. Fifteen patients with confirmed dengue infections, who developed encephalopathy, were recruited from two tertiary care hospitals in Colombo, Sri Lanka. Among the factors that contributed to encephalopathy were: Acute liver failure (73%, electrolyte imbalances (80% and shock (40%. Five (33.3% patients developed seizures. Disseminated intravascular coagulation was seen in five (33.3%. Secondary bacterial infections were observed in 8 (53.3% of our patients. The overall mortality rate was 47%.
Kandiah, Prem A; Kumar, Gagan
Hepatic encephalopathy occurs ubiquitously in all causes of advanced liver failure, however, its implications on mortality diverge and vary depending upon acuity and severity of liver failure. This associated mortality has decreased in subsets of liver failure over the last 20 years. Aside from liver transplantation, this improvement is not attributable to a single intervention but likely to a combination of practical advances in critical care management. Misconceptions surrounding many facets of hepatic encephalopathy exists due to heterogeneity in presentation, pathophysiology and outcome. This review is intended to highlight the important concepts, rationales and strategies for managing hepatic encephalopathy.
Cash, W J
Hepatic encephalopathy (HE) is defined as a metabolically induced, potentially reversible, functional disturbance of the brain that may occur in acute or chronic liver disease. Standardized nomenclature has been proposed but a standardized approach to the treatment, particularly of persistent, episodic and recurrent encephalopathy associated with liver cirrhosis has not been proposed. This review focuses on the pathogenesis and treatment of HE in patients with cirrhosis. The pathogenesis and treatment of hepatic encephalopathy in fulminant hepatic failure is quite different and is reviewed elsewhere.
Kimer, Nina; Krag, Aleksander; Gluud, Lise L
Hepatic encephalopathy is a complex disease entity ranging from mild cognitive dysfunction to deep coma. Traditionally, treatment has focused on a reduction of ammonia through a reduced production, absorption, or clearance. Rifaximin is a nonabsorbable antibiotic, which reduces the production of ...... and safety of long-term treatment with rifaximin and evaluate effects of combination therapy with lactulose and branched-chain amino acids for patients with liver cirrhosis and hepatic encephalopathy.......Hepatic encephalopathy is a complex disease entity ranging from mild cognitive dysfunction to deep coma. Traditionally, treatment has focused on a reduction of ammonia through a reduced production, absorption, or clearance. Rifaximin is a nonabsorbable antibiotic, which reduces the production...
Vierling, John M
Both covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE) impair the ability to operate machinery. The legal responsibilities of US physicians who diagnose and treat patients with hepatic encephalopathy vary among states. It is imperative that physicians know the laws regarding reporting in their state. OHE represents a neuropsychiatric impairment that meets general reporting criteria. The medical advisory boards of the states have not identified OHE as a reportable condition. In the absence of validated diagnostic guidelines, physicians are not obligated to perform tests for CHE. There is a need for explicit guidance from professional associations regarding this issue.
Basu, P Patrick; Shah, Niraj James
Hepatic encephalopathy (HE) shows a wide spectrum of neuropsychiatric manifestations. A combined effort with neuropsychological and psychometric evaluation has to be performed to recognize the syndrome, whereas minimal HE (MHE) is largely under-recognized. Subtle symptoms of MHE can only be diagnosed through specialized neuropsychiatric testing. Early diagnosis and treatment may drastically improve the quality of life for many cirrhotic patients. Further research to gain better insight into the pathophysiology and diagnostic accuracy of HE will help determine future management strategies.
Leise, Michael D; Poterucha, John J; Kamath, Patrick S; Kim, W Ray
Hepatic encephalopathy (HE) develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis. With the goal of reviewing the evidence for treatment and prevention of overt hepatic encephalopathy, pubmed was searched using search terms hepatic encephalopathy AND treatment, limited to human studies from January 1, 2003, through December 1, 2013, and supplemented by key references. The inpatient incidence of HE is approximately 23,000 annually, and management of these patients is common for internists and subspecialists. Treatment of the hospitalized patient with HE has changed in recent years. Treatment entails 2 phases: induction and maintenance of remission. Most cases of significant HE are precipitated by infection, gastrointestinal bleeding, medications, or other culprits. All patients should be evaluated for secondary triggers of HE, and treatment should be initiated with a nonabsorbable disaccharide (ie, lactulose) in most patients. Rifaximin (off label) can be added in patients not responding to lactulose. Neomycin is a less preferred alternative to rifaximin owing to its adverse effect profile. Other therapies, including zinc, L-ornithine-L-aspartate, and branched-chain amino acids, can be considered for patients not responding to disaccharides and nonabsorbable antibiotics. Large portosystemic shunts may be embolized in patients with medically refractory recurrent or severe HE with otherwise well-compensated cirrhosis. Molecular Adsorbent Recirculating System is now available for patients with severe HE who do not respond to medical therapy. It is critically important that patients hospitalized with significant HE continue maintenance therapy at the time of dismissal to prevent further episodes. Patients with a first-time episode of HE can be administered lactulose, and careful instructions should be provided to patients and caregivers about dose titration to achieve 3 bowel movements daily. Patients with recurrent HE episodes
Mohammad Reza SALEHIOMRAN
Full Text Available How to Cite this Article: Salehi Omran MR, Nooreddini H, Baghdadi F. Acute Necrotizing Encephalopathy of Childhood; A Case Report. Iran J Child Neurol. 2013 Spring;7(2:51-54. AbstractAcute Necrotizing Encephalopathy of Childhood (ANEC is an atypical disease followed by respiratory or gastrointestinal infection, high fever, which is accompanied with rapid alteration of consciousness and seizures. This disease is seen nearly exclusively in East Asian infants and children who had previously a good health. Serial MRI examinations demonstrated symmetric lesions involving the thalami, brainstem, cerebellum, and white matter. This disease has a poor prognosis, often culminating in profound morbidity and mortality. A 22-month infant with ANEC hospitalized in Amirkola Children Hospital has been evaluated. References1. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan. Brain Dev. 1997 Mar;19(2:81-92. Review.2. Wang HS, Huang SC. Acute necrotizing encephalopathy of childhood. Chang Gung Med J 2001 Jan;24(1:1-10.3. Campistol J, Gassió R, Pineda M, Fernandez-Alvarez E. Acute necrotizing encephalopathy of childhood (infantile bilateral thalamic necrosis: two non-Japanese cases. Dev Med Child Neurol 1998 Nov;40(11:771-4.4. Ito Y, Ichiyama T, Kimura H, Shibata M, Ishiwada N, Kuroki H, Furukawa S, Morishima T. Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory cytokines in influenza-virus-associated encephalopathy. J Med Virol 1999 Aug;58(4:420-5.5. Sugaya N. Influenza-associated encephalopathy in Japan. Semin Pediatr Infect Dis 2002 Apr;13(2:79-84. Review.6. Skelton BW, Hollingshead MC, Sledd AT, Phillips CD, Castillo M. Acute necrotizing encephalopathy of childhood: typical findings in an atypical disease. Pediatr Radiol 2008 Jul; 38(7:810-3.7. Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute necrotizing encephalopathy of childhood
D V Neverovsky
Full Text Available The differential diagnosis of dyscirculatory encephalopathy is one of the topical problems in Russian neurology. Forty-seven patients diagnosed with dyscirculatory encephalopathy and followed up in the polyclinic were examined. Only in 9 (19.2% of them, the diagnosis was confirmed. Most patients were established to have other diseases, among which there were primary depressive and/or anxiety disorders (34%, primary headache (23.4, benign paroxysmal positional vertigo (BPPV (8.5%, and Alzheimer’s disease (10.6%. The paper describes patients with migraine and BPPV, in whom the detection and treatment of these diseases have yielded a positive effect. The examination of patients diagnosed with dyscirculatory encephalopathy with investigations of their cognitive and emotional functions, otoneurological examination, and psychiatric consultation (if indicated makes it possible to identify other diseases presenting with the symptoms similar to dyscirculatory encephalopathy and to prescribe effective treatments.
The presence of hepatic encephalopathy (HE) within 4 weeks is part of the criteria for defining acute-on-chronic liver failure (ACLF). The pathophysiology of HE is complex, and hyperammonemia and cerebral hemodynamic dysfunction appear to be central in the pathogenesis of encephalopathy. Recent data also suggest that inflammatory mediators may have a significant role in modulating the cerebral effect of ammonia. Multiple prospective and retrospective studies have shown that hepatic encephalopathy in ACLF patients is associated with higher mortality, especially in those with grade III-IV encephalopathy, similar to that of acute liver failure (ALF). Although significant cerebral edema detected by CT in ACLF patients appeared to be less common, specialized MRI imaging was able to detect cerebral edema even in low grade HE. Ammonia-focused therapy constitutes the basis of current therapy, as in the treatment of ALF. Emerging treatment strategies focusing on modulating the gut-liver-circulation-brain axis are discussed.
Stephan vom Dahl; Gerald Kircheis; Dieter Haussinger
@@INTRODUCTION Hepatic encephalopathy ( HE) is a frequent complication of chronic liver disease .It is defined as a characteristic functional and reversible alteration of the mental state ,due to impaired liver function and / or increased portosystemic shunting .
Mariano Malaguarnera; Giovanni Pistone; Rampello Elvira; Carmelo Leotta; Linda Scarpello; Rampello Liborio
AIM: To evaluate the influence of L-carnitine on mental conditions and ammonia effects on patients with hepatic encephalopathy (HE).METHODS: One hundred and fifty patients (10 patients with alcoholism, 41 patients with hepatitis virus B infection, 78 patients with hepatitis C virus infection,21 patients with cryptogenetic cirrhosis) meeting the inclusion criteria were randomized into group A receiving a 90-d treatment with L-carnitine (2 g twice a day) or into group B receiving placebo in double blind.RESULTS: At the end of the study period, a significant decrease in NH4 fasting serum levels was found in patients with hepatic encephalopathy (P＜0.05) afler the treatment with levocarnitine (LC). Significant differences were also found between symbol digit modalities test and block design in patients with hepatic encephalopathy (P＜0.05).CONCLUSION: Results of our study suggest an important protective effect of L-carnitine against ammonia-precipitated encephalopathy in cirrhotic patients.
Ong, Chin-Sing; McConnell, James R.; Chu, Wei-Kom
Liver failure can induce gradations of encephalopathy from mild to stupor to deep coma. The objective of this study is to investigate and quantify the variation of biochemical compounds in the brain in patients with liver failure and encephalopathy, through the use of water- suppressed, localized in-vivo Proton Magnetic Resonance Spectroscopy (HMRS). The spectral parameters of the compounds quantitated are: N-Acetyl Aspartate (NAA) to Creatine (Cr) ratio, Choline (Cho) to Creatine ratio, Inositol (Ins) to Creatine ratio and Glutamine-Glutamate Amino Acid (AA) to Creatine ratio. The study group consisted of twelve patients with proven advanced chronic liver failure and symptoms of encephalopathy. Comparison has been done with results obtained from five normal subjects without any evidence of encephalopathy or liver diseases.
Full Text Available Overview Alternate Names: PharmGKB Accession Id: PA164924608 Publications related to Acute...uman genetics. 2009. Neilson Derek E, et al. Common Searches Search Medline Plus Search CTD Pharm GKB: Acute Necrotizing Encephalopathy ...
Full Text Available Posterior reversible encephalopathy syndrome (PRES is characterized by the following symptoms: seizures, impaired consciousness and/or vision, vomiting, nausea, and focal neurological signs. Diagnostic imaging includes examination by magnetic resonance (MR and computed tomography (CT, where brain edema is visualized bi-laterally and symmetrically, predominantly posteriorly, parietally, and occipitally. Case report. We presented a 73-year-old patient with the years-long medical history of hipertension and renal insufficiency, who developed PRES with the symptomatology of the rear cranium. CT and MR verified changes in the white matter involving all lobes on both sides of the brain. After a two-week treatment (antihypertensive, hypolipemic and rehydration therapy clinical improvement with no complications occurred, with complete resolution of changes in the white matter observed on CT and MR. Conclusion. PRES is a reversible syndrome in which the symptoms withdraw after several days to several weeks if early diagnosis is made and appropriate treatment started without delay.
Full Text Available Posterior Reversible Encephalopathy Syndrome (PRES is a clinic radiological entity, characterized by variable associations of seizure activity, consciousness impairment, headache, visual abnormalities, nausea and vomiting and focal neurological signs. The global incidence of PRES is not known. It can develop in association with conditions like exposure to toxic agents, hypertension, infection and eclampsia was present in 7%. So, here I am presenting a case of our patient of 22 years primigravida, who presented with ante partum eclampsia at 28 weeks of gestation and delivered vaginally by induction of labor. Post-delivery she developed PRES which was diagnosed by MRI. [Int J Reprod Contracept Obstet Gynecol 2014; 3(4.000: 1155-1156
Jo, Yong Min; Lee, Sung Wook; Han, Sang Young; Baek, Yang Hyun; Ahn, Ji Hye; Choi, Won Jong; Lee, Ji Young; Kim, Sang Ho; Yoon, Byeol A
Nonconvulsive status epilepticus has become an important issue in modern neurology and epileptology. This is based on difficulty in definitively elucidating the condition and its various clinical phenomena and on our inadequate insight into the intrinsic pathophysiological processes. Despite nonconvulsive status epilepticus being a situation that requires immediate treatment, this disorder may not be appreciated as the cause of mental status impairment. Although the pathophysiology of nonconvulsive status epilepticus remains unknown, this disorder is thought to lead to neuronal damage, so its identification and treatment are important. Nonconvulsive status epilepticus should be considered in the differential diagnosis of patients with liver cirrhosis presenting an altered mental status. We report a case of a 52-year-old male with liver cirrhosis presenting an altered mental status. He was initially diagnosed with hepatic encephalopathy but ultimately diagnosed with nonconvulsive status epilepticus by electroencephalogram.
Lough, Mary E
Wernicke's encephalopathy (WE) is a life threatening neurological disorder that results from thiamine (Vitamin B1) deficiency. Clinical signs include mental status changes, ataxia, occulomotor changes and nutritional deficiency. The conundrum is that the clinical presentation is highly variable. WE clinical signs, brain imaging, and thiamine blood levels, are reviewed in 53 published case reports from 2001 to 2011; 81 % (43/53) were non-alcohol related. Korsakoff Syndrome or long-term cognitive neurological changes occurred in 28 % (15/53). Seven WE cases (13 %) had a normal magnetic resonance image (MRI). Four WE cases (8 %) had normal or high thiamine blood levels. Neither diagnostic tool can be relied upon exclusively to confirm a diagnosis of WE.
Wicklund, Meredith R; Knopman, David S
A 71-year-old woman with myelofibrosis on chemotherapy experienced an acute illness with nausea, vomiting, and diarrhea. Two weeks later, she developed an acute confusional state characterized by disorientation and fluctuating alertness with normal speech and language. Her neurologic examination demonstrated an upper motor neuron pattern of right hemiparesis. She reported double vision though ophthalmoparesis was not appreciated. Her gait was normal. While hospitalized, she developed generalized tonic-clonic seizures. Brain MRI revealed a small area of restricted diffusion of the left precentral gyrus (figure). She was diagnosed with a stroke with secondary seizures; however, as the confusional state resolved, she developed profound retrograde and anterograde amnesia. Review of the brain MRI showed high T2 signal in the medial thalamus and contrast enhancement of the mamillary bodies; a diagnosis of Wernicke-Korsakoff syndrome was entertained and she was started on thiamine replacement. The encephalopathy and hemiparesis resolved though she remains severely amnestic.
Full Text Available A 36-years-old man on phenytoin, levetiracetam, and sodium valproate presented with acute confusion. Routine investigations including serum valproate and phenytoin concentration were normal. His serum ammonia concentration was raised. His valproate was held and 2 days later he recovered with concordant normalisation of serum ammonia concentration. Urea acid cycle disorder was ruled out, and a diagnosis of valproate induced hyperammonemic encephalopathy (VHE was made. Asymptomatic hyperammonemia occurs in 15–50% of valproate-treated patients, and while the true incidence of VHE is not known, it is a recognized complication of sodium valproate treatment. VHE typically presents acutely with impaired consciousness, lethargy, and vomiting. Valproate concentrations may be in the therapeutic range, and liver function tests are typically “normal.” Treatment for VHE consists of ceasing valproate and providing supportive care. Some have advocated carnitine replacement.
Full Text Available The method of transcranial electrostimulation (TES was used for treating patients with alcoholic encephalopathy against the background of the basic treatment, which includes nootropics, normotimics, soporifics, over-all strengthening therapy and other devices. The course of treatment consisted of 10 daily procedures lasting for 30 minutes. The TES influence was evaluated according to the clinical state, the neurologic status, including EEG (electroencephalogram, the psychometric scales were also used for evaluating the manifestation of depression, anxiety and working memory in comparison with appropriate indices in the control group of patients, who were being treated by the traditional method. TES led to normalization of health state, neurologic status and vegetative innervation, the reduction in pathologic inclination, which corresponded to general improvement of the state of patients, EEG indices and psychometric scales
Galgano, Michael A; Cantu, Robert; Chin, Lawrence S
Chronic traumatic encephalopathy (CTE) is a devastating neuropsychological condition afflicting a small percentage of athletes partaking in high-impact sports. The onset of symptoms lags years behind the inciting events. Repetitive minor head injuries are felt to be the main etiology behind CTE. Routine radiographic imaging generally is unremarkable in cases of CTE. Functional magnetic resonance imaging (fMRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) are advanced MRI-based sequences that have shown promise in detecting early radiographic findings that may be reflective of CTE. Progressive neuronal loss is the histopathological hallmark of this neurodegenerative disease. Strategizing earlier detection techniques is paramount in delivering optimal care to athletes afflicted with CTE.
Hippocampal neuronal apoptosis accompanied by impairment of cognitive function occurs in primary diabetic encephalopathy. In this study, we investigated the neuroprotective mechanism of the iridoid glycoside, aucubin, using rats (n=8). Diabetes mellitus was induced in the rats by intraperitoneal (i.p.) injection of streptozotocin (60 mg/kg body weight). After 65 d, half of the DM rats were administered aucubin (5 mg/kg; i.p.) for 15 d, yielding treatment DM+A. A third group of rats received no strepto- zotocin or aucibin, and served as controls (CON). Encephalopathy was assessed using Y-maze be- havioral testing. Rats were euthanized on Day 87, and hippocampi were excised for visual (light and transmission electron microscopic) and immunochemical (Western blot; immunohistochemical) as- sessments of the CA1 subfield for apoptosis and expression of regulatory proteins Bcl-2 and Bax. Treatment responses to all the parameters examined (body weight, plasma glucose, Y-maze error rates, pyramidal cell ultrastructure, proportions of apoptotic cells, levels of expression of Bcl-2 and Bax, and survivability of neuronal cells) were identical: there were highly significant differences between DM and CON groups (P<0.001), but the effects were significantly moderated (P<0.01) in DM+A compared with DM. These findings confirm the association of apoptosis with the encephalopathic effects of diabetes mellitus, and suggest a major role of the expression levels of Bcl-2 and Bax in the regulation of apop- totic cell death. All of the results suggest that aucubin could effectively inhibit apoptosis by modulating the expressions of Bcl-2 and Bax genes.
XUE HongYu; JIN LiJi; JIN Lei; ZHANG Peng; LI DanQing; XIA YanQiu; LU YaNan; XU YongPing
Hippocampal neuronal apoptosis accompanied by impairment of cognitive function occurs in primary diabetic encephalopathy. In this study, we investigated the neuroprotective mechanism of the iridoid glycoside, aucubin, using rats (n=8). Diabetes mellitus was induced in the rats by intraperitoneal (i.p.) injection of streptozotocin (60 mg/kg body weight). After 65 d, half of the DM rats were administered aucubin (5 mg/kg;i.p.) for 15 d, yielding treatment DM+A. A third group of rats received no strepto-zotocin or aucibin, and served as controls (CON). Encephalopathy was assessed using Y-maze be-havioral testing. Rats were euthanized on Day 87, and hippocampi were excised for visual (light and transmission electron microscopic) and immunochemical (Western blot;immunohistochemical) as-sessments of the CA1 subfield for apoptosis and expression of regulatory proteins Bcl-2 and Bax. Treatment responses to all the parameters examined (body weight, plasma glucose, Y-maze error rates, pyramidal cell ultrastructure, proportions of apoptotic cells, levels of expression of Bcl-2 and Bax, and survivability of neuronal cells) were identical: there were highly significant differences between DM and CON groups (P<0.001), but the effects were significantly moderated (P<0.01) in DM+A compared with DM. These findings confirm the association of apoptosis with the encephalopathic effects of diabetes mellitus, and suggest a major role of the expression levels of Bcl-2 and Bax in the regulation of apop-totic cell death. All of the results suggesf that aucubin could effectively inhibit apoptosis by modulating the expressions of Bcl-2 and Bax genes.
Rajeev Philip; Sanjay Saran; Manish Gutch; Keshavkumar Gupta
Hashimoto's encephalopathy (HE) is a rare steroid-responsive encephalopathy syndrome, which can have highly variable neuropsychiatric manifestations and can go unrecognized for a long time. HE is a diagnosis of exclusion and should be kept in mind when evaluating a patient with a cognitive dysfunction and high titers of anti-thyroid antibodies as it responds dramatically to steroids. Steroid responsive myoclonus can be a presentation of HE.
Kankirawatana, P; Leonard, H; Ellaway, C; Scurlock, J; Mansour, A; Makris, C M; Dure, L S; Friez, M; Lane, J; Kiraly-Borri, C; Fabian, V; Davis, M; Jackson, J; Christodoulou, J; Kaufmann, W E; Ravine, D; Percy, A K
MECP2 mutations mainly occur in females with Rett syndrome. Mutations have been described in 11 boys with progressive encephalopathy: seven of nine with affected sisters and two de novo. The authors report four de novo occurrences: three pathogenic and one potentially pathogenic. Common features include failure to thrive, respiratory insufficiency, microcephaly, and abnormal motor control. MECP2 mutations should be assessed in boys with progressive encephalopathy and one or more of respiratory insufficiency, abnormal movements or tone, and intractable seizures.
Yoon, Sook Ja; Choi, Yun Sun; Shin, Chung Ho; Cho, Sung Bum; Cho, Jae Min; Kim, Hyun Sook; Han, Tae Il; Yoon, Yong Kyu [Eulji Univ. School of Medicine, Seoul (Korea, Republic of)
Hemorrhagic shock and encephalopathy syndrome (HSES) is a sudden-onset symptom complex that involves multisystem failure and includes encephalopathy, shock, coma, convulsions, prerenal azotemia, hepatic dysfunction, and bleeding coagulopathy and progressive thrombocytopenia in previously healthy infants and children. Its radiologic findings have rarely been reported, and it has not been described in Korea. We present a case of clinically diagnosed HSES, and include the CT and MRI findings.
We report isoniazid (INH)-induced encephalopathy in two male patients on hemodialysis. One of them had tuberculous adenitis, and the other had pulmonary tuberculosis. Both were given rifampicin, INH, pyrazinamide, and ethambutol with pyridoxine 40 mg/day. Two patients developed disturbances in consciousness. After excluding other causes, INH-induced encephalopathy was suspected so the drug was stopped and dose of pyridoxine increased. Both patients retained their consciousness within 1 week a...
Saroj S Yadav
Full Text Available Acute encephalopathy with biphasic seizures and reduced diffusion (AESD is a syndrome of encephalopathy characterized by biphasic seizures and altered consciousness in the acute stage followed in the subacute stage by restricted diffusion in the subcortical white matter on magnetic resonance imaging. The etiology of AESD has been attributed to viral infection like influenza A and human herpes virus 6. The exact pathogenesis of AESD is uncertain. Here we report a case of AESD, diagnosed based on clinicoradiological correlation.
Takeshi Hayashi, Kimihiko HattoriDepartment of Neurology, Fuji Heavy Industries Health Insurance Corporation, Ota General Hospital, Ota, Gunma, JapanAbstract: Most patients contract hypoxic encephalopathy after suffering a cardiac arrest. They usually endure severe neurological sequelae and the temporal profile of the disease progression remains unclear. This case study shows how the effects of hypoxic encephalopathy continue to progress for several years after the initial event. Up to eight ...
曾溢滔; 张美兰; 陈美珏; 周霞娣; 黄英; 任兆瑞; 黄淑帧; 胡明信; 吴学清; 高建明; 张斌; 徐慧如
This study analyses the bovine SRY DNA sequence by direct sequencing procedure, followed by the designation of the PCR primers specific for bovine SRY. Using PCR amplification of bovine SRY gene, the embryo sex was determined. The results of the embryo sex identification were confirmed after the embryo transfer and pregnancies.
Amauri Alcindo Alfieri; Alice Fernandes Alfieri; Luis Álvaro Leuzzi Junior
All over de World the Enzootic Bovine Leukosis is a important viral infection in cattle herds. This revision points out topics relative to the etiological agent, clinical signals, diagnosis methods, control and prophylaxis of the infection.A Leucose Enzoótica Bovina é uma infecção viral amplamente disseminada em rebanhos bovinos de todo o mundo. Esta revisão tem por objetivo apresentar tópicos relacionados ao agente etiológico, à doença clínica e aos métodos de diagnóstico, controle e profila...
Kobtan, Abdelrahman A; El-Kalla, Ferial S; Soliman, Hanan H; Zakaria, Soha S; Goda, Mohamed A
Hepatic encephalopathy is a serious complication of liver failure. Until now, the precise pathophysiologic mechanisms are not fully determined. It has been demonstrated that manganese plays an important role in the pathogenesis of hepatic encephalopathy. Therefore, we studied manganese levels in serum of cirrhotic patients with hepatic encephalopathy in relation to grading and recurrence of hepatic encephalopathy. One hundred persons were enrolled in the study, 80 cirrhotic patients with or without encephalopathy and 20 healthy controls. Hepatic encephalopathy was diagnosed clinically and by laboratory findings. Serum manganese levels were measured in all participants. The grading of hepatic encephalopathy was significantly correlated to the severity of liver dysfunction. The mean serum manganese level was significantly higher in cirrhotic patients than in controls and in cirrhotic patients with encephalopathy than in those without encephalopathy. It was also significantly higher in patients with advanced grading of hepatic encephalopathy. Serum manganese level was positively correlated to number of recurrences of encephalopathy during a 6-month follow-up period. Serum manganese levels were able to predict recurrence of hepatic encephalopathy within 6 months following the episode. Serum manganese levels are positively correlated to the modified Child-Pugh score of cirrhosis as well as grading and number of recurrences of hepatic encephalopathy. Higher manganese levels seem to be related to worsening of the condition, and its measurement may be used as a predictor of repeated recurrences.
Noh, Young; Kim, Dong Wook; Chu, Kon; Lee, Soon-Tae; Jung, Keun-Hwa; Moon, Hye-Jin; Lee, Sang Kun
Metabolic encephalopathy is a rare but serious complication of valproic acid (VPA) therapy that usually presents with impaired consciousness or increased seizure frequency. Although it has been suggested that topiramate (TPM) increases the risk of VPA-induced encephalopathy, the additional risk in patients receiving TPM therapy has not been evaluated. We reviewed all adult patients who took VPA between January 2005 and February 2009 at the Seoul National University Hospital and identified patients with VPA-induced encephalopathy based on clinical and electroencephalography (EEG) data. Information on sex, age, serum ammonia level, serum VPA level, liver function test, and EEG was collected from patient registry and medical data. We enrolled 8,372 patients who received VPA therapy and 1,236 patients who received VPA/TPM combination therapy. We identified 11 patients with VPA-induced encephalopathy (0.13%), 7 of whom received a combination therapy of VPA and TPM. The odds ratio of VPA-induced encephalopathy with TPM over that without TPM was 10.16. There were no significant differences in sex distribution, number of antiepileptic agents, ammonia level, VPA serum level, underlying diseases, dosage of VPA, duration of VPA treatment, treatment of encephalopathy, and outcomes between the two groups. Our study showed that the prevalence of VPA-induced encephalopathy is approximately 0.1% among patients treated with VPA and that the risk of this condition, although still low, can increase by approximately 10 times in the presence of TPM therapy. Based on these results, we suggest that TPM should be carefully used in patients receiving VPA treatment.
Hashimoto's encephalopathy (HE) is a controversial neurological disorder that includes a group of heterogeneous neurological symptoms and the increased level of antithyroid antibodies. The clinical manifestations of HE may include encephalopathic features such as convulsion, behavioral and psychiatric abnormality, movement disorders and coma. Although HE has been believed to be correlated with Hashimoto's thyroiditis or thyroid dysfunction,the most common immuno-logical abnormality of HE is the presence of increased antibodies of antithyroglobulin or antimicrosomal. At present,it is still unclear as to whether the increased antithyroid antibodies is abiogenetic dysimmunity secondary to encephalopathy or it does cause the occurrence of disease. The effective reaction of HE to hormone or plasmapheresis also supported the hypothesis that this belonged to the immune pathogenic mechanism.%桥本脑病(HE)是一种目前尚存在争议的神经系统功能紊乱,包括患者出现的一组异质性的神经系统症状以及抗甲状腺抗体的水平增高.HE的临床表现可包括脑病的特点,如抽搐、精神行为异常、运动障碍和昏迷.尽管被认为与桥本甲状腺炎或甲状腺功能紊乱相关,HE最常见的免疫学异常是出现血清抗甲状腺球蛋白抗体(TG Ab)或抗甲状腺过氧化物酶(antimicrosomal)抗体(TMAb)的增高.目前尚不清楚抗甲状腺抗体的增高是继发于脑病的一种偶发免疫异常还是其确实导致了疾病的发生.HE对激素或者血浆置换等治疗的有效反应也支持这种属于免疫异常发病机制的推论.
Tao, N; DePeters, E J; Freeman, S; German, J B; Grimm, R; Lebrilla, C B
Bovine milk oligosaccharides have several potentially important biological activities including the prevention of pathogen binding to the intestinal epithelial and as nutrients for beneficial bacteria. It has been suggested that milk oligosaccharides are an important source of complex carbohydrates as supplements for the food and the pharmaceutical industries. However, only a small number of structures of bovine milk oligosaccharides (bMO) are known. There have been no systematic studies on bMO. High-performance mass spectrometry and separation methods are used to evaluate bMO, and nearly 40 oligosaccharides are present in bovine milk. Bovine milk oligosaccharides are composed of shorter oligomeric chains than are those in human milk. They are significantly more anionic with nearly 70%, measured abundances, being sialylated. Additionally, bMO are built not only on the lactose core (as are nearly all human milk oligosaccharides), but also on lactose amines. Sialic acid residues include both N-acetyl and N-glycolylneuraminic acid, although the former is significantly more abundant.
Exosomes are 40-100 nm membrane vesicles of endocytic origin and are found in blood, urine, amniotic fluid, bronchoalveolar lavage (BAL) fluid, as well as human and bovine milk. Exosomes are extracellular organelles important in intracellular communication/signaling, immune function, and biomarkers ...
Schetters, T.; Dubey, J.P.; Adrianarivo, A.; Frankena, K.; Romero, J.J.; Pérez, E.; Heuer, C.; Nicholson, C.; Russell, D.; Weston, J.
This article summarises the most relevant data of presentations delivered at the 19th International Conference of the World Association for the Advancement of Veterinary Parasitology (WAAVP) held in New Orleans, LA, USA, from 10 to 14 August 2003) in a symposium session on bovine neosporosis. The sy
Kang, Woo-Hyuk; Na, Ju-Young; Kim, Meyung-Kug; Yoo, Bong-Goo
Hashimoto’s encephalopathy is an immune-mediated disorder characterized by acute or subacute encephalopathy related to increased anti-thyroid antibodies. Clinical manifestations of Hashimoto’s encephalopathy may include stroke-like episodes, altered consciousness, psychosis, myoclonus, abnormal movements, seizures, and cognitive dysfunction. Acute cognitive dysfunction with convulsion as initial clinical manifestations of Hashimoto’s encephalopathy is very rare. We report a 65-year-old man wh...
Savlan, Ilona; Liakina, Valentina; Valantinas, Jonas
Hepatic encephalopathy is a neuropsychiatric complication of liver cirrhosis the symptoms of which may vary from imperceptible to severe, invaliding, and even lethal. Minimal hepatic encephalopathy is also important because of its tendency to impair patients' cognitive functions and quality of life. The polyetiological pathogenesis of hepatic encephalopathy is intensively studied. A general consensus exists that not only excess of ammonia but also inflammatory, oxidative, and other processes are significant in the development of hepatic encephalopathy.
Gluud, C; Koretz, RL
Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids. Treatment with BCAA may therefore have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids (BCAA) to aromatic amino acids. Treatment with BCAA may therefore have a beneficial effect on patients with hepatic encephalopathy....
Full Text Available Abstract Many cases of coeliac disease, a gastrointestinal autoimmune disorder caused by sensitivity to gluten, can remain in a subclinical stage or undiagnosed. In a significant proportion of cases (10–15% gluten intolerance can be associated with central or peripheral nervous system and psychiatric disorders. A 38-year-old man was admitted as to our department an inpatient for worsening anxiety symptoms and behavioural alterations. After the addition of second generation antipsychotic to the therapeutic regimen, the patient presented neuromotor impairment with high fever, sopor, leukocytosis, raised rhabdomyolysis-related indicators. Neuroleptic malignant syndrome was strongly suspected. After worsening of his neuropsychiatric conditions, with the onset of a frontal cognitive deficit, bradykinesia and difficulty walking, dysphagia, anorexia and hypoferraemic anaemia, SPET revealed a reduction of cerebral perfusion and ENeG results were compatible with a mainly motor polyneuropathy. Extensive laboratory investigations gave positive results for anti-gliadin antibodies, and an appropriate diet led to a progressive remission of the encephalopathy.
Maria Carmela Tartaglia
Full Text Available Chronic traumatic encephalopathy (CTE is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer’s disease and frontotemporal lobar degeneration. The aim of this perspective is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.
Poser, C M; Kassirer, M R; Peyser, J M
A survey of 67 pregnancies in 51 professional women (physicians, psychologists, nurses, administrators, etc.) revealed the occurrence of symptoms of cognitive dysfunction such as forgetfulness, disorientation, confusion and reading difficulties in 28 pregnancies occurring in 21 women. These were unrelated to such factors as age of delivery, percentage weight gain, the baby's sex or birth weight, alcohol consumption, smoking, a history of migraine or allergy or other symptoms occurring during pregnancy such as sleepiness and lack of concentration, irritability, loss of interest in job or nightmares. Nor was there any correlation with hypertension, proteinuria, glycosuria, ketonuria, anemia, or morning sickness. Furthermore, these cognitive disturbances were not related to depression or sleep deprivation. Despite these symptoms, none of the women suffering from them were forced to interrupt their professional activities during pregnancy. The syndrome of benign encephalopathy of pregnancy should be recognized so that simple precautions can be taken to prevent any interference with professional or other activities. The etiology of the syndrome is unknown.
Jung, Young-Chul; Chanraud, Sandra; Sullivan, Edith V
There is considerable evidence that neuroimaging findings can improve the early diagnosis of Wernicke's encephalopathy (WE) in clinical settings. The most distinctive neuroimaging finding of acute WE are cytotoxic edema and vasogenic edema, which are represented by bilateral symmetric hyperintensity alterations on T2-weighted MR images in the periphery of the third ventricle, periaqueductal area, mammillary bodies and midbrain tectal plate. An initial bout of WE can result in Korsakoff's syndrome (KS), but repeated bouts in conjunction with its typical comorbidity, chronic alcoholism, can result in signs of tissue degeneration in vulnerable brain regions. Chronic abnormalities identified with neuroimaging enable examination of brain damage in living patients with KS and have expanded the understanding of the neuropsychological deficits resulting from thiamine deficiency, alcohol neurotoxicity, and their comorbidity. Brain structure and functional studies indicate that the interactions involving the thalamus, mammillary bodies, hippocampus, frontal lobes, and cerebellum are crucial for memory formation and executive functions, and the interruption of these circuits by WE and chronic alcoholism can contribute substantially to the neuropsychological deficits in KS.
Full Text Available Alcohol is considered to be the most common exogenous toxins, causing encephalopathy. The defeat of almost all parts of the nervous system should be assigned to the special features of ethanol. Neurophysiological mechanisms of development of substance dependence are based in the stem and limbic structures of the brain that are involved in ensuring the regulation of emotional state, mood, motivation sphere, psychophysical tone of human behavior in general and its adaptation to the environment. Stress or disruption of the normal functioning of these structures can lead to the formation of abstinence syndrome, affective disorders in remission and craving for alcohol. Dopaminergic and opioid (endorphin system play an important role in the genesis of various mental and motor disorders. In some way alcohol dependence can be regarded as an endorfinodefitsitnoe disease with a pathogenetic point of view. Activating of opioidereal system by trans-cranial electrical stimulation promotes the restoration of disturbed emotional, cognitive and autonomic functions, reduces craving for alcohol and in that way increases the effectiveness of rehabilitation treatment
Oliviero; Riggio; Lorenzo; Ridola; Chiara; Pasquale
Type-C hepatic encephalopathy(HE) is a severe complication of cirrhosis,which seriously affects quality of life and is strongly related to patient survival.Treatment based on a classical pharmacological approach that is aimed at reducing the production of gut-derived toxins,such as ammonia,is still under debate.Currently,results obtained from clinical trials do not support any specific treatment for HE and our competence in testing old and new treatment modalities by randomized controlled trials with appropriate clinically relevant end-points urgently needs to be improved.On the other hand,patients who are at risk for HE are now identifiable,based on studies on the natural history of the disease.Today,very few studies that are specifically aimed at establishing whether HE may be prevented are available or in progress.Recent studies have looked at non absorbable disaccharides or antibiotics and other treatment modalities,such as the modulation of intestinal flora.In the treatment of severe stage HE,artificial liver supports have been tested with initial positive results but more studies are needed.
Jian Li; Ang Li; Yibing Weng; Shuwen Zhang; Meili Duan
Sepsis-associated encephalopathy (SAE) is a diffuse and acute cerebral dysfunction caused by sepsis. Many sepsis patients exhibit acute deterioration in mental status during the early stage of disease, and central nervous system dysfunction has been shown to increase patient mortality. The present study selected 284 sepsis patients who were admitted to the Intensive Care Unit of Beijing Friendship Hospital, Capital Medical University, from January to December 2009. The patients were assigned to SAE and non-SAE patient groups according to SAE occurrence. SAE incidence was 37.68%, and mortality was significantly greater in SAE patients compared with non-SAE patients (41.12% vs. 17.51%, P < 0.01). Univariate analysis and multivariate logistic regression analysis indicated lower arterial partial pressure of oxygen and greater alanine aminotransferase and Acute Physiology and Chronic Health Evaluation II scores in the SAE group compared with the non-SAE group. Arterial partial pressure of oxygen, alanine aminotransferase, and Acute Physiology and Chronic Health Evaluation II scores were determined to be potential risk factors for SAE.
Kaplan, Peter W; Sutter, Raoul
Patients with acute confusional states (often referred to as encephalopathy or delirium) pose diagnostic and management challenges for treating physicians. Encephalopathy is associated with a high morbidity and mortality rate, and the diagnosis rests on clinical grounds but may also be supported by the finding of electroencephalographic (EEG) evidence for diffuse cerebral dysfunction. The myriad cerebral transmitter and metabolic disruptions are generated by systemic organ system failures, principal among which are those of the liver, kidneys, lungs, heart, and endocrine system, along with the effects of exogenous toxins and medications. In most cases, several of these organ failures together contribute to the confusional state, frequently in the context of a diffuse cerebral atrophy that affects the aging brain. This special issue of the Journal of Clinical Neurophysiology is dedicated to exploring the electrophysiology of these conditions. It reviews the pathophysiology, psychiatric manifestations, clinical and imaging correlations of the many causes and types of encephalopathy. A literature review of the EEG abnormalities in the various types of encephalopathy provides an overview that ranges from paraneoplastic causes, through organ system failures, postcardiorespiratory arrest, to postoperative delirium. The issue is supplemented by tables of relevant clinical correlations, graphs, Venn diagrams, and the use of mathematical modeling used to explain how defects in the neuronal interplay might generate the EEG patterns seen in encephalopathy. We hope that this assembly will act as a springboard for further discussion and investigation into the EEG underpinnings, clinical correlations, diagnosis. and prognostication of these common and morbid disturbances of brain function.
Full Text Available Posterior reversible encephalopathy syndrome (PRES is characterized by acute onset of headache, nausea, focal neurological deficits or seizures along with radiological findings of white matter defects in the parietal and occipital lobes. Causes of PRES include uremia, hypertensive encephalopathy, eclampsia and immunosuppressive medications. Usually, the treat-ment of choice involves correcting the underlying abnormality. We describe an unusual case of recurrent PRES caused by uremia during a lupus flare in a patient with biopsy-proven Class IV Lupus Nephritis (LN with vasculitis. PRES in systemic lupus erythematosis (SLE is a rare clin-ical phenomenon and, when reported, it is associated with hypertensive encephalopathy. Our patient did not have hypertensive crisis, but had uremic encephalopathy. The patient′s PRES-related symptoms resolved after initiation of hemodialysis. The temporal correlation of the correc-tion of the uremia and the resolution of the symptoms of PRES show the etiology to be uremic encephalopathy, making this the first reported case of uremia-induced PRES in Class IV LN with vasculitis.
Full Text Available Abstract Prion diseases are transmissible neurodegenerative conditions affecting human and a wide range of animal species. The pathogenesis of prion diseases is associated with the accumulation of aggregates of misfolded conformers of host-encoded cellular prion protein (PrPC. Animal prion diseases include scrapie of sheep and goats, bovine spongiform encephalopathy (BSE or mad cow disease, transmissible mink encephalopathy, feline spongiform encephalopathy, exotic ungulate spongiform encephalopathy, chronic wasting disease of cervids and spongiform encephalopathy of primates. Although some cases of sporadic atypical scrapie and BSE have also been reported, animal prion diseases have basically occurred via the acquisition of infection from contaminated feed or via the exposure to contaminated environment. Scrapie and chronic wasting disease are naturally sustaining epidemics. The transmission of BSE to human has caused more than 200 cases of variant Cruetzfeldt-Jacob disease and has raised serious public health concerns. The present review discusses the epidemiology, clinical neuropathology, transmissibility and genetics of animal prion diseases.
E. D. Belousova
Full Text Available The author represents the review and discussion of current scientific literature devoted to epileptic encephalopathy with continuous spikes-waves activity during sleep — the special form of partly reversible age-dependent epileptic encephalopathy, characterized by triad of symptoms: continuous prolonged epileptiform (spike-wave activity on EEG in sleep, epileptic seizures and cognitive disorders. The author describes the aspects of classification, pathogenesis and etiology, prevalence, clinical picture and diagnostics of this disorder, including the peculiar anomalies on EEG. The especial attention is given to approaches to the treatment of epileptic encephalopathy with continuous spikeswaves activity during sleep. Efficacy of valproates, corticosteroid hormones and antiepileptic drugs of other groups is considered. The author represents own experience of treatment this disorder with corticosteroids, scheme of therapy and assessment of efficacy.
Byung Ju Kang
Full Text Available Wernicke’s encephalopathy is a reversible but potentially critical disease caused by thiamine deficiency. Most patients complain of symptoms such as ophthalmoplegia, ataxia and confusion. Heavy alcohol drinking is commonly associated with the disease, but other clinical conditions also can provoke it. In pregnant women, hyperemesis gravidarum can lead to the depletion of body thiamine due to poor oral intake and a high metabolic demand. We report a case of Wernicke’s encephalopathy following hyperemesis gravidarum in a 36-year-old female at 20 weeks of pregnancy, who visited our hospital because of shock with vaginal bleeding. This case suggests that although the initial presentation may include atypical symptoms (e.g., shock or bleeding, Wernicke’s encephalopathy should be considered, and thiamine replacement should be performed in pregnant women with neurologic symptoms and poor oral intake.
Full Text Available Abstract Introduction Hashimoto's encephalopathy is a neurological disorder of unknown cause associated with thyroid autoimmunity. The disease occurs primarily in the fifth decade of life and may present in two types - a sudden vasculitic type or a progressive subacute type associated to cognitive dysfunction, confusion and memory loss. Case presentation We report the case of a 62-year-old Hispanic woman, previously healthy, who developed a subacute onset of declining upper brain function. Serologic studies demonstrated high levels of antithyroid antibodies. Electroencephalographic and magnetic resonance image findings were consistent with Hashimoto's encephalopathy. Conclusion Hashimoto's encephalopathy is a diagnosis of exclusion. This unusual disorder is often under-recognized because of the multiple and protracted neurocognitive manifestations; therefore, it is important to be aware of the clinical manifestations to make a correct diagnosis.
Gul Mert, Gülen; Horoz, Ozden Ozgur; Herguner, M Ozlem; Incecik, Faruk; Yildizdas, R Dincer; Onenli Mungan, Neslihan; Yuksel, Bilgin; Altunbasak, Sakir
Hashimoto's encephalopathy is a rare clinically heterogenous condition consisting of encephalopathy, seizures and variable neurological and psychiatric manifestations, accompanied by high titres of serum antithyroid antibodies. We described the clinical and laboratory findings of four children (aged 8-17 years) with Hashimoto's encephalopathy. The clinical features of three patients at presentation included refractory epilepsy, and confusion, and one patient presented with behavioral and cognitive changes. During their presentation, two of them were in euthyroid, and the others were in hypothyroid status. All patients manifested increased antithyroid antibodies. Two patients improved with steroid treatment. The others responded to plasmapheresis instead of corticosteroid treatment. Physicians' awareness of this complication is of great importance because most patients respond dramatically to the treatment.
Full Text Available Hepatic encephalopathy (HE is a common long term complication of porto-systemic shunt. We report herein the case of a 59-year-old man with Child-Pugh A cirrhosis treated successfully 9 years earlier with distal splenorenal shunt for uncontrolled variceal bleeding. In the last year, he developed a severe and persistent hepatic encephalopathy secondary to the shunt, which was resistant to medical therapy. As liver transplantation was not available and obliteration of the shunt was hazardous, we performed subtotal colectomy in order to reduce ammonia production. This therapeutic option proved successful, as the grade of encephalopathy decreased and the patient improved. Our experience indicates that colonic exclusion should be considered as an option in the management of HE refractory to medical treatment in highly selected patients when liver transplantation is not available or even as a bridge given the long waiting time on lists.
Patidar, Kavish R; Bajaj, Jasmohan S
Hepatic encephalopathy (HE) is part of a spectrum of neurocognitive changes in cirrhosis. HE is divided into 2 broad categories based on severity: covert hepatic encephalopathy (CHE) and overt hepatic encephalopathy (OHE). CHE has a significant impact on a patient's quality of life, driving performance, and recently has been associated with increased hospitalizations and death. Likewise, OHE is associated with increased rates of hospitalizations and mortality, and poor quality of life. Given its significant burden on patients, care takers, and the health care system, early diagnosis and management are imperative. In addition, focus also should be directed on patient and family member education on the disease progression and adherence to medications. Treatment strategies include the use of nonabsorbable disaccharides, antibiotics (ie, rifaximin), and, potentially, probiotics. Other therapies currently under further investigation include L-ornithine-L-aspartate, ornithine phenylacetate, glycerol phenylbutyrate, molecular adsorbent recirculating system, and albumin infusion.
Mohamed Adnane Berdai
Full Text Available Wernicke’s encephalopathy is caused by severe thiamine deficiency; it is mostly observed in alcoholic patients. We report the case of a 28-year-old woman, at 17 weeks of gestational age, with severe hyperemesis gravidarum. She presented with disturbance of consciousness, nystagmus, ophthalmoplegia, and ataxia. The resonance magnetic imagery showed bilaterally symmetrical hyperintensities of thalamus and periaqueductal area. The case was managed with very large doses of thiamine. The diagnosis of Wernicke’s encephalopathy was confirmed later by a low thiamine serum level. The patient was discharged home on day 46 with mild ataxia and persistent nystagmus. Wernicke’s encephalopathy is a rare complication of hyperemesis gravidarum. It should be diagnosed as early as possible to prevent long-term neurological sequela or death. Thiamine supplementation in pregnant women with prolonged vomiting should be initiated, especially before parenteral dextrose infusion. Early thiamine replacement will reduce maternal morbidity and fetal loss rate.
Ana Cecilia Arana-Guajardo
Full Text Available Context Acute pancreatitis can lead to prolonged fasting and malnutrition. Many metabolic changes, including thiamine deficiency, may lead to the well know pancreatic encephalopathy. In this condition however the thiamine deficiency is rarely suspected. Case report We report the case of a 17-year-old woman with severe acute pancreatitis who developed mental status changes and ophthalmoplegia. A magnetic resonance image showed hyperintensive signals in periventricular areas, medial thalamus, and mammillary bodies, findings consistent with the diagnosis of Wernicke encephalopathy. Thiamine treatment reversed neurological complications. Conclusion Wernicke encephalopathy secondary to thiamine deficiency should be considered as a possible cause of acute mental status changes in patients with acute pancreatitis and malnutrition. Prophylactic doses of thiamine could be considered in susceptible patients.
Gluud, Lise Lotte; Dam, Gitte; Les, Iñigo
-chain amino acids (BCAA) versus control interventions has evaluated if BCAA may benefit people with hepatic encephalopathy. OBJECTIVES: To evaluate the beneficial and harmful effects of BCAA versus any control intervention for people with hepatic encephalopathy. SEARCH METHODS: We identified trials through...... randomised clinical trials including 827 participants with hepatic encephalopathy classed as overt (12 trials) or minimal (four trials). Eight trials assessed oral BCAA supplements and seven trials assessed intravenous BCAA. The control groups received placebo/no intervention (two trials), diets (10 trials...... between BCAA and controls (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.69 to 1.11; 760 participants; 15 trials; moderate quality of evidence). We found no evidence of small-study effects. Sensitivity analyses of trials with a low risk of bias found no beneficial or detrimental effect of BCAA...
Torre Delgadillo, Aldo; Guerrero-Hernández, Ignacio; Uribe, Misael
The term minimal hepatic encephalopathy (MHE) refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy; the prevalence is as high as 84% in patients with hepatic cirrhosis. This cirrhosis complication is generally not perceived by physician, and diagnosis can only be made by neuropsychological tests and other especial measurements like evoked potentials and image studies like positron emission tomography. Diagnosis of minimal hepatic encephalopathy may have prognostic and therapeutic implications in cirrhotic patients. The present review pretends to explore the clinic, therapeutic, diagnosis and prognostic aspects of this complication.
Turner, A; Jeyaratnam, D; Haworth, F; Sinha, M D; Hughes, E; Cohen, B; Jin, L; Kidd, I M; Rigden, S P A; MacMahon, E
Two children, boys of 8 and 13 years, presented with measles-associated encephalopathy several years after kidney transplantation for congenital nephrotic syndrome. In the absence of prior clinical measles, the neurological symptoms initially eluded diagnosis, but retrospective analysis of stored samples facilitated the diagnosis of measles-associated encephalopathy without recourse to biopsy of deep cerebral lesions. Each had received a single dose of measles mumps and rubella vaccine before 12 months of age. Prior vaccination, reduction of immunosuppression and treatment with intravenous immunoglobulin and ribavirin may have contributed to their survival. Persistent measles virus RNA shedding, present in one child, was not controlled by treatment with i.v. ribavirin. Two years later, both patients continue to have functioning allografts with only minimal immunosuppression. These cases illustrate the difficulty in diagnosing measles-associated encephalopathy in the immunocompromised host, even in the era of molecular diagnostics, and highlight the renewed threat of neurological disease in communities with incomplete herd immunity.
Full Text Available How to Cite This Article: Dara N, Sayyari AA, Imanzadeh F. Hepatic Encephalopathy: Early Diagnosis in Pediatric Patients With Cirrhosis. Iran J Child Neurol. 2014 Winter; 8(1:1-11.ObjectiveAs acute liver failure (ALF and chronic liver disease (cirrhosis continue to increase in prevalence, we will see more cases of hepatic encephalopathy.Primary care physician are often the first to suspect it, since they are familiar with the patient’s usual physical and mental status. This serious complication typically occurs in patients with severe comorbidities and needs multidisciplinary evaluation and care. Hepatic encephalopathy should be considered in any patient with acute liver failure and cirrhosis who presents with neuropsychiatric manifestations, decrease level of consciousness (coma, change of personality, intellectualand behavioral deterioration, speech and motor dysfunction.Every cirrhotic patient may be at risk; potential precipitating factors should be addressed in regular clinic visits. The encephalopathy of liver disease may be prominent, or can be present in subtle forms, such as decline of school performance, emotional outbursts, or depression.“Subtle form” of hepatic encephalopathy may not be obvious on clinical examination, but can be detected by neurophysiologic and neuropsychiatric testing.References:Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998.Hepatology 2002;35:716-21.BleiAT,Cordoba J. Hepatic encephalopathy. AmJ Gastroenterol 2001;96:1968–76.Vaquero J,Chung C, Cahill ME, BleiAT. Pathogenesis of hepatic encephalopathy in acute liver failure. Semin Liver Dis 2003;23:259-69.Bajaj JS, Wade JB, Sanyal AJ. Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy
Lenz, V; Vargas, M I; Bin, J F; Bogorin, A; Grebici-Guessoum, M; Jacques, C; Marin, H; Zöllner, G; Dietemann, J L
Wernicke encephalopathy (Wernicke-Korsakoff encephalopathy) is related to thiamine deficiency. We report the MRI findings in four patients with visualization of bilateral and symmetrical hyperintense foci on T2W and FLAIR images involving the periaqueductal gray matter, the mamillary bodies and around the third ventricle. Diffusion weighted images obtained in two patients demonstrated mild hypersignal in the same areas. Contrast enhancement within the mamillary bodies was noted in one patient. Follow-up MRI obtained in three patients showed rapid regression of signal abnormalities without correlation with good clinical outcome.
Sivkova, S N; Bogdanov, E I; Zaĭkova, F M; Morozova, E A; Aiupova, V A; Zabbarova, A T; Shaĭmardanova, R M
Fever-induced refractory epileptic encephalopathy of school-age children is a rare epileptic syndrome that causes difficulties in diagnosis at the initial stage of disease. It is characterized by sudden onset with multifocal refractory status epilepticus in previously healthy children with normal development. Later, children suffer from resistant focal epilepsy in the combination with cognitive deficit and behavioral difficulties. Authors describe a clinical case of fever-induced refractory epileptic encephalopathy of school-age children in a child of 7 years old. Aspects of etiology, pathogenesis, clinical manifestation, differential diagnosis, treatment and prognosis of the disease are discussed.
Ataseven, Hilmi; Yüksel, Ilhami; Gültuna, Selcan; Köklü, Seyfettin; Uysal, Serkan; Basar, Omer; Sasmaz, Nurgül
Mucormycosis is an acutely fatal infection that occurs in immuncompromised patients. Cirrhosis is an acquired immune deficiency state and those patients are more prone to develop opportunistic infections. A 42-years-old cirrhotic man was admitted to our gastroenterology clinic with hepatic encephalopathy. Although he recovered from encephalopathy with supportive measurements, he developed paresthesia on the face. He was diagnosed with rhinocerebral mucormycosis and antifungal therapy was administered. Surgical treatment couldn.t be performed because of his bleeding diathesis and poor general condition. He succumbed on the 12th day of his admission.
Full Text Available Acute necrotizing encephalopathy of childhood (ANEC is a rare form of acute encephalopathy of unknown etiology characterized by typical symmetrical lesions in the thalami, with variable involvement of the white matter, brainstem and cerebellum. Clinically there is a rapid neurologic deterioration after a short period of a nonspecific viral-like illness associated with gastrointestinal or respiratory signs. Asian children are especially affected. Here we present a 3-year-old boy admitted to our hospital with fever and deterioration of consciousness. The diagnosis of ANEC was made by radiologic findings [Cukurova Med J 2014; 39(3.000: 641-645