Science.gov

Sample records for spongiform encephalopathies memorandum

  1. Medicinal and other products and human and animal transmissible spongiform encephalopathies: memorandum from a WHO meeting.

    PubMed Central

    1997-01-01

    The report in March 1996 of 10 human cases of a novel from of Creutzfeldt-Jakob disease in the United Kingdom, and its possible link to the agent that causes bovine spongiform encephalopathy (BSE), raises many questions about the safety of animal-derived products and by-products entering the food chain or being used in medicine. This Memorandum updates the preventive measures put forward in 1991 to minimize the risks associated with the use of bovine-derived materials in medicinal products and medical devices. PMID:9509622

  2. Bovine Spongiform Encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Bovine spongiform encephalopathy (BSE), also referred to as “mad cow disease” is a chronic, non-febrile, neuro-degenerative disease affecting the central nervous system. The transmissible spongiform encephalopathies (TSEs) of domestic animals, of which BSE is a member includes scrapie of sheep...

  3. Bovine Spongiform Encephalopathy

    USDA-ARS?s Scientific Manuscript database

    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...

  4. The transmissible spongiform encephalopathies of livestock

    USDA-ARS?s Scientific Manuscript database

    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...

  5. Public health issues and clinical and neurological characteristics of the new variant of Creutzfeldt-Jakob disease and other human and animal transmissible spongiform encephalopathies: memorandum from two WHO meetings.

    PubMed Central

    1996-01-01

    The transmissible spongiform encephalopathies (TSEs) include bovine spongiform encephalopathy (BSE), which was first described in 1986 in cattle in the United Kingdom, but has occurred subsequently also in other countries, and Creutzfeldt-Jakob disease (CJD) in humans, which is rare but with a worldwide distribution. Recently a new variant form of CJD, with a characteristic clinical and pathological phenotype, has been identified in the United Kingdom in a series of 11 young patients. This Memorandum reports the findings of two WHO Consultations. The first, held on 2-3 April 1996, issued conclusions and recommendations on certain animal products in order to protect the health of consumers. The second, held on 14-16 May 1996, examined, inter alia, the findings associated with the new variant of CJD, compared these findings with those for other TSEs, and proposed a protocol for the diagnosis and surveillance of CJD and related diseases. PMID:9002325

  6. Spongiform Encephalopathy in a Miniature Zebu

    PubMed Central

    Botteron, Catherine; Wenker, Christian; Café-Marçal, Valeria; Oevermann, Anna; Haase, Bianca; Leeb, Tosso; Heim, Dagmar; Zurbriggen, Andreas

    2006-01-01

    The first case of spongiform encephalopathy in a zebu (Bos indicus) was identified in a zoo in Switzerland. Although histopathologic and immunohistochemical analyses of the central nervous system indicated a diagnosis of bovine spongiform encephalopathy (BSE), molecular typing showed some features different from those of BSE in cattle (B. taurus). PMID:17326950

  7. Bovine Spongiform Encephalopathy: Atypical Pros and Cons

    USDA-ARS?s Scientific Manuscript database

    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...

  8. Cell culture models of transmissible spongiform encephalopathies.

    PubMed

    Béranger, F; Mangé, A; Solassol, J; Lehmann, S

    2001-11-30

    In this review, we describe the generation and use of cell culture models of transmissible spongiform encephalopathies, also known as prion diseases. These models include chronically prion-infected cell lines, as well as cultures expressing variable amounts of wild-type, mutated, or chimeric prion proteins. These cell lines have been widely used to investigate the biology of both the normal and the pathological isoform of the prion protein. They have also contributed to the comprehension of the pathogenic processes occurring in transmissible spongiform encephalopathies and in the development of new therapeutic approaches of these diseases.

  9. 76 FR 38667 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-01

    ... HUMAN SERVICES Food and Drug Administration Transmissible Spongiform Encephalopathies Advisory Committee... be open to the public. Name of Committee: Transmissible Spongiform Encephalopathies Advisory... available at the following link. Transmissible Spongiform Encephalopathies Advisory Committee http://fda...

  10. Transmissible Spongiform Encephalopathy and Meat Safety

    NASA Astrophysics Data System (ADS)

    Ward, Hester J. T.; Knight, Richard S. G.

    Prion diseases or transmissible spongiform encephalopathies (TSEs) comprise a wide-ranging group of neurodegenerative diseases found in animals and humans. They have diverse causes and geographical distributions, but have similar pathological features, transmissibility and, are ultimately, fatal. Central to all TSEs is the presence of an abnormal form of a normal host protein, namely the prion protein. Because of their potential transmissibility, these diseases have wide public health ramifications.

  11. Experimental Interspecies Transmission Studies of the Transmissible Spongiform Encephalopathies to Cattle: Comparison to Bovine Spongiform Encephalopathy in Cattle

    USDA-ARS?s Scientific Manuscript database

    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. Since the emergence of BSE and its pr...

  12. Typical and atypical cases of bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    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...

  13. Quantitative Risk Assessment of Bovine Spongiform Encephalopathy

    NASA Astrophysics Data System (ADS)

    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.

  14. 78 FR 11207 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-15

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Transmissible Spongiform Encephalopathies Advisory Committee... be open to the public. Name of Committee: Transmissible Spongiform Encephalopathies Advisory...

  15. Fundamental immunological problems associated with "transmissible spongiform encephalopathies".

    PubMed

    Ebringer, Alan; Rashid, Taha; Wilson, Clyde

    2015-02-01

    "Bovine spongiform encephalopathy", "scrapie", as well as Creutzfeldt-Jakob disease and kuru belong to a group of related neurological conditions termed "transmissible spongiform encephalopathies". These diseases are based on the LD50 measurement whereby saline brain homogenates are injected into experimental animals and when 50% of them develop symptoms, this is considered as transmission of the disease, but the gold standard for diagnosis is autopsy examination. However, an untenable assumption is being made in that saline brain homogenates do not cause tissue damage but it is known since the time of Pasteur, that they give rise to "post-rabies vaccination allergic encephalomyelitis". This is the fundamental flaw in the diagnosis of these diseases. A way forward, however, is to examine infectious agents, such as Acinetobacter which show molecular mimicry with myelin and elevated levels of antibodies to this microbe are found in multiple sclerosis patients and animals affected by "bovine spongiform encephalopathy".

  16. Bovine spongiform encephalopathy in Sweden: an H-type variant

    USDA-ARS?s Scientific Manuscript database

    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...

  17. Atypical bovine spongiform encephalopathies, France, 2001-2007.

    PubMed

    Biacabe, Anne-Gaëlle; Morignat, Eric; Vulin, Johann; Calavas, Didier; Baron, Thierry G M

    2008-02-01

    In France, through exhaustive active surveillance, approximately 17.1 million adult cattle were tested for bovine spongiform encephalopathy from July 2001 through July 2007; approximately 3.6 million were >8 years of age. Our retrospective Western blot study of all 645 confirmed cases found that 7 were H-type and 6 were L-type.

  18. Bovine Spongiform Encephalopathy Infectivity in Greater Kudu (Tragelaphus strepsiceros)

    PubMed Central

    Kirkwood, James K.; Dawson, Michael; Spencer, Yvonne I.; Green, Robert B.; Wells, Gerald A.H.

    2004-01-01

    Of all the species exposed naturally to the bovine spongiform encephalopathy (BSE) agent, the greater kudu (Tragelaphus strepsiceros), a nondomesticated bovine from Africa, appears to be the most susceptible to the disease. We present the results of mouse bioassay studies to show that, contrary to findings in cattle with BSE in which the tissue distribution of infectivity is the most limited recorded for any of the transmissible spongiform encephalopathies (TSE), infectivity in greater kudu with BSE is distributed in as wide a range of tissues as occurs in any TSE. BSE agent was also detected in skin, conjunctiva, and salivary gland, tissues in which infectivity has not previously been reported in any naturally occurring TSE. The distribution of infectivity in greater kudu with BSE suggests possible routes for transmission of the disease and highlights the need for further research into the distribution of TSE infectious agents in other host species. PMID:15207051

  19. Bovine spongiform encephalopathy infectivity in greater kudu (Tragelaphus strepsiceros).

    PubMed

    Cunningham, Andrew A; Kirkwood, James K; Dawson, Michael; Spencer, Yvonne I; Green, Robert B; Wells, Gerald A H

    2004-06-01

    Of all the species exposed naturally to the bovine spongiform encephalopathy (BSE) agent, the greater kudu (Tragelaphus strepsiceros), a nondomesticated bovine from Africa, appears to be the most susceptible to the disease. We present the results of mouse bioassay studies to show that, contrary to findings in cattle with BSE in which the tissue distribution of infectivity is the most limited recorded for any of the transmissible spongiform encephalopathies (TSE), infectivity in greater kudu with BSE is distributed in as wide a range of tissues as occurs in any TSE. BSE agent was also detected in skin, conjunctiva, and salivary gland, tissues in which infectivity has not previously been reported in any naturally occurring TSE. The distribution of infectivity in greater kudu with BSE suggests possible routes for transmission of the disease and highlights the need for further research into the distribution of TSE infectious agents in other host species.

  20. Laboratory activities involving transmissible spongiform encephalopathy causing agents

    PubMed Central

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed. PMID:24055928

  1. PRIONS AND THE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

    EPA Science Inventory

    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...

  2. PRIONS AND THE TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES

    EPA Science Inventory

    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...

  3. Stability properties of PrPSc from cattle with experimental transmissible spongiform encephalopathies

    USDA-ARS?s Scientific Manuscript database

    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...

  4. A collaborative Canadian-United Kingdom evaluation of an immunohistochemistry protocol to diagnose bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    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...

  5. Risk management of the transmissible spongiform encephalopathies in North America.

    PubMed

    Kellar, J A; Lees, V W

    2003-04-01

    As North American Free Trade Agreement partners, Canada, the United States of America (USA) and Mexico apply independent but harmonised transmissible spongiform encephalopathy (TSE) risk management strategies in observance of Office International des Epizooties guidelines. The divergence between bovine spongiform encephalopathy (BSE) risk management approaches in North American and Europe reflects comparatively reduced external and internal BSE risks in North America. The external quarantine and internal surveillance measures adopted for BSE respond to several iterations of national risk assessments initiated in the early 1990s and revised as recently as 2002. Feed bans applied since 1997 to preclude establishment of BSE also bear the potential to limit intra-species and inter-species exposure to scrapie, chronic wasting disease (CWD) and transmissible mink encephalopathy (TME). Surveillance continues for the four TSEs through collaborative efforts of national and sub-national veterinary infrastructures and accompanying laboratory networks. Mexico has never identified the presence of any TSE. The last diagnosed case of TME in North America dates back to 1985. Since the only recognised appearance in Canada through an import from Great Britain in 1993, BSE has not been detected in North America. Scrapie and CWD remain at generally low prevalence in Canada and the USA. Independent but harmonised eradication programmes target elimination of the latter two diseases.

  6. [Risk assessment for importing bovine spongiform encephalopathy (BSE)].

    PubMed

    Hörnlimann, B; Guidon, D; Griot, C

    1994-07-01

    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.

  7. Spongiform encephalopathy in an arabian oryx (Oryx leucoryx) and a greater kudu (Tragelaphus strepsiceros)

    PubMed

    Kirkwood, J K; Wells, G A; Wilesmith, J W; Cunningham, A A; Jackson, S I

    1990-10-27

    Clinical, pathological and epidemiological details of scrapie-like encephalopathies are described in an arabian oryx and a greater kudu. Clinical signs included ataxia and loss of condition with a short, progressive clinical course (22 and three days, respectively). Histopathological examination of the brains revealed spongiform encephalopathy characteristic of that observed in scrapie and bovine spongiform encephalopathy (BSE). It seems probable that these cases have a common aetiology with BSE. Scrapie-like spongiform encephalopathies have now been described in five species of exotic artiodactyls in Britain indicating a, hitherto inapparent, wider range of ruminant species as natural hosts for these diseases.

  8. Experimental interspecies transmission studies of the transmissible spongiform encephalopathies to cattle: comparison to bovine spongiform encephalopathy in cattle.

    PubMed

    Hamir, Amir N; Kehrli, Marcus E; Kunkle, Robert A; Greenlee, Justin J; Nicholson, Eric M; Richt, Jürgen A; Miller, Janice M; Cutlip, Randall C

    2011-05-01

    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. © 2011 The Author(s)

  9. Bovine spongiform encephalopathy surveillance in the Republic of Korea.

    PubMed

    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

    2012-12-01

    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.

  10. Use of murine bioassay to resolve ovine transmissible spongiform encephalopathy cases showing a bovine spongiform encephalopathy molecular profile.

    PubMed

    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

    2012-05-01

    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.

  11. Transmission of sheep-bovine spongiform encephalopathy to pigs.

    PubMed

    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

    2016-01-07

    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.

  12. Risk management of transmissible spongiform encephalopathies in Europe.

    PubMed

    Heim, D; Kihm, U

    2003-04-01

    Bovine spongiform encephalopathy (BSE) was first described in the United Kingdom (UK) in November 1986. After the introduction of an active surveillance system, most countries in Europe have reported BSE cases in the cattle population. This indicates that the use of active surveillance in addition to passive surveillance is important to assess the true BSE status in a country. Scrapie, a transmissible spongiform encephalopathy (TSE) in sheep and goats, has been reported in countries throughout the world with a few notable exceptions. Concern was expressed that BSE could have been introduced into sheep and goats. Currently, distinguishing between scrapie and BSE in small ruminants is only possible through lengthy experiments in mice. Preliminary results of active surveillance, introduced in 2002, show that significant under-reporting occurred. The history of BSE in cattle shows that risk assessments concerning the risk in a given country were often ignored and subsequent risk management decisions were inaccurate, i.e. although the risk was probable, no measures were taken in terms of either animal or human health. Furthermore, the effect of the measures taken was often overestimated and these had to be amended several times. The most important action to prevent new cases of TSEs occurring is by banning the feeding meat-and-bone meal (MBM) to ruminants. Further measures to be considered are the exclusion of specified risk material and carcasses from rendering, the process parameters for rendering of animal waste and the prevention of cross-contamination of feed with MBM. The most important measures to protect the consumer are the ban on specified risk material, such as brain and spinal cord, which may contain particularly high concentrations of the BSE agent, and the ban on mechanically recovered meat. The most important measures taken in Europe and the scientific background thereof are described and discussed.

  13. The transmissible spongiform encephalopathies (prion diseases): a review for dental surgeons.

    PubMed

    Gill, D S; Tredwin, C J; Gill, S K; Ironside, J W

    2001-12-01

    The transmissible spongiform encephalopathies (prion diseases) are a fatal group of neurological diseases characterised by the accumulation of an abnormal form of prion protein in the brain. In humans, these disorders occur in sporadic, acquired and familial forms. Outbreaks of bovine spongiform encephalopathy, predominantly in the United Kingdom, and the emergence of a clinically and pathologically distinct human prion disease, variant CJD, has generated much interest in the transmissible spongiform encephalopathies. As the agent is detectable in lymphoid and neural tissue in variant CJD, clinicians should be aware of the possibility of cross infection of the causative agent. This is particularly important because the abnormal prion protein is resistant to routine sterilisation procedures. This article reviews the transmissible spongiform encephalopathies, and summarises guidelines concerning prevention of crossinfection when treating patients with or at risk of developing prion disease.

  14. 78 FR 73993 - Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-10

    ... 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 on...

  15. 77 FR 20319 - Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-04-04

    ...; ] 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 document...

  16. Discontools: Identifying gaps in controlling bovine spongiform encephalopathy.

    PubMed

    Simmons, M; Ru, G; Casalone, C; Iulini, B; Cassar, C; Seuberlich, T

    2017-08-10

    This article summarizes the 2016 update of the DISCONTOOLS project gap analysis on bovine spongiform encephalopathy (BSE), which was based on a combination of literature review and expert knowledge. Uncertainty still exists in relation to the pathogenesis, immunology and epidemiology of BSE, but provided that infected material is prohibited from entering the animal feed chain, cases should continue to decline. BSE does not appear to spread between cattle, but if new strains with this ability appear then control would be considerably more difficult. Atypical types of BSE (L-BSE and H-BSE) have been identified, which have different molecular patterns and pathology, and do not display the same clinical signs as classical BSE. Laboratory transmission experiments indicate that the L-BSE agent has zoonotic potential. There is no satisfactory conclusion regarding the origin of the BSE epidemic. C-BSE case numbers declined rapidly following strict controls banning ruminant protein in animal feed, but occasional cases still occur. It is unclear whether these more recent cases indicate inadequate implementation of the bans, or the possibility that C-BSE might occur spontaneously, as has been postulated for H- and L-BSE. All of this will have implications once existing bans and levels of surveillance are both relaxed. Immunochemical tests can only be applied post-mortem. There is no immunological basis for diagnosis in the live animal. All aspects of disease control are expensive, particularly surveillance, specified risk material removal and feed controls. There is pressure to relax feed controls, and concurrent pressure from other sources to reduce surveillance. While the cost benefit argument can be applied successfully to either of these approaches, it would be necessary to maintain the ban on intraspecies recycling and some baseline surveillance. However, the potential risk is not limited to intraspecies recycling; recycling with cross-species transmission may be an

  17. Lingering doubts about spongiform encephalopathy and Creutzfeldt-Jakob disease.

    PubMed

    Narang, H K

    2001-07-01

    Bovine spongiform encephalopathy (BSE) is an infectious disease and has been transmitted orally to many other animals, including humans. There is clear evidence of maternal transmission, although disagreement on the source of the BSE agent remains. The current theories link the origin of BSE to common scrapie in sheep. Twenty different strains of the scrapie agent have been isolated from sheep. A search of the literature indicates two distinct clinical syndromes in sheep, both of which have been called scrapie. I have designated these Type I (the common type), which exhibits itchiness and lose their wool, and Type II, which exhibits trembling and ataxia. Sheep inoculated with BSE develop Type II scrapie and they exhibit trembling. When cattle or mink are injected with the Type I strain, only a few will develop a clinical disease. By contrast, no clinical disease has so far been shown in cattle or mink by feeding them with Type I-infected sheep brains. However, either by injecting or feeding with the BSE strain, 100% of calves and mink develop the clinical disease. Evidence suggests that Type II is the cause of BSE. Identical clinical signs of Type II trembling are found in kuru and many of the recent cases of Creutzfeldt-Jakob disease. The BSE agent has caused spongiform encephalopathies (SEs) in domestic cats, tigers, and in some species of ruminants in zoos. The nature of the BSE agent remains unchanged when passaged through a range of species, irrespective of their genetic make up, demonstrating that variations in the host PrP gene are not a major factor in the susceptibility to the BSE agent. Since more than 85 zoo animals of many species have been diagnosed with SEs, from these studies it seems reasonable to conclude that the BSE agent can infect almost all mammalian species, including humans. For eradication of BSE and to reduce the risk of infection to humans, the development of a vaccine against BSE is suggested. Such a possibility should be fully explored.

  18. The human transmissible spongiform encephalopathies (TSEs): implications for dental practitioners.

    PubMed

    Porter, S; Scully, C; Ridgway, G L; Bell, J

    2000-04-22

    Transmissible spongiform encephalopathies (TSEs) are rare, fatal degenerative brain diseases which affect humans and certain animals, and are caused by inheritance or acquisition of prions (PrPs). Inherited TSEs include Fatal Familial Insomnia (FFI), Gerstmann-Straussler-Scheinker syndrome (GSS) and other less well clinically characterised disorders, while the human infective TSEs include sporadic, iatrogenic and variant Creutzfeldt-Jakob disease (vCJD). The causative prions are found especially in neural tissues and spinal fluid, and in the case of vCJD, in lymphoreticular tissue. Available epidemiological evidence suggests that normal social or routine clinical contact with affected patients does not present a risk to health care workers, relatives or the community. Isolation of patients is not considered necessary. Nevertheless as the prions are resistant to conventional chemical, irradiation and heat sterilisation methods, highly specific cross-infection control measures are required for the dental management of patients with, or at notable risk, of TSE. The present article reviews current knowledge of the clinical consequences of prion disease and provides information regarding necessary changes to the cross-infection routine when managing patients infected, or at risk of, prion disease.

  19. A quantitative risk assessment for bovine spongiform encephalopathy in Japan.

    PubMed

    Kadohira, M; Stevenson, M A; Høgåsen, H R; de Koeijer, A

    2012-12-01

    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 comprised of a stochastic spreadsheet calculation model with the following inputs: (1) the origin and quantity of live cattle and meat and bone meal imported into Japan, (2) the age distribution of native cattle, and (3) the estimated annual basic reproduction ratio (R(0) ) for BSE. The estimated probability of having zero detectable cases in Japan in 2015 was 0.90 (95% CI 0.83-0.95). The corresponding value for 2020 was 0.99 (95% CI 0.98-0.99). The model predicted that detectable cases may occur in Japan beyond 2015 because of the assumption that continued transmission was permitted to occur (albeit at a very low level) after the 2001 ban on the importation and domestic use of all processed animal proteins for the production of animal feed and for fertilizer. These results reinforce the need for animal health authorities to monitor the efficacy of control measures so that the future course of the BSE epidemic in Japan can be predicted with greater certainty. © 2012 Society for Risk Analysis.

  20. Foodborne Transmission of Bovine Spongiform Encephalopathy to Nonhuman Primates

    PubMed Central

    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

    2013-01-01

    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. PMID:23647575

  1. Foodborne transmission of bovine spongiform encephalopathy to nonhuman primates.

    PubMed

    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

    2013-05-01

    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.

  2. Direct costs of bovine spongiform encephalopathy control measures in Germany.

    PubMed

    Probst, C; Gethmann, J M; Heuser, R; Niemann, H; Conraths, F J

    2013-12-01

    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. © 2013 Blackwell Verlag GmbH.

  3. Susceptibility of European red deer (Cervus elaphus elaphus) to alimentary challenge with bovine spongiform encephalopathy.

    PubMed

    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

    2015-01-01

    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

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

    PubMed Central

    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

    2015-01-01

    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

  5. Identification of a heritable polymorphism in the bovine prion gene associated with genetic transmissible spongiform encephalopathy: evidence of heritable BSE

    USDA-ARS?s Scientific Manuscript database

    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...

  6. Identification of a heritable polymorphism in bovine PRNP associated with genetic transmissible spongiform encephalopathy: evidence of heritable BSE

    USDA-ARS?s Scientific Manuscript database

    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...

  7. Bovine spongiform encephalopathy in Sweden: an H-type variant.

    PubMed

    Gavier-Widén, Dolores; Nöremark, Maria; Langeveld, Jan P M; Stack, Mick; Biacabe, Anne-Gaëlle; Vulin, Johann; Chaplin, Melanie; Richt, Jürgen A; Jacobs, Jorg; Acín, Cristina; Monleón, Eva; Renström, Lena; Klingeborn, Berndt; Baron, Thierry G M

    2008-01-01

    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, because several molecular features of the protease-resistant prion protein (PrP(res)) were different from classical BSE. The differences included higher susceptibility for proteinase K, higher molecular weight of the PrP(res) bands, affinity to the N-terminus-specific antibodies 12B2 and P4, and peculiar banding pattern with antibody SAF84 showing an additional band at the 14 kDa position. The molecular characteristics were in accordance to previous descriptions of H-type BSE. This report shows that a range of Western blot techniques and antibodies can be applied to confirm H-type BSE and further describes that the ratio of the amounts of PrPres#1 and PrPres#2, after deglycosylation, depends on the antibody used during processing. Immunohistochemistry on sections of medulla at the level of the obex applying antibodies with epitopes covering a broad range of the PrP sequence showed accumulation of disease-specific PrP (PrP(d)) in the gray matter. Fine punctate deposition in the neuropil was the most predominant type and was more severe in BSE target nuclei. The types of PrP(d) deposition are described in comparison with classical BSE. PrP-gene sequencing showed 6 copy octarepeat alleles and no abnormalities. It is postulated that the disease had a spontaneous origin, rather than having had been acquired in the BSE epidemic.

  8. A Heparin Purification Process Removes Spiked Transmissible Spongiform Encephalopathy Agent.

    PubMed

    Bett, Cyrus; Grgac, Ksenija; Long, Dianna; Karfunkle, Michael; Keire, David A; Asher, David M; Gregori, Luisa

    2017-01-23

    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.

  9. Bovine spongiform encephalopathy in South America: a regional preventive approach.

    PubMed

    van Gelderen, C; Gimeno, E J; Schudel, A A

    2003-04-01

    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.

  10. Highly sensitive detection of small ruminant bovine spongiform encephalopathy within transmissible spongiform encephalopathy mixes by serial protein misfolding cyclic amplification.

    PubMed

    Gough, Kevin C; Bishop, Keith; Maddison, Ben C

    2014-11-01

    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). Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  11. Pathobiology and diagnosis of animal transmissible spongiform encephalopathies: current knowledge, research gaps, and opportunities

    USDA-ARS?s Scientific Manuscript database

    Transmissible spongiform encephalopathies (TSEs) are fatal neurologic diseases that can affect several animal species and human beings. There are four animal TSE agents found in the United States: scrapie of sheep and goats; chronic wasting disease (CWD) of deer, elk, and moose; transmissible mink ...

  12. Comparative aspects of bovine spongiform encephalopathy isolates found in the U.S.

    USDA-ARS?s Scientific Manuscript database

    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...

  13. Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle

    PubMed Central

    Iwamaru, Yoshifumi; Imamura, Morikazu; Miyazawa, Kohtaro; Matsuura, Yuichi; Masujin, Kentaro; Murayama, Yuichi; Yokoyama, Takashi

    2017-01-01

    To determine oral transmissibility of the L-type bovine spongiform encephalopathy (BSE) prion, we orally inoculated 16 calves with brain homogenates of the agent. Only 1 animal, given a high dose, showed signs and died at 88 months. These results suggest low risk for oral transmission of the L-BSE agent among cattle. PMID:28098532

  14. Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle.

    PubMed

    Okada, Hiroyuki; Iwamaru, Yoshifumi; Imamura, Morikazu; Miyazawa, Kohtaro; Matsuura, Yuichi; Masujin, Kentaro; Murayama, Yuichi; Yokoyama, Takashi

    2017-02-01

    To determine oral transmissibility of the L-type bovine spongiform encephalopathy (BSE) prion, we orally inoculated 16 calves with brain homogenates of the agent. Only 1 animal, given a high dose, showed signs and died at 88 months. These results suggest low risk for oral transmission of the L-BSE agent among cattle.

  15. Comparison of Abnormal Prion Protein Glycoform Patterns from Transmissible Spongiform Encephalopathy Agent-Infected Deer, Elk, Sheep, and Cattle

    PubMed Central

    Race, Richard E.; Raines, Anne; Baron, Thierry G. M.; Miller, Michael W.; Jenny, Allen; Williams, Elizabeth S.

    2002-01-01

    Analysis of abnormal prion protein glycoform patterns from chronic wasting disease (CWD)-affected deer and elk, scrapie-affected sheep and cattle, and cattle with bovine spongiform encephalopathy failed to identify patterns capable of reliably distinguishing these transmissible spongiform encephalopathy diseases. However, PrP-res patterns sometimes differed among individual animals, suggesting infection by different or multiple CWD strains in some species. PMID:12414979

  16. Biochemical and immunohistochemical characterization of feline spongiform encephalopathy in a German captive cheetah.

    PubMed

    Eiden, Martin; Hoffmann, Christine; Balkema-Buschmann, Anne; Müller, Matthias; Baumgartner, Katrin; Groschup, Martin H

    2010-11-01

    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.

  17. Laboratory activities involving transmissible spongiform encephalopathy causing agents: risk assessment and biosafety recommendations in Belgium.

    PubMed

    Leunda, Amaya; Van Vaerenbergh, Bernadette; Baldo, Aline; Roels, Stefan; Herman, Philippe

    2013-01-01

    Since the appearance in 1986 of epidemic of bovine spongiform encephalopathy (BSE), a new form of neurological disease in cattle which also affected human beings, many diagnostic and research activities have been performed to develop detection and therapeutic tools. A lot of progress was made in better identifying, understanding and controlling the spread of the disease by appropriate monitoring and control programs in European countries. This paper reviews the recent knowledge on pathogenesis, transmission and persistence outside the host of prion, the causative agent of transmissible spongiform encephalopathies (TSE) in mammals with a particular focus on risk (re)assessment and management of biosafety measures to be implemented in diagnostic and research laboratories in Belgium. Also, in response to the need of an increasing number of European diagnostic laboratories stopping TSE diagnosis due to a decreasing number of TSE cases reported in the last years, decontamination procedures and a protocol for decommissioning TSE diagnostic laboratories is proposed.

  18. Fluorescence Spectroscopy of the Retina for the Screening of Bovine Spongiform Encephalopathy.

    PubMed

    Bhattacharjee, Ujjal; Graham, Catherine; Czub, Stefanie; Dudas, Sandor; Rasmussen, Mark A; Casey, Thomas A; Petrich, Jacob W

    2016-01-13

    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.

  19. Cows for fear: is BSE a threat to human health? Bovine spongiform encephalopathy.

    PubMed Central

    Josephson, J

    1998-01-01

    In 1996, a new variant of Creutzfeldt-Jakob disease (vCJD)-a disease that causes lack of coordination, muscle twitching or jerking, dementia, and, eventually, death-suddenly appeared in Great Britain. It is believed that the victims contracted the disease from eating the beef of cattle stricken with bovine spongiform encephalopathy (BSE), or mad cow disease. As of December 1997, at least 25 people in the United Kingdom and France have contracted vCJD. PMID:9485478

  20. [Maternal transmission or bovine spongiform encephalopathy in the case of "Cindy" disproved].

    PubMed

    Baumgartner, B G; Margan, U; Olek, K; Wagner, V; Brenig, B

    1997-09-01

    On December 27th, 1996 a Galloway cattle named "Cindy" died of bovine spongiform encephalopathy (BSE) in Höxter. So far all cases of BSE reported in Germany have been imported from the UK. However, the identity and origin of "Cindy" was not clear. DNA sequence analysis of the mitochondrial D-loop region and DNA typing of micro-satellite sites finally revealed that "Cindy" was imported from the UK as well.

  1. Public risk perception of relaxation of transmissible spongiform encephalopathies (TSE) measures in Europe.

    PubMed

    Dressel, K; Perazzini, A; Ru, G; Van Wassenhove, W

    2011-01-01

    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.

  2. Bovine spongiform encephalopathy: a tipping point in One Health and Food Safety.

    PubMed

    Hope, James

    2013-01-01

    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.

  3. Squirrel monkeys (Saimiri sciureus) infected with the agent of bovine spongiform encephalopathy develop tau pathology.

    PubMed

    Piccardo, P; Cervenak, J; Yakovleva, O; Gregori, L; Pomeroy, K; Cook, A; Muhammad, F S; Seuberlich, T; Cervenakova, L; Asher, D M

    2012-07-01

    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. Published by Elsevier Ltd.

  4. Autoantibodies to Brain Components and Antibodies to Acinetobacter calcoaceticus Are Present in Bovine Spongiform Encephalopathy

    PubMed Central

    Tiwana, Harmale; Wilson, Clyde; Pirt, John; Cartmell, William; Ebringer, Alan

    1999-01-01

    Bovine spongiform encephalopathy (BSE) is a neurological disorder, predominantly of British cattle, which belongs to the group of transmissible spongiform encephalopathies together with Creutzfeldt-Jakob disease (CJD), kuru, and scrapie. Autoantibodies to brain neurofilaments have been previously described in patients with CJD and kuru and in sheep affected by scrapie. Spongiform-like changes have also been observed in chronic experimental allergic encephalomyelitis, at least in rabbits and guinea pigs, and in these conditions autoantibodies to myelin occur. We report here that animals with BSE have elevated levels of immunoglobulin A autoantibodies to brain components, i.e., neurofilaments (P < 0.001) and myelin (P < 0.001), as well as to Acinetobacter calcoaceticus (P < 0.001), saprophytic microbes found in soil which have sequences cross-reacting with bovine neurofilaments and myelin, but there were no antibody elevations against Agrobacterium tumefaciens or Escherichia coli. The relevance of such mucosal autoantibodies or antibacterial antibodies to the pathology of BSE and its possible link to prions requires further evaluation. PMID:10569779

  5. Phenotypic Similarity of Transmissible Mink Encephalopathy in Cattle and L-type Bovine Spongiform Encephalopathy in a Mouse Model

    PubMed Central

    Bencsik, Anna; Biacabe, Anne-Gaëlle; Morignat, Eric; Bessen, Richard A.

    2007-01-01

    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. PMID:18258040

  6. Phenotypic similarity of transmissible mink encephalopathy in cattle and L-type bovine spongiform encephalopathy in a mouse model.

    PubMed

    Baron, Thierry; Bencsik, Anna; Biacabe, Anne-Gaëlle; Morignat, Eric; Bessen, Richard A

    2007-12-01

    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.

  7. Spongiform encephalopathy in a herd of greater kudu (Tragelaphus strepsiceros): epidemiological observations.

    PubMed

    Kirkwood, J K; Cunningham, A A; Wells, G A; Wilesmith, J W; Barnett, J E

    1993-10-09

    A small herd of greater kudu, derived from three individuals, has been maintained at the Zoological Society of London since 1970. Spongiform encephalopathy has been diagnosed in five out of eight of the animals born in this herd since 1987. With the possible exception of the first confirmed case, none of these is thought to have been exposed to feeds containing ruminant-derived protein. The pattern of incidence suggests that greater kudu are very susceptible to the disease and that natural lateral transmission may have occurred among them.

  8. Assessing the susceptibility of transgenic mice overexpressing deer prion protein to bovine spongiform encephalopathy.

    PubMed

    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

    2014-02-01

    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.

  9. Bad news and good news: what the dentist needs to know about transmissible spongiform encephalopathies.

    PubMed

    Gonzales, T S; Rushing, E J

    1998-05-01

    Since reports of the "mad cow disease" epidemic in Great Britain erupted in the international press, sensational and intimidating articles about the risk that bovine spongiform encephalopathy and related diseases may pose to humans have appeared. The bad news is that compelling scientific evidence suggests so-called prion disease can and has infected humans, although the overall risk appears to be low. Furthermore, at present, there is no reliable antemortem diagnosis, specific treatment, or vaccine to prevent the disease. The agent thought to be responsible for this unusual class of disease is a rogue protein (called a prion) that, unlike all other agents known to cause infectious disease, contains neither DNA nor RNA. According to a popular hypothesis, normal membrane-associated prion proteins undergo conformational changes that can cause disease. The "bad" prion forms cause holes or a spongy appearance in the brain in all disease variants, hence the generic designation of spongiform encephalopathy. The good news is that risk for exposure to prion disease is exceedingly remote in the dental practice and that current universal infection control procedures are probably sufficient.

  10. [Prions: where do we stand 20 years after the appearance of bovine spongiform encephalopathy?].

    PubMed

    Crozet, Carole; Lehmann, Sylvain

    2007-12-01

    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.

  11. Central nervous system extracellular matrix changes in a transgenic mouse model of bovine spongiform encephalopathy.

    PubMed

    Costa, Carme; Tortosa, Raül; Vidal, Enric; Padilla, Danielle; Torres, Juan Maria; Ferrer, Isidre; Pumarola, Martí; Bassols, Anna

    2009-11-01

    Bovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy characterised by accumulation of resistant prion protein (PrP(BSE)), neuronal loss, spongiosus and glial cell proliferation. In this study, properties of the extracellular matrix (ECM) were investigated in boTg110 transgenic mice over-expressing the bovine cellular prion protein (PrP(c)) and infected with BSE. Using immunohistochemistry with Wisteria floribunda agglutinin as a specific marker for perineuronal nets (PNNs) and antibodies against aggrecan and hyaluronic acid binding protein, loss of ECM was correlated with PrP(BSE) accumulation and activation of astrocytes and microglia. PrP(BSE) accumulation and glial cell activation were detected from the earliest stages of the disease and increased in the terminal stages. Decreases in PNNs, aggrecan and hyaluronic acid were observed only in the terminal stages and correlated with the distribution of PrP(BSE) and activated glial cells. This study suggests that the loss of PNNs, aggrecan and hyaluronic acid is a consequence of PrP(BSE) accumulation. Degradation of ECM in BSE may be due to secretion of degradative enzymes by activated glial cells.

  12. Central nervous system gene expression changes in a transgenic mouse model for bovine spongiform encephalopathy

    PubMed Central

    2011-01-01

    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. PMID:22035425

  13. EU-approved rapid tests might underestimate bovine spongiform encephalopathy infection in goats.

    PubMed

    Meloni, Daniela; Bozzetta, Elena; Langeveld, Jan P M; Groschup, Martin H; Goldmann, Wilfred; Andrèoletti, Olivier; Lantier, Isabelle; Van Keulen, Lucien; Bossers, Alex; Pitardi, Danilo; Nonno, Romolo; Sklaviadis, Theodoros; Ingravalle, Francesco; Peletto, Simone; Colussi, Silvia; Acutis, Pier Luigi

    2017-03-01

    We report the diagnostic sensitivity of 3 EU-approved rapid tests (ELISAs; 1 from IDEXX and 2 from Bio-Rad) for the detection of transmissible spongiform encephalopathy diseases in goats. Ninety-eight goat brainstem samples were tested. All the rapid tests had 100% specificity and ≥80% sensitivity, with the IDEXX test significantly more sensitive than the 2 Bio-Rad tests. All tests detected 100% of samples from goats with clinical scrapie, but missed 8% (IDEXX) to 33% (Bio-Rad SG) of samples from preclinical goats. Importantly, only IDEXX picked up all samples from clinical bovine spongiform encephalopathy (BSE)-infected goats, whereas the other 2 rapid tests missed 15% (Bio-Rad SG) to 25% (Bio-Rad SAP). These results show that a fraction of preclinical scrapie infections are likely missed by EU surveillance, with sensitivity of detection strongly dependent on the choice of the rapid test. Moreover, a significant proportion of clinical BSE infections are underestimated by using either Bio-Rad test. Assuming that the same sensitivity on preclinical goats would also occur in BSE-infected goats, our data suggest that IDEXX is likely the most sensitive test for detecting preclinical field cases of BSE infection in goats, although with an 8% failure rate. These results raise some concerns about the reliability of current EU surveillance figures on BSE infection in goats.

  14. Generation of a persistently infected MDBK cell line with natural bovine spongiform encephalopathy (BSE).

    PubMed

    Tark, Dongseob; Kim, Hyojin; Neale, Michael H; Kim, Minjeong; Sohn, Hyunjoo; Lee, Yoonhee; Cho, Insoo; Joo, Yiseok; Windl, Otto

    2015-01-01

    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.

  15. Central nervous system gene expression changes in a transgenic mouse model for bovine spongiform encephalopathy.

    PubMed

    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

    2011-10-28

    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.

  16. Generation of a Persistently Infected MDBK Cell Line with Natural Bovine Spongiform Encephalopathy (BSE)

    PubMed Central

    Tark, Dongseob; Kim, Hyojin; Neale, Michael H.; Kim, Minjeong; Sohn, Hyunjoo; Lee, Yoonhee; Cho, Insoo; Joo, Yiseok; Windl, Otto

    2015-01-01

    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. PMID:25647616

  17. Inactivation of transmissible spongiform encephalopathy agents during the manufacture of dicalcium phosphate from bone.

    PubMed

    Grobben, A H; Steele, P J; Somerville, R A; Taylor, D M

    2006-03-18

    Dicalcium phosphate was prepared from industrial crushed bone artificially contaminated with transmissible spongiform encephalopathy agents in two experiments carried out in an accurately scaled-down laboratory model of the industrial manufacturing process. In one experiment, 10 g of mouse brain infected with the 301V strain of mouse-passaged bovine spongiform encephalopathy agent was added to the crushed bone; in the other experiment, 10 g of hamster brain infected with the 263K strain of hamster-passaged scrapie agent was added. Samples of the infectious brain and dried dicalcium phosphate were assayed for the amount of 301V or 263K infectivity present. The titre of infectivity of the 301V-infected brain was 10(7.7) intracerebral ID50/g; that of the 263K-infected brain was 10(8.0) intracerebral ID50/g. The titres of the dried samples of dicalcium phosphate were 10(2.5) ID50/g in the experiment spiked with 301V and 10(2.7) ID50/g in the experiment spiked with 263K. The calculated clearance factors were 10(3.9) for the experiment with 301V and 10(3.8) for the experiment with 263K.

  18. Possible Case of Maternal Transmission of Feline Spongiform Encephalopathy in a Captive Cheetah

    PubMed Central

    Bencsik, Anna; Debeer, Sabine; Petit, Thierry; Baron, Thierry

    2009-01-01

    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 2nd 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, PrPd 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. PMID:19738899

  19. Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative prion disease that affects cattle and can be transmitted to human beings as new variant Creutzfeldt-Jakob disease (vCJD). A protease-resistant, disease-associated isoform of the prion protein (PrP**Sc) accumulates in the central ner...

  20. Unique properties of the classical bovine spongiform encephalopathy strain and its emergence from H-type bovine spongiform encephalopathy substantiated by VM transmission studies.

    PubMed

    Bencsik, Anna; Leboidre, Mikael; Debeer, Sabine; Aufauvre, Claire; Baron, Thierry

    2013-03-01

    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.

  1. The early history of the transmissible spongiform encephalopathies exemplified by scrapie.

    PubMed

    Schneider, Kurt; Fangerau, Heiner; Michaelsen, Britta; Raab, Wolfgang H-M

    2008-12-16

    Transmissible spongiform encephalopathies (TSE) is a group of diseases that is unique in comprising disorders that can occur sporadically, are hereditary and/or infectious. The transmissible pathogen--the prion--is distinct from all other pathogens in being devoid of nucleic acids. During the elucidation of these disorders, many different--and contradictory--theories have been put forward. Early researchers, mostly driven by the economic impact of these diseases on sheep farming, engaged in heavy disputes concerning heredity vs. infectivity of scrapie. Following the experimental demonstration of scrapie's infectivity during the 20th century, research focused on the characterization of the nature of the transmissible agent. The current work comprehensively summarizes the available early literature on TSE research. A review of the historical literature is presented, describing the efforts in breeding, transmission experiments, and theories about the nature of the infectious agent.

  2. Vertical Transmission of Bovine Spongiform Encephalopathy Prions Evaluated in a Transgenic Mouse Model

    PubMed Central

    Castilla, J.; Brun, A.; Díaz-San Segundo, F.; Salguero, F. J.; Gutiérrez-Adán, A.; Pintado, B.; Ramírez, M. A.; del Riego, L.; Torres, J. M.

    2005-01-01

    In this work we show evidence of mother-to-offspring transmission in a transgenic mouse line expressing bovine PrP (boTg) experimentally infected by intracerebral administration of bovine spongiform encephalopathy (BSE) prions. PrPres was detected in brains of newborns from infected mothers only when mating was allowed near to the clinical stage of disease, when brain PrPres deposition could be detected by Western blot analysis. Attempts to detect infectivity in milk after intracerebral inoculation in boTg mice were unsuccessful, suggesting the involvement of other tissues as carriers of prion dissemination. The results shown here prove the ability of BSE prions to spread centrifugally from the central nervous system to peripheral tissues and to offspring in a mouse model. Also, these results may complement previous epidemiological data supporting the occurrence of vertical BSE transmission in cattle. PMID:15956610

  3. [Analysis of risk factors associated with bovine spongiform encephalopathy in Argentina].

    PubMed

    Cané, B G; Gimeno, E J; Manetti, J C; Van Gelderen, C; Ulloa, E; Schudel, A A

    1993-12-01

    Epidemiological studies conducted in the United Kingdom have revealed the risk factors involved in the epidemic of bovine spongiform encephalopathy (BSE). This has facilitated a detailed study of risk factors associated with the possible introduction of BSE into Argentina. An analysis has been made of the numbers and geographical distribution of cattle in the country, the structure of the Veterinary Services responsible for controlling animal diseases, the way in which cattle and sheep are slaughtered, and the use of slaughter waste in the feed industry. The results of this analysis form the basis of a discussion of whether scrapie or BSE could become endemic in Argentina through contaminated feed or another route. The authors conclude that Argentina may be regarded as free from BSE, and that the importation of infected bovines is the sole potential risk for introduction of BSE in the future.

  4. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution, and current concerns.

    PubMed Central

    Brown, P.; Will, R. G.; Bradley, R.; Asher, D. M.; Detwiler, L.

    2001-01-01

    The epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom, which began in 1986 and has affected nearly 200,000 cattle, is waning to a conclusion, but leaves in its wake an outbreak of human Creutzfeldt-Jakob disease, most probably resulting from the consumption of beef products contaminated by central nervous system tissue. Although averaging only 10-15 cases a year since its first appearance in 1994, its future magnitude and geographic distribution (in countries that have imported infected British cattle or cattle products, or have endogenous BSE) cannot yet be predicted. The possibility that large numbers of apparently healthy persons might be incubating the disease raises concerns about iatrogenic transmissions through instrumentation (surgery and medical diagnostic procedures) and blood and organ donations. Government agencies in many countries continue to implement new measures to minimize this risk. PMID:11266289

  5. The clearance of viruses and transmissible spongiform encephalopathy agents from biologicals.

    PubMed

    Farshid, Mahmood; Taffs, Rolf E; Scott, Dorothy; Asher, David M; Brorson, Kurt

    2005-10-01

    The viral and transmissible spongiform encephalopathy (TSE) safety of therapeutics of biological origin (biologicals) is greatly influenced by the nature and degree of variability of the source material and by the mode of purification. Plasma-derived and recombinant DNA products currently have good viral safety records, but challenges remain. In general, large enveloped viruses are easier to remove from biologicals than small 'naked' viruses. Monoclonal antibodies and recombinant DNA biopharmaceuticals are derived from relatively homogeneous source materials and purified by multistep schemes that are robust and amenable to scientific analysis and engineering improvement. Viral clearance is more challenging for blood and cell products, as they are complex and labile. Source selection (e.g. country of origin, deferral for CJD risk factors) currently occupies the front line for ensuring that biologicals are free of TSE agents, but robust methods for their clearance from products are under development.

  6. Atypical variants of bovine spongiform encephalopathy: rare diseases with consequences for BSE surveillance and control.

    PubMed

    Boujon, C; Serra, F; Seuberlich, T

    2016-03-01

    Occurring for the first time in 1986 in the United Kingdom, bovine spongiform encephalopathy (BSE), the so-called "mad-cow disease", has had unprecedented consequences in veterinary public health. The implementation of drastic measures, including the ban of meat-and-bone-meal from livestock feed and the removal of specified risk materials from the food chain has eventually resulted in a significant decline of the epidemic. The disease was long thought to be caused by a single agent, but since the introduction of immunochemical diagnostic techniques, evidence of a phenotypic variation of BSE has emerged. Reviewing the literature available on the subject, this paper briefly summarizes the current knowledge about these atypical forms of BSE and discusses the consequences of their occurrence for disease control measures.

  7. Classical Bovine Spongiform Encephalopathy by Transmission of H-Type Prion in Homologous Prion Protein Context

    PubMed Central

    Andréoletti, Olivier; Lacroux, Caroline; Prieto, Irene; Lorenzo, Patricia; Larska, Magdalena; Baron, Thierry; Espinosa, Juan-Carlos

    2011-01-01

    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. PMID:21888788

  8. Polymorphism of the prion protein gene (PRNP) in Polish cattle affected by classical bovine spongiform encephalopathy.

    PubMed

    Gurgul, Artur; Czarnik, Urszula; Urszula, Czarnik; Larska, Magdalena; Polak, Mirosław P; Strychalski, Janusz; Słota, Ewa

    2012-05-01

    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.

  9. Predominant involvement of the cerebellum in guinea pigs infected with bovine spongiform encephalopathy (BSE).

    PubMed

    Furuoka, H; Horiuchi, M; Yamakawa, Y; Sata, T

    2011-05-01

    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. Copyright © 2010 Elsevier Ltd. All rights reserved.

  10. Properties of L-type bovine spongiform encephalopathy in intraspecies passages.

    PubMed

    Okada, H; Iwamaru, Y; Kakizaki, M; Masujin, K; Imamura, M; Fukuda, S; Matsuura, Y; Shimizu, Y; Kasai, K; Mohri, S; Yokoyama, T

    2012-09-01

    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.

  11. Disease characteristics of bovine spongiform encephalopathy following inoculation into mice via three different routes.

    PubMed

    Vickery, Christopher M; Beck, Katy E; Simmons, Marion M; Hawkins, Stephen A C; Spiropoulos, John

    2013-10-01

    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. © 2013 Crown Copyright. International Journal of Experimental Pathology published by John Wiley & Sons Ltd.

  12. Detection and Localisation of PrPSc in the Liver of Sheep Infected with Scrapie and Bovine Spongiform Encephalopathy

    PubMed Central

    Everest, Sally J.; Ramsay, Andrew M.; Chaplin, Melanie J.; Everitt, Sharon; Stack, Michael J.; Neale, Michael H.; Jeffrey, Martin; Moore, S. Jo; Bellworthy, Susan J.; Terry, Linda A.

    2011-01-01

    Prions are largely contained within the nervous and lymphoid tissue of transmissible spongiform encephalopathy (TSE) infected animals. However, following advances in diagnostic sensitivity, PrPSc, a marker for prion disease, can now be located in a wide range of viscera and body fluids including muscle, saliva, blood, urine and milk, raising concerns that exposure to these materials could contribute to the spread of disease in humans and animals. Previously we demonstrated low levels of infectivity in the liver of sheep experimentally challenged with bovine spongiform encephalopathy. In this study we show that PrPSc accumulated in the liver of 89% of sheep naturally infected with scrapie and 100% of sheep challenged with BSE, at both clinical and preclinical stages of the disease. PrPSc was demonstrated in the absence of obvious inflammatory foci and was restricted to isolated resident cells, most likely Kupffer cells. PMID:21589864

  13. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-type bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from normal cellular prion protein to pathogenic misfolded conformation. This conversion has been used for in vitro assays including serial protein misfolding amplification...

  14. Bovine PrP expression levels in transgenic mice influence transmission characteristics of atypical bovine spongiform encephalopathy.

    PubMed

    Wilson, Rona; Hart, Patricia; Piccardo, Pedro; Hunter, Nora; Casalone, Cristina; Baron, Thierry; Barron, Rona M

    2012-05-01

    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.

  15. Bovine PrP expression levels in transgenic mice influence transmission characteristics of atypical bovine spongiform encephalopathy

    PubMed Central

    Wilson, Rona; Hart, Patricia; Piccardo, Pedro; Hunter, Nora; Casalone, Cristina; Baron, Thierry

    2012-01-01

    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. PMID:22302882

  16. Presence of subclinical infection in gene-targeted human prion protein transgenic mice exposed to atypical bovine spongiform encephalopathy.

    PubMed

    Wilson, Rona; Dobie, Karen; Hunter, Nora; Casalone, Cristina; Baron, Thierry; Barron, Rona M

    2013-12-01

    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.

  17. Dissociation of Prion Protein Amyloid Seeding from Transmission of a Spongiform Encephalopathy

    PubMed Central

    Piccardo, Pedro; King, Declan; Telling, Glenn; Manson, Jean C.

    2013-01-01

    Misfolding and aggregation of proteins are common pathogenic mechanisms of a group of diseases called proteinopathies. The formation and spread of proteinaceous lesions within and between individuals were first described in prion diseases and proposed as the basis of their infectious nature. Recently, a similar “prion-like” mechanism of transmission has been proposed in other neurodegenerative diseases such as Alzheimer's disease. We investigated if misfolding and aggregation of corrupted prion protein (PrPTSE) are always associated with horizontal transmission of disease. Knock-in transgenic mice (101LL) expressing mutant PrP (PrP-101L) that are susceptible to disease but do not develop any spontaneous neurological phenotype were inoculated with (i) brain extracts containing PrPTSE from healthy 101LL mice with PrP plaques in the corpus callosum or (ii) brain extracts from mice overexpressing PrP-101L with neurological disease, severe spongiform encephalopathy, and formation of proteinase K-resistant PrPTSE. In all instances, 101LL mice developed PrP plaques in the area of inoculation and vicinity in the absence of clinical disease or spongiform degeneration of the brain. Importantly, 101LL mice did not transmit disease on serial passage, ruling out the presence of subclinical infection. Thus, in both experimental models the formation of PrPTSE is not infectious. These results have implications for the interpretation of tests based on the detection of protein aggregates and suggest that de novo formation of PrPTSE in the host does not always result in a transmissible prion disease. In addition, these results question the validity of assuming that all diseases due to protein misfolding can be transmitted between individuals. PMID:24027305

  18. In vitro amplification of H-type atypical bovine spongiform encephalopathy by protein misfolding cyclic amplification

    PubMed Central

    O‘Connor, Matthew J.; Bishop, Keith; Workman, Robert G.; Maddison, Ben C.

    2017-01-01

    ABSTRACT The in vitro amplification of prions by serial protein misfolding cyclic amplification has been shown to detect PrPSc to levels at least as sensitive as rodent bioassay but in a fraction of the time. Bovine spongiform encephalopathy is a zoonotic prion disease in cattle and has been shown to occur in 3 distinct forms, classical BSE (C-BSE) and 2 atypical BSE forms (L-BSE and H-BSE). Atypical forms are usually detected in asymptomatic, older cattle and are suggested to be spontaneous forms of the disease. Here, we show the development of a serial protein misfolding cyclic amplification method for the detection of H-BSE. The assay could detect PrPSc from 3 distinct experimental isolates of H-BSE, could detect PrPSc in as little as 1×10−12 g of brain material and was highly specific. Additionally, the product of serial protein misfolding cyclic amplification at all dilutions of seed analyzed could be readily distinguished from L-BSE, which did not amplify, and C-BSE, which had PrPSc with distinct protease K-resistance and protease K-resistant PrPSc molecular weights. PMID:28281929

  19. On the Question of Sporadic or Atypical Bovine Spongiform Encephalopathy and Creutzfeldt-Jakob Disease

    PubMed Central

    McShane, Lisa M.; Zanusso, Gianluigi; Detwiler, Linda

    2006-01-01

    Strategies to investigate the possible existence of sporadic bovine spongiform encephalopathy (BSE) require systematic testing programs to identify cases in countries considered to have little or no risk of orally acquired disease or to detect a stable occurrence of atypical cases in countries in which orally acquired disease is disappearing. To achieve 95% statistical confidence that the prevalence for sporadic BSE is no greater than 1 per million (i.e., the annual incidence of sporadic Creutzfeldt-Jakob disease [CJD] in humans) would require negative tests in 3 million randomly selected older cattle. A link between BSE and sporadic CJD has been suggested on the basis of laboratory studies but is unsupported by epidemiologic observation. Such a link might yet be established by the discovery of a specific molecular marker or of particular combinations of trends over time of typical and atypical BSE and various subtypes of sporadic CJD, as their numbers are influenced by a continuation of current public health measures that exclude high-risk bovine tissues from the animal and human food chains. PMID:17326930

  20. Assessing transmissible spongiform encephalopathy species barriers with an in vitro prion protein conversion assay

    USGS Publications Warehouse

    Johnson, Christopher J.; Carlson, Christina M.; Morawski, Aaron R.; Manthei, Alyson; Cashman, Neil R.

    2015-01-01

    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.

  1. Assessing Transmissible Spongiform Encephalopathy Species Barriers with an In Vitro Prion Protein Conversion Assay

    PubMed Central

    Johnson, Christopher J.; Carlson, Christina M.; Morawski, Aaron R.; Manthei, Alyson; Cashman, Neil R.

    2015-01-01

    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 vitro prion 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. PMID:25867521

  2. Spatial analysis of bovine spongiform encephalopathy in Galicia, Spain (2000-2005).

    PubMed

    Allepuz, A; López-Quílez, A; Forte, A; Fernández, G; Casal, J

    2007-05-16

    In Spain, the first bovine spongiform encephalopathy (BSE) case was detected in 2000 in a cow born in the Galicia region (Northwestern Spain). From then and until October 2005, 590 cases were detected, 223 of them in Galicia. In 1994, meat and bone meal (MBM) was banned on ruminant feed and, in 1996, an EU decision mandating an overall change in MBM processing was implemented. This decision was gradually applied in the territory and not enforced before July 1998. The objective of this study was to explore clustering of BSE cases and estimate the standard incidence ratio (SIR) of BSE in Galicia. Our study was based on the BSE cases detected during the surveillance period 2000-2005 in the Galicia region. These cases were divided, based on birth date, into two periods: animals born from 1994 to July 1998, and those born after July 1998. We tested the role of cross-contamination on the geographical SIR distribution for both periods. Hierarchical Bayesian models were used to model the overdispersion and lack of independence of the SIR estimates. The geographical distribution of the standard incidence ratio of BSE between both periods was different. In the second period, the SIR was reduced in some areas. The reduction in these areas could be attributable to the changes in the processing of MBM. We did not find any statistical link between the poultry population and the standard incidence ratio, but pig population had a positive effect.

  3. Infectivity in skeletal muscle of cattle with atypical bovine spongiform encephalopathy.

    PubMed

    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

    2012-01-01

    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.

  4. [Prion diseases. Subacute spongiform encephalopathies in humans and animals (neural "anthropo- and zooprionoses")].

    PubMed

    Kod'ousek, R

    1999-01-01

    General review concerning current problems of subacute spongiform encephalopathies (Prion-diseases) in humans and in animals. The work is based on the aetiological conception of "Prion" as an allosteric conformational variant of the Prion-protein with autocatalytic "infectious" properties. The therm "Anthropoprionosis" and "Zooprionosis" are recommended by the author for human and animal Prion-diseases. Actual medical problems of various Prion-diseases are discussed in more detail, particularly those of aetiopathogenesis, genetics and molecular-biological principles in Prion-replication as well as the consensual neuropathological and clinical diagnostical criteria. Neuropathological findings are evaluated based on personal experience of diagnosed and/or consulted CJD-cases. On the ultrastructural level the morphological proof of abnormal secondary phagosomes in neurons of the CNS with accumulation of protein material ("prionosomes") is documented. Finally, the risks of CJD and the infectious potential of various organs and contaminated materials are also mentioned. In the methodical part, safety precautions in handling histological material from stereotactic biopsies and necropsies of brain are described, including safety techniques of autopsy in cases of CJD.

  5. Nonenzymatic glycation at the N terminus of pathogenic prion protein in transmissible spongiform encephalopathies.

    PubMed

    Choi, Yeong-Gon; Kim, Jae-Il; Jeon, Yong-Chul; Park, Seok-Joo; Choi, Eun-Kyoung; Rubenstein, Richard; Kascsak, Richard J; Carp, Richard I; Kim, Yong-Sun

    2004-07-16

    Transmissible spongiform encephalopathies (TSEs) are transmissible neurodegenerative diseases characterized by the accumulation of an abnormally folded prion protein, termed PrPSc, and the development of pathological features of astrogliosis, vacuolation, neuronal cell loss, and in some cases amyloid plaques. Although considerable structural characterization of prion protein has been reported, neither the method of conversion of cellular prion protein, PrPC, into the pathogenic isoform nor the post-translational modification processes involved is known. We report that in animal and human TSEs, one or more lysines at residues 23, 24, and 27 of PrPSc are covalently modified with advanced glycosylation end products (AGEs), which may be carboxymethyl-lysine (CML), one of the structural varieties of AGEs. The arginine residue at position 37 may also be modified with AGE, but not the arginine residue at position 25. This result suggests that nonenzymatic glycation is one of the post-translational modifications of PrP(Sc). Furthermore, immunostaining studies indicate that, at least in clinically affected hamsters, astrocytes are the first site of this glycation process.

  6. The evolution of risk perceptions related to bovine spongiform encephalopathy--Canadian consumer and producer behavior.

    PubMed

    Yang, Jun; Goddard, Ellen

    2011-01-01

    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.

  7. Emergence of a novel bovine spongiform encephalopathy (BSE) prion from an atypical H-type BSE.

    PubMed

    Masujin, Kentaro; Okada, Hiroyuki; Miyazawa, Kohtaro; Matsuura, Yuichi; Imamura, Morikazu; Iwamaru, Yoshifumi; Murayama, Yuichi; Yokoyama, Takashi

    2016-03-07

    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.

  8. Autoantibody to glial fibrillary acidic protein in the sera of cattle with bovine spongiform encephalopathy.

    PubMed

    Nomura, Sachiko; Miyasho, Taku; Maeda, Naoyuki; Doh-ura, Katsumi; Yokota, Hiroshi

    2009-08-01

    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.

  9. The Canadian Management of Bovine Spongiform Encephalopathy in Historical and Scientific Perspective, 1990-2014.

    PubMed

    Quimby, Alexandra E; Shamy, Michel C F

    2015-11-01

    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.

  10. Emergence of a novel bovine spongiform encephalopathy (BSE) prion from an atypical H-type BSE

    PubMed Central

    Masujin, Kentaro; Okada, Hiroyuki; Miyazawa, Kohtaro; Matsuura, Yuichi; Imamura, Morikazu; Iwamaru, Yoshifumi; Murayama, Yuichi; Yokoyama, Takashi

    2016-01-01

    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. PMID:26948374

  11. Gene expression in the medulla following oral infection of cattle with bovine spongiform encephalopathy.

    PubMed

    Almeida, Luciane M; Basu, Urmila; Khaniya, Bina; Taniguchi, Masaaki; Williams, John L; Moore, Stephen S; Guan, Le Luo

    2011-01-01

    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.

  12. A stochastic model of the bovine spongiform encephalopathy epidemic in Canada.

    PubMed

    Oraby, Tamer; Al-Zoughool, Mustafa; Elsaadany, Susie; Krewski, Daniel

    2016-01-01

    Bovine spongiform encephalopathy (BSE) appeared in the United Kingdom in the mid 1980s, and has been attributed to the use of meat and bone meal (MBM) in cattle feed contaminated with a scrapie-like agent. Import of infectious materials from a country where BSE has occurred is believed to be the major factor underlying the spread of the BSE epidemic to other countries. This study presents a new stochastic model developed to estimate risk of BSE from importation of cattle infected with the BSE agent. The model describes the propagation of the BSE agent through the Canadian cattle herd through rendering and feeding processes, following importation of cattle with infectious prions. This model was used estimate the annual number of newly infected animals each year over the period 1980-2019. Model predictions suggested that the number of BSE infections in Canada might have been approximately 40-fold greater than the actual number of clinically diagnosed cases. Under complete compliance with the 2007 ban on feeding MBM, this model further predicts that BSE is disappearing from the Canadian cattle system. A series of sensitivity analyses was also conducted to test the robustness of model predictions to alternative assumptions about factors affecting the evolution of the Canadian BSE epidemic.

  13. Mathematical Models for Estimating the Risks of Bovine Spongiform Encephalopathy (BSE).

    PubMed

    Al-Zoughool, Mustafa; Cottrell, David; Elsaadany, Susie; Murray, Noel; Oraby, Tamer; Smith, Robert; Krewski, Daniel

    2015-01-01

    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.

  14. Microarray analysis in caudal medulla of cattle orally challenged with bovine spongiform encephalopathy.

    PubMed

    Almeida, L M; Basu, U; Williams, J L; Moore, S S; Guan, L L

    2011-10-25

    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 < 0.01); 81 DE genes had gene ontology functions, which included synapse function, calcium ion regulation, immune and inflammatory response, apoptosis, and cytoskeleton organization; 13 of these genes were found to be involved in 26 different Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The expression of five DE genes associated with synapse function (tachykinin, synuclein, neuropeptide Y, cocaine, amphetamine-responsive transcript, and synaptosomal-associated protein 25 kDa) and three DE genes associated with calcium ion regulation (parvalbumin, visinin-like, and cadherin) was further validated in the medulla tissue of cattle at different infection times (6, 12, 42, and 45 months post-infection) by qRT-PCR. These data will contribute to a better understanding of the molecular mechanisms of neuropathology in bovine species.

  15. Isolation from Cattle of a Prion Strain Distinct from That Causing Bovine Spongiform Encephalopathy

    PubMed Central

    Béringue, Vincent; Reine, Fabienne; Laï, Thanh Lan; Chenais, Nathalie; Tilly, Gaëlle; Biacabé, Anne-Gaëlle; Baron, Thierry; Vilotte, Jean-Luc; Laude, Hubert

    2006-01-01

    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 (PrPres) isolated from brains of affected animals or humans. However, alternate PrPres 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 PrPres 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. PMID:17054396

  16. Distribution of abnormal prion protein in a sheep affected with L-type bovine spongiform encephalopathy.

    PubMed

    Matsuura, Y; Iwamaru, Y; Masujin, K; Imamura, M; Mohri, S; Yokoyama, T; Okada, H

    2013-07-01

    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. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. PRNP and SPRN genes polymorphism in atypical bovine spongiform encephalopathy cases diagnosed in Polish cattle.

    PubMed

    Gurgul, Artur; Polak, Mirosław Paweł; Larska, Magdalena; Słota, Ewa

    2012-08-01

    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.

  18. Neuropathological changes in auditory brainstem nuclei in cattle with experimentally induced bovine spongiform encephalopathy.

    PubMed

    Fukuda, S; Okada, H; Arai, S; Yokoyama, T; Mohri, S

    2011-01-01

    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. Copyright © 2010 Elsevier Ltd. All rights reserved.

  19. SCRG1, a potential marker of autophagy in transmissible spongiform encephalopathies.

    PubMed

    Dron, Michel; Bailly, Yannick; Beringue, Vincent; Haeberlé, Anne-Marie; Griffond, Bernadette; Risold, Pierre-Yves; Tovey, Michael G; Laude, Hubert; Dandoy-Dron, Françoise

    2006-01-01

    The Scrg1 gene was initially discovered as one of the genes upregulated in transmissible spongiform encephalopathies (TSE). Scrg1 encodes a highly conserved, cysteine-rich protein expressed principally in the central nervous system. The protein is targeted to the Golgi apparatus and large dense-core vesicles/secretory granules in neurons. We have recently shown that the Scrg1 protein is widely induced in neurons of scrapie-infected mice, suggesting that Scrg1 is involved in the host response to stress and/or the death of neurons. At the ultrastructural level, Scrg1 is associated with dictyosomes of the Golgi apparatus and autophagic vacuoles of degenerative neurons. It is well known that apoptosis plays a major role in the events leading to neuronal cell death in TSE. However, autophagy was identified in experimentally induced scrapie a long time ago and was recently reevaluated as a possible cell death program in prion diseases. The consistent association of Scrg1 with autophagic structures typical of scrapie is in agreement with the recruitment of Golgi-specific proteins in this degradation process and we suggest that Scrg1 might be used as a specific probe to identify neuronal autophagy in TSE.

  20. Experimental challenge of cattle with German atypical bovine spongiform encephalopathy (BSE) isolates.

    PubMed

    Balkema-Buschmann, A; Ziegler, U; McIntyre, L; Keller, M; Hoffmann, C; Rogers, R; Hills, B; Groschup, M H

    2011-01-01

    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.

  1. Failure to demonstrate involvement of antibodies to Acinetobacter calcoaceticus in transmissible spongiform encephalopathies of animals.

    PubMed

    Nielsen, K; Widdison, J; Balachandran, A; Stevenson, D; Algire, J

    2002-10-28

    Acinetobacter calcoaceticus, a soil microbe, contains molecular sequences which resemble those found in neurofilaments of the brain tissue. It was hypothesized that if cattle ingest large amounts of feedstuff containing A. calcoaceticus, they may develop an autoimmune reaction, with consequences of pathological changes associated with transmissible spongiform encephalopathies (TSEs). The hypothesis was tested using a small number of serum samples collected from cattle and it was found that affected individuals had elevated serum antibody levels to this organism. If this finding was substantiated, it would provide a possible means of diagnosing TSEs in vivo. In the present communication, a larger number of cattle, elk and sheep with or without TSEs were tested using A. calcoaceticus whole cell and lipopolysaccharide antigens as well as myelin basic protein (MBP). It was found that antibody levels in normal and affected animals overlapped considerably, thus casting doubt on the usefulness of these antigens as diagnostic tools for TSEs and on the hypothesis of A. calcoaceticus being a cause of TSEs.

  2. Assessing transmissible spongiform encephalopathy species barriers with an in vitro prion protein conversion assay.

    PubMed

    Johnson, Christopher J; Carlson, Christina M; Morawski, Aaron R; Manthei, Alyson; Cashman, Neil R

    2015-03-10

    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 vitro prion 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.

  3. In vitro prion protein conversion suggests risk of bighorn sheep (Ovis canadensis) to transmissible spongiform encephalopathies

    USGS Publications Warehouse

    Johnson, Christopher J.; Morawski, A.R.; Carlson, C.M.; Chang, H.

    2013-01-01

    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

  4. In vitro prion protein conversion suggests risk of bighorn sheep (Ovis canadensis) to transmissible spongiform encephalopathies

    PubMed Central

    2013-01-01

    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 (A136R154Q171 genotype). 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 A136R154Q171 genotype 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

  5. Consumer reactions to risk information on bovine spongiform encephalopathy in Japan

    PubMed Central

    Yasunaga, Hideo; Obana, Naoya; Ogawa, Toshio; Imamura, Tomoaki

    2010-01-01

    Objectives To investigate the impact of information on foodborne disease on consumers, we quantified consumers’ anxiety, purchasing behaviors, and willingness-to-pay (WTP) in response to the reading of newspaper articles published in 2001 that documented the first cow in Japan to be infected with bovine spongiform encephalopathy (BSE). Methods An online questionnaire survey of 993 females aged 20–59 years was conducted in 2007. The participants were randomly selected from the general population via the Internet and were divided into three groups. Each group was assigned a different number of BSE-related articles to read, namely, two, four, and six articles, respectively. Each participant described her personal level of anxiety, underlying reasons for her anxiety, and changes in purchasing behavior after reading the articles. The respondents who wanted to buy guaranteed-safe beef were asked to state their maximal WTP. Results The level of anxiety was significantly lower and distrust of the relevant administration significantly greater in the group asked to read six articles than in the other groups. The WTP value for guaranteed beef was approximately 1.3-fold higher than the regular purchase price, with significant differences between groups. In the ‘six-article’ group, the ratio between WTP and the regular purchase price was significantly less than that in the ‘four-article’ group. Conclusions These findings suggest that the anxiety of consumers can be reduced if they receive an appropriate amount of published information. WTP may be linked to the contents of the articles. PMID:21432560

  6. Quantitative analysis of wet-heat inactivation in bovine spongiform encephalopathy

    SciTech Connect

    Matsuura, Yuichi; Ishikawa, Yukiko; Bo, Xiao; Murayama, Yuichi; Yokoyama, Takashi; Somerville, Robert A.; Kitamoto, Tetsuyuki; Mohri, Shirou

    2013-03-01

    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.

  7. Infectivity in Skeletal Muscle of Cattle with Atypical Bovine Spongiform Encephalopathy

    PubMed Central

    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

    2012-01-01

    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 PrPres 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. PMID:22363650

  8. Immunohistochemical distinction between preclinical bovine spongiform encephalopathy and scrapie infection in sheep.

    PubMed

    Thuring, C M A; van Keulen, L J M; Langeveld, J P M; Vromans, M E W; van Zijderveld, F G; Sweeney, T

    2005-01-01

    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 < or = 6 monthly intervals post-infection and examined immunohistochemically for PrPSc. Third eyelid protuberances were difficult to identify, resulting in many unsuitable samples; however, third eyelid samples shown to contain lymphoid follicles were invariably negative for PrPSc. In contrast, tonsillar biopsy samples became positive for PrPSc from 11 to 20 months post-infection. Consistent differences in the morphology of PrPSc granules in tingible body 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.

  9. Evidence of subclinical prion disease in aged mice following exposure to bovine spongiform encephalopathy.

    PubMed

    Brown, Karen L; Mabbott, Neil A

    2014-01-01

    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.

  10. Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy

    PubMed Central

    Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano

    2016-01-01

    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

  11. Prevalent abnormal prion protein in human appendixes after bovine spongiform encephalopathy epizootic: large scale survey.

    PubMed

    Gill, O Noel; Spencer, Yvonne; Richard-Loendt, Angela; Kelly, Carole; Dabaghian, Reza; Boyes, Lynnette; Linehan, Jacqueline; Simmons, Marion; Webb, Paul; Bellerby, Peter; Andrews, Nick; Hilton, David A; Ironside, James W; Beck, Jon; Poulter, Mark; Mead, Simon; Brandner, Sebastian

    2013-10-15

    To carry out a further survey of archived appendix samples to understand better the differences between existing estimates of the prevalence of subclinical infection with prions after the bovine spongiform encephalopathy epizootic and to see whether a broader birth cohort was affected, and to understand better the implications for the management of blood and blood products and for the handling of surgical instruments. Irreversibly unlinked and anonymised large scale survey of archived appendix samples. Archived appendix samples from the pathology departments of 41 UK hospitals participating in the earlier survey, and additional hospitals in regions with lower levels of participation in that survey. 32,441 archived appendix samples fixed in formalin and embedded in paraffin and tested for the presence of abnormal prion protein (PrP). Of the 32,441 appendix samples 16 were positive for abnormal PrP, indicating an overall prevalence of 493 per million population (95% confidence interval 282 to 801 per million). The prevalence in those born in 1941-60 (733 per million, 269 to 1596 per million) did not differ significantly from those born between 1961 and 1985 (412 per million, 198 to 758 per million) and was similar in both sexes and across the three broad geographical areas sampled. Genetic testing of the positive specimens for the genotype at PRNP codon 129 revealed a high proportion that were valine homozygous compared with the frequency in the normal population, and in stark contrast with confirmed clinical cases of vCJD, all of which were methionine homozygous at PRNP codon 129. This study corroborates previous studies and suggests a high prevalence of infection with abnormal PrP, indicating vCJD carrier status in the population compared with the 177 vCJD cases to date. These findings have important implications for the management of blood and blood products and for the handling of surgical instruments.

  12. A pilot study for targeted surveillance of bovine spongiform encephalopathy in Nigeria.

    PubMed

    Nwankiti, O O; Ikeh, E I; Asala, O; Seuberlich, T

    2013-06-01

    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. © 2012 Blackwell Verlag GmbH.

  13. Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy.

    PubMed

    Xerxa, Elena; Barbisin, Maura; Chieppa, Maria Novella; Krmac, Helena; Vallino Costassa, Elena; Vatta, Paolo; Simmons, Marion; Caramelli, Maria; Casalone, Cristina; Corona, Cristiano; Legname, Giuseppe

    2016-01-01

    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.

  14. Changes in retinal function and morphology are early clinical signs of disease in cattle with bovine spongiform encephalopathy.

    PubMed

    Greenlee, M Heather West; Smith, Jodi D; Platt, Ekundayo M; Juarez, Jessica R; Timms, Leo L; Greenlee, Justin J

    2015-01-01

    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.

  15. Changes in Retinal Function and Morphology Are Early Clinical Signs of Disease in Cattle with Bovine Spongiform Encephalopathy

    PubMed Central

    West Greenlee, M. Heather; Smith, Jodi D.; Platt, Ekundayo M.; Juarez, Jessica R.; Timms, Leo L.; Greenlee, Justin J.

    2015-01-01

    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. PMID:25756286

  16. Aquaporin 1 and aquaporin 4 overexpression in bovine spongiform encephalopathy in a transgenic murine model and in cattle field cases.

    PubMed

    Costa, Carme; Tortosa, Raül; Rodríguez, Agustín; Ferrer, Isidre; Torres, Juan Maria; Bassols, Anna; Pumarola, Martí

    2007-10-17

    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.

  17. Transcytosis of murine-adapted bovine spongiform encephalopathy agents in an in vitro bovine M cell model.

    PubMed

    Miyazawa, Kohtaro; Kanaya, Takashi; Takakura, Ikuro; Tanaka, Sachi; Hondo, Tetsuya; Watanabe, Hitoshi; Rose, Michael T; Kitazawa, Haruki; Yamaguchi, Takahiro; Katamine, Shigeru; Nishida, Noriyuki; Aso, Hisashi

    2010-12-01

    Transmissible spongiform encephalopathies (TSE), including bovine spongiform encephalopathy (BSE), are fatal neurodegenerative disorders in humans and animals. BSE appears to have spread to cattle through the consumption of feed contaminated with BSE/scrapie agents. In the case of an oral infection, the agents have to cross the gut-epithelial barrier. We recently established a bovine intestinal epithelial cell line (BIE cells) that can differentiate into the M cell type in vitro after lymphocytic stimulation (K. Miyazawa, T. Hondo, T. Kanaya, S. Tanaka, I. Takakura, W. Itani, M. T. Rose, H. Kitazawa, T. Yamaguchi, and H. Aso, Histochem. Cell Biol. 133:125-134, 2010). In this study, we evaluated the role of M cells in the intestinal invasion of the murine-adapted BSE (mBSE) agent using our in vitro bovine intestinal epithelial model. We demonstrate here that M cell-differentiated BIE cells are able to transport the mBSE agent without inactivation at least 30-fold more efficiently than undifferentiated BIE cells in our in vitro model. As M cells in the follicle-associated epithelium are known to have a high ability to transport a variety of macromolecules, viruses, and bacteria from gut lumen to mucosal immune cells, our results indicate the possibility that bovine M cells are able to deliver agents of TSE, not just the mBSE agent.

  18. Transcytosis of Murine-Adapted Bovine Spongiform Encephalopathy Agents in an In Vitro Bovine M Cell Model▿ † #

    PubMed Central

    Miyazawa, Kohtaro; Kanaya, Takashi; Takakura, Ikuro; Tanaka, Sachi; Hondo, Tetsuya; Watanabe, Hitoshi; Rose, Michael T.; Kitazawa, Haruki; Yamaguchi, Takahiro; Katamine, Shigeru; Nishida, Noriyuki; Aso, Hisashi

    2010-01-01

    Transmissible spongiform encephalopathies (TSE), including bovine spongiform encephalopathy (BSE), are fatal neurodegenerative disorders in humans and animals. BSE appears to have spread to cattle through the consumption of feed contaminated with BSE/scrapie agents. In the case of an oral infection, the agents have to cross the gut-epithelial barrier. We recently established a bovine intestinal epithelial cell line (BIE cells) that can differentiate into the M cell type in vitro after lymphocytic stimulation (K. Miyazawa, T. Hondo, T. Kanaya, S. Tanaka, I. Takakura, W. Itani, M. T. Rose, H. Kitazawa, T. Yamaguchi, and H. Aso, Histochem. Cell Biol. 133:125-134, 2010). In this study, we evaluated the role of M cells in the intestinal invasion of the murine-adapted BSE (mBSE) agent using our in vitro bovine intestinal epithelial model. We demonstrate here that M cell-differentiated BIE cells are able to transport the mBSE agent without inactivation at least 30-fold more efficiently than undifferentiated BIE cells in our in vitro model. As M cells in the follicle-associated epithelium are known to have a high ability to transport a variety of macromolecules, viruses, and bacteria from gut lumen to mucosal immune cells, our results indicate the possibility that bovine M cells are able to deliver agents of TSE, not just the mBSE agent. PMID:20861256

  19. Transmissibility of H-Type Bovine Spongiform Encephalopathy to Hamster PrP Transgenic Mice

    PubMed Central

    Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Yokoyama, Takashi

    2015-01-01

    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. PMID:26466381

  20. Transmissibility of H-Type Bovine Spongiform Encephalopathy to Hamster PrP Transgenic Mice.

    PubMed

    Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Yokoyama, Takashi

    2015-01-01

    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.

  1. Time and frequency domain analysis of heart rate variability in cattle affected by bovine spongiform encephalopathy

    PubMed Central

    2011-01-01

    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 grouped by gender, and HRV

  2. Risks of transmitting ruminant spongiform encephalopathies (prion diseases) by semen and embryo transfer techniques.

    PubMed

    Wrathall, A E; Holyoak, G R; Parsonson, I M; Simmons, H A

    2008-09-15

    Early experiments suggested that scrapie transmission via sheep embryos was a possibility, and gave rise to much controversy. However, when account is taken of the complex genetic effects on ovine susceptibility to scrapie, and of the several different scrapie strains with different clinical and pathological effects, the overall conclusion now is that transmission of classical scrapie by embryo transfer is very unlikely if appropriate precautions are taken. Recent embryo transfer studies have confirmed this. Other studies in sheep have shown that from about the middle of pregnancy the placental trophoblast is liable to scrapie infection in genetically susceptible ewes if the fetus is also susceptible. Since the contrary is also true, use of resistant ewes as embryo recipients could add to the safety of the embryo transfer, at least for classical scrapie. There has been little recent research on scrapie transmission via semen in sheep, and, with hindsight, the early studies, though negative, were inadequate. There is scant information on scrapie transfer via goat semen or embryos, although one study did find that bovine spongiform encephalopathy (BSE) was not transmitted via goat embryos. In cattle it has been shown that, if appropriate precautions are taken, the risks of transmitting BSE via semen and in vivo-derived embryos are negligible, and this conclusion has gained worldwide acceptance. Research on TSE transmission via reproductive technologies in deer has not yet been done, but information on the pathogenesis and epidemiology of chronic wasting disease (CWD) of deer, and on transmission risks in other species, provides optimism that transmission of CWD via semen and embryos of deer is unlikely. The presence of TSE infectivity in blood and various other tissues of infected animals, particularly sheep, gives rise to concerns that certain biological products currently used in reproductive technologies, e.g. pituitary gonadotrophins for superovulation, and

  3. Surveillance for Transmissible Spongiform Encephalopathy in Scavengers of White-Tailed Deer Carcasses in the Chronic Wasting Disease Area of Wisconsin

    USDA-ARS?s Scientific Manuscript database

    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 an...

  4. Insights into Chronic Wasting Disease and Bovine Spongiform Encephalopathy Species Barriers by Use of Real-Time Conversion.

    PubMed

    Davenport, Kristen A; Henderson, Davin M; Bian, Jifeng; Telling, Glenn C; Mathiason, Candace K; Hoover, Edward A

    2015-09-01

    The propensity for transspecies prion transmission is related to the structural characteristics of the enciphering and new host PrP, although the exact mechanism remains incompletely understood. The effects of variability in prion protein on cross-species prion transmission have been studied with animal bioassays, but the influence of prion protein structure versus that of host cofactors (e.g., cellular constituents, trafficking, and innate immune interactions) remains difficult to dissect. To isolate the effects of protein-protein interactions on transspecies conversion, we used recombinant PrP(C) and real-time quaking-induced conversion (RT-QuIC) and compared chronic wasting disease (CWD) and classical bovine spongiform encephalopathy (cBSE) prions. To assess the impact of transmission to a new species, we studied feline CWD (fCWD) and feline BSE (i.e., feline spongiform encephalopathy [FSE]). We cross-seeded fCWD and FSE into each species' full-length, recombinant PrP(C) and measured the time required for conversion to the amyloid (PrP(Res)) form, which we describe here as the rate of amyloid conversion. These studies revealed the following: (i) CWD and BSE seeded their homologous species' PrP best; (ii) fCWD was a more efficient seed for feline rPrP than for white-tailed deer rPrP; (iii) conversely, FSE more efficiently converted bovine than feline rPrP; (iv) and CWD, fCWD, BSE, and FSE all converted human rPrP, although not as efficiently as homologous sCJD prions. These results suggest that (i) at the level of protein-protein interactions, CWD adapts to a new species more readily than does BSE and (ii) the barrier preventing transmission of CWD to humans may be less robust than estimated. We demonstrate that bovine spongiform encephalopathy prions maintain their transspecies conversion characteristics upon passage to cats but that chronic wasting disease prions adapt to the cat and are distinguishable from the original prion. Additionally, we showed that

  5. Minimal involvement of the circumventricular organs in the pathogenesis of spontaneously arising and experimentally induced classical bovine spongiform encephalopathy.

    PubMed

    Sisó, S; Martin, S; Konold, T; Hawkins, S A C; Thurston, L; Simmons, M M; Stack, M J; Jeffrey, M; González, L

    2012-01-01

    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. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  6. Complementary studies detecting classical bovine spongiform encephalopathy infectivity in jejunum, ileum and ileocaecal junction in incubating cattle.

    PubMed

    Fast, Christine; Keller, Markus; Balkema-Buschmann, Anne; Hills, Bob; Groschup, Martin H

    2013-12-21

    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.

  7. The presence of disease-associated prion protein in skeletal muscle of cattle infected with classical bovine spongiform encephalopathy.

    PubMed

    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

    2014-01-01

    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.

  8. Complementary studies detecting classical bovine spongiform encephalopathy infectivity in jejunum, ileum and ileocaecal junction in incubating cattle

    PubMed Central

    2013-01-01

    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. PMID:24359408

  9. Bovine spongiform encephalopathy: is it time to relax BSE-related measures in the context of international trade?

    PubMed

    Matthews, D; Adkin, A

    2011-04-01

    Bovine spongiform encephalopathy (BSE) has presented serious challenges to both the World Organisation for Animal Health and national governments, in defining and implementing appropriate national control measures, and in agreeing trade rules that permit safe trade in cattle and bovine products. Precautionary trade rules were initially necessary, based upon the science of sheep scrapie, but research into BSE later enabled BSE-specific trade rules to be developed. As a result, current rules on trade are underpinned by a sound body of knowledge on BSE. Declining epidemics in most affected countries confirm the appropriateness of current precautions. Nevertheless, risk is primarily dependent on the prevalence of infection with BSE. In the face of low prevalence scenarios, certain precautionary measures in the Terrestrial Animal Health Code may now be considered excessive. A thorough review is therefore deemed appropriate.

  10. Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits

    PubMed Central

    2011-01-01

    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 (PrPSc). To investigate the topographical distribution and deposition patterns of immunolabeled PrPSc, 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 PrPSc was prominent throughout the brain. Stellate-type immunolabeled PrPSc was conspicuous in the gray matter of the cerebral cortex, basal ganglia, and thalamus, but not in the brainstem. In addition, PrPSc 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 PrPSc accumulation. PMID:21699704

  11. Experimental H-type bovine spongiform encephalopathy characterized by plaques and glial- and stellate-type prion protein deposits.

    PubMed

    Okada, Hiroyuki; Iwamaru, Yoshifumi; Imamura, Morikazu; Masujin, Kentaro; Matsuura, Yuichi; Shimizu, Yoshihisa; Kasai, Kazuo; Mohri, Shirou; Yokoyama, Takashi; Czub, Stefanie

    2011-06-23

    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.

  12. Infectious titres of sheep scrapie and bovine spongiform encephalopathy agents cannot be accurately predicted from quantitative laboratory test results.

    PubMed

    González, Lorenzo; Thorne, Leigh; Jeffrey, Martin; Martin, Stuart; Spiropoulos, John; Beck, Katy E; Lockey, Richard W; Vickery, Christopher M; Holder, Thomas; Terry, Linda

    2012-11-01

    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).

  13. Trends in scientific activity addressing transmissible spongiform encephalopathies: a bibliometric study covering the period 1973–2002

    PubMed Central

    Sanz-Casado, Elías; Ramírez-de Santa Pau, Margarita; Suárez-Balseiro, Carlos A; Iribarren-Maestro, Isabel; de Pedro-Cuesta, Jesús

    2006-01-01

    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. PMID:17026743

  14. Detection of bovine spongiform encephalopathy-specific PrP(Sc) by treatment with heat and guanidine thiocyanate.

    PubMed

    Meyer, R K; Oesch, B; Fatzer, R; Zurbriggen, A; Vandevelde, M

    1999-11-01

    The conversion of a ubiquitous cellular protein (PrP(C)), an isoform of the prion protein (PrP), to the pathology-associated isoform PrP(Sc) is one of the hallmarks of transmissible spongiform encephalopathies such as bovine spongiform encephalopathy (BSE). Accumulation of PrP(Sc) has been used to diagnose BSE. Here we describe a quantitative enzyme-linked immunosorbent assay (ELISA) that involves antibodies against epitopes within the protease-resistant core of the PrP molecule to measure the amount of PrP in brain tissues from animals with BSE and normal controls. In native tissue preparations, little difference was found between the two groups. However, following treatment of the tissue with heat and guanidine thiocyanate (Gh treatment), the ELISA discriminated BSE-specific PrP(Sc) from PrP(C) in bovine brain homogenates. PrP(Sc) was identified by Western blot, centrifugation, and protease digestion experiments. It was thought that folding or complexing of PrP(Sc) is most probably reversed by the Gh treatment, making hidden antigenic sites accessible. The digestion experiments also showed that protease-resistant PrP in BSE is more difficult to detect than that in hamster scrapie. While the concentration of PrP(C) in cattle is similar to that in hamsters, PrP(Sc) sparse in comparison. The detection of PrP(Sc) by a simple physicochemical treatment without the need for protease digestion, as described in this study, could be applied to develop a diagnostic assay to screen large numbers of samples.

  15. The prion protein gene polymorphisms associated with bovine spongiform encephalopathy susceptibility differ significantly between cattle and buffalo.

    PubMed

    Zhao, Hui; Du, Yanli; Chen, Shunmei; Qing, Lili; Wang, Xiaoyan; Huang, Jingfei; Wu, Dongdong; Zhang, Yaping

    2015-12-01

    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. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Identification of a Heritable Polymorphism in Bovine PRNP Associated with Genetic Transmissible Spongiform Encephalopathy: Evidence of Heritable BSE

    PubMed Central

    Richt, Juergen A.; Kehrli, Marcus E.; Greenlee, Justin J.

    2008-01-01

    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. PMID:18698343

  17. Frequently Asked Questions on BSE (Bovine Spongiform Encephalopathy or Mad Cow Disease)

    MedlinePlus

    ... also includes scrapie of sheep and goats and chronic wasting disease (CWD) of elk and deer. Q. What are ... include, among others, scrapie in sheep and goats, chronic wasting disease in deer and elk, transmissible mink encephalopathy, and ...

  18. Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein.

    PubMed

    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

    2012-07-01

    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.

  19. Increased susceptibility of transgenic mice expressing human PrP to experimental sheep bovine spongiform encephalopathy is not due to increased agent titre in sheep brain tissue

    PubMed Central

    Plinston, Chris; Hart, Patricia; Hunter, Nora; Manson, Jean C.

    2014-01-01

    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. PMID:24828334

  20. Increased susceptibility of transgenic mice expressing human PrP to experimental sheep bovine spongiform encephalopathy is not due to increased agent titre in sheep brain tissue.

    PubMed

    Plinston, Chris; Hart, Patricia; Hunter, Nora; Manson, Jean C; Barron, Rona M

    2014-08-01

    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. © 2014 The Authors.

  1. Elevated manganese levels in blood and central nervous system occur before onset of clinical signs in scrapie and bovine spongiform encephalopathy.

    PubMed

    Hesketh, S; Sassoon, J; Knight, R; Hopkins, J; Brown, D R

    2007-06-01

    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.

  2. Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy.

    PubMed

    Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Iwamaru, Yoshihumi; Imamura, Morikazu; Matsuura, Yuichi; Arai, Shozo; Fukuda, Shigeo; Murayama, Yuichi; Yokoyama, Takashi

    2017-01-01

    H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in cattle. During passaging of H-BSE in transgenic bovinized (TgBoPrP) mice, a novel phenotype of BSE, termed BSE-SW emerged and was characterized by a short incubation time and host weight loss. To investigate the biological and biochemical properties of the BSE-SW prion, a transmission study was conducted in cattle, which were inoculated intracerebrally with brain homogenate from BSE-SW-infected TgBoPrP mice. The disease incubation period was approximately 15 months. The animals showed characteristic neurological signs of dullness, and severe spongiform changes and a widespread, uniform distribution of disease-associated prion protein (PrP(Sc)) were observed throughout the brain of infected cattle. Immunohistochemical PrP(Sc) staining of the brain revealed the presence of intraglial accumulations and plaque-like deposits. No remarkable differences were identified in vacuolar lesion scores, topographical distribution patterns, and staining types of PrP(Sc) in the brains of BSE-SW- vs H-BSE-infected cattle. PrP(Sc) deposition was detected in the ganglia, vagus nerve, spinal nerve, cauda equina, adrenal medulla, and ocular muscle. Western blot analysis revealed that the specific biochemical properties of the BSE-SW prion, with an additional 10- to 12-kDa fragment, were well maintained after transmission. These findings indicated that the BSE-SW prion has biochemical properties distinct from those of H-BSE in cattle, although clinical and pathologic features of BSW-SW in cattle are indistinguishable from those of H-BSE. The results suggest that the 2 infectious agents, BSE-SW and H-BSE, are closely related strains.

  3. Abnormalities in Brainstem Auditory Evoked Potentials in Sheep with Transmissible Spongiform Encephalopathies and Lack of a Clear Pathological Relationship

    PubMed Central

    Konold, Timm; Phelan, Laura J.; Cawthraw, Saira; Simmons, Marion M.; Chaplin, Melanie J.; González, Lorenzo

    2016-01-01

    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

  4. Guinea Pig Prion Protein Supports Rapid Propagation of Bovine Spongiform Encephalopathy and Variant Creutzfeldt-Jakob Disease Prions.

    PubMed

    Watts, Joel C; Giles, Kurt; Saltzberg, Daniel J; Dugger, Brittany N; Patel, Smita; Oehler, Abby; Bhardwaj, Sumita; Sali, Andrej; Prusiner, Stanley B

    2016-11-01

    The biochemical and neuropathological properties of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) prions are faithfully maintained upon transmission to guinea pigs. However, primary and secondary transmissions of BSE and vCJD in guinea pigs result in long incubation periods of ∼450 and ∼350 days, respectively. To determine if the incubation periods of BSE and vCJD prions could be shortened, we generated transgenic (Tg) mice expressing guinea pig prion protein (GPPrP). Inoculation of Tg(GPPrP) mice with BSE and vCJD prions resulted in mean incubation periods of 210 and 199 days, respectively, which shortened to 137 and 122 days upon serial transmission. In contrast, three different isolates of sporadic CJD prions failed to transmit disease to Tg(GPPrP) mice. Many of the strain-specified biochemical and neuropathological properties of BSE and vCJD prions, including the presence of type 2 protease-resistant PrP(Sc), were preserved upon propagation in Tg(GPPrP) mice. Structural modeling revealed that two residues near the N-terminal region of α-helix 1 in GPPrP might mediate its susceptibility to BSE and vCJD prions. Our results demonstrate that expression of GPPrP in Tg mice supports the rapid propagation of BSE and vCJD prions and suggest that Tg(GPPrP) mice may serve as a useful paradigm for bioassaying these prion isolates. Variant Creutzfeldt-Jakob disease (vCJD) and bovine spongiform encephalopathy (BSE) prions are two of the prion strains most relevant to human health. However, propagating these strains in mice expressing human or bovine prion protein has been difficult because of prolonged incubation periods or inefficient transmission. Here, we show that transgenic mice expressing guinea pig prion protein are fully susceptible to vCJD and BSE prions but not to sporadic CJD prions. Our results suggest that the guinea pig prion protein is a better, more rapid substrate than either bovine or human prion protein for

  5. A pilot study of the impact of bovine spongiform encephalopathy on the futures of rural youth and Canadian farming.

    PubMed

    Cook, Trevor M; Brook, Ryan K; Sindhwani, Madhu; Thurston, Wilfreda E

    2011-01-01

    There is an abundance of literature examining the economic impact of Canada's bovine spongiform encephalopathy (BSE) outbreak, but few studies examined the impact of such a crisis on health at the individual, family, or community levels. In particular, rural youth represent an under-researched population despite being at risk for a unique set of social and health concerns. In this pilot study, our objectives were to explore how rural youth responded to Canada's BSE crisis and how they perceived themselves, their families, and their communities to have been impacted. Seven youths (n = 7), recruited from within a university setting using a snowball sampling method, were interviewed. They represent a segment of rural, agriculturally based youth who are resilient due to good parental support. Although they reported high stress in their families during the immediate crisis in 2003, they did not report lasting high levels of stress or negative health effects due to BSE. They did report a decline in rural community health, identifying a reduction in community activities and in the participation of families in community activities. Participants identified elements that discourage youth from pursuing farming as a career and expressed concern for the future of family farming. The results are discussed in terms of the ability of agriculturally based youth to make the transition to adulthood. The implications have importance for future research and policy that addresses the structural supports for choice making, the long-term success for rural youth in transitioning to adult status, and the future of agriculture.

  6. Sheep-passaged bovine spongiform encephalopathy agent exhibits altered pathobiological properties in bovine-PrP transgenic mice.

    PubMed

    Espinosa, Juan Carlos; Andréoletti, Olivier; Castilla, Joaquín; Herva, María Eugenia; Morales, Mónica; Alamillo, Elia; San-Segundo, Fayna Díaz; Lacroux, Caroline; Lugan, Séverine; Salguero, Francisco Javier; Langeveld, Jan; Torres, Juan María

    2007-01-01

    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 from BSE-infected sheep was examined and compared to the transmission of original cattle BSE in cattle and sheep scrapie prions. Our results indicate no transmission barrier for sheep BSE prions to infect BoPrP-Tg110 mice, but the course of the disease is accelerated compared to the effects of the original BSE isolate. The shortened incubation period of sheep BSE in the model was conserved in subsequent passage in BoPrP-Tg110 mice, indicating that it is not related to infectious titer differences. Biochemical signature, lesion profile, and PrP(Sc) deposition pattern of both cattle and sheep BSE were similar. In contrast, all three sheep scrapie isolates tested showed an evident transmission barrier and further adaptation in subsequent passage. Taken together, those data indicate that BSE agent can be altered by crossing a species barrier, raising concerns about the virulence of this new prion towards other species, including humans. The BoPrP-Tg110 mouse bioassay should be considered as a valuable tool for discriminating scrapie and BSE in sheep.

  7. Foodborne Transmission of Bovine Spongiform Encephalopathy to Non-Human Primates Results in Preclinical Rapid-Onset Obesity

    PubMed Central

    Strom, Alexander; Yutzy, Barbara; Kruip, Carina; Ooms, Mark; Schloot, Nanette C.; Roden, Michael; Scott, Fraser W.; Loewer, Johannes; Holznagel, Edgar

    2014-01-01

    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. PMID:25090610

  8. Descriptive epidemiological features of cases of bovine spongiform encephalopathy born after July 31, 1996 in Great Britain.

    PubMed

    Wilesmith, J W; Ryan, J B M; Arnold, M E; Stevenson, M A; Burke, P J

    2010-08-21

    This paper describes the results of analyses of the epidemiological features of the 164 cases of bovine spongiform encephalopathy (BSE) in Great Britain that were born after the introduction of the reinforced legislation introduced on August 1, 1996 (BARB cases) and that were detected before December 31, 2008. This additional control measure prohibited the use of mammalian meat and bone meal (MMBM) in feed for farm animals to prevent further exposure of cattle to the BSE agent. There was a pronounced reduction in the risk of infection, by three orders of magnitude, for cattle born after July 31, 1996 compared with that for cattle born earlier, and a statistically significant exponential reduction in the estimated prevalence between successive annual birth cohorts after this date. There was no evidence that a significant number of these cases occurred as a result of a maternally associated risk factor, infection from environmental contamination (other than from feedstuffs) or as a result of a genetically based aetiology. The epidemiological features were consistent with an exogenous feedborne source as a result of a reliance on imported feedstuffs in Great Britain and the later introduction of a ban on the use of MMBM in other EU member states on January 1, 2001.

  9. Impact of potential changes to the current bovine spongiform encephalopathy surveillance programs for slaughter cattle and fallen stock in Japan.

    PubMed

    Sugiura, Katsuaki; Murray, Noel; Shinoda, Naoki; Onodera, Takashi

    2009-07-01

    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.

  10. Neuroanatomical distribution of disease-associated prion protein in experimental bovine spongiform encephalopathy in cattle after intracerebral inoculation.

    PubMed

    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

    2012-01-01

    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.

  11. Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle - an update.

    PubMed

    Konold, Timm; Arnold, Mark E; Austin, Anthony R; Cawthraw, Saira; Hawkins, Steve A C; Stack, Michael J; Simmons, Marion M; Sayers, A Robin; Dawson, Michael; Wilesmith, John W; Wells, Gerald A H

    2012-12-05

    To provide information on dose-response and aid in modelling the exposure dynamics of the BSE epidemic in the United Kingdom groups of cattle were exposed orally to a range of different doses of brainstem homogenate of known infectious titre from clinical cases of classical bovine spongiform encephalopathy (BSE). Interim data from this study was published in 2007. This communication documents additional BSE cases, which occurred subsequently, examines possible influence of the bovine prion protein gene on disease incidence and revises estimates of effective oral exposure. Following interim published results, two further cattle, one dosed with 100 mg and culled at 127 months post exposure and the other dosed with 10 mg and culled at 110 months post exposure, developed BSE. Both had a similar pathological phenotype to previous cases. Based on attack rate and incubation period distribution according to dose, the dose estimate at which 50% of confirmed cases would be clinically affected was revised to 0.15 g of the brain homogenate used in the experiment, with a 95% confidence interval of 0.03-0.79 g. Neither the full open reading frame nor the promoter region of the prion protein gene of dosed cattle appeared to influence susceptibility to BSE, but this may be due to the sample size. Oral exposure of cattle to a large range of doses of a BSE brainstem homogenate produced disease in all dose groups. The pathological presentation resembled natural disease. The attack rate and incubation period were dependent on the dose.

  12. Bovine spongiform encephalopathy induces misfolding of alleged prion-resistant species cellular prion protein without altering its pathobiological features.

    PubMed

    Vidal, Enric; Fernández-Borges, Natalia; Pintado, Belén; Ordóñez, Montserrat; Márquez, Mercedes; Fondevila, Dolors; Torres, Juan María; Pumarola, Martí; Castilla, Joaquín

    2013-05-01

    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.

  13. Foodborne transmission of bovine spongiform encephalopathy to non-human primates results in preclinical rapid-onset obesity.

    PubMed

    Strom, Alexander; Yutzy, Barbara; Kruip, Carina; Ooms, Mark; Schloot, Nanette C; Roden, Michael; Scott, Fraser W; Loewer, Johannes; Holznagel, Edgar

    2014-01-01

    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.

  14. Acquired transmissibility of sheep-passaged L-type bovine spongiform encephalopathy prion to wild-type mice.

    PubMed

    Okada, Hiroyuki; Masujin, Kentaro; Miyazawa, Kohtaro; Yokoyama, Takashi

    2015-07-13

    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.

  15. Genotype-dependent molecular evolution of sheep bovine spongiform encephalopathy (BSE) prions in vitro affects their zoonotic potential.

    PubMed

    Krejciova, Zuzana; Barria, Marcelo A; Jones, Michael; Ironside, James W; Jeffrey, Martin; González, Lorenzo; Head, Mark W

    2014-09-19

    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. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Transcriptome analysis of the medulla tissue from cattle in response to bovine spongiform encephalopathy using digital gene expression tag profiling.

    PubMed

    Basu, Urmila; Almeida, Luciane; Olson, N Eric; Meng, Yan; Williams, John L; Moore, Stephen S; Guan, Le Luo

    2011-01-01

    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.

  17. Analysis of gene expression in white blood cells of cattle orally challenged with bovine amyloidotic spongiform encephalopathy.

    PubMed

    Panelli, Simona; Strozzi, Francesco; Capoferri, Rossana; Barbieri, Ilaria; Martinelli, Nicola; Capucci, Lorenzo; Lombardi, Guerino; Williams, John L

    2011-01-01

    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.

  18. The epidemics of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: current status and future prospects.

    PubMed Central

    Smith, Peter G.

    2003-01-01

    The large epidemic of bovine spongiform encephalopathy (BSE) in the United Kingdom has been in decline since 1992, but has spread to other countries. The extensive control measures that have been put in place across the European Union and also in Switzerland should have brought the transmission of BSE under control in these countries, provided that the measures were properly enforced. Postmortem tests on brain tissue enable infected animals to be detected during the late stages of the incubation period, but tests that can be performed on live animals (including humans) and that will detect infections early are urgently needed. The number of infected animals currently entering the food chain is probably small, and the controls placed on bovine tissues in the European Union and Switzerland should ensure that any risks to human health are small and diminishing. Vigilance is required in all countries, especially in those in which there has been within-species recycling of ruminant feed. Fewer than 150 people, globally, have been diagnosed with variant Creutzfeldt-Jakob disease (vCJD), but there are many uncertainties about the future course of the epidemic because of the long and variable incubation period. Better control measures are necessary to guard against the possibility of iatrogenic transmission through blood transfusion or contaminated surgical instruments. These measures will required sensitive and specific, diagnostic tests and improved decontamination methods. PMID:12751420

  19. Genotype-dependent Molecular Evolution of Sheep Bovine Spongiform Encephalopathy (BSE) Prions in Vitro Affects Their Zoonotic Potential*

    PubMed Central

    Krejciova, Zuzana; Barria, Marcelo A.; Jones, Michael; Ironside, James W.; Jeffrey, Martin; González, Lorenzo; Head, Mark W.

    2014-01-01

    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. PMID:25100723

  20. Transcriptional changes in the brains of cattle orally infected with the bovine spongiform encephalopathy agent precede detection of infectivity.

    PubMed

    Tang, Yue; Xiang, Wei; Hawkins, Steve A C; Kretzschmar, Hans A; Windl, Otto

    2009-09-01

    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.

  1. Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle.

    PubMed

    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

    2007-04-01

    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).

  2. Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease

    PubMed Central

    Fernández-Borges, Natalia; Espinosa, Juan Carlos; Marín-Moreno, Alba; Aguilar-Calvo, Patricia; Asante, Emmanuel A.; Kitamoto, Tetsuyuki; Mohri, Shirou; Andréoletti, Olivier

    2017-01-01

    Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features. PMID:28820136

  3. Brain-Specific Superoxide Dismutase 2 Deficiency Causes Perinatal Death with Spongiform Encephalopathy in Mice.

    PubMed

    Izuo, Naotaka; Nojiri, Hidetoshi; Uchiyama, Satoshi; Noda, Yoshihiro; Kawakami, Satoru; Kojima, Shuji; Sasaki, Toru; Shirasawa, Takuji; Shimizu, Takahiko

    2015-01-01

    Oxidative stress is believed to greatly contribute to the pathogenesis of various diseases, including neurodegeneration. Impairment of mitochondrial energy production and increased mitochondrial oxidative damage are considered early pathological events that lead to neurodegeneration. Manganese superoxide dismutase (Mn-SOD, SOD2) is a mitochondrial antioxidant enzyme that converts toxic superoxide to hydrogen peroxide. To investigate the pathological role of mitochondrial oxidative stress in the central nervous system, we generated brain-specific SOD2-deficient mice (B-Sod2(-/-)) using nestin-Cre-loxp system. B-Sod2(-/-) showed perinatal death, along with severe growth retardation. Interestingly, these mice exhibited spongiform neurodegeneration in motor cortex, hippocampus, and brainstem, accompanied by gliosis. In addition, the mutant mice had markedly decreased mitochondrial complex II activity, but not complex I or IV, in the brain based on enzyme histochemistry. Furthermore, brain lipid peroxidation was significantly increased in the B-Sod2(-/-), without any compensatory alterations of the activities of other antioxidative enzymes, such as catalase or glutathione peroxidase. These results suggest that SOD2 protects the neural system from oxidative stress in the perinatal stage and is essential for infant survival and central neural function in mice.

  4. Pyroglutamyl-N-terminal prion protein fragments in sheep brain following the development of transmissible spongiform encephalopathies

    PubMed Central

    Gielbert, Adriana; Thorne, Jemma K.; Hope, James

    2015-01-01

    Protein misfolding, protein aggregation and disruption to cellular proteostasis are key processes in the propagation of disease and, in some progressive neurodegenerative diseases of the central nervous system, the misfolded protein can act as a self-replicating template or prion converting its normal isoform into a misfolded copy of itself. We have investigated the sheep transmissible spongiform encephalopathy, scrapie, and developed a multiple selected reaction monitoring (mSRM) mass spectrometry assay to quantify brain peptides representing the “ragged” N-terminus and the core of ovine prion protein (PrPSc) by using Q-Tof mass spectrometry. This allowed us to identify pyroglutamylated N-terminal fragments of PrPSc at residues 86, 95 and 101, and establish that these fragments were likely to be the result of in vivo processes. We found that the ratios of pyroglutamylated PrPSc fragments were different in sheep of different breeds and geographical origin, and our expanded ovine PrPSc assay was able to determine the ratio and allotypes of PrP accumulating in diseased brain of PrP heterozygous sheep; it also revealed significant differences between N-terminal amino acid profiles (N-TAAPs) in other types of ovine prion disease, CH1641 scrapie and ovine BSE. Variable rates of PrP misfolding, aggregation and degradation are the likely basis for phenotypic (or strain) differences in prion-affected animals and our mass spectrometry-based approach allows the simultaneous investigation of factors such as post-translational modification (pyroglutamyl formation), conformation (by N-TAAP analysis) and amino-acid polymorphisms (allotype ratio) which affect the kinetics of these proteostatic processes. PMID:25988175

  5. Quantitative risk assessment for bovine spongiform encephalopathy in low- or zero-prevalence countries: the example of Norway.

    PubMed

    Hogasen, Helga Rachel; de Koeijer, Aline A

    2007-10-01

    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 distribution of expected cases as well as the relative impact of different challenges is estimated. The model consists of a simple, transparent, and practical deterministic spreadsheet calculation model, in which the following country-specific inputs are entered: (i) annual imports of live cattle and meat and bone meal, (ii) age distribution of native cattle, and (iii) estimated annual basic reproduction ratio (R(0)) for BSE. Results for Norway indicate that the highest risk of BSE cases was in 1989, when a total BSE risk of 0.13 cases per year was expected. After that date, the year-to-year decrease in risk ranged between 3% and 47%, except for a secondary peak in 1994 at 0.06 cases per year. The primary peak was almost entirely (99%) attributable to the importation of 11 cattle from the United Kingdom between 1982 and 1986. The secondary peak, in 1994, originated mainly from the recycling of the U.K. imported cattle (92%). In 2006, the remaining risk was 0.0003 cases per year, or 0.001 per million cows per year, with a maximal age-specific incidence of 0.03 cases per million per year in 10-year-old cattle. Only 15% of the cases were expected in imported cattle. The probability of having zero cases in Norway in 2006 was estimated to be 99.97%. The model and results are compared to previous risk assessments of Norway by the EU.

  6. Comparative Susceptibility of Sheep of Different Origins, Breeds and PRNP Genotypes to Challenge with Bovine Spongiform Encephalopathy and Scrapie

    PubMed Central

    Houston, Fiona; Goldmann, Wilfred; Foster, James; González, Lorenzo; Jeffrey, Martin; Hunter, Nora

    2015-01-01

    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

  7. Comparative Susceptibility of Sheep of Different Origins, Breeds and PRNP Genotypes to Challenge with Bovine Spongiform Encephalopathy and Scrapie.

    PubMed

    Houston, Fiona; Goldmann, Wilfred; Foster, James; González, Lorenzo; Jeffrey, Martin; Hunter, Nora

    2015-01-01

    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

  8. Characterization of an unusual transmissible spongiform encephalopathy in goat by transmission in knock-in transgenic mice.

    PubMed

    Wilson, Rona; King, Declan; Hunter, Nora; Goldmann, Wilfred; Barron, Rona M

    2013-08-01

    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.

  9. Relationship between clinical signs and postmortem test status in cattle experimentally infected with the bovine spongiform encephalopathy agent

    PubMed Central

    2010-01-01

    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 BSE-like signs or sign

  10. Relationship between clinical signs and postmortem test status in cattle experimentally infected with the bovine spongiform encephalopathy agent.

    PubMed

    Konold, Timm; Sayers, A Robin; Sach, Amanda; Bone, Gemma E; van Winden, Steven; Wells, Gerald A H; Simmons, Marion M; Stack, Michael J; Wear, Angus; Hawkins, Steve A C

    2010-12-09

    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. 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. 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 BSE-like signs or sign combinations occur in inoculated

  11. Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism

    PubMed Central

    Greenlee, Justin J.; Smith, Jodi D.; West Greenlee, M. Heather; Nicholson, Eric M.

    2012-01-01

    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 PrPSc isoform, a strong labeling of all 3 PrPSc 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. PMID:22715405

  12. Clinical and pathologic features of H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism.

    PubMed

    Greenlee, Justin J; Smith, Jodi D; West Greenlee, M Heather; Nicholson, Eric M

    2012-01-01

    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.

  13. Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy.

    PubMed

    Franz, Martin; Eiden, Martin; Balkema-Buschmann, Anne; Greenlee, Justin; Schatzl, Hermann; Fast, Christine; Richt, Jürgen; Hildebrandt, Jan-Peter; Groschup, Martin H

    2012-12-01

    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.

  14. Biological and biochemical characterization of L-type-like bovine spongiform encephalopathy (BSE) detected in Japanese black beef cattle

    PubMed Central

    Masujin, Kentaro; Shu, Yujing; Yamakawa, Yoshio; Hagiwara, Ken'ichi; Sata, Tetsutaro; Matsuura, Yuichi; Iwamaru, Yoshifumi; Imamura, Morikazu; Okada, Hiroyuki; Mohri, Shirou

    2008-01-01

    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 PrPSc were pathologically observed in the brain of BSE/JP24 prion affected TgBoPrP mice. The molecular weight and glycoform ratio of PrPSc in BSE/JP24 were different from those in C-BSE, and PrPSc 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. PMID:19158500

  15. Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys

    PubMed Central

    Cervenak, Juraj; Bu, Ming; Miller, Lindsay; Asher, David M.

    2014-01-01

    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 (PrPTSE), 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 PrPTSE 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. PMID:24769839

  16. Detection and Discrimination of Classical and Atypical L-Type Bovine Spongiform Encephalopathy by Real-Time Quaking-Induced Conversion

    PubMed Central

    Orrú, Christina D.; Favole, Alessandra; Corona, Cristiano; Mazza, Maria; Manca, Matteo; Groveman, Bradley R.; Hughson, Andrew G.; Acutis, Pier Luigi; Caramelli, Maria; Zanusso, Gianluigi

    2015-01-01

    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. PMID:25609728

  17. Complex proteinopathy with accumulations of prion protein, hyperphosphorylated tau, α-synuclein and ubiquitin in experimental bovine spongiform encephalopathy of monkeys.

    PubMed

    Piccardo, Pedro; Cervenak, Juraj; Bu, Ming; Miller, Lindsay; Asher, David M

    2014-07-01

    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.

  18. Detection and discrimination of classical and atypical L-type bovine spongiform encephalopathy by real-time quaking-induced conversion.

    PubMed

    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

    2015-04-01

    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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  19. Estimating the impact on the food chain of changing bovine spongiform encephalopathy (BSE) control measures: the BSE control model.

    PubMed

    Adkin, A; Webster, V; Arnold, M E; Wells, G A H; Matthews, D

    2010-02-01

    The decline in the bovine spongiform encephalopathy (BSE) epidemic in Great Britain (GB) demands a review of control strategies to ensure that they remain proportionate. Amongst controls that are subject to review are those intended to minimise the risk of BSE exposure of consumers through food. Such risk mitigation steps are costly, and the relative impact of each in terms of human exposure to BSE infectivity is not known. This risk assessment, termed the BSE Control Model, aims to estimate by use of stochastic simulation the impact of testing of cattle at slaughter and the removal of Specified Risk Materials (SRM) on potential BSE infectivity consumed. This paper describes the use of the model to investigate the effect of different risk management methods that have been or could be implemented between 2005 and 2010. Our results suggest that the amount of infectivity consumed in 2005 with the Over Thirty Month (OTM) rule in place was a mean of 0.03 bovine oral ID(50) (BO ID(50)). This is an extremely low amount, particularly considering that it would be spread over, on average, 236 infected carcases that would be further sub-divided into portions for human consumption. The highest contributor to the total amount of infectivity consumed per year is spinal contamination at carcase splitting (35%). In 2006 the OTM scheme was discontinued and head meat was again permitted into the food chain. These changes resulted in an increase in the amount of infectivity consumed, rising to an estimated 28 BO ID(50) in 2006, and 19 BO ID(50) in 2007. In 2008 the age at removal of vertebral column was raised from 24 to 30 months, and an estimated 24 BO ID(50) of infectivity was consumed. At the beginning of 2009 the age at testing of cattle was raised to 48 months for healthy slaughter, emergency slaughter and fallen stock. Under these conditions, an estimated mean of 24 BO ID(50) will be consumed in 2009, decreasing to 20 BO ID(50) in 2010. Even though presented in terms of bovine

  20. The epidemiology of bovine spongiform encephalopathy in the Republic of Ireland before and after the reinforced feed ban.

    PubMed

    Ryan, Eoin; McGrath, Guy; Sheridan, Hazel; More, Simon J; Aznar, Inma

    2012-06-01

    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

  1. Assessing the time taken for a surveillance system to detect a re-emergence of bovine spongiform encephalopathy in cattle.

    PubMed

    Simons, Robin R L; Arnold, Mark E; Adkin, Amie

    2017-03-01

    During the bovine spongiform encephalopathy (BSE) epidemic in July 2001 the European Commission established a surveillance scheme for the comprehensive sampling of all BSE clinical suspects, healthy slaughter (HS) animals >30months, and all emergency slaughter and fallen stock animals tested when >24months. With the exponential decline in classical BSE cases, this comprehensive surveillance system has been successively modified to become risk-based, targeting those exit streams and ages where cases from the original epidemic are most likely to be detected. Such reductions in testing are not without losses in the information subsequently collected, which could affect the sensitivity of the surveillance system to relatively small changes in the underlying prevalence of BSE across the European Union (EU). Here we report on a cohort-based approach to estimate the time taken for EU surveillance to observe a theoretical re-emergence of BSE in cattle. A number of surveillance schemes were compared. The baseline scheme considered detection being triggered by at least one case in the 'age window' 48-72 months in the fallen stock or emergency slaughter exit streams. Alternative schemes changed the start and end of this age window as well as considering testing for HS cattle. Under the baseline scheme, an estimated 15 years would lapse ([2.5th, 97.5th] percentiles=[10,24]) prior to detection, during which time 2867 infected animals ([2.5th, 97.5th]=[1722,6967]) would enter the slaughter population. These animals would be predominantly young animals (majority <24months) showing no clinical signs. This baseline scheme reduced the time to detection by 2 years, compared to a scheme where only clinical suspects were tested assuming BSE symptoms are recognised to the same degree by veterinary surgeons. Additional testing of younger animals did not improve detection as young infected animals were unlikely to test positive, but testing of older animals reduced the time to detection

  2. Progressive accumulation of the abnormal conformer of the prion protein and spongiform encephalopathy in the obex of nonsymptomatic and symptomatic Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease

    USDA-ARS?s Scientific Manuscript database

    Chronic wasting disease (CWD), a transmissible spongiform encephalopathy, has been reported in captive and free-ranging cervids. An abnormal isoform of a prion protein (PrP-CWD) has been associated with CWD in Rocky Mountain elk (Cervus elaphus nelsoni) and this prion protein can be detected with i...

  3. A comparison of classical and H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism in wild type and EK211 cattle following intracranial inoculation

    USDA-ARS?s Scientific Manuscript database

    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...

  4. H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism: clinical and pathologic features in wild-type and E211K cattle following intracranial inoculation

    USDA-ARS?s Scientific Manuscript database

    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 ...

  5. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy

    PubMed Central

    Hwang, Soyoun; Greenlee, Justin J.

    2017-01-01

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from the normal cellular prion protein to the pathogenic misfolded conformation (PrPSc). This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. Extensive work has been done to demonstrate that RT-QuIC is a rapid, specific, and highly sensitive prion detection assay. RT-QuIC uses recombinant prion protein to detect minute amounts of PrPSc. RT-QuIC has been successfully used to detect PrPSc from different prion diseases with a variety of substrates including hamster, human, sheep, bank vole, bovine and chimeric forms of prion protein. However, recombinant bovine prion protein has not been used to detect transmissible mink encephalopathy (TME) or to differentiate types of bovine spongiform encephalopathy (BSE) in samples from cattle. We evaluated whether PrPSc from TME and BSE infected cattle can be detected with RT-QuIC using recombinant bovine prion proteins, and optimized the reaction conditions to specifically detect cattle TME and to discriminate between classical and atypical BSE by conversion efficiency. We also found that substrate composed of the disease associated E211K mutant protein can be effective for the detection of TME in cattle and that wild type prion protein appears to be a practical substrate to discriminate between the different types of BSEs. PMID:28225797

  6. Use of bovine recombinant prion protein and real-time quaking-induced conversion to detect cattle transmissible mink encephalopathy prions and discriminate classical and atypical L- and H-Type bovine spongiform encephalopathy.

    PubMed

    Hwang, Soyoun; Greenlee, Justin J; Nicholson, Eric M

    2017-01-01

    Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving conversion from the normal cellular prion protein to the pathogenic misfolded conformation (PrPSc). This conversion has been used for in vitro assays including serial protein misfolding amplification and real-time quaking induced conversion (RT-QuIC). RT-QuIC can be used for the detection of prions in a variety of biological tissues from humans and animals. Extensive work has been done to demonstrate that RT-QuIC is a rapid, specific, and highly sensitive prion detection assay. RT-QuIC uses recombinant prion protein to detect minute amounts of PrPSc. RT-QuIC has been successfully used to detect PrPSc from different prion diseases with a variety of substrates including hamster, human, sheep, bank vole, bovine and chimeric forms of prion protein. However, recombinant bovine prion protein has not been used to detect transmissible mink encephalopathy (TME) or to differentiate types of bovine spongiform encephalopathy (BSE) in samples from cattle. We evaluated whether PrPSc from TME and BSE infected cattle can be detected with RT-QuIC using recombinant bovine prion proteins, and optimized the reaction conditions to specifically detect cattle TME and to discriminate between classical and atypical BSE by conversion efficiency. We also found that substrate composed of the disease associated E211K mutant protein can be effective for the detection of TME in cattle and that wild type prion protein appears to be a practical substrate to discriminate between the different types of BSEs.

  7. Coexistence of two forms of disease-associated prion protein in extracerebral tissues of cattle infected with H-type bovine spongiform encephalopathy.

    PubMed

    Okada, Hiroyuki; Miyazawa, Kohtaro; Masujin, Kentaro; Yokoyama, Takashi

    2016-08-01

    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.

  8. Experimental classical bovine spongiform encephalopathy: definition and progression of neural PrP immunolabeling in relation to diagnosis and disease controls.

    PubMed

    Simmons, M M; Spiropoulos, J; Webb, P R; Spencer, Y I; Czub, S; Mueller, R; Davis, A; Arnold, M E; Marsh, S; Hawkins, S A C; Cooper, J A; Konold, T; Wells, G A H

    2011-09-01

    Tissues from sequential-kill time course studies of bovine spongiform encephalopathy (BSE) were examined to define PrP immunohistochemical labeling forms and map disease-specific labeling over the disease course after oral exposure to the BSE agent at two dose levels. Study was confined to brainstem, spinal cord, and certain peripheral nervous system ganglia-tissues implicated in pathogenesis and diagnosis or disease control strategies. Disease-specific labeling in the brainstem in 39 of 220 test animals showed the forms and patterns observed in natural disease and invariably preceded spongiform changes. A precise temporal pattern of increase in labeling was not apparent, but labeling was generally most widespread in clinical cases, and it always involved neuroanatomic locations in the medulla oblongata. In two cases, sparse labeling was confined to one or more neuroanatomic nuclei of the medulla oblongata. When involved, the spinal cord was affected at all levels, providing no indication of temporal spread within the cord axis or relative to the brainstem. Where minimal PrP labeling occurred in the thoracic spinal cord, it was consistent with initial involvement of general visceral efferent neurons. Labeling of ganglia involved only sensory ganglia and only when PrP was present in the brainstem and spinal cord. These experimental transmissions mimicked the neuropathologic findings in BSE-C field cases, independent of dose of agent or stage of disease. The model supports current diagnostic sampling approaches and control measures for the removal and destruction of nervous system tissues in slaughtered cattle.

  9. Rapid assessment of bovine spongiform encephalopathy prion inactivation by heat treatment in yellow grease produced in the industrial manufacturing process of meat and bone meals.

    PubMed

    Yoshioka, Miyako; Matsuura, Yuichi; Okada, Hiroyuki; Shimozaki, Noriko; Yamamura, Tomoaki; Murayama, Yuichi; Yokoyama, Takashi; Mohri, Shirou

    2013-07-09

    Prions, infectious agents associated with transmissible spongiform encephalopathy, are primarily composed of the misfolded and pathogenic form (PrPSc) of the host-encoded prion protein. Because PrPSc retains infectivity after undergoing routine sterilizing processes, the cause of bovine spongiform encephalopathy (BSE) outbreaks are suspected to be feeding cattle meat and bone meals (MBMs) contaminated with the prion. To assess the validity of prion inactivation by heat treatment in yellow grease, which is produced in the industrial manufacturing process of MBMs, we pooled, homogenized, and heat treated the spinal cords of BSE-infected cows under various experimental conditions. Prion inactivation was analyzed quantitatively in terms of the infectivity and PrPSc of the treated samples. Following treatment at 140°C for 1 h, infectivity was reduced to 1/35 of that of the untreated samples. Treatment at 180°C for 3 h was required to reduce infectivity. However, PrPSc was detected in all heat-treated samples by using the protein misfolding cyclic amplification (PMCA) technique, which amplifies PrPScin vitro. Quantitative analysis of the inactivation efficiency of BSE PrPSc was possible with the introduction of the PMCA50, which is the dilution ratio of 10% homogenate needed to yield 50% positivity for PrPSc in amplified samples. Log PMCA50 exhibited a strong linear correlation with the transmission rate in the bioassay; infectivity was no longer detected when the log PMCA50 of the inoculated sample was reduced to 1.75. The quantitative PMCA assay may be useful for safety evaluation for recycling and effective utilization of MBMs as an organic resource.

  10. Does the Presence of Scrapie Affect the Ability of Current Statutory Discriminatory Tests To Detect the Presence of Bovine Spongiform Encephalopathy?

    PubMed Central

    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.

    2015-01-01

    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. PMID:26041899

  11. Further characterisation of transmissible spongiform encephalopathy phenotypes after inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain.

    PubMed

    Konold, Timm; Nonno, Romolo; Spiropoulos, John; Chaplin, Melanie J; Stack, Michael J; Hawkins, Steve A C; Cawthraw, Saira; Wilesmith, John W; Wells, Gerald A H; Agrimi, Umberto; Di Bari, Michele A; Andréoletti, Olivier; Espinosa, Juan C; Aguilar-Calvo, Patricia; Torres, Juan M

    2015-07-24

    The infectious agent responsible for the bovine spongiform encephalopathy (BSE) epidemic in Great Britain is a transmissible spongiform encephalopathy (TSE) strain with uniform properties but the origin of this strain remains unknown. Based on the hypothesis that classical BSE may have been caused by a TSE strain present in sheep, cattle were inoculated intracerebrally with two different pools of brains from scrapie-affected sheep sourced prior to and during the BSE epidemic to investigate resulting disease phenotypes and characterise their causal agents by transmission to rodents. As reported in 2006, intracerebral inoculation of cattle with pre-1975 and post-1990 scrapie brain pools produced two distinct disease phenotypes, which were unlike classical BSE. Subsequent to that report none of the remaining cattle, culled at 10 years post inoculation, developed a TSE. Retrospective Western immunoblot examination of the brains from TSE cases inoculated with the pre-1975 scrapie pool revealed a molecular profile similar to L-type BSE. The inoculation of transgenic mice expressing the bovine, ovine, porcine, murine or human prion protein gene and bank voles with brains from scrapie-affected cattle did not detect classical or atypical BSE strains but identified two previously characterised scrapie strains of sheep. Characterisation of the causal agents of disease resulting from exposure of cattle to naturally occurring scrapie agents sourced in Great Britain did not reveal evidence of classical or atypical BSE, but did identify two distinct previously recognised strains of scrapie. Although scrapie was still recognizable upon cattle passage there were irreconcilable discrepancies between the results of biological strain typing approaches and molecular profiling methods, suggesting that the latter may not be appropriate for the identification and differentiation of atypical, particularly L-type, BSE agents from cattle experimentally infected with a potential mixture of

  12. Abnormal prion protein is associated with changes of plasma membranes and endocytosis in bovine spongiform encephalopathy (BSE)-affected cattle brains.

    PubMed

    Ersdal, C; Goodsir, C M; Simmons, M M; McGovern, G; Jeffrey, M

    2009-06-01

    Transmissible spongiform encephalopathies (TSEs) or prion diseases are fatal neurodegenerative diseases of man and animals characterized by vacuolation and gliosis of neuropil and the accumulation of abnormal isoforms of a host protein known as prion protein (PrP). It is widely assumed that the abnormal isoforms of PrP (PrP(d), disease-specific form of PrP) are the proximate cause of neurodegeneration. To determine the nature of subcellular changes and their association with PrP(d) we perfusion-fixed brains of eight bovine spongiform encephalopathy (BSE)-affected cows and three control cattle for immunogold electron microscopy at two different neuroanatomical sites. All affected cattle presented plasma membrane alterations of dendrites and astrocytes that were labelled for PrP(d). PrP(d) on membranes of dendrites and occasionally of neuronal perikarya was associated with abnormal endocytotic events, including bizarre coated pits and invagination of the plasma membrane. BSE-affected cattle also presented excess and abnormal multivesicular bodies, sometimes associated to the plasma membrane perturbations. In contrast, two TSE-specific lesions, vacuolation and rare tubulovesicular bodies, were not labelled for PrP(d) as were a number of other nonspecific lesions, such as autophagy and dystrophic neurites. At least two different morphological pathways to vacuoles were recognized. When compared with other TSEs, these changes are common to those of sheep and rodent scrapie and shows that there are consistent membrane toxicity properties of PrP(d). This toxicity involves an aberration of endocytosis. However, it is by no means clear that the lesions are of sufficient severity to result in clinical deficits.

  13. Does the Presence of Scrapie Affect the Ability of Current Statutory Discriminatory Tests To Detect the Presence of Bovine Spongiform Encephalopathy?

    PubMed

    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

    2015-08-01

    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. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  14. Rapid assessment of bovine spongiform encephalopathy prion inactivation by heat treatment in yellow grease produced in the industrial manufacturing process of meat and bone meals

    PubMed Central

    2013-01-01

    Background Prions, infectious agents associated with transmissible spongiform encephalopathy, are primarily composed of the misfolded and pathogenic form (PrPSc) of the host-encoded prion protein. Because PrPSc retains infectivity after undergoing routine sterilizing processes, the cause of bovine spongiform encephalopathy (BSE) outbreaks are suspected to be feeding cattle meat and bone meals (MBMs) contaminated with the prion. To assess the validity of prion inactivation by heat treatment in yellow grease, which is produced in the industrial manufacturing process of MBMs, we pooled, homogenized, and heat treated the spinal cords of BSE-infected cows under various experimental conditions. Results Prion inactivation was analyzed quantitatively in terms of the infectivity and PrPSc of the treated samples. Following treatment at 140°C for 1 h, infectivity was reduced to 1/35 of that of the untreated samples. Treatment at 180°C for 3 h was required to reduce infectivity. However, PrPSc was detected in all heat-treated samples by using the protein misfolding cyclic amplification (PMCA) technique, which amplifies PrPScin vitro. Quantitative analysis of the inactivation efficiency of BSE PrPSc was possible with the introduction of the PMCA50, which is the dilution ratio of 10% homogenate needed to yield 50% positivity for PrPSc in amplified samples. Conclusions Log PMCA50 exhibited a strong linear correlation with the transmission rate in the bioassay; infectivity was no longer detected when the log PMCA50 of the inoculated sample was reduced to 1.75. The quantitative PMCA assay may be useful for safety evaluation for recycling and effective utilization of MBMs as an organic resource. PMID:23835086

  15. Stability properties of PrPSc from cattle with experimental transmissible spongiform encephalopathies: use of a rapid whole homogenate, protease-free assay

    PubMed Central

    2013-01-01

    Background Transmissible Spongiform Encephalopathies (TSEs), including scrapie in sheep, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME), and bovine spongiform encephalopathy (BSE), are fatal diseases of the nervous system associated with accumulation of misfolded prion protein (PrPSc). Different strains of TSEs exist, associated with different PrPSc conformations that can be probed by the stability assay, in which PrPSc is treated with increasing concentrations of the denaturant guanidine hydrochloride (GdnHCl). Results Here, we provide the first comprehensive application of a rapid, protease-free version of the GdnHCl stability assay to brain tissue from cattle experimentally infected with various TSE isolates. Consistent with previous findings from a single Japanese isolate, the L-type isolates of BSE are not distinguishable from classical BSE in this assay. In contrast, H-type isolates of BSE, including our unique isolate of E211K BSE, exhibit higher stability than classical BSE, suggesting that its increased protection against protease digestion at the BSE N-terminus is associated with a higher stability in GdnHCl. While the difference in stability in our version of the assay is likely not large enough for effective use in a diagnostic laboratory setting, the use of alternative experimental conditions may enhance this effect. TSEs from other natural host species that have been passaged in cattle, including CWD and TME, were not distinguishable from classical BSE, while isolates of cattle passaged scrapie exhibited a slight increase in stability as compared to classical BSE. Conclusions These results suggest that the core of PrPSc, as probed in this assay, has similar stability properties among cattle-passaged TSE isolates and that the conformational differences that lead to changes in the proteinase K cleavage site do not cause large changes in the stability of PrPSc from TSE-affected cattle. However, the stability differences

  16. Enhanced virulence of sheep-passaged bovine spongiform encephalopathy agent is revealed by decreased polymorphism barriers in prion protein conversion studies.

    PubMed

    Priem, Jan; Langeveld, Jan P M; van Keulen, Lucien J M; van Zijderveld, Fred G; Andreoletti, Olivier; Bossers, Alex

    2014-03-01

    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. These polymorphisms in PrP also modulate the PrP conversion underlying TSE agent replication. Here we demonstrate that single-round protein misfolding cyclic amplification (PMCA) can be used to assess species and polymorphism barriers at the molecular level. We assessed those within and between the ovine and bovine species in vitro using a variety of natural scrapie and experimentally generated cross-species BSE agents. These BSE agents include ovBSE-ARQ isolates (BSE derived from sheep having the ARQ/ARQ PrP genotype), and two unique BSE-derived variants: BSE passaged in VRQ/VRQ sheep and a cow BSE agent isolate generated by back-transmission of ovBSE-ARQ into its original host. PMCA allowed us to quantitatively determine PrP conversion profiles that correlated with known in vivo transmissibility and susceptibility in the two ruminant species in which strain-specific molecular signatures, like its molecular weight after protease digestion, were maintained. Furthermore, both BSE agent isolates from ARQ and VRQ sheep demonstrated a surprising transmission profile in which efficient transmissions to both sheep and bovine variants was combined. Finally, all data support the notion that ARQ-derived sheep BSE points to a significant increase in virulence compared to all other tested scrapie- and BSE-derived variants reflected by the increased conversion efficiencies of previously inefficient convertible PrP variants (including the so-called "resistant" sheep ARR variant). Prion diseases such as scrapie in sheep and goats, BSE in cattle, and Creutzfeldt-Jakob disease (CJD) in humans are fatal neurodegenerative diseases caused by prions. BSE is known to be transmissible to a

  17. Enhanced Virulence of Sheep-Passaged Bovine Spongiform Encephalopathy Agent Is Revealed by Decreased Polymorphism Barriers in Prion Protein Conversion Studies

    PubMed Central

    Priem, Jan; Langeveld, Jan P. M.; van Keulen, Lucien J. M.; van Zijderveld, Fred G.; Andreoletti, Olivier

    2014-01-01

    ABSTRACT 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. These polymorphisms in PrP also modulate the PrP conversion underlying TSE agent replication. Here we demonstrate that single-round protein misfolding cyclic amplification (PMCA) can be used to assess species and polymorphism barriers at the molecular level. We assessed those within and between the ovine and bovine species in vitro using a variety of natural scrapie and experimentally generated cross-species BSE agents. These BSE agents include ovBSE-ARQ isolates (BSE derived from sheep having the ARQ/ARQ PrP genotype), and two unique BSE-derived variants: BSE passaged in VRQ/VRQ sheep and a cow BSE agent isolate generated by back-transmission of ovBSE-ARQ into its original host. PMCA allowed us to quantitatively determine PrP conversion profiles that correlated with known in vivo transmissibility and susceptibility in the two ruminant species in which strain-specific molecular signatures, like its molecular weight after protease digestion, were maintained. Furthermore, both BSE agent isolates from ARQ and VRQ sheep demonstrated a surprising transmission profile in which efficient transmissions to both sheep and bovine variants was combined. Finally, all data support the notion that ARQ-derived sheep BSE points to a significant increase in virulence compared to all other tested scrapie- and BSE-derived variants reflected by the increased conversion efficiencies of previously inefficient convertible PrP variants (including the so-called “resistant” sheep ARR variant). IMPORTANCE Prion diseases such as scrapie in sheep and goats, BSE in cattle, and Creutzfeldt-Jakob disease (CJD) in humans are fatal neurodegenerative diseases caused by prions. BSE is known to

  18. A model to assess the risk of the introduction into Japan of the bovine spongiform encephalopathy agent through imported animals, meat and meat-and-bone meal.

    PubMed

    Sugiura, K; Ito, K; Yokoyama, R; Kumagai, S; Onodera, T

    2003-12-01

    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.

  19. Surveillance for transmissible spongiform encephalopathy in scavengers of white-tailed deer carcasses in the chronic wasting disease area of wisconsin

    USGS Publications Warehouse

    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.

    2009-01-01

    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.

  20. Detection of bovine central nervous system tissue as bovine spongiform encephalopathy risk material by real-time reverse transcriptase-PCR in raw and cooked beef products.

    PubMed

    Shi, Xi-Ju; Ma, Gui-Ping; Li, Bing-Ling; Yang, Jin-Liang; Yu-Wang; Li, Yan-Xin; Liu, Xu-Hui; Liu, Quan-Guo

    2008-01-01

    There is increasing evidence of the association of the new variant of Creutzfeldt-Jacob disease (nvCJD) in humans with bovine spongiform encephalopathy (BSE) in cattle. Many countries established legislation of banning central nervous system (CNS) tissues, which are regarded as BSE-specified risk materials (SRM), in human food supply because of the potential transmission of BSE to humans. A real-time reverse transcriptase-PCR assay using the bovine glial fibrillary acidic protein (GFAP) mRNA template for the detection of CNS tissues in raw and cooked beef products was developed in this study. The results showed that (1) this method can detect CNS tissues from bovine and ovine origins, but not from porcine and avian ones; (2) GFAP mRNA can only be detected from brain and spinal cords rather than other tissues; (3) the GFAP mRNA was detectable in CNS tissues even after dilution to 0.001%; and (4) the assay was unaffected by heat treatment at 100 degrees C for 30 min or storage at room temperature for 4 days, and at 4 degrees C for at least 15 days.

  1. Transcript level of erythroid differentiation-related factor, a candidate surrogate marker for transmissible spongiform encephalopathy diseases in blood, shows a broad range of variation in healthy individuals.

    PubMed

    Glock, Barbara; Winter, Maya; Rennhofer, Simone O; Brunhölzl, Elisabeth; Tröscher, Doris; Reisacher, Rosemarie B K; Mayr, Wolfgang R

    2003-12-01

    In 2001, it was demonstrated that the expression of the erythroid differentiation-related factor (EDRF) is reduced in lymphatic tissues of rodents and cattle as well as in whole blood of sheep that suffer from transmissible spongiform encephalopathy. To determine whether the normal range of EDRF expression varies in healthy individuals, mRNA levels were measured in whole blood samples from 106 healthy blood donors by quantitative real-time RT-PCR. Furthermore, the correlations of transcript levels with individual physical characteristics were analyzed. In addition, EDRF expression was examined in total RNA samples from a lymph node and the intestine. The data show that EDRF mRNA levels in healthy persons vary within a total range of 2 log units as well as they display a weak correlation with body height. Furthermore, it was found that EDRF is also expressed in lymph nodes and the intestine. Owing to its broad range of variation, measuring the EDRF expression does not seem to be a good surrogate marker, unless an altered expression is distinctively different from the varying level in healthy humans.

  2. In-situ spectroscopic investigation of transmissible spongiform encephalopathies: application of Fourier-transform infrared spectroscopy to a scrapie-hamster model

    NASA Astrophysics Data System (ADS)

    Kneipp, Janina; Lasch, Peter; Beekes, Michael; Naumann, Dieter

    2002-03-01

    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.

  3. Neuroanatomical distribution of disease-associated prion protein in cases of bovine spongiform encephalopathy detected by fallen stock surveillance in Japan.

    PubMed

    Okada, Hiroyuki; Iwamaru, Yoshihumi; Imamura, Morikazu; Masujin, Kentaro; Matsuura, Yuichi; Shimizu, Yoshihisa; Kasai, Kazuo; Takata, Masuhiro; Fukuda, Shigeo; Nikaido, Satoshi; Fujii, Kei; Onoe, Sadao; Mohri, Shirou; Yokoyama, Takashi

    2011-11-01

    Bovine spongiform encephalopathy (BSE) is a fatal neurodegenerative disorder of cattle characterized by accumulation of the disease-associated prion protein (PrP(Sc)) in the central nervous system (CNS). The immunohistochemical patterns and distribution of PrP(Sc) were investigated in the CNS, brains, and spinal cords of 7 naturally occurring BSE cases confirmed by the fallen stock surveillance program in Japan. No animals showed characteristic clinical signs of the disease. Coronal slices of 14 different brain areas in each case were immunohistochemically analyzed using an anti-prion protein antibody. Immunolabeled PrP(Sc) deposition was widely observed throughout each brain and spinal cord. Intense PrP(Sc) deposition was greater in the thalamus, brainstem, and spinal cord of the gray matter than in the neocortices. The topographical distribution pattern and severity of PrP(Sc) accumulation were mapped and plotted as immunohistochemical profiles of the different brain areas along the caudal-rostral axis of the brain. The distribution pattern and severity of the immunolabeled PrP(Sc) in the CNS were almost the same among the 7 cases analyzed, suggesting that the naturally occurring cases in this study were at the preclinical stage of the disease. Immunohistochemical mapping of the PrP(Sc) deposits will be used to clarify the different stages of BSE in cattle.

  4. Detection of disease-associated prion protein in the optic nerve and the adrenal gland of cattle with bovine spongiform encephalopathy by using highly sensitive immunolabeling procedures.

    PubMed

    Okada, Hiroyuki; Iwamaru, Yoshifumi; Fukuda, Shigeo; Yokoyama, Takashi; Mohri, Shirou

    2012-04-01

    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.

  5. Expression of genes involved in the T cell signalling pathway in circulating immune cells of cattle 24 months following oral challenge with Bovine Amyloidotic Spongiform Encephalopathy (BASE).

    PubMed

    Trovato, Andrea; Panelli, Simona; Strozzi, Francesco; Cambulli, Caterina; Barbieri, Ilaria; Martinelli, Nicola; Lombardi, Guerino; Capoferri, Rossana; Williams, John L

    2015-05-09

    Bovine Amyloidotic Spongiform Encephalopathy (BASE) is a variant of classical BSE that affects cows and can be transmitted to primates and mice. BASE is biochemically different from BSE and shares some molecular and histo-pathological features with the MV2 sub-type of human sporadic Creutzfeld Jakob Disease (sCJD). The present work examined the effects of BASE on gene expression in circulating immune cells. Ontology analysis of genes differentially expressed between cattle orally challenged with brain homogenate from cattle following intracranial inoculation with BASE and control cattle identified three main pathways which were affected. Within the immune function pathway, the most affected genes were related to the T cell receptor-mediated T cell activation pathways. The differential expression of these genes in BASE challenged animals at 10,12 and 24 months following challenge, vs unchallenged controls, was investigated by real time PCR. The results of this study show that the effects of prion diseases are not limited to the CNS, but involve the immune system and particularly T cell signalling during the early stage following challenge, before the appearance of clinical signs.

  6. Is there a decline in bovine spongiform encephalopathy cases born after reinforced feed bans? A modelling study in EU member states.

    PubMed

    Arnold, M E; Simons, R R L; Hope, J; Gibbens, N; Adkin, A L

    2017-08-01

    Occasional cases of classical bovine spongiform encephalopathy (BSE) still continue to occur within the European Union (EU) for animals born after reinforced feed bans (BARBs), which should in theory have eliminated all risk of infection. The study aimed to determine (i) whether a common rate of decline of BSE infection was evident across EU member states, i.e. to determine whether control measures have been equally effective in all member states, (ii) whether there was any evidence of spontaneous occurrence of BSE in the data and (iii) the expected date for the last BSE case in UK. It was found that there was no significant difference in the rate of decline of BSE prevalence between member states, with a common rate of decline of 33·9% per annum (95% CI 30·9-37%) in successive annual birth cohorts. Trend analysis indicated an ultimate decline to 0 prevalence, suggesting that spontaneous occurrence does not explain the majority of cases. Projecting forward the trends from the back-calculation model indicated that there was approximately a 50% probability of further cases in the UK, and should the current rate of decline continue, there remains the possibility of further occasional cases up until 2026.

  7. L-type bovine spongiform encephalopathy in genetically susceptible and resistant sheep: changes in prion strain or phenotypic plasticity of the disease-associated prion protein?

    PubMed

    Nicot, Simon; Bencsik, Anna; Migliore, Sergio; Canal, Dominique; Leboidre, Mikael; Agrimi, Umberto; Nonno, Romolo; Baron, Thierry

    2014-03-01

    Sheep with prion protein (PrP) gene polymorphisms QQ171 and RQ171 were shown to be susceptible to the prion causing L-type bovine spongiform encephalopathy (L-BSE), although RQ171 sheep specifically propagated a distinctive prion molecular phenotype in their brains, characterized by a high molecular mass protease-resistant PrP fragment (HMM PrPres), distinct from L-BSE in QQ171 sheep. The resulting infectious and biological properties of QQ171 and RQ171 ovine L-BSE prions were investigated in transgenic mice expressing either bovine or ovine PrP. In both mouse lines, ovine L-BSE transmitted similarly to cattle-derived L-BSE, with respect to survival periods, histopathology, and biochemical features of PrPres in the brain, as well as splenotropism, clearly differing from ovine classic BSE or from scrapie strain CH1641. Nevertheless and unexpectedly, HMM PrPres was found in the spleen of ovine PrP transgenic mice infected with L-BSE from RQ171 sheep at first passage, reminiscent, in lymphoid tissues only, of the distinct PrPres features found in RQ171 sheep brains. The L-BSE agent differs from both ovine classic BSE or CH1641 scrapie maintaining its specific strain properties after passage in sheep, although striking PrPres molecular changes could be found in RQ171 sheep and in the spleen of ovine PrP transgenic mice.

  8. Detection of Atypical H-Type Bovine Spongiform Encephalopathy and Discrimination of Bovine Prion Strains by Real-Time Quaking-Induced Conversion.

    PubMed

    Masujin, Kentaro; Orrú, Christina D; Miyazawa, Kohtaro; Groveman, Bradley R; Raymond, Lynne D; Hughson, Andrew G; Caughey, Byron

    2016-03-01

    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. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  9. Bovine spongiform encephalopathy associated insertion/deletion polymorphisms of the prion protein gene in the four beef cattle breeds from North China.

    PubMed

    Zhu, Xiang-Yuan; Feng, Fu-Ying; Xue, Su-Yuan; Hou, Ting; Liu, Hui-Rong

    2011-10-01

    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.

  10. Detection of Disease-associated Prion Protein in the Optic Nerve and the Adrenal Gland of Cattle with Bovine Spongiform Encephalopathy by Using Highly Sensitive Immunolabeling Procedures

    PubMed Central

    Iwamaru, Yoshifumi; Fukuda, Shigeo; Yokoyama, Takashi; Mohri, Shirou

    2012-01-01

    A sensitive immunohistochemical procedure, the tyramide signal amplification (TSA) system, was applied to detect the localization of immunolabeled disease-associated prion protein (PrPSc) 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 PrPSc was occasionally detected in the astrocytes, microglia, and myelin sheath adjacent to the axon. Clustered PrPSc was also scattered in association with microglial cells and astrocytes of the optic nerve. In the adrenal gland, PrPSc immunolabeling was confined within the sympathetic nerve fibers and endings. The results suggest that (1) PrPSc 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 PrPSc in the extracerebral tissues of BSE-affected cattle. PMID:22260993

  11. The pathological and molecular but not clinical phenotypes are maintained after second passage of experimental atypical bovine spongiform encephalopathy in cattle.

    PubMed

    Konold, Timm; Phelan, Laura J; Clifford, Derek; Chaplin, Melanie J; Cawthraw, Saira; Stack, Michael J; Simmons, Marion M

    2014-10-02

    Atypical bovine spongiform encephalopathies (BSEs), classified as H-type and L-type BSE based on the Western immunoblot profiles, are naturally occurring diseases in cattle, which are phenotypically different to classical BSE. Transmission studies in cattle using the intracerebral route resulted in disease where the phenotypes were maintained irrespective of BSE type but clinically affected cattle with a shorter survival time displayed a nervous form whereas cattle with a longer survival time displayed a dull form. A second transmission study is reported here where four cattle were intracerebrally inoculated with brain tissue from experimentally infected cattle presenting with either the nervous or dull form of H- or L-type BSE to determine whether the phenotype is maintained. The four inoculated cattle were culled at 16.5-19.5 months post inoculation after presenting with difficulty getting up, a positive scratch response (all) and dullness (three cattle), which was not observed in two non-inoculated control cattle, each housed with either group of inoculated cattle. Only the inoculated cattle had detectable prion protein in the brain based on immunohistochemical examination, and the Western immunoblot profile was consistent with the H-type or L-type BSE of the respective donor cattle. Second passage of H-type and L-type BSE in cattle produced a TSE where the majority of cattle displayed the dull form regardless of clinical disease form of the donor cattle. The pathological and molecular phenotypes of H- and L-type BSE were maintained.

  12. Detection and partial discrimination of atypical and classical bovine spongiform encephalopathies in cattle and primates using real-time quaking-induced conversion assay.

    PubMed

    Levavasseur, Etienne; Biacabe, Anne-Gaëlle; Comoy, Emmanuel; Culeux, Audrey; Grznarova, Katarina; Privat, Nicolas; Simoneau, Steve; Flan, Benoit; Sazdovitch, Véronique; Seilhean, Danielle; Baron, Thierry; Haïk, Stéphane

    2017-01-01

    The transmission of classical bovine spongiform encephalopathy (C-BSE) through contaminated meat product consumption is responsible for variant Creutzfeldt-Jakob disease (vCJD) in humans. More recent and atypical forms of BSE (L-BSE and H-BSE) have been identified in cattle since the C-BSE epidemic. Their low incidence and advanced age of onset are compatible with a sporadic origin, as are most cases of Creutzfeldt-Jakob disease (CJD) in humans. Transmissions studies in primates and transgenic mice expressing a human prion protein (PrP) indicated that atypical forms of BSE may be associated with a higher zoonotic potential than classical BSE, and require particular attention for public health. Recently, methods designed to amplify misfolded forms of PrP have emerged as promising tools to detect prion strains and to study their diversity. Here, we validated real-time quaking-induced conversion assay for the discrimination of atypical and classical BSE strains using a large series of bovine samples encompassing all the atypical BSE cases detected by the French Centre of Reference during 10 years of exhaustive active surveillance. We obtained a 100% sensitivity and specificity for atypical BSE detection. In addition, the assay was able to discriminate atypical and classical BSE in non-human primates, and also sporadic CJD and vCJD in humans. The RT-QuIC assay appears as a practical means for a reliable detection of atypical BSE strains in a homologous or heterologous PrP context.

  13. Mapping of neurotrophins and their receptors in the adult mouse brain and their role in the pathogenesis of a transgenic murine model of bovine spongiform encephalopathy.

    PubMed

    Marco-Salazar, P; Márquez, M; Fondevila, D; Rabanal, R M; Torres, J M; Pumarola, M; Vidal, E

    2014-05-01

    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. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Significant differences in incubation times in sheep infected with bovine spongiform encephalopathy result from variation at codon 141 in the PRNP gene.

    PubMed

    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

    2012-12-01

    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.

  15. Immunohistochemical detection of disease-associated prion protein in the peripheral nervous system in experimental H-type bovine spongiform encephalopathy.

    PubMed

    Okada, H; Iwamaru, Y; Yokoyama, T; Mohri, S

    2013-07-01

    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.

  16. Detection of Atypical H-Type Bovine Spongiform Encephalopathy and Discrimination of Bovine Prion Strains by Real-Time Quaking-Induced Conversion

    PubMed Central

    Masujin, Kentaro; Orrú, Christina D.; Miyazawa, Kohtaro; Groveman, Bradley R.; Raymond, Lynne D.; Hughson, Andrew G.

    2016-01-01

    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. PMID:26739160

  17. Spontaneous obesity-linked type 2 diabetes in the absence of islet amyloid in a cynomolgus monkey infected with bovine spongiform encephalopathy.

    PubMed

    Strom, A; Yutzy, B; Kruip, C; Völker, I; Schloot, N C; Roden, M; Scott, F W; Löwer, J; Holznagel, E

    2013-09-01

    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.

  18. Immunohistochemical studies of scrapie archival material from Irish ARQ/ARQ sheep for evidence of bovine spongiform encephalopathy-derived disease.

    PubMed

    Sharpe, A; McElroy, M; Langeveld, J P M; Bassett, H; O'Donoghue, A M; Sweeney, T

    2005-08-01

    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 (PrP(d)) patterns in archival tissues of 38 Irish ARQ/ARQ sheep diagnosed as scrapie-affected were compared to those in four Dutch BSE-challenged sheep. When medulla oblongata was immunolabelled with an antibody directed against amino acids 93-99 of ovine prion protein (ovPrP), intraneuronal PrP(d) was apparent in all 38 Irish sheep but was absent in BSE-challenged sheep. When lymphoid follicles were immunolabelled with antibodies directed against amino acids 93-106 of ovPrP, granule clusters of PrP(d) were seen in 34 of the 38 Irish sheep. Follicles of the remaining four archive sheep contained either no PrP(d) or single PrP(d) granules, similar to follicles from BSE-challenged sheep. Based on the medulla results, none of the archival cases had BSE-derived disease. The identification of some scrapie sheep with little or no intrafollicular PrP(d) suggests that this technique may be limited in discriminating between the two diseases.

  19. Profiling the culprit in Alzheimer's disease (AD): bacterial toxic proteins - Will they be significant for the aetio-pathogenesis of AD and the transmissible spongiform encephalopathies?

    PubMed

    Schmitt, H Peter

    2007-01-01

    The aetiology of Alzheimer's disease (AD) and the transmissible spongiform encephalopathies (tSEs) is still elusive. The concept that prion protein (PrP(Sc)) is the aetiological agent (infectious protein) in the tSEs has recently been questioned. In AD, the cause of the aberrant cleavage of the beta-amyloid precursor protein (APP), resulting in the production of amyloidogenic Abeta fragments, has yet remained obscure. Moreover, the amyloid hypothesis of AD has been seriously challenged. In both AD and the tSEs, pathogens of various nature, including bacteria, have been discussed as possible causal factors. However, aetiological considerations have completely neglected microbial products such as the bacterial toxic proteins (BTPs). The present paper is aimed at drawing a "culprit profile" of these toxic molecules that can exert, at low-dosage, neuro-degeneration through various effects. Clearly, BTPs may affect cell-surface receptors including modulatory amine transmitter receptor expression, block neuro-transmitter release, increase intra-cellular Ca(2+) levels, affect intra-cellular signal transduction, change cyto-skeletal processing, alter synaptic transmission, influence APP proteolysis, interact with cell surface proteins like PrP(C) or their GPI anchors, act as chaperones inducing conformational change in proteins (e.g., PrP(C) to PrP(Sc)), alter lipid membrane integrity by affecting phospholipases or forming pores and channels, induce vacuolar (spongiform) change and elicit inflammatory reactions with cytokine production including cytokines that were demonstrated in the AD brain. Like PrP(Sc), BTPs can be heat-stable and acid-resistant. BTPs can meet the key-proteins of AD and tSEs in the lipid-rich domains of the plasma membrane called rafts. Basically, this might enable them to initiate a large variety of unfavourable molecular events, eventually resulting in pathogenetic cascades as in AD and the tSEs. All in all, their profile lends support to the

  20. Gerstmann-Sträussler-Scheinker syndrome,fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies.

    PubMed

    Collins, S; McLean, C A; Masters, C L

    2001-09-01

    Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru constitute major human prion disease phenotypes. Each has been successfully transmitted in animal models and all are invariably fatal neurodegenerative disorders, with the brains of affected individuals harbouring variable amounts of an abnormal, protease-resistant form of the prion protein (PrPres), which is inextricably linked to pathogenesis and transmissibility. Classical sporadic CJD is the most common human transmissible spongiform encephalopathy (TSE), but recently the variant form (vCJD), first described in the UK in 1996, has drawn considerable attention. In contrast to sporadic CJD, FFI and GSS are almost invariably genetically determined TSEs, caused by a range of mutations within the open reading frame of the prion protein gene (PRNP) on chromosome 20. By definition, the nosologic term FFI is reserved for patients manifesting prominent insomnia, generally in combination with dysautonomia, myoclonus, and eventual dementia, with the predominant pathologic changes lying within the thalami and a specific underlying mutation in PRNP. GSS, however, encompasses a more diverse clinical spectrum ranging from progressive cerebellar ataxia or spastic paraparesis (both usually in combination with dementia), to isolated cognitive impairment resembling Alzheimer's disease. Additional extra-pyramidal features, which may respond to dopaminergic therapy can also be seen. Neuropathological findings are also relatively diverse, partly overlapping with those found in Alzheimer's disease, especially the presence of neurofibrillary tangles (NFTs). Although GSS and FFI in their classical forms are differentiable clinical profiles, such divisions may have no intrinsic biological validity given the considerable intra-familial clinico-pathological diversity so commonly seen. Kuru constitutes a horizontally transmitted prion disease, which after a lengthy

  1. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins.

    PubMed

    Lee, D C; Stenland, C J; Miller, J L; Cai, K; Ford, E K; Gilligan, K J; Hartwell, R C; Terry, J C; Rubenstein, R; Fournel, M; Petteway, S R

    2001-04-01

    Experimental evidence from rodent models indicates that blood can contain transmissible spongiform encephalopathy (TSE) infectivity, which suggests a potential risk for TSE transmission via proteins isolated from human plasma. Because methods that can reduce TSE infectivity typically are detrimental to protein function, infectivity must be removed to ensure the safety of these therapeutic proteins. Animal bioassays are conventionally used to detect infectivity, but the pathogenic form of the prion protein (PrP(Sc)) can serve as a marker for TSE infectivity. Seven plasma protein-purification steps were performed after the plasma intermediates were spiked with TSE-infected material. Resulting fractions were analyzed for PrP(Sc) by using a Western blot assay and for TSE infectivity by using an animal bioassay. Western blots were quantitated by an endpoint dilution analysis, and infectivity titers were calculated by the Spearman-Kärber method. PrP(Sc) partitioning paralleled TSE infectivity partitioning, regardless of the nature of the protein-purification step. The detection ranges for PrP(Sc) and infectivity were 0 to 5.3 log and 1.1 to 8.9 log median infectious dose per unit, respectively. Clearance of PrP(Sc) and infectivity ranged from 1.0 to 6.0 log. Purification steps for isolating therapeutic proteins from human plasma showed the removal of both PrP(Sc) and TSE infectivity. PrP(Sc) partitioning coincided with infectivity partitioning, which showed a close relationship between PrP(Sc) and TSE infectivity. By exploiting this association, the in vitro Western blot assay for PrP(Sc) was valuable for estimating the partitioning of TSE infectivity during plasma protein purification.

  2. Detection and partial discrimination of atypical and classical bovine spongiform encephalopathies in cattle and primates using real-time quaking-induced conversion assay

    PubMed Central

    Levavasseur, Etienne; Biacabe, Anne-Gaëlle; Comoy, Emmanuel; Culeux, Audrey; Grznarova, Katarina; Privat, Nicolas; Simoneau, Steve; Flan, Benoit; Sazdovitch, Véronique; Seilhean, Danielle; Baron, Thierry; Haïk, Stéphane

    2017-01-01

    The transmission of classical bovine spongiform encephalopathy (C-BSE) through contaminated meat product consumption is responsible for variant Creutzfeldt-Jakob disease (vCJD) in humans. More recent and atypical forms of BSE (L-BSE and H-BSE) have been identified in cattle since the C-BSE epidemic. Their low incidence and advanced age of onset are compatible with a sporadic origin, as are most cases of Creutzfeldt-Jakob disease (CJD) in humans. Transmissions studies in primates and transgenic mice expressing a human prion protein (PrP) indicated that atypical forms of BSE may be associated with a higher zoonotic potential than classical BSE, and require particular attention for public health. Recently, methods designed to amplify misfolded forms of PrP have emerged as promising tools to detect prion strains and to study their diversity. Here, we validated real-time quaking-induced conversion assay for the discrimination of atypical and classical BSE strains using a large series of bovine samples encompassing all the atypical BSE cases detected by the French Centre of Reference during 10 years of exhaustive active surveillance. We obtained a 100% sensitivity and specificity for atypical BSE detection. In addition, the assay was able to discriminate atypical and classical BSE in non-human primates, and also sporadic CJD and vCJD in humans. The RT-QuIC assay appears as a practical means for a reliable detection of atypical BSE strains in a homologous or heterologous PrP context. PMID:28231300

  3. Sulfated dextrans enhance in vitro amplification of bovine spongiform encephalopathy PrP(Sc) and enable ultrasensitive detection of bovine PrP(Sc).

    PubMed

    Murayama, Yuichi; Yoshioka, Miyako; Masujin, Kentaro; Okada, Hiroyuki; Iwamaru, Yoshifumi; Imamura, Morikazu; Matsuura, Yuichi; Fukuda, Shigeo; Onoe, Sadao; Yokoyama, Takashi; Mohri, Shirou

    2010-10-04

    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. 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. 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.

  4. PrP-C1 fragment in cattle brains reveals features of the transmissible spongiform encephalopathy associated PrP(sc).

    PubMed

    Serra, Fabienne; Müller, Joachim; Gray, John; Lüthi, Ramona; Dudas, Sandor; Czub, Stefanie; Seuberlich, Torsten

    2017-03-15

    Three different types of bovine spongiform encephalopathy (BSE) are known and supposedly caused by distinct prion strains: the classical (C-) BSE type that was typically found during the BSE epidemic, and two relatively rare atypical BSE types, termed H-BSE and L-BSE. The three BSE types differ in the molecular phenotype of the disease associated prion protein, namely the N-terminally truncated proteinase K (PK) resistant prion protein fragment (PrP(res)). In this study, we report and analyze yet another PrP(res) type (PrP(res-2011)), which was found in severely autolytic brain samples of two cows in the framework of disease surveillance in Switzerland in 2011. Analysis of brain tissues from these animals by PK titration and PK inhibitor assays ruled out the process of autolysis as the cause for the aberrant PrP(res) profile. Immunochemical characterization of the PrP fragments present in the 2011 cases by epitope mapping indicated that PrP(res-2011) corresponds in its primary sequence to the physiologically occurring PrP-C1 fragment. However, high speed centrifugation, sucrose gradient assay and NaPTA precipitation revealed biochemical similarities between PrP(res-2011) and the disease-associated prion protein found in BSE affected cattle in terms of detergent insolubility, PK resistance and PrP aggregation. Although it remains to be established whether PrP(res-2011) is associated with a transmissible disease, our results point out the need of further research on the role the PrP-C1 aggregation and misfolding in health and disease.

  5. Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges.

    PubMed

    Konold, Timm; Bone, Gemma E; Clifford, Derek; Chaplin, Melanie J; Cawthraw, Saira; Stack, Michael J; Simmons, Marion M

    2012-03-08

    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. 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. 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 the sampling regimes and methods that are currently in use.

  6. Experimental H-type and L-type bovine spongiform encephalopathy in cattle: observation of two clinical syndromes and diagnostic challenges

    PubMed Central

    2012-01-01

    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 the sampling regimes and

  7. Fukuoka-1 strain of transmissible spongiform encephalopathy agent infects murine bone marrow-derived cells with features of mesenchymal stem cells

    PubMed Central

    Cervenakova, Larisa; Akimov, Sergey; Vasilyeva, Irina; Yakovleva, Oksana; McKenzie, Carroll; Cervenak, Juraj; Piccardo, Pedro; Asher, David M.

    2011-01-01

    BACKGROUND The possible risk of iatrogenic transmissible spongiform encephalopathies (TSEs, prion diseases) from transplantation of bone marrow-derived mesenchymal stem cells (MSCs) is uncertain. While most cell lines resist infection, a few propagate TSE agents. STUDY DESIGN AND METHODS We generated MSC-like (MSC-L) cell cultures from bone marrow (BM) of mice inoculated with the human-derived Fukuoka-1 (Fu) strain of TSE agent. Cultured cells were characterized for various markers and cellular prion protein (PrPC) by FACS and for PrPC and its pathologic TSE-associated form (PrPTSE) by Western blotting (WB). Cell cultures were tested for their susceptibility to infection with Fu in vitro. Infectivity of one Fu-infected cell culture was assayed in mice. RESULTS BM cells from Fu-infected mice expressed neither PrPC nor PrPTSE after three days in culture as demonstrated by WB. Cells adherent to plastic and maintained under two different culture conditions became spontaneously immortalized and began to express PrPC at about the same time. One culture became transformed shortly after exposure to Fu in vitro and remained persistently infected, continuously generating PrPTSE through multiple passages; infectivity of cultured cells was confirmed by intracerebral inoculation of lysates into mice. Both persistently TSE-infected and uninfected cells expressed a number of typical MSC markers. CONCLUSION BM-derived MSC-L cells of mice became persistently infected with the Fu agent under certain conditions in culture—conditions that differ substantially from those currently used to develop investigational human stem cell therapies. PMID:21303371

  8. Ultrasensitive detection of PrP(Sc) in the cerebrospinal fluid and blood of macaques infected with bovine spongiform encephalopathy prion.

    PubMed

    Murayama, Yuichi; Masujin, Kentaro; Imamura, Morikazu; Ono, Fumiko; Shibata, Hiroaki; Tobiume, Minoru; Yamamura, Tomoaki; Shimozaki, Noriko; Terao, Keiji; Yamakawa, Yoshio; Sata, Tetsutaro

    2014-11-01

    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. © 2014 The Authors.

  9. Effect of Q211 and K222 PRNP Polymorphic Variants in the Susceptibility of Goats to Oral Infection With Goat Bovine Spongiform Encephalopathy.

    PubMed

    Aguilar-Calvo, Patricia; Fast, Christine; Tauscher, Kerstin; Espinosa, Juan-Carlos; Groschup, Martin H; Nadeem, Muhammad; Goldmann, Wilfred; Langeveld, Jan; Bossers, Alex; Andreoletti, Olivier; Torres, Juan-María

    2015-08-15

    The prion protein-encoding gene (PRNP) is one of the major determinants for scrapie occurrence in sheep and goats. However, its effect on bovine spongiform encephalopathy (BSE) transmission to goats is not clear. Goats harboring wild-type, R/Q211 or Q/K222 PRNP genotypes were orally inoculated with a goat-BSE isolate to assess their relative susceptibility to BSE infection. Goats were killed at different time points during the incubation period and after the onset of clinical signs, and their brains as well as several peripheral tissues were analyzed for the accumulation of pathological prion protein (PrP(Sc)) and prion infectivity by mouse bioassay. R/Q211 goats displayed delayed clinical signs compared with wild-type goats. Deposits of PrP(Sc) were detected only in brain, whereas infectivity was present in peripheral tissues too. In contrast, none of the Q/K222 goats showed any evidence of clinical prion disease. No PrP(Sc) accumulation was observed in their brains or peripheral tissues, but very low infectivity was detected in some tissues very long after inoculation (44-45 months). These results demonstrate that transmission of goat BSE is genotype dependent, and they highlight the pivotal protective effect of the K222 PRNP variant in the oral susceptibility of goats to BSE. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  10. A Bayesian back-calculation method to estimate the risk of bovine spongiform encephalopathy (BSE) in Canada during the period 1996-2011.

    PubMed

    Al-Zoughool, Mustafa; Oraby, Tamer; Krewski, Daniel

    2016-01-01

    Seventeen typical cases of bovine spongiform encephalopathy (BSE) were detected in Canada the period of 2003-2011. The clinical incidence of BSE was censored by early slaughter, death, or exportation of infected cattle due to the long incubation period of BSE disease. The aim of this study was to estimate the infection incidence of BSE in birth cohorts during 1996-2004 and project infection frequency through to 2007. An estimate of the number of asymptomatic infected cattle slaughtered for human consumption is also provided. The number of incident, asymptomatic cases was assumed to follow a Poisson process. A Bayesian back-calculation approach was used to project the risk of contracting BSE in those birth cohorts. Model parameters and inputs were taken from scientific literature and governmental data sources. The projected number of infected cattle in birth cohorts spanning the period 1996-2007 was 492, with median 95% credible interval 258-830. If the requirement to remove specified risk material (SRM) from cattle prior to entering the food chain was not in place, the predicted number of slaughtered infected in the human food chain from 1996-2010 was 298, with a 95% credible interval 156-500. The magnitude of the BSE epidemic in Canada for 1996-2007 birth cohorts was estimated to be approximately 28-fold higher than the number of clinical cases detected through to October 2011. Although some of those cattle were slaughtered for human consumption, the requirement of SRM removal may have prevented most of the infectious material from entering the food chain.

  11. Evaluation of rapid post-mortem test kits for bovine spongiform encephalopathy (BSE) screening in Japan: Their analytical sensitivity to atypical BSE prions.

    PubMed

    Hagiwara, Ken'ichi; Iwamaru, Yoshifumi; Tabeta, Naoko; Yokoyama, Takashi; Tobiume, Minoru

    2017-03-04

    A classical type of bovine spongiform encephalopathy (C-BSE), recognized in 1987, had a large impact on public health due to its zoonotic link to variant Creutzfeldt-Jakob disease by the human consumption of dietary products contaminated with the C-BSE prion. Thus, a number of countries implemented BSE surveillance using rapid post-mortem test kits that were approved for detection of the C-BSE prion in the cattle brain. However, as atypical BSE (L- and H-BSE) cases emerged in subsequent years, the efficacy of the kits for the detection of atypical BSE prions became a matter of concern. In response to this, laboratories in the European Union and Canada evaluated the kits used in their countries. Here, we carried out an evaluation study of NippiBL®, a kit currently used for BSE screening in Japan. By applying the kit to cattle brains of field cases of C-BSE and L-BSE, and an experimental case of H-BSE, we showed its comparable sensitivities to C, L-, and H-BSE prions, and satisfactory performance required by the European Food Safety Authority. In addition to NippiBL®, two kits (TeSeE® and FRELISA®) formerly used in Japan were effective for detection of the L-BSE prion, although the two kits were unable to be tested for the H-BSE prion due to the discontinuation of domestic sales during this study. These results indicate that BSE screening in Japan is as effective as those in other countries, and it is unlikely that cases of atypical BSE have been overlooked.

  12. No H- and L-type cases in Belgium in cattle diagnosed with bovine spongiform encephalopathy (1999-2008) aging seven years and older.

    PubMed

    Dobly, Alexandre; Langeveld, Jan; van Keulen, Lucien; Rodeghiero, Caroline; Durand, Stéphanie; Geeroms, Riet; Van Muylem, Patrick; De Sloovere, Jessica; Vanopdenbosch, Emmanuel; Roels, Stefan

    2010-05-21

    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. 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. 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.

  13. Sulfated Dextrans Enhance In Vitro Amplification of Bovine Spongiform Encephalopathy PrPSc and Enable Ultrasensitive Detection of Bovine PrPSc

    PubMed Central

    Murayama, Yuichi; Yoshioka, Miyako; Masujin, Kentaro; Okada, Hiroyuki; Iwamaru, Yoshifumi; Imamura, Morikazu; Matsuura, Yuichi; Fukuda, Shigeo; Onoe, Sadao; Yokoyama, Takashi; Mohri, Shirou

    2010-01-01

    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 PrPSc, a protease-resistant misfolded isoform of the cellular prion protein PrPC. Protein misfolding cyclic amplification (PMCA) is a highly sensitive technique used to detect minute amounts of scrapie PrPSc. However, the current PMCA technique has been unsuccessful in achieving good amplification in cattle. The detailed distribution of PrPSc in BSE-affected cattle therefore remains unknown. Methodology/Principal Findings We report here that PrPSc 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 PrPSc from the saliva, palatine tonsils, lymph nodes, ileocecal region, and muscular tissues of BSE-affected cattle. Individual differences in the distribution of PrPSc in spleen and cerebrospinal fluid samples were observed in terminal-stage animals. However, the presence of PrPSc in blood was not substantiated in the BSE-affected cattle examined. Conclusions/Significance The distribution of PrPSc is not restricted to the nervous system and can spread to peripheral tissues in the terminal disease stage. The finding that PrPSc 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. PMID:20957174

  14. Immunohistochemical characteristics of disease-associated PrP are not altered by host genotype or route of inoculation following infection of sheep with bovine spongiform encephalopathy.

    PubMed

    Martin, Stuart; González, Lorenzo; Chong, Angela; Houston, Fiona E; Hunter, Nora; Jeffrey, Martin

    2005-03-01

    It has previously been reported that disease-associated prion protein (PrP(d)) derived from natural scrapie and from sheep infected experimentally with bovine spongiform encephalopathy (BSE) differed in respect of their immunohistochemical and immunoblotting properties. For BSE, however, these initial observations were restricted to orally challenged sheep of the ARQ/ARQ PrP genotype. Here, extended examinations were performed on 28 sheep that developed neurological signs after BSE experimental infection by one of three routes. Intracerebrally infected ARQ/ARQ sheep showed more widespread and abundant accumulations of PrP(d) in tissues of the lymphoreticular system (LRS) than VRQ/VRQ animals, whereas no peripheral PrP(d) was detected in ARR/ARR sheep. The intensity and dissemination of PrP(d) accumulation in LRS tissues were less than those found previously in orally dosed sheep. AHQ/AHQ sheep challenged orally and ARQ/AHQ and ARQ/ARQ animals infected intravenously showed similar LRS-tissue PrP(d) distributions and levels to those of ARQ/ARQ sheep infected intracerebrally. The patterns of intra- and extracellular immunoreactivity to different PrP antibodies in brain and LRS tissues and the immunoblotting characteristics of PrP(res) from brain samples remained constant, irrespective of the route of inoculation and the PrP genotype, and were the same as described previously for ARQ/ARQ sheep dosed orally with BSE. These results suggest that the intracellular truncation of BSE PrP(d) and the proteinase K cleavage site of BSE PrP(res) are not altered by PrP genotype or by route of inoculation and that, therefore, screening tests based on these properties can be applied to identify potential sheep BSE cases occurring naturally.

  15. First case of feline spongiform encephalopathy in a captive cheetah born in France: PrP(sc) analysis in various tissues revealed unexpected targeting of kidney and adrenal gland.

    PubMed

    Lezmi, Stephane; Bencsik, Anna; Monks, Eoin; Petit, Thierry; Baron, Thierry

    2003-05-01

    Feline spongiform encephalopathy (FSE), affecting domestic and captive feline species, is a prion disease considered to be related to bovine spongiform encephalopathy. Here we report an immunohistological analysis of the first FSE-affected cheetah born in France. The duration of clinical signs, of which ataxia was the main one, was about 8 weeks. The distribution of abnormal prion protein (PrP(sc)) was studied by immunohistochemistry within 27 different tissues. Different antibodies were used to visualise abnormal PrP deposits in situ. PrP(sc )accumulation was detected in the central nervous system (cerebral cortex, cerebellum, brain stem, spinal cord, retina), in peripheral nerves and in lymphoid organs. PrP(sc) deposits were not observed within the enteric nervous system nor in several other organs, such as pancreas, ovary, liver and muscle. More interestingly, unusual PrP(sc )deposits were observed within the zona fasciculata/reticularis of the adrenal gland and within some glomeruli of the kidney raising the question of possible PrP(sc) excretion. The sympathetic innervation of these two organs was visualised and compared to the distribution of PrP(sc) deposits. Our results suggest the possibility that the infectious agent is spread by both haematogenous and nervous pathways.

  16. Subcritical Water Hydrolysis Effectively Reduces the In Vitro Seeding Activity of PrPSc but Fails to Inactivate the Infectivity of Bovine Spongiform Encephalopathy Prions

    PubMed Central

    Murayama, Yuichi; Yoshioka, Miyako; Okada, Hiroyuki; Takata, Eri; Masujin, Kentaro; Iwamaru, Yoshifumi; Shimozaki, Noriko; Yamamura, Tomoaki; Yokoyama, Takashi; Mohri, Shirou; Tsutsumi, Yuji

    2015-01-01

    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

  17. A comparative study of modified confirmatory techniques and additional immuno-based methods for non-conclusive autolytic bovine spongiform encephalopathy cases.

    PubMed

    Sarasa, Rocío; Becher, Dietmar; Badiola, Juan J; Monzón, Marta

    2013-10-18

    In the framework of the Bovine Spongiform Encephalopathy (BSE) surveillance programme, samples with non-conclusive results using the OIE confirmatory techniques have been repeatedly found. It is therefore necessary to question the adequacy of the previously established consequences of this non-conclusive result: the danger of failing to detect potentially infected cattle or erroneous information that may affect the decision of culling or not of an entire bovine cohort. Moreover, there is a very real risk that the underreporting of cases may possibly lead to distortion of the BSE epidemiological information for a given country.In this study, samples from bovine nervous tissue presenting non-conclusive results by conventional OIE techniques (Western blot and immunohistochemistry) were analyzed. Their common characteristic was a very advanced degree of autolysis. All techniques recommended by the OIE for BSE diagnosis were applied on all these samples in order to provide a comparative study. Specifically, immunohistochemistry, Western blotting, SAF detection by electron microscopy and mouse bioassay were compared. Besides, other non confirmatory techniques, confocal scanning microscopy and colloidal gold labelling of fibrils, were applied on these samples for confirming and improving the results. Immunocytochemistry showed immunostaining in agreement with the positive results finally provided by the other confirmatory techniques. These results corroborated the suitability of this technique which was previously developed to examine autolysed (liquified) brain samples. Transmission after inoculation of a transgenic murine model TgbovXV was successful in all inocula but not in all mice, perhaps due to the very scarce PrPsc concentration present in samples.Electron microscopy, currently fallen into disuse, was demonstrated to be, not only capable to provide a final diagnosis despite the autolytic state of samples, but also to be a sensitive diagnostic alternative for

  18. Subcritical Water Hydrolysis Effectively Reduces the In Vitro Seeding Activity of PrPSc but Fails to Inactivate the Infectivity of Bovine Spongiform Encephalopathy Prions.

    PubMed

    Murayama, Yuichi; Yoshioka, Miyako; Okada, Hiroyuki; Takata, Eri; Masujin, Kentaro; Iwamaru, Yoshifumi; Shimozaki, Noriko; Yamamura, Tomoaki; Yokoyama, Takashi; Mohri, Shirou; Tsutsumi, Yuji

    2015-01-01

    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

  19. Removal of transmissible spongiform encephalopathy prion from large volumes of cell culture media supplemented with fetal bovine serum by using hollow fiber anion-exchange membrane chromatography.

    PubMed

    Chou, Ming Li; Bailey, Andy; Avory, Tiffany; Tanimoto, Junji; Burnouf, Thierry

    2015-01-01

    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

  20. Transmissible Spongiform Encephalopathies (Prion Diseases)

    MedlinePlus

    ... Symptoms of TSEs vary, but they commonly include personality changes, psychiatric problems such as depression, lack of ... Symptoms of TSEs vary, but they commonly include personality changes, psychiatric problems such as depression, lack of ...

  1. 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.

    PubMed

    Okada, Hiroyuki; Iwamaru, Yoshihumi; Imamura, Morikazu; Masujin, Kentaro; Yokoyama, Takashi; Mohri, Shirou

    2010-11-01

    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.

  2. Foodborne-Transmitted Prions From the Brain of Cows With Bovine Spongiform Encephalopathy Ascend in Afferent Neurons to the Simian Central Nervous System and Spread to Tonsils and Spleen at a Late Stage of the Incubation Period.

    PubMed

    Holznagel, Edgar; Yutzy, Barbara; Kruip, Carina; Bierke, Par; Schulz-Schaeffer, Walter; Löwer, Johannes

    2015-11-01

    Protease-resistant prion protein (PrP(res)) accumulation in lymphoreticular tissues indicates prion infection. To date, tonsillectomy and appendectomy samples have been used in population prevalence surveys to detect clinically silent carriers of variant Creutzfeldt-Jakob disease (vCJD). However, the temporal sequence of prion spread in the human body is still not known. We therefore traced the temporal-spatial pattern of PrP(res) accumulation in the body of a simian vCJD model. Cynomolgus monkeys were fed brain of (eleven) cows with bovine spongiform encephalopathy, and some were euthanized before and some after onset of neurological signs. PrP(res) was detected in tissues by a paraffin-embedded tissue blot technique and a semiquantitative Western immunoblot assay. Bovine spongiform encephalopathy (BSE)-associated prions were preferentially transported from the gut to the central nervous system (CNS) along sensory nerve fibers and initially entered the simian CNS at lumbar spinal cord levels. In asymptomatic animals, we found BSE in 50% and 12% of gut- and tonsil-derived samples, respectively. Unlike in rodents and ruminants, foodborne BSE-associated prions entered the simian CNS via afferent neurons. From sites of initial CNS invasion, prions spread centrifugally to tonsils and spleen at an advanced stage of the incubation period, thus explaining why tonsil specimens were not reliable for detection of simian disease carriers before onset of clinical signs. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice.

    PubMed

    Jaumain, Emilie; Quadrio, Isabelle; Herzog, Laetitia; Reine, Fabienne; Rezaei, Human; Andréoletti, Olivier; Laude, Hubert; Perret-Liaudet, Armand; Haïk, Stéphane; Béringue, Vincent

    2016-12-01

    Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP(C)) and the infecting pathological PrP assemblies (PrP(Sc)) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP(C) and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP(Sc) signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. Since the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

  4. First demonstration of transmissible spongiform encephalopathy-associated prion protein (PrPTSE) in extracellular vesicles from plasma of mice infected with mouse-adapted variant Creutzfeldt-Jakob disease by in vitro amplification.

    PubMed

    Saá, Paula; Yakovleva, Oksana; de Castro, Jorge; Vasilyeva, Irina; De Paoli, Silvia H; Simak, Jan; Cervenakova, Larisa

    2014-10-17

    The development of variant Creutzfeldt-Jakob disease (vCJD) in three recipients of non-leukoreduced red blood cells from asymptomatic donors who subsequently developed the disease has confirmed existing concerns about the possible spread of transmissible spongiform encephalopathies (TSEs) via blood products. In addition, the presence of disease-associated misfolded prion protein (PrP(TSE)), generally associated with infectivity, has been demonstrated in the blood of vCJD patients. However, its origin and distribution in this biological fluid are still unknown. Various studies have identified cellular prion protein (PrP(C)) among the protein cargo in human blood-circulating extracellular vesicles released from endothelial cells and platelets, and exosomes isolated from the conditioned media of TSE-infected cells have caused the disease when injected into experimental mice. In this study, we demonstrate the detection of PrP(TSE) in extracellular vesicles isolated from plasma samples collected during the preclinical and clinical phases of the disease from mice infected with mouse-adapted vCJD and confirm the presence of the exosomal marker Hsp70 in these preparations. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. First Demonstration of Transmissible Spongiform Encephalopathy-associated Prion Protein (PrPTSE) in Extracellular Vesicles from Plasma of Mice Infected with Mouse-adapted Variant Creutzfeldt-Jakob Disease by in Vitro Amplification*

    PubMed Central

    Saá, Paula; Yakovleva, Oksana; de Castro, Jorge; Vasilyeva, Irina; De Paoli, Silvia H.; Simak, Jan; Cervenakova, Larisa

    2014-01-01

    The development of variant Creutzfeldt-Jakob disease (vCJD) in three recipients of non-leukoreduced red blood cells from asymptomatic donors who subsequently developed the disease has confirmed existing concerns about the possible spread of transmissible spongiform encephalopathies (TSEs) via blood products. In addition, the presence of disease-associated misfolded prion protein (PrPTSE), generally associated with infectivity, has been demonstrated in the blood of vCJD patients. However, its origin and distribution in this biological fluid are still unknown. Various studies have identified cellular prion protein (PrPC) among the protein cargo in human blood-circulating extracellular vesicles released from endothelial cells and platelets, and exosomes isolated from the conditioned media of TSE-infected cells have caused the disease when injected into experimental mice. In this study, we demonstrate the detection of PrPTSE in extracellular vesicles isolated from plasma samples collected during the preclinical and clinical phases of the disease from mice infected with mouse-adapted vCJD and confirm the presence of the exosomal marker Hsp70 in these preparations. PMID:25157106

  6. 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.

    PubMed

    Murayama, Y; Ono, F; Shimozaki, N; Shibata, H

    2016-02-12

    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. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Bov-tA short interspersed nucleotide element sequences in circulating nucleic acids from sera of cattle with bovine spongiform encephalopathy (BSE) and sera of cattle exposed to BSE.

    PubMed

    Schütz, Ekkehard; Urnovitz, Howard B; Iakoubov, Leonid; Schulz-Schaeffer, Walter; Wemheuer, Wilhelm; Brenig, Bertram

    2005-07-01

    Circulating nucleic acids (CNA) are known to be enriched in repetitive DNA sequences in humans. Here, bovine sera CNA were analyzed to determine if cell stress-related short interspersed nucleotide elements (SINEs) could be detected in sera from cattle associated with bovine spongiform encephalopathy (BSE). Nucleic acids were extracted, amplified, cloned, and sequenced from the sera of protease-resistant prion protein (PrP(res))-positive cattle (n = 2) and sera from BSE-cohort cows (n = 6); 150 out of 163 clones revealed the presence of, on average, an 80-bp sequence from the 3' region of Bov-tA SINE. A PCR protocol was developed that differentially identified SINE-associated CNA in BSE-exposed versus normal cattle. CNA were extracted from a serum vesicular fraction after controlled blood collection and processing procedures. Sera from four confirmed cases of BSE, 137 BSE-exposed cohort animals associated with eight confirmed BSE cases, and 845 healthy, PrP(res)-negative control cows were tested. All four sera from confirmed BSE cases were repeatedly reactive in the assay. BSE-exposed cohorts had a 100-fold higher occurrence of repeatedly reactive individuals per cohort (average = 63%; range = 33% to 91%), compared to healthy controls (average = 0.6%; P < 0.001). This study shows that BSE-confirmed and cohort animals possess a unique profile of SINE-associated serum CNA that can be utilized as a marker that highly correlates to BSE exposure.

  8. Bov-tA Short Interspersed Nucleotide Element Sequences in Circulating Nucleic Acids from Sera of Cattle with Bovine Spongiform Encephalopathy (BSE) and Sera of Cattle Exposed to BSE

    PubMed Central

    Schütz, Ekkehard; Urnovitz, Howard B.; Iakoubov, Leonid; Schulz-Schaeffer, Walter; Wemheuer, Wilhelm; Brenig, Bertram

    2005-01-01

    Circulating nucleic acids (CNA) are known to be enriched in repetitive DNA sequences in humans. Here, bovine sera CNA were analyzed to determine if cell stress-related short interspersed nucleotide elements (SINEs) could be detected in sera from cattle associated with bovine spongiform encephalopathy (BSE). Nucleic acids were extracted, amplified, cloned, and sequenced from the sera of protease-resistant prion protein (PrPres)-positive cattle (n = 2) and sera from BSE-cohort cows (n = 6); 150 out of 163 clones revealed the presence of, on average, an 80-bp sequence from the 3′ region of Bov-tA SINE. A PCR protocol was developed that differentially identified SINE-associated CNA in BSE-exposed versus normal cattle. CNA were extracted from a serum vesicular fraction after controlled blood collection and processing procedures. Sera from four confirmed cases of BSE, 137 BSE-exposed cohort animals associated with eight confirmed BSE cases, and 845 healthy, PrPres-negative control cows were tested. All four sera from confirmed BSE cases were repeatedly reactive in the assay. BSE-exposed cohorts had a 100-fold higher occurrence of repeatedly reactive individuals per cohort (average = 63%; range = 33% to 91%), compared to healthy controls (average = 0.6%; P < 0.001). This study shows that BSE-confirmed and cohort animals possess a unique profile of SINE-associated serum CNA that can be utilized as a marker that highly correlates to BSE exposure. PMID:16002628

  9. 9 CFR 94.18 - Restrictions on importation of meat and edible products from ruminants due to bovine spongiform...

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... and edible products from ruminants due to bovine spongiform encephalopathy. 94.18 Section 94.18... importation of meat and edible products from ruminants due to bovine spongiform encephalopathy. (a)(1) Bovine... as provided in paragraph (c) of this section, milk, and milk products) from ruminants that have...

  10. 9 CFR 94.18 - Restrictions on importation of meat and edible products from ruminants due to bovine spongiform...

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... and edible products from ruminants due to bovine spongiform encephalopathy. 94.18 Section 94.18... importation of meat and edible products from ruminants due to bovine spongiform encephalopathy. (a)(1) Bovine... as provided in paragraph (c) of this section, milk, and milk products) from ruminants that have...

  11. 9 CFR 94.18 - Restrictions on importation of meat and edible products from ruminants due to bovine spongiform...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... and edible products from ruminants due to bovine spongiform encephalopathy. 94.18 Section 94.18... importation of meat and edible products from ruminants due to bovine spongiform encephalopathy. (a)(1) Bovine... as provided in paragraph (c) of this section, milk, and milk products) from ruminants that have...

  12. 9 CFR 94.18 - Restrictions on importation of meat and edible products from ruminants due to bovine spongiform...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... and edible products from ruminants due to bovine spongiform encephalopathy. 94.18 Section 94.18... importation of meat and edible products from ruminants due to bovine spongiform encephalopathy. (a)(1) Bovine... as provided in paragraph (c) of this section, milk, and milk products) from ruminants that have...

  13. Detection of bovine spongiform encephalopathy, ovine scrapie prion-related protein (PrPSc) and normal PrPc by monoclonal antibodies raised to copper-refolded prion protein.

    PubMed

    Thackray, Alana M; Madec, Jean-Yves; Wong, Edmond; Morgan-Warren, Robert; Brown, David R; Baron, Thierry; Bujdoso, Raymond

    2003-02-15

    Prion-related protein (PrP) is a glycosylphosphatidylinositol-linked cell-surface protein expressed by a wide variety of cells, including those of the nervous system and the immune system. Several functions of normal cellular PrP (PrPc) have been proposed that may be associated with the capacity of this protein to bind copper. In the present study, we describe the generation of a panel of monoclonal antibodies raised to copper-refolded PrP, which may be used to analyse the normal and disease-associated forms of this protein. The anti-PrP monoclonal antibodies were reactive by Western blot and ELISA with recombinant murine PrPc refolded in the presence or absence of either copper or manganese, and with the disease-susceptible allelic form V136R154Q171 ('VRQ'; where single-letter amino-acid notation has been used) and disease-resistant allelic form A136R154R171 ('ARR') of recombinant ovine PrPc. FACS analysis of lymphoid cells using these monoclonal antibodies showed that wild-type non-activated mouse lymphocytes expressed little, if any, PrPc. These monoclonal antibodies were shown to react with the unglycosylated and monoglycosylated forms of PrPSc (abnormal disease-specific conformation of PrP) in prion-infected tissue samples from all of the different species tested by Western blot. In addition, this analysis allowed one to make a distinction between bovine spongiform encephalopathy ('BSE') and scrapie PrPSc) isolates from experimentally infected sheep on the basis of their different electrophoretic mobilities.

  14. A Comparison of Classical and H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism in Wild-Type and EK211 Cattle Following Intracranial Inoculation

    PubMed Central

    Moore, S. Jo; West Greenlee, M. Heather; Smith, Jodi D.; Vrentas, Catherine E.; Nicholson, Eric M.; Greenlee, Justin J.

    2016-01-01

    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

  15. The first Canadian indigenous case of bovine spongiform encephalopathy (BSE) has molecular characteristics for prion protein that are similar to those of BSE in the United Kingdom but differ from those of chronic wasting disease in captive elk and deer

    PubMed Central

    2004-01-01

    Abstract Brain tissue from a case of bovine spongiform encephalopathy (BSE) from Alberta was subjected to a Western immunoblotting technique to ascertain the molecular profile of any disease-specific, abnormal prion protein, that is, prion protein that is protease-resistant (PrPres). This technique can discriminate between isolates from BSE, ovine scrapie, and sheep experimentally infected with BSE. Isolates of brain tissue from the BSE case in Alberta, 3 farmed elk with chronic wasting disease (CWD) from different parts of Saskatchewan, and 1 farmed white-tailed deer with CWD from Edmonton, Alberta, were examined alongside isolates of brain tissue from BSE, ovine scrapie, and sheep experimentally infected with BSE from the United Kingdom (UK). The molecular weights of PrPres and the cross reactions to 2 specific monoclonal antibodies (mAbs) were determined for each sample. The BSE isolates from Canada and the UK had very similar PrPres molecular weights and reacted with only 1 of the 2 mAbs. The PrPres isolated from both elk and white-tailed deer with CWD had a higher molecular weight profile than did the corresponding PrPres from the scrapie and BSE isolates. The PrPres from CWD cases cross reacted with both mAbs, a property shared with PrPres in isolates from scrapie but not with PrPres isolates from BSE or sheep experimentally infected with BSE. The results from this study seem to confirm that the PrPres isolated from the BSE case in Alberta has similar molecular properties to the PrPres isolated from a BSE case in the UK, and that it differs in its molecular and immunological characteristics from the CWD and scrapie cases studied. PMID:15532881

  16. A Comparison of Classical and H-Type Bovine Spongiform Encephalopathy Associated with E211K Prion Protein Polymorphism in Wild-Type and EK211 Cattle Following Intracranial Inoculation.

    PubMed

    Moore, S Jo; West Greenlee, M Heather; Smith, Jodi D; Vrentas, Catherine E; Nicholson, Eric M; Greenlee, Justin J

    2016-01-01

    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.

  17. Influence of breed and genotype on the onset and distribution of infectivity and disease-associated prion protein in sheep following oral infection with the bovine spongiform encephalopathy agent.

    PubMed

    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

    2015-01-01

    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

  18. Modelling the trend of bovine spongiform encephalopathy prevalence in France: Use of restricted cubic spline regression in age-period-cohort models to estimate the efficiency of control measures.

    PubMed

    Sala, Carole; Morignat, Eric; Ducrot, Christian; Calavas, Didier

    2009-07-01

    An age-period-cohort (APC) analysis was used to assess the trend in prevalence of bovine spongiform encephalopathy (BSE) in France over time in relation to the control measures adopted since onset of the epidemic. Restricted cubic regression splines were used to model the functional forms of the non-linear effects of age at screening, birth cohort and date of diagnosis of the tested animals. The data of the 2001-2007 period of surveillance was analysed using 1-year categorisation. A categorical analysis was performed as control to check the accuracy of the sets of knots in the spline models, which were selected according to the Akaike Information Criterion (AIC). Knot selection was based on a priori knowledge of the disease and the dates of implementation of the five main BSE control measures. It was assumed that disease prevalence was a function of exposure to BSE and that changes in the exposure of cattle to BSE were mainly due to the control measures. The effects of the five main control measures were discussed in relation to the trend in BSE risk for the successive birth cohorts. The six selected models confirmed that all measures participated in disease control. However, characterization of the respective effect of individual measures was not straightforward due to the very low disease prevalence, incompletely tested cohorts and probably cumulative and overlapping effects of successive measures. The ban of importation of meat and bone meal (MBM) from the UK and the ban of use of MBM in bovines were insufficient to control the epidemic. The decline in the BSE epidemic more likely originated from implementation of the ban of MBM use in all ruminants in 1994, whose effect was probably reinforced by the evolution in perception of the BSE risk following evidence of BSE transmission to humans. Finally, the respective effects of the last two measures (prohibition of the use of specific risk material in 1996 and total MBM ban in 2000) could not be characterized as

  19. Prions and the human transmissible spongiform encephalopathies.

    PubMed

    Scully, Crispian; Smith, Andrew J; Bagg, Jeremy

    2003-07-01

    The last 5 years have seen the emergence of a new disease in humans (vCJD), mainly in the United Kingdom. This emergence has been accompanied by an explosion of scientific data on a novel group of the responsible infectious agents called prions and has profound implications for infection control and transfusion policies. Also of concern is the finding of prions in neural, gingival, pulpal, and salivary tissue in animal models and significant titers of infectivity from extraneural organs (particularly, in cases of vCJD, in lymphoreticular tissues). There is limited information on the presence of prion proteins in the oral tissues from human studies. Because of the differences in patterns of disease in animal models and in strains of prion protein, it is difficult to extrapolate directly these findings to humans, but it illustrates a potential for transmission by way of the dental route. High levels of infectivity may be present in tissues early in the incubation period and before clinical signs and symptoms. The dental profession must turn its attention to the routine decontamination of dental instruments to ensure that these procedures are performed to the highest regulatory standard. Clinicians and manufacturers must work closely together to develop instruments that are either single use or can be presented in a form that can be more easily decontaminated. Clinicians must pay close attention to manufacturers' decontamination instructions and must not reuse items designated as single use, such as endodontic files. Improvements in compliance with these requirements will not only reduce the risk of transmission of TSEs but also other less tenacious infectious agents.

  20. Bovine Spongiform Encephalopathy: Production and Inspection

    MedlinePlus

    ... Administrative Forms Standard Forms Skip Navigation Z7_0Q0619C0JGR010IFST1G5B10H1 Web Content Viewer (JSR 286) Actions ${title} Loading... / Topics / ... FSIS Further Strengthens Protections Against BSE Z7_0Q0619C0JGR010IFST1G5B10H3 Web Content Viewer (JSR 286) Actions ${title} Loading... Z7_ ...

  1. Spongiform neurodegenerative disease in a Persian kitten.

    PubMed

    Salvadori, Claudia; Lossi, Laura; Arispici, Mario; Cantile, Carlo

    2007-06-01

    A congenital encephalopathy with spongiform degeneration and prominent neuronal apoptosis was observed in a 4-month-old Persian male cat with a history of depressed mental status and ataxia. On clinical examination, signs included right head tilt, ventroflexion of the head and neck, and tetraparesis. Histological examination of the central nervous system revealed multifocal, bilateral and symmetrical vacuolar degeneration of the neuropil, mainly involving the cerebellar and vestibular nuclei area, the caudal colliculi, the mesencephalic nuclei, the tegmental area and the deeper layer of the cerebral cortex. Accumulation of phosphorylated neurofilaments was detected in neuronal perikarya of the deep cortical layers, hippocampus and thalamus. Numerous pyknotic and apoptotic neurons were also observed in the cerebral cortex. These neuropathological changes differ from those observed in previous reports of spongiform degeneration of the grey matter in cats and were suggestive of a congenital neurodegenerative disease.

  2. 9 CFR 94.18 - Restrictions on importation of meat and edible products from ruminants due to bovine spongiform...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... and edible products from ruminants due to bovine spongiform encephalopathy. 94.18 Section 94.18... § 94.18 Restrictions on importation of meat and edible products from ruminants due to bovine spongiform... ruminants that have been in any of the regions listed in paragraph (a) of this section is prohibited....

  3. Progressive accumulation of the abnormal conformer of the prion protein and spongiform encephalopathy in the obex of nonsymptomatic and symptomatic Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease.

    PubMed

    Spraker, Terry R; Gidlewski, Thomas; Powers, Jenny G; Nichols, Tracy; Balachandran, Aru; Cummings, Bruce; Wild, Margaret A; VerCauteren, Kurt; O'Rourke, Katherine I

    2015-07-01

    The purpose of our study was to describe the progressive accumulation of the abnormal conformer of the prion protein (PrP(CWD)) and spongiform degeneration in a single section of brain stem in Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease (CWD). A section of obex from 85 CWD-positive elk was scored using the presence and abundance of PrP(CWD) immunoreactivity and spongiform degeneration in 10 nuclear regions and the presence and abundance of PrP(CWD) in 10 axonal tracts, the subependymal area of the fourth ventricle, and the thin subpial astrocytic layer (glial limitans). Data was placed in a formula to generate an overall obex score. Data suggests that PrP(CWD) immunoreactivity and spongiform degeneration has a unique and relatively consistent pattern of progression throughout a section of obex. This scoring technique utilizing a single section of obex may prove useful in future work for estimating the presence and abundance of PrP(CWD) in peripheral tissues and the nervous system in elk with CWD. © 2015 The Author(s).

  4. Comparison of Transmissible Mink Encephalopathy Isolates in Raccoons

    USDA-ARS?s Scientific Manuscript database

    Owing to its susceptibility to various transmissible spongiform encephalopathies (TSE) and relatively short incubation times, the raccoon (Procyon lotor) has been suggested as a model for TSE strain differentiation. Transmissible mink encephalopathy (TME) is a prion disease of undetermined origin in...

  5. Evaluation of the zoonotic potential of transmissible mink encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Successful transmission of Transmissible Mink Encephalopathy (TME) to cattle supports the bovine hypothesis to 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 as...

  6. Hashimoto's encephalopathy.

    PubMed

    Chen, H C; Marsharani, U

    2000-05-01

    Hashimoto's encephalopathy is a subacute condition associated with autoimmune thyroiditis. Its presentation varies from focal neurologic deficits to global confusion. Unlike encephalopathy associated with hypothyroidism, Hashimoto's encephalopathy responds to steroid therapy and not thyroxine replacement.

  7. Memorandum of Understanding.

    SciTech Connect

    Siple, Bud H.

    2014-07-01

    A Memorandum of Understanding establishes a clear understanding of how an agreement is going to be implemented. The Memorandum of Understanding allows all involved to specifically understand that they are agreeing to the same thing and the terms are clearly identified. It also includes the clear distinction of functions and the level of involvement of the agencies involved. Specifically, a Memorandum of Understanding gives a chance to all of those involved in the agreement to see on paper as to what they all have agreed to.

  8. Memorandums of Understanding

    EPA Pesticide Factsheets

    Since 2006, the Green Team has signed memorandums of understanding [MOU's] with local professional sports teams, major real estate firms and developers, and colleges and universities to reduce the environmental impacts of their buildings and projects.

  9. Experimental Inoculation of Spiroplasma mirum and Transmissible Mink Encephalopathy (TME) into Raccoons (Procyon lotor)

    USDA-ARS?s Scientific Manuscript database

    To determine if Spiroplasma mirum would be capable of producing lesions of spongiform encephalopathy in raccoons (Procyon lotor), 5 groups (n = 5) of raccoon kits were inoculated intracerebrally with either S. mirum and/or transmissible mink encephalopathy (TME). Two other groups (n = 5) of raccoon...

  10. Abnormal regulation of TSG101 in mice with spongiform neurodegeneration.

    PubMed

    Jiao, Jian; Sun, Kaihua; Walker, Will P; Bagher, Pooneh; Cota, Christina D; Gunn, Teresa M

    2009-10-01

    Spongiform neurodegeneration is characterized by the appearance of vacuoles throughout the central nervous system. It has many potential causes, but the underlying cellular mechanisms are not well understood. Mice lacking the E3 ubiquitin ligase Mahogunin Ring Finger-1 (MGRN1) develop age-dependent spongiform encephalopathy. We identified an interaction between a "PSAP" motif in MGRN1 and the ubiquitin E2 variant (UEV) domain of TSG101, a component of the endosomal sorting complex required for transport I (ESCRT-I), and demonstrate that MGRN1 multimonoubiquitinates TSG101. We examined the in vivo consequences of loss of MGRN1 on TSG101 expression and function in the mouse brain. The pattern of TSG101 ubiquitination differed in the brains of wild-type mice and Mgrn1 null mutant mice: at 1 month of age, null mutant mice had less ubiquitinated TSG101, while in adults, mutant mice had more ubiquitinated, insoluble TSG101 than wild-type mice. There was an associated increase in epidermal growth factor receptor (EGFR) levels in mutant brains. These results suggest that loss of MGRN1 promotes ubiquitination of TSG101 by other E3s and may prevent its disassociation from endosomal membranes or cause it to form insoluble aggregates. Our data implicate loss of normal TSG101 function in endo-lysosomal trafficking in the pathogenesis of spongiform neurodegeneration in Mgrn1 null mutant mice.

  11. Disease-associated prion protein in neural and lymphoid tissues of mink (Mustela vison) inoculated with transmissible mink encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Transmissible mink encephalopathy (TME) is a prion disorder of farmed raised mink. As with the other transmissible spongiform encephalopathies, the disorder is associated with accumulation of the misfolded prion protein in the brain and an invariably fatal outcome. TME outbreaks have been rare but...

  12. Scientific integrity memorandum

    NASA Astrophysics Data System (ADS)

    Showstack, Randy

    2009-03-01

    U.S. President Barack Obama signed a presidential memorandum on 9 March to help restore scientific integrity in government decision making. The memorandum directs the White House Office of Science and Technology Policy to develop a strategy within 120 days that ensures that "the selection of scientists and technology professionals for science and technology positions in the executive branch is based on those individuals' scientific and technological knowledge, credentials, and experience; agencies make available to the public the scientific or technological findings or conclusions considered or relied upon in policy decisions; agencies use scientific and technological information that has been subject to well-established scientific processes such as peer review; and agencies have appropriate rules and procedures to ensure the integrity of the scientific process within the agency, including whistleblower protection."

  13. Toxic Encephalopathy

    PubMed Central

    Kim, Jae Woo

    2012-01-01

    This article schematically reviews the clinical features, diagnostic approaches to, and toxicological implications of toxic encephalopathy. The review will focus on the most significant occupational causes of toxic encephalopathy. Chronic toxic encephalopathy, cerebellar syndrome, parkinsonism, and vascular encephalopathy are commonly encountered clinical syndromes of toxic encephalopathy. Few neurotoxins cause patients to present with pathognomonic neurological syndromes. The symptoms and signs of toxic encephalopathy may be mimicked by many psychiatric, metabolic, inflammatory, neoplastic, and degenerative diseases of the nervous system. Thus, the importance of good history-taking that considers exposure and a comprehensive neurological examination cannot be overemphasized in the diagnosis of toxic encephalopathy. Neuropsychological testing and neuroimaging typically play ancillary roles. The recognition of toxic encephalopathy is important because the correct diagnosis of occupational disease can prevent others (e.g., workers at the same worksite) from further harm by reducing their exposure to the toxin, and also often provides some indication of prognosis. Physicians must therefore be aware of the typical signs and symptoms of toxic encephalopathy, and close collaborations between neurologists and occupational physicians are needed to determine whether neurological disorders are related to occupational neurotoxin exposure. PMID:23251840

  14. Instability of familial spongiform encephalopathy-related prion mutants

    SciTech Connect

    Watanabe, Yasuko; Hiraoka, Wakako; Shimoyama, Yuhei; Horiuchi, Motohiro; Kuwabara, Mikinori; Inanami, Osamu

    2008-02-01

    We examined the influence of D177N (D178N in humans) mutation on the conformational stability of the S2 region of moPrP{sup C} with varying pHs by using the SDSL-ESR technique. The ESR spectrum of D177N at pH 7.5 was narrower than that of Y161R1, referred to as WT{sup *}. The ESR spectrum of D177N did not change when pH in the solution decreased to pH 4.0. Our results suggested that the disappearance of a salt bridge (D177-R163) induced the increase in the instability of S2 region. Moreover, the line shape of the ESR spectrum obtained from H176S neighboring the salt bridge linked to the S2 region was similar to D177N. These results indicate that the protonation of H176 is strongly associated with the stability of S2 region. These findings are important for understanding the mechanism by which the disruption of the salt bridge in the S2 region forms the pathogenic PrP{sup Sc} structure in hereditary prion disease.

  15. Retinal Fluorescence Spectroscopy for Diagnosis of Transmissible Spongiform Encephalopathies

    USDA-ARS?s Scientific Manuscript database

    Central nervous system (CNS) tissue provides optical signatures that can be detected with great sensitivity. The fundamental hypothesis proposed in this study was that diseased or damaged central nervous system (CNS) tissue produces optical signals that can be detected and made useful for diagnosti...

  16. Monitoring of clinical signs in goats with transmissible spongiform encephalopathies

    PubMed Central

    2010-01-01

    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. PMID:20202205

  17. Bovine Spongiform Encephalopathy (BSE), or Mad Cow Disease

    MedlinePlus

    ... on this page will be unavailable. For more information about this message, please visit this page: About ... of the transmissible agent is not well understood. Currently, the most accepted theory is that the agent is a modified form ...

  18. Memorandums of Understanding with Australia

    EPA Pesticide Factsheets

    In February 2016, U.S. EPA and the Australian Department of Agriculture and Water Resources signed a Memorandum of Understanding on Water. This was an update to the March 2011 Memorandum of Understanding on the same topic. Both documents are available bel

  19. 36 CFR 223.242 - Supplemental guidance, Memorandum of Agreements and Memorandums of Understanding.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., Memorandum of Agreements and Memorandums of Understanding. 223.242 Section 223.242 Parks, Forests, and Public... Supplemental guidance, Memorandum of Agreements and Memorandums of Understanding. Consistent with subparts G... Agreement and Memorandums of Understanding to promote local collaboration, issue resolution, and local...

  20. Epileptic Encephalopathies.

    PubMed

    Germain, Blair; Maria, Bernard L

    2017-01-01

    Epileptic encephalopathies encompass a heterogeneous group of epilepsy syndromes that manifest with cognitive, behavioral, and neurologic deficits, seizures that are often intractable and multiform, aggressive electroencephalographic paroxysmal activity, and sometimes early death. As more is learned about the etiologies and manifestations of epileptic encephalopathies, progress has been made toward better treatment options. However, there is still a great need for further randomized controlled trials and research to help create clinically effective therapies. The 2015 Neurobiology of Disease in Children symposium, held in conjunction with the 44th annual meeting of the Child Neurology Society, aimed to (1) describe the clinical concerns involving diagnosis and treatment, (2) review the current status of understanding in the pathogenesis of epileptic encephalopathy, (3) discuss clinical management and therapies for epileptic encephalopathy, and (4) define future directions of research. This article summarizes the presentations and includes an edited transcript of question-and-answer sessions.

  1. [Wernicke encephalopathy].

    PubMed

    Djelantik, M; Bloemkolk, D; Tijdink, J

    2015-01-01

    Wernicke encephalopathy is an acute neuropsychiatric disease with heterogeneous symptoms, including changes in mental status, ataxia and ocular abnormalities; if left untreated, these symptoms can lead to morbidity and even to mortality. The treatment is thiamine suppletion. Because of the heterogeneity of the symptoms and the high risk of morbidity and mortality if the symptoms are not treated, it is vitally important that on observing a patient's early symptoms the clinician immediately suspects that the symptoms could point to Wernicke encephalopathy.

  2. Memorandum from Secretary Tayloe Murphy

    EPA Pesticide Factsheets

    This page provides the memorandum sent by Secretary Tayloe Murphy to the Chesapeake Bay Program Principals' Staff Committee (PSC) that summarized the comprehensive set of agreements made by Bay watershed partners.

  3. Pancreatic encephalopathy

    PubMed Central

    Sharf, B.; Bental, E.

    1971-01-01

    A 58 year old woman presenting with abdominal distress and a neuropsychiatric disturbance with evidence of focal neurological deficit is described. A diagnosis of pancreatic encephalopathy was made, and the patient was treated accordingly with pancreatic anti-enzymes. A survey of the literature is presented. Images PMID:5315218

  4. EPA-DOT Memorandum of Understanding (MOU)

    EPA Pesticide Factsheets

    National Memorandum of Understanding Between the U.S. Department of Transportation and the U.S. Environmental Protection Agency (EPA Publication #EPA-420-F-00-020 and EPA-DOT Memorandum of Understanding (MOU) on Transportation Conformity.

  5. [Hashimoto encephalopathy].

    PubMed

    Pocsay, Gábor; Gazdag, Andrea; Engelhardt, József; Szaniszló, István; Szolnoki, Zoltán; Forczek, Gabriella; Mikló, László

    2013-08-18

    The authors present a case report and review the literature on Hashimoto encephalopathy. The onset of the disease may be marked by focal and then progressively generalized seizures or other neurological symptoms, but a cognitive decline or various psychiatric symptoms may also emerge. High levels of anti-thyroid peroxidase antibodies and/or anti-thyroglobulin antibodies are present in the serum. Corticosteroid treatment usually results in an improvement of symptoms. The syndrome is frequently overlooked and, therefore, the authors strongly recommend testing serum thyroid autoantibodies in cases with encephalopathy of unknown origin independently on the presence of thyroid disease in the patient or family history. The importance of long-term immunosuppressive treatment should also be stressed.

  6. Experimental transmission of transmissible spongiform encephalopathies (scrapie, chronic wasting disease, transmissible mink encephalopathy) to cattle and their differentiation from bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    Background: 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...

  7. Experimental transmission of transmissible spongiform encephalopathies (scrapie, chronic wasting disease, transmissible mink encephalopathy) to cattle and their differentiation from bovine spongiform encephalopathy

    USDA-ARS?s Scientific Manuscript database

    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 ...

  8. Clinical features in prion protein-deficient and wild-type cattle inoculated with transmissible mink encephalopathy (TME)

    USDA-ARS?s Scientific Manuscript database

    Background: Transmissible spongiform encephalopathies (TSEs) or prion diseases are caused by the propagation of a misfolded form (PrP**d) of the normal cellular prion protein, PrP**c. Recently, we have reported the generation and characterization of PrP**C-deficient cattle (PrP-/-) produced by a seq...

  9. NASA USAID Memorandum of Understanding

    NASA Image and Video Library

    2011-04-25

    USAID Administrator Rajiv Shah, left, and NASA Administrator Charles Bolden shake hands after signing a five-year memorandum of understanding, Monday, April 25, 2011, at NASA Headquarters in Washington. The agreement formalizes ongoing agency collaborations that use Earth science data to address developmental challenges, and to assist in disaster mitigation and humanitarian responses. The agreement also encourages NASA and USAID to apply geospatial technologies to solve development challenges affecting the United States and developing countries. Photo Credit: (NASA/Paul E. Alers)

  10. NASA USAID Memorandum of Understanding

    NASA Image and Video Library

    2011-04-25

    USAID Administrator Rajiv Shahspeaks prior to signing a five-year memorandum of understanding with NASA, Monday, April 25, 2011, at NASA Headquarters in Washington. The agreement formalizes ongoing agency collaborations that use Earth science data to address developmental challenges, and to assist in disaster mitigation and humanitarian responses. The agreement also encourages NASA and USAID to apply geospatial technologies to solve development challenges affecting the United States and developing countries. Photo Credit: (NASA/Paul E. Alers)

  11. NASA USAID Memorandum of Understanding

    NASA Image and Video Library

    2011-04-25

    USAID Administrator Rajiv Shah, left, and NASA Administrator Charles Bolden sign a five-year memorandum of understanding, Monday, April 25, 2011, at NASA Headquarters in Washington. The agreement formalizes ongoing agency collaborations that use Earth science data to address developmental challenges, and to assist in disaster mitigation and humanitarian responses. The agreement also encourages NASA and USAID to apply geospatial technologies to solve development challenges affecting the United States and developing countries. Photo Credit: (NASA/Paul E. Alers)

  12. NASA USAID Memorandum of Understanding

    NASA Image and Video Library

    2011-04-25

    USAID Administrator Rajiv Shah speaks prior to signing a five-year memorandum of understanding with NASA, Monday, April 25, 2011, at NASA Headquarters in Washington. The agreement formalizes ongoing agency collaborations that use Earth science data to address developmental challenges, and to assist in disaster mitigation and humanitarian responses. The agreement also encourages NASA and USAID to apply geospatial technologies to solve development challenges affecting the United States and developing countries. Photo Credit: (NASA/Paul E. Alers)

  13. USDA Memorandum of Understanding Signing

    NASA Image and Video Library

    2008-07-22

    U.S. Senator Kay Bailey Hutchison, R-Texas looks on as Secretary of Agriculture Ed Schafer, left, shakes hands with NASA Administrator Michael Griffin after signing a memorandum of understanding (MOU) between NASA and USDA Wednesday, July 23, 2008, at the Russell Senate Office Building in Washington. The MOU will enable the USDA's Agricultural Research Service (ARS) to conduct plant and animal related research on the International Space Station (ISS). Photo Credit: (NASA/Bill Ingalls)

  14. Experimental inoculation of raccoons (Procyon lotor) with Spiroplasma mirum and transmissible mink encephalopathy (TME).

    PubMed

    Hamir, Amir N; Greenlee, Justin J; Stanton, Thad B; Smith, Jodi D; Doucette, Stephanie; Kunkle, Robert A; Stasko, Judith A; Richt, Juergen A; Kehrli, Marcus E

    2011-01-01

    The primary objective of this study was to determine whether or not Spiroplasma mirum would be capable of producing lesions of transmissible spongiform encephalopathy (TSE) when inoculated in raccoons (Procyon lotor) and, if that was possible, to compare the clinicopathological findings with those of transmissible mink encephalopathy (TME) in the same experimental model. For this purpose, 5 groups (n = 5) of raccoon kits were inoculated intracerebrally with either S. mirum and/or TME. Two other groups (n = 5) of raccoon kits served as sham-inoculated controls. All animals inoculated with TME, either alone or in combination, showed clinical signs of neurologic disorder and were euthanized within 6 mo post-inoculation (MPI). None of the carcasses revealed gross lesions. Spongiform encephalopathy was observed by light microscopy and the presence of abnormal disease-causing prion protein (PrP(d)) was detected by immunohistochemistry (IHC) and Western blot (WB) techniques in only the raccoons administered TME. Raccoons inoculated with Spiroplasma, but not administered TME agent, were euthanized at 30 MPI. They did not show clinical neurologic signs, their brains did not have lesions of spongiform encephalopathy, and their tissues were negative for S. mirum by polymerase chain reaction (PCR) and for PrP(d) by IHC and WB techniques. The results of this study indicate that Spiroplasma mirum does not induce TSE-like disease in raccoons.

  15. Experimental inoculation of raccoons (Procyon lotor) with Spiroplasma mirum and transmissible mink encephalopathy (TME)

    PubMed Central

    Hamir, Amir N.; Greenlee, Justin J.; Stanton, Thad B.; Smith, Jodi D.; Doucette, Stephanie; Kunkle, Robert A.; Stasko, Judith A.; Richt, Juergen A.; Kehrli, Marcus E.

    2011-01-01

    The primary objective of this study was to determine whether or not Spiroplasma mirum would be capable of producing lesions of transmissible spongiform encephalopathy (TSE) when inoculated in raccoons (Procyon lotor) and, if that was possible, to compare the clinicopathological findings with those of transmissible mink encephalopathy (TME) in the same experimental model. For this purpose, 5 groups (n = 5) of raccoon kits were inoculated intracerebrally with either S. mirum and/or TME. Two other groups (n = 5) of raccoon kits served as sham-inoculated controls. All animals inoculated with TME, either alone or in combination, showed clinical signs of neurologic disorder and were euthanized within 6 mo post-inoculation (MPI). None of the carcasses revealed gross lesions. Spongiform encephalopathy was observed by light microscopy and the presence of abnormal disease-causing prion protein (PrPd) was detected by immunohistochemistry (IHC) and Western blot (WB) techniques in only the raccoons administered TME. Raccoons inoculated with Spiroplasma, but not administered TME agent, were euthanized at 30 MPI. They did not show clinical neurologic signs, their brains did not have lesions of spongiform encephalopathy, and their tissues were negative for S. mirum by polymerase chain reaction (PCR) and for PrPd by IHC and WB techniques. The results of this study indicate that Spiroplasma mirum does not induce TSE-like disease in raccoons. PMID:21461191

  16. A model memorandum of collaboration: a proposal.

    PubMed Central

    Fawcett, S B; Francisco, V T; Paine-Andrews, A; Schultz, J A

    2000-01-01

    The authors propose a model memorandum of collaboration for use by state and community partnerships, support organizations, and grantmakers in working together to build healthier communities. Described as an idealized social contract, the model memorandum lays out interrelated responsibilities for the key parties. PMID:10968751

  17. Autoimmune encephalopathies

    PubMed Central

    Leypoldt, Frank; Armangue, Thaís; Dalmau, Josep

    2014-01-01

    Over the last 10 years the continual discovery of novel forms of encephalitis associated with antibodies to cell-surface or synaptic proteins has changed the paradigms for diagnosing and treating disorders that were previously unknown or mischaracterized. We review here the process of discovery, the symptoms, and the target antigens of twelve autoimmune encephatilic disorders, grouped by syndromes and approached from a clinical perspective. Anti-NMDAR encephalitis, several subtypes of limbic encephalitis, stiff-person spectrum disorders, and other autoimmune encephalitides that result in psychosis, seizures, or abnormal movements are described in detail. We include a novel encephalopathy with prominent sleep dysfunction that provides an intriguing link between chronic neurodegeneration and cell-surface autoimmunity (IgLON5). Some of the caveats of limited serum testing are outlined. In addition, we review the underlying cellular and synaptic mechanisms that for some disorders confirm the antibody pathogenicity. The multidisciplinary impact of autoimmune encephalitis has been expanded recently by the discovery that herpes simplex encephalitis is a robust trigger of synaptic autoimmunity, and that some patients may develop overlapping syndromes, including anti-NMDAR encephalitis and neuromyelitis optica or other demyelinating diseases. PMID:25315420

  18. Pathogenesis of Hepatic Encephalopathy

    PubMed Central

    Ciećko-Michalska, Irena; Szczepanek, Małgorzata; Słowik, Agnieszka; Mach, Tomasz

    2012-01-01

    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. PMID:23316223

  19. CFTC-EPA Memorandum of Understanding

    EPA Pesticide Factsheets

    Memorandum of Understanding Between the Environmental Protection Agency and the Commodity Futures Trading Commission on the Sharing of Information Available to EPA Related to the Functioning of Renewable Fuel and Related Markets

  20. Integrated Vegetation Management Practices Memorandum of Understanding

    EPA Pesticide Factsheets

    Memorandum of Understanding between EPA and the Edison Electric Institute, U.S. Department of Agriculture (Forest Service), and U.S. Department of the Interior (Bureau of Land Management, Fish and Wildlife Service, and National Park Service for IVM.

  1. 48 CFR 249.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 3 2011-10-01 2011-10-01 false Settlement negotiation... Settlement negotiation memorandum. Follow the procedures at PGI 249.110 for preparation of a settlement negotiation memorandum. ...

  2. 48 CFR 249.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 3 2012-10-01 2012-10-01 false Settlement negotiation... Settlement negotiation memorandum. Follow the procedures at PGI 249.110 for preparation of a settlement negotiation memorandum. ...

  3. 48 CFR 249.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 3 2014-10-01 2014-10-01 false Settlement negotiation... Settlement negotiation memorandum. Follow the procedures at PGI 249.110 for preparation of a settlement negotiation memorandum. ...

  4. 48 CFR 249.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 3 2013-10-01 2013-10-01 false Settlement negotiation... Settlement negotiation memorandum. Follow the procedures at PGI 249.110 for preparation of a settlement negotiation memorandum. ...

  5. 48 CFR 249.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Settlement negotiation... Settlement negotiation memorandum. Follow the procedures at PGI 249.110 for preparation of a settlement negotiation memorandum. ...

  6. Implementing the Deputy Administrator's Risk Characterization Memorandum, May 26, 1992

    EPA Pesticide Factsheets

    The purpose of this memorandum is to implement in the Superfund program the reccomendations of the Deputy Administrator in his memorandum of February 26, 1992, 'Guidance on risk characterization for risk managers and risk assessors.'

  7. 4 CFR Appendix I to Part 83 - Memorandum of Understanding

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 4 Accounts 1 2010-01-01 2010-01-01 false Memorandum of Understanding I Appendix I to Part 83 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS Pt. 83, App. I Appendix I to Part 83—Memorandum of Understanding This memorandum of understanding constitutes an...

  8. 4 CFR Appendix I to Part 83 - Memorandum of Understanding

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 4 Accounts 1 2013-01-01 2013-01-01 false Memorandum of Understanding I Appendix I to Part 83 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS Pt. 83, App. I Appendix I to Part 83—Memorandum of Understanding This memorandum of understanding constitutes an...

  9. 4 CFR Appendix I to Part 83 - Memorandum of Understanding

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 4 Accounts 1 2012-01-01 2012-01-01 false Memorandum of Understanding I Appendix I to Part 83 Accounts GOVERNMENT ACCOUNTABILITY OFFICE RECORDS PRIVACY PROCEDURES FOR PERSONNEL RECORDS Pt. 83, App. I Appendix I to Part 83—Memorandum of Understanding This memorandum of understanding constitutes an...

  10. 8 CFR 273.6 - Memorandum of Understanding.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Memorandum of Understanding. 273.6 Section... ACT § 273.6 Memorandum of Understanding. (a) Carriers may apply to enter into a Memorandum of Understanding (MOU) with the Service for an automatic reduction, refund, or waiver of fines imposed under...

  11. The brain in experimental portal-systemic encephalopathy. I. Morphological changes in three animal models.

    PubMed

    Pilbeam, C M; Anderson, R M; Bhathal, P S

    1983-08-01

    Morphological features of three models of portal-systemic encephalopathy in the rat were studied and compared with plasma ammonia levels and clinical observations. Carbon tetrachloride-induced cirrhosis with terminal coma produced a wide variety of structural changes in the brain whose severity was related to plasma ammonia levels at the time of death. These changes included diffuse gliosis, Alzheimer cells and focal neuronal necrosis but did not include spongiform changes in cerebral or cerebellar cortex. Porta-caval anastomosis (PCA) did not appear to produce any significant neurological symptoms. Rats with PCA of durations 1-30 weeks were studied and over this time the structural changes included astrocytic nuclear swelling, swelling of perivascular astrocytic foot-processes and spongiform change in the molecular layer of the cerebellum. No evidence of Alzheimer cells or gliosis was seen and plasma ammonia levels at no stage exceed twice the normal levels. Porta-caval anastomosis followed by gavage feeding with ammoniated cationic exchange resin produced severe neurological symptoms and marked hyperammonaemia. In these animals not only astrocytes but oligodendrocytes and neurons showed nuclear and cytoplasmic swelling and numerous Alzheimer type II cells were seen, together with a diffuse gliosis, but no evidence of spongiform change in the cerebral or cerebellar cortex was seen. It is concluded that ammonium ions are important in the genesis of morphological changes in the brain in rat models of portal-systemic encephalopathy, but the relevance of these changes to neurological dysfunction is uncertain.

  12. [Memorandum - research funding of prevention].

    PubMed

    Walter, U; Gold, C; Hoffmann, W; Jahn, I; Töppich, J; Wildner, M; Dubben, S; Franze, M; John, J; Kliche, T; Lehmann, H; Naegele, G; Nöcker, G; Plaumann, M; Pott, E; Robra, B-P

    2012-08-01

    The memorandum of the research funding of prevention has been devised within the framework of the Prevention Research Funding Programme of the Federal Ministry of Education and Research. It consists not only of the obtained findings of the research-practice co-operation but also of recommendations for the implementation of prospective, innovational, effective, practice-oriented and sustainable research. The respective knowledge has been acquired from quantitative surveys on the experiences of scientists and practice partners within the prevention research funding project as well as from extensive qualitative methods of structured group evaluation. A participatory co-operation between research and practice based on mutual respect, trust and recognition is seen as mandatory for the further development of both prevention and health promotion research. Research and practice partners are required to engage in an ab initio collaboration starting from the conception phase, whereby it is advisable to encourage and fortify the communication between research, practice and funding partners by systematic surveillance in form of a meta-project. In addition, the inclusion of the target population from the outset and on a collaborative basis is considered as beneficial in order to ensure the practical application of the research findings. Furthermore, innovatory research designs which are able to provide a framework for internal flexibility, continuous re-assessment and adjustment are fundamental for the implementation of practice-oriented research. Moreover, a dynamic co-operation between different groups of interest not only depends on sharing responsibility but also on sufficient funding for both research and practice, which is particularly important for the transfer and communication of the attained findings. With regard to the evaluation of both effectiveness and sustainability of interventions, a research funding project is required which makes long-term results possible

  13. Noncirrhotic hyperammonaemic encephalopathy.

    PubMed

    Laish, Ido; Ben Ari, Ziv

    2011-10-01

    Adult hyperammonaemia is associated with severe liver disease in 90% of cases. In the remainder, noncirrhotic causes should be considered. Measurements of serum ammonia level must be part of the basic work-up in all patients presenting with encephalopathy of unknown origin, even when liver function is normal. Clinician awareness of noncirrhotic hyperammonaemic encephalopathy can contribute to early diagnosis and the initiation of sometimes life-saving treatment. This review focuses on the physiology, aetiology and underlying mechanisms of noncirrhotic hyperammonaemic encephalopathy and discusses the available treatment modalities.

  14. Satellite-Based Educational Services. Technical Memorandum.

    ERIC Educational Resources Information Center

    Operations Research, Inc., Silver Spring, MD.

    This memorandum contains engineering information relevant to the use of communication satellites for educational purposes. Information is provided for ground terminals as well as satellites. Satellite related issues addressed include: (1) expected life of service of various satellites, (2) constraints on the availability of the satellites, (3)…

  15. Satellite-Based Educational Services. Technical Memorandum.

    ERIC Educational Resources Information Center

    Operations Research, Inc., Silver Spring, MD.

    This memorandum contains engineering information relevant to the use of communication satellites for educational purposes. Information is provided for ground terminals as well as satellites. Satellite related issues addressed include: (1) expected life of service of various satellites, (2) constraints on the availability of the satellites, (3)…

  16. Research needs in taeniasis—cysticercosis (Memorandum)*

    PubMed Central

    1976-01-01

    This Memorandum discusses the epidemiology of taeniasis—cysticercosis, particularly the survival of taeniid eggs in nature, and goes on to consider diagnostic procedures (parasitological and serological), resistance to infection, pathogenesis and clinical pathology, chemotherapy, and the economic and social consequences of infection. Topics requiring further research are listed, and recommendations are made concerning the approach to the problem. PMID:1085668

  17. NASA ESA Sign Memorandum of Understanding

    NASA Image and Video Library

    2009-09-11

    NASA Adminiistrator Charles F. Bolden, left, and Jean-Jacques Dordain, Director General of the European Space Agency (ESA), shake hands, Friday, Sept. 11, 2009, after signing a Space Transportation Memorandum of Understanding (MOU) at NASA Headquarters in Washington. Photo Credit: (NASA/Paul E. Alers)

  18. Hypertensive brain stem encephalopathy.

    PubMed

    Liao, Pen-Yuan; Lee, Chien-Chang; Chen, Cheng-Yu

    2015-01-01

    A 48-year-old man presented with headache and extreme hypertension. Computed tomography showed diffuse brain stem hypodensity. Magnetic resonance imaging revealed diffuse brain stem vasogenic edema. Hypertensive brain stem encephalopathy is an uncommon manifestation of hypertensive encephalopathy, which classically occurs at parietooccipital white matter. Because of its atypical location, the diagnosis can be challenging. Moreover, the coexistence of hypertension and brain stem edema could also direct clinicians toward a diagnosis of ischemic infarction, leading to a completely contradictory treatment goal.

  19. Retinal function and morphology are altered in cattle infected with the prion disease transmissible mink encephalopathy.

    PubMed

    Smith, J D; Greenlee, J J; Hamir, A N; Richt, J A; Greenlee, M H West

    2009-09-01

    Transmissible spongiform encephalopathies (TSEs) are a group of diseases that result in progressive and invariably fatal neurologic disease in both animals and humans. TSEs are characterized by the accumulation of an abnormal protease-resistant form of the prion protein in the central nervous system. Transmission of infectious TSEs is believed to occur via ingestion of prion protein-contaminated material. This material is also involved in the transmission of bovine spongiform encephalopathy ("mad cow disease") to humans, which resulted in the variant form of Creutzfeldt-Jakob disease. Abnormal prion protein has been reported in the retina of TSE-affected cattle, but despite these observations, the specific effect of abnormal prion protein on retinal morphology and function has not been assessed. The objective of this study was to identify and characterize potential functional and morphologic abnormalities in the retinas of cattle infected with a bovine-adapted isolate of transmissible mink encephalopathy. We used electroretinography and immunohistochemistry to examine retinas from 10 noninoculated and 5 transmissible mink encephalopathy-inoculated adult Holstein steers. Here we show altered retinal function, as evidenced by prolonged implicit time of the electroretinogram b-wave, in transmissible mink encephalopathy-infected cattle before the onset of clinical illness. We also demonstrate disruption of rod bipolar cell synaptic terminals, indicated by decreased immunoreactivity for the alpha isoform of protein kinase C and vesicular glutamate transporter 1, and activation of Müller glia, as evidenced by increased glial fibrillary acidic protein and glutamine synthetase expression, in the retinas of these cattle at the time of euthanasia due to clinical deterioration. This is the first study to identify both functional and morphologic alterations in the retinas of TSE-infected cattle. Our results support future efforts to focus on the retina for the development of

  20. Current pathogenetic aspects of hepatic encephalopathy and noncirrhotic hyperammonemic encephalopathy.

    PubMed

    Cichoż-Lach, Halina; Michalak, Agata

    2013-01-07

    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.

  1. Using linked household-level data sets to explain consumer response to bovine spongiform encepalopathy (BSE) in Canada.

    PubMed

    Wang, Xin; Maynard, Leigh J; Butler, J S; Goddard, Ellen W

    2011-01-01

    Household-level Canadian meat purchases from 2002 to 2008 and a Food Opinions Survey conducted in 2008 were used to explore consumer responses to bovine spongiform encephalopathy (BSE) at the national level in Canada. Consumption in terms of the number of unit purchases was analyzed with a random-effects negative binomial model. In this study, household heterogeneity in meat purchases was partially explained using data from a self-reported food opinions survey. Of special interest was the hypothesis that consumers responded consistently to BSE in a one-time survey and in actual meat purchase behavior spanning years. Regional differences appeared, with consumers in eastern Canada reacting most negatively to BSE. Consumers responded more to the perception that food decision makers are honest about food safety than to the perception that they are knowledgeable, in maintaining beef purchases during BSE events.

  2. [Hashimoto's encephalopathy - rare encephalopathy with good prognosis].

    PubMed

    Kaczmarczyk, Aleksandra; Patalong-Ogiewa, M; Krzystanek, E

    2016-01-01

    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.

  3. Posterior reversible encephalopathy syndrome: a variant of hypertensive encephalopathy.

    PubMed

    Mirza, Ayoub

    2006-06-01

    Posterior reversible encephalopathy syndrome (PRES) is a recently described variant of hypertensive encephalopathy characterized by headache, visual disturbances and altered mental function. Its causes are diverse and in contrast to hypertensive encephalopathy, it can develop without significant elevation of blood pressure. This syndrome is mostly reversible when correctly managed; however, failure to recognize it can lead to cerebral infarction and death.

  4. Frequently Asked Questions on BSE (Bovine Spongiform Encephalopathy or Mad Cow Disease)

    MedlinePlus

    ... Topics Animals Biotechnology Climate Solutions Conservation Data Disaster Farming Food and Nutrition Forestry Health and Safety Organic ... One Health Biotechnology Climate Solutions Conservation Data Disaster Farming Food and Nutrition Forestry Health and Safety Organic ...

  5. 75 FR 55803 - Transmissible Spongiform Encephalopathies Advisory Committee; Notice of Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-14

    ... the variant Creutzfeldt-Jakob disease (vCJD) agent in U.S.-licensed plasma-derived Factor VIII and (2) labeling of blood and blood components and plasma-derived products, including plasma-derived albumin and products containing plasma-derived albumin, to address the possible risk of transmission of vCJD. On...

  6. 78 FR 72979 - Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-04

    ... loans because they cannot get them back. The commenter stated that zoo ruminants have no history of BSE... populations. The commenter is incorrect that zoo ruminants have no history of BSE. BSE has been reported in...

  7. 77 FR 29914 - Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-21

    ...: For information concerning live ruminants, contact Dr. Betzaida Lopez, Import Animal Staff... information regarding ruminant products and for other information regarding this proposed rule, contact...

  8. Detergents modify proteinase K resistance of PrPSc in different transmissible spongiform encephalopathies (TSEs)

    PubMed Central

    Breyer, Johanna; Wemheuer, Wiebke M.; Wrede, Arne; Graham, Catherine; Benestad, Sylvie L.; Brenig, Bertram; Richt, Jürgen A.; Schulz-Schaeffer, Walter J.

    2012-01-01

    Prion diseases are diagnosed by the detection of their proteinase K-resistant prion protein fragment (PrPSc). Various biochemical protocols use different detergents for the tissue preparation. We found that the resistance of PrPSc 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 adsorbtion 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 PrPSc 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 PrPSc can be very different. The results obtained here may be helpful during the development or improvement of a PrPSc 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 PrPSc that may stabilize the aggregates. PMID:22226540

  9. Detergents modify proteinase K resistance of PrP Sc in different transmissible spongiform encephalopathies (TSEs).

    PubMed

    Breyer, Johanna; Wemheuer, Wiebke M; Wrede, Arne; Graham, Catherine; Benestad, Sylvie L; Brenig, Bertram; Richt, Jürgen A; Schulz-Schaeffer, Walter J

    2012-05-25

    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. Copyright © 2011 Elsevier B.V. All rights reserved.

  10. 77 FR 15847 - Bovine Spongiform Encephalopathy; Importation of Bovines and Bovine Products

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-16

    ... close of the comment period for the proposed rule, a case of BSE in a dairy cow of Canadian origin in... region of origin and the APHIS Administrator as adequate to prevent contamination or commingling of the.... As noted above, after a BSE-infected cow of Canadian origin was discovered in Washington State in...

  11. 78 FR 72859 - Concurrence With OIE Risk Designations for Bovine Spongiform Encephalopathy

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-04

    ... for Import and Export, VS, APHIS, 4700 River Road, Unit 38, Riverdale, MD 20737-1231; (301) 851-3300... or controlled risk can be accessed on the APHIS Web site at http://www.aphis.usda.gov/import_export... Export Services, 4700 River Road Unit 38, Riverdale, MD 20737. Under the regulations, APHIS may classify...

  12. T cells infiltrate the brain in murine and human transmissible spongiform encephalopathies.

    PubMed

    Lewicki, Hanna; Tishon, Antoinette; Homann, Dirk; Mazarguil, Honoré; Laval, Françoise; Asensio, Valerie C; Campbell, Iain L; DeArmond, Stephen; Coon, Bryan; Teng, Chao; Gairin, Jean Edouard; Oldstone, Michael B A

    2003-03-01

    CD4 and CD8 T lymphocytes infiltrate the parenchyma of mouse brains several weeks after intracerebral, intraperitoneal, or oral inoculation with the Chandler strain of mouse scrapie, a pattern not seen with inoculation of prion protein knockout (PrP(-/-)) mice. Associated with this cellular infiltration are expression of MHC class I and II molecules and elevation in levels of the T-cell chemokines, especially macrophage inflammatory protein 1beta, IFN-gamma-inducible protein 10, and RANTES. T cells were also found in the central nervous system (CNS) in five of six patients with Creutzfeldt-Jakob disease. T cells harvested from brains and spleens of scrapie-infected mice were analyzed using a newly identified mouse PrP (mPrP) peptide bearing the canonical binding motifs to major histocompatibility complex (MHC) class I H-2(b) or H-2(d) molecules, appropriate MHC class I tetramers made to include these peptides, and CD4 and CD8 T cells stimulated with 15-mer overlapping peptides covering the whole mPrP. Minimal to modest K(b) tetramer binding of mPrP amino acids (aa) 2 to 9, aa 152 to 160, and aa 232 to 241 was observed, but such tetramer-binding lymphocytes as well as CD4 and CD8 lymphocytes incubated with the full repertoire of mPrP peptides failed to synthesize intracellular gamma interferon (IFN-gamma) or tumor necrosis factor alpha (TNF-alpha) cytokines and were unable to lyse PrP(-/-) embryo fibroblasts or macrophages coated with (51)Cr-labeled mPrP peptide. These results suggest that the expression of PrP(sc) in the CNS is associated with release of chemokines and, as shown previously, cytokines that attract and retain PrP-activated T cells and, quite likely, bystander activated T cells that have migrated from the periphery into the CNS. However, these CD4 and CD8 T cells are defective in such an effector function(s) as IFN-gamma and TNF-alpha expression or release or lytic activity.

  13. Animal Meal: Production and Determination in Feedstuffs and the Origin of Bovine Spongiform Encephalopathy

    NASA Astrophysics Data System (ADS)

    Hahn, Heinz

    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.

  14. Memorandum for the evaluation of diagnostic measures.

    PubMed

    1990-12-01

    In contrast to therapeutic methods no general guidelines have as yet been formulated for the investigation of diagnostic measures. Previous studies have often delivered results that have not been interpretable. This situation was obviously unsatisfactory since staff, apparatus and financial resources were not being meaningfully employed. For these reasons the present memorandum was drawn up by a working group of the GMDS. It is intended to provide a framework for the evaluation of diagnostic measures. The process for the evaluation of diagnostic tests has by analogy to the procedure for the registration of drugs been divided into four clearly defined phases: Phase 1: preliminary technical and methodological investigations; Phase 2: estimation of test parameters in selected patients; Phase 3: Controlled diagnostic study; Phase 4: Investigation of the effectiveness; continuing risk-benefit analysis. Studies on new diagnostic tests should be designed according to the guidelines formulated in this memorandum. Many already established tests will require examination according to the criteria described here.

  15. Anthrax: memorandum from a WHO meeting.

    PubMed Central

    1996-01-01

    The risk of anthrax can be reduced through international collaboration in health education and training, promotion of research, and provision of scientific and technical advice. These issues were discussed by a WHO Working Group on Anthrax in September 1995, and this Memorandum presents their priority concerns and recommendations in several areas: surveillance, epidemiology, diagnosis in humans and in animals, prevention and control, and international cooperation. PMID:9002326

  16. Anthrax: memorandum from a WHO meeting.

    PubMed

    1996-01-01

    The risk of anthrax can be reduced through international collaboration in health education and training, promotion of research, and provision of scientific and technical advice. These issues were discussed by a WHO Working Group on Anthrax in September 1995, and this Memorandum presents their priority concerns and recommendations in several areas: surveillance, epidemiology, diagnosis in humans and in animals, prevention and control, and international cooperation.

  17. Mechanisms underlying uremic encephalopathy.

    PubMed

    Scaini, Giselli; Ferreira, Gabriela Kozuchovski; Streck, Emilio Luiz

    2010-06-01

    In patients with renal failure, encephalopathy is a common problem that may be caused by uremia, thiamine deficiency, dialysis, transplant rejection, hypertension, fluid and electrolyte disturbances or drug toxicity. In general, encephalopathy presents with a symptom complex progressing from mild sensorial clouding to delirium and coma. This review discusses important issues regarding the mechanisms underlying the pathophysiology of uremic encephalopathy. The pathophysiology of uremic encephalopathy up to now is uncertain, but several factors have been postulated to be involved; it is a complex and probably multifactorial process. Hormonal disturbances, oxidative stress, accumulation of metabolites, imbalance in excitatory and inhibitory neurotransmitters, and disturbance of the intermediary metabolism have been identified as contributing factors. Despite continuous therapeutic progress, most neurological complications of uremia, like uremic encephalopathy, fail to fully respond to dialysis and many are elicited or aggravated by dialysis or renal transplantation. On the other hand, previous studies showed that antioxidant therapy could be used as an adjuvant therapy for the treatment of these neurological complications.

  18. Infantile mitochondrial encephalopathy.

    PubMed

    Uziel, Graziella; Ghezzi, Daniele; Zeviani, Massimo

    2011-08-01

    Individually rare, when taken as a whole, genetic inborn errors of metabolism (IEM) account for a significant proportion of early onset encephalopathy. Prompt diagnosis is crucial to assess appropriate investigation and can sometimes warrant successful therapy. Recent improvements in technology and expansion of knowledge on the biochemical and molecular basis of these disorders allow astute child neurologists and paediatricians to improve the early diagnosis of these genetically determined defects. However, because of rarity and heterogeneity of these disorders, IEM encephalopathies are still a formidable challenge for most physicians. The most frequent cause of childhood IEM encephalopathy is mitochondrial disease, whose biochemical 'signature' is faulty energy supply due to defects of the last component of the oxidative pathways residing within mitochondria, i.e. the mitochondrial respiratory chain. Copyright © 2011. Published by Elsevier Ltd.

  19. Minimal hepatic encephalopathy.

    PubMed

    Zamora Nava, Luis Eduardo; Torre Delgadillo, Aldo

    2011-06-01

    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.

  20. [Hashimoto's encephalopathy and autoantibodies].

    PubMed

    Yoneda, Makoto

    2013-04-01

    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

  1. Burn encephalopathy in children.

    PubMed

    Mohnot, D; Snead, O C; Benton, J W

    1982-07-01

    Among 287 children with burns treated over a recent two-year period, 13 (5%) showed evidence of encephalopathy. The major clinical symptoms were an altered sensorium and seizures. The majority of symptoms began later than 48 hours after the burn and were accompanied by multiple metabolic aberrations including hypocalcemia. Three children had a relapsing course, and 1 had temporarily enlarged cerebral ventricles. Eleven children improved to normal. In the majority of instances, burn encephalopathy probably reflects central nervous system dysfunction resulting from complex metabolic, hematological, and hemodynamic abnormalities rather than from a single metabolic abnormality.

  2. The basic reality of mind and spongiform diseases.

    PubMed

    Axelsson, S

    2001-11-01

    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

  3. 77 FR 43127 - Further Amendment to Memorandum Describing Authority and Assigned Responsibilities of the General...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-23

    ... BOARD Further Amendment to Memorandum Describing Authority and Assigned Responsibilities of the General... Relations Board is amending the memorandum describing the authority and assigned responsibilities of the... amendment to Board memorandum describing the authority and assigned responsibilities of the General...

  4. Spatial correlation between the prevalence of transmissible spongiform diseases and British soil geochemistry.

    PubMed

    Imrie, C E; Korre, A; Munoz-Melendez, G

    2009-02-01

    Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurological conditions affecting a number of mammals, including sheep and goats (scrapie), cows (BSE), and humans (Creutzfeldt-Jakob disease). The diseases are widely believed to be caused by the misfolding of the normal prion protein to a pathological isoform, which is thought to act as an infectious agent. Outbreaks of the disease are commonly attributed to contaminated feed and genetic susceptibility. However, the implication of copper and manganese in the pathology of the disease, and its apparent geographical clustering, have prompted suggestions of a link with trace elements in the environment. Nevertheless, studies of soils at regional scales have failed to provide evidence of an environmental risk factor. This study uses geostatistical techniques to investigate the correlations between the distribution of TSE prevalence and soil geochemical variables across the UK according to different spatial scales. A similar spatial pattern in scrapie and BSE occurrence is identified, which may be linked with increasing pH and total organic carbon, and decreasing iodine concentration. However, the pattern also resembles that of the density of dairy farming. Nevertheless, despite the low spatial resolution of the TSE data available for this study, the fact that significant correlations are detected indicates there is a possibility of a link between soil geochemistry, scrapie, and BSE. It is suggested that further investigations of the prevalence of TSE and environmental exposure to trace metals should take into account the factors affecting their bioavailability.

  5. Management of covert hepatic encephalopathy.

    PubMed

    Waghray, Abhijeet; Waghray, Nisheet; Mullen, Kevin

    2015-03-01

    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.

  6. Scrapie-like encephalopathy in a greater kudu (Tragelaphus strepsiceros) which had not been fed ruminant-derived protein.

    PubMed

    Kirkwood, J K; Wells, G A; Cunningham, A A; Jackson, S I; Scott, A C; Dawson, M; Wilesmith, J W

    1992-04-25

    A 19-month-old greater kudu (Tragelaphus strepsiceros), whose dam had died 15 months earlier with spongiform encephalopathy, required euthanasia after developing severe ataxia and depression with an apparently sudden onset. No macroscopic abnormalities were detected on post mortem examination but a scrapie-like spongiform encephalomyelopathy was apparent on histopathological examination of brain and segments of spinal cord. Negative stain electron microscopy of proteinase K-treated detergent extracts of tissue from the brain stem revealed the presence of scrapie associated fibrils, and a 25 to 28 kDa band comparable with that identified as abnormal PrP (prion protein) from the brains of domestic cattle with spongiform encephalopathy was detected using rabbit antiserum raised against mouse PrP. The animal was born nine months after the statutory ban on the inclusion of ruminant-derived protein in ruminant feeds and, as no other possible sources of the disease were apparent, it appears likely that the infection was acquired from the dam.

  7. Management of Hepatic Encephalopathy

    PubMed Central

    Wright, G.; Chattree, A.; Jalan, R.

    2011-01-01

    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. PMID:21994873

  8. KCNQ2 encephalopathy

    PubMed Central

    Millichap, John J.; Park, Kristen L.; Tsuchida, Tammy; Ben-Zeev, Bruria; Carmant, Lionel; Flamini, Robert; Joshi, Nishtha; Levisohn, Paul M.; Marsh, Eric; Nangia, Srishti; Narayanan, Vinodh; Ortiz-Gonzalez, Xilma R.; Patterson, Marc C.; Pearl, Phillip L.; Porter, Brenda; Ramsey, Keri; McGinnis, Emily L.; Taglialatela, Maurizio; Tracy, Molly; Tran, Baouyen; Venkatesan, Charu; Weckhuysen, Sarah

    2016-01-01

    Objective: To advance the understanding of KCNQ2 encephalopathy genotype–phenotype relationships and to begin to assess the potential of selective KCNQ channel openers as targeted treatments. Methods: We retrospectively studied 23 patients with KCNQ2 encephalopathy, including 11 treated with ezogabine (EZO). We analyzed the genotype–phenotype relationships in these and 70 previously described patients. Results: The mean seizure onset age was 1.8 ± 1.6 (SD) days. Of the 20 EEGs obtained within a week of birth, 11 showed burst suppression. When new seizure types appeared in infancy (15 patients), the most common were epileptic spasms (n = 8). At last follow-up, seizures persisted in 9 patients. Development was delayed in all, severely in 14. The KCNQ2 variants identified introduced amino acid missense changes or, in one instance, a single residue deletion. They were clustered in 4 protein subdomains predicted to poison tetrameric channel functions. EZO use (assessed by the treating physicians and parents) was associated with improvement in seizures and/or development in 3 of the 4 treated before 6 months of age, and 2 of the 7 treated later; no serious side effects were observed. Conclusions: KCNQ2 variants cause neonatal-onset epileptic encephalopathy of widely varying severity. Pathogenic variants in epileptic encephalopathy are clustered in “hot spots” known to be critical for channel activity. For variants causing KCNQ2 channel loss of function, EZO appeared well tolerated and potentially beneficial against refractory seizures when started early. Larger, prospective studies are needed to enable better definition of prognostic categories and more robust testing of novel interventions. Classification of evidence: This study provides Class IV evidence that EZO is effective for refractory seizures in patients with epilepsy due to KCNQ2 encephalopathy. PMID:27602407

  9. Malaria diagnosis: Memorandum from a WHO Meeting*

    PubMed Central

    1988-01-01

    This Memorandum reviews (1) the diagnostic requirements for malaria control within the primary health care system; (2) the current methods of malaria diagnosis used both in the clinic and in epidemiological studies; (3) the status of research on alternative methods to microscopy for the diagnosis of malaria; and (4) the application of new diagnostic methods in individual cases, in the community, and in the mosquito and their possible integration into existing epidemiological studies and control programmes. It also identifies priorities for the development and validation of new and reliable diagnostic techniques, and makes recommendations for the improvement, standardization, and utilization of current methodology. PMID:3061674

  10. 48 CFR 49.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 1 2014-10-01 2014-10-01 false Settlement negotiation... CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.110 Settlement negotiation memorandum. (a) The TCO shall, at the conclusion of negotiations, prepare a settlement negotiation memorandum...

  11. 48 CFR 49.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 1 2013-10-01 2013-10-01 false Settlement negotiation... CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.110 Settlement negotiation memorandum. (a) The TCO shall, at the conclusion of negotiations, prepare a settlement negotiation memorandum...

  12. 48 CFR 49.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 1 2011-10-01 2011-10-01 false Settlement negotiation... CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.110 Settlement negotiation memorandum. (a) The TCO shall, at the conclusion of negotiations, prepare a settlement negotiation memorandum...

  13. 48 CFR 49.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 1 2012-10-01 2012-10-01 false Settlement negotiation... CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.110 Settlement negotiation memorandum. (a) The TCO shall, at the conclusion of negotiations, prepare a settlement negotiation memorandum...

  14. 48 CFR 315.372 - Preparation of negotiation memorandum.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Preparation of negotiation... CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Source Selection 315.372 Preparation of negotiation memorandum. The Contracting Officer shall prepare a negotiation memorandum, or summary...

  15. 48 CFR 49.110 - Settlement negotiation memorandum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Settlement negotiation memorandum. 49.110 Section 49.110 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.110 Settlement negotiation memorandum...

  16. Cat scratch encephalopathy.

    PubMed

    Silver, B E; Bean, C S

    1991-06-01

    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.

  17. Hypertensive encephalopathy and cerebral infarction.

    PubMed

    Edvardsson, Bengt

    2014-01-01

    Hypertensive encephalopathy is one cause of posterior reversible encephalopathy syndrome. Hypertensive encephalopathy and cerebral infarction have only been reported in a few individual case reports. A 51-year-old woman presented with hypertensive encephalopathy. T2-weighted images from magnetic resonance imaging showed hyperintense lesions in both occipital and parietal lobes. Diffusion-weighted imaging showed that this represented cytotoxic oedema and perfusion magnetic resonance imaging revealed reduced blood volume and flow. The magnetic resonance imaging was repeated 5 months later and subtotal regression of theT2-hyperintensity had occurred. However, small bilateral infarcts were seen on T1-weighted images. Perfusion magnetic resonance imaging presented reduced blood volume and flow on the right side. The patient in this report had posterior reversible encephalopathy syndrome caused by hypertensive encephalopathy. Magnetic resonance imaging of the brain showed bilateral cytotoxic oedema that partially resolved and resulted in small infarcts. The imaging findings are compatible with posterior reversible encephalopathy syndrome with subtotal resolution and infarct evolution. The case report suggests that the presence of hypertensive encephalopathy and posterior reversible encephalopathy syndrome should alert clinicians and lead to prompt treatment in order to prevent cerebral damage.

  18. [EEG manifestations in metabolic encephalopathy].

    PubMed

    Lin, Chou-Ching K

    2005-09-01

    Normal brain function depends on normal neuronal metabolism, which is closely related to systemic homeostasis of metabolites, such as glucose, electrolytes, amino acids and ammonia. "Metabolic encephalopathy" indicates diffuse brain dysfunction caused by various systemic derangements. Electroencephalogram (EEG) is widely used to evaluate metabolic encephalopathy since 1937, when Berger first observed slow brain activity induced by hypoglycemia. EEG is most useful in differentiating organic from psychiatric conditions, identifying epileptogenicity, and providing information about the degree of cortical or subcortical dysfunction. In metabolic encephalopathy, EEG evolution generally correlates well with the severity of encephalopathy. However, EEG has little specificity in differentiating etiologies in metabolic encephalopathy. For example, though triphasic waves are most frequently mentioned in hepatic encephalopathy, they can also be seen in uremic encephalopathy, or even in aged psychiatric patients treated with lithium. Spike-and-waves may appear in hyper- or hypo-glycemia, uremic encephalopathy, or vitamin deficiencies, etc. Common principles of EEG changes in metabolic encephalopathy are (1) varied degrees of slowing, (2) assorted mixtures of epileptic discharge, (3) high incidence of triphasic waves, and (4), as a rule, reversibility after treatment of underlying causes. There are some exceptions to the above descriptions in specific metabolic disorders and EEG manifestations are highly individualized.

  19. Hashimoto encephalopathy: literature review.

    PubMed

    Zhou, J Y; Xu, B; Lopes, J; Blamoun, J; Li, L

    2017-03-01

    Hashimoto encephalopathy (HE) presents as an encephalopathy without central nervous system infection or tumor. HE is associated with autoimmune thyroiditis and is thus considered to be an autoimmune disorder. The prevalence of HE is low, but death and status epilepticus have been reported. HE manifests with a wide range of symptoms that include behavioral changes and confusion. Elevated thyroid antibodies are present in the majority of cases and are required for the diagnosis of HE. Normal brain MRI findings are found in the majority of patients diagnosed with HE. The most consistent CSF abnormality noted in HE patients is the presence of elevated protein. Most HE patients respond well to steroid therapy. Clinical improvements are also observed with IV immunoglobulin and plasmapheresis. In conclusion, it is now generally accepted that the diagnosis of HE must include encephalopathy characterized by cognitive impairment associated with psychiatric features, such as hallucinations, delusions, and paranoia. Autoimmune encephalitis and prion disease should be considered in the differential diagnosis due to the similarity of the clinical features of these conditions to those of HE. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Pharmacoeconomics of hepatic encephalopathy.

    PubMed

    Neff, Guy

    2010-05-01

    Understanding and appreciating the science of pharmacoeconomics have become even more important for health care providers and insurers during the recent economic downturn. Evaluating the true costs of any disease is complex; both direct costs, such as costs of drug therapy and the provision of care, and indirect costs, such as lost earnings and reduced quality of life, must be taken into account. With chronic liver disease, the most recent data indicate that direct costs were more than $2 billion whereas indirect costs were more than $450 million. Hepatic encephalopathy, a common complication of chronic liver disease, contributes to this economic burden. Although patients' length of stay during hospitalization for hepatic encephalopathy decreased from almost 9 days to 6 days (and has remained stable over the past few years) from 1993 to 2007, hospitalization costs rose from $13,000 to $30,000/hospital stay. In addition, 22% of patients were discharged directly to nursing homes or rehabilitation centers, which increases total costs. When assessing therapy for hepatic encephalopathy, it is important to consider the total costs of the disease, not just treatment costs. Although more expensive on a daily basis than lactulose, rifaximin has been shown to reduce hospitalization rates, has a better adverse-effect profile, and increases patient compliance. One study found that rifaximin produced a cost savings/patient/year of more than $3000 over lactulose therapy.

  1. 7 CFR 28.117 - Fee for new memorandum or certificate.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 7 Agriculture 2 2014-01-01 2014-01-01 false Fee for new memorandum or certificate. 28.117 Section... Standards Act Fees and Costs § 28.117 Fee for new memorandum or certificate. For each new memorandum or... minimum fee of $5.00 per sheet. If the memorandum is provided by means of a computer diskette, the fee for...

  2. [Memorandum prevention research - research areas and methods].

    PubMed

    Walter, U; Nöcker, G; Plaumann, M; Linden, S; Pott, E; Koch, U; Pawils, S; Altgeld, T; Dierks, M L; Frahsa, A; Jahn, I; Krauth, C; Pomp, M; Rehaag, R; Robra, B P; Süß, W; Töppich, J; Trojan, A; von Unger, H; Wildner, M; Wright, M

    2012-10-01

    From 2004 to 2012, the German Ministry of Education and Research (BMBF) established its first funding programme for the promotion of prevention research. 60 projects on primary prevention and health promotion and the meta-project entitled "Cooperation for Sustainable Prevention Research" (KNP) received BMBF grants under this programme during this period. The experience and knowledge gained and recommendations arising from the research funded under this programme are compiled in memorandum format. The "Memorandum on Prevention Research - Research Areas and Methods" highlights 5 research areas that are considered to be especially relevant from the perspective of the involved scientists and practice partners.The promotion of structural development and sustainability enhancement in disease prevention and health promotion are central areas that should branch out from existing nuclei of crystallization. Improving the health competence of the population and of specific subpopulations is another major area. Research in these areas should contribute to the development of theoretical concepts and to the empirical testing of these concepts. The transfer of knowledge for effective use of developed disease prevention and health promotion programmes and measures is still a scarcely researched area. Among other things, studies of the transfer of programmes from one context to another, analyses of the coop-eration between politics and science, and the continued theoretical and conceptual development of transfer research are needed. Long-term data on the effects of intervention studies are also needed for proper evaluation of sustainability. The latter dem-onstrates the importance of method development in disease prevention and health promotion research as an area that should receive separate funding and support. This research should include, in particular, studies of the efficacy of complex interventions, health economic analyses, and participative health research. © Georg Thieme

  3. [Posterior reversible encephalopathy syndrome].

    PubMed

    Petrović, Branko; Kostić, Vladimir; Sternić, Nadezda; Kolar, Jovo; Tasić, Nebojsa

    2003-01-01

    Reversible Posterior Leukoencephalopathy Syndrome was introduced into clinical practice in 1996 in order to describe unique syndrome, clinically expressed during hypertensive and uremic encephalopathy, eclampsia and during immunosuppressive therapy [1]. First clinical investigations showed that leucoencephalopathy is major characteristic of the syndrome, but further investigations showed no significant destruction in white cerebral tissue [2, 3, 4]. In majority of cases changes are localise in posterior irrigation area of the brain and in the most severe cases anterior region is also involved. Taking into consideration all above mentioned facts, the suggested term was Posterior Reversible Encephalopathy Syndrome (PRES) for the syndrome clinically expressed by neurological manifestations derived from cortical and subcortical changes localised in posterior regions of cerebral hemispheres, cerebral trunk and cerebellum [5]. Patient, aged 53 years, was re-hospitalized in Cardiovascular Institute "Dediwe" two months after successful aorto-coronary bypass performed in June 2001 due to the chest bone infection. During the treatment of the infection (according to the antibiogram) in September 2001, patient in evening hours developed headache and blurred vision. The recorded blood pressure was 210/120 mmHg so antihypertensive treatment was applied (Nifedipin and Furosemid). After this therapy there was no improvement and intensive headache with fatigue and loss of vision developed. Neurological examination revealed cortical blindness and left hemiparesis. Manitol (20%, 60 ccm every 3 hours) and i.v. Nytroglicerin (high blood pressure). Brain CT revealed oedema of parieto-occipital regions of both hemispheres, more emphasized on the right. (Figure 1a, b, c). There was no sign of focal ischemia even in deeper sections (Figure 1d, e, f). Following three days enormous high blood pressure values were registered. On the fourth day the significant clinical improvement occurred

  4. SCN2A encephalopathy

    PubMed Central

    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

    2015-01-01

    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

  5. Pathophysiology of epileptic encephalopathies.

    PubMed

    Lado, Fred A; Rubboli, Guido; Capovilla, Giuseppe; Capovilla, Pippo; Avanzini, Giuliano; Moshé, Solomon L

    2013-11-01

    The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike-wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.

  6. Memorandum of Understanding with the University of Southern Mississippi

    EPA Pesticide Factsheets

    The purpose of the Memorandum of Understanding signed June 29, 2015 is to increase cooperation between the University of Southern Mississippi and the U.S Environmental Protection Agency’s Gulf of Mexico Program in areas of mutual interest.

  7. Memorandum of Understanding for Improving Environmental Management of Electronic Assets

    EPA Pesticide Factsheets

    This is a memorandum of understanding between the U.S. Postal Service, Department of Defense, Department of Energy, Department of Interior and EPA to improve the environmental management of the government's electronic assets.

  8. Clean Air Act Section 112(r) Inspection Guidance Distribution Memorandum

    EPA Pesticide Factsheets

    This memorandum issues and makes immediately effective the document, Guidance for Conducting Risk Management Program Inspections under Clean Air Act Section 112(r), which supersedes the 1999 document on auditing risk management plans/programs.

  9. Memorandum of Understanding with Pearl River Community College

    EPA Pesticide Factsheets

    The purpose of the Memorandum of Understanding is to increase cooperation between Pearl River Community College and the U.S Environmental Protection Agency’s Gulf of Mexico Program in areas of mutual interest.

  10. Laboratory support for poliomyelitis eradication: memorandum from a WHO meeting.

    PubMed Central

    1989-01-01

    This Memorandum summarizes the conclusions and recommendations of the participants at the Consultation on Strategy for Isolation and Characterization of Poliovirus Strains and Surveillance of Wild Polioviruses held in Geneva, 28-30 November 1988. PMID:2572355

  11. Memorandum of Understanding with Northwest Food Processors Association

    SciTech Connect

    2009-02-01

    The Northwest Food Processors Association (NWFPA) and the U.S. Department of Energy entered into this memorandum of understanding to work collaboratively to reduce energy intensity by 25% within ten years.

  12. Clean Water Act Section 404(q):Memorandum of Agreement

    EPA Pesticide Factsheets

    A memorandum of agreement between EPA and the Army Corps of Engineers to minimize, to the maximum extent practicable, duplication, needless paperwork and delays in the issuance of permits related to Section 404(q) of the Clean Water Act.

  13. Memorandum of Understanding with the Mississippi Gulf Coast Community College

    EPA Pesticide Factsheets

    The purpose of the Memorandum of Understanding signed October 1, 2013 is to increase cooperation between Mississippi Gulf Coast Community College and the U.S Environmental Protection Agency’s Gulf of Mexico Program in areas of mutual interest.

  14. Hypertension and hypertensive encephalopathy.

    PubMed

    Price, Raymond S; Kasner, Scott E

    2014-01-01

    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. © 2014 Elsevier B.V. All rights reserved.

  15. Chronic traumatic encephalopathy.

    PubMed

    Omalu, Bennet

    2014-01-01

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative syndrome, which is caused by single, episodic, or repetitive blunt force impacts to the head and transfer of acceleration-deceleration forces to the brain. CTE presents clinically as a composite syndrome of mood disorders and behavioral and cognitive impairment, with or without sensorimotor impairment. Symptoms of CTE may begin with persistent symptoms of acute traumatic brain injury (TBI) following a documented episode of brain trauma or after a latent period that may range from days to weeks to months and years, up to 40 years following a documented episode of brain trauma or cessation of repetitive TBI. Posttraumatic encephalopathy is distinct from CTE, can be comorbid with CTE, and is a clinicopathologic syndrome induced by focal and/or diffuse, gross and/or microscopic destruction of brain tissue following brain trauma. The brain of a CTE sufferer may appear grossly unremarkable, but shows microscopic evidence of primary and secondary proteinopathies. The primary proteinopathy of CTE is tauopathy, while secondary proteinopathies may include, but are not limited to, amyloidopathy and TDP proteinopathy. Reported prevalence rates of CTE in cohorts exposed to TBI ranges from 3 to 80% across age groups.

  16. [Memorandum registry for health services research].

    PubMed

    Müller, D; Augustin, M; Banik, N; Baumann, W; Bestehorn, K; Kieschke, J; Lefering, R; Maier, B; Mathis, S; Rustenbach, S J; Sauerland, S; Semler, S C; Stausberg, J; Sturm, H; Unger, C; Neugebauer, E A M

    2010-11-01

    On August 30, 2010, the German Network for Health Services Research [Deutsches Netzwerk Versorgungsforschung e. V. (DNVF e. V.)] approved the Memorandum III "Methods for Health Services Research", supported by their member societies mentioned as authors and published in this Journal [Gesundheitswesen 2010; 72: 739-748]. Registries in Health Services Research vary in their aims and research questions as well as in their designs, methods of data collection, and statistical analyses. This paper aims to provide both a methodological guideline for developers to ensure a high quality of a planned registry and, to provide an instrument for users of data from registries to assess their overall quality. First, the paper provides a definition of registries and presents an overview of objectives in Health Services Research where registries can be useful. Second, several areas of methodological importance for the development of registries are presented. This includes the different phases of a registry (i. e., conceptual and preliminary design, implementation), technical organisation of a registry, statistical analysis, reporting of results, data protection, and ethical/legal aspects. From these areas, several criteria are deduced to allow the assessment of the quality of a registry. Finally, a checklist to assess a registry's quality is presented. © Georg Thieme Verlag KG Stuttgart · New York.

  17. Treatment of epileptic encephalopathies.

    PubMed

    McTague, Amy; Cross, J Helen

    2013-03-01

    Epileptic encephalopathy is defined as a condition where the epileptic activity itself may contribute to the severe neurological and cognitive impairment seen, over and above that which would be expected from the underlying pathology alone. The epilepsy syndromes at high risk of this are a disparate group of conditions characterized by epileptic seizures that are difficult to treat and developmental delay. In this review, we discuss the ongoing debate regarding the significance of inter-ictal discharges and the impact of the seizures themselves on the cognitive delay or regression that is a common feature of these syndromes. The syndromes also differ in many ways and we provide a summary of the key features of the early-onset epileptic encephalopathies including Ohtahara and West syndromes in addition to later childhood-onset syndromes such as Lennox Gastaut and Doose syndromes. An understanding of the various severe epilepsy syndromes is vital to understanding the rationale for treatment. For example, the resolution of hypsarrhythmia in West syndrome is associated with an improvement in cognitive outcome and drives treatment choice, but the same cannot be applied to frequent inter-ictal discharges in Lennox Gastaut syndrome. We discuss the evidence base for treatment where it is available and describe current practice where it is not. For example, in West syndrome there is some evidence for preference of hormonal treatments over vigabatrin, although the choice and duration of hormonal treatment remains unclear. We describe the use of conventional and newer anti-epileptic medications in the various syndromes and discuss which medications should be avoided. Older possibly forgotten treatments such as sulthiame and potassium bromide also have a role in the severe epilepsies of childhood. We discuss hormonal treatment with particular focus on the treatment of West syndrome, continuous spike wave in slow wave sleep (CSWS)/electrical status epilepticus in slow wave

  18. [Prevention of hepatic encephalopathy].

    PubMed

    Morillas, Rosa M; Sala, Marga; Planas, Ramon

    2014-06-06

    Hepatic encephalopathy (HE) is a frequent complication of cirrhosis which, in addition to producing a great social impact, deteriorates the quality of life of patients and is considered a sign of advanced liver disease and therefore a clinical indication for liver transplant evaluation. Patients who have had episodes of HE have a high risk of recurrence. Thus, after the HE episode resolves, it is recommended: control and prevention of precipitating factors (gastrointestinal bleeding, spontaneous bacterial peritonitis, use of diuretics with caution, avoid nervous system depressant medications), continued administration of non-absorbable disaccharides such as lactulose or lactitol, few or non-absorbable antibiotics such as rifaximin and assess the need for a liver transplant as the presence of a HE episode carries a poor prognosis in cirrhosis. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  19. Gasoline sniffing and lead encephalopathy.

    PubMed Central

    Ross, C. A.

    1982-01-01

    Gasoline sniffing is endemic in northern Manitoba and perhaps throughout much of northern Canada. Its most serious complication is lead encephalopathy, which can be fatal. Most of the toxic effects are thought to be due to tetraethyl lead and its metabolites. The specific treatment is chelation therapy, for which a protocol has been developed at the Health Sciences Centre, Winnipeg. Lead encephalopathy, however, is a manifestation of social, cultural and psychologic malaise. PMID:7139470

  20. Approval of Alternative Test Method for Puerto Nuevo Wastewater Treatment Plant, San Juan, Puerto Rico Memorandum

    EPA Pesticide Factsheets

    This December 2008 memorandum is from Conniesue Oldham of the Measurement Technology Group to Marcus E. Kantz in EPA Region 2. This memorandum is regarding a request to use an alternative test method at the Puerto Neuvo wastewater treatment plant

  1. 75 FR 29561 - Memorandum of Understanding Between the Food and Drug Administration and Drugs.Com

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-05-26

    ... No. FDA-2010-N-0004] [FDA 225-09-0012] Memorandum of Understanding Between the Food and Drug...: The Food and Drug Administration (FDA) is providing notice of a memorandum of understanding (MOU...

  2. 76 FR 60114 - Section 306 Monitoring of Paraguay: Memorandum of Understanding on Intellectual Property Rights...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-09-28

    ... successfully entered into a Memorandum of Understanding on Intellectual Property Rights. USTR subsequently... enforcement of intellectual property rights. Dates: Submissions from the general public and foreign... ``Paraguay Memorandum of Understanding on Intellectual Property Rights'' in the ``Type comment'' field...

  3. NASA/UH signing of memorandum of understanding

    NASA Image and Video Library

    1996-10-02

    NASA/University of Houston (UH) signing of memorandum of understanding. Johnson Space Center (JSC) Director George Abbey signs a memorandum of understanding with University of Houston's President Glenn Goerke and University of Houston Clear Lake President Williams Staples. UH will supply post-doctoral researchers to JSC for more than 15 projects of scientific interest to both JSC and the university. Seated from left are, Abbey, Goerke and Staples. Standing from left are David Criswell, director of the Institute of Space Systems Operations; Texas State Representatives Michael Jackson, Robert Talton and Talmadge Heflin. View appears in Space News Roundup v35 n41 p4, 10-18-96.

  4. [Autopsy room and the July 30th 2004 memorandum].

    PubMed

    Canas, Frédéric; Guillou, Pierre-José; Lorin de la Grandmaison, Geoffroy; Diebold, Marie-Danièle; Patey, Martine; Bureau-Chalot, Florence; Bajolet, Odile; Jeunehomme, Gérard; Bernard, Mary-Hélène; Durigon, Michel; Pluot, Michel

    2005-06-01

    With the July 30th 2004 memorandum, for the first time a text is specifically dedicated to the architecture of the autopsy room. This memorandum reaffirms certain technical specifications stated in the May 7th 2001 decree applicable to hospital mortuaries. It supplements or modifies certain elements, particularly liquid waste processing, which will require new arrangements in death chambers and new expenditures for hospital administrations. It includes the principle of precaution and requires a new approach to handling human corpses in the autopsy room.

  5. A Taxonomy for the Composition of Memorandum Subject Lines: Facilitating Writer Choice in Managerial Contexts.

    ERIC Educational Resources Information Center

    Rogers, Priscilla S.

    1990-01-01

    Studies the significance of memorandum subject lines (the thematic titles or topic statements of memorandums) through an analysis of 483 memorandums. Describes a taxonomy which classifies a subject line as either neutral (introducing a topic without revealing the writer's intention) or directed (revealing intention). Argues that the taxonomy…

  6. 37 CFR 11.53 - Proposed findings and conclusions; post-hearing memorandum.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... conclusions; post-hearing memorandum. 11.53 Section 11.53 Patents, Trademarks, and Copyrights UNITED STATES..., Investigations, and Proceedings § 11.53 Proposed findings and conclusions; post-hearing memorandum. Except in... proposed findings and conclusions and a post-hearing memorandum in support of the proposed findings and...

  7. 37 CFR 11.53 - Proposed findings and conclusions; post-hearing memorandum.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... conclusions; post-hearing memorandum. 11.53 Section 11.53 Patents, Trademarks, and Copyrights UNITED STATES..., Investigations, and Proceedings § 11.53 Proposed findings and conclusions; post-hearing memorandum. Except in... proposed findings and conclusions and a post-hearing memorandum in support of the proposed findings and...

  8. 37 CFR 11.53 - Proposed findings and conclusions; post-hearing memorandum.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... conclusions; post-hearing memorandum. 11.53 Section 11.53 Patents, Trademarks, and Copyrights UNITED STATES..., Investigations, and Proceedings § 11.53 Proposed findings and conclusions; post-hearing memorandum. Except in... proposed findings and conclusions and a post-hearing memorandum in support of the proposed findings and...

  9. 37 CFR 11.53 - Proposed findings and conclusions; post-hearing memorandum.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... conclusions; post-hearing memorandum. 11.53 Section 11.53 Patents, Trademarks, and Copyrights UNITED STATES..., Investigations, and Proceedings § 11.53 Proposed findings and conclusions; post-hearing memorandum. Except in... proposed findings and conclusions and a post-hearing memorandum in support of the proposed findings and...

  10. 37 CFR 11.53 - Proposed findings and conclusions; post-hearing memorandum.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... conclusions; post-hearing memorandum. 11.53 Section 11.53 Patents, Trademarks, and Copyrights UNITED STATES..., Investigations, and Proceedings § 11.53 Proposed findings and conclusions; post-hearing memorandum. Except in... proposed findings and conclusions and a post-hearing memorandum in support of the proposed findings and...

  11. 46 CFR 502.182 - Complaint and memorandum of facts and arguments and filing fee.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 9 2010-10-01 2010-10-01 false Complaint and memorandum of facts and arguments and... PROVISIONS RULES OF PRACTICE AND PROCEDURE Shortened Procedure § 502.182 Complaint and memorandum of facts... attached a memorandum of the facts, subscribed and verified according to § 502.112, and of...

  12. 46 CFR 502.182 - Complaint and memorandum of facts and arguments and filing fee.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 9 2011-10-01 2011-10-01 false Complaint and memorandum of facts and arguments and... PROVISIONS RULES OF PRACTICE AND PROCEDURE Shortened Procedure § 502.182 Complaint and memorandum of facts... attached a memorandum of the facts, subscribed and verified according to § 502.112, and of...

  13. 20 CFR 662.300 - What is the Memorandum of Understanding (MOU)?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 20 Employees' Benefits 4 2014-04-01 2014-04-01 false What is the Memorandum of Understanding (MOU)? 662.300 Section 662.300 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION, DEPARTMENT OF... Memorandum of Understanding for the One-Stop Delivery System § 662.300 What is the Memorandum...

  14. Chronic traumatic encephalopathy.

    PubMed

    Yi, Juneyoung; Padalino, David J; Chin, Lawrence S; Montenegro, Philip; Cantu, Robert C

    2013-01-01

    Sports-related concussion has gained increased prominence, in part due to media coverage of several well-known athletes who have died from consequences of chronic traumatic encephalopathy (CTE). CTE was first described by Martland in 1928 as a syndrome seen in boxers who had experienced significant head trauma from repeated blows. The classic symptoms of impaired cognition, mood, behavior, and motor skills also have been reported in professional football players, and in 2005, the histopathological findings of CTE were first reported in a former National Football League (NFL) player. These finding were similar to Alzheimer's disease in some ways but differed in critical areas such as a predominance of tau protein deposition over amyloid. The pathophysiology is still unknown but involves a history of repeated concussive and subconcussive blows and then a lag period before CTE symptoms become evident. The involvement of excitotoxic amino acids and abnormal microglial activation remain speculative. Early identification and prevention of this disease by reducing repeated blows to the head has become a critical focus of current research.

  15. Canine congenital portosystemic encephalopathy.

    PubMed

    Maddison, J E

    1988-08-01

    The case records of 21 dogs with congenital portosystemic encephalopathy are reviewed. The disorder was most common in Australian cattledogs (blue heelers; 8 cases), Old English sheepdogs (3 cases) and Maltese terriers (3 cases). Extra-hepatic shunts occurred in small breeds, with the exception of 1 cattledog, while intra-hepatic shunts occurred in the medium to large breeds. The most common clinical pathology abnormalities were abnormal ammonia tolerance, mild to moderate increases in plasma alanine aminotransferase or alkaline phosphatase concentrations, decreased total serum protein concentrations, increased fasting ammonia concentrations and ammonium biurate crystalluria. Radiological examination revealed that all the dogs had a small liver. The kidneys were enlarged in 5 of 10 dogs in which kidney size could be estimated. Surgical ligation of an extra-hepatic shunt was successful in 2 of 4 dogs in which it was attempted. Medical management resulted in alleviation of clinical signs in 5 of 8 dogs. The period of successful treatment ranged from a few months to over a year.

  16. Transmissible encephalopathies in animals.

    PubMed Central

    Kimberlin, R H

    1990-01-01

    Scrapie in sheep and goats is the best known of the transmissible encephalopathies of animals. The combination of maternal transmission of infection and long incubation periods effectively maintains the infection in flocks. A single sheep gene (Sip) controls both experimental and natural scrapie and the discovery of allelic markers could enable the use of sire selection in the control of the natural disease. Studies of experimental rodent scrapie show that neuroinvasion occurs by spread of infection from visceral lymphoreticular tissues along nerve fibers to mid-thoracic cord. The slowness of scrapie is due to restrictions on replication and cell-to-cell spread of infection affecting neuroinvasion and subsequent neuropathogenesis. Probably both stages in mice are controlled by Sinc gene, the murine equivalent of Sip. The glycoprotein PrP may be the normal product of Sinc gene. Posttranslationally modified PrP forms the disease specific "scrapie associated fibrils" and may also be a constituent of the infectious agent. Scrapie-like diseases have been reported in mink and several species of ruminants including cattle. All of them may be caused by the recycling of scrapie infected sheep material in animal feed. The human health implications are discussed. PMID:2407328

  17. Sepsis-associated encephalopathy.

    PubMed

    Gofton, Teneille E; Young, G Bryan

    2012-10-01

    Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction that occurs secondary to infection in the body without overt CNS infection. SAE is frequently encountered in critically ill patients in intensive care units, and in up to 70% of patients with severe systemic infection. The severity of SAE can range from mild delirium to deep coma. Seizures and myoclonus are infrequent and cranial nerves are almost always spared, but most severe cases have an associated critical illness neuromyopathy. Development of SAE probably involves a number of mechanisms that are not mutually exclusive and vary from patient to patient. Substantial neurological and psychological morbidities often occur in survivors. Mortality is almost always due to multiorgan failure rather than neurological complications, and is almost 70% in patients with severe SAE. Further research into the pathophysiology, management and prevention of SAE is needed. This Review discusses the epidemiology and clinical presentation of SAE. Recent evidence for SAE pathophysiology is outlined and a diagnostic approach to patients with this syndrome is presented. Lastly, prognosis and management of SAE is discussed.

  18. Sepsis Associated Encephalopathy.

    PubMed

    Chaudhry, Neera; Duggal, Ashish Kumar

    2014-01-01

    Sepsis associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis. It is characterized by diffuse brain dysfunction secondary to infection elsewhere in the body without overt CNS infection. The pathophysiology of SAE is complex and multifactorial including a number of intertwined mechanisms such as vascular damage, endothelial activation, breakdown of the blood brain barrier, altered brain signaling, brain inflammation, and apoptosis. Clinical presentation of SAE may range from mild symptoms such as malaise and concentration deficits to deep coma. The evaluation of cognitive dysfunction is made difficult by the absence of any specific investigations or biomarkers and the common use of sedation in critically ill patients. SAE thus remains diagnosis of exclusion which can only be made after ruling out other causes of altered mentation in a febrile, critically ill patient by appropriate investigations. In spite of high mortality rate, management of SAE is limited to treatment of the underlying infection and symptomatic treatment for delirium and seizures. It is important to be aware of this condition because SAE may present in early stages of sepsis, even before the diagnostic criteria for sepsis can be met. This review discusses the diagnostic approach to patients with SAE along with its epidemiology, pathophysiology, clinical presentation, and differential diagnosis.

  19. Sepsis-associated encephalopathy.

    PubMed

    Cotena, Simona; Piazza, Ornella

    2012-01-01

    Sepsis-associated encephalopathy (SAE) is defined as a diffuse or multifocal cerebral dysfunction induced by the systemic response to the infection without clinical or laboratory evidence of direct brain infection. Its pathogenesis is multifactorial. SAE generally occurs early during severe sepsis and precedes multiple-organ failure. The most common clinical feature of SAE is the consciousness alteration which ranges from mildly reduced awareness to unresponsiveness and coma. Diagnosis of SAE is primarily clinical and depends on the exclusion of other possible causes of brain deterioration. Electroencephalography (EEG) is almost sensitive, but it is not specific for SAE. Computed Tomography (CT) head scan generally is negative in case of SAE, while Magnetic Resonance Imaging (MRI) can show brain abnormalities in case of SAE, but they are not specific for this condition. Somatosensitive Evoked Potentials (SEPs) are sensitive markers of developing cerebral dysfunction in sepsis. Cerebrospinal fluid (CBF) analysis is generally normal, a part an inconstant elevation of proteins concentration. S100B and NSE have been proposed like biomarkers for diagnosis of SAE, but the existing data are controversial. SAE is reversible even if survivors of severe sepsis have often long lasting or irreversible cognitive and behavioral sequel; however the presence of SAE can have a negative influence on survival. A specific therapy of SAE does not exist and the outcome depends on a prompt and appropriate treatment of sepsis as whole.

  20. Sepsis Associated Encephalopathy

    PubMed Central

    Chaudhry, Neera; Duggal, Ashish Kumar

    2014-01-01

    Sepsis associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis. It is characterized by diffuse brain dysfunction secondary to infection elsewhere in the body without overt CNS infection. The pathophysiology of SAE is complex and multifactorial including a number of intertwined mechanisms such as vascular damage, endothelial activation, breakdown of the blood brain barrier, altered brain signaling, brain inflammation, and apoptosis. Clinical presentation of SAE may range from mild symptoms such as malaise and concentration deficits to deep coma. The evaluation of cognitive dysfunction is made difficult by the absence of any specific investigations or biomarkers and the common use of sedation in critically ill patients. SAE thus remains diagnosis of exclusion which can only be made after ruling out other causes of altered mentation in a febrile, critically ill patient by appropriate investigations. In spite of high mortality rate, management of SAE is limited to treatment of the underlying infection and symptomatic treatment for delirium and seizures. It is important to be aware of this condition because SAE may present in early stages of sepsis, even before the diagnostic criteria for sepsis can be met. This review discusses the diagnostic approach to patients with SAE along with its epidemiology, pathophysiology, clinical presentation, and differential diagnosis. PMID:26556425

  1. CT and MRI findings of cyclosporine-related encephalopathy and hypertensive encephalopathy.

    PubMed

    Yamamoto, Akira; Hayakawa, Katsumi; Houjyou, Makoto

    2002-05-01

    We present the MRI and CT findings of one child with cyclosporine-related encephalopathy, and one child with hypertensive encephalopathy following cyclosporine-related encephalopathy. The imaging findings were shown well on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MR images. Cyclosporine-related encephalopathy was distributed predominantly in the posterior white matter. Hypertensive encephalopathy showed similar changes of CT attenuation, but with wider distribution. These two disorders seem to have the same pathogenesis.

  2. Sepsis associated encephalopathy (SAE): a review.

    PubMed

    Green, Rebecca; Scott, L Keith; Minagar, Alireza; Conrad, Steven

    2004-05-01

    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.

  3. [Risk factors for preterm encephalopathy].

    PubMed

    Kornacka, Maria K; Bokiniec, Renata; Bargiel, Agata

    2009-08-01

    Encephalopathy in a common neonatological sense is a term referring to a complex of clinical symptoms occurring in term infants in the first days of their life as a result of hypoxic-ischemic lesions. However, if we accept the encyclopedic definition of encephalopathy as a vast or multifocal brain lesions caused by a variety of factors, we may use the term to describe all patients with traumatic, hypoxic or toxic brain lesions, and therefore also newborns at different levels of maturity. Contrary to term newborns, in which case the hypoxic-ischemic encephalopathy are mostly intrauterine, for preterm infants there is a number of factors which destroy neural tissue postnatally The occurrence of those factors is often influenced by elements of essential intensive care. The article describes the most common biochemical disturbances and clinical causes.

  4. Electroencephalography of autoimmune limbic encephalopathy.

    PubMed

    Kaplan, Peter W; Sutter, Raoul

    2013-10-01

    There is an increasing recognition of autoimmune limbic encephalopathy with the hope for earlier diagnosis and expedited and improved treatment. Although antibody testing remains the definitive clinical diagnostic feature, the presentation of a rapid dementia, behavioral changes, and seizures leads to investigation using cerebral imaging, electroencephalography, and cerebrospinal fluid to confirm the diagnosis and also to exclude similar disorders. The electroencephalographer may be asked to comment on the types of electroencephalography abnormality and provide input toward the diagnosis of limbic encephalopathy. This article reviews the literature on limbic paraneoplastic and nonparaneoplastic encephalopathies, providing descriptions and examples of the electroencephalography findings. Typically, there are patterns of slow theta and delta activity and different patterns of temporal and frontal epileptic activity.

  5. Parent Experience of Neonatal Encephalopathy.

    PubMed

    Lemmon, Monica E; Donohue, Pamela K; Parkinson, Charlamaine; Northington, Frances J; Boss, Renee D

    2017-03-01

    We aimed to characterize the parent experience of caring for an infant with neonatal encephalopathy. In this mixed-methods study, we performed semistructured interviews with parents whose infants were enrolled in an existing longitudinal cohort study of therapeutic hypothermia between 2011 and 2014. Thematic saturation was achieved after 20 interviews. Parent experience of caring for a child with neonatal encephalopathy was characterized by 3 principal themes. Theme 1: Many families described cumulative loss and grief throughout the perinatal crisis, critical neonatal course, and subsequent missed developmental milestones. Theme 2: Families experienced entangled infant and broader family interests. Theme 3: Parents evolved into and found meaning in their role as an advocate. These data offer insight into the lived experience of parenting an infant with neonatal encephalopathy. Primary data from parents can serve as a useful framework to guide the development and interpretation of parent-centered outcomes.

  6. GNAO1 encephalopathy

    PubMed Central

    Danti, Federica Rachele; Galosi, Serena; Romani, Marta; Montomoli, Martino; Carss, Keren J.; Raymond, F. Lucy; Parrini, Elena; Bianchini, Claudia; McShane, Tony; Dale, Russell C.; Mohammad, Shekeeb S.; Shah, Ubaid; Mahant, Neil; Ng, Joanne; McTague, Amy; Samanta, Rajib; Vadlamani, Gayatri; Valente, Enza Maria; Leuzzi, Vincenzo; Kurian, Manju A.

    2017-01-01

    Objective: To describe better the motor phenotype, molecular genetic features, and clinical course of GNAO1-related disease. Methods: We reviewed clinical information, video recordings, and neuroimaging of a newly identified cohort of 7 patients with de novo missense and splice site GNAO1 mutations, detected by next-generation sequencing techniques. Results: Patients first presented in early childhood (median age of presentation 10 months, range 0–48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16. Conclusions: Our findings support the causative role of GNAO1 mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia. PMID:28357411

  7. Inflammation in Epileptic Encephalopathies.

    PubMed

    Shandra, Oleksii; Moshé, Solomon L; Galanopoulou, Aristea S

    2017-01-01

    West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12%-15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate proinflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review, we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of WS? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation? © 2017 Elsevier Inc. All rights reserved.

  8. 7 CFR 28.58 - New memorandum or certificate; issuance.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... CONTAINER REGULATIONS COTTON CLASSING, TESTING, AND STANDARDS Regulations Under the United States Cotton... 7 Agriculture 2 2010-01-01 2010-01-01 false New memorandum or certificate; issuance. 28.58 Section 28.58 Agriculture Regulations of the Department of Agriculture AGRICULTURAL MARKETING...

  9. Final Department of Defense - State Memorandum of Agreement (DSMOA)

    EPA Pesticide Factsheets

    This page contains the final version of the model Department of Defense - State Memorandum of Agreement (DSMOA), developed by the Association of State and Territorial Solid Waste Management Officials (ASTSWMO) and the Department of Defense (DoD) with assistance from representatives of the National Association of Attorneys General (NAAG) and the National Governors' Association (NGA).

  10. 12 CFR 220.5 - Special memorandum account.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... memorandum account (SMA) may be maintained in conjunction with a margin account. A single entry amount may be used to represent both a credit to the SMA and a debit to the margin account. A transfer between the... from the SMA reduces the single entry amount. (b) The SMA may contain the following entries:...

  11. 12 CFR 220.5 - Special memorandum account.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... memorandum account (SMA) may be maintained in conjunction with a margin account. A single entry amount may be used to represent both a credit to the SMA and a debit to the margin account. A transfer between the... from the SMA reduces the single entry amount. (b) The SMA may contain the following entries:...

  12. Transportation Requirements for Improved Racial Balance. Research Memorandum No. 6.

    ERIC Educational Resources Information Center

    Ross, Howard R.; Moon, Albert E.

    This memorandum presents the costs of transporting students to achieve racial balance in the San Francisco public schools. The costs of a district owned school bus system are analyzed for a four year implementation period. Costs of different sizes and types of buses and of major operating requirements (including parking, buildings, staff, and…

  13. 48 CFR 315.372 - Preparation of negotiation memorandum.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false Preparation of negotiation... CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Source Selection 315.372 Preparation of... discussed in FAR 15.308. The memorandum also satisfies the requirement for preparation of a...

  14. 48 CFR 315.372 - Preparation of negotiation memorandum.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false Preparation of negotiation... CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Source Selection 315.372 Preparation of... discussed in FAR 15.308. The memorandum also satisfies the requirement for preparation of a...

  15. 48 CFR 315.372 - Preparation of negotiation memorandum.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false Preparation of negotiation... CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Source Selection 315.372 Preparation of... discussed in FAR 15.308. The memorandum also satisfies the requirement for preparation of a...

  16. 48 CFR 6101.11 - Conferences; conference memorandum [Rule 11].

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 7 2010-10-01 2010-10-01 false Conferences; conference memorandum . 6101.11 Section 6101.11 Federal Acquisition Regulations System CIVILIAN BOARD OF CONTRACT APPEALS, GENERAL SERVICES ADMINISTRATION CONTRACT DISPUTE CASES 6101.11 Conferences; conference...

  17. Degrees Conferred: 2000-01 Update. Informational Memorandum.

    ERIC Educational Resources Information Center

    Wisconsin Univ. System, Madison. Office of Policy Analysis and Research.

    This memorandum contains facts about degrees conferred by institutions in the University of Wisconsin (UW) System in 2000-2001. Overall, the UW System conferred 28,217 degrees in 2000-2001. Of these, 969 were Associate Degrees, and 20,927 were Bachelors Degrees. There were 4,952 Masters Degrees, and 759 Doctoral Degrees, with 610 professional…

  18. Michigan Community College Virtual Learning Collaborative Memorandum of Understanding.

    ERIC Educational Resources Information Center

    Michigan Community Coll. Association, Lansing.

    This memorandum of understanding was written to establish the general framework for collaboration among Michigan community colleges in support of technology-mediated courses. It also serves as a formal consortium agreement among member colleges so that students can receive financial assistance while enrolled in courses offered through the Michigan…

  19. FY2015 Analysis of the Teamwork USA Program. Memorandum

    ERIC Educational Resources Information Center

    Howard, Mark

    2015-01-01

    The Department of Research and Evaluation (DRE) has completed an analysis of the performance of students who participated in the Teamwork USA Program, administered in FY2014 at three District schools. Teamwork USA hopes to improve student achievement at select Title I elementary schools via its Instrumental Music Program grant. This memorandum to…

  20. Memorandum of Understanding (MOU) with National Association of Manufacturers

    SciTech Connect

    2007-06-01

    This Memorandum of Understanding (MOU) lays out the working agreement between the National Association of Manufacturers and EERE. The intent of the MOU is to support a variety of activities assisting manufacturing facilities to initiate and implement an energy management program, adopt clean energy and efficiency technologies, and to achieve continual efficiency improvements and intensity reductions.

  1. Laboratory techniques for rapid diagnosis of viral infections: a Memorandum*

    PubMed Central

    1977-01-01

    This Memorandum evaluates rapid laboratory techniques for the diagnosis of viral infections, especially with a view to their use in developing countries. These techniques comprise the detection of viral antigens by immunofluorescence and immunoperoxidase techniques and methods of viral antibody and antigen determination by the enzyme immunoassay technique. A number of general and specific recommendations are made. PMID:330016

  2. Protein and energy requirements: a joint FAO/WHO Memorandum*

    PubMed Central

    1979-01-01

    Since the publication in 1973 of the report of a Joint FAO/WHO Ad Hoc Expert Committee on protein and energy requirements, some investigations have indicated that the safe levels of protein intake recommended in that report may be too low. This Memorandum reviews the current situation and makes further recommendations where necessary. PMID:311713

  3. Memorandums, Interoffice Communication. Student's Manual and Instructor's Manual.

    ERIC Educational Resources Information Center

    Snapp, Jane

    Supporting performance objective 84 of the V-TECS (Vocational-Technical Education Consortium of States) Secretarial Catalog, both a set of student materials and an instructor's manual on typing memorandums are included in this packet. (The packet is the third in a set of fifteen on typewriting--CE 016 920-934.) The student materials include a…

  4. Emerging infectious diseases: memorandum from a WHO meeting.

    PubMed Central

    1994-01-01

    A meeting of international experts exchanged information on recent activities dealing with new, emerging and re-emerging diseases, discussed ways of responding to this problem and to other communicable disease threats, and reviewed WHO's activities and role in this area. This Memorandum summarizes the various presentations and concludes with the recommendations and specific tasks for action at every level. PMID:7867129

  5. Emerging infectious diseases: Memorandum from a WHO meeting*

    PubMed Central

    1998-01-01

    A meeting of international experts exchanged information on recent activities dealing with new, emerging and re-emerging diseases, discussed ways of responding to this problem and to other communicable disease threats, and reviewed WHO's activities and role in this area. This Memorandum summarizes the various presentations and concludes with the recommendations and specific tasks for action at every level.

  6. Columbia Estuary Ecosystem Restoration Program. 2012 Synthesis Memorandum

    DTIC Science & Technology

    2013-01-01

    contribution of estuarine habitats to adult returns and population viability. Continued estuary monitoring is needed to more fully characterize ...U.S. Geological Survey   xv Contents Executive Summary...Process ........................................................ 1.3  1.2  Memorandum Contents and Organization

  7. 48 CFR 315.372 - Preparation of negotiation memorandum.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... factors, such as— (1) A comparison of cost factors proposed for the current requirement with actual... of current cost or pricing data. (5) Other required special approvals. (6) If the contract represents... discussed in FAR 15.308. The memorandum also satisfies the requirement for preparation of a...

  8. 40 CFR 281.24 - Memorandum of agreement.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 26 2010-07-01 2010-07-01 false Memorandum of agreement. 281.24 Section 281.24 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) APPROVAL OF STATE UNDERGROUND STORAGE TANK PROGRAMS Components of a Program Application § 281.24...

  9. Reduction-in-Force (RIF). A Legal Memorandum.

    ERIC Educational Resources Information Center

    Zirkel, Perry A.; Bargerstock, Charles T.

    This legal memorandum provides an overview of the growing body of legislation and litigation concerning reduction in force (RIF). The focus of the article is the suspension or dismissal of teachers for reasons unrelated to their competence or behavior. Cases concerning other professional personnel such as principals, or other staffing strategies…

  10. Transportation Requirements for Improved Racial Balance. Research Memorandum No. 6.

    ERIC Educational Resources Information Center

    Ross, Howard R.; Moon, Albert E.

    This memorandum presents the costs of transporting students to achieve racial balance in the San Francisco public schools. The costs of a district owned school bus system are analyzed for a four year implementation period. Costs of different sizes and types of buses and of major operating requirements (including parking, buildings, staff, and…

  11. Melanoma-Associated Spongiform Scleropathy in Oculodermal Melanocytosis with Primary Orbital Melanoma

    PubMed Central

    Ranjit, Roshni U.; Leyngold, Ilya M.; Margo, Curtis E.

    2016-01-01

    Purpose To describe spongiform scleropathy in a patient with oculodermal melanosis and without evidence of uveal melanoma. Methods Clinical-pathological correlation conducted in compliance with HIPPA (Health Insurance Privacy and Portability Act) regulations. Results Melanoma-associated spongiform scleropathy was an incidental finding in an 87-year-old woman with oculodermal melanocytosis treated for primary orbital melanoma. All previously reported cases of this scleropathy have been associated with uveal melanoma. Conclusions The mechanism of scleral degeneration in melanoma-associated spongiform scleropathy is unknown, and its clinical and prognostic significance is speculative. This is the first case of a so-called melanoma-associated spongiform scleropathy reported in an eye without uveal melanoma. PMID:27843909

  12. Intravenous Heroin-Associated Delayed Spongiform Leukoencephalopathy: Case Report and Reviews of the Literature.

    PubMed

    Pirompanich, Pattarin; Chankrachang, Siwaporn

    2015-07-01

    Heroin-associated spongiform leukoencephalopathy is a rare, and sometimes fatal, condition usually caused by vapor inhalation of heroin. The authors report a 41-year-old man who was diagnosed with delayed spongiform leukoencephalopathy three weeks after injecting heroin intravenously. He had been admitted to another hospital due to acute heroin overdose, which had occurred four hours after intravenous injection of an unknown amount of heroin. His clinical condition showed progressive improvement and he was discharged 12 days after admission. Three weeks after this episode, his cognitive functioning declined. Akinetic mutism, spasticity and hyperreflexia of all extremities were observed. Electroencephalography (EEG) and imaging of the brain showed typical characteristics of spongiform leukoencephalopathy. The three and six-month follow-up of the patient showed clinical improvement and this was corroborated through EEG measures and brain imaging. The discussion summarizes eight previously reported cases of intravenous heroin associated spongiform leukoencephalopathy and compares them to the authors'case.

  13. Prussian blue caged in spongiform adsorbents using diatomite and carbon nanotubes for elimination of cesium.

    PubMed

    Hu, Baiyang; Fugetsu, Bunshi; Yu, Hongwen; Abe, Yoshiteru

    2012-05-30

    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. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Hashimoto's encephalopathy cases: Chinese experience.

    PubMed

    Tang, Yi; Xing, Yi; Lin, Michael T; Zhang, Jin; Jia, Jianping

    2012-07-24

    Hashimoto's encephalopathy is a poorly understood syndrome consisting of heterogeneous neurological symptoms and high serum antithyroid antibody titers, typically responding to steroids. More clinical series studies are required to characterize the clinical, laboratory and imaging features, and outcomes, especially in the Chinese population. We analyzed the clinical, laboratory, and imaging features and outcomes of thirteen consecutive patients with Hashimoto's encephalopathy diagnosed in Xuan Wu Hospital, Beijing from 2005 to 2010 retrospectively. Cognitive impairment (84.6%) and psychiatric symptoms (38.5%) were the most frequent symptoms. Seizures (30.8%) and myoclonus (7.7%) were less common than previously described. Three (23.1%) patients showed abnormal signals in hippocampus or temporal lobe, which were believed related to their memory disorders or seizures. MRI changes showed resolution paralleling clinical improvement in one patient. Among eight patients who received steroid therapy, five patients recovered, one patient improved with residual deficits, and two patients relapsed or had no effect. Among five non-steroid treated patients, three patients experienced stable remission with antiepileptic drugs or general neurotrophic therapy, and two patients experienced continuous deterioration. Most patients with Hashimoto's encephalopathy showed good response to steroids. Some patients improved without steroid therapy. Considering its reversible course, we recommend that Hashimoto's encephalopathy should always be in the differential diagnosis while evaluating disorders of the central nervous system.

  15. 9 CFR 96.2 - Prohibition of casings due to African swine fever and bovine spongiform encephalopathy.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... the casings are derived from the small intestine, the casings are derived from that part of the small intestine that is eligible for use as human food in accordance with the requirements established by the Food...

  16. 9 CFR 96.2 - Prohibition of casings due to African swine fever and bovine spongiform encephalopathy.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... the casings are derived from the small intestine, the casings are derived from that part of the small intestine that is eligible for use as human food in accordance with the requirements established by the Food...

  17. 9 CFR 96.2 - Prohibition of casings due to African swine fever and bovine spongiform encephalopathy.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... the casings are derived from the small intestine, the casings are derived from that part of the small intestine that is eligible for use as human food in accordance with the requirements established by the Food..., the casings are not derived from the small intestine or, if the casings are derived from the small...

  18. 9 CFR 96.2 - Prohibition of casings due to African swine fever and bovine spongiform encephalopathy.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... the casings are derived from the small intestine, the casings are derived from that part of the small intestine that is eligible for use as human food in accordance with the requirements established by the Food...

  19. 9 CFR 96.2 - Prohibition of casings due to African swine fever and bovine spongiform encephalopathy.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... the casings are derived from the small intestine, the casings are derived from that part of the small intestine that is eligible for use as human food in accordance with the requirements established by the Food...

  20. Altered expression of CRMPs in the brain of bovine spongiform encephalopathy-infected mice during disease progression.

    PubMed

    Auvergnon, Nathalie; Reibel, Sophie; Touret, Monique; Honnorat, Jérôme; Baron, Thierry; Giraudon, Pascale; Bencsik, Anna

    2009-03-19

    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.

  1. A quantitative assessment of the risk of transmission of bovine spongiform encephalopathy by tallow-based calf milk-replacer.

    PubMed

    Paisley, Larry G; Hostrup-Pedersen, Julie

    2004-04-30

    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.

  2. Kangaroo rats exhibit spongiform degeneration of the central auditory system similar to that found in gerbils.

    PubMed

    McGinn, M D; Faddis, B T

    1997-02-01

    Kangaroo rats develop spongiform degeneration of the central auditory system similar to that seen in the gerbil. Light microscopic and transmission electron microscopic study of the cochlear nucleus and auditory nerve root (ANR) of Dipodomys deserti and D. merriami show that spongiform lesions develop in dendrites and oligodendrocytes of the cochlear nucleus and in oligodendrocytes of the ANR that are morphologically indistinguishable from those extensively described in the Mongolian gerbil, Meriones unguiculatus. As in Mongolian gerbils, the spongiform degeneration in Dipodomys were much more numerous in animals continually exposed to modest levels of low-frequency noise (< 75 dB SPL). The kangaroo rats with extensive spongiform degeneration also show slightly, but significantly, elevated auditory brainstem evoked response (ABR) thresholds to low-frequency stimuli, a result also found in Mongolian gerbils. These results suggest that the elevated ABR thresholds may be the result of spongiform degeneration. Because low-frequency noise-induced spongiform degeneration has now been shown in the cochlear nucleus of animals from separate families of Rodentia (Heteromyidae and Muridae), the possibility should be investigated that similar noise-induced degenerative changes occur in the central auditory system of other mammals with good low-frequency hearing.

  3. Genetics Home Reference: STXBP1 encephalopathy with epilepsy

    MedlinePlus

    ... Conditions STXBP1 encephalopathy with epilepsy STXBP1 encephalopathy with epilepsy Printable PDF Open All Close All Enable Javascript ... the expand/collapse boxes. Description STXBP1 encephalopathy with epilepsy is a condition characterized by recurrent seizures (epilepsy), ...

  4. Exercise Desert Rock, Staff Memorandums. Army, Camp Desert Rock, Nevada.

    DTIC Science & Technology

    1957-01-01

    I AD-AGAG 257 EXERCISE DESERT ROCK LAS VEGAS NV F/6 IS/ 3 EXERCISE DESERT ROCK, STAFF MEMORANDUMS. ARMY. CAMP DESERT ROCK-ETClUlCASIFE mm95i mm... Exercise Safety Progra - . 1. PUrose: To establish ane’ffective safety progr.Rm toreduce, and keep to a minimum, accident,1 manpower and monetary losses. at...agencies will be- followed. Supervispry personnel will: become familiar with those that Pre applicable to thei£r... operations. The Exercise Safety

  5. AGU signs memorandum of agreement with Asia Oceania Geosciences Society

    NASA Astrophysics Data System (ADS)

    McEntee, Chris

    2012-03-01

    AGU has taken the latest step in building strategic alliances with partner groups by signing a memorandum of agreement with the Asia Oceania Geosciences Society (AOGS). This agreement is based on the common interests of our members and will allow us to strengthen our respective organizations by - exchanging information on key programs and initiatives; - expanding membership of both our organizations through possible joint programs; - offering additional educational opportunities, professional services, and student programs; and - extending benefits to members of both organizations.

  6. Destruction of variola virus: memorandum from a WHO meeting.

    PubMed Central

    1994-01-01

    This Memorandum discusses the fate of variola virus stocks which have been kept in two WHO Collaborating Centres, as well as cloned DNA fragments of variola virus genome, smallpox vaccine, and seed vaccinia virus for the production of this vaccine. General and specific recommendations are given concerning destruction of variola virus; storage, distribution and handling of cloned DNA fragments of variola virus genome; and about stocks of smallpox vaccine. PMID:7867128

  7. Trends in Enrollment: Fall 2002 Update. Informational Memorandum.

    ERIC Educational Resources Information Center

    Wisconsin Univ. System, Madison. Office of Policy Analysis and Research.

    This memorandum contains tables of data about enrollment in institutions in the University of Wisconsin (UW) System in fall 2001 and some information about trends over time. The fall 2002 full-time equivalent (FTE) enrollment was 135,653, up 1,952 (1.5%) from fall 2001. The fall 2002 headcount enrollment was 160,635, up 1,202 (0.8%) from fall…

  8. Trends in Enrollment: Fall 2001 Update. Informational Memorandum.

    ERIC Educational Resources Information Center

    Wisconsin Univ. System, Madison. Office of Policy Analysis and Research.

    This memorandum contains tables of data about enrollment in institutions in University of Wisconsin (UW) System institutions in fall 2001 and some information about trends over time. The fall 2001 full-time equivalent (FTE) enrollment of 133,701 was up 2,316 (1.8%) from fall 2000. The fall 2001 headcount enrollment of 159,433 was up 2,457 (1.6%)…

  9. Student Financial Aid: 2000-01 Update. Informational Memorandum.

    ERIC Educational Resources Information Center

    Wisconsin Univ. System, Madison. Office of Policy Analysis and Research.

    This memorandum provides information about students granted financial aid in the University of Wisconsin (UW) system in 2000-2001 and earlier years. The total financial aid provided UW students was $497.8 million, up $29.8 million from 1999-2000. Total loan dollars for UW students were up $17.5 million from 1999-2000 to $340.3 million. Total grant…

  10. Student Financial Aid: 2001-02 Update. Informational Memorandum.

    ERIC Educational Resources Information Center

    Wisconsin Univ. System, Madison. Office of Policy Analysis and Research.

    This memorandum provides information about students granted financial aid in the University of Wisconsin (UW) system in 2001-2002 and earlier years. The total financial aid provided to UW students was $550.0 million, up $52.2 million from 2000-2001. Total loan dollars for UW students totaled $371.2 million, up $30.9 million from 2000-2001. UW…

  11. Challenges in diagnosing hepatic encephalopathy.

    PubMed

    Weissenborn, K

    2015-02-01

    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.

  12. The posterior reversible encephalopathy syndrome.

    PubMed

    Sanjay, K Mandal; Partha, P Chakraborty

    2008-09-01

    The posterior/potentially reversible encephalopathy syndrome is a unique syndrome encountered commonly in hypertensive encephalopathy. A 13-year-old boy presented with of intermittent high grade fever, throbbing headache and non-projective vomiting for 5 days. The patient had a blood pressure of 120/80 mmHg but fundoscopy documented grade 3 hypertensive retinopathy. The patient improved symptomatically following conservative management. However, on the 5(th) post-admission day headache reappeared, and blood pressure measured at that time was 240/120 mmHg. Neuroimaging suggested white matter abnormalities. Search for the etiology of secondary hypertension led to the diagnosis of pheochromocytoma. Repeated MRI after successful surgical excision of the tumor patient showed reversal of white matter abnormalities. Reversible leucoencephalopathy due to pheochromocytoma have not been documented in literature previously.

  13. [Wernicke encephalopathy accompanying linitis plastica].

    PubMed

    Soós, Zsuzsanna; Salamon, Mónika; Oláh, Roland; Czégeni, Anna; Salamon, Ferenc; Folyovich, András; Winkler, Gábor

    2014-01-05

    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.

  14. Preterm Hypoxic–Ischemic Encephalopathy

    PubMed Central

    Gopagondanahalli, Krishna Revanna; Li, Jingang; Fahey, Michael C.; Hunt, Rod W.; Jenkin, Graham; Miller, Suzanne L.; Malhotra, Atul

    2016-01-01

    Hypoxic–ischemic encephalopathy (HIE) is a recognizable and defined clinical syndrome in term infants that results from a severe or prolonged hypoxic–ischemic episode before or during birth. However, in the preterm infant, defining hypoxic–ischemic injury (HII), its clinical course, monitoring, and outcomes remains complex. Few studies examine preterm HIE, and these are heterogeneous, with variable inclusion criteria and outcomes reported. We examine the available evidence that implies that the incidence of hypoxic–ischemic insult in preterm infants is probably higher than recognized and follows a more complex clinical course, with higher rates of adverse neurological outcomes, compared to term infants. This review aims to elucidate the causes and consequences of preterm hypoxia–ischemia, the subsequent clinical encephalopathy syndrome, diagnostic tools, and outcomes. Finally, we suggest a uniform definition for preterm HIE that may help in identifying infants most at risk of adverse outcomes and amenable to neuroprotective therapies. PMID:27812521

  15. Wernicke's encephalopathy following hyperemesis gravidarum

    PubMed Central

    Kantor, Sandeep; Prakash, Sadanandan; Chandwani, Juhi; Gokhale, Antara; Sarma, Kalpana; Albahrani, Maher J.

    2014-01-01

    Wernicke's encephalopathy (WE) is a potentially reversible yet serious neurological manifestation caused by vitamin B1(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. PMID:24701066

  16. Encephalopathies: the emerging diabetic complications.

    PubMed

    Sima, Anders A F

    2010-12-01

    Diabetic encephalopathies are now accepted complications of diabetes. They appear to differ in type 1 and type 2 diabetes as to underlying mechanisms and the nature of resulting cognitive deficits. The increased incidence of Alzheimer's disease in type 2 diabetes is associated with insulin resistance, hyperinsulinemia and hyperglycemia, and commonly accompanying attributes such as hypercholesterolemia, hypertension and obesity. The relevance of these disorders as to the emergence of dementia and Alzheimer's disease is discussed based on epidemiological studies. The pathobiology of accumulation of β-amyloid and tau the hallmarks of Alzheimer's disease are discussed based on experimental data. Type 1 diabetic encephalopathy is likely to increase as a result of the global increase in the incidence of type 1 diabetes and its occurrence in increasingly younger patients. Alzheimer-like changes and dementia are not prominently increased in type 1 diabetes. Instead, the type 1 diabetic encephalopathy involves learning abilities, intelligence development and memory retrieval resulting in impaired school and professional performances. The major underlying component here appears to be insulin deficiency with downstream effects on the expression of neurotrophic factors, neurotransmitters, oxidative and apoptotic stressors resulting in defects in neuronal integrity, connectivity and loss commonly occurring in the still developing brain. Recent experimental data emphasize the role of impaired central insulin action and provide information as to potential therapies. Therefore, the underlying mechanisms resulting in diabetic encephalopathies are complex and appear to differ between the two types of diabetes. Major headway has been made in our understanding of their pathobiology; however, many questions remain to be clarified. In view of the increasing incidence of both type 1 and type 2 diabetes, intensified investigations are called for to expand our understanding of these

  17. Communication Challenges in Neonatal Encephalopathy.

    PubMed

    Lemmon, Monica E; Donohue, Pamela K; Parkinson, Charlamaine; Northington, Frances J; Boss, Renee D

    2016-09-01

    Families must process complex information related to neonatal encephalopathy and therapeutic hypothermia. In this mixed methods study, semi-structured interviews were performed with parents whose infants were enrolled in an existing longitudinal cohort study of therapeutic hypothermia between 2011 and 2014. Thematic saturation was achieved after 20 interviews. Parental experience of communicating with clinicians was characterized by 3 principle themes. Theme 1 highlighted that a fragmented communication process mirrored the chaotic maternal and neonatal course. Parents often received key information about neonatal encephalopathy and therapeutic hypothermia from maternal clinicians. Infant medical information was often given to 1 family member (60%), who felt burdened by the responsibility to relay that information to others. Families universally valued the role of the bedside nurse, who was perceived as the primary source of communication for most (75%) families. Theme 2 encompassed the challenges of discussing the complex therapy of therapeutic hypothermia: families appreciated clinicians who used lay language and provided written material, and they often felt overwhelmed by technical information that made it hard to understand the "big picture" of their infant's medical course. Theme 3 involved the uncertain prognosis after neonatal encephalopathy. Parents appreciated specific expectations about their infant's long-term development, and experienced long-term distress about prognostic uncertainty. Communicating complex and large volumes of information in the midst of perinatal crisis presents inherent challenges for both clinicians and families. We identified an actionable set of communication challenges that can be addressed with targeted interventions. Copyright © 2016 by the American Academy of Pediatrics.

  18. Metabolic Causes of Epileptic Encephalopathy

    PubMed Central

    Pearl, Phillip L.

    2013-01-01

    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. PMID:23762547

  19. Delegation of Authority Under the Community Environmental Response Facilitation Act (CERFA) - Decision Memorandum

    EPA Pesticide Factsheets

    This memorandum concerns how the Office of Enforcement (OE) proposed that two new authorities under the Community Environmental Response Facilitation Act (CERFA) be delegated to the Regional Administrators.

  20. The Consolidated Human Activity Database — Master Version (CHAD-Master) Technical Memorandum

    EPA Pesticide Factsheets

    This technical memorandum contains information about the Consolidated Human Activity Database -- Master version, including CHAD contents, inventory of variables: Questionnaire files and Event files, CHAD codes, and references.

  1. Delegation of Authority Under the Community Environmental Response Facilitation Act (CERFA) - Decision Memorandum

    EPA Pesticide Factsheets

    This memorandum concerns how the Office of Enforcement (OE) proposed that two new authorities under the Community Environmental Response Facilitation Act (CERFA) be delegated to the Regional Administrators.

  2. Memorandum of the Establishment of Cleanup Levels for CERCLA Sites with Radioactive Contamination

    EPA Pesticide Factsheets

    This memorandum presents clarifying guidance for establishing protective cleanup levels for radioactive contamination at Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA) sites.

  3. Brownfields Green Avenue Sites: Technical Memorandum - Conceptual Design for Sustainable Redevelopment

    EPA Pesticide Factsheets

    This technical memorandum briefly describes the site and proposed conceptual site plan, indicates conceptual design considerations, specifies recommended green and sustainable features, and offers other recommendations

  4. Rifaximin in the treatment of hepatic encephalopathy

    PubMed Central

    Iadevaia, Maddalena Diana; Prete, Anna Del; Cesaro, Claudia; Gaeta, Laura; Zulli, Claudio; Loguercio, Carmelina

    2011-01-01

    Hepatic encephalopathy is a challenging complication in patients with advanced liver disease. It can be defined as a neuropsychiatric syndrome caused by portosystemic venous shunting, ranging from minimal to overt hepatic encephalopathy or coma. Its pathophysiology is still unclear, although increased levels of ammonia play a key role. Diagnosis of hepatic encephalopathy is currently based on specific tests evaluating the neuropsychiatric state of patients and their quality of life; the severity of hepatic encephalopathy is measured by the West Haven criteria. Treatment of hepatic encephalopathy consists of pharmacological and corrective measures, as well as nutritional interventions. Rifaximin received approval for the treatment of hepatic encephalopathy in 2010 because of its few side effects and pharmacological benefits. The aim of this work is to review the use and efficacy of rifaximin both in acute and long-term management of hepatic encephalopathy. Treatment of overt hepatic encephalopathy involves management of the acute episode as well as maintenance of remission in those patients who have previously experienced an episode, in order to improve their quality of life. The positive effect of rifaximin in reducing health care costs is also discussed. PMID:24367227

  5. Diagnostic and prognostic factors for acute encephalopathy.

    PubMed

    Motojima, Yukiko; Nagura, Michiaki; Asano, Yoshitaka; Arakawa, Hiroshi; Takada, Eiko; Sakurai, Yoshio; Moriwaki, Koichi; Tamura, Masanori

    2016-11-01

    Acute encephalopathy has the possibility of sequelae. While early treatment is required to prevent the development of sequelae, differential diagnosis is of the utmost priority. The aim of this study was therefore to identify parameters that can facilitate early diagnosis and prediction of outcome of acute encephalopathy. We reviewed the medical charts of inpatients from 2005 to 2011 and identified 33 patients with febrile status epilepticus. Subjects were classified into an acute encephalopathy group (n = 20) and a febrile convulsion group (n = 13), and the parameters serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), ammonia (NH3 ), cerebrospinal fluid (CSF) tau protein, and CSF interleukin-6 compared between them. Furthermore, the relationship between each parameter and prognosis was investigated in the encephalopathy group. Significant differences in serum AST, ALT, and LDH were observed between the febrile convulsion and acute encephalopathy group. Moreover, a significant difference in serum LDH was noted between the patients with and without developmental regression at the time of hospital discharge in the encephalopathy group. In particular, CSF tau protein was found to be highly likely to indicate progress, with CSF tau protein >1000 pg/dL associated with poor prognosis leading to developmental regression. Serum AST, ALT and LDH may be related to early diagnosis and prognosis, and should be carefully investigated in patients with encephalopathy. CSF tau protein could also be used as an indicator of poor prognosis in acute encephalopathy. © 2016 Japan Pediatric Society.

  6. Hashimoto's encephalopathy in children and adolescents.

    PubMed

    Erol, Ilknur; Saygi, Semra; Alehan, Füsun

    2011-12-01

    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.

  7. Neuronal degeneration in the gerbil brainstem is associated with spongiform lesions.

    PubMed

    McGinn, M D; Faddis, B T

    1998-05-01

    Spongiform lesions arise in dendrites and glia in the brainstem of domestic Mongolian gerbils. Most pronounced within the cochlear nucleus (CN), this disorder is dynamic and progressive; the lesions increase in number, size, and extent with age. It has not been clear whether these spongioid lesions either cause or are associated with significant neural degeneration. In contrast, feral Mongolian gerbils (wild-trapped in Tuva) and their offspring show few spongiform lesions. The Tuvan gerbils provide an appropriate within-species control. We compared degeneration in the brainstem of domestic and Tuvan gerbils using the amino-cupric-silver (ACS) stain of de Olmos et al. [(1994) Neurotoxicol. Teratol., 16:545-561]. Positive histologic controls were provided by cerebellar stab wounds in domestic gerbils and by unilateral kainic acid injections into the CN of Tuvan gerbils. The ACS stain revealed extensive degeneration of axons, terminals, dendrites, and neurons in the brainstem of domestic gerbils. Neurodegeneration was most pronounced in the CN and was coextensive with spongiform lesions. Neurodegeneration was also seen in the trapezoid body, lateral lemniscus, and inferior colliculus, but was less pronounced than in the CN. The cerebellar stab wounds resulted in silver-stained Purkinje cells restricted to the stab wound local region. Kainic acid produced extensive neuronal and spongiform degeneration of the injected CN that was very similar to that spontaneously occurring in domestic gerbils. In contrast, the non-injected CN of Tuvan gerbils showed no neuronal or spongiform degeneration with the ACS stain. We conclude that, in domestic gerbils, the naturally occurring spongiform lesions of the CN and the accompanying neurodegeneration are both results of a common mechanism, most probably excitotoxic.

  8. Development of vaccines against shigellosis: Memorandum from a WHO Meeting*

    PubMed Central

    1987-01-01

    Endemic shigellosis is a worldwide problem, with a high morbidity rate in most developing countries; substantial mortality may also occur, especially with disease caused by Shigella dysenteriae serotype 1. The limited efficacy of current measures to control this infection makes the development of vaccines for the prevention of shigellosis particularly important. This Memorandum describes the clinical features of and immunity to shigellosis, summarizes the present status of efforts to develop suitable vaccines, and lists the topics that should be given priority in research. PMID:3495364

  9. Progress in the rapid diagnosis of viral infections: a Memorandum*

    PubMed Central

    1978-01-01

    This Memorandum reports the progress that has been made over the past year in the development of laboratory techniques for the rapid diagnosis of viral infections. Progress is reported in the use of the immunoperoxidase and immunofluorescence techniques for detecting viruses in respiratory secretions, the use of the glutaraldehyde and periodate methods for peroxidase conjugation, the application of enzyme immunoassay techniques in the detection of viral antigens and antibodies, and training in the use of these techniques. A number of recommendations for further research are made. PMID:352567

  10. Memorandum of Understanding for Hydropower Two-Year Progress Report

    SciTech Connect

    2012-04-01

    On March 24, 2010, the Department of the Army (DOA) through the U.S. Army Corps of Engineers (USACE or Corps), the Department of Energy, and the Department of the Interior signed the Memorandum of Understanding (MOU) for Hydropower. The purpose of the MOU is to “help meet the nation’s needs for reliable, affordable, and environmentally sustainable hydropower by building a long-term working relationship, prioritizing similar goals, and aligning ongoing and future renewable energy development efforts.” This report documents efforts so far.

  11. The EEG of tropical encephalopathies.

    PubMed

    Mallewa, Macpherson; Birbeck, Gretchen L

    2013-10-01

    In addition to encountering most of the conditions treated by clinicians in the West, clinicians in the tropics are faced with unique tropical encephalopathies. These are largely but not entirely infectious in nature. Despite the relatively low cost of EEG technology, it remains unavailable in many low-income tropical settings even at the tertiary care level. Where available, the EEG recordings and interpretation are often of unacceptable quality. Nonetheless, there are existing data on the EEG patterns seen in malaria and a number of tropical viral, bacterial, and parasitic infestations.

  12. [Wernicke encephalopathy in alcoholic patients].

    PubMed

    Chamorro Fernández, A J; Marcos Martín, M; Laso Guzmán, F J

    2011-10-01

    A 67-year old male was brought to the hospital by his family because he had been suffering from somnolence, bradypsychia and gait disturbance for one week. He lived alone, reported an ethanol intake higher than 100-120 g/day. His diet was limited in quality and amount. The physical examination showed stigmata of chronic liver disease. The neurological exam revealed right-side cerebellar tremor, bilateral dysmetria and gait ataxia as well as hyporeflexia in the lower limbs. He was diagnosed of Wernicke encephalopathy. How should this patient be evaluated and treated?

  13. 7 CFR 28.59 - Lost memorandum or certificate may be replaced by duplicate.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... United States Cotton Standards Act Certificates and Memoranda § 28.59 Lost memorandum or certificate may... 7 Agriculture 2 2010-01-01 2010-01-01 false Lost memorandum or certificate may be replaced by duplicate. 28.59 Section 28.59 Agriculture Regulations of the Department of Agriculture...

  14. NNSA Signs Memorandum with Kuwait to Increase Cooperation on Nuclear Safeguards and Nonproliferation

    ScienceCinema

    Thomas D'Agostino

    2016-07-12

    On June 23, 2010, the National Nuclear Security Administration (NNSA) signed a Memorandum of Cooperation on nuclear safeguards and other nonproliferation topics with the Kuwait National Nuclear Energy Committee (KNNEC). NNSA Administrator Thomas D'Agostino and KNNEC's Secretary General, Dr. Ahmad Bishara, signed the memorandum at a ceremony at U.S. Department of Energy headquarters in Washington.

  15. 75 FR 17418 - Memorandum of Understanding Between the Food and Drug Administration, United States Department of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-06

    ... HUMAN SERVICES Food and Drug Administration Memorandum of Understanding Between the Food and Drug... Health AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is providing notice of a memorandum of understanding (MOU) between the Food and...

  16. 76 FR 18754 - Notice of Availability of a Memorandum of Understanding Between the Federal Energy Regulatory...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-05

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF ENERGY Federal Energy Regulatory Commission Notice of Availability of a Memorandum of Understanding Between the Federal... Birds This notice announces the availability of a Memorandum of Understanding (MOU) between the Federal...

  17. 7 CFR Exhibit B to Subpart A of... - Memorandum of Understanding and Blanket Commodity Lien Waiver

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 7 Agriculture 14 2010-01-01 2009-01-01 true Memorandum of Understanding and Blanket Commodity Lien...—Memorandum of Understanding and Blanket Commodity Lien Waiver The Farmers Home Administration or its... without unnecessarily impairing or undermining the respective security interests of FmHA or its successor...

  18. 48 CFR 1415.406-70 - Department of the Interior price negotiation memorandum (PNM).

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... price negotiation memorandum (PNM). 1415.406-70 Section 1415.406-70 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Contract Pricing 1415.406-70 Department of the Interior price negotiation memorandum (PNM). (a) Policy. In...

  19. 48 CFR 1415.406-70 - Department of the Interior price negotiation memorandum (PNM).

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... price negotiation memorandum (PNM). 1415.406-70 Section 1415.406-70 Federal Acquisition Regulations System DEPARTMENT OF THE INTERIOR CONTRACTING METHODS AND CONTRACT TYPES CONTRACTING BY NEGOTIATION Contract Pricing 1415.406-70 Department of the Interior price negotiation memorandum (PNM). (a) Policy. In...

  20. Internal Revenue Service General Counsel's Memorandum threatens tax exemption for charitable hospitals.

    PubMed

    Ball, D W

    1992-01-01

    A recent memorandum from the General Counsel of the Internal Revenue Service changes the standard against which tax exempt entities will be measured, which change can adversely affect charitable hospitals' tax exempt status. In addition, the memorandum makes clear that a violation of the Anti-Kickback statute, discussed in Mr. Aaron's article, is inconsistent with tax exempt status.