Showing papers by "Herbert Budka published in 2011"

Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy

Abstract: Progressive supranuclear palsy (PSP) is a movement disorder with prominent tau neuropathology. Brain diseases with abnormal tau deposits are called tauopathies, the most common of which is Alzheimer's disease. Environmental causes of tauopathies include repetitive head trauma associated with some sports. To identify common genetic variation contributing to risk for tauopathies, we carried out a genome-wide association study of 1,114 individuals with PSP (cases) and 3,247 controls (stage 1) followed by a second stage in which we genotyped 1,051 cases and 3,560 controls for the stage 1 SNPs that yielded P ≤ 10−3. We found significant previously unidentified signals (P < 5 × 10−8) associated with PSP risk at STX6, EIF2AK3 and MOBP. We confirmed two independent variants in MAPT affecting risk for PSP, one of which influences MAPT brain expression. The genes implicated encode proteins for vesicle-membrane fusion at the Golgi-endosomal interface, for the endoplasmic reticulum unfolded protein response and for a myelin structural component.

Scientific Opinion on the public health hazards to be covered by inspection of meat (swine)

Abstract: A qualitative risk assessment identified Salmonella spp., Yersinia enterocolitica, Toxoplasma gondii and Trichinella spp. as the most relevant biological hazards in the context of meat inspection of swine. A comprehensive pork carcass safety assurance is the only way to ensure their effective control. This requires setting targets to be achieved in/on chilled carcasses, which also informs what has to be achieved earlier in the food chain. Improved Food Chain Information (FCI) enables risk-differentiation of pig batches (hazard-related) and abattoirs (process hygiene-related). Risk reduction measures at abattoir level are focused on prevention of microbial contamination through technology- and process hygiene-based measures (GMP/GHP- and HACCP-based), including omitting palpation/incision during post-mortem inspection in routine slaughter, as well as hazard reduction/inactivation meat treatments if necessary. At farm level, risk reduction measures are based on herd health programmes, closed breeding pyramids and GHP/GFP. Chemical substances listed in Council Directive 96/23/EC were ranked into four categories. Dioxins, dioxin-like polychlorinated biphenyls and chloramphenicol were ranked as being of high potential concern. However, chemical substances in pork are unlikely to pose an immediate or short term health risk for consumers. Opportunities for risk-based inspection strategies by means of differentiated sampling plans taking into account FCI were identified. Regular update of sampling programmes and inclusion of inspection criteria for the identification of illicit use of substances were also recommended. Meat inspection is a key component of the overall surveillance system for pig health and welfare but information is currently under-utilised. The changes proposed to the pig meat inspection system will lead to some reduction in the detection probability of diseases and welfare conditions. The difference is likely to be minimal for diseases/conditions that affect several organs. To mitigate the reduced detection probability, palpation and/or incision should be conducted as a follow-up to visual inspection whenever abnormalities are seen

Peroxisomal alterations in Alzheimer's disease

Abstract: In Alzheimer’s disease (AD), lipid alterations are present early during disease progression. As some of these alterations point towards a peroxisomal dysfunction, we investigated peroxisomes in human postmortem brains obtained from the cohort-based, longitudinal Vienna-Transdanube Aging (VITA) study. Based on the neuropathological Braak staging for AD on one hemisphere, the patients were grouped into three cohorts of increasing severity (stages I–II, III–IV, and V–VI, respectively). Lipid analyses of cortical regions from the other hemisphere revealed accumulation of C22:0 and very long-chain fatty acids (VLCFA, C24:0 and C26:0), all substrates for peroxisomal β-oxidation, in cases with stages V–VI pathology compared with those modestly affected (stages I–II). Conversely, the level of plasmalogens, which need intact peroxisomes for their biosynthesis, was decreased in severely affected tissues, in agreement with a peroxisomal dysfunction. In addition, the peroxisomal volume density was increased in the soma of neurons in gyrus frontalis at advanced AD stages. Confocal laser microscopy demonstrated a loss of peroxisomes in neuronal processes with abnormally phosphorylated tau protein, implicating impaired trafficking as the cause of altered peroxisomal distribution. Besides the original Braak staging, the study design allowed a direct correlation between the biochemical findings and the amount of neurofibrillary tangles (NFT) and neuritic plaques, quantified in adjacent tissue sections. Interestingly, the decrease in plasmalogens and the increase in VLCFA and peroxisomal volume density in neuronal somata all showed a stronger association with NFT than with neuritic plaques. These results indicate substantial peroxisome-related alterations in AD, which may contribute to the progression of AD pathology.

Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy.

Abstract: The E200K mutation is the most frequent prion protein gene (PRNP) mutation detected worldwide that is associated with Creutzfeldt-Jakob disease (CJD) and thought to have overlapping features with sporadic CJD, yet detailed neuropathological studies have not been reported. In addition to the prion protein, deposition of tau, α-synuclein, and amyloid-β has been reported in human prion disease. To describe the salient and concomitant neuropathological alterations, we performed a systematic clinical, neuropathological, and biochemical study of 39 individuals carrying the E200K PRNP mutation originating from different European countries. The most frequent clinical symptoms were dementia and ataxia followed by myoclonus and various combinations of further symptoms, including vertical gaze palsy and polyneuropathy. Neuropathological examination revealed relatively uniform anatomical pattern of tissue lesioning, predominating in the basal ganglia and thalamus, and also substantia nigra, while the deposition of disease-associated PrP was more influenced by the codon 129 constellation, including different or mixed types of PrPres detected by immunoblotting. Unique and prominent intraneuronal PrP deposition involving brainstem nuclei was also noted. Systematic examination of protein depositions revealed parenchymal amyloid-β in 53.8%, amyloid angiopathy (Aβ) in 23.1%, phospho-tau immunoreactive neuritic profiles in 92.3%, neurofibrillary degeneration in 38.4%, new types of tau pathology in 33.3%, and Lewy-type α-synuclein pathology in 15.4%. TDP-43 and FUS immunoreactive protein deposits were not observed. This is the first demonstration of intensified and combined neurodegeneration in a genetic prion disease due to a single point mutation, which might become an important model to decipher the molecular interplay between neurodegeneration-associated proteins.

Genesis of mammalian prions: from non-infectious amyloid fibrils to a transmissible prion disease.

Abstract: The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrPSc template. Here we report that authentic PrPSc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrPSc and lack any detectable PrPSc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrPSc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrPSc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrPSc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.

Sporadic Creutzfeldt–Jakob Disease

Abstract: Sporadic Creutzfeldt-Jakob disease (CJD), the most common human prion disease, is generally regarded as a spontaneous neurodegenerative illness, arising either from a spontaneous PRNP somatic mutation or a stochastic PrP structural change. Alternatively, the possibility of an infection from animals or other source remains to be completely ruled out. Sporadic CJD is clinically characterized by rapidly progressive dementia with ataxia, myoclonus, or other neurologic signs and, neuropathologically, by the presence of aggregates of abnormal prion protein, spongiform change, neuronal loss, and gliosis. Despite these common features the disease shows a wide phenotypic variability which was recognized since its early descriptions. In the late 1990s the identification of key molecular determinants of phenotypic expression and the availability of a large series of neuropathologically verified cases led to the characterization of definite clinicopathologic and molecular disease subtypes and to an internationally recognized disease classification. By showing that these disease subtypes correspond to specific agent strain-host genotype combinations, recent transmission studies have confirmed the biologic basis of this classification. The introduction of brain magnetic resonance imaging techniques such as fluid-attenuated inversion recovery and diffusion-weighted imaging sequences and cerebrospinal fluid biomarker assays for the detection of brain-derived proteins as well as real-time quaking-induced conversion assay, allowing the specific detection of prions in accessible biologic fluids and tissues, has significantly contributed to the improved accuracy of the clinical diagnosis of sporadic CJD in recent years.

A peculiar constellation of tau pathology defines a subset of dementia in the elderly

Abstract: Sporadic tauopathies are characterized by differential cellular and topographical predominance of phospho-tau immunoreactivity and biochemical distinction of the tau protein. Established entities include progressive supranuclear palsy, corticobasal degeneration, Pick’s disease, and argyrophilic grain disease. During a community-based longitudinal study on aging, we detected tau pathologies not compatible with these categories. We immunostained for different phospho-tau epitopes, 4R and 3R tau isoforms, α-synuclein, amyloid-β, and phospho-TDP-43, analyzed the MAPT and ApoE genes, and performed western blotting for the tau protein. The mean age of patients (4 women, 3 men) was 83.8 years. Clinical presentations combined dementia with psychiatric symptoms and/or parkinsonism. In addition to neurofibrillary tangles and diffuse neuronal cytoplasmic tau immunoreactivity, the neuropathology was characterized by peculiar cytopathologies (diffuse granular immunopositivity of astrocytic processes and patchy accumulation of thin threads) in a distinctive distribution (frontal and temporal cortices, hippocampus, amygdala, basal ganglia, locus coeruleus, and substantia nigra). Argyrophilic grains were detected in four patients. Few to moderate densities of neuritic plaques but widespread phospho-TDP-43 pathology was observed in five patients. There was variability in the H1/H2 and ApoE alleles and biochemical features of tau protein. We propose these cases as complex tauopathy with a characteristic constellation: some features of primary tauopathies and Alzheimer’s disease mixed with additional cytopathologies including a distinctive astrogliopathy, in a characteristic distribution of lesions. These complex tauopathies in the elderly deserve specific diagnostic and eventually therapeutic considerations.

Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease.

Abstract: Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

Fibulin-5 mutations link inherited neuropathies, age-related macular degeneration and hyperelastic skin.

Abstract: To identify the disease-causing gene responsible for an autosomal dominantly inherited Charcot–Marie–Tooth neuropathy subtype in a family excluded for mutations in the common Charcot–Marie–Tooth genes, we used array-based sequence capture to simultaneously analyse the disease-linked protein coding exome at chromosome 14q32. A missense mutation in fibulin-5 , encoding a widely expressed constituent of the extracellular matrix that has an essential role in elastic fibre assembly and has been shown to cause cutis laxa, was detected as the only novel non-synonymous sequence variant within the disease interval. Screening of 112 index probands with unclassified Charcot–Marie–Tooth neuropathies detected two further fibulin-5 missense mutations in two families with Charcot–Marie–Tooth disease and hyperextensible skin. Since fibulin-5 mutations have been described in patients with age-related macular degeneration, an additional 300 probands with exudative age-related macular degeneration were included in this study. Two further fibulin-5 missense mutations were identified in six patients. A mild to severe peripheral neuropathy was detected in the majority of patients with age-related macular degeneration carrying mutations in fibulin-5 . This study identifies fibulin-5 as a gene involved in Charcot–Marie–Tooth neuropathies and reveals heterozygous fibulin-5 mutations in 2% of our patients with age-related macular degeneration. Furthermore, it adumbrates a new syndrome by linking concurrent pathologic alterations affecting peripheral nerves, eyes and skin to mutations in the fibulin-5 gene. * Abbreviation : FBLN5 : fibulin-5

Joint Scientific Opinion on any possible epidemiological or molecular association between TSEs in animals and humans

Abstract: The existing scientific evidence that links animal and human TSEs is reviewed and discussed. The challenges involved in identifying TSEs as zoonoses are described and the example of the process that led to the establishment of a link between Bovine Spongiform Encephalopathy (BSE) and variant Creutzfeldt-Jakob Disease (vCJD) is reviewed. The strain diversity of animal and human TSE agents and the factors influencing the capacity of TSE agents to cross the species transmission barrier are also discussed. The scientific opinion critically assesses the tools and methodologies currently available to study and evaluate the possible association of animal and human TSEs, focussing on epidemiological and laboratory methods. The available scientific evidence on Classical BSE, Atypical BSE (H-type and L-type), Classical scrapie, Atypical scrapie, Chronic Wasting Disease (CWD), Transmissible Mink Encephalopathy (TME) and human TSEs is reviewed. The conclusions state that, at present, the only TSE agent demonstrated to be zoonotic is the Classical BSE agent. Active screening has allowed the identification of three new forms of animal TSEs (H-type Atypical BSE, L-type Atypical BSE and Atypical scrapie), but the information obtained has major limitations due to the unknown sensitivity of the current monitoring system for these TSEs. There is no epidemiological evidence to suggest that Classical scrapie is zoonotic. The epidemiological data are too limited to conclude whether the Atypical scrapie agent has a zoonotic potential. Transmission experiments to human PrP transgenic mice or primates suggest that some TSE agents other than the Classical BSE agent in cattle (namely L-type Atypical BSE, Classical BSE in sheep, TME, CWD agents) might have zoonotic potential and indicate that that of the L-type Atypical BSE agent appears similar or even higher than that of the Classical BSE agent. A single study reported efficient transmission of a natural sheep Classical scrapie isolate to primates

Unclassifiable tauopathy associated with an A152T variation in MAPT exon 7.

Abstract: Mutations in the microtubule-associated tau (MAPT) gene are associated clinically with frontotemporal dementia with or without supranuclear palsy, corticobasal syndrome or parkinsonism. Here we present clinical, neuropathological, genetic and biochemical data on a patient with an A152T variation in exon 7 of MAPT. A 63-year-old man presented with memory disturbance and later speech disorder, followed by progressive dementia and terminally myoclonus together with periodic sharp waves in EEG. Duration of illness was 5 years. Similar neuropsychiatric symptoms were reported in the patient's father. Neuropathological evaluation revealed neuronal loss mainly in the frontal and temporal cortices and substantia nigra. Abundant phospho-tau immunoreactive thread-like structures and diffuse staining of neuronal cytoplasm predominated in the frontal and temporal cortex, and hippocampus. There was a lack of astrocytic plaques and tufted astrocytes, and only a moderate number of oligodendroglial coiled bodies were seen. Tau pathology was characterized by the 4R tau isoform; immunoblot revealed bands at 64 and 68 kDa, and ultrastructure of filaments was compatible with twisted ribbons. Pathogenic mutations have not been reported in exon 7. Our observation of an apparently familial disorder with a novel neuropathological phenotype suggests a possible pathogenic role of this MAPT gene variation, which might be different from mutations affecting the microtubule binding.

Scientific Opinion on Hatchery Waste as animal by-products

Abstract: The risk posed by the possible use of dead-in-shell chicks for the production of processed petfood was assessed. According to current legislation two processing methods were considered i) treatment to a minimum Fc value of 3; and ii) treatment of at least 90°C throughout the substance of the final product. A list of the possible pathogens potentially present in the material to be treated was compiled and the available literature data was used to assess the ability of the processing methods to inactivate the most resistant pathogens identified. The processing methods were assessed assuming that the heat treatments would be performed in a moist environment. Spores of Clostridium botulinum were identified as the most resistant hazard potentially present in the material to be processed. Circovirus and parvovirus, and Enterococcus faecium were considered respectively as the most resistant viruses and non-sporulating bacterium to heat treatment. Moreover, depending on storage conditions, the generation of bacterial toxins could be possible. Consequently, the processing methods considered were assessed against their ability to inactivate those hazards. The risk related to the use of dead-in-shell chicks, submitted to a conventional heat treatment to a minimum Fc value of 3 in a moist environment, for the production of canned petfood was considered negligible. No indication is given in the current regulation on the processing time and heating method needed for the treatment at 90°C throughout the substance of the final product. A treatment lasting 18 seconds can assure a rapid destruction of the non-sporeforming bacteria identified as hazards. However, this treatment is not able to inactivate other relevant hazards such as bacterial spores, thermoresistant viruses and some toxins. The final risk posed by the agents that may survive this treatment additionally depends on several factors and cannot be considered to be negligible

Advocacy for Neuropathology

Abstract: Project Secretary Dr Homa Adle-Biassette Inserm U676, Université Paris Diderot Hôpital Robert Debré 48 Bd Sérurier 75019 Paris France Fax: +33-1-40031995 E-mail: homa.adle@inserm.fr Dear Reader, I write this after returning from an Advocacy Workshop in Brussels, Belgium, that was jointly organized by the Federation of European Neuroscience Societies (FENS) and the Society for Neuroscience (SfN) (see http://www.sfn.org/index.aspx?pagename=FENS_ Advocacy_Workshop). I participated on behalf of Euro-CNS, the European Confederation of Neuropathological Societies. The main aim of the workshop was to work on strategies for national neuroscience societies to promote the importance of neuroscience research with policy makers in order to obtain financial support at times of globally shrinking resources. This is more than pertinent also for national societies of neuropathology and the ISN. It was fascinating to learn about the many facets of approaches to advocacy in science and biomedicine. FENS, with an extremely well organized administrative framework, is still exploring future strategies, while the SfN has already established its approach, utilizing dedicated staff that are well experienced in productively lobbying legislators and other policy makers. The Canadian Association for Neuroscience has been particularly successful in teaming up with top-notch industrial representatives, the British Neuroscience Association has listed advocacy at the top of its wish list, and the European Brain Council solicits partnerships between biomedical researchers, clinicians, industry, patients and their families. In a nutshell, successful strategies seemingly rely on two very simple but pivotal factors—1) formation of alliances, and 2) being active, both re-active and pro-active. As alliances are essential, neuropathology has to do more, MUCH more, to partner with basic and clinical neurosciences. Soberingly, neuropathologists seem to be poorly represented within the large scientific societies mentioned above, and our representation in influential clinical bodies seems to be no better. Among no less that 193 contributing experts of the “Consensus Document on European Brain Research” (Di Luca et al, Europ J Neurosci 2011; 33: 768–818) that deals with all aspects of neurological disorders, I could find only ONE neuropathologist. Aren’t WE THE experts on neurological diseases (together with others)? So, if we want to increase support, we must come out of our ivory towers and become much more visible to our partners and the public. Being active, re-active and pro-active, is an obvious recipe for almost everything in life, but is not that easy to translate into reality. It demands our minds, hearts, time and dedication. The ISN has already started some promising activity in advocacy: in order to foster local development and support of neuropathology, “ISN Information Days” have been organized to show to local basic and clinical neuroscientists what up-to-date neuropathology can offer them in clinical service, research and teaching. The ISN Subcommitte on Training and Education, with its Chairperson Prof. Francesco Scaravilli, has supported local hosts in organizing successful annual events in Sofia, Bulgaria (2009) and Istanbul, Turkey (2010). This year another ISN Information Day will be held in Surabaya, Java, Indonesia (Sept. 17–18, 2011). The ISN invites everybody who might be interested in hosting such a future event to contact Prof. Scaravilli or myself. Thus, it’s time to act and join forces if we want to steer our beloved discipline into a promising future. The ISN is willing to lead in this, but it is up to you as individual neuropathologists to follow suit and make a difference by your personal engagement.

Complex tauopathies vs. tangle predominant dementia Response to the Letter from Professor Kurt Jellinger

Abstract: We are grateful to Professor Jellinger for his comments. In Table 3 of our paper [1], we thought it would be useful to summarize only the salient histopathological features of entities that would be considered for a differential diagnosis. As with all such didactic tables, not all features of lesser importance could be listed. Indeed, Iseki et al. [2] mentioned thorn-shaped astrocytes in the CA1 subregion in neurofibrillary tangle predominant dementia (NFTD), but Jellinger and Bancher [3] indicated that ‘‘Tau-IR astroglial inclusions, such as tufted astrocytes (...) and astrocytic plaques (...) were rarely observed on reexamination of personal cases’’. In another paper, Jellinger and Attems [4] mentioned tufted astrocytes as a rare phenomenon similar to Alzheimer disease, and astrocytic plaques as rare/occasional. However, we agree with Professor Jellinger that the astrogliopathy in the complex tauopathy described by our group [1] differs from that described in NFTD both morphologically and on the level of anatomical distribution. While ghost tangles are a very important component of the neuropathology of NFTD, our cases of the complex tauopathy only occasionally exhibited these, which thus were not included in Table 3. We hope that further cases of the complex tauopathy will be reported. Indeed, in the follow-up of the VITA study that initiated us to report these cases, we have already observed further cases. It is a challenge not only to consider and diagnose such cases, but also to understand still more the pathobiological basis of such peculiar neurodegenerative constellations.

Scientific Opinion on a summary of scientific studies undertaken by the UK Food Standards Agency to support a proposed production method for smoked “skin-on” sheep meat

Abstract: The scientific validity and relevance for safety assessment of a series of studies aimed at exploring the potential for the safe production of burnt fleece skin-on sheep carcasses are assessed. The main findings obtained by these studies are described, including their microbiological and chemical aspects. It is concluded that the hazard identification presented in the studies under assessment does not cover all potential biological and chemical hazards and information on their fate during the process. Limitations found in microbiological and chemical aspects of the studies as conducted are highlighted and discussed. It is pointed out that, as designed and conducted, the studies describe a hygienic production method for burnt fleece skin-on sheep carcasses based on gas flame singeing and provide a first step of information that is useful for further consideration of biological and chemical hazards and may serve as the basis for development of processes for safe production of skin-on sheep carcasses. The studies under assessment did not evaluate or verify the food safety of burnt fleece skin-on sheep carcasses under variable conditions in comparison to conventional skin-off carcasses. Overall, they are insufficient to support the conclusion that the burnt fleece skin-on sheep carcasses produced by the method described were suitable for human consumption or hygienically and microbiologically similar to conventionally produced skin-off carcasses. Similarly, the information supplied is insufficient to conclude that the process presented results in levels of harmful smoke-derived chemicals similar to those in other smoked foods which represent a low level of concern for human health

Scientific Opinion on a review of the BSE-related risk in bovine intestines

Abstract: The opinion reviews a 2007 opinion of the French Food Safety Agency (AFSSA), which, referring to the current situation in France, concluded that the current removal of the whole intestine from bovine animals of all ages as specified risk material could be limited to the ileum. It is concluded that the model used in the AFSSA opinion is an appropriate tool to estimate the Classical BSE prevalence in cattle cohorts in countries with extensive surveillance systems and the maximum number of undetected Classical BSE cases that could enter into the food chain in a particular country. It is concluded that the AFSSA methodology cannot be used to make inference to situations other than the French situation to assess the Classical BSE-related risk in bovine intestines. The new scientific data available are reviewed. These data, which add some new elements, concur and confirm the presence of limited amounts of PrPSc and/or infectivity in parts of the intestine other than ileum of Classical BSE infected cattle under experimental inoculation (jejunum) and natural exposure (distal jejunum and colon). The new scientific information further confirms the presence of consistent amounts of PrPSc and infectivity in the ileum of Classical BSE infected cattle under experimental inoculation and natural exposure. Due to limitations in the data currently available, an accurate quantification of the amount of infectivity in the intestinal parts other than ileum of Classical BSE infected cattle at different stages of the incubation period cannot be provided. It is also concluded that, due to the continuous decline of the Classical BSE epidemic, the current Classical BSE exposure risk from bovine intestines has declined correspondingly. Exposure to Atypical BSE from the consumption of bovine intestines cannot be assessed at this stage and research on the pathogenesis of Atypical BSE is recommended

Long-term clinical improvement of progressive multifocal leukoencephalopathy associated with prominent inflammatory response and follicular lymphoma.

Abstract: 1 Department of Neurology, Semmelweis University Faculty of Medicine, Budapest, Hungary, 2 MR Research Center, Semmelweis University Faculty of Medicine, Budapest, Hungary, 3 1st Department of Internal Medicine, Semmelweis University Faculty of Medicine, Budapest, Hungary, 4 1st Department of Pathology and Experimental Cancer Research, Semmelweis University Faculty of Medicine, Budapest, Hungary, 5 Clinical Institute of Virology, Medical University of Vienna, Vienna, Austria, and 6 Institute of Neurology, Medical University of Vienna, Vienna, Austria